Johannes D. Veldhuis’s research while affiliated with Mayo Clinic - Rochester and other places

The hypothalamus is the central regulator of reproductive hormone secretion. Pulsatile secretion of gonadotropin releasing hormone (GnRH) is fundamental to physiological stimulation of the pituitary gland to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). Furthermore, GnRH pulsatility is altered in common reproductive disorders such as polycystic ovary syndrome (PCOS) and hypothalamic amenorrhea (HA). LH is measured routinely in clinical practice using an automated chemiluminescent immunoassay method and is the gold standard surrogate marker of GnRH. LH can be measured at frequent intervals (e.g., 10 minutely) to assess GnRH/LH pulsatility. However, this is rarely done in clinical practice because it is resource intensive, and there is no open-access, graphical interface software for computational analysis of the LH data available to clinicians. Here we present hormoneBayes, a novel open-access Bayesian framework that can be easily applied to reliably analyze serial LH measurements to assess LH pulsatility. The framework utilizes parsimonious models to simulate hypothalamic signals that drive LH dynamics, together with state-of-the-art (sequential) Monte-Carlo methods to infer key parameters and latent hypothalamic dynamics. We show that this method provides estimates for key pulse parameters including inter-pulse interval, secretion and clearance rates and identifies LH pulses in line with the widely used deconvolution method. We show that these parameters can distinguish LH pulsatility in different clinical contexts including in reproductive health and disease in men and women (e.g., healthy men, healthy women before and after menopause, women with HA or PCOS). A further advantage of hormoneBayes is that our mathematical approach provides a quantified estimation of uncertainty. Our framework will complement methods enabling real-time in-vivo hormone monitoring and therefore has the potential to assist translation of personalized, data-driven, clinical care of patients presenting with conditions of reproductive hormone dysfunction.

The hypothalamus is the central regulator of reproductive hormone secretion. Pulsatile secretion of gonadotropin releasing hormone (GnRH) is fundamental to physiological stimulation of the pituitary gland to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). Furthermore, GnRH pulsatility is altered in common reproductive disorders such as polycystic ovary syndrome (PCOS) and hypothalamic amenorrhea (HA). LH is measured routinely in clinical practice using an automated chemiluminescent immunoassay method and is the gold standard surrogate marker of GnRH. LH can be measured at frequent intervals (e. g., 10 minutely) to assess GnRH/LH pulsatility. However, this is rarely done in clinical practice because it is resource intensive, and there is no user-friendly and accessible method for computational analysis of the LH data available to clinicians. Here we present hormoneBayes, a novel open-access Bayesian framework that can be easily applied to reliably analyze serial LH measurements to assess LH pulsatility. The framework utilizes parsimonious models to simulate hypothalamic signals that drive LH dynamics, together with state-of-the-art (sequential) Monte-Carlo methods to infer key parameters and latent hypothalamic dynamics. We show that this method provides estimates for key pulse parameters including inter-pulse interval, secretion and clearance rates and identifies LH pulses in line with the current gold-standard deconvolution method. We show that these parameters can distinguish LH pulsatility in different clinical contexts including in reproductive health and disease in men and women (e. g., healthy men, healthy women before and after menopause, women with HA or PCOS). A further advantage of hormoneBayes is that our mathematical approach provides a quantified estimation of uncertainty. Our framework will complement methods enabling real-time in-vivo hormone monitoring and therefore has the potential to assist translation of personalized, data-driven, clinical care of patients presenting with conditions of reproductive hormone dysfunction. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

The hypothalamus is the central regulator of reproductive hormone secretion. Pulsatile secretion of gonadotropin-releasing hormone (GnRH) is fundamental to physiological stimulation of the pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Furthermore, GnRH pulsatility is altered in common reproductive disorders such as polycystic ovary syndrome (PCOS) and hypothalamic amenorrhea (HA). LH is measured routinely in clinical practice using an automated chemiluminescent immunoassay method and is the gold standard surrogate marker of GnRH. LH can be measured at frequent intervals (e.g., 10 minutely) to assess GnRH/LH pulsatility. However, this is rarely done in clinical practice because it is resource-intensive, and there is no user-friendly and accessible method for computational analysis of the LH data available to clinicians. Here we present hormoneBayes, a novel open-access Bayesian framework that can be easily applied to reliably analyze serial LH measurements to assess LH pulsatility. The framework utilizes parsimonious models to simulate hypothalamic signals that drive LH dynamics, together with state-of-the-art (sequential) Monte-Carlo methods to infer key parameters and latent hypothalamic dynamics. We show that this method provides estimates for key pulse parameters including inter-pulse interval, secretion and clearance rates and identifies LH pulses in line with the current gold-standard deconvolution method. We show that these parameters can distinguish LH pulsatility in different clinical contexts including in reproductive health and disease in men and women (e.g., healthy men, healthy women before and after menopause, women with HA or PCOS). A further advantage of hormoneBayes is that our mathematical approach provides a quantified estimation of uncertainty. Our framework will complement methods enabling real-time in-vivo hormone monitoring and therefore has the potential to assist the translation of personalized, data-driven, clinical care of patients presenting with conditions of reproductive hormone dysfunction.

Study question: What is the role of the hypothalamic neuropeptide neurokinin B (NKB) and its interaction with kisspeptin on GnRH/LH secretion in women with polycystic ovary syndrome (PCOS)? Summary answer: Administration of neurokinin 3 receptor antagonist (NK3Ra) for 7 days reduced LH and FSH secretion and LH pulse frequency in women with PCOS, whilst the stimulatory LH response to kisspeptin-10 was maintained. What is known already: PCOS is characterized by abnormal GnRH/LH secretion. NKB and kisspeptin are master regulators of GnRH/LH secretion, but their role in PCOS is unclear. Study design, size, duration: The NK3Ra MLE4901, 40 mg orally twice a day, was administered to women with PCOS for 7 days (n = 8) (vs no treatment, n = 7). On the last day of NK3Ra administration or the equivalent day in those not treated, women were randomized to 7-h kisspeptin-10 (4 µg/kg/h i.v.) or vehicle infusion. This was repeated with the alternate infusion in a subsequent cycle. Participants/materials, setting, methods: Subjects were women with PCOS, studied in a Clinical Research Facility. Reproductive hormones were measured before and after NK3Ra administration. On the last day of NK3Ra administration (or the equivalent cycle day in untreated women), all women attended for an 8-h frequent blood sampling to allow analysis of the pulsatile LH secretion. Main results and the role of chance: NK3Ra reduced LH secretion (4.0 ± 0.4 vs 6.5 ± 0.8 IU/l, P < 0.05) and pulse frequency (0.5 ± 0.1 vs 0.8 ± 0.1 pulses/h, P < 0.05); FSH secretion was also reduced (2.0 ± 0.3 vs 2.5 ± 0.4 IU/l, P < 0.05). Without NK3Ra pre-treatment, kisspeptin-10 increased LH secretion (5.2 ± 0.5 to 7.8 ± 1.0 IU/L, P < 0.05), with a positive relationship to oestradiol concentrations (r2 = 0.59, P < 0.05). After NK3Ra administration, the LH response to kisspeptin-10 was preserved (vehicle 3.5 ± 0.3 vs 9.0 ± 2.2 IU/l with kisspeptin-10, P < 0.05), but the positive correlation with oestradiol concentrations was abolished (r2 = 0.07, ns. after NK3Ra). FSH secretion was increased by kisspeptin-10 after NK3Ra treatment, but not without NK3Ra treatment. Limitations, reasons for caution: The study did not explore the dose relationship of the effect of NK3R antagonism. The impact of obesity or other aspects of the variability of the PCOS phenotype was not studied due to the small number of subjects. Wider implications of the findings: These data demonstrate the interactive regulation of GnRH/LH secretion by NKB and kisspeptin in PCOS, and that the NKB system mediates aspects of oestrogenic feedback. Study funding/competing interest(s): Wellcome Trust through Scottish Translational Medicine and Therapeutics Initiative (102419/Z/13/A) and MRC grants (G0701682 to R.P.M. and R.A.A.) and MR/N022556/1 to the MRC Centre for Reproductive Health. This work was performed within the Edinburgh Clinical Research Facility. J.T.G. has undertaken consultancy work for AstraZeneca and Takeda Pharmaceuticals and is an employee of Boehringer Ingelheim. R.P.M. has consulted for Ogeda and was CEO of Peptocrine. R.A.A. has undertaken consultancy work for Merck, Ferring, NeRRe Therapeutics and Sojournix Inc. J.D.V. and K.S. have nothing to disclose. Trial registration number: N/A.

The well-documented hormonal disturbance in a general obese population is characterised by an increase in insulin secretion and a decrease in growth hormone (GH) secretion. Such hormonal disturbance promotes an increase in fat mass, which deteriorates obesity and accelerates the development of insulin resistance and type 2 diabetes. While the pathological consequence is alarming, the pharmaceutical approach attempting to correct such hormonal disturbance remains limited. By applying an emerging anti-diabetic drug, the sodium-glucose cotransporter 2 inhibitor, dapagliflozin (1mg/kg/day for 10 weeks), to a hyperphagic obese mouse model, we observed a significant improvement in insulin and GH secretion as early as 4 weeks after the initiation of the treatment. Restoration of pathological disturbance of insulin and GH secretion reduced fat accumulation and preserved lean body mass in the obese animal model. Such phenotypic improvement followed with concurrent improvements in glucose and lipid metabolism, insulin sensitivity, as well as the expression of metabolic genes that were regulated by insulin and GH. In conclusion, 10 weeks of treatment with dapagliflozin effectively reduces hyperinsulinemia and restores pulsatile GH secretion in the hyperphagic obese mice with considerable improvement in lipid and glucose metabolism. Promising outcomes from this study may provide insights into drug intervention to correct hormonal disturbance in obesity to delay the diabetes progression.

Context Glucagon increases energy expenditure; consequently, glucagon receptor agonists are in development for the treatment of obesity. Obesity negatively impacts 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 To investigate the effect of glucagon administration on reproductive hormone secretion in healthy young men. Design Single-blinded, randomized, placebo-controlled crossover study. Setting Clinical Research Facility, Imperial College Healthcare NHS Trust. Participants Eighteen healthy eugonadal men (mean±SEM: age 25.1±1.0years; BMI 22.5±0.4kg/m2; testosterone 21.2±1.2nmol/L). Intervention Eight-hour intravenous infusion of 2pmol/kg/min glucagon or rate-matched vehicle infusion. Main Outcome Measures Luteinizing hormone (LH) pulsatility; LH, follicle stimulating hormone (FSH) and testosterone levels. Results Although glucagon administration induced metabolic effects (insulin AUC: vehicle 1065±292min.µU/mL vs glucagon 2098±358min.µU/mL, p<0.0001), it did not affect LH pulsatility (number of LH pulses/500min: vehicle 4.7±0.4, glucagon 4.2±0.4, p=0.22). 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.

Circulating growth hormone (GH) concentrations increase during pregnancy in mice and remain pituitary-derived. Whether abundance or activation of the GH secretagogue, ghrelin increase during pregnancy or in response to dietary octanoic acid supplementation are unclear. We therefore measured circulating GH profiles in late pregnant C57BL/6J mice and in aged-matched non-pregnant females, fed standard laboratory chow supplemented with 5% octanoic or palmitic (control) acid (n=4-13/group). Serum total and acyl-ghrelin concentrations, stomach and placenta ghrelin mRNA and protein expression, Pcsk1 (encoding prohormone convertase 1/3) and Mboat4 (membrane bound O-acyl transferase 4) mRNA were determined at zeitgeber (ZT) 13 and ZT23. Total and basal GH secretion were higher in late pregnant than non-pregnant mice (P<0.001), regardless of diet. At ZT13, serum concentrations of total (P=0.004), but not acyl-ghrelin, and the density of ghrelin-positive cells in the gastric antrum (P=0.019) were higher, and gastric Mboat4 and Pcsk1 mRNA expression were lower in pregnant than non-pregnant mice at ZT23. In the placenta, ghrelin protein was localised mostly to labyrinthine trophoblast cells. Serum acyl-, but not total, ghrelin was lower at mid-pregnancy than in non-pregnant mice, but not different at early or late pregnancy. In conclusion, dietary supplementation with 5% octanoic acid did not increase activation of ghrelin in female mice. Our results further suggest that increases in maternal GH secretion throughout murine pregnancy are not due to circulating acyl-ghrelin acting at the pituitary. Nevertheless, time-dependent increased circulating total ghrelin could potentially increase ghrelin action in tissues that express the acylating enzyme and receptor.

The impact of chronic training on pituitary function is best understood by a basic appraisal of the neuroendocrine physiology of any given individual axis and the more complex interactive pathophysiology among axes. Interaxes interactions have received relatively little attention. Even evaluating a single neuroendocrine axis in its dynamic state is a complicated challenge, given combined feedforward and feedback activities among the key control loci within any given axis. For example, in the case of the growth hormone (GH) and insulin-like growth factor 1 (IGF-1) axis, hypothalamic GH-releasing hormone (GHRH) secreted by arcuate nuclei stimulates pituitary GH secretion acutely, whereas the somatostatinergic system originating in the paraventricular nuclei opposes GHRH action. These two neuronal inputs are reciprocally interconnected by intrahypothalamic synapses and common impinging neuromodulator pathways. In addition, secreted GH feeds back on brain GH receptors, stimulating somatostatin secretion and possibly inhibiting GHRH release. Available GH secreted into the bloodstream triggers IGF-1 production in various target tissues, and circulating IGF-1 is capable of inhibiting pituitary GH secretion indirectly and directly. Such feedforward (GHRHs driving GH secretion) and feedback (GHs inhibiting its own secretion, IGF-1 s inhibiting GH secretion, and so forth) dynamic control mechanisms in principle can be modified by the effects of exercise at one or more levels within the axis. Moreover, multiple determinants modulate neuroendocrine responses to training, such as the body composition of the individual, concurrent stress and/or weight loss, gender, diet and energy balance, concomitant drug or hormone use, age, puberty, pregnancy, and/or lactational status.

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, randomised, 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 0.8pmol/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 luteinizing hormone (LH) pulses (number of LH pulses/500min: 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±112min.IU/L, GLP-1 1216±112min.IU/L, p=0.86) and testosterone AUC (vehicle 10893±615min.nmol/L, GLP-1 11088±792min.nmol/L, p=0.77) did not significantly differ during vehicle and GLP-1 administration. GLP-1 significantly reduced food intake (vehicle 15.7±1.3kcal/kg, GLP-1 13.4±1.3kcal/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.