glucagon-like-peptide-1 and Infertility

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) have become firmly established in the treatment of type 2 diabetes and obesity, disorders frequently associated with diminished reproductive health. Understanding of the role of GLP-1 and GLP-1 RAs in reproduction is currently limited and largely unaddressed in clinical studies.. The purpose of this narrative review is to provide a comprehensive overview of the role of GLP-1 in reproduction and to address a therapeutic perspective that can be derived from these findings.. We performed a series of PubMed database systemic searches, last updated on 1 February 2019, supplemented by the authors' knowledge and research experience in the field. A search algorithm was developed incorporating the terms glucagon-like peptide-1, GLP-1, glucagon-like peptide-1 receptor, GLP-1R, or incretins, and this was combined with terms related to reproductive health. The PICO (Population, Intervention, Comparison, Outcome) framework was used to identify interventional studies including GLP-1 RAs and dipeptidyl peptidase-4 (DPP-4) inhibitors, which prevent the degradation of endogenously released GLP-1. We identified 983 potentially relevant references. At the end of the screening process, we included 6 observational (3 preclinical and 3 human) studies, 24 interventional (9 preclinical and 15 human) studies, 4 case reports, and 1 systematic and 2 narrative reviews.. The anatomical distribution of GLP-1 receptor throughout the reproductive system and observed effects of GLP-1 in preclinical models and in a few clinical studies indicate that GLP-1 might be one of the important modulating signals connecting the reproductive and metabolic system. The outcomes show that there is mostly stimulating role of GLP-1 and its mimetics in mammalian reproduction that goes beyond mere weight reduction. In addition, GLP-1 seems to have anti-inflammatory and anti-fibrotic effects in the gonads and the endometrium affected by obesity, diabetes, and polycystic ovary syndrome (PCOS). It also seems that GLP-1 RAs and DPP-4 inhibitors can reverse polycystic ovary morphology in preclinical models and decrease serum concentrations of androgens and their bioavailability in women with PCOS. Preliminary data from interventional clinical studies suggest improved menstrual regularity as well as increased fertility rates in overweight and/or obese women with PCOS treated with GLP-1 RAs in the preconception period.. GLP-1 RAs and DPP-4 inhibitors show promise in the treatment of diabetes and obesity-related subfertility. Larger interventional studies are needed to establish the role of preconception intervention with GLP-1 based therapies, assessing fertility outcomes in obesity, PCOS, and diabetes-related fertility problems. The potential impact of the dose- and exposure time-response of different GLP-1 RAs need further exploration. Future research should also investigate sex-specific variability of GLP-1 on reproductive outcomes, in particular on the gonads where the observations in males are most conflicting.

Topics: Animals; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Gonadal Disorders; Humans; Hypoglycemic Agents; Incretins; Infertility; Male; Obesity; Polycystic Ovary Syndrome; Reproduction; Weight Loss

Insulin-like factor 5 (INSL5), a member of the insulin superfamily, is expressed in the colorectum and hypothalamus. To facilitate studies into the role of INSL5, we generated Insl5(-/-) mice by gene targeting. Insl5(-/-) mice were born in the expected Mendelian ratio, reached normal body weight, but displayed impaired male and female fertility that are due to marked reduction in sperm motility and irregular length of the estrous cycle. Furthermore, Insl5(-/-) mice showed impairment in glucose homeostasis with characteristic elevation of serum glucose levels at an advanced age. Glucose and insulin tolerance tests revealed that the increased blood glucose in Insl5(-/-) mice was due to glucose intolerance resulting from reduced insulin secretion. Morphometric and immunohistological analyses revealed that the Insl5(-/-) mice had markedly reduced average islets area and β-cell numbers. Furthermore, immunohistochemistry showed the expression of INSL5 in enteroendocrine cells in the colorectal epithelium and the presence of its putative receptor relaxin family peptide receptor 4 in pancreatic islet cells. These results suggest the potential role of INSL5 signaling in the regulation of insulin secretion and β-cell homeostasis.

Topics: Animals; Cell Proliferation; Estrous Cycle; Female; Fertility; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Homeostasis; Infertility; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Mice, Knockout; Peptide Hormones; Receptors, G-Protein-Coupled; Receptors, Peptide; Sperm Motility