Acute Effects of Glucagon on Reproductive Hormone Secretion in Healthy Men

Abstract Context Glucagon increases energy expenditure; consequently, glucagon receptor agonists are in development for the treatment of obesity. Obesity negatively affects the reproductive axis, and hypogonadism itself can exacerbate weight gain. Therefore, knowledge of the effects of glucagon receptor agonism on reproductive hormones is important for developing therapeutics for obesity; but reports in the literature about the effects of glucagon receptor agonism on the reproductive axis are conflicting. Objective The objective of this work is to investigate the effect of glucagon administration on reproductive hormone secretion in healthy young men. Design A single-blinded, randomized, placebo-controlled crossover study was conducted. Setting The setting of this study was the Clinical Research Facility, Imperial College Healthcare NHS Trust. Participants Eighteen healthy eugonadal men (mean ± SEM: age 25.1 ± 1.0 years; body mass index 22.5 ± 0.4 kg/m2; testosterone 21.2 ± 1.2 nmol/L) participated in this study. Intervention An 8-hour intravenous infusion of 2 pmol/kg/min glucagon or rate-matched vehicle infusion was administered. Main Outcome Measures Luteinizing hormone (LH) pulsatility; LH, follicle-stimulating hormone (FSH), and testosterone levels were measured. Results Although glucagon administration induced metabolic effects (insulin area under the curve: vehicle 1065 ± 292 min.µU/mL vs glucagon 2098 ± 358 min.µU/mL, P < .001), it did not affect LH pulsatility (number of LH pulses/500 min: vehicle 4.7 ± 0.4, glucagon 4.2 ± 0.4, P = .22). Additionally, there were no significant differences in circulating LH, FSH, or testosterone levels during glucagon administration compared with vehicle administration. Conclusions Acute administration of a metabolically active dose of glucagon does not alter reproductive hormone secretion in healthy men. These data are important for the continued development of glucagon-based treatments for obesity.

Download Full-text

Elinzanetant (NT-814), a Neurokinin 1,3 Receptor Antagonist, Reduces Estradiol and Progesterone in Healthy Women

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab108 ◽

2021 ◽

Author(s):

Steve Pawsey ◽

Edouard Gregory Mills ◽

Elizabeth Ballantyne ◽

Kirsteen Donaldson ◽

Mary Kerr ◽

...

Keyword(s):

Luteal Phase ◽

Hormone Secretion ◽

Reproductive Hormones ◽

Controlled Study ◽

Vasomotor Symptoms ◽

Reproductive Hormone ◽

Novel Therapy ◽

Serum Progesterone ◽

Hormone Levels ◽

Healthy Women

Abstract Context The ideal therapy for endometriosis (EM) and uterine fibroids (UF) would suppress estrogenic drive to the endometrium and myometrium, whilst minimizing vasomotor symptoms and bone loss associated with current treatments. An integrated neurokinin-kisspeptin system involving Substance P and neurokinin B acting at the neurokinin (NK) receptors 1 and 3, respectively, modulates reproductive hormone secretion and represents a therapeutic target. Objective To assess the effects of the novel NK1,3 antagonist elinzanetant on reproductive hormone levels in healthy women. Design Randomized, single-blinded, placebo-controlled study. Participants/Intervention Thirty-three women attended for 2 consecutive menstrual cycles. In each cycle blood samples were taken on days 3/4, 9/10, 15/16 and 21/22 to measure serum reproductive hormones. In cycle 2, women were randomized to receive once daily oral elinzanetant 40, 80, 120 mg or placebo (N=8 or 9 per group). Results Elinzanetant dose-dependently lowered serum luteinizing hormone, estradiol (120 mg median change across cycle: -141.4 pmol/L, P=0.038) and luteal phase progesterone (120 mg change from baseline on day 21/22: -19.400 nmol/L, P=0.046). Elinzanetant 120 mg prolonged the cycle length by median of 7.0 days (P=0.023). Elinzanetant reduced the proportion of women with a luteal phase serum progesterone concentration >30 nmol/L (a concentration consistent with ovulation) in a dose-related manner in cycle 2 (P=0.002). Treatment did not produce vasomotor symptoms. Conclusions NK1,3 receptor antagonism with elinzanetant dose-dependently suppressed the reproductive axis in healthy women, with the 120 mg dose lowering estradiol to potentially ideal levels for UF and EM. As such, elinzanetant may represent a novel therapy to manipulate reproductive hormone levels in women with hormone driven disorders.

Download Full-text

Effects of Glucagon-like Peptide-1 on the Reproductive Axis in Healthy Men

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa072 ◽

2020 ◽

Vol 105 (4) ◽

pp. 1119-1125 ◽

Cited By ~ 1

Author(s):

Chioma Izzi-Engbeaya ◽

Sophie Jones ◽

Yoshibye Crustna ◽

Pratibha C Machenahalli ◽

Deborah Papadopoulou ◽

...

Keyword(s):

Food Intake ◽

Follicle Stimulating Hormone ◽

Hormone Secretion ◽

Area Under The Curve ◽

Healthy Men ◽

Reproductive Axis ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Glucose Stimulated Insulin Secretion ◽

Stimulating Hormone

Abstract Context Glucagon-like peptide-1 (GLP-1) potently reduces food intake and augments glucose-stimulated insulin secretion. Recent animal data suggest that GLP-1 may also influence reproduction. As GLP-1 receptor agonists are currently widely used in clinical practice to treat obesity/type 2 diabetes, it is necessary to determine the effects of GLP-1 on the reproductive system in humans. Objective To investigate the effects of GLP-1 administration on the reproductive axis in humans. Design Single-blind, randomized, placebo-controlled crossover study. Setting Clinical Research Facility, Imperial College Healthcare NHS Trust. Participants Eighteen healthy men (mean age 24.7 ± 0.1years, mean BMI 22.1 ± 0.4kg/m2). Intervention Eight-hour intravenous infusion of 0.8 pmol/kg/min GLP-1 or rate-matched vehicle infusion. Main Outcome Measures Number of luteinizing hormone (LH) pulses, LH, follicle-stimulating hormone (FSH), and testosterone levels. Results The number of LH pulses (number of LH pulses/500 min: vehicle 4.2 ± 0.4, GLP-1 4.5 ± 0.3, P = 0.46), LH area under the curve (AUC) (vehicle 1518 ± 88min.IU/L, GLP-1 1524 ± 101min.IU/L, P = 0.95), follicle-stimulating hormone AUC (vehicle 1210 ± 112 min IU/L, GLP-1 1216 ± 112 min IU/L, P = 0.86), and testosterone AUC (vehicle 10893 ± 615 min nmol/L, GLP-1 11088 ± 792 min nmol/L, P = 0.77) did not significantly differ during vehicle and GLP-1 administration. Glucagon-like peptide-1 significantly reduced food intake (vehicle 15.7 ± 1.3 kcal/kg, GLP-1 13.4 ± 1.3 kcal/kg, P = 0.01). Conclusions In contrast to the animal literature, our data demonstrate that acute GLP-1 administration does not affect reproductive hormone secretion in healthy men.

Download Full-text

Clinical effects of kisspeptin on reproductive hormone secretion, LH pulsatility and oocyte maturation

Endocrine Abstracts ◽

10.1530/endoabs.34.yep1.2 ◽

2014 ◽

Author(s):

Channa Jayasena ◽

Ali Abbara ◽

Alexander Comninos ◽

Gurjinder Nijher ◽

Johannes Veldhuis ◽

...

Keyword(s):

Oocyte Maturation ◽

Hormone Secretion ◽

Clinical Effects ◽

Reproductive Hormone ◽

Lh Pulsatility

Download Full-text

Patterns of reproductive hormone secretion in hibernating Turkish hamsters

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1987.253.2.r329 ◽

1987 ◽

Vol 253 (2) ◽

pp. R329-R336 ◽

Cited By ~ 2

Author(s):

J. M. Darrow ◽

L. Yogev ◽

B. D. Goldman

Keyword(s):

Temporal Pattern ◽

Follicle Stimulating Hormone ◽

Hormone Secretion ◽

Winter Season ◽

Reproductive Hormones ◽

Reproductive Hormone ◽

Hormone Levels ◽

Short Day ◽

Testicular Recrudescence ◽

Testicular Size

Changes in gonadal state and in circulating reproductive hormones [follicle-stimulating hormone (FSH), prolactin (PRL), and testosterone] were studied for 30 wk in male Turkish hamsters (Mesocricetus brandti) induced to hibernate by exposure to a short-day, cold environment [10:14-h light-dark (LD) cycle, 6 +/- 1 degree C]. Similar measures were compared in hamsters maintained under short-day warm conditions (10:14-h LD, 21 +/- 2 degrees C). A decrease in testicular size and in hormone levels was observed after 9-12 wk of short-day exposure in all animals. After 24 wk, hormone levels rose again, accompanied by testicular recrudescence, in short-day warm hamsters and in hamsters that failed to hibernate in the cold. For animals that hibernated the temporal pattern of endocrine and gonadal changes differed only slightly in comparison. Testicular recrudescence of hibernators lagged approximately 3 wk behind that of short-day warm hamsters. Hormone levels were generally lower in hibernators sampled during bouts of torpor than during bouts of spontaneous arousal from torpor. A marked elevation of serum FSH was observed in aroused hibernators well before the end of the hibernation season (at 21 wk of short-day exposure). Mean testosterone and PRL values had increased by wk 27, after hibernation was terminated in the majority of animals. These results indicate that testosterone may not be essential for the termination of the hibernation season. The data also suggest that an endogenous timing mechanism, resistant to the decreased body temperature experienced during torpor, may function to trigger a resurgence of the neuroendocrine-gonadal axis at the end of the winter season.

Download Full-text

Intranasal Kisspeptin Administration Stimulates Reproductive Hormone Secretion in Healthy Men

Endocrine Abstracts ◽

10.1530/endoabs.77.oc1.4 ◽

2021 ◽

Author(s):

Edouard G Mills ◽

Magda Swedrowska ◽

Layla Thurston ◽

Maria Phylactou ◽

Bijal Patel ◽

...

Keyword(s):

Hormone Secretion ◽

Reproductive Hormone ◽

Healthy Men

Download Full-text

Kisspeptin and the control of emotions, mood and reproductive behaviour

Journal of Endocrinology ◽

10.1530/joe-18-0269 ◽

2018 ◽

Vol 239 (1) ◽

pp. R1-R12 ◽

Cited By ~ 8

Author(s):

Edouard G A Mills ◽

Waljit S Dhillo ◽

Alexander N Comninos

Keyword(s):

Reproductive Behaviour ◽

Brain Regions ◽

Positive Influence ◽

Reproductive Hormones ◽

Reproductive Hormone ◽

Partner Preference ◽

Reproductive Axis ◽

Gonadotrophin Releasing Hormone ◽

Copulatory Behaviour

Reproduction is fundamental for the survival of all species and requires meticulous synchronisation of a diverse complement of neural, endocrine and related behaviours. The reproductive hormone kisspeptin (encoded by the KISS1/Kiss1 gene) is now a well-established orchestrator of reproductive hormones, acting upstream of gonadotrophin-releasing hormone (GnRH) at the apex of the hypothalamic–pituitary–gonadal (HPG) reproductive axis. Beyond the hypothalamus, kisspeptin is also expressed in limbic and paralimbic brain regions, which are areas of the neurobiological network implicated in sexual and emotional behaviours. We are now forming a more comprehensive appreciation of extra-hypothalamic kisspeptin signalling and the complex role of kisspeptin as an upstream mediator of reproductive behaviours, including olfactory-driven partner preference, copulatory behaviour, audition, mood and emotion. An increasing body of research from zebrafish to humans has implicated kisspeptin in the integration of reproductive hormones with an overall positive influence on these reproductive behaviours. In this review, we critically appraise the current literature regarding kisspeptin and its control of reproductive behaviour. Collectively, these data significantly enhance our understanding of the integration of reproductive hormones and behaviour and provide the foundation for kisspeptin-based therapies to treat related disorders of body and mind.

Download Full-text

The Roles of the Amygdala Kisspeptin System

Seminars in Reproductive Medicine ◽

10.1055/s-0039-3400462 ◽

2019 ◽

Vol 37 (02) ◽

pp. 064-070 ◽

Cited By ~ 1

Author(s):

Edouard G. A. Mills ◽

Kevin T. O'Byrne ◽

Alexander N. Comninos

Keyword(s):

Pubertal Timing ◽

Hormone Secretion ◽

Reproductive Physiology ◽

Receptor Expression ◽

Reproductive Hormone ◽

Cognate Receptor ◽

Reproductive Axis ◽

Reproductive Neuroendocrinology ◽

Potential Use

AbstractThe hypothalamic hormone kisspeptin (encoded by the KISS1/kiss1 gene) is the master regulator of the reproductive axis with its role in controlling gonadotrophin hormone secretion now well characterized. However, identification of kisspeptin and its cognate receptor expression within the amygdala, a key limbic brain region whose functions contribute to a broad range of physiological and behavioral processes, has heightened interest concerning kisspeptins' role in the broader aspects of reproductive physiology. In this review, we detail the important developments and key studies examining the emerging functions of this kisspeptin population. These studies provide novel advances in our understanding of the mechanisms controlling reproductive neuroendocrinology by defining the crucial role of the amygdala kisspeptin system in modulating pubertal timing, reproductive hormone secretion, and pulsatility, as well as its influence in governing-related behaviors. To this end, the role of the amygdala kisspeptin system in integrating reproductive hormone secretion with behavior sheds new light onto the potential use of kisspeptin-based therapeutics for reproductive and related psychosexual disorders.

Download Full-text

The Effects of Kisspeptin-10 on Reproductive Hormone Release Show Sexual Dimorphism in Humans

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2011-1408 ◽

2011 ◽

Vol 96 (12) ◽

pp. E1963-E1972 ◽

Cited By ~ 63

Author(s):

Channa N. Jayasena ◽

Gurjinder M. K. Nijher ◽

Alexander N. Comninos ◽

Ali Abbara ◽

Adam Januszewki ◽

...

Keyword(s):

Sexual Dimorphism ◽

Menstrual Cycle ◽

Reproductive Hormones ◽

Follicular Phase ◽

Reproductive Hormone ◽

Hormone Release ◽

Men And Women ◽

Healthy Men ◽

Gonadotropin Release ◽

Serum Lh

Abstract 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 iv 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 iv 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 iv bolus, sc bolus, or iv infusion of kisspeptin-10 at maximal doses of 10 nmol/kg, 32 nmol/kg, and 720pmol/kg/min, respectively. In women during the preovulatory phase, serum LH and FSH were elevated after iv 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.

Download Full-text