STATE-OF-THE-ART REVIEW IN ENDOCRINOLOGY
The role of KNDy neurons in human reproductive health
2024 Volume 71 Issue 8 Pages 733-743
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2024 Volume 71 Issue 8 Pages 733-743
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.
Female reproductive function is regulated by the hypothalamic-pituitary-gonadal axis (HPG axis). Gonadotropin-releasing hormone (GnRH) produced in the hypothalamus acts on gonadotropin-producing cells (gonadotrophs) in the anterior pituitary gland, triggering the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). During the follicular phase, pituitary gonadotropin-producing cells secrete significant amounts of FSH, which promotes follicle development, while there is an LH surge during ovulation. FSH is predominantly secreted if the frequency of GnRH secretion from the hypothalamus is slow (<1 pulse every 2–3 h), whereas LH is predominantly secreted if it is fast (>1 pulse every hour) in primates [1, 2]. In addition, the frequency of LH pulses, which is known to reflect GnRH pulse frequency, has been reported to vary among animal species [3]. Therefore, GnRH pulse frequency intervals related to the specificity of gonadotropin secretion may also differ among animal species.
The pulsatile secretion of GnRH is regulated by negative feedback from estrogen and progesterone produced in the ovaries. The GnRH/LH surge that triggers ovulation is induced by positive feedback from estrogen [4]. However, estrogen receptors, which play a major role in positive and negative feedback mechanisms, are not expressed on GnRH neurons. Therefore, it was believed that the feedback was not directly mediated by GnRH neurons but by other neurons expressing estrogen receptors, the existence of which was unknown for a long time [5].
Kisspeptin was initially isolated from human placenta as an endogenous ligand for the orphan G protein-coupled receptor and was named metastin because it suppresses cancer metastasis [6]. In humans, kisspeptin is encoded by the KISS1 gene, which is located on the long arm of chromosome 1, band 32. The KISS1 gene first gives rise to an inactive, preprocessed kisspeptin comprising 145 amino acids. This prepro-kisspeptin is then cleaved intracellularly to make four biologically active peptides: kisspeptin-54 (KP54), kisspeptin-14 (KP14), kisspeptin-13 (KP13), and kisspeptin-10 (KP10). These peptides have the same amino acid sequence at the C terminus, namely, an Arg (arginine)-Phe (phenylalanine) residue RF-amide structure and bind to and activate the KISS1 receptor with high affinity. KP54 is considered the major product of the human KISS1 gene [7].
Both KISS1 and KISS1R are highly expressed in the placenta, gonads, and hypothalamus and are also widely expressed in other peripheral tissues, including the pituitary, stomach, liver, pancreas, and cardiovascular system [8].
Hypogonadotropic hypogonadism occurs when the pituitary gland does not secrete gonadotropins. Patients with hypogonadotropic hypogonadism lack secondary sex characteristics and are infertile due to amenorrhea in women and lack of spermatogenesis in men. Hypogonadotropic hypogonadism is congenitally GnRH deficient and is also called congenital hypogonadotropic hypogonadism (CHH). Kalman syndrome, a well-known cause of CHH, is due to mutations in genes such as KAL1. Many genetic mutations have been found, including those in GnRH receptors and GnRH [9].
In 2003, two groups successively reported the discovery of new gene mutations in families with congenital hypogonadism. One reported the discovery of a G protein-coupled receptor 54 (GPR54) gene mutation in a family in which five of the eight siblings had CHH [10]. The endogenous ligand for the GPR54 receptor is metastin, which had already been found as a suppressor of cancer metastasis and is encoded by the KISS1 gene [6]. The five affected siblings, both males and females, had very low serum gonadotropin levels, and three of the five responded to the GnRH challenge test. The second group reported a family in which 6 of 19 individuals had hypogonadotropic hypogonadism and GPR54 receptor gene mutation [11]. These patients had complete loss of the pulsatile secretion of LH, but exogenous administration of GnRH restored its pulsatile secretion. These findings suggested that signaling through GPR54 is deeply involved in the regulation of reproductive function. Subsequent studies revealed the presence of GPR54 (later named kisspeptin receptor [KISS1R]) in GnRH neurons and, furthermore, that Kiss-1 neurons express estrogen receptor α (ERα) [12]. Metastin was renamed kisspeptin after it was shown to regulate GnRH secretion upstream of GnRH.
In 2008, a loss-of-function mutation in the KISS1R followed by an activating mutation was reported. This female patient was diagnosed with precocious puberty with accelerated breast growth and pubic hair at 7 years of age. Serum LH and FSH levels were normal, estradiol levels were slightly elevated, and gonadotropin levels were hyporesponsive after stimulation with GnRH [13].
Mutations in the KISS1 gene have also been reported. The proposita had no breast development and a bone age of 13 years when she was 14.9 years old. Pelvic ultrasound showed a hypoplastic uterus and ovaries lacking follicles. Serum gonadotropin and estradiol levels were extremely low, and gonadotropin levels were hyporesponsive to GnRH stimulation. Four of her 14 relatives had similar symptoms [14].
Activating genetic mutations in KISS1 causes symptoms of precocious puberty. In a genetic analysis of 83 patients with precocious puberty [15], mutations in the KISS1 gene were found in three patients. One of the patients, a boy, had secondary sex characteristics beginning at 12 months of age. Hormonal evaluation showed elevated blood gonadotropin and testosterone levels.
The discovery of KISS1R mutations in the family with hypogonadotropic hypogonadism [10, 11] showed that kisspeptin is a major regulator of the HPG axis. Subsequent animal studies, mainly in rodents, detected kisspeptin neurons in two regions of the hypothalamus, the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC), which mediate positive and negative sex steroid feedback, respectively [16-20].
Kiss1 neurons in the ARC region also co-express neurokinin B (NKB) and dynorphin A. Accordingly, kisspeptin neurons in the ARC region are referred to as KNDy neurons, an acronym for kisspeptin, NKB, and dynorphin A (Fig. 1) [21-24]. It has been reported that synchronous episodes of calcium activity in the ARC Kiss1 neuron population correlated almost perfectly with pulsatile secretion of LH in gonadectomized mice [25]. These results suggest that ARC Kiss1 neurons function as pulse generators in the hypothalamus. Furthermore, experiments in goats have shown that NKB activates neuronal activity while dynorphin A inhibits neuronal activity [22]. In female global Kiss1 knockout (KO) rats, the LH pulse was completely suppressed. Transfection of Kiss1 into more than 20% of the KNDy neurons in these Kiss1 KO rats recovered follicle development and the LH pulse. Furthermore, in conditioned ARC Kiss1 KO rats, the LH pulse was completely suppressed [26]. It is now suggested that the interaction of NKB and dynorphin A in KNDy neurons in the arcuate nucleus causes pulsatile excitation, resulting in the pulses of kisspeptin secretion, which in turn cause the pulsatile secretion of GnRH [27].
Schematic diagram showing the relationship between KNDy neurons and gonadotropin-releasing hormone (GnRH) neurons in rodents and in humans
Kisspeptin neurons are located in the anterior ventral periventricular nucleus (AVPV) and arcuate nucleus (ARC) in rodents, and kisspeptin neurons in the ARC co-express NKB and dynorphin (KNDy neurons). In humans, kisspeptin neurons are present in the preoptic area (POA) and the infundibular nucleus (equivalent to the ARC in rodents). Kiss-1 neurons in the infundibular nucleus may function as both AVPV and ARC in rodents, but few studies have investigated the anatomical expression regions of kisspeptin that mediate positive estrogen feedback in humans, and thus details are scarce.
In humans, patients with mutations in TAC3 (encoding NKB) or TACR3 (encoding neurokinin receptor 3 [NK3R]) have a hypogonadotropic phenotype [28]. Furthermore, continuous administration of kisspeptin to patients with TACR3 mutations rescues gonadotropin secretion, suggesting that NKB has a prokinetic effect on kisspeptin secretion and regulates gonadotropin secretion in humans [29].
It is now widely believed that AVPV Kiss1 neurons mediate E2 positive feedback to GnRH neurons in rodents (Fig. 1). AVPV Kiss1 neurons express abundant ERα and strongly increase Kiss1 gene expression in response to elevated E2 [18]. Nonspecific knockdown of ERα in AVPV Kiss1 neurons was reported to blunt the LH surge in mice [30]. Furthermore, in female mice in which ERα of AVPV Kiss1 neurons were specifically knocked down, the LH surge was significantly blunted and the luteal number was reduced, although the cycle remained normal [31]. This suggests that AVPV Kiss1 neurons play a role in positive feedback.
In humans, kisspeptin neurons are present in the infundibular nucleus and preoptic area [32] (Fig. 1). Although few studies have examined the anatomically expressed regions of kisspeptin that mediate positive feedback in humans, several studies have reported that kisspeptin neurons in the infundibular nucleus may function as both AVPV and ARC in rodents [12, 33, 34], but this remains to be clarified. In formalin-fixed hypothalamus from human autopsy specimens, kisspeptin and NKB are co-expressed in neurons of the infundibular nucleus, which corresponds to the rodent arcuate nucleus. Neurons in the infundibular nucleus are also reported to express dynorphin mRNA, but the amount of dynorphin mRNA is lower in postmenopausal women than in premenopausal women [35]. However, dynorphin expression is rarely seen in neurons co-expressing kisspeptin and NKB, and co-expression with substance P has been observed [36, 37]. Thus, the type and importance of neuropeptides expressed in KNDy neurons may vary by species, sex, and age.
The usefulness of kisspeptin in the diagnosis of hypothalamic function in CHH is being investigated. Intravenous administration of GnRH to patients with CHH results in lower blood LH levels than after its administration to healthy eugonadal men, but administration of KP54 leads to even lower blood LH levels than GnRH. In addition, CHH patients with impaired olfaction, such as in Kallmann syndrome, which is caused by impaired migration of GnRH neurons to the hypothalamus, have lower LH elevations after KP54 administration than CHH patients without olfactory impairment. This suggests that kisspeptin may allow for more detailed examination of the lesions responsible for GnRH deficiency [38].
Several studies have investigated whether kisspeptin is useful in the treatment of hypogonadotropic hypogonadism and hypothalamic amenorrhea. Subcutaneous administration of KP54 twice daily to hypogonadotropic amenorrheic patients increased the frequency of LH pulses and blood LH levels but the LH response significantly reduced after 14 days of subcutaneous administration. This was due to desensitization of the kisspeptin receptor, and kisspeptin itself is considered inappropriate for treating hypothalamic amenorrhea [39]. Thus, a KISS1R agonist called MVT-602, which has a longer duration of action than KP54, was developed. After a single subcutaneous injection of MVT-602, both LH and FSH increased more rapidly in hypothalamic amenorrheic patients than in normal women, and the effect lasted for more than 48 h. This raises the possibility that MVT-602 may have therapeutic potential [40].
Precocious and delayed pubertyAs mentioned above, mutations in kisspeptin or the Kiss-1R gene can cause precocious puberty or delayed puberty. Furthermore, there has been a report on the prognostic value of kisspeptin in patients with late onset of puberty [41]. After the intravenous administration of KP10 and GnRH to patients with delayed puberty, some patients’ blood LH levels responded to kisspeptin while others’ did not. In addition, the responders subsequently reached puberty, whereas the non-responders reached 18 years of age without showing any physical signs of puberty. Thus, the authors concluded that the response of LH to kisspeptin accurately predicted the subsequent onset of puberty.
Artificial reproductive technologyIn in vitro fertilization (IVF), the ovaries are generally stimulated with FSH products, while the endogenous LH surge is suppressed with GnRH agonists or antagonists. After the follicles have developed sufficiently, an LH surge is mimicked with human chorionic gonadotropin (hCG) preparations or induced GnRH agonists to promote oocyte maturation. The development of a large number of follicles during this period increases the risk of the development of ovarian hyperstimulation syndrome (OHSS), which can lead to renal failure and thrombosis [42, 43]. In a natural menstrual cycle, kisspeptin triggers an LH surge by mediating positive estrogenic feedback. Therefore, attempts have been made to use kisspeptin as a trigger. Generally, hCG used as a trigger has a longer duration and a higher peak LH value than the physiological LH surge; GnRH agonists have the same duration as the physiological LH surge but a higher peak LH value. Thus, the risk of OHSS is increased with hCG and GnRH agonists [44]. The Kiss1R agonist MVT-602 produces to the same duration as the physiological LH surge and the same LH peak, while KP54 induces the same peak as LH but a shorter duration than the physiological LH surge [40, 42]. This would lower the risk of OHSS. KP54 may also act directly on the ovaries and inhibit the production of vascular endothelial growth factor, which is one of the factors aggravating OHSS [42]. Three randomized trials using KP54 as a trigger have been reported. In each trial, the number of oocytes retrieved, number of oocytes matured, number of embryos transferred, and clinical pregnancy rate were comparable to those induced with conventional hCG or GnRH agonists, with fewer cases of moderate or severe OHSS [45-47]. Therefore, the number of cases of OHSS related to kisspeptin is not significant. Thus, induction with kisspeptin may be useful for patients at high risk of OHSS.
Menopausal disordersVasomotor symptoms (VMSs) such as sweating and flushing are typical symptoms of menopause and the common treatment is estrogen replacement therapy, which is not available for women at risk of breast cancer or thrombosis.
KNDy neurons project to the median preoptic nucleus (MnPO) in rodents [48]. The MnPO is the first hypothalamic region to receive information from cutaneous thermoreceptors and transmit it to the central nervous system to regulate heat dissipation effectors, making the MnPO an important component of the thermoregulatory pathway [49]. MnPO neurons have been shown to express NK3R mRNA in rats [50], suggesting that KNDy neurons might regulate the heat defense pathway through NKB signaling in the MnPO. During menopause, the negative feedback of estrogen activates Kiss-1 and NK3R on KNDy neurons [51].
Four NK3R inhibitors have been tested in clinical trials. The NK3R antagonist MLE4901 (pavinetant) was the first drug found to ameliorate hot flashes; 40 mg of oral MLE4901 twice daily reduced the frequency and severity of hot flashes experienced by perimenopausal women. However, treatment-emergent adverse events included liver dysfunction [52]. The NK1R/NK3R antagonist NT-814 (elinzanetant, 150 mg, once daily) also decreased hot flashes and night sweats versus placebo in perimenopausal women [53]. In addition, oral elinzanetant 120 mg daily reduced VMS frequency versus placebo. It also produced clinically meaningful improvements in sleep and quality of life measures. Elinzanetant was well tolerated. The most frequently reported treatment-emergent adverse events in all treatment groups were headache, somnolence, and diarrhea, most of which were mild or moderate [54]. In patients taking tamoxifen or aromatase inhibitors after breast cancer, the NK3R antagonist Q-122 (100 mg, orally once daily) significantly improved VMS symptoms compared with placebo. Treatment-related adverse events were hot flashes, diarrhea, and urinary tract infection and were generally mild to moderate [55]. Another NK3R antagonist, fezolinetant (ESN364, 90 mg, twice daily), significantly reduced VMS scores and improved VMS severity and quality of life compared to placebo [56]. In a phase III trial of fezolinetant 30 mg or 45 mg once daily, there was a statistically significant reduction in hot flash frequency and severity compared to placebo, and the effect continued for 52 weeks. Most treatment-emergent adverse events were generally asymptomatic and transient and resolved during or after treatment discontinuation [57]. Because NK3R antagonists do not improve hot flashes by increasing estrogen secretion, they can be taken by women with a history of thrombosis or breast cancer, for whom estrogen is contraindicated.
Polycystic ovary syndromePatients with polycystic ovary syndrome (PCOS) have an elevated frequency of LH pulses. The LH elevation increases androgen production in ovarian theca cells [58, 59]. Studies have shown that the elevated androgens act on androgen receptors in KISS1 neurons in the hypothalamic infundibular nucleus, disrupting the negative feedback mechanism. Locally in the ovary, the KISS1/NKB system is also active in ovarian granulosa cells, and KISS1/KISS1R and NKB/NK3R expression have been reported to be reduced and follicle development impaired in patients with PCOS [60].
Although blood kisspeptin levels are higher in thin PCOS patients than in healthy controls [61], repeated 21-day subcutaneous administration of KP54 to 7 amenorrheic, rarely menstruating, PCOS patients resulted in a slight increase in blood LH levels in 5 of them. There was growth of a dominant follicle with subsequent ovulation in 2 patients; there was follicle growth but no ovulation in 1 patient; desensitization was observed in 1 patient; and no follicular response was detected in 1 patient [62]. Kisspeptin induces LH more strongly than FSH does. PCOS patients are not suitable for ovulation induction because of the high baseline LH and the risk of exacerbating the relative FSH deficiency.
Therefore, NK3R antagonists are expected to be new candidates for the treatment of PCOS. NKB and Kiss1 gene expression are increased in several animal models of PCOS, and it is thought that KNDy neuron hyperactivity may cause PCOS by enhancing GnRH pulses. Patients with PCOS who received the NK3R antagonist MLE4901 had significantly lower LH levels, LH pulse frequency, and a total testosterone area under the curve compared to the placebo group [63]. Patients with PCOS who also received the NK3R antagonist ESN364 had significantly lower LH and total testosterone levels, but their menstrual cycles did not recover [64]. These data suggest that treatment targeting KNDy neurons may produce favorable changes in biochemical biomarkers in PCOS patients but that the expected changes in symptoms may take time.
Although dynorphin has been studied in mouse models of PCOS, no studies to date have investigated its use in human patients with PCOS. In PCOS model mice, the sexual cycle is arrested. However, administration of a dynorphin receptor agonist difelikefalin restored the sexual cycle, induced ovulation, and reduced blood testosterone levels [65]. How dynorphin acts in the infundibular nucleus of the human brain remains unknown, but it could be a new therapeutic candidate for PCOS.
Hypoactive sexual desire disorderHyposexuality is caused by an imbalance between excitatory and inhibitory neural pathways in the prefrontal cortex and limbic system involved in the sexual response, leading to increased inhibition, lower excitement, and decreased responsiveness. It is a very common disorder with a prevalence of 10%–40% [66]. Serotonin receptor 5-HT1A agonists/5-HT2A antagonists and melanocortin 4 receptor agonists have been used, but their efficacy is limited by adverse events such as dizziness and nausea. Other neurotransmitters such as dopamine, noradrenaline, and oxytocin have been investigated as potential therapeutic candidates but have not shown clear efficacy. Therefore, the development of new therapeutic agents is awaited [67]. Several studies have suggested that Kiss1 neurons are involved in the control of sexual behavior. It has been reported that Kiss–/– female mice do not exhibit male selection or lordosis but recover after treatment with KP10 [68]. In addition, acute ablation of approximately 70% of kisspeptin neurons in the RP3V of adult female (OVX + E + P) mice also resulted in severe impairment of stooping behavior, which was restored with a single injection of KP10 [68]. Regarding the involvement of kisspeptin in sexual behavior, kisspeptin and Kiss-1R are expressed in the limbic system, which includes the amygdala, in rodents [69-71] and humans [6, 72] and are said to regulate emotional and sexual behavior [73]. Selective activation of kisspeptin innervation of the mouse posterodorsal medial amygdala also significantly increases the time that males spend investigating estrous females and the duration of social interactions [74]. Kisspeptin has been suggested to act on brain pathways that control male and female reproductive behavior in rodents [75, 76].
Based on the results of previous animal studies, the potential therapeutic efficacy of kisspeptin for the treatment of hypoactive sexual desire disorder (HSDD) has been investigated. The results showed that KP54 inactivated the left inferior and middle frontal gyri and activated the right post-central and supramarginal gyri in women. These two brain regions are associated with sexual interest. In addition, the right temporoparietal junction, a brain region associated with interest in attractive faces, was inactivated. In women with HSDD, administration of KP54 activated the hippocampus, an important brain region involved in female libido, during sexual videos [67]. This effect was also observed in men, suggesting that kisspeptin has potential as a treatment for HSDD.
PregnancyKisspeptin was first discovered in the placenta as an endogenous ligand for GPR54 [6]. In humans, the serum levels of kisspeptin increase rapidly during pregnancy [77]. Kisspeptin might be associated with placental trophoblast infiltration. Indeed, kisspeptin is expressed in placental syncytial trophoblasts, and its receptor is expressed on both cellular and syncytial trophoblasts in humans [78, 79]. Furthermore, KISS1 expression has been reported to be more abundant in placental trophoblast cells in early pregnancy than in mid-pregnancy [80].
Administration of gonadotropins and E2 to kisspeptin KO mice has been reported to result in infertility, although ovulation and fertilization are possible [81]. Leukemia inhibitory factor (LIF) is a cytokine required for implantation in mice, and LIF derived from the uterine gland induces embryo attachment and stromal cell dedifferentiation [82]. LIF to these kisspeptin KO mice restored implantation ability, suggesting that kisspeptin is a regulator of LIF and is an important factor for embryo implantation [81]. In addition, kisspeptin has been associated with maternal immune tolerance by decreasing placental matrix metalloproteinase activity, inhibiting trophoblast migration [80, 83], and increasing the differentiation of naive T cells into regulatory T cells [84]. Therefore, it is possible that low kisspeptin levels may reduce maternal immune tolerance and increase the risk of miscarriage.
These factors led to the investigation of kisspeptin as a biomarker for miscarriage. In normal pregnancies, blood kisspeptin levels increase linearly with the number of weeks of gestation but, in patients with miscarriages, blood kisspeptin levels are significantly lower than in normal pregnancies at all gestational ages. The combination of kisspeptin with blood hCG has been reported to improve diagnostic accuracy [85].
In preeclampsia, kisspeptin concentrations decrease, particularly in the first and second trimesters of pregnancy, and decrease further with increasing severity [84, 86]. In contrast, kisspeptin concentrations have been reported to increase in the third trimester of pregnancy in preeclampsia [87]. Other studies have reported that kisspeptin concentrations are consistently reduced in pregnancies with fetal growth restriction [87, 88]. Furthermore, blood kisspeptin levels were also reported to be higher in pregnant women with preterm delivery and lower in those with gestational diabetes mellitus [87]. Thus, blood kisspeptin levels may be a biomarker for miscarriage and obstetric complications.
The reproductive regulatory mechanisms of the HPG axis including kisspeptin and its clinical applications are shown in Fig. 2. Until recently, GnRH analogs and gonadotropins have been widely used as agents that act on the HPG axis. GnRH receptor agonists and antagonists are widely used in the treatment of sex hormone-dependent diseases as well as assisted reproductive medicine. Clomiphene, through a feedback mechanism in the HPG axis, and gonadotropin agents directly stimulate follicle and sperm formation [89, 90]. However, the discovery of kisspeptin has led to the development of drugs that modulate the HPG axis from further upstream of GnRH. Kisspeptin agonists are currently being evaluated for use in the diagnosis and treatment of gonadal disorders. Furthermore, the involvement of the Kiss-1 system in hot flashes and sexual desire has also become clear, expanding the potential for clinical application (Fig. 3). NKB receptor antagonists are potential new drugs for the treatment of hot flashes and PCOS, and kisspeptin are potential new drugs for the treatment of HSDD. The dynorphin receptor agonist difelikefalin is presently being developed for the treatment of pruritus. If the role of dynorphin in the HPG axis can be further elucidated, it is expected to be a future candidate for the treatment of reproductive disorders [91].
Reproductive regulatory mechanisms of the HPG axis including kisspeptin and its clinical applications
Gonadotropin-releasing hormone (GnRH) analogs and gonadotropins have been widely used as agents acting on the hypothalamic-pituitary-gonadal axis, but the discovery of kisspeptin has expanded the potential for clinical application.
Data on the use of the Dyn receptor agonist difelikefalin were obtained using PCOS mouse models.
A timeline of the major discoveries regarding kisspeptin
With the isolation of kisspeptin in 2001 and the 2003 reports of KISS1R mutations in families with congenital hypogonadism, the mechanism of reproductive regulation by kisspeptin is being elucidated. These discoveries led to the clinical application of kisspeptin and NKB.
The discovery of KISS1R mutations in human hypogonadal patients led to a major shift in reproductive endocrinology research. Numerous subsequent animal studies have revealed the physiological effects of kisspeptin on the HPG axis, leading to the elucidation of the human pathophysiology and the development of treatments. Further studies in humans and animals should be conducted to build on the previous research.
The authors report no conflicts of interest.
