Orexins and male reproduction

Abstract

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.

Full text

233
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 INFO ABSTRACT
Article history:
Received 21 May 2019
Revision 29 June 2019
Accepted 22 July 2019
Available online 7 October 2019
Keywords:
Obesity
Orexin
Testis
Steroidogenesis
Spermatogenesis
Corresponding author: Pallav Sengupta, Ph.D., Department of Physiology, Faculty of
Medicine and Biomedical Sciences, MAHSA University, Malaysia.
Tel: +60176369621
E-mail: pallav_cu@yahoo.com
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
Asian Pacific Journal of Reproduction
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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.
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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
receptors[41].
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
revealed.
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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