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The Role of Estradiol in Male Reproductive Function


Abstract and Figures

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.
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Asian Journal of Andrology (2016) 18, 1–6
© 2016 AJA, SIMM & SJTU. All rights reserved 1008-682X;
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 deciency and hypogonadism, both
estrogen and testosterone were required to increase libido, whereas
neither hormone could achieve the eect 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 inuence
of estrogen on libido. When castrate levels of androgens were
reached(T<50ng dl−1), uniform adverse eects 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 eect on libido at
low levels of testosterone, a limited number of studies have looked into
the eect of estradiol supplementation in eugonadal men and reported
conicting results. One study with continuous estradiol administration
Role of estradiol in the brain
e eect of estradiol on libido is seen at various levels of regulation,
starting with direct eects in the brain(Figure1). Areas of the brain
that control sexual behavior in mammals are thought to do so via
pheromones that induce specic sexual eects 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 fulll 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 eect at low testosterone levels
To discern the eect of estradiol, it is important to evaluate its eect
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
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, 1–6; 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 (
Received: 19 August 2015; Revised: 10 November 2015; Accepted: 19 November 2015
Open Access
Male Fertility
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The role of estradiol in male reproductive function
M Schulster et al
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 unaected.12
Uncontrolled case reports also have shown conicting results.
Aman with aromatase deciency was noted to have a relevant increase
in sexual behavior with estrogen supplementation,13 while other
aromatase‑decient 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
denitive evidence one‑way or the other regarding estradiol’s eects
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 etal. looked at the eects 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 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 aects sexual desire in men.20 ese studies provide evidence
that both estrogen and testosterone are necessary for normal libido
in testosterone‑decient 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 eect of estradiol on male sexual desire is linked to
testosterone levels, as there are dierent 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 eect 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 eect 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
aects 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 signicant positive correlation between endogenous
plasma estradiol levels and cortical 5‑HT2A binding in men, with no
independent eects 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
inuences that reaches beyond sexual desire including mood regulation
and cognition.33 is fact makes its true impact on sexual desire and
behavior dicult to fully elucidate.
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 aer day 12 of life showed no structural
abnormalities.39 In addition to inuence on structure, estrogen has a
signicant inuence on penile vasculature. Acase–control study of
male outpatients with ED with venous leakage showed that the only
dierence 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 eect on erectile
function through increased venous leakage.40
Figure 1: The role of estrogen in male reproduction.
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The role of estradiol in male reproductive function
M Schulster et al
Estrogen also acts at the level of the brain to inuence 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 eect 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 eects 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, signicantly 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 eects 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 dierence, these ndings provide an interesting
and compelling initial step in elucidating estrogen's separate and direct
eect on ED outside of its role in testosterone suppression(Figure1).
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(Figure1).
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 specically 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 modiable 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 aect 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 eects 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 signicant 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 signicantly to the hormonal
milieu within the tubules(Figure2).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 inuence 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 signicant 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 eect 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 eect of LH on the mature Leydig cells, ultimately producing
a net eect of androgen inhibition.71
Figure 2: The role of estradiol in spermatogenesis.
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Asian Journal of Andrology
The role of estradiol in male reproductive function
M Schulster et al
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, specically 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 eect 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. Areduction 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
eect 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 eects 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 eect on germ cells is a more
recent discovery. Aromatase has been conrmed 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 inuences on Leydig and Sertoli
cells, as described above, a stimulatory eect 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 eectively 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
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 dierent novel mutations in ERs have
been identied, 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.
e exact role of estradiol in each area of male sexual function including
libido, erectile function, and spermatogenesis, is dicult to determine.
Acomplex balance of testosterone, estradiol, aromatase, and ERs in the
testes, penis, and brain conrms 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
aect 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 5ng dl−1 correlate to a decrease in libido.
Considering the complexity and taking into account some conicting
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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... The activity of aromatase enzyme 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 [25]. ...
... The role of estrogen in male reproduction [25] The exact role of estradiol in each area of male sexual function including libido, spermatogenesis, and erectile function is difficult to determine. A complex balance of testosterone, estradiol, aromatase, and estrogen receptors in brain, testes, and penis, confirmed the indispensable and highly regulated hormonal interaction of estrogen in the male. ...
... Finally, estradiol levels should be considered when treating men with testosterone, as estradiol levels below 5 ng/dl correlate to a decrease in libido. More understanding of these mechanisms may prove the using of estradiol and become clinically useful in treating diminished libido, erectile dysfunction, and perhaps even oligospermia [25]. ...
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Background: The dysfunction in sexual ability has effects on the quality of life in men. Oxytocin plays a role in sexual and social behaviors. Hyperprolactemic males had erectile dysfunction. Endogenous estrogens in men, are not only important for health integrity but can additionally cause the promotion of many diseases. Objectives: The current review aimed to high light on the role of oxytocin, prolactin, and estrogen in male sexual functions. Oxytocin neurons have been heavily implicated in mediating sexual behavior in both humans and animals. Oxytocin hormone regulates social behaviors such as mating, maternal/paternal care, and bonding. Oxytocin levels rise during mating in females and males in humans and animals and may mediate anxiolytic/calming effects of sexual activity and antidepressant effects. Oxytocin's role in regulating erection and ejaculation has been studied in mice and rats. Oxytocinergic projections from the paraventricular nucleus to the hippocampus, medulla oblongata, and spinal cord facilitate penile erection. Prolactin (PRL) serves a dual function both as a circulatory hormone and as a cytokine. PRL is known to be involved in the control of male copulatory behavior in humans, mice, rats, and other rodent models. It release during copulation in males and has a positive modulation for various aspects of testicular functions which hinting at the crucial role of prolactin in male reproduction. The lower concentration of prolactin was associated with reduced seminal vesicle volume and ejaculate in the infertile human male. Hypoprolactinemia has been associated with premature ejaculation and erectile dysfunction. Hyperprolactinemia can be caused by tumors, drugs, or idiopathic, leading to alterations in sexual behavior as loss of libido and erectile dysfunction. It is also reported that it can cause endocrine disturbances leading to abnormal levels of testosterone, FSH, and LH. Chronic hyperprolactinaemia suppresses copulatory behaviour in animal models and yields sexual dysfunction and other side effects in men. In men, testosterone acting via its action on androgen receptors may be dependent on the action of aromatase enzyme on of testosterone and converting it to estradiol (E2). Estrogens act through ERα and ERβ at the plasma membrane and in the nucleus to regulate functions of many organs in men. The role of estradiol action on libido is seen at various levels of regulation, starting with direct effects in the brain. Not only does estradiol modulate sexual behavior in the adult male, it also appears to organize the early brain to program sexual behavior. The exact role of estradiol in each area of male sexual function including libido, spermatogenesis, and erectile function is difficult to determine. A complex balance of testosterone, estradiol, aromatase, and estrogen receptors in brain, testes, and penis, confirmed the indispensable and highly regulated hormonal interaction of estrogen in the male. Conclusion: It can be concluded that oxytocin hormone regulates social behaviors such as mating, maternal/paternal care, and bonding. PRL is involved in the control of male copulatory behavior in humans, rats, mice, and other rodent models. Hypoprolactinemia has been associated with reduced seminal vesicle volume, premature ejaculation, and erectile dysfunction. Hyperprolactinemia can be caused by tumors, drugs, or idiopathic, leading to alterations in sexual behavior as loss of libido and erectile dysfunction. Also, hyperprolactemic males had erectile dysfunction. Estradiol modulates sexual behavior in the adult male, and appears to organize the early brain to program sexual behavior.
... Progestogens are the first products of cholesterol side cleavage in gonadal tissues during sex hormones synthesis [35][36][37], and the most potent family member is progesterone (P4) [35][36][37]. On the other hand, there are three natural estrogens, known as estrone (E1), 17β-estradiol (E2), and estriol (E3) [22]. ...
... Progestogens are the first products of cholesterol side cleavage in gonadal tissues during sex hormones synthesis [35][36][37], and the most potent family member is progesterone (P4) [35][36][37]. On the other hand, there are three natural estrogens, known as estrone (E1), 17β-estradiol (E2), and estriol (E3) [22]. ...
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Abstract Several epidemiological studies have reported that the use of female sex steroid hormones could reduce the risk of colon cancer (CRC). This review summarizes the available data related to estradiol (E2) and progesterone (P4) single and dual treatments in CRC male and female in vitro and in vivo models, mainly from preclinical studies, alongside their potential molecular mechanisms. Most of the studies showed that E2 exogenous treatment and/or reactivation of its beta receptor (ERβ) significantly inhibited cell proliferation, induced cell cycle arrest, and promoted apoptosis by modulating several molecular pathways. Likewise, the inhibition of ERα receptors produced similar antitumorigenic actions, both in vivo and in vitro, suggesting that E2 could have dual opposing roles in CRC that are dependent on the expression profile of its nuclear receptors. The available studies on P4 are scarce, and the results revealed that in vitro and in vivo treatments with natural and synthetic progesterone were also associated with promising tumoricidal actions. Nevertheless, the combination of E2 with P4 showed enhanced anticancer activities compared with their monotherapy protocols in male–female cell lines and animals. Collectively, the studies suggested that the female sex steroid hormones could provide a novel and effective therapeutic strategy against CRC.
... Similarly, a strong positive significant correlation was observed between testicular size and testosterone levels in ram testes (Camela et al., 2019). During the breeding activity, testosterone levels was accompanied by estrogen levels as the testosterone to estradiol ratio is essential in erectile function, the process of spermatogenesis and libido index (Schulster et al., 2016). The increased estradiol levels in postpubertal bucks could be due to the vasodilator effect of estradiol on penile vasculature in the erection process (Shirai et al., 2004). ...
This study aimed to compare the testicular morphometry, mediastinum thickness, hormonal levels, hemody-namic, echogenicity, and heterogeneity in Baladi bucks at prepubertal and postpubertal stages. Five bucks (Capra hircus) were evaluated in two different stages of growth: prepubertal (age 4.5±0.6 months; 15.0±3.0 kg) and post-pubertal stages (age 13.0±1.3 months; 33.0±2.5 kg). Scrotal circumference, testicular dimensions, mediastinum thickness, echogenicity, heterogeneity, Doppler parameters, semen collection, testosterone, es-tradiol, follicle-stimulating hormone (FSH), luteinizing hormones (LH), and nitric oxide metabolites (NOMs) were measured. There was an (P<0.05) elevation of the testicular length, width, and scrotal circumference. Mediastinum thickness and colored areas toward and away from probe were increased (P<0.05) in post-pu-bertal age (2.18±0.01, 6556±32.58, and 7845±65.44) compared to pre-pubertal one (1.27±0.96, 4290±42.12, and 5144±54.24). The spectral graph was characterized by low resistance (RI), moderate pulsatility (PI) with high peak velocity, and low endpoints in the post-pubertal stage while the endpoint was equal to zero in young bucks. The post-pubertal age was associated with a marked decline (P<0.05) in echogenicity, heterogeneity, and RI, while estradiol, testosterone, and NOMs levels were increased (P<0.05). It could be concluded that the post-pubertal stage in Baladi bucks is associated with changes in testicular width, length, mediastinum thickness , RI, scrotal circumference, echogenicity, pixel heterogeneity, testicular colored area away and toward the probe, end-diastolic point, testosterone, nitric oxide, and estradiol levels, as all those variables are considered an accurate markers for the onset of sexual maturity in Baladi bucks.
... Any anti-androgenic exposure may reduce plasma testosterone concentration, which might cause spermatogenesis dysfunction. Spermatogenesis is also modulated at every level by estrogen, from the 2 of 23 hypothalamus-pituitary-gonadal axis to the testis cells constituted by Leydig, Sertoli and germ cells [4]. In the ovary, estrogen and progesterone are key steroid hormones in the complex regulation of female reproductive functions [5]. ...
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Similar to environmental factors, EDCs (endocrine-disrupting chemicals) can influence gene expression without modifying the DNA sequence. It is commonly accepted that the transgenerational inheritance of parentally acquired traits is conveyed by epigenetic alterations also known as “epimutations”. DNA methylation, acetylation, histone modification, RNA-mediated effects and extracellular vesicle effects are the mechanisms that have been described so far to be responsible for these epimutations. They may lead to the transgenerational inheritance of diverse phenotypes in the progeny when they occur in the germ cells of an affected individual. While EDC-induced health effects have dramatically increased over the past decade, limited effects on sperm epigenetics have been described. However, there has been a gain of interest in this issue in recent years. The gametes (sperm and oocyte) represent targets for EDCs and thus a route for environmentally induced changes over several generations. This review aims at providing an overview of the epigenetic mechanisms that might be implicated in this transgenerational inheritance.
... For example, testosterone can be metabolized into dihydrotestosterone or estradiol to activate ERs (Handa et al., 2009). Additionally, estradiol plays a critical role in male sexual functions (for review, see Schulster et al., 2016) and testosterone is also important for females (Davis and Wahlin-Jacobsen, 2015). Men express ERα and ERβ on their vasculature, although it is not clear whether they provide similar cardioprotective effects as reported in women (Arnlöv et al., 2006;Cooke et al., 2017). ...
Full-text available
Prevalence of mental disorders, including major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ) are increasing at alarming rates in our societies. Growing evidence points toward major sex differences in these conditions, and high rates of treatment resistance support the need to consider novel biological mechanisms outside of neuronal function to gain mechanistic insights that could lead to innovative therapies. Blood-brain barrier alterations have been reported in MDD, BD and SZ. Here, we provide an overview of sex-specific immune, endocrine, vascular and transcriptional-mediated changes that could affect neurovascular integrity and possibly contribute to the pathogenesis of mental disorders. We also identify pitfalls in current literature and highlight promising vascular biomarkers. Better understanding of how these adaptations can contribute to mental health status is essential not only in the context of MDD, BD and SZ but also cardiovascular diseases and stroke which are associated with higher prevalence of these conditions.
The positive health impacts of dance and dance/movement therapy can be seen all the way down to the molecular level. This narrative-style review illustrates this connection by presenting a collection of clinical and preclinical studies that evaluate the effects of dance activities on hormones and other small-molecule metabolites within the human body. The results of these studies show that dance activities can increase levels of nitric oxide, serotonin, estrogen hormones, and HDL cholesterol, while they can decrease levels of dopamine, serum glucose, serum triglycerides, and LDL cholesterol. Levels of cortisol can either be increased or decreased, depending on the type of dance. Many of these results parallel the biomolecular effects of traditional (non-dance) exercise activities, although some contrasting results can also be seen. The concentrations of these molecules and their distributions throughout the body impact health and a wide variety of disease states. This connection to the molecular level provides a perspective for understanding how it is that dance activities are able to affect larger-scale physiological and psychological responses and lead to the positive health outcomes that are observed in many situations.
Background There has been a decrease in sperm concentration in recent years. Concurrently, there were important dietary changes, including an increase in sugar-sweetened beverage intake (SSB). The relation between SSB and male reproduction functions in humans are barely described in the literature. Methods Cross-sectional study with 209 participants (18–23 years old) recruited during one year in Murcia, Spain. All men provided semen and blood samples the same day. SSB consumption was evaluated using a 101-item validated food frequency questionnaire. Reproductive hormones were analysed from serum samples, obtaining levels of follicle-stimulating hormone, inhibin B, luteinizing hormone, estradiol, and testosterone. The evaluation of semen analysis followed the WHO guidelines and consisted of seminal volume, sperm concentration, total sperm count, percentage of morphologically normal sperm, and percentage of motile sperm. SSB intake association with semen parameters and hormone levels were examined using multiple linear regression. Results Men in the highest quartile of the SSB intake had a higher percentage of morphologically normal sperm, 37.4% [6.1, 68.3] (p, trend = 0.047) and higher estradiol levels (9.5% [−3.5, 22.5] (p, trend = 0.047) than those in the first quartile. SSB intake was unrelated to other semen quality parameters or reproductive hormone levels. Conclusions Our results indicate that sperm morphology and estradiol levels may be associated with sugar-sweetened beverage intake. These findings might be explained by physiological metabolism homeostasis, though more studies are required to confirm these results and draw conclusions in other male populations.
Numerous studies conducted to study the role of testosterone in erectile dysfunction (ED) extensively, but less is known of the association between estradiol level and ED. To assess the strong association between estradiol and ED by quantitatively synthesizing all studies evaluating the relationship between estradiol and ED. An extensive literature search was conducted by two authors independently in three electronic databases, including PubMed, Web of Science and Cochrane Library, up to January 10, 2021. The Patient Population or Problem, Intervention, Comparison, Outcomes and Setting (PICOS) were used for inclusion criteria to identify studies. The Newcastle‐Ottawa Scale was applied to assess the quality of studies. The standardized mean difference (SMD) and their corresponding 95% confidence intervals (95% CIs) were used to compare the estradiol level between ED patients and healthy subjects, and the pooled OR and 95%CI were used to evaluate the strong association between estradiol level and ED. Finally, six studies were included in this meta‐analysis, satisfying predefined inclusion criteria. Five studies were considered to be high quality, and only one was judged of moderate quality. The estradiol level of ED patients was statistically higher than that in healthy subjects (SMD 0.45, 95%CI 0.28–0.63, p <0.0001). The pooled OR demonstrated that the estradiol was correlated to the ED significantly (OR 1.08, 95%CI 1.05–1.12, p <0.0001). Subgroup analyses were conducted based on age, diagnosis way, country, sample size, detection method and estradiol level. There was no substantial change in the result of SMD ranging from 0.41 (95% CI 0.31–0.51) to 0.53 (95% CI 0.44–0.62) when performing sensitivity analysis. No publication bias was detected by the Begg test or Egger test. This meta‐analysis demonstrated that the estradiol level is correlated to ED significantly.
Estradiol is an endogenous hormone that affects many physiological functions in humans; thus, the demand for its detection has been increasing. Gold nanoparticle (AuNP)-based colorimetric sensors with split aptamers offer an easy-to-operate detection method for estradiol. However, the assay performance is still unmet. Here, we report a simple and sensitive colorimetric assay for the detection of estradiol, based on the target-induced recycling assembly of split aptamer fragments. This method contains three DNA fragments that remain in a metastable state without a target. After adding estradiol, the split aptamers assemble with the target, which can be regenerated by helper DNA, resulting in the formation of a three-way junction (3WJ)-like structure and the recycling of recognition. The generation of the 3WJ-like DNA structure causes the formation of unstable AuNPs, enhancing the salt-induced aggregation of AuNPs. The assay shows a detection limit of 0.7 nM, which is better than those of other aptamer-based detection methods. Moreover, the assay enables the detection of estradiol spiked in urine by avoiding any interference from contaminants. The colorimetric assay includes anti-estradiol DNA split aptamers, accounting for no false responses to non-target molecules. Therefore, the results demonstrated that it has application potential for the detection of estradiol in a complex matrix.
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The reproductive system of male mice homozygous for a mutation in the estrogen receptor (ER) gene (ER knock-out; ERKO) appears normal at the anatomical level. However, these males are infertile, indicating an essential role for ER-mediated processes in the regulation of male reproduction. Adult ERKO male mice have significantly fewer epididymal sperm than heterozygous or wild-type males. Although spermatogenesis is occurring in some seminiferous tubules of 3- to 5-month-old ERKO males, other tubules either have a dilated lumen and a disorganized seminiferous epithelium with few spermatogenic cells or lack a lumen and contain mainly Sertoli cells. There are no obvious differences in seminiferous tubules at 10 days of age between wild-type and ERKO mice, but the lumen in ERKO males is dilated in all seminiferous tubules by 20 days. However, spermatogenesis progresses and similar numbers of sperm are present in the cauda epididymis of ERKO and wild-type males until 10 weeks of age. Disruption of spermatogenesis and degeneration of the seminiferous tubules become apparent after 10 weeks in the caudal pole of the testis and progresses in a wave to the cranial pole by 6 months. However, the seminal vesicles, coagulating glands, prostate, and epididymis do not appear to be altered morphologically in ERKO mice. Serum testosterone levels are somewhat elevated, but LH and FSH levels are not significantly different from those in wild-type males. Sperm from 8- to 16-week-old mice have reduced motility and are ineffective at fertilizing eggs in vitro. In addition, ERKO males housed overnight with hormone-primed wild-type females produce significantly fewer copulatory plugs than do heterozygous or wild-type males. These results suggest that estrogen action is required for fertility in male mice and that the mutation of the ER in ERKO males leads to reduced mating frequency, low sperm numbers, and defective sperm function.
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Spermatogenesis, a highly conserved process in vertebrates, is mainly under the hypothalamic-pituitary control, being regulated by the secretion of pituitary gonadotropins, follicle stimulating hormone, and luteinizing hormone, in response to stimulation exerted by gonadotropin releasing hormone from hypothalamic neurons. At testicular level, gonadotropins bind specific receptors located on the somatic cells regulating the production of steroids and factors necessary to ensure a correct spermatogenesis. Indeed, besides the endocrine route, a complex network of cell-to-cell communications regulates germ cell progression, and a combination of endocrine and intra-gonadal signals sustains the production of high quality mature spermatozoa. In this review, we focus on the recent advances in the area of the intra-gonadal signals supporting sperm development.
Gonadal steroids and FSH are key regulators of Sertoli cell function. N-Cadherin (N-cad) is a calcium-dependent cell adhesion molecule that mediates Sertoli cell-germ cell interactions. We recently demonstrated that steroids, in particular estradiol, are potent regulators of testicular N-cad messenger RNA (mRNA) levels in vivo. In view of the cooperative effects of steroids and FSH on Sertoli cell-germ cell interactions, we examined the combined effects of these hormones on N-cad mRNA levels in cultured mouse Sertoli cells. FSH was capable of increasing N-cad mRNA levels 2-fold in these cells. The effects of FSH on N-cad mRNA levels in cultured Sertoli cells were mimicked by cAMP-inducing agents. Treatment of the Sertoli cell cultures with FSH and estradiol stimulated N-cad mRNA levels 3-fold, whereas steroids alone had no effect on N-cad mRNA levels. These studies demonstrate that FSH and estradiol in combination are required to achieve maximal N-cad mRNA levels in cultured Sertoli cells. The results obt...
This study aimed to identify the mechanism(s) for impairment of spermatogenesis in adulthood in rats treated neonatally with estrogens. Rats were treated (days 2–12) with 10, 1, or 0.1 μg diethylstilbestrol (DES), 10 μg ethinyl estradiol (EE), 10 mg/kg of a GnRH antagonist (GnRHa), or vehicle and killed in adulthood. DES/EE caused dose-dependent reductions in testis weight, total germ cell volume per testis, and Sertoli cell volume per testis. Sertoli cell number at 18 days of age in DES-treated rats was reduced dose dependently. GnRHa treatment caused changes in these parameters similar to those in rats treated with 10 μg DES. Plasma FSH levels were elevated (P < 0.001) to similar levels in all treatment groups regardless of differences in Sertoli cell number and levels of inhibin B; the latter reflected Sertoli cell number, but levels were disproportionately reduced in animals treated with high doses of DES/EE. Neonatal estrogen treatment, but not GnRHa, caused dose-dependent reductions (40–80%) in plas...
Reduced endogenous estrogen and hemicastration both stimulate proliferation of porcine Sertoli cells. The objective of these experiments was to compare the temporal pattern of response to each stimulus and the response to the combined stimuli as indications of shared or separate mechanisms. Within a replicate, one littermate was treated weekly with the canola oil vehicle and remained intact, one littermate was treated weekly with the vehicle and one testis was removed at day 8, one littermate was treated weekly with the aromatase inhibitor letrozole to reduce endogenous estrogens and remained intact, and the fourth littermate was treated weekly with letrozole and one testis was removed at day 8. Four replicates were evaluated at 2 wks of age, five replicates evaluated at 6.5 wks of age, and five replicates evaluated at 11 wks of age with treatment ceasing at 6 wks of age. Sertoli cell numbers were determined following GATA4 labeling using the optical dissector method. Estradiol, estrogen conjugates, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and inhibin were determined by radioimmunoassay. Hemicastration appeared to have a rapid effect on Sertoli cell proliferation but letrozole treatment had no apparent effect on Sertoli cell numbers at 2 wks of age. Both letrozole treatment and hemicastration had stimulated Sertoli cell proliferation by 6.5 wks of age, although the magnitude of the hemicastration response was much greater. Letrozole appeared to have minimal interaction with hemicastration at this age. Letrozole and hemicastration together increased Sertoli cell numbers at 11 wks of age compared with either treatment alone. Estradiol and estrogen conjugates were dramatically reduced by aromatase inhibition as anticipated; treatment-induced changes in inhibin, LH or FSH were minimal. The differences in timing of response and the positive interaction at 11 wks of age suggest that hemicastration and letrozole stimulate proliferation of Sertoli cells by two initially different pathways.