A detailed understanding of the paracrine, endocrine and molecular mechanisms regulating follicle and oocyte growth and maturation in vivo are critically important for the production of high -quality oocytes for use in vitro during assisted conception treatment.

The mechanism involved in the release of the hormones through each gland has an important influence on regulating the functions of the human body. Hypothalamus regulates the signals to enable different functioning like growth and aging, reproduction, insulin secretions and other essential functions of the body. Although, there are a lot of factors to be considered in Assisted Conception Technique , but the three major factors are : Quality of the uterus(endometrial lining) , Sperm quality(morphological study) , Follicle stimulation, and oocyte retrieval. In in-vitro fertilization, constant monitoring and evaluation of follicle maturation and growth leads to retrieval of high quality oocytes. Essentially, hormone secretion and mechanism at the molecular level regulate and control follicular growth.

Mechanism Regulating Follicle Growth and Maturation

Folliculogenesis is the maturation of the ovarian follicles, which depends upon paracrine, endocrine, and molecular interactions. In the in-vivo fertilization process and assisted in-vivo fertilization, follicle growth and development in both ovulatory and anovulatory ovaries happens with constantly receiving signals from the paracrine. The follicle to oocyte development; from the primordial follicle stage (30-40 um) to the ovulation (17-19 mm) receives different paracrine signaling varying from the secretions of the pituitary to the metabolic changes to molecular regulation and the cell to cell interaction with the somatic cell for follicular activation. The activation of the follicular factors include gonadotropins(GnRH) interactions, metabolic factors , steroids and other growth factors produced in follicles, which are essential for a signaling governing the follicular growth , development and maturation. These signals affect each other critically, and the coordination between these signals is most important for production and retrieval of oocytes. On the day2 of mensural cycle when the endometrium sheds , pituitary starts to release Follicle Stimulating Hormone(FSH) , Luteinizing Hormone(LH) and some other realizing hormones like Thyroxine Stimulating Hormone(TSH) , Prolactin(PRL) in the blood stream. Evidence and studies have proved that paracrine mechanisms hold major role in ovarian physiology. Paracrine factors diffuses the signals to the ovaries about the production of pituitary hormones , meanwhile, ovaries produce estradiol and progesterone responsible for follicle growth and endometrial thickening. In assisted conception techniques, it is important to know factors like Anti-Mullerian Hormone ((AMH) which reflects the ovarian reserve) , FSH , LH and Antral Follicle Count ((AFC) on ultrasonography). During in-vitro fertilizations it is necessary to stimulate the ovaries with hormone-induced medications like FSH , LH , GnRH , estradiol , leuprolide , HMG(Human Menopausal Gonadotropin , HCG(Human Chronic Gonadotropin) for 8 to 14 days starting from day2 of mensural cycle. Essentially and predictably the most common factors that predicts the quality and count of oocytes to be retrieved are : AMH levels, AFC and age. AMH levels is the ovarian reserve count , also the predictor of how many follicles is an ovary capable of maturing. The Antral Follicle Count (AFC) in done on ultrasonography to count number of antral follicles. However , studies have proven that any female above age of 35 , starts to naturally lose quality of oocytes produced by the ovary. This indicates that the age plays an important role for considering the quality of oocyte to expect. Therefore , in any ovarian stimulation it is important to consider all factors so as to retrieve good and high quality oocytes.

Ovarian Stimulation

Hypothalamus controls the production of hormones throughout the body, it stimulates the cell 2 gonadotropins anterior to the pituitary to release GnRH present on the 8p21 which further releases FSH and LH. The release of FSH signals the ovaries to start the follicular phase of the mensural cycle, which also signals the ovaries to produce estradiol and progesterone. The ovaries in the feedback mechanism in return influence the release of GnRH from the pituitary. High concentrations of FSH stimulates the growth of antral follicles, and granulosa cell, which leads to their proliferation and differentiation, and further encourages the action of aromatase (enzyme) in the conversion of the basic androgens to androstenedione and testosterone to estrogen. The rising concentration of FSH levels induces LH receptors on the dominant follicle. The LH surge is triggered when the concentrations of the estradiol have reached a considerably critical point. Functionally LH encourages the production of androgens by theca cells. The androgens, androstenedione, and testosterone then induced by FSH are now passed on to the granulosa cells, which interact with aromatase (CYP19). The function of aromatase is to convert androgens, androstenedione and testosterone into osteogeny, further to estradiol and also estrone. Aromatase acts on estrogen production, which is earlier controlled by FSH and now by LH. Therefore,the function of theca cells are controlled by LH, and granulosa cells are controlled by FSH. During assisted ovarian stimulation, GnRH is administered ovulation is successfully induced. If FSH is only used to induce ovulation by directly stimulating the ovaries, the lack of LH and the lack of production of androgen substrate allows the growth of follicles but does not produce estradiol. The combination of FSH along with other stimulating factors also helps in retrieving good quality oocytes. Once the follicles have reached the desired size of 17-19mm (considering the dominant follicle) , ovulation is triggered. Ovulation is triggered by hCG or recombinant LH in cases when large follicles are expected to be obtained, but unfortunately in this case implantation does not occur due to lack of estrogen stimulation on the endometrium thickening.

Conclusion

The process of reproduction takes paracrine and endocrine functions hand-in-hand with constant changes in molecular interaction and feedback mechanism to undergo follicle growth to ovulation which will further lead to implantation. The patient response to controlled ovarian stimulation is an essential factor associated with successful clinical outcomes for IVF-ET treatment. A poor and failure to achieve desired ovarian response is either due to idiopathic factors or other factors relevant to the condition of patient age , hormone imbalance, AMH levels, and also unknown factors underlying failed ovarian response. The hypothalamus controls the endocrine and paracrine, which primarily does the cell signaling at the basic hormone interaction and concentration that constantly changes for cell growth and maturation. The paracrine functioning can be monitored and not controlled while endocrine secretions can be induced, controlled and monitored. For a successful assisted conception technique, it is necessary to understand the interaction and functioning of different hormones of ovaries and how they respond to the GnRH induced to the body. Constant monitoring of the externally acted sources on the ovaries is essential until the dominant follicle is ready to rupture. However, paracrine interaction with endocrine secretion cannot be administered without proper signaling from the hypothalamus, ovarian stimulation is complex yet critical to monitor and analysis for successful clinical pregnancy.

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