As previously stated in our latest blog posts, the ovary is comprised of several cell types (somatic cells and germ), and undergoes dramatic changes in structure during menstrual cycle. Every step of folliculogenesis is controlled by the relevant hormones through hypothalamic-pituitary-ovarian (HPO) axis. The endocrine control of reproduction starts in hypothalamus with secretion of gonadotropin-releasing hormone (GnRH) in pulses that stimulates anterior pituitary gland, which in turn secretes luteinizing hormone (LH), and follicle-stimulating hormone (FSH).
FSH stimulates the growth of follicles, production of granulosa cells, and appearance of LH receptors on granulosa cells. Levels of estrogen produced by granulosa cells rise until threshold is achieved that elicits LH surge which is a trigger for ovulation. It is important to note that low levels of estrogen cause a negative feedback on FSH and LH secretion, also high levels of estrogen give a positive feedback. High levels of progesterone support negative feedback from estrogens, also keep FSH and LH levels low. Follicle activation is dependent of physical environment in addition to hormonal pathways. The more rigid ovarian cortex, the harder the follicle growth, and that biochemical environment modulates follicular response to hormones.
The role of steroids in follicular growth has been properly reviewed. Progesterone regulates granulosa cells, follicle rupture, and supports embryo implantation and pregnancy. Androgens appear to promote folliculogenesis in early stages, also it enhances FSH-mediated differentiation of granulosa cells and play roles in oocyte maturation. Androgen homeostasis in developing antral and preantral follicle is crucial for growth and oocyte maturation. Those findings are very important in treating fertility issues caused by polycystic ovarian syndrome (PCOS). Estrogen promotes follicle growth, facilitating granulosa cells differentiation, and induces receptors for FSH and LH. The main role of estrogen in folliculogenesis is enhancement through estrogen receptor b, and it appears to regulate cyclic gonadotropin release in ovulation process. However, it doesn’t seem to have an impact on oocyte quality and developmental potential.
Mechanism for LH surge is very complex, and timing is crucial in order to achieve a fully matured and grown oocyte ready for fertilization. Oocytes are dormant in prophase 1 and need to complete first meiotic division in order to be mature for fertilization, they don’t have LH receptors so LH surge acts through alternating pathways. A limited number of ligands that are induced by the LH surge to promote germinal vesicle breakdown, and resumption of meiosis.
It is interesting to analyze the effect of ovulation triggering in controlled ovarian hyperstimulation protocols. The differences in beta HCG and GnRH agonist are triggering and their effect on luteal phase of the cycle and endometrial receptivity. Beta HCG shares the same receptors as LH owing it to similar structure to LH and is therefore used as a trigger ovulation in females undergoing controlled ovarian hyperstimulation. It has a longer half-life when compared to LH and causes multiple corpora lutea and brings the patient to a higher risk of ovarian hyperstimulation syndrome, a potentially dangerous state for a patient with serious consequences. GnRH triggering as an alternative has shown a significant reduction and sometimes complete elimination of OHSS symptoms.
Anti-Müllerian hormone (AMH) is produced by developing oocytes and granulosa cells, it exerts a negative inhibitory effect on primordial follicles transitioning to primary follicles, and it is an indirect marker for ovarian reserve. AMH serum levels were monitored and the conclusion was done that its concentrations declined over time and it correlates with antral follicle count (AFC) and age and that it is a good marker for ovarian reserve. AMH may regulate the efficiency of the usage of the primordial follicle pool, and thus have a confirmed role in the determination when female will enter menopause. There is a difference of AMH expressed in cumulus and granulosa cells of large antral and preovulatory follicles and cumulus cells had significantly higher levels of AMH. AMH may exert intrafollicular functions in preovulatory follicles and can be related to follicular health.
There are some external hormones too that can have an effect on estrous cycle, and folliculogenesis besides sexual hormones. Allopregnanolone, which is a neuro-steroid, effects sexual behavior and anxiety and can have an effect on estrous cycle by interfering with regression of corpus luteum prolonging its existence, decreasing the number of developing follicles. Since ovaries have receptors for cortisol, they are susceptible to its effects. There is evidence for free cortisol accumulation in preovulatory follicle and that cortisol may reduce inflammatory reactions after ovulation and that corpus luteum benefits from it too.