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In the early 2000s, metastin, an endogenous ligand for G protein-coupled receptor 54 (GPR54), was discovered in human placental extracts. In 2003, GPR54 receptor mutations were found in a family with congenital hypogonadotropic hypogonadism. Metastin was subsequently renamed kisspeptin after its coding gene, Kiss1. Since then, studies in mice and other animals have revealed that kisspeptin is located at the apex of the hypothalamic-pituitary-gonadal axis and regulates reproductive functions by modulating gonadotropin-releasing hormone (GnRH). In rodents, kisspeptin (Kiss1) neurons localize to two regions, the hypothalamic arcuate nucleus (ARC) and the anteroventral periventricular nucleus (AVPV). ARC Kiss1 neurons co-express neurokinin B (NKB) and dynorphin and are thus termed KNDy neurons. Kiss1 neurons in humans are concentrated in the infundibular nucleus (equivalent to the ARC), with few Kiss1 neurons localized to the preoptic area (equivalent to the AVPV), and the mechanisms underlying GnRH surge secretion in humans are poorly understood. However, peripheral administration of kisspeptin to humans promotes gonadotropin secretion, and administration of kisspeptin to patients with hypothalamic amenorrhea or congenital hypogonadotropic hypogonadism restores the pulsatile secretion of GnRH/luteinizing hormone. Thus, kisspeptin undoubtedly plays an important role in reproductive function in humans. Studies are currently underway to develop kisspeptin receptor agonists or antagonists for clinical application. Modification of KNDy neurons by NKB agonists/antagonists is also being attempted to develop therapeutic agents for various menstrual abnormalities, including polycystic ovary syndrome and menopausal hot flashes. Here, we review the role of kisspeptin in humans and its clinical applications.

Polycystic ovary syndrome (PCOS) is one of the most common reproductive disorders in women worldwide, and its symptoms are mainly manifested as ovulation, endocrine and metabolic abnormalities. Although the pathogenesis of PCOS is not yet clear, more and more studies have demonstrated that high-concentration androgen-induced neuroendocrine disorders play a role in the pathogenesis of PCOS. The KNDy neurons in the hypothalamus play an important role in regulating female reproductive function. Recent studies have found that excessive concentrations of androgens may alter the regulation of GnRH by the KNDy neuronal network in the hypothalamus region, interfering with the hypothalamic -pituitary -ovarian/adrenal/ adipocyte axis, which may increase the production of downstream target organs. The vicious cycle of excess androgens, aggravates the symptoms of PCOS. Therefore, it may be possible to treat PCOS patients by reducing androgen effects on neuroendocrine, restoring sensitivity to steroid feedback, and normalizing LH/FSH pulses by modulating GnRH secretion during critical developmental windows. [ABSTRACT FROM AUTHOR]

This article highlights key milestones in GnRH research that have occurred in the 50 plus years since the discovery of the decapeptide. It is by no means exhaustive and inevitably reflects our limitations and idiosyncratic perspectives. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that KNDy neurons located in the hypothalamic arcuate nucleus (ARC), which are reported to express kisspeptin, neurokinin B, and dynorphin A, are indispensable for the gonadotropin-releasing hormone (GnRH) pulse generation that results in rhythmic GnRH secretion. The aims of the present study were to investigate the effects of peripheral administration of the neurokinin 3 receptor (NK3R/TACR3, a receptor for neurokinin B) antagonist, SB223412, on GnRH pulse-generating activity and pulsatile luteinizing hormone (LH) secretion in ovariectomized Shiba goats treated with luteal phase levels of estrogen. The NK3R antagonist was infused intravenously for 4 h {0.16 or 1.6 mg/(kg body weight [BW]·4 h)} during which multiple unit activity (MUA) in the ARC was recorded, an electrophysiological technique commonly employed to monitor GnRH pulse generator activity. In a separate experiment, the NK3R antagonist (40 or 200 mg/[kg BW·day]) was administered orally for 7 days to determine whether the NK3R antagonist could modulate pulsatile LH secretion when administered via the oral route. Intravenous infusion of the NK3R antagonist significantly increased the interval of episodic bursts of MUA compared with that of the controls. Oral administration of the antagonist for 7 days also significantly prolonged the interpulse interval of LH pulses. The results of this study demonstrate that peripheral administration of an NK3R antagonist suppresses pulsatile LH secretion by acting on the GnRH pulse generator, suggesting that NK3R antagonist administration could be used to modulate reproductive functions in ruminants.

In the early 2000s, metastin, an endogenous ligand for G protein-coupled receptor 54 (GPR54), was discovered in human placental extracts. In 2003, GPR54 receptor mutations were found in a family with congenital hypogonadotropic hypogonadism. Metastin was subsequently renamed kisspeptin after its coding gene, Kiss1. Since then, studies in mice and other animals have revealed that kisspeptin is located at the apex of the hypothalamic-pituitary-gonadal axis and regulates reproductive functions by modulating gonadotropin-releasing hormone (GnRH). In rodents, kisspeptin (Kiss1) neurons localize to two regions, the hypothalamic arcuate nucleus (ARC) and the anteroventral periventricular nucleus (AVPV). ARC Kiss1 neurons co-express neurokinin B (NKB) and dynorphin and are thus termed KNDy neurons. Kiss1 neurons in humans are concentrated in the infundibular nucleus (equivalent to the ARC), with few Kiss1 neurons localized to the preoptic area (equivalent to the AVPV), and the mechanisms underlying GnRH surge secretion in humans are poorly understood. However, peripheral administration of kisspeptin to humans promotes gonadotropin secretion, and administration of kisspeptin to patients with hypothalamic amenorrhea or congenital hypogonadotropic hypogonadism restores the pulsatile secretion of GnRH/luteinizing hormone. Thus, kisspeptin undoubtedly plays an important role in reproductive function in humans. Studies are currently underway to develop kisspeptin receptor agonists or antagonists for clinical application. Modification of KNDy neurons by NKB agonists/antagonists is also being attempted to develop therapeutic agents for various menstrual abnormalities, including polycystic ovary syndrome and menopausal hot flashes. Here, we review the role of kisspeptin in humans and its clinical applications.

Context: SJX-653 is a novel neurokinin 3 receptor (NK3R) antagonist. The NK3 pathway is a central regulator of gonadotropin releasing hormone (GnRH) secretion and has also been implicated in the generation of hot flashes. Therefore, decreases of luteinizing hormone (LH) and testosterone in men serve as sensitive pharmacodynamic (PD) markers of central NK3 antagonism.Objective: To characterize the safety, tolerability, pharmacokinetics, and pharmacodynamic activity of SJX-653 in healthy men.Design: A randomized, placebo-controlled, double-blind, single ascending dose study.Setting: Phase 1 unit.Patients or Other Participants: Seven cohorts of 6 healthy men 18-45 years of age (4:2 randomization to SJX-653/placebo per cohort).Intervention(s): Single oral doses of 0.5-90 mg SJX-653.Main Outcome Measure(s): Safety assessments and serial pharmacokinetic (PK)/PD measurements.Results: SJX-653 was well tolerated at all dose levels. Cmax and AUC0-24 increased in a dose-proportional manner. The terminal elimination half-life ranged between 9.8 and 12.5 hours independent of dose. A statistically significant, dose-dependent, reversible reduction of LH and testosterone was observed with near maximal effect after 15 mg and little to no effect at 4.5 mg. Maximal LH reduction was 70 ± 7% (mean ± sd) at 6 hours after 30 mg SJX-653 versus 10 ± 43% for placebo (P = 0.0006); maximal T reduction was of 68 ± 5% at 8 hours after 60 mg SJX-653 versus 18 ± 11% for placebo (P < 0.0001). The plasma IC50 for LH reduction was 33 ng/mL.Conclusions: These data demonstrate clinical proof-of-mechanism for SJX-653 as a potent centrally-acting NK3R antagonist. [ABSTRACT FROM AUTHOR]

Pulsatile gonadotropin-releasing hormone (GnRH) secretion is indispensable for reproduction in mammals. Kisspeptin neurons in the hypothalamic arcuate nucleus (ARC), referred to as KNDy neurons because of the coexpression of neurokinin B and dynorphin A, are considered as components of the GnRH pulse generator that produces rhythmic GnRH secretion. The present study aimed to investigate if peripheral administration of PF-4455242, a κ-opioid receptor (KOR, a dynorphin A receptor) antagonist, facilitates pulsatile luteinizing hormone (LH) secretion and GnRH pulse generator activity in estrogen-treated ovariectomized Shiba goats to determine the possibility of using KOR antagonists to artificially control ovarian activities. PF-4455242 was intravenously infused for 4 h (1 or 10 μmol/kg body weight/4 h) or as a single subcutaneous injection (1 or 10 μmol/kg body weight). In a separate experiment, the same KOR antagonist (10 μmol/kg body weight/4 h) was intravenously infused during the recording of multiple unit activity (MUA) in the ARC that reflects the activity of the GnRH pulse generator to test the effects of KOR antagonist administration on GnRH pulse generator activity. Intravenous infusion and single subcutaneous injection of the KOR antagonist significantly increased the frequency of LH pulses compared with controls. Intravenous infusion of KOR antagonist also significantly increased the frequency of episodic bursts in the MUA. The present study demonstrates that peripherally administered KOR antagonist stimulates pulsatile LH secretion by acting on the GnRH pulse generator, and peripheral administration of PF-4455242 can be used to facilitate pulsatile LH secretion, which in turn facilitates ovarian activities in farm animals. • Peripheral administration of a KOR antagonist increased the frequency of LH pulses. • Peripheral infusion of a KOR antagonist increased multiple unit activity in the ARC. • KOR antagonist stimulates LH pulses by acting on the GnRH pulse generator. [ABSTRACT FROM AUTHOR]

Pulsatile secretion of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) decreases during aging. Kisspeptin (encoded by Kiss1 ) neurons in the arcuate nucleus coexpress neurokinin B ( Tac3 ) and dynorphin ( Pdyn ) and are critical for regulating the GnRH/LH pulse. We therefore examined kisspeptin neurons by histochemistry and pulsatile LH release in rats aged 2–3 (Young), 12–13 (Young-Middle), 19–22 (Late-Middle), and 24–26 (Old) months. Total LH concentrations, sampled for 3 hours, decreased in both sexes with aging. In females, numbers of Tac3 and Pdyn neurons were significantly reduced in all aging rats, and numbers of Kiss1 neurons were significantly reduced in Late-Middle and Old rats. In males, numbers of all 3 neuron-types were significantly decreased in all aging rats. GnRH agonist induced LH release in all animals; however, the increased LH concentration in all aging rats was less than that in Young rats. These results suggest that expression of each gene in kisspeptin neurons may be controlled individually during aging, and that reduction of their expression or change in pituitary responsiveness may cause attenuated pulsatile LH secretion. [ABSTRACT FROM AUTHOR]

KNDy neurons are named for their co-expression of three neuropeptides, kisspeptin, neurokinin B (NKB) and dynorphin A (DynA). These cells, located in the hypothalamic arcuate nucleus (ARC), are associated with generation of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) pulses to control follicular growth and steroidogenesis. However, subcellular sorting mechanisms for secretory vesicles containing these neuropeptides have not been elucidated. In this study, we analyzed the localization pattern of kisspeptin, NKB and DynA in the ARC of the ovariectomized rat immediately treated with estrogen using immunoelectron microscopy. First, we identified neuropeptides by dual-labeled fluorescence immunohistochemistry, with results indicating all three neuropeptides co-express within individual ARC cells in female rats. Next, we investigated the subcellular localization pattern of kisspeptin, NKB, and/or DynA using post-embedding double immunoelectron microscopy, indicating that each type of neuropeptide is contained within separate and individual neurosecretory vesicles. This suggests sorting and packaging of kisspeptin, NKB and DynA is differentially regulated within KNDy neurons. Our findings facilitate understanding of regulatory mechanisms underlying kisspeptin secretion in KNDy neurons, and generation of GnRH/LH pulses induced by kisspeptin in the ARC. [ABSTRACT FROM AUTHOR]

Introduction : Although international clinical practice guidelines recognize a continued role for menopausal hormone therapy (HT), particularly for symptomatic women <60 years of age or within 10 years of menopause, safety and tolerability concerns have discouraged HT use due to potential links with a perceived increased risk of hormone-dependent cancers, and an established risk of stroke and venous thromboembolism. There is therefore a need for safe, effective non-hormonal therapy for relief of menopausal vasomotor symptoms (VMS). Areas covered : This narrative review summarizes the dataset accrued for fezolinetant, a neurokinin-3 receptor (NK3R) antagonist in clinical development for menopause-associated VMS. Expert opinion : Altered signaling in neuroendocrine circuits at menopause leads to VMS wherein NK3R activity plays a key role to modulate the thermoregulatory center in a manner conducive to triggering the 'hot flash' response. Thus, a new generation of NK3R antagonists has entered clinical development to specifically target the mechanistic basis of VMS. Fezolinetant is the most advanced NK3R antagonist in terms of stage of clinical development. Results to date have demonstrated rapid and substantial reduction in VMS frequency and severity and associated improvements in health-related quality of life. NK3R antagonists offer a non-hormonal alternative to HT for the treatment of menopause-related VMS.

Accumulating evidence suggests that KNDy neurons located in the hypothalamic arcuate nucleus (ARC), which are reported to express kisspeptin, neurokinin B, and dynorphin A, are indispensable for the gonadotropin-releasing hormone (GnRH) pulse generation that results in rhythmic GnRH secretion. The aims of the present study were to investigate the effects of peripheral administration of the neurokinin 3 receptor (NK3R/TACR3, a receptor for neurokinin B) antagonist, SB223412, on GnRH pulse-generating activity and pulsatile luteinizing hormone (LH) secretion in ovariectomized Shiba goats treated with luteal phase levels of estrogen. The NK3R antagonist was infused intravenously for 4 h {0.16 or 1.6 mg/(kg body weight [BW]·4 h)} during which multiple unit activity (MUA) in the ARC was recorded, an electrophysiological technique commonly employed to monitor GnRH pulse generator activity. In a separate experiment, the NK3R antagonist (40 or 200 mg/[kg BW·day]) was administered orally for 7 days to determine whether the NK3R antagonist could modulate pulsatile LH secretion when administered via the oral route. Intravenous infusion of the NK3R antagonist significantly increased the interval of episodic bursts of MUA compared with that of the controls. Oral administration of the antagonist for 7 days also significantly prolonged the interpulse interval of LH pulses. The results of this study demonstrate that peripheral administration of an NK3R antagonist suppresses pulsatile LH secretion by acting on the GnRH pulse generator, suggesting that NK3R antagonist administration could be used to modulate reproductive functions in ruminants.

A population of neurons in the arcuate nucleus (ARC) coexpresses kisspeptin, neurokinin B (NKB), and dynorphin, and therefore they are referred to as KNDy neurons. It has been suggested that KNDy neurons participate in several brain functions, including the control of reproduction. The present study aimed to advance our understanding of the anatomy of the KNDy neural system. We first produced an antiserum against goat kisspeptin. After confirming its specificity, the antiserum was used to histochemically detect kisspeptin-positive signals. Using the colocalization of kisspeptin and NKB immunoreactivity as a marker for KNDy neurons, we mapped distributions of their cell somata and fibers in the whole brain (except the cerebellum) of ovariectomized (OVX) goats. KNDy neuronal somata were distributed throughout the ARC, and were particularly abundant in its caudal aspect. KNDy neuronal fibers projected into several areas within the septo-preoptic-hypothalamic continuum, such as the ARC, median eminence, medial preoptic nucleus, and bed nucleus of the stria terminalis. Kisspeptin immunoreactivity was not found outside of the continuum. We then addressed to the hypothesis that substance P (SP) is also involved in the KNDy neural system. Double-labeling immunohistochemistry for kisspeptin and SP revealed that KNDy neurons did not coexpress SP, but nearly all of the KNDy neuronal somata were surrounded by fibers containing SP in the OVX goats. The present results demonstrate anatomical evidence for a robust association between the KNDy and SP neural systems.

Kisspeptin (KISS1; encoded by Kiss1) neurons in the arcuate nucleus (ARC) coexpress tachykinin 3 (TAC3; also known as neurokinin B) and dynorphin A (PDYN). Accordingly, they are termed KNDy neurons and considered to be crucial in generating pulsatile release of gonadotropin-releasing hormone. Accumulating evidence suggests that Kiss1 and Tac3 are negatively regulated by estrogen. However, it has not been fully determined whether and how estrogen modulates Pdyn and PDYN. Here, we examined the expression of Pdyn mRNA and PDYN by in situ hybridization and immunohistochemistry, respectively, in the ARC of female rats after ovariectomy (OVX) and OVX plus low- or high-dose beta-estradiol (E2) replacement. We also investigated the effect of E2 on expression of Kiss1, KISS1, Tac3, and TAC3. Furthermore, colocalization of PDYN and estrogen receptor alpha (ESR1) was determined. Subsequently, we found that low-dose E2 treatment had no effect on Pdyn mRNA-expressing cells, but increased PDYN-immunoreactive (ir) cell numbers. In contrast, high-dose E2 treatment resulted in prominent reductions in both Pdyn mRNA-expressing and PDYN-ir cell numbers. Changes induced by low or high doses of E2 were similarly observed in the expression of Kiss1, KISS1, Tac3, and TAC3. The majority of PDYN-ir neurons coexpressed ESR1 in all groups. Our results indicate that E2 regulates the expression of PDYN, as well as KISS1 and TAC3, with regulation by E2 differing according to its levels., (© The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)