Role of Estradiol in Men and Its Management

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Nelson Vergel

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Check your estradiol (sensitive) blood levels cheaply: DiscountedLabs.com


REGISTERED MEMBERS: DOWNLOAD ATTACHED ESTRADIOL LECTURE HANDOUT AT THE BOTTOM OF THIS POST




Click here for a comprehensive article about the 18 things you should know about estradiol in men


By Nelson Vergel, BsChE, MBA

Note: This thread has 54 posts (3 pages).

Testosterone is the precursor hormone for estradiol. Estradiol is a hormone more abundant in women than men that are produced by the aromatization of testosterone in the liver, fat, and other cells. Nature created it for a reason. It has been shown to be responsible for healthy bone density but its role in men's sex drive, body composition, and other variables is a source of great debate.

When the HPT hormonal axis senses that testosterone or estradiol is high, it automatically decreases or shuts down testosterone production.

Many anti-aging or men's health clinics prescribe anastrozole, a blocker of estradiol production, to men who start testosterone replacement (TRT). Higher estradiol blood levels not only can cause breast tissue growth (gynecomastia) but also water retention (edema). Some people speculate that high estradiol can also lead to erectile dysfunction but no scientific papers have been published on this subject. Since higher testosterone blood levels can originate higher estradiol levels, the belief is that using anastrozole will prevent breast tissue growth and erectile dysfunction by lowering any potential increase in estradiol. However, we have no data on how high is too high when it comes to this hormone in men. Some even speculate that low testosterone-to-estradiol ratios may be more closely correlated to gynecomastia and erectile problems than estradiol alone.

The truth about these speculations is starting to emerge but we still do not have enough data to say what the upper value of the optimal range of estradiol really is. We have a lot of evidence about the lower side of the optimal range since it has been found that estradiol blood levels below 10-20 pg/ml can increase bone loss in men. A recently published study also nicely demonstrated that low estradiol can be associated with higher fat mass and lower sexual function in men. So, be very careful when a clinic wants to put you on this drug without first justifying its use.


Another concerning fact is that many clinics may be using the wrong estradiol test that may be over-estimating the levels of this hormone in men. A sensitive estradiol test more accurately measures estradiol in men instead of the regular test that costs less.

Sensitive Estradiol Blood Test: The Only Accurate Assay for Men

Fortunately, most men on TRT do not develop gynecomastia even without using anastrozole (gynecomastia is common in bodybuilders who may use high doses of testosterone, however). Those that have gynecomastia at TRT doses (100-200 mg of injectable testosterone or 5-10 grams of testosterone gel per day) may be genetically predisposed to having more aromatase activity or have liver dysfunction. Treating all men who start TRT with anastrozole from the start may be counterproductive since this may lower estradiol to very low levels. Some physicians monitor estradiol blood levels after 6-8 weeks of having a man start TRT alone using the ultrasensitive estradiol test to determine if anastrozole use is warranted. Doses range from 0.25 mg per week to some clinics using excessive doses of 1 mg three times per week. After 4-6 weeks on anastrozole, its dose can be adjusted to ensure than estradiol is not under 20 pg/ml. Fortunately, many men on TRT do not need anastrozole at all.

What to Do if You Crashed Your Estradiol?

So we wait for more studies that will clarify the role and optimal ranges of estradiol. Here are a few studies that we already have available based on the role investigated.

Low High estradiol symptoms men.jpg

Why is estradiol important for men?

One of the most common problems reported on ExcelMale: I crashed my estradiol

More articles on estradiol in men: Click here

Estradiol in Men: Impact on Cognitive Function and Heart Disease during Testosterone Therapy | Discounted Labs

Estradiol in Men on TRT: Impact on Brain and Heart

Estradiol's Role in Men's Health: Top 18 Facts

Estradiol Blood Level in Men: Why It is Important

Is Estradiol a Friend or Enemy of Men?

Men’s Heart Disease Partly Due to Low Estrogen
estradiol in men benefits.JPG

sources of estrogen in men.JPG
testosterone injectiobs effect on estradiol.JPG
 

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Nelson Vergel

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This study shows what happens to sexual function and body composition at different blood levels of testosterone and/or estradiol.


Gonadal Steroids and Body Composition, Strength, and Sexual Function in Men

N Engl J Med. Sep 12, 2013; 369(11): 1011;1022.

All participants received goserelin acetate (Zoladex, AstraZeneca), at a dose of 3.6 mg subcutaneously at weeks 0, 4, 8, and 12, to suppress endogenous gonadal steroids. Participants were then randomly assigned to receive 0 g (placebo), 1.25 g, 2.5 g, 5 g, or 10 g of a topical 1% testosterone gel (AndroGel, Abbott Laboratories) daily for 16 weeks. Participants in cohort 2 also received anastrozole (Arimidex, AstraZeneca) at a dose of 1 mg daily to block the aromatization of testosterone to estrogen. Participants were unaware of the study-group assignments.
Participants were seen every 4 weeks. At each visit, fasting blood samples were obtained to measure gonadal steroid levels, and questionnaires were administered to assess physical function, health status, vitality, and sexual function. At baseline and week 16, body fat and lean mass were assessed by means of dual-energy x-ray absorptiometry (DXA); subcutaneous- and intraabdominal-fat areas and thigh-muscle area were measured by means of computed tomography (CT); and lower-extremity strength was determined by means of a leg press. Data on bone homeostasis (bone-turnover markers and bone mineral density), risk factors for cardiovascular disease (blood pressure, lipids, and insulin sensitivity), and levels of leptin and prostate-specific antigen were also collected but are not included in the present report.

"...we found that lean mass, muscle size, and strength are regulated by androgens (testosterone); fat accumulation is primarily a consequence of estrogen deficiency (low estradiol); and sexual function is regulated by both androgens and estrogens. Delineation of the degrees of hypogonadism at which undesirable consequences develop and of the relative roles of androgens (testosterone) and estrogens in each outcome should facilitate the development of more rational approaches to the diagnosis and treatment of hypogonadism in men."



Source: Gonadal Steroids and Body Composition, Strength, and Sexual Function in Men
 
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Nelson Vergel

Founder, ExcelMale.com
Thread starter #3
The study posted in the second post above showed that low estradiol may be linked to higher fat in men. Here is a study done in female rats that is pretty much concluding the same thing.

Estradiol May Prevent Fat Accumulation


At least in female rodents...


"administration of supplemental doses of estradiol appeared to prevent fat accumulation and overcome leptin resistance in ovarian-intact and ovariectomized female high-fat-diet mice, they wrote online in the journal Endocrinology.
But response to estradiol treatment in the high-fat-diet animals depended on endogenous estrogenic status, they cautioned.
"When estradiol (E2) was cyclically administered to ovarian-intact HFD-fed mice for 12 weeks, the animals gained significantly less weight than ovarian-intact vehicle controls (P<0.01)," the researchers wrote. "This difference was mainly due to reduced caloric intake and not to an increase in energy expenditure or locomotor activity."
 
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Nelson Vergel

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Finally, a good article on estradiol and aromatase inhibitors!!

THE DOWNSIDE OF AROMATASE INHIBITION: SIDE EFFECTS WORTH IT?


"Truthfully, it is impossible to state whether anyone has been harmed by using aromatase inhibitors for performance- or physique-enhancement; it simply is not tracked. These two drugs are oral (a similar drug, Aromasin®, is injected); they generally do not cause physically perceived, short-term symptoms; and they are rarely used long-term. These factors instill a false sense of security in users.

Yet, there are problems that may arise as a result of aromatase inhibition, particularly aggressive aromatase inhibition that suppresses estrogen concentrations to very low values. Estrogen (primarily estradiol, but let's stay with the generic term estrogen for simplicity's sake) is not a metabolic waste product in men, a primordial remnant of no greater perceived value than the appendix. It is a functioning hormone that is anabolic in some tissues (e.g., bone, fat, breast); a stimulatory hormone (i.e., enhances production of certain circulating proteins in the liver); a metabolic modifier (affects endocrine hormones as well as carrier protein concentrations, such as binding globulins for vitamin D and sex hormones); a neurosteroid affecting neurotransmitter action, behavior, and emotions; an endocrine regulator; and has other functions.

It is irrational to think that there would not be hazards when concentrations are artificially suppressed well below the lowest extreme of the physiologic range, just as occurs when estrogen is elevated past the upper limit of normal. What, then, are some of the possible consequences to creating an estrogen deficiency in adult males?"
Source: Muscular Development Magazine
 
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Nelson Vergel

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RECOMMENDED ULTRASENSITIVE ESTRADIOL BLOOD TESTS FOR MEN:

Sensitive Estradiol Blood Test: The Only Accurate Assay for Men


Comparisons of Immunoassay and Mass Spectrometry Measurements of Serum Estradiol Levels and Their Influence on Clinical Association Studies in Men


"In conclusion, our findings suggest interference in the standard immunoassay-based E2 analyses, possibly by CRP or a CRP-associated factor. Although this interference does not seem to affect association studies between immunoassay E2 levels and skeletal parameters, we propose a re-evaluation of previous association studies between immunoassay-based E2 levels and inflammation-related outcomes. In addition, MS-based assays are to be preferred for the quantification of E2 levels in men."


This is the most precise estradiol test for me provided by Labcorp:

Estradiol, LCMS (Endocrine Sciences)

Test Number: 500108 Liquid chromatography/tandem mass spectrometry (LC/MS-MS)


This is the test performed by Quest Diagnostics:

Estradiol, Ultrasensitive, LC/MS/MS

Test Code 30289
Methodology

Liquid Chromatography Tandem Mass Spectrometry (LC/MS/MS)


This is the right estradiol test
sensitive_estradiol_test.jpg
 
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Nelson Vergel

Founder, ExcelMale.com
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High Estradiol in Men Not Associated with ED

Testosterone replacement improves quality of life and is aromatized in men in adipose tissues to estrogen. Hyperestrogenism is believed to be harmful to male sexuality. This is a description of our experience of screening 34,016 men in the Low T Centers, of which approximately 50% were converted to treatment. Men were treated with injectable testosterone, and we have available data from 2009 to 2014.


The data were extracted from our electronic health record (AdvancedMD) of 35 Low T Centers across the United States. In all, 7,215 (20.2%) out of the 34,016 patients had high estradiol levels defined as >/=42.6 pg/ml. Estradiol was measured using electro-chemiluminescence immunoassay.


Of the patients who had high estradiol levels, the age distribution was as follows: 132/989 (13.3%) were older than 65 years, 3,753/16,955 (22.1%) were between 45 and 65 years; 2,968/15,857 (18.7%) were between 25 and 44 years, 7/215 (3.3%) were younger than 25 years. The difference between extreme age groups (<25 and >/=65) was statistically significant using a chi-square test (p = .013). The correlation coefficient of serum estradiol to age was .53, SD = 8.21.


It was observed that practitioners used aromatase inhibitor and selective estrogen receptor modulator to treat symptoms of hyperestrogenism, irrespective of blood estradiol levels. Gynecomastia was rarely documented as a reason for the prescription.


OUR FINDING WAS THAT HIGH ESTRADIOL LEVELS WERE NOT ASSOCIATED WITH HIGHER RATES OF LOW LIBIDO BUT ESTABLISHED HIGHER RATES OF DOCUMENTED LOW LIBIDO WITH THOSE WITH NORMAL OR LOWER ESTRADIOL LEVELS. The difference was statistically significant (p < .05).


Tan RS, Cook KR, Reilly WG. High estrogen in men after injectable testosterone therapy: the low T experience. Am J Mens Health 2015;9(3):229-34.

__________________________________________________________


One study that capped estradiol at 35 pg/mL did so after reviewing data in older men with an average of 320 ng/dL of total testosterone who had history of cardiovascular disease.

NEGATIVE ESTRADIOL STUDY:
Testosterone, DHT and Estradiol and Mortality in Older Men


Not one study has looked at the effect of estradiol on cardiovascular, edema, erectile function, gynecomastia incidence and mood in men on TRT with TT levels above 500 ng/ml. NOT ONE. I am not saying high estradiol is not a problem. What I am saying is that men with higher TT can accommodate more estradiol than men with low TT. Using the same upper limit for both populations makes no sense at all unless proven by a study. The Life Extension article that started this craze plus our preconceived judgment of a "female" hormone has not served us well in this field.

It is my belief that over 50 % of men on TRT should not have been prescribed anastrozole at baseline but at week 6 or 8 of follow up and using the correct LC/MS testing assay for estradiol.

Nipple sensitivity, like penis sensitivity, increases with estradiol. The former has nothing to do with gynecomastia. Also, the majority of cases of edema have nothing to do with high estradiol levels. These two considerations are overused and abused in the clinical world.

Like DHT, estradiol is downstream of testosterone not to diminish its effect but to enhance it.

Men with a history of gynecomastia (mostly those with high IGF-1 and a genetic predisposition) may be more sensitive to higher levels of estradiol than others. But most men not on anastrozole do not ever get gynecomastia.

I consider Dr. Mongentaler the smartest TRT doctor in the world. He hardly mentions estradiol in his talks and had done a review of studies that left him with the same questions I have.

We have broken through the myths of TRT causing prostate cancer and heart attacks. The next myth to be broken will be the estradiol one. We just need more data from physicians groups willing to follow men with TT over 500 ng/dL and hopefully stratify them up to 1500 ng/dL.

You can download the paper attached to this post (registered members only).
 

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Nelson Vergel

Founder, ExcelMale.com
Thread starter #7
A well-written article that provides caution in decreasing estradiol too much.

Muscle Growth and the Estrogen Connection


No longer viewed solely as a “female” sex steroid, the role of estrogen in muscle growth is undeniable. A multi-faceted growth agent, estrogen works hand in hand with testosterone to maximize many of the body's key anabolic and anti-catabolic processes in a dose-dependent manner. Although science has yet to reveal the amount of estrogen required to maximize muscle hypertrophy, bodybuilders should be cautioned against the over-suppression of estrogen, as the evidence suggests that the current trend of maintaining estrogen levels within the low-normal range is unlikely to provide full muscle building benefits.

Muscle Growth and the Estrogen Connection

_________________________________________

A review of estradiol as a male hormone:

Estradiol as a male hormone

(From European Society of Endocrinology 2019 , Russel et al, Approved May 2019)

Evidence has been accumulating that, in men, some of the biological actions traditionally attributed to testosterone acting via the androgen receptor may, in fact, be dependent on its aromatisation to estradiol (E2). In men, E2 circulates at concentrations exceeding those of postmenopausal women, and estrogen receptors are expressed in many male reproductive and somatic tissues. Human studies contributing evidence for the role of E2 in men comprise rare case reports of men lacking aromatase or a functional estrogen receptor alpha, short term experiments manipulating sex steroid milieu in healthy men, men with organic hypogonadism or men with prostate cancer treated with androgen deprivation therapy (ADT), and from observational studies in community-dwelling men. The collective evidence suggests that, in men, E2 is an important hormone for hypothalamic-pituitary-testicular axis regulation, reproductive function, growth hormone-insulin-like growth factor-1 axis regulation, bone growth and maintenance of skeletal health, body composition and glucose metabolism, and vasomotor stability. In other tissues, particularly brain, elucidation of the clinical relevance of E2 actions requires further research. From a clinical perspective, the current evidence supports the use of testosterone as the treatment of choice in male hypogonadism, rather than aromatase inhibitors (which raise testosterone and lower E2), selective androgen receptor modulators, and selective estrogen receptor modulators (with insufficiently understood tissue-specific estrogenic effects). Finally, E2 treatment, either as add-back to conventional ADT (androgen deprivation therapy for prostate cancer) or as the sole mode of ADT could be a useful strategy for men with prostate cancer.
 
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Nelson Vergel

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Another study warns about low estrogen in men:

"The study was presented at the Endocrine Society's 97th annual meeting this month. In addition to finding that higher levels of testosterone led to lower HDL, and that estrogen didn't affect HDL, Yu's team found that low levels of estrogen led to higher fasting blood sugar levels, worsening insulin resistance and increasing fat in muscles. The latter indicates developing diabetes, a risk factor for heart disease."

Men's Heart Disease Partly Due to Low Estrogen
 
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Nelson Vergel

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SAT-237: High Aromatase Activity in Men with Low Testosterone Is Associated with Higher Spine BMD, Increased Truncal Fat Mass and Reduced Lean Mass


Abstract:Background: Because the aromatase enzyme catalyzes the conversion of testosterone to estradiol, the activity of this enzyme could be important in the musculoskeletal health of men with low testosterone.

Objective: To determine the influence of aromatase activity on the bone mineral density (BMD) and body composition of patients with low testosterone.

Methods: The baseline data of ninety patients, between 40 to 74 years old, participating in a genetic study of response to testosterone therapy in men with low testosterone (i.e. <300 ng/dl) were analyzed. BMD and body composition were measured by dual-energy x-ray absorptiometry. Serum testosterone was measured by automated immunoassay, estradiol by ultrasensitive enzyme immunoassay, and sex hormone binding globulin by enzyme immunoassay.

Results: Men in the highest tertile of estradiol to testosterone ratio (E2/T) had the highest spine BMD (p=<0.048), highest truncal fat (p=0.046) and lowest total lean body mass (p=0.045). A similar pattern was observed in the upper extremities, i.e. fat mass significantly increased (p=0.047) while lean mass significantly decreased (p=0.034) with increasing E2/T tertiles.

Conclusions: Our findings suggest that in men with low testosterone, aromatase activity could be an important determinant of musculoskeletal health. Men with high aromatase activity are able to maintain a higher BMD despite low circulating testosterone but have lower lean and higher truncal fat mass compared to those with lower aromatase activity.


Values are Means±SD, E2/T: estradiol to testosterone ratio, FEI: free estradiol index, FAI: free androgen index
*p<0.05 tertile 1 vs. tertile 3.
**p<0.05 tertile 2 vs. tertile 3.
 
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Nelson Vergel

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Effects of Aromatase Inhibition on Bone Mineral Density and Bone Turnover in Older Men with Low Testosterone Levels

The Journal of Clinical Endocrinology & Metabolism
Volume 94, Issue 12

Context: Aging is associated with declining gonadal steroid production, low bone mineral density (BMD), and fragility fractures. The efficacy and safety of testosterone replacement in older men remains uncertain.

Objective: The objective of the study was to assess the effects of aromatase inhibition on BMD in older men with low testosterone levels.

Design and Setting: This was a 1-yr, double-blind, randomized, placebo-controlled trial that was conducted at a tertiary care academic center in Boston, MA.
Participants: Participants included 69 men aged 60+ yr with borderline or low testosterone levels and hypogonadal symptoms.

Intervention: Intervention included 1 mg anastrozole daily or placebo.

Main Outcome Measures: Changes in gonadal steroid hormone levels, BMD, and bone turnover markers were measured.

Results: Mean serum testosterone increased from 319 ± 93 ng/dl at baseline to 524±139 ng/dl at month 3 (P < 0.0001) and declined slightly to 474 ± 145 ng/dl by 1 yr. Estradiol levels decreased from 15 ± 4 pg/ml at baseline to 12 ± 4 pg/ml at month 3 and then remained stable (P< 0.0001). Posterior-anterior (PA) spine BMD decreased in the anastrozole group as compared with placebo (P = 0.0014). In the anastrozole group, PA spine BMD decreased from 1.121 to 1.102 ± 0.138 g/cm whereas in the placebo group, PA spine BMD increased from 1.18 g/cm to 1.189 ± 0.146 g/cm. Qualitatively similar, but not statistically significant, changes occurred at the other sites. Bone turnover markers were not affected by anastrozole therapy.
 

Nelson Vergel

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Testosterone Needs Estrogen's Help to Inhibit Depression

"Kabbaj's latest paper was published in Biological Psychiatry.He already knew that testosterone had a protective effect on males, just as estrogen and progesterone do on females. He also knew that most testosterone was converted into estrogen in the brain. What he didn't know was that those anxiety- and depression-inhibiting effects couldn't be produced unless the testosterone was first converted to estrogen.
“There is an enzyme in the brain that 'mediates' the conversion of testosterone into estrogen,” Kabbaj said. “We inhibited that enzyme in a specific brain area implicated in the regulation of mood. And when you do that, you lose the antidepressant effect of testosterone. So the conversion is very important.”
His lab targeted the hippocampus area of the brain, where testosterone acts through what's known as the MAPK pathway to induce its antidepressant and anti-anxiety effects.
“But we have to be careful about that pathway,” Kabbaj said, “because it's also implicated in cellular growth and cancer. Therefore, we're looking for other pathways that don't have these effects. It's complicated. Nothing is ever simple, but we'll get there.”

Testosterone needs estrogen's help to inhibit depression - Florida State University News
 

Nelson Vergel

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estradiol brain effects.gif



"There are further experiments on rats that clarify how testosterone acts in the brain. If estradiol is injected into the hypothalamus of a castrated rat instead of testosterone, it works just as well in restoring normal intromission and ejaculation. If one injects DHT—a very potent androgen that cannot be converted to estradiol—no recovery is seen. These findings together suggest that, when testosterone enters the hypothalamus, it is converted to estradiol (by the enzyme aromatase), and estradiol then facilitates sexual behavior (Nelson, 2011). Consistent with this interpretation, both the enzyme aromatase and estrogen receptors are present in the hypothalamus. Furthermore, the administration of drugs that block the action of aromatase interferes with the behavioral effects of testosterone. Thus we can conclude that the conversion (or “aromatization”) of testosterone to estradiol is necessary for male sexual behavior in rats. So much for the notion that estrogens are “female” hormones."

There is also some uncertainty about the importance of the aromatization process (the conversion of testosterone to estradiol in the brain) for human sexuality. There have been suggestions that testosterone acts directly on the brain in primates and does not require conversion to estradiol. Aromatization clearly does play some role, however. Aromatase-blocking drugs interfere with sexual activity in male monkeys, and men who are congenitally deficient in the aromatase enzyme have a low sex drive, which can be increased by the administration of estradiol. It seems most likely that the effects of testosterone on men's sexuality are partly direct (via androgen receptors) and partly indirect (via aromatization and estrogen receptors), but the differences between these two kinds of effects remain to be worked out."

Human Sexuality 4e: Web Topics
 
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Nelson Vergel

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Am J Respir Crit Care Med. 2015 Dec 10. [Epub ahead of print]

Higher Estradiol and Lower Dehydroepiandrosterone-Sulfate Levels Are Associated With Pulmonary Arterial Hypertension in Men.

Ventetuolo CE1, Baird GL2, Barr RG3, Bluemke DA4, Fritz JS5, Hill NS6, Klinger JR7, Lima JA8, Ouyang P9, Palevsky HI10, Palmisciano AJ11, Krishnan I12, Pinder D13, Preston IR14, Roberts KE15, Kawut SM16.



Abstract

RATIONALE:
Recent studies have focused on the role of female sex and estradiol (E2) in pulmonary arterial hypertension (PAH), but it is not known whether sex hormones are risk factors for PAH in men.

OBJECTIVES:
We performed a case-control study to determine whether hormone levels (E2, dehydroepiandrosterone-sulfate [DHEA-S], and testosterone) are associated with PAH in men.

METHODS:
Plasma sex hormone levels in men with idiopathic, heritable, or connective tissue disease-associated PAH were compared to those from age- and body mass index-matched men without clinical cardiovascular disease.

MEASUREMENTS AND MAIN RESULTS:
There were 23 cases with PAH (70% had idiopathic PAH, 65% were functional class III/IV) and 67 controls. Higher E2 and E2:testosterone levels were associated with the risk of PAH (OR per 1 ln[E2:testosterone] = 6.0, 95% CI 2.2 - 16.4, p = 0.001) while higher levels of DHEA-S were associated with a reduced risk (OR per 1 ln[DHEA-S] = 0.1, 95% CI 0.0 - 0.3, p = 0.001). E2 and DHEA-S levels were strong predictors of case status (c-statistic for both 0.82) but testosterone was not (c-statistic 0.53). Higher levels of E2 were associated with shorter six-minute walk distances (p = 0.03) whereas higher levels of DHEA-S were associated with lower right atrial pressure (p = 0.02) and pulmonary vascular resistance (p = 0.01) in men with PAH.

CONCLUSIONS:
Higher levels of E2 and lower levels of DHEA-S were associated with PAH in men. Sex-based differences in sex hormone processing and signaling may contribute to unique phenotypes in pulmonary vascular disease.
 
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