Female Fertility: It Takes Two to Tango

The ovary is a complex and well-orchestrated organ with important exocrine and endocrine functions in sexual reproduction and maintenance of secondary sexual characteristics. The germ cells (oocytes) and somatic cells (granulosa cells, thecal cells, and stromal cells) of the ovary work in a highly integrated manner to control oocyte development and to secrete sex steroids and protein hormones. The most important role of the ovary is its cyclical maturation of ovarian follicles followed by establishment of a dominant follicle (Graafian follicle) and subsequent release of an oocyte. This process, termed folliculogenesis, requires a precise sequence and temporal pattern of gene expression by the theca and granulosa cells and the oocyte. Folliculogenesis can be divided into two phases: the gonadotropin-independent (preantral) and gonadotropin-dependent (antral) periods. The preantral phase is controlled mainly by locally produced growth factors through autocrine/paracrine mechanisms (1) and can take up to 300 days. The antral period, on the other hand, is highly dependent on follicle-stimulating hormone (FSH)/luteinizing hormone (LH), and development of follicles to the preovulatory stage can take up to 50 days. In mice and humans, inactivation of the pulsatile release of FSH through mutations in the FSHβ subunit or FSH receptor gene prevents selection of a dominant follicle resulting in absence of antral follicles.

A follicular unit is composed of an oocyte, granulosa cells, and theca cells. Of these, only granulosa cells express follicle-stimulating hormone receptors (FSHRs) (2). FSHR signaling pathways play a fundamental role in growth and differentiation of the dominant follicle. They promote follicular fluid formation, cell proliferation, estradiol production, and LH receptor expression. The mechanisms by which FSHR activation in granulosa cells result in successful progression of one follicle into the antral phase, whereas other follicles undergo atresia, are unclear.

Ovarian follicles, particularly the dominant follicle, release numerous growth factors, including insulinlike growth factors (IGFs) and IGF-binding proteins with important paracrine/autocrine actions (2, 3). In mice, insulinlike growth factor 1 receptors (IGF1Rs) are selectively expressed in granulosa cells of healthy growing ovarian follicles in a pattern similar to that of FSHR. Insulinlike growth factor 1 (IGF1) stimulates follicular steroidogenesis (either alone or in synergy with gonadotropins). Whereas IGF1 knockout mice have primordial follicles, follicle development stops at the preantral stage, notably because of decreased FSHR expression. Thus, in humans and rodents, even in the presence of FSH, folliculogenesis cannot proceed in the absence of IGF1R activation. The molecular mechanisms mediating these important effects of IGF1 remain largely unknown.

It has been hypothesized that the role of IGF is to amplify gonadotropin hormonal actions (4). Molecular studies in mice have shown that although FSH does not affect IGF1 expression, IGF1 augments granulosa cell FSHR expression, suggesting that ovarian IGF1 expression serves to enhance granulosa cell FSH responsiveness (5). Zhou et al. (5) further demonstrated that FSH actions on granulosa cell differentiation in vitro depend on the presence of IGF1 and active IGF1R and that IGF1R inhibition blocks FSH-induced follicle growth in immature rats.

There is abundant evidence that the intracellular pathways activated by FSHR and the IGF1R cooperate closely to maintain normal granulosa cell function (Fig. 1). FSHR activates the cyclic adenosine monophosphate/protein kinase A pathway, phosphoinositide 3-kinase pathway/protein kinase B (AKT), and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways that also mediate IGF1 actions (6, 7).

Figure 1.

Proposed molecular pathways by which granulosa cell IGF1R and FSHR collaborate to generate follicular maturity. AKT phosphorylation requires both IGF1R and FSHR activation and is essential for granulosa cell differentiation, proliferation, and survival. More importantly, failure of IGF1R to phosphorylate AKT inhibits advancement of folliculogenesis. cAMP, cyclic adenosine monophosphate; CREB, cAMP response element binding protein; ERK, extracellular signal-regulated kinase; GC, granulosa cell; mTOR, mechanistic target of rapamycin; P, phosphorylation; PI3K, phosphoinositide 3-kinase; PIP3, phosphatidylinosiitol (3,4,5)-triphosphate; PKA, protein kinase A.

In this issue of Endocrinology, Baumgarten et al. (8) demonstrate an obligatory role of IGF1R in the regulation of survival, proliferation, and differentiation of granulosa cells during folliculogenesis in vivo. Prior in vivo studies were thwarted by the severe defects and short life span in mouse models with globally deficient IGF1 or IGF1R (9). A clever strategy was used to generate granulosa cell-specific IGF1R knockout mice. Animals carrying both Esr2Cre and Cyp19Cre were used to obtain maximal recombination of the IGF1R floxed allele, thereby generating mice with undetectable IGF1R transcripts in granulosa cells (IGF1R^gcko). Follicular development did not progress beyond the preantral stage in IGF1R^gcko mice.

Previously, it was proposed that the role of IGF1 was to augment FSHR expression in granulosa cells of dominant follicles (5). Here, the authors reveal that granulosa cell expression of FSHR was similar in wild-type and IGF1R^gcko mice. Nonetheless, FSH failed to stimulate AKT phosphorylation in IGF1R^gcko. Because AKT phosphorylation is essential for differentiation of granulosa cells, the authors hypothesize that this is the true mechanism by which IGF1-IGF1R signaling is crucial for granulosa cell growth and differentiation. Granulosa cell IGF1R was crucial for escape from apoptosis during transition from primary to secondary follicles. IGF1R, therefore, is an important partner with FSHR for advanced follicle survival. These findings may have important implications for ovarian cancer. Increased IGF expression is often an indication of drug resistance. Further characterization of FSHR/IGFR molecular mechanisms may provide novel ovarian cancer therapies. In addition, it is possible that these finding may improve our understanding of female fertility, puberty, and menopause, as well as allow safer and more effective ovulation induction in women with polycystic ovarian syndrome, diminished ovarian reserve, and primary ovarian sufficiency. The role of puberty, aging, ovarian toxins, and steroid hormone signaling pathways on IGF1R-FHSR crosstalk is a fertile field for research.