The hypothalamic-pituitary-gonadal (HPG) axis coordinates reproductive function and incorporates gonadal sex steroid feedback to regulate gonadotropin secretion in a homeostatic manner. In females, ovarian estrogens and progestins act as the primary negative feedback signals to suppress luteinizing hormone (LH) release, whereas in males, androgens, such as testosterone (T), typically provide this feedback. However, androgens can also exert feedback effects on the female HPG axis, particularly in conditions where circulating T levels exceed that of the normal female physiological range. Three clinically relevant examples are anabolic substance abuse, testosterone therapy, and polycystic ovary syndrome (PCOS; recently renamed polyendocrine metabolic ovarian syndrome [PMOS]). Despite shared exposure to "androgen excess," these different hyperandrogenic states are associated with strikingly different neuroendocrine phenotypes. In testosterone therapy and anabolic substance abuse, high exogenous androgen exposure in or above the male physiological range typically suppresses LH secretion and disrupts ovulatory cycling, mimicking enhanced negative feedback on the HPG axis. Conversely, in PMOS, endogenous elevations in T, high for a female but below the male physiological range, are associated with increased LH secretion, acyclicity, and anovulation. The mechanisms underlying these divergent LH outcomes remain unclear but may reflect, in part, differences in the source of androgens (exogenous vs. endogenous), circulating androgen concentrations, and development timing and/or duration of androgen exposure. This review synthesizes current clinical and preclinical evidence to compare distinct models of hyperandrogenemia with respect to the female HPG axis and aims to illuminate how endogenous and exogenous androgens with different features differentially alter female neuroendocrine function.

Infertility affects over 10% of women of reproductive age, with ovulatory dysfunction being the leading cause. Despite its widespread prevalence, the mechanisms behind infertility and anovulation are not fully understood. Recently, we reported infertility, ovulation failure, and severe ovarian abnormalities in mice lacking salt-inducible kinase 3 (SIK3). However, this phenotype was not fully replicated in mice in which SIK3 was deleted in granulosa cells. Since SIK3 is also expressed in theca cells, we generated SIK3 knockout mice specifically targeting SIK3 loss in androgen-producing theca cells (SIK3C17TCKO). These mice are infertile, have irregular estrous cycles, and produce fewer oocytes after gonadotropin treatment compared to controls. Histological examination revealed enlarged, cystic ovaries with hemorrhagic follicles and a significant increase in multinucleated giant cells, indicating inflammation and ovarian aging. Additionally, SIK3C17TCKO ovaries exhibited increased CYP17A1 expression, an enzyme crucial for androgen synthesis, resulting in higher serum testosterone levels. Consistent with in vivo results, knocking down SIK3 in primary mouse theca-interstitial cells in vitro significantly raised Cyp17a1 expression and testosterone production. This suggests that androgen excess may contribute to the severe ovarian dysfunction observed in SIK3C17TCKO mice. Overall, this study further highlights the vital role of SIK3 in ovarian function and identifies theca cells as key targets of this kinase. The phenotype of SIK3C17TCKO mice closely resembles many features of polycystic ovary syndrome (PCOS), making it a valuable model for studying PCOS pathophysiology and potential treatments for ovulatory disorders.

Obesity and polycystic ovary syndrome (PCOS) in women are associated with significant reproductive dysfunction, manifesting as hormonal imbalances, anovulation, and subfertility. These conditions not only impair reproductive outcomes but also contribute to a reduced quality of life. Crucially, obesity and PCOS share a bidirectional relationship. While obesity can trigger and worsen PCOS manifestations, the convergence of these two conditions has contributed significantly to the growing incidence of female infertility. This review critically examines liraglutide's mechanistic role and therapeutic potential in mediating metabolic restoration and improving the fertility outcomes in women burdened by obesity and PCOS. A literature search was conducted in original databases from inception until March 2025 in PubMed, Google Scholar, Cochrane Library, Scopus, and Web of Science using the following keywords pertinently: "GLP-1R", "liraglutide", "female reproductive system", "polycystic ovarian syndrome", "ovarian function", and "pregnancy outcomes". Accumulated evidence suggests that liraglutide promotes greater weight loss and improves reproductive outcomes in women with obesity and PCOS by regulating endocrine parameters, reducing systemic inflammation, restoring menstrual cyclicity, and supporting folliculogenesis. It improves reproductive outcomes by increasing natural conception rates and improving responses to assisted reproductive techniques (ART). However, with all the positive outcomes, the major limitations of using this drug for weight loss are the need for daily subcutaneous injections, cost, and gastrointestinal adverse effects. Long-term assessment of the sustained efficacy and impact on reproductive outcomes, including the pattern of ovulation and offspring health, is warranted. This review consolidated present findings and emphasized areas for further exploration to better inform clinical decision-making and future research directions.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in fertile women, with an estimated prevalence of 10-15%. It is a heterogeneous disease characterized by a complex pathogenesis. Genetic predisposition, neuroendocrine regulation disorders, and environmental influences play a key role. Dysregulation of the hypothalamic-pituitary-ovarian axis occurs with subsequent chronic anovulation, hyperandrogenemia, and metabolic abnormalities. Phenotypic variability reflects different pathophysiological mechanisms - based on genomic association studies, three subtypes of PCOS can be distinguished: reproductive, metabolic, and indeterminate. PCOS is one of the main causes of female infertility and a risk factor for the development of cardiometabolic diseases. Objective: The aim of the article is to summarize current recommendations of the European Society of Human Reproduction and Embryology (ESHRE 2023) regarding the diagnosis and treatment of polyendocrine metabolic ovarian syndrome (PMOS) in patients with fertility disorders and to demonstrate their practical application through a selected clinical case.

Polycystic ovary syndrome (PCOS) is a major cause of infertility due to chronic anovulation, and current treatments like metformin are not effective for all patients. Evidence on pioglitazone's role in restoring ovulation is limited, particularly among South Asian women where PCOS prevalence is high. This study, conducted in Lahore from January to June 2025, evaluated pioglitazone in 95 PCOS patients. After six months of treatment, 72.6% of patients achieved restored ovulation with improved hormonal profiles. Pioglitazone thus emerges as an effective alternative to metformin, improving menstrual cycles, ovulation, hyperandrogenism, and reducing the risk of type 2 diabetes.

Bovine embryo transfer (ET) has been a consistently growing market worldwide with in vitro produced (IVP) embryos now far outnumbering those produced by traditional superovulation. Because transfer of a viable blastocyst-stage embryo to the uterus bypasses many of the potential biological causes of early pregnancy failure associated with artificial insemination (AI; anovulation, sperm transport, fertilization failure, early embryonic death), pregnancy success should logically be higher following ET than following AI. However, this is not always the case. One of the main factors contributing to this paradox is pregnancy loss following ET, particularly with IVP embryos. This greater embryo mortality presents a significant obstacle to more widespread use of IVP embryos. Improvements in embryo culture media as well as in our understanding of the underlying physiological and molecular regulation of early embryo development and embryo-maternal communication leading to a successful pregnancy will significantly contribute to improved reproductive efficiency and sustainability in agri-food production.

Obesity is a multifactorial condition that profoundly affects female reproductive health through endocrine, metabolic, and inflammatory mechanisms that disrupt the hypothalamic-pituitary-gonadal (HPG) axis. Women with obesity frequently develop menstrual irregularities, anovulation, amenorrhea, infertility, polycystic ovary syndrome (PCOS), impaired endometrial receptivity, and adverse pregnancy outcomes. Central obesity and insulin resistance contribute to hyperinsulinemia, reduced sex hormone-binding globulin (SHBG) levels, hyperandrogenism, altered gonadotropin secretion, and impaired folliculogenesis, while adipokines such as leptin and chronic inflammation further impair ovarian steroidogenesis and ovulatory function. Obesity-related oxidative stress and lipotoxicity also negatively affect oocyte quality, embryo development, implantation, and assisted reproductive technology outcomes, increasing the risk of gestational diabetes, preeclampsia, miscarriage, and preterm birth. This review evaluates the therapeutic potential of pharmacological weight-loss therapies in obesity-associated female reproductive dysfunction. A comprehensive literature review was conducted using various databases, focusing on anti-obesity pharmacotherapy on obesity, infertility and fertility in reproductive-aged women. Evidence suggests that several FDA-approved and off-label anti-obesity agents, including orlistat, liraglutide, semaglutide, phentermine/topiramate, bupropion/naltrexone, metformin, exenatide, and tirzepatide, may improve reproductive outcomes primarily indirectly through weight reduction and metabolic improvement. GLP-1 receptor agonists, particularly liraglutide, semaglutide, and exenatide, appear especially promising, demonstrating beneficial effects on insulin sensitivity, menstrual regularity, ovulation, androgen levels, and pregnancy rates in women with PCOS. Tirzepatide, a dual GLP-1/GIP receptor agonist, has shown potent weight-loss and metabolic effects with potential indirect fertility benefits. Metformin improves insulin sensitivity and is widely used in PCOS to regulate androgen levels and restore ovulation, although its effects on pregnancy and live birth rates remain controversial. However, evidence for several agents remains limited, and concerns persist regarding reproductive safety during pregnancy. Overall, anti-obesity pharmacotherapy may represent an important adjunctive strategy for improving reproductive and metabolic health in women with obesity, although larger randomized clinical trials are still required.