Taylor_Speroff's Clinical Gynecologic Endocrinology and Infe

258 Section II • Clinical Endocrinology

follicles are separated from the somatic cells by a surround ing basement membrane. In some primordial follicles, the pregranulosa cells become cuboidal and proliferate, the oocyte enlarges and produces a zona pellucida (an extracel lular glycoprotein matrix deposited between the oocyte and the granulosa cells), and a surrounding layer of thecal cells develops. The remainder stay quiescent until sometime later. The molecular events that regulate primordial follicle for mation and that stimulate or inhibit the initiation of follicular development are understood poorly but appear to involve a variety of factors, all locally produced and regulated, includ ing members of the transforming growth factor β (TGF- β ) superfamily of proteins and another family of trophic factors called neurotrophins. Activins, inhibins, antimüllerian hor mone (AMH), and bone morphogenetic proteins (BMPs) are members of the TGF- β family of proteins. Activins promote and inhibins retard primordial follicle development, and their relative local concentrations in the fetal ovary during the time of follicle assembly may determine the size of the ovarian follicular pool. 71 AMH appears to be an important inhibitor of primordial follicle growth, and BMPs exert the opposite effect. 71 AMH action is mediated, at least in part, by the tran scription factor Osterix (Osx), which influences regression of müllerian ducts. 72 Neurotrophins and their receptors are essential for the differentiation and survival of various neu ronal populations in the central and peripheral nervous sys tems, but their presence in the developing ovary suggests they also play a role in ovarian development. Four mammalian neurotrophins have been identified, including nerve growth factor (NGF), brain-derived neurotropic factor (BDNF), neu rotrophin-3 (NT-3), and neurotrophin 4/5 (NT-4/5), all of which exert their actions via binding to high-affinity trans membrane tyrosine kinase receptors encoded by members of the trk proto-oncogene family (NGF to TrkA, BDNF and NT-4/5 to TrkB, and NT-3 to TrkC). 73 Observations in NGF- and TrkA-null mice indicate that NGF stimulates the prolifer ation of ovarian mesenchymal cells during the early stages of follicular assembly and promotes differentiation and synthesis of follicle-stimulating hormone (FSH) receptors in granulosa cells. Similar experiments with TrkB -null mice suggest that TrkB signaling is required for oocyte survival after follicular assembly and for preantral follicular development. 73 The spe cific signaling mechanisms that mediate the effects of activins, inhibins, BMPs, and neurotrophins remain to be established. Other paracrine factors mediate a bidirectional commu nication between oocytes and their surrounding granulosa cells. Oocytes are linked to their investment of granulosa cells via gap junctions, which allow passage of small mol ecules such as ions (e.g., calcium), metabolites (e.g., pyru vate, nucleic acids, inositol), amino acids (e.g., l-alanine), cholesterol, and intracellular signaling molecules (e.g., cyclic adenosine monophosphate, cAMP) between granulosa cells and oocytes. In mice, targeted deletions of gap junction proteins (known as connexins), disrupt follicular and oocyte development. 70,74–76

Basal lamina

Leydig cells

Germ cells

Sertoli cells

Endothelial cells

Peritubular myoid cells

FIGURE 8.4

Ovary Differentiation and Development In females lacking a Y chromosome and SRY , the bipotential gonad begins to differentiate into an ovary about 2 weeks later than testis development begins in the male. Normal ovarian differentiation requires the presence of germ cells; in their absence, the gonadal somatic cells fail to differentiate, indi cating some form of communication between germ cells and somatic cells. 53 Wnt4 and Rspo1 are two genes that play an important role in ovarian differentiation; XX mice with targeted deletions of either gene develop ovotestes contain ing sex cords and functional Leydig cells. 43 Wnt4 expression suppresses the migration of mesonephric endothelial and steroidogenic cells as occurs in the developing testis. This action of Wnt4 is dependent on Rspo1 . 41,43 Rspo1 expression is specifically up-regulated in XX somatic cells from the earli est stages of gonadal differentiation and encodes a secreted protein that, like WNT4, activates the β -catenin signaling pathway in somatic cells, resulting in a loss of cell-cell adhe sion between female germ cells, which is a prerequisite for their entry into meiosis. 43 Consequently, directly or indirectly, RSPO1 regulates female germ cell and ovarian differentiation, by promoting events required for initiation of meiosis, by inhibiting migration of mesonephric cells via Wnt4 expres sion, and by down-regulating Sox9 , which drives testis differ entiation. Thus, whereas testis differentiation is directed by somatic cells, ovary differentiation requires communica tion between somatic cells and germ cells. 70 Gradually, the developing ovary becomes organized into an outer cortex and an inner medullary region, which ulti mately regresses, leaving behind a compressed nest of vestigial tubules and Leydig cells in the hilar region known as the rete ovarii. By 20 weeks of gestation, the ovary achieves mature compartmentalization, consisting of an active cortex contain ing follicles exhibiting early stages of maturation and atre sia, and a developing stroma. Within the cortex, primordial

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