Gut Hormones GLP-1 and GIP Emerge as Unexpected Players in Women’s Health

The blockbuster drugs that have transformed the treatment of diabetes and obesity may be poised for an unlikely second act: the clinic of women’s health. A comprehensive narrative review published in Health Science Reports examines how incretins—the gut-derived hormones GLP-1 and GIP that have made drugs like semaglutide and tirzepatide household names—exert effects that reach far beyond blood sugar control, touching the ovary, the uterus and the hormonal circuitry that governs fertility. Drawing on literature spanning January 1995 to July 2026 from PubMed, Web of Science and Embase, the authors systematically map the biology of these hormones and their emerging role in conditions ranging from polycystic ovary syndrome to endometrial cancer.

Incretins occupy a central position in the entero-insular axis, the signalling network by which the gut primes the pancreas to release insulin after a meal in a glucose-dependent manner. GLP-1, a 30-amino-acid polypeptide secreted by L cells of the terminal ileum and colon, binds a G protein-coupled receptor distributed across pancreatic islets, adipose tissue, the cardiovascular system, the central nervous system and, crucially, the reproductive organs. Its classical action involves activation of the cAMP/PKA cascade in pancreatic beta cells, enhancing insulin gene transcription and glucose-dependent insulin secretion. The hormone also regulates voltage-dependent calcium channels to promote calcium influx, suppresses glucagon release from alpha cells, and engages the PI3K pathway to sharpen peripheral insulin sensitivity.

The molecular picture has grown considerably richer in recent years. Researchers identified the adipokine zinc-alpha2-glycoprotein as a possible mediator of the metabolic benefits of GLP-1 receptor agonists, with twelve weeks of liraglutide treatment significantly elevating circulating ZAG levels in patients with type 2 diabetes. Other teams have explored ways to boost the body’s own GLP-1 output: the dietary compound imperatorin and glycyrrhizic acid, a principal component of licorice, both activate the TGR5 receptor to enhance GLP-1 secretion in experimental models. Even receptor architecture is proving malleable—bioluminescence resonance energy transfer studies revealed that the GLP-1 receptor can form heterodimers with the secretin receptor in islet cells, altering calcium signalling and inducing cross-desensitisation between the two receptors.

GIP, the second major incretin, is a 42-amino-acid peptide produced by K cells in the duodenum and jejunum. Though less intensively studied than GLP-1, it promotes insulin biosynthesis, supports beta-cell differentiation and survival, and enhances fat storage and bone formation. Work by Samms and colleagues showed that GIP enhances lipoprotein lipase activity in adipocytes through a PI3K/PKB-LKB1/AMPK-TORC2 signalling axis, promoting lipid uptake and storage while increasing insulin sensitivity. Intriguingly, GIP and GLP-1 signalling appear intertwined: N-glycosylation-deficient GIP receptors can be functionally rescued by co-expression with wild-type GLP-1 receptors, hinting at functional heterodimerisation between the two receptor classes.

The most clinically mature application in gynaecology is polycystic ovary syndrome, a condition characterised by hyperandrogenemia and insulin resistance that affects a growing number of women worldwide. Studies have confirmed abnormal secretion of both GIP and GLP-1 in patients with PCOS, and clinical research has shown that GLP-1 receptor agonists such as liraglutide and semaglutide can improve menstrual regularity, raise ovulation rates and reduce body fat. Mechanistically, the agonist exenatide was found to improve insulin resistance in PCOS rats by activating the AMPKalpha-SIRT1 pathway, while GLP-1 receptor agonists more broadly bolster antioxidant defences via the Nrf2/ARE pathway and reduce endoplasmic reticulum stress through modulation of the PERK pathway.

Genetic evidence adds weight to the GIP connection. A two-sample Mendelian randomisation analysis found that genetic activation of the GIP receptor is associated with a reduced risk of PCOS, and animal work shows that GIP signalling regulates the oestrous cycle and female fertility through the pituitary-gonadal axis. The gut microbiome may also be a critical link: dysbiosis in PCOS elevates the microbial metabolite agmatine, which activates the farnesoid X receptor and suppresses GLP-1 secretion from intestinal L cells, contributing to insulin resistance and ovarian dysfunction. This agmatine-FXR-GLP-1 axis offers a compelling explanation for how gut health, metabolism and reproduction converge in the syndrome.

Beyond the ovary, incretins display striking anti-inflammatory and anti-fibrotic properties with direct relevance to uterine disease. GLP-1 suppresses macrophage inflammatory factors including IL-1beta, IL-6 and TNF-alpha, and gene therapy studies in obese diabetic mice showed reduced macrophage infiltration of adipose tissue and inhibition of NF-kappaB and JNK signalling. In models of intrauterine adhesion, semaglutide alleviated fibrosis and inflammation by modulating NF-kappaB and reducing fibrotic markers such as ACTA2, COL1A1 and FN, while dulaglutide improved endometrial thickness and reduced collagen deposition by suppressing M1 macrophage polarisation and the TGF-beta/Smad2 pathway. Preclinical studies likewise suggest GLP-1 receptor agonists can inhibit the proliferation of ectopic endometrial cells in endometriosis through PI3K/Akt and NF-kappaB pathways.

The anti-tumour signals are tantalising but preliminary. In endometrial cancer cell lines, liraglutide inhibited proliferation in a time- and concentration-dependent manner, activating AMPK, upregulating progesterone receptors and synergising with medroxyprogesterone acetate. Autophagy appears central: liraglutide induced autophagic cell death by increasing LC3 expression and p-AMPKalpha while decreasing SQSTM1. For ovarian cancer, GLP-1 receptor expression has been documented in some tumour tissues, and agonists can curb proliferation and invasion via AMPK in vitro—but the authors are careful to stress that these anti-tumour effects may be partly secondary to weight loss and improved metabolic status, and direct effects require clinical validation.

Perhaps the most conceptually ambitious frontier is the brain-gut axis. Incretins directly modulate the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, and electrophysiological recordings show GLP-1 acting on GnRH neurons to increase firing rates and GABAergic synaptic input. GLP-1 receptor agonists may increase pulsatile GnRH release via the hypothalamic kisspeptin system, influencing luteinising hormone secretion, while peripherally promoting follicular development and oocyte maturation through effects on theca cells. GIP receptor knockout mice exhibit disrupted oestrous cycles and reduced fertility, underscoring GIP’s non-redundant role. Notably, a dual GLP-1/oestrogen agonist improved ovarian cyclicity and insulin sensitivity in PCOS mouse models without direct estrogenic proliferative effects on the uterus.

Clinical translation, however, demands caution. Combination therapy with metformin outperforms metformin alone for weight, BMI and insulin sensitivity, and semaglutide reduced lingual fat in women with PCOS in a randomised trial—yet adverse events are more frequent with combination regimens, and real-world data show 17.8% of patients are non-responders to semaglutide or liraglutide for obesity. Gastrointestinal symptoms remain the most common side effects, and safety concerns persist regarding gallbladder disorders, pancreatitis and rodent C-cell findings. Use in pregnancy and lactation is not recommended, with regulators advising contraception and a two-month washout before conception. For endometriosis, intrauterine adhesions and gynaecological cancers, the evidence remains almost entirely preclinical. The authors call for large, multicentre randomised trials with reproductive outcomes as primary endpoints, dedicated exploration of dual GIP/GLP-1 agonists such as tirzepatide, and tissue-specific studies to disentangle direct hormonal actions from the indirect fruits of metabolic improvement. Incretin-based therapy, they conclude, represents a promising interdisciplinary bridge between endocrinology and gynaecology—one whose full span has yet to be built.

Subject of Research: The role and mechanisms of the incretin hormones GLP-1 and GIP in gynaecological diseases

Article Title: The Role and Mechanism of Incretins in Gynaecologic Diseases

Article References: Yan, J., Cao, M., Ding, Y., Zhang, Y., Sun, Y., Jiang, G., Zhang, Y., Kang, L., Zhou, X., Luo, J., & Li, B. (2026). The Role and Mechanism of Incretins in Gynaecologic Diseases. Endocrinology, Diabetes & Metabolism, 9(5), Article e70340. https://doi.org/10.1002/edm2.70340

Image Credits: AI Generated

DOI: 10.1002/edm2.70340

Keywords: incretins, GLP-1, GIP, polycystic ovary syndrome, endometrial cancer, endometriosis, intrauterine adhesions, insulin resistance, brain-gut axis, GLP-1 receptor agonists, semaglutide, women's health