The role of glucagon-like peptide-1 in reproduction: from physiology to therapeutic perspective.
Jensterle Mojca,Janez Andrej,Fliers Eric,DeVries J Hans,Vrtacnik-Bokal Eda,Siegelaar Sarah E
Human reproduction update
BACKGROUND: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. OBJECTIVE AND RATIONALE: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. SEARCH METHODS: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. OUTCOMES: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. WIDER IMPLICATIONS: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.
10.1093/humupd/dmz019
Orexin antagonism and substance-P: Effects and interactions on polycystic ovary syndrome in the wistar rats.
Journal of ovarian research
BACKGROUND:Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder without definitive treatments. Orexin and Substance-P (SP) neuropeptides can affect the ovarian steroidogenesis. Moreover, there are limited studies about the role of these neuropeptides in PCOS. We aimed here to clarify the effects of orexins and SP in PCOS as well as any possible interactions between them. METHODS:For this purpose, the animals (n = five rats per group) received intraperitoneally a single dose of SB-334,867-A (orexin-1 receptor antagonist; OX1Ra), JNJ-10,397,049 (orexin-2 receptor antagonist; OX2Ra), and CP-96,345 (neurokinin-1 receptor antagonist; NK1Ra), alone or in combination with each other after two months of PCOS induction. The blocking of orexin and SP receptors was studied in terms of ovarian histology, hormonal changes, and gene expression of ovarian steroidogenic enzymes. RESULTS:The antagonists' treatment did not significantly affect the formation of ovarian cysts. In the PCOS groups, the co-administration of OX1Ra and OX2Ra as well as their simultaneous injections with NK1Ra significantly reversed testosterone levels and Cyp19a1 gene expression when compared to the PCOS control group. There were no significant interactions between the PCOS groups that received NK1Ra together with one or both OX1R- and OX2R-antagonists. CONCLUSION:The blocking of the orexin receptors modulates abnormal ovarian steroidogenesis in the PCOS model of rats. This suggests that the binding of orexin-A and -B to their receptors reduces Cyp19a1 gene expression while increasing testosterone levels.
10.1186/s13048-023-01168-4
Polycystic Ovary Syndrome and the Neuroendocrine Consequences of Androgen Excess.
Comprehensive Physiology
Polycystic ovary syndrome (PCOS) is a major endocrine disorder strongly associated with androgen excess and frequently leading to female infertility. Although classically considered an ovarian disease, altered neuroendocrine control of gonadotropin-releasing hormone (GnRH) neurons in the brain and abnormal gonadotropin secretion may underpin PCOS presentation. Defective regulation of GnRH pulse generation in PCOS promotes high luteinizing hormone (LH) pulsatile secretion, which in turn overstimulates ovarian androgen production. Early and emerging evidence from preclinical models suggests that maternal androgen excess programs abnormalities in developing neuroendocrine circuits that are associated with PCOS pathology, and that these abnormalities are sustained by postpubertal elevation of endogenous androgen levels. This article will discuss experimental evidence, from the clinic and in preclinical animal models, that has significantly contributed to our understanding of how androgen excess influences the assembly and maintenance of neuroendocrine impairments in the female brain. Abnormal central gamma-aminobutyric acid (GABA) signaling has been identified in both patients and preclinical models as a possible link between androgen excess and elevated GnRH/LH secretion. Enhanced GABAergic innervation and drive to GnRH neurons is suspected to contribute to the pathogenesis and early manifestation of neuroendocrine derangement in PCOS. Accordingly, this article also provides an overview of GABA regulation of GnRH neuron function from prenatal development to adulthood to discuss possible avenues for future discovery research and therapeutic interventions. © 2022 American Physiological Society. Compr Physiol 12:3347-3369, 2022.
10.1002/cphy.c210025
Kisspeptin and neurokinin B analogs use in gynecological endocrinology: where do we stand?
Szeliga A,Podfigurna A,Bala G,Meczekalski B
Journal of endocrinological investigation
BACKGROUND:Recent studies have found that kisspeptin/neurokinin B/dynorphin neurons (KNDy neurons) in the infundibular nucleus play a crucial role in the reproductive axis. Analogs, both agonists and antagonists, of kisspeptin and neurokinin B (NKB) are particularly important in explaining the physiological role of KNDy in the reproductive axis in animals. The use of kisspeptin and NKB analogs has helped elucidate the regulators of the hypothalamic reproductive axis. PURPOSE:This review describes therapeutic uses of Kiss-1 and NKB agonists, most obviously the use of kisspeptin agonists in the treatment for infertility and the induction of ovulation. Kisspeptin antagonists may have potential clinical applications in patients suffering from diseases associated with enhanced LH pulse frequency, such as polycystic ovary syndrome or menopause. The inhibition of pubertal development using Kiss antagonists may be used as a therapeutic option in precocious puberty. Kisspeptin antagonists have been found capable of inhibiting ovulation and have been proposed as novel contraceptives. Hypothalamic amenorrhea and delayed puberty are conditions in which normalization of LH secretion may potentially be achieved by treatment with both kisspeptin and NKB agonists. NKB antagonists are used to treat vasomotor symptoms in postmenopausal women, providing rapid relief of symptoms while supplanting the need for exogenous estrogen exposure. CONCLUSIONS:There is a wide spectrum of therapeutic uses of Kiss-1 and NKB agonists, including the management of infertility, treatment for PCOS, functional hypothalamic amenorrhea or postmenopausal vasomotor symptoms, as well as contraceptive issues. Nevertheless, further research is needed before kisspeptin and NKB analogs are fully incorporated in clinical practice.
10.1007/s40618-019-01160-0
Beyond GnRH, LH and FSH: The role of kisspeptin on hypothalalmic-pituitary gonadal (HPG) axis pathology and diagnostic consideration.
JPMA. The Journal of the Pakistan Medical Association
Kisspeptin as a neuropeptide was established initially as regulator for gonadotropin-releasing hormone for pulse frequency and intensity. In the current review, initial search on PubMed was done with key word "Kisspeptin" with further filters to include reviews and trials from the last 10 years. Of the 313 articles shortlisted, 160(51%) dealt with kisspeptin pathology and diagnostic evaluation in various physiological conditions like puberty, while 57(18.2%) dealt with pathological conditions like hypogonadism, 53(17%) infertility, and 43(13.7%) with polycystic ovarian syndrome. This review explored existing data regarding understanding of the negative and positive influences on the kisspeptin hormone-release kinetics. It highlighted the recently identified ligands and pathways which could affect the gonadal steroids, including various metabolic alterations and environmental triggers. Also, the review highlighted the kisspepetin/G-protein coupled receptor-54 interaction which were influenced by neighbouring endocannabinoid system, Gamma aminobutyric acid (GABA)-ergic neuronal outputs and other chemical agents. It was also highlighted that the release of kisspepetin was identified as a group of neurons termed kisspeptin, neurokinin B, and dynorphin, or KNDy, in the arcuate nuclei. The data indicated the use of kisspepetin as a diagnostic marker for precocious puberty, puberty confirmation, hypogonadism, infertility and polycystic ovarian syndrome.
10.47391/JPMA.133
Beta endorphin in serum and follicular fluid of PCOS- and non-PCOS women.
Jaschke Nikolai,Lunger Fabian,Wildt Ludwig,Seeber Beata
Archives of gynecology and obstetrics
PURPOSE:To compare the concentrations of beta endorphin in serum and follicular fluid (FF) of PCOS- and non-PCOS women. Secondarily, to investigate associations between beta endorphin and other parameters. METHODS:Fifty-nine women undergoing in vitro fertilization (IVF) were included in the study. Sixteen were stratified to the PCOS group using the Rotterdam criteria. The remaining 43 women served as controls. Follicular fluid was collected during oocyte retrieval and peripheral blood sampling was performed on the same day. Beta endorphin concentrations in serum and follicular fluid, serum levels of insulin, glucose, LH, estradiol and progesterone were measured. Additionally, testosterone was measured before starting the stimulation protocol. RESULTS:There was no difference in beta endorphin levels between PCOS- and non-PCOS women. The concentration of the peptide was higher in serum than in FF, likely due to collection of FF after ovulation induction and corresponding to the early luteal phase. We found a significant correlation between the number of mature Metaphase II (MII) oocytes retrieved and beta endorphin concentration in FF. In women with biochemical hyperandrogenemia, beta endorphin levels in FF correlated with testosterone levels. CONCLUSION:Beta Endorphin concentrations in serum and FF do not differ between PCOS- and non PCOS-women undergoing IVF. However, together with sex hormones, beta endorphin might play a key role in oocyte maturation.
10.1007/s00404-018-4793-6
Increased Vasoactive Intestinal Peptide (VIP) in polycystic ovary syndrome patients undergoing IVF.
Frontiers in endocrinology
Introduction:Polycystic ovary syndrome (PCOS) is a common multifactorial and polygenic disorder of the endocrine system, affecting up to 20% of women in reproductive age with a still unknown etiology. Follicular fluid (FF) represents an environment for the normal development of follicles rich in metabolites, hormones and neurotransmitters, but in some instances of PCOS the composition can be different. Vasoactive intestinal peptide (VIP) is an endogenous autonomic neuropeptide involved in follicular atresia, granulosa cell physiology and steroidogenesis. Methods:ELISA assays were performed to measure VIP and estradiol levels in human follicular fluids, while AMH, FSH, LH, estradiol and progesterone in the plasma were quantified by chemiluminescence. UHPLC/QTOF was used to perform the untargeted metabolomic analysis. Results:Our ELISA and metabolomic results show: i) an increased concentration of VIP in follicular fluid of PCOS patients (n=9) of about 30% with respect to control group (n=10) (132 ± 28 pg/ml versus 103 ± 26 pg/ml, p=0,03) in women undergoing fertilization (IVF), ii) a linear positive correlation (p=0.05, r=0.45) between VIP concentration and serum Anti-Müllerian Hormone (AMH) concentration and iii) a linear negative correlation between VIP and noradrenaline metabolism. No correlation between VIP and estradiol (E2) concentration in follicular fluid was found. A negative correlation was found between VIP and noradrenaline metabolite 3,4-dihydroxyphenylglycolaldehyde (DOPGAL) in follicular fluids. Conclusion:VIP concentration in follicular fluids was increased in PCOS patients and a correlation was found with noradrenaline metabolism indicating a possible dysregulation of the sympathetic reflex in the ovarian follicles. The functional role of VIP as noradrenergic modulator in ovarian physiology and PCOS pathophysiology was discussed.
10.3389/fendo.2024.1331282
Molecular characterization of extracellular vesicles derived from follicular fluid of women with and without PCOS: integrating analysis of differential miRNAs and proteins reveals vital molecules involving in PCOS.
Journal of assisted reproduction and genetics
PURPOSE:To elucidate the characterization of extracellular vesicles (EVs) in the follicular fluid-derived extracellular vesicles (FF-EVs) and discover critical molecules and signaling pathways associating with the etiology and pathobiology of PCOS, the differentially expressed miRNAs (DEmiRNAs) and differentially expressed proteins profiles (DEPs) were initially explored and combinedly analyzed. METHODS:First, the miRNA and protein expression profiles of FF-EVs in PCOS patients and control patients were compared by RNA-sequencing and tandem mass tagging (TMT) proteomic methods. Subsequently, Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes were used to analyze the biological function of target genes of DEmiRNAs and DEPs. Finally, to discover the functional miRNA-target gene-protein interaction pairs involved in PCOS, DEmiRs target gene datasets and DEPs datasets were used integratedly. RESULTS:A total of 6 DEmiRNAs and 32 DEPs were identified in FF-EVs in patients with PCOS. Bioinformatics analysis revealed that DEmiRNAs target genes are mainly involved in thiamine metabolism, insulin secretion, GnRH, and Apelin signaling pathway, which are closely related to the occurrence of PCOS. DEPs also closely related to hormone metabolism processes such as steroid hormone biosynthesis. In the analysis integrating DEmiRNAs target genes and DEPs, two molecules, GRAMD1B and STPLC2, attracted our attention that are closely associated with cholesterol transport and ceramide biosynthesis, respectively. CONCLUSION:Dysregulated miRNAs and proteins in FF-EVs, mainly involving in hormone metabolism, insulin secretion, neurotransmitters regulation, adipokine expression, and secretion, may be closely related to PCOS. The effects of GRAMD1B and STPLC2 on PCOS deserve further study.
10.1007/s10815-023-02724-z
Investigational and experimental GnRH analogs and associated neurotransmitters.
Blumenfeld Zeev
Expert opinion on investigational drugs
INTRODUCTION:The GnRH agonistic analogs enable for desensitizing the hypothalamo-pituitary-gonadal axis in malignant and benign conditions where minimizing the production of sex hormones, or blocking ovulation is necessary. The possible indications are prostate cancer, benign prostate hyperplasia, breast cancer, endometriosis, precocious puberty, uterine leiomyomata, assisted reproduction (ART)/in vitro fertilization (IVF), PCOS, minimizing the gonadotoxic effect of chemotherapy in young women, and possibly ovarian cancer. Areas covered: The aim of the current review is to summarize, giving a critical overview, of the investigational GnRH agonists, and shortly discuss the difference between the GnRH agonists, antagonists, Kisspeptin, and Neurokinin B analogs. Expert opinion: The broad armamentarium of agonists may make it possible, in the future, to expand the indications and uses of these analogs, choosing and specifically tailoring the analog to the required effect, while minimizing side effects.
10.1080/13543784.2017.1323869
Exenatide, Dapagliflozin, or Phentermine/Topiramate Differentially Affect Metabolic Profiles in Polycystic Ovary Syndrome.
Elkind-Hirsch Karen E,Chappell N,Seidemann Ericka,Storment John,Bellanger Drake
The Journal of clinical endocrinology and metabolism
CONTEXT:Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors reduce weight and improve insulin sensitivity via different mechanisms. OBJECTIVE:The efficacy of once-weekly exenatide (EQW) and dapagliflozin (DAPA) alone and coadministered (EQW/DAPA), DAPA/extended-release (ER) metformin (DAPA/MET), and phentermine topiramate extended release (PHEN/TPM) on metabolic parameters, body composition, and sex hormones were examined in obese women with PCOS. METHODS:Nondiabetic women (n = 119; aged 18-45 years) with a body mass index (BMI) greater than 30 and less than 45 and polycystic ovary syndrome (National Institutes of Health criteria) were randomly assigned in a single-blinded fashion to EQW (2 mg weekly); DAPA (10 mg daily), EQW/DAPA (2 mg weekly/10 mg daily), DAPA (10 mg)/MET (2000 mg XR daily), or PHEN (7.5 mg)/TPM (46 mg ER daily) treatment for 24 weeks. Study visits at baseline and 24 weeks included weight, blood pressure (BP), waist (WC) measures, and body composition evaluated by dual-energy x-ray absorptiometry (DXA). Oral glucose tolerance tests were conducted to assess glycemia and mean blood glucose (MBG), and compute insulin sensitivity (SI) and secretion (IS) measures. Sex steroids, free androgen index (FAI), and lipid profiles were measured in the fasting sample. RESULTS:EQW/DAPA and PHEN/TPM resulted in the most loss of weight and total body fat by DXA, and WC. Despite equivalent reductions in BMI and WC with PHEN/TPM, only EQW/DAPA and EQW resulted in significant improvements in MBG, SI, and IS. Reductions in fasting glucose, testosterone, FAI, and BP were seen with all drugs. CONCLUSION:Dual therapy with EQW/DAPA was superior to either alone, DAPA/MET and PHEN/TPM in terms of clinical and metabolic benefits in this patient population.
10.1210/clinem/dgab408
Neurotransmitter, neuropeptide and gut peptide profile in PCOS-pathways contributing to the pathophysiology, food intake and psychiatric manifestations of PCOS.
Ilie Ioana R
Advances in clinical chemistry
Polycystic ovary syndrome (PCOS) is a major health problem with a heterogeneous hormone-imbalance and clinical presentation across the lifespan of women. Increased androgen production and abnormal gonadotropin-releasing hormone (GnRH) release and gonadotropin secretion, resulting in chronic anovulation are well-known features of the PCOS. The brain is both at the top of the neuroendocrine axis regulating ovarian function and a sensitive target of peripheral gonadal hormones and peptides. Current literature illustrates that neurotransmitters regulate various functions of the body, including reproduction, mood and body weight. Neurotransmitter alteration could be one of the reasons for disturbed GnRH release, consequently directing the ovarian dysfunction in PCOS, since there is plenty evidence for altered catecholamine metabolism and brain serotonin or opioid activity described in PCOS. Further, the dysregulated neurotransmitter and neuropeptide profile in PCOS could also be the reason for low self-esteem, anxiety, mood swings and depression or obesity, features closely associated with PCOS women. Can these altered central brain circuits, or the disrupted gut-brain axis be the tie that would both explain and link the pathogenesis of this disorder, the occurrence of depression, anxiety and other mood disorders as well as of obesity, insulin resistance and abnormal appetite in PCOS? This review intends to provide the reader with a comprehensive overview of what is known about the relatively understudied, but very complex role that neurotransmitters, neuropeptides and gut peptides play in PCOS. The answer to the above question may help the development of drugs to specifically target these central and peripheral circuits, thereby providing a valuable treatment for PCOS patients that present to the clinic with GnRH/LH hypersecretion, obesity or psychiatric manifestations.
10.1016/bs.acc.2019.11.004