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
he 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 so-
matic 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 fol-
lowed by establishment of a dominant follicle (Graafian
follicle) and subsequent release of an oocyte. This pro-
cess, 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) pe-
riods. The preantral phase is controlled mainly by locally
produced growth factors through autocrine/paracrine
mechanisms (1) and can take up to 300 days. The an-
tral 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, in-
activation of the pulsatile release of FSH through mu-
tations in the FSHb 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 ex-
press 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
ISSN Print 0013-7227 ISSN Online 1945-7170
Printed in USA
Copyright © 2017 Endocrine Society
Received 9 May 2017. Accepted 11 May 2017.
For article see page 2309
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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 se-
lectively 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 gonad-
otropins). 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, fol-
liculogenesis 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 expres-
sion, 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 path-
ways activated by FSHR and the IGF1R cooperate closely to
maintain normal granulosa cell function (Fig. 1). FSHR
activates the cyclic adenosine monophosphate/protein
Abbreviations: AKT, protein kinase B; FSH, follicle-stimulating hormone; FSHR, follicle-
stimulating hormone receptor; IGF, insulinlike growth factor; IGF1, insulinlike growth
factor 1; IGF1R, insulinlike growth factor 1 receptor; IGF1Rgcko, insulinlike growth factor 1
receptor transcripts in granulosa cells; LH, luteinizing hormone.
doi: 10.1210/en.2017-00447
doi: 10.1210/en.2017-00447 https://academic.oup.com/endo 2075

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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/
protein kinase B (AKT), and mitogen-activated protein
kinase/extracellular signal-regulated kinase pathways
that also mediate IGF1 actions (6, 7).
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 (IGF1Rgcko). Follicular
development did not progress beyond the preantral
stage in IGF1Rgcko 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 IGF1Rgcko mice. Nonetheless, FSH failed to
stimulate AKT phosphorylation in IGF1Rgcko. 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 apo-
ptosis during transition from primary to secondary fol-
licles. IGF1R, therefore, is an important partner with
FSHR for advanced follicle survival. These findings may
have important implications for ovarian cancer. In-
creased IGF expression is often an indication of drug
resistance. Further characterization of FSHR/IGFR mo-
lecular 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.
Acknowledgments
Address all correspondence and requests for reprints to: Patricia
T. Jimenez, MD, Department of Obstetrics and Gynecology,
Division of Reproductive Endocrinology, University of Texas
Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas,
Texas 75390. E-mail: ptj6305@gmail.com.
This work received support from Grant K12 HD000849,
awarded to the Reproductive Scientist Development Program
by the Eunice Kennedy Shriver National Institute of Child
2076 Chen and Jimenez IGFR1 Is Crucial for Folliculogenesis
Health & Human Development and by the Burroughs Well-
come Fund, as part of the Reproductive Scientist Development
Program.
Disclosure Summary: The authors have nothing to disclose.
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