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    It Takes Two To Tango

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    N EW S A ND V IE W S

    Female Fertility: It Takes Two to Tango

    Lucy X. Chen1 and Patricia T. Jimenez1


    1
    Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Texas
    Southwestern Medical Center, Dallas, Texas 75390

    Downloaded from https://academic.oup.com/endo/article/158/7/2074/3920684 by guest on 13 October 2021


    he ovary is a complex and well-orchestrated organ mechanisms by which FSHR activation in granulosa cells
    with important exocrine and endocrine functions result in successful progression of one follicle into the
    in sexual reproduction and maintenance of secondary antral phase, whereas other follicles undergo atresia,
    sexual characteristics. The germ cells (oocytes) and so- are unclear.
    matic cells (granulosa cells, thecal cells, and stromal cells) Ovarian follicles, particularly the dominant follicle,
    of the ovary work in a highly integrated manner to release numerous growth factors, including insulinlike
    control oocyte development and to secrete sex steroids growth factors (IGFs) and IGF-binding proteins with
    and protein hormones. The most important role of the important paracrine/autocrine actions (2, 3). In mice,
    ovary is its cyclical maturation of ovarian follicles fol- insulinlike growth factor 1 receptors (IGF1Rs) are se-
    lowed by establishment of a dominant follicle (Graafian lectively expressed in granulosa cells of healthy growing
    follicle) and subsequent release of an oocyte. This pro- ovarian follicles in a pattern similar to that of FSHR.
    cess, termed folliculogenesis, requires a precise sequence Insulinlike growth factor 1 (IGF1) stimulates follicular
    and temporal pattern of gene expression by the theca and steroidogenesis (either alone or in synergy with gonad-
    granulosa cells and the oocyte. Folliculogenesis can be otropins). Whereas IGF1 knockout mice have primordial
    divided into two phases: the gonadotropin-independent follicles, follicle development stops at the preantral stage,
    (preantral) and gonadotropin-dependent (antral) pe- notably because of decreased FSHR expression. Thus, in
    riods. The preantral phase is controlled mainly by locally humans and rodents, even in the presence of FSH, fol-
    produced growth factors through autocrine/paracrine liculogenesis cannot proceed in the absence of IGF1R
    mechanisms (1) and can take up to 300 days. The an- activation. The molecular mechanisms mediating these
    tral period, on the other hand, is highly dependent on important effects of IGF1 remain largely unknown.
    follicle-stimulating hormone (FSH)/luteinizing hormone It has been hypothesized that the role of IGF is to amplify
    (LH), and development of follicles to the preovulatory gonadotropin hormonal actions (4). Molecular studies in
    stage can take up to 50 days. In mice and humans, in- mice have shown that although FSH does not affect IGF1
    activation of the pulsatile release of FSH through mu- expression, IGF1 augments granulosa cell FSHR expres-
    tations in the FSHb subunit or FSH receptor gene sion, suggesting that ovarian IGF1 expression serves to
    prevents selection of a dominant follicle resulting in enhance granulosa cell FSH responsiveness (5). Zhou et al.
    absence of antral follicles. (5) further demonstrated that FSH actions on granulosa cell
    A follicular unit is composed of an oocyte, granulosa differentiation in vitro depend on the presence of IGF1 and
    cells, and theca cells. Of these, only granulosa cells ex- active IGF1R and that IGF1R inhibition blocks FSH-
    press follicle-stimulating hormone receptors (FSHRs) (2). induced follicle growth in immature rats.
    FSHR signaling pathways play a fundamental role in There is abundant evidence that the intracellular path-
    growth and differentiation of the dominant follicle. They ways activated by FSHR and the IGF1R cooperate closely to
    promote follicular fluid formation, cell proliferation, maintain normal granulosa cell function (Fig. 1). FSHR
    estradiol production, and LH receptor expression. The activates the cyclic adenosine monophosphate/protein

    ISSN Print 0013-7227 ISSN Online 1945-7170 Abbreviations: AKT, protein kinase B; FSH, follicle-stimulating hormone; FSHR, follicle-
    Printed in USA stimulating hormone receptor; IGF, insulinlike growth factor; IGF1, insulinlike growth
    Copyright © 2017 Endocrine Society factor 1; IGF1R, insulinlike growth factor 1 receptor; IGF1Rgcko, insulinlike growth factor 1
    Received 9 May 2017. Accepted 11 May 2017. receptor transcripts in granulosa cells; LH, luteinizing hormone.

    For article see page 2309

    2074 https://academic.oup.com/endo Endocrinology, July 2017, 158(7):2074–2076 doi: 10.1210/en.2017-00447


    doi: 10.1210/en.2017-00447 https://academic.oup.com/endo 2075

    Downloaded from https://academic.oup.com/endo/article/158/7/2074/3920684 by guest on 13 October 2021


    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.

    kinase A pathway, phosphoinositide 3-kinase pathway/ crucial for granulosa cell growth and differentiation.
    protein kinase B (AKT), and mitogen-activated protein Granulosa cell IGF1R was crucial for escape from apo-
    kinase/extracellular signal-regulated kinase pathways ptosis during transition from primary to secondary fol-
    that also mediate IGF1 actions (6, 7). licles. IGF1R, therefore, is an important partner with
    In this issue of Endocrinology, Baumgarten et al. (8) FSHR for advanced follicle survival. These findings may
    demonstrate an obligatory role of IGF1R in the regulation have important implications for ovarian cancer. In-
    of survival, proliferation, and differentiation of granulosa creased IGF expression is often an indication of drug
    cells during folliculogenesis in vivo. Prior in vivo studies resistance. Further characterization of FSHR/IGFR mo-
    were thwarted by the severe defects and short life span in lecular mechanisms may provide novel ovarian cancer
    mouse models with globally deficient IGF1 or IGF1R therapies. In addition, it is possible that these finding may
    (9). A clever strategy was used to generate granulosa improve our understanding of female fertility, puberty,
    cell-specific IGF1R knockout mice. Animals carrying and menopause, as well as allow safer and more effective
    both Esr2Cre and Cyp19Cre were used to obtain ovulation induction in women with polycystic ovarian
    maximal recombination of the IGF1R floxed allele, syndrome, diminished ovarian reserve, and primary
    thereby generating mice with undetectable IGF1R ovarian sufficiency. The role of puberty, aging, ovarian
    transcripts in granulosa cells (IGF1Rgcko). Follicular toxins, and steroid hormone signaling pathways on
    development did not progress beyond the preantral IGF1R-FHSR crosstalk is a fertile field for research.
    stage in IGF1Rgcko mice.
    Previously, it was proposed that the role of IGF1 Acknowledgments
    was to augment FSHR expression in granulosa cells of
    Address all correspondence and requests for reprints to: Patricia
    dominant follicles (5). Here, the authors reveal that
    T. Jimenez, MD, Department of Obstetrics and Gynecology,
    granulosa cell expression of FSHR was similar in wild-
    Division of Reproductive Endocrinology, University of Texas
    type and IGF1Rgcko mice. Nonetheless, FSH failed to Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas,
    stimulate AKT phosphorylation in IGF1Rgcko. Because Texas 75390. E-mail: ptj6305@gmail.com.
    AKT phosphorylation is essential for differentiation This work received support from Grant K12 HD000849,
    of granulosa cells, the authors hypothesize that this is awarded to the Reproductive Scientist Development Program
    the true mechanism by which IGF1-IGF1R signaling is by the Eunice Kennedy Shriver National Institute of Child
    2076 Chen and Jimenez IGFR1 Is Crucial for Folliculogenesis Endocrinology, July 2017, 158(7):2074–2076

    Health & Human Development and by the Burroughs Well- 3. Wang HS, Chard T. IGFs and IGF-binding proteins in the regulation
    come Fund, as part of the Reproductive Scientist Development of human ovarian and endometrial function. J Endocrinol. 1999;
    161(1):1–13.
    Program.
    4. Adashi EY. The IGF family and folliculogenesis. J Reprod Immunol.
    Disclosure Summary: The authors have nothing to disclose. 1998;39(1-2):13–19.
    5. Zhou P, Baumgarten SC, Wu Y, Bennett J, Winston N, Hirshfeld-
    Cytron J, Stocco C. IGF-I signaling is essential for FSH stimulation of
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