Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine disorder associated with hyperandrogenism and anovulation. Although a spectrum disorder, many women with PCOS exhibit elevated luteinizing hormone (LH) pulse frequency and an elevated LH to follicle stimulating hormone ratio. This aberrant pattern of gonadotrophin signalling drives many of the downstream ovarian features of PCOS, including increased androgen synthesis, and indicates neuroendocrine impairments upstream. Decreased responsiveness to gonadal steroid hormone negative feedback in PCOS patients points toward dysfunction within the gonadotropin-releasing hormone (GnRH) neuronal network in the brain. Excessive androgen exposure during development or over pubertal onset can recapitulate the neuroendocrine pathology of PCOS in pre-clinical models, and these models have been fundamental in beginning to pick apart the specific central mechanisms involved. This mini-review will briefly describe the pathology of PCOS associated with high frequency GnRH/LH pulses and then highlight what is currently known, and yet to be discovered, about the central mechanisms involved.
Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism and chronic anovulation. Although the etiology of PCOS is unknown, perturbations of gonadotropin secretion are one of the hallmarks of this disorder. In normal menstrual physiology, the monotropic rise of plasma follicle-stimulating hormone (FSH) during the luteal-follicular transition is critical for follicular development and subsequent ovulation. One of the mechanisms by which FSH is differentially synthesized involves the luteal slowing of gonadotropin-releasing hormone (GnRH) pulse frequency by ovarian steroids. In PCOS, plasma leutinizing hormone (LH) is commonly increased, FSH is typically in the lower follicular range, and LH (and by inference GnRH) pulse frequency is persistently rapid at approximately one LH pulse per hour. The etiology of the neuroendocrine abnormalities in PCOS remain unclear; however, recent studies have revealed decreased sensitivity of the GnRH pulse generator to inhibition by ovarian steroids, particularly progesterone. This abnormality is reversed by the androgen receptor antagonist flutamide, suggesting that elevated androgen levels may alter the sensitivity of the hypothalamic GnRH pulse generator to steroid inhibition and lead to enhanced LH secretion. As such, women with PCOS require higher levels of progesterone to slow the frequency of GnRH pulse secretion, resulting in inadequate FSH synthesis and persistent LH stimulation of ovarian androgens. The decreased sensitivity of the GnRH pulse generator may help to explain the genesis of PCOS during puberty. In normal early puberty, sleep-entrained increases in LH stimulate ovarian steroids, which subsequently suppress LH frequency and amplitude during the subsequent day. In hyperandrogenemic girls destined to develop PCOS, this nocturnal increase in ovarian steroids may not be adequate to suppress the GnRH pulse generator, leading to a persistently rapid LH pulse frequency, impaired FSH production, and inadequate follicular development.
Rossi SP et al., 2023·Molecular and cellular endocrinology
Antioxidant actions of melatonin and its impact on testicular function and fertility have already been described. Considering that Sertoli cells contribute to provide structural support and nutrition to germ cells, we evaluated the effect of melatonin on oxidative state and lactate metabolism in the immature murine TM4 cell line and in immature hamster Sertoli cells. A prooxidant stimulus applied to rodent Sertoli cells expressing MT1/MT2 receptors, increased lipid peroxidation whereas decreased antioxidant enzymes (superoxide dismutase 1, catalase, peroxiredoxin 1) expression and catalase activity. These changes were prevented by melatonin. Furthermore, melatonin stimulated lactate dehydrogenase (LDH) expression/activity via melatonin receptors, and increased intracellular lactate production in rodent Sertoli cells. Interestingly, oral melatonin supplementation in infertile men positively regulated LDHA testicular mRNA expression. Overall, our work provides insights into the potential benefits of melatonin on Sertoli cells contributing to testicular development and the future establishment of a sustainable spermatogenesis.
Numerous evidences have alerted on the toxic effects of the exposure to glyphosate on living organisms. Glyphosate is the herbicide most used in crops such as maize and soybean worldwide, which implies that several non-target species are at a high risk of exposure. Although the Environmental Protection Agency (EPA-USA) has reaffirmed that glyphosate is safe for users, there are controversial studies that question this statement. Some of the reported effects are due to exposure to high doses; however, recent evidences have shown that exposure to low doses could also alter the development of the female reproductive tract, with consequences on fertility. Different animal models of exposure to glyphosate or glyphosate-based herbicides (GBHs) have shown that the effects on the female reproductive tract may be related to the potential and/or mechanisms of actions of an endocrine-disrupting compound. Studies have also demonstrated that the exposure to GBHs alters the development and differentiation of ovarian follicles and uterus, affecting fertility when animals are exposed before puberty. In addition, exposure to GBHs during gestation could alter the development of the offspring (F1 and F2). The main mechanism described associated with the endocrine-disrupting effect of GBHs is the modulation of estrogen receptors and molecules involved in the estrogenic pathways. This review summarizes the endocrine-disrupting effects of exposure to glyphosate and GBHs at low or "environmentally relevant" doses in the female reproductive tissues. Data suggesting that, at low doses, GBHs may have adverse effects on the female reproductive tract fertility are discussed.
Follistatin is an activin-binding protein, which inhibits activin bioactivity in several biological systems. In the present study it is demonstrated that preincubation of iodinated activin A with follistatin, purified from porcine follicular fluid, completely abolished the binding of activin to activin type IIA, IIB2 and IIB4 receptors, and consequently to activin type IB receptor, transiently transfected in COS cells. Binding of activin A to membrane proteins on the activin-responsive P19 embryonal carcinoma cells was also prevented by this follistatin preparation. The same results were obtained with a carboxy-terminally truncated form of follistatin (FS-288), which is only present in minor amounts in the purified follistatin preparation. Since FS-288 has a high affinity for heparan sulfate proteoglycans on the cell surface, we tested whether membrane-bound FS-288 presents activin A to the different activin receptors, thereby facilitating activin binding. FS-288 did bind to the cell surface of transfected COS cells, but inhibited the binding of activin A to its receptors IIA, IIB2 and IIB4. Furthermore, after addition of FS-288 to K562 erythroleukemia cells, the total binding of activin via cell surface-bound FS-288 was increased, whereas the binding of activin A to activin type II and type I receptors present on these cells was inhibited. These findings reveal that different forms of follistatin can neutralize activin bioactivity by interference with binding of activin to all known activin type II receptors, rather than that they inhibit the binding of the type I receptor to the activin/activin type II receptor complex. In addition, our studies indicate that cell surface-associated follistatin cannot present ligand to signalling receptors.