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Context: Hyperprolactinemia suppresses gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) pulses. The hypothalamic neuropeptide kisspeptin potently stimulates the secretion of GnRH. The effects of exogenous kisspeptin administration on GnRH pulse generation in the setting of hyperprolactinemia have not previously been explored., Objective: This work aimed to examine the effects of kisspeptin on GnRH secretion, as reflected by LH secretion, in women with hyperprolactinemia., Methods: Women with hyperprolactinemia (n = 11) participated in two 12-hour visits. Before study visits, participants underwent washout of dopamine agonist and/or combined oral contraceptive. Frequent blood sampling was performed (1 sample was collected every 10 minutes). Visit 1 involved no intervention, to examine baseline LH pulsatility. During visit 2, kisspeptin 112-121 (0.24 nmol/kg) was administered every 1 hour, for 10 hours. At hour 11, one intravenous bolus of GnRH (75 ng/kg) was administered., Results: Repetitive intravenous bolus kisspeptin administration increased the total number of LH pulses in the setting of hyperprolactinemia. The interpulse interval declined during the same time frames. LH pulse amplitude did not change, but the mean LH rose. In 6 participants with progesterone levels suggestive of an anovulatory state, mean LH and estradiol levels increased significantly at visit 2. In the entire cohort, follicle-stimulating hormone and prolactin levels did not change significantly across the 2 visits. A total of 73% of subjects exhibited an LH pulse within 30 minutes of first kisspeptin dose., Conclusion: Kisspeptin is capable of stimulating hypothalamic GnRH-induced LH pulses in the setting of hyperprolactinemia., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Osteoporosis results from disturbances in bone formation and resorption. Recent nonhuman data suggest that the reproductive hormone kisspeptin directly stimulates osteoblast differentiation in vitro and thus could have clinical therapeutic potential. However, the effects of kisspeptin on human bone metabolism are currently unknown., Objective: To assess the effects of kisspeptin on human bone metabolism in vitro and in vivo., Methods: In vitro study: of Mono- and cocultures of human osteoblasts and osteoclasts treated with kisspeptin. Clinical study: Randomized, placebo-controlled, double-blind, 2-way crossover clinical study in 26 men investigating the effects of acute kisspeptin administration (90 minutes) on human bone metabolism, with blood sampling every 30 minutes to +90 minutes. Cells for the in vitro study were from 12 male blood donors and 8 patients undergoing hip replacement surgery. Twenty-six healthy eugonadal men (age 26.8 ± 5.8 years) were included in the clinical study. The intervention was Kisspeptin (vs placebo) administration. The main outcome measures were changes in bone parameters and turnover markers., Results: Incubation with kisspeptin in vitro increased alkaline phosphatase levels in human bone marrow mesenchymal stem cells by 41.1% (P = .0022), and robustly inhibited osteoclastic resorptive activity by up to 53.4% (P < .0001), in a dose-dependent manner. Kisspeptin administration to healthy men increased osteoblast activity, as evidenced by a 20.3% maximal increase in total osteocalcin (P = .021) and 24.3% maximal increase in carboxylated osteocalcin levels (P = .014)., Conclusion: Collectively, these data provide the first human evidence that kisspeptin promotes osteogenic differentiation of osteoblast progenitors and inhibits bone resorption in vitro. Furthermore, kisspeptin acutely increases the bone formation marker osteocalcin but not resorption markers in healthy men, independent of downstream sex steroid levels. Kisspeptin could therefore have clinical therapeutic application in the treatment of osteoporosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: The hormone kisspeptin has crucial and well-characterized roles in reproduction. Emerging data from animal models also suggest that kisspeptin has important metabolic effects including modulation of food intake. However, to date there have been no studies exploring the effects of kisspeptin on brain responses to food stimuli in humans., Objective: This work aims to investigate the effects of kisspeptin administration on brain responses to visual food stimuli and psychometric parameters of appetite, in healthy men., Design: A double-blinded, randomized, placebo-controlled, crossover study was conducted., Participants: Participants included 27 healthy, right-handed, eugonadal men (mean ± SEM: age 26.5 ± 1.1 years; body mass index 23.9 ± 0.4 kg/m2)., Intervention: Participants received an intravenous infusion of 1 nmol/kg/h of kisspeptin or rate-matched vehicle over 75 minutes., Main Outcome Measures: Measurements included change in brain activity on functional magnetic resonance imaging in response to visual food stimuli and change in psychometric parameters of appetite, during kisspeptin administration compared to vehicle., Results: Kisspeptin administration at a bioactive dose did not affect brain responses to visual food stimuli or psychometric parameters of appetite compared to vehicle., Conclusions: This is the first study in humans investigating the effects of kisspeptin on brain regions regulating appetite and demonstrates that peripheral administration of kisspeptin does not alter brain responses to visual food stimuli or psychometric parameters of appetite in healthy men. These data provide key translational insights to further our understanding of the interaction between reproduction and metabolism., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Kisspeptin stimulates the reproductive endocrine cascade in both men and women. Circulating sex steroids are thought to modulate the ability of kisspeptin to stimulate gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) release., Objective: To probe the effects of sex steroids on kisspeptin-stimulated GnRH-induced LH pulses., Participants: Eight healthy postmenopausal women., Intervention: Subjects underwent every-10-minute blood sampling to measure GnRH-induced LH secretion at baseline and in response to a continuous kisspeptin infusion (12.5 µg/kg/h) over 24 hours. A subset of the participants also received kisspeptin (0.313 µg/kg) and GnRH (75 ng/kg) intravenous boluses., Results: Postmenopausal women are resistant to the stimulatory effect of continuous kisspeptin on LH secretion. Postmenopausal women receiving estradiol replacement therapy are also resistant to kisspeptin initially, but they demonstrate a significant increase in LH pulse amplitude in direct proportion to the circulating estradiol concentration and duration of kisspeptin administration., Conclusions: Kisspeptin administration has complex effects on GnRH, and by extension, on LH secretion. The ability of kisspeptin to affect LH secretion can be modulated by the ambient sex-steroid milieu in a time- and dose-dependent manner., (Copyright © 2017 Endocrine Society)

Context: Kisspeptin and neurokinin B (NKB) are obligate for normal gonadotropin secretion, but their hierarchy is unexplored in normal women., Objective: To investigate the interaction between kisspeptin and NKB on estrogen-regulated LH secretion., Design: Women were treated with neurokinin-3 receptor (NK3R) antagonist followed by transdermal estradiol to induce LH secretion 48 hours later, with kisspeptin-10 or vehicle infusion during estrogen administration in a 2-way crossover study., Setting: Clinical research facility., Patients or Other Participants: Healthy females with regular menses., Intervention(s): NK3R antagonist AZD4901 40 mg twice daily orally was taken from cycle day 4-6 for 6 days (n = 10, with 10 no treatment controls). Transdermal estradiol patches (200 μg/d) were applied after 5 days of NK3R antagonist treatment. At 24-hour estradiol treatment, women were randomized to 7-hour kisspeptin-10 (4 μg/kg/h) or vehicle iv infusion, with the alternate infusion in a subsequent cycle., Main Outcome Measure(s): Plasma gonadotropin and estradiol secretion., Results: After an initial suppression, LH secretion was increased 48 hours after estradiol treatment. Kisspeptin-10 increased LH secretion during the inhibitory phase, and LH remained elevated beyond the discontinuation of kisspeptin-10 infusion. NK3R antagonist decreased LH pulse frequency (0.5 ± 0.2 vs 0.7 ± 0.2 pulses/h, P < .05) and stimulated FSH response to kisspeptin-10 infusion (10.7 ± 11.0 vs 5.0 ± 3.6 IU/L, P < .05) with a nonsignificant rise in LH. The duration of LH response was blunted, with LH being lower at 48 hours (7.5 ± 4.8 vs 15.0 ± 11.4 IU/L, P < .05)., Conclusions: These data demonstrate that NKB signaling regulates GnRH/LH secretion in normal women, and is predominantly proximal to kisspeptin in mediating estrogenic positive and negative feedback on LH secretion.

Context: Some patients with idiopathic hypogonadotropic hypogonadism (IHH) undergo spontaneous activation of their hypothalamic-pituitary-gonadal axis resulting in normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal., Objective: To assess the responsiveness of the GnRH neuronal network to exogenous kisspeptin administration in IHH patients who have undergone reversal., Participants: Six men with congenital IHH and evidence for reversal., Intervention: Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to iv boluses of kisspeptin (0.24-2.4 nmol/kg) and GnRH (75 ng/kg)., Results: Individuals with sustained reversal of their hypogonadotropism (spontaneous LH pulses) responded to exogenous kisspeptin with a GnRH-induced LH pulse. Individuals who had reversal but then subsequently suffered relapse of their IHH (loss of spontaneous LH pulsatility) did not respond to kisspeptin., Conclusions: The ability of kisspeptin to stimulate a GnRH-induced LH pulse correlates with the presence of endogenous LH pulses. These data suggest that reversal of hypogonadotropism, and by extension sexual maturation, may be due to the acquisition of kisspeptin responsiveness.

Context: Kisspeptin is the most powerful known stimulus of GnRH-induced LH secretion across mammalian species. However, the effects of kisspeptin are just being explored, and the dynamics of kisspeptin responsiveness across the menstrual cycle are incompletely understood., Objective: The objective of the study was to characterize the effects of kisspeptin on GnRH secretion in healthy women in different phases of the menstrual cycle., Participants and Intervention: Ten women in the early follicular phase, three women in the late follicular (preovulatory) phase, and 14 women in the midluteal phase received a bolus of kisspeptin 112-121 0.24 nmol/kg iv. An additional four women in the early to midfollicular phase received kisspeptin 112-121 0.72 nmol/kg iv., Results: The response to kisspeptin varied depending on the phase of the menstrual cycle. LH pulses were observed immediately after kisspeptin administration in all luteal and preovulatory women. However, only half the women in the early follicular phase had unambiguous kisspeptin responses. Increasing the kisspeptin dose did not increase the LH response in early to midfollicular phase women. Kisspeptin did not appear to reset the GnRH pulse generator in women as it does in men., Conclusions: Differences in responses to exogenous kisspeptin across the menstrual cycle suggest that kisspeptin tone is higher in the early follicular phase compared with other cycle phases. The mechanisms that determine the timing of GnRH pulse generation in men and women appear to be distinct.

Background: Kisspeptin peptides are critical in human reproductive physiology and are potential therapies for infertility. Kisspeptin-10 stimulates gonadotropin release in both male and female rodents. However, few studies have investigated the effects of kisspeptin-10 on gonadotropin release in humans, and none have investigated the effect in women. If kisspeptin is to be useful for treating reproductive disease, its effects in both men and women must be established., Aim: To compare the effects of kisspeptin-10 administration on reproductive hormone release in healthy men and women., Methods: Intravenous bolus kisspeptin-10 was administered to men and women (n = 4-5 per group). Subcutaneous bolus and i.v. infusion of kisspeptin-10 was also administered to female women (n = 4-5 per group). Circulating reproductive hormones were measured., Results: In healthy men, serum LH and FSH were elevated after i.v. bolus kisspeptin-10, at doses as low as 0.3 and 1.0 nmol/kg, respectively. In healthy women during the follicular phase of the menstrual cycle, no alterations in serum gonadotropins were observed after i.v. bolus, s.c. bolus, or i.v. infusion of kisspeptin-10 at maximal doses of 10 nmol/kg, 32 nmol/kg, and 720 pmol/kg/min, respectively. In women during the preovulatory phase, serum LH and FSH were elevated after i.v. bolus kisspeptin-10 (10 nmol/kg)., Conclusion: Kisspeptin-10 stimulates gonadotropin release in men as well as women during the preovulatory phase of menstrual cycle but fails to stimulate gonadotropin release in women during the follicular phase. The sexual dimorphism of the responsiveness of healthy men and women to kisspeptin-10 administration has important clinical implications for the potential of kisspeptin-10 to treat disorders of reproduction.