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Our concept of human ovarian reserve presumes that the ovary develops several million nongrowing follicles (NGFs) at around 5 months of gestational age. Over the life span of a female, it undergoes a monthly cycle of oocyte maturation as well as integrated endocrine function, which results in a gradual decline of these NGFs. This process continues up to the age of menopause, around 50–51 years, when approximately 1000 NGFs remain ( Fig. 4.1 ). In light of this fact, several biomarkers have evolved to predict as well as evaluate the existing ovarian oocyte pool and foresee the procreative capacity of a human female. More importantly, advanced and assisted reproductive techniques (ARTs) depend heavily upon this background information. Hence, it is a matter of concern to understand the current scientific concepts and available evaluation parameters for ovarian reserve. To make matters even more complex, several hereditary diseases and systemic conditions are associated with decreased ovarian reserve (DOR), which needs to be thoroughly entailed in the clinical situation as well.
Nature has designed ovaries to provide a composite endocrine and reproductive function in a human female. The cascade of events happening during a menstrual cycle is the interplay of various hormones, which help in the fulfillment of these functions. These hormones originate not only from the ovaries but involve the hypothalamus and pituitary gland. However, there are certain autocrine and paracrine factors working alongside the pituitary ovarian axis that have critical roles in reproductive function. These include transforming growth factor-β (TGF-β) family peptides: inhibin A, inhibin B, activin, and the anti-Mullerian hormones.
A clear description of cortex and medulla in the ovaries is not universally defined, but for functional understanding, cortex includes an area of developing and maturing germ cells, while the medulla is a composition of loose connective tissue. Further details of cortex include surface germinal epithelium, followed by loose mesenchymal cells interspersed between cortical sex cords. This close placement of germ cells and mesangium is meant to provide a well-nurtured and interactive environment for the timely maturation of ovarian follicles. One end of each ovary is designated as the hilum, which aligns the blood vessels and lymphatics to and from the ovaries and provides a surface attachment in the form of mesovarium to the broad ligament.
Ovaries are surrounded by a cuboidal germ cell epithelium. This is formed during embryogenesis by the differentiation of somatic cell lineage into primordial germ cells. Several growth factors and ligand interaction lead to the final settlement of these primordial cells on the genital ridge, after which they are referred to as oogonia . From there starts the development of primordial follicles with oogonia transforming into mitotic stage oocytes . These primordial oocytes then differentiate further into primary oocytes within the primary follicles ( Fig. 4.2 ). Finally, any progenitor cell’s capability to differentiate into primordial cells is stopped at the stage when oocytes enter into meiosis, and subsequently, further maturation is arrested. This landmark developmental step usually happens around the 8th week of gestation. In reproductive biology, this checkpoint has been conceptualized to mark the final oocyte pool in a human female for her lifetime. However, several experiments over the last decade have negated this concept. On the contrary, clear confirmation about ovarian stem cell reserve and its role in forming an essential component of ovarian reserve is still under development.
After having laid down the essential cellular pillar for human development, it is important to understand its functional chemistry. Several intraovarian paracrine factors and genes take part in the recruitment of early primordial follicles for the developing cohort as detailed in Table 4.1 .
Paracrine factors | Genes |
---|---|
FIGLA; factor in the germline-α | NOBOX; newborn oogenesis homeobox gene |
Foxl2; forkhead box L2 | BMP15; bone morphogenetic protein 15 gene |
KIT; kit receptor | BRCA1; breast cancer type 1 susceptibility protein gene |
KITL; kit ligand | LHCGR; luteinizing hormone/choriogonadotropin receptor gene |
IGF; insulin-like growth factor | STAR; steroidogenic acute regulatory protein gene |
GDF9; growth differentiation factor 9 | CYP11A1; side-chain cleavage enzyme gene |
AMH; anti-Mullerian hormone | HSD3B2; 3β-hydroxysteroid dehydrogenase isomerase type 2 gene |
NGF; nerve growth factor | CYP17A1; 17-hydroxylase/17,20-lyase gene |
BDNF; brain-derived neurotrophic factor | |
NT-3 and NT-4; neurotrophin-3 and neurotrophin-4 | |
GDNF; glial cell line-derived neurotrophic factor | |
Inhibin A and inhibin B | |
Activin |
Stages from primary, secondary, and tertiary follicular growths are therefore follicular-stimulating hormone (FSH)-independent and occur over several menstrual cycles after puberty. Maturation of oocytes beyond the meiotic stage comes under the prepubertal FSH effect when each oocyte becomes surrounded by granulosa cell layer. This layer eventually converts into a selected Graafian follicle at the time of puberty when FSH levels are raised in a critical time frame. In each menstrual cycle, the estradiol levels reach their peak near mid-cycle resulting in the complete maturation of a dominant ovarian follicle to mark the process of ovulation . But it is only after the luteinizing hormone (LH) surge that ovulation occurs, releasing a mature ovum for fertilization.
The transition of the Graafian follicle to corpus luteum after ovulation, a process called luteinization , and its sustainability are dependent on the continuous supply of LH or its surrogate human chorionic gonadotropin. The key function of constant large production of progesterone from corpus luteum depends on low density lipoprotein (LDL)-cholesterol and functional mitochondrial steroidogenic acute regulatory (STAR) protein. If pregnancy does not take place, then the life of corpus luteum is around 14 days; subsequently, it converts into corpus albicans .
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