Role of Estradiol (Estrogen) in Men and Its Management

[Nelson Vergel]

STUDY LOOKING AT EFFECT OF ESTRADIOL ON MORTALITY IN MEN:

Weakness of this study: Men who were older, sicker and with average T of 325 ng/dL. Can these results be extrapolated for men with higher T who are younger and healthier? I doubt it. Unless we follow T/E2 ratios, we can't conclude much from these data.

This study found that estradiol levels of < 21.80 pg/ml and > 30.11 pg/ml resulted in greater mortality in men.


Abstract

CONTEXT:

Androgen deficiency is common in men with chronic heart failure (HF) and is associated with increased morbidity and mortality. Estrogens are formed by the aromatization of androgens; therefore, abnormal estrogen metabolism would be anticipated in HF.


OBJECTIVE:

To examine the relationship between serum concentration of estradiol and mortality in men with chronic HF and reduced left ventricular ejection fraction (LVEF).


DESIGN, SETTING, AND PARTICIPANTS:

A prospective observational study at 2 tertiary cardiology centers (Wroclaw and Zabrze, Poland) of 501 men (mean [SD] age, 58 [12] years) with chronic HF, LVEF of 28% (SD, 8%), and New York Heart Association [NYHA] classes 1, 2, 3, and 4 of 52, 231, 181, and 37, respectively, who were recruited between January 1, 2002, and May 31, 2006. The cohort was divided into quintiles of serum estradiol

quintile 1, < 12.90 pg/mL;
quintile 2, 12.90-21.79 pg/mL;
quintile 3, 21.80-30.11 pg/mL;
quintile 4, 30.12-37.39 pg/mL;
and quintile 5, > or = 37.40 pg/mL.

Quintile 3 was considered prospectively as the reference group.


MAIN OUTCOME MEASURES:

Serum concentrations of estradiol and androgens (total testosterone and dehydroepiandrosterone sulfate [DHEA-S]) were measured using immunoassays.


RESULTS:

Among 501 men with chronic HF, 171 deaths (34%) occurred during the 3-year follow-up. Compared with quintile 3, men in the lowest and highest estradiol quintiles had increased mortality (adjusted hazard ratio

---

, 4.17; 95% confidence interval [CI], 2.33-7.45 and HR, 2.33; 95% CI, 1.30-4.18; respectively; P < .001). These 2 quintiles had different clinical characteristics (quintile 1: increased serum total testosterone, decreased serum DHEA-S, advanced NYHA class, impaired renal function, and decreased total fat tissue mass; and quintile 5: increased serum bilirubin and liver enzymes, and decreased serum sodium; all P < .05 vs quintile 3). For increasing estradiol quintiles, 3-year survival rates adjusted for clinical variables and androgens were 44.6% (95% CI, 24.4%-63.0%), 65.8% (95% CI, 47.3%-79.2%), 82.4% (95% CI, 69.4%-90.2%), 79.0% (95% CI, 65.5%-87.6%), and 63.6% (95% CI, 46.6%-76.5%); respectively (P < .001).

Reference:

Circulating estradiol and mortality in men with systolic chronic heart failure.
JAMA 2009 May 13;301(18):1892-901.

 

[Nelson Vergel]

STUDY LOOKING AT THE EFFECT OF ESTRADIOL ON BONE DENSITY IN MEN:


This study followed young and older men's testosterone and estradiol to see their impact on bone density. Estradiol below 11 pg/ml was associated with increased bone loss.

Abstract

Estrogen appears to play an important role in determining bone mineral density in men, but it remains unclear whether estrogen primarily determines peak bone mass or also affects bone loss in elderly men. Thus, we assessed longitudinal rates of change in bone mineral density in young (22-39 yr; n = 88) vs. elderly (60-90 yr; n = 130) men and related these to circulating total and bioavailable estrogen and testosterone levels. In young men, bone mineral density increased significantly over 4 yr at the mid-radius and ulna and at the total hip (by 0.3-0.43%/yr), whereas it decreased in the elderly men at the forearm sites (by 0.49-0.66%/yr), but did not change at the total hip. The rate of increase in bone mineral density at the forearm sites in the young men was significantly correlated with serum total and bioavailable estradiol and estrone levels, but not with total or bioavailable testosterone levels. In the elderly men, the rates of bone loss at the forearm sites were most closely associated with serum bioavailable estradiol levels rather than bioavailable testosterone levels. Moreover, elderly men with bioavailable estradiol levels below the median [40 pmol/liter (11 pg/ml)] had significantly higher rates of bone loss and levels of bone resorption markers than men with bioavailable estradiol levels above 40 pmol/liter. These data thus indicate that estrogen plays a key role both in the acquisition of peak bone mass in young men and in bone loss in elderly men. Moreover, our findings suggest that age-related decreases in bioavailable estradiol levels to below 40 pmol/liter may well be the major cause of bone loss in elderly men. This subset of men is perhaps most likely to benefit from preventive therapy.

Reference:

Relationship of Serum Sex Steroid Levels to Longitudinal Changes in Bone Density in Young Versus Elderly Men. The Journal of Clinical Endocrinology & Metabolism August 1, 2001 vol. 86 no. 83555-3561

 

[Nelson Vergel]

TWO STUDIES LOOKING INTO THE EFFECT OF HIGH ESTRADIOL ON LIBIDO IN MEN ON TESTOSTERONE THERAPY


I have been warning men and clinics not to be so aggressive in treating estradiol in men with the overuse of anastrozole. Here is a recent study was done in Houston.


Elevated serum estradiol is associated with increased libido in men receiving testosterone replacement therapy (TRT), according to researchers.

In a study of 423 men on TRT, Ranjith Ramasamy, MD, working with Larry Lipshultz, MD, at the Baylor College of Medicine in Houston, measured subjects' testosterone and estradiol levels and asked the men to rate the quality of their libido using a five-point Likert scale (1= terrible, 5 = excellent). The researchers categorized the men as having low or high testosterone (below or above 300 ng/dL, respectively) and low or high estradiol (below 5 and above 5 ng/dL (50 pg/mL), respectively).

Men with high serum testosterone levels reported significantly greater libido than men with low level and those with high serum estradiol levels had significantly greater libido than subjects with low levels. In all, 60.4% of men with both high testosterone and estradiol levels reported very good or excellent libido (score as 4 or 5) compared with 31.3% of participants with both low testosterone and estradiol levels, the researchers reported in European Urology (published online ahead of print

Source

 

[Nelson Vergel]

High Estrogen in Men After Injectable Testosterone Therapy

The Low T Experience

Robert Tan, Low T Institute, Southlake, TX, USA
Robert S. Tan, 3311 Richmond #205, Houston, TX 77098, USA.

Abstract

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 &#8805;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).

Source

 

[Nelson Vergel]

Plasma Estradiol Concentrations and Effect of HCG on Plasma Estradiol and Testosterone in Normal Men and Women and Patients with Endocrine Disorders

Abstract
Plasma estradiol concentrations were determined by radioimmunoassay in various endocrine disorders using antiserum to estradiol-17β succinyl bovine serum albumin. Clinical significance and diagnostic value of plasma estradiol were assessed in hypothalamic-pituitary, adrenal and gonadal disorders. In general, estradiol concentration was correlated well with the degree of sexual maturity and was of great diagnostic use. Plasma estradiol in females mainly originated from the ovary, while the testis is the principal source of estradiol in males. The adrenal gland seemed to play a minor role as a source of estradiol at least in normal males and females. The role of estradiol in gynecomastia and in liver disease was also investigated. More than a half of the cases with gynecomastia had elevated concentrations of plasma estradiol, which probably explains the pathogenesis of this manifestation. Cirrhotic patients showed frequently hyperestrogenemia probably due to delayed disappearance of estradiol. In the study of stimulation with human chorionic gonadotropin (HCG), 3, 000 IU daily for three days in ten normal men, the peripheral concentrations of estradiol showed maximun and fourfold increases 24 hours after the lst injection of HCG. The testosterone levels, on the other hand, increased stepwise and reached a maximum of about two times preinjection levels 24 hours after the 3rd injection. In gonadal disorders, HCG produced various patterns of plasma estradiol and testosterone in accordance with the gonadal conditions and dissociated response patterns of both sex hormones were frequently found. The determination of plasma estradiol was useful in the study of the function of not only the ovary, but also the testis and the simultaneous measurement of plasma estradiol and testosterone after HCG administration presented interesting informations about pathophysiology of gonadal disorders.

The following graphics were based on the old estradiol test (immoassay-based), so actual levels should be lower when using the more accurate sensitive estradiol blood test (lipquid chromatography- Mass Spectrometry based). Values are shown in picograms per milliliter.

 

[Nelson Vergel]

Video: Estradiol in Men: Interview with Urology Professor Dr Ranjith Ramasamy

 

[Nelson Vergel]

Estradiol In Men – Why Is It Important For Optimal Health And Fitness Performance – Part 1

 

[Nelson Vergel]

Finally, a study comparing the regular versus sensitive estradiol tests.

Study: Comparison of total estradiol measured by immunoassay and LC-MS/MS (sensitive)

Of the subjects, 60 men had total estradiol measured by both the assays. The mean and median total estradiol concentrations measured by immunoassay were 3.95 ± 1.31 and 3.9 [3.1–4.8] ng/dL, respectively. In contrast, the mean and median total estradiol concentrations measured by LC-MS/MS were lower by almost half (2.16 ± 1.66 and 1.9 [0.8–3.2] ng/dL, respectively; P < 0.001 for comparison with immunoassay). The total estradiol concentrations measured by the two assays correlated only weakly (r = 0.37, P = 0.004).
Reference

 

[Nelson Vergel]

Another good reason not to lower your estradiol too much. Estradiol is important for maintaining good cholesterol blood levels.


J Clin Endocrinol Metab. 1994 Apr;78(4):855-61.
Physiological levels of estradiol stimulate plasma high density lipoprotein cholesterol levels in normal men.


Abstract
Premenopausal women have a lower risk of coronary artery disease than men or postmenopausal women; estrogens are thought to contribute to this lower risk. Administration of exogenous estrogen to post-menopausal women increases plasma high density lipoprotein (HDL) cholesterol and may reduce mortality from coronary disease in users. Although many investigations have examined the roles of estrogen in the regulation of lipoproteins in women, little attention has been directed to estrogen regulation of lipids in men. We designed a paradigm to study the role of physiological levels of estradiol (E2) on plasma lipoproteins in healthy men. We used a GnRH antagonist, Nal-Glu, to suppress endogenous steroid hormones in healthy men. We then administered testosterone (T) enanthate (100 mg, im, weekly) to restore T levels to the baseline range, and we administered an aromatase inhibitor, testolactone (Teslac), to prevent the normal conversion of T to E2, thereby producing a selective estrogen deficiency state in normal young men. As controls, we administered Nal-Glu and T along with placebo Teslac to a separate group of men; a third group of men received all placebo medications. We found that in men who received Nal-Glu plus T plus Teslac, E2 levels were profoundly suppressed during treatment, whereas T levels remained in the baseline range. Plasma HDL cholesterol, particularly, the HDL2 fraction, decreased significantly in response to the low serum E2 level. Plasma apoprotein-AI levels also decreased significantly. Plasma LDL and triglyceride levels did not change. All hormone and lipoprotein parameters returned to baseline within 4 weeks after treatment ended. In men who received Nal-Glu plus T, plasma HDL and apoprotein-AI decreased, but these decreases did not achieve statistical significance. Only a small decrease in HDL2 cholesterol was seen in these men. There were no hormonal or lipid changes in the placebo group. We conclude that in men, physiological levels of E2 are important in maintaining plasma levels of HDL cholesterol, especially the HDL2 fraction. These observations suggest that estrogen, in the amount normally produced in men, may offer some degree of protection against cardiovascular disease in males, as they do in women.

 

[Nelson Vergel]

Evidence of the Effect of Low Estradiol on Fracture Risk in Men

 

[Nelson Vergel]

 

[Nelson Vergel]

For references on each micronutrient: https://www.spectracell.com/media/uploaded/3/0e2064995_391estrogenwheel.pdf

 

[Nelson Vergel]

 

[Nelson Vergel]

Impact of Estrogens in Males and Androgens in Females

Androgens and estrogens are known to be critical regulators of mammalian physiology and development. While these two classes of steroids share similar structures (in general, estrogens are derived from androgens via the enzyme aromatase), they subserve markedly different functions via their specific receptors.

In the past, estrogens such as estradiol were thought to be most important in the regulation of female biology, while androgens such as testosterone and dihydrotestosterone were believed to primarily modulate development and physiology in males.

However, the emergence of patients with deficiencies in androgen or estrogen hormone synthesis or actions, as well as the development of animal models that specifically target androgen- or estrogen-mediated signaling pathways, have revealed that estrogens and androgens regulate critical biological and pathological processes in both males and females.

In fact, the concept of "male" and "female" hormones is an oversimplification of a complex developmental and biological network of steroid actions that directly impacts many organs. In this Review, we will discuss important roles of estrogens in males and androgens in females.

Hammes SR, Levin ER. Impact of estrogens in males and androgens in females. J Clin Invest 2019;129:1818-26.

Paper attached (Only viewed if you are registered and logged in)

 

[Nelson Vergel]

The Anxiolytic and Antidepressant-like Effects of Testosterone and Estrogen in Gonadectomized Male Rat


Abstract

Background

While the influence of testosterone levels on vulnerability to affective disorders is not straightforward, research suggests this hormone may confer some degree of resiliency in men. We recently demonstrated a role for the dentate gyrus in mediating testosterone's protective effects on depressive-like behavior in gonadectomized male rats. Here, testosterone may exert its effects through androgen receptor-mediated mechanisms or via local aromatization to estradiol.

Methods

Gonadectomized male rats were implanted with a placebo, testosterone, or estradiol pellet, and subsequent protective anxiolytic- and antidepressant-like effects of testosterone and its aromatized metabolite, estradiol, were then investigated in the open field and sucrose preference tests, respectively. Moreover, their influence on gene expression in the hippocampus was analyzed by genome-wide complementary DNA microarray analysis. Finally, the contribution of testosterone's aromatization within the dentate gyrus was assessed by local infusion of the aromatase inhibitor fadrozole, whose efficacy was confirmed by liquid chromatography-tandem mass spectrometry.

Results

Both hormones had antidepressant-like effects associated with a substantial overlap in transcriptional regulation, particularly in synaptic plasticity- and mitogen-activated protein kinase pathway-related genes. Further, chronic aromatase inhibition within the dentate gyrus blocked the protective effects of testosterone.

Conclusions

Both testosterone and estradiol exhibit anxiolytic- and antidepressant-like effects in gonadectomized male rats, while similarly regulating critical mediators of these behaviors, suggesting common underlying mechanisms. Accordingly, we demonstrated that testosterone's protective effects are mediated, in part, by its aromatization in the dentate gyrus. These findings thus provide further insight into a role for estradiol in mediating the protective anxiolytic- and antidepressant-like effects of testosterone.

 

[Nelson Vergel]

Age-Specific Serum Total and Free Estradiol Concentrations in Healthy Men in US Nationally Representative Samples

 

[Nelson Vergel]

Aromatized Estrogens Amplify Nocturnal Growth Hormone Secretion in Testosterone-Replaced Older Hypogonadal Men

Ferdinand Roelfsema, Rebecca J Yang, Paul Y Takahashi, Dana Erickson, Cyril Y Bowers, Johannes D Veldhuis
The Journal of Clinical Endocrinology & Metabolism, Volume 103, Issue 12, December 2018, Pages 4419–4427, Aromatized Estrogens Amplify Nocturnal Growth Hormone Secretion in Testosterone-Replaced Older Hypogonadal Men
Published: 18 July 2018 Article history

Abstract

Context
Testosterone (T) increases GH secretion in older men with a relative lack of T, in hypogonadal men of all ages, and in patients undergoing sex reassignment. The role of estradiol (E2) in men is less well defined.

Objective
To assess the contribution of aromatization of T to spontaneous nocturnal and stimulated GH secretion.

Participants
Four groups of healthy older men (N = 74, age range 57 to 77 years) were studied. The gonadotropic axis was clamped with the gonadotropin-releasing hormone antagonist degarelix. Three groups received T and one group placebo addback. Two T-replaced groups were treated with anastrozole (an aromatase inhibitor) and either placebo or E2 addback.

Main Outcome Measures
Ten-minute GH concentration profiles were quantified by deconvolution analysis, after overnight (2200 to 0800 hours) sampling, and after combined IV injection of GHRH (0.3 µg/kg) and GHRH-2 (0.3 µg/kg) and withdrawal of a 2-hour somatostatin infusion (1 µg/kg/h).

Results
E2 addback during aromatase inhibition increased basal (P = 0.046), pulsatile (P = 0.020), and total (P = 0.018) GH secretion by 60% to 70%. E2 did not potentiate GH secretory stimuli. Logarithmically transformed pulsatile GH secretion correlated strongly and positively with concurrent E2 concentrations overall (P = 0.028) and under anastrozole treatment (P = 0.005).

Conclusion
E2 administration in older men transdermally stimulates overnight pulsatile GH secretion. The exact site of E2 action cannot be ascertained from these experiments but may include hypothalamic loci involved in GH regulation, especially because GH secretagogue effects on somatotrope pituitary cells were not affected.

 

[Nelson Vergel]

Estradiol is an Important Hormone for Men

 

[Nelson Vergel]

How to Predict Estradiol and DHT at Different Testosterone Doses

I was able to come up with a table using the predictive model equation derived from data in this study: The Effects of Injected Testosterone Dose and Age on the Conversion of Testosterone to Estradiol and Dihydrotestosterone in Young and Older Men Summary This video discusses a research paper...

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[Nelson Vergel]

Estradiol is an Important Hormone for Men

* read full paper (pdf) MECHANISMS IN ENDOCRINOLOGY Estradiol as a male hormone Nicholas Russell and Mathis Grossmann Abstract Evidence has been accumulating that, in men, some of the biological actions traditionally attributed to testosterone acting via the androgen receptor may...

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