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Asian Journal of Andrology (2016) 18, 435–440
© 2016 AJA, SIMM & SJTU. All rights reserved 1008-682X
www.asiaandro.com; www.ajandrology.com
estradiol has been shown to increase libido.6 is nding 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 deciency and hypogonadism, both
estrogen and testosterone were required to increase libido, whereas
neither hormone could achieve the eect 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 inuence
of estrogen on libido. When castrate levels of androgens were
reached(T<50ng dl−1), uniform adverse eects of hot ashes, 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.10 is 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. us, 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 eect on libido at
low levels of testosterone, a limited number of studies have looked into
the eect of estradiol supplementation in eugonadal men and reported
conicting results. One study with continuous estradiol administration
ASSOCIATION BETWEEN LIBIDO AND ESTRADIOL
Role of estradiol in the brain
e eect of estradiol on libido is seen at various levels of regulation,
starting with direct eects in the brain(Figure1). Areas of the brain
that control sexual behavior in mammals are thought to do so via
pheromones that induce specic sexual eects 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 fulll a number of functions in the central nervous system, both
convert testosterone to estrogen with aromatase. e 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. us, 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 eect at low testosterone levels
To discern the eect of estradiol, it is important to evaluate its eect
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
INVITED REVIEW
The role of estradiol in male reproductive function
Michael Schulster1, Aaron M Bernie1, Ranjith Ramasamy2
Traditionally, testosterone and estrogen have been considered to be male and female sex hormones, respectively. However,
estradiol, the predominant form of estrogen, also plays a critical role in male sexual function. Estradiol in men is essential for
modulating libido, erectile function, and spermatogenesis. Estrogen receptors, as well as aromatase, the enzyme that converts
testosterone to estrogen, are abundant in brain, penis, and testis, organs important for sexual function. In the brain, estradiol
synthesis is increased in areas related to sexual arousal. In addition, in the penis, estrogen receptors are found throughout the
corpus cavernosum with high concentration around neurovascular bundles. Low testosterone and elevated estrogen increase the
incidence of erectile dysfunction independently of one another. In the testes, spermatogenesis is modulated at every level by
estrogen, starting with the hypothalamus-pituitary-gonadal axis, followed by the Leydig, Sertoli, and germ cells, and finishing with
the ductal epithelium, epididymis, and mature sperm. Regulation of testicular cells by estradiol shows both an inhibitory and a
stimulatory influence, indicating an intricate symphony of dose-dependent and temporally sensitive modulation. Our goal in this
review is to elucidate the overall contribution of estradiol to male sexual function by looking at the hormone’s effects on erectile
function, spermatogenesis, and libido.
Asian Journal of Andrology (2016) 18, 435–440; doi: 10.4103/1008-682X.173932; published online: 23 February 2016
Keywords: estrogen; testosterone; spermatogenesis; erectile function; estrogen receptor; aromatase
1Department of Urology, New York–Presbyterian Hospital, Weill Cornell Medical College, New York, USA; 2Department of Urology, Miller School of Medicine, University of
Miami, Miami, FL, USA.
Correspondence: Dr. R Ramasamy (ramasamy@miami.edu)
Received: 19 August 2015; Revised: 10 November 2015; Accepted: 19 November 2015
Open Access
Male Fertility
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436
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 40years demonstrated that sexual activity was unaected.12
Uncontrolled case reports also have shown conicting results.
Aman with aromatase deciency was noted to have a relevant increase
in sexual behavior with estrogen supplementation,13 while other
aromatase-decient men noted no change in their sexual function.14
ese natural models, which have the potential to provide some clarity,
along with results of the limited trials undertaken, have not provided
denitive evidence one-way or the other regarding estradiol’s eects
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). e 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 etal. looked at the eects of testosterone and
estrogen on male sexual function. ey 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 etal. in 2014 showed that libido was increased in men
receiving TST when testosterone levels were>300ng dl−1 and estradiol
levels were>5ng dl−1. Most compelling is the fact that in men with
serum testosterone<300ng 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 aects sexual desire in men.20 ese studies provide evidence
that both estrogen and testosterone are necessary for normal libido
in testosterone-decient 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 eect of estradiol on male sexual desire is linked to
testosterone levels, as there are dierent 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.21 is is thought to be due to an
imbalance between the inhibitory and stimulatory eect 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 eect 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,24–26 higher levels of estrogen
also have been associated with less depression in older patients of
both sexes.27 In addition, estrogen supports serotonin levels and
aects the amount of 5-HT receptors in the brain, and depending on
receptor subtype, there is sexual inhibition or facilitation.28–30 A recent
study showed a signicant positive correlation between endogenous
plasma estradiol levels and cortical 5-HT2A binding in men, with no
independent eects 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
inuences that reaches beyond sexual desire including mood regulation
and cognition.33 is fact makes its true impact on sexual desire and
behavior dicult to fully elucidate.
ASSOCIATION BETWEEN ESTRADIOL AND ERECTILE
FUNCTION
Erectile function is multifaceted with a necessary combination of nerve,
vessel, and endocrine actions that work together to produce subsequent
penile structural changes in a coordinated fashion. Smooth muscle,
endothelium, and cell-to-cell communications via gap junctions are
essential to erectile function, and thus pathology in any one of these
can lead to ED.34 e pathophysiology and clinical role of testosterone
in erectile function have been studied extensively.35–37 Androgens are
necessary for the penis to grow and develop, and also contribute to
the physiology of erections.38
Estrogen in animal models impedes normal penile development,
including reduced bulk of the bulbospongiosus muscle, reduction
of the spaces in corpus cavernosum, and an accumulation of fat
cells within existing spaces that lead to ED in adult life. Notably, the
reported exposure was limited to early development, and rats that were
exposed to exogenous estradiol aer day 12 of life showed no structural
abnormalities.39 In addition to inuence on structure, estrogen has a
signicant inuence on penile vasculature. Acase–control study of
male outpatients with ED with venous leakage showed that the only
dierence between the men with and without ED was an increased
estradiol level. e authors concluded that estradiol increases venous
vascular permeability via VEGF and has a detrimental eect on erectile
function through increased venous leakage.40
Figure 1: The role of estrogen in male reproduction.
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Estrogen also acts at the level of the brain to inuence erectile
function. Estrogen inhibits the hypothalamus-pituitary axis and
subsequently follicle-stimulating hormone(FSH) and LH, thus
reducing circulating testosterone.41–43 Testosterone is necessary for
normal erectile function, and low testosterone produces decreased
firmness, ability to maintain erections and number of erections
achieved, all of which are improved with testosterone administration.44,45
e administration of exogenous estradiol has the ability to cause ED
through an inhibitory eect on testosterone production. is was
demonstrated in animals, where exogenous estrogen administration
not only reduced testosterone levels, but also diminished the structural
integrity of the corpus cavernosum with less viable smooth muscle
and an increase in connective tissue.46 Similarly, in humans taking
estrogen, a reduction is seen in spontaneous erections and nocturnal
penile tumescence correlating with a reduction in testosterone levels.47
e eects of estrogen on erectile function discussed above largely
occur as a function of its ability to decrease circulating testosterone. In
addition, increased severity of ED, assessed with the International Index
for Erectile Function,48 in men with low testosterone levels is worsened
with high estrogen levels implying an additive effect by the two
hormones.49 However, while low testosterone increases the incidence
of ED, elevated estrogen levels do as well.40 is point, coupled with
the fact that the corpus cavernosum vasculature and urothelium have
extensive ERs, signicantly more than other steroid receptors, and
particularly around the neurovascular bundle, suggests mechanisms of
ED separate from and in addition to central testosterone inhibition.50,51
Evidence from animal models demonstrates this independent
role of estradiol in erectile function. Stimulation of ER receptors has
been shown to have anti-apoptotic eects on endothelium, and the
loss of this function in the crura was associated with ED.52 Similarly,
when ED was induced by high estrogen levels, testosterone therapy
was not helpful in restoring erections as long as the estrogen milieu
was maintained.53 While animal models have not provided conclusive
evidence, and the pathophysiology of erectile function is more complex
than simple hormone dierence, these ndings provide an interesting
and compelling initial step in elucidating estrogen's separate and direct
eect on ED outside of its role in testosterone suppression(Figure1).
ROLE OF ESTRADIOL IN SPERMATOGENESIS
Testosterone has long been known to be the dominant sex hormone
in men. However, estrogen is found at detectable levels at multiple
points of development and contributes to spermatogenesis(Figure1).
In addition, an abnormal T/E ratio(<10) has been associated with
decreased semen parameters, and administration of an aromatase
inhibitor normalized the ratio and improved sperm concentration,
motility, and morphology.20 Targeting estrogen levels has clinical value
when optimizing sperm retrieval rates in men with nonobstructive
azoospermia (NOA). Sperm retrieval rates were seen to increase
1.4-fold either by decreasing estradiol directly and normalizing the
T/E ratios with aromatase inhibitors or indirectly blocking estradiol
centrally with clomiphene citrate, in turn, increasing gonadotropin
secretion.54 Although it has not been made clear if the improvement in
spermatogenesis is specically due to the reduction of estradiol in the
testes when normalizing the T/E ratio, it is clear that estrogen levels
play an important and modiable clinical impact on spermatogenesis
in men with NOA. In addition, varicocele has long been known to
have an adverse impact on fertility and sex hormone production,
and while the mechanism of this aect is unknown, estrogen has
been linked.55,56 Semen analysis of “varicocele” sperm showed a
marked reduction in both ER alpha and beta receptors as well as
a reduced response to estradiol’s necessary eects on motility and
acrosin activity.56
Estradiol has been shown to exist not only in the reproductive
tract of the adult male, but in the brain as well.57 In various species
including humans, a more signicant concentration exists in the male
reproductive tract and semen than in the serum.58 While it has been
shown clearly that Leydig and Sertoli cells produce estradiol, newer
research has demonstrated that estradiol synthesis by germ cells within
the seminiferous tubules contributes signicantly to the hormonal
milieu within the tubules(Figure2).59 Aromatase has also been found
in early development in all germ cells, especially during meiotic and
postmeiotic stages of spermatogenesis, and in the later development
of ejaculated spermatozoa.60 However, it is the presence of ERs in
these cells and their precursors that provides compelling evidence that
estrogen has an inuence over spermatogenesis.61
Leydig cells–self‑regulation and testosterone control via estradiol
Leydig cells, under the influence of LH, secrete testosterone,
which in turn acts on Sertoli and peritubular cells, as well as
vasculature, allowing them to nurture the budding spermatogonia to
spermatozoa.62 At birth, fetal Leydig stem cells are not progenitors of
the adult form. However, they remain in small numbers in the adult
testes as a distinct cell population that is important for the generation
of their adult counterparts.63 Aromatase is present largely in mature
Leydig cells, producing a signicant amount of the estradiol in the
testes.64,65 In addition, ER mRNA has been shown to exist in both cell
precursor and mature populations.66 When subjected to an alkylating
agent toxic to Leydig cell populations, male rats which then had
subsequent estradiol exposure during a critical stage of development
experienced a blockage in the reappearance of mature Leydig
cells.67 us, Leydig cells, at least in part, self-regulate via estrogen
modulation by potentially controlling the extant population of fetal
Leydig cells in a paracrine fashion. Furthermore, there is evidence
suggesting that estrogen inhibits the LH eect on Leydig cells68 and
that excess estrogen exposure reduces serum testosterone levels via this
inhibition. e subsequent reduction of testosterone in turn reduces
the number of viable sperm.69,70 Taken together, the evidence shows
that estrogen plays a major role in the overall growth, development,
and function of Leydig cells, in one role acting as a modulator of
precursor populations and, in another role inhibiting steroidogenesis
via the eect of LH on the mature Leydig cells, ultimately producing
a net eect of androgen inhibition.71
Figure 2: The role of estradiol in spermatogenesis.
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Sertoli cells–contributions of estradiol to the immature testes and
sperm maturation
While a major source of estrogen in the adult testes is the Leydig cell,
Sertoli cells produce most of the estrogen in the immature testes.60 In
multiple species, aromatase mRNA was detected in Sertoli cells at every
stage of sperm development.72 In addition, it has recently been shown
that ERs, specically the beta type and G protein estrogen receptors are
present in male rats’ S ertoli cells dur ing de velopment and are subjected
to modulation by estradiol in concert with FSH.73–75 e overall eect of
this modulation is inhibition, as shown by the antagonism of estrogen
in neonatal animal testes with subsequent increase in Sertoli cell
population.76,77 In addition, male neonatal rat testes exposed to estradiol
displayed a subsequent dose-dependent reduction of 20%–70% of testes
weight. Areduction of sperm production with poor motility was also
dose-dependent, with the upper range doses of estradiol producing
complete azoospermia. ese changes are androgen-dependent and
have been linked to a down regulation of ARs on Sertoli cells via the
eect of estradiol on the coexisting ERs.78
Finally, it is known that Sertoli cells must “recognize” developing
sperm, as the perpetual and cyclical topological relationship is directly
related to the maturation process of spermatogonia.79 is process
is essential as the immature sperm progress in the apical direction,
mature, and eventually secrete into the tubules. It has been shown
that FSH in combination with estradiol is necessary for the mRNA
transcription of N-cadherin, the protein responsible for cell-to-cell
adhesion.80,81 us, the dynamic process of spermatogenesis involving
Sertoli cells separating and reforming tight junctions via N-cadherins
is, at least in part, regulated by estrogen.
Germ cells–autocrine and paracrine eects of estradiol
Testosterone produced by Leydig cells and FSH from the anterior
pituitary are necessary for Sertoli cells to transduce signals and
produce factors that nurture germ cells.82,83 In addition, when
testosterone is withdrawn from germ cells by administering ethane
1,2-dimethanesulfonate, an alkylating agent that selectively kills
Leydig cells in adult rat testes, apoptosis is induced via the Fas/Bcl-2
system.84 While this requirement of testosterone for germ cell survival
is well established, evidence of estrogen’s eect on germ cells is a more
recent discovery. Aromatase has been conrmed in the cytoplasm
surrounding elongated spermatids, as well as ejaculated sperm, and
a link exists between estradiol production in sperm and capacitation
and the acrosome reaction. When placed in a noncapacitating
medium, only estradiol and aromatizable steroids were able to increase
sperm motility and migration, making estradiol necessary for sperm
maturation and successful fertilization.85
In the neonatal period, the major portion of estradiol is synt hesized
by Sertoli cells, and germ cell precursors are stimulated through
plasma membrane ERs.86 In addition, as germ cells multiply and begin
producing estradiol, the hormone inhibits aromatase in Sertoli cells
in a paracrine fashion to allow them subsequently to proliferate and
nurture the spermatogonia to maturity.87 Along with estradiol from
Leydig cells, the estrogens produced by germ cells allow for autocrine
self-stimulation, thus creating a positive fe edback loop promoting germ
cell and subsequent paracrine Sertoli cell propagation.88
Unlike estrogen’s inhibitory inuences on Leydig and Sertoli
cells, as described above, a stimulatory eect is seen with germ cells.
Like Sertoli and Leydig cells, ERs and aromatase are found in germ
cells, again suggesting the production of as well as modulation by
estradiol.86,89,90 It was once thought that Leydig cells produced most of
the estrogen in the adult testes, but new evidence shows that germ cells
produce anywhere from 50% to 60% of the hormone.60,91 Most recently,
it has been demonstrated that estradiol, along with platelet-derived
growth factor(PDGF), stimulates germ cell proliferation that is
dose-dependent and nonadditive, giving Sertoli cells a way to regulate
the germ cells’ entry into mitosis via estradiol production.92,93 When
incubating mature human seminiferous tubules without survival
factors, even low concentrations of estradiol eectively enhanced
germ cell production by the inhibition of apoptosis. us, estrogen
has proven to be a potent hormone necessary for germ cell survival.94
Seemingly, contradictory to this is the fact that excess estrogen acts as
an inhibitor of spermatogenesis in human95 as well as rat models.70,78,96
However, it is likely the inhibitory effect of estrogen on Sertoli
cells, rather than on germ cells, that causes the overall inhibition of
spermatogenesis.
An interesting case report from the New England Journal of
Medicine describing a man with an estrogen receptor mutation with
normal sexual development and relatively normal semen parameters
warrants discussion. While the patient had a low normal sperm density,
a seemingly contradictory fact to the evidence presented above, his
sperm viability was well below normal at 18%, and fertility could
not be assessed.97 In male mouse models, the targeted disruption of
estrogen receptors led to alteration in spermatogenesis and infertility;
however, in human models, many dierent novel mutations in ERs have
been identied, some in infertile men and some in men with normal
fertility.98,99 Perhaps, this means relatively normal sexual parameters
can be explained by a mutation or receptor type that does not confer
infertility. e authors did not address that, however this point once
again addresses the complexity of estradiol on male sexual function
and demonstrates why further study is needed.
CONCLUSIONS
e exact role of estradiol in each area of male sexual function including
libido, erectile function, and spermatogenesis, is dicult to determine.
Acomplex balance of testosterone, estradiol, aromatase, and ERs in the
testes, penis, and brain conrms an indispensable and highly regulated
hormonal interaction of estrogen in the male. ERs and aromatase
share topographic locations with pheromones in the brain, making it
clear that estrogen contributes to early sexual development as well as
sexual behavior in adulthood. Estrogen can sustain libido as well as
aect the amount of serotonin receptors in the brain modulating mood,
mental state, cognition, and emotion. Erectile function is adversely
affected by estrogen exposure in early penile development, and
exposure to estradiol in the mature penis leads to increased vascular
permeability with increased ED. ED from increased estradiol exposure
is independent of testosterone level. In addition, spermatogenesis is
dependent upon estradiol to some extent, as all cells involved in the
process of sperm production contain aromatase and express ERs.
Finally, estradiol levels should be considered when treating men with
TST, as estradiol levels below 5ng dl−1 correlate to a decrease in libido.
Considering the complexity and taking into account some conicting
data, more research is necessary so that when better understood,
estradiol can become clinically useful in treating diminished libido,
ED, and perhaps even oligospermia.
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