Estrogen in Men: Roles and Emerging Knowledge

Nelson Vergel · Jun 7, 2023

Introduction

Most men would not believe that estradiol as a male hormone as they are unaware about the role that estradiol (E2) plays in the maintenance of men's health. In particular, the roles of E2 are emphasized in relation to sperm quality and quantity [1,] the regulation of the growth hormone and insulin-like growth factor-1 (GH-IGF-1) axis [3,] bone growth and the maintenance of skeletal health [4,] body composition and glucose metabolism [5,] vasomotor stability [6,] and brain function [8].

Estradiol is a hormone more abundant in women than men that is produced by the aromatization of testosterone in liver, fat and other cells [1]. It has been shown to be responsible for healthy bone density [2], but its role in men's sex drive, body composition and other variables is debated [3]. High estradiol blood levels can cause gynecomastia in the presence of low testosterone [4]. Anastrozole, a blocker of estradiol production, is prescribed to men who start testosterone replacement (TRT) [5]. However, there is no data on how high is too high when it comes to estradiol in men [6].

The Essential Role of Aromatase in the Production of E2

Aromatase is an enzyme that converts androstenedione and testosterone into E2 in males [3]. According to the research that has been done, the hormone E2 is critically important in the control of a variety of different elements of male health [6].

E2 and the Function of the Male Reproductive System

The modulation of spermatogenesis is one of the key functions that E2 performs in the male reproductive system. It carries out its duties as a paracrine factor in the Sertoli cells of the testis, where it encourages the maturation and division of germ cells [1]. E2 also has an effect on the hypothalamic-pituitary-gonadal axis, which is the system that regulates testosterone secretion and spermatogenesis [1, 7].

The Effect of E2 on the Growth Hormone-IGF-1 Axis

It has been proven that E2 plays a significant role in the regulation of the GH-IGF-1 axis in men [3]. In healthy men, there is a positive correlation between the levels of E2 and the levels of serum IGF-1. It is possible that E2 uses negative feedback to limit GH secretion.

The Effects of E2 on the Development and Health of Bones and Skeletons

E2 is a crucial hormone for the growth and upkeep of men's bones, as well as their overall skeletal health. It does so by promoting osteoblast differentiation and activity and suppressing osteoclast differentiation and activity [4] [11]. In this way, it exerts an indirect influence on these features.

The Influence of E2 on the Composition of the Body as well as Glucose Metabolism

E2 has an effect on both the makeup of a man's physique as well as his glucose metabolism. It appears to selectively accelerate the accumulation of body fat in subcutaneous regions while at the same time limiting the accumulation in visceral regions [5]. Additionally, it has been demonstrated that E2 can improve glucose metabolism in hypogonadal men [5].

Regulation of Vasomotor Stability by E2 and Its Effects

Additionally, E2 contributes to the regulation of vasomotor stability in males. It is believed that the production of nitric oxide (NO) is a mediator of the vasomotor actions of ethyl ester.

The Role of Nitric Oxide in Vasodilation

Nitric oxide, often known as NO, is an important physiological mediator that plays a role in a wide variety of biological activities, some of which are associated with the cardiovascular system. In the setting of the vascular system, NO plays an important function in vasodilation, controlling blood pressure, preventing blood clots, and stimulating angiogenesis [1, 2, 5].

The Effects of Estrogen on NO Production and Vasodilation

It has been demonstrated that estrogens, in general, can have an effect on the generation of NO and, as a result, can mediate vasodilation. They can use both direct and indirect processes to achieve the desired vasodilatory effects. Direct mechanisms involve attaching to estrogen receptors that are present on the endothelial cells and increasing the generation of NO. This, in turn, causes the blood vessels to become more dilated. Altering the synthesis and release of other vasoactive chemicals, such as prostaglandins, which could affect NO production, is an example of one of the indirect mechanisms that could be at play.

The Need for Further Research

Please be aware that despite the fact that the idea that NO synthesis mediates the vasodilation effects of E2 is reasonable based on the known actions of estrogens and NO, further research is required to determine the particular role that E2 plays in this process. In light of this, in order to get a more precise comprehension, it would be essential to consult the original literature or more current research investigations that place a particular emphasis on the role that E2 plays in modifying NO production and vasodilation.

Potential Side Effects of Testosterone Therapy and the Role of Aromatase Inhibitors

When men undertake testosterone therapy (TTh), their estrogen levels may increase, and this may, in some instances, result in the development of nipple or breast soreness or even gynecomastia (the formation of male breast tissue in males). This can be a clear indicator that aromatase inhibitors should be used to reduce the amount of estrogen in the body.

A Critical Review of Current Evidence

In spite of this, there is not sufficient evidence to justify the routine use of aromatase inhibitors in conjunction with TTH in the absence of indications of estrogen excess. Although testosterone levels returned to normal after therapy with an aromatase inhibitor, the symptoms of low testosterone did not improve, according to the findings of one randomized controlled trial.

Potential Risks of Overuse of Aromatase Inhibitors

In addition, decreasing estrogen levels below a key threshold may raise the likelihood of developing osteoporotic changes and decrease insulin sensitivity, particularly in people who are receiving TTH. These risks may be increased in people who are already at higher risk for developing osteoporosis.

The Case for Individualized Treatment Approach

The study did not find any proof to back up the claim that using TTH in combination with aromatase inhibitors or other medications would result in relative estrogen decreases that would be superior to TTH alone in terms of benefits. On the other hand, it was shown that certain TTH-treated men who had elevated estrogen levels but did not experience any clinical improvements from TTH did respond to actions taken to lower estrogen levels. These efforts included either a reduction in the amount of testosterone or the use of aromatase inhibitors. When this occurs, DXA monitoring is an option that should be examined.

Estradiol: Overview and Effects

Estradiol is a hormone more abundant in women than men that is produced by the aromatization of testosterone in liver, fat and other cells [1]. It has been shown to be responsible for healthy bone density [2], but its role in men's sex drive, body composition and other variables is debated [3].

Impact of High Estradiol Levels

High estradiol blood levels can cause gynecomastia in the presence of low testosterone [4]. Anastrozole, a blocker of estradiol production, is prescribed to men who start testosterone replacement (TRT) [5]. However, there is no data on how high is too high when it comes to estradiol in men [6].

Low Estradiol: Risks and Treatment

Low estradiol can be associated with higher fat mass and lower sexual function in men [7], so it is important to be careful when a clinic wants to put you on this drug without first justifying its use [8]. The most important details are that many clinics may be using the wrong estradiol test [9], and that most men on testosterone replacement therapy (TRT) do not develop gynecomastia even without using anastrozole [10].

Testosterone and Estradiol: A Complex Relationship

Some physicians monitor estradiol blood levels after 6-8 weeks of TRT initiation using the sensitive estradiol test to determine if anastrozole use is warranted [11]. After 4-6 weeks on anastrozole, its dose can be adjusted to ensure that estradiol is not under 20 pg/ml [12]. The body of evidence suggests that testosterone in men is mediated by the ERs (estrogen receptors) after its biotransformation by the aromatase P450 inhibitors in the tissues [13].

Estradiol's Role in Physiology

These estrogen-mediated actions include feedback regulation of LH, regulation of skeletal homeostasis, lipid metabolism, cardiovascular physiology, and brain and spermatogenesis [14].

Estradiol in Hypogonadism

Estradiol serum concentration in adult males is around 20-30 pg/ml, with a production rate of 45 g/d [15]. Low levels of estradiol are associated with increased fat and decrease in sexual desire and erectile function compared to higher levels [16].

Studies and Findings

This study found that estradiol levels of 21.80 pg/ml and > 30.11 pg/ml resulted in greater mortality in men with hypogonadism, suggesting that estrogen deficiency is largely responsible for some of the key consequences of male hypogonadism [17]. Estrogens have a fundamental role in the regulation of body fat and sexual function, and this suggests that measuring estradiol might be helpful in assessing the risk of sexual dysfunction, bone loss, or fat accumulation in men with hypogonadism [18].

Estradiol and Chronic Heart Failure

A study examined the relationship between serum concentration of estradiol and mortality in men with chronic heart failure and reduced left ventricular ejection fraction (LVEF) [19]. Results showed that men in the lowest and highest estradiol quintiles had increased mortality, while those in the highest quintile had increased survival rates [19].

Estradiol's Impact on Bone Density

Estradiol below 11 pg/ml was associated with increased bone loss [20]. Estrogen deficiency is common in men with chronic HF and is associated with increased morbidity and mortality [21]. Estrogen appears to play an important role in determining bone mineral density in men, but it is unclear if it also affects bone

Estrogen in Men: Studies

Estradiol is a hormone more abundant in women than men that is produced by the aromatization of testosterone in liver, fat and other cells [1]. It has been shown to be responsible for healthy bone density [2], but its role in men's sex drive, body composition and other variables is debated [3]. High estradiol blood levels can cause gynecomastia in the presence of low testosterone [4]. Anastrozole, a blocker of estradiol production, is prescribed to men who start testosterone replacement (TRT) [5]. However, there is no data on how high is too high when it comes to estradiol in men [6].

Low estradiol can be associated with higher fat mass and lower sexual function in men [7], so it is important to be careful when a clinic wants to put you on this drug without first justifying its use [8]. The most important details are that many clinics may be using the wrong estradiol test [9], and that most men on testosterone replacement therapy (TRT) do not develop gynecomastia even without using anastrozole [10]. Some physicians monitor estradiol blood levels after 6-8 weeks of TRT initiation using the sensitive estradiol test to determine if anastrozole use is warranted [11]. After 4-6 weeks on anastrozole, its dose can be adjusted to ensure that estradiol is not under 20 pg/ml [12]. The body of evidence suggests that testosterone in men is mediated by the ERs (estrogen receptors) after its biotransformation by the aromatase P450 inhibitors in the tissues [13].

These estrogen-mediated actions include feedback regulation of LH, regulation of skeletal homeostasis, lipid metabolism, cardiovascular physiology, and brain and spermatogenesis [14]. Estradiol serum concentration in adult males is around 20-30 pg/ml, with a production rate of 45 g/d [15]. Low levels of estradiol are associated with increased fat and decrease in sexual desire and erectile function compared to higher levels [16]. This study found that estradiol levels of 21.80 pg/ml and > 30.11 pg/ml resulted in greater mortality in men with hypogonadism, suggesting that estrogen deficiency is largely responsible for some of the key consequences of male hypogonadism [17]. Estrogens have a fundamental role in the regulation of body fat and sexual function, and this suggests that measuring estradiol might be helpful in assessing the risk of sexual dysfunction, bone loss, or fat accumulation in men with hypogonadism [18].

A study examined the relationship between serum concentration of estradiol and mortality in men with chronic heart failure and reduced left ventricular ejection fraction (LVEF) [19]. Results showed that men in the lowest and highest estradiol quintiles had increased mortality, while those in the highest quintile had increased survival rates [19]. Estradiol below 11 pg/ml was associated with increased bone loss [20]. Estrogen deficiency is common in men with chronic HF and is associated with increased morbidity and mortality [21]. Estrogen appears to play an important role in determining bone mineral density in men, but it is unclear if it also affects bone loss in elderly men [22].

Another study assessed longitudinal rates of change in bone mineral density in young and elderly men and related these to circulating total and bioavailable estrogen and testosterone levels [23]. The rate of increase in bone mineral density at the forearm sites in the young men was significantly correlated to serum total and bioavailable estradiol and estrone levels, but not with total or bioavailable testosterone levels [23].

Elderly men with bioavailable estradiol levels below the median had significantly higher rates of bone loss and levels of bone resorption markers than men with bioavailable estradiol levels above 40 pmol/liter [23]. Ranjith Ramasamy and Larry Lipshultz conducted a study of 423 men on TRT and found that those with high testosterone and estradiol levels had significantly greater libido than those with low levels [24]. The results are expected to be presented at the American Urological Association annual meeting in Orlando [24].

Hyperestrogenism is believed to be harmful to male sexuality [25]. A study screening 34,016 men in Low T Centers revealed that 7,215 (20.2%) had high estradiol levels [26]. The age distribution of those with high estradiol levels 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 [26]. The correlation coefficient of serum estradiol to age was .53 [26]. Low blood levels of estradiol (E2) are associated with brittle bones in old men, according to a new study [27].

Age-adjusted models showed that E2 and free E2 but not testosterone (T) associated significantly inversely with cortical porosity [28]. Free E2 also associated significantly with trabecular bone volume fraction, but this association did not remain significant after further adjustment [28]. Low serum E2 may reduce cortical bone strength and increase fracture risk in older men [29].

Conclusion

The hormone estradiol, also known as E2, has emerged as a key player in a myriad of biological functions in males. It is involved in the regulation of sperm health, the growth hormone-insulin-like growth factor-1 axis, bone health, body composition, glucose metabolism, vasomotor stability, and brain function. The key enzyme aromatase, which facilitates the conversion of androstenedione and testosterone to E2, is integral to these processes.

Understanding the role of E2 in male physiology helps shape our approach to health issues like low testosterone and the potential side effects of testosterone therapy. While the use of aromatase inhibitors can sometimes be beneficial in managing the effects of elevated estrogen levels, more evidence is needed before they can be recommended for routine use alongside testosterone therapy.

It is also crucial to consider the balance between testosterone and E2 in the male body, as overly suppressing estrogen levels might lead to unintended consequences such as osteoporotic changes and decreased insulin sensitivity. As we deepen our understanding of E2's role in the body, it becomes clear that a nuanced, individualized approach to treatment is needed to balance the benefits and risks.

Finally, there are still many open questions about the specific mechanisms through which E2 influences different aspects of male health. For example, the relationship between E2 and nitric oxide in mediating vasodilation remains to be fully elucidated. Therefore, more research is required to continue building a comprehensive understanding of E2's role in men's health. As we continue to learn, our approach to male hormonal health will evolve, bringing about new strategies for maintaining and improving men's health.

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References:

1 Estrogen in Men: How It Works and What High or Low Levels Mean

2 Estrogen in men: Symptoms of high and low levels, and more

3 https://academic.oup.com/ejendo/article/181/1/R23/6654090

4 The Importance of Estrogen (Estradiol) in Men’s Health

5 The Role of Estrogen in Men’s Health

6 Estrogen: Hormone, Function, Levels & Imbalances

7 https://eje.bioscientifica.com/downloadpdf/journals/eje/181/1/EJE-18-1000.pdf

9 Role of E2 in Men and Its Management | Testosterone Wisdom

10 What does Estradiol do?

11 https://eje.bioscientifica.com/view/journals/eje/181/1/EJE-18-1000.xml

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