The Dual Role of Ovarian Follicles in Human Health and Disease The total number of follicle-enclosedoocytes in the ovary is set at birth.5 In a 20 week human fetus, there are approximately 7-8 million oocytes inthe immature gonad. The most rapid period of oocyte loss occurs in utero and only 1 million oocytes remain inthe ovary at birth. After birth, the rate of oocyte loss slows and is quite steady, with a gradual loss to apopulation of about 400,000 oocytes at the time of menarche. Less than 500 of the 400,000 oocytes eventuallyovulate in an ordered or methodical fashion. The follicle serves two roles in the adult: it provides the potentialfor sexual propagation and produces appropriate levels of steroid and peptide hormones to controlreproductive and non-reproductive tissue function. Normal follicle selection occurs in response to folliclestimulatinghormone (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 transductionpathway causes a switch in SF-1-LRH1 occupancy on the inhibin a-subunit promoter, resulting in theproduction of ovarian inhibin (and see Project II for an in-depth description of this regulatory pathway).1'7Inhibin feeds back to the pituitary and blocks a constitutive activin signal, thereby reducing circulating FSHlevels to pre-surge levels (and see Project III for an in depth description of activin and its interaction with itsreceptor).1'8'11 The granulosa cells then proliferate in conjunction with final cytoplasmic maturation of theoocyte, culminating in the release of a fertilizable egg at the time of ovulation (see Project /for details on theregulation 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 ormature good quality gametes contributes to human infertility. Unlike any other process in the body, thematuration 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 follicleenclosedegg is reduced more quickly than chronological age alone would predict. This phenomenologycreates the dual problems of infertility (in those wishing to reproduce) and loss of premenopausal hormonehomeostasis. Thus, two major questions are posed, how are individual follicles selected from the large startingpool and what contributes to the quality of their genetic content?Hormones Regulate Follicle Selection There are three phases of follicular development defined by theactions of endocrine hormones and paracrine-acting factors. The initial development of primordial follicles toprimary through early secondary stages is generally considered independent of gonadotropin control.12 Thesestages occur in the absence of FSH and luteinizing hormone (LH), as shown in studies of gonadotropinknockout 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- andtheca 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 producedby primordial oocytes and contribute to primordial follicle quiescence.16'1? Developing follicles also produceanti-Mullerian hormone (AMH), which also inhibits primordial follicle activation and development.18 Signals ofunknown origin induce BMP15 expression in oocytes, which stimulates granulosa cell proliferation (in allspecies except mice).19 Additionally, bFGF expression from oocytes upregulates kit ligand (KL) expression ingranulosa cells. Kit ligand from granulosa cells in turn stimulates stromal and theca cell growth20'22 andenhances theca cell recruitment from the surrounding stromal cells.23 As a result, theca cells express BMP4/7and the cells align along a basement membrane of primary and secondary follicles.24'25 At this point indevelopment, the oocyte produces growth differentiation factor 9 (GDF9), which may maintain theca cell.
Showing the most recent 10 out of 63 publications
