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Testosterone Beliefs VS Science Lecture | TRT Therapy | TRT for Men | Testosterone Facts | Estradiol

Dr. Keith Nichols explores testosterone myths vs. science, covering declining levels, treatment, estradiol, and evidence-based facts in men's health.

Key Takeaways

  • Men’s testosterone levels have declined significantly over the past 50+ years independent of age and obesity.
  • This decline has led to lower population reference ranges, risking underdiagnosis of testosterone deficiency.
  • Testosterone therapy should be guided by evidence, not assumptions or social media misinformation.
  • Estradiol plays a complex role in testosterone therapy and must be managed carefully with attention to study design and patient factors.
  • Androgen status depends on more than just serum testosterone levels; multiple physiological factors influence outcomes.

What the video covers

  • Dr. Keith Nichols presents a detailed lecture to clarify misconceptions about testosterone therapy using scientific evidence.
  • The video reviews multiple large-scale studies documenting a significant, age-independent decline in testosterone levels in men over decades.
  • It discusses how this decline has shifted normal reference ranges downward, potentially causing underdiagnosis and undertreatment of testosterone deficiency.
  • The lecture covers physiology, including the roles of DHT and estradiol, and the importance of interpreting estradiol management carefully in testosterone therapy.
  • Dr. Nichols emphasizes the limitations of relying on social media for medical information and encourages a disciplined, evidence-based approach.
  • The video addresses current treatment guidelines and testosterone use in various male populations, including sexual function and dysfunction.
  • It highlights that androgen status is not solely determined by serum testosterone but involves multiple factors influencing individual response.
  • The lecture critiques common assumptions about estradiol’s role in sexual dysfunction and stresses the need to consider confounding factors like obesity.
  • Data from randomized controlled trials and population surveys such as NHANES are used to support the discussion.
  • The overall message is to set aside opinion and focus on scientific literature to improve diagnosis and treatment of testosterone deficiency.

Chapters

  1. 00:00 Introduction and Purpose of Lecture
  2. 14:46 Magnitude of Testosterone Decline and Predictors
  3. 30:28 Testosterone Effects on Muscle Mass
  4. 45:48 Efficacy of Testosterone Therapy and Treatment Targets
  5. 62:06 Complexity of Androgen Status Beyond Serum Testosterone
  6. 77:15 Population Studies on Testosterone and Estradiol Levels
  7. 92:00 Mathematical Models and Interpretation of Testosterone/Estradiol
  8. 106:38 Physiological Role of Estradiol in Testosterone Therapy
  9. 121:43 Clinical Data on Testosterone, DHT, and Aromatization
  10. 137:02 Summary and Evidence-Based Conclusions

Answers

Questions about this video

What evidence supports the claim that testosterone levels are declining in men?

Multiple large population studies from the US, Denmark, Finland, and Israel show a significant age-independent decline in testosterone levels over decades, which cannot be explained by obesity or lifestyle factors.

Why is it important to manage estradiol levels carefully during testosterone therapy?

Estradiol influences tissue-level signaling and sexual function, and improper management can lead to misinterpretation of symptoms. Studies show that therapeutic benefits depend on whether aromatization to estradiol is preserved, suppressed, or controlled.

Why should testosterone therapy not rely solely on serum testosterone levels?

Serum testosterone alone does not fully represent androgen status because other factors like hormone metabolism, receptor sensitivity, and conversion to DHT and estradiol also affect clinical outcomes.

Full Transcript — Download SRT & Markdown

00:01
Speaker A
My name is Dr. Keith Nichols, and I am the medical director for Tier 1 Health and Wellness. Over the past year, I have dedicated myself to preparing this lecture in an effort to bring greater clarity to serve a long-held belief
00:12
Speaker A
surrounding the use of testosterone. My goal is to determine what is truly supported by the medical literature from what has been shaped by assumption, opinion, or repetition. In the age of social media, misinformation has become increasingly widespread, often amplified
00:28
Speaker A
by self-proclaimed experts, making it more important than ever to return to the evidence and examine these issues through a scientific lens. This lecture was not designed for those who prefer to rely on short TikTok, Instagram, or other social media clips for
00:41
Speaker A
information, but for those who understand that meaningful learning requires time, attention, and intellectual discipline. I would not recommend trying to absorb it all in one single setting, but rather approaching it in smaller sections so the material can be fully considered and digest it
00:56
Speaker A
before moving on. This lecture was prepared at the request of my patients and colleagues to help guide them through the misinformation surrounding testosterone and to separate evidence-based fact from fiction.
01:08
Speaker A
We are going to cover a wide range of topics today related to testosterone, including the declining levels in men, normal reference ranges for testosterone, DHT and estradiol, the underlying physiology, current treatment guidelines, the use of testosterone in different populations of men, sexual
01:26
Speaker A
function and dysfunction in men on testosterone, and a review of the medical literature, particularly as it relates to estradiol.
01:34
Speaker A
As we discuss estradiol management with testosterone therapy, careful interpretation of the literature requires more than simply reviewing interventions and outcomes. It also requires examining what was and what was not done in these trials and whether therapeutic benefit occurred with
01:48
Speaker A
preserved, suppressed, or controlled aromatization. Before we begin, I would like to express my sincere gratitude to my good friend and mentor Dr. Neil Rousier for the wisdom, insight, and guidance he has shared with me over the years. With his
02:03
Speaker A
help, I was able to overcome severe symptoms of testosterone deficiency, and my life was forever changed for the better. Dr. Rousier gave me my life back, and I will be forever grateful for that.
02:14
Speaker A
What motivates me every day is the privilege of doing for others what he did for me. So with that, let's set opinion aside and turn to the literature and examine what the evidence actually shows.
02:27
Speaker A
Testosterone beliefs versus science. The problem is not that people are not educated. The problem is that they are educated just enough to believe what they've been taught and not educated enough to question what they've been taught. Richard Feman.
02:42
Speaker A
Let's begin by reviewing the evidence demonstrating the decline in testosterone levels among men, as this provides important context for understanding the downward shift in laboratory reference ranges.
02:52
Speaker A
This study by Travis is the first paper documenting the decline of testosterone levels in American men. This paper looked at the testosterone levels in 2,769 men aged 45 to 79 years born between 1916 and 1945 and over a 17-year period of
03:08
Speaker A
time collected three sets of data. The first testosterone collection was 1987 to 89, the second 95 to 97, and the third 2002 to 2004. At baseline, which was 87 to 89, the median serum testosterone level was 501 nanograms per deciliter. And
03:27
Speaker A
at the first follow-up, it was 435, and at the second follow-up, it was 391.
03:32
Speaker A
This represents an age-matched decline of 1.2% per year. So, a 60-year-old man in 2004 had a testosterone level about 20% lower than a 60-year-old man in 1987.
03:44
Speaker A
He wrote, "We observe a substantial age-independent decline in testosterone that does not appear to be attributable to observed changes in explanatory factors, including health and lifestyle characteristics such as smoking and obesity." This study by Anderson conducted on over
04:01
Speaker A
5,000 Danish men shows that those born in the 1960s have on average 14% lower testosterone levels than males from the 1920s.
04:11
Speaker A
In this study published in the European Journal of Endocrinology, over 3,000 men were divided into six age groups. They were also divided into seven birth cohort groups according to their year of birth. What they found was that the
04:23
Speaker A
serum testosterone levels decreased in men aged 60 to 69 years who were born in 1913 to 1922 from 631 nanograms per deciliter to 397 nanograms per deciliter
04:36
Speaker A
in men aged 60 to 69 years born between 1942 and 1951. They also found that the serum testosterone levels decreased from 760 nanograms per deciliter in 20 to 25-year-old men born from 1942 to 1951 to 550
04:52
Speaker A
nanograms per deciliter in 20 to 25-year-old men born between 1970 and 1977. They wrote, "In this study, we observed a clear age and BMI independent birth cohort effect on serum testosterone concentrations measured in Finnish men.
05:07
Speaker A
Our study is the third large population study to demonstrate a declining trend in serum testosterone of men in a similar fashion as seen in a USA and Danish population, which were the first two studies we reviewed.
05:20
Speaker A
This study by Chadic looked at the testosterone levels in over 100,000 Israeli males between January of 2006 and March of 2019. At age 21, levels declined from 561 nanograms per deciliter in 2006 to 2009 to 511 nanograms per
05:38
Speaker A
deciliter from 2016 to 2019. They wrote, "The decline is unlikely to be explained by increasing rates of obesity." Many studies that we will be reviewing today use data from NHANES. NHANES is the National Health and Nutrition Examination Survey. NHANES is a
05:55
Speaker A
national survey that measures the health and nutrition of adults and children in the United States. The CDC's National Center for Health Statistics conducts NHANES. NHANES is the only national health survey that includes health exams and laboratory tests for participants of
06:08
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all ages. The NHANES program began in the early 1960s, and since 1999 it has been conducted without interruption, which is referred to as continuous NHANES.
06:19
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Locashwar et al. used NHANES data to look at the testosterone levels in over 4,000 adolescent and young adult men from 1999 to 2016. The average testosterone levels decreased from 605 nanograms per deciliter in 1999 and 2000 to 451 nanograms per deciliter in 2015 and
06:39
Speaker A
2016. They wrote, "Adolescent and young adult males' total testosterone levels are used as the benchmark for normal levels of total testosterone, and thus a decline in total testosterone in this population will cause a change in accepted normal levels of total testosterone in future
06:55
Speaker A
decades. Clinically, this might lead to undertreatment of testosterone deficiency in the future." This paper by Santi reviewed the literature for studies that included testosterone measurements for any reason and healthy men between 1971 and 2024.
07:12
Speaker A
1,256 papers were reviewed, which consisted of 1,154 study groups and involved a total of over 1 million subjects with a mean age of 42 years. As you can see in these figures, there was a significant reduction in testosterone
07:26
Speaker A
serum levels across the years of measurement for all age groups. They wrote, "This analysis describes for the first time a significant decrease in mean total testosterone serum levels in over 1 million healthy men over the last 55 years. A significant reduction in
07:42
Speaker A
testosterone serum levels across the years of measurement was observed independent from BMI and age, suggesting a genuine testosterone decrease."
07:51
Speaker A
In summary, over the past several decades, men's testosterone levels have shown a pathological age-independent decline that cannot be explained by obesity and is most likely driven by environmental factors. This pathological decline in testosterone has shifted the population's normal reference range
08:09
Speaker A
downward, leading to a systemic underdiagnosis and undertreatment of men experiencing symptoms of testosterone deficiency. The physiological need for testosterone has n
08:22
Speaker A
Let's now review the normal ranges for testosterone, free testosterone, and estradiol. Let's start with the normal range for total testosterone.
08:33
Speaker A
This study in 2006 by Lazaru, of which Abraham Morgan was a co-author, looked at the reference ranges for testosterone in 25 different labs. What they found was that the low reference values ranged from 130 to 450 NOGS per deciliter and
08:47
Speaker A
the upper values ranged from 486 to 1,593 NOGS per deciliter. So for those of you that think a level of 1500 is somehow harmful or dangerous, a level of 1500 was normal in some labs in 2006.
09:02
Speaker A
From 2011 to 2017, the normal range for testosterone at LabCore was based on this study by Basin that looked at healthy non-obese young men in the Framingham Heart Study. The reference range established for testosterone in this study was 348 natagrams per
09:18
Speaker A
deciliter to 1,197 nanogs per deciliter. This 2017 study by Travis looked at the testosterone levels in four cohorts of men in the United States and Europe that were 19 to 39 years of age with a BMI less than 30. They cross-calibrated the
09:35
Speaker A
assays used for each cohort against a higher order method and calibrator developed by the CDC and then harmonized the local values to the CDC standardized measurements. The harmonized reference range for total testosterone in these men was 264 NOGS per deciliter to 916
09:51
Speaker A
nanogs per deciliter. In July of 2017, LabCore revised its reference range for total testosterone from 348 to 1197 to 264 to 916 nanogs per deciliter based on the Travis study.
10:07
Speaker A
Now, how did this change affect men from a clinical standpoint? Between 2011 and June of 2017, a completely asymptomatic man on testosterone with a level of 1100 was told that his levels were normal and healthy. After the 2017 change, those
10:23
Speaker A
same levels were reclassified as supra physiologic and now considered potentially dangerous and harmful, leading to a decrease in dosage and potential recurrence of symptoms.
10:33
Speaker A
Exactly what the Locash War study warned us could happen. These are the diagnostic thresholds for testosterone deficiency and treatment target levels across multiple guidelines. The International Society for Sexual Medicine, Canadian Medical Association, British Society for Sexual Medicine, American Urology Association,
10:51
Speaker A
the Endocrine Society, and the European Association of Urology. As you can see, there's no consensus on a threshold level of testosterone that defines testosterone deficiency, nor is there a consensus on target levels while on treatment. In the United States, the
11:06
Speaker A
indocrine society guidelines are among the most widely recognized, accepted and follows. The indocrine society requires a level of less than 264 for a diagnosis of hypogonadism and the treatment target range is 350 to 600 nanogs per deciliter. Let's now question the
11:22
Speaker A
current endocrine society guidelines using a threshold level of testosterone to diagnose testosterone deficiency, aiming for the mid-normal physiologic range and maintain levels within the normal physiologic range during treatment.
11:34
Speaker A
First question, is there any evidence to support using a threshold level of testosterone 264 NOGS per deciliter to diagnose testosterone deficiency?
11:45
Speaker A
This study by Zipman did not find a clear-cut threshold for late onset hypogonadism. It did find that androgen induced prevalence of loss of libido or vigor increased below testosterone concentrations of 15 nanomles per liter or 432 nanogs per deciliter which is
12:02
Speaker A
well above the 264 nanogs per deciliter endocrine society threshold. This study by Scoville looked at 352 men complaining of low testosterone. Serum testosterone levels were collected on the same date that the men completed a androgen deficiency and aging male
12:18
Speaker A
questionnaire. And what they found was that hypogonatal symptoms in men aged less than 40 years can be associated with a total testosterone level of less than 400. Decreased energy, sadness, decreased strength and endurance, decreased ability to play sports, and
12:34
Speaker A
deterioration in work performance were most strongly associated with serum total testosterone levels of less than 400 nanogs per deciliter. Once again, much higher than the 264 Nanograms per deciliter endocrine society threshold.
12:49
Speaker A
Threshold levels for the diagnosis of testosterone deficiency were discussed at the 2015 international expert consensus conference in Prague, Czech Republic. And one of the resolutions was that there is no testosterone concentration threshold that reliably distinguishes those who will respond to
13:05
Speaker A
treatment from those who will not. No study has revealed a single testosterone threshold that reliably separates those who experience signs and symptoms of testosterone deficiency from those who do not, nor who will likely respond to treatment.
13:20
Speaker A
These are the difficulties with establishing a threshold for testosterone deficiency. Interindividual variability between men. The magnitude of decrease in testosterone concentration in an individual is more important than the absolute value.
13:33
Speaker A
Interindividual variability in SHBG levels. Genetic variations in androgen receptor sensitivity based on the length of the KAG repeat length.
13:43
Speaker A
Enter individual variability. In this study by Keller, 52 hypoganatom men underwent 260 testosterone pellet implantations over a 5-year period. As the pellets dissolve, testosterone levels were measured when androgen deficiency symptoms returned in each man. And what they found was that the
14:02
Speaker A
threshold for androgen deficiency symptoms occurs at a highly reproducible blood testosterone concentration in hypogonatal men. That is men reach a distinctively individual trigger level for androgen deficiency symptoms and seek treatment at similar blood testosterone concentrations each time.
14:19
Speaker A
Yet this trigger differs widely between men. Each person had a consistent testosterone threshold for androen deficiency symptoms that differ marketkedly between individuals. This paper helps explain why one man may be significantly symptomatic at a testosterone level of 400, for instance,
14:35
Speaker A
while another may be entirely asymptomatic. This individual variability is precisely why a single testosterone threshold should not be universally applied to all men.
14:46
Speaker A
Magnitude of testosterone decline more important than absolute value. This 2011 study by Holm published in aging mail found that change in testosterone concentrations over time is a better predictor of late onset hypogonism than the actual concentrations of testosterone.
15:04
Speaker A
Interindividual variability in sex hormone binding globbulin. Variability in SHBG concentrations among individuals influences the concentration of free testosterone for any given total tea concentration. The normal range for SHBG at LabCore for young men aged 20 to 49 years is 16.5 to 55.9.
15:26
Speaker A
In these young men, a high normal SHBG can result in a 45% lower free testosterone level than a low normal SHBG for the same total testosterone concentration. As shown in this example, a total testosterone level of 600 and a
15:41
Speaker A
man with low SHBG results in a free testosterone level of 16.7 nanogs per deciliter. That same man, if he had a high SHBG of 55 with the same testosterone level of 600, would have a free testosterone of 9.26 NOGS per
15:55
Speaker A
deciliter, 45% lower. The normal range changes for men greater than 49 years of age to 19.3 to 76.4.
16:05
Speaker A
In this example, a high normal SHBG in older men resulted in a 57% lower free testosterone level than a low normal SHBG.
16:14
Speaker A
Now, these slides are not intended to suggest that sex hormone binding globulin should be lowered. Their purpose is to simply illustrate that a man may have normal serum testosterone concentrations yet still have a low free testosterone level depending on his
16:26
Speaker A
SHBG. Personally, I do not routinely measure sex hormone binding globin because I assess free testosterone directly utilizing the equilibrium dialysis method. In cases of elevated SHBG, the most effective approach is not to lower SHBG itself, but to increase free
16:43
Speaker A
testosterone by appropriately increasing the testosterone dose. Androgen receptor sensitivity based on KAG repeat length.
16:52
Speaker A
I get asked all the time, what is a CAG repeat? Well, in order to understand a CAG repeat, we will need to review protein synthesis.
17:02
Speaker A
Let's start with the definition of a chromosome. A chromosome is a thread-like structure composed of a single highly coiled molecule of DNA wrapped around proteins known as histones which stores genetic information. Humans have 46 chromosomes, 23 pairs with 22 pairs of autotosomes
17:20
Speaker A
and one pair of sex chromosomes, the XX or XY. One set of the 23 chromosomes is inherited from the mother and the other 23 come from the father.
17:30
Speaker A
Chromosomes are made of DNA or deoxy ribboucleic acid. DNA stores the genetic instructions necessary for building proteins and RNA. It consists of two antiparallel strands forming a double helix. DNA is a linear molecule composed of four basic building blocks called
17:48
Speaker A
nucleotides. DNA nucleotides also called bases consist of adanine, thymine, guanine and cyazine represented by A, T, G, and C. Nucleotides bond opposing strands with A always bonding with T and G always bonding with C as seen in this
18:07
Speaker A
representation of DNA. G always bonding with C, A always bonding with T. A gene is a segment of DNA that has the information necessary for the synthesis of a functional biologic product, protein or RNA. The sequence of bases in
18:23
Speaker A
a gene AT, C and G translate to an amino acid sequence. A triplet or codon is a sequence of three DNA or RNA nucleotides that corresponds with a specific amino acid. For example, C A the KAG standing for cytosine, adanine, and guanine is a
18:44
Speaker A
codon for the amino acid glutamine. Humans have 20 standard amino acids to build proteins with nine of these being essential, which must come from the diet and the body making the other 11.
18:57
Speaker A
These are the RNA codons for each amino acid. Note that most of the amino acids have more than one codon, but no amino acid shares a codon. As you can see, glutamine is represented by two codons, C AA and CA A.
19:14
Speaker A
Protein synthesis begins with a gene or a segment of DNA as represented by this picture. Transcription is the process by which information in a strand of DNA is copied to messenger RNA. Translation is the process by which a protein is
19:31
Speaker A
synthesized from the information contained in messenger RNA. And then proteins are chains of amino acids. So we start with a gene which is transcribed to messenger RNA which is then translated into amino acids which create a protein.
19:48
Speaker A
The androgen receptor gene is located on the X chromosome and encodes the androen receptor protein consisting of 919 amino acids. Here's our chromosome. Here's a gene, which is a segment of DNA. And this is our gene here. The AR gene
20:06
Speaker A
consists of eight exxons and seven variablesiz introns. Intron are non-coding regions that do not directly translate into proteins. Whereas exxons are coding regions that contain instructions for protein synthesis. So here are our eight exxons. The androen receptor protein consists of four
20:24
Speaker A
structurally and functionally distinct domains. the N terminal domain, the DNA binding domain, the hinge domain and the C terminal lian binding domain. So once again we have the chromosome and then the gene transcribed to RNA translated to the protein which is the androgen
20:42
Speaker A
receptor protein with its four distinct domains in terminal domain DNA binding domain hinge region and the C terminal lian binding domain.
20:54
Speaker A
In exxon one of the androgen receptor gene there is a stretch of DNA made up the of the triplet C A repeated over and over. Here is exxon one. Each CAG codes for the amino acid glutamine. So this
21:07
Speaker A
region forms a polylutamine track in the intern terminal domain of the AR protein. So once again chromosome gene transcribed translated into the AR protein. The number of KAG repeats in exxon one gets translated and forms that polyutamine track in the intern terminal
21:29
Speaker A
domain. Here the KAG repeat length is usually about 9 to 36 repeats and is genetically determined.
21:37
Speaker A
Shorter KAG length equals greater androgen sensitivity. Longer CAG length, less androgen sensitivity. Two men with the same serum testosterone levels can have very different biologic androgen effects depending on KAG length. That is the interindividual variability in androgen sensitivity. Androgen status does not
21:55
Speaker A
equate to serum testosterone alone. The KAG repeat length is a concrete example that the androgen status of an individual is not determined solely by the serum testosterone levels. Now, what literature supports KAG repeats and receptor sensitivity?
22:14
Speaker A
This study by Canali in Italian men is one of the foundational papers that looks at and receptor KAG repeat length and ties that to clinical hypogonism despite normal testosterone levels. They investigated whether genetic variation in the androal receptor could explain
22:29
Speaker A
why some men have hypogonatal symptoms even when serum testosterone is normal. And they found that there is no significant difference in total testosterone between symptomatic men and controls. Mean total testosterone of 40 to 40 nanogs per deciliter in both
22:43
Speaker A
groups. Symptomatic men had significantly longer CAG repeats. Repeat length of 24 plus or - 2.9. controls had shorter repeats, an average of 21.5 plus or minus 1.7. Genetic variations in androgen receptor sensitivity can influence androgen effects independently of testosterone levels.
23:03
Speaker A
In this study by Lou in Taiwanese men, they asked the question, does and receptor sensitivity, KAG repeat length, modify the relationship between serum testosterone and andropausal symptoms?
23:15
Speaker A
Andropausal symptoms are not determined by serum testosterone alone. AR CAG repeat length alone did not affect testosterone levels. AR genetics affect response to testosterone not production.
23:27
Speaker A
A total testosterone less than 340 NOGS per deciliter. The men were symptomatic regardless of androen receptor CAG length. That is because androgen deficiency overwhelms receptor effects.
23:40
Speaker A
A total testosterone of greater than 340 NOGS per deciliter. Then the AR CAG length becomes decisive. Men with a CAG length of greater than 25 had two times higher odds of andropausal symptoms despite normal testosterone levels.
23:54
Speaker A
Again above the 264 nanogs per deciliter required for a diagnosis of hypogodinism by the endocrine society.
24:02
Speaker A
To summarize the clinical significance androgen receptor sensitivity indexed by KAG repeat length becomes clinically revalent only when testosterone is in the normal range. Low testosterone causes symptoms regardless of receptor sensitivity. And normal testosterone requires a sensitive receptor to feel
24:20
Speaker A
normal. Normal testosterone is not biologically normal for everyone. Testosterone thresholds are population statistics, not individual physiology.
24:30
Speaker A
In men with normal testosterone levels, androgen receptor sensitivity, not serum testosterone, determines symptoms. We have now reviewed difficulties with establishing a threshold for testosterone deficiency and they included interindividual variability between men. The magnitude of decrease in testosterone concentrations in an
24:51
Speaker A
individual is more important than the absolute value. Interindividual variability in sex hormone binding globulin levels and genetic variations in androgen receptor sensitivity based on the KAG repeat length. You should now have a more clear understanding of the limitations associated with the
25:08
Speaker A
indocrine society's reliance on a single universal threshold for diagnosing testosterone deficiency. Dr. Morgan Tyler in his paper current diagnostic criteria for testosterone deficiency are inadequate made several recommendations.
25:22
Speaker A
A key study to be performed is to take a population of men with a defined symptom or set of symptoms characteristics of testosterone deficiency and expose them to treatment regardless of baseline testosterone levels. And in fact, that is exactly what we do clinically. The
25:38
Speaker A
majority of men that are on testosterone do not meet the strict criteria for a diagnosis of hypogenism. These men have normal levels of testosterone but symptoms characteristic of testosterone deficiency and therefore testosterone is being used off label to treat those
25:52
Speaker A
symptoms. He also recommended that clinicians would do well to think about testosterone levels providing information as to the likelihood of symptomatic response rather than normal versus abnormal. The majority of testosterone deficiency symptoms are non-specific.
26:08
Speaker A
Clinicians should evaluate and address any other potential causes before initiating testosterone therapy. If the patient remains symptomatic after addressing all other factors, a trial of testosterone therapy may be warranted.
26:20
Speaker A
What is a trial of testosterone therapy? I would tend to agree with the British Society for Sexual Medicine guidelines on the definition of a trial of testosterone therapy. Assessment of treatment outcome and decisions regarding continuation of testosterone therapy should be based on improvement
26:36
Speaker A
in signs and symptoms of testosterone deficiency. Failure to benefit within a reasonable time frame defined as 6 months for libido, sexual function, muscle function, and improved body fat should prompt this continuation of treatment. Further investigation for other causes of the symptoms is then
26:52
Speaker A
essential. Testosterone therapy is effective when used to correct true and deficiency and the symptoms directly linked to it. Men who experience limited benefit typically fall into three categories. Those with unrealistic expectations, those attempting to treat non-testosterone related conditions with
27:10
Speaker A
testosterone, and those seeking testosterone therapy for underlying psychiatric or personality disorders. Question number two, is there any evidence to support aiming for the mid-normal physiologic range 350 to 600 NOGS per deciliter in men on testosterone therapy or would higher
27:28
Speaker A
levels provide more benefits? This excellent commentary by Caliber and Hackett is relevant because it discusses important topics such as using testosterone to maintain lean muscle mass during low calorie dieting, a key consideration in this GLP1 agonist era.
27:43
Speaker A
It also reviews dose response studies that show a correlation between higher testosterone levels and increased lean muscle mass and decreased fat mass. They wrote, "Achieving higher testosterone levels during testosterone treatment, albeit still within the safe therapeutic range, may not only prevent loss of lean
27:59
Speaker A
mass, but also possibly contribute to a greater loss of fat mass in the context of a negative energy balance. It is likely necessary to raise testosterone levels to the mid or higher end of the physiologic range in order to realize
28:10
Speaker A
clinically meaningful gains in lean body mass or muscle mass depending on how it is measured or prevent its loss during a diet. Age related sarcopenia involves the progressive loss of muscle mass and strength which compromises physical function and increases the likelihood of
28:25
Speaker A
falls and disability. Target interventions such as testosterone therapy are effective strategies for reversing these losses and most important of all preventing frailty. Now let's review some of the dose response studies discussed in this commentary.
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This study dose response effects of sex hormone concentrations on body composition and atypicines in medically castrated healthy men administered graded doses of testosterone gel. It was a randomized control trial to determine whether serum concentrations of testosterone and its metabolites estradi
28:55
Speaker A
and DHT exert dose dependent effects on body composition and metabolic markers in healthy men. It involved healthy men aged 25 to 55 years that received daily transdermal tea gel at graded doses for 12 weeks. There were six treatment
29:09
Speaker A
groups, placebo and those that received 1.25, 2.5, 5, 10, or 15 grams of testosterone gel daily. They found that testosterone gel produced graded dose dependent increases in testosterone, DHT, and estradiol. Increase in lean mass and decrease in fat mass occurred
29:28
Speaker A
in a dose dependent manner with the greatest gains at higher achieved testosterone levels. Increase in lean mass correlated with testosterone, estradiol and DHT levels. Higher testosterone, estradiol and DHT levels were associated with greater fat mass reduction. Change in fat mass inversely
29:46
Speaker A
correlated with on treatment serum sex steroids with a stronger correlation with serum estradiol than testosterone concentration.
29:54
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There were no significant changes in fasting glucose, insulin, ataponectin, leptin or lipids. Increased lean mass strongly and positively correlated with serum concentrations of all three sex steroids as these rise in a colinear fashion with transermal testosterone administration.
30:11
Speaker A
And as you can see, higher levels of testosterone, higher levels of estradiol, and higher levels of DHT resulted in an increase in the loss of fat mass. Whereas higher levels of testosterone, higher levels of estradiol and higher levels of DHT resulted in a
30:28
Speaker A
greater increase in lean muscle mass. And the greatest increase occurred at higher levels of testosterone, including 35, 40, and 50 nanomles per liter. That correlates with the testosterone level of 1008, 1,152, and 1440 nanogs per deciliter. Well above the mid-normal range. They wrote,
30:49
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"In healthy men, higher serum concentrations of testosterone, DHT, and estradile were associated with greater increases in lean mass and decreases in fat mass. Our findings support a concentration dependent relationship between serum sex steroids and body composition changes in men. Our results
31:05
Speaker A
underscore the importance of considering the respective metabolic effects of estradiol and DHT in men. In contrast to the historical focus on testosterone, estradiol management in this study, estradiol was measured but not managed or manipulated and levels rose dose
31:21
Speaker A
dependently with increasing testosterone. Estradiol was allowed to rise physiologically with testosterone and emerged as a positive dose dependent correlate of improved body composition rather than a variable requiring suppression. Higher estradiol correlated with greater increases in lean mass.
31:37
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Higher estradiol correlated with greater reductions in fat mass. The anabolic effects of testosterone in men reflect combined androgen and estrogen signaling with estradiol contributing critically to the anabolic response. Interventions that disrupt testosterone estradile coupling such as aromatase inhibitors
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attenuates downstream anabolic effects. Routine estradile suppression is not supported by the physiology demonstrated in controlled dose response studies in which intact aromatization and higher estradile levels correlate positively with improvements in lean mass and fat mass during testosterone administration.
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This study by basin effective testosterone supplementation with and without a dual five alpha reductase inhibitor on fat-free mass in men with suppressed testosterone production was a randomized control trial in healthy men with normal testosterone levels aged 18 to 50 years for 20 weeks. They received
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testosterone either at 50 milligrams, 125, 300 or 600 milligrams per week. Each dose was paired with either placebo or dutasteride at 2.5 milligrams.
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Therefore, there were eight treatment groups. The study was designed to isolate the role of DHT while holding testosterone exposure constant to determine if the conversion of testosterone to DHT is necessary for testosterone's anabolic effects on skeletal muscle and other androgen
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dependent outcomes. The primary outcome measured was change in fat-free mass. Secondary outcomes included change in fat mass, muscle strength, sexual function, prostate volume, sebum production, hematocrit and lipid levels.
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These are the baseline characteristics of the participants including the average testosterone levels which range from 590 to 842 nanogs per deciliter.
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And here are their baseline testosterone levels before treatment. In the testosterone plus dutasteride group, the mean testosterone level is 519 for the 50 milligram dosage, 895 for the 125 milligram doses, 1,76 for the 300 milligram dosage, and 3,898
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nanogs per deciliter for the 600 mg per week dosage. In this group, DHT was suppressed by 90% or more across all dose groups. In the testosterone plus placebo, the mean testosterone level is 385 NOGS per deciliter for the 50 mgram
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dosage, 822 for the 125 milligram, 1,72 for the 300 mg, and 3,578 ngs per deciliter for the 600 mg per week dosage. It's important to point out that testosterone levels decreased from baseline in the 50 mgram dosage groups.
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They found that changes in fat-free mass, lean body mass, leg press strength, and chest press strength increased in a dose response manner, and fat mass decreased in a dose response manner. There was no significant difference in fat-free mass gains
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between placebo and dutasteride groups. There was no significant difference in secondary outcomes between placebo and dutasteride groups. The conclusion conversion of testosterone DHT is not essential for mediating its anabolic effects on muscle. Skeletal muscle expresses low five alpha reductase
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activity and intramuscular androen signaling is predominantly mediated by testosterone not DHT. DHT appears more revalent for androgen sensitive tissues such as the prostate and skin. This study explains why men on five alpha reductase inhibitors can increase lean muscle mass on testosterone therapy. As
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demonstrated in this study, the benefits increased significantly at testosterone levels above the mid-normal range of 350 to 600. Estradi management in this study. Estradi was not measured or controlled despite testosterone levels reaching the thousands. Improvements in fat-free mass, lean body mass, leg and
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chest press strength and fat mass occurred under conditions of unrestricted estrogen conversion from testosterone. Estradile is required for full anabolic, metabolic, sexual, and skeletal responses to testosterone. If benefit occurred without estradile suppression, estradile suppression is not required for benefit.
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This study, testosterone threshold levels and link tissue mass targets needed to enhance skeletal muscle strength and function, the Hora trial.
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It was a randomized control trial in 112 men aged 65 to 90 years with baseline average testosterone levels of 493 nanogs per deciliter. They're randomized to two doses of testosterone 5 g or 10 grams of gel daily and three growth
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hormone doses 0 3 or 5 microgram per kilogram per day. The study measured change in serum testosterone and IGF-1 levels. They measured body composition, total leaning body mass and appendicular skeletal muscle mass. They measured muscle strength with one repetition max
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bilateral leg press, leg extension, leg flexion, latisimus pull down, and chest press. Function was measured by stair climbing and physical activity scale for the elderly. The study was to determine if there is a threshold rise in testosterone and muscle mass you have to
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obtain before strength and function actually improve and does adding growth hormone lower that testosterone requirement. They found that increases in lean mass above the median change of 1.5 kilogram for total lean body mass and above 0.8 kilograms for appendicular
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skeletal muscle mass were associated with significant increases in muscle strength and improvements in physical function. They then evaluated the level of testosterone required to reach these target gains and if the addition of growth hormone lowered that testosterone requirement. For participants who
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received only testosterone, increases in total testosterone of 1,046 nanograms per deciliter and 898 nanogs per deciliter are needed to increase lean body mass by 1.5 kg and appendicular skeletal muscle mass by 0.8 kg. And it's important to note that these are
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increases over their baseline testosterone levels which were over 400. For participants who received testosterone in any dose of growth hormone, increases of 944 nanogs per deciliter and 912 nanogs per deciliter were needed to increase lean body mass by 1.5 kg and appendicular skeletal
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muscle mass by 0.8 kg. Once again, these are increases over baseline. To reach those threshold gains, they needed large increases in testosterone and the addition of growth hormone lowered the levels required to reach those target gains in lean body mass and appendicular
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skeletal muscle mass. They reported, "Our data highlight the importance of titrating the dose of the anabolic therapy to achieve a target circulating hormone level necessary to induce threshold gains and skeletal muscle mass that adequately improve muscle function.
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The hormone trial shows that testosterone has a clear anabolic threshold. Below it, lean mass, strength, and function do not improve, which explains why many trials with testosterone utilizing lower dosages to maintain levels in the mid to lower range fail.
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Insufficient dosing guarantees insufficient outcomes. Estradiol management in the hormone trial. Estradiol was not measured. No attempt was made to suppress, control or optimize estradiol. Estradiol was allowed to rise naturally via aromatization of testosterone. Hormma preserved normal testosterone. Estradi
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coupling. Beneficial changes in body composition, strength and function occurred under physiologic estradiol exposure. In the hormone trial, testosterone concentrations were substantially increased, often into the high, normal, and super physiologic ranges. Yet, the study did not report a clinical meaningful pattern of estrogen
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mediated adverse effects that necessitated estradiol suppression. This study that we're about to discuss is why this lechure was a year in the making, as it required the review of hundreds of studies. Every individual study cited within the systematic reviews and other
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review articles along with every additional study presented today was downloaded and carefully examined. This is a systematic review by Huo Etall and it examined 156 randomized control trials published between January the 1st 1950 and April the 9th 2016. They
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evaluated the use of testosterone for cardiovascular disease or surrogates of cardiovascular disease, sexual function, muscle strength, mood and cognition.
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They excluded studies involving bodybuilding contraceptive effectiveness, the treatment of any condition in women or children, non-testosterone treatments, and non-randomized control trials. When you review the paper, they have numbers beside each study, and those numbers represent the fivepoint JAD score or
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Oxford quality scoring system. It is a widely used tool for assessing the methodological quality of randomized control trials based on three key areas.
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Randomization, blinding, and withdrawals or dropouts. A total score of three or higher generally indicates high quality while two or less indicates low quality.
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This is a summary of the studies showing the effects of testosterone on cardiovascular endpoints.
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Cardiovascular endpoints continued. A summary of the studies showing favorable effects on lipids. Favorable effects continued as well as study showing a lack of favorable effects on lipids. A summary of the studies showing the effect of testosterone on inflammatory
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and coagulation markers. A summary of the studies showing the effect of testosterone on sexual function.
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Sexual function continued. More sexual function studies. A summary of the studies showing the effects of testosterone on muscle weakness and wasting in men. Continued studies on muscle wasting and weakness.
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Studies on muscle wasting and weakness and HIV positive men. A summary of the studies showing the effects of testosterone on mood and behavior as well as in men with psychiatric disorders.
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Continued studies in men with psychiatric disorders, including HIV positive and negative men. Continued studies in HIV negative men with psychiatric disorders.
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A summary of the studies showing the effects of testosterone on cognition. Continued studies on cognition.
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And this is a summary of their findings. Testosterone supplementation did not show consistent benefit for cardiovascular risk, sexual function, mood and behavior, or cognition. Studies that examined clinical cardiovascular endpoints have not favored testosterone therapy over placebo. Testosterone is
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ineffective in treating erectile dysfunction and controlled trials did not show a consistent effect on libido.
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Testosterone supplementation consistently increased muscle strength but did not have beneficial effects on physical function. Most studies on mood related points found no beneficial effect of testosterone treatment on personality, psychological well-being or mood. The prescription of testosterone supplementation for low testosterone for
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cardiovascular health, sexual function, physical function, mood, or cognitive function is without support from randomized control trials. For those of you that are on testosterone therapy, how many of you would agree with these findings? Let's take a closer look at
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the data and understand the reasoning behind their conclusions. Here's their summary of the sexual function studies. Of 47 studies that assessed sexual function or satisfaction, 24 studies did not show improvements in any sexual function endpoint. Of 31 studies that evaluated
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erectile dysfunction, 15 found no improvement with testosterone therapy. 12 studies included men with erectile dysfunction, eight found no benefit of testosterone over placebo. Of 23 studies that specifically reported changes in libido, eight found no effect. Now, if time permitted, we could examine all of
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the lack of benefit studies for all the areas examined. But at this time, we'll examine just the studies that demonstrated no effect on sexual function and look for any shared patterns or confounding variables. When you evaluate the sexual function, no
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benefit studies, you see that the negative sexual function trials cluster into either pharmacocinetic under exposure or vascular and co-orbidity driven non-response. not proof that testosterone replacement lacks erectile efficacy. Many of the men in the no benefit studies had vascular and
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coorbidity erectile dysfunction from conditions including diabetes, alcoholism with cerosis, major depressive disorder, HIV with coexia, COPD, advanced age, arterial insufficiency, Alzheimer's disease, endothelial dysfunction, anemia of chronic renal disease, advanced cancer, and testicular dysfunction secondary to cytotoxic cancer therapy. Populations
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with vascular and coorbidity driven erectile dysfunction are unlikely to respond to testosterone therapy. Testosterone deficiency is only one of the potential causes of erectile dysfunction. Testosterone therapy is effective in men with erectile dysfunction secondary to androgen deficiency but will not improve vascular
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ED, neurogenic ED or ED related to multiple severe coorbidities. Pharmacocinetic underexposure was a common factor in the no benefit studies.
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The treatment of erectile dysfunction requires time and adequate sustained exposure to testosterone. Most of the lack of benefit studies were of short duration, typically less than 12 weeks.
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The men had inadequate androgen exposure. Many with fixed dosing, no titration, no documented achieved steadyst state levels, and they only reached low normal testosterone levels, typically 300 to 450 nanogs per deciliter. Many trials showing no benefit fail to raise or sustain
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testosterone into a known range from dose response studies to produce physiologic effects. Thus, absence of benefit often reflects inadequate exposure rather than absence of testosterone efficacy. Many of these studies also used an older oral testosterone formulation, andreol. With
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andreol levels are unreliable and heavily dependent on meal timing and fat content. Typically these studies had troughs that were not consistently elevated typically below 300 nanogs per deciliter. When we look at the pharmacocinetics of andriol we see that
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levels are not sustained in a therapeutic range even with twice daily dosing. With once daily doses of 100 mg we get peak levels around 432 nanogs per deciliter. With 200 mg once daily peak levels typically are around 489 nanogs
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per deciliter. And with 200 milligrams B dosing peaks are typically 576 nanogs per deciliter. But pay attention to the troughs. The troughs with all dosing are less than 200 nanogs per deciliter.
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Typically around 5 nanomles per liter or 144 nanogs per deciliter. These are just more examples of the lack of efficacy when targeting the mid-normal range with testosterone therapy. Out of the 156 randomized control trials included in this systematic review, only one used an
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aromatase inhibitor. It was a randomized control trial in 60 healthy men aged 50 to 90 years to determine the contribution of testosterone and estradiol on cognitive function. They were divided into three groups.
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Testosterone plus placebo, testosterone plus anaststerol, and placebo. Testosterone increased 238% in the testosterone and the testosterone and eststerol groups. Estradile increased an average of 81% in the testosterone group and decreased 50% in the testosterone and eststerol group. Spatial memory
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improved in both the testosterone and testosterone and eststerol groups. Verbal memory improved only in the testosterone group. The findings were spatial memory does not require aromatization into estradiol. The verbal memory benefit of testosterone depends on conversion into estradiol. Some
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cognitive domains depend on intact estradiol signaling while others can be supported by just androgenic mechanisms alone. Estradiol management in the beneficial studies in this systematic review. Estradiol was not actively controlled or suppressed. Improvements in cardiovascular endpoints, sexual function, muscle weakness or wasting,
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mood and behavior and cognition all occurred with intact aromatization. Estrazyol was allowed to rise proportionately with testosterone. All the positive randomized control trials preserved physiologic testosterone to estradiol conversion. The randomized evidence supporting testosterone therapy benefits was generated under conditions
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of preserved aromatization, not estradiol suppression or management. If estradiol suppression were necessary for optimal testosterone replacement outcomes, all of the trials that preserved esters would have failed. They did not. Estradi suppression is widely practiced, but not evidence-based and
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randomized outcomes trials. This review by Dr. Gman reviews and summarizes the results of four landmark testosterone randomized control trials.
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The team trial, the T trials, the TD4M trial, and the Traverse trial. And we can thank the traverse trial for having the blackbox warning removed from testosterone with regard to cardiovascular risk. In his summary, he writes, "Testosterone therapy had modest
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but clinically significant benefits on average self-reported energy and mood, sexual function and satisfaction. Modestly improved objectively assess muscle strength and timed walking distance. Modestly improved some aspects of physical function without effect on fall risk. increased bone density and
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strength did not significantly increase the risk of myocardial inffection, stroke or prostate cancer. When we review the purported outcomes, the terms modest appears repeatedly. Importantly, achieved testosterone concentrations in these trials are generally restored to the low to mid-normal range. Here are
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the median and mean levels obtained in all four studies. The team trial had a median testosterone treatment of 562 nanogs per deciliter. The T trials, the mean testosterone levels achieved were 501 nanograms per deciliter. The TD4M trial, the mean trough levels were 461
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to 518 NOGS per deciliter. And in the traverse trial, the medium trough levels were 325 to 386 NOGS per deciliter.
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Decades of control dose response trials demonstrate graded improvements in lean mass, strength, body composition, and functional capacity as testosterone concentrations rise across the physiologic and super physiologic spectrum. Therefore, the magnitude of benefit observed in these landmark trials entirely consistent with the
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relatively conservative testosterone exposure achieved. When exposure is conservative, outcomes are correspondingly conservative. Estradi management. Estradi was measured in all four studies but was not controlled or suppressed. All benefits occurred with physiologic testosterone restoration and intact arommonization.
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No estradiol suppression strategy was required to produce these outcomes. Collectively, the landmark trials defined the therapeutic effects of testosterone under conditions of physiologic testosterone to estradiol coupling rather than hormonal disruption. Testosterone does not act in isolation. It functions within a coupled
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indocrine system in which aromatization to estradile is not a side effect but a biologic feature. Across the four trials, testosterone was restored to physiologic concentrations in estradile rose proportionately. None of these landmark trials suppressed estradiol.
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None required aromatase inhibition to achieve benefit. At present, there is no randomized control data that demonstrates controlling estradiol enhances therapeutic outcomes. whereas disrupting physiologic testosterone to estradile coupling has been shown to attenuate established benefits. Question number three, does exogenous
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testosterone produce the same physiologic effects as endogenous production when the same serum concentrations are achieved? And is there any evidence to support staying within the normal physiologic range while on treatment? Keep in mind the normal physiologic range has been
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shifted downward secondary to the decreased production of testosterone in men. This study by Basin was to determine the effects of graded doses of testosterone on body composition, muscle size, strength, power, sexual and cognitive functions, prostate specific antigen, plasma lipids, hemoglobin, and
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IGF-1 levels, and healthy young men. It was a randomized double blind three-phase study with a four-week control, a 20we treatment phase, and a 16we recovery phase. It involved 61 healthy eugenatal men aged 18 to 35 years and 54 completed the study. Their
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indogenous testosterone was suppressed with monthly gonadotropen releasing hormone agonist. They were then randomized through weekly testosterone and ananthate for 20 weeks at 25 50 125 300 or 600 mg.
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The mean nadir testosterone levels measured in nanogs per deciliter 7 days after the injection were 253 for the 25 milligram dosage, 306 for the 50 mgram dosage, 542 for the 125 mg dosage, 1,345 for the 300 mg dosage, and 2,370
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for the 600 mg dosage. Fat-ree mass increased 3.4 kg in the 125 mg dosage, 5.2 2 kg in the 300 and 7.9 kg in the 600 mg dosage. Fat mass increased in the 25 and 50 mg dosages and was stable or
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decreased at higher dosages. Muscle size increased in a dose dependent manner. Thigh volume increased by 56, 84, and 126 cm cubed at the 125, 300, and 600 mg dosages. There was no significant change in the 25 and 50 mgram dosages.
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Strength and power changes correlated with testosterone concentrations and muscle size and were greatest at the 300 and 600 mg dosages. There was no significant change in the 25 and 50 milligram dosages. IGF-1 levels increased dose dependently especially at
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higher doses. It increased 74 ngs per deciliter at the 300 milligram dosage and 77 nanogs per deciliter at the 600 milligram dosage. sexual function, visual spatial cognition and mood did not change significantly at any dose.
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There were no serious adverse events in any participant and acne was the most common side effect. Also want to point out that the testosterone levels actually decreased in the 25 milligram dosages from 593 to 253 and from 566 to
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306 in the 50 milligram dosage. Testosterone exhibits a clear concentration dependent relationship with fat-free mass, muscle size, strength, power, and IGF-1 levels with progressively greater responses observed at higher serum testosterone concentrations, including those at or above the upper physiologic range.
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Estradi management in the study, estradi was not measured, controlled, or suppressed. Testosterone was increased across subphysiologic to superphysiologic ranges with proportional rises in estradiol.
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Increases in fat-free mass, muscle size, strength, power, and IGF-1 levels occurred with physiologic aromatization intact. No changes in sexual function, visual spatial cognition, or mood with unrestricted aromatization. In the basin graded dose response studies, anabolic benefit occurred in the setting of
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intact testosterone estradiol coupling across the full spectrum of exposure including superphysiologic testosterone levels. As testosterone increase, aromatization would be expected to rise proportionally. Importantly, no clinical dominant estrogenic adverse signal emerged that required routine pharmacologic suppression. Physiologic testosterone to estradile conversion was
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preserved and therapeutic benefit was demonstrated within that normal endocrine framework. Advocating routine aromatase inhibition in this context therefore represents a deliberate alteration of established physiology without randomized evidence demonstrating superior patient important outcomes compared to testosterone therapy alone. This article was produced
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by the Baylor group that includes Dr. Cara who is also one of the researchers in the traverse trial.
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It was a retrospected chart review of 184 patients that underwent testosterone therapy in their clinic. And these are patients being treated in a private practice group. They were divided into two groups that either had physiologic levels with a median testosterone level
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of 468, range 308 to 644 nanogs per deciliter, or super physiologic levels with median levels of 1552 with a range of 1,279 to,700 nanogs per deciliter.
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They write, "Despite widespread concerns, these findings suggest that although patients treated to achieve superphysiologic testosterone levels had a higher incidence of polyythemeia, there were no significant difference in the rates of other adverse events after testosterone replacement therapy between
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patients treated to obtain physiologic versus superhysiologic testosterone levels. There was no significant difference in the rates of venus throboism, major adverse cardiac events, deep vein thrombosis, myioardial inffection or stroke. Even well-known researchers realize that some men need super physiologic levels of testosterone
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for symptomatic improvement. This is an excellent study by Dr. Rebecca Glazer and it can be applied to both sexes. It was entitled testosterone implants in women pharmarmacological dosing for a physiologic effect. The objective was to determine the therapeutic serum testosterone levels in
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women treated with subcutaneous pellets. 285 pre and postmenopausal women with symptoms of androgen deficiency were treated with testosterone pellets for at least one year. The testosterone measured 4 weeks after insertion and when androgen deficiency symptoms returned.
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What she found was that the mean testosterone levels at 4 weeks was 299 plus orus 107 nanogs per deciliter. and she states this mean value is four to six times the upper limit of normal for endogenous production. The lab core
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normal range for premenopausal women is 10 to 55 and for postmenopausal women is 7 to 40 nanogs per deciliter. She also reported the mean testosterone levels when symptoms returned was 184 plus or - 74 nanogs per deciliter with a range of
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47 to 461 nanogs per deciliter over four times the upper limit of normal for indogenous production. There were no reported adverse drug events. Side effects included increased facial hair, acne, and 1% reported perceived voice changes. No clitoromegaly reported. She
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writes, "There is no evidence to support that testosterone levels on therapy should remain within ranges for indogenous production. There is no clinical evidence supporting the recommendation that serum levels of testosterone on therapy should remain within the upper limits of indogenous
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production for a young healthy female. It has been documented in the past that serum testosterone levels on subcutaneous implant therapy are higher than indogenous ranges and that more consistent benefit is seen with testosterone levels that exceed the normal range. Long-term data exists on
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the safety, tolerability, and efficacy of those doses in up to 40 years of therapy. In addition, significantly higher doses of testosterone used to treat breast cancer patients and female to-male transgender patients have been studied and found to be safe. She points
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out the treatment of male transgender patients. So let's briefly look at that. Here is the endocrine society guidelines for the treatment of trans individuals.
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It states clinicians can use either parental or transermal preparations to achieve testosterone values in the normal male range. This is depending on the specific assay but typically 320 to,000 nanogs per deciliter. They recommend testosterone ananthate or cipionate at 1 to 200 mgram subqri every
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2 weeks for testosterone ananthate and cypionate. The testosterone levels should be measured midway between injections. It is ironic that the integr society guidelines for trans men often permit testosterone levels up to 1,000 while the therapeutic target level for
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men with testosterone deficiency is 350 to 600 nanogs per deciliter. This study by Dr. Trish discusses the safety of treating trans males with pharmacologic doses of testosterone. This was a literature review of femaleto-male transexuals treated with super physiologic or pharmacological doses of
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testosterone over long periods of time to determine whether major adverse health outcomes occurred under these much higher androgen exposures. He writes, "The data from the studies reported in the literature to date strongly suggest that treatment of female tomale transgenders with super
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physiologic doses of testosterone had minimal adverse effects. No increase in mortality, breast cancer, vascular disease, or other major health problems were reported. There were no significant adverse effects reported in femaleto-male transsexuals treated with pharmacological doses of testosterone.
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We can treat female to-male transsexuals with super physiologic doses of testosterone safely, but we can't treat males with testosterone deficiency with super physiologic doses out of safety concerns.
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Dr. Glazer in her paper also writes, "Physiologic dosing of testosterone in women has been shown to be clinically ineffective. The simplistic concept of using a single serum testosterone level to guide therapy ignores the complexity of physiological events from production
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released to biological effect and totally disregards the significant contribution of local production as well as age related changes.
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Testosterone can be produced via two distinct pathways. The delta 5 pathway involving pregnnenolone 17 hydroxypnolone DHEA and androstendion and the delta 4 pathway involving progesterone 17 hydroxy progesterone and androstendion.
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The delta 5 pathway is 11 times more efficient than the delta 4 pathway making it the primary route of testosterone production in the male testes.
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When the body makes testosterone endogenously it does so through a carefully regulated system. Signals from the brain tell the testes how much to produce and the hormone is released in close coordination with other hormones.
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This creates a balanced well-timed environment that allows tissue to respond efficiently. When testosterone is given exogenously, it bypasses this built-in control system. The hormone circulates broadly through the bloodstream without the same fine-tuned signaling. In some individuals, especially those whose tissues are less
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sensitive to testosterone, this may mean higher serum levels are needed to achieve the same effects at the tissue level than the body would normally accomplish through its own natural production. In other words, we may need more when we take it exogenously to get
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the same effects as when we make it endogenously. Dr. Glazer writes, "We propose that testosterone dosing should be based on adequate clinical efficacy similar to insulin dosing where individual biological effect and tolerability determines dosing rather than serum levels based on endogenous production.
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Pharmacologic dosing is treating the symptoms, not the levels. Physiologic dosing is treating to a number such as the mid-normal range.
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Androgen status does not equal serum testosterone alone. It is of fundamental importance to understand that serum testosterone levels are not the sole indicator of androgen status. Several other factors are equally vital in determining how androgens affect an individual. This explains why man can
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present with classic deficiency symptoms despite having normal lab results and why some individuals require levels above the standard reference range to achieve symptomatic relief. Let's review some of the other determinants of androgen status.
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In this paper by Dr. Kurthers the paradox dividing testosterone deficiency symptoms and androgen assays. A closer look at the cellular and molecular mechanisms of androgen action. The testosterone deficiency syndrome paradox is that classic testosterone deficiency symptoms correlate poorly with serum
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testosterone because androgen deficiency can arise from low supply andor impaired tissue action androgen resistance at multiple biologic levels. He describes five levels at which testosterone production and action can be impaired.
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Level one, impaired androgen synthesis or regulation, which is a production problem. This can be seen with aging, testicular disorders, stress and illness, lifestyle and environmental factors and medications. Level two, increased androgen binding. Increased sex hormone binding globulin which we
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have previously discussed will result in increased androgen binding. Level three reduced tissue responsiveness an end organ problem. Aging and disease alter tissue structure and profusion lowering androgen delivery and response. Level four decreased androgen receptor activity. Genetic variation tag repeat
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length as well as age related decreases in the number of androen receptors can occur. Level five, impaired transcription translation, which is a post-receptor signaling problem. Even in the presence of adequate hormone and receptors, any impairment in downstream machinery can limit androgen's effects.
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Dr. Kurther's models reframes testosterone deficiency as a multi-level disorder of androgen supply and androgen action, analogist to insulin deficiency and insulin resistance. This explains why symptoms can be severe despite normal serum testosterone and why some individuals may need higher levels of
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testosterone to overcome what he terms androgen resistance. Testosterone not only has to be made in adequate amounts, but it has to be delivered and used effectively by tissues. Dr. Kurthers along with Dr. Ruseier are some of the first, if not the first, to advocate for
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treating symptoms, not levels. Let's now review the limitations of guidelines. In this editorial written by Dr. John Powers and published in the Archives of Internal Medicine, he writes, "Guidelines are not just summaries of the evidence. They are also
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interpretations of that evidence by guideline authors who bring to the process their own conscious and unconscious biases. A recent study of the quality of evidence and cardiology guidelines showed that of more than 7,000 recommendations, a meeting of 11%
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were based on data from randomized control trials and 48% on expert opinion, case studies, or standards of care. Lee and Balemeer report on a similar analysis of guidelines and infectious disease. Their study shows that of more than 4,000 recommendations,
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14% were based on data from randomized control trials and 55% on opinion or case studies. Both studies show that although the number of recommendations increased across time, few of the new recommendations were based on randomized control trial data. He has pointed out
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that guidelines are more opinion than data driven and they are recommendations not mandates. Let's look at them. Here is the American Urology Associate guidelines for the management of testosterone deficiency. While these guidelines do not necessarily establish the standard of care, the AUA seeks to
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recommend and to encourage compliance by practitioners with current best practices related to the condition being treated. As medical knowledge expands and technology advances, the guidelines will change. Today, these evidence-based guidelines statements represent not absolute mandates, but provisional proposals for treatment under the
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specific conditions described in each document. For all these reasons, the guidelines do not preempt physician judgment in individual cases. Here is the endocrine society guidelines for the treatment of men with hypogonadism.
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The endocrine society's clinical practice guidelines are developed to be of assistance to endocrinologists by providing guidance and once again recommendations for particular areas of practice. The guidelines should not be considered inclusive of all proper approaches or methods or exclusive
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others. The guidelines cannot guarantee any specific outcome nor do they establish a standard of care. The guidelines are not intended to dictate the treatment of a particular patient.
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Treatment decisions must be made based on the independent judgment of healthcare providers and each patients individual circumstances.
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The use of a threshold level of testosterone to diagnose testosterone deficiency, aiming for the mid-normal physiologic range, and maintaining levels within the normal physiologic range during treatment are based on opinions, not science. Free testosterone, the normal range. There is
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currently no standardization of free testosterone assays and no harmonized reference ranges currently exist. Equilibrium dialysis remains the most sensitive and specific method for assessing free testosterone.
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This study by Antonio low free testosterone is associated with hypogonatal signs and symptoms in men with normal total testosterone identifies the importance of free testosterone in the diagnosis of hypogonism in men with hypogonatal symptoms. The objective of the study was
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Speaker A
to investigate if low free testosterone or low total testosterone is more strongly associated with the testosterone deficiency symptoms. It involved 3,334 men aged 40 to 79 years from the European male AG study. They were divided into four groups. Normal
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testosterone free testosterone, normal testosterone, low free testosterone, low testosterone, normal free testosterone, and low testosterone low free testosterone. Low testosterone was defined as a testosterone level less than 300 nanogs per deciliter and low free testosterone was defined as less
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than six nanogs per deciliter. The study assessed sexual, physical and psychological symptoms. They evaluated hormone levels, biochemical measurements, body composition and bone density.
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And these are the results. Men with normal total testosterone and normal free testosterone were asymptomatic. Men with normal testosterone and low free testosterone had a decrease in hemoglobin, decrease in lean mass, decrease in bone density, and increased sexual and physical symptoms. Men with
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Speaker A
low total testosterone and low free testosterone also had a decrease in hemoglobin, decrease in bone density, decrease in lean mass, and an increase in sexual and physical symptoms. Men with low total testosterone but normal free testosterone had a decrease in
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hemoglobin but no significant symptoms or change in lean mass or bone density. He reported that low free testosterone even in the presence of normal total testosterone is associated with androgen deficiency related symptoms. Normal free testosterone despite low total
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testosterone is not associated with cognate symptoms. Therefore free testosterone levels should be assessed in men with suspected hypogonatal symptoms.
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Speaker A
This is the normal range for free testosterone utilizing equilibrium dialysis at quest diagnostics and that normal range is 35 to 155 pogs per milliliter or 3.5 to 15.5 nanogs per deciliter. This normal range was internally derived. Therefore there is
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no information about the health status or the total testosterone levels in these men. This is the normal range for free testosterone utilizing equilibrium dialysis at LabCore. Like Quest Diagnostics, they were internally derived. Therefore, there is no information about the health status or
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the total testosterone levels in these men. And the normal range at LabCore is 52 to 280 pogs per milliliter or 5.2 to 28 nanogs per deciliter.
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Speaker A
Now let's look at a study from the journal andrology where we can see the details about how the normal values were obtained and compare the results to LabCore and Quest. The objective of this study was to determine reference
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Speaker A
intervals for free testosterone in healthy non-obese men by age groups as well as in healthy young men 19 to 39 years old. Free testosterone was measured in 145 healthy non-obese men 19 years or older utilizing equilibrium dialysis.
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And these are the results utilizing the 2.5th and 97.5th percentiles. The reference intervals for free testosterone in all men was 66 to 309 pogs per milliliter. And for men 19 to 39 years of age it was 120 to 368 pogs
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per milliliter. Or for all men it was 6.6 to 30.9 per deciliter. In men 19 to 39 years of age it was 12.8 to 36.8 nanogs per deciliter.
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Speaker A
Let's now compare the free testosterone ranges. As you can see, lab corpse reference range is nearly twice as high as Quest. As a result, a man on treatment with a free testosterone level of 25 would be considered super
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physiologic by Quest and might have his dose reduced, whereas that same level would fall comfortably within LabCore's normal range. Qualification for treatment is also affected by the lower limit of these ranges, which is 3.5 at Quest and 5.2 at LabCore. In my
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experience, it often takes a very symptomatic or significantly unwell man to have a free testosterone level below 3.5 or even 5.2. It is also important to remember that the reference ranges used by both LabCore and Quest were internally derived. And at least in the
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Speaker A
case of Quest, the population used to establish a range may have included men with relatively poor health and low total testosterone levels. Now, compare those laboratory reference ranges with the data from the journal Andrology Study. For men aged 19 to 39 years, the
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reported normal free testosterone range was 12 to 36.8. If Quest and LabCore adopted a range such as this, more men would qualify for treatment based on a lower limit of normal closer to 12 and more men would be treated adequately
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Speaker A
since a free testosterone level of 36.8 would still be considered normal. Clinically, that matters because many men experience substantial improvement at levels within that range. Under the present circumstances, I recommend getting your free testosterone levels measured at LabCore instead of Quest.
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Speaker A
Estradi, the normal range. In this section, we're going to look at testosterone and estradiol levels using inhanes data as well as look at the testosterone and estradiol levels in clinical studies to better understand what the normal estradile range
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Speaker A
represents. The Quest Diagnostics reference range for estradile in men is less than or equal to 29 pags per milliliter.
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Speaker A
However, this range was internally derived and no publicly available data have been provided regarding the health status or testosterone levels of the men used to establish it. The lab corp reference range for estradile men is 8 to 35 pogs per milliliter. However, like
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Quest Diagnostics, this range was internally derived and no publicly available data have been provided regarding the health status or testosterone levels of the men used to establish it. I contacted Lavcore for information regarding how the normal range was established. And I was told by
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their director, Dr. Kelly Chung, that they no longer had that data and that the normal range was developed a couple of decades ago and most likely represented volunteers that worked at the lab. So, we have no information regarding the details of how Quest
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Speaker A
Diagnostics or LabCore developed their normal estradile ranges in men. As we further evaluate the normal estradile range, we're going to use the normal range for estradile at lab core of 8 to 35 since it is the most frequently
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referenced. I'm now going to review the data on testosterone and estradile levels and show you the testosterone levels that the normal estradile range of 8 to 35 represents.
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Speaker A
Using inhanes data, we can go back and look at testosterone and estradile levels in men over the last several decades. These are the median estradiol levels for inhanes 3 1988 to 1994 and inhanes 1999 to 2004. Looking at the 20
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to 39 year old age group and inhanes 3 all men estradile levels were 36.5 45.5 and 33.7. In the same age group and in hannes 99 to 2004 all men estradile levels were 28.1 36.5 and 28.1 peak grounds per milliliter. In
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Speaker A
the 40 to 59year-old age groups, the same inhanes data showed a estradi level of 33.6, 39, 30.9, 36.9, and 25.2.
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Speaker A
60 and above, estradile levels were 34, 38.8 32.8 26.7, 33.3, and 22.3. Now let's look at the median testosterone levels from the same inhanes data. In 20 to 39year-old males all men testosterone levels were 599 and continuous inhanes it was 542 nanogs per
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Speaker A
deciliter. 40 to 59y old age group 486 and 445 60 plus 435 and 392 nanogs per deciliter for all men.
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Speaker A
Now let's pair the testosterone and estradiol levels. Now, the estradiol levels are broken down by race and ethnicity, and the testosterone levels included all men without breaking the levels down by race and ethnicity. In order to compare all men estradiol
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Speaker A
levels to all men testosterone levels, you simply average the estradile levels of all men non-Hispanic white, non-Hispanic black, and Mexican-American in each age group. So, when we pair the data, here are the results.
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Speaker A
These are the results for the median testosterone and median estradile levels for inhanes 3 1988 to 1991 all men for age 20 to 39 median testosterone levels were 599 which correlated with an estradile level of 38 pics per
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milliliter. At age 40 to 59 testosterone levels of 486 correlated with estradi levels of 35 pogs per milliliter. And at age 60 plus testosterone 435 correlated with estradi levels of 35 pogs per milliliter.
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Speaker A
Looking at inhanes 1999 to 2004. Age 20 to 29 testosterone levels were 542 which correlated with an estradile level of 31. At age 40 to 59 testosterone levels of 445 correlated with estradile levels of 31. And at age 60 plus testosterone
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Speaker A
levels of 392 correlated with estradiol levels of 27 peak grams per milliliter. These were all median levels.
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Speaker A
Now we just evaluated median levels. But now let's look at average testosterone and estradile levels from the same inhanes data. In the 1988 to 1991 data, average testosterone levels of 537 correlated with estradi levels of 35.7.
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Speaker A
In the 1999 to 2004 data, testosterone levels of 534 correlate with an average estradi level of 29.67.
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Speaker A
They also broke the levels down by age groups. 1988 to 1991, ages 20 to 24, 45 to 69, and age greater than 70 had testosterone levels of 549, 520, and 515 respectively. and that correlated with estradiol levels of 35.5, 35.36, and
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Speaker A
38.61. Looking at the 1999 to 2004 data, in the same age groups, testosterone levels of 529, 538, and 534 correlated with estradi levels of 29.4, 29.9, and 29.9.
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Speaker A
Here's a 2021 study from the journal Andria where they evaluated three inhanes continuous cycles. The average testosterone levels of 516 correlated with estradiol levels of 33.12 in the complete population. For testosterone levels less than 250, an average testosterone level of 182 correlated
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Speaker A
with a estradile level of 22.49. And for testosterone levels of greater than 250, the average testosterone level of 546 correlated with estradile levels of 34.11.
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Speaker A
In this 2007 Danish study published in the journal of clinical indocratology and metabolism, they looked at the testosterone and estradile levels in 20 to 29 year old men. They looked at a reference population, non-obese population, and an obese population.
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Speaker A
Now, the low-risk reference population were men at low risk for secondary androgen deficiency. and they ruled out subjects that had small testes, chronic disease, subclinical hypothyroidism, significant alcohol intake, anabolic steroid use and chronic disease etc.
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Speaker A
These are reported in international units. So they are reported in nanomles per liter for testosterone and peam moles per liter for estradiol but they have been converted into American units.
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Speaker A
When we look at the upper limit for both testosterone and estradiol in each group, we find that the reference population total testosterone of 191 correlates with an estradi level of 45.2.
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Speaker A
For the non-obese, a total testosterone level of 182 correlates with an estradile level of 45.7. And for the obese population, a total testosterone level of 844 correlates with an estradile level of 39.2 pogs per milliliter.
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Speaker A
This is a 2006 study from the Annals of Internal Medicine on endogenous sex hormones and cardiovascular disease incidents in men. They divided men into four quartortiles. They based the four cortiles on the distribution of each hormone level in the study population
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Speaker A
measured at baseline. In other words, they took the men's baseline testosterone, estradiol, and DHEA levels, ranked them from lowest to highest, and then divided them into four roughly equal groups with quartile one being the lowest levels and quartile 4
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being the highest levels. And the values are means in this study. For all participants, a total testosterone of 520 correlates with an estradile level of 30.3. Quartortile one had a testo average testosterone level of 330 which correlated with an estradile level of
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Speaker A
15. Quartortile 2 had an average testosterone level of 450 which correlated with an estradile level of 24.6.
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Speaker A
Cortile 3 testosterone level of 560 correlates with a estradiol level of 33.8. And in quartile 4 testosterone levels of 740 correlates with estradile levels of 47.6.
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Speaker A
Now, even though we are focusing on testosterone and estradiol levels and not focusing on study results in this section, it is interesting that those with higher testosterone and estradiol levels had less age adjusted 10-year cardiovascular disease incidents and
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Speaker A
lower hazard ratios. As you can see, quartile 3 and quartortile 4, as you go up in testosterone and estradile levels, the hazard ratios decline.
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The study found that serum testosterone and DHEA levels were not statistically significantly associated with incident cardiovascular disease. A higher serum estradiol level is associated with lower risk for cardiovascular disease events in older men. The findings are consistent with the hypothesis that
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Speaker A
endogenous estrogen has vascular protective influences in men. Instead of continuing to look at baseline levels, let's now look at the estradile levels in men on testosterone therapy when levels are raised to the mid-normal range. We'll start by looking
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Speaker A
at the testosterone and estradile levels in the study by Stevens Shields. Relation of testosterone, dihydro testosterone, and estradi with changes in outcome measures in the testosterone trials.
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Speaker A
These are the baseline characteristics of all men involved in the testosterone trials as well as in the bone trial. So for all men a testosterone level of 231 nanogs per deciliter correlates with an estradile level of 20.3 and in the bone
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trial a total testosterone level of 229 correlates with an estradi level of 20.5. A median total testosterone level of approximately 500 correlates with a median estradile level in the mid to low30s. As you can see this is the
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Speaker A
median total testosterone levels in the low 500s and here is the median estradile level in the low to mid30s.
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Speaker A
Again, even though we're specifically looking at testosterone and estradiol levels, it's still important to mention the study results as it relates to estradiol increases in sexual desire with increasing estradi were the largest with high change in DHT and total
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Speaker A
testosterone. The increase in sexual desire did not seem to increase with total testosterone and holding changes in estradiol and DHT constant. Estradile change had the highest variable importance followed by DHT and total testosterone. The changes in sexual desire were most robustly associated
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with estradiol, consistent with studies of men with congenital deficiency of the aromatase enzyme and randomized trials in which administration of aromatase inhibitors suppressed sexual desire even in the presence of normal testosterone levels. The higher the level of estradiol, the better. Now look at data
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Speaker A
from the traverse trial and compare testosterone to estradiol levels. The traverse trial reported values in two ways. overall which is the top half here includes all randomized patients who received at least one dose even if they later stopped taking testosterone. The
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Speaker A
on treatment the bottom values here includes only values while patients were actively taking the study drug and excludes post discontinuation labs. Now let's compare testosterone and estradi levels at baseline month 12 and month 36 since that's where we have measurements
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of both testosterone and estradiol. Baseline average testosterone levels of 220 correlates with a baseline estradiol level of 21. At month 12, 440 correlates with a estradile level of 31. At month 36, a level of 428 correlates with an
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estradile level of 31 as well. On treatment results, average testosterone levels of 220 correlates with an estradile level of 21. Average testosterone levels of 441 correlate with estradi levels of 31. And then average testosterone levels of 432 correlate with estradile levels of 32.
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Speaker A
Looking at the testosterone and estradile levels in the sexual function study from the traverse trial, we can compare testosterone levels at months 12 and 36. These are the baseline characteristics of the participants and total testosterone levels of 220
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correlated with an estradile level of 21. The sexual function study the baseline levels were 220 for testosterone and 20.9 for estradiol and these are the on treatment levels. At month 12 the average testosterone level was 477 which correlated with an estradi level
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Speaker A
of 32.6 a total testosterone level of 406 correlated with an estradi level of 29.2. We have now been able to compare baseline testosterone and estradile levels in men not on testosterone as well as compare on treatment levels of
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testosterone and estradi when testosterone was raised to the mid-normal range. And here is what we find. The normal estradile range of 8 to 35 does not apply to all of the achievable levels of testosterone while on testosterone therapy. It represents
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Speaker A
the normal estradile levels for men with average total testosterone levels less than 600 nanogs per deciliter. It does not apply to men with total testosterone levels greater than 600 NOGS per deciliter. The normal estradile range of 8 to 35 is based on men not on
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Speaker A
testosterone with levels less than 600 NOGS per deciliter. It should not be applied to men on testosterone therapy with levels greater than 600.
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Speaker A
Using population-based data and randomized trials in which testosterone was increased to the mid-n normal range, we can apply the normal estradi range from labcore to average testosterone levels above or below 600 nanogs per deciliter. If a testosterone level is
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Speaker A
less than 600 and estradiol is less than 8, low E2. Testosterone level less than 600, estradile 8 to 35, normal E2.
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Speaker A
Testosterone level less than 600, E2 greater than 35, high E2. Testosterone greater than 600, E2 less than 35, low E2, and testosterone level greater than 600, E2 greater than 35, what is normal E2? What is considered a high E2 with a
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Speaker A
testosterone level greater than 600? As we continue to look at clinical data and human physiology, the essential questions become, is applying a fixed estradi reference range clinically meaningful across different testosterone concentrations? What if anything constitutes high estradiol when serum
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testosterone exceeds 600 NOGS per deciliter? The answers to those questions will become much more clear by the end of this lecture.
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Testosterone therapy and estradiol DHT. Let's briefly review testosterone physiology and the conversion of testosterone into its active metabolites DHT and estradiol.
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Whether testosterone is produced endogenously or taken exogenously, it travels down three pathways. The direct pathway where testosterone acts directly on muscle. The amplification pathway where it is converted into DHT and tissues such as the prostate and skin.
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And then the diversification pathway where it is converted into estradiol and tissues such as the brain, bone, and vascular endothelium.
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In this review, Dr. Her office Jarvis highlights the physiologic importance of both testosterone and estradiol in men and women. He proposes and I agree that testosterone is best understood as three hormones in one. Testosterone, dihydrotestosterone and estradiol.
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Together these hormones act synergistically to produce the full range of testosterone's biological effects in men. In fact, a substantial portion of these benefits are mediated through testosterone's active metabolite estradiol.
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He writes in males te's conversion to E2 is fundamental to bone and vascular health as well as prevention of excess visceral atyposity and the promotion of insulin sensitivity via activation of the estrogen receptors. Optimizing levels of both hormones may be
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beneficial to protect patients from cardioabolic disease and frailty during aging. Endogenous tea promotes cardiovascular health in males via conversion to E2. Anecdotally, male patients on TRT often acquire about their E2 levels due to fear of too much female hormone. Men's health clinics
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even prescribe aromatase inhibitors to suppress E2 production while raising tea concentrations. However, we discussed the essential role of te's conversion to E2 in male bone and vascular health as well as glucose and lipid homeostasis, not to mention libido and erectile
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function. Thus, it is our view that E2 should not be suppressed in men. And in fact, clinical trials of E2 supplementation should be considered in some men on TRT to decrease LDL cholesterol and improve endothelial function. Finally, current laboratory
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Speaker A
measurements of serum T and E2 levels, total or free, poorly reflect tissue and cellular T and E2 concentrations, catabolism, and elimination.
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the effects of injected testosterone dose and age on the conversion of testosterone to estradile and dihydrotestosterone in young and older men. We're now going to look at what occurs with estradile and DHT when testosterone is raised into the upper
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physiologic and supra physiologic ranges. The objective of this study was to evaluate age and dose related differences in estradile and DHT levels in response to graded doses of testosterone in young and older men. 51 young and older men were randomly
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assigned to receive weekly doses of testosterone at 25, 50, 125, 300, or 600 milligrams for 5 months. During testosterone administration, estradile and DHT levels exhibit saturable increases with dose. Mechanistic modeling of free hormone data revealed that the conversion of testosterone to
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estradile and DHT were both consistent with saturableism mitten kinetics. Let's review Michaelis Mitten kinetics.
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In biochemistry, Michaelis mitten kinetics is the simplest case of enzyme kinetics applied to enzyme catalyzed reactions of one substrate and one product. Aromatase the enzyme, testosterone is a substrate and estradile is the product. Vmax is the maximum reaction rate or velocity of an
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enzyatically catalyzed reaction when the enzyme is saturated with substrate represented by this graph. Substrate is testosterone concentration and the y-axis represents estradiol levels. At low substrate concentration or low testosterone levels, the conversion into estradiol is linear. As we increase
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testosterone levels, we ultimately run out of aromatase enzyme and estradile cannot be increased any further. And that is represented by the vmax.
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Once again, the x-axis is testosterone and the y-axis is estradiol. Testosterone is represented by the red dots and the aromatase enzyme is represented by the yellow half circles.
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Ultimately with increasing testosterone levels, we run out of aromatase enzyme represented by this picture.
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What the study found was that total and free E2 levels increase dose dependently in both young and older men. Total and free E2 levels and E2 to testosterone ratios during tea administration were higher in older than younger men. DHT
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testosterone ratios were dose related but did not differ between young and older men. In this study, they used the combined baseline and on treatment data for each treatment group and developed a mathematical model describing how rising testosterone levels translate into
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Speaker A
corresponding changes in estradile and DHT. Using these mathematical models, spreadsheets can be utilized to illustrate the estradile and DHT changes with increasing levels of testosterone.
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Now understand this is a mathematical model in an effort to predict levels. They did not actually achieve all of the achievable levels of testosterone and measure estradile directly. These models should not be interpreted as universal normal ranges or targets that can be
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applied to all men, but instead viewed as a modelbased predictions for this specific study population under these study conditions.
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Using the predicted DHT equation for young men in this study, we can estimate levels of DHT with increasing levels of testosterone. So as you can see as we increase testosterone DHT levels will increase and the testosterone DHT ratio
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will increase with increasing levels of testosterone as well. The same occurs in older men. The conversion of testosterone to DHT whether it be young or older men slows down as the five alpha reductase enzyme availability decreases. For instance, when we go from
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a testosterone level of 100 to 1,000, there is an increase of DHT of 68.6. 7 nanogs per deciliter. But when we go from,00 to 2,00 there is only an increase of 37.8 nanogs per deciliter.
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Using the predicted estradile equations for young men in this study, we can estimate the estradile levels with increasing levels of testosterone. And these are the predicted values for the younger men in this study. And this is the same applied for older men. In both
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Speaker A
young and older men with increasing levels of testosterone, the testosterone to estradile ratio increases as aromatase enzyme availability decreases.
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For instance, once again, going from 100 to 1,000 level of testosterone, there's an increase in estradile of 47.2 pogs per milliliter. Going from,00 to 2,000, there is only an increase of 20.5 pogs per milliliter. The conversion of testosterone and estradile slows down
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Speaker A
secondary to less aromatase enzyme availability based on Michaelis mitten kinetics and also with increasing levels of testosterone the testosterone to estradile ratio increases in everyone based on enzyme kinetics.
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When you look at the total E2 versus testosterone curves in older men represented here, they have curves that are approximately 30 to 40% higher than in young men consistent with a higher maximum rate of whole body aromatization.
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And this is what occurs with aging. There is a decrease in lean muscle mass and an increase in fat mass. This is what contributes to insulin resistance as we age. Approximately 70% of your insulin sensitivity is related to your
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Speaker A
lean muscle mass. As we age, what we are trying to accomplish with nutrition and exercise and hormone optimization is the prevention or reversal of insulin resistance by maintaining our lean muscle mass and lowering fat mass. And as you have learned, testosterone helps
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us do that in a dose response manner. In other words, better the levels, better the benefits.
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This is a very simplified graph of Michaelis Mitten Kinetics for the conversion of testosterone into estradiol. We can raise testosterone levels in a linear fashion with increasing doses, but estradiol ultimately plateaus because aromatase enzyme capacity is finite and saturable.
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Testosterone to estradiol ratio. There is no randomized control trial defined ideal testosterone to estradiol ratio.
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The concept of an ideal serum testosterone to estile ratio remains unsupported by randomized control data and oversimplifies complex endocrine physiology. Every major testosterone therapy trial allowed normal aromatization and benefits were achieved without targeting a specific testosterone to estradiol ratio.
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Different tissues require different androgen estrogen balance. Different tissues vary in their dependence on androgen and estrogen signaling.
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Therefore, no single circulating ratio can be expected to optimize function across all tissues. Even if we could find an ideal ratio for one system, it may not be ideal for another. Serum estradile levels do not reflect tissue estradiol. Circulating estradiol does
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Speaker A
not reflect in paracin conversion of testosterone to estradile within target tissues where local aromatase activity mediates critical biologic effects.
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Suppressing aromatase to achieve a ratio disrupts local estrogen signaling that labs cannot measure. The endocrine system is not a ratio problem. It is a threshold dependent tissue specific locally regulated system. Ratio obsession oversimplifies complex endocrine regulation.
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Should reference ranges for estradiol be determined for healthy men receiving testosterone therapy stratified by age and testosterone levels which would provide testosterone level specific reference ranges for serum estradiol.
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This could certainly be accomplished but it has significant limitations. Interpretation of serumstradial in men requires recognition of its limitations as an endocrine biioarker. Circulating concentrations do not measure local aromatization, receptor saturation, or tissue specific threshold status.
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Circulating levels provide only indirect insight into biologic activity. Consequently, serum estradile serves as an imperfect surrogate for biologically relevant tissue estrogen signaling. In addition, no different than testosterone, it is the free fraction that is biologically active, which is
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very rarely measured. Dr. Chung writes in his paper estradi for the mitigation of adverse effects of androgen vetorration therapy. In comparing blood levels of E2 and testosterone with biological effects, it is important to recognize that E2 is produced locally from aromatase and
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target tissues and acts in a paracin fashion. In healthy men and in studies of medically castrated men undergoing graded testosterone adback, serum levels of E2 reflect the total E2 that is diffused into the blood from all tissues having been synthesized by aromatase and
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Speaker A
escaped local tissue metabolism. These blood levels, no matter how accurately measured, are an indirect reflection of total estrogen signaling. We are measuring the overflow of a locally produced hormone and assuming it reflects intracellular receptor signaling. That assumption is
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biologically unsound. When testosterone increases, more substrate is available. Aomatase converts a fraction into estradiol. Some of that estradiol diffuses into the circulation.
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These are the different hormone signaling types. Endocrine signaling is when the hormone travels through the bloodstream to reach target tissues.
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Autorine signaling is when a hormone is released by the cell and acts back on the cell surface. Paracrine is when it is released by a cell and acts on nearby cells and then inocrine is where it is produced inside the cell and m and stays
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inside the cell. It is of fundamental importance to understand the differences between testosterone and estradile signaling in men. Testosterone functions primarily as a circulating endocrine hormone delivered through the bloodstream to target tissues. In contrast, most estradi action in men,
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especially in the brain, bone, atapost tissue, and vascular endothelium is inocrine. Entroine signaling target cells such as a brain, bone, vascular endothelium.
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Testosterone enters the cell. Aromatase enzyme converts testosterone to estradiol locally. Estradi binds to the estradile alpha and beta receptors inside the nucleus. Gene transcription occurs. There's no secretion, no circulation, no serum reflection.
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Introen signaling is intracellular hormone action without secretion. And that is why serum estradile cannot fully represent tissue estrogen activity in men. Tissue estradiol exposure is largely determined by local aromatase activity and testosterone availability.
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Not serum estradiol. Serum estradiol does not reflect tissue estrogen signaling. Since most estrogen action in men is inocrine and paragrin not endocrine, serum levels do not accurately reflect tissue levels. Serum E2 is a crude proxy for tissue levels.
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Testosterone is delivered. Estradile is manufactured locally in tissues such as the brain, bones, atapost tissue and vascular endothelium.
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Testosterone circulates in the bloodstream and acts directly on tissue. Estradiolamin however is largely made locally inside tissues from testosterone. Endocrine estradiol is a minority component of total estrogen signaling from the testes and systemic spillover from peripheral aromatization.
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Tissues that utilize endocrine estradile include the hypothalamus and pituitary for negative feedback and the liver for lipoprotein modulation. If we ranked signaling by dominance in men, inrine would be the primary driver, paracrine significant contributor and endocrine measurable but not dominant. Many
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tissues particularly the brain estradile is synthesized in siteu and functions within micro domains. These tissues are not dependent on circulating estradiol delivery. These tissues feed themselves and are not fed by serum estradiol.
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Lowering serum dial with an aromatase inhibitor also suppresses local tissue aromatization thereby reducing the generation of a hormone that is critical for normal tissue specific function and potentially predisposing to tissue specific failure.
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These are the testosterone and estradile dose response curves. Testosterone in muscle behaves more linearly following a graded dose response pattern. As testosterone rises, androgen receptor activation increases. Lean mass increases in a graded fashion. Strength improves proportionately and fat mass
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decreases proportionally. Think of testosterone like a dimmer switch. More testosterone, more receptor activation, more anabolic effect. Less testosterone, less activation.
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Estradiol behaves in a threshold dependent nonlinear fashion as represented by the orange curve. Estersle does not behave like a dimmer switch. Instead, it behaves like a minimum requirement system. Below a certain threshold, tissues fail. Above that threshold, additional benefit
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plateaus. Excess suppression results in rapid dysfunction. This creates a threshold curve, not a straight line.
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Think of estraol like oil in an engine. Too little results in damage enough the system runs normally. More oil does not improve engine performance. Each tissue brain, bone, vascular endothelium, atapost tissue, libido, sexual function, etc. has a different estradiol failure
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threshold. Each tissue has a different estradi threshold, receptor profile, and time course of injury. A normal serum E2 does not guarantee adequate tissue estrogen.
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Estradi deficiency manifests by tissue, not by a single serum number. Suppressing estradi below physiologic minimum causes tissue specific failure.
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Serum E2 is a crude proxy, not a target to be aimed for. When we suppress estradi to normal, we often push tissues below their survival threshold.
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All hormone systems have three zones. Deficiency zone below the threshold, physiological operating zone, and saturation plateau zone. Estradile signaling plateaus because receptor numbers finite, co-activator proteins are finite, downstream transcription saturates, and neural circuits have sealant effects. It's important to
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mention that testosterone does not behave the same way in every tissue. In muscle, it acts through direct androen receptor binding and unlike enzyme limited systems, a clear saturation point has not yet been established within studied ranges. And receptor
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expression also increases as androgen levels rise. This suggests that testosterone has one dose response curve in muscle and a different one in other tissues such as the brain. We will explore those tissue specific testosterone curves in more detail later
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in the presentation. Both aromatase activity and estrogen receptor signaling are saturable. Accordingly, rising testosterone does not generate unlimited linear increases in estradiol and rising estradiol does not produce unlimited linear increases in estrogen signaling. Concerns about estradile rising uncontrollably are not
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supported by enzyme or receptor kinetics. But what about the concerns that rising serum estradiol is going to add on top of the estradile produced in the tissues?
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The assertion by those who believe rising serum estradile linearly adds to intracellular estradiol to produce cumulative estrogenic effects is inconsistent with receptor phicodnamics and inroen physiology. Estrogen receptor signaling is saturable, tissue specific and threshold dependent. The additive stacking model is biologically
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simplistic and inconsistent with observed physiology. Estrogen signaling in men follows threshold biology, saturation kinetics, tissue compartmentalization, and receptor limited signaling. It does not follow linear stacking arithmetic.
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I will inevitably be asked if estradile in men is primarily intro and paracrine, why does increasing circulating estradi with exogenous therapy in men with low E2 still produce clinical benefit?
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Introine dominance does not mean systemic estradile is irrevalent. Introen estradile requires adequate testosterone and adequate aromatase expression. If either is limited, local production fails and tissue deficiency occurs. When estradiol is low, adding systemic estradile restores threshold.
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When estradile is already sufficient, additional estradile does not produce proportional new effects as the signaling plateaus. Oral estradiol moves someone from deficiency to sufficiency.
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It does not convert sufficiency to toxicity in a linear fashion. In men with profound estrogen dial deficiency, including some undergoing androgen deprivation therapy, raising circulating estradile can improve symptoms related to estrogen loss. Now, this may appear inconsistent with the concept that
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estradile signaling in men is predominantly intricine and paragrin, but the two are not mutually exclusive.
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Entric physiology describes the dominant mechanism of local estrogen generation under normal circumstances. It does not imply that circulating estradile lacks biologic revalence. Rather, systemic estradile can still diffuse into tissues, contribute to receptor occupancy, and restore function when local and circulating estradile
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availability fall below tissue specific thresholds. Think of intricine estradile production in men as the electricity generated and used inside a house. While circulating endocrine estradile is more like a backup generator that helps support the system when local supply is
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inadequate. Entricine dominance does not preclude responsiveness to circulating estradiol. Estradiol freely diffuses across membranes and participates in concentration dependent equilibrium between plasma and tissue compartments.
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In states of deficiency, raising systemic estradile restores receptor occupancy and tissue level signaling. This reflects threshold correction rather than additive amplification beyond physiological sufficiency. Entric biology explains baseline physiology.
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Systemic estradile explains therapeutic rescue. Individual factors affecting estradiol levels. The rates of conversion of testosterone to DHT and estradiol vary among men due to polymorphisms of genes that encode the steroid 5 alpha reductase and the aromatase enzyme as well as other host
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specific factors that affect the activity of these enzymes. Dr. Stevens Shields, Journal of Clinical Endocrinology and Metabolism 2022.
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In this study by Ericson, genetic variations in sex steroid related genes as predictors of serum estrogen levels in men, the investigators wanted to determine whether common genetic variants in sex steroid related genes predict serum estradile and testosterone levels in men. The study showed that men
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with a common aromatase polymorphism RS2470152 had approximately 11% higher estradiol levels than those without the polymorphism.
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Let's look at the factors affecting Vmax. Vmax value is influenced by three main factors namely enzyme concentration, temperature and pH.
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Enzyme concentration. Vmax depends on the amount of enzyme present. And the higher the amount of enzyme, the higher the V-max of it. If we increase fat mass, we increase aromatase and we increase Vmax. If we decrease fat mass,
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we decrease aromatase and we'll decrease Vmax. Let's review the Finkelstein study. Gonatal steroids and body composition, strength, and sexual function in men. In this study, they sought to determine the relative degree of testosterone deficiency, estradile deficiency, or both at which undesirable changes in
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body composition, strength, and sexual function begin to occur and whether those changes are due to androgen deficiency, estrogen deficiency, or both. It involved 400 healthy men 20 to 50 years of age with indogenous testosterone and estradile suppressed.
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198 men received either placebo or 1.25, 2.5, 5 or 10 grams of testosterone gel daily for 16 weeks. 202 men received placebo gel or testosterone gel and 1 milligram of anastriol daily. Changes in the percentage of body fat and in lean
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mass were the primary outcomes. Subcutaneous and intraabdominal fat areas, b muscle area and strength, and sexual function were also assessed. I've heard critics argue that 1 milligram of anastradol daily is clinically excessive, but this critique overlooks the study's design. The objective was
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not to evaluate the therapeutic safety of aromatase inhibitors, but to isolate the physiological roles of androgens and estrogens. By using a highdosese aromatase inhibitor to fully suppress the conversion of testosterone to estradiol, researchers could clearly observe the distinct effects of each
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hormone, a clarity that a lower partial dose would have not provided. In fact, they explained this very clearly in the study. Because estradiol is a metabolite of testosterone, it is difficult to distinguish the effects of androgens from those of estrogens in
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observational studies or even in randomized control trials if aromatizable androgens are used without the administration of an aromatase inhibitor. Aromatase inhibitor trials don't test testosterone. They test androgen signaling in isolation.
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Let's look at the mean absolute change from baseline and sexual desire and erectile function according to testosterone dose and cohort. They reported that aromatase inhibition was associated with significant decreases in sexual desire and erectile function.
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Both androgens and estrogens contributed to the maintenance of normal libido and erectile function. Looking at the mean percent change from baseline and percentage of body fat, lean body mass, subcutaneous and intraabdominal fat area, thigh muscle area, and leg press strength according
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to testosterone dose and cohort. In the groups that received testosterone inhibition of estrogen synthesis cohort two in red as compared with intact estrogen synthesis cohort one in blue was associated with significant increases in the percentage of body fat,
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subcutaneous fat area and intradominal fat area and with significant decreases in sexual desire and erectile function.
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These findings provide additional evidence of an independent effect of estradiol on these measures because increases in visceral fat reduce insulin sensitivity and are associated with diabetes in the metabolic syndrome. The market increase in intraabdominal fat with aromatase inhibition could pertain
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to an increase in cardiovascular disease with long-term estrogen deficiency. This is another mechanism to increase V-Max.
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Aromatase inhibitors increase visceral body fat which increases the amount of the aromatase enzyme. Conclusions of the Finkelstein study.
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The amount of testosterone required to maintain lean mass, fat mass, strength, and sexual function varied widely in men. Androgen deficiency accounted for decreases in lean mass, muscle size, and strength. Estrogen deficiency primarily accounted for increases in body fat.
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Both contributed to the decline in sexual function. This is a video that came across my YouTube feed. Estrogen management trends in men, and it was done by a young lady by the name of DJ Madson. Now, in this
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video, they discussed testosterone to estradile ratios as though they are clinically important, emphasized measuring serum estradile and keeping it within a specific range, and raised concerns that estradile may continue to rise uncontrollably. Yet, none of those claims are supported by randomized data,
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physiology, enzyme kinetics, or receptor biology. Both aromatase activity and estrogen receptor signaling are saturable, meaning that estradiol production is not unlimited. And once estrogen receptors are saturated, additional estradile cannot produce progressively greater effects. She also made a statement about her husband who
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is also a bodybuilder. Take someone like my husband for example who is very lean at all times and he aromatizes at the drop of a hat. Now we just reviewed the Finkelestein studies which showed a market increase in intraabdominal fat
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with aromatase inhibition. And now you know the reason why her husband aromatizes at the drop of a hat. It's because the more he takes the aromatase inhibitor, the more visceral fat he develops and the more he aromatizes when
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he doesn't take it. He is creating the very problem he is trying to avoid. The practice of using aromatase inhibitors to control estradi men on testosterone therapy did not originate in evidence-based medicine. It originated in the bodybuilding community. The
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aromatase inhibition is one of the major factors in their development of premature cardiovascular disease. Many of the problems men encounter on testosterone therapy arise from advice and practices borrowed from the bodybuilding community. Although both involve testosterone, they are
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fundamentally different. Testosterone therapy is evidence-based medical care aimed at restoring health and normal physiology, while the bodybuilding culture accepts drug abuse and health trade-offs in pursuit of performance and muscle mass. Advice from a performance-enhancement drug culture has no place guiding legitimate testosterone
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therapy. Testosterone therapy in older men with a focus on estradiol management. Age related testosterone deficiency merits treatment. Let's review the evidence on testosterone therapy in older men from Dr. Tracia's comprehensive summary. We will review the benefits and we'll also focus on how
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estrogen was measured, managed, or accounted for in the referenced clinical studies. Here's a list of the studies on benefits of testosterone therapy in older men.
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This paper consisted of 55 randomized control trials, eight observational studies, two prospective studies, and one alternate case control trial. I will now summarize the beneficial effects of testosterone therapy in all of these studies.
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With regard to sexual function, there was increased sexual desire, libido, improved sexual activity, improved erectile function, increased spontaneous erections, improved sexual motivation and performance, improvement in sexual dysfunction scores on mood, well-being and quality of life.
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There was improved mood, reduction in depressive symptoms, improvement in aging male symptom scale, improved health related quality of life, improved psychological well-being.
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on body composition. There was increased lean body mass, decreased fat mass including visceral fat, decreased waist circumference, improved muscle mass distribution, improved trunk and core muscle mass.
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With regard to strength and physical performance, there was increased muscle strength, improved leg power, improved stair climbing power, improved walking ability, modest improvement in six-minute walk distance, attenuation of age- related decline in V2 max, improved physical performance and mobility.
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On bone health, there was increased bone mineral density, improved tbecular bone architecture, reduced bone resorption markers, and there was prevention of bone loss in the femeral neck.
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Hematologic effects, increased hemoglobin, correction of unexplained anemia and correction of anemia of known causes.
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Metabolic effects there was reduced body weight, reduced BMI, reduced waist circumference, improved insulin sensitivity, improved glycemic control, reduced insulin resistance, improvement in metabolic syndrome components, sustained weight loss in obese hypoganatommen.
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Let's look at estrogen management in all of these studies. All benefits in sexual function, mood, well-being, quality of life, body composition, strength and physical performance, bone health, hematologic effects, and metabolic effects occurred with intact physiologic aromatization.
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No study utilized an aromatase inhibitor yet benefits occurred. If the evidence shows benefit without estradi suppression, then suppressing estradile represents a deviation from the evidence, not an extension of it.
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suppressing estradile abandons the evidence. You cannot claim evidence-based practice while modifying the very physiology under which the evidence was generated.
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The efficacy data supporting testosterone therapy reflect intact testosterone estradiol coupling. Those advocating routine estradile suppression therefore represent a departure from the physiological conditions under which benefit was established and require independent randomized evidence demonstrating preserved or superior clinical outcomes under estradile
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suppression. Presently there is zero randomized evidence that suppressing estradile improves these outcomes. If you alter the physiology under which benefit was proven, the obligation to prove benefit is yours. Those advocating estradile suppression or control carry the burden of proof not the clinicians
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preserving normal physiology. The burden of proof is not on physiologic replacement. It is on those proposing to disrupt it.
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Testosterone therapy in overweight or obese men with a focus on estradiol management. In medicine, repeated falsehoods can solidify into established facts and eventually dogma, which are principles presented by authorities as incontrovertibly true. A historic case study is the long-held belief
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surrounding testosterone and prostate cancer. For over 50 years, the medical community accepted that testosterone caused prostate cancer and that raising testosterone levels in a man with prostate cancer would accelerate tumor growth. Often described metaphorically as pouring gasoline on a fire. Where did
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this fear originate? This belief stemmed from the over interterpretation of data from a single patient in a 1941 study.
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The prevailing logic was that since lowering testosterone slows cancer growth, raising it must have the opposite effect. However, logical assumptions do not always align with physiological reality. It was not until Harvard urologist Dr. Abraham Morgan Tyler challenged the androgen hypothesis
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that this long-standing dogma was overturned, preventing countless men from being unnecessarily denied testosterone therapy. Conventional wisdom for many is that when an overweight or obese man starts testosterone that he should utilize an aromatase inhibitor to keep him from
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overromatizing and developing estrogen symptoms. Is this necessary? Is this what the literature supports? These are the categories of obesity.
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Overweight is a BMI of 25 to 29.9. Class one obesity a BMI of 30 to 34.9. Class 2 obesity, a BMI of 35 to 39.9. And then class 3 obesity is a BMI greater than 40, known as severe obesity, previously
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known as morbid obesity. This review by Dr. Tresh examines the contemporary data on testosterone therapy in overweight and obese men, focusing on changes in lean body mass, fat mass, body composition, and weight loss. In addition, we will examine how
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estrogen was measured, managed, or accounted for in the clinical studies. Table one displays 28 studies in which testosterone therapy resulted in increases in lean body mass and decreases in total fat mass.
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Table two summarizes 20 studies demonstrating that testosterone therapy significantly reduces body weight, waist circumference, and BMI.
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Based on this review of 48 studies, testosterone therapy provides significant benefits for overweight and obese men that include a decrease in fat mass, weight, BMI, waist circumference, insulin resistance, hemoglobin A1C, fasting glucose, total cholesterol, LDL cholesterol, triglycerides, C reactive
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protein, tumor necrosis factor alpha, corateed intermediate thickness, fatigue, liver fat, liver enz, enzymes and systolic and diastolic blood pressure. It ameliorates all metabolic syndrome components, abdominal obesity, dysipidemia, elevated fasting glucose and hypertension. It increases lean body mass, HDL cholesterol, erectile
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function libido vigor energy and quality of life. Now, let's review how estrogen was managed in these 48 studies. Two of these studies utilized an aromatase inhibitor and one was the final sign study that we have already reviewed and the other was by Dang at
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all. The aim of this randomized control trial was to determine if testosterone administration in young obese men improved body composition and insulin sensitivity and if inhibiting metabolism of testosterone to estradile or DHT would change these outcomes. It was a
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randomized control trial in 57 men aged 21 to 51 with a BMI of greater than 30 for 20 weeks. They received testosterone gel 10 grams daily. They were divided into four groups. Placebo, testosterone only, testosterone plus anastrol and
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testosterone plus dutasteride. Percent fat-free mass significantly increased and percent fat mass significantly decreased in the testosterone with dutasteride group and the testosterone only group. percent fat-free mass or percent fat mass did not significantly change in the placebo or the testosterone and anastol group.
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Data from this study show that inhibiting reduction of administered testosterone to DHT improved body composition and insulin sensitivity in young diabetic obese men while inhibiting aromatization of administered testosterone to estradiol or placebo did not. Our data add to the body of
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evidence that estradiol is essential for decreasing fat and improving insulin sensitivity in men. In this study, utilizing aromatase inhibitor attenuated the beneficial effects of testosterone on increasing fat-free mass and decreasing fat mass. Estradile is required for the metabolic benefit.
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Testosterone increased lean mass and reduced fat mass, but this alone did not improve insulin sensitivity. Insulin sensitivity required preserved estradiol.
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Here is a comparison of romatase inhibitor and five alpha reductase inhibitor trials. DHT is not required for testosterone's anabolic effects in muscle. Estradiol is required to preserve lean mass, strength, sexual function, and bone integrity during testosterone therapy. Estradiol is
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required to decrease fat mass. Estradi management in these studies. Once again on the left are all the benefits of testosterone therapy in overweight and obese men from these studies. All benefits occurred with unrestricted aromatization.
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Attenuation of benefits occurred in the two AI studies. The metabolic and weight loss benefits attributed to testosterone cannot be separated from estrogen physiology in these studies. We did not see improvement in body composition after E2 suppression. The clinical
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outcomes from testosterone therapy are the sum of androgen receptor activation and estrogen receptor activation. That is not theory. That is physiology. In every major randomized trial demonstrating improvements in lean mass, bone density, sexual function, and body composition, aromatization was
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preserved, allowing testosterone and estradile to rise together. When estradi was pharmacologically suppressed, several benefits were attenuated. This tells us something critical. Estradile contributes positively to therapeutic outcomes. So if someone claims you must control estradile optimize TRT outcomes in overweight or obese men, the evidence
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of burden is simple. Show randomized control trials where controlling or suppressing estradile improves outcomes versus physiologic testosterone therapy.
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That body of evidence is essentially absent. The benefits of testosterone therapy in obese and overweight men were achieved without aromatase inhibitors and with normal aromatization intact. Because those benefits were obtained under physiologic testosterone to estradile conversion, suppressing or controlling
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estradile represents a departure from the conditions under which the evidence was generated. Anyone advocating routine estradile suppression or control in obese or overweight men carries the burden of proof that altering this physiology improves outcomes over testosterone therapy alone. Such outcome
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data is currently absent. Testosterone therapy and overweight and obese men. Beyond the cardioabolic and weight loss benefits of testosterone therapy and obese men, we must also consider its impact on sexual health. specifically how the aromatization of testosterone into estradiol may cause worsening
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sexual function or other symptoms of estrogen excess. Let's evaluate the literature specifically looking at the effects of testosterone on sexual function or causing sexual dysfunction in overweight and obese men.
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Before we begin evaluating studies, it's important to understand what the numbers represent in the aging males symptom scale as well as in the international index of erectile function. The aging male symptom scale is a validated questionnaire designed to assess
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symptoms associated with aging and specifically testosterone deficiency in men. The scale includes a series of 17 questions divided into three domains.
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Psychological, somatic, and sexual symptoms. Each symptom is rated on a scale, one being no symptoms and five being extremely severe. A score of less than 26, no symptoms of testosterone deficiency. A score of 27 to 36 mild symptoms of testosterone deficiency. 37
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to 49 moderate and a score of greater than 50 is severe symptoms of testosterone deficiency.
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The international index of erectile function is a validated questionnaire used to measure the severity of erectile dysfunction and monitor improvements with treatment. The questionnaire consists of 15 items divided into five domains. Erectile function questions 1 through five and 15 focuses on the
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ability to achieve and maintain an erection suitable for intercourse. Orgasmic function questions 9 and 10 assesses the ability to achieve orgasm.
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Sexual desire questions 11 and 12 evaluates the level of sexual interest or libido. Intercourse satisfaction questions 6 through 8 measure satisfaction during sexual activity.
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Overall satisfaction questions 13 and 14 examines the general satisfaction with sexual relationships. Responses for each item were scored on a liyker scale, zero or one being lowest function and five being the highest function. The scores for each domain are summed to give
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domain specific scores. A total score helps classify the severity of erectile dysfunction. A score of 26 to 30 is no erectile dysfunction. 17 to 25 mild ED, 11 to 16 moderate ED, and 6 to 10 severe ED. To summarize, with the AG males
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symptom scale, the lower the number, the better, and with the International Index of erectile function, the higher the number, the better. Before evaluating overweight and obese men on testosterone therapy for presumed symptoms of elevated estradiol, it is important to
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first examine a few of the main studies commonly cited to justify estradile control in men receiving testosterone therapy because of estrogen causing sexual dysfunction. The first is this paper by Belladelli. Hyperestrogenism is associated with sexual function impairment in men findings from a
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cross-sectional real life study. This was a retrospective data analysis on 547 men seeking first medical help for a new onset erectile dysfunction at a single andrology center. They measured circulating hormones and defined hyperestrogenism as estradile above 42.6 peak rounds per milliliter
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utilizing data from the tan at all study in 2015. Coorbidities were scored with the Charleston coorbidity index.
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Sexual function was assessed with the international index of erectile function questionnaire. Before examining the study in detail, let's take a look at the TAN study that they used to define hyperestrogenism and also review the Charleston coorbidity index.
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This is the TAN at all study and it was a retrospective multi-enter medical chart review in men treated at 35 low T centers from 2009 to 2014. They measure testosterone and estradile levels and reviewed the ICD9 diagnosis codes for
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each patient. They reported in our centers estradile measurement is outsourced to labcore and high estradile is defined as equal or above 42.6 pog grounds per milliliter. So their definition of high estradi was based off of the labcore normal range. They
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reported our study did not link high estradile levels with diminished sexual performance. Paradoxically, patients with low estradile below 42.6 pigs milliliter had more patients complaining of low libido. Patients with higher estradile levels above 42.6 had less sexual dysfunction problems
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identified by their providers. Our finding was that high estradile levels were not associated with higher rates of low libido, but established higher rates of documented low libido with those with normal or low estradiol levels.
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Ironically, Belladella used this study for their definition of hyperestrogenism. But yet, this study found higher estrogen levels were associated with less sexual dysfunction and better libido compared to low estrogen levels.
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The exact opposite of the Belladelli study. The Charleston co-orbidity index is a widely used validated method to predict 10-year mortality by scoring 19 specific medical conditions weighted 1 through six based on risk plus age adjustments.
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A score of one would be given for conditions such as diabetes or chronic lung disease. A score of two for solid tumor or diabetes with complications. A score of three for moderate to severe liver disease. And a score of six for
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metastatic cancer. There was an age adjustment. Add one point for each decade over 40 years of age. One point for those that are 50 to 59 years old, two for 60 to 69 years old, three for 70 to 79 year olds, and four for 80 to 89
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year olds. The higher the score, the lower the estimated 10ear survival rate. It is considered the gold standard for clinical research co-orbidity assessment.
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Back to the Belladelli study, they reported one out of five men seeking first medical help for erectile dysfunction showed elevated serum estradiol levels. Men with hyperestrogenism were older, had a higher rate of coorbidities, had higher serum total testosterone values than
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those with normal estradiol values. Serum estradile levels are positively correlated with total testosterone levels but negatively correlated with international index of erectile function scores of clinical revolence. Men with hyperestrogenism had higher rates of coorbidities, greater ED severity and
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worse orgasmic function. Association, confounding and interpretive bias. This was an observational cross-sectional retrospective analysis which can show association, correlation and co-occurrence but cannot show causation. This was a cross-sectional observational study. So we can identify associations between hormone levels and
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sexual function but it cannot establish causality or justify a treatment intervention. This was a baseline observation in men not on testosterone therapy.
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They reported one out of five men seeking first medical help for ED showed elevated estradiol levels suggestive of hyperestrogenism.
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Well, therefore, four out of five men with ED had normal estradiol levels. This paper does not show that elevated estradile explains ED in most men. It shows the opposite. Most men with ED in this cohort did not have elevated
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estradiol. That means elevated estradile cannot reasonably be framed as the explanation for ED in most men in this cohort. At most, it identifies a subset of ED patients who had higher estradiol.
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Hyperestrogenism was defined as estradiol greater than 42.6 pogs per milliliter utilizing the cutoff from tanetall which evaluated elevated estrogen levels in men receiving injectable testosterone therapy and used the labcore upper reference value. That threshold was not derived from this
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cohort and was not clearly validated as a clinical meaningful cutoff for erectile dysfunction or sexual dysfunction. The definition of hyperestrogenism is statistically convenient but biologically and clinically underjustified.
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Residual and unmeasured confounding. The paper did adjust for some factors such as age, BMI, coorbidity index, total testosterone, estradile levels, smoking and alcohol. But key erectile dysfunction confounders were missing or only coarsely measured. They did not control for central atyposity. They did
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not measure waist circumference or visceral fat. There was metabolic data missing such as fasting glucose, hemoglobin A1C, triglycerides, HDL cholesterol, and blood pressure.
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psychiatric and psychological factors. They did not control for depression, anxiety, stress, relationship issues as those strongly influence IF scores. They did not control for lifestyle factors such as physical activity, sleep apnnea, and diet were not fully characterized.
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Medications that impair sexual function such as opioids, SSRIs, beta blockers, five alpha reductase inhibitors, and anti psychotics, etc. were not controlled for and they can all independently worsen ED and libido.
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Other endocrine factors such as prolactin, thyroid, and cortisol were not measured. So with so many unmeasured variables, it's hard to claim that estradile is an independent driver rather than a proxy for a sicker metabolic and comorbid profile.
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Interpretation versus stata. They reported men with hyper estrogenism were older, had a higher rate of coorbidities and higher serum total testosterone values than those with normal estradiol values.
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This study is a clear example of interpretive bias. The author singled out estradile despite the fact that elevated testosterone traveled with it and the observed association remained heavily confounded. The bias is not hidden in the data. It's revealable what
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the authors chose to blame. Let's take a closer look. Men with hyperestrogenism were older.
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Age independently tracks with worse erectile function, more vascular disease, more medication use, and mo more coorbidity. Age can push both sides of the association at once. Worse sexual function and a different hormone profile. Estradile increases with age.
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Older age may explain both the hormone pattern and the worse sexual outcomes. Men with hyper estrogenism had more coorbidities. Men with high estradiol had a higher rate of coorbidities. 26% of them had a Charleston coorbidity index greater than or equal to one
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versus 7.4% for the normal estradiol group. That's almost a four times higher prevalence of serious chronic disease in the high estradiol group.
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These coorbidities and their treatments are independent potent causes of ED and orgasmic dysfunction. Vascular and indotheal damage occurs in conditions like diabetes, hypertension and coronary artery disease. Neuropathy and nerve damage occurs with diabetic neuropathy and poststroke neurologic deficits. Many of these conditions are
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treated with medications that directly worsen sexual function such as beta blockers SSRIs antiscychotics and opioids. All of which blunt libido, energy, and performance and can worsen both erectile quality and orgasmic intensity.
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These coorbidities alone could explain the more severe ED and worse orgasmic function in the high estradile group.
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Hyperestrogenism was simply a marker of a sicker, more comorbid phenotype. And the coorbidities themselves could fully account for the worst sexual function independent of estradiol. They singed out high estradile as the culprit for impaired sexual function when in fact it
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was nothing more than an innocent bystander. Men with hyperestrogenism had higher serum total testosterone levels.
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Because testosterone and estradile covaried, the study cannot uniquely assign causality to estradiol. Choosing estradi as the culprit reflects interpretive bias, not proof from the data set. Testosterone was higher.
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Estradi was higher. sexual function was worse, but only E2 was blamed. If both testosterone and estradile are higher in the group with worse sexual function, you cannot simply decide that estradile is to blame while ignoring testosterone.
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Cross-sectional data cannot separate drivers. In a cross-sectional data set, if men with worse ED have both higher E2 and higher testosterone, the data do not tell you which hormone, if either, is driving the association.
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Estradi was singled out by assumption. That is not physiology. That is narrative selection. Men with high E2 were older, had more coorbidities and higher testosterone levels.
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The title of the paper once again is hyperestrogenism is associated with sexual function impairment in men. By the same logic the authors used for estradiol, someone could have written the paper as older age is associated with sexual function impairment in men
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or multiple coorbidities are associated with sexual function impairment in men or even better high testosterone is associated with sexual function impairment in men. What the study actually showed in a tertiary ED clinic, men with worse sexual function had
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higher estradile, higher testosterone, older age, and greater comorbidity burden. Higher estradile traveled with higher testosterone, older age, and more comorbidity. And that whole cluster was associated with worse sexual function.
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The higher estradile was simply a marker of a older, sicker, more comorbid phenotype. Estradile management.
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Belladelli at all does not show that estradile causes sexual dysfunction in menal testosterone therapy nor that blocking estradile improves outcomes. It is not evidence for routine AI use. You cannot use an observational EDI paper to justify druginduced estradile
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suppression on testosterone therapy. Association in sick men is not evidence for suppressing estradile in treated men. This paper does not validate AI use. It only exposes a failure of inference.
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If you're proposing to override normal aromatization with a drug, you need direct interventional data showing that blocking E2 improves outcomes in men on TRT. This paper does not provide that.
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Nowhere close. The next paper is by Zuniga. The association between elevated serum estradi levels and clinically significant erectile dysfunction in men presenting for andrological evaluation.
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The goal of this study was to determine whether higher estradile levels are associated with clinically significant erectile dysfunction in men presenting for andrological evaluation.
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It was a retrospective obsational study of 256 men seen in a specialty andrology urology practice over 18 months.
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Erectile function was assessed using the male sexual health questionnaire. Estrad and testosterone were measured by morning iminoassay.
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Multivaried analysis adjusted for age, total testosterone, BMI, and smoking. Key findings of the study.
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Men with clinically significant ED were older, 55 years versus 42 years. Higher BMI also trended towards statistical significance. Higher CRM was associated with clinically significant ED 23.6 PAGS per mill versus 20.7. Not that big of a difference. A lowest regression curve
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was used post hawk to define an E2 level of 32 pogs per milliliter that negatively impacts erectile function.
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A lowest regression curve is a smooth line drawn through a scatter plot to show the overall pattern or trend in the data without forcing the data to fit a straight line or a single mathematical equation. It stands for locally weighted
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scatterplot smoothing. Study weaknesses. Study design. This was a retrospective observational study not an interventional trial. It can show association, correlation and co-occurrence but cannot show causation.
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It cannot show that estradile caused the erectile dysfunction and it certainly cannot show that lower estradile would improve erectile dysfunction.
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Measurement method. Estradi was measured by iminoassay not LCMS or the ultra sensitive estradiol test. Estradi was measured by aminoassay which a which is a poor method for the low estradile concentrations typically seen in men making small differences in cutoffs less
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reliable. That matters here because the entire paper hinges on small differences in estradile within the low male range.
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Weak clinical separation. The mean estradile difference between groups was only 2.9 pogs per milliliter with broad overlap in standard deviations.
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That is enough for a statistical signal, but it's not a convincing biological separation on which to build a treatment doctrine. In other words, this does not identify a clean clinically obvious high estradile ED phenotype.
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Post hawk threshold. The 32 pograms per millilar cutff was not prespecified. It was chosen after looking at the lowest curve in the same data set. That is dataderived thresholding which is fine for hypothesis generation but weak for clinical decision-making unless
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externally validated. It is even more fragile because the authors first excluded excluded 12 men whose estradile values were more than two standard deviations above the mean then derived a high estradile cutoff from the trimmed data set. They didn't discover a
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biological threshold. They manufactured one from the data. Lab timing. Hormone values are allowed to be drawn within 90 days of questionnaire completion. That is a very loose exposure outcome window for a symptom like erectile function. A single iminoassay estradile value
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obtained sometime within the prior 3 months is a shaky basis for causal interpretation. Residual and unmeasured confounding. The paper adjusted for only five variables.
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estradiol, total testosterone, age, BMI, and smoking. It did not control for alcohol use and liver disease, central atyposity. They did not measure waist circumference or visceral fat. It did not control for metabolic data such as fasting glucose, hemoglobin A1C,
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triglycerides, HDL cholesterol, or blood pressure. It did not control for psychiatric or psychological factors such as depression, anxiety, stress, or relationship issues. They did not control for lifestyle factors such as physical activity, sleep apnnea and diet which was not fully characterized. They
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did not control for medications that impair sexual function such as opioids, SSRIs, beta blockers, balpha reductase inhibitors, antiscychotics etc. All of these can independently worsen erectile dysfunction and libido. It did not account for other other endocrine factors such as prolactin, thyroid or
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cortisol. The paper's own introduction acknowledges that ED is strongly influenced by cardiovascular disease, metabolic syndrome, diabetes, and other factors, but yet major erectile dysfunction confounders were not adequately controlled.
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Residual age confounding. Age was the strongest signal in the paper. It had a highly significant p value. Age was a major competing explanation in this study. Men with clinically significant ED were substantially older than controls 55 versus 43 and age is one of the
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strongest established predictors of erectile dysfunction. Although estradile remains statistically significant after adjustment, the model cannot eliminate residual age related compounding, especially given the many age- linked causes of ED that were not fully controlled. This paper does not show
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estradile causes ED. It shows that older men with worse erections also had slightly higher estradile. It does not prove estradile caused the problem rather than aging and its coorbidities.
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These findings are more appropriately interpreted as showing that slightly higher estradile tracked with erectile dysfunction in an older higher risk population. Not that estradile was proven to be the independent pathophysiologic driver. This study cannot separate whether estradile is
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causal, incidental or simply reflecting age- related metabolic dysfunction. Burden of proof for estradiol management. A retrospective correlation is not treatment evidence. This paper showed association only, not that estradile caused the ED and not that lower and estradile improves it. The
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proposed cutoff is not validated. The 32 pram per milliliter cutoff was not discovered. It was created after the data was already known. It cannot be treated as a clinical target. The study was not defi designed to justify AI use
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on testosterone therapy. This study is hypothesis generating not practice changing. It does not support aromatase inhibitor use on testosterone therapy. It was not a testosterone therapy trial, not a aromatase inhibitor trial and not a demonstration that estradile suppression improves outcomes.
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You do not get to suppress a physiological hormone because of a retrospective association. The burden of proof is on the person altering physiology, not on the person preserving it. If you want to block estradile, you must show prospective
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evidence of superior outcomes versus testosterone therapy with intact aromatization. This study by zoo effect of estradile on penile erection a cross-sectional study.
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Speaker A
It was a single center cross-sectional study. It involved 135 men with erectile dysfunction defined by an IEF score of less than or equal to 21.
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The setting was an andrology clinic in China from 2012 to 2017. They examined whether serum estradi was associated with nocturnal penal erection quality measured by rigidiscan.
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They looked separately at penile tip rigidity of greater than or equal to 60% and penile base rigidity greater than or equal to 60%. They consider rigidity of greater than or equal to 60% to be an effective erection. All patients had
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normal nocturnal erectile activity. when comprised of at least one erection with a rigidity of greater than or equal to 60% at penile tip or base lasting longer than 10 minutes.
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They measured multiple lab variables including blood pressure, blood glucose, HDL cholesterol, FSH LH as described in table one. They report, "We excluded patients who had a history of neurologic disease, genital or spinal cord injuries, morbid obesity, use of drugs
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that affect erectile function, bleeding disorders, penile fibrosis, hypertension diabetes hypoganism and or abnormal androgen profile. The mean testosterone levels in this study were 458 nanogs per deciliter and the mean estradi levels were 56.62 pogs per milliliter.
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Main findings. They reported no clear relationship between estradiol and penile tip erection duration. They reported a negative association between estral and penile base erection duration. They further divided men by whether base fragidity of greater than or equal to 60% lasted less than or
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equal to 10 minutes or greater than 10 minutes and claimed the inverse relationship with estradile was more apparent in the group with longer base erection time. Their conclusion was that the estradile inhibits penile erection especially at the penile base.
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The strengths of this study it used an objective physiologic test rigan rather than relying only on symptom questionnaires.
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It measured multiple hormonal and metabolic variables. It attempted multivariable adjustment rather than simple bariate correlation alone. It explored an unusual question, tip versus base erection differences.
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Study weaknesses. The study was cross-sectional. Therefore, it can only show association, not causation. So, the paper cannot prove that higher est caused poor erection, that lowering estradile would improve erections, or that estradile is the driving hormonal abnormality.
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The statistical reporting is internally inconsistent and repeatedly reports coefficients like you see here. That does not make sense as written. If the 95% confidence interval includes one, the result is not statistically significant. Yet, the paper still reports a p value of less than 0.05.
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The statistical results do not support a strong conclusion. Although the authors describe the findings as significant, the printed confidence intervals include one, which indicates that no statistically reliable association was demonstrated as reported. At minimum, this creates internal inconsistency in
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the analysis. At worse, it raises concern that the results were misreported or overinterpreted as written in the paper. The actual data do not strongly support the bold conclusion that estradile inhibits erectile function. The results are much weaker than the wording suggest. The reported
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associations are small. The confidence intervals are wide. The statistical reporting is contradictory. The tip findings are essentially negative. And even the base findings are not robustly convincing as presented.
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There was no noned control group. That means the study cannot answer whether estradile differs between men with and without ED, whether estradile predicts the presence of ED, or whether estradile is a risk factor for ED in the general
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male population. It only examines variation within an already selected ED group. So, it is not a strong design for making broad claims about estradile and male erectile physiology.
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Weaknesses continued. Important compounders were not addressed. BMI, waist circumference, visceral atoposity, smoking, alcohol, sleep apnnea, depression anxiety relationship stress, and thyroid status, etc. With so many unmeasured variables, it's hard to claim that estradile is an independent driver rather than a proxy for a sicker
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metabolic and comorbid profile. Serum estradile is an imperfect biioarker for tissue level estrogen signaling. This is a physiological limitation of the paper. The study assumes that a single serum estradile measurement meaningly reflects estrogenic action at the penile tissues.
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They only excluded men with morbid obesity, which is a BMI of greater than 40, not men that were overweight or had class one or two obesity.
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In the published methods, they explicitly exclude morbid obesity, but they did not report BMI, waist circumference, or body composition measures as part of the core data set shown in the paper. One of the most glaring weaknesses of the study is its
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failure to account for atyposity. Faced with an average estradile of 56 pigs per milliliter in men in their early 30s, the most plausible explanation is not primary estradiopathology, but unmeasured overweight or class one 2 obesity, especially since only morbid
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obesity was excluded. The absence of BMI, waist circumference, and body composition data is a major limitation, and they failed to control for the most obvious compounder. Most likely, atyposity was driving both the elevated estradile and the erectile dysfunction.
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Why this paper does not justify aromatase inhibitors on testosterone therapy? Wrong population, wrong inference. This was a cross-sectional ED study, not a TRT trial, and it excluded men with hypogonadism and abnormal androgen profiles. No intervention, no proof of benefit. The authors did not
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give testosterone, did not use an aromatase inhibitor, and did not show that lowering estradile improved erections or any clinical outcome.
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Confounding overwhelms the claim. They excluded morbid obesity, but not all obesity. Lesser degrees of atyposity could still raise estradile through aromatization and independently worsen erectile function. The statistics do not support the strong conclusion. The paper reports significant findings yet the
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printed confidence intervals crosses one indicating the results are not statistically significant. Association is not a treatment indication. Even if the association were real, it would not justify disrupting normal testosterone estradile physiology in mental testosterone therapy without randomized evidence of net benefit.
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Speaker A
This paper does not show that aromatase inhibitors improve testosterone replacement therapy outcomes. It only shows how weak associations get over interterpreted. This was not a TRT study, not an AI study, not evidence for estradile suppression.
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Let's briefly examine the mechanisms of obesitydriven erectile dysfunction by reviewing this paper with Dr. Trish. He writes, "Obesity is a major risk factor for the metabolic syndrome, vascular disease diabetes hypertension endothelial dysfunction, and androgen deficiency. All of which contribute to
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the pathophysiology of ED. A study by Kaia reported 79% of men presenting with ED have a BMI of 25 or higher and men with a BMI greater than 30 have three times greater risk of sexual dysfunction compared with normal men. Obesity
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promotes inflammatory responses and contributes to endothelial dysfunction. Organic ED can be vascular, neurologic, anatomic and endocrine in origin.
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Vascular ED the most common form mainly results from endothelial dysfunction. Obesity and its coorbidities are associated with reduced plasma testosterone levels. Obesity is associated with increased estradiol levels. We have reviewed literature showing that testosterone therapy in obese men raises both testosterone and
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estradile while improving metabolic parameters, body composition, and sexual function. When estradile is suppressed, those benefits are attenuated. Obese men with erectile dysfunction also have elevated estradiol. But that does not establish estradiol as the cause of this dysfunction. It is the obesitydriven
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hypogenism, endothelial dysfunction, insulin resistance and inflammatory cytoine ex excess that are the underlying drivers of vascular injury and impaired erectile function. In that context, elevated estradile is better understood as a marker of the obese metabolic state rather than the primary
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pathologic agent. Looking at figure one, visceral atapost tissue is a dynamic endocrine organ that secretes a host of biochemical modulators and pro-inflammatory factors contributing to systemic and peripheral vascular inflammation. These include interlucan 6, tumor necrosis factor alpha, leptin resistin angotensin and
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also decreases atonectin. Adtopenectin is a protein hormone secreted by fat cells that plays a crucial role in regulating glucose levels, lipid metabolism and insulin sensitivity. Now these inflammatory mediators lead to a pro-inflammatory state contributing to the onset of hypertension, dysipidemia,
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diabetes, thrombosis and arththerosclerosis. Looking at figure two, these pro-inflammatory factors result in a decrease in nitric oxide synthes and nitric oxide activity as well as an increase in adhesion molecules causing endothelial injury and dysfunction. This leads to a pathophysiological state
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involving reduced hemodynamics to the peripheral tissues including the penis. Thus, inflammatory cytoines produced by visceral ataposity can have a profound and damaging effect on the vascular endothelium in the small penile vessels leading to erectile dysfunction.
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Dr. Trish writes, "Testosterone treatment for ED ameliorates metabolic syndrome components and improves endothelial function. Testosterone therapy in men with androgen deficiency demonstrated an improvement in erectile function and increased muscle mass and decreased visceral fat. Furthermore, androgens have been shown to inhibit the
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expression and release of cytoines and chemocines. Androgen deprivation therapy is associated with increased levels of pro-inflammatory factors and decreased anti-inflammatory cytoines.
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Interestingly, testosterone therapy prevents a gain in visceral atapost tissue in non-obese aging men and reduces the production of pro-inflammatory cytoines.
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I've included the 22 reference studies in this paragraph. All of the benefits with testosterone therapy in these studies were obtained with intact physiologic aromatization. None used an aromatase inhibitor.
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If the benefits of testosterone therapy were demonstrated under intact aromatization, the obligation is on those who suppress estradile to prove they preserve or enhance these outcomes, not assume it.
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This is a review article by Caliber and SADE discussing the use of testosterone for the prevention and treatment of obesity in men. We will be examining in more detail a few of the studies referenced in this article with specific
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attention to worsening sexual function or symptoms of elevated estradiol. This paper includes 207 references and only one used in aromatase inhibitor and it was the finalign study that we've already reviewed.
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Effects of long-term testosterone therapy on patients with diabetes. Results of observational studies of pulled analysis in obese hypogonata men with type 2 diabetes. This study involved 156 obese diabetic men with testosterone deficiency treated with testosterone undeinoate for up to six
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years. Improvements occurred in all cardiomatabolic parameters measured including systolic and diastolic blood pressure as noted by baseline and then the endpoint. As you can see even the blood pressure significantly improved.
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Systolic blood pressure went down significantly as did diastolic blood pressure. All parameters improved. Now let's address those that claim estradile can be the cause of an increase in blood pressure or hypertension in men on testosterone. Both systolic and
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diastolic blood pressure decreased in these obese men with normal physiologic aromatization intact. Estradi was not measured or controlled and yet benefits occurred. Estradiol is vasoddilatory not a vaso suppressor. Experimental clinical literature shows estrogen signaling can increase nitric oxide bioavailability
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improve vascular relaxation and in hypogonado men even lower blood pressure with estrogen supplementation. Flaming estradile ignores basic vascular physiology.
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This study by Kamazerov at all showed that lowd dose estrogen supplementation in hypogon man is well tolerated lowers blood pressure and may affect vascular reactivity in a manner that is potentially beneficial through several mechanisms including enhancement of basil nitric oxide release and
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attenuation of vasoc constrictor responses to angotensin 2 and norepinephrine. When testosterone therapy is first initiated, some men experience transient sodium and water retention, leading to plasma volume expansion and a temporary rise in blood pressure. This effect is usually self-limited and often improves
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over several weeks with sodium restriction, adequate hydration, and increased aerobic activity. It tends to be more common in men that are insulin resistant and have underlying metabolic dysfunction and not also have a diet that is high in sodium.
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This was a landmark study by Yasine and it showed for the first time that testosterone therapy in men with hypoganism prevents progression from pre-diabetes to type 2 diabetes.
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229 men with pre-diabetes and total testosterone levels less than 348 nanogs per deciliter were treated with testosterone undecinate and followed for eight years. They reported, "Our study shows for the first time that long-term testosterone therapy completely prevents progression of pre-diabetes to avert
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type 2 diabetes in men with hypogonadism and pre-diabetes. Here are the baseline characteristics in the testosterone group and the control group as well as the changes noted at 8 years. As you can see from the supplementary data, there was
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improvement in all measures in the testosterone group compared to the controls. There was nothing that did not improve with testosterone therapy that they measured.
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Focusing on sexual function, baseline AMS scores were 52.2 graded as severe symptoms of testosterone deficiency and IIE IEF scores were 8.2 which is considered moderate ED. Remember the higher the IEF score the better and the lower the AMS score the better.
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After eight years, the average AMS score decreased 18.3 points to 34, which we considered mild symptoms of testosterone deficiency. The IEF score increased 8.4 points to 19.9, which is now considered mild ED.
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All of the positive changes, including the improvement from severe symptoms of testosterone deficiency to mild symptoms of testosterone deficiency, as well as from moderate ED to mild ED, all occurred with intact aromization.
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Estradile was not measured or controlled and yet benefits still occurred. This paper supports the efficacy of testosterone therapy without disrupting testosterone estradile physiology. Those advocating estradile suppression must prove that adding it improves outcomes beyond testosterone therapy alone.
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This study by SADE looked at the effects of long-term treatment with testosterone on weight and waist size in 411 hypogodo men with obesity classes one through three. observational data from two registry studies. Remember from the previous slide that class one obesity is
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a BMI of 30 to 34.9, class 2 35 to 39.59 and class 3 a BMI greater than 40. Table one are the baseline characteristics of the men in this study and as you can see they had significant BMIs 35 32 37 and
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41.9. Table two are the changes in metabolic, prostate, and quality of life parameters at baseline and following long-term treatment up to eight years. Baseline IIEF scores were 13.8, 15.6, and 17 for class 1, 2, and class 3 obesity,
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respectively. After long-term treatment with testosterone, the IIEF scores increased in all three classes to 24.8, 24.5, and 25.4, all considered mild ED.
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The AMS scores dropped 32.5 points to 19.7 for class one. It dropped 33.4 points to 19.4 for class 2 and it dropped 38 points to 17.8 for class 3 obesity, which correlates with no symptoms of testosterone deficiency for
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all classes. Treating obese and severely obese men with testosterone without an aromatase inhibitor significantly improved sexual function and resolved symptoms of testosterone deficiency.
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Estradi was not measured or controlled and yet benefits still occurred. In this long-term registry of 411 obese hypogonatal men, including men with morbid obesity, testosterone therapy produced substantial and sustained improvement across anthropometric, metabolic, inflammatory, sexual and quality of life measures. These outcomes
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were achieved with testosterone therapy alone under preserved testosterone to estradile physiology not with aromatase inhibition or deliberate estradile suppression. Accordingly, the study does not support claims that estradile requires routine control for benefits to occur. On the contrary, it shows that
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major clinical improvement occurred while aromatization remained intact. The burden therefore rest entirely on advocates of estradile suppression to prove that disrupting a physiologic pathway associated with benefit improves outcomes rather than undermining them.
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Advocates for estradile control in normal or obese men are not correcting failure. They are interfering with success.
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This is an important study by hater at all showing the remission of type 2 diabetes following long-term treatment with injectable testosterone and decinoate in patients with hypoganism and type 2 diabetes. 11-year data from a realworld registry study. It consisted
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of 178 men with testosterone levels less than 350 with symptoms of hypoganism treated with testosterone undeinoate for 11 years. They reported long-term testosterone therapy in men with type 2 diabetes and hypogonism improves glycemic control and insulin resistance.
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Remission of diabetes occurred in onethird of the patients. Table one includes the baseline characteristics of the treated men and controls. The average weight of the treated group was 250 lbs and the average BMI was 36.5.
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Focusing on testosterone deficiency symptoms and erectile function, the treated group had an average AMS score of 54.7 and an IEF score of 16.1, which corresponds to severe symptoms of testosterone deficiency and moderate erectile dysfunction. Table two are the
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changes 11 years from baseline. As you can see, improvements occurred in every parameter measured. The AMS score dropped an average of 31 points to 23.9 and the IEF score increased an average of 10.2 2 to 26 which corresponds to no
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symptoms of testosterone deficiency and no erectile dysfunction. There was once again a significant decrease in systolic and diastolic blood pressure of 32 mm and 19 mm respectively.
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This paper shows that substantial metabolic and clinical benefit occurred with testosterone therapy alone without estradile suppression. If you want to add an aromatase inhibitor, the burden is on you to show that it improves outcomes beyond testosterone alone.
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There are no randomized outcome data showing that routine aromatase inhibition during testosterone therapy improves clinical outcomes compared with testosterone therapy alone. The burden for those that promote estradile control is to provide a randomized trial that shows testosterone plus an aromatase
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inhibitor improves diabetes remission, insulin resistance, body composition or sexual outcomes more than testosterone alone.
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In this study by SADE, long-term treatment with testosterone undeenoid injections in men with hypogenism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer and mortality. They treated 412 patients with different degrees of erectile dysfunction with testosterone undeenoic
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for up to 12 years. 393 men served as controls. Table one are the baseline characteristics of the men in the study.
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The no ED or mild ED group had an average age of 57.7 years, a BMI of 33.7, systolic blood pressure of 152, diastolic blood pressure of 92.4, an AMS score of 55, and an IEF score of 24.2.
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The moderate and severe ED group had an average age of 57.7, a BMI of 32.8, systolic blood pressure of 151, diastolic blood pressure 88.8, 8 an AMS score of 49.5 and an IIFF score of 15.1.
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Both groups at baseline were older overweight men with hypertension in addition to different degrees of ED and severe symptoms of testosterone deficiency.
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These are the changes at 10 years from baseline. All anthropometric parameters improved from baseline in both treatment groups. In the no or mild ED treatment group, systolic blood pressure went down 19.4, 4 diastolic blood pressure 11.5 BMI went down 5.8 AMS scores went down
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31.9 and IF scores went up 4.4 in the moderate and severe ED treatment group systolic blood pressure went down 22.5 diastolic blood pressure 11.1 BMI 5.8 8 AMS scores went down 27.3 and IEF scores went up 11.1.
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The no or mild ED treatment group now had no erectile dysfunction and the moderate to severe ED treatment group also had no erectile dysfunction.
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In both treatment groups, the AMS score equaled no symptoms of testosterone deficiency. He reported, "The main findings of this study are that long-term testosterone therapy with testosterone undeenoid injections for up to 12 years substantially improves erectile function, anthropometric and
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cardioabolic risk factors, prostate cancer incidents, and urinary function. It is notable that the benefits of testosterone therapy are even stronger in patients with moderate or severe ED at baseline than in patients with no or mild ED at baseline. An interesting
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finding in our study is that erectile function continues to improve for nine years. It was previously believed that maximum improvement erectile function are achieved after 3 to six months of testosterone therapy. Based on this belief, several clinical guidelines
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recommend that men with borderline hypogonism should be given a therapeutic trial of testosterone therapy for three months such as the Can Canadian Medical Association or 6 months, the British Society for Sexual Medicine, or 12 months, the International Society for
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Sexual Medicine. Our data clearly showed that a therapeutic trial of testosterone therapy for even one year is not enough to achieve maximum benefit of testosterone therapy on erectile function.
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Estradiol management. The improvements in sexual functions were achieved without measuring estradile as a therapeutic target. This study places the burden of proof on those advocating estradile control because the sexual benefits were achieved without it. All of the supported benefits occurred under
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conditions of intact aromatization, not estradiol suppression. This study supports restoring testosterone physiology, not disrupting it with routine estradile suppression.
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If estradile control were necessary, these benefits would not have occurred without it. But they did. No aromatase inhibitor was required to achieve benefit in any man. What worked was testosterone restoration, not estradile suppression or control. If the outcomes
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were achieved with intact aromatization, then routine estradile suppression is an added intervention in search of evidence. The study supports restoration of normal physiology, not routine disruption of it. Routine estradile suppression or control remains an unproven add-on when the therapeutic
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benefits were achieved without it. Before someone argues for adding an aromatase inhibitor, they first have to explain why the documented benefits occurred without one. You cannot claim estradiol control is required when the documented sexual improvement occurred in its absence.
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Those advocating estradile control need to prove that adding an aromatase inhibitor improves outcomes beyond testosterone therapy alone. If estradile control improves sexual outcomes, where is the testosterone therapy versus testosterone therapy plus AI trial showing it? There is not one.
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Supra physiologic testosterone levels. Do they impair sexual function or cause other symptoms attributable to estrogen excess?
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The effects of superphysiologic doses of testosterone on muscle size and strength in normal men. This is a study by basin that looked at normal men treated with 600 milligs of testosterone and anth for 10 weeks.
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He stated super physiologic doses of testosterone especially when combined with strength training increase fat-free mass and muscle size and strength in normal men. In this study, estradi was not measured or managed, and testosterone levels exceeded 3,000.
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No differences were found between the exercise groups and the no exercise groups, or between the placebo groups and the testosterone groups in any of the five subcategories of anger assessed by the multi-dimensional anger inventory. No significant changes in
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mood or behavior were reported by the men on the mood inventory or by their living partners, spouses, or parents on the observer mood inventory. Acne developed in three men receiving testosterone and one receiving placebo and two men receiving testosterone
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reported breast tenderness, but no other side effects were noted. No sexual side effects reported.
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Here's the published paper specific to the effects of superhysiologic doses of testosterone on mood and behavior.
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Superphysiological doses of testosterone when administered to normal men in a control setting do not increase angry behavior.
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These data do not exclude the possibility that still higher doses of multiple steroids might provoke angry behavior in men with pre-existing psychopathology.
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Our study failed to detect any significant effects of testosterone treatment on mood or the subsets of angry behavior examined.
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No estrogenic effects on mood or behavior reported. We've already viewed the findings of the basin study testosterone dose uh response relationships and healthy young men in detail. But now let's look at the reported adverse effects.
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Hemoglobin levels decreased significantly in men receiving the 50 mgram dose but increased at the 600 milligram dose. The changes in hemoglobin were positively correlated with testosterone concentrations.
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Changes in plasma HDL cholesterol were negatively dependent on testosterone dose and correlated with testosterone concentrations.
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Two men in the 25 milligram group, five in the 50 mgram group, three in the 125 milligram group, seven in the 300 milligram group, and two in the 600 mgram group developed acne. I've been asking for years for someone to provide
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a study or studies where testosterone therapy was associated with erectile dysfunction. No one has provided me with one, so I guess I'll do it for them.
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This was missing on the first slide, but at the bottom you'll see one man receiving the 50 milligram dose reported decreased ability to achieve erections.
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In the basin dose response studying young men, one participant in the 50 milligram group reported decreased ability to achieve erections. It did not occur in the higher dose groups where testosterone and by extension estradile would have expected to rise the most.
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Therefore, it is not reasonable to attribute that isolated complaint to testosterone induced estradi excess.
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Because men in the 50 milligram arm experienced a significant reduction in serum testosterone from a baseline mean of 566 nanogs per deciliter to 306 nanogs per deciliter during treatment.
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Given that estradile production in men is largely derived from circulating testosterone, estradile exposure in this group would also be expected to decrease rather than increase. This isolated erectile complaint is more appropriately interpreted as occurring in the setting of relative androgen and estrogen
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reduction, not excess estradiol exposure. Back to the study by basin that we have reviewed in detail earlier in the lecture. To refresh your memory, it was a randomized control trial in healthy men with normal testosterone levels aged 18 to 50 years for 20 weeks. They were
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given testosterone and antha 50, 125, 300, or 600 milligrams per week. Each dose was paired with either placebo or dutasteride at 2.5 milligrams a day. And there were eight treatment groups.
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And here's what you've been looking for hidden in the supplementary data. Let's exclude the testosterone plus dutasteride group since we know five alpha reductase inhibitors are known to cause erectile dysfunction in some men and instead focus on the testosterone
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only treatment group. Decreased libido was reported in three men in the 50 milligrams per week dose. Two men at 125 milligrams per week. two men at 300 milligrams per week and one man at 600 milligrams per week. Erectile
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dysfunction was reported in one man at 50 milligrams per week, two in the 125 milligram group, and one in the 300 mgram group and no men in the 600 milligram group. Delayed orgasm was reported in one man in the 300 milligram
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per week group and an ejaculation was reported in one man in the 125 mgram per week group. Similar to the previous study, the testosterone levels in the 50 milligram group significantly decre decrease from a mean baseline level of
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697 nogs per deciliter to 385 nanogs per deciliter and estradile would be expected to decrease accordingly. Again, testosterone and estradile reduction, not estradile excess, is a more plausible explanation for the adverse sexual effects in this group.
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Interestingly, the 600 milligram per week group had the least sexual complaints. Is estradiol to blame for these adverse sexual symptoms in the 125, 300, and 600 mgram dosage groups, or is it possibly secondary to something else? Let's find out.
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Before we discuss potential explanations, let's review normal sexual function. Normal sexual function is a balance between excitatory factors and inhibitory factors. The excitatory factors include the sex steroids, testosterone, DHT and estradiol, dopamine oxytocin melanoortin and norepinephrine. The inhibitory factors
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include serotonin, opioids, endocanabonoids, and prolactin. We're now going to review the mechanism of action of some of the medications used in the treatment of sexual dysfunction.
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Addi flabanserin is FDA approved for the treatment of hypoactive sexual desire disorder in both premenopausal and post-menopausal women. It's used off label in men. It's it's a centrally acting postsaptic serotonin 1A receptor agonist and a serotonin 2a antagonist
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that produces a decrease in serotonin activity and an increase in dopamine and epinephrine activity in brain pathways associated with sexual desire.
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Valysi brealanotide. It's FDA approved for the treatment of premenopausal women with acquired generalized hypoactive sexual desire disorder. It's used off label in men. It's a melanoorton receptor agonist which non- selectively activates melanoortin 1 2 3 four and five receptors. Activation of the
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melanoortin 4 receptor modifies brain pathways involved in sexual response and stimulates the release of dopamine.
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There is no medication for delayed ejaculation or an orgasmia that is FDA approved. But table three includes a list of medications that have been used in the medical literature for treating delayed ejaculation and an orgasmia.
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They include kbergolene, wellbutrin, oxytocin boobar ephedrin yohimine amanthadine apomorphine just to name a few.
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The strongest mechanisms in the treatment of delayed ejaculation and anorasmia are to increase dopamine, reduce serotonin mediated inhibition or increase sympathetic tone. Kerbergine for instance increases dopamine and suppresses prolactin. Wellbutrin increases dopamine and norepinephrine.
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Boobar a partial serotonin agonist at serotonin 1a receptors. Pseudoedrin increases norepinephrine. Epinephrine also increases norepinephrine. Amantine increases dopamine and apomorphine also increases dopamine.
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Let's now look at the inhibitors of sexual function. Prolactin in men. Hyper prolactinmia is most often the cause of low libido and erectile dysfunction.
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High prolactin levels suppress the pulsatile release of hypothalamic gonadotropen releasing hormone leading to decreased production of LH and FSH resulting in decreased testosterone production and impairs spermatogenesis.
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Men with hyperlactylmia have sexual dysfunction even when testosterone is still in the normal range which suggests testosterone independent central effects. There is also evidence that prolactin may directly inhibit erectile function not just indirectly through low testosterone.
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Prolactin levels of greater than 35 naggs per milliliter have been associated with a more than 10-fold increased probability of reporting hypoactive sexual desire.
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Serotonin. Serotonin acts on the smooth muscles of the vascular system of the genitals and other sexual organs to produce vasoc constriction and vasoddilation.
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In the central nervous system, it has an inhibitory role on erectile function, lubrication and sexual interest.
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Selective serotonin reuptake inhibitors impair ejaculatory and orgasmic function and frequently inhibit erectile function, lubrication, and sexual interest.
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Medications that increase serotonin, such as SSRIs, are well known for their sexual side effects. SSR related sexual dysfunction, is estimated to affect between 30 and 70% of users. Common symptoms include general anesthesia where there's a decrease in sensation
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and numbness in the genital area, decreased libido, erectile dysfunction, pleasureless or weak orgasm, delayed ejaculation and orgasmia and nipple insensitivity.
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I have personal experience with the sexual side effects associated with these medications. When my colleagues attempted to treat my hypoginism with multiple SSRI, I experienced many of these adverse effects firsthand.
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These are the American Urology Association guidelines for erectile dysfunction as well as for disorders of ejaculation.
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It's important to point out that no medication used in the treatment of hypoactive sexual desire disorder, erectile dysfunction, or delayed ejaculation and an orgasmia lower estradiol as a mechanism of action. No current guidelines include lowering estradiol as a treatment recommendation.
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The hormonal regulation of men's sexual desire, arousal, and penile erection recommendations from the fifth international consultation on sexual medicine was published in sexual medicine reviews in 2025.
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They recommended clinicians should consider that both androgen receptor and estrogen receptor cooperate in the regulation of male sexual desire.
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Clinicians should consider not prescribing non-aromatizable androgens or aromatase inhibitors to treat low desire in hypocodon men. Clinicians may consider the role of estrogens on erectile function still controversial.
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Clinicians should not consider estrogen measurement in the assessment of erectile function. There are those that continue to make unsupported claims that estradile impairs erectile dysfunction, but those claims are based on observations, not interventional studies, where estradiol has been shown to have a positive effect
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on erectile function. They went on to state, "A recent metaanalysis of the available trials shows us that the use of aromatase inhibitors is associated with a reduced libido. Overall, the evidence suggests that estradile in the brain might participate in regulating sexual desire
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in men. However, epidemiological studies did not show a significant relationship between circulating estradiol and sexual desire in men. A possible explanation is that brain estrogen levels which affect sexual desire are most probably formed locally from testosterone through aromatase rather than originating from
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circulating estradiol which consequently does not accurately describe the intra cerebral estrogen amount. Again the measurement of serum estradile has very limited applications. Serum estradile is nothing more than a crude proxy for tissue estrogen signaling.
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Now that we have a better understanding of the excitatory and inhibitory mechanisms involved in sexual function, we can address the potential mechanisms of testosterone induced sexual side effects in some of the men from this study.
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Before moving forward, I want to be very clear. I acknowledge that these side effects can occur in a very small percentage of men. I say this not just from a clinical standpoint because I personally experienced them when starting testosterone therapy.
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So, what's the cause? If you haven't figured it out by now, it's serotonin. Serotonin is what puts the brakes on sex, not estradiol.
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Testosterone increases serotonin activity in the central nervous system. And in a small population of biologically susceptible men, it can contribute to sexual side effects. The inc incidence is only a small fraction of that seen with SSRIs, which are far
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more potent. But even if the prevalence is only 1 to 2%, that still represents 10 to 20,000 affected men for every 1 million men on testosterone. These are the men who tend to populate internet forums and online discussions seeking
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help, not the 98 to 99% of men without symptoms. As I mentioned on the previous slide, I experienced these symptoms when I first started testosterone therapy, and they weren't as severe, but very similar to what I experienced when I was
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placed on SSRIs. Let's now look at a few studies on the relationship between testosterone and serotonin.
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This study by Perfaulk testosterone levels in healthy men correlate negatively with serotonin 4 receptor binding. It involved 41 healthy men ages 20 to 56. It evaluated if serum levels of estradile and testosterone were associated with serotonin 4 receptor
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binding as imaged by a PET scan. Serotonin 4 receptor binding is used as a marker for overall serotonin tone.
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Higher serotonin 4 receptor binding equals lower serotonin activity. Serotonurgic tone. Lower serotonin 4 receptor binding equals higher serotonin activity. Serotonurgic tone.
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Higher serum testosterone levels are associated with lower global serotonin 4 receptor binding indicating higher serotonin tone. serum estradiol levels had no effect on global serotonin for receptor binding.
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Now there's question marks behind that sentence and we're going to take a closer look on the next slide about why those question marks are there as I continue. In the brain testosterone can act on androgen receptors or it can
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be aromatized to estradile that acts on estrogen receptors. Estrogen beta receptors are located in the serotinergic neurons where androgen receptors are not. Thus any effects of testosterone on serotonin signaling would be medi mediated by indirect mechanisms or by its aromatization to
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estradiol. Cumulative evidence supports a link between sex hormones in particular estradiol testosterone and serotonin signaling. Reducing the amount of estradile biomatase inhibition leads to reduced serotonin levels in terminal axon regions. Thus one mechanism by which androgens could affect serotonin
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levels is through its effects on estrogen receptors after conversion to estradile in the rafé nuclei. The current findings are consistent with the decrease in serotonin levels observed in animals after inhibition of aromatase suggesting that testosterone is necessary for keeping serotonin levels
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high. The positive association between peripheral testosterone levels and central serotonin levels observed here supports the notion that testosterone may have a protective effect on depressive mood by mechanisms involving serotonin.
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With regard to the statement, serum estradiol had no effect on global serotonin 4 receptor binding.
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Now we can put what you've learned about the limitations of measuring serum eststerile to good use.
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Why do you think that serum estradiol was not associated with increased serotonin tone but testosterone was? The absence of serotoninergic association between circulating estradiol and serotonin 4 receptor binding should not be interpreted as evidence that estradile is biologically in irrelevant
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to central serotoninergic tone. Remember testosterone is an endocrine hormone in men and estradile is predominantly inocrine and paracrine. Serum testosterone better reflects the androgen substrate available to the brain for direct androgen effects and for local aromatization to estradiol.
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Estradile in the brain is made locally and not fed by serum levels. Serum estradiol does not equate to brain estradiol signaling. Serum estradile is a weak proxy for tissue level estradiol signaling. It reflects circulating levels, not tissue levels. This helps
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explain why two men with similar serum estradi levels may have very different clinical experiences and why some men with levels perceived as high remain asymptomatic while others report symptoms.
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Serum dile was the wrong compartment to measure for the question being asked. The key issue is compartment mismatch.
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Serum was measured but the relevant biology occurs within tissues. The lack of association between serumstradial and global serotonin 4 receptor binding reflects a measurement limitation rather than proof that estradile is unimportant in serotoninergic tone.
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A simple way to view it is serum testosterone enters the brain underos local aromatase conversion into estradile which binds to the estrogen receptor and then generates serotonin system effects. And this is further supported by the next study.
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In this study by Ryberg, they evaluated the contribution of circulating sex steroids to the levels in the cerebral spinal fluid. And what they found was for all sex steroids except estradiol, strong associations between corresponding cerebral spinal fluid and
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serum levels were observed. There was no correlation between estradile in the cerebral spinal fluid and estradile in serum. Once again, there was no correlation between estradile in the cerebral spinal fluid and estradile in serum. Serum testosterone tracked cerebral spinal fluid testosterone.
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Serum estradile did not track cerebral spinal fluid estradiol. CNS estradile reflects local conversion. Serum estradiol does not reflect tissue estradiol.
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Highdosese testosterone treatment increases serotonin transporter binding in transgender people. 33 transgender individuals, 14 female to male and 19 male to female, all hormone naive at baseline. 11 female and 24 male cisgender controls. PET scans of the brain were obtained with a tracer that
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binds to the serotonin transporter before treatment. They also received a PET scan after four weeks and then after four months of treatment. Female to male transgenders received highdosese testosterone.
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Serotonin transporter binding was used as a marker for serotonin levels. Increased serotonin transporter binding equals increased serotonin. Decreased serotonin transporter binding equals decreased serotonin.
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In this study, we found that testosterone treatment in female to- male transsexuals significantly increase serotonin transporter binding after one month as well as after four months of treatment. We therefore suggest that testosterone treatment in female to male affected serotonin transporter binding
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via aromatization to estradiol and activation of estrogen receptors. Our results indicate increases in serotonin transporter binding occur when testosterone and aromatized estradiol increases. Recent animal research indicates that androgen therapy elevates serotonin levels and that this is dependent on aromatase activity.
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Accordingly, exogenous androgen increases aromatization to estradiol which leads to increases in serotonin synthesis and availability via estrogen receptors. Taken together, our data indicate that testosterone treatment of female to male increased serotonin levels which thereby increase serotonin transporter expression.
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I included this study by Kettle's daughter at all to explain why some men like myself develop sexual side effects and others don't. Seroteneuric activity estimated by EEG loudness dependent auditory evoked potentials as a predictor of sexual SSRI side effects.
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Loudness dependence of the auditory vote potential is an EEG based biioarker inversely linked to serotonin activity.
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This study looked at 90 patients with major depressive disorder. They obtained LDAP before a 8we treat week treatment with an SSRI. Sexual function was measured before and after treatment together with sexual SSRI related side effects. Low LD-AP equals higher
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baseline serotonin activity and high LDAP equals lower baseline serotonin activity. What they found was that LDAP was not associated with pre-treatment sexual function. This indicates it specifically predicts SSR uh induced effects rather than depression related sexual dysfunction. Low pre-treatment LDAP
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indicating high serotoninergic activity was associated with increased SSRI related sexual side effects predominantly difficulty reaching orgasm with a predicted accuracy of 87%.
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When baseline serotonin tone is already high indicated by low LDAP the addition of an SSRI appears to raise serotonin activity beyond a threshold where sexual function becomes impaired.
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It has been my clinical experience of personal experience along with my research findings that the sexual side effects observed in a minority of men after initiating testosterone therapy reflects a serotonin threshold phenomenon rather than a ad direct adverse effect of estradiol itself. In
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biologically predisposed individuals with relatively high baseline serotonin tone, the testosterone induced increases in estradiol may further amplify serotinergic signaling and push sexual function beyond an inhibitory threshold.
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The result may be impaired libido, erectile dysfunction, genital anesthesia and impaired ejaculatory orgasmic function in a pattern resembling SSRI associated sexual dysfunction. This is not estradile excess. It is serotonin susceptibility.
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Even after reading this, some will still say, "See, I told you it was estradiol." But if you're going to blame estradiol, then you must assign equal blame to testosterone. Because without circulating testosterone as a substrate, the brain cannot synthesize estradiol.
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Sexual dysfunction on testosterone therapy. Testosterone indirectly contributes. Estradiol indirectly contributes. Serotonin directly contributes. The sexual dysfunction that a small percentage of men experience on testosterone is directly related to serotonin. It is not estradiol. It has never been estradiol. It has always been
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serotonin. So, if blame is going to be a sign, let's at least put blame on the correct offender. Now that we have a better understanding of the excitatory and inhibitory factors involved in sexual function, let's go back and look
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at the study before we discuss treatment options. Now, in this study, these men had very good baseline testosterone levels without any symptoms of testosterone deficiency or sexual dysfunction prior to treatment.
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Here's the supplementary data again. The baseline testosterone levels were obtained at peak while the on treatment levels were obtained at the trough one week after the previous injection.
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The men in the 50 milligram dose had a significant reduction in their testosterone levels.
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The remaining groups had significant increases in their testosterone levels. Their troughs were significantly higher than their baseline levels. And remember, the trough is the lowest level of testosterone measured just before the next scheduled injection. At the 50 milligram dose, their baseline
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testosterone levels are 697 and they dropped to 385 on treatment. The 125 milligram dose had a baseline of 701.
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Their trough increased to 822. The 300 milligram dose 667 baseline testosterone level with a treatment trough of 1,72.
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And the 600 mgram dose had a baseline testosterone level of 776 and a treatment trough of 3,578.
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In the 50 mgram group, the significant reduction in testosterone diminished excitatory neurotransmitter signaling and contributed to erectile dysfunction.
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If you reduce testosterone by nearly 50% in healthy yugenatom men, the appearance of erectile symptoms in some participants is not surprising. It's physiologically predictable. In the higher dose groups, testosterone rose substantially above baseline, increase in serotonin tone beyond the threshold
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tolerated in susceptible individuals and thereby contributing to erectile dysfunction. The lower dose and higher dose groups exhibited similar symptoms, but the underlying mechanisms were different. In other words, same different symptoms, different causes.
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Now, let's discuss the treatment options. Treatment options include discontinued testosterone therapy, medication management, give it time to resolve, lower testosterone dosage, treatment of choice.
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Discontinued therapy. When a medication related adverse effect occurs, clinicians should discuss all reasonable management options, including discontinuation of therapy. Even if discontinuation is not the best option, the patient should be given the opportunity to make an informed decision.
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The use of testosterone can be divided into three basic categories. Medical use, misuse, and abuse. Medical use is testosterone therapy for the treatment of testosterone deficiency symptoms or hypogenism. Discontinuation not recommended in this group. Misuse is testosterone therapy without symptoms of
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testosterone deficiency or hypogenism. Just the everyone else is doing it. So, I thought I'd do it.
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Abuse is testosterone therapy in high doses purely for performance-enhancement purposes. Now, I would not recommend discontinuing testosterone therapy when it is being used for a legitimate medical indication. However, in individuals using testosterone for non-medical purposes, discontinuation can be a reasonable treatment option.
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Medication management. The recommended medication will depend on the dominant symptoms. If it is predominantly erectile dysfunction, then we could use the PD5 inhibitors like Viagra, Seialis, Levitra, Stendra. If it is mainly low libido, delayed orgasm or an orgasmia,
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well, we can use the drugs we've gone over previously. Wellbutrin, Boobar, Yohimine, Aantine, Cobergine, etc. And then of course, aromatase inhibitors.
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This is the least favorable option and not recommended. There are far better options that will maintain all of the beneficial effects of testosterone.
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This is probably as good a time as any to discuss my personal history with aromatase inhibitors. For the first two years after starting testosterone therapy, I took them and I prescribed them. Like many of you, I had heard and
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read that this is how testosterone therapy is supposed to be done. I accepted it without questioning it. If everybody was doing it, I assumed it must be right. Even while attending Dr.
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Rusier's conferences and listening to him speak about the harms of romatase inhibitors, I remained skeptical. Like many others, I found myself asking, "How could one man be right when so many others were saying the opposite?" For two years, I immersed myself in the
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medical literature, determined to prove him wrong. But despite my best efforts, the literature kept leading me to the same conclusion. He was right.
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And here's the part that I'm not proud of. I continued taking an aromatase inhibitor.
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This is how strong belief perseverance can be. Sometimes the hardest part of medicine is not finding the evidence.
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It's having the courage to abandon what the evidence does not support. The turning point came when my wife Angie confronted me. I still remember her saying, "Keith, you say you practice evidence-based medicine. You've spent two years researching romance inhibitors
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and found no evidence supporting their use. So why are you still taking one?" The question forced me to confront the inconsistent between what I claimed to believe and what I was actually doing.
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That was the day I stopped. And I still remember how hard it was to take that bottle of an asterisol and throw it in the trash can. Not because it was medication, but because it represented a belief I had defended, a habit I had
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normalized, and an idea that I had not wanted to let go of. Sometimes it takes someone wiser than ourselves to help us see clearly. So, Angie, thank you.
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The AI cycle. I was this guy. Testosterone therapy. increased testosterone, increase estradiol, increased serotonin, and some of us get erectile dysfunction, those that have a biologic predisposition. We then reach for the aromatase inhibitor. It decreases estradiol along with
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decreasing the benefits of testosterone. It decreases serotonin and then we have improvement erectile dysfunction and then the cycle repeats itself. Men are using aromatase inhibitors to lower estradile as a proxy to lower serotonin and in doing so are attenuating the
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beneficial effects of testosterone. It is a classic case of throwing the baby out with the bath water. Even blocking estradile a little bit blunts testosterone's full physiologic effect.
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If testosterone therapy is done correctly, there should be no need for an aromatase inhibitor. When most of us are 18 to 20 years old with excellent testosterone levels, we did not need an aromatase inhibitor. It should be no
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different when testosterone therapy is done correctly. Give it time to resolve. This was the treatment option that I chose and it worked for me just as it worked for my patients that also made this choice.
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Let's briefly talk about the honeymoon effect because it ties into this treatment option. The honeymoon effect with testosterone is the early phase usually in the first few weeks to months when correcting low levels produces a dramatic boost in
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energy mood libido motivation and overall well-being. In some men, the rapid onsets of benefits can create a feeling of euphoria. As physiologic adaptation occurs, the dramatic effects plateau and settles into a more stable baseline, while the longerterm therapeutic benefits continue to
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develop. Men can experience a psychological letdown when the dramatic honeymoon effects fade and interpret this as treatment failure. Some men spend months or years manipulating their so-called protocols in an attempt to recreate the initial honeymoon phase. At that point, the pursuit is no longer
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about achieving physiological replacement, but about chasing a fleeting subjective high that was never meant to be permanent. The equivalent of a heroin addict chasing the dragon. The attenuation of the honeymoon effect should be viewed as physiologic equilibration rather than loss of
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efficacy. So the honeymoon effect can include increased energy and vitality, improved mood, increased libido, improved sexual function, increased motivation and drive, increased confidence, improved mental clarity, and better gym performance.
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These are actual messages from patients over the last year and are classic examples of the honeymoon period. Hey Dr. Nichols, quick question. I have been taking all of my prescribed meds every day and night. I still feel great and I
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have way more energy and mental clarity than when I started. However, I feel like it has calmed down. Is it normal to have an initial spike and then fall off to some degree? As I first got started, my sexual drive was off the charts and
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it seemed to even feel better. The drive was amazing. Now, I still have drive and have no issues performing and keeping an erection, but the actual drive seems to be down to some degree. Also, my energy level seemed to really jump and has now
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seemed to calm down a bit. Still better than before. I have tried to evaluate everything that I'm doing to make sure there isn't something I'm doing that I could potentially cause this. Any thoughts or suggestions or is this just
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normal to have that initial spike and then a normalization? Second message. Keith, is there any chance the formulation between bottles of test could have been altered or different in any way? The first 30 days was amazing in terms of muscle size
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growth, weight gain, the way I felt, etc. Last week, I started on the second bottle, almost immediately starting to feel like I was losing some of the progress I'd been steadily making. Then this morning, my body weight is down six
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pounds from last week and all other factors being identical. It is very deflating. Well, as most of you know, you don't gain significant muscle size in 30 days. But nonetheless, these are classic examples of the honeymoon period that we deal with as providers.
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The dramatic effects of the honeymoon period are linked to testosterone's influence on neurotransmitters, especially dopamine, serotonin, and norepinephrine. Dopamine, as it increases with testosterone, increases libido and sexual arouses, increases motivation and goal- directed behavior, increases mood, pleasure, and energy,
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decreases anhidonia, serotonin, decreases anxiety, improves uh mood stability, potentially blunts libido, but it offsets depressive symptoms.
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Norepinephrine increases alertness, arousal, attention. Pay attention. It increases blood pressure and heart rate. It increases a stress response and potential increased anxiety or irritability.
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So blaming estradiol for perceived anxiety, irritability, increased heart rate, and the secondary elevation in blood pressure mistakes the physiology.
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It is the increase in norepinephrine that is the meteor of these effects, not estradiol.
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Just as the honeymoon effects fade with physiological adaptation, side effects related to the initial rise in serotonin will diminish over time as well.
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It worked for me and it works for my patients. Understandably, most men are reluctant to tolerate side effects for a few weeks to a couple of months while waiting for them to resolve. The choice of treatment strategy generally depends
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on symptom severity. When symptoms are relatively mild, a reasonable option is to allow time for physiologic adaptation. as this approach was effective for myself and my patients that also chose this options. My treatment of choice and my preference is
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the next option. Lower the testosterone dosage. Testosterone therapy is a balancing act between raising levels to improve symptoms of deficiency and avoiding unwanted side effects. Lowering the dosage to a level that maintains symptomatic improvement and eliminates side effects is the treatment of choice
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and has worked for every single patient. It may require only a temporary dose reduction if the side effects resolve after which the dose can be gradually titrated upward if needed. A romatase inhibitors may provide a quicker but only temporary solution. When the dosage
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is lowered, it may take several days to a week or more for the benefits of that adjustment to become evident. In contrast, a potent medication used to treat breast cancer may produce a more immediate effect. Unfortunately, many men lack the patience for a lasting
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solution and instead seek a quick fix. But that quick fix can come with long-term consequences.
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From a psychological standpoint, men tend to avoid lowering their dosage. If any medication other than testosterone were causing side effects, and those side effects could be eliminated by lowering the dose, the men would do so without hesitation.
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We'll hear, "If I lower my dosage, I will feel terrible like I did before I started." This is a common reason men give me for not wanting to reduce their dose.
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However, if a man is experiencing symptoms from higher levels of testosterone, appropriately lowering the dose will not produce symptoms of deficiency. That reason does not follow normal physiology. Many times what a man thinks he needs and what he actually
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needs can differ significantly. An example is before if a man starts testosterone with a level of 350 nanogs per deciliter and is very symptomatic and we treat him to a level of 1350 but he develops side effects. Lowering the
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level to 10,00 will not result in symptoms of a testosterone deficiency. It's just mentally men hate to lower their dose. And that treatment, the treatment between the ears, that 4 in between the ears, can be the hardest part to treat in some men. I lower my
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dose, then I will lose all the benefits and gains I've made. This is what I see as one of the primary reasons why men won't lower their dose and instead continue taking aromatase inhibitors.
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What they're actually saying is if I lower my dose, then that will affect my muscle size and strengthen and have a negative effect on my gym performance and I won't be jacked all the time.
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This is the real problem. More testosterone is not always better to resolve symptoms of a testosterone deficiency. More testosterone is always better at increasing lean muscle mass.
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This is what causes most of the trouble for men. When the focus shifts from symptomatic improvement to the performance enhancement effects of testosterone and being jacked, the balance is tipped in the wrong direction, leading men to take more than
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they need or can tolerate at times. Now, let's examine the physiologic basis for these statements before turning to a discussion of testosterone dosing.
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Testosterone does not produce a single uniform dose response across all tissues. In skeletal muscle, its effects are relatively graded and nearlinear across much of the studied range.
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Whereas in many other tissues such as the brain, it acts in a threshold dependent nonlinear fashion like estradiol. In tissues other than muscle, there's a saturation point for the androgen receptors. The blue is represented by muscle and then the brain
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and other tissues are represented by the threshold and plateau. Testosterone acts differently in muscle than it does in all other tissues.
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Across graded testosterone dosage, lean mass, muscle size, strength, and power increase in a dose dependent fashion.
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Androgen receptor expression is upregulated. Satellite cells activate. Myonuclear number increases. MTOR signaling increases. There's an increase in protein synthesis. This linear dose response curve is what is used in extremely high doses by bodybuilders.
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More testosterone, more lean muscle mass. Testosterone in the brain. This is where we get our feel-good effects.
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Many of the feel-good effects are mediated by local conversion into estradiol. Brain estrogen and androen receptors have finite density. Receptors saturate at physiologic levels and receptors do not upregulate like muscle androgen receptors. There's a saturation point to the feel-good effects of testosterone.
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And once that saturation point is reached, further increases in testosterone do not continue to improve energy, mood, libido, or cognition. This helps explain why raising testosterone from 1,200 to 2400 or higher, for instance, does not result in limitless
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euphoria. You can't just keep feeling better and better and better. There's an end point to better, and that is when the androen receptors are fully saturated in the brain. In contrast, lean muscle mass can continue to increase in a dose response matter even
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though central nervous system mediated effects have plateaued. Now, let's take what we've learned about androgen physiology and apply it to clinical practice and the dosing of testosterone.
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Let's briefly review the pharmacodnamics of testosterone. Each man has a minimal effective concentration below which symptoms of testosterone deficiency begin to appear. And this differs between men as you've already learned.
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There is also a maximum tolerated concentration above which side effects may develop. The space between those two thresholds is the therapeutic window and that is where we aim to keep patients during testosterone therapy regardless of the delivery method. This is similar
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to what occurs in healthy young men whose testosterone levels naturally remain within a range that is neither too high nor too low for their individual needs. Men with increased androen receptor sensitivity often associated with shorter CAG repeats may
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have a narrower therapeutic window. It may take only a small amount to of testosterone to relieve symptoms and they may develop side effects at relatively modest increases in concentration. In contrast, men with longer CAG repeats and lower and
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receptor sensitivity may have a wider therapeutic window requiring higher dosage concentrations to achieve symptom relief while tolerating higher levels without significant side effects.
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This is an example of testosterone underdosing as well as excessive dosing. We're well outside the therapeutic window.
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This is an example of dose being too high as well as too low. We never want to rise above the maximum tolerated concentration or drop below the minimal effective concentration.
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This is typically what you're going to see with a high dose and long injection interval. You'll go above the maximum tolerated concentration. Then you'll be in the therapeutic window for a while.
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Then you'll be below your minimal effective concentration. Let's quickly look at the diaral variation of testosterone levels in men.
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The effect of diarr variation on clinical measurements of serum testosterone and other sex hormone levels in men. What they found was that in men 30 to 40 years old, testosterone levels are 20 to 20% lower at 4:00 than
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they were at 8:00. The difference declined with age with a 10% difference of men at 70 years of age.
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In this study by Patusac, they looked at the pharmacocinetics of testosterone therapies in relation to diural variation of serum testosterone levels as men age. The blue line is the estimated diural testosterone in young men and the yellow line is in older men
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and they looked at various types of testosterone administration. A is weekly subcutaneous testosterone and anth administration. B is the average mean testosterone profiles for IM testosterone cipionate and ananthate and indicinoate over two weeks. C is 900 milligrams of subdermal pellets. D is 4
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milligrams daily of a transdermal patch. E was the average mean testosterone profiles of 100 milligrams of Testum, 40 milligrams of forta, 1.6% 6% androgel and 2% axeron.
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F nasal gel at 90 milligs three times daily. G 30 milligrams of bucle mucid hes applied twice daily. And then h tw twice daily 200 milligram oral testosterone undecinate capsules. What they found was that daily transdermal gels and solution and nasal and oral tea
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products provide a consistent serum tea level within physiologic range in most patients. The daily dosing frequency of the topical gel products results in a pharmacocinetic profile with a resemblance to that of indogenous tea in younger males. With testosterone
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therapy, serum testosterone may be returned to levels within the normal physiologic range and symptoms associated with low tea may be improved.
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However, no testosterone therapy product precisely simulates the endogenous diaral tea variation observed in young and older men. Let's go back and look really quickly again. Here are your transermals right here. kind of close closest thing than of anything else.
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This is what we're trying to accomplish with testosterone therapy and it is why I personally find that more frequent administration whether it be testosterone cream or injections is often the most effective approach. The goal is to minimize peaks and troughs so
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that testosterone levels remain within the therapeutic window above the minimum effective concentration and below the maximum tolerated concentration. This is much closer to what we experienced when we were young and producing testosterone naturally. We did not have too much and
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we did not have too little for our individual needs. I have found that you can obtain symptomatic improvement in every man starting with either daily cream or daily testosterone injections as that minimizes any significant peaks and troughs. Daily cream is easy. It
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takes me about 11 seconds twice a day to apply my testosterone cream. Daily injections on the other hand can be more difficult to sustain long term. For men who prefer injections, I recommend starting with daily injections and identifying the testosterone levels that
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relieves deficiency symptoms without causing side effects. That gives us a baseline. Once a man is ready to reduce the frequency, he can move to every other day injections. If he feels no different than when he did with daily
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injections, then every other day becomes his new schedule. later if he wants to try three injections per week, Monday and Wednesday and Friday, he again has a baseline for comparison based on how he felt with daily and every other day
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injections. If there is still no meaningful difference, then three times per week may be an appropriate long-term schedule. I do not recommend injecting less than three times per week. From a clinical standpoint, I find it much easier and smoother to transition from
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more frequent to less frequent injections than to start with an infrequent schedule and then increase frequency later if symptom control is inadequate.
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I've frequently get asked, "Doc, what testosterone levels do you aim for?" And the answer is, I do not aim for any specific testosterone level. I treat to symptomatic improvement. But I can say what levels of free testosterone that
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95% of the men I treat have when they experience symptomatic improvement. A free testosterone level of approximately 30 NOGS per deciliter plus or minus 5 is where I see 95% of men improve on testosterone therapy. A free tea of 25
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to 35 nanogs per deciliter puts 95% of men above their minimal effective concentration and in the therapeutic range. 2.5% may need more and 2.5% may need less.
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We previously reviewed this study in the free testosterone section. The free testosterone levels that I see resulting in significant clinical improvement are consistent with the upper limit of normal free tea levels seen in healthy non-obese 19 to 39 year
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old men in this study. If only LabCore and Quest would have used this population of men with developing their normal values. Before we move into the next slide, I want to make it clear that I do not pro promote the misuse or abuse
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of testosterone or any other substance for that matter. There are many times when a man's levels get to what I consider excessive, and I will lower the dose. I am well aware that there are going to be differing opinions on what
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excessive is. For myself, that would be a free testosterone outside of the 60s. When the free testosterone is in the 60s or less, every parameter of health that I can measure improves.
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What about free testosterone levels above 35 nanograms per deciliter? There are times when a man's free testosterone level rises above not only the upper reference limits reported by Laporn Quest, which in my view are set quite low, but also above 35 NOGS per
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deciliter, sometimes reaching 50 or 60. When that occurs, the question is not the number alone, but how best to respond clinically. What are the management options when that occurs? One option is to lower the level. If the patient is uncomfortable with the
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number, then the number should be reduced to one that they are comfortable with. Next option is to lower the level if the patient is experiencing unwanted side effects.
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But what about that patient that's feeling great, completely asymptomatic with no side effects? This is where your understanding of the different response curves for testosterone come to play. When a man's free testosterone is in the 50 to 60
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nanogram per deciliter range, he is already above the saturation point for the subjective feel-good effects, but he can continue to derive additional anabolic and metabolic benefits. In other words, he may have more than enough testosterone to resolve symptoms
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of deficiency while still experiencing further improvements in lean muscle mass strength endurance exercise tolerance, recovery, and a reduction in both visceral and subcutaneous fat. The reduction in visceral fat is especially important because of its close relationship to insulin resistance and
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metabolic health. Here we are on the the linear dose response curve for muscle and then here's of course our threshold and plateau in all the other tissues for testosterone.
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It can be explained to the patient in this way. Your free testosterone may be 50 or 60 but that should not be misinterpreted to mean that you need that level to remain free of deficiency symptoms. You may have that level, but
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you do not necessarily need that level, and the distinction matters. You could lower your dose and it will have no effect on how you feel. I make this point because men often misinterpret a free testosterone of 50 or 60 as their
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personal minimum requirement and then worry if a future lab falls below that range, their symptoms will automatically return. That is not the case because they remain well above the saturation point for symptom relief. Now, after having this discussion, I have had
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dozens of men message me a couple of months later to say they decided to lower their dose just to see what would happen. Dozens have told me now, "You know what, Doc? I just wanted to see what would happen if I lowered my dose."
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So, I did, and I didn't feel any different. I felt exactly the same. So, I'm going to stay on the lower dose because it cost me less and I feel the same as I did with the higher levels.
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This is an important time to point out that when a man has a free testosterone of 50 or 60, he has more than enough to overcome any symptoms of testosterone deficiency. and any symptoms that remain at those levels are not related to
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testosterone. He needs to look for other causes and address those. There's a time in treatment when you reach a free testosterone of 50 or 60. That's when you can look at the patient with 100% certainty that any remaining symptoms
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are not related to testosterone. They have more than they would ever need to resolve symptoms of a deficiency. But what about those that say you don't know the long-term harm of having those levels?
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It is worth remembering that some laboratories in 2006 reported upper reference limits as high as 1,593.
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Testosterone has been used and abused for decades. If higher levels are causing the kind of widespread harm people claim, we would have seen that epidemic by now. We have not.
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For those of you that say higher testosterone levels might cause harm, I will quote Dr. Riier in medicine. If we say that it might, it means that it doesn't. because if it did, we would say that it does. Decades of use, no
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epidemic of harm, only exaggerated fear. Let's now transition and address some of the comments made by those promoting the use of aromatase inhibitors.
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Estradiol guidelines say it should be measured. This is one of the statements made by proponents of estradiol measurement and control. We've already discussed at length the limitations of measuring serum estradiol and the fact that serum levels do not reflect tissue
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level estradiol activity. We also reviewed hundreds of studies in which estradiol was neither routinely measured nor actively controlled yet meaningful therapeutic outcomes were still observed. Even so, some continue to argue that the guidelines require estradile measurement in menal
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testosterone therapy and that any physician who does not routinely measure it is practicing poor medicine. That is a serious claim and it raises a simple question. Do the data and the guidelines actually support routine estradiol measurement in men receiving
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testosterone therapy. These are the American Urology Association guidelines for menal testosterone therapy. They state serum estradile should be measured in testosterone deficient patients who present with breast symptoms or gynecomastia prior to the commencement of testosterone therapy and in all
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patients on aromatase inhibitors. It is otherwise optional when checking total testosterone levels. The American Urology Association does not recommend the routine measurement or controlling of estradiol and men on testosterone therapy unless they're developing breast symptoms, gynecomastia, or on an
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aromatase inhibitor. It is otherwise optional. With regard to gynecomastia, they state clinicians should be aware that symptomatic gynecomastia or other breast symptoms are an uncommon side effect in men on testosterone therapy. In randomized placebo control trials involving testosterone therapy, this has
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been a rarely reported adverse event. Among all of the studies included in the evidence report for this guideline, only three returned gynecomastia events.
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The Endocrine Society does not recommend measuring or controlling estradile in men on testosterone therapy. No recommendations at all. But they do point out that gynecomastia is an uncommon adverse event for which there is weak evidence of association with
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testosterone administration. They state the frequency of breast enlargement, sleep apnnea and prostate events has been low in trials of young men with hypogonadism.
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These are various testosterone therapy guidelines and estradile recommendations. The British Society of Sexual Medicine does not recommend measuring or controlling estradile in men on testosterone therapy. The Canadian Medical Association does not recommend measuring or controlling estradile in men on testosterone
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therapy. Canadian Urology Association serum estradile should be measured in testosterone deficient patients who present with breast symptoms or gynecomastia prior to the commencement of testosterone therapy. Otherwise, the Canadian Urology Association does not recommend measuring or controlling estradile and men on testosterone
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therapy. The International Society for Sexual Medicine does not recommend measuring or controlling estradile and menal testosterone therapy. And the European Urology Association does not recommend measuring or controlling estradile and men on testosterone therapy. The claim that guidelines mandate routine estradile measurement in
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all men on testosterone therapy is an exaggeration, not a factual reading of the guidelines. Current guidance supports selective estradile testing in specific clinical settings, not universal measurement in every man on treatment.
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This is one of the most recent publications on hormone replacement therapy and contributors include Abraham Morgan, Mohit Kira, Antonio Biano, Al Dubaged Trace, Michael Zitman and Ped said all are considered leading experts.
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These are the excerpts regarding estradiol. Note that testosterone therapy producing high testosterone is expected to increase estradile levels which is instrumental in fat mass reduction, bone and vascular health as well as libido and erectile function.
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Therefore, in menal testosterone therapy, aromatase inhibitors should not be used to lower estradiol. The metabolism of testosterone to estradile explains a large part of testosterone's beneficial effects in males as testosterone treatment suppresses atyposity in hypogano men. But this
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effect is not observed following the addition of an aromatase inhibitor. Reduction in fat is the most likely testosterone mediated antid-diabetic action in the TD4M study. It is likely estradiol dependent even if estradile did not appear as a major mediator
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because serum estradile concentrations are a poor reflection of tissue estradile output. There are no recommendations for estradile to be routinely measured or controlled in menal testosterone therapy. Quite the opposite actually.
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These are the recommendations on the diagnosis, treatment, and monitoring of testosterone deficiency in men. These recommendations do not include measuring estradile in men on testosterone therapy. They state aromatase inhibitors such as an estastol and let lower estrogen levels by blocking the
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aromatase enzyme, which converts testosterone to estradiol. Estrogens are vitally important players in many physiologic functions in men, including bone metabolism, cardiovascular health, spiratenesis, cognition, and sexual function. In addition, the use of these preparations for testosterone deficiency is off label. Hence, we recommend
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against the use of these drugs in men with testosterone deficiency. No guidelines recommend the routine measurement of estradiol or controlling estradile in men on testosterone therapy. None.
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The measurement of estradile and men on testosterone therapy has been driven by a false narrative fueled by ideology, repetition, and agenda rather than scientific truth.
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Estradiol. Many claim that it causes cancer. Testosterone has been used for approximately 90 years. In the next slide, I'll review the randomized studies showing an increased incidence of cancer in men on testosterone.
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This is a complete list of the studies showing an increased incidence of cancer in men on testosterone. As you can see, it is blank because there are none. This is also a slide that can be used to illustrate the improved outcomes in men
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on testosterone utilizing an aromatase inhibitor compared to testosterone alone. It is blank because there are none.
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There is no randomized data demonstrating that testosterone therapy or the associated rise in estradiol causes cancer in men. It has been feared by many and proven by none. If someone claims that the increase in estradiol from testosterone therapy causes cancer,
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the burden of proof is on them to produce the medical data that proves it.
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While this is not equivalent to giving testosterone to cisgender men and thereby increasing estradiol, it is helpful to look more broadly at cancer incidents in transgender populations, especially in transgender women receiving estradiol. Looking at the results of these two studies,
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the overall cancer incidence in transgender women does not appear to be significantly higher than cisgender men.
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When looking at all cancers combined, multiple large cohort studies have found no significant difference in overall cancer incidence between transgender individuals, including trans women and matched cisgender controls. The 2025 systematic review found only five eligible studies with two suggesting
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increased cancer risk, which were breast, and three not showing it, and concluded that the evidence is still inconclusive. Overall, the Dutch study showed a significant increased risk of breast cancer in trans women compared with cisgender men, but lower than
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cisgender women. Breast cancer is the only cancer that has been observed more frequently in trans women, although the literature remains inconsistent with some studies demonstrating increased risk and others failing to confirm it.
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Estradiol high estradile symptoms look the same as low estradiol symptoms. This statement is commonly repeated in many testosterone replacement therapy circles, but it did not originate for randomized outcome data.
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In endocrinology, opposite hormonal states produce different physiological effects. Low T does not look like high tea. Low cortisol does not look like high cortisol. Estradiol is not the exception. In endocrinology, hormone deficiency and hormone excess produce distinct physiologic patterns.
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Randomized data do not demonstrate that low and high estradile produce identical symptom syndromes in men. Same symptoms is not an evidence-based conclusion.
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It's an inference drawn from a vague non-specific symptom list. When symptoms are non-specific, it becomes easy to attribute them to either high or low estradi. The appearance of similarity arises largely from reliance on non-specific symptoms such as fatigue,
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mood change, low libido, poor sleep, and fluid retention, etc. None of which are sufficiently specific to distinguish estradile deficiency from estradi excess. They look the same as what people say when they are relying on symptoms that are too non-specific to
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distinguish physiology. Vague symptom overlap is not evidence of physiologic equivalence. Shared symptoms do not mean shared physiology. In men, low and high estradile can share a few non-specific complaints, but overlap is not equivalence. no different than men with low testosterone can share
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non-specific complaints with men with normal or high testosterone levels. Men with normal or high testosterone levels can still experience fatigue, mood change, libido fluctuation, and poor sleep, etc., which are multiffactoral and occur in all men regardless of testosterone levels. So, the real issue
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is not that the two states are the same. It's that people are overinterpreting non-specific symptoms.
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This is a chart showing the differences between aromatase deficiency and aromatase excess. As you can see, they differ. Low bone renal density with aromatase deficiency, accelerated bone maturation with aromatase excess, delayed closure of the growth plate with aromatase deficiency and premature
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maturation with aromatase excess. With aromatase deficiency, they have increased atyposity and metabolic abnormalities. Not a hallmark syndrome of the excess syndrome. With aromatase deficiency, breast tissue is not a defining feature, but gynecomastia and tenderness is common with aromatase
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excess. And the list goes on. One is autotoal recessive, the other dominant. These are distinct syndromes, distinct physiology, not a mirror image.
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Aromatase deficiency and aromatase excess in men represent distinct and non-ymmetrical clinical syndromes underscoring the physiological importance of estradile and male health.
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If high and low estradile produced identical syndromes, aromatase deficiency and aromatase excess would look the same clinically. They do not.
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The claim that both states look the same survives only if one restricts the discussion to vague symptoms that are so non-specific that they can't be used to diagnose estrogen status at all.
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The idea that low E2 and high E2 look the same in men was not elevated by data. It was elevated by repetition. A vague symptom narrative got echoed often enough that many now mistake familiarity with evidence and repetition for
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physiology. It is a recycled symptom narrative that has been repeated so often that it now masquerades as clinical truth.
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Estradi the sweet spot serum estradiol does not equal tissue estradiol signaling. The estradiol sweet spot rest on a surrogate assumption that serum estradiol reflects tissue estradi biology. Tissue estrogen action is determined by local synthesis, receptor dynamics and tissue specific signaling
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that serum cannot directly measure. A circulating number is thus being treated as a proxy for local physiology. That is not established biology but imperence built on a surrogate. Serum estradile is measurable. tissue estrobiology is what matters and is not measurable. The sweet
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spot assumes they are interchangeable, but that is not evidence-based endocrinology. The sweet spot argument collapses under its own logic. We already know what happens when testosterone and estradile are uncoupled. Benefits decline. That means estradile is contributing to the
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therapeutic outcome. Once that is established, the claim that partially suppressing estradile into a sweet spot somehow improves the result is no longer physiology. It is an unsupported belief.
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There is no proven enhancement zone hiding between intact aromatization and full suppression. If estradile contributes to the therapeutic effects of testosterone, as every major randomized trial indicates, then suppression, whether complete or partial, represents attenuation of those benefits.
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This figure illustrates the hypothetical nonlinear enhancement model that underlies the estradi sweet spot concept. This graph depicts what proponents of the sweet spot must assume that partially suppressing estradile produces better clinical results than allowing normal testosterone estradile coupling. In other words, the middle
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yellow bar is shown higher than intact aromatization because the claim requires the existence of a hidden enhancement zone in which modest estradile reduction somehow improves body composition, metabolic outcomes or sexual function beyond what is achieved under physiologic conditions. The problem is
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that this proposed middle peak has never been demonstrated in randomized trials, nor is it supported by the established literature showing attenuation of benefit when estradiol is suppressed.
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This graph is not a representation of established medical evidence or known physiology, but instead a visual representation of the unproven assumption behind the sweet spot argument. The sweet spot is an assumption layered on top of another assumption. First that serum estradile
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reflects tissue biology and second that partial suppression improves outcomes. Neither claim is supported by medical data or physiology. The estradile sweet spot is a marketing gimmick masquerading as physiology.
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This figure shows the physiologic gradient of testosterone estradile coupling. With intact coupling shown in green, normal aromatization is preserved and the full benefits of testosterone therapy are achieved. With full aromatase inhibition shown in red, testosterone and estradile are fully
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uncoupled and the result is the greatest attenuation of therapeutic benefit. The middle yellow bar represents a so-called sweet spot. But physiologically, it should not be interpreted as a zone of enhancement or superior efficacy. It is simply a state of partial uncoupling and
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therefore partial attenuation. Less impairment than full suppression, but impairment nonetheless. The central error of the sweet spot model is that it relabels reduced harm as added benefit.
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The sweet spot is not a gain in benefit. It is a smaller loss mistaken for improvement. Strip away the branding and the sweet spot is exactly what it has always been. An unsupported assumption presented as though it were established
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science. This figure makes the issue plain. The evidence supports intact coupling. The data show attenuation with suppression and the sweet spot exists only as an assumption in between. The middle bar is not a proven enhancement zone. It is
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simply less impairment than full suppression. The sweet spot is not optimization. It is partial impairment rebranded. It is nothing more than an unsupported belief polished into a talking point.
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The estradiol sweet spot is not an evidence-based target. It is a marketing friendly label attached to an unvalidated assumption and repeated until it sounds like science. It was built from assumption, repetition, and marketing, not medical science. A catchy
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label does not convert conjecture into clinical truth. Aromatization was present before romatase inhibitors existed. Yet, testosterone therapy still produced its recognized benefits for decades without routine estrogen suppression. That means aromatase inhibitor proponents are not restoring standard physiology. They are alternate
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and the burden is on them to prove that disrupting normal testosterone estradiol coupling even a little bit improves outcomes rather than blunts them. I will get gynecomastia if I don't use an aromatase inhibitor.
236:52
Speaker A
These are the European Academy of Andrology guidelines for the evaluation and treatment of gynecomastia.
236:58
Speaker A
They state, "We recommend watchful waiting after treatment of underlying pathology or discontinuation of the administration/abuse of substances associated with gynecomastia such as anabolic steroids.
237:10
Speaker A
We do not recommend the use of selective estrogen receptor modulators, aromatase inhibitors or non-aromatizable androgens in the treatment of gynecomastia. In general, surgical treatment is a therapy of choice for patients with long-asting gynecomastia and it is the cure.
237:26
Speaker A
The European Academy of Andrology doesn't recommend selective estrogen receptor modulators, and I'm not a big proponent of their use either. At times, they have to be used for fertility, but otherwise, I prefer to avoid them. The selective estrogen receptor modulators
237:40
Speaker A
include Clomid and Enlomophane. They are antagonist of the estrogen receptor in the hypothalamus and pituitary, resulting in an increase in testosterone, FSH, and LH. They take advantage of an evolutionary protective mechanism. decrease in estradiol, increase in testosterone production to
237:57
Speaker A
increase estradiol. Estradile is vitally important. Their mechanism of action tells you the importance of estradi in men. If estradi were unimportant in men, blocking its feedback would not be a therapeutic strategy.
238:11
Speaker A
Gynecomastia, it is a rare and uncommon event in men on testosterone therapy. It occurs in men with pre-existing biologic susceptibility.
238:21
Speaker A
Routine prophylactic aromatase inhibitor use is not recommended by any guidelines. Routine aromatase inhibition creates a hormone deficiency to prevent a rare event that most men were never going to experience. 99.9% of men that are on testosterone will not experience
238:37
Speaker A
gynecomastia. You should address a rare event if it occurs, not before it occurs. The attempt at prevention is more physiologically disruptive than the event being prevented.
238:49
Speaker A
Estradiol Many claim that it is estradile that causes acne. This is an excellent review article by Del Roso on the effects of androgens in the development of acne vulgaris. The development of acne on testosterone therapy is an androgenic skin effect,
239:06
Speaker A
not an estradiol effect. Androgens increase sebum production which provides a favorable environment for bacterial growth. The excess sebum also leads to hypercarotinization promoting comedone formation. Proliferation of bacteria in addition to other inflammatory mediators triggers inflammatory mechanisms involved in the formation of acne
239:26
Speaker A
lesions. In women, estrogen containing combined oral contraceptives are an established acne treatment. In their paper, they report combined oral contraceptives are available for the treatment of acne bulgaras and female patients. The mechanism of action of combined oral contraceptives and acne
239:42
Speaker A
bulgaras treatment is attributed to their anti-androgenic actions which include decreasing androgen synthesis suppressing five alpha reductase activity and blocking the androgen receptor. If estradiol were the culprit, estrogen therapy would worsen acne.
239:57
Speaker A
Menstrual breakouts are caused by premenstrual hormonal fluctuations that increase androgenic stimulation at the sebaceous gland in acne prone skin. So they are better explained by shifting hormonal balance than by the claim that high estradiol causes acne.
240:12
Speaker A
Estradiol burden of proof for enomatase inhibition. Those who advocate the use of aromatase inhibitors in men on testosterone therapy carry the burden of proof not those that preserve intact physiology.
240:27
Speaker A
The benefits of testosterone therapy were demonstrated under conditions of intact aromatization not estradiol suppression or control.
240:35
Speaker A
So if you claim aromatase inhibitors improve treatment, then produce the randomized evidence showing superior outcomes over testosterone alone. Not anecdotes, not internet folklore, not recycled symptom narratives, and not post hawk explanations for laboratory values. Show that men do better,
240:55
Speaker A
function better, and remain healthier with estradile suppression than without it. If you cannot, then the claim is unproven. The burden of proof remains yours. And what you're doing is not evidence-based medicine. It is physiologic interference searching for justification.
241:12
Speaker A
Those promoting aromatase inhibitors and men on testosterone therapy need to stop speaking as though the burden lies with everyone else. It does not. If you believe aromatase inhibitors belong in routine testosterone management, then bring the evidence and put it on the
241:26
Speaker A
screen. Until then, it's nothing more than a personal belief dressed up as protocol. And belief does not overrule physiology.
241:35
Speaker A
Testosterone, beliefs versus science. Final thoughts. First, it was testosterone. Now, it is estradiol. For decades, testosterone was feared as a driver of prostate cancer. Not because the evidence was strong, but because a flawed interpretation of 1941 data was
241:55
Speaker A
repeated until it hardened into medical doctrine. When Dr. Abraham Morgan re-examined the foundation of that belief, he discovered that it had never been supported by solid medical evidence. The use of aromatase inhibitors in men on testosterone reflects the same problem. It was never
242:10
Speaker A
established by strong clinical evidence showing better outcomes. Instead, it was adopted first as belief, then repeated as practice, and eventually defended as though it were science. When the evidence is actually examined, the scientific support is not there. This is
242:27
Speaker A
how myths survive in medicine. Fear creates them, repetition normalizes them, and dogma protects them. Like the testosterone prostate cancer myth, the claimed need for aromatase inhibitors in men on testosterone was never built on scientific truth, but on fiction
242:45
Speaker A
repeated until it was mistaken for fact. I'll leave you with a quote from Dr.
242:49
Speaker A
Morgan Taler regarding the use of aromatase inhibitors in men on testosterone. It's a belief, not science. Dr. Abraham Morgan, thank you for your time and attention. And until next time, follow evidence, not ideology.
243:05
Speaker A
Follow data, not dogma. Follow truth, not fiction.
Topics: testosterone testosterone therapy TRT men's health estradiol DHT testosterone decline hormone replacement endocrinology testosterone deficiency

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