GnRH pulse generator activity in mouse models of polycystic ovary syndrome

eLife, Год журнала: 2025, Номер 13

Опубликована: Янв. 6, 2025

One in ten women their reproductive age suffer from polycystic ovary syndrome (PCOS) that, alongside subfertility and hyperandrogenism, typically presents with increased luteinizing hormone (LH) pulsatility. As such, it is suspected that the arcuate kisspeptin (ARN KISS ) neurons represent GnRH pulse generator are dysfunctional PCOS. We used here vivo GCaMP fiber photometry other approaches to examine behavior of two mouse models began peripubertal androgen (PPA) model PCOS but found had a reduction frequency ARN neuron synchronization events (SEs) drive LH pulses. Examining prenatal (PNA) PCOS, we observed highly variable patterns activity no significant differences detected SEs, pulsatile secretion, or serum testosterone, estradiol, progesterone concentrations. However, machine learning approach identified acyclic PNA mice continued exhibit cyclical similar normal mice. The SEs was significantly algorithm-identified ‘diestrous stage’ compared controls. In addition, exhibited reduced feedback suppression gonadotrophs were also less sensitive GnRH. These observations demonstrate importance understanding existence indicates presence complex phenotype deficits at multiple levels hypothalamo-pituitary-gonadal axis.

Язык: Английский

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The Emerging Therapeutic Potential of Kisspeptin and Neurokinin B

Endocrine Reviews, Год журнала: 2023, Номер 45(1), С. 30 - 68

Опубликована: Июль 20, 2023

Abstract Kisspeptin (KP) and neurokinin B (NKB) are neuropeptides that govern the reproductive endocrine axis through regulating hypothalamic gonadotropin-releasing hormone (GnRH) neuronal activity pulsatile GnRH secretion. Their critical role in health was first identified after inactivating variants genes encoding for KP or NKB signaling were shown to result congenital hypogonadotropic hypogonadism a failure of pubertal development. Over past 2 decades since their discovery, wealth evidence from both basic translational research has laid foundation potential therapeutic applications. Beyond KP's function hypothalamus, it is also expressed placenta, liver, pancreas, adipose tissue, bone, limbic regions, giving rise several avenues use diagnosis treatment pregnancy, metabolic, behavioral disorders. The played by stimulating thermoregulatory center mediate menopausal hot flashes led development medications antagonize its action as novel nonsteroidal agent this indication. Furthermore, ability antagonism partially suppress (but not abolish) supported various disorders including polycystic ovary syndrome, uterine fibroids, endometriosis. This review will provide comprehensive up-to-date overview preclinical clinical data have paved way diagnostic applications NKB.

Язык: Английский

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KNDy Neurons of the Hypothalamus and Their Role in GnRH Pulse Generation: an Update

Endocrinology, Год журнала: 2023, Номер 165(2)

Опубликована: Дек. 23, 2023

Abstract There is considerable evidence that synchronized activity within a reciprocally connected population of cells in the arcuate nucleus (ARC) coexpressing kisspeptin, neurokinin B (NKB), and dynorphin (KNDy cells) crucial for generation gonadotrophin-releasing hormone (GnRH) pulses mammals. The initial “KNDy hypothesis” proposed pulsatile GnRH secretion elicited by episodic kisspeptin release from KNDy following activation termination NKB dynorphin, respectively. Since then, role as critical component pulse generator has been further supported studies at single-cell level, demonstrating both necessary sufficient pulsatility. In addition, there have modifications expansion original hypothesis, including work glutamate synchronization cell network, functional interactions with other ARC subpopulations, existence species differences generation. Here we review these recent changes discuss how translation findings led to development new therapies disorders related We also outline gaps knowledge are currently limiting application research clinic, particularly regarding primates.

Язык: Английский

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Obesity Alters POMC and Kisspeptin Neuron Cross Talk Leading to Reduced Luteinizing Hormone in Male Mice

Journal of Neuroscience, Год журнала: 2024, Номер 44(28), С. e0222242024 - e0222242024

Опубликована: Май 14, 2024

Obesity is associated with hypogonadism in males, characterized by low testosterone and sperm number. Previous studies determined that these stem from dysregulation of hypothalamic circuitry regulates reproduction, unknown mechanisms. Herein, we used mice fed chronic high-fat diet, which mimics human obesity, to determine mechanisms impairment at the level hypothalamus, particular gonadotropin-releasing hormone (GnRH) neurons regulate luteinizing (LH), then testosterone. Consistent obese humans, demonstrated lower LH, pulse frequency LH secretion, but unchanged pituitary responsiveness GnRH. regulated pulsatile GnRH controlled kisspeptin. Peripheral central kisspeptin injections, DREADD-mediated activation neurons, were suppressed mice. Thus, investigated regulators secretion. We response NMDA was mice, corresponding fewer glutamate receptors may be critical for synchronization. Given also interact anorexigenic POMC are affected examined their cross talk, either or injection αMSH, a product POMC, abolished This accompanied diminished levels αMSH receptor, MC4R, neurons. Together, our obesity leads downregulation frequency, leading hypogonadism.

Язык: Английский

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Endogenous opiates and behavior: 2023

Peptides, Год журнала: 2024, Номер 179, С. 171268 - 171268

Опубликована: Июнь 28, 2024

Язык: Английский

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Targeted inhibition of kisspeptin neurons reverses hyperandrogenemia and abnormal hyperactive LH secretion in a preclinical mouse model of polycystic ovary syndrome

Human Reproduction, Год журнала: 2024, Номер 39(9), С. 2089 - 2103

Опубликована: Июль 9, 2024

Abstract STUDY QUESTION Do hyperactive kisspeptin neurons contribute to abnormally high LH secretion and downstream hyperandrogenemia in polycystic ovary syndrome (PCOS)-like conditions can inhibition of rescue such endocrine impairments? SUMMARY ANSWER Targeted endogenous neuron activity a mouse model PCOS reduced the pulse healthy control levels. WHAT IS KNOWN ALREADY is reproductive disorder characterized by hyperandrogenemia, anovulation, and/or ovaries, along with hallmark feature abnormal hyper-pulsatility, but mechanisms underlying impairments remain unclear. A chronic letrozole (LET; aromatase inhibitor) recapitulates phenotypes, including testosterone, pulses. LET PCOS-like females also have increased hypothalamic neuronal activation which may drive their this has not been tested. DESIGN, SIZE, DURATION Transgenic KissCRE+/hM4Di female mice or littermates Cre− controls were treated placebo, (50 µg/day) induce phenotype, followed acute (once) (2 weeks) clozapine-N-oxide (CNO) exposure chemogenetically inhibit cells (n = 6 10 mice/group). PARTICIPANTS/MATERIALS, SETTING, METHODS Key measures, vivo patterns circulating testosterone levels, assessed before after selective compared between groups controls. Alterations body weights measured pituitary ovarian gene expression was determined qRT-PCR. MAIN RESULTS AND THE ROLE OF CHANCE Acute targeted successfully lowered (P < 0.05). Likewise, suppression reversed previously levels 0.05) down rescued 0. 05). LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Ovarian morphology study. Additionally, models offer mechanistic insights into neuroendocrine processes perfectly mirror women. WIDER IMPLICATIONS FINDINGS These data support hypothesis that overactive impairments, occur Our findings complement recent clinical investigations using NKB receptor antagonists lower women suggest pharmacological dose-dependent modulation be valuable future therapeutic target clinically treat hyperandrogenism elevated FUNDING/COMPETING INTEREST(S) This research supported NIH grants R01 HD111650, HD090161, HD100580, P50 HD012303, AG078185, R24 HD102061, pilot project award from British Society for Neuroendocrinology. There are no competing interests.

Язык: Английский

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Prolactin-mediates a lactation-induced suppression of arcuate kisspeptin neuronal activity necessary for lactational infertility in mice

eLife, Год журнала: 2025, Номер 13

Опубликована: Янв. 17, 2025

The specific role that prolactin plays in lactational infertility, as distinct from other suckling or metabolic cues, remains unresolved. Here, deletion of the receptor (Prlr) forebrain neurons arcuate kisspeptin resulted failure to maintain normal lactation-induced suppression estrous cycles. Kisspeptin immunoreactivity and pulsatile LH secretion were increased these mice, even presence ongoing stimulation lactation. GCaMP fibre photometry revealed episodic activity is rapidly suppressed pregnancy this was maintained throughout early Deletion Prlr reactivation prior a premature return reproductive cycles These observations show dynamic variation neuronal associated with hormonal changes lactation, provide direct evidence action on necessary for suppressing fertility during lactation mice.

Язык: Английский

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KNDy neurones and GnRH/LH pulse generation: Current understanding and future aspects

Journal of Neuroendocrinology, Год журнала: 2023, Номер 35(9)

Опубликована: Май 2, 2023

Abstract Uncovering the central mechanism underlying mammalian reproduction is warranted to develop new therapeutic approaches for reproductive disorders in humans and domestic animals. The present study focused on role of arcuate kisspeptin neurones (also known as KNDy neurones) an intrinsic gonadotropin‐releasing hormone (GnRH) pulse generator, which plays a fundamental via stimulation pituitary gonadotropin synthesis release thereby gametogenesis steroidogenesis gonads mammals. We also discuss that inhibits pulsatile GnRH/gonadotropin under negative energy balance, considering often occur during malnutrition livestock.

Язык: Английский

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KNDy neurons as the GnRH pulse generator: Recent studies in ruminants

Peptides, Год журнала: 2023, Номер 164, С. 171005 - 171005

Опубликована: Март 27, 2023

Язык: Английский

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Long-term Recordings of Arcuate Nucleus Kisspeptin Neurons Across the Mouse Estrous Cycle

Endocrinology, Год журнала: 2024, Номер 165(3)

Опубликована: Янв. 16, 2024

The arcuate nucleus kisspeptin (ARNKISS) neurons represent the GnRH pulse generator that likely drives pulsatile gonadotropin secretion in all mammals. Using an improved GCaMP fiber photometry system enabling long-term continuous recordings, we aimed to establish a definitive profile of ARNKISS neuronal activity across murine estrous cycle. As noted previously, substantial reduction frequency neuron synchronization events (SEs) occurs on late proestrus and extends into estrus. SE amplitude remains constant throughout During metestrus, unexpectedly detected many multipeak SEs where occurred rapidly, within 160 seconds each other. By applying machine learning-based, k-means clustering analysis, were further able detect within-stage variability patterns activity. Estrous cycle-dependent changes around time lights off. We also find mild stressor such as vaginal lavage reduces for up 3 hours. These observations provide comprehensive account cycle, highlight new pattern activity, introduce approach analyzing population behavior.

Язык: Английский

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