The female reproductive system regulates the hormonal changes responsible for puberty and adult reproductive function. Normal reproductive function in women requires the dynamic integration of hormonal signals from the hypothalamus, pituitary, and ovary, resulting in repetitive cycles of follicle development, ovulation, and preparation of the endometrial lining of the uterus for implantation should conception occur.
For further discussion of related topics, see the following chapters: hyperandrogenic disorders (Chap. 49), menstrual cycle disorders (Chap. 50), gynecologic malignancies (Chap. 97), sexually transmitted diseases (Chap. 130), male hormonal contraception (Chap. 346), menopause (Chap. 348), and sexual differentiation (Chap. 349).
The ovary orchestrates the development and release of a mature oocyte and also elaborates hormones (e.g., estrogen, progesterone, inhibin, relaxin) that are critical for pubertal development and preparation of the uterus for conception, implantation, and the early stages of pregnancy. To achieve these functions in repeated monthly cycles, the ovary undergoes some of the most dynamic changes of any organ in the body. Primordial germ cells can be identified by the third week of gestation and their migration to the genital ridge is complete by 6 weeks' gestation. Germ cells persist within the genital ridge, are then referred to as oogonia, and are essential for induction of ovarian development. Although one X chromosome undergoes X inactivation in somatic cells, it is reactivated in oogonia and genes on both X chromosomes are required for normal ovarian development. A streak ovary containing only stromal cells is found in patients with 45,X Turner's syndrome (Chap. 349).
The germ cell population expands, and starting at ˜8 weeks' gestation, oogonia begin to enter prophase of the first meiotic division and become primary oocytes. This allows the oocyte to be surrounded by a single layer of flattened granulosa cells to form a primordial follicle (Fig. 347-1). Granulosa cells are derived from mesonephric cells that invade the ovary early in its development, pushing the germ cells to the periphery. Although recent studies have reopened the debate, the weight of evidence strongly supports the concept that the ovary contains a nonrenewable pool of germ cells. Through the combined processes of mitosis, meiosis, and atresia, the population of oogonia reaches its maximum of 6–7 million by 20 weeks' gestation, after which there is a progressive loss of both oogonia and primordial follicles through the process of atresia. At birth, oogonia are no longer present in the ovary, and only 1–2 million germ cells remain in the form of primordial follicles (Fig. 347-2). The oocyte persists in prophase of the first meiotic division until just before ovulation, when meiosis resumes.
Stages of ovarian development from the arrival of the migratory germ cells at the genital ridge through gonadotropin-independent and gonadotropin-dependent phases that ultimately result in ovulation of a mature oocyte. FSH, follicle-stimulating hormone; LH, luteinizing hormone.
Ovarian germ cell number is maximal at mid-gestation, then decreases precipitously.
The quiescent primordial follicles are recruited to further growth and differentiation through a highly regulated process that limits the size of the developing cohort to ensure that folliculogenesis can continue throughout the reproductive life span. This initial recruitment of primordial follicles to form primary follicles (Fig. 347-1) is characterized by growth of the oocyte and the transition from squamous to cuboidal granulosa cells. The theca interna cells that surround the developing follicle begin to form as the primary follicle grows. Acquisition of a zona pellucida by the oocyte and the presence of several layers of surrounding cuboidal granulosa cells mark the development of secondary follicles. It is at this stage that granulosa cells develop follicle-stimulating hormone (FSH), estradiol, and androgen receptors and communicate with one another through the development of gap junctions.
Bidirectional signaling between the germ cells and the somatic cells in the ovary are a necessary component underlying the maturation of the oocyte and the capacity for hormone secretion. For example, the oocyte-derived factor in the germlineα(FIGα) is required for initial follicle formation. Anti-müllerian hormone [AMH, also known as mullerian inhibiting substance (MIS)] and activins derived from somatic cells induce the development of primary follicles from primordial follicles. Oocyte-derived growth differentiation factor 9 (GDF-9) is required for migration of pre-theca cells to the outer surface of the developing follicle. GDF-9 is also required for formation of secondary follicles, as are granulosa cell–derived KIT ligand (KITL) and the forkhead transcription factor (FOXL2). All of these genes are potential candidates for premature ovarian failure in women, and mutations in the human FOXL2 gene have been shown to cause the syndrome of blepharophimosis/ ptosis/epicanthus inversus, which is associated with ovarian failure.
The early stages of follicle growth are primarily driven by intraovarian factors and may take up to a year from the time of initial recruitment. Maturation to the state required for ovulation, including the resumption of meiosis in the oocyte, requires the combined stimulus of FSH and luteinizing hormone (LH) (Fig. 347-1) and can be accomplished within weeks. This phase of recruitment of secondary follicles from the resting follicle pool requires the direct action of FSH. Accumulation of follicular fluid between the layers of granulosa cells creates an antrum that divides the granulosa cells into two functionally distinct groups: mural cells that line the follicle wall and cumulus cells that surround the oocyte (Fig. 347-3). Recent evidence suggests that, in addition to its role in normal development of the mullerian system, the WNT signaling pathway is required for normal antral follicle development and may also play a role in ovarian steroidogenesis. A single dominant follicle emerges from ...