Kisspeptin and its G protein-coupled receptor KISS1R play key roles in mammalian reproduction due to their involvement in the onset of puberty and control of the hypothalamic-pituitary-gonadal axis. However, recent studies have indicated a potential role of extra-hypothalamic kisspeptin in reproductive function. Here, we summarize recent advances in our understanding of the physiological significance of kisspeptin/KISS1R in the peripheral reproductive system (including the ovary, testis, uterus, and placenta) and the potential role of kisspeptin/KISS1R in reproductive diseases. A comprehensive understanding of the expression, function, and potential molecular mechanisms of kisspeptin/KISS1R in the peripheral reproductive system will contribute to the diagnosis, treatment and prevention of reproductive diseases.

Patients with polycystic ovary syndrome (PCOS), characterized by anovulation, hyperandrogenemia and polycystic ovaries, are still vulnerable to undergo recurrent pregnancy loss and premature labor even though the ovulatory process is pharmacologically recovered. However, its potential mechanism remains unknown. Thus, our aim was to investigate the effect and mechanism of hyperandrogenemia and flutamide (a non-steroidal anti-androgen) on the embryo implantation and pregnancy during mid-pregnancy. We used a mouse model in which PCOS-like hyperandrogenemia was induced by subcutaneous injection of testosterone propionate. In this model, we observed the effect of hyperandrogenemia and flutamide on the decidualization, angiogenesis and uNK cells by methods of immunohistochemistry, quantitative PCR, western blotting and Dolichos biflorus agglutinin (DBA) lectin staining. Testosterone and flutamide treatment did not significantly influence the numbers of implanted embryo compared with the control group. However, different doses of testosterone significantly increased the ratio of resorbed /implanted embryo, decreased the level of prl8a2 mRNA and cyclin D3 protein, inhibited the uterine angiogenesis and reduced the numbers of uNK cells, but combined treatment with flutamide markedly decreased the resorbed embryos, increased expressions of prl8a2 mRNA and cyclin D3 protein and angiogenesis and numbers of uNK cells. Flutamide treatment can efficiently ameliorate the hyperandrogenemia-induced the disorders in aspects of decidualization, angiogenesis and uNK cells, which further improve the poor endometrial receptivity in PCOS patients.

Di(2-ethylhexyl) phthalate (DEHP) exposure reduces embryo implantations, increases embryonic loss, and decreases fetal body weights. However, whether it is associated with the alteration of luteal function remains unknown. Thus, our aim in this study was to explore the effect and mechanism of DEHP on luteal function in pregnant mice in vivo. Mice were administered DEHP by gavage at 125, 250, 500 mg/kg/day from gestational days (GD) 1 to 9 or 13. Levels of serum progesterone and estradiol were measured by radioimmunoassay. The numbers and sizes of corpora lutea were calculated by ovarian histomorphology. Steroidogenic enzymes were assessed by qRT-PCR. CD31 protein was detected by immunocytochemistry, and prostaglandin F2alpha (PGF2alpha) levels were evaluated by enzyme immunoassay. Treatment with DEHP significantly inhibited progesterone secretion in pregnant mice in a dose-dependent manner but did not inhibit estradiol production on GD 9 and 13. Treatment also showed concomitant decreases in transcript levels for key steroidogenic enzymes (CYP11A, 3β-HSD, and StAR) on GD 13. Furthermore, DEHP administration significantly reduced the numbers and sizes of corpora lutea on GD 13. No significant changes in the ratio of ovary weight vs. body weight were observed between the control group and treated animals on GD 9 and 13. In addition, treatment with DEHP significantly inhibited CD31 expression of corpora lutea, whereas plasma PGF2alpha levels in DEHP treatment groups were significantly higher compared with the control groups on GD 9 and 13. The results show DEHP significantly inhibits luteal function of pregnant mice in vivo, with a mechanism that seems to involve the down-regulation of progesterone and steroidogenic enzymes message RNA, the decrease in CD31 expression, and the increase in PGF2alpha secretion.

Follicle-stimulating hormone (FSH), a glycoprotein hormone synthesized and secreted by the anterior pituitary gland, plays a critical role in reproductive development and regulation by binding to FSH receptor (FSHR). Beyond reproductive tissue, FSHRs have been identified in various non-reproductive tissues, indicating broader functions. FSH levels chronically rise during menopause and remain elevated in postmenopausal life. This increase in FSH level has been indicated to be associated with heightened risk of several non-reproductive diseases, including osteoporosis, hypercholesterolemia, type 2 diabetes mellitus, obesity, cardiovascular disease, Alzheimer’s disease, and certain cancers. In this review, we will examine the role of FSH-FSHR signaling in the pathogenesis of these non-reproductive diseases and explore therapeutic strategies targeting FSH-FSHR signaling pathways.

APLN, APELA and their common receptor APLNR (composing the apelinergic axis) have been described in various species with extensive body distribution and multiple physiological functions. Recent studies have witnessed emerging intracellular cascades triggered by APLN and APELA which play crucial roles in female reproductive organs, including hypothalamus-pituitary-gonadal axis, ovary, oviduct, uterus and placenta. However, a comprehensive summary of APLN and APELA roles in physiology and pathology of female reproductive system has not been reported to date. In this review, we aim to concentrate on the general characteristics of APLN and APELA, as well as their specific physiological roles in female reproductive system. Meanwhile, the pathological contexts of apelinergic axis dysregulation in the obstetrics and gynecology are also summarized here, suggesting its potential prospect as a diagnostic biomarker and/or therapeutic intervention in the polycystic ovary syndrome, ovarian cancer, preeclampsia and gestational diabetes mellitus.