Estrogen in Men: Roles and Emerging Knowledge

Introduction

Most men would not believe that estradiol is a male hormone, as they are unaware of the role that estradiol (E2) plays in the maintenance of men's health. E2 is important for many things, including the quality and quantity of sperm [1,] controlling the GH-IGF-1 axis [3,] bone growth and keeping bones healthy [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 the 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 therapy (TRT) [5]. However, there is no data on how high is too high when it comes to estradiol in men [6].

Introduction
The Essential Role of Aromatase in the Production of E2
- E2 and the Function of the Male Reproductive System
The Effect of E2 on the Growth Hormone-IGF-1 Axis
The Effects of E2 on the Development and Health of Bones and Skeletons
The Influence of E2 on the Composition of the Body as well as Glucose Metabolism
Regulation of Vasomotor Stability by E2 and Its Effects
Potential Side Effects of Testosterone Therapy and the Role of Aromatase Inhibitors
Estradiol: Overview and Effects
- Impact of High Estradiol Levels
- Low Estradiol: Risks and Treatment
Testosterone and Estradiol: A Complex Relationship
- Estradiol's Role in Physiology
Estradiol in Hypogonadism
- Studies and Findings
Estradiol and Chronic Heart Failure
Estradiol's Impact on Bone Density
Estrogen in Men: Studies
Conclusion
References:

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. Working as a paracrine factor, it does its job in the Sertoli cells of the testis, where it helps germ cells mature and divide [1]. It also changes the hypothalamic-pituitary-gonadal axis, which controls the production of testosterone and the making of sperm [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. People think that the production of nitric oxide (NO) plays a role in how ethyl ester affects blood vessels.

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. There are direct mechanisms that involve attaching to estrogen receptors on endothelial cells and making more NO. This, in turn, causes the blood vessels to become more dilated. One of the indirect ways that could be at work is by changing the production and release of other vasoactive chemicals, like prostaglandins, which could have an effect on NO production.

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. Because of this, to get a better understanding, it would be important to look at the original research papers or more recent studies that focus on the part that E2 plays in changing 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

Even so, there is not enough proof to support the regular use of aromatase inhibitors along with TTH when there are not any signs of estrogen overload. 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 evidence to support the claim that taking TTH with aromatase inhibitors or other medicines would lead to lower levels of estrogen that would be better than taking TTH by itself. 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

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 therapy (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

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 after aromatase P450 inhibitors biotransform testosterone in the tissues, the ERs (estrogen receptors) in men mediate its effects [13].

Estradiol's Role in Physiology

Some of the things that estrogen does are control LH feedback, skeletal homeostasis, lipid metabolism, cardiovascular physiology, brain development, 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

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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