U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.

Cover of Endotext

Endotext [Internet].

Show details

Physiology of GnRH and Gonadotropin Secretion

, , , , and .

Author Information and Affiliations

Last Update: January 5, 2022.


Gonadotropin hormone-releasing hormone (GnRH) is the key regulator of the reproductive axis. Its pulsatile secretion determines the pattern of secretion of the gonadotropins follicle stimulating hormone and luteinizing hormone, which then regulate both the endocrine function and gamete maturation in the gonads. Recent years have seen rapid developments in how GnRH secretion is regulated, with the discovery of the kisspeptin-neurokinin-dynorphin neuronal network in the hypothalamus. This mediates both positive and negative sex steroid feedback control of GnRH secretion, in conjunction with other neuropeptides and neurotransmitters. This review describes the main features of this regulatory system, including how its anatomical arrangements interact with functional control, and describes key differences between rodent and larger mammalian systems. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.


Since the discovery of Gonadotropin Releasing Hormone (GnRH), an extensive body of literature has established it as the pivotal central regulator of human reproduction. However, the GnRH neuronal network, per se lacks the cellular machinery to fully integrate developmental, environmental, endocrine and metabolic factors that influence its secretion. For example, GnRH neurons do not express the principal estrogen receptor alpha (ER-alpha), which is required for sex-steroid mediated control of gonadotropin secretion (1). Intermediate signaling pathways must therefore exist to mediate gonadal steroid feedback. Current evidence, accumulated since the discovery of Kisspeptin-Neurokinin B-Dynorphin (KNDy) neuronal network in the last decade, suggests a pivotal role for this network in the regulation of pulsatile GnRH secretion by integrating nutrient, endocrine and environmental signals, and thus the control of downstream hypothalamic-pituitary-gonadal (HPG) axis.

The HPG axis anatomically comprises of:


The hypothalamus (especially the infundibular nucleus, the human homologue of the arcuate nucleus) where the KNDy and GnRH-producing neurons are located.


The anterior pituitary, where Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) are secreted by gonadotropes.


The gonads, responsible for the production of both sex steroids and gametes, under the influences of LH and FSH.

As with other endocrine systems, positive and negative feedback regulate HPG axis (2,3). In this chapter, we have focused on human data. Where human data is limited, data from other species are leveraged.


The Discovery of GnRH

GnRH was isolated from porcine hypothalami and structurally identified as a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly·NH2) five decades ago (4-6). This decapeptide was shown to potently stimulate LH and FSH release from the pituitary in a number of mammalian species (6,7). Early literature referred to this peptide as the ‘Luteinizing Hormone-Releasing Hormone (LH-RH)’, but more recently, it is widely referenced as Gonadotropin Releasing Hormone (GnRH) -reflecting the stimulatory role on the secretion of both gonadotropins – i.e., LH and FSH (8).

Diverse forms of GnRH and its receptor exist among vertebrates, with over twenty primary structures across species, suggesting that GnRH system developed early in the evolutionary sequence (9,10). The GnRH structure was first identified is mammalian, and is therefore referred to as GnRH I (9,11). Subsequently, another structurally different vertebrate GnRH sequence was first identified from chicken brain -this is now referred to as GnRH II (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2) (10,12). A third form has also been described in fish - GnRH III (9,12). In mammals, hypophysiotropic functions are limited to GnRH I, therefore in the human context GnRH I is referred to as GnRH (13) and we will use this terminology for this review.

Neuroanatomy of GnRH Neurons

GnRH neurons originate in the medial olfactory placode during embryological development and migrate along the olfactory bulb to their final positions within the hypothalamus (14,15). A number of factors contributing to this GnRH neuron migratory process have been identified: anosmin-1 (the product of KAL gene) (16), neuropilins (17), leukemia inhibitory factor (18), fibroblast growth factor receptor 1 (19), fibroblast growth factor receptor 8 (20), polysialic form of neural adhesion molecule (PSA-NCAM) (21), among others (22). Defective GnRH migration leads to Kallmann syndrome, characterized by hypogonadotropic hypogonadism due to GnRH deficiency and anosmia (15). Mutations in prokineticin genes (PROK1 and PROK2) lead to hypogonadotropic hypogonadism without anosmia, suggesting that factors other than suboptimal migration can also lead to functional deficiencies in GnRH (15,23,24).

GnRH cell bodies are located in the medial preoptic area (POA) and in the arcuate/infundibular nucleus of the hypothalamus, forming a neuronal network with projections to the median eminence (25). GnRH is secreted from the median eminence into the fenestrated capillaries of portal circulation, carried to the anterior pituitary (25). In humans, the number of GnRH neurons has been estimated to range between 1000 to 1500 (9,14). The co-location of GnRH neurons with other central regulators allows the GnRH network to be influenced by a range of neuroendocrine and metabolic inputs (26).

GnRH Secretion and Pulsatility

Two distinct modes of GnRH secretion have been described: pulsatile and surge modes (26). Pulsatile mode refers to episodic release of GnRH, with distinct pulses of GnRH secretion into the portal circulation with undetectable GnRH concentrations between pulses. The surge mode of GnRH secretion occurs in females, during the pre-ovulatory phase, in which the presence of GnRH in the portal circulation appears to be persistent (26,27).

Direct pulsatile GnRH release was initially demonstrated in ovariectomized rhesus monkeys using serial samples of portal blood (28). Pulsatile pattern of GnRH secretion was demonstrated subsequently in humans through serial blood sampling during pituitary surgery (29). Abolishment of LH pulses by GnRH antisera (30,31) and its reestablishment with GnRH analogues (30) suggest that LH pulses are determined by the underlying GnRH pulsatility. The LH pulsatility was first detected during an attempt to validate a radioimmunoassay to measure serum LH in rhesus monkeys, where marked variations in LH levels was noticed (32). Further studies confirmed the pulsatile nature of LH secretion (33-35). In women, the frequency and amplitude of LH pulses were noted to be dependent on the menstrual cycle phase, with pulses every 1 to 2 hours during the early follicular phase eventually merging into a continuous mid-cycle surge, and decreased pulse frequency to every 4 hours during the luteal phase (36). In humans, LH pulse frequency is now used as a surrogate of GnRH pulsatility, as ethical considerations and technical challenges preclude sampling of hypophyseal blood or cerebrospinal fluid to measure GnRH concentrations directly (37,38).

The importance of GnRH pulsatility on LH and FSH secretion was first demonstrated in rhesus monkeys, where endogenous GnRH secretion was abolished by hypothalamic radio-frequency. Pulsatile GnRH reinstated gonadotropin secretion in these animals, whereas continuous GnRH only elicited a transient response. Moreover, the switch from continuous to pulsatile GnRH administration allowed recovery of gonadotropin secretion (39).

GnRH neurons coordinate their activity, but the precise mechanism of this remains unclear (27,40), and is the subject of continuing investigations. Episodic multi-unit electrical activity at medial basal hypothalamus (MBH) is correlated with LH release, suggesting that ‘GnRH pulse generator’ is anatomically located at MBH – or closely linked to it neurohormonally (41,42). GnRH neurons show intrinsic electrical pulsatility. GnRH cell lines derived from mouse hypothalamic and fetal olfactory placode GnRH neurons both demonstrate intrinsic pulsatility in vitro (26,43,44). Functionally, the ‘GnRH pulse generator’ relies on complex relations between glutamatergic cells, GnRH and other neurons, and likely other elements are involved, of which the kisspeptin-neurokinin B-opioid pathway may have a pivotal intermediary role in the regulation of GnRH pulsatility (45).

Differential Regulation of LH and FSH

The stimulatory effects of GnRH on LH and FSH secretion are not identical (46). FSH secretion is more irregular than LH in both humans and sheep, which is essentially related to the pulsatility and different stimulatory effects of GnRH, but also other factors might be relevant, such as differences in LH and FSH storage (more scarce for the FSH), existence of different gonadotropes subpopulations or diverse response times to GnRH (47). In ovariectomized sheep administered GnRH antisera, pulsatile secretion of LH was completely inhibited (undetectable LH levels within 24 hours), while the FSH concentration fell more slowly and remained detectable (30). It has been estimated that 93% of the GnRH pulses were associated with FSH pulses and, unlike LH, a constitutive secretion of FSH appears to exist (48). The frequency of GnRH input has been demonstrated to selectively regulate gonadotropin subunit gene transcription: rapid GnRH pulse rates increase α and LH-β and slow GnRH pulse frequency increases FSH-β gene transcription (49-51). Moreover, with progressive increases in GnRH frequency (from one pulse every 120 to 60 min, from 60 to 30 min, and from 30 to 15 min) in GnRH deficient men, mean LH rose concurrently with a decrease in LH pulse amplitude, while FSH remained unchanged (52).

Biological and Clinical Relevance of GnRH Pulsatility

Appropriate modulation of LH pulse frequency is essential for pubertal maturation and reproductive function. In infancy, LH pulsatile secretion is increased (often termed mini-puberty), likely reflecting pulsatile GnRH secretion, but soon becomes quiescent (53). This pre-pubertal suppression of HPG axis has been shown to occur in agonadal humans (54) and primates (55), suggesting that hypothalamo-hypophyseal factors play a role in post-natal quiescence of the reproductive axis, until puberty sets in.

The onset of pubertal maturation is heralded by the development of a pattern of steady acceleration in LH pulsatility (56). In children, higher basal and GnRH stimulated LH concentrations are observed in early childhood (<5 years). This is subdued mid-childhood (5-11 years) and increase thereafter with pubertal development (54,57). Conceptually, an abnormal reactivation of GnRH pulse frequency is the central mechanism associated with precocious or delayed puberty (14).

In women, the pattern of GnRH secretion is essential for the regulation of the menstrual cycle (Figure 1) (58,59). LH pulse frequency is slow in the luteal phase, and increasingly speeds up during the follicular and the pre-ovulatory phases, presumably reflecting changes in GnRH pulse frequency (60). Abnormalities in GnRH - and hence LH pulse frequency - are associated with a number of reproductive endocrine disorders. In hypothalamic amenorrhea, a condition associated with anovulatory amenorrhea and hypoestrogenemia, LH pulse frequency (and by inference GnRH) is lower than expected for the prevailing steroid profile and is comparable to luteal phase pulsatility (37). LH pulse frequency in hyperprolactinemic women is also lower than in healthy women, requiring dopaminergic preparations, such as bromocriptine to regulate prolactin secretion and restore LH pulse frequency (38). In polycystic ovary syndrome LH pulse frequency and amplitude are higher throughout the menstrual cycle in comparison to that observed in healthy women, contributing to chronic anovulation (61-64).

Figure 1. . Hormonal oscillations through the menstrual cycle.

Figure 1.

Hormonal oscillations through the menstrual cycle. In the early follicular phase of the menstrual cycle, the initial increase in FSH stimulates follicular recruitment and maturation. The consequent secretion of estradiol (E2) selectively inhibits FSH release (needed for selection of the dominant follicle) and maintains rapid GnRH pulsatility during the late follicular phase. The persistent rapid GnRH pulses increases LH, which further stimulates E2 secretion, culminating in positive E2 feedback to produce the mid-cycle LH surge. During the LH surge, GnRH levels appear to be consistently elevated and remain elevated as LH declines, suggesting that the frequency of GnRH pulse has become very rapid or continuous, which results in desensitization of LH secretion (possibly the mechanism to terminate the LH surge). After ovulation, luteinization of the ruptured follicle results in progesterone secretion which reduces the frequency of GnRH pulses. With the demise of corpus luteum, E2, progesterone and inhibin levels fall, and the GnRH pulse frequency increases, leading to follicular maturation in the next cycle. (Adapted from: Marshall JC, Dalkin AC, Haisenleder DJ, Paul SJ, Ortolano GA, Kelch RP. Gonadotropin-releasing hormone pulses: regulators of gonadotropin synthesis and ovulatory cycles. Recent Prog Horm Res. 1991;47:155-187)


Whilst the central role attributed to GnRH remains undisputed, its effective function requires input from other neuronal networks. For instance, the absence of estrogen receptor alpha (ER-alpha) expression on GnRH neurons suggests the need for an intermediate signaling pathway to mediate gonadal steroid feedback (1). The discovery of kisspeptin signaling in neuroendocrine regulation of human reproduction revolutionized the current understanding of the HPG axis. Kisspeptin signaling pathway is increasingly recognized as essential for normal puberty, gonadotropin secretion, and regulation of reproduction (65-67). Other relevant kisspeptin roles have been identified such as regulation of sexual and social behavior, emotional brain processing, mood, audition, olfaction, metabolism, body composition, cardiac function, among others (68-73).

Discovery of KNDy Neuronal Network

KiSS1, the gene encoding kisspeptins, was first described in 1996 as a suppressor of metastasis in human malignant melanoma (74,75). This gene was discovered in Hershey and named in accordance to the famous chocolates ‘Hershey’s Kisses’; the inclusion of ‘SS’ is indicative of ‘suppressor sequence’. The KiSS1 gene maps to chromosome 1q32 and includes four exons of which the first two are not translated (76). The gene encodes the precursor 145 amino acid peptide, which is cleaved down to a 54 amino acid peptide. This peptide can be truncated to 14, 13 and 10 amino-acid peptides, all sharing the C-terminal sequence (77,78). These peptides are collectively referred to as kisspeptins - and Kp-10, Kp-13, Kp-14 and Kp-54 are suggested abbreviations for human kisspeptins (79). In 2001, kisspeptins were identified as ligands for the orphan G–protein receptor 54 (GPR54) (80-82), currently named KISS1R (79). KISS1R is localized to human chromosome 19p13.3 and it has five exons, encoding a 398-amino acid protein with seven trans-membrane domains (78,81). Upon binding by kisspeptin, KISS1R activates phospholipase C and recruits intracellular messengers, inositol triphosphate and diacylglycerol, which in turn lead to the release of calcium and activation of protein kinase C (81-83).

A reproductive role for kisspeptin in humans became apparent from patients with pubertal disorders which were associated with KISS1R mutations (84,85). A number of inactivating mutations of Kiss1 and Kiss1r have since been reported in animal models with phenotypes characterized by pubertal delay (86). An activating mutation in KISS1R has been described in a girl with precocious puberty: when compared to cells with wild-type transfected GPR54, cells with this mutation showed prolonged inositol phosphate accumulation and phosphorylation of extracellular signal–regulated kinase, suggesting extended activation of intracellular signaling by the mutant GPR54 (87). Missense mutations have also been reported in KISS1 gene in three unrelated children with central precocious puberty (88). Functional studies of these mutant peptides demonstrated higher resistance to in vitro degradation but normal affinity to KISS1R, thus suggestive of increased bioavailability as the mechanism by which these abnormal kisspeptins induce precocious puberty (88).

A role for neurokinin B in the hypothalamic regulation was also demonstrated when genetic studies in patients from consanguineous families with hypogonadotropic hypogonadism were found to have missense mutations in TAC3 (encodes neurokinin B) and TACR3 (encodes neurokinin B receptor) (89). Other cases have been reported since (90-93).

There is also long-standing evidence for the role of opioid system in reproduction. In 1980, Wilkes reported the localization of β endorphin in the human hypothalamus (94). Studies involving the administration of naloxone and naltrexone (opioid antagonists) to humans showed stimulatory effects on LH secretion (95,96), and other studies supported the notion that endogenous opioids play a role in the control of HPG axis (97-101). In 2007, it was demonstrated that dynorphin and kisspeptin are co-localized along with neurokinin B in the same hypothalamic neuronal population in sheep, therefore termed KNDy (Kisspeptin-Neurokinin B-Dynorphin) neurons, highlighting the possible interconnection between these neuropeptides in the control of GnRH and gonadotropin secretion (102,103). The co-localization of kisspeptin, neurokinin B and dynorphin has also been demonstrated in humans (104).

Kisspeptin neurons have also other important neuroanatomical relationships, such as with neuronal nitric oxide synthase neurons as demonstrated in prepubertal female sheep (105), or with somatostatin neurons in the rat hypothalamus (106).

Neuroanatomy of KNDy Neuronal Network

In humans, kisspeptin neurons are distributed in the rostral Pre-optic Area (POA) and in the infundibular nucleus in the hypothalamus (Figure 2) (104,107). In both male and female autopsy samples, the majority of kisspeptin cell bodies are identified in the infundibular nucleus, and a second dense population of kisspeptin neurons in the rostral POA (104). The infundibular nucleus (arcuate nucleus in non-human species) is similar across species but the rostral region is more species specific (104,108,109). In rodents, the rostral population is located in the anteroventral periventricular nucleus (AVPV) and the periventricular nucleus, the continuum of this region named as the rostral periventricular region of the third ventricle (RP3V) (108,110). Humans and ruminants lack this well-defined RP3V population of kisspeptin neurons, which are more scattered within the preoptic region (109,111).

Kisspeptin axons form dense plexuses in the human infundibular stalk, where the secretion of GnRH occurs (104). Axo-somatic, axo-dendritic and axo-axonal contacts between kisspeptin and GnRH axons were demonstrated at this level, showing that kisspeptin and GnRH networks are in close proximity (104,112). Moreover, GnRH neurons express Kiss1r mRNA, reinforcing the notion of kisspeptin involvement in GnRH secretion (113-115).

Figure 2. . Neuroanatomy of kisspeptin-GnRH pathway and the control of HPG axis in humans and rodents.

Figure 2.

Neuroanatomy of kisspeptin-GnRH pathway and the control of HPG axis in humans and rodents. Kisspeptin signals directly to GnRH neurons, which express KISS1R. The location of kisspeptin neurons within the hypothalamus is species specific, residing within the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus in rodents, and within the preoptic area (POA) and the infundibular nucleus in humans. Kisspeptin neurons in the infundibular nucleus (humans)/arcuate nucleus (rodents) co-express neurokinin B and dynorphin (KNDy neurons), which autosynaptically regulate kisspeptin secretion (via neurokinin B receptor and kappa opioid peptide receptor). In humans, infundibular KNDy neurons relay negative (red) and positive (green) feedbacks, whereas in rodents the negative and positive steroid feedbacks are mediated via arcuate nucleus and AVPV respectively. The role of human POA kisspeptin neurons in sex steroid feedback is not yet clear. (Adapted from: Skorupskaite K, George JT, Anderson RA. The kisspeptin-GnRH pathway in human reproductive health and disease. Human Reproduction Update. 2014;20:485-500)

Three-quarters of kisspeptin-immunoreactive cells in the human infundibular nucleus of the hypothalamus co-express neurokinin B and dynorphin (KNDy neurons) (104,116). KNDy neurons in rodents and ruminants are localized in the arcuate nucleus of the hypothalamus. However, neurokinin B and dynorphin are absent from kisspeptin neurons in the hypothalamic POA (Figure 2) (67,111). This differential expression of neuropeptides may reflect distinct functions of these two kisspeptin populations.

Significant kisspeptin expression was also demonstrated in extra-hypothalamic sites, including in limbic and paralimbic brain regions, such as medial amygdala, cingulate, globus pallidus, hippocampus, putamen and thalamus, key areas of neurobiological control of sexual and emotional behaviors (reviewed in detail in (117)), as well as peripherally in organs like ovary, testis, uterus and placenta where the kisspeptin system may also play a part in reproduction function (118,119).

Interactions Between Kisspeptin, Neurokinin B and Dynorphin

KDNy neurons act synergistically to induce coordinated and pulsatile GnRH secretion by regulating the neuroactivity of other KDNy cells. This is supported by the existence of neurokinin B and kappa opioid peptide receptors (receptor for dynorphin) within the KNDy cells, but not kisspeptin receptors, which are predominantly expressed on GnRH neurons (116,120,121). Neuron-neuron and neuron-glia communications via gap junctions contribute for the synchronized activities among KNDy neurons (122).

Neurokinins (A and B) are members of the tachykinin family of peptides, which stimulate three related GPCRs (encoded by TACR1, TACR2 and TACR3) (123). Neurokinin B acts predominantly on TACR3. Neurokinin B stimulates kisspeptin neurons, which in turn lead to GnRH secretion (67,124). Neurokinin B signaling regulates GnRH/LH secretion in healthy women, and it is crucial for the mediation of the estrogenic positive and negative feedback on LH secretion (125-127). There is rapidly increasing interest in the therapeutic value of neurokinin antagonists in several indications in reproductive health, recently reviewed in (128).

In women with polycystic ovary syndrome, the administration of neurokinin 3 receptor antagonists markedly reduced serum LH concentration and pulse frequency, as well as serum testosterone (129-131). A recent study confirmed a complex crosstalk between neurokinin B and kisspeptin pathways in the regulation of GnRH secretion in polycystic ovary syndrome. In this study, kisspeptin-10 infusion given to women with polycystic ovary syndrome increased LH secretion with a direct relationship to estradiol exposure. Neurokinin 3 receptor antagonism reduced LH secretion and pulsatility, and whilst LH response to kisspeptin-10 was preserved, its relationship with circulating estradiol was not. More interestingly, although kisspeptin-10 increased LH pulse frequency, changes in other parameters of LH secretory pattern were prevented when co-administered with neurokinin 3 receptor antagonists (131).

In postmenopausal women, seven day treatment with neurokinin 3 receptor antagonist decreased LH secretion, but not FSH secretion, as well as lead to a remarkable reduction in hot flushes (132). Neurokinin 3 receptor antagonism efficiency in treating menopausal hot flushes has been also demonstrated in other clinical trials (133,134), thus supporting its therapeutical role in menopausal vasomotor symptoms (135-137). In healthy men, neurokinin B signaling display a central role for the reproductive function, and this is functionally upstream of kisspeptin-mediated GnRH secretion: LH, FSH and testosterone secretion decreased during the administration of a neurokinin 3 receptor antagonist, while kisspeptin-10 administration restored LH secretion to the same degree before and during neurokinin 3 receptor antagonist treatment (138).

An increase in the expression of Kiss1 in the hypothalamic neurons was observed following senktide (agonist of neurokinin B) administration (139), and its stimulatory effects were abolished in Gpr54 knock-out male (140). In ovariectomized goats, neurokinin B stimulated LH secretion through electrical multi-unit activity corresponded to LH secretion, suggesting a hypothalamic site for this GnRH pulse generation (141). GnRH antagonists abolished the stimulatory effect of neurokinin B, demonstrating its site of action to be functionally higher than the GnRH receptor (142,143).

Studies involving the administration of opioid antagonists to humans have shown stimulatory effects on LH secretion in late follicular and mid-luteal phase (95,96), and together with other studies (97-101), highlight the inhibitory input by dynorphins on kisspeptin signaling, and consequently on GnRH/gonadotropin secretion. Through the stimulatory effects of neurokinin B and kisspeptin, and the inhibitory action of dynorphin, these neuropeptides coordinate pulsatile GnRH and LH secretion (Figure 2) (144,145).

Kisspeptin-mediated GnRH secretion is sex steroid dependent. Estrogen and progesterone modulate kisspeptin activity though the sex-steroid receptors expressed on kisspeptin neurons at both AVPV and the arcuate nucleus (146-148). Furthermore, two distinct populations of kisspeptin neurons, the infundibular/arcuate region of which interacts with neurokinin B and dynorphin, appear to mediate distinct sex-steroid pathways (discussed in more detail in sections 4.1-4.4). Briefly, in humans, KNDy neurons in the infundibular nucleus alone are involved in negative and positive sex-steroid feedback, whereas in rodents positive sex-steroid feedback seems to be mediated via kisspeptin neurons in the AVPV region and negative sex-steroid feedback via the arcuate KNDy neurons (Figure 2) (67,107,148,149).

Stimulatory Effect of Kisspeptin on GnRH and Gonadotropin Secretion

Kisspeptin is a potent stimulator of the HPG axis – and in fact, it is the most potent GnRH secretagogue currently known. Kisspeptin signals directly to the hypothalamic GnRH neurons via kisspeptin receptor to release GnRH into the portal circulation, which in turn stimulates the anterior pituitary gonadotropes to produce LH and FSH (124,150).

The stimulatory effects of kisspeptin on LH secretion have been documented in animal models (151-154). This is consistent with human studies, where kisspeptin increases both LH and FSH secretion with the preferential stimulatory effect on the former (67,155-165). Kissppetin-54 was first administered in healthy men as an intravenous infusion with dose-dependent rise in LH secretion (157). Since then kisspeptin was administered in different isoforms (kisspeptin-54 and kisspeptin-10), different routes (subcutaneous and intravenous), different types of exposure (continuous and bolus), to healthy men and women and in endocrine disease models with low gonadotropin output, all showing stimulatory effect of kisspeptin on LH secretion (fully reviewed in (67)).

Pulsatile GnRH secretion correlates with LH pulsatility, prompting investigation of the effect of kisspeptin on regulating LH pulse frequency. LH pulse frequency and amplitude were increased following intravenous infusion of kisspeptin-10 in healthy men (160), and subcutaneous bolus of kisspeptin-54 in healthy women (162). The hypothalamic response to kisspeptin-54 and the pituitary response to GnRH are preserved in healthy older men (166). Kisspeptin also stimulates LH pulse frequency in reproductive endocrine disorders of low LH pulsatility, including hypothalamic amenorrhea, defects in the neurokinin B pathway and hypogonadal men with diabetes (93,167,168). Indeed, kisspeptin-54 and kisspeptin-10, as well as kisspeptin agonists like MVT-602 (previously known as TAK-448) are able to stimulate physiological reproductive hormone secretion in individuals with functional hypogonadism related to deficient GnRH secretion, such as in hypothalamic amenorrhea or polycystic ovary syndrome (169,170).

Kisspeptin regulates GnRH and subsequently gonadotropin secretion through Kiss1r, as suggested by Messager who demonstrated no detectable LH levels in response to kisspeptin in Kiss1r knockout mice (115). The prevention of the stimulatory effect of kisspeptin on LH secretion by GnRH antagonists indicate that kisspeptin action is GnRH-mediated (114,152,171-173). This is further supported by the observation that kisspeptin cause depolarization of GnRH neurons (113) and stimulate GnRH release from hypothalamic explants (174,175). The expression of GnRH mRNA is upregulated in GnRH neurons following kisspeptin administration (176). Moreover, in patients with impaired functional capacity of GnRH neurons (idiopathic hypogonadotropic hypogonadism), the same dose of kisspeptin failed to induce LH response seen in healthy men and women (177). In female rats, ablation of KNDy neurons resulted in hypogonadotropic hypogonadism, confirming its role in the maintenance of normal LH levels and to estrous cyclicity (178).

Some investigators have demonstrated a direct stimulatory effect of kisspeptin on gonadotropes, but this direct stimulatory action of kisspeptin on gonadotropes remains debatable (179-183). Kiss1 and Kiss1r gene expression has been shown in gonadotropes, and gonadotropin secretion from the pituitary explants was observed following exposure to kisspeptin (77,179-182). Moreover, LHβ and FSHβ gene expression was upregulated in the primary pituitary cells treated with kisspeptin. Whilst kisspeptin can directly regulate gonadotropins at the transcriptional level, it appears to be less relevant than the GnRH-mediated action (67,182,183).

Desensitization Effect of Chronic or Continuous Exposure to Kisspeptin

Continuous administration of GnRH desensitizes the HPG axis by downregulation of GnRH receptors and desensitization of gonadotropes, following an initial stimulatory effect (39). It is therefore important to ascertain the effects of continuous exposure to kisspeptin on the HPG axis. Efforts have been made to assess the impact of continuous infusions of kisspeptin in a number of animal experiments (115,184-187). In adult rats, continuous administration of kisspeptin-54 increased serum LH and free testosterone on day one, but this stimulatory effect was lost after 2 days, indicative of kisspeptin receptor desensitization (187). In rhesus monkeys, the continuous administration of kisspeptin-10 resulted in suppression of LH secretion, indicating desensitization of kisspeptin receptor (185). The kisspeptin receptor has been shown to desensitize in vitro (184). In sheep, infusion of kisspeptin-10 resulted in acute increase in serum LH levels, which declined by the end of 4 hour infusion, while GnRH remained elevated following the discontinuation of kisspeptin-10 administration. This suggests that desensitization to GnRH could be occurring at the level of pituitary gonadotropes (115).

Consistent with animal studies, Jayasena et al. demonstrated that in women with hypothalamic amenorrhea an initial increase in LH and FSH secretion was not sustained following twice daily subcutaneous kisspeptin-54 administration for two weeks (164). Other studies in humans employing continuous or repeated kisspeptin administration provide conflicting evidence for kisspeptin-mediated desensitization and appear to be dose-related (160,168). High doses of kisspeptin may induce desensitization, but this is not apparent at lower doses (67). Sustained LH secretion and increased LH pulsatility was demonstrated with lower dose of kisspeptin-54 (0.01-1nmol/kg/h) infusion for 8 hours in women with hypothalamic amenorrhea (168) and kisspeptin-10 (3.1 nmol/kg/h) infusion for 22.5 hours in healthy men (160). In contrast, LH secretion was not maintained in three healthy men during the 24 hour infusion of kisspeptin-10 at 9.2 nmol/kg/h (the highest dose used in humans so far), although serum LH did not fall to the castrate levels and remained well above baseline at end of infusion (188).

Kisspeptin receptor agonist analogues, TAK-488 and TAK-683, induce desensitization when administered to healthy men (189,190). However, the ability of natural kisspeptin fragments to downregulate the HPG axis in humans remains to be established, and is to date complicated by differences in study protocols, in terms of isoform of kisspeptin used, duration (8 hours-2 weeks), mode and route of kisspeptin administration, lower doses of kisspeptin in human studies compared to animal, and the endocrine profile of the study participants (men versus women versus hypothalamic amenorrhea).

Sexual Dimorphism in Kisspeptin Signaling

The response to kisspeptin is different in men and women. In men, kisspeptin potently stimulates the release of LH, but in women the effect of kisspeptin is variable and dependent on the phase of menstrual cycle (67). Whilst men respond to the modest doses of kisspeptin, LH response to kisspeptin in healthy women is minimal and inconsistent in the early follicular phase but greatest in the pre-ovulatory phase of the menstrual cycle (157-159,165). This indicates that in addition to the fluctuations in sex-steroid milieu, other mechanisms, such as changes in pituitary sensitivity to GnRH or GnRH network responsiveness to kisspeptin regulate the sensitivity to kisspeptin throughout the menstrual cycle (67,121,191).

Not only there is sexual dimorphism in gonadotropin response to kisspeptin, but there are also anatomical differences. Female hypothalami have significantly more kisspeptin fibers and kisspeptin cell bodies than men (161). Only a few kisspeptin cell bodies are present in the male infundibular nucleus and none in the rostral periventricular nucleus, which is on contrary to the female hypothalami with abundant kisspeptin network in both of these hypothalamic nuclei (104). These sex differences in kisspeptin neurons appear to be established early during perinatal development through the action of sex steroids (121,192).

These marked functional and anatomical differences may reflect sexually dimorphic roles of kisspeptin between both sexes, influencing their reproductive functions, namely the sex steroid feedback in GnRH and gonadotropin secretion (67).

Kisspeptin, GnRH and Puberty

Kisspeptin is crucial for normal pubertal development, the discovery of which formed the basis for the obligate role of kisspeptin signaling in the control of reproductive function (193). More than a decade ago two independent groups identified ‘inactivating’ mutations in KISS1R in patients with hypogonadotropic hypogonadism presenting with pubertal delay (84,85). Recently, a male patient with a biallelic loss-of-function KISS1R mutation was described who had undergone a normal and timely puberty, although as a child he had presented with microphallus and bilateral cryptorchidism. This suggests different levels of dependence of the hypothalamic-pituitary-gonadal axis on kisspeptin signaling during the reproductive life span, with the mini-puberty of infancy appearing more dependent on the kisspeptin system than is adolescent puberty (194). On the other hand, activating mutations in KISS1R and KISS1 were then described in children with central precocious puberty (87,88).

Hypothalamic expression of Kiss1 and Kiss1R mRNA is upregulated at puberty (113,153,195), and the percentage of GnRH neurons depolarizing in response to kisspeptin increases from juvenile (25%) to pubertal (50%) and to adult mice (>90%) (113), suggesting that GnRH neurons may acquire sensitivity to kisspeptin across puberty. In monkeys, kisspeptin-54 secretion and pulsatility increased at the onset of puberty (196). Moreover, the exogenous administration of kisspeptin resulted in earlier puberty in rats and monkeys (195,197), whereas kisspeptin antagonists delayed puberty in rats (173) and inhibited GnRH release in pubertal monkeys (198). In other study, daily injections of a synthetic kisspeptin analog has been shown to significantly advance puberty in prepubertal female mice (199). GnRH neuron-specific Kiss1r knockout mouse showed a delay in pubertal onset, abnormal estrous cyclicity in female and abnormal external genitalia in male (microphallus, decreased anogenital distance associated with failure of preputial gland separation) (200).

Exogenous kisspeptin stimulated GnRH-induced LH secretion in patients with hypogonadism resulted in a spontaneous and permanent activation of their hypothalamic-pituitary-gonadal axis, whereas patients with idiopathic hypogonadotropic hypogonadism and no spontaneous LH pulsatility did not respond to kisspeptin, suggesting that the reversal of hypogonadism, sexual maturation and puberty may well be associated with the acquisition of kisspeptin responsiveness which in turn signals the emergence of reproductive endocrine activity (201). A recent study, 15 children with delayed puberty were administered intravenous kisspeptin and displayed divergent responses, with seven subjects having no response to kisspeptin, whereas others having either robust response (comparable to those of adults) or intermediate responses as perceived in one case (202).

GnRH release during puberty appears to require a cooperative mechanism between the kisspeptin and NKB networks. Agonists and antagonists of kisspeptin and NKB were administered into the stalk-median eminence (region with high concentration of GnRH, kisspeptin and NKB neuroterminal fibers), and it was found that both kisspeptin-10 and the NK3R agonist senktide stimulated GnRH release in a dose-responsive manner in prepubertal and pubertal monkeys. However, senktide-induced GnRH release was blocked in the presence of a KISS1R antagonist and the kisspeptin-induced GnRH release was blocked in the presence of NK3R antagonist in pubertal monkeys, leading to the notion that a reciprocal signaling mechanism between kisspeptin and NKB exists and is possibly necessary for a normal puberty (203).

These data together emphasizes that disrupted kisspeptin-GPR54-NKB signaling leads to hypogonadotropic hypogonadism, reinforcing the critical role of kisspeptin in puberty.


Development and maintenance of normal reproductive function requires a coordinated interplay between neuroendocrine, metabolic and environmental factors. The GnRH-gonadotropin system plays a central role in the regulation of reproduction by integrating different signals and factors (Figure 3) (121,191).

Figure 3. . Neuroendocrine regulation of GnRH/gonadotropin secretion.

Figure 3.

Neuroendocrine regulation of GnRH/gonadotropin secretion. The GnRH-gonadotropin system plays a central role in the regulation of reproduction by integrating different neuroendocrine, metabolic and environmental signals/factors. The KNDy signaling has a key role in this process by integrating some of these signals and by regulating GnRH neurons.

Overview of Sex Steroid Feedback

A crucial role for sex steroids in the regulation of GnRH neurons and/or gonadotropes in humans was initially proposed as serial blood sampling and gonadotropin assays in women through phases of menstrual cycle showed an uneven distribution, with a clear mid-cycle surge in LH and FSH. Two mechanisms were proposed to mediate this effect: first, GnRH secretion is altered in response to the steroid milieu; second, sensitivity of the gonadotropes to a GnRH input is sex-steroid dependent, although the exact mechanism remains controversial due to inter-species variation (204).

Hypothalamic secretion of GnRH increases during proestrus in rats (205), sheep (206) and non-human primates (207). Pulsatile once hourly administration of exogenous GnRH restored ovulation in Rhesus monkeys with hypothalamic lesions which abolished GnRH secretion, suggesting that it was the ‘ebb and flow’ of ovarian estrogen feedback acting directly on the pituitary which triggered an LH surge (208). In humans, endogenous GnRH secretion is potentially diminished during the pre-ovulatory LH surge and the suppression of gonadotropin secretion is greater with lower doses of a GnRH receptor antagonist during the mid-cycle surge in comparison to the other phases of the menstrual cycle (209). This suggests that pituitary gonadotrope sensitivity to GnRH is enhanced during the mid-cycle surge. Administration of exogenous estradiol or testosterone in men with hypogonadotropic hypogonadism receiving pulsatile GnRH therapy, decreased gonadotropin concentrations, demonstrating inhibitory effects of sex-steroids at the level of pituitary (210). A direct effect of estrogen on gonadotropes is further demonstrated by the inhibition of LH secretion from rat pituitary gonadotropes in vitro (211). Literature to date suggests that there is a dual-site sex-steroid feedback in the regulation of gonadotropin secretion, occurring at the level of both pituitary and hypothalamus (212-217).

Estrogen Feedback

Patterns of GnRH and LH secretion across the menstrual cycle are modulated by estradiol feedback. A biphasic effect of estradiol on gonadotropin secretion has long been established and it is essential for normal menstrual cycle, with an initial negative feedback (greater suppression of FSH) and a subsequent positive feedback (more prominent for LH) (32). However, the basis for estrogen feedback has been long unclear. GnRH neurons do not express estrogen receptor alpha (ER-alpha) (218,219), and therefore a mediator between gonads and hypothalamus was missed. Recent evidence suggests that kisspeptin and neurokinin B (126) appears to be providing this “missing link” as a key regulator of both negative and positive estrogen feedback (67,121).

KNDy neurons in the infundibular nucleus in humans and the arcuate nucleus in other mammals mediate negative estrogen feedback. Estrogen suppresses kisspeptin and neurokinin B release from KNDy neurons, which reduce their stimulatory input to GnRH neurons. Simultaneously, there is a relative deficiency in dynorphin signaling as part of this negative feedback, releasing the inhibitory action on kisspeptin signaling (Figure 2) (67). Immunohistochemical staining of the postmenopausal female hypothalami showed up-regulated expression of KISS1 mRNA and hypertrophy of kisspeptin neurons in the infundibular nucleus when compared to the premenopausal women (107). These hypertrophied kisspeptin neurons co-localized with ER-alpha, had increased expression of neurokinin B and decreased levels of prodynorphin mRNA (220-222). The above evidence for the involvement of the infundibular KNDy system in mediating negative estrogen feedback in humans is consistent with animal studies. Kisspeptin neurons in the arcuate nucleus show frequent co-localization with ER-alpha (148,223). In ovariectomized animals, the expression of Kiss1 and neurokinin B mRNA was up-regulated but prodynorphin mRNA reduced in the arcuate nucleus (equivalent to the infundibular nucleus in humans), and this was reversed by estrogen replacement (99,111,116,224-228). Postmenopausal women are resistant to the stimulatory effect of kisspeptin on LH secretion (132,229), but postmenopausal women receiving estradiol replacement therapy are only resistant to kisspeptin initially and then they do demonstrate a remarkable increase in LH pulse amplitude with direct correlation to the circulating levels of estradiol and duration of kisspeptin administration (229). However, neurokinin B regulates gonadotropin secretion in postmenopausal women, and antagonizing the neurokinin 3 receptor modestly decreases LH secretion in this context (132). Interestingly, the use of fezolinetant (a neurokinin 3 receptor antagonist) has been shown to effectively reduce the menopause-related vasomotor symptoms owing to its inhibitory effect in the hypothalamic thermoregulatory center, and thus presenting a potential non-hormonal treatment option for menopausal women (134).

Negative estrogen feedback switches to positive feedback in the late follicular phase of menstrual cycle, in order to induce the pre-ovulatory LH surge. Recent evidence support the role of kisspeptin in generating the LH surge: during an assisted conception cycle, kisspeptin-54, used instead of a routinely administered human chorionic gonadotropin, induced an LH surge, and oocyte maturation, with a subsequent live term birth (227). Repeated twice-daily administration of kisspeptin-54 shortened the menstrual cycle, suggesting that the onset of LH surge was advanced (161). This is further supported by antagonistic studies in animal models, where the administration of kisspeptin antiserum or antagonists blunt/prevent LH peak, whilst kisspeptin advances LH surge (198,230,231). However, kisspeptin-mediated positive estrogen feedback has marked anatomical variations between humans and other species. In rodents, positive estrogen feedback is mediated via the AVPV nucleus, which is absent in humans, other primates and sheep (Figure 2). The expression of Kiss1 mRNA in the AVPV nucleus is low following an ovariectomy, but is dramatically increased with estrogen treatment and at the time of LH surge (148,149). In sheep, positive estrogen feedback is mediated though the arcuate nucleus, where the expression of Kiss1 mRNA is the greatest at the pre-ovulatory LH surge (182). There are no studies looking at the anatomical region of estrogen mediating positive feedback in humans. Although there does not appear to be two distinct anatomical populations of kisspeptin neurons to relay negative and positive sex-steroid feedback in humans, it is possible that separate signaling pathways exists to mediate gonadal steroid feedback.

Whilst it is clear that kisspeptin is involved in estrogen-induced mid-cycle gonadotropin surge, the role of KNDy neurons in positive estrogen feedback is less obvious. In sheep, the expression of neurokinin B mRNA was increased during the LH surge, and neurokinin B receptor agonist senktide induced LH secretion mimicking its mid-cycle surge (232,233). However, this has not been reproduced in other species, including humans (168). In summary, KNDy neurons mediate negative estrogen feedback in the infundibular nucleus in humans and the arcuate nucleus in other species. Positive estrogen feedback is mediated via kisspeptin neurons, which show marked inter-species anatomical variation.

In addition to the gonads, the brain is one of the major organs producing estradiol, and recently a number of studies demonstrated that estradiol is synthesized and released in the hypothalamus (i.e. neuroestradiol) contributing to the regulation of GnRH release, particularly regarding its positive feedback effect during the preovulatory GnRH/LH surge (234).

Progesterone Feedback

Progesterone reduces LH pulse frequency in healthy women. LH secretory pattern in women exposed to exogenous progesterone was comparable to LH profile observed in the mid-luteal phase, demonstrating that progesterone plays a central role in the luteal phase of menstrual cycle (235). These inhibitory effects of progesterone on gonadotropin secretion are mediated by the progesterone receptor (PR) (236). The suppressive effect of progesterone on LH secretion was diminished in the context of estrogen deficiency, while co-administration of estradiol restored it (236), suggesting an interplay between these sex steroids. However, the presence of PR on only a small subset of GnRH neurons (237-239) led to the notion that intermediaries are involved in mediating inhibitory progesterone signal to GnRH neurons.

There is evidence that KNDy neurons play a role in mediating progesterone feedback on GnRH through dynorphin signaling (Figure 2) (99,116). PR have been demonstrated to be co-localized with dynorphin in the KNDy neurons (147) and progesterone increased dynorphin concentrations (240). Moreover, the number of preprodynorphin mRNA expressing cells decreased in postmenopausal women (222) and in ovariectomized ewes, but normalized with exogenous progesterone to luteal levels (240).

Testosterone Feedback

Testosterone exerts negative feedback on gonadotropin secretion. Early studies verified that LH and FSH pulse frequency are enhanced in hypogonadal men and exogenous testosterone decreases gonadotropin secretion, suggesting that testosterone have an inhibitory effect on GnRH secretion (216,241).

Few GnRH neurons express androgen receptors (AR) (242). GnRH neurons were thus considered to be reliant on an intermediary neuronal population to mediate testosterone feedback. A key role for KNDy neurons in this mediation has been suggested, as these neurons express AR which directly mediate the androgen feedback. The androgen feedback may also rely on the aromatization of testosterone, as testosterone-induced suppression of Kiss1 mRNA in the rodent arcuate nucleus is identical to that observed with estradiol, but more than that observed with dihydrotestosterone administration (243). The cross-talk between AR and ER was suggested from animal studies: AR expression was downregulated in the prostate following neonatal estrogen exposure (244), and AR transcription was modulated following a co-transfection of AR and ER (245).

Navarro has described a role for KNDy neurons in mediating the negative testosterone feedback on GnRH secretion, and provided evidence that neurokinin B released from KNDy neurons is part of an auto-feedback loop that generates the pulsatile secretion of Kiss1 and GnRH in male mice: Kiss1 and dynorphin mRNA are regulated by testosterone through estrogen and androgen receptor-dependent pathways; KNDy neurons express neurokinin B receptor whereas GnRH neurons do not, and senktide (an agonist for the neurokinin B receptor) activates KNDy neurons leading to gonadotropin secretion but has no discernible effect on GnRH neurons (246). Other studies demonstrated that the suppression of gonadotropin secretion using testosterone is associated with a reduction of Kiss1 mRNA in the hypothalamus (114,195,247). Moreover, post-orchidectomy rise in LH in rodents can be blocked by kisspeptin antagonists, further suggesting that kisspeptin system mediates the hypothalamic androgen feedback (173).

Stress and Glucocorticoids

Physical and psychological stress is associated with hypothalamic amenorrhea, possibly though the activation of hypothalamic-pituitary-adrenal (HPA) axis (248,249). Experimental evidence points towards a cortisol-mediated suppression of gonadotropin secretion as the main key pathway to explain stress-induced gonadotropin suppression (55,250-257). The negative effect of cortisol on HPG axis is recognized to occur at both pituitary and hypothalamic levels. There are also data suggesting that upstream factors in the HPA axis, such as Corticotropin Releasing Hormone (CRH) and vasopressin may play a mediatory role (258,259).

Cortisol secretion in women with hypothalamic amenorrhea is elevated (251), and evening adrenocorticotropic hormone (ACTH) and cortisol concentrations are higher in excessive exercise (250,254). Administration of exogenous glucocorticoids to eugonadal women was associated with a decrease in LH pulse frequency, suggesting that glucocorticoids have a negative action on GnRH secretion (257). In ovine portal blood, cortisol administration led to a decrease in GnRH pulse frequency (256). Inferences of cortisol effects on gonadotropin secretion were also derived from observations in women and men with Cushing’s syndrome (condition associated with excessive cortisol secretion), where exogenous GnRH preferentially stimulates FSH whilst LH remains unchanged (252,255). The resolution of male hypogonadotropic hypogonadism was also observed in men with remission of Cushing’s disease (255).

This negative input of cortisol on the HPG axis may be modulated by sex-steroid hormones, and kisspeptin signaling has also been implicated in the process. Cortisol alone had no impact on GnRH pulsatility in ovariectomized ewes, but the co-administration of estradiol and progesterone led to a 70% decrease in GnRH secretion (256). Decreased hypothalamic Kiss1 mRNA expression has been observed during exposure to stress or exogenous glucocorticoids. The role of kisspeptin in mediating stress inputs is further supported by the expression of glucocorticoid receptor on murine kisspeptin neurons (260).

Hypothalamic CRH neurons, important regulators of the stress response, also directly modulate GnRH excitability in a dose-dependent and receptor-specific manner, and the GnRH response to CRH is influenced by estrogens (261). Intracerebroventricular administration of CRH in female rats suppressed LH pulsatility and the LH surge, and this suppression was enhanced by estrogens (262).


Prolactin is a well-known inhibitor of GnRH release and a suppressor of the HPG axis. The association between hyperprolactinemia and reproductive dysfunction has long been established, accounting for 14% of secondary amenorrhea and hypogonadism cases (263) and for a third of women presenting with infertility (264,265). Hyperprolactinemia is evident in 16% of men with erectile dysfunction and in 11% of men with oligospermia (266). The decreased pulsatility of LH in hyperprolactinemia responds to bromocriptine (267). GnRH therapy has restored ovulation and normal luteal function in bromocriptine resistant hyperprolactinemic women (268,269), suggesting that prolactin exerts inhibition through direct reduction of GnRH secretion.

The neuroendocrine pathway by which prolactin inhibits GnRH pulse frequency remains to be fully elucidated. A direct action of prolactin on the GnRH neuronal network is possible (270,271). Prolactin has also been demonstrated to influence other systems, including GABA (272), β endorphins (273), neuropeptide Y (274) and dopaminergic systems (275). Recent data suggest that kisspeptin signaling may be involved too, as kisspeptin neurons express prolactin receptors (276). In rodent models, kisspeptin neurons in the arcuate nucleus modulate dopamine release from dopaminergic neurons, thereby regulating prolactin secretion (277). Kiss1 expression is decreased in lactation, a physiological state associated with hyperprolactinemia (278). Prolactin-sensitive GABA and kisspeptin neurons were identified in regions of the rat hypothalamus (276). Moreover, in a mouse model of anovulatory hyperprolactinemia (induced by a continuous infusion of prolactin), Kiss1 mRNA levels were diminished and peripheral administration of kisspeptin restored gonadotropin secretion and ovarian cyclicity (279). There are also other animal studies reporting an inhibitory effect of prolactin on Kiss1 expression (280,281). This data suggests that kisspeptin is a possible link between hyperprolactinemia and GnRH deficiency. The administration of kisspeptin-10 reactivated the gonadotropin secretion in women with hyperprolactinemia-induced hypogonadotropic amenorrhea, suggesting that GnRH deficiency in the context of hyperprolactinemia is, at least in part, mediated by an impaired hypothalamic kisspeptin secretion (282).

On the other hand, kisspeptins appears to have a stimulatory effect on prolactin release, as demonstrated in a recent study in ovariectomized rats which had intracerebroventricular injections of kisspeptin-10 with subsequent increase in prolactin release, and this required the estrogen receptor-alpha and was potentiated by progesterone via progesterone receptor activation (283).

Nutrition and Metabolism

A link between energy balance and reproductive function enables organisms to survive to reproductive maturity and to withstand the energy needs of parturition, lactation and other parental behaviors. This link optimizes reproductive success under fluctuating metabolic conditions (284). Kisspeptin signaling may link nutrition/metabolic status and reproduction by sensing energy stores and translate this information into GnRH secretion (285). These relations elucidate further associations between reproductive dysfunction and metabolic disturbances, such as diabetes, obesity or anorexia nervosa (67,286,287).

Food deprivation impairs GnRH and gonadotropin secretion, and leptin (a satiety hormone secreted by adipose tissue, the levels of which drop in response to fasting) plays a role in this inter-regulation by stimulating LH release (67,288-290). Periods of fasting and calorie restriction decrease LH pulse frequency and increase pulse amplitude (284,291-293). Administration of recombinant leptin increased LH pulse frequency in women with hypothalamic amenorrhea (294) and prevented fasting-induced drop in testosterone and LH pulsatility in healthy men (295). Moreover, humans with mutations in leptin or in leptin receptor show hypogonadism (296). Thus, the crosstalk between kisspeptin and leptin is relevant for reproduction and fertility (71), including in the setting of assisted reproduction techniques (297).

Kisspeptin neurons may have a role in mediating the metabolic signals of leptin on the control of HPG axis, as 40% of the arcuate kisspeptin neurons express leptin receptors in contrast to the GnRH neurons, where leptin receptors are absent (298-301). Food deprivation is associated with a decrease in kisspeptin, and subsequent reduction in gonadotropin secretion (302-305). Levels of low Kiss1 mRNA expression in the leptin-deficient mice are partially upregulated by leptin (149). Moreover, exogenous kisspeptin restored vaginal opening (marker of sexual maturation) in malnourished rodents (302). Animal models of type 1 diabetes, characterized by insulin deficiency and impaired cellular nutrition, had hypogonadotropic hypogonadism and decreased Kiss1 mRNA expression. Repeated administration of kisspeptin to these rodents increased prostate and testis weight (306). It is plausible that a relative deficiency of kisspeptin secretion is a mechanism for hypogonadotropic hypogonadism in patients with obesity and diabetes (167). In hypogonadal men with type 2 diabetes, kisspeptin-10 increased LH secretion and pulse frequency (167). Although early studies appeared to suggest a direct link between kisspeptin and leptin, it seems that the neuronal pathway whereby leptin modulates GnRH is far more complex (307,308). Only partial restoration in Kiss1 mRNA in leptin-deficiency and normal pubertal development and fertility observed in selective leptin receptor deletion from kisspeptin neurons suggest that kisspeptin may link reproduction and metabolism through other ways than leptin (149,309). Proopiomelanocortin (POMC), agouti-related peptide, neuropeptide Y, ghrelin, and cocaine- and amphetamine-regulated transcript (CART) expressing neurons have been linked to this process (285,301). Kisspeptin neurons communicate with POMC and neuropeptide Y neurons and are able to modulate the expression of relevant genes in these cells (298). Several studies have suggested that ghrelin can interact directly with hypothalamic neurons leading to suppression of gonadotropins release, and thus impairing fertility, an effect that is dependent of the estradiol milieu (285,310-312).

GABA (Gamma-Amino Butyric Acid)

GABA has also been implicated as a regulator of GnRH secretion. Although GABA is classically an inhibitory neurotransmitter in the central nervous system, most mature GnRH neurons are stimulated by GABA, which has attributed to GABA an excitatory action in HPG axis. The precise physiology of this mechanism is still unclear (313-317), but it may be related to the bidirectional interactions between GABA and kisspeptin pathways, as well as between these and GnRH neurons, in a variety of ways throughout development (318). In early development, GABA seems to increase KISS1 expression in embryonic phase and early postnatally, while in the absence of GABAergic input the expression of KISS1 declines (318,319). In the prepubertal period, the central restraint on GnRH secretion seems to be mediated by GABA possibly acting directly via kisspeptin neurons (318). In the peri-pubertal phase, the antagonism of GABA and the intrinsic disinhibition of kisspeptin neurons seem to be critical in puberty initiation and development (320,321). In the adulthood, the interactions between GnRH-GABA-kisspeptin become more complex with HPG axis function critically dependent on such interactions. For instance, the preovulatory surge does not occur in the absence of GABA signaling, thus neurons co-expressing GABA and kisspeptin seem crucial in providing double excitatory input to GnRH neurons at the time of ovulation (318,322).

Other Neuropeptides

In addition to KNDy system and GABA, other peptides and neurotransmitters have been shown to influence GnRH-gonadotrope system: vasoactive intestinal polypeptide (VIP), vasopressin, catecholamines, nitric oxide, neurotensin, gonadotropin-inhibitory hormone (GnIH) /RFamide related peptide-3 (RFRP-3) (317), nucleobindin-2/nesfatin-1 (323). Excitatory inputs to the HPG axis may be mediated by VIP, catecholamines, glutamate and possibly vasopressin, whereas GnIH in birds, or its mammalian homolog RFRP-3, provide inhibitory inputs (324-328). RFRP neuronal populations have been detected mainly in the hypothalamic dorsomedial nucleus or adjacent regions, and they have projections to several hypothalamic areas including the arcuate nucleus, paraventricular nucleus, ventromedial nucleus and the lateral hypothalamus, all areas with major roles in the regulation of reproduction and energy balance (329,330). RFRP-3, encoded by the gene Rfrp, inhibits the electric firing of GnRH and kisspeptin neurons (325,331), which results in a suppression of GnRH-induced gonadotropin release with consequent inhibition of the reproductive axis (332). This RFRP-3 inhibitory input on the gonadotropin release is influenced by estrogens, and may well be involved in their negative feedback. Estrogens reduce RFRP-3 expression and RFRP-3 neuronal activation (333,334).


Complex neuroendocrine networks coordinate the regulation of reproduction, integrating a wide range of internal and external environmental inputs and signals. GnRH, the principal regulator of reproduction integrates cues from sex steroids, stress, glucocorticoids, nutritional and metabolic status, prolactin and other peptides, to controls gonadotropin secretion and subsequently gonadal function. Recently, the KNDy neuronal network has emerged as essential gatekeeper of GnRH release and thus reproduction, fertility and puberty. Translational clinical studies, exploring kisspeptin and neurokinin B activity in various physiological and pathological states are pivotal to explore potential clinical applications for these novel neuropeptides and their agonists as well as antagonists, may underpin future management of some disorders with dysfunctional GnRH pulsatility, such polycystic ovary syndrome, hypothalamic amenorrhea, infertility, obesity, or pubertal disorders.


Herbison AE, Theodosis DT. Localization of oestrogen receptors in preoptic neurons containing neurotensin but not tyrosine hydroxylase, cholecystokinin or luteinizing hormone-releasing hormone in the male and female rat. Neuroscience. 1992;50(2):283–298. [PubMed: 1359459]
Fink G. Neuroendocrine regulation of pituitary function: general principles. Neuroendocrinology in Physiology and Medicine. 2000:p.107-134.
Tena-Sempere M. Hypothalamic KiSS-1: the missing link in gonadotropin feedback control? Endocrinology. 2005;146(9):3683–3685. [PubMed: 16105827]
Baba Y, Matsuo H, Schally AV. Structure of the porcine LH- and FSH-releasing hormone. II. Confirmation of the proposed structure by conventional sequential analyses. Biochem Biophys Res Commun. 1971;44(2):459–463. [PubMed: 4946067]
Matsuo H, Arimura A, Nair RM, Schally AV. Synthesis of the porcine LH- and FSH-releasing hormone by the solid-phase method. Biochem Biophys Res Commun. 1971;45(3):822–827. [PubMed: 4942726]
Schally AV, Arimura A, Kastin AJ, Matsuo H, Baba Y, Redding TW, Nair RM, Debeljuk L, White WF. Gonadotropin-releasing hormone: one polypeptide regulates secretion of luteinizing and follicle-stimulating hormones. Science. 1971;173(4001):1036–1038. [PubMed: 4938639]
Schally AV, Arimura A, Baba Y, Nair RM, Matsuo H, Redding TW, Debeljuk L. Isolation and properties of the FSH and LH-releasing hormone. Biochem Biophys Res Commun. 1971;43(2):393–399. [PubMed: 4930860]
Schally AV. Use of GnRH in preference to LH-RH terminology in scientific papers. Hum Reprod. 2000;15(9):2059–2061. [PubMed: 10967015]
Millar RP. GnRHs and GnRH receptors. Anim Reprod Sci. 2005;88(1-2):5–28. [PubMed: 16140177]
Okubo K, Nagahama Y. Structural and functional evolution of gonadotropin-releasing hormone in vertebrates. Acta Physiol (Oxf). 2008;193(1):3–15. [PubMed: 18284378]
Miyamoto K, Hasegawa Y, Nomura M, Igarashi M, Kangawa K, Matsuo H. Identification of the second gonadotropin-releasing hormone in chicken hypothalamus: evidence that gonadotropin secretion is probably controlled by two distinct gonadotropin-releasing hormones in avian species. Proc Natl Acad Sci U S A. 1984;81(12):3874–3878. [PMC free article: PMC345324] [PubMed: 6427779]
White SA, Bond CT, Francis RC, Kasten TL, Fernald RD, Adelman JP. A second gene for gonadotropin-releasing hormone: cDNA and expression pattern in the brain. Proc Natl Acad Sci U S A. 1994;91(4):1423–1427. [PMC free article: PMC43171] [PubMed: 8108425]
Gault PM, Maudsley S, Lincoln GA. Evidence that gonadotropin-releasing hormone II is not a physiological regulator of gonadotropin secretion in mammals. J Neuroendocrinol. 2003;15(9):831–839. [PubMed: 12899677]
Balasubramanian R, Dwyer A, Seminara SB, Pitteloud N, Kaiser UB, Crowley WF Jr. Human GnRH deficiency: a unique disease model to unravel the ontogeny of GnRH neurons. Neuroendocrinology. 2010;92(2):81–99. [PMC free article: PMC3214927] [PubMed: 20606386]
Mitchell AL, Dwyer A, Pitteloud N, Quinton R. Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory. Trends Endocrinol Metab. 2011;22(7):249–258. [PubMed: 21511493]
Cariboni A, Pimpinelli F, Colamarino S, Zaninetti R, Piccolella M, Rumio C, Piva F, Rugarli EI, Maggi R. The product of X-linked Kallmann's syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons. Hum Mol Genet. 2004;13(22):2781–2791. [PubMed: 15471890]
Cariboni A, Hickok J, Rakic S, Andrews W, Maggi R, Tischkau S, Parnavelas JG. Neuropilins and their ligands are important in the migration of gonadotropin-releasing hormone neurons. J Neurosci. 2007;27(9):2387–2395. [PMC free article: PMC6673474] [PubMed: 17329436]
Magni P, Dozio E, Ruscica M, Watanobe H, Cariboni A, Zaninetti R, Motta M, Maggi R. Leukemia inhibitory factor induces the chemomigration of immortalized gonadotropin-releasing hormone neurons through the independent activation of the Janus kinase/signal transducer and activator of transcription 3, mitogen-activated protein kinase/extracellularly regulated kinase 1/2, and phosphatidylinositol 3-kinase/Akt signaling pathways. Mol Endocrinol. 2007;21(5):1163–1174. [PubMed: 17299136]
Dode C, Levilliers J, Dupont JM, De Paepe A, Le Du N, Soussi-Yanicostas N, Coimbra RS, Delmaghani S, Compain-Nouaille S, Baverel F, Pecheux C, Le Tessier D, Cruaud C, Delpech M, Speleman F, Vermeulen S, Amalfitano A, Bachelot Y, Bouchard P, Cabrol S, Carel JC, Delemarre-van de Waal H, Goulet-Salmon B, Kottler ML, Richard O, Sanchez-Franco F, Saura R, Young J, Petit C, Hardelin JP. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet. 2003;33(4):463–465. [PubMed: 12627230]
Kim SH, Hu Y, Cadman S, Bouloux P. Diversity in fibroblast growth factor receptor 1 regulation: learning from the investigation of Kallmann syndrome. J Neuroendocrinol. 2008;20(2):141–163. [PubMed: 18034870]
Yoshida K, Rutishauser U, Crandall JE, Schwarting GA. Polysialic acid facilitates migration of luteinizing hormone-releasing hormone neurons on vomeronasal axons. J Neurosci. 1999;19(2):794–801. [PMC free article: PMC6782189] [PubMed: 9880599]
Kaprara A, Huhtaniemi IT. The hypothalamus-pituitary-gonad axis: Tales of mice and men. Metabolism. 2017 [PubMed: 29223677]
Martin C, Balasubramanian R, Dwyer AA, Au MG, Sidis Y, Kaiser UB, Seminara SB, Pitteloud N, Zhou QY, Crowley WF Jr. The role of the prokineticin 2 pathway in human reproduction: evidence from the study of human and murine gene mutations. Endocr Rev. 2011;32(2):225–246. [PMC free article: PMC3365793] [PubMed: 21037178]
Pitteloud N, Zhang C, Pignatelli D, Li JD, Raivio T, Cole LW, Plummer L, Jacobson-Dickman EE, Mellon PL, Zhou QY, Crowley WF Jr. Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A. 2007;104(44):17447–17452. [PMC free article: PMC2077276] [PubMed: 17959774]
Clifton DKS, R.A. . Neuroendocrinology of reproduction. Yen & Jaffe's Reproductive Endocrinology JF Strauss and RL Barberi, Elsevier. 2009.
Maeda K, Ohkura S, Uenoyama Y, Wakabayashi Y, Oka Y, Tsukamura H, Okamura H. Neurobiological mechanisms underlying GnRH pulse generation by the hypothalamus. Brain Res. 2010;1364:103–115. [PubMed: 20951683]
Moenter SM, DeFazio AR, Pitts GR, Nunemaker CS. Mechanisms underlying episodic gonadotropin-releasing hormone secretion. Front Neuroendocrinol. 2003;24(2):79–93. [PubMed: 12762999]
Carmel PW, Araki S, Ferin M. Pituitary stalk portal blood collection in rhesus monkeys: evidence for pulsatile release of gonadotropin-releasing hormone (GnRH). Endocrinology. 1976;99(1):243–248. [PubMed: 820547]
Antunes JL, Carmel PW, Housepian EM, Ferin M. Luteinizing hormone-releasing hormone in human pituitary blood. J Neurosurg. 1978;49(3):382–386. [PubMed: 355605]
Caraty A, Martin GB, Montgomery G. A new method for studying pituitary responsiveness in vivo using pulses of LH-RH analogue in ewes passively immunized against native LH-RH. Reprod Nutr Dev. 1984;24(4):439–448. [PubMed: 6435222]
Lincoln GA, Fraser HM. Blockade of episodic secretion of luteinizing hormone in the ram by the administration of antibodies to luteinizing hormone releasing hormone. Biol Reprod. 1979;21(5):1239–1245. [PubMed: 391291]
Knobil E, Plant TM, Wildt L, Belchetz PE, Marshall G. Control of the rhesus monkey menstrual cycle: permissive role of hypothalamic gonadotropin-releasing hormone. Science. 1980;207(4437):1371–1373. [PubMed: 6766566]
Bolt DJ. Changes in the concentration of luteinizing hormone in plasma of rams following administration of oestradiol, progesterone or testosterone. J Reprod Fertil. 1971;24(3):435–438. [PubMed: 5548634]
Dierschke DJ, Bhattacharya AN, Atkinson LE, Knobil E. Circhoral oscillations of plasma LH levels in the ovariectomized rhesus monkey. Endocrinology. 1970;87(5):850–853. [PubMed: 4991672]
Naftolin F, Yen SS, Tsai CC. Rapid cycling of plasma gonadotrophins in normal men as demonstrated by frequent sampling. Nat New Biol. 1972;236(64):92–93. [PubMed: 4502465]
Yen SS, Tsai CC. The biphasic pattern in the feedback action of ethinyl estradiol on the release of pituitary FSH and LH. J Clin Endocrinol Metab. 1971;33(6):882–887. [PubMed: 5135628]
Reame NE, Sauder SE, Case GD, Kelch RP, Marshall JC. Pulsatile gonadotropin secretion in women with hypothalamic amenorrhea: evidence that reduced frequency of gonadotropin-releasing hormone secretion is the mechanism of persistent anovulation. J Clin Endocrinol Metab. 1985;61(5):851–858. [PubMed: 3900122]
Sauder SE, Frager M, Case GD, Kelch RP, Marshall JC. Abnormal patterns of pulsatile luteinizing hormone secretion in women with hyperprolactinemia and amenorrhea: responses to bromocriptine. J Clin Endocrinol Metab. 1984;59(5):941–948. [PubMed: 6434588]
Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E. Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Science. 1978;202(4368):631–633. [PubMed: 100883]
Rasmussen DD. Episodic gonadotropin-releasing hormone release from the rat isolated median eminence in vitro. Neuroendocrinology. 1993;58(5):511–518. [PubMed: 8115019]
Thiery JC, Pelletier J. Multiunit activity in the anterior median eminence and adjacent areas of the hypothalamus of the ewe in relation to LH secretion. Neuroendocrinology. 1981;32(4):217–224. [PubMed: 7219674]
Wilson RC, Kesner JS, Kaufman JM, Uemura T, Akema T, Knobil E. Central electrophysiologic correlates of pulsatile luteinizing hormone secretion in the rhesus monkey. Neuroendocrinology. 1984;39(3):256–260. [PubMed: 6504270]
Martinez de la Escalera G, Choi AL, Weiner RI. Generation and synchronization of gonadotropin-releasing hormone (GnRH) pulses: intrinsic properties of the GT1-1 GnRH neuronal cell line. Proc Natl Acad Sci U S A. 1992;89(5):1852–1855. [PMC free article: PMC48551] [PubMed: 1542682]
Terasawa E, Keen KL, Mogi K, Claude P. Pulsatile release of luteinizing hormone-releasing hormone (LHRH) in cultured LHRH neurons derived from the embryonic olfactory placode of the rhesus monkey. Endocrinology. 1999;140(3):1432–1441. [PubMed: 10067872]
Ezzat A, Pereira A, Clarke IJ. Kisspeptin is a component of the pulse generator for GnRH secretion in female sheep but not the pulse generator. Endocrinology. 2015;156(5):1828–1837. [PubMed: 25710282]
Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR. Gonadotropin-releasing hormone receptors. Endocr Rev. 2004;25(2):235–275. [PubMed: 15082521]
Pincus SM, Padmanabhan V, Lemon W, Randolph J, Rees Midgley A. Follicle-stimulating hormone is secreted more irregularly than luteinizing hormone in both humans and sheep. J Clin Invest. 1998;101(6):1318–1324. [PMC free article: PMC508686] [PubMed: 9502773]
Padmanabhan V, McFadden K, Mauger DT, Karsch FJ, Midgley AR Jr. Neuroendocrine control of follicle-stimulating hormone (FSH) secretion. I. Direct evidence for separate episodic and basal components of FSH secretion. Endocrinology. 1997;138(1):424–432. [PubMed: 8977432]
Dalkin AC, Haisenleder DJ, Ortolano GA, Ellis TR, Marshall JC. The frequency of gonadotropin-releasing-hormone stimulation differentially regulates gonadotropin subunit messenger ribonucleic acid expression. Endocrinology. 1989;125(2):917–924. [PubMed: 2502379]
Haisenleder DJ, Dalkin AC, Ortolano GA, Marshall JC, Shupnik MA. A pulsatile gonadotropin-releasing hormone stimulus is required to increase transcription of the gonadotropin subunit genes: evidence for differential regulation of transcription by pulse frequency in vivo. Endocrinology. 1991;128(1):509–517. [PubMed: 1702704]
Kaiser UB, Jakubowiak A, Steinberger A, Chin WW. Differential effects of gonadotropin-releasing hormone (GnRH) pulse frequency on gonadotropin subunit and GnRH receptor messenger ribonucleic acid levels in vitro. Endocrinology. 1997;138(3):1224–1231. [PubMed: 9048630]
Spratt DI, Finkelstein JS, Butler JP, Badger TM, Crowley WF Jr. Effects of increasing the frequency of low doses of gonadotropin-releasing hormone (GnRH) on gonadotropin secretion in GnRH-deficient men. J Clin Endocrinol Metab. 1987;64(6):1179–1186. [PubMed: 3106396]
Waldhauser F, Weissenbacher G, Frisch H, Pollak A. Pulsatile secretion of gonadotropins in early infancy. Eur J Pediatr. 1981;137(1):71–74. [PubMed: 6791927]
Conte FA, Grumbach MM, Kaplan SL, Reiter EO. Correlation of luteinizing hormone-releasing factor-induced luteinizing hormone and follicle-stimulating hormone release from infancy to 19 years with the changing pattern of gonadotropin secretion in agonadal patients: relation to the restraint of puberty. J Clin Endocrinol Metab. 1980;50(1):163–168. [PubMed: 6985614]
Pohl CR, deRidder CM, Plant TM. Gonadal and nongonadal mechanisms contribute to the prepubertal hiatus in gonadotropin secretion in the female rhesus monkey (Macaca mulatta). J Clin Endocrinol Metab. 1995;80(7):2094–2101. [PubMed: 7608261]
Boyar R, Finkelstein J, Roffwarg H, Kapen S, Weitzman E, Hellman L. Synchronization of augmented luteinizing hormone secretion with sleep during puberty. N Engl J Med. 1972;287(12):582–586. [PubMed: 4341276]
Roth JC, Kelch RP, Kaplan SL, Grumbach MM. FSH and LH response to luteinizing hormone-releasing factor in prepubertal and pubertal children, adult males and patients with hypogonadotropic and hypertropic hypogonadism. J Clin Endocrinol Metab. 1972;35(6):926–930. [PubMed: 4564162]
Marshall JC, Dalkin AC, Haisenleder DJ, Griffin ML, Kelch RP. GnRH pulses--the regulators of human reproduction. Trans Am Clin Climatol Assoc. 1993;104:31–46. [PMC free article: PMC2376610] [PubMed: 1343446]
Marshall JC, Dalkin AC, Haisenleder DJ, Paul SJ, Ortolano GA, Kelch RP. Gonadotropin-releasing hormone pulses: regulators of gonadotropin synthesis and ovulatory cycles. Recent Prog Horm Res. 1991;47:155–187. [PubMed: 1745819]
Yen SS, Tsai CC, Naftolin F, Vandenberg G, Ajabor L. Pulsatile patterns of gonadotropin release in subjects with and without ovarian function. J Clin Endocrinol Metab. 1972;34(4):671–675. [PubMed: 5012772]
Arroyo A, Laughlin GA, Morales AJ, Yen SS. Inappropriate gonadotropin secretion in polycystic ovary syndrome: influence of adiposity. J Clin Endocrinol Metab. 1997;82(11):3728–3733. [PubMed: 9360532]
Morales AJ, Laughlin GA, Butzow T, Maheshwari H, Baumann G, Yen SS. Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab. 1996;81(8):2854–2864. [PubMed: 8768842]
Waldstreicher J, Santoro NF, Hall JE, Filicori M, Crowley WF Jr. Hyperfunction of the hypothalamic-pituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotroph desensitization. J Clin Endocrinol Metab. 1988;66(1):165–172. [PubMed: 2961784]
Yen SS, Vela P, Rankin J. Inappropriate secretion of follicle-stimulating hormone and luteinizing hormone in polycystic ovarian disease. J Clin Endocrinol Metab. 1970;30(4):435–442. [PubMed: 5435284]
Beltramo M, Dardente H, Cayla X, Caraty A. Cellular mechanisms and integrative timing of neuroendocrine control of GnRH secretion by kisspeptin. Mol Cell Endocrinol. 2014;382(1):387–399. [PubMed: 24145132]
Jayasena CN, Abbara A, Izzi-Engbeaya C, Comninos AN, Harvey RA, Gonzalez Maffe J, Sarang Z, Ganiyu-Dada Z, Padilha AI, Dhanjal M, Williamson C, Regan L, Ghatei MA, Bloom SR, Dhillo WS. Reduced levels of plasma kisspeptin during the antenatal booking visit are associated with increased risk of miscarriage. J Clin Endocrinol Metab. 2014;99(12):E2652–2660. [PMC free article: PMC4255122] [PubMed: 25127195]
Skorupskaite K, George JT, Anderson RA. The kisspeptin-GnRH pathway in human reproductive health and disease. Hum Reprod Update. 2014;20(4):485–500. [PMC free article: PMC4063702] [PubMed: 24615662]
Clarke SA, Dhillo WS. Kisspeptin across the human lifespan:evidence from animal studies and beyond. J Endocrinol. 2016;229(3):R83–98. [PubMed: 27340201]
Comninos AN, Dhillo WS. Emerging Roles of Kisspeptin in Sexual and Emotional Brain Processing. Neuroendocrinology. 2018;106(2):195–202. [PubMed: 28866668]
Dudek M, Ziarniak K, Sliwowska JH. Kisspeptin and Metabolism: The Brain and Beyond. Front Endocrinol (Lausanne). 2018;9:145. [PMC free article: PMC5911457] [PubMed: 29713310]
Wahab F, Atika B, Ullah F, Shahab M, Behr R. Metabolic Impact on the Hypothalamic Kisspeptin-Kiss1r Signaling Pathway. Front Endocrinol (Lausanne). 2018;9:123. [PMC free article: PMC5882778] [PubMed: 29643834]
Wolfe A, Hussain MA. The Emerging Role(s) for Kisspeptin in Metabolism in Mammals. Front Endocrinol (Lausanne). 2018;9:184. [PMC free article: PMC5928256] [PubMed: 29740399]
Yang L, Comninos AN, Dhillo WS. Intrinsic links among sex, emotion, and reproduction. Cell Mol Life Sci. 2018;75(12):2197–2210. [PMC free article: PMC5948280] [PubMed: 29619543]
Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE, Welch DR. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst. 1996;88(23):1731–1737. [PubMed: 8944003]
Ciaramella V, Della Corte CM, Ciardiello F, Morgillo F. Kisspeptin and Cancer: Molecular Interaction, Biological Functions, and Future Perspectives. Front Endocrinol (Lausanne). 2018;9:115. [PMC free article: PMC5890175] [PubMed: 29662466]
West A, Vojta PJ, Welch DR, Weissman BE. Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor gene (KISS1). Genomics. 1998;54(1):145–148. [PubMed: 9806840]
Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brezillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, Blanpain C, Schiffmann SN, Vassart G, Parmentier M. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem. 2001;276(37):34631–34636. [PubMed: 11457843]
Pasquier J, Kamech N, Lafont AG, Vaudry H, Rousseau K, Dufour S. Molecular evolution of GPCRs: Kisspeptin/kisspeptin receptors. J Mol Endocrinol. 2014;52(3):T101–117. [PubMed: 24577719]
Gottsch ML, Navarro VM, Zhao Z, Glidewell-Kenney C, Weiss J, Jameson JL, Clifton DK, Levine JE, Steiner RA. Regulation of Kiss1 and dynorphin gene expression in the murine brain by classical and nonclassical estrogen receptor pathways. J Neurosci. 2009;29(29):9390–9395. [PMC free article: PMC2819182] [PubMed: 19625529]
Lee DK, Nguyen T, O'Neill GP, Cheng R, Liu Y, Howard AD, Coulombe N, Tan CP, Tang-Nguyen AT, George SR, O'Dowd BF. Discovery of a receptor related to the galanin receptors. FEBS Lett. 1999;446(1):103–107. [PubMed: 10100623]
Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, Szekeres PG, Sarau HM, Chambers JK, Murdock P, Steplewski K, Shabon U, Miller JE, Middleton SE, Darker JG, Larminie CG, Wilson S, Bergsma DJ, Emson P, Faull R, Philpott KL, Harrison DC. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem. 2001;276(31):28969–28975. [PubMed: 11387329]
Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, Ishibashi Y, Watanabe T, Asada M, Yamada T, Suenaga M, Kitada C, Usuki S, Kurokawa T, Onda H, Nishimura O, Fujino M. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001;411(6837):613–617. [PubMed: 11385580]
Liu X, Lee K, Herbison AE. Kisspeptin excites gonadotropin-releasing hormone neurons through a phospholipase C/calcium-dependent pathway regulating multiple ion channels. Endocrinology. 2008;149(9):4605–4614. [PMC free article: PMC6116891] [PubMed: 18483150]
de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A. 2003;100(19):10972–10976. [PMC free article: PMC196911] [PubMed: 12944565]
Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O'Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349(17):1614–1627. [PubMed: 14573733]
Chan YM, Broder-Fingert S, Wong KM, Seminara SB. Kisspeptin/Gpr54-independent gonadotrophin-releasing hormone activity in Kiss1 and Gpr54 mutant mice. J Neuroendocrinol. 2009;21(12):1015–1023. [PMC free article: PMC2789182] [PubMed: 19840236]
Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S, Seminara SB, Mendonca BB, Kaiser UB, Latronico AC. A. GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med. 2008;358(7):709–715. [PMC free article: PMC2859966] [PubMed: 18272894]
Silveira LG, Noel SD, Silveira-Neto AP, Abreu AP, Brito VN, Santos MG, Bianco SD, Kuohung W, Xu S, Gryngarten M, Escobar ME, Arnhold IJ, Mendonca BB, Kaiser UB, Latronico AC. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab. 2010;95(5):2276–2280. [PMC free article: PMC2869552] [PubMed: 20237166]
Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Imamoglu S, Akalin NS, Yuksel B, O'Rahilly S, Semple RK. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet. 2009;41(3):354–358. [PMC free article: PMC4312696] [PubMed: 19079066]
Gianetti E, Tusset C, Noel SD, Au MG, Dwyer AA, Hughes VA, Abreu AP, Carroll J, Trarbach E, Silveira LF, Costa EM, de Mendonca BB, de Castro M, Lofrano A, Hall JE, Bolu E, Ozata M, Quinton R, Amory JK, Stewart SE, Arlt W, Cole TR, Crowley WF, Kaiser UB, Latronico AC, Seminara SB. TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. J Clin Endocrinol Metab. 2010;95(6):2857–2867. [PMC free article: PMC2902066] [PubMed: 20332248]
Guran T, Tolhurst G, Bereket A, Rocha N, Porter K, Turan S, Gribble FM, Kotan LD, Akcay T, Atay Z, Canan H, Serin A, O'Rahilly S, Reimann F, Semple RK, Topaloglu AK. Hypogonadotropic hypogonadism due to a novel missense mutation in the first extracellular loop of the neurokinin B receptor. J Clin Endocrinol Metab. 2009;94(10):3633–3639. [PMC free article: PMC4306717] [PubMed: 19755480]
Young J, Bouligand J, Francou B, Raffin-Sanson ML, Gaillez S, Jeanpierre M, Grynberg M, Kamenicky P, Chanson P, Brailly-Tabard S, Guiochon-Mantel A. TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans. J Clin Endocrinol Metab. 2010;95(5):2287–2295. [PubMed: 20194706]
Young J, George JT, Tello JA, Francou B, Bouligand J, Guiochon-Mantel A, Brailly-Tabard S, Anderson RA, Millar RP. Kisspeptin restores pulsatile LH secretion in patients with neurokinin B signaling deficiencies: physiological, pathophysiological and therapeutic implications. Neuroendocrinology. 2013;97(2):193–202. [PMC free article: PMC3902960] [PubMed: 22377698]
Wilkes MM, Watkins WB, Stewart RD, Yen SS. Localization and quantitation of beta-endorphin in human brain and pituitary. Neuroendocrinology. 1980;30(2):113–121. [PubMed: 6986578]
Quigley ME, Yen SS. The role of endogenous opiates in LH secretion during the menstrual cycle. J Clin Endocrinol Metab. 1980;51(1):179–181. [PubMed: 7380991]
Veldhuis JD, Rogol AD, Samojlik E, Ertel NH. Role of endogenous opiates in the expression of negative feedback actions of androgen and estrogen on pulsatile properties of luteinizing hormone secretion in man. J Clin Invest. 1984;74(1):47–55. [PMC free article: PMC425183] [PubMed: 6429197]
Boukhliq R, Goodman RL, Berriman SJ, Adrian B, Lehman MN. A subset of gonadotropin-releasing hormone neurons in the ovine medial basal hypothalamus is activated during increased pulsatile luteinizing hormone secretion. Endocrinology. 1999;140(12):5929–5936. [PubMed: 10579360]
Genazzani AD, Gastaldi M, Petraglia F, Battaglia C, Surico N, Volpe A, Genazzani AR. Naltrexone administration modulates the neuroendocrine control of luteinizing hormone secretion in hypothalamic amenorrhoea. Hum Reprod. 1995;10(11):2868–2871. [PubMed: 8747034]
Goodman RL, Coolen LM, Anderson GM, Hardy SL, Valent M, Connors JM, Fitzgerald ME, Lehman MN. Evidence that dynorphin plays a major role in mediating progesterone negative feedback on gonadotropin-releasing hormone neurons in sheep. Endocrinology. 2004;145(6):2959–2967. [PubMed: 14988383]
Shoupe D, Montz FJ, Lobo RA. The effects of estrogen and progestin on endogenous opioid activity in oophorectomized women. J Clin Endocrinol Metab. 1985;60(1):178–183. [PubMed: 2981084]
Walsh JP, Clarke IJ. Effects of central administration of highly selective opioid mu-, delta- and kappa-receptor agonists on plasma luteinizing hormone (LH), prolactin, and the estrogen-induced LH surge in ovariectomized ewes. Endocrinology. 1996;137(9):3640–3648. [PubMed: 8756528]
Cheng G, Coolen LM, Padmanabhan V, Goodman RL, Lehman MN. The kisspeptin/neurokinin B/dynorphin (KNDy) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in sheep. Endocrinology. 2010;151(1):301–311. [PMC free article: PMC2803147] [PubMed: 19880810]
Goodman RL, Lehman MN, Smith JT, Coolen LM, de Oliveira CV, Jafarzadehshirazi MR, Pereira A, Iqbal J, Caraty A, Ciofi P, Clarke IJ. Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology. 2007;148(12):5752–5760. [PubMed: 17823266]
Hrabovszky E, Ciofi P, Vida B, Horvath MC, Keller E, Caraty A, Bloom SR, Ghatei MA, Dhillo WS, Liposits Z, Kallo I. The kisspeptin system of the human hypothalamus: sexual dimorphism and relationship with gonadotropin-releasing hormone and neurokinin B neurons. Eur J Neurosci. 2010;31(11):1984–1998. [PubMed: 20529119]
Bedenbaugh MN, O'Connell RC, Lopez JA, McCosh RB, Goodman RL, Hileman SM. Kisspeptin, gonadotrophin-releasing hormone and oestrogen receptor alpha colocalise with neuronal nitric oxide synthase neurones in prepubertal female sheep. J Neuroendocrinol. 2018;30(1) [PMC free article: PMC5786465] [PubMed: 29178496]
Dufourny L, Delmas O, Teixeira-Gomes AP, Decourt C, Sliwowska JH. Neuroanatomical connections between kisspeptin neurones and somatostatin neurones in female and male rat hypothalamus: a possible involvement of SSTR1 in kisspeptin release. J Neuroendocrinol. 2018:e12593. [PubMed: 29543369]
Rometo AM, Krajewski SJ, Voytko ML, Rance NE. Hypertrophy and increased kisspeptin gene expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized monkeys. J Clin Endocrinol Metab. 2007;92(7):2744–2750. [PubMed: 17488799]
Clarkson J, Herbison AE. Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology. 2006;147(12):5817–5825. [PMC free article: PMC6098691] [PubMed: 16959837]
Pompolo S, Pereira A, Estrada KM, Clarke IJ. Colocalization of kisspeptin and gonadotropin-releasing hormone in the ovine brain. Endocrinology. 2006;147(2):804–810. [PubMed: 16293663]
Clarkson J, d'Anglemont de Tassigny X, Colledge WH, Caraty A, Herbison AE. Distribution of kisspeptin neurones in the adult female mouse brain. J Neuroendocrinol. 2009;21(8):673–682. [PubMed: 19515163]
Oakley AE, Clifton DK, Steiner RA. Kisspeptin signaling in the brain. Endocr Rev. 2009;30(6):713–743. [PMC free article: PMC2761114] [PubMed: 19770291]
Uenoyama Y, Inoue N, Pheng V, Homma T, Takase K, Yamada S, Ajiki K, Ichikawa M, Okamura H, Maeda KI, Tsukamura H. Ultrastructural evidence of kisspeptin-gonadotrophin-releasing hormone (GnRH) interaction in the median eminence of female rats: implication of axo-axonal regulation of GnRH release. J Neuroendocrinol. 2011;23(10):863–870. [PubMed: 21815953]
Han SK, Gottsch ML, Lee KJ, Popa SM, Smith JT, Jakawich SK, Clifton DK, Steiner RA, Herbison AE. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci. 2005;25(49):11349–11356. [PMC free article: PMC6725899] [PubMed: 16339030]
Irwig MS, Fraley GS, Smith JT, Acohido BV, Popa SM, Cunningham MJ, Gottsch ML, Clifton DK, Steiner RA. Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology. 2004;80(4):264–272. [PubMed: 15665556]
Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci U S A. 2005;102(5):1761–1766. [PMC free article: PMC545088] [PubMed: 15665093]
Lehman MN, Coolen LM, Goodman RL. Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology. 2010;151(8):3479–3489. [PMC free article: PMC2940527] [PubMed: 20501670]
Mills EGA, Dhillo WS, Comninos AN. Kisspeptin and the control of emotions, mood and reproductive behaviour. J Endocrinol. 2018;239(1):R1–R12. [PubMed: 30306845]
Cao Y, Li Z, Jiang W, Ling Y, Kuang H. Reproductive functions of Kisspeptin/KISS1R Systems in the Periphery. Reprod Biol Endocrinol. 2019;17(1):65. [PMC free article: PMC6689161] [PubMed: 31399145]
Hu KL, Chang HM, Zhao HC, Yu Y, Li R, Qiao J. Potential roles for the kisspeptin/kisspeptin receptor system in implantation and placentation. Hum Reprod Update. 2019;25(3):326–343. [PMC free article: PMC6450039] [PubMed: 30649364]
Burke MC, Letts PA, Krajewski SJ, Rance NE. Coexpression of dynorphin and neurokinin B immunoreactivity in the rat hypothalamus: Morphologic evidence of interrelated function within the arcuate nucleus. J Comp Neurol. 2006;498(5):712–726. [PubMed: 16917850]
Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev. 2012;92(3):1235–1316. [PubMed: 22811428]
Ikegami K, Minabe S, Ieda N, Goto T, Sugimoto A, Nakamura S, Inoue N, Oishi S, Maturana AD, Sanbo M, Hirabayashi M, Maeda KI, Tsukamura H, Uenoyama Y. Evidence of involvement of neurone-glia/neurone-neurone communications via gap junctions in synchronised activity of KNDy neurones. J Neuroendocrinol. 2017;29(6) [PubMed: 28475285]
Topaloglu AK, Semple RK. Neurokinin B signalling in the human reproductive axis. Mol Cell Endocrinol. 2011;346(1-2):57–64. [PubMed: 21807065]
Navarro VM, Bosch MA, Leon S, Simavli S, True C, Pinilla L, Carroll RS, Seminara SB, Tena-Sempere M, Ronnekleiv OK, Kaiser UB. The integrated hypothalamic tachykinin-kisspeptin system as a central coordinator for reproduction. Endocrinology. 2015;156(2):627–637. [PMC free article: PMC4298326] [PubMed: 25422875]
Skorupskaite K, George JT, Veldhuis JD, Anderson RA, Neurokinin B. Regulates Gonadotropin Secretion, Ovarian Follicle Growth, and the Timing of Ovulation in Healthy Women. J Clin Endocrinol Metab. 2018;103(1):95–104. [PMC free article: PMC5761486] [PubMed: 29040622]
Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA. Interactions Between Neurokinin B and Kisspeptin in Mediating Estrogen Feedback in Healthy Women. J Clin Endocrinol Metab. 2016;101(12):4628–4636. [PMC free article: PMC5155690] [PubMed: 27636018]
Skorupskaite K, George J, Anderson RA. Role of a neurokinin B receptor antagonist in the regulation of ovarian function in healthy women. Lancet. 2015;385 Suppl 1:S92. [PubMed: 26312915]
Skorupskaite K, Anderson RA. Hypothalamic neurokinin signalling and its application in reproductive medicine. Pharmacol Ther. 2021:107960. [PubMed: 34273412]
George JT, Kakkar R, Marshall J, Scott ML, Finkelman RD, Ho TW, Veldhuis J, Skorupskaite K, Anderson RA, McIntosh S, Webber L, Neurokinin B. Receptor Antagonism in Women With Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled Trial. J Clin Endocrinol Metab. 2016;101(11):4313–4321. [PubMed: 27459523]
Fraser GL, Obermayer-Pietsch B, Laven J, Griesinger G, Pintiaux A, Timmerman D, Fauser B, Lademacher C, Combalbert J, Hoveyda HR, Ramael S. Randomized Controlled Trial of Neurokinin 3 Receptor Antagonist Fezolinetant for Treatment of Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2021 [PMC free article: PMC8372662] [PubMed: 34000049]
Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA. Kisspeptin and neurokinin B interactions in modulating gonadotropin secretion in women with polycystic ovary syndrome. Hum Reprod. 2020;35(6):1421–1431. [PMC free article: PMC7316500] [PubMed: 32510130]
Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA. Neurokinin 3 Receptor Antagonism Reveals Roles for Neurokinin B in the Regulation of Gonadotropin Secretion and Hot Flashes in Postmenopausal Women. Neuroendocrinology. 2018;106(2):148–157. [PubMed: 28380486]
Prague JK, Roberts RE, Comninos AN, Clarke S, Jayasena CN, Nash Z, Doyle C, Papadopoulou DA, Bloom SR, Mohideen P, Panay N, Hunter MS, Veldhuis JD, Webber LC, Huson L, Dhillo WS. Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389(10081):1809–1820. [PMC free article: PMC5439024] [PubMed: 28385352]
Depypere H, Timmerman D, Donders G, Sieprath P, Ramael S, Combalbert J, Hoveyda HR, Fraser GL. Treatment of Menopausal Vasomotor Symptoms With Fezolinetant, a Neurokinin 3 Receptor Antagonist: A Phase 2a Trial. J Clin Endocrinol Metab. 2019;104(12):5893–5905. [PubMed: 31415087]
Prague JK, Dhillo WS. Treating hot flushes with a neurokinin 3 receptor antagonist. Oncotarget. 2017;8(63):106153–106154. [PMC free article: PMC5739713] [PubMed: 29290928]
Prague JK, Dhillo WS. Neurokinin 3 receptor antagonism - the magic bullet for hot flushes? Climacteric. 2017;20(6):505–509. [PubMed: 29040006]
Anderson RA, Skorupskaite K, Sassarini J. The neurokinin B pathway in the treatment of menopausal hot flushes. Climacteric. 2019;22(1):51–54. [PubMed: 30572747]
Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA. Neurokinin 3 receptor antagonism decreases gonadotropin and testosterone secretion in healthy men. Clin Endocrinol (Oxf). 2017;87(6):748–756. [PubMed: 28802064]
Navarro VM, Castellano JM, McConkey SM, Pineda R, Ruiz-Pino F, Pinilla L, Clifton DK, Tena-Sempere M, Steiner RA. Interactions between kisspeptin and neurokinin B in the control of GnRH secretion in the female rat. Am J Physiol Endocrinol Metab. 2011;300(1):E202–210. [PMC free article: PMC3774070] [PubMed: 21045176]
Garcia-Galiano D, van Ingen Schenau D, Leon S, Krajnc-Franken MA, Manfredi-Lozano M, Romero-Ruiz A, Navarro VM, Gaytan F, van Noort PI, Pinilla L, Blomenrohr M, Tena-Sempere M. Kisspeptin signaling is indispensable for neurokinin B, but not glutamate, stimulation of gonadotropin secretion in mice. Endocrinology. 2012;153(1):316–328. [PubMed: 22067321]
Wakabayashi Y, Nakada T, Murata K, Ohkura S, Mogi K, Navarro VM, Clifton DK, Mori Y, Tsukamura H, Maeda K, Steiner RA, Okamura H. Neurokinin B and dynorphin A in kisspeptin neurons of the arcuate nucleus participate in generation of periodic oscillation of neural activity driving pulsatile gonadotropin-releasing hormone secretion in the goat. J Neurosci. 2010;30(8):3124–3132. [PMC free article: PMC6633939] [PubMed: 20181609]
Ramaswamy S, Seminara SB, Ali B, Ciofi P, Amin NA, Plant TM. Neurokinin B stimulates GnRH release in the male monkey (Macaca mulatta) and is colocalized with kisspeptin in the arcuate nucleus. Endocrinology. 2010;151(9):4494–4503. [PMC free article: PMC2940495] [PubMed: 20573725]
Ramaswamy S, Seminara SB, Plant TM. Evidence from the agonadal juvenile male rhesus monkey (Macaca mulatta) for the view that the action of neurokinin B to trigger gonadotropin-releasing hormone release is upstream from the kisspeptin receptor. Neuroendocrinology. 2011;94(3):237–245. [PMC free article: PMC3238032] [PubMed: 21832818]
Navarro VM. Interactions between kisspeptins and neurokinin B. Adv Exp Med Biol. 2013;784:325–347. [PMC free article: PMC3858905] [PubMed: 23550013]
Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA. Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J Neurosci. 2009;29(38):11859–11866. [PMC free article: PMC2793332] [PubMed: 19776272]
Ciofi P, Krause JE, Prins GS, Mazzuca M. Presence of nuclear androgen receptor-like immunoreactivity in neurokinin B-containing neurons of the hypothalamic arcuate nucleus of the adult male rat. Neurosci Lett. 1994;182(2):193–196. [PubMed: 7715808]
Foradori CD, Coolen LM, Fitzgerald ME, Skinner DC, Goodman RL, Lehman MN. Colocalization of progesterone receptors in parvicellular dynorphin neurons of the ovine preoptic area and hypothalamus. Endocrinology. 2002;143(11):4366–4374. [PubMed: 12399433]
Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA. Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology. 2005;146(9):3686–3692. [PubMed: 15919741]
Smith JT, Acohido BV, Clifton DK, Steiner RA. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J Neuroendocrinol. 2006;18(4):298–303. [PubMed: 16503925]
George JT, Seminara SB. Kisspeptin and the hypothalamic control of reproduction: lessons from the human. Endocrinology. 2012;153(11):5130–5136. [PMC free article: PMC3473216] [PubMed: 23015291]
Arreguin-Arevalo JA, Lents CA, Farmerie TA, Nett TM, Clay CM. KiSS-1 peptide induces release of LH by a direct effect on the hypothalamus of ovariectomized ewes. Anim Reprod Sci. 2007;101(3-4):265–275. [PubMed: 17055196]
Gottsch ML, Cunningham MJ, Smith JT, Popa SM, Acohido BV, Crowley WF, Seminara S, Clifton DK, Steiner RA. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology. 2004;145(9):4073–4077. [PubMed: 15217982]
Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci U S A. 2005;102(6):2129–2134. [PMC free article: PMC548549] [PubMed: 15684075]
Smith JT, Li Q, Pereira A, Clarke IJ. Kisspeptin neurons in the ovine arcuate nucleus and preoptic area are involved in the preovulatory luteinizing hormone surge. Endocrinology. 2009;150(12):5530–5538. [PubMed: 19819940]
Chan YM, Butler JP, Pinnell NE, Pralong FP, Crowley WF Jr, Ren C, Chan KK, Seminara SB. Kisspeptin resets the hypothalamic GnRH clock in men. J Clin Endocrinol Metab. 2011;96(6):E908–915. [PMC free article: PMC3100758] [PubMed: 21470997]
Chan YM, Butler JP, Sidhoum VF, Pinnell NE, Seminara SB. Kisspeptin administration to women: a window into endogenous kisspeptin secretion and GnRH responsiveness across the menstrual cycle. J Clin Endocrinol Metab. 2012;97(8):E1458–1467. [PMC free article: PMC3410261] [PubMed: 22577171]
Dhillo WS, Chaudhri OB, Patterson M, Thompson EL, Murphy KG, Badman MK, McGowan BM, Amber V, Patel S, Ghatei MA, Bloom SR. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab. 2005;90(12):6609–6615. [PubMed: 16174713]
Dhillo WS, Chaudhri OB, Thompson EL, Murphy KG, Patterson M, Ramachandran R, Nijher GK, Amber V, Kokkinos A, Donaldson M, Ghatei MA, Bloom SR. Kisspeptin-54 stimulates gonadotropin release most potently during the preovulatory phase of the menstrual cycle in women. J Clin Endocrinol Metab. 2007;92(10):3958–3966. [PubMed: 17635940]
George JT, Anderson RA, Millar RP. Kisspeptin-10 stimulation of gonadotrophin secretion in women is modulated by sex steroid feedback. Hum Reprod. 2012;27(12):3552–3559. [PubMed: 22956346]
George JT, Veldhuis JD, Roseweir AK, Newton CL, Faccenda E, Millar RP, Anderson RA. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men. J Clin Endocrinol Metab. 2011;96(8):E1228–1236. [PMC free article: PMC3380939] [PubMed: 21632807]
Jayasena CN, Comninos AN, Nijher GM, Abbara A, De Silva A, Veldhuis JD, Ratnasabapathy R, Izzi-Engbeaya C, Lim A, Patel DA, Ghatei MA, Bloom SR, Dhillo WS. Twice-daily subcutaneous injection of kisspeptin-54 does not abolish menstrual cyclicity in healthy female volunteers. J Clin Endocrinol Metab. 2013;98(11):4464–4474. [PMC free article: PMC4111853] [PubMed: 24030945]
Jayasena CN, Comninos AN, Veldhuis JD, Misra S, Abbara A, Izzi-Engbeaya C, Donaldson M, Ghatei MA, Bloom SR, Dhillo WS. A single injection of kisspeptin-54 temporarily increases luteinizing hormone pulsatility in healthy women. Clin Endocrinol (Oxf). 2013;79(4):558–563. [PubMed: 23452073]
Jayasena CN, Nijher GM, Abbara A, Murphy KG, Lim A, Patel D, Mehta A, Todd C, Donaldson M, Trew GH, Ghatei MA, Bloom SR, Dhillo WS. Twice-weekly administration of kisspeptin-54 for 8 weeks stimulates release of reproductive hormones in women with hypothalamic amenorrhea. Clin Pharmacol Ther. 2010;88(6):840–847. [PubMed: 20980998]
Jayasena CN, Nijher GM, Chaudhri OB, Murphy KG, Ranger A, Lim A, Patel D, Mehta A, Todd C, Ramachandran R, Salem V, Stamp GW, Donaldson M, Ghatei MA, Bloom SR, Dhillo WS. Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis. J Clin Endocrinol Metab. 2009;94(11):4315–4323. [PubMed: 19820030]
Jayasena CN, Nijher GM, Comninos AN, Abbara A, Januszewki A, Vaal ML, Sriskandarajah L, Murphy KG, Farzad Z, Ghatei MA, Bloom SR, Dhillo WS. The effects of kisspeptin-10 on reproductive hormone release show sexual dimorphism in humans. J Clin Endocrinol Metab. 2011;96(12):E1963–1972. [PMC free article: PMC3232613] [PubMed: 21976724]
Abbara A, Narayanaswamy S, Izzi-Engbeaya C, Comninos AN, Clarke SA, Malik Z, Papadopoulou D, Clobentz A, Sarang Z, Bassett P, Jayasena CN, Dhillo WS. Hypothalamic Response to Kisspeptin-54 and Pituitary Response to Gonadotropin-Releasing Hormone Are Preserved in Healthy Older Men. Neuroendocrinology. 2018;106(4):401–410. [PMC free article: PMC6008875] [PubMed: 29544222]
George JT, Veldhuis JD, Tena-Sempere M, Millar RP, Anderson RA. Exploring the pathophysiology of hypogonadism in men with type 2 diabetes: kisspeptin-10 stimulates serum testosterone and LH secretion in men with type 2 diabetes and mild biochemical hypogonadism. Clin Endocrinol (Oxf). 2013;79(1):100–104. [PubMed: 23153270]
Jayasena CN, Abbara A, Veldhuis JD, Comninos AN, Ratnasabapathy R, De Silva A, Nijher GM, Ganiyu-Dada Z, Mehta A, Todd C, Ghatei MA, Bloom SR, Dhillo WS. Increasing LH pulsatility in women with hypothalamic amenorrhoea using intravenous infusion of Kisspeptin-54. J Clin Endocrinol Metab. 2014;99(6):E953–961. [PMC free article: PMC4207927] [PubMed: 24517142]
Abbara A, Eng PC, Phylactou M, Clarke SA, Richardson R, Sykes CM, Phumsatitpong C, Mills E, Modi M, Izzi-Engbeaya C, Papadopoulou D, Purugganan K, Jayasena CN, Webber L, Salim R, Owen B, Bech P, Comninos AN, McArdle CA, Voliotis M, Tsaneva-Atanasova K, Moenter S, Hanyaloglu A, Dhillo WS. Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders. J Clin Invest. 2020;130(12):6739–6753. [PMC free article: PMC7685751] [PubMed: 33196464]
Szeliga A, Podfigurna A, Bala G, Meczekalski B. Kisspeptin and neurokinin B analogs use in gynecological endocrinology: where do we stand? J Endocrinol Invest. 2020;43(5):555–561. [PubMed: 31838714]
Li XF, Kinsey-Jones JS, Cheng Y, Knox AM, Lin Y, Petrou NA, Roseweir A, Lightman SL, Milligan SR, Millar RP, O'Byrne KT. Kisspeptin signalling in the hypothalamic arcuate nucleus regulates GnRH pulse generator frequency in the rat. PLoS One. 2009;4(12):e8334. [PMC free article: PMC2789414] [PubMed: 20016824]
Millar RP, Roseweir AK, Tello JA, Anderson RA, George JT, Morgan K, Pawson AJ. Kisspeptin antagonists: unraveling the role of kisspeptin in reproductive physiology. Brain Res. 2010;1364:81–89. [PubMed: 20858467]
Roseweir AK, Kauffman AS, Smith JT, Guerriero KA, Morgan K, Pielecka-Fortuna J, Pineda R, Gottsch ML, Tena-Sempere M, Moenter SM, Terasawa E, Clarke IJ, Steiner RA, Millar RP. Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J Neurosci. 2009;29(12):3920–3929. [PMC free article: PMC3035813] [PubMed: 19321788]
Thompson EL, Patterson M, Murphy KG, Smith KL, Dhillo WS, Todd JF, Ghatei MA, Bloom SR. Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol. 2004;16(10):850–858. [PubMed: 15500545]
Tovar S, Vazquez MJ, Navarro VM, Fernandez-Fernandez R, Castellano JM, Vigo E, Roa J, Casanueva FF, Aguilar E, Pinilla L, Dieguez C, Tena-Sempere M. Effects of single or repeated intravenous administration of kisspeptin upon dynamic LH secretion in conscious male rats. Endocrinology. 2006;147(6):2696–2704. [PubMed: 16513831]
Novaira HJ, Ng Y, Wolfe A, Radovick S. Kisspeptin increases GnRH mRNA expression and secretion in GnRH secreting neuronal cell lines. Mol Cell Endocrinol. 2009;311(1-2):126–134. [PMC free article: PMC3534746] [PubMed: 19576263]
Chan YM, Lippincott MF, Butler JP, Sidhoum VF, Li CX, Plummer L, Seminara SB. Exogenous kisspeptin administration as a probe of GnRH neuronal function in patients with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2014;99(12):E2762–2771. [PMC free article: PMC4255107] [PubMed: 25226293]
Mittelman-Smith MA, Krajewski-Hall SJ, McMullen NT, Rance NE. Ablation of KNDy Neurons Results in Hypogonadotropic Hypogonadism and Amplifies the Steroid-Induced LH Surge in Female Rats. Endocrinology. 2016;157(5):2015–2027. [PMC free article: PMC4870865] [PubMed: 26937713]
Gutierrez-Pascual E, Martinez-Fuentes AJ, Pinilla L, Tena-Sempere M, Malagon MM, Castano JP. Direct pituitary effects of kisspeptin: activation of gonadotrophs and somatotrophs and stimulation of luteinising hormone and growth hormone secretion. J Neuroendocrinol. 2007;19(7):521–530. [PubMed: 17532794]
Richard N, Galmiche G, Corvaisier S, Caraty A, Kottler ML. KiSS-1 and GPR54 genes are co-expressed in rat gonadotrophs and differentially regulated in vivo by oestradiol and gonadotrophin-releasing hormone. J Neuroendocrinol. 2008;20(3):381–393. [PubMed: 18208554]
Smith JT, Coolen LM, Kriegsfeld LJ, Sari IP, Jaafarzadehshirazi MR, Maltby M, Bateman K, Goodman RL, Tilbrook AJ, Ubuka T, Bentley GE, Clarke IJ, Lehman MN. Variation in kisspeptin and RFamide-related peptide (RFRP) expression and terminal connections to gonadotropin-releasing hormone neurons in the brain: a novel medium for seasonal breeding in the sheep. Endocrinology. 2008;149(11):5770–5782. [PMC free article: PMC2584593] [PubMed: 18617612]
Smith JT, Rao A, Pereira A, Caraty A, Millar RP, Clarke IJ. Kisspeptin is present in ovine hypophysial portal blood but does not increase during the preovulatory luteinizing hormone surge: evidence that gonadotropes are not direct targets of kisspeptin in vivo. Endocrinology. 2008;149(4):1951–1959. [PubMed: 18162520]
Witham EA, Meadows JD, Hoffmann HM, Shojaei S, Coss D, Kauffman AS, Mellon PL. Kisspeptin regulates gonadotropin genes via immediate early gene induction in pituitary gonadotropes. Mol Endocrinol. 2013;27(8):1283–1294. [PMC free article: PMC3725344] [PubMed: 23770611]
Pampillo M, Camuso N, Taylor JE, Szereszewski JM, Ahow MR, Zajac M, Millar RP, Bhattacharya M, Babwah AV. Regulation of GPR54 signaling by GRK2 and {beta}-arrestin. Mol Endocrinol. 2009;23(12):2060–2074. [PMC free article: PMC5419131] [PubMed: 19846537]
Ramaswamy S, Seminara SB, Pohl CR, DiPietro MJ, Crowley WF Jr, Plant TM. Effect of continuous intravenous administration of human metastin 45-54 on the neuroendocrine activity of the hypothalamic-pituitary-testicular axis in the adult male rhesus monkey (Macaca mulatta). Endocrinology. 2007;148(7):3364–3370. [PubMed: 17412800]
Seminara SB, Dipietro MJ, Ramaswamy S, Crowley WF Jr, Plant TM. Continuous human metastin 45-54 infusion desensitizes G protein-coupled receptor 54-induced gonadotropin-releasing hormone release monitored indirectly in the juvenile male Rhesus monkey (Macaca mulatta): a finding with therapeutic implications. Endocrinology. 2006;147(5):2122–2126. [PubMed: 16469799]
Thompson EL, Murphy KG, Patterson M, Bewick GA, Stamp GW, Curtis AE, Cooke JH, Jethwa PH, Todd JF, Ghatei MA, Bloom SR. Chronic subcutaneous administration of kisspeptin-54 causes testicular degeneration in adult male rats. Am J Physiol Endocrinol Metab. 2006;291(5):E1074–1082. [PubMed: 16787965]
Lippincott MFS, V.F.; Seminara, S. Continuously administered kisspeptin as a pseudo-antagonist of the kisspeptin receptor. The Endocrine Society’s 95th Annual Meeting, ENDO 2013, San Francisco, Abstract SAT 2134-2163. 2013.
MacLean DB, Matsui H, Suri A, Neuwirth R, Colombel M. Sustained exposure to the investigational Kisspeptin analog, TAK-448, down-regulates testosterone into the castration range in healthy males and in patients with prostate cancer: results from two phase 1 studies. J Clin Endocrinol Metab. 2014;99(8):E1445–1453. [PubMed: 24762108]
Scott G, Ahmad I, Howard K, MacLean D, Oliva C, Warrington S, Wilbraham D, Worthington P. Double-blind, randomized, placebo-controlled study of safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-683, an investigational metastin analogue in healthy men. Br J Clin Pharmacol. 2013;75(2):381–391. [PMC free article: PMC3579253] [PubMed: 22803642]
Christian CA, Moenter SM. The neurobiology of preovulatory and estradiol-induced gonadotropin-releasing hormone surges. Endocr Rev. 2010;31(4):544–577. [PMC free article: PMC3365847] [PubMed: 20237240]
Kauffman AS. Coming of age in the kisspeptin era: sex differences, development, and puberty. Mol Cell Endocrinol. 2010;324(1-2):51–63. [PMC free article: PMC2902563] [PubMed: 20083160]
Terasawa E, Garcia JP, Seminara SB, Keen KL. Role of Kisspeptin and Neurokinin B in Puberty in Female Non-Human Primates. Front Endocrinol (Lausanne). 2018;9:148. [PMC free article: PMC5897421] [PubMed: 29681889]
Shahab M, Lippincott M, Chan YM, Davies A, Merino PM, Plummer L, Mericq V, Seminara S. Discordance in the Dependence on Kisspeptin Signaling in Mini Puberty vs Adolescent Puberty: Human Genetic Evidence. J Clin Endocrinol Metab. 2018;103(4):1273–1276. [PMC free article: PMC6276658] [PubMed: 29452377]
Navarro VM, Castellano JM, Fernandez-Fernandez R, Barreiro ML, Roa J, Sanchez-Criado JE, Aguilar E, Dieguez C, Pinilla L, Tena-Sempere M. Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide. Endocrinology. 2004;145(10):4565–4574. [PubMed: 15242985]
Keen KL, Wegner FH, Bloom SR, Ghatei MA, Terasawa E. An increase in kisspeptin-54 release occurs with the pubertal increase in luteinizing hormone-releasing hormone-1 release in the stalk-median eminence of female rhesus monkeys in vivo. Endocrinology. 2008;149(8):4151–4157. [PMC free article: PMC2488227] [PubMed: 18450954]
Plant TM, Ramaswamy S, Dipietro MJ. Repetitive activation of hypothalamic G protein-coupled receptor 54 with intravenous pulses of kisspeptin in the juvenile monkey (Macaca mulatta) elicits a sustained train of gonadotropin-releasing hormone discharges. Endocrinology. 2006;147(2):1007–1013. [PubMed: 16282350]
Pineda R, Garcia-Galiano D, Roseweir A, Romero M, Sanchez-Garrido MA, Ruiz-Pino F, Morgan K, Pinilla L, Millar RP, Tena-Sempere M. Critical roles of kisspeptins in female puberty and preovulatory gonadotropin surges as revealed by a novel antagonist. Endocrinology. 2010;151(2):722–730. [PubMed: 19952274]
Decourt C, Robert V, Anger K, Galibert M, Madinier JB, Liu X, Dardente H, Lomet D, Delmas AF, Caraty A, Herbison AE, Anderson GM, Aucagne V, Beltramo M. A synthetic kisspeptin analog that triggers ovulation and advances puberty. Sci Rep. 2016;6:26908. [PMC free article: PMC4887910] [PubMed: 27245315]
Novaira HJ, Sonko ML, Hoffman G, Koo Y, Ko C, Wolfe A, Radovick S. Disrupted kisspeptin signaling in GnRH neurons leads to hypogonadotrophic hypogonadism. Mol Endocrinol. 2014;28(2):225–238. [PMC free article: PMC3896637] [PubMed: 24422632]
Lippincott MF, Chan YM, Delaney A, Rivera-Morales D, Butler JP, Seminara SB. Kisspeptin Responsiveness Signals Emergence of Reproductive Endocrine Activity: Implications for Human Puberty. J Clin Endocrinol Metab. 2016;101(8):3061–3069. [PMC free article: PMC4971332] [PubMed: 27214398]
Chan YM, Lippincott MF, Kusa TO, Seminara SB. Divergent responses to kisspeptin in children with delayed puberty. JCI Insight. 2018;3(8) [PMC free article: PMC5931121] [PubMed: 29669934]
Garcia JP, Guerriero KA, Keen KL, Kenealy BP, Seminara SB, Terasawa E. Kisspeptin and Neurokinin B Signaling Network Underlies the Pubertal Increase in GnRH Release in Female Rhesus Monkeys. Endocrinology. 2017;158(10):3269–3280. [PMC free article: PMC5659687] [PubMed: 28977601]
Midgley AR Jr, Jaffe RB. Regulation of human gonadotropins. X. Episodic fluctuation of LH during the menstrual cycle. J Clin Endocrinol Metab. 1971;33(6):962–969. [PubMed: 5135635]
Levine JE, Bauer-Dantoin AC, Besecke LM, Conaghan LA, Legan SJ, Meredith JM, Strobl FJ, Urban JH, Vogelsong KM, Wolfe AM. Neuroendocrine regulation of the luteinizing hormone-releasing hormone pulse generator in the rat. Recent Prog Horm Res. 1991;47:97–151. [PubMed: 1745827]
Clarke IJ. Gonadotrophin-releasing hormone secretion (GnRH) in anoestrous ewes and the induction of GnRH surges by oestrogen. J Endocrinol. 1988;117(3):355–360. [PubMed: 3292694]
Pau KY, Berria M, Hess DL, Spies HG. Preovulatory gonadotropin-releasing hormone surge in ovarian-intact rhesus macaques. Endocrinology. 1993;133(4):1650–1656. [PubMed: 8404606]
Knobil E, Plant TM. The hypothalamic regulation of LH and FSH secretion in the rhesus monkey. Res Publ Assoc Res Nerv Ment Dis. 1978;56:359–372. [PubMed: 414314]
Hall JE, Taylor AE, Martin KA, Rivier J, Schoenfeld DA, Crowley WF Jr. Decreased release of gonadotropin-releasing hormone during the preovulatory midcycle luteinizing hormone surge in normal women. Proc Natl Acad Sci U S A. 1994;91(15):6894–6898. [PMC free article: PMC44304] [PubMed: 8041716]
Bagatell CJ, Dahl KD, Bremner WJ. The direct pituitary effect of testosterone to inhibit gonadotropin secretion in men is partially mediated by aromatization to estradiol. J Androl. 1994;15(1):15–21. [PubMed: 8188534]
Emons G, Ortmann O, Thiessen S, Knuppen R. Effects of estradiol and some antiestrogens (clomiphene, tamoxifen, and hydroxytamoxifen) on luteinizing hormone secretion by rat pituitary cells in culture. Arch Gynecol. 1986;237(4):199–211. [PubMed: 3516082]
Finkelstein JS, O'Dea LS, Whitcomb RW, Crowley WF Jr. Sex steroid control of gonadotropin secretion in the human male. II. Effects of estradiol administration in normal and gonadotropin-releasing hormone-deficient men. J Clin Endocrinol Metab. 1991;73(3):621–628. [PubMed: 1908485]
Hayes FJ, Seminara SB, Decruz S, Boepple PA, Crowley WF Jr. Aromatase inhibition in the human male reveals a hypothalamic site of estrogen feedback. J Clin Endocrinol Metab. 2000;85(9):3027–3035. [PubMed: 10999781]
Kerin JF, Liu JH, Phillipou G, Yen SS. Evidence for a hypothalamic site of action of clomiphene citrate in women. J Clin Endocrinol Metab. 1985;61(2):265–268. [PubMed: 3924949]
Kesner JS, Wilson RC, Kaufman JM, Hotchkiss J, Chen Y, Yamamoto H, Pardo RR, Knobil E. Unexpected responses of the hypothalamic gonadotropin-releasing hormone "pulse generator" to physiological estradiol inputs in the absence of the ovary. Proc Natl Acad Sci U S A. 1987;84(23):8745–8749. [PMC free article: PMC299623] [PubMed: 3317420]
Pitteloud N, Dwyer AA, DeCruz S, Lee H, Boepple PA, Crowley WF Jr, Hayes FJ. Inhibition of luteinizing hormone secretion by testosterone in men requires aromatization for its pituitary but not its hypothalamic effects: evidence from the tandem study of normal and gonadotropin-releasing hormone-deficient men. J Clin Endocrinol Metab. 2008;93(3):784–791. [PMC free article: PMC2266963] [PubMed: 18073301]
Veldhuis JD, Evans WS, Rogol AD, Thorner MO, Stumpf P. Actions of estradiol on discrete attributes of the luteinizing hormone pulse signal in man. Studies in postmenopausal women treated with pure estradiol. J Clin Invest. 1987;79(3):769–776. [PMC free article: PMC424195] [PubMed: 3818948]
Herbison AE. Multimodal influence of estrogen upon gonadotropin-releasing hormone neurons. Endocr Rev. 1998;19(3):302–330. [PubMed: 9626556]
McDevitt MA, Glidewell-Kenney C, Jimenez MA, Ahearn PC, Weiss J, Jameson JL, Levine JE. New insights into the classical and non-classical actions of estrogen: evidence from estrogen receptor knock-out and knock-in mice. Mol Cell Endocrinol. 2008;290(1-2):24–30. [PMC free article: PMC2562461] [PubMed: 18534740]
Rance NE, McMullen NT, Smialek JE, Price DL, Young WS 3rd. Postmenopausal hypertrophy of neurons expressing the estrogen receptor gene in the human hypothalamus. J Clin Endocrinol Metab. 1990;71(1):79–85. [PubMed: 2370302]
Rance NE, Young WS 3rd. Hypertrophy and increased gene expression of neurons containing neurokinin-B and substance-P messenger ribonucleic acids in the hypothalami of postmenopausal women. Endocrinology. 1991;128(5):2239–2247. [PubMed: 1708331]
Rometo AM, Rance NE. Changes in prodynorphin gene expression and neuronal morphology in the hypothalamus of postmenopausal women. J Neuroendocrinol. 2008;20(12):1376–1381. [PMC free article: PMC2893873] [PubMed: 19094085]
Franceschini I, Lomet D, Cateau M, Delsol G, Tillet Y, Caraty A. Kisspeptin immunoreactive cells of the ovine preoptic area and arcuate nucleus co-express estrogen receptor alpha. Neurosci Lett. 2006;401(3):225–230. [PubMed: 16621281]
Abel TW, Voytko ML, Rance NE. The effects of hormone replacement therapy on hypothalamic neuropeptide gene expression in a primate model of menopause. J Clin Endocrinol Metab. 1999;84(6):2111–2118. [PubMed: 10372719]
Eghlidi DH, Haley GE, Noriega NC, Kohama SG, Urbanski HF. Influence of age and 17beta-estradiol on kisspeptin, neurokinin B, and prodynorphin gene expression in the arcuate-median eminence of female rhesus macaques. Endocrinology. 2010;151(8):3783–3794. [PMC free article: PMC2940528] [PubMed: 20519367]
Goodman RL, Holaskova I, Nestor CC, Connors JM, Billings HJ, Valent M, Lehman MN, Hileman SM. Evidence that the arcuate nucleus is an important site of progesterone negative feedback in the ewe. Endocrinology. 2011;152(9):3451–3460. [PMC free article: PMC3159787] [PubMed: 21693677]
Jayasena CN, Abbara A, Comninos AN, Nijher GM, Christopoulos G, Narayanaswamy S, Izzi-Engbeaya C, Sridharan M, Mason AJ, Warwick J, Ashby D, Ghatei MA, Bloom SR, Carby A, Trew GH, Dhillo WS. Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization. J Clin Invest. 2014;124(8):3667–3677. [PMC free article: PMC4109525] [PubMed: 25036713]
Sandoval-Guzman T, Rance NE. Central injection of senktide, an NK3 receptor agonist, or neuropeptide Y inhibits LH secretion and induces different patterns of Fos expression in the rat hypothalamus. Brain Res. 2004;1026(2):307–312. [PubMed: 15488494]
Lippincott MF, Chan YM, Rivera Morales D, Seminara SB. Continuous Kisspeptin Administration in Postmenopausal Women: Impact of Estradiol on Luteinizing Hormone Secretion. J Clin Endocrinol Metab. 2017;102(6):2091–2099. [PMC free article: PMC5470760] [PubMed: 28368443]
Clarkson J, d'Anglemont de Tassigny X, Moreno AS, Colledge WH, Herbison AE. Kisspeptin-GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge. J Neurosci. 2008;28(35):8691–8697. [PMC free article: PMC6670827] [PubMed: 18753370]
Kinoshita M, Tsukamura H, Adachi S, Matsui H, Uenoyama Y, Iwata K, Yamada S, Inoue K, Ohtaki T, Matsumoto H, Maeda K. Involvement of central metastin in the regulation of preovulatory luteinizing hormone surge and estrous cyclicity in female rats. Endocrinology. 2005;146(10):4431–4436. [PubMed: 15976058]
Billings HJ, Connors JM, Altman SN, Hileman SM, Holaskova I, Lehman MN, McManus CJ, Nestor CC, Jacobs BH, Goodman RL. Neurokinin B acts via the neurokinin-3 receptor in the retrochiasmatic area to stimulate luteinizing hormone secretion in sheep. Endocrinology. 2010;151(8):3836–3846. [PMC free article: PMC2940514] [PubMed: 20519368]
Li Q, Millar RP, Clarke IJ, Smith JT. Evidence that Neurokinin B Controls Basal Gonadotropin-Releasing Hormone Secretion but Is Not Critical for Estrogen-Positive Feedback in Sheep. Neuroendocrinology. 2015;101(2):161–174. [PubMed: 25677216]
Terasawa E. Neuroestradiol in regulation of GnRH release. Horm Behav. 2018 [PMC free article: PMC6941749] [PubMed: 29626484]
Soules MR, Steiner RA, Clifton DK, Cohen NL, Aksel S, Bremner WJ. Progesterone modulation of pulsatile luteinizing hormone secretion in normal women. J Clin Endocrinol Metab. 1984;58(2):378–383. [PubMed: 6420438]
Skinner DC, Evans NP, Delaleu B, Goodman RL, Bouchard P, Caraty A. The negative feedback actions of progesterone on gonadotropin-releasing hormone secretion are transduced by the classical progesterone receptor. Proc Natl Acad Sci U S A. 1998;95(18):10978–10983. [PMC free article: PMC28006] [PubMed: 9724815]
Fox SR, Harlan RE, Shivers BD, Pfaff DW. Chemical characterization of neuroendocrine targets for progesterone in the female rat brain and pituitary. Neuroendocrinology. 1990;51(3):276–283. [PubMed: 1970131]
King JC, Tai DW, Hanna IK, Pfeiffer A, Haas P, Ronsheim PM, Mitchell SC, Turcotte JC, Blaustein JD. A subgroup of LHRH neurons in guinea pigs with progestin receptors is centrally positioned within the total population of LHRH neurons. Neuroendocrinology. 1995;61(3):265–275. [PubMed: 7898631]
Skinner DC, Caraty A, Allingham R. Unmasking the progesterone receptor in the preoptic area and hypothalamus of the ewe: no colocalization with gonadotropin-releasing neurons. Endocrinology. 2001;142(2):573–579. [PubMed: 11159827]
Foradori CD, Goodman RL, Adams VL, Valent M, Lehman MN. Progesterone increases dynorphin a concentrations in cerebrospinal fluid and preprodynorphin messenger ribonucleic Acid levels in a subset of dynorphin neurons in the sheep. Endocrinology. 2005;146(4):1835–1842. [PubMed: 15650077]
Matsumoto AM, Bremner WJ. Modulation of pulsatile gonadotropin secretion by testosterone in man. J Clin Endocrinol Metab. 1984;58(4):609–614. [PubMed: 6421864]
Herbison AE, Skinner DC, Robinson JE, King IS. Androgen receptor-immunoreactive cells in ram hypothalamus: distribution and co-localization patterns with gonadotropin-releasing hormone, somatostatin and tyrosine hydroxylase. Neuroendocrinology. 1996;63(2):120–131. [PubMed: 9053776]
Smith JT, Dungan HM, Stoll EA, Gottsch ML, Braun RE, Eacker SM, Clifton DK, Steiner RA. Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology. 2005;146(7):2976–2984. [PubMed: 15831567]
Woodham C, Birch L, Prins GS. Neonatal estrogen down-regulates prostatic androgen receptor through a proteosome-mediated protein degradation pathway. Endocrinology. 2003;144(11):4841–4850. [PubMed: 12960060]
Kumar MV, Leo ME, Tindall DJ. Modulation of androgen receptor transcriptional activity by the estrogen receptor. J Androl. 1994;15(6):534–542. [PubMed: 7721655]
Navarro VM, Gottsch ML, Wu M, Garcia-Galiano D, Hobbs SJ, Bosch MA, Pinilla L, Clifton DK, Dearth A, Ronnekleiv OK, Braun RE, Palmiter RD, Tena-Sempere M, Alreja M, Steiner RA. Regulation of NKB pathways and their roles in the control of Kiss1 neurons in the arcuate nucleus of the male mouse. Endocrinology. 2011;152(11):4265–4275. [PMC free article: PMC3198996] [PubMed: 21914775]
Shibata M, Friedman RL, Ramaswamy S, Plant TM. Evidence that down regulation of hypothalamic KiSS-1 expression is involved in the negative feedback action of testosterone to regulate luteinising hormone secretion in the adult male rhesus monkey (Macaca mulatta). J Neuroendocrinol. 2007;19(6):432–438. [PubMed: 17504437]
Chrousos GP, Torpy DJ, Gold PW. Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system: clinical implications. Ann Intern Med. 1998;129(3):229–240. [PubMed: 9696732]
Kalantaridou SN, Makrigiannakis A, Zoumakis E, Chrousos GP. Stress and the female reproductive system. J Reprod Immunol. 2004;62(1-2):61–68. [PubMed: 15288182]
Barron JL, Noakes TD, Levy W, Smith C, Millar RP. Hypothalamic dysfunction in overtrained athletes. J Clin Endocrinol Metab. 1985;60(4):803–806. [PubMed: 2982908]
Berga SL, Mortola JF, Girton L, Suh B, Laughlin G, Pham P, Yen SS. Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab. 1989;68(2):301–308. [PubMed: 2493024]
Boccuzzi G, Angeli A, Bisbocci D, Fonzo D, Giadano GP, Ceresa F. Effect of synthetic luteinizing hormone releasing hormone (LH-RH) on the release of gonadotropins in Cushing's disease. J Clin Endocrinol Metab. 1975;40(5):892–895. [PubMed: 1092712]
Breen KM, Oakley AE, Pytiak AV, Tilbrook AJ, Wagenmaker ER, Karsch FJ. Does cortisol acting via the type II glucocorticoid receptor mediate suppression of pulsatile luteinizing hormone secretion in response to psychosocial stress? Endocrinology. 2007;148(4):1882–1890. [PubMed: 17204556]
Luger A, Deuster PA, Kyle SB, Gallucci WT, Montgomery LC, Gold PW, Loriaux DL, Chrousos GP. Acute hypothalamic-pituitary-adrenal responses to the stress of treadmill exercise. Physiologic adaptations to physical training. N Engl J Med. 1987;316(21):1309–1315. [PubMed: 3033504]
Luton JP, Thieblot P, Valcke JC, Mahoudeau JA, Bricaire H. Reversible gonadotropin deficiency in male Cushing's disease. J Clin Endocrinol Metab. 1977;45(3):488–495. [PubMed: 198424]
Oakley AE, Breen KM, Clarke IJ, Karsch FJ, Wagenmaker ER, Tilbrook AJ. Cortisol reduces gonadotropin-releasing hormone pulse frequency in follicular phase ewes: influence of ovarian steroids. Endocrinology. 2009;150(1):341–349. [PMC free article: PMC2630911] [PubMed: 18801903]
Saketos M, Sharma N, Santoro NF. Suppression of the hypothalamic-pituitary-ovarian axis in normal women by glucocorticoids. Biol Reprod. 1993;49(6):1270–1276. [PubMed: 8286608]
Breen KM, Karsch FJ. New insights regarding glucocorticoids, stress and gonadotropin suppression. Front Neuroendocrinol. 2006;27(2):233–245. [PubMed: 16712908]
Chen MD, Ordog T, O'Byrne KT, Goldsmith JR, Connaughton MA, Knobil E. The insulin hypoglycemia-induced inhibition of gonadotropin-releasing hormone pulse generator activity in the rhesus monkey: roles of vasopressin and corticotropin-releasing factor. Endocrinology. 1996;137(5):2012–2021. [PubMed: 8612542]
Kinsey-Jones JS, Li XF, Knox AM, Wilkinson ES, Zhu XL, Chaudhary AA, Milligan SR, Lightman SL, O'Byrne KT. Down-regulation of hypothalamic kisspeptin and its receptor, Kiss1r, mRNA expression is associated with stress-induced suppression of luteinising hormone secretion in the female rat. J Neuroendocrinol. 2009;21(1):20–29. [PubMed: 19094090]
Phumsatitpong C, Moenter SM. Estradiol-Dependent Stimulation and Suppression of Gonadotropin-Releasing Hormone Neuron Firing Activity by Corticotropin-Releasing Hormone in Female Mice. Endocrinology. 2018;159(1):414–425. [PMC free article: PMC5761586] [PubMed: 29069304]
Mitchell JC, Li XF, Breen L, Thalabard JC, O'Byrne KT. The role of the locus coeruleus in corticotropin-releasing hormone and stress-induced suppression of pulsatile luteinizing hormone secretion in the female rat. Endocrinology. 2005;146(1):323–331. [PubMed: 15486230]
Bohnet HG, Dahlen HG, Wuttke W, Schneider HP. Hyperprolactinemic anovulatory syndrome. J Clin Endocrinol Metab. 1976;42(1):132–143. [PubMed: 765352]
Diaz S, Seron-Ferre M, Cardenas H, Schiappacasse V, Brandeis A, Croxatto HB. Circadian variation of basal plasma prolactin, prolactin response to suckling, and length of amenorrhea in nursing women. J Clin Endocrinol Metab. 1989;68(5):946–955. [PubMed: 2715293]
Molitch ME. Pregnancy and the hyperprolactinemic woman. N Engl J Med. 1985;312(21):1364–1370. [PubMed: 3887166]
De Rosa M, Zarrilli S, Di Sarno A, Milano N, Gaccione M, Boggia B, Lombardi G, Colao A. Hyperprolactinemia in men: clinical and biochemical features and response to treatment. Endocrine. 2003;20(1-2):75–82. [PubMed: 12668871]
Moult PJ, Rees LH, Besser GM. Pulsatile gonadotrophin secretion in hyperprolactinaemic amenorrhoea an the response to bromocriptine therapy. Clin Endocrinol (Oxf). 1982;16(2):153–162. [PubMed: 6802531]
Lecomte P, Lecomte C, Lansac J, Gallier J, Sonier CB, Simonetta C. Pregnancy after intravenous pulsatile gonadotropin-releasing hormone in a hyperprolactinaemic woman resistant to treatment with dopamine agonists. Eur J Obstet Gynecol Reprod Biol. 1997;74(2):219–221. [PubMed: 9306123]
Polson DW, Sagle M, Mason HD, Adams J, Jacobs HS, Franks S. Ovulation and normal luteal function during LHRH treatment of women with hyperprolactinaemic amenorrhoea. Clin Endocrinol (Oxf). 1986;24(5):531–537. [PubMed: 3539412]
Grattan DR, Jasoni CL, Liu X, Anderson GM, Herbison AE. Prolactin regulation of gonadotropin-releasing hormone neurons to suppress luteinizing hormone secretion in mice. Endocrinology. 2007;148(9):4344–4351. [PubMed: 17569755]
Milenkovic L, D'Angelo G, Kelly PA, Weiner RI. Inhibition of gonadotropin hormone-releasing hormone release by prolactin from GT1 neuronal cell lines through prolactin receptors. Proc Natl Acad Sci U S A. 1994;91(4):1244–1247. [PMC free article: PMC43133] [PubMed: 8108395]
Kolbinger W, Beyer C, Fohr K, Reisert I, Pilgrim C. Diencephalic GABAergic neurons in vitro respond to prolactin with a rapid increase in intracellular free calcium. Neuroendocrinology. 1992;56(2):148–152. [PubMed: 1407368]
Sarkar DK, Yen SS. Hyperprolactinemia decreases the luteinizing hormone-releasing hormone concentration in pituitary portal plasma: a possible role for beta-endorphin as a mediator. Endocrinology. 1985;116(5):2080–2084. [PubMed: 3157564]
Li C, Chen P, Smith MS. Neuropeptide Y and tuberoinfundibular dopamine activities are altered during lactation: role of prolactin. Endocrinology. 1999;140(1):118–123. [PubMed: 9886815]
Moore KE. Interactions between prolactin and dopaminergic neurons. Biol Reprod. 1987;36(1):47–58. [PubMed: 3552068]
Kokay IC, Petersen SL, Grattan DR. Identification of prolactin-sensitive GABA and kisspeptin neurons in regions of the rat hypothalamus involved in the control of fertility. Endocrinology. 2011;152(2):526–535. [PubMed: 21177834]
Szawka RE, Ribeiro AB, Leite CM, Helena CV, Franci CR, Anderson GM, Hoffman GE, Anselmo-Franci JA. Kisspeptin regulates prolactin release through hypothalamic dopaminergic neurons. Endocrinology. 2010;151(7):3247–3257. [PubMed: 20410200]
Yamada S, Uenoyama Y, Kinoshita M, Iwata K, Takase K, Matsui H, Adachi S, Inoue K, Maeda KI, Tsukamura H. Inhibition of metastin (kisspeptin-54)-GPR54 signaling in the arcuate nucleus-median eminence region during lactation in rats. Endocrinology. 2007;148(5):2226–2232. [PubMed: 17289848]
Sonigo C, Bouilly J, Carre N, Tolle V, Caraty A, Tello J, Simony-Conesa FJ, Millar R, Young J, Binart N. Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration. J Clin Invest. 2012;122(10):3791–3795. [PMC free article: PMC3461919] [PubMed: 23006326]
Araujo-Lopes R, Crampton JR, Aquino NS, Miranda RM, Kokay IC, Reis AM, Franci CR, Grattan DR, Szawka RE. Prolactin regulates kisspeptin neurons in the arcuate nucleus to suppress LH secretion in female rats. Endocrinology. 2014;155(3):1010–1020. [PubMed: 24456164]
Brown RS, Herbison AE, Grattan DR. Prolactin regulation of kisspeptin neurones in the mouse brain and its role in the lactation-induced suppression of kisspeptin expression. J Neuroendocrinol. 2014;26(12):898–908. [PubMed: 25207795]
Millar RP, Sonigo C, Anderson RA, George J, Maione L, Brailly-Tabard S, Chanson P, Binart N, Young J. Hypothalamic-Pituitary-Ovarian Axis Reactivation by Kisspeptin-10 in Hyperprolactinemic Women With Chronic Amenorrhea. J Endocr Soc. 2017;1(11):1362–1371. [PMC free article: PMC5686678] [PubMed: 29264460]
Aquino NSS, Araujo-Lopes R, Henriques PC, Lopes FEF, Gusmao DO, Coimbra CC, Franci CR, Reis AM, Szawka RE. alpha-Estrogen and Progesterone Receptors Modulate Kisspeptin Effects on Prolactin: Role in Estradiol-Induced Prolactin Surge in Female Rats. Endocrinology. 2017;158(6):1812–1826. [PubMed: 28387824]
Schneider JE. Energy balance and reproduction. Physiol Behav. 2004;81(2):289–317. [PubMed: 15159173]
Yeo SH, Colledge WH. The Role of Kiss1 Neurons As Integrators of Endocrine, Metabolic, and Environmental Factors in the Hypothalamic-Pituitary-Gonadal Axis. Front Endocrinol (Lausanne). 2018;9:188. [PMC free article: PMC5932150] [PubMed: 29755406]
Dandona P, Dhindsa S. Update: Hypogonadotropic hypogonadism in type 2 diabetes and obesity. J Clin Endocrinol Metab. 2011;96(9):2643–2651. [PMC free article: PMC3167667] [PubMed: 21896895]
George JT, Millar RP, Anderson RA. Hypothesis: kisspeptin mediates male hypogonadism in obesity and type 2 diabetes. Neuroendocrinology. 2010;91(4):302–307. [PubMed: 20628262]
Bergendahl M, Aloi JA, Iranmanesh A, Mulligan TM, Veldhuis JD. Fasting suppresses pulsatile luteinizing hormone (LH) secretion and enhances orderliness of LH release in young but not older men. J Clin Endocrinol Metab. 1998;83(6):1967–1975. [PubMed: 9626127]
Bergendahl M, Veldhuis JD. Altered pulsatile gonadotropin signaling in nutritional deficiency in the male. Trends Endocrinol Metab. 1995;6(5):145–159. [PubMed: 18406696]
Weigle DS, Duell PB, Connor WE, Steiner RA, Soules MR, Kuijper JL. Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels. J Clin Endocrinol Metab. 1997;82(2):561–565. [PubMed: 9024254]
Loucks AB, Thuma JR. Luteinizing hormone pulsatility is disrupted at a threshold of energy availability in regularly menstruating women. J Clin Endocrinol Metab. 2003;88(1):297–311. [PubMed: 12519869]
Loucks AB, Verdun M, Heath EM. Low energy availability, not stress of exercise, alters LH pulsatility in exercising women. J Appl Physiol (1985). 1998;84(1):37-46. [PubMed: 9451615]
Schreihofer DA, Amico JA, Cameron JL. Reversal of fasting-induced suppression of luteinizing hormone (LH) secretion in male rhesus monkeys by intragastric nutrient infusion: evidence for rapid stimulation of LH by nutritional signals. Endocrinology. 1993;132(5):1890–1897. [PubMed: 8477642]
Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004;351(10):987–997. [PubMed: 15342807]
Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest. 2003;111(9):1409–1421. [PMC free article: PMC154448] [PubMed: 12727933]
Farooqi IS, O'Rahilly S. Leptin: a pivotal regulator of human energy homeostasis. Am J Clin Nutr. 2009;89(3):980S–984S. [PubMed: 19211814]
Rehman R, Jamil Z, Khalid A, Fatima SS. Cross talk between serum Kisspeptin-Leptin during assisted reproduction techniques. Pak J Med Sci. 2018;34(2):342–346. [PMC free article: PMC5954376] [PubMed: 29805405]
Backholer K, Smith JT, Rao A, Pereira A, Iqbal J, Ogawa S, Li Q, Clarke IJ. Kisspeptin cells in the ewe brain respond to leptin and communicate with neuropeptide Y and proopiomelanocortin cells. Endocrinology. 2010;151(5):2233–2243. [PubMed: 20207832]
Cunningham MJ, Clifton DK, Steiner RA. Leptin's actions on the reproductive axis: perspectives and mechanisms. Biol Reprod. 1999;60(2):216–222. [PubMed: 9915984]
Fernandez-Fernandez R, Martini AC, Navarro VM, Castellano JM, Dieguez C, Aguilar E, Pinilla L, Tena-Sempere M. Novel signals for the integration of energy balance and reproduction. Mol Cell Endocrinol. 2006;254-255:127–132. [PubMed: 16759792]
Quennell JH, Mulligan AC, Tups A, Liu X, Phipps SJ, Kemp CJ, Herbison AE, Grattan DR, Anderson GM. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology. 2009;150(6):2805–2812. [PMC free article: PMC2732287] [PubMed: 19179437]
Castellano JM, Navarro VM, Fernandez-Fernandez R, Nogueiras R, Tovar S, Roa J, Vazquez MJ, Vigo E, Casanueva FF, Aguilar E, Pinilla L, Dieguez C, Tena-Sempere M. Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology. 2005;146(9):3917–3925. [PubMed: 15932928]
Luque RM, Kineman RD, Tena-Sempere M. Regulation of hypothalamic expression of KiSS-1 and GPR54 genes by metabolic factors: analyses using mouse models and a cell line. Endocrinology. 2007;148(10):4601–4611. [PubMed: 17595226]
Roa J, Garcia-Galiano D, Varela L, Sanchez-Garrido MA, Pineda R, Castellano JM, Ruiz-Pino F, Romero M, Aguilar E, Lopez M, Gaytan F, Dieguez C, Pinilla L, Tena-Sempere M. The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system. Endocrinology. 2009;150(11):5016–5026. [PubMed: 19734277]
Wahab F, Ullah F, Chan YM, Seminara SB, Shahab M. Decrease in hypothalamic Kiss1 and Kiss1r expression: a potential mechanism for fasting-induced suppression of the HPG axis in the adult male rhesus monkey (Macaca mulatta). Horm Metab Res. 2011;43(2):81–85. [PMC free article: PMC4119764] [PubMed: 21154197]
Castellano JM, Navarro VM, Fernandez-Fernandez R, Roa J, Vigo E, Pineda R, Dieguez C, Aguilar E, Pinilla L, Tena-Sempere M. Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats. Diabetes. 2006;55(9):2602–2610. [PubMed: 16936210]
Elias CF. Leptin action in pubertal development: recent advances and unanswered questions. Trends Endocrinol Metab. 2012;23(1):9–15. [PMC free article: PMC3251729] [PubMed: 21978495]
Hill JW, Elmquist JK, Elias CF. Hypothalamic pathways linking energy balance and reproduction. Am J Physiol Endocrinol Metab. 2008;294(5):E827–832. [PMC free article: PMC5724360] [PubMed: 18285524]
Donato J Jr, Cravo RM, Frazao R, Gautron L, Scott MM, Lachey J, Castro IA, Margatho LO, Lee S, Lee C, Richardson JA, Friedman J, Chua S Jr, Coppari R, Zigman JM, Elmquist JK, Elias CF. Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. J Clin Invest. 2011;121(1):355–368. [PMC free article: PMC3007164] [PubMed: 21183787]
Frazao R, Dungan Lemko HM, da Silva RP, Ratra DV, Lee CE, Williams KW, Zigman JM, Elias CF. Estradiol modulates Kiss1 neuronal response to ghrelin. Am J Physiol Endocrinol Metab. 2014;306(6):E606–614. [PMC free article: PMC3948981] [PubMed: 24473434]
Kluge M, Schussler P, Schmidt D, Uhr M, Steiger A. Ghrelin suppresses secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in women. J Clin Endocrinol Metab. 2012;97(3):E448–451. [PubMed: 22259063]
Martini AC, Fernandez-Fernandez R, Tovar S, Navarro VM, Vigo E, Vazquez MJ, Davies JS, Thompson NM, Aguilar E, Pinilla L, Wells T, Dieguez C, Tena-Sempere M. Comparative analysis of the effects of ghrelin and unacylated ghrelin on luteinizing hormone secretion in male rats. Endocrinology. 2006;147(5):2374–2382. [PubMed: 16455774]
Donoso AO, Lopez FJ, Negro-Vilar A. Cross-talk between excitatory and inhibitory amino acids in the regulation of luteinizing hormone-releasing hormone secretion. Endocrinology. 1992;131(3):1559–1561. [PubMed: 1354606]
Leranth C, MacLusky NJ, Sakamoto H, Shanabrough M, Naftolin F. Glutamic acid decarboxylase-containing axons synapse on LHRH neurons in the rat medial preoptic area. Neuroendocrinology. 1985;40(6):536–539. [PubMed: 3892354]
Mijiddorj T, Kanasaki H, Sukhbaatar U, Oride A, Kyo S. DS1, a delta subunit-containing GABA(A) receptor agonist, increases gonadotropin subunit gene expression in mouse pituitary gonadotrophs. Biol Reprod. 2015;92(2):45. [PubMed: 25519184]
Moore AM, Prescott M, Marshall CJ, Yip SH, Campbell RE. Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome. Proc Natl Acad Sci U S A. 2015;112(2):596–601. [PMC free article: PMC4299257] [PubMed: 25550522]
Watanabe M, Fukuda A, Nabekura J. The role of GABA in the regulation of GnRH neurons. Front Neurosci. 2014;8:387. [PMC free article: PMC4246667] [PubMed: 25506316]
Di Giorgio NP, Bizzozzero-Hiriart M, Libertun C, Lux-Lantos V. Unraveling the connection between GABA and kisspeptin in the control of reproduction. Reproduction. 2019;157(6):R225–R233. [PubMed: 30844750]
Kanasaki H, Tumurbaatar T, Oride A, Hara T, Okada H, Kyo S. Gamma-aminobutyric acidA receptor agonist, muscimol, increases KiSS-1 gene expression in hypothalamic cell models. Reprod Med Biol. 2017;16(4):386–391. [PMC free article: PMC5715903] [PubMed: 29259493]
Kurian JR, Keen KL, Guerriero KA, Terasawa E. Tonic control of kisspeptin release in prepubertal monkeys: implications to the mechanism of puberty onset. Endocrinology. 2012;153(7):3331–3336. [PMC free article: PMC3380308] [PubMed: 22585828]
Terasawa E, Kurian JR, Guerriero KA, Kenealy BP, Hutz ED, Keen KL. Recent discoveries on the control of gonadotrophin-releasing hormone neurones in nonhuman primates. J Neuroendocrinol. 2010;22(7):630–638. [PMC free article: PMC2908205] [PubMed: 20456608]
Piet R, Kalil B, McLennan T, Porteous R, Czieselsky K, Herbison AE. Dominant Neuropeptide Cotransmission in Kisspeptin-GABA Regulation of GnRH Neuron Firing Driving Ovulation. J Neurosci. 2018;38(28):6310–6322. [PMC free article: PMC6596098] [PubMed: 29899026]
Hatef A, Unniappan S. Gonadotropin-releasing hormone, kisspeptin, and gonadal steroids directly modulate nucleobindin-2/nesfatin-1 in murine hypothalamic gonadotropin-releasing hormone neurons and gonadotropes. Biol Reprod. 2017;96(3):635–651. [PubMed: 28339602]
Christian CA, Moenter SM. Vasoactive intestinal polypeptide can excite gonadotropin-releasing hormone neurons in a manner dependent on estradiol and gated by time of day. Endocrinology. 2008;149(6):3130–3136. [PMC free article: PMC2408801] [PubMed: 18326000]
Ducret E, Anderson GM, Herbison AE. RFamide-related peptide-3, a mammalian gonadotropin-inhibitory hormone ortholog, regulates gonadotropin-releasing hormone neuron firing in the mouse. Endocrinology. 2009;150(6):2799–2804. [PubMed: 19131572]
Lee EJ, Moore CT, Hosny S, Centers A, Jennes L. Expression of estrogen receptor-alpha and c-Fos in adrenergic neurons of the female rat during the steroid-induced LH surge. Brain Res. 2000;875(1-2):56–65. [PubMed: 10967299]
Miller BH, Olson SL, Levine JE, Turek FW, Horton TH, Takahashi JS. Vasopressin regulation of the proestrous luteinizing hormone surge in wild-type and Clock mutant mice. Biol Reprod. 2006;75(5):778–784. [PubMed: 16870944]
Palm IF, Van Der Beek EM, Wiegant VM, Buijs RM, Kalsbeek A. Vasopressin induces a luteinizing hormone surge in ovariectomized, estradiol-treated rats with lesions of the suprachiasmatic nucleus. Neuroscience. 1999;93(2):659–666. [PubMed: 10465449]
Leon S, Tena-Sempere M. Dissecting the Roles of Gonadotropin-Inhibitory Hormone in Mammals: Studies Using Pharmacological Tools and Genetically Modified Mouse Models. Front Endocrinol (Lausanne). 2015;6:189. [PMC free article: PMC4700143] [PubMed: 26779117]
Qi Y, Oldfield BJ, Clarke IJ. Projections of RFamide-related peptide-3 neurones in the ovine hypothalamus, with special reference to regions regulating energy balance and reproduction. J Neuroendocrinol. 2009;21(8):690–697. [PubMed: 19500220]
Liu X, Herbison AE. Kisspeptin Regulation of Neuronal Activity throughout the Central Nervous System. Endocrinol Metab (Seoul). 2016;31(2):193–205. [PMC free article: PMC4923402] [PubMed: 27246282]
Acevedo-Rodriguez A, Kauffman AS, Cherrington BD, Borges CS, Roepke TA, Laconi M. Emerging insights into Hypothalamic-pituitary-gonadal (HPG) axis regulation and interaction with stress signaling. J Neuroendocrinol. 2018 [PMC free article: PMC6129417] [PubMed: 29524268]
Kriegsfeld LJ, Mei DF, Bentley GE, Ubuka T, Mason AO, Inoue K, Ukena K, Tsutsui K, Silver R. Identification and characterization of a gonadotropin-inhibitory system in the brains of mammals. Proc Natl Acad Sci U S A. 2006;103(7):2410–2415. [PMC free article: PMC1413747] [PubMed: 16467147]
Molnar CS, Kallo I, Liposits Z, Hrabovszky E. Estradiol down-regulates RF-amide-related peptide (RFRP) expression in the mouse hypothalamus. Endocrinology. 2011;152(4):1684–1690. [PubMed: 21325049]
Copyright © 2000-2024, MDText.com, Inc.

This electronic version has been made freely available under a Creative Commons (CC-BY-NC-ND) license. A copy of the license can be viewed at http://creativecommons.org/licenses/by-nc-nd/2.0/.

Bookshelf ID: NBK279070PMID: 25905297


  • PubReader
  • Print View
  • Cite this Page


Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...