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Role of estradiol in the brain
The effect of estradiol on libido is seen at various levels of regulation, starting with direct effects in the brain (Figure 1). Areas of the brain that control sexual behavior in mammals are thought to do so via pheromones that induce specific sexual effects on the autonomic nervous system, including changes in mood and sexual arousal. Pheromones produce increased activity in the medial preoptic area/anterior hypothalamus.1 Neurons, the most basic electrical information-transmitting cells in the central nervous system and peripheral nervous system, as well as astrocytes, star-shaped glial cells which fulfill a number of functions in the central nervous system, both convert testosterone to estrogen with aromatase. The preoptic area and anterior hypothalamus contain the highest levels of aromatase and estrogen receptors (ERs) in male rodents.2,3 Similarly, it is well known that selective serotonin reuptake inhibitors diminish libido. Serotonin receptors follow a pattern of distribution similar to that of ERs in the brain.4 However, the interaction of estradiol and serotonin is complex and will subsequently be addressed. Finally, aromatase activity is highest in the brain during development. Thus, not only does estradiol modulate sexual behavior in the adult male, it also appears to organize the early brain to program sexual behavior.3
Estradiol effect at low testosterone levels
To discern the effect of estradiol, it is important to evaluate its effect on libido at both low and normal levels of circulating testosterone. Decreased testosterone is clearly associated with low libido in males.5 In men with diminished testosterone, the administration of exogenous estradiol has been shown to increase libido.6 This finding is supported by rodent studies demonstrating that castrated animals given exogenous estrogen show an increase in sexual activity in a dose- and temporal-dependent manner.7 In addition, in a unique case report of a male patient with aromatase deficiency and hypogonadism, both estrogen and testosterone were required to increase libido, whereas neither hormone could achieve the effect alone suggesting that estrogen plays a necessary role in sexual desire in the setting of low testosterone.8
Similarly, patients with prostate cancer treated with androgen deprivation therapy (ADT) serve as a good model for the influence of estrogen on libido. When castrate levels of androgens were reached (T <50 ng dl-1), uniform adverse effects of hot flashes, erectile dysfunction (ED), and decrease in libido were reported.9 When comparing androgen receptor (AR) blockers versus castration, the former had better outcomes in maintaining sexual activity, presumably by increased testosterone conversion to estrogen.10This evidence, though indirect, does perhaps suggest that elevated estrogen in men with low or absent testosterone can sustain libido. In addition, administering estradiol to men undergoing ADT for prostate cancer could possibly reduce damage to areas of the brain associated with sexual performance. Thus, an overall increase in sexual quality of life could be achieved.6
Role of estradiol in eugonadal men
While estradiol has been shown to have a positive effect on libido at low levels of testosterone, a limited number of studies have looked into the effect of estradiol supplementation in eugonadal men and reported conflicting results. One study with continuous estradiol administration in men who had normal testosterone levels showed decreases in sexual interest, fantasy, masturbation, and erections.11 In contrast, a randomized, double-blind study conducted on 50 men ages between 20 and 40 years demonstrated that sexual activity was unaffected.12
Uncontrolled case reports also have shown conflicting results. A man with aromatase deficiency was noted to have a relevant increase in sexual behavior with estrogen supplementation,13 while other aromatase-deficient men noted no change in their sexual function.14 These natural models, which have the potential to provide some clarity, along with results of the limited trials undertaken, have not provided definitive evidence one-way or the other regarding estradiol's effects on libido in the eugonadal male.
Role of estradiol in hypogonadal men treated with testosterone supplementation therapy
Perhaps, most relevant to the discussion is the use of testosterone supplementation therapy (TST). The goal of TST, regardless of the method used, should be to maintain not only physiologic levels of testosterone, but also its metabolites, including estradiol which optimizes libido.15
In men with secondary hypogonadism (functioning testes and relatively low levels of luteinizing hormone [LH] and testosterone), clomiphene citrate was used to increase testosterone by acting centrally on the ER weakly. Clomiphene citrate administration raised endogenous testosterone while increasing the testosterone to estradiol (T/E) ratio.16 Also, in a later study, clomiphene citrate administered to hypogonadal men produced an increase in libido, energy, and sense of well-being.17
In 2013, Finkelstein et al. looked at the effects of testosterone and estrogen on male sexual function. They found that the administration of testosterone with and without aromatase inhibitors markedly impaired sexual function when aromatization was inhibited.18 In addition, a study by Ramasamy et al. in 2014 showed that libido was increased in men receiving TST when testosterone levels were >300 ng dl-1 and estradiol levels were >5 ng dl-1. Most compelling is the fact that in men with serum testosterone <300 ng dl-1, sexual drive was seen to be markedly higher when estradiol levels were >5 ng dl-1.19 In addition, when patients with low testosterone were treated with letrozole, a potent aromatase inhibitor, libido was decreased, suggesting that complete elimination of estradiol and decreasing the T/E ratio too severely, adversely affects sexual desire in men.20 These studies provide evidence that both estrogen and testosterone are necessary for normal libido in testosterone-deficient men. Clinically, the dependence of libido in hypogonadal men on both testosterone and estrogen indicates that a cautious approach to the use of aromatase inhibitors is warranted and that the T/E ratio has an impact. It might be reasonable that while prescribing TST one should monitor the levels of both testosterone and estrogen and their relationship to each other.
Clearly, the effect of estradiol on male sexual desire is linked to testosterone levels, as there are different outcomes when estrogen is administered at low and normal testosterone levels. Another example of this duality is seen in men with androgen resistance, where unfettered estrogen is able to stimulate subsequent breast development. However, in men with normal androgen receptor activity, estradiol is unable to stimulate breast development.(If you have gyno issues it's not high e2 it's androgen resistance!!)21 This is thought to be due to an imbalance between the inhibitory and stimulatory effect of these hormones.22,23 Whatever the pathophysiology in breast development or libido, these hormones seem to be inextricably linked in the complicated physiology of male sexuality and development.
Finally, the effect of estradiol on mood must be considered. As mood can correlate with sexual interest, it is reasonable to consider these data when discussing the role of estradiol on libido. While cognition, well-being, and depressive symptoms improve in men whose low testosterone levels were corrected,24,25,26higher levels of estrogen also have been associated with less depression in older patients of both sexes.27In addition, estrogen supports serotonin levels and affects the amount of 5-HT receptors in the brain, and depending on receptor subtype, there is sexual inhibition or facilitation.28,29,30 A recent study showed a significant positive correlation between endogenous plasma estradiol levels and cortical 5-HT2A binding in men, with no independent effects on these receptors from testosterone.31 In addition, when serotonin binds to these 5-HT2A receptors in the cortex, limbic system, hypothalamus, and midbrain, sexual desire is inhibited with subsequent induction of refractoriness and sexual satiety.32 The interaction of estrogen with serotonin is complex, with overlapping influences that reaches beyond sexual desire including mood regulation and cognition.33 This fact makes its true impact on sexual desire and behavior difficult to fully elucidate.
Estradiol and erectile function and more - The role of estradiol in male reproductive function
The effect of estradiol on libido is seen at various levels of regulation, starting with direct effects in the brain (Figure 1). Areas of the brain that control sexual behavior in mammals are thought to do so via pheromones that induce specific sexual effects on the autonomic nervous system, including changes in mood and sexual arousal. Pheromones produce increased activity in the medial preoptic area/anterior hypothalamus.1 Neurons, the most basic electrical information-transmitting cells in the central nervous system and peripheral nervous system, as well as astrocytes, star-shaped glial cells which fulfill a number of functions in the central nervous system, both convert testosterone to estrogen with aromatase. The preoptic area and anterior hypothalamus contain the highest levels of aromatase and estrogen receptors (ERs) in male rodents.2,3 Similarly, it is well known that selective serotonin reuptake inhibitors diminish libido. Serotonin receptors follow a pattern of distribution similar to that of ERs in the brain.4 However, the interaction of estradiol and serotonin is complex and will subsequently be addressed. Finally, aromatase activity is highest in the brain during development. Thus, not only does estradiol modulate sexual behavior in the adult male, it also appears to organize the early brain to program sexual behavior.3
Estradiol effect at low testosterone levels
To discern the effect of estradiol, it is important to evaluate its effect on libido at both low and normal levels of circulating testosterone. Decreased testosterone is clearly associated with low libido in males.5 In men with diminished testosterone, the administration of exogenous estradiol has been shown to increase libido.6 This finding is supported by rodent studies demonstrating that castrated animals given exogenous estrogen show an increase in sexual activity in a dose- and temporal-dependent manner.7 In addition, in a unique case report of a male patient with aromatase deficiency and hypogonadism, both estrogen and testosterone were required to increase libido, whereas neither hormone could achieve the effect alone suggesting that estrogen plays a necessary role in sexual desire in the setting of low testosterone.8
Similarly, patients with prostate cancer treated with androgen deprivation therapy (ADT) serve as a good model for the influence of estrogen on libido. When castrate levels of androgens were reached (T <50 ng dl-1), uniform adverse effects of hot flashes, erectile dysfunction (ED), and decrease in libido were reported.9 When comparing androgen receptor (AR) blockers versus castration, the former had better outcomes in maintaining sexual activity, presumably by increased testosterone conversion to estrogen.10This evidence, though indirect, does perhaps suggest that elevated estrogen in men with low or absent testosterone can sustain libido. In addition, administering estradiol to men undergoing ADT for prostate cancer could possibly reduce damage to areas of the brain associated with sexual performance. Thus, an overall increase in sexual quality of life could be achieved.6
Role of estradiol in eugonadal men
While estradiol has been shown to have a positive effect on libido at low levels of testosterone, a limited number of studies have looked into the effect of estradiol supplementation in eugonadal men and reported conflicting results. One study with continuous estradiol administration in men who had normal testosterone levels showed decreases in sexual interest, fantasy, masturbation, and erections.11 In contrast, a randomized, double-blind study conducted on 50 men ages between 20 and 40 years demonstrated that sexual activity was unaffected.12
Uncontrolled case reports also have shown conflicting results. A man with aromatase deficiency was noted to have a relevant increase in sexual behavior with estrogen supplementation,13 while other aromatase-deficient men noted no change in their sexual function.14 These natural models, which have the potential to provide some clarity, along with results of the limited trials undertaken, have not provided definitive evidence one-way or the other regarding estradiol's effects on libido in the eugonadal male.
Role of estradiol in hypogonadal men treated with testosterone supplementation therapy
Perhaps, most relevant to the discussion is the use of testosterone supplementation therapy (TST). The goal of TST, regardless of the method used, should be to maintain not only physiologic levels of testosterone, but also its metabolites, including estradiol which optimizes libido.15
In men with secondary hypogonadism (functioning testes and relatively low levels of luteinizing hormone [LH] and testosterone), clomiphene citrate was used to increase testosterone by acting centrally on the ER weakly. Clomiphene citrate administration raised endogenous testosterone while increasing the testosterone to estradiol (T/E) ratio.16 Also, in a later study, clomiphene citrate administered to hypogonadal men produced an increase in libido, energy, and sense of well-being.17
In 2013, Finkelstein et al. looked at the effects of testosterone and estrogen on male sexual function. They found that the administration of testosterone with and without aromatase inhibitors markedly impaired sexual function when aromatization was inhibited.18 In addition, a study by Ramasamy et al. in 2014 showed that libido was increased in men receiving TST when testosterone levels were >300 ng dl-1 and estradiol levels were >5 ng dl-1. Most compelling is the fact that in men with serum testosterone <300 ng dl-1, sexual drive was seen to be markedly higher when estradiol levels were >5 ng dl-1.19 In addition, when patients with low testosterone were treated with letrozole, a potent aromatase inhibitor, libido was decreased, suggesting that complete elimination of estradiol and decreasing the T/E ratio too severely, adversely affects sexual desire in men.20 These studies provide evidence that both estrogen and testosterone are necessary for normal libido in testosterone-deficient men. Clinically, the dependence of libido in hypogonadal men on both testosterone and estrogen indicates that a cautious approach to the use of aromatase inhibitors is warranted and that the T/E ratio has an impact. It might be reasonable that while prescribing TST one should monitor the levels of both testosterone and estrogen and their relationship to each other.
Clearly, the effect of estradiol on male sexual desire is linked to testosterone levels, as there are different outcomes when estrogen is administered at low and normal testosterone levels. Another example of this duality is seen in men with androgen resistance, where unfettered estrogen is able to stimulate subsequent breast development. However, in men with normal androgen receptor activity, estradiol is unable to stimulate breast development.(If you have gyno issues it's not high e2 it's androgen resistance!!)21 This is thought to be due to an imbalance between the inhibitory and stimulatory effect of these hormones.22,23 Whatever the pathophysiology in breast development or libido, these hormones seem to be inextricably linked in the complicated physiology of male sexuality and development.
Finally, the effect of estradiol on mood must be considered. As mood can correlate with sexual interest, it is reasonable to consider these data when discussing the role of estradiol on libido. While cognition, well-being, and depressive symptoms improve in men whose low testosterone levels were corrected,24,25,26higher levels of estrogen also have been associated with less depression in older patients of both sexes.27In addition, estrogen supports serotonin levels and affects the amount of 5-HT receptors in the brain, and depending on receptor subtype, there is sexual inhibition or facilitation.28,29,30 A recent study showed a significant positive correlation between endogenous plasma estradiol levels and cortical 5-HT2A binding in men, with no independent effects on these receptors from testosterone.31 In addition, when serotonin binds to these 5-HT2A receptors in the cortex, limbic system, hypothalamus, and midbrain, sexual desire is inhibited with subsequent induction of refractoriness and sexual satiety.32 The interaction of estrogen with serotonin is complex, with overlapping influences that reaches beyond sexual desire including mood regulation and cognition.33 This fact makes its true impact on sexual desire and behavior difficult to fully elucidate.
Estradiol and erectile function and more - The role of estradiol in male reproductive function
