Gonadotropin-inhibitory hormone (GnIH) was first discovered in the Japanese quail, and peptides with a C-terminal LPXRFamide sequence, the signature protein structure defining GnIH orthologs, are well conserved across vertebrate species, including fish, reptiles, amphibians, avians, and mammals. In the mammalian brain, three RFamide-related proteins (RFRP-1, RFRP-2, RFRP-3 = GnIH) have been identified as orthologs to the avian GnIH. GnIH is found primarily in the hypothalamus of all vertebrate species, while its receptors are distributed throughout the brain including the hypothalamus and the pituitary. The primary role of GnIH as an inhibitor of gonadotropin-releasing hormone (GnRH) and pituitary gonadotropin release is well conserved in mammalian and non-mammalian species. Circadian rhythmicity of GnIH, regulated by light and seasons, can influence reproductive activity, mating behavior, aggressive behavior, and feeding behavior. There is a potential link between circadian rhythms of GnIH, anxiety-like behavior, sleep, stress, and infertility. Therefore, in this review, we highlight the functions of GnIH in biological rhythms, social behaviors, and reproductive and non-reproductive activities across a variety of mammalian and non-mammalian vertebrate species.
Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that belongs to the RFamide peptide family and was first identified in the quail brain. From the discovery of avian GnIH, orthologous GnIH peptides have been reported in a variety of vertebrates, including mammals, amphibians, teleosts and agnathans, but also in protochordates. It has been clearly established that GnIH suppresses reproduction in avian and mammalian species through its inhibitory actions on brain GnRH and pituitary gonadotropins. In addition, GnIH also appears to be involved in the regulation of feeding, growth, stress response, heart function and social behavior. These actions are mediated via G protein-coupled GnIH receptors (GnIH-Rs), of which two different subtypes, GPR147 and GPR74, have been described to date. With around 30,000 species, fish represent more than one-half of the total number of recognized living vertebrate species. In addition to this impressive biological diversity, fish are relevant because they include model species with scientific and clinical interest as well as many exploited species with economic importance. In spite of this, the study of GnIH and its physiological effects on reproduction and other physiological processes has only been approached in a few fish species, and results obtained are in some cases conflicting. In this review, we summarize the information available in the literature on GnIH sequences identified in fish, the distribution of GnIH and GnIH-Rs in central and peripheral tissues, the physiological actions of GnIH on the reproductive brain-pituitary-gonadal axis, as well as other reported effects of this neuropeptide, and existing knowledge on the regulatory mechanisms of GnIH in fish.
We assessed the analytical performance of the Abbott IMxTM immunoassay analyser for total beta human chorionic gonadotropin (Beta hCG), follicle-stimulating hormone (FSH) and luteinising hormone (LH). The within-run CVs for various analyte concentrations were 2% to 6% while those for between-run imprecision in routine assay ranged from 4% to 10%. IMxTM values correlated well with radioimmunoassay for beta hCG, and immunoradiometric assay for FSH and LH; the correlation coefficients (r) were 0.97, 0.99 and 0.98 for total beta hCG, FSH and LH respectively. The average sensitivities were approximately 3.1, 0.2 and 0.5 iu/l for beta hCG, FSH and LH, respectively. Sample carry-over was not detected and there was negligible cross-reaction between LH and beta hCG in the respective assays. The automatic sample dilution protocol for beta hCG was superior to the manual procedure. The IMxTM is easy to operate and is able to process 24 samples in 40-45 minutes.
Gonadotropin-inhibitory hormone (GnIH) was discovered as a novel hypothalamic peptide that inhibits gonadotropin release in the quail. The presence of GnIH-homologous peptides and its receptors (GnIHRs) have been demonstrated in various vertebrate species including teleosts, suggesting that the GnIH-GnIHR family is evolutionarily conserved. In avian and mammalian brain, GnIH neurons are localized in the hypothalamic nuclei and their neural projections are widely distributed. GnIH acts on the pituitary and gonadotropin-releasing hormone neurons to inhibit reproductive functions by decreasing gonadotropin release and synthesis. In addition, GnIH-GnIHR signaling is regulated by various factors, such as environmental cues and stress. However, the function of fish GnIH orthologs remains inconclusive because the physiological properties of fish GnIH peptides are debatable. This review summarizes the current research progress in GnIH-GnIHR signaling and their physiological functions in vertebrates with special emphasis on non-mammalian vertebrate species.
We report here on a longitudinal study of stress and women's reproduction in a small Kaqchikel Mayan community in rural Guatemala. Current understanding of the effects of stress on the reproductive axis in women is mostly derived from clinical studies of individual stressors. Little is known, however, about the cumulative effects of "real life" stress. Cortisol increases in response to a broad variety of individual stressors (Tilbrook et al., 2002). In this article, we evaluate the association between daily fluctuations in women's urinary cortisol and reproductive hormones: estrone conjugates (E(1)C), pregnandiol glucuronide (PdG), luteinizing hormone (LH), and follicle stimulating hormone (FSH). To assess the association between daily changes in cortisol levels and changes in the profiles of the reproductive hormones, we used a random coefficients model based on polynomial regression. The sample includes 92 menstrual cycles provided by 24 participants over a year-long prospective study. Increases in urinary cortisol levels were associated with significant increases in gonadotrophin and progestin levels during the follicular phase. Also, in a time window between days 4 and 10 after ovulation, increased cortisol levels were associated with significantly lower progestin levels. These results are significant because untimely increases in gonadotrophins and low midluteal progesterone levels have previously been reported to impinge on the ovulatory and luteinization processes and to reduce the chances of successful implantation (Ferin, 1999; Baird et al., 1999). Future research should consider the possibility that stress may affect fecundability and implantation without necessarily causing amenorrhoea or oligomenorrhoea.
The superovulatory response to gonadotrophin treatment during different months of the year was investigated in Kambing kacang goats, a tropical breed, in Malaysia. Sixty-three cycling does, fitted with progesterone impregnated intravaginal sponges for 17 days, received two days before sponge withdrawal, an intramuscular injection of either 10, 15 or 20 mg of follicle stimulating hormone (FSH) or 500, 1000 or 1500 iu of equine chorionic gonadotrophin (eCG). The dose of FSH was divided into four decreasing daily doses and each daily dose was subdivided into two and administered at 07.00 and 19.00. Fifty-four does detected in oestrus were mated with fertile bucks. The ovarian response was determined by laparoscopy and eggs were recovered surgically five or six days after oestrus. The ovulatory response (mean +/- standard deviation) based on corpora lutea was higher in the FSH (13.4 +/- 8.4 corpora lutea per doe, n = 20) than the eCG-treated groups (6.4 +/- 5.1 corpora lutea per doe, n = 25) but the difference was not significant (P greater than 0.05). Does responded to gonadotrophins throughout the year with more than 50 per cent of does responding during the rainy months compared with less than 35 per cent responding during the dry months. This difference was statistically significant (P less than 0.05). Egg recovery was better in the FSH (6.8 +/- 5.3 per doe, n = 20) than the eCG groups (3.0 +/- 3.8 per doe, n = 21) but the difference was not significant (P greater than 0.05).
Since the discovery of gonadotropin-releasing hormone (GnRH) in mammals at the beginning of the 1970s, it was generally accepted that GnRH is the only hypothalamic neuropeptide regulating gonadotropin release in mammals and other vertebrates. In 2000, however, gonadotropin-inhibitory hormone (GnIH), a novel hypothalamic neuropeptide that actively inhibits gonadotropin release, was discovered in quail. Numerous studies over the past decade and a half have demonstrated that GnIH serves as a key player regulating reproduction across vertebrates, acting on the brain and pituitary to modulate reproductive physiology and behavior. In the latter case, recent evidence indicates that GnIH can regulate reproductive behavior through changes in neurosteroid, such as neuroestrogen, biosynthesis in the brain. This review summarizes the discovery of GnIH, and the contributions to GnIH research focused on its mode of action, regulation of biosynthesis, and how these findings advance our understanding of reproductive neuroendocrinology.
The gonadotropin-releasing hormone (GnRH) stimulation test is a valuable tool in diagnosing and differentiating causes of early pubertal occurrences. Utility of the test can be limited in some instances, however, including the early phases of pubertal hypothalamic-pituitary-gonadal axis activation, in girls showing commonly overlapping pictures, and in obese children due to excess circulating estrogen that suppresses luteinizing hormone (LH). A lack of consistent baseline and stimulated gonadotropin cutoffs observed in different studies also contributes to limitations in testing. Nevertheless, early detection of true pathological causes for pubertal disorders is needed to allow prompt treatment and better prognosis. While basal LH can be beneficial as a good screening tool for detecting pubertal disorder, it does not preclude the need for GnRH testing. The aim of this review was to highlight the role of GnRH stimulation tests and varying testing cutoffs in diagnosis of precocious puberty and its classification.
This is the first report in South East Asia of a singleton frozen embryo donation pregnancy for hypergonadotrophic hypogonadism. The hormonal profile was compared with that of a control group of normal uncomplicated singleton pregnancies in Singapore. The plasma beta hCG levels were lower compared to those of our normal uncomplicated singleton pregnancies at 2 to 3 weeks after the embryo transfer but became comparable at 4 to 5 weeks after embryo transfer. The successful vaginal delivery and the obstetric complications developed in this case are discussed.
Stress impairs the hypothalamic-pituitary-gonadal (HPG) axis, probably through its influence on the hypothalamic-pituitary-adrenal (= interrenals in the teleost, HPI) axis leading to reproductive failures. In this study, we investigated the response of hypothalamic neuropeptides, gonadotropin-inhibitory hormone (GnIH), a component of the HPG axis, and corticotropin-releasing hormone (CRH) a component of the HPI axis, to acute social defeat stress in the socially hierarchical male Nile tilapia (Oreochromis niloticus). Localization of GnIH cell bodies, GnIH neuronal processes, and numbers of GnIH cells in the brain during acute social defeat stress was studied using immunohistochemistry. Furthermore, mRNA levels of GnIH and CRH in the brain together with GnIH receptor, gpr147, and adrenocorticotropic hormone (ACTH) in the pituitary were quantified in control and socially defeated fish. Our results show, the number of GnIH-immunoreactive cell bodies and GnIH mRNA levels in the brain and the levels of gpr147 mRNA in the pituitary significantly increased in socially defeated fish. However, CRH and ACTH mRNA levels did not change during social defeat stress. Further, we found glucocorticoid type 2b receptor mRNA in laser captured immunostained GnIH cells. These results show that acute social defeat stress activates GnIH biosynthesis through glucocorticoid receptors type 2b signalling but does not change the CRH and ACTH mRNA expression in the tilapia, which could lead to temporary reproductive dysfunction.
Social behaviors are key components of reproduction, because they are essential for successful fertilization. Social behaviors, such as courtship, mating, and aggression, are strongly associated with sex steroids, such as testosterone, estradiol, and progesterone. Secretion of sex steroids from the gonads is regulated by the hypothalamus-pituitary-gonadal (HPG) axis in vertebrates. Gonadotropin-releasing hormone (GnRH) is a pivotal hypothalamic neuropeptide that stimulates gonadotropin release from the pituitary. In recent years, the role of neuropeptides containing the C-terminal Arg-Phe-NH2 (RFamide peptides) has been emphasized in vertebrate reproduction. In particular, two key RFamide peptides, kisspeptin and gonadotropin-inhibitory hormone (GnIH), emerged as critical accelerator and suppressor of gonadotropin secretion. Kisspeptin stimulates GnRH release by directly acting on GnRH neurons, whereas GnIH inhibits gonadotropin release by inhibiting kisspeptin, GnRH neurons, or pituitary gonadotropes. These neuropeptides can regulate social behavior by regulating the HPG axis. However, distribution of neuronal fibers of GnRH, kisspeptin, and GnIH neurons is not limited within the hypothalamus, and the existence of extrahypothalamic neuronal fibers suggests direct control of social behavior within the brain. It has traditionally been shown that central administration of GnRH can stimulate female sexual behavior in rats. Recently, it was shown that Kiss1, one of the paralogs of kisspeptin peptide family, regulates fear responses in zebrafish and GnIH inhibits sociosexual behavior in birds. Here, we highlight recent findings regarding the role of GnRH, kisspeptin, and GnIH in the regulation of social behaviors in fish, birds, and mammals and discuss their importance in future biological and biomedical research.
Reproduction is associated with the circadian system, primarily as a result of the connectivity between the biological clock in the suprachiasmatic nucleus (SCN) and reproduction-regulating brain regions, such as preoptic area (POA), anteroventral periventricular nucleus (AVPV), and arcuate nucleus (ARC). Networking of the central pacemaker to these hypothalamic brain regions is partly represented by close fiber appositions to specialized neurons, such as kisspeptin and gonadotropin-releasing hormone (GnRH) neurons; accounting for rhythmic release of gonadotropins and sex steroids. Numerous studies have attempted to dissect the neurochemical properties of GnRH neurons, which possess intrinsic oscillatory features through the presence of clock genes to regulate the pulsatile and circadian secretion. However, less attention has been given to kisspeptin, the upstream regulator of GnRH and a potent mediator of reproductive functions including puberty. Kisspeptin exerts its stimulatory effects on GnRH secretion via its cognate Kiss-1R receptor that is co-expressed on GnRH neurons. Emerging studies have found that kisspeptin neurons oscillate on a circadian basis and that these neurons also express clock genes that are thought to regulate its rhythmic activities. Based on the fiber networks between the SCN and reproductive nuclei such as the POA, AVPV, and ARC, it is suggested that interactions among the central biological clock and reproductive neurons ensure optimal reproductive functionality. Within this neuronal circuitry, kisspeptin neuronal system is likely to "time" reproduction in a long term during development and aging, in a medium term to regulate circadian or estrus cycle, and in a short term to regulate pulsatile GnRH secretion.
Postweaning social isolation reduces the amplitude of the daily variation of CLOCK protein in the brain and induces lower reproductive activity. Gonadotropin-inhibitory hormone (GnIH) acts as an inhibitor in the reproductive system and has been linked to stress. Social isolation has been shown to lower neuronal activity of GnIH-expressing neurons in the dorsomedial hypothalamus (DMH). The exact mechanism by which social isolation may affect GnIH is still unclear. We investigated the impact of social isolation on regulatory cellular mechanisms in GnIH neurons. We examined via immunohistochemistry the expression of CLOCK protein at four different times throughout the day in GnIH cells tagged with enhanced fluorescent green protein (EGFP-GnIH) in 9-week-old adult male rats that have been raised for 6 weeks under postweaning social isolation and compared them with group-raised control rats of the same age. We also studied the expression of β-catenin-which has been shown to be affected by circadian proteins such as Bmal1-in EGFP-GnIH neurons to determine whether it could play a role in linking CLOCK in GnIH neurons. We found that social isolation modifies the pattern of CLOCK expression in GnIH neurons in the DMH. Socially isolated rats displayed greater CLOCK expression in the dark phase, while control rats displayed increased CLOCK expression in the light phase. Furthermore, β-catenin expression pattern in GnIH cells was disrupted by social isolation. This suggests that social isolation triggers changes in CLOCK and GnIH expression, which may be associated with an increase in nuclear β-catenin during the dark phase.
Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that decreases gonadotropin synthesis and release by directly acting on the gonadotrope or by decreasing the activity of gonadotropin-releasing hormone (GnRH) neurons. GnIH is also called RFamide-related peptide in mammals or LPXRFamide peptide in fishes due to its characteristic C-terminal structure. The primary receptor for GnIH is GPR147 that inhibits cAMP production in target cells. Although most of the studies in mammals, birds, and fish have shown the inhibitory action of GnIH in the hypothalamic-pituitary-gonadal (HPG) axis, several in vivo studies in mammals and many in vivo and in vitro studies in fish have shown its stimulatory action. In mouse, although the firing rate of the majority of GnRH neurons is decreased, a small population of GnRH neurons is stimulated by GnIH. In hamsters, GnIH inhibits luteinizing hormone (LH) release in the breeding season when their endogenous LH level is high but stimulates LH release in non-breeding season when their LH level is basal. Besides different effects of GnIH on the HPG axis depending on the reproductive stages in fish, higher concentration or longer duration of GnIH administration can stimulate their HPG axis. These results suggest that GnIH action in the HPG axis is modulated by sex-steroid concentration, the action of neuroestrogen synthesized by the activity of aromatase stimulated by GnIH, estrogen membrane receptor, heteromerization and internalization of GnIH, GnRH, and estrogen membrane receptors. The inhibitory and stimulatory action of GnIH in the HPG axis may have a physiological role to maintain reproductive homeostasis according to developmental and reproductive stages.
LPXRFamide (LPXRFa) peptides have been characterized for their ability to inhibit gonadotropin (GTH) release in birds and stimulate growth hormone (GH) release in frogs. However, their involvement in regulating the reproductive hypothalamo-pituitary-gonadal axis in mammals and fish is inconclusive. To study the role of LPXRFa peptides in the regulation of GTH secretion, we cloned tilapia LPXRFa and LPXRF receptor (LPXRF-R). Processing of the tilapia preproLPXRFa liberated three mature LPXRFa peptides that varied in size and post-translational modifications. Phylogenetic analysis of LPXRFa and the closely related RFamide peptide PQRFa showed clear clustering of each peptide sequence with its orthologs from various vertebrates. Signal-transduction analysis of the tilapia LPXRF-R in COS-7 cells showed clear stimulation of CRE-dependent luciferase activity, whereas the human NPFFR1 showed suppression of forskolin-induced CRE-dependent activity in this system. Administration of the tilapia pyroglutaminated LPXRFa-2 peptide to primary cell culture of tilapia pituitaries, or to reproductive female tilapia by ip injection, positively regulated both LH and FSH release in vivo and in vitro. Using double-labeled fluorescent in-situ hybridization and immunofluorescence, βLH cells were found to co-express both tilapia lpxrf and tilapia lpxrf-r mRNA, whereas some of the βFSH cells coexpressed only lpxrf-r mRNA. No coexpression of tilapia lpxrf-r was identified in GH-positive cells. These findings suggest that the LPXRFa system is a potent positive regulator of the reproductive neuroendocrine axis of tilapia.
The effects of high and low jumping exercise intensities combined with honey on bone and gonadotrophins were investigated in eighty four 9 week-old female rats.
The effects of different estrus synchronization techniques on follicular development and estrus response were studied in 81 nulliparous Boer does. The does were divided into nine groups. Eight of the nine groups were synchronized with prostaglandin F2-alpha (PGF(2α)) or flugestone acetate (FGA) or their combinations, and the ninth group was a control group. In addition to the above combinations, four of the eight synchronized groups were given 5 mg follicle-stimulating hormone (FSH) and the remaining four groups were administered 300 IU equine chorionic gonadotrophin (eCG). Posttreatment follicular development was monitored until ovulation occurred using a real-time B-mode ultrasound scanner (Aloka, 500 SSD, Japan), with a 7.5-MHz transrectal linear probe. All the does from the synchronized groups that were given eCG exhibited oestrus while only 88.9% of the does synchronized with FSH showed estrus. The estrus response was observed to be the least among the does synchronized with PGF(2α) + FSH (33.3%) combination followed closely by the FGA + FSH (42.9%) combinations. It was observed that the combinations of FGA + PGF(2α) + FSH resulted in increased percentage of estrus response, duration of estrus, and ovulation. The number of follicles was higher (P < 0.05) in FSH-synchronized groups than the eCG-synchronized groups. It was concluded that the best estrus synchronization protocol in goats is the FGA + eCG with or without PGF(2α). However, the PGF(2α) + FGA + FSH method of estrus synchronization is the most promising combination for further development as a better alternative to estrus synchronization with eCG in does.
Newly discovered kisspeptin (metastin), encoded by the Kiss1/KISS1 gene, is considered as a major gatekeeper of puberty through the regulation of GnRH. In the present study, we cloned a novel kisspeptin gene (kiss2) in the zebrafish Danio rerio and the medaka Oryzias latipes, which encodes a sequence of 125 and 115 amino acids, respectively, and its core sequence (FNLNPFGLRF, F-F form) is different from the previously characterized kiss1 (YNLNSFGLRY, Y-Y form). Our in silico data mining shows kiss1 and kiss2 are highly conserved across nonmammalian vertebrate species, and we have identified two putative kisspeptins in the platypus and three forms in Xenopus. In the brain of zebrafish and medaka, in situ hybridization and laser capture microdissection coupled with real-time PCR showed kiss1 mRNA expression in the ventromedial habenula and the periventricular hypothalamic nucleus. The kiss2 mRNA expression was observed in the posterior tuberal nucleus and the periventricular hypothalamic nucleus. Quantitative real-time PCR analysis during zebrafish development showed a significant increase in zebrafish kiss1, kiss2 (P < 0.002), gnrh2, and gnrh3 (P < 0.001) mRNA levels at the start of the pubertal phase and remained high in adulthood. In sexually mature female zebrafish, Kiss2 but not Kiss1 administration significantly increased FSH-beta (2.7-fold, P < 0.05) and LH-beta (8-fold, P < 0.01) mRNA levels in the pituitary. These results suggest that the habenular Kiss1 and the hypothalamic Kiss2 are potential regulators of reproduction including puberty and that Kiss2 is the predominant regulator of gonadotropin synthesis in fish.
Hypersexuality refers to abnormally increased or extreme involvement in any sexual activity. It is clinically challenging, presents trans-diagnostically and there is extensive medical literature addressing the nosology, pathogenesis and neuropsychiatric aspects in this clinical syndrome. Classification includes deviant behaviours, diagnosable entities related to impulsivity, and obsessional phenomena. Some clinicians view an increase in sexual desire as 'normal' i.e. psychodynamic theorists consider it as egodefensive at times alleviating unconscious anxiety rooted in intrapsychic conflicts. We highlight hypersexuality as multi-dimensional involving an increase in sexual activity that is associated with distress and functional impairment. The aetiology of hypersexuality is multi-factorial with differential diagnoses that include major psychiatric disorders (e.g. bipolar disorder), adverse effects of treatments (e.g. levodopatreatment), substance-induced disorders (e.g. amphetamine substance use), neuropathological disorders (e.g. frontal lobe syndrome), among others. Numerous neurotransmitters are implicated in its pathogenesis, with dopamine and noradrenaline playing a crucial role in the neural reward pathways and emotionally- regulated limbic system neural circuits. The management of hypersexuality is determined by the principle of de causa effectu evanescent, if the causes are treated, the effect may disappear. We aim to review the role of pharmacological agents causing hypersexuality and centrally acting agents treating the associated underlying medical conditions. Bio-psycho-social determinants are pivotal in embracing the understanding and guiding management of this complex and multi-determined clinical syndrome.
Subcutaneous body fat and Quetelet's Indices (QI) of 52, 18-29 year old normal female volunteers were determined. These body mass indices were then grouped according to the phase of each subject's menstrual cycle, early or late follicular and early or late luteal phase. The subcutaneous body fat is 27.07 +or- 1.0% in the early follicular but drops to 24.68 +or- 1.84% in the late follicular phase. The value then rises significantly higher than that in the late follicular phase to 30.14 +or- 1.15% (P0.02) in the early luteal drops to 27.17 +or- 0.55% towards the level of the early follicular phase (P0.05). Variations in the values of QI during each menstrual cycle exactly mirror those for subcutaneous body fat. The fall in the 2 body mass indices during the late follicular phase coincides somewhat with the established preovulatory LH and FSH surges as well as the high levels of estrogen of this period. On the other hand the significant rise in the 2 parameters during the early luteal phase coincides with the marked rise in the ratio of progesterone to estrogen. Clearly, increased levels of progesterone relative to estrogen appear to cause an increase in the body fat during each menstrual cycle. The implication of this finding for women on contraceptive pills which are predominantly progesterone and those whose normal menstrual cycle is "interrupted" at the early luteal phase by a successful fertilization raises very interesting questions with regards to prediction of ovulation.