How Sex Hormones and Metabolic Hormones Talk to Each Other Across a Woman’s Life

Fertility and energy metabolism are deeply intertwined throughout a woman’s life, from sexual development through pregnancy, lactation and menopause. Reproduction is an energetically demanding enterprise, and the body must decide, moment to moment, whether its resources allow it. A new review published in Discover Endocrinology and Metabolism lays out the mechanisms by which sex hormones and metabolic hormones converge in the brain to make those decisions, and why the breakdown of this conversation after menopause may open the door to obesity and type 2 diabetes.

The two hormonal groups at the center of this crosstalk are the metabolic hormones—chiefly insulin, leptin, adiponectin, glucagon-like peptide-1 (GLP-1) and ghrelin—and the sex hormones, mainly estrogens, progesterone and androgens. Both sets of signals meet at the hypothalamic-pituitary-gonadal axis, a hub in the brain that integrates information about the body’s energy status and regulates reproduction. The authors illustrate the principle with leptin, an adipose-derived hormone that informs the brain about the size of energy reserves. When reserves are sufficient, leptin indirectly stimulates the release of gonadotropin-releasing hormone, the master switch of fertility, ensuring that the costly business of reproduction is only initiated when the body can afford it.

Each metabolic hormone carries a distinct message. Insulin, secreted by the beta cells of the pancreatic islets, shuttles glucose into skeletal muscle, liver and adipose tissue, suppresses hepatic glucose production and, in the brain, acts on pro-opiomelanocortin (POMC) neurons that promote satiety while inhibiting neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons that drive hunger. Leptin, produced in proportion to fat mass, binds the long-form leptin receptor in the arcuate nucleus of the hypothalamus and triggers the JAK/STAT pathway, recruiting and phosphorylating STAT3, which then dimerizes, enters the nucleus and activates the POMC gene. Adiponectin, by contrast, falls as body fat rises; it sensitizes tissues to insulin, boosts fatty acid oxidation in muscle and protects the vasculature, with its receptors AdipoR1 and AdipoR2 activating AMPK and PPARα signaling both peripherally and in the hypothalamus.

GLP-1, released by intestinal L cells after a meal, stimulates insulin secretion through the GLP-1 receptor on pancreatic beta cells and suppresses appetite via hypothalamic POMC neurons. Notably, GLP-1 receptors sit on a subset of POMC neurons that express little or no leptin receptor, revealing a hidden heterogeneity within an apparently uniform neuronal population. Ghrelin, the lone orexigenic voice among these messengers, rises from the stomach lining before meals and activates NPY/AgRP neurons through its GHS-R1a receptor and the PLC/IP3/Ca2+ pathway, signaling energy deficits to the brain.

The review then turns to estradiol, the principal female sex hormone, which the authors highlight for its protective effect against obesity and type 2 diabetes. Estradiol, produced mainly by the ovaries but also by adipose tissue and the adrenal glands, follows a characteristic rhythm: it climbs during the follicular phase, peaks just before ovulation, shows a smaller luteal peak and varies within each day, with morning highs. At menopause, ovarian production drops drastically to very low but steady levels—a sudden hormonal loss with no equivalent in males, which the authors describe as a natural model for studying metabolic disorders linked to hormonal decline. Estradiol signals mainly through the estrogen receptors ERα and ERβ, acting as a nuclear transcription factor in the classical pathway and triggering rapid membrane-initiated cascades in a less typical one; ERα is the dominant mediator of metabolic regulation.

The heart of the review is the synergy between estradiol and each metabolic hormone. At physiological levels typical of premenopausal women, estrogen enhances insulin sensitivity and lowers blood glucose, partly because estradiol and insulin signaling converge on the PI3K/Akt cascade in the brain, where co-stimulation produces stronger activation than either hormone alone. Yet hyperestrogenic states, seen in some cases of gestational diabetes, polycystic ovary syndrome and ovarian hyperstimulation syndrome, can instead induce insulin resistance, apparently by direct interference with insulin and its receptors—making estrogen’s effect strongly level-dependent. With leptin, the parallels are striking: estradiol reduces body weight in leptin-deficient ob/ob mice, estrogen deficiency promotes central leptin resistance, and a recent study identified Cited1, a co-transcription factor in POMC neurons, as forming a Cited1–ERα–STAT3 complex that mediates synergistic control of feeding and obesity.

The GLP-1 story is among the most clinically suggestive. Experimental work shows that estrogen directly stimulates GLP-1 secretion from intestinal L cells in an ERβ-dependent manner and potentiates the anorectic response to central GLP-1 receptor activation, with combined action recruiting neurons in the paraventricular hypothalamus and the supramammillary nucleus. Consistent with these preclinical findings, GLP-1-based incretin therapies are generally more effective in human females than in males, a difference that disappears after menopause. A dual GLP-1–estradiol agonist has already shown superior glucose-lowering capability compared with GLP-1 monotherapy in diabetic mouse models. Evidence for ghrelin, by contrast, remains inconsistent: estradiol deficiency raises plasma ghrelin in animals, yet estrogen supplementation in postmenopausal women increased active ghrelin in one clinical study, possibly confounded by measurement of inactive ghrelin forms. Paradoxically, estradiol appears to reduce ghrelin’s orexigenic potency even while increasing ghrelin receptor availability, by recruiting ghrelin-responsive kisspeptin neurons that suppress rather than stimulate food intake.

Menopause exposes what happens when this synergy is withdrawn. As estrogen declines, resistance to both leptin and insulin often emerges, with impaired hypothalamic STAT3 activation proposed as one mechanism. Ovariectomized mice develop glucose intolerance and insulin resistance, and both central and peripheral estradiol administration can reverse these effects, likely through enhanced POMC neuron excitability; similar treatment restores leptin sensitivity in ovariectomized rats. Supporting a causal link, hormone replacement therapy in postmenopausal women is associated with improvements in glucose handling and visceral adiposity, although the authors caution that prolonged therapy is unlikely to be a long-term protective option. Intriguingly, ovarian dysfunction and falling estradiol rather increase adiponectin concentrations, which may partly mitigate the adverse metabolic shift. The authors point instead toward estrogen receptor co-activators as a promising research avenue—molecules that could restore metabolic hormone sensitivity without estrogen’s widespread effects on the body.

Pregnancy rewrites the hormonal script altogether. From mid-gestation, placental hormones impose a state of insulin resistance on maternal tissues, sparing glucose for the fetus, while the pancreas expands beta-cell mass to compensate. Early pregnancy is anabolic, storing fat and reserves; the third trimester turns catabolic, shifting maternal metabolism toward lipids and preserving glucose for the fetus. New placental messengers enter the picture: placental growth hormone gradually replaces pituitary growth hormone and acts as an insulin antagonist; human placental lactogen becomes the dominant lactogenic hormone, promoting insulin resistance and expanding maternal beta cells; and human chorionic gonadotropin sustains progesterone production by the corpus luteum. Meanwhile, traditional metabolic hormones adopt new roles—hyperleptinemia coexists with unchecked appetite, pointing to pregnancy-induced leptin resistance driven by reduced brain leptin transport and dampened JAK/STAT signaling, while adiponectin declines with advancing gestation and low early-pregnancy adiponectin may signal risk of gestational diabetes.

The therapeutic implications are only beginning to be explored. Hormone replacement therapy modestly reduces abdominal fat and improves insulin resistance; GLP-1 receptor agonists remain effective for weight management even at low estrogen levels; and the dual GLP-1/GIP agonist tirzepatide significantly reduces weight across premenopause, perimenopause and postmenopause. One recent study found that weight loss responses to semaglutide improved in postmenopausal women under hormone replacement therapy, hinting that deliberately exploiting hormonal synergy could sharpen incretin-based therapies. During pregnancy, however, GLP-1 receptor agonists are not approved because of limited human data; while first-trimester exposure studies have not identified increased rates of major congenital malformations, animal studies report reduced fetal weight and skeletal abnormalities, and use is currently discouraged. The review’s broader message is that estradiol does not merely coexist with metabolic hormones—it actively tunes the brain’s responsiveness to them, through pathways like PI3K/Akt and JAK/STAT and co-transcriptional factors such as Cited1. Understanding that tuning, the authors argue, could unlock new treatments for the metabolic vulnerabilities that emerge when the reproductive spectrum shifts.

Subject of Research: Neuroendocrine crosstalk between sex hormones and metabolic hormones across the female reproductive lifespan

Article Title: Neuroendocrine crosstalk between sex and metabolic hormones: mechanisms and implications across the female reproductive spectrum

Article References: Goulet, V., Léveillé, D., Li, J., & Fisette, A. (2026). Neuroendocrine crosstalk between sex and metabolic hormones: mechanisms and implications across the female reproductive spectrum. Discover Endocrinology and Metabolism, 2(1), Article 1. https://doi.org/10.1007/s44417-026-00014-7

Image Credits: AI Generated

DOI: 10.1007/s44417-026-00014-7

Keywords: estradiol, leptin, insulin, GLP-1, adiponectin, ghrelin, menopause, pregnancy, hypothalamus, metabolic disease, hormone replacement therapy, incretin therapies