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Orexins (or hypocretins) are hypothalamic neuropeptides with a multitude of physiological functions. They occur in two known forms, namely, orexin A and orexin B with a common precursor, preproorexin. The orexin receptors (orexin 1R and orexin 2R) belong to the Family of G-protein coupled receptors. The primary function of the orexin system, i.e. the orexins, their receptors and associated neuronal circuitries, perhaps is to increase spontaneous physical activity and food intake, thereby promoting an increase in energy expenditure. Reports suggest that orexins may be the key brain components to mediate the mechanism of obesity resistance. Recent research also has thrown lights upon a significant role of orexins, especially orexin A, in regulation of male reproductive functions owing to their receptor expressions in vital testicular cells, such as Leydig cells, Sertoli cells as well as spermatozoa at different developmental stages, even in the epididymis and penis. Moreover, orexins have been reported to greatly influence gonadotropin-releasing hormone neurons and their secretions to regulate reproductive functions via modulation of the hypothalamic-pituitary-gonadal axis. Evidence thus implicates participation of orexins in steroidogenesis, spermatogenesis, transportation and maturation of sperm as well as in the control of penile function. However, further research is required in this direction to elucidate the mechanisms by which orexins play a role in different testicular functions and effect of orexins on semen quality.
doi: 10.4103/2305-0500.268145
Orexins and male reproduction
Pallav Sengupta1, Sulagna Dutta2, Maiza Tusimin3, Ivan Rolland Karkada1
1Department of Physiology, Faculty of Medicine and Biomedical Sciences, MAHSA University, Malaysia
2Department of Oral Biology and Biomedical Sciences, Faculty of Dentistry, MAHSA University, Malaysia
3Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Malaysia
Article history:
Received 21 May 2019
Revision 29 June 2019
Accepted 22 July 2019
Available online 7 October 2019
Corresponding author: Pallav Sengupta, Ph.D., Department of Physiology, Faculty of
Medicine and Biomedical Sciences, MAHSA University, Malaysia.
Tel: +60176369621
1. Introduction
Orexins or hypocretins (OX/HCRT) are hypothalamic
neuropeptides and mediate various physiological functions in
humans and other mammals. It exists in two forms: orexin-A
(OXA) and orexin B (OXB) which are derived from a common
precursor, prepro-orexin (PPO). They act via the orexin receptors
(OX1R and OX2R) which are transmembrane G-protein coupled
receptors (OX2R)[1]. OX/HACRT system includes orexins,
their receptors and HCRT-producing cell bodies widespread in
hypothalamus, projection to the noradrenergic locus coeruleus
and lesser projections to the basal ganglia, thalamic regions, the
medullary reticular formation, the nucleus of the solitary tract,
dorsal raphe nuclei, amygdala, cortical regions, the olfactory bulb,
suprachiasmatic nucleus, basal forebrain, cholinergic brainstem
and the spinal cord[2]. Orexins are well known to play a significant
role in sleep-wakefulness cycle[3,4], emotion[5,6], food intake
Orexins (or hypocretins) are hypothalamic neuropeptides with a multitude of physiological
functions. They occur in two known forms, namely, orexin A and orexin B with a common
precursor, preproorexin. The orexin receptors (orexin 1R and orexin 2R) belong to the Family
of G-protein coupled receptors. The primary function of the orexin system, i.e. the orexins,
their receptors and associated neuronal circuitries, perhaps is to increase spontaneous physical
activity and food intake, thereby promoting an increase in energy expenditure. Reports
suggest that orexins may be the key brain components to mediate the mechanism of obesity
resistance. Recent research also has thrown lights upon a significant role of orexins, especially
orexin A, in regulation of male reproductive functions owing to their receptor expressions
in vital testicular cells, such as Leydig cells, Sertoli cells as well as spermatozoa at different
developmental stages, even in the epididymis and penis. Moreover, orexins have been reported
to greatly influence gonadotropin-releasing hormone neurons and their secretions to regulate
reproductive functions via modulation of the hypothalamic-pituitary-gonadal axis. Evidence
thus implicates participation of orexins in steroidogenesis, spermatogenesis, transportation and
maturation of sperm as well as in the control of penile function. However, further research is
required in this direction to elucidate the mechanisms by which orexins play a role in different
testicular functions and effect of orexins on semen quality.
Asian Pacific Journal of Reproduction 2019; 8(5): 233-238
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How to cite this article: Sengupta P, Dutta S, Tusimin M, Karkada IR. Orexins and
male reproduction. Asian Pac J Reprod 2019; 8(5): 233-238.
Review Article
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234 Pallav Sengupta et al./ Asian Pacific Journal of Reproduction (2019)233-238
behavior[7], and energy metabolism[8]. In recent years, the endocrine
and reproductive functions of orexins are also surfacing which
mainly depends upon integrated neuroendocrine mechanisms[9].
OXA has been found to influence the activities of gonadotropin-
releasing hormone (GnRH) neurons and gonadotropin-secreting
pituitary cells[10]. GnRH neurons are the prime integrator of internal
and external cues in regulation of sexual maturity and fertility. It
has been suggested that energy homeostasis strongly associates
with reproductive functions. Orexins may play additional roles in
the regulation of these reproduction functions. There is a growing
body of evidence indicating that OX/HCRT modulates reproduction
interacting with the hypothalamic-pituitary-gonadal (HPG)
axis in mammals[11,12]. Also the ability of exogenous orexins to
alter endocrine functions has now been mirrored by its potential
involvement in treatment of reproductive disorders[13].
This review aims to provide a clear updated concept regarding
(a) the distribution of orexin receptors in reproductive tissues, (b)
the influence of orexins over the HPG, and (c) the possible role of
orexins in male reproductive functions.
2. Orexins and orexin receptors
OX/HCRTs are the highly conserved peptide product of PPO (130
amino acid), with two enzymatically cleaved HCRT peptides: HCRT1/
OXA (33 amino acid) and HCRT2/OXB (28 amino acid)[14]. OXA
binds more selectively to OX1R, while OX2R has similar affinity
for both OXA and OXB[1]. Orexin structures and their receptors are
suggested to be greatly conserved in all mammals. The genes for
both of these receptors are found to be widely expressed throughout
the rodent brain as well, but the distribution and role of OX1R differ
from those of the OX2R[15] Furthermore, the orexinergic system also
prevails and operates in several peripheral tissues apart from their
distributions and functions in central nervous system[16,17].
3. Orexin receptors in reproductive tissues
Orexins play a significant role in the regulation of male
reproductive functions. Their significant roles in spermatogenesis
and steroidogenesis have been evidenced through
immunolocalization of orexin receptors in the Sertoli cells, Leydig
cells, resting spermatocytes, spermatogonia, round, oval and
elongated spermatids[18,19]. Both OX1R and OX2R are expressed
in the testicular cells, epididymis, seminal vesicle, and in the penis,
while the PPO was expressed only in the epididymis and penis[13,18-
21]. Studies have also confirmed the localization of orexin receptors,
OXA and OX1R in both the testicular interstitium and the tubular
compartments throughout the postnatal period. Studies revealed
that on the first postpartum day, OXA and OX1R-expressions can
be found in the gonocytes, fetal Leydig cells and Sertoli cells; on
the tenth postpartum day, orexins, as well as their receptors, can be
detected in the Leydig cells, Sertoli cells, spermatogonia and early
spermatocytes; while on thirtieth and ninetieth postpartum days
the study showed OXA and OX1R-immunopositive signals from
the Sertoli cells, spermatogonia, spermatocytes, spermatids and
Leydig cells. These reports indicate that owing to the considerable
expressions of OXA and OX1R in the testis, orexins play a vital
role in spermatogenesis and steroidogenesis, which are yet to be
completely understood[22].
Sexually dimorphic expression of PPO mRNA has been evident
in the rodent hypothalamus with higher levels in female rats than
in the male rats. Whereas, the pituitary OX1R mRNA levels were
found to be higher in male rats than in female rats. mRNAs for
PPO and orexin receptors were found to be differentially expressed
in peripheral tissues in both the genders. Moreover, it has been
demonstrated that the effects of gonadal steroids, 17-β estradiol
and testosterone, on mRNA expression of PPO in female rats and
orexin receptor in male rats were different. They also differed in
their actions over pituitary OX1Rs and adrenal OX2Rs. These
observations suggest that the orexin receptors may have a significant
role in sex-specific neuroendocrine and endocrine regulations over
reproductive functions. Orexin receptors are expressed in the female
reproductive tract in altered fashion according to the different
reproductive cycle phases, as dictated by the hormonal profile and
light-darkness cycle[23]. There are some studies addressing the
regulation of pituitary hormones by orexinergic system[24,25], but
the mechanism how other hormonal milieu affects the orexinergic
system, is not yet clear. Silveyra et al had determined the expressions
of hypothalamic and pituitary levels of PPO, OX1R and OX2R in
female Sprague-Dawley rats at various estrous stages correlating the
same with the endocrine milieu, food intake and light-darkness cycle.
The report suggests that expression of OX1R and OX2R increases
in both the hypothalamus and pituitary, during proestrus phase while
the expressions remain unaltered in estrus or diestrus. Moreover,
the hypothalamic PPO expression had shown increase only during
the proestrus phase[26]. Nitkiewicz et al[27] have also compared
the expression of the PPO gene in porcine endometrium and
myometrium and the intensity of OXA-and OXB-immunoreactivity
in endometrial glandular and luminal epithelium and stroma as well
as the myometrial longitudinal and circular muscles during the four
stages of the estrous cycle. The highest PPO mRNA expression was
observed in the endometrium and myometrium on days 14-16 of the
estrous cycle. The myometrial PPO gene expression was vivid than
in the endometrium on days 2–3 of the cycle, while the endometrial
gene expression was markedly higher in later phase (days 17–19)[27].
Expressions of PPO mRNA and OX1R, but not OX2R were
found in different cells in the rat testis[19,28]. Whereas, in human
testis, OX1R and OX2R mRNA expressions but not PPO mRNA
were found[13]. In vitro slice preparation and in vivo experiments
demonstrated that OXA could stimulate basal testosterone
secretion[18,28-30]. These studies also provided hints regarding low
OX1R gene expressions also in the Leydig cells[13,20,29,31]. Studies
revealed that orexins operate through activation of the phospholipase
Cpathway via induction of inositol triphosphate production, and in
this regard, OXB have been shown to be more potent.
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4. Role of orexins in modulation of HPG axis
The HPG axis is the principal endocrine axis for the regulation
of reproductive functions, and is under the influence of several
other hormonal and neuronal crosstalks such as thyroid[32-34],
kisspeptin[35], melatonin[36], other metabolic hormones[37], etc.
Orexin immunoreactive fibers have overlapping distributions with
the GnRH neuronal system in the septo-preoptic and the arcuate
nucleus-median eminence region that is suggestive of the influence
of orexins in the modulation of pituitary luteinizing hormone (LH)
secretion via regulation of GnRH release[38]. Although the studies
on the effect of orexins upon the HPG axes mostly used female
rodent as laboratory model, the overall observation suggests that
orexins greatly influence GnRH neurons and their secretions to
regulate reproductive functions via alterations in the HPG axis[38].
Since orexins alter the pulse of GnRH release, they play a vital role
in regulating LH secretion from the anterior pituitary that in turn
may modulate steroidogenesis in the Leydig cells in male, thereby
affecting testicular functions.
Pu et al[24] demonstrated that OXA or OXB injection through
intracerebroventricular route could stimulate LH secretion in a dose-
and time-related fashion in estradiol benzoate and progesterone
pre-treated ovariectomized rats. However, the effects of exogenous
orexins injection were shown to depend upon the status of ovarian
steroids. It has been observed that ovariectomized rats treated with
17β-estradiol and progesterone followed by orexins injection,
showed an increased plasma LH levels which may suggest that
estrogen upregulates orexin receptors[39]. Orexin-mediated LH
response in the hypothalamus appears to be site-specific and be
carried out by OX1R, located on the GnRH cells[38]. Thus, orexins
may potentially stimulate GnRH from the hypothalamus, but is
dependent upon other steroidal interference.
In sheep, orexinergic neurons are mostly found in the dorsomedial
hypothalamic nucleus, zona incerta, lateral hypothalamic and
perifornical areas[40]. A substantial number of GnRH cells
are in close contact with the orexin immunoreactive terminals
which indicate a role of orexins in the regulation of GnRH cells.
Hypothalamic areas concerned with neuroendocrine functions also
have been reported to express orexin receptor mRNAs[40].
Orexins can indirectly act through β-endorphins (endogenous
opioid peptides) to suppress GnRH secretion[41]. Orexin
neurons course through the arcuate nucleus innervating the
proopiomelanocortin neurons, which are β-endorphin precursors.
It had been shown that co-administration of naloxone, an opioid
antagonist, with orexins reversed the effect of orexins on the mean
LH concentration and the GnRH pulse frequency. This observation
suggests that β-endorphin is involved in actions of orexins to
reduce LH concentration and hypothalamic GnRH release pulse
frequency[41]. Unlike OXA, naloxone had no influence upon OXB
which still significantly suppressed LH level and its pulse frequency.
Hence, OXB perhaps is not dependent upon β-endorphin pathway
for its effects on hypothalamic GnRH secretion. Since orexins have
been seen to regulate the anterior pituitary responsiveness towards
GnRH for LH secretion, it may be suggested that gonadotrophs
express a considerable number of orexin receptors. The somatotrophs
and corticotrophs already have been proven to bear both the orexin
5. Orexins, obesity and testicular functions
The word ‘orexin’ is adapted from the Greek word referring
to ‘appetite’. Activation of the orexin system can increase both
spontaneous physical activity and food intake, and its primary
function is to promote an increase in energy expenditure[42,43].
While obesity and overweight have turned pandemic over recent
years, there are individuals who may naturally resist obesity.
Reports suggest that orexins or hypocretins may be a key brain
component that mediates the mechanism of obesity resistance[44,45].
Research on obesity resistance in animal models has demonstrated
positive correlations of increased orexins in spontaneous physical
activity. This orexin-induced spontaneous physical activity has been
postulated to be a major contributor to obesity resistance through
enhanced non-exercise activity thermogenesis[46]. However, the
underlying mechanism of how central hypothalamic orexin signaling
regulates spontaneous physical activity is not yet completely
Obesity presents have several physiological disturbances, of which
impairment in normal reproductive functions being one such issue of
major concern[47,48]. It is suggested that obesity positively associates
with male infertility[49,50]. In an attempt to clarify the mechanism by
which obesity affects male fecundity and semen quality, the role of
various obesity-related hormones in regulation of male reproductive
functions have been studied, such as adiponectin, obestatin, ghrelin,
leptin among others[37].
It has been discussed in previous sections that orexins have been
reported to greatly influence GnRH neurons and their secretions.
Several studies using rodent models indicate that orexins increase
significantly the aromatase (Cyp19) gene expression in the
hypothalamus of male rats. Aromatase is an enzyme which converts
androgens to estradiol in the hypothalamus. Aromatase cytochrome
P450 is an enzyme coded by Cyp19 gene. This enzyme converts
androgens like testosterone to estradiol in peripheral tissues and in
the brain[41,51]. It is further noted that hypothalamic interneurons-
including neuropeptide Y, pre-opiomelanocortin or ghrelin may play
a role in mediating the inhibitory effects of orexins on HPG axis[21,
52,53], which is a complex integrated network influenced by central
and peripheral signals.
Previous research has shown that the central injection of orexins
significantly increased the Cyp19 gene expression and estradiol
hormone levels in the hypothalamus of male rats[54]. Orexins are
hypothalamic neuropeptides which mainly poise inhibitory effects on
reproductive axis[24,55]. OXA has been shown to decrease the mean
serum level of the LH and testosterone[56]. Orexins may regulate the
reproductive axis by influencing secretions of GnRH and LH[11].
From the umpteen animal research it is evident that peptides like
orexins are important in the regulation of testicular functions[57].
Recent data have thrown lights upon a significant role of orexins,
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236 Pallav Sengupta et al./ Asian Pacific Journal of Reproduction (2019)233-238
especially OXA, in the regulation of male reproductive functions
owing to their receptor expressions in vital testicular cells, such as
the Leydig cells, Sertoli cells as well as spermatozoa at different
developmental stages, even in the epididymis and penis[13,58,59]. It
has also been reported that increase in orexins dosage to rats highly
stimulated testosterone secretion from testis[29]. Adrenal glands
as well as the gonads, require four key steroidogenic enzymes
to synthesize testosterone, among which the 3β-hydroxysteroid
dehydrogenase (3β-HSD) is considered the most important[60]. The
3β-HSD expression has been detected in several organs[61-63] and
is also an immunohistochemical marker to determine testosterone
synthesis. Orexins have been shown to stimulate 3βHSD
expression in adrenocortical cells[64] and in rat primary Leydig
cells[65] suggesting that orexins may regulate steroidogenesis in
steroidogenic cells. The expression of functional orexin receptors in
testicular peritubular myoid cells and the induction of phospholipase
C/inositol triphosphate cascade may promote further testicular
functions. Orexins thus possess differential impacts upon each male
reproductive tissue, and the pleiotropic effects of orexin receptors
may be suggested to involve multiple signaling pathways. It has been
hypothesized that orexins may influence testosterone production
via the orexin receptors in Leydig cells, which again may regulate
expression of orexin receptors in other tissues, thereby establishing a
positive feedback loop[13].
6. Orexins and male reproductive behavior
The cell bodies of neurons with HCRTs/OXs are present in the
lateral and dorsal hypothalamus and project to various areas of the
brain concerned with sexual behavior. These areas include the medial
preoptic area, paraventricular nucleus, and the ventral tegmental
area[9]. In a pioneer study showcasing the possible functions of
orexins in sexual behavior showed that HCRT1/OXA administration
into the medial preoptic area enhanced sexual arousal and copulatory
performance[66]. Consequent studies revealed an increase in
immunoreactivity in hypocretin/orexin neurons during copulation in
male rats[67]. Moreover, systemic administration of an OX-1 receptor
antagonist in rats was shown to downregulate copulatory behavior.
It had been suggested that orexins may also act in a steroid-sensitive
fashion to aid the rewarding sensation of natural stimuli such as sex,
by activating the mesolimbic dopaminergic system[67]. This concept
has been challenged by specific studies on the role of orexin neurons
in sexual behavior in male rats using particular neural activation
markers and selective neuronal lesions[68]. The net findings of
these studies are that activation of orexin neurons increases when
a receptive or non-receptive female is presented without any
further activation, or when there are cues predicting sexual reward.
While, orexin neuron lesions decreased the latencies to mount and
intromission during the first mating trials. It can thereby be put
forth that orexins may not be vital for male sexual performance but
is essential in sexual arousal mainly in naive animals and may be
critical for sexual reward processing[68].
The above studies implicate the participation of orexins in
steroidogenesis, spermatogenesis, transportation and maturation
of sperm and in the control of penile function including the
maintenance of penile erection. A substantial number of researches
are required in this direction to elucidate the mechanisms of orexins
action on different testicular functions[13] and most importantly
on the effect of orexins on semen quality, which is the universally
accepted parameter to gauge male fertility[69-73].
7. Conclusions
Orexins, discovered not long ago, are the molecules of high
interest in research due to their versatility. Besides, its crucial role
in the regulation of energy balances, reward systems, emotions,
and arousal, emerging data suggest direct effects of orexins upon
the GnRH neurons and regulation of reproduction. Most of the
studies on orexins demonstrated the anatomic architecture of the
orexinergic system and its role in some key peripheral functions,
either by the actions of orexins on central control system or directly
via its interaction with the peripheral effectors. Despite substantial
evidence on the expression of orexin receptors in hypothalamus,
anterior pituitary and testicular cells like the Leydig cells, Sertoli
cells and spermatozoa at different developmental stages, the exact
physiological role of orexin in male reproduction needs a lot more
investigations. There are several open questions regarding the
roles of orexins on HPG axis, modulation of male reproductive
hormones and their signal transduction pathways. Nevertheless, it
may be hypothesized that orexin may act upon the hypothalamus
and pituitary to modulate the influence of HPG endocrine axis
upon testicular functions; or it may act directly via its receptors in
major testicular cells like Leydig cells and Sertoli cells to regulate
steroidogenesis and spermatogenesis; and even may act on the germ
cells to determine their viability and development. Altogether, the
existing evidences suggest that the orexinergic system might act as a
common association among crucial functions like reproduction with
other centrally controlled functions like energy balance, alertness
and the inner biological clock.
Conflict of interest statement
The authors declare that there is no conflict of interest.
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... Adipose tissue is a toxic depot of triglycerides, and is a vital endocrine organ releasing adipokines, whose actions of mechanism have paucity of evidence (1). The role of adipokines is to preserve energy homeostasis, having other endocrine axes with direct influences on various organs, which are emerging with the advent of research in these realms (2). Metabolic disorders, like obesity, can jeopardized adipose tissue hormonal milieu, effecting health factors (3). ...
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Objective: The role of adiponectin in sperm function is inconclusive and there is a paucity of evidence. Obesity shows an ambiguous influence on sperm motility, and male subfertility. The aim of this study was to compare the role of adiponectin and sperm functional parameters among obese and non-obese men. Materials and Methods: In this comprehensive study, 64 male patients were included, and were classified as non-obese [body mass index (BMI)< 24.9 kg/m2, n=32] and obese (BMI >25 kg/m 2 , n=32) groups. Sperm analysis, was conducted using World Health Organization (WHO) 2010 standards. Real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) were used for the analysis of adiponectin gene expression and protein levels, respectively. Sperm viability was assessed using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT test), Acridine orange (AO) test was utilized to detect DNA denaturation, and sperm chromatin dispersion (SCD) technique was used to investigate the fragmentation of DNA. Results: In obese men, adiponectin gene expression (P<0.0001) and protein levels (P<0.001) were significantly lower compared to the non-obese group. Additionally, sperm motility, was significantly lower in the obese group. The rapid progressive (RP) motility was less in obese men in comparison to the non-obese group (P<0.001). Sperm count and morphology were not significantly different in the two groups. DNA denaturation and DNA fragmentation were significantly more frequent in the obese group than in non-obese men (P<0.05) and (P<0.01), respectively. The obese men showed significantly lower sperm viability compared to the non-obese group (P<0.05). Conclusion: This study showed no significant correlation between the evaluated variables (sperm parameter, sperm viability, DNA fragmentation and integrity), and obesity in men. Based on these results, adiponectin may potentially play positive role in sperm function for acquiring fertility.
... Physiological energy homeostasis finds intricate association with reproductive functions. Energy balance is maintained via regulation of food intake behavior, energy expenditure, and storage [7][8][9][10]. ...
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To investigation the correlation between reproductive hormones (FSH, LH and Testosterone) with the semen parameters (semen volume, sperm concentration, sperm motility and normal morphology percent) of infertile patient. The study was carried out in the Fertility Center in AL-Sader Medical City and local laboratories, through January 2022 to April 2022. Semen samples were obtained from fifty (50) infertile men. The Parameters for the semen analysis were analyzed and classified according to the WHO criteria (WHO, 1999). Patients should give their semen for analysis in the laboratory by masturbation. All patients should have at least two separate samples to be analyzed, the second sample collected by blood aspiration and used the centrifuge to separated the serum, the VIDAS® device is used to determine the hormones rate. The significant negative correlation (P<0.05) for two hormones the follicle stimulating hormone and luteinizing hormone with all Sperm parameters, in addition to that the significant positive correlation (P<0.05) between testosterone hormone and all sperm parameters: Semen volume (r= 0.211) Sperm concentration, (r=0.612), Progressive motility Percent (A+B) (r=0.355) and normal morphology percent (r=0.312) respectively. Increase Levels of LH and FSH hormones as well as to decrease levels of testosterone negatively affect the sperm parameters of infertile Patients.
... Orexins are best known as an arousal neuropeptide; it reduces ROS-induced cell damage [107,108] and stimulates several steroidogenic enzymes in Leydig cells, thus increasing the testosterone production [109,110] (Fig. 1). ...
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Background The global prevalence of obesity has soared to a concerning height in the past few decades. Interestingly, the global decline in semen quality is a parallel occurrence that urges researchers to evaluate if obesity is among the most essential causatives of male infertility or subfertility. Main body Obesity may alter the synchronized working of the reproductive-endocrine milieu, mainly the hypothalamic-pituitary-gonadal (HPG) axis along with its crosstalks with other reproductive hormones. Obesity-mediated impairment in semen parameters may include several intermediate factors, which include physical factors, essentially increased scrotal temperature due to heavy adipose tissue deposits, and systemic inflammation and oxidative stress (OS) initiated by various adipose tissue-derived pro-inflammatory mediators. Obesity, via its multifaceted mechanisms, may modulate sperm genetic and epigenetic conformation, which severely disrupt sperm functions. Paternal obesity reportedly has significant adverse effects upon the outcome of assisted reproductive techniques (ARTs) and the overall health of offspring. Given the complexity of the underlying mechanisms and rapid emergence of new evidence-based hypotheses, the concept of obesity-mediated male infertility needs timely updates and pristine understanding. Conclusions The present review comprehensively explains the possible obesity-mediated mechanisms, especially via physical factors, OS induction, endocrine modulation, immune alterations, and genetic and epigenetic changes, which may culminate in perturbed spermatogenesis, disrupted sperm DNA integrity, compromised sperm functions, and diminished semen quality, leading to impaired male reproductive functions.
... Obesity stimulates the release of hormones from adipose tissue, including leptin, ghrelin, orexins, obestatin, adiponectin, and other metabolic hormones, which possess unique roles in reproductive functions [8,[135][136][137][138][139]. Leptin regulates the satiety center and body weight primarily through three hypothalamic leptin-sensitive neurons: neuropeptide Y, γ-aminobutyric acid (aminobutyric acid), and proopiomelanocortin neurons [140]. ...
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Male infertility is approaching a concerning prevalence worldwide, and inflicts various impacts on the affected couple. The hormonal assessment is a vital component of male fertility evaluation as endocrine disorders are markedly reversible causatives of male infertility. Precise hormonal regulations are prerequisites to maintain normal male fertility parameters. The core male reproductive event, spermatogenesis, entails adequate testosterone concentration, which is produced via steroidogenesis in the Leydig cells. Physiological levels of both the gonadotropins are needed to achieve normal testicular functions. The hypothalamus-derived gonadotropin-releasing hormone (GnRH) is considered the supreme inducer of the gonadotropins and thereby the subsequent endocrine reproductive events. This hypothalamic–pituitary–gonadal (HPG) axis may be modulated by the thyroidal or adrenal axis and numerous other reproductive and nonreproductive hormones. Disruption of this fine hormonal balance and their crosstalk leads to a spectrum of endocrinopathies, inducing subfertility or infertility in men. This review article will discuss the most essential endocrinopathies associated with male factor infertility to aid precise understanding of the endocrine disruptions-mediated male infertility to encourage further research to reveal the detailed etiology of male infertility and perhaps to develop more customized therapies for endocrinopathy-induced male infertility.
... GnRH is the key regulator of gonadotrophin and sex hormone release 112 . Other hormones that serves as the markers off metabolic status are insulin-like growth factor 113 , insulin 113 , ghrelin 5 , leptin 6 , resistin 21 , adiponectin 114 , obestatin 8 , orexins 115 , growth hormone and many others [116][117][118][119] . These hormones crosstalk with the key male reproductive hormones to regulate the metabolism and overall male reproductive functions 120 . ...
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Adipokines, mostly produced by white adipose tissues, have been established to be endocrine factors which are also essential in energy homeostasis. More recently, their contribution in fertility regulation has been recommended. Resistin as well as visfatin are unique adipocyte-derived signaling chemicals whose expressions enhance in advanced obesity and are implicated in insulin resistance as well as type-2 diabetes. They are also found to be immune modulators and may participate in aggravating inflammatory responses which may partly explain obesity-mediated systemic inflammation. They are yet much less explored adipokines with potential to regulate metabolic rate, immune homeostasis as well as fertility. These adipokines are shown to be expressed in the hypothalamus in an area in charge of energy balance. Evidence suggest that they can potentially affect the hypothalamo-pituitary-gonadal (HPG) axis thereby modulating reproductive functions. They are also found to be expressed highly by the testes. In rodents, resistin and visfatin may positively modulate Leydig cell number and steroidogenesis. Additionally, visfatin exists in the human spermatozoa and may play role in the sperm maturation. However, reports on the impact of resistin and visfatin on human male fertility are inconsistent. In this article, we review the available literature on the role resistin and visfatin on male reproduction and integrate the mechanisms to discuss if they act as sensor for body energy dyshomeostatis and modulate male reproductive functions as per the metabolic status.
... [4][5][6][7][8][9][10] The association of male infertility with obesity has recently received a lot of attention, 11,12 adipokines may have a role in the underlying mechanisms that lead to obesity-related male infertility. [13][14][15][16] Obesity is marked by excessive deposition of white adipose tissues, which highly express chemerin and exaggerate the obesity-induced systemic inflammation. This may lead to induction of oxidative stress, 17,18 which adversely affects the reproductive hormonal regulatory axis 19 as well as can mediate direct disruption to male reproductive tissues. ...
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Adipokines are peptides produced mainly by the fat tissue adipocytes and their levels are sensitive to alterations in metabolic state. While there is little known about the impact of adipokines on male reproductive control, both animal-based experimental data and clinical research suggest that they can influence numerous male fertility indices. Chemerin is a newly found adipokine which is generally recognized as a chemoattractant and chemokine. Chemerin has been correlated with inflammatory reactions and metabolic imbalances, as seen in various metabolic syndromes. A sex dimorphic chemerin expression pattern has also been shown with greater levels in men in comparison to women. Chemerin can thus be offered as a potential new candidate in the connection among metabolic disorders, inflammation and male reproduction. The present article explores the multidimensional metabolic and inflammatory roles of chemerin and discusses its impact upon the male reproduction.
... OXA is a hypothalamic neuropeptide which has a specific role in regulation of male reproductive axis and tract. 112 Parallel to central hypothalamus, OXA and its OX1R also present in peripheral organs. Earlier studies done using animal model have suggested that both OXA and OX1R located and expressed in adult mouse testis and their role in testicular development during neonatal period was also demonstrated. ...
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Orexins are hypothalamus-derived neuropeptides with versatile functions. The most explored domains of orexins’ functions are their influence on the central nervous system (CNS) implicated in the regulation of sleep/wakefulness cycle, food intake behavior, energy homeostasis, and cognitive processes. Orexins reportedly bear two isoforms, orexin-A (OXA) and orexin-B (OXB), that act via their specific G protein-coupled receptor (GPCR), OX1R and OX2R. These peptides also play vital roles in various other peripheral organs where they regulate metabolism, neuroendocrine functions, blood pressure, as well as reproductive functions. Interestingly orexins also exhibit immuno-regulatory, anti-inflammatory properties and facilitate the mechanism of obesity resistance. Recent research has also shed light on significant role of orexins, in particular orexin A, in regulating reproductive functions in male since the Leydig cells, Sertoli cells, germ cells in various stages of the development, and even the epididymis and penis, manifest the OXA receptor. It will be intriguing to explore the properties of the orexins in reversing obesity, downregulation of inflammatory responses and mediation of male reproductive functions. The present article thus reviews these multitudinous properties of orexins and comprehends the possible connection among the behavioral, metabolic, anti-inflammatory functions of orexins with their roles in male reproduction
... 1 The major purpose of these adipokines is the management of energy homeostasis, while their crosstalks with various other endocrine axes in addition to their absolute impact upon various other organs are emerging with the introduction of research study in these realms. [2][3][4][5][6] The adipose tissue hormonal milieu is jeopardized in case of metabolic syndrome such as obesity 3,7 , whose occurrence is expediting at a worrying rate all over the world. The concurrent global decrease in male fertility [8][9][10][11][12][13] , has brought about a substantial number of researches routed to uncover the precise correlation between metabolic diseases like in case of obesity and also male reproductive dysfunctions. ...
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One of the most prevalent serum adipokines, adiponectin, is well-known for its function in regulating insulin sensitivity and preventing the metabolic syndrome from developing. Adiponectin is expressed in numerous components of the testis and studies claim that adiponectin may have positive paracrine effects on testicular functions. Adiponectin, on the other hand, inhibits hypothalamic-pituitary-gonadal (HPG) axis thereby that may affect testicular testosterone production. It is a strong anti-inflammatory and antioxidant molecule that may have beneficial effects on male reproductive in addition to its metabolic functions. In obese men, reduction in adiponectin levels may partly decipher the multitudinous pathways linking obesity-mediated metabolic disturbances, inflammation, and male infertility or subfertility. This article provides an overview of the actions of adipokines in energy homeostasis, metabolic balance, inflammation, and male reproduction, hence drawing a connexon between obesity-mediated dyshomeostasis in metabolism and immune functions and male reproductive disruptions.
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Adropin is a novel peptide hormone with multidimensional functionalities awaiting to be unveiled completely. This hormone is encoded by the 'energy homeostasis-associated' (Enho) gene. It is primarily produced by the liver, while to some extent by the brain, circulatory system and numerous other peripheral tissues. In the twelve years of its discovery, studies have established that adropin has essential role in body weight management, glucose and lipid balance, and is salubrious in a variety of illnesses. Exploring the potential of adropin in male infertility studies will be fascinating. Metabolic disorders, inflammation, and oxidative stress (OS) are among the main underlying mechanisms of male infertility. Since this molecule reduces body adiposity, possesses anti-inflammatory as well as antioxidant properties, it may have potential role in restoration of male fertility. In this review, we amalgamate the evidence available on physiological, metabolic, and immune functions of adropin and thereafter address the possible role of adropin in male reproduction.
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Irisin is a novel skeletal muscle- and adipose tissue-secreted peptide. It is conventionally regarded as an adipomyokine and is a cleaved fragment of Fibronectin type III domain-containing protein 5 (FNDC5). It is involved in the browning of white adipose tissue, glucose tolerance, and reversing of metabolic disruptions. Fertility is closely linked to energy metabolism and the endocrine function of the adipose tissue. Moreover, there is established association between obesity and male infertility. Irisin bears strong therapeutic promise in obesity and its associated disorders, as well as shown to improve male reproductive functions. Thus, irisin is a molecule of great interest in exploring the amelioration of metabolic syndrome or obesity-induced male infertility. In this review we aim to enumerate the most significant aspects of irisin actions and discuss its involvement in energy homeostasis and male reproduction. Though current and future research on irisin is very promiscuous, a number of clarifications are still needed to reveal its full potential as a significant medicinal target in several human diseases including male infertility.
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The aim of the present study is to evaluate the presence of ghrelin and orexin in the testicular tissue of patients who have undergone microscopic testicular sperm extraction (micro‐TESE) due to idiopathic non‐obstructive azoospermia. Seventy azoospermic cases were included in this study; serum hormone levels were measured and genetic investigations were performed. The patients were divided into two groups: micro‐TESE (+) and micro‐TESE (−). The number of Leydig cells and stained cells in the seminiferous tubules were counted under a light microscope, and we analyzed ghrelin and orexin activity. The relationship between serum hormone levels and ghrelin and orexin distributions in testicular tissue was evaluated according to micro‐TESE results. While sperm was found in 33 cases (47.1%), micro‐TESE was negative in 37 cases (52.9%). Peptide hormone activity in testicular tissue was higher in micro‐TESE (+) cases. However, interstitial orexin (p = 0.038) and ghrelin (p = 0.002) activity showed statistically meaningful differences. Many different peptides, genes, and other unknown mechanisms play important roles in testicular function. In particular, the peptides orexin and ghrelin may play regulatory roles in testicular function in humans.
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Melatonin, conventionally accepted as a pineal gland secretion, is a neuromodulator whose physiological concentrations are regulated by circadian rhythms. Alteration in melatonin levels owing to circadian influences is a major regulator of reproductive functions in animal species that are seasonal breeders. Attributing to its antioxidant properties and capability to cross physiological barriers, such as the blood-brain barrier, the blood-testis barrier as well as having almost no toxicity, melatonin finds high relevance in amelioration of male fertility parameters. Melatonin may affect male reproductive functions by influencing the release of hypothalamic gonadotropin-releasing hormone and pituitary luteinizing hormone, which are among the key hormones in regulation of male reproduction. It may directly act on testicular cells to influence testicular functions. The property of melatonin most essential for testicular functions is its ability to scavenge free radicals, thereby preventing testicular oxidative damage. This article summarizes the updated data on the versatility of melatonin as an endogenous rhythm setter, as an antioxidant molecule and its possible physiological impacts in male reproductive functions.
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Thyroid hormones have been well studied for its relevance to male reproduction in the last few decades. They are considered as essential regulators of male reproductive functions and play vital roles in male gonadal developments. Hyperthyroidism and hypothyroidism both affect testicular functions and influence neuroendocrine regulations over reproductive functions via the crosstalk between the hypothalamic-pituitary-thyroid axis and the hypothalamic-pituitary-gonadal axis. The alterations in the male reproductive hormonal milieu by thyroid hormones may lead to reduced testosterone levels and deterioration of semen quality. However, there are very few reports on the direct effects of thyroid disorders upon testicular functions and semen quality. This article aims to review the available literature to present a concise updated concept on the regulation of male reproductive functions by the thyroid hormones, and the possible mechanism by which thyroid dysfunctions affects testicular functions.
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Obesity has become a global pandemic since the last few decades with prevalence in more than one-third of the population in the United States. Another concurrent global health concern is the declining trend in male fecundity in terms of semen quality. Male infertility etiology is multifactorial with obesity serving as one of the major causatives. An array of research is directed in unveiling the potential mechanism underlying the obesity-induced male subfertility or infertility. Obesity may alter the hormonal milieu of the hypothalamic- pituitary-gonadal axis, its crosstalks with other metabolic hormones, upregulates secretion of adipose tissue-derived hormones and other factors, thus influencing the endocrine regulation of male reproduction. Obesity may also directly impair testicular functions by inducing genetic and epigenetic alterations in spermatozoa, disrupting sperm morphology and functions. Given the complexity of the condition of obesity and the multivariate etiopathology of male subfertility/ infertility, this review is aimed to provide an updated concept on how obesity mediated hormonal modulation may affect male fertility parameters.
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Male reproductive functions are mediated by different hormones whose orchestrations remain a major research interest. The ‘master’ regulator hormonal axis is the hypothalamo- pituitary-gonadal/testicular axis which is led by the pulsatile release of hypothalamic gonadotropin-releasing hormone. This, in turn, stimulates the anterior pituitary trophic hormones, the luteinizing hormone and follicle-stimulating hormone. Luteinizing hormone and follicle-stimulating hormone act upon the testicular cells, the Leydig cells for steroidogenesis and Sertoli cells to aid spermatogenesis, respectively. This primary axis is influenced by an array of other testicular hormones, metabolic hormones, and different regulatory factors. These hormonal crosstalks influence the intricate testicular functions, sexual behavior and semen quality in men. Given the growing concern in the last few decades over the increasing prevalence of male subfertility and/or infertility mostly in terms of deteriorating semen quality, it is required to find its underlying mechanisms. In this regard, the endocrine regulation of testicular functions is of prime importance in the determination of semen quality and sperm functions. This review article aims to present a concise updated overview on the mechanism by which the key hormones integrate the male reproductive functions and maintain the semen quality.
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It is an established fact that orexin plays an important role in regulating the reproductive axis and the secretions of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH). However, its precise cellular and molecular mechanisms are not fully recognized. Accordingly, the aim of the present study is to find out whether the central injection of orexin A (OXA) and its antagonists, SB-334867 (as orexin receptor antagonist 1; OX1RA) and JNJ-10397049 (as orexin receptor antagonist 2; OX2RA), either alone or in combination, can leave any impact on the reproductive axis (either hormonal or behavioral) in the male Wistar rats. Furthermore, in order to see whether OXA signals can be relayed through the pathway of kisspeptin/neurokinin B/dynorphin (known as KNDy neurons, a neural network which works upstream of GnRH neurons) or not, the relative gene expression of these neuropeptides were measured. Overall, the data from radioimmunoassay revealed that OXA significantly decreases the mean serum level of LH and testosterone and, in a similar vein, its antagonists neutralize this impact. Moreover, data from real-time quantitative PCR indicated that OXA has significantly reduced the hypothalamic expression of Gnrh. In this line, the gene expressions of Kisspeptin and Neurokinin b decreased. However, OXA antagonists neutralize this impact. Also, the expression of Dynorphin gene was upregulated by the following application of the OXA. The results of this study are related to the impact of orexin on the reproductive axis. It is recommended that KNDy neurons as the interneural pathway relay the information of orexin to the GnRH neurons.
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Reports of the increasing incidence of male infertility paired with decreasing semen quality have triggered studies on the effects of lifestyle and environmental factors on the male reproductive potential. There are numerous exogenous and endogenous factors that are able to induce excessive production of reactive oxygen species (ROS) beyond that of cellular antioxidant capacity, thus causing oxidative stress. In turn, oxidative stress negatively affects male reproductive functions and may induce infertility either directly or indirectly by affecting the hypothalamus-pituitary-gonadal (HPG) axis and/or disrupting its crosstalk with other hormonal axes. This review discusses the important exogenous and endogenous factors leading to the generation of ROS in different parts of the male reproductive tract. It also highlights the negative impact of oxidative stress on the regulation and cross-talk between the reproductive hormones. It further describes the mechanism of ROS-induced derangement of male reproductive hormonal profiles that could ultimately lead to male infertility. An understanding of the disruptive effects of ROS on male reproductive hormones would encourage further investigations directed towards the prevention of ROS-mediated hormonal imbalances, which in turn could help in the management of male infertility.
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Thyroid hormones and their impacts on male reproduction have been reported in numerous studies in past few decades. They are the crucial players in the regulation of male gonadal developments and reproductive functions. An excess or deficit of thyroid hormones not only alter the testicular functions but also interrupts neuroendocrine axis through the crosstalk between hypothalamic-pituitary-thyroid (HPT) axis and hypothalamic-pituitary-gonadal (HPG) axis. These changes result in decreased testosterone level and altered seminal plasma components which affect semen quality. The reports on the direct effects of thyroid disorders on semen quality are scanty. Thus, this review scrutinizes the available literature and aims to elucidate (a) the normal thyroidal regulations of semen parameters, (b) effects of hypothyroidism on semen quality (c) effects of hyperthyroidism on semen quality, and (d) the possible mechanism of action of thyroid dysfunctions on the alterations of semen quality. This review also highlights the limitations of the studies carried out so far and accentuates the necessity of large-scale human studies and animal studies specifically focusing on the molecular events of thyroid disorder-induced alterations in semen quality.
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Objective: To reveal the trend in alterations of sperm counts in Asian men over the past 50 years. Methods: This study reviewed all the published reports to unveil the specific pattern of alterations of sperm concentrations in Asian men from 1965 till 2015. The time-related changes in sperm concentration were studied using linear regression analyses. Results: The present study elucidated the trend using the reports from Carlsen et al (1965-1990) and non-Carlsen studies published until 2015, on fertile Asian men. In the reports of Carlsen et al., no overall declining trend in Asian men (r = 0.509, P = 0.760) was observed during this tenure, but non- Carsen reports showed a significant time-dependent decline of sperm concentration (r = -0.754, P = 0.005) in Asian men. This present review also showed a mild time-dependant decline in sperm concentration (-0.44×106/mL/year, 95% CI: -0.65 to -0.23; r = -0.473, P = 0.040) which accounted for an overall 22.17% decrease in past 50 years. Conclusions: This study brings to the forefront that sperm concentration among Asian men follows a mild declining trend over the period of 50 years, and further studies addressing the causes of this decline are required.
Aims The aim of the present study is to examine the orexin A (OXA) signaling can leave any impact on the hypothalamic-pituitary-gonadal (HPG) axis and this impact can be relayed through the pathway of RF amide-related peptide-3 (RFRP-3, the mammalian ortholog of the avian gonadotropin-inhibitory hormone)/G-protein coupled receptor (GPR)-147 (RFRP-3 receptor) as a novel target for controlling of HPG axis in the male rats. Materials and Methods Male rats were categorized randomly into experimental groups including control vehicle, OXA, and its antagonists’ group and went through to surgical cannulation into the third ventricle. After the intracerebroventricular injection of each solution, blood samples were collected for measurements of the LH and testosterone using radioimmunoassay method. Hypothalamus of the animals were isolated for analysis of the relative expression of Rfrp-3/Gpr-147 along with Gnrh gene by Real time-PCR. Also, in the different cohort of animal sexual behavior test was done. Results It was shown that OXA significantly decreases the mean serum level of the LH and testosterone and, at the same time, its antagonists neutralize this impact. Moreover, we demonstrated that OXA has reduced the hypothalamic gene expression of Gnrh and increased the expression of Rfrp-3 and Gpr-147 genes. While OXA antagonists neutralize this impact. Conclusions The results of this study are related to the impact of orexin on the HPG axis. It is recommended that RFRP-3/GPR-147 system as the interneural pathway relay the data of orexin to the neurons of GnRH.