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Part 2: Testosterone Beliefs VS Science Lecture | TRT Therapy | TRT for Men — Transcript

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0:00estradiol the normal range. In this
0:02section, we're going to look at
0:04testosterone and estradiol levels using
0:06inhanes data as well as look at the
0:08testosterone and estradiol levels in
0:10clinical studies to better understand
0:11what the normal estradiol range
0:13represents.
0:15The quest diagnostics reference range
0:17for estradile in men is less than or
0:20equal to 29 pags per milliliter.
0:23However, this range was internally
0:25derived and no publicly available data
0:27have been provided regarding the health
0:28status or testosterone levels of the men
0:31used to establish it. The lab corp
0:34reference range for estradi men is 8 to
0:3635 pogs per milliliter. However, like
0:39quest diagnostics, this range was
0:41internally derived and no publicly
0:43available data have been provided
0:44regarding the health status or
0:46testosterone levels of the men used to
0:47establish it. I contacted LabCore for
0:50information regarding how the normal
0:51range was established and I was told by
0:53their director Dr. Kelly Chung that they
0:56no longer had that data and that the
0:57normal range was developed a couple of
0:59decades ago and most likely represented
1:01volunteers that worked at the lab. So we
1:04have no information regarding the
1:05details of how Quest Diagnostics or
1:07LabCore developed their normal estradile
1:09ranges in men. As we further evaluate
1:12the normal estradiol range, we're going
1:13to use the normal range for estradi at
1:15labcore of 8 to 35 since it is the most
1:18frequently referenced. I'm now going to
1:20review the data on testosterone and
1:21estradile levels and show you the
1:23testosterone levels that the normal
1:24estradile range of 8 to 35 represents.
1:29Using inhanes data, we can go back and
1:31look at testosterone and estradile
1:32levels in men over the last several
1:34decades. These are the median estradile
1:36levels for inhanes 3 1988 to 1994 and
1:40inhanes 1999 to 2004. Looking at the 20
1:44to 39year-old age group and inhanes 3
1:47all men estradile levels were 36.5
1:5045.5
1:52and 33.7. In the same age group and
1:54inhanes 99 to 2004 all men estradi
1:58levels were 28.1 36.5
2:01and 28.1 pogs per milliliter. In the 40
2:04to 59 year old age groups, the same
2:06inhanes data showed a estradile level of
2:0933.6, 39, 30.9, 36.9, and 25.2.
2:1560 and above, estradile levels were 34,
2:1938.8,
2:2032.8,
2:2226.7,
2:2433.3, and 22.3.
2:27Now let's look at the median
2:28testosterone levels from the same
2:30inhanes data. In 20 to 39year-old males
2:34all men testosterone levels were 599
2:37and continuous inhanes it was 542 nanogs
2:40per deciliter. 40 to 59y old age group
2:43486 and 445 60 plus 435 and 392 nanogs
2:50per deciliter for all men. Now let's
2:54pair the testosterone and estradiol
2:56levels. Now, the estradiol levels are
2:58broken down by race and ethnicity, and
2:59the testosterone levels included all men
3:01without breaking the levels down by race
3:03and ethnicity. In order to compare all
3:05men estradiol levels to all men
3:07testosterone levels, you simply average
3:09the estradile levels of all men,
3:11non-Hispanic white, non-Hispanic black,
3:13and Mexican-American in each age group.
3:15So, when we pair the data, here are the
3:17results.
3:19These are the results for the median
3:21testosterone and median estradile levels
3:22for inhanes 3 1988 to 1991. All men for
3:26age 20 to 39 median testosterone levels
3:29were 599 which correlated with an
3:31estradi level of 38 pogs per milliliter.
3:34At age 40 to 59 testosterone levels of
3:36486 correlated with estradi levels of 35
3:40pogs per milliliter. And at age 60 plus
3:43testosterone 435 correlated with estradi
3:46levels of 35 pogs per milliliter.
3:49Looking at Inhannes 1999 to 2004 age 20
3:54to 29 testosterone levels were 542
3:57which correlated with an estradile level
3:59of 31. At age 40 to 59 testosterone
4:02levels of 445 correlated with estradi
4:04levels of 31. And at age 60 plus
4:07testosterone levels of 392 correlated
4:09with estradi levels of 27 pics per
4:12milliliter. These were all median
4:13levels. Now we just evaluated median
4:16levels. But now let's look at average
4:18testosterone and estradile levels from
4:20the same inhanes data. In the 1988 to
4:231991 data, average testosterone levels
4:26of 537
4:27correlated with estradi levels of 35.7.
4:30In the 1999 to 2004 data, testosterone
4:34levels of 534
4:36correlate with an average estradi level
4:38of 29.67.
4:40They also broke the levels down by age
4:42groups. 1988 to 1991, ages 20 to 24, 45
4:47to 69, and age greater than 70 had
4:50testosterone levels of 549, 520, and
4:54515, respectively. And that correlated
4:56with estradiol levels of 35.5, 35.36,
5:00and 38.61.
5:02Looking at the 1999 to 2004 data in the
5:05same age groups, testosterone levels of
5:07529, 538, and 534 correlated with
5:11estradi levels of 29.4, 29.9, and 29.9.
5:17Here's a 2021 study from the journal
5:19Andrgia where they evaluated three
5:22inhanes continuous cycles. The average
5:24testosterone levels of 516 correlated
5:27with estradiol levels of 33.12 in the
5:30complete population. For testosterone
5:32levels less than 250, an average
5:34testosterone level of 182 correlated
5:37with a estradi level of 22.49.
5:40And for testosterone levels of greater
5:42than 250, the average testosterone level
5:44of 546 correlated with estradiol levels
5:47of 34.11.
5:49In this 2007 Danish study published in
5:52the journal of clinical endocrinology
5:54and metabolism, they looked at the
5:56testosterone and estradile levels in 20
5:58to 29 year old men. They looked at a
6:00reference population, non-obese
6:03population, and an obese population.
6:05Now, the low-risk reference population
6:07were men at low risk for secondary
6:08androgen deficiency. and they ruled out
6:10subjects that had small testes, chronic
6:12disease, subclinical hypothyroidism,
6:14significant alcohol intake, anabolic
6:16steroid use and chronic disease etc.
6:19These are reported in international
6:21units. So they are reported in nanomles
6:23per liter for testosterone and pikam
6:25moles per liter for estradiol but they
6:27have been converted into American units.
6:29When we look at the upper limit for both
6:32testosterone and estradiol in each
6:34group, we find that the reference
6:36population total testosterone of 191
6:39correlates with an estradile level of
6:4045.2.
6:42For the non-obese, a total testosterone
6:44level of 182 correlates with an
6:46estradile level of 45.7.
6:49And for the obese population, a total
6:51testosterone level of 844 correlates
6:53with an estradi level of 39.2 pogs per
6:56milliliter.
6:58This is a 2006 study from the Annals of
7:00Internal Medicine on endogenous sex
7:02hormones and cardiovascular disease
7:04incidents in men. They divided men into
7:07four quartortiles. They based the four
7:10cortiles on the distribution of each
7:12hormone level in the study population
7:13measured at baseline. In other words,
7:15they took the men's baseline
7:16testosterone, estradiol, and DHEA
7:19levels, ranked them from lowest to
7:21highest, and then divided them into four
7:23roughly equal groups with quartile one
7:25being the lowest levels and quartile 4
7:28being the highest levels. And the values
7:30are means in this study for all
7:32participants. A total testosterone of
7:35520 correlates with an estradiol level
7:38of 30.3. Quartortile one had a testo
7:41average testosterone level of 330 which
7:43correlated with an estradile level of
7:4515. Quartortile 2 had an average
7:48testosterone level of 450 which
7:50correlated with an estradile level of
7:5224.6.
7:53Quartortile 3 testosterone level of 560
7:57correlates with a estradile level of
7:5933.8. And in quartile 4 testosterone
8:02levels of 740 correlates with estradile
8:05levels of 47.6.
8:08Now, even though we are focusing on
8:10testosterone and estradiol levels and
8:12not focusing on study results in this
8:13section, it is interesting that those
8:15with higher testosterone and estradile
8:17levels had less age adjusted 10-year
8:19cardiovascular disease incidents and
8:22lower hazard ratios. As you can see,
8:24quartile 3 and cortile 4. As you go up
8:26in testosterone and estradiol levels,
8:28the hazard ratios decline.
8:31The study found that serum testosterone
8:33and DHEA levels were not statistically
8:36significantly associated with incident
8:38cardiovascular disease. A higher serum
8:40estradiol level is associated with lower
8:42risk for cardiovascular disease events
8:44in older men. The findings are
8:46consistent with the hypothesis that
8:47indogenous estrogen has vasculive
8:49influences in men.
8:52Instead of continuing to look at
8:53baseline levels, let's now look at the
8:55estradile levels in men on testosterone
8:57therapy when levels are raised to the
8:59mid-normal range. We'll start by looking
9:02at the testosterone and estradile levels
9:03in the study by Stevens Shields.
9:05Relation of testosterone, dihydro
9:07testosterone and estradile with changes
9:09and outcome measures in the testosterone
9:11trials.
9:13These are the baseline characteristics
9:15of all men involved in the testosterone
9:17trials as well as in the bone trial. So
9:19for all men, a testosterone level of 231
9:22nanogs per deciliter correlates with an
9:24estradile level of 20.3. And in the bone
9:27trial, a total testosterone level of 229
9:30correlates with an estradi level of
9:3120.5.
9:34A median total testosterone level of
9:35approximately 500 correlates with a
9:37median estradile level in the mid to
9:39low30s. As you can see, this is the
9:42median total testosterone levels in the
9:43low 500s. And here is the median estradi
9:45level in the low to mid30s. Again, even
9:49though we're specifically looking at
9:50testosterone and estradiol levels, it's
9:52still important to mention the study of
9:54results as it relates to estradiol.
9:56Increases in sexual desire with
9:57increasing estradi were the largest with
9:59high change in DHT and total
10:01testosterone. The increase in sexual
10:03desire did not seem to increase with
10:04total testosterone and holding changes
10:06in estradile and DHT constant. Estradi
10:09change had the highest variable
10:11importance followed by DHT and total
10:13testosterone. The changes in sexual
10:15desire were most robustly associated
10:16with estradiol, consistent with studies
10:18of men with congenital deficiency of the
10:20aromatase enzyme and randomized trials
10:22in which administration of aromatase
10:24inhibitors suppressed sexual desire even
10:26in the presence of normal testosterone
10:28levels. The higher the level of
10:30estradiol, the better. Now look at data
10:33from the traverse trial and compare
10:35testosterone to estradiol levels. The
10:38traverse trial reported values in two
10:40ways. overall which is the top half here
10:43includes all randomized patients who
10:45received at least one dose even if they
10:47later stopped taking testosterone. The
10:50on treatment the bottom values here
10:52includes only values while patients were
10:54actively taking the study drug and
10:56excludes post discontinuation labs. Now
10:58let's compare testosterone and estradile
11:00levels at baseline month 12 and month 36
11:03since that's where we have measurements
11:05of both testosterone and estradiol.
11:07baseline average testosterone levels of
11:09220 correlates with a baseline estradile
11:12level of 21. At month 12, 440 correlates
11:16with a estradile level of 31. At month
11:1936, a level of 428 correlates with an
11:22estradile level of 31 as well. On
11:24treatment results, average testosterone
11:26levels of 220 correlates with an
11:28estradile level of 21. Average
11:31testosterone levels of 441
11:33correlate with estradi levels of 31. And
11:36then average testosterone levels of 432
11:39correlate with estradile levels of 32.
11:42Looking at the testosterone and
11:43estradile levels in the sexual function
11:45study from the traverse trial,
11:48we can compare testosterone levels at
11:50months 12 and 36. These are the baseline
11:53characteristics of the participants and
11:55total testosterone levels of 220
11:58correlated with an estradile level of
12:0021. The sexual function study the
12:02baseline levels were 220 for
12:04testosterone and 20.9 for estradiol and
12:08these are the on treatment levels. At
12:10month 12 the average testosterone level
12:12was 477
12:14which correlated with an estradi level
12:16of 32.6. A total testosterone level of
12:19406 correlated with an estradile level
12:22of 29.2. We have now been able to
12:25compare baseline testosterone and
12:26estradile levels in men not on
12:28testosterone as well as compare on
12:30treatment levels of testosterone and
12:31estradi when testosterone was raised to
12:33the mid-normal range. And here is what
12:35we find. The normal estradile range of 8
12:38to 35 does not apply to all of the
12:40achievable levels of testosterone while
12:42on testosterone therapy. It represents
12:45the normal estradile levels for men with
12:47average total testosterone levels less
12:49than 600 nanogs per deciliter. It does
12:52not apply to men with total testosterone
12:53levels greater than 600 NOGS per
12:56deciliter. The normal estradile range of
12:588 to 35 is based on men not on
13:00testosterone with levels less than 600
13:02NOGS per deciliter. It should not be
13:04applied to men on testosterone therapy
13:06with levels greater than 600.
13:09Using population-based data and
13:11randomized trials in which testosterone
13:13was increased to the bidn normal range,
13:15we can apply the normal estradile range
13:17from labcore to average testosterone
13:19levels above or below 600 nanogs per
13:21deciliter. If a testosterone level is
13:24less than 600 and estradiol is less than
13:268, low E2. Testosterone level less than
13:29600, estradile 8 to 35, normal E2.
13:33Testosterone level less than 600, E2
13:35greater than 35, high E2. Testosterone
13:38greater than 600, E2 less than 35, low
13:42E2 and testosterone level greater than
13:44600, E2 greater than 35, what is normal
13:47E2? What is considered a high E2 with a
13:50testosterone level greater than 600? As
13:52we continue to look at clinical data and
13:54human physiology, the essential
13:56questions become, is applying a fixed
13:58estradiol reference range clinically
14:00meaningful across different testosterone
14:02concentrations? What if anything
14:04constitutes high estradiol when serum
14:06testosterone exceeds 600 NOGS per
14:08deciliter? The answers to those
14:10questions will become much more clear by
14:12the end of this lecture.
14:15Testosterone therapy and estradiol DHT.
14:20Let's briefly review testosterone
14:22physiology and the conversion of
14:24testosterone into its active metabolites
14:26DHT and estradiol.
14:29Whether testosterone is produced
14:30endogenously or taken exogenously, it
14:33travels down three pathways. The direct
14:35pathway where testosterone acts directly
14:38on muscle. The amplification pathway
14:40where it is converted into DHT and
14:42tissues such as the prostate and skin.
14:45And then the diversification pathway
14:47where it is converted into estradile and
14:49tissues such as the brain, bone, and
14:51vascular endothelium.
14:53In this review, Dr. Mavis Jarvis
14:56highlights the physiologic importance of
14:58both testosterone and estradiol in men
15:00and women. He proposes and I agree that
15:03testosterone is best understood as three
15:05hormones in one. Testosterone,
15:07dihydrotestosterone and estradiol.
15:10Together these hormones act
15:12synergistically to produce the full
15:13range of testosterone's biologic effects
15:15in men. In fact, a substantial portion
15:18of these benefits are mediated through
15:19testosterone's active metabolite
15:21estradiol.
15:23He writes in males te's conversion to E2
15:27is fundamental to bone and vascular
15:28health as well as prevention of excess
15:31visceral atyposity and the promotion of
15:33insulin sensitivity via activation of
15:35the estrogen receptors. Optimizing
15:38levels of both hormones may be
15:39beneficial to protect patients from
15:40cardioabolic disease and frailty during
15:43aging. Endogenous tea promotes
15:45cardiovascular health in males via
15:47conversion to E2. Anecdotally, male
15:51patients on TRT often acquire about
15:53their E2 levels due to fear of too much
15:55female hormone. Men's health clinics
15:57even prescribe aromatase inhibitors to
15:59suppress E2 production while raising tea
16:02concentrations. However, we discussed
16:05the essential role of te's conversion to
16:07E2 in male bone and vascular health as
16:09well as glucose and lipid homeostasis,
16:12not to mention libido and erectile
16:13function. Thus, it is our view that E2
16:16should not be suppressed in men and in
16:17fact clinical trials of E2
16:19supplementation should be considered in
16:21some men on TRT to decrease LDL
16:23cholesterol and improve endothelial
16:26function. Finally, current laboratory
16:28measurements of serum T and E2 levels
16:30total or free poorly reflect tissue and
16:33cellular T and E2 concentrations,
16:36catabolism and elimination.
16:39the effects of injected testosterone
16:41dose and age on the conversion of
16:43testosterone to estradiol and
16:45dihydrotestosterone in young and older
16:47men. We're now going to look at what
16:49occurs with estradile and DHT when
16:52testosterone is raised into the upper
16:53physiologic and supra physiologic
16:55ranges.
16:57The objective of this study was to
16:58evaluate age and dose related
17:00differences in estradile and DHT levels
17:02in response to graded doses of
17:04testosterone in young and older men. 51
17:07young and older men were randomly
17:09assigned to receive weekly doses of
17:11testosterone at 25,50,
17:14125, 300, or 600 milligrams for 5
17:16months. During testosterone
17:18administration, estradiol and DHT levels
17:21exhibit saturable increases with dose.
17:24Mechanistic modeling of free hormone
17:25data revealed that the conversion of
17:27testosterone to estradile and DHT were
17:29both consistent with saturable Michaelis
17:32Mitten kinetics. Let's review Michaelis
17:35Mitten kinetics.
17:37In biochemistry, Michaelis mitten
17:39kinetics is the simplest case of enzyme
17:41kinetics applied to enzyme catalyzed
17:43reactions of one substrate and one
17:45product. Aromatase the enzyme,
17:47testosterone is a substrate and
17:49estradiol is the product. Vmax is the
17:52maximum reaction rate or velocity of an
17:54enzyatically catalyzed reaction when the
17:56enzyme is saturated with substrate
17:59represented by this graph. Substrate is
18:02testosterone concentration and the
18:04y-axis represents estradiol levels. At
18:07low substrate concentration or low
18:09testosterone levels, the conversion into
18:12estradiol is linear. As we increase
18:14testosterone levels, we ultimately run
18:15out of aromatase enzyme and estradiol
18:18cannot be increased any further and that
18:20is represented by the vmax.
18:23Once again, the x-axis is testosterone
18:26and the y-axis is estradiol.
18:28Testosterone is represented by the red
18:29dots and the aromatase enzyme is
18:31represented by the yellow half circles.
18:33Ultimately with increasing testosterone
18:36levels, we run out of aromatase enzyme
18:38represented by this picture.
18:40What the study found was that total and
18:42free E2 levels increase dose dependently
18:45in both young and older men. Total and
18:48free E2 levels and E2 to testosterone
18:50ratios during tea administration were
18:52higher in older than younger men. DHT
18:56testosterone ratios were dose related
18:59but did not differ between young and
19:01older men. In this study, they used the
19:04combined baseline and on treatment data
19:07for each treatment group and developed a
19:09mathematical model describing how rising
19:11testosterone levels translate into
19:13corresponding changes in estradile and
19:15DHT. Using these mathematical models,
19:18spreadsheets can be utilized to
19:20illustrate the estradile and DHT changes
19:22with increasing levels of testosterone.
19:24Now understand this is a mathematical
19:26model in an effort to predict levels.
19:28They did not actually achieve all of the
19:30achievable levels of testosterone and
19:31measure estradile directly. These models
19:34should not be interpreted as universal
19:35normal ranges or targets that can be
19:37applied to all men, but instead viewed
19:39as a model based predictions for this
19:41specific study population under these
19:43study conditions.
19:45Using the predicted DHT equation for
19:47young men in this study, we can estimate
19:49levels of DHT with increasing levels of
19:51testosterone. So, as you can see, as we
19:54increase testosterone, DHT levels will
19:57increase and the testosterone DHT ratio
20:00will increase with increasing levels of
20:01testosterone as well. The same occurs in
20:05older men. The conversion of
20:07testosterone to DHT, whether it be young
20:09or older men, slows down as the five
20:12alpha reductase enzyme availability
20:13decreases. For instance, when we go from
20:16a testosterone level of 100 to 1,000,
20:19there is an increase of DHT of 68.6. 7
20:23nanogs per deciliter. But when we go
20:25from,00
20:26to 2,00 there is only an increase of
20:2937.8 nanogs per deciliter.
20:33Using the predicted estradile equations
20:35for young men in this study, we can
20:36estimate the estradile levels with
20:38increasing levels of testosterone. And
20:39these are the predicted values for the
20:41younger men in this study. And this is
20:44the same applied for older men. In both
20:47young and older men with increasing
20:49levels of testosterone, the testosterone
20:51to estradile ratio increases as
20:53aromatase enzyme availability decreases.
20:56For instance, once again going from 100
20:59to 1,000 level of testosterone, there's
21:02an increase in estradile of 47.2 pogs
21:05per milliliter. Going from,00 to 2,000,
21:08there is only an increase of 20.5 pogs
21:11per milliliter. The conversion of
21:13testosterone estradile slows down
21:15secondary to less aromatase enzyme
21:17availability based on Michaelis mitten
21:19kinetics and also with increasing levels
21:21of testosterone the testosterone to
21:23estradile ratio increases in everyone
21:26based on enzyme kinetics.
21:29When you look at the total E2 versus
21:32testosterone curves in older men
21:34represented here, they have curves that
21:36are approximately 30 to 40% higher than
21:38in young men consistent with a higher
21:40maximum rate of whole body
21:42aromatization.
21:43And this is what occurs with aging.
21:45There is a decrease in lean muscle mass
21:47and an increase in fat mass. This is
21:49what contributes to insulin resistance
21:50as we age. Approximately 70% of your
21:53insulin sensitivity is related to your
21:55lean muscle mass. As we age, what we are
21:57trying to accomplish with nutrition and
21:59exercise and hormone optimization is the
22:01prevention or reversal of insulin
22:03resistance by maintaining our lean
22:05muscle mass and lowering fat mass. And
22:07as you have learned, testosterone helps
22:10us do that in a dose response manner. In
22:13other words, better the levels, better
22:15the benefits.
22:17This is a very simplified graph of
22:19Michaelis Mitten kinetics for the
22:20conversion of testosterone into
22:21estradiol. We can raise testosterone
22:24levels in a linear fashion with
22:25increasing doses, but estradile
22:27ultimately plateaus because aromatase
22:29enzyme capacity is finite and saturable.
22:33Testosterone to estradiol ratio. There
22:36is no randomized control trial defined
22:39ideal testosterone to estradiol ratio.
22:42The concept of an ideal serum
22:44testosterone to estile ratio remains
22:46unsupported by randomized control data
22:48and oversimplifies complex endocrine
22:51physiology. Every major testosterone
22:53therapy trial allowed normal
22:55aromatization and benefits were achieved
22:57without targeting a specific
22:58testosterone to estradiol ratio.
23:01Different tissues require different
23:02androgen estrogen balance. Different
23:05tissues vary in their dependence on
23:06androgen and estrogen signaling.
23:08Therefore, no single circulating ratio
23:11can be expected to optimize function
23:12across all tissues. Even if we could
23:14find an ideal ratio for one system, it
23:17may not be ideal for another. Serum
23:19estradiol levels do not reflect tissue
23:21estradiol. Circulating estradiol does
23:24not reflect intricine and paracin
23:26conversion of testosterone to estradile
23:28within target tissues where local
23:30aromatase activity mediates critical
23:32biological effects. Suppressing
23:34aromatase to achieve a ratio disrupts
23:36local estrogen signaling that labs
23:38cannot measure. The endocrine system is
23:40not a ratio problem. It is a threshold
23:43dependent tissue specific locally
23:45regulated system. Ratio obsession
23:48oversimplifies complex endocrine
23:50regulation.
23:52Should reference ranges for estradiol be
23:54determined for healthy men receiving
23:56testosterone therapy stratified by age
23:58and testosterone levels which would
24:00provide testosterone level specific
24:02reference ranges for serum estradiol.
24:04This could certainly be accomplished but
24:06it has significant limitations.
24:08Interpretation of serum estradile in men
24:10requires recognition of its limitations
24:12as an endocrine biioarker. Circulating
24:15concentrations do not measure local
24:17aromatization, receptor saturation, or
24:19tissue specific threshold status.
24:22Circulating levels provide only indirect
24:24insight into biologic activity.
24:26Consequently, serum estradile serves as
24:29an imperfect surrogate for biologically
24:31relevant tissue estrogen signaling. In
24:33addition, no different than
24:34testosterone, it is the free fraction
24:36that is biologically active, which is
24:38very rarely measured.
24:41Dr. Chung writes in his paper estradiol
24:43for the mitigation of adverse effects of
24:45androgen vestruation therapy in
24:47comparing blood levels of E2 and
24:49testosterone with biological effects. It
24:51is important to recognize that E2 is
24:53produced locally from aromatase and
24:54target tissues and acts in a paracin
24:57fashion in healthy men and in studies of
24:59medically castrated men undergoing
25:01graded testosterone adback. Serum levels
25:04of E2 reflect the total E2 that is
25:06diffused into the blood from all tissues
25:08having been synthesized by aromatase and
25:10escaped local tissue metabolism. These
25:13blood levels, no matter how accurately
25:15measured, are an indirect reflection of
25:16total estrogen signaling. We are
25:19measuring the overflow of a locally
25:21produced hormone and assuming it
25:23reflects intracellular receptor
25:24signaling. That assumption is
25:26biologically unsound. When testosterone
25:29increases, more substrate is available.
25:31Aromatase converts a fraction into
25:33estradiol. Some of that estradiol
25:35diffuses into the circulation.
25:38These are the different hormone
25:39signaling types. Endocrine signaling is
25:41when the hormone travels through the
25:43bloodstream to reach target tissues.
25:46Autocrine signaling is when a hormone is
25:48released by the cell and acts back on
25:50the cell surface. Paracrine is when it
25:53is released by a cell and acts on nearby
25:56cells. And then inrine is where it is
25:59produced inside the cell and m and stays
26:02inside the cell. It is of fundamental
26:05importance to understand the differences
26:07between testosterone and estradiol
26:09signaling in men. Testosterone functions
26:11primarily as a circulating endocrine
26:13hormone delivered through the
26:15bloodstream to target tissues. In
26:17contrast, most estradile action in men
26:19especially in the brain, bone, atapost
26:22tissue and vascular endothelium is
26:24inrine.
26:26Entroine signaling target cells such as
26:28a brain, bone, vascular endothelial.
26:31Testosterone enters the cell. Aromatase
26:34enzyme converts testosterone to
26:35estradile locally. Estradi binds to the
26:38estradile alpha and beta receptors
26:40inside the nucleus. Gene transcription
26:42occurs. There's no secretion, no
26:45circulation, no serum reflection.
26:48Introine signaling is intracellular
26:50hormone action without secretion. And
26:52that is why serum estradile cannot fully
26:54represent tissue estrogen activity in
26:56men. Tissue estradiol exposure is
26:58largely determined by local aromatase
27:00activity and testosterone availability.
27:03Not serum estradiol.
27:06Serum estradiol does not reflect tissue
27:09estrogen signaling. Since most estrogen
27:11action in men is inrine and paragrin not
27:14endocrine, serum levels do not
27:16accurately reflect tissue levels. Serum
27:18E2 is a crude proxy for tissue levels.
27:22Testosterone is delivered. Estradiol is
27:24manufactured locally in tissues such as
27:26the brain, bones, atapost tissue, and
27:28vascular endothelium. Testosterone
27:31circulates in the bloodstream and acts
27:32directly on tissue. Estradylamin,
27:35however, is largely made locally inside
27:37tissues from testosterone. Endocrine
27:39estradiol is a minority component of
27:41total estrogen signaling from the testes
27:44and systemic spillover from peripheral
27:46aromatization.
27:47Tissues that utilize indicestile include
27:50the hypothalamus and pituitary for
27:51negative feedback and the liver for
27:53lipoprotein modulation. If we ranked
27:56signaling by dominance in men, indroin
27:58would be the primary driver, paracrine
28:01significant contributor and endocrine
28:03measurable but not dominant. Many
28:05tissues particularly the brain estradile
28:08is synthesized in sight to and functions
28:09within micro domains. These tissues are
28:12not dependent on circulating estradiol
28:14delivery. These tissues feed themselves
28:18and are not fed by serum eststerol.
28:20Lowering serum dial with an aromatase
28:23inhibitor also suppresses local tissue
28:25aromatization thereby reducing the
28:27generation of a hormone that is critical
28:29for normal tissue specific function and
28:32potentially predisposing to tissue
28:34specific failure.
28:36These are the testosterone and estradile
28:38dose response curves. Testosterone in
28:41muscle behaves more linearly following a
28:44graded dose response pattern. As
28:46testosterone rises, androgen receptor
28:48activation increases, lean mass
28:50increases in a graded fashion, strength
28:53improves proportionately, and fat mass
28:55decreases proportionally. Think of
28:57testosterone like a dimmer switch. More
28:59testosterone, more receptor activation,
29:02more anabolic effect. Less testosterone,
29:05less activation.
29:06Estradiolle behaves in a threshold
29:08dependent nonlinear fashion as
29:10represented by the orange curve.
29:13Estradle does not behave like a dimmer
29:15switch. Instead, it behaves like a
29:18minimum requirement system. Below a
29:20certain threshold, tissues fail. Above
29:22that threshold, additional benefit
29:24plateaus. Excess suppression results in
29:26rapid dysfunction. This creates a
29:28threshold curve, not a straight line.
29:31Think of estraol like oil in an engine.
29:34Too little results in damage enough the
29:36system runs normally. More oil does not
29:38improve engine performance. Each tissue,
29:41brain, bone, vascular endothelium,
29:43atapost tissue, libido, sexual function,
29:46etc. has a different estradiol failure
29:49threshold.
29:51Each tissue has a different estradiol
29:53threshold, receptor profile, and time
29:55course of injury. A normal serum E2 does
29:58not guarantee adequate tissue estrogen.
30:01Estradi deficiency manifests by tissue,
30:03not by a single serum number.
30:06Suppressing estradi below physiologic
30:08minimum causes tissue specific failure.
30:11Serum E2 is a crude proxy, not a target
30:13to be aimed for. When we suppress
30:15estradi to normal, we often push tissues
30:18below their survival threshold.
30:21All hormone systems have three zones.
30:23Deficiency zone below the threshold,
30:25physiologic operating zone, and
30:27saturation plateau zone. Estradi
30:30signaling plateaus because receptor
30:32number is finite, co-activator proteins
30:35are finite, downstream transcription
30:37saturates, and neural circuits have
30:39sealant effects. It's important to
30:41mention that testosterone does not
30:43behave the same way in every tissue. In
30:45muscle, it acts through direct androgen
30:47receptor binding and unlike enzyme
30:49limited systems, a clear saturation
30:51point has not yet been established
30:53within studied ranges. Androen receptor
30:55expression also increases as androgen
30:57levels rise. This suggests that
30:59testosterone has one dose response curve
31:01in muscle and a different one in other
31:02tissues such as the brain. We will
31:04explore those tissue specific
31:06testosterone curves in more detail later
31:08in the presentation.
31:10Both aromatase activity and estrogen
31:12receptor signaling are saturable.
31:14Accordingly, rising testosterone does
31:17not generate unlimited linear increases
31:19in estradiol and rising estradiol does
31:21not produce unlimited linear increases
31:23in estrogen signaling. Concerns about
31:26estradiol rising uncontrollably are not
31:28supported by enzyme or receptor
31:30kinetics. But what about the concerns
31:32that rising serum estradiol is going to
31:34add on top of the estradile produced in
31:36the tissues?
31:37The assertion by those who believe
31:39rising serum estradile linearly adds to
31:41intracellular estradiol to produce
31:43cumulative estrogenic effects is
31:45inconsistent with receptor phicodnamics
31:47and intric physiology. Estrogen receptor
31:50signaling is saturable, tissue specific
31:52and threshold dependent. The additive
31:55stacking model is biologically
31:56simplistic and inconsistent with
31:58observed physiology. Estrogen signaling
32:00in men follows threshold biology,
32:02saturation kinetics, tissue
32:04compartmentalization, and receptor
32:06limited signaling. It does not follow
32:08linear stacking arithmetic.
32:11I will inevitably be asked if estradiol
32:14in men is primarily intro and paracrine.
32:16Why does increasing circulating estradi
32:18with exogenous therapy in men with low
32:20E2 still produce clinical benefit?
32:23Introine dominance does not mean
32:25systemic estradile is irrevalent.
32:28Introine estradile requires adequate
32:29testosterone and adequate aromatase
32:32expression. If either is limited, local
32:35production fails and tissue deficiency
32:37occurs. When estradile is low, adding
32:39systemic estradile restores threshold.
32:41When estradile is already sufficient,
32:44additional estradile does not produce
32:45proportional new effects as the
32:47signaling plateaus. Oral estradile moves
32:50someone from deficiency to sufficiency.
32:52It does not convert sufficiency to
32:54toxicity in a linear fashion. In men
32:57with profound estrogen dial deficiency,
33:00including some undergoing androgen
33:02deprivation therapy, raising circulating
33:04estradiol can improve symptoms related
33:06to estrogen loss. Now, this may appear
33:08inconsistent with the concept that
33:10estradile signaling in men is
33:11predominantly intricine and paragrin,
33:13but the two are not mutually exclusive.
33:16Entric physiology describes the dominant
33:18mechanism of local estrogen generation
33:20under normal circumstances. It does not
33:22imply that circulating estradiol lacks
33:24biologic revolence. Rather, systemic
33:26estradiol can still diffuse into
33:28tissues, contribute to receptor
33:30occupancy, and restore function when
33:32local and circulating estradile
33:33availability fall below tissue specific
33:35thresholds. Think of intricate estradile
33:38production in men as the electricity
33:40generated and used inside a house while
33:42circulating endocrine estradile is more
33:44like a backup generator that helps
33:46support the system when local supply is
33:48inadequate.
33:50Intricine dominance does not preclude
33:52responsiveness to circulating estradiol.
33:55Estradi freely diffuses across membranes
33:57and participates in concentration
33:59dependent equilibrium between plasma and
34:01tissue compartments. In states of
34:03deficiency, raising systemic estradile
34:05restores receptor occupancy and tissue
34:07level signaling. This reflects threshold
34:10correction rather than additive
34:11amplification beyond physiological
34:13sufficiency. Entricine biology explains
34:16baseline physiology. Systemic estradile
34:19explains therapeutic rescue.
34:23Individual factors affecting estradiol
34:25levels. The rates of conversion of
34:28testosterone to DHT and estradiol vary
34:31among men due to polymorphisms of genes
34:33that encode the steroid 5 alpha
34:34reductase and the aromatase enzyme as
34:37well as other host specific factors that
34:39affect the activity of these enzymes.
34:41Dr. Stevens Shields, Journal of Clinical
34:43Endocrinology and Metabolism, 2022.
34:47In this study by Ericson, genetic
34:49variations in sex steroid related genes
34:51as predictors of serum estrogen levels
34:53in men, the investigators wanted to
34:55determine whether common genetic
34:57variance in sex steroid related genes
34:59predict serum estradile and testosterone
35:00levels in men. The study showed that men
35:02with a common aromatase polymorphism
35:05RS2470152
35:08had approximately 11% higher estradiol
35:11levels than those without the
35:12polymorphism.
35:14Let's look at the factors affecting
35:16Vmax. Vmax value is influenced by three
35:19main factors namely enzyme
35:21concentration, temperature, and pH.
35:24Enzyme concentration. Vmax depends on
35:26the amount of enzyme present. And the
35:28higher the amount of enzyme, the higher
35:30the Vmax of it. If we increase fat mass,
35:33we increase aromatase and we increase
35:35V-max. If we decrease fat mass, we
35:37decrease aromatase and we'll decrease
35:39Vmax.
35:41Let's review the Finkelstein study.
35:43Gonatal steroids and body composition,
35:45strength, and sexual function in men. In
35:48this study, they sought to determine the
35:49relative degree of testosterone
35:51deficiency, estradile deficiency, or
35:53both at which undesirable changes in
35:55body composition, strength, and sexual
35:57function begin to occur and whether
35:59those changes are due to androgen
36:00deficiency, estrogen deficiency, or
36:03both. It involved 400 healthy men 20 to
36:0650 years of age with indogenous
36:08testosterone and estradiol suppressed.
36:11198 men received either placebo or 1.25,
36:152.5, 5, or 10 grams of testosterone gel
36:18daily for 16 weeks. 202 men received
36:22placebo gel or testosterone gel and 1
36:24milligram of anastraol daily. Changes in
36:27the percentage of body fat and in lean
36:29mass were the primary outcomes.
36:30Subcutaneous and intraabdominal fat
36:32areas, thigh muscle area and strength,
36:34and sexual function were also assessed.
36:36I've heard critics argue that 1
36:38milligram of anastradol daily is
36:40clinically excessive, but this critique
36:42overlooks the study's design. The
36:45objective was not to evaluate the
36:46therapeutic safety of aromatase
36:48inhibitors, but to isolate the
36:49physiological roles of androgens and
36:51estrogens. By using a highdosese
36:54aromatase inhibitor to fully suppress
36:56the conversion of testosterone to
36:57estradiol, researchers could clearly
36:59observe the distinct effects of each
37:01hormone, a clarity that a lower partial
37:03dose would have not provided.
37:06In fact, they explain this very clearly
37:08in the study. Because estradiol is a
37:10metabolite of testosterone, it is
37:12difficult to distinguish the effects of
37:14androgens from those of estrogens in
37:16observational studies or even in
37:17randomized control trials if
37:19aromatizable androgens are used without
37:21the administration of an aromatase
37:22inhibitor. Aromatase inhibitor trials
37:24don't test testosterone. They test
37:27androgen signaling in isolation.
37:30Let's look at the mean absolute change
37:32from baseline is sexual desire and
37:33erectile function according to
37:35testosterone dose and cohort. They
37:37reported that aromatase inhibition was
37:39associated with significant decreases in
37:41sexual desire and erectile function.
37:43Both androgens and estrogens contributed
37:45to the maintenance of normal libido and
37:47erectile function.
37:49Looking at the mean percent change from
37:51baseline and percentage of body fat,
37:53lean body mass, subcutaneous and
37:55intraabdominal fat area, thigh muscle
37:57area, and leg press strength according
37:59to testosterone dose and cohort. In the
38:02groups that received testosterone,
38:03inhibition of estrogen synthesis, cohort
38:05two in red, as compared with intact
38:08estrogen synthesis, cohort one in blue,
38:10was associated with significant
38:11increases in the percentage of body fat,
38:14subcutaneous fat area, and
38:15intraabdominal fat area, and with
38:17significant decreases in sexual desire
38:19and erectile function. These findings
38:21provide additional evidence of an
38:22independent effect of estradiol on these
38:24measures. Because increases in visceral
38:26fat reduce insulin sensitivity and are
38:28associated with diabetes in the
38:30metabolic syndrome, the market increase
38:32in intraabdominal fat with aromatase
38:34inhibition could pertain to an increase
38:36in cardiovascular disease with long-term
38:38estrogen deficiency. This is another
38:40mechanism to increase V-max. Aromatase
38:43inhibitors increase visceral body fat
38:45which increases the amount of the
38:46aromatase enzyme.
38:49Conclusions of the Finkelstein study.
38:51The amount of testosterone required to
38:53maintain lean mass, fat mass, strength,
38:55and sexual function varied widely in
38:57men. Androgen deficiency accounted for
38:59decreases in lean mass, muscle size, and
39:02strength. Estrogen deficiency primarily
39:04accounted for increases in body fat.
39:05Both contributed to the decline in
39:07sexual function.
39:10This is a video that came across my
39:11YouTube feed. Estrogen management trends
39:14in men, and it was done by a young lady
39:16by the name of DJ Madson. Now, in this
39:18video, they discussed testosterone to
39:20estradile ratios as though they are
39:22clinically important, emphasized
39:24measuring serum estradiol and keeping it
39:26within a specific range, and raised
39:28concerns that estradile may continue to
39:30rise uncontrollably. Yet, none of those
39:33claims are supported by randomized data,
39:35physiology, enzyme kinetics, or receptor
39:38biology. Both aromatase activity and
39:40estrogen receptor signaling are
39:42saturable, meaning that estradiol
39:44production is not unlimited. And once
39:46estrogen receptors are saturated,
39:48additional estradile cannot produce
39:50progressively greater effects. She also
39:52made a statement about her husband who
39:54is also a bodybuilder. Take someone like
39:56my husband for example who is very lean
39:58at all times and he aromatizes at the
40:00drop of a hat. Now we just reviewed the
40:02Finkelstein studies which showed a
40:04market increase in intraabdominal fat
40:06with aromatase inhibition. And now you
40:08know the reason why her husband
40:10aromatizes at the drop of a hat. It's
40:12because the more he takes the aromatase
40:14inhibitor, the more visceral fat he
40:16develops and the more he aromatizes when
40:18he doesn't take it. He is creating the
40:20very problem he is trying to avoid. The
40:23practice of using aromatase inhibitors
40:24to control estradile in men on
40:26testosterone therapy did not originate
40:28in evidence-based medicine. It
40:30originated in the bodybuilding
40:31community. The aromatase inhibition is
40:33one of the major factors in their
40:35development of premature cardiovascular
40:36disease. Many of the problems men
40:38encounter on testosterone therapy arise
40:41from advice and practices borrowed from
40:43the bodybuilding community. Although
40:44both involve testosterone, they are
40:46fundamentally different. Testosterone
40:48therapy is evidence-based medical care
40:50aimed at restoring health and normal
40:51physiology, while the bodybuilding
40:53culture accepts drug abuse and health
40:55trade-offs in pursuit of performance and
40:58muscle mass. Advice from a
41:00performance-enhancement drug culture has
41:02no place guiding legitimate testosterone
41:04therapy.
41:07Testosterone therapy in older men with a
41:10focus on estradiol management.
41:12Age related testosterone deficiency
41:14merits treatment. Let's review the
41:16evidence on testosterone therapy in
41:18older men from Dr. Tracia's
41:19comprehensive summary. We will review
41:21the benefits and we'll also focus on how
41:23estrogen was measured, managed, or
41:26accounted for in the referenced clinical
41:28studies.
41:29Here's a list of the studies on benefits
41:31of testosterone therapy in older men.
41:35This paper consisted of 55 randomized
41:38control trials, eight observational
41:40studies, two prospective studies, and
41:42one alternate case control trial. I will
41:45now summarize the beneficial effects of
41:46testosterone therapy in all of these
41:49studies.
41:50With regard to sexual function, there
41:52was increased sexual desire libido,
41:55improved sexual activity, improved
41:57erectile function, increased spontaneous
41:59erections, improved sexual motivation
42:01and performance, improvement in sexual
42:04dysfunction scores
42:06on mood, well-being and quality of life.
42:08There was improved mood, reduction in
42:10depressive symptoms, improvement in
42:12aging male symptom scale, improved
42:14health related quality of life, improved
42:16psychological well-being.
42:18on body composition. There was increased
42:21lean body mass, decreased fat mass
42:23including visceral fat, decreased waist
42:25circumference, improved muscle mass
42:27distribution, improved trunk and core
42:30muscle mass. With regard to strength and
42:33physical performance, there was
42:35increased muscle strength, improved leg
42:37power, improved stair climbing power,
42:39improved walking ability, modest
42:41improvement in six-minute walk distance,
42:44attenuation of age- related decline in
42:45V2 max, improved physical performance
42:48and mobility.
42:50On bone health, there was increased bone
42:52mineral density, improved tbecular bone
42:55architecture, reduced bone resorption
42:57markers, and there was prevention of
42:58bone loss in the femeral neck.
43:01Hematologic effects, increased
43:03hemoglobin, correction of unexplained
43:05anemia and correction of anemia of known
43:08causes.
43:09Metabolic effects there was reduced body
43:11weight, reduced BMI, reduced waist
43:14circumference, improved insulin
43:16sensitivity, improved glycemic control,
43:19reduced insulin resistance, improvement
43:21in metabolic syndrome components,
43:23sustained weight loss in obese
43:24hypoganatommen.
43:27Let's look at estrogen management in all
43:29of these studies.
43:32All benefits in sexual function, mood,
43:35well-being, quality of life, body
43:37composition, strength and physical
43:38performance, bone health, hematologic
43:41effects, and metabolic effects occurred
43:43with intact physiologic aromatization.
43:46No study utilized an aromatase inhibitor
43:49yet benefits occurred. If the evidence
43:51shows benefit without estradile
43:52suppression, then suppressing estradile
43:54represents a deviation from the
43:56evidence, not an extension of it.
43:58suppressing estradile abandons the
44:00evidence. You cannot claim
44:01evidence-based practice while modifying
44:03the very physiology under which the
44:05evidence was generated.
44:07The efficacy data supporting
44:09testosterone therapy reflect intact
44:11testosterone estradiol coupling. Those
44:14advocating routine estradiol suppression
44:16therefore represent a departure from the
44:18physiological conditions under which
44:19benefit was established and require
44:21independent randomized evidence
44:23demonstrating preserved or superior
44:25clinical outcomes under estradile
44:27suppression. Presently there is zero
44:30randomized evidence that suppressing
44:31estradile improves these outcomes.
44:35If you alter the physiology under which
44:37benefit was proven, the obligation to
44:39prove benefit is yours. Those advocating
44:42estradile suppression or control carry
44:44the burden of proof not the clinicians
44:46preserving normal physiology. The burden
44:49of proof is not on physiologic
44:51replacement. It is on those proposing to
44:53disrupt it.
44:56Testosterone therapy in overweight or
44:58obese men with a focus on estradiol
45:01management. In medicine, repeated
45:03falsehoods can solidify into established
45:06facts and eventually dogma, which are
45:08principles presented by authorities as
45:10incontrovertibly true. A historic case
45:12study is the long-held belief
45:14surrounding testosterone and prostate
45:15cancer. For over 50 years, the medical
45:18community accepted that testosterone
45:19caused prostate cancer and that raising
45:22testosterone levels in a man with
45:23prostate cancer would accelerate tumor
45:25growth. Often described metaphorically
45:27as pouring gasoline on a fire. Where did
45:30this fear originate? This belief stemmed
45:32from the over interterpretation of data
45:34from a single patient in a 1941 study.
45:37The prevailing logic was that since
45:38lowering testosterone slows cancer
45:40growth, raising it must have the
45:42opposite effect. However, logical
45:45assumptions do not always align with
45:46physiological reality. It was not until
45:49Harvard urologist Dr. Abraham Morgan
45:51challenged the androgen hypothesis that
45:53this long-standing dogma was overturned,
45:55preventing countless men from being
45:57unnecessarily denied testosterone
45:59therapy. Conventional wisdom for many is
46:02that when an overweight or obese man
46:04starts testosterone that he should
46:06utilize an aromatase inhibitor to keep
46:08him from overromatizing and developing
46:11estrogen symptoms. Is this necessary? Is
46:14this what the literature supports?
46:17These are the categories of obesity.
46:19Overweight is a BMI of 25 to 29.9. Class
46:22one obesity a BMI of 30 to 34.9. Class 2
46:26obesity, a BMI of 35 to 39.9. And then
46:30class 3 obesity is a BMI greater than
46:3240, known as severe obesity, previously
46:35known as morbid obesity.
46:38This review by Dr. Tresh examines the
46:40contemporary data on testosterone
46:42therapy in overweight and obese men,
46:44focusing on changes in lean body mass,
46:46fat mass, body composition, and weight
46:49loss. In addition, we will examine how
46:51estrogen was measured, managed, or
46:53accounted for in the clinical studies.
46:57Table one displays 28 studies in which
46:59testosterone therapy resulted in
47:01increases in lean body mass and
47:03decreases in total fat mass.
47:05Table two summarizes 20 studies
47:08demonstrating that testosterone therapy
47:09significantly reduces body weight, waist
47:12circumference, and BMI.
47:14Based on this review of 48 studies,
47:17testosterone therapy provides
47:18significant benefits for overweight and
47:20obese men that include a decrease in fat
47:23mass, weight, BMI, waist circumference,
47:27insulin resistance, hemoglobin A1C,
47:30fasting glucose, total cholesterol, LDL
47:33cholesterol, triglycerides, C reactive
47:36protein, tumor necrosis factor alpha,
47:39corateed intermediate thickness,
47:41fatigue, liver fat, liver enzyme, enmes
47:44and systolic and diastolic blood
47:46pressure. It ameliorates all metabolic
47:49syndrome components, abdominal obesity,
47:51dysipidemia, elevated fasting glucose
47:54and hypertension. It increases lean body
47:56mass, HDL cholesterol, erectile
47:59function, libido, vigor, energy, and
48:02quality of life. Now, let's review how
48:04estrogen was managed in these 48
48:06studies. Two of these studies utilize an
48:09aromatase inhibitor and one was the
48:10final sign study that we have already
48:12reviewed and the other was by Dang at
48:14all. The aim of this randomized control
48:17trial was to determine if testosterone
48:19administration in young obese men
48:21improved body composition and insulin
48:23sensitivity and if inhibiting metabolism
48:25of testosterone to estradile or DHT
48:28would change these outcomes. It was a
48:30randomized control trial in 57 men aged
48:3221 to 51 with a BMI of greater than 30
48:35for 20 weeks. They received testosterone
48:37gel 10 grams daily. They were divided
48:40into four groups. Placebo, testosterone
48:43only, testosterone plus anastriol and
48:46testosterone plus dutasteride.
48:49Percent fat-free mass significantly
48:51increased and percent fat mass
48:53significantly decreased in the
48:55testosterone with dutasteride group and
48:58the testosterone only group. percent
49:00fat-free mass or percent fat mass did
49:03not significantly change in the placebo
49:05or the testosterone and an estastol
49:07group. Data from this study showed that
49:09inhibiting reduction of administered
49:11testosterone to DHT improved body
49:13composition and insulin sensitivity in
49:15young diabetic obese men while
49:18inhibiting aromatization of administered
49:19testosterone to estradiol or placebo did
49:22not. Our data add to the body of
49:24evidence that estradiol is essential for
49:26decreasing fat and improving insulin
49:28sensitivity in men. In this study,
49:32utilizing aromatase inhibitor attenuated
49:34the beneficial effects of testosterone
49:36on increasing fat-free mass and
49:38decreasing fat mass. Estradile is
49:40required for the metabolic benefit.
49:42Testosterone increased lean mass and
49:44reduced fat mass, but this alone did not
49:47improve insulin sensitivity. Insulin
49:49sensitivity required preserved
49:51estradiol.
49:53Here is a comparison of romatase
49:54inhibitor and five alpha reductase
49:56inhibitor trials. DHT is not required
50:00for testosterone's anabolic effects in
50:02muscle. Estradiol is required to
50:04preserve lean mass, strength, sexual
50:06function, and bone integrity during
50:08testosterone therapy. Estradi is
50:10required to decrease fat mass.
50:13Estradi management in these studies.
50:16Once again on the left are all the
50:18benefits of testosterone therapy in
50:20overweight and obese men from these
50:22studies. All benefits occurred with
50:24unrestricted aromatization.
50:26Attenuation of benefits occurred in the
50:28two AI studies. The metabolic and weight
50:31loss benefits attributed to testosterone
50:32cannot be separated from estrogen
50:34physiology in these studies. We did not
50:37see improvement in body composition
50:38after E2 suppression. The clinical
50:41outcomes from testosterone therapy are
50:43the sum of androgen receptor activation
50:45and estrogen receptor activation. That
50:47is not theory. That is physiology. In
50:50every major randomized trial
50:51demonstrating improvements in lean mass,
50:53bone density, sexual function, and body
50:55composition, aromatization was
50:57preserved, allowing testosterone and
50:59estradile to rise together. When
51:01estradiol was pharmacologically
51:03suppressed, several benefits were
51:05attenuated. This tells us something
51:06critical. Estradile contributes
51:09positively to therapeutic outcomes. So
51:11if someone claims you must control
51:12estradile optimize TRT outcomes in
51:15overweight or obese men, the evidence of
51:17burden is simple. Show randomized
51:19control trials where controlling or
51:21suppressing estradiol improves outcomes
51:24versus physiologic testosterone therapy.
51:27That body of evidence is essentially
51:29absent.
51:30The benefits of testosterone therapy in
51:32obese and overweight men were achieved
51:34without aromatase inhibitors and with
51:36normal aromatization intact. Because
51:39those benefits were obtained under
51:40physiologic testosterone to estradile
51:42conversion, suppressing or controlling
51:44estradile represents a departure from
51:46the conditions under which the evidence
51:48was generated. Anyone advocating routine
51:51estradile suppression or control in
51:52obese or overweight men carries the
51:55burden of proof that altering this
51:56physiology improves outcomes over
51:58testosterone therapy alone. Such outcome
52:01data is currently absent.
52:04Testosterone therapy and overweight and
52:07obese men.
52:09Beyond the cardioabolic and weight loss
52:11benefits of testosterone therapy and
52:13obese men, we must also consider its
52:15impact on sexual health. specifically
52:17how the aromatization of testosterone
52:19into estradiol may cause worsening
52:21sexual function or other symptoms of
52:23estrogen excess. Let's evaluate the
52:26literature specifically looking at the
52:28effects of testosterone on sexual
52:29function or causing sexual dysfunction
52:31in overweight and obese men.
52:35Before we begin evaluating studies, it's
52:37important to understand what the numbers
52:39represent in the aging males symptom
52:41scale as well as in the international
52:43index of erectile function. The aging
52:46male symptom scale is a validated
52:48questionnaire designed to assess
52:49symptoms associated with aging and
52:51specifically testosterone deficiency in
52:53men. The scale includes a series of 17
52:56questions divided into three domains.
52:58Psychological, somatic, and sexual
53:01symptoms. Each symptom is rated on a
53:03scale, one being no symptoms and five
53:06being extremely severe. A score of less
53:09than 26, no symptoms of testosterone
53:11deficiency. A score of 27 to 36 mild
53:15symptoms of testosterone deficiency, 37
53:17to 49 moderate, and a score of greater
53:20than 50 is severe symptoms of
53:22testosterone deficiency. The
53:24international index of erectile function
53:27is a validated questionnaire used to
53:29measure the severity of erectile
53:30dysfunction and monitor improvements
53:32with treatment. The questionnaire
53:35consists of 15 items divided into five
53:37domains. Erectile function questions 1
53:39through 5 and 15 focuses on the ability
53:42to achieve and maintain an erection
53:44suitable for intercourse. Orgasmic
53:46function questions 9 and 10 assesses the
53:50ability to achieve orgasm. Sexual desire
53:53questions 11 and 12 evaluates the level
53:56of sexual interest or libido.
53:58Intercourse satisfaction. Questions 6
54:01through 8 measure satisfaction during
54:03sexual activity. Overall satisfaction
54:06questions 13 and 14 examines the general
54:09satisfaction with sexual relationships.
54:11Responses for each item were scored on a
54:13liyker scale, zero or one being lowest
54:15function and five being the highest
54:17function. The scores for each domain are
54:20summed to give domain specific scores. A
54:22total score helps classify the severity
54:24of erectile dysfunction. A score of 26
54:27to 30 is no erectile dysfunction. 17 to
54:3025 mild ED, 11 to 16 moderate ED, and 6
54:35to 10 severe ED. To summarize, with the
54:39aging males symptom scale, the lower the
54:42number the better, and with the
54:43International Index of Erectile
54:44Function, the higher the number, the
54:46better. Before evaluating overweight and
54:49obese men on testosterone therapy for
54:51presumed symptoms of elevated estradiol,
54:54it is important to first examine a few
54:56of the main studies commonly cited to
54:57justify estradile control in men
54:59receiving testosterone therapy because
55:01of estrogen causing sexual dysfunction.
55:04The first is this paper by Belladelli.
55:06Hyperestrogenism is associated with
55:08sexual function impairment in men.
55:10Findings from a cross-sectional real
55:12life study. This was a retrospective
55:14data analysis on 547 men seeking first
55:18medical help for a new onset erectile
55:19dysfunction at a single andrology
55:21center. They measured circulating
55:24hormones and defined hyperestrogenism as
55:26estradile above 42.6 peak rounds per
55:30milliliter
55:31utilizing data from the tan at all study
55:34in 2015.
55:35Coorbidities were scored with the
55:37Charleston coorbidity index. Sexual
55:40function was assessed with the
55:41international index of erectile function
55:43questionnaire. Before examining the
55:46study in detail, let's take a look at
55:47the TAN study that they used to define
55:50hyperestrogenism and also review the
55:52Charleston coorbidity index.
55:55This is the tan at all study and it was
55:58a retrospective multi-enter medical
56:00chart review in men treated at 35 low T
56:03centers from 2009 to 2014. They measure
56:07testosterone and estradile levels and
56:09reviewed the ICD9 diagnosis codes for
56:11each patient. They reported in our
56:14centers estradile measurement is
56:16outsourced to labcore and high estradile
56:18is defined as equal or above 42.6 pogs
56:22per milliliter. So their definition of
56:24high estradi was based off of the lab
56:26core normal range. They reported our
56:29study did not link high estradi levels
56:32with diminished sexual performance.
56:34Paradoxically,
56:35patients with low estradile below 42.6
56:38picagos per milliliter had more patients
56:40complaining of low libido. Patients with
56:42higher estradile levels above 42.6 had
56:45less sexual dysfunction problems
56:47identified by their providers. Our
56:49finding was that high estradile levels
56:51were not associated with higher rates of
56:52low libido, but established higher rates
56:55of documented low libido with those with
56:56normal or low estradile levels.
56:59Ironically, Belladella used this study
57:02for their definition of
57:03hyperestrogenism.
57:04But yet, this study found higher
57:06estrogen levels were associated with
57:07less sexual dysfunction and better
57:09libido compared to low estrogen levels.
57:11The exact opposite of the Belladelli
57:13study.
57:15The Charleston co-orbidity index is a
57:17widely used validated method to predict
57:1910-year mortality by scoring 19 specific
57:22medical conditions weighted 1 through
57:24six based on risk plus age adjustments.
57:27A score of one would be given for a
57:28condition such as diabetes or chronic
57:30lung disease. A score of two for solid
57:33tumor or diabetes with complications. A
57:35score of three for moderate to severe
57:37liver disease. And a score of six for
57:39metastatic cancer. There was an age
57:41adjustment. Add one point for each
57:43decade over 40 years of age. One point
57:46for those that are 50 to 59 years old,
57:48two for 60 to 69 years old, three for 70
57:51to 79 year olds, and four for 80 to 89
57:55year olds. The higher the score, the
57:57lower the estimated 10-year survival
57:59rate. It is considered the gold standard
58:01for clinical research coorbidity
58:03assessment.
58:05Back to the Belladelli study, they
58:07reported one out of five men seeking
58:10first medical help for erectile
58:11dysfunction showed elevated serum
58:13estradiol levels. Men with
58:15hyperestrogenism were older, had a
58:18higher rate of coorbidities, had higher
58:20serum total testosterone values than
58:22those with normal estradiol values.
58:25Serum estradile levels are positively
58:27correlated with total testosterone
58:28levels but negatively correlated with
58:30international index of erectile function
58:32scores of clinical revolence. Men with
58:36hyperestrogenism had higher rates of
58:38coorbidities greater ED severity and
58:40worse orgasmic function
58:44association
58:45confounding and interpretive bias.
58:48This was an observational
58:50cross-sectional retrospective analysis
58:53which can show association, correlation
58:56and co-occurrence but cannot show
58:58causation. This was a cross-sectional
59:01observational study. So we can identify
59:03associations between hormone levels and
59:05sexual function but it cannot establish
59:08causality or justify a treatment
59:10intervention. This was a baseline
59:12observation in men not on testosterone
59:14therapy.
59:16They reported one out of five men
59:18seeking first medical help for ED showed
59:20elevated estradiol levels suggestive of
59:23hyperestrogenism.
59:24Well, therefore, four out of five men
59:27with ED had normal estradile levels.
59:30This paper does not show that elevated
59:32estradile explains ED in most men. It
59:35shows the opposite. Most men with ED in
59:37this cohort did not have elevated
59:39estradiol. That means elevated estradiol
59:42cannot reasonably be framed as the
59:44explanation for ED in most men in this
59:46cohort. At most, it identifies a subset
59:49of ED patients who had higher estradiol.
59:53Hyperestrogenism was defined as
59:54estradiol greater than 42.6 pogs per
59:57milliliter utilizing the cutoff from tan
1:00:00at all which evaluated elevated estrogen
1:00:02levels in men receiving injectable
1:00:03testosterone therapy and used the lab
1:00:05core upper reference value. That
1:00:07threshold was not derived from this
1:00:09cohort and was not clearly validated as
1:00:11a clinically meaningful cutoff for
1:00:13erectile dysfunction or sexual
1:00:14dysfunction. The definition of
1:00:17hyperestrogenism is statistically
1:00:19convenient but biologically and
1:00:20clinically underjustified
1:00:23residual and unmeasured compounding. The
1:00:27paper did adjust for some factors such
1:00:28as age, BMI, coorbidity index, total
1:00:32testosterone, estradiol levels, smoking,
1:00:35and alcohol. But key erectile
1:00:38dysfunction confounders were missing or
1:00:40only coarsely measured. They did not
1:00:42control for central ataposity. They did
1:00:45not measure waist circumference or
1:00:46visceral fat. There was metabolic data
1:00:49missing such as fasting glucose,
1:00:50hemoglobin A1C, triglycerides, HDL
1:00:53cholesterol, and blood pressure.
1:00:55psychiatric and psychological factors.
1:00:57They did not control for depression,
1:01:00anxiety, stress, relationship issues as
1:01:02those strongly influence IEF scores.
1:01:06They did not control for lifestyle
1:01:07factors such as physical activity, sleep
1:01:09apnnea, and diet were not fully
1:01:11characterized. Medications that impair
1:01:13sexual function such as opioids, SSRIs,
1:01:16beta blockers, five alpha reductase
1:01:18inhibitors, and anti psychotics etc.
1:01:20were not controlled for and they can all
1:01:22independently worsen ED and libido.
1:01:26Other endocrine factors such as
1:01:27prolactin, thyroid, and cortisol were
1:01:29not measured. So with so many unmeasured
1:01:31variables, it's hard to claim that
1:01:33estradile is an independent driver
1:01:35rather than a proxy for a sicker
1:01:37metabolic and comorbid profile.
1:01:41Interpretation versus stata. They
1:01:44reported men with hyperestrogenism were
1:01:47older, had a higher rate of coorbidities
1:01:49and higher serum total testosterone
1:01:51value than those with normal estradi
1:01:54values.
1:01:55This study is a clear example of
1:01:57interpretive bias. The author singled
1:01:59out estradi despite the fact that
1:02:01elevated testosterone traveled with it
1:02:03and the observed association remained
1:02:05heavily confounded. The bias is not
1:02:07hidden in the data. It's revealable what
1:02:09the authors chose to blame. Let's take a
1:02:12closer look.
1:02:14Men with hyperestrogenism were older.
1:02:17Age independently tracks with worse
1:02:19erectile function, more vascular
1:02:21disease, more medication use, and mo
1:02:24more coorbidity.
1:02:25Age can push both sides of the
1:02:27association at once. Worse sexual
1:02:29function and a different hormone
1:02:31profile. Estradile increases with age.
1:02:34Older age may explain both the hormone
1:02:36pattern and the worse sexual outcomes.
1:02:41Men with hyperestrogenism had more
1:02:43coorbidities.
1:02:45Men with high estradiol had a higher
1:02:48rate of coorbidities. 26% of them had a
1:02:51Charleston coorbidity index greater than
1:02:53or equal to one versus 7.4% for the
1:02:56normal estradiol group. That's almost a
1:02:59four times higher prevalence of serious
1:03:01chronic disease in the high estradiol
1:03:03group.
1:03:05These coorbidities and their treatments
1:03:07are independent potent causes of ED and
1:03:09orgasmic dysfunction.
1:03:12Vascular and indotheal damage occurs in
1:03:14conditions like diabetes, hypertension
1:03:17and coronary artery disease. Neuropathy
1:03:20and nerve damage occurs with diabetic
1:03:21neuropathy and poststroke neurologic
1:03:23deficits. Many of these conditions are
1:03:26treated with medications that directly
1:03:27worsen sexual function such as beta
1:03:29blockers, SSRIs, antiscychotics, and
1:03:32opioids. All of which blunt libido,
1:03:35energy, and performance and can worsen
1:03:37both erectile quality and orgasmic
1:03:39intensity.
1:03:40These coorbidities alone could explain
1:03:43the more severe ED and worse orgasmic
1:03:45function in the high estradiol group.
1:03:48Hyperestrogenism was simply a marker of
1:03:51a sicker, more comorbid phenotype, and
1:03:54the coorbidities themselves could fully
1:03:55account for the worst sexual function
1:03:57independent of estradile. They singled
1:04:00out high estradile as the culprit for
1:04:01impaired sexual function when in fact it
1:04:03was nothing more than an innocent
1:04:05bystander.
1:04:07Men with hyperestrogenism had higher
1:04:09serum total testosterone levels.
1:04:13Because testosterone and estradile
1:04:14covaried, the study cannot uniquely
1:04:16assign causality to estradiol.
1:04:19Choosing estradile as the culprit
1:04:21reflects interpretive bias, not proof
1:04:23from the data set. Testosterone was
1:04:26higher, estradile was higher. sexual
1:04:29function was worse but only E2 was
1:04:31blamed. If both testosterone and
1:04:34estradile are higher in the group with
1:04:35worse sexual function, you cannot simply
1:04:37decide that estradile is to blame while
1:04:39ignoring testosterone.
1:04:42Cross-sectional data cannot separate
1:04:44drivers. In a cross-sectional data set,
1:04:47if men with worse ED have both higher E2
1:04:49and higher testosterone, the data do not
1:04:52tell you which hormone, if either, is
1:04:54driving the association.
1:04:56Estradi was singled out by assumption.
1:05:00That is not physiology. That is
1:05:02narrative selection.
1:05:05Men with high E2 were older, had more
1:05:07coorbidities and higher testosterone
1:05:10levels.
1:05:11The title of the paper once again is
1:05:13hyperestrogenism is associated with
1:05:15sexual function impairment in men. By
1:05:18the same logic the authors used for
1:05:20estradiol, someone could have written
1:05:22the paper as older age is associated
1:05:24with sexual function impairment in men
1:05:27or multiple coorbidities are associated
1:05:29with sexual function impairment in men
1:05:31or even better high testosterone is
1:05:34associated with sexual function
1:05:35impairment in men.
1:05:37What the study actually showed in a
1:05:39tertiary ED clinic, men with worse
1:05:41sexual function had higher estradile,
1:05:43higher testosterone, older age, and
1:05:46greater comorbidity burden. Higher
1:05:48estradile traveled with higher
1:05:50testosterone, older age, and more
1:05:52coorbidity. And that whole cluster was
1:05:55associated with worse sexual function.
1:05:57The higher estradile was simply a marker
1:05:59of a older, sicker, more comorbid
1:06:02phenotype.
1:06:05Estradiol management.
1:06:07Belladelli at all does not show that
1:06:10estradile causes sexual dysfunction in
1:06:12mental testosterone therapy nor that
1:06:14blocking estradile improves outcomes. It
1:06:16is not evidence for routine AI use. You
1:06:19cannot use an observational ED paper to
1:06:22justify drug induced estradile
1:06:24suppression on testosterone therapy.
1:06:26Association in sick men is not evidence
1:06:29for suppressing estradile in treated
1:06:31men. This paper does not validate AI
1:06:34use. It only exposes a failure of
1:06:36inference.
1:06:38If you're proposing to override normal
1:06:39aromatization with a drug, you need
1:06:41direct interventional data showing that
1:06:43blocking E2 improves outcomes in men on
1:06:46TRT. This paper does not provide that.
1:06:49Nowhere close.
1:06:52The next paper is by Zuna.
1:06:55The association between elevated serum
1:06:57estradiol levels and clinically
1:06:58significant erectile dysfunction in men
1:07:00presenting for andrological evaluation.
1:07:03The goal of this study was to determine
1:07:05whether higher estradile levels are
1:07:06associated with clinically significant
1:07:08erectile dysfunction in men presenting
1:07:10for andrological evaluation.
1:07:12It was a retrospective obsational study
1:07:15of 256 men seen in a specialty andrology
1:07:18urology practice over 18 months.
1:07:21Erectile function was assessed using the
1:07:23male sexual health questionnaire.
1:07:25Estradile and testosterone were measured
1:07:27by morning iminoassay.
1:07:29Multivaried analysis adjusted for age,
1:07:32total testosterone, BMI, and smoking.
1:07:36Key findings of the study.
1:07:39Men with clinically significant ED were
1:07:41older, 55 years versus 42 years. Higher
1:07:45BMI also trended towards statistical
1:07:47significance. Higher Serum Masterdine
1:07:50was associated with clinically
1:07:51significant ED 23.6 pics per milliliter
1:07:55versus 20.7. Not that big of a
1:07:57difference. A lowest regression curve
1:08:00was used post hawk to define an E2 level
1:08:02of 32 pogs per milliliter that
1:08:04negatively impacts erectile function.
1:08:07A lowest regression curve is a smooth
1:08:09line drawn through a scatter plot to
1:08:11show the overall pattern or trend in the
1:08:13data without forcing the data to fit a
1:08:15straight line or a single mathematical
1:08:17equation. It stands for locally weighted
1:08:19scatter plot smoothing.
1:08:22Study weaknesses. Study design. This was
1:08:26a retrospective observational study not
1:08:29an interventional trial. It can show
1:08:31association, correlation and
1:08:34co-occurrence but cannot show causation.
1:08:38It cannot show that estradile caused the
1:08:40erectile dysfunction and it certainly
1:08:42cannot show that lower estradi would
1:08:43improve erectile dysfunction.
1:08:46Measurement method. Estradile was
1:08:48measured by iminoassay not LCMS or the
1:08:51ultra sensitive estradiol test. Estradi
1:08:54was measured by iminoassay which which
1:08:56is a poor method for the low estradile
1:08:58concentrations typically seen in men
1:09:00making small differences in cut offs
1:09:02less reliable. That matters here because
1:09:04the entire paper hinges on small
1:09:06differences in estradiol within the low
1:09:08male range. Weak clinical separation.
1:09:12The mean estradile difference between
1:09:13groups was only 2.9 pogs per milliliter
1:09:16with broad overlap in standard
1:09:18deviations.
1:09:19That is enough for a statistical signal,
1:09:21but it's not a convincing biological
1:09:23separation on which to build a treatment
1:09:25doctrine. In other words, this does not
1:09:27identify a clean clinically obvious high
1:09:29estradile ED phenotype
1:09:33post hawk threshold. The 32 pograms per
1:09:36millilar cutoff was not prescified. It
1:09:38was chosen after looking at the lowest
1:09:40curve in the same data set. That is
1:09:43datadived thresholding which is fine for
1:09:45hypothesis generation but weak for
1:09:47clinical decision-making unless
1:09:49externally validated. It is even more
1:09:51fragile because the authors first
1:09:52excluded excluded 12 men whose estradile
1:09:55values were more than two standard
1:09:56deviations above the mean then derived a
1:09:59high estradile cutoff from the trimmed
1:10:01data set. They didn't discover a
1:10:03biological threshold. They manufactured
1:10:06one from the data. Lab timing. Hormone
1:10:09values are allowed to be drawn within 90
1:10:11days of questionnaire completion. That
1:10:13is a very loose exposure outcome window
1:10:15for a symptom like erectile function. A
1:10:18single iminoassay estradile value
1:10:20obtained sometime within the prior 3
1:10:21months is a shaky basis for causal
1:10:24interpretation.
1:10:27Residual and unmeasured confounding. The
1:10:30paper adjusted for only five variables.
1:10:32estradiol, total testosterone, age, BMI,
1:10:36and smoking. It did not control for
1:10:39alcohol use and liver disease, central
1:10:42atyposity. They did not measure waist
1:10:44circumference or visceral fat. It did
1:10:47not control for metabolic data such as
1:10:48fasting glucose, hemoglobin A1C,
1:10:51triglycerides, HDL, cholesterol, or
1:10:53blood pressure. It did not control for
1:10:55psychiatric or psychological factors
1:10:57such as depression, anxiety, stress, or
1:11:01relationship issues. They did not
1:11:02control for lifestyle factors such as
1:11:04physical activity, sleep apnnea and diet
1:11:06which was not fully characterized. They
1:11:09did not control for medications that
1:11:10impair sexual function such as opioids,
1:11:13SSRIs, beta blockers, bala reductase
1:11:16inhibitors, antiscychotics etc. All of
1:11:18these can independently worsen erectile
1:11:20dysfunction and libido. It did not
1:11:23account for other other endocrine
1:11:24factors such as prolactin, thyroid or
1:11:26cortisol. The paper's own introduction
1:11:29acknowledges that ED is strongly
1:11:31influenced by cardiovascular disease,
1:11:33metabolic syndrome, diabetes, and other
1:11:35factors, but yet major erectile
1:11:37dysfunction confounders were not
1:11:39adequately controlled.
1:11:41Residual age confounding.
1:11:44Age was the strongest signal in the
1:11:45paper. It had a highly significant p
1:11:48value. Age was a major competing
1:11:51explanation in this study. Men with
1:11:53clinically significant ED were
1:11:54substantially older than controls 55
1:11:56versus 43 and age is one of the
1:11:59strongest established predictors of
1:12:00erectile dysfunction. Although estradile
1:12:03remains statistically significant after
1:12:04adjustment, the model cannot eliminate
1:12:06residual age- related confounding,
1:12:08especially given the many age- linked
1:12:10causes of ED that were not fully
1:12:11controlled. This paper does not show
1:12:14estradile causes ED. It shows that older
1:12:17men with worse erections also had
1:12:19slightly higher estradile. It does not
1:12:21prove estradile caused the problem
1:12:22rather than aging and its co-orbidities.
1:12:25These findings are more appropriately
1:12:26interpreted as showing that slightly
1:12:28higher estradile tracked with erectile
1:12:30dysfunction in an older higher risk
1:12:32population, not that estradile was
1:12:34proven to be the independent
1:12:35pathophysiologic driver. This study
1:12:38cannot separate whether estradile is
1:12:40causal, incidental or simply reflecting
1:12:42age- related metabolic dysfunction.
1:12:46Burden of proof for estradiol
1:12:48management. A retrospective correlation
1:12:51is not treatment evidence. This paper
1:12:53showed association only, not that
1:12:55estradile caused the ED and not that
1:12:57lowering estradile improves it. The
1:13:00proposed cutoff is not validated. The 32
1:13:03pil cutff was not discovered. It was
1:13:06created after the data was already
1:13:08known. It cannot be treated as a
1:13:10clinical target. The study was not defi
1:13:13designed to justify AI use on
1:13:15testosterone therapy.
1:13:17This study is hypothesis generating not
1:13:19practice changing. It does not support
1:13:21aromatase inhibitor use on testosterone
1:13:23therapy. It was not a testosterone
1:13:26therapy trial, not a aromatase inhibitor
1:13:28trial and not a demonstration that
1:13:30estradile suppression improves outcomes.
1:13:34You do not get to suppress a
1:13:35physiological hormone because of a
1:13:37retrospective association. The burden of
1:13:40proof is on the person altering
1:13:42physiology, not on the person preserving
1:13:44it. If you want to block estradile, you
1:13:47must show prospective evidence of
1:13:48superior outcomes versus testosterone
1:13:50therapy with intact aromatization.
1:13:54This study by zoo effect of estradiol on
1:13:57penile erection a cross-sectional study.
1:14:00It was a single center cross-sectional
1:14:02study. It involved 135 men with erectile
1:14:05dysfunction defined by an IEF score of
1:14:08less than or equal to 21. The setting
1:14:12was an andrology clinic in China from
1:14:142012 to 2017. They examined whether
1:14:17serum estradi was associated with
1:14:18nocturnal penal erection quality
1:14:20measured by rigidiscan.
1:14:22They looked separately at penile tip
1:14:24rigidity of greater than or equal to 60%
1:14:27and penile base rigidity greater than or
1:14:29equal to 60%. They considered rigidity
1:14:32of greater than or equal to 60% to be an
1:14:35effective erection. All patients had
1:14:37normal nocturnal erectile activity.
1:14:40when comprised of at least one erection
1:14:42with rigidity of greater than or equal
1:14:44to 60% at penile tip or base lasting
1:14:47longer than 10 minutes.
1:14:50They measured multiple lab variables
1:14:52including
1:14:54blood pressure, blood glucose, HDL
1:14:56cholesterol, FSH LH as described in
1:14:59table one. They report, "We excluded
1:15:02patients who had a history of neurologic
1:15:04disease, genital or spinal cord
1:15:06injuries, morbid obesity, use of drugs
1:15:08that affect erectile function, bleeding
1:15:10disorders, penile fibrosis,
1:15:13hypertension, diabetes, hypogadism, and
1:15:16or abnormal androgen profile. The mean
1:15:19testosterone levels in this study were
1:15:21458 nanogs per deciliter and the mean
1:15:24estradile levels were 56.62
1:15:27pogs per milliliter.
1:15:30Main findings. They reported no clear
1:15:32relationship between estradile and
1:15:34penile tip erection duration. They
1:15:36reported a negative association between
1:15:38estral and penile base erection
1:15:40duration. They further divided men by
1:15:42whether base rigidity of greater than or
1:15:44equal to 60% lasted less than or equal
1:15:46to 10 minutes or greater than 10 minutes
1:15:48and claimed the inverse relationship
1:15:50with estradile was more apparent in the
1:15:51group with longer base erection time.
1:15:54Their conclusion was that the estradile
1:15:55inhibits penile erection especially at
1:15:58the penile base.
1:16:00The strengths of this study it used an
1:16:03objective physiologic test rigiscan
1:16:05rather than relying only on symptom
1:16:06questionnaires.
1:16:08It measured multiple hormonal and
1:16:10metabolic variables.
1:16:12It attempted multivariable adjustment
1:16:14rather than simple barvariate
1:16:16correlation alone. It explored an
1:16:18unusual question tip versus base
1:16:21erection differences.
1:16:23study weaknesses. The study was
1:16:26cross-sectional. Therefore, it can only
1:16:28show association, not causation. So, the
1:16:31paper cannot prove that higher est
1:16:33caused poor erection, that lowering
1:16:35estral would improve erections, or that
1:16:37estradile is the driving hormonal
1:16:39abnormality.
1:16:41The statistical reporting is internally
1:16:43inconsistent and repeatedly reports
1:16:45coefficients like you see here. That
1:16:48does not make sense as written. If the
1:16:5095% confidence interval includes one,
1:16:53the result is not statistically
1:16:55significant. Yet, the paper still
1:16:57reports a p value of less than 0.05.
1:17:00The statistical results do not support a
1:17:02strong conclusion. Although the authors
1:17:04describe the findings as significant,
1:17:06the printed confidence intervals include
1:17:08one, which indicates that no
1:17:10statistically reliable association was
1:17:12demonstrated as reported. At minimum,
1:17:15this creates internal inconsistency in
1:17:17the analysis. At worse, it raises
1:17:19concern that the results are misreported
1:17:21or over interterpreted as written in the
1:17:23paper. The actual data do not strongly
1:17:26support the bold conclusion that
1:17:28estradile inhibits erectile function.
1:17:30The results are much weaker than the
1:17:32wording suggests. The reported
1:17:34associations are small. The confidence
1:17:37intervals are wide. The statistical
1:17:39reporting is contradictory. The tip
1:17:42findings are essentially negative. And
1:17:44even the base findings are not robustly
1:17:46convincing as presented.
1:17:48There was no noned control group. That
1:17:52means the study cannot answer whether
1:17:54estradile differs between men with and
1:17:56without ED, whether estradile predicts
1:17:59the presence of ED, or whether estradile
1:18:01is a risk factor for ED in the general
1:18:03male population. It only examines
1:18:05variation within an already selected ED
1:18:07group. So, it is not a strong design for
1:18:10making broad claims about estradile and
1:18:12male erectile physiology.
1:18:15weaknesses continued. Important
1:18:17compounders were not addressed. BMI,
1:18:20waist circumference, visceral atyposity,
1:18:23smoking, alcohol, sleep apnnea,
1:18:27depression, anxiety, relationship
1:18:29stress, and thyroid status, etc. With so
1:18:32many unmeasured variables, it's hard to
1:18:34claim that estradile is an independent
1:18:36driver rather than a proxy for a sicker
1:18:38metabolic and comorbid profile. Serum
1:18:42estradile is an imperfect biomarker for
1:18:44tissue level estrogen signaling. This is
1:18:46a physiological limitation of the paper.
1:18:49The study assumes that a single serum
1:18:51estradile measurement meaningly reflects
1:18:52estrogenic action at the penile tissues.
1:18:56They only excluded men with morbid
1:18:57obesity, which is a BMI of greater than
1:18:5940, not men that were overweight or had
1:19:01class one or two obesity.
1:19:05In the published methods, they
1:19:06explicitly exclude morbid obesity, but
1:19:08they do not report BMI, waist
1:19:10circumference, or body composition
1:19:12measures as part of the core data set
1:19:14shown in the paper. One of the most
1:19:16glaring weaknesses of the study is its
1:19:18failure to account for atyposity. Faced
1:19:20with an average estradile of 56 pigs per
1:19:23milliliter in men in their early 30s,
1:19:24the most plausible explanation is not
1:19:27primary estradiopathology, but
1:19:29unmeasured overweight or class one two
1:19:32obesity, especially since only morbid
1:19:34obesity was excluded. The absence of
1:19:36BMI, waist circumference, and body
1:19:39composition data is a major limitation,
1:19:41and they failed to control for the most
1:19:42obvious compounder. Most likely,
1:19:45atyposity was driving both the elevated
1:19:47estradile and the erectile dysfunction.
1:19:51Why this paper does not justify
1:19:53aromatase inhibitors on testosterone
1:19:55therapy? Wrong population, wrong
1:19:57inference. This was a cross-sectional ED
1:20:00study, not a TRT trial, and it excluded
1:20:03men with hypogonadism and abnormal
1:20:05androgen profiles. No intervention, no
1:20:09proof of benefit. The authors did not
1:20:11give testosterone, did not use an
1:20:13aromatase inhibitor, and did not show
1:20:15that lowering estradile improved
1:20:17erections or any clinical outcome.
1:20:20Confounding overwhelms the claim. They
1:20:23excluded morbid obesity, but not all
1:20:25obesity. Lesser degrees of atyposity
1:20:27could still raise estradile through
1:20:28aromatization and independently worsen
1:20:31erectile function. The statistics do not
1:20:34support the strong conclusion. The paper
1:20:36reports significant findings yet the
1:20:38printed confidence intervals crosses one
1:20:41indicating the results are not
1:20:42statistically significant.
1:20:44Association is not a treatment
1:20:46indication. Even if the association were
1:20:49real, it would not justify disrupting
1:20:51normal testosterone estradile physiology
1:20:53in menal testosterone therapy without
1:20:55randomized evidence of net benefit.
1:20:58This paper does not show that aromatase
1:21:00inhibitors improve testosterone
1:21:02replacement therapy outcomes. It only
1:21:04shows how weak associations get over
1:21:06interterpreted. This is not a TRT study,
1:21:09not an AI study, not evidence for
1:21:11estradile suppression.
1:21:14Let's briefly examine the mechanisms of
1:21:16obesitydriven erectile dysfunction by
1:21:18reviewing this paper of Dr. Trish. He
1:21:21writes, "Obesity is a major risk factor
1:21:23for the metabolic syndrome, vascular
1:21:25disease, diabetes, hypertension,
1:21:28endothelial dysfunction, and androgen
1:21:30deficiency, all of which contribute to
1:21:32the pathophysiology of ED. A study by
1:21:35Kaia reported 79% of men presenting with
1:21:38ED have a BMI of 25 or higher and men
1:21:41with a BMI greater than 30 have three
1:21:42times greater risk of sexual dysfunction
1:21:45compared with normal men. Obesity
1:21:47promotes inflammatory responses and
1:21:49contributes to endothelial dysfunction.
1:21:52Organic ED can be vascular, neurologic,
1:21:56anatomic and endocrine in origin.
1:21:58Vascular ED the most common form mainly
1:22:00results from endothelial dysfunction.
1:22:03Obesity and its coorbidities are
1:22:04associated with reduced plasma
1:22:06testosterone levels. Obesity is
1:22:09associated with increased estradiol
1:22:11levels. We have reviewed literature
1:22:14showing that testosterone therapy in
1:22:15obese men raises both testosterone and
1:22:17estradile while improving metabolic
1:22:19parameters, body composition, and sexual
1:22:22function. When estradile is suppressed,
1:22:24those benefits are attenuated. Obese men
1:22:27with erectile dysfunction also have
1:22:29elevated estradiol. But that does not
1:22:31establish estradile as the cause of this
1:22:33dysfunction. It is the obesitydriven
1:22:35hypoganism, endothelial dysfunction,
1:22:38insulin resistance, and inflammatory
1:22:40cytoine ex excess that are the
1:22:42underlying drivers of vascular injury
1:22:44and impaired erectile function. In that
1:22:47context, elevated estradile is better
1:22:50understood as a marker of the obese
1:22:52metabolic state rather than the primary
1:22:54pathologic agent.
1:22:56Looking at figure one, visceral atapost
1:22:59tissue is a dynamic endocrine organ that
1:23:01secretes a host of biochemical
1:23:02modulators and pro-inflammatory factors
1:23:05contributing to systemic and peripheral
1:23:07vascular inflammation. These include
1:23:09interlucan 6, tumor necrosis factor
1:23:11alpha, leptin resistin angotensin. It
1:23:16also decreases ataponctin. Adopeneectin
1:23:19is a protein hormone secreted by fat
1:23:20cells that plays a crucial role in
1:23:22regulating glucose levels, lipid
1:23:23metabolism and insulin sensitivity. Now
1:23:27these inflammatory mediators lead to a
1:23:29pro-inflammatory state contributing to
1:23:30the onset of hypertension, dysipidemia,
1:23:33diabetes, thrombosis and
1:23:34arththerosclerosis.
1:23:36Looking at figure two, these
1:23:38pro-inflammatory factors result in a
1:23:41decrease in nitric oxide synthes and
1:23:43nitric oxide activity as well as an
1:23:44increase in adhesion molecules causing
1:23:47endothelial injury and dysfunction. This
1:23:49leads to a pathophysiological state
1:23:51involving reduced hemodynamics to the
1:23:52peripheral tissues including the penis.
1:23:55Thus, inflammatory cytoines produced by
1:23:58visceral atyposity can have a profound
1:23:59and damaging effect on the vascular
1:24:01endothelium in the small penile vessels
1:24:03leading to erectile dysfunction.
1:24:06Dr. Trish writes, "Testosterone
1:24:09treatment for ED ameliorates metabolic
1:24:11syndrome components and improves
1:24:13endothelial function. Testosterone
1:24:15therapy in men with androgen deficiency
1:24:16demonstrated an improvement in erectile
1:24:18function and increased muscle mass and
1:24:20decreased visceral fat. Furthermore,
1:24:23androgens have been shown to inhibit the
1:24:24expression and release of cytoines and
1:24:26chemocines. Androgen deprivation therapy
1:24:29is associated with increased levels of
1:24:30pro-inflammatory factors and decreased
1:24:32anti-inflammatory cytoines.
1:24:35Interestingly, testosterone therapy
1:24:37prevents a gain in visceral atapost
1:24:38tissue in non-obese aging men and
1:24:41reduces the production of
1:24:42pro-inflammatory cytoines.
1:24:44I've included the 22 reference studies
1:24:47in this paragraph. All of the benefits
1:24:49with testosterone therapy in these
1:24:51studies were obtained with intact
1:24:53physiologic aromatization. None use an
1:24:56aromatase inhibitor.
1:24:58If the benefits of testosterone therapy
1:25:00were demonstrated under intact
1:25:02aromatization, the obligation is on
1:25:04those who suppress estradile to prove
1:25:06they preserve or enhance these outcomes,
1:25:08not assume it.
1:25:11This is a review article by Caliber and
1:25:13SADE discussing the use of testosterone
1:25:15for the prevention and treatment of
1:25:16obesity in men. We will be examining in
1:25:19more detail a few of the studies
1:25:20referenced in this article with specific
1:25:22attention to worsening sexual function
1:25:24or symptoms of elevated estradiol. This
1:25:27paper includes 207 references and only
1:25:30one using an aromatase inhibitor and it
1:25:32was the final sign study that we've
1:25:33already reviewed.
1:25:36Effects of long-term testosterone
1:25:38therapy on patients with diabetes.
1:25:40Results of observational studies of
1:25:41pulled analysis and obese hypogonatam
1:25:43men with type 2 diabetes. This study
1:25:46involved 156 obese diabetic men with
1:25:49testosterone deficiency treated with
1:25:51testosterone undeonate for up to six
1:25:53years. Improvements occurred in all
1:25:55cardiomatabolic parameters in measured
1:25:58including systolic and diastolic blood
1:26:00pressure as noted by baseline and then
1:26:03the endpoint. As you can see even the
1:26:05blood pressure significantly improved.
1:26:07Systolic blood pressure went down
1:26:08significantly as did diastolic blood
1:26:10pressure. All parameters improved. Now
1:26:14let's address those that claim estradile
1:26:15can be the cause of an increase in blood
1:26:17pressure or hypertension in men on
1:26:19testosterone. Both systolic and
1:26:21diastolic blood pressure decreased in
1:26:23these obese men with normal physiologic
1:26:25aromatization intact. Estradi was not
1:26:27measured or controlled and yet benefits
1:26:29occurred. Estradiol is vasoddilatory not
1:26:32a vasos suppressor. Experimental and
1:26:34clinical literature shows estrogen
1:26:36signaling can increase nitric oxide
1:26:38bioavailability, improve vascular
1:26:40relaxation and in hypogonado men even
1:26:42lower blood pressure with estrogen
1:26:44supplementation. Blaming estradile
1:26:46ignores basic vascular physiology.
1:26:50This study by Kamazerof at all showed
1:26:53that lowd dose estrogen supplementation
1:26:55in hypogonal men is well tolerated
1:26:57lowers blood pressure and may affect
1:26:59vascular reactivity in a manner that is
1:27:01potentially beneficial through several
1:27:03mechanisms including enhancement of
1:27:04basil nitric oxide release and
1:27:06attenuation of vasoc constrictor
1:27:08responses to angotensin 2 and
1:27:10norepinephrine.
1:27:12When testosterone therapy is first
1:27:14initiated, some men experience transient
1:27:17sodium and water retention, leading to
1:27:19plasma volume expansion and a temporary
1:27:21rise in blood pressure. This effect is
1:27:23usually self-limited and often improves
1:27:25over several weeks with sodium
1:27:26restriction, adequate hydration, and
1:27:29increased aerobic activity. It tends to
1:27:32be more common in men that are insulin
1:27:33resistant and have underlying metabolic
1:27:35dysfunction and not also have a diet
1:27:37that is high in sodium.
1:27:40This was a landmark study by Yasine and
1:27:43it showed for the first time that
1:27:44testosterone therapy in men with
1:27:45hypogonetism prevents progression from
1:27:48pre-diabetes to type 2 diabetes. 229 men
1:27:51with pre-diabetes and total testosterone
1:27:53levels less than 348 nanogs per
1:27:56deciliter were treated with testosterone
1:27:57undecinate and followed for eight years.
1:28:00They reported, "Our study shows for the
1:28:02first time that long-term testosterone
1:28:04therapy completely prevents progression
1:28:06of pre-diabetes to avert type 2 diabetes
1:28:08in men with hypogonadism and
1:28:10pre-diabetes.
1:28:12Here are the baseline characteristics in
1:28:14the testosterone group and the control
1:28:16group as well as the changes noted at 8
1:28:18years. As you can see from the
1:28:20supplementary data, there was
1:28:21improvement in all measures in the
1:28:23testosterone group compared to the
1:28:24controls. There was nothing that did not
1:28:26improve with testosterone therapy that
1:28:28they measured.
1:28:30Focusing on sexual function, baseline
1:28:32AMS scores were 52.2 graded as severe
1:28:35symptoms of testosterone deficiency and
1:28:37IIE IF scores were 8.2 which is
1:28:40considered moderate ED. Remember the
1:28:43higher the IEF score the better and the
1:28:46lower the AMS score the better.
1:28:49After eight years, the average AMS score
1:28:52decreased 18.3 points to 34, which we
1:28:56considered mild symptoms of testosterone
1:28:58deficiency. The IEF score increased 8.4
1:29:01points to 19.9, which is now considered
1:29:04mild ED.
1:29:06All of the positive changes, including
1:29:08the improvement from severe symptoms of
1:29:09testosterone deficiency to mild symptoms
1:29:11of testosterone deficiency, as well as
1:29:13from moderate ED to mild ED, all
1:29:15occurred with intact aromatization.
1:29:18Estradi was not measured or controlled
1:29:19and yet benefits still occurred. This
1:29:22paper supports the efficacy of
1:29:23testosterone therapy without disrupting
1:29:25testosterone estradile physiology. Those
1:29:28advocating estradile suppression must
1:29:30prove that adding it improves outcomes
1:29:32beyond testosterone therapy alone.
1:29:35This study by SADE looked at the effects
1:29:38of long-term treatment with testosterone
1:29:39on weight and waist size in 411 hypogly
1:29:43men with obesity classes 1 through3
1:29:45observational data from two registry
1:29:47studies. Remember from the previous
1:29:49slide that class one obesity is a BMI of
1:29:5230 to 34.9
1:29:54class 2 35 to 39 and class 3 a BMI
1:29:58greater than 40. Table one are the
1:30:01baseline characteristics of the men in
1:30:03this study and as you can see they had
1:30:05significant BMIs 35 32 37 and 41.9.
1:30:11Table two are the changes in metabolic
1:30:14prostate and quality of life parameters
1:30:16at baseline and following long-term
1:30:18treatment up to eight years. Baseline
1:30:20IIEF scores were 13.8, 15.6 and 17 for
1:30:25class 1 2 and class 3 obesity
1:30:28respectively. After long-term treatment
1:30:30with testosterone, the IIEF scores
1:30:32increased in all three classes to 24.8,
1:30:3524.5, and 25.4. All considered mild ED.
1:30:40The AMS scores dropped 32.5 points to
1:30:4319.7 for class 1. It dropped 33.4 points
1:30:47to 19.4 for class 2, and it dropped 38
1:30:50points to 17.8 for class 3 obesity,
1:30:52which correlates with no symptoms of
1:30:54testosterone deficiency for all classes.
1:30:57Treating obese and severely obese men
1:30:59with testosterone without an aromatase
1:31:00inhibitor significantly improved sexual
1:31:02function and resolved symptoms of
1:31:04testosterone deficiency. Estradi was not
1:31:07measured or controlled and yet benefits
1:31:09still occurred. In this long-term
1:31:11registry of 411 obese hypogonado men,
1:31:15including men with morbid obesity,
1:31:17testosterone therapy produced
1:31:18substantial and sustained improvement
1:31:20across anthropometric, metabolic,
1:31:23inflammatory, sexual, and quality of
1:31:26life measures. These outcomes were
1:31:28achieved with testosterone therapy alone
1:31:30under preserved testosterone to
1:31:32estradile physiology, not with aromatase
1:31:35inhibition or deliberate estradile
1:31:37suppression. Accordingly, the study does
1:31:39not support claims that estradile
1:31:41requires routine control for benefits to
1:31:43occur. On the contrary, it shows that
1:31:46major clinical improvement occurred
1:31:47while aromatization remained intact. The
1:31:50burden, therefore, rest entirely on
1:31:51advocates of estradile suppression to
1:31:53prove that disrupting a physiologic
1:31:55pathway associated with benefit improves
1:31:57outcomes rather than undermining them.
1:32:00Advocates for estradile control in
1:32:02normal or obese men are not correcting
1:32:04failure. They are interfering with
1:32:06success.
1:32:08This is an important study by hater at
1:32:10all showing the remission of type two
1:32:13diabetes following long-term treatment
1:32:14with injectable testosterone and
1:32:16decinoate in patients with hypogenism
1:32:18and type 2 diabetes. 11-year data from a
1:32:20realworld registry study. It consisted
1:32:24of 178 men with testosterone levels less
1:32:26than 350 with symptoms of hypoganism
1:32:29treated with testosterone undeinoic for
1:32:3111 years. They reported long-term
1:32:34testosterone therapy in men with type 2
1:32:36diabetes and hypogonetism improves
1:32:38glycemic control and insulin resistance.
1:32:40Remission of diabetes occurred in
1:32:42onethird of the patients.
1:32:44Table one includes the baseline
1:32:46characteristics of the treated men and
1:32:48controls. The average weight of the
1:32:50treated group was 250 lbs and the
1:32:52average BMI was 36.5.
1:32:55Focusing on testosterone deficiency
1:32:57symptoms and erectile function, the
1:32:59treated group had an average AMS score
1:33:00of 54.7 and an IIFF score of 16.1, which
1:33:05corresponds to severe symptoms of
1:33:06testosterone deficiency and moderate
1:33:08erectile dysfunction. Table two are the
1:33:11changes 11 years from baseline. As you
1:33:13can see, improvements occurred in every
1:33:15parameter measured. The AMS score
1:33:17dropped an average of 31 points to 23.9
1:33:20and the IEF score increased an average
1:33:23of 10.2 22 to 26 which corresponds to no
1:33:26symptoms of testosterone deficiency and
1:33:28no erectile dysfunction. There was once
1:33:31again a significant decrease in systolic
1:33:33and diastolic blood pressure of 32 mm
1:33:35and 19 mm respectively.
1:33:38This paper shows that substantial
1:33:40metabolic and clinical benefit occurred
1:33:42with testosterone therapy alone without
1:33:43estradiol suppression. If you want to
1:33:46add an aromatase inhibitor, the burden
1:33:47is on you to show that it improves
1:33:49outcomes beyond testosterone alone.
1:33:51There are no randomized outcome data
1:33:53showing that routine aromatase
1:33:54inhibition during testosterone therapy
1:33:56improves clinical outcomes compared with
1:33:58testosterone therapy alone. The burden
1:34:01for those that promote estradiol control
1:34:03is to provide a randomized trial that
1:34:05shows testosterone plus an aromatase
1:34:07inhibitor improves diabetes remission
1:34:09insulin resistance body composition or
1:34:12sexual outcomes more than testosterone
1:34:14alone.
1:34:15In this study by SADE, long-term
1:34:18treatment with testosterone undouinism
1:34:21alleviates erectile dysfunction and
1:34:23reduces risk of major adverse
1:34:25cardiovascular events, prostate cancer
1:34:27and mortality. They treated 412 patients
1:34:30with different degrees of erectile
1:34:32dysfunction with testosterone undeonic
1:34:34for up to 12 years. 393 men served as
1:34:37controls. Table one are the baseline
1:34:40characteristics of the men in the study.
1:34:42The no ED or mild ED group had an
1:34:45average age of 57.7 years, a BMI of
1:34:4833.7, systolic blood pressure of 152,
1:34:52diastolic blood pressure of 92.4, an AMS
1:34:55score of 55, and an IEF score of 24.2.
1:35:00The moderate and severe ED group had an
1:35:02average age of 57.7,
1:35:04a BMI of 32.8, systolic blood pressure
1:35:07of 151, diastolic blood pressure 88.8,
1:35:10an AMS score of 49.5 and an IIEF score
1:35:14of 15.1.
1:35:16Both groups at baseline were older
1:35:17overweight men with hypertension in
1:35:19addition to different degrees of ED and
1:35:21severe symptoms of testosterone
1:35:23deficiency.
1:35:25These are the changes at 10 years from
1:35:27baseline. All anthropometric parameters
1:35:29improved from baseline in both treatment
1:35:31groups. In the no or mild ED treatment
1:35:34group, systolic blood pressure went down
1:35:3619.4, 4, diastolic blood pressure 11.5,
1:35:40BMI went down 5.8, AMS scores went down
1:35:4431.9, and IF scores went up 4.4. In the
1:35:48moderate and severe ED treatment group,
1:35:51systolic blood pressure went down 22.5,
1:35:53diastolic blood pressure 11.1, BMI 5.8,
1:35:57AMS scores went down 27.3, and IF scores
1:36:01went up 11.1.
1:36:03The no or mild ED treatment group now
1:36:05had no erectile dysfunction and the
1:36:07moderate to severe ED treatment group
1:36:09also had no erectile dysfunction.
1:36:12In both treatment groups, the AMS score
1:36:15equal no symptoms of testosterone
1:36:17deficiency.
1:36:18He reported, "The main findings of this
1:36:21study are that long-term testosterone
1:36:22therapy with testosterone undeenoid
1:36:24injections for up to 12 years
1:36:26substantially improves erectile
1:36:28function, anthropometric and
1:36:29cardometabolic risk factors, prostate
1:36:31cancer incidents, and urinary function.
1:36:34It is notable that the benefits of
1:36:35testosterone therapy are even stronger
1:36:37in patients with moderate or severe ED
1:36:39at baseline than in patients with no or
1:36:41mild ED at baseline. An interesting
1:36:43finding in our study is that erectile
1:36:45function continues to improve for nine
1:36:47years. It was previously believed that
1:36:49maximum improvement erectile function
1:36:51are achieved after 3 to six months of
1:36:53testosterone therapy. Based on this
1:36:55belief, several clinical guidelines
1:36:57recommend that men with borderline
1:36:58hypogonism should be given a therapeutic
1:37:00trial of testosterone therapy for 3
1:37:02months such as the Can Canadian Medical
1:37:03Association or 6 months, the British
1:37:05Society for Sexual Medicine, or 12
1:37:08months, the International Society for
1:37:09Sexual Medicine. Our data clearly showed
1:37:11that a therapeutic trial of testosterone
1:37:13therapy for even one year is not enough
1:37:15to achieve maximum benefit of
1:37:17testosterone therapy on erectile
1:37:19function.
1:37:21Estradiome management. The improvements
1:37:24in sexual functions were achieved
1:37:25without measuring estradile as a
1:37:27therapeutic target. This study places
1:37:29the burden of proof on those advocating
1:37:31estradile control because the sexual
1:37:33benefits were achieved without it. All
1:37:36of the supported benefits occurred under
1:37:37conditions of intact aromatization, not
1:37:39estradile suppression.
1:37:41This study supports restoring
1:37:43testosterone physiology, not disrupting
1:37:46it with routine estradile suppression.
1:37:48If estradile control were necessary,
1:37:50these benefits would not have occurred
1:37:51without it. But they did. No aromatase
1:37:55inhibitor was required to achieve
1:37:56benefit in any man. What worked was
1:37:59testosterone restoration, not estradile
1:38:01suppression or control. If the outcomes
1:38:04were achieved with intact aromatization,
1:38:06then routine estradile suppression is an
1:38:08added intervention in search of
1:38:09evidence. The study supports restoration
1:38:12of normal physiology, not routine
1:38:14disruption of it. Routine estradile
1:38:17suppression or controlled remains an
1:38:19unproven add-on when the therapeutic
1:38:20benefits were achieved without it.
1:38:22Before someone argues for adding an
1:38:24aromatase inhibitor, they first have to
1:38:26explain why the documented benefits
1:38:27occurred without one. You cannot claim
1:38:30estradile control is required when the
1:38:32documented sexual improvement occurred
1:38:34in its absence.
1:38:36Those advocating estradile control need
1:38:38to prove that adding an aromatase
1:38:39inhibitor improves outcomes beyond
1:38:41testosterone therapy alone. If estradile
1:38:43control improves sexual outcomes, where
1:38:45is the testosterone therapy versus
1:38:47testosterone therapy plus AI trial
1:38:49showing it? There is not one.

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