The Dual Role of Ovarian Follicles in Human Health and Disease The total number of follicle-enclosed oocytes in the ovary is set at birth.5 In a 20 week human fetus, there are approximately 7-8 million oocytes in the immature gonad. The most rapid period of oocyte loss occurs in utero and only 1 million oocytes remain in the ovary at birth. After birth, the rate of oocyte loss slows and is quite steady, with a gradual loss to a population of about 400,000 oocytes at the time of menarche. Less than 500 of the 400,000 oocytes eventually ovulate in an ordered or methodical fashion. The follicle serves two roles in the adult: it provides the potential for sexual propagation and produces appropriate levels of steroid and peptide hormones to control reproductive and non-reproductive tissue function. Normal follicle selection occurs in response to folliclestimulating hormone (FSH) action on preantral follicles that express sufficient levels of the FSH receptor (FSHR) via stimulation of intracellular cAMP levels.6 Subsequent activation of the PKA signal transduction pathway causes a switch in SF-1-LRH1 occupancy on the inhibin a-subunit promoter, resulting in the production of ovarian inhibin (and see Project II for an in-depth description of this regulatory pathway).1'7 Inhibin feeds back to the pituitary and blocks a constitutive activin signal, thereby reducing circulating FSH levels to pre-surge levels (and see Project III for an in depth description of activin and its interaction with its receptor).1'8"11 The granulosa cells then proliferate in conjunction with final cytoplasmic maturation of the oocyte, culminating in the release of a fertilizable egg at the time of ovulation (see Project /for details on the regulation of the ovarian follicle signaling pathways controlling coordinated granulosa cell-oocyte maturation). The release of a fertilizable oocyte is the defining role of the female reproductive axis. The inability to recruit or mature good quality gametes contributes to human infertility. Unlike any other process in the body, the maturation of eggs is time delimited and must occur before the supply of follicles is exhausted at menopause. Moreover, egg quality diminishes with time, and in some women, both the quantity and quality of the follicleenclosed egg is reduced more quickly than chronological age alone would predict. This phenomenology creates the dual problems of infertility (in those wishing to reproduce) and loss of premenopausal hormone homeostasis. Thus, two major questions are posed, how are individual follicles selected from the large starting pool and what contributes to the quality of their genetic content? Hormones Regulate Follicle Selection There are three phases of follicular development defined by the actions of endocrine hormones and paracrine-acting factors. The initial development of primordial follicles to primary through early secondary stages is generally considered independent of gonadotropin control.12 These stages occur in the absence of FSH and luteinizing hormone (LH), as shown in studies of gonadotropin knockout mice,13'14 and a hypogonadotropic pituitary mouse model.15 Instead, early follicle assembly, granulosa cell proliferation and oocyte maturation depend on a sequence of local oocyte-, granulosa- and theca cell-derived factors. Neither these factors nor the sequence of events is completely understood. Roughly, it is thought that platelet-derived growth factor (PDGF) and bone morphogenic protein 6 (BMP6) are produced by primordial oocytes and contribute to primordial follicle quiescence.16'1? Developing follicles also produce anti-Mullerian hormone (AMH), which also inhibits primordial follicle activation and development.18 Signals of unknown origin induce BMP15 expression in oocytes, which stimulates granulosa cell proliferation (in all species except mice).19 Additionally, bFGF expression from oocytes upregulates kit ligand (KL) expression in granulosa cells. Kit ligand from granulosa cells in turn stimulates stromal and theca cell growth20"22 and enhances theca cell recruitment from the surrounding stromal cells.23 As a result, theca cells express BMP4/7 and the cells align along a basement membrane of primary and secondary follicles.24'25 At this point in development, the oocyte produces growth differentiation factor 9 (GDF9), which may maintain theca cell .