Metabolic Homeostasis and Women’s Reproductive Health: A Bidirectional Dialogue

A major review published in Nature Metabolism on 15 October 2026 argues that female reproductive health cannot be understood in isolation from metabolism. Led by Xiao Liu, Lili Yang, Jingjing Jiang, Hsun-Ming Chang and Liangshan Mu, the synthesis brings together epidemiological, mechanistic and clinical evidence to propose an integrated framework in which dynamic, bidirectional crosstalk between key metabolic organs and endocrine mediators shapes female reproductive function across the entire life course. The authors contend that disruption of this network underlies a broad spectrum of reproductive dysfunction, from ovarian disorders to reproductive ageing and cardiometabolic risk, and they call for a systemic, metabolism-focused reframing of women’s health.

At the heart of the review is the concept of metabolic homeostasis, the tightly regulated equilibrium of energy intake, storage and expenditure that keeps blood glucose, lipids and hormones within physiological ranges. The hypothalamic-pituitary-ovarian axis, which governs follicle development, ovulation and steroid hormone production, is exquisitely sensitive to this equilibrium. Nutritional status is relayed to the brain largely through adipokines such as leptin and adiponectin, which act on hypothalamic neurons including kisspeptin and AgRP neurons that gate the release of gonadotropin-releasing hormone. When energy stores are abundant or depleted, these signals shift, altering the timing of puberty, the regularity of menstrual cycles and the quality of ovulation.

Leptin, secreted by adipose tissue in proportion to fat mass, provides a permissive signal for the onset of puberty and for maintaining adult fertility. Experimental work in mice shows that leptin signalling in AgRP neurons modulates puberty onset and that AgRP-to-Kiss1 neuron communication links nutritional state to fertility. In the ovary itself, leptin has modulatory effects on steroidogenesis in granulosa and theca cells, and it can antagonise the insulin-like growth factor I augmentation of steroidogenesis. Adiponectin, by contrast, is generally insulin-sensitising and anti-inflammatory, and its deficiency in mice leads to female subfertility and ovarian dysfunction. Low adiponectin levels are consistently observed in women with polycystic ovary syndrome, and recent systematic reviews in adolescent girls reinforce this association.

Estrogen emerges as a central regulator of energy homeostasis. It improves insulin sensitivity and suppresses hepatic gluconeogenesis through the transcription factor Foxo1, and an estrogen receptor alpha-derived peptide has been shown to improve glucose homeostasis during obesity. Estrogen also regulates adipose tissue health, influencing fat distribution and adipokine secretion. This relationship runs in both directions: adipose tissue expresses aromatase, converting androgens to estrogens, and women with metabolic dysfunction show increased adipose indices of androgen catabolism and aromatization. The liver, meanwhile, produces sex hormone-binding globulin, the primary gatekeeper of steroid hormone action, whose expression is suppressed by inflammatory cytokines such as IL-1β and TNFα and by insulin resistance, thereby increasing free androgen and estrogen bioavailability.

The review pays particular attention to polycystic ovary syndrome, recently renamed polyendocrine metabolic ovarian syndrome following a multistep global consensus process. This renaming reflects the recognition that the condition is not merely an ovarian disorder but a systemic metabolic-endocrine disease. Women with the syndrome have substantially elevated rates of metabolic syndrome, insulin resistance, type 2 diabetes and metabolic dysfunction-associated steatotic liver disease. Longitudinal data from a United Kingdom primary care database demonstrated that androgen excess in these women predicts nonalcoholic fatty liver disease, and Mendelian randomisation analyses suggest causal links between sex hormones and hepatic fat accumulation. Conversely, androgens exacerbate hepatic triglyceride accumulation by downregulating microsomal triglyceride transfer protein, and dihydrotestosterone induces liver steatosis via transcriptional regulation of SCAP in normal-weight female mice.

Reproductive ageing represents another critical intersection. Follicle-stimulating hormone, which rises as ovarian reserve declines, has been shown to regulate fat accumulation and redistribution in ageing through the Gαi/Ca²⁺/CREB pathway, to enhance hepatic gluconeogenesis via GRK2-mediated AMPK hyperphosphorylation, and to induce postmenopausal dyslipidemia by inhibiting hepatic cholesterol metabolism. Blocking FSH has been shown to inhibit hepatic cholesterol biosynthesis and reduce serum cholesterol in experimental models. These findings suggest that the hormonal shifts of the menopausal transition are not merely passive consequences of ovarian ageing but active drivers of cardiometabolic risk, helping to explain why cardiovascular disease risk accelerates after menopause.

Pregnancy adds a further layer of complexity. Gestational diabetes mellitus affects a substantial proportion of pregnancies worldwide, and maternal insulin resistance is associated with placental miR-3940-3p expression in late pregnancy. Insulin-mediated immune dysfunction has been implicated in the development of preeclampsia, and maternal obesity increases the risk of preterm delivery. The review also highlights that a history of miscarriage or stillbirth predicts future diabetes risk, while preterm birth and low birth weight are associated with nonalcoholic fatty liver disease in community-based cohorts. These bidirectional associations underscore that metabolic and reproductive health are intertwined from preconception through postmenopause.

On the therapeutic front, the review critically evaluates lifestyle interventions, metabolic surgery and pharmacological therapies. Time-restricted eating has been tested in a randomised controlled trial for body weight management in women with polycystic ovary syndrome, and ketogenic diets have been systematically reviewed for their effects on the condition. Exercise interventions, particularly high-intensity training, show promise for improving both cardiometabolic and reproductive outcomes. Bariatric surgery has been shown in the BAMBINI multicentre randomised controlled trial to restore spontaneous ovulation in women living with polycystic ovary syndrome and obesity. Among pharmacological options, metformin remains a mainstay, with evidence supporting its role in ovulation induction and metabolic improvement, though questions remain about its long-term effects on offspring growth when used during pregnancy.

Glucagon-like peptide-1 receptor agonists represent a rapidly evolving therapeutic class. Liraglutide has been shown in randomised studies to improve weight, body composition and hormonal parameters in women with obesity and polycystic ovary syndrome, and to increase IVF pregnancy rates in poor responders. Combination therapy with metformin and semaglutide has shown promise in prospective randomised trials, and preclinical work suggests that GLP-1-based multi-agonist therapy may offer superior metabolic improvement of polycystic ovary syndrome traits compared with single-agent approaches. Sodium-glucose cotransporter inhibitors, including canagliflozin, have also been evaluated in randomised trials and show noninferiority to metformin in certain metabolic endpoints. The review notes that these agents may act not only through weight loss but also through direct effects on ovarian GLP-1 receptors and the gut-gonadal axis.

Looking forward, the authors emphasise precision approaches that account for genetic and epigenetic heterogeneity. Variants in genes such as THADA, INSR, TOX3 and DENND1A have been linked to metabolic syndrome or insulin resistance in women with polycystic ovary syndrome, and DNA methylation of the AMHRII and INSR genes has been associated with disease pathogenesis. Environmental exposures, including per- and polyfluoroalkyl substances in drinking water, have been linked to gestational diabetes, hypertension and preeclampsia in nationwide register-based studies. The review concludes that reframing female reproductive disorders from a systemic metabolic perspective offers a path toward more effective, personalised interventions that address both reproductive and cardiometabolic outcomes simultaneously, rather than treating them as separate clinical domains.

Subject of Research: The bidirectional relationship between metabolic homeostasis and female reproductive function across the life course

Article Title: Metabolic homeostasis and women’s reproductive health

Article References: Liu, X., Yang, L., Jiang, J., Chang, H.-M., & Mu, L. (2026). Metabolic homeostasis and women’s reproductive health. Nature Metabolism. https://doi.org/10.1038/s42255-026-01646-1

Image Credits: AI Generated

DOI: 10.1038/s42255-026-01646-1

Keywords: metabolic homeostasis, women's reproductive health, polycystic ovary syndrome, polyendocrine metabolic ovarian syndrome, insulin resistance, leptin, adiponectin, estrogen, GLP-1 receptor agonists, metformin, reproductive ageing, gestational diabetes