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Molecular and Cellular Endocrinology 179 (2001) 39 – 46

Gonadotropic control of ovarian follicular growth and
S.G. Hillier
Reproducti6e Medicine Laboratory, Department of Reproducti6e and De6elopmental Sciences,
Uni6ersity of Edinburgh Centre for Reproducti6e Biology, 37 Chalmers Street, Edinburgh EH3 9EW, UK

Development-related paracrine cues that sensitize follicles to follicle stimulating hormone (FSH) and luteinizing hormone (LH)
are crucial to the emergence of a single dominant follicle in each ovulatory menstrual cycle. Sex steroids, insulin-like growth
factors and members of the transforming growth factor-b superfamily are key players in the follicular paracrine system. FSH acts
through membrane-associated granulosa cell receptors (FSHR) to stimulate granulosa cell proliferation and differentiation. The
most responsive follicle at the beginning of the cycle is the first to produce estrogen and express granulosa cell LHR. Paracrine
signalling activated by FSH and LH sustains growth and oestrogen secretion until an ovulation-inducing LH surge is discharged
by the pituitary gland. LH then reprogrammes granulosa cell function, leading to terminal differentiation (luteinization) rupture
of the follicle wall, and release of the fertilizable egg. The genes regulated by the LH surge orchestrate profound changes in sex
steroid production, metabolism and action which are necessary for ovulation. Preovulatory granulosa cells also increase their
ability to metabolise cortisone to cortisol, which may be part of a local anti-inflammatory mechanism to promote rapid healing
of the ruptured ovarian surface. © 2001 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Gonadotropins; Ovary; Ovulation

1. Introduction

2. The new biology of FSH and LH

The ovaries are amongst the most dynamic and
plastic tissues in the body, with the monthly cycle of
follicular maturation, ovulation and (in absence of
pregnancy) resorption of the corpus luteum occurring
300 – 400 times throughout the average woman’s reproductive lifespan. The endocrine control of this
process by follicle-stimulating hormone (FSH) and
luteinizing hormone (LH) rests on a network of extracellular and intracellular molecular interactions, the
complexity of which reflects the unique histogenetic
origins and specialized functions of the cell types that
constitute the ovaries. Understanding these interactions is key to defining new targets for pharmaceutical manipulation of ovarian function, towards new
and improved forms of fertility treatment. This review
briefly surveys recent developments in some of these

Although FSH and LH were first isolated and
purified over 50 years ago, neither gonadotropin was
available in a completely pure form until recently.
Clinicians usually relied on the use of urinary gonadotropin extracts containing FSH with varying
amounts of LH, making it difficult to selectively alter
the dose of either gonadotropin, while experimentalists resorted to scarce and expensive pituitary preparations of varying purity. The breakthrough came
with the preparation of pure, recombinant FSH and
LH by using Chinese Hamster Ovary cells transfected
with expression vectors carrying human cDNAs encoding the common a gonadotropin subunit with one
or other of the b-subunits (Recombinant Human
FSH Product Development Group, 1998). This advance has resulted in the availability of pharmaceutical grade ‘pure’ FSH and LH preparations that are
finding uses in a clinical setting and which have also
provided powerful new tools in experimental endocrinology (Smyth et al., 1995).

E-mail address: (S.G. Hillier).

0303-7207/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved.
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1989). 1993) and the Alzheimer gene STM2 (Levy-Lahad et al... providing the first direct evidence that FSH induces the granulosa cell hCG/ LHR. 1991)... The transmembrane and intracellular G-protein binding domains of the receptor are encoded by the last exon. 1974). Tonic stimulation of immature granulosa cells by FSH via FSHR stimulates intracellular cAMP formation and activation of genes required for proliferation and differentiation. Little information exists about the transcription regulators that mediate cellular responses to these signals.. the response to FSH includes expression of LHR. also increasing inositol lipid hydrolysis and activation of protein kinase C. 1991). Gonadotropin receptors Paralleling this advance in the molecular biology of FSH and LH was the cloning and expression of the gonadotropin receptors (R). That work confirmed gonad-specific expression of an abundant  2. 1974). This may give rise to encoded products with different functions. saturable.... Post-receptor signaling pathways that impact on gonadotropin action include the serine/threonine kinase mothers against dpp (MAD) cell signaling pathway (Li et al. 1990) confirmed that FSHR and LHR are structurally related members of the seven transmembrane domain G-protein associated receptor superfamily that includes TSHR. giving rise to a binding protein with high specificity for FSH. Following the cloning of the rat LHR (McFarland et al.5 and  2. Segaloff and Ascoli. 2. C/EBP beta is a critical downstream target of G-protein-coupled LHR signaling (Pall et al.6 kb (Segaloff et al. The gene splice variants transcribed from the FSHR gene are not as numerous as for the LHR gene (Huhtaniemi. . 1998). multiple ovarian LHR transcripts were identified with two major transcripts of 6. GHR (Baumann. it was also shown that treatment of animals with FSH in vivo led to increased binding of 125 I-hCG to granulosa cells. 1993). 1998).6 kb-sized FSHR mRNA and a less abundant 5... Application of in situ hybridisation showed LHR mRNAs to be located exclusively in the thecal cells of immature follicles but present in both thecal and granulosa cells of mature. For instance. therefore much of the heterogeneity is associated with the extracellular LH binding domain (Ji and Ji. 1997). 1990) and shown to involve increased LHR gene transcription (Shi and Segaloff. Late during preovulatory follicular growth. 1995). The extracellular ligand-binding domain of FSHR is encoded by the first nine exons of the FSHR gene. 1998). persisting throughout preovulatory follicular development. The presence of specific human chorionic gonadotropin (hCG)/LH binding sites on thecal/interstital cells was also revealed by autoradiography. 1989.. also coupled to PKA (Abell et al. cAMP production. Quantitative assessment of the hCG/LH receptor on thecal-interstitial cells (Magoffin and Erickson.8 kb-sized LHR mRNA transcript codes for a truncated receptor protein corresponding to the extracellular domain of the receptor. The extracellular domain of the GHR is secreted and has been shown to modulate GH action (Baumann. 1994. 1991) and in vivo (Segaloff et al. 1979) were subsequently confirmed in vitro. which is activated by members of the transforming growth factorb (TGFb) superfamily (Massague. 1997. However.. Radioligand-binding analysis confirmed the presence of specific.. b-adrenoreceptor (Collins.. 1990).G. and activation of protein kinase A (PKA) (Richards. Whether this also occurs with LHR is not known. Direct FSH induction of granulosa cell LHR mRNA was confirmed in vitro (Piquette et al.0 kb transcript. Long known to be membrane-associated receptors coupled to adenylyl cyclasemediated intracellular signalling. 1997). using 125- hCG as a surrogate LH to specifically label hCG/LH binding sites in rat ovarian sections (Zeleznik et al. 1990).. Variable transcription of this gene leads to a complex pattern of about 13 gene-splice variants. Richards et al.. Sterneck et al. the 1.. 1994). Hillier / Molecular and Cellular Endocrinology 179 (2001) 39–46 2. which could theoretically function as a plasma binding protein. 1994). Importantly. 1998)..40 S. the tissue distribution and developmental regulation of FSHR gene expression was finally mapped (Camp et al. Prior to onset of the mid-cycle LH surge that triggers ovulation (see below) tonic stimulation of mature granulosa cells by LH via LHR mimics the action of FSH. Post-receptor signaling The post-receptor signaling systems that relay gonadotropin action into the cell nucleus rest mainly on adenylyl cyclase. In ovary. in situ hybridisation showed FSHR mRNA to be localised exclusively to the granulosa cells of healthy follicles. Higher (surge) concentrations of LH dramatically up-regulate PKA signaling. high-affinity FSH binding sites in granulosa cell membranes (Nimrod et al. The first direct evidence that granulosa cells express FSHR was obtained by autoradiographic localization of 125I-labelled FSH binding to immature rat ovarian sections (Zeleznik et al. 1976). With the isolation of cDNA clones encoding rat FSHR (Sprengel et al. altering the expression panel of other genes that co-ordinate final stages of follicular development and ovulation (Robker and Richards.. antral follicles (Camp et al.1.2. the cloning and sequencing of gonadotropin-R cDNAs (McFarland et al.. 1990. 1982) and induction of the hCG/LH receptor on granulosa cells by FSH (Erickson et al. Sprengel et al. 1991). 1994). 1996). The gene encoding the LHR protein contains 11 exons (Segaloff et al.

when FSH-induced genes fall under LH control. 1997) and many other cytokines (Adashi. Much of this can be explained by the local production of polypeptide growth/differentiation factors. FSH-dependent progression.. the follicle ceases to grow. 1999). 1998a) and chemokines (Karstrom-Encrantz et al. During late granulosa cell maturity induced by FSH. 1992). 1995. Other substances implicated are epidermal growth factor (EGF)/transforming growth factora/TGFa (Foghi et al. Intriguingly. luteinizes and commences secretion of progesterone. Intriguingly. 1998. The inductive action of FSH on granulosa cell development that facilitates this response to LH includes alterations in the post-receptor mechanisms through which granulosa cells respond to gonadotropins and other extracellular factors. Thus.... Lamm et al. 1996). 1999b). Richards et al. converts cortisone to cortisol) whereas 11bHSD2 is an dehydrogenase (inactivates cortisol to cortisone. 1985.. 1999a). 1998b). Peluso. 1991) and growth differentiation factor 9 (GDF-9) (Elvin et al. 1998). 1998). a major serum mitogen for cells of mesenchymal origin (Heldin. 1994. IGF-II) (Adashi. Hillier. Parrott and Skinner... angiogenic and proteolytic changes that lead to follicular rupture.. Park-Sarge and Sarge.b. The surge initiates a gene cascade in granulosa cells. 1995) such as inhibin and activin (Hillier. steroids and other extracellular substances that mediate and modulate gonadotropin action.e. Those genes encode pro-inflammatory factors such as interleukin-1b. Stewart. suggesting that LHR density is relatively greater than FSHR density or that the LHR is more effectively coupled to cAMP generation. 1999) but the primary intracellular drive comes from cAMP (Richards et al. 1997).G.. itself triggered by the sustained high circulating level of estradiol produced by the preovulatory follicle. Terranova and Rice. 4. Hillier / Molecular and Cellular Endocrinology 179 (2001) 39–46 3.. 1992). Parrott and Skinner. Since 11bHSD1 functions mainly as a C11 reductase (i.. 2000). Lamm et al. Although it is a continuum.. 1998). the products of which initiate luteinization.. leading to oestrogen secretion and ovulation (Zeleznik and Hillier. which occurs from birth to senescence independent of gondotropic support. 1998). it is estimated to take 2– 3 months for a primordial follicle to develop to the point of ovulation (Gougeon. 1997. proteases necessary for tissue remodelling (Liu et al. and LH-responsive maturation.. Ravindranath et al.. Paracrine growth/differentiation factors The best characterized ovarian growth factors to-date are insulin-like growth factors I and II (IGF-I. 1998a). 1999). Richards et al. 1998). along with the pro/anti-inflammatory. Laitinen et al. 1996). scatter factor (SCF)/hepatocyte growth factor (HGF. The follicular paracrine system A striking feature of the ovaries as endocrine targets is the shifting pattern of gonadotropin sensitivity displayed by individual ovarian cell types. Morris and Richards. nerve growth factor (NGF) (Mayerhofer et al. Duffy et al.. and agents of progesterone production (steroidogenic acute regulatory protein-StAR) (Ronen-Fuhrmann et al. interleukin-1bR (Adashi. 1992). vascular endothelial growth factor (VEGF. 1998). 1995). keratinocyte growth factor (KGF. 1998) and action (progesterone receptors-PR) (Natraj and Richards.. 1993. 1998. Platelet-derived growth factor (PDGF). 1996. The ovulationinducing LH surge triggers the expression of a panel of ‘high-tone’ cAMP response genes that lead to terminal granulosa cell differentiation and follicular rupture. LH has a relatively stronger effect than FSH on cAMP formation in vitro (Yong et al. Relative roles of FSH and LH During adulthood when ovulatory menstrual cycles occur. the changes induced by LH favour local accumulation of anti-inflammatory cortisol at a time when rapid healing of the ruptured surface is required to rapidly restore normal ovarian function (Hillier and Tetsuka.. Clemens et al. 1998b) and members of the TGFb superfamily (Gaddy-Kurten et al. signal the egg to commence meiotic maturation and lead to rupture of the follicle wall (Conti et al. 4. fibroblast growth factors (FGFs) (Reynolds and Redmer. 1998)..1. 1998a) and prostaglandin endoperoxide synthase-2 (COX-2. 1998). LH also simultaneously suppresses granulosa cell division (Yong et al. the three-dimensional structures of gonadotropins bear structural similarities to PDGF and other members of the so-called cystine knot family . 1996). 1996). angiogenic factors such as VEGF (Ravindranath et al. Signalling via Ca2 + /inositol lipid hydrolysis and tyrosine kinase pathways are involved (Morris et al.. 1992a). the life-cycle of a preovulatory follicle can be broken down into three successive phases initiation. McGee and Hsueh.. 1984. The stimulatory action of LH on granulosa cell 11bHSD1 gene expres- 41 sion in vitro is mimicked by interleukin-1b (Tetsuka et al. 1997. Ovulation is triggered by the mid-cycle LH surge. requiring tonic stimulation by FSH..S.. neurotrophin receptors such as TrkA (Mayerhofer et al. has been shown to stimulate thecal cell mitosis in vitro — an effect that is augmented by the additional presence of other growth factors such as EGF (May et al. 1992a. Some of the better known participants in this paracrine dialogue will now be discussed. the LH surge also induces 11b-hydroxysteroid dehydrogenase type 1 (11bHSD1) and simultaneously down-regulates 11bHSD2 expression in granulosa cells of preovulatory follicles (Tetsuka et al. tumour necrosis factora (TNFa. 1992..

Thus regardless of the contributions made by insulin or IGFs to the control of follicular androgen production.1. 1995) stimulate thecal/stromal androgen synthesis in vitro. the expression of which are developmentally regulated (el-Roeiy et al.. anti-Mu¨ llerian hormone (AMH).. 1988). As secreted ovarian hormones they participate in longloop feedback regulation of pituitary gonadotropin secretion. Characteristically.. The relevance of the paracrine IGF-I hypothesis to the human ovary was initially challenged by observations that human granulosa cells do not express the IGF-I gene. 1995).. Nahum et al.. At such early stages of development.. 4.. 1989.G. Granulosa cells express androgen receptors (AR) throughout antral and . 1993).. 1998). 1991b. human granulosa cells do express IGF-II (Hernandez et al.3. the IGFs and the inhibins/activins ar of particular relevance and will be considered further here. inhibins. Hillier / Molecular and Cellular Endocrinology 179 (2001) 39–46 of growth factors (Lapthorn et al. On the other hand.. the remarkable structural similarities between LH.. 1991a). Thereby the stimulatory action of inhibin on thecal androgen synthesis gains sway during late preovulatory follicular development. possibly aided by granulosa-derived IGFBPs that sequester and inhibit the actions of IGFs (Ling et al. 1993) and measurements of immunoreactive inhibin production by granulosa cells in vitro (Hillier et al. FSH stimulates the production of IGF-I by granulosa cells. 1995).. which is under LH control (Smyth et al. when androgen is required in increasing amounts as a substrate for oestrogen synthesis (Hillier. 1991) and in vivo (Meunier et al. 4.. activin predominates in immature follicles where it promotes FSH-induced mitosis and FSH induced steroidogenic differentiation (Miro and Hillier. and both insulin (Barbieri et al. FSH and other members of the cystine-knot growth factor family suggests that gonadotrophins have... which is fundamental to folliculogenesis. 1991). Androgens Androgens are synthesised in thecal cells through cell-specific expression of P45017a (CYP17). 1994.. In the rat ovary.1.. 1986) and IGF-I (Hillier et al.. while within the ovaries they serve autocrine and paracrine roles that contribute to normal preovulatory development and function. 1994). suggesting a paracrine role for granulosa cell-derived IGF-I in the regulation of thecal androgen synthesis (Hernandez et al. IGF-II and IGF-binding proteins (IGFBPs. Based on patterns of inhibin/activin subunit mRNA expression in vitro (Turner et al.2. 1992. Adashi. at least thirty other proteins including the three pituitary glycoprotein hormones (FSH. Schwall et al.. specific growth regulatory functions (Lapthorn et al. 4. IGFs Ovarian follicular cells varyingly express genes encoding IGF-I.c). Although physiological concentrations of insulin. Adashi et al..42 S. 1993. activins... 1995). Paracrine regulation of steroid synthesis During the human menstrual cycle. 4. IGF-BPs pro- duced by ovarian cells and may also participate in the local mediation/modulation of gonadotrophin action (Ling et al. and therefore likely to have a physiological paracrine role in regulating androgen production by human ovaries (Nahum et al. Hillier et al. 1995).. 1991).2. Roberts et al. Inhibins and acti6ins Activins and inhibins produced by granulosa cells have potent modulatory actions on thecal androgen synthesis: activin being inhibitory and inhibin stimulatory (Hsueh et al. Pei et al. 4. inhibin greatly enhances the actions of all three factors in vitro (Nahum et al. Paracrine steroid action Steroids produced by ovarian cells have critically important roles in the regulation of ovarian function.2. Gonadotropins differ from most other known cystine-knot regulatory factors in that they signal through G-protein coupled receptors instead of receptor serine/tyrosine kinases (Massague. GDF-9. 1997). which is equipotent with IGF-I at the level of thecal androgen synthesis. Antral follicles too immature to secrete estrogen do not need androgen as an aromatase precursor (Hillier et al. and based on sequence homology.or heterodimers. 1988. Thecal cells from normal human ovaries have been shown to possess receptors for insulin and IGFs (Poretsky et al. hCG. 1989.3. Zhou and Bondy. 1985. 1991c.2. 1994).. 1993). or in an evolutionary sense once had.. IGF-I and IGFII can stimulate thecal androgen production.. Hernandez et al.. 1995). However. Inhibin and the activin-binding protein follistatin are produced in progressively greater amounts relative to activin by granulosa cells as follicles mature (Nakatani et al. androgen synthesis may be suppressed due to the preponderance of activin relative to inhibin. Piferrer et al. 1990. the protomers of which predominantly consist of b-strand secondary structure with a characteristic clustering of three cystine bridges known as the cystine-knot motif (Lapthorn et al.. 1987. LH released by the pituitary gland provides the major endocrine drive to thecal androgen synthesis. paracrine regulation by inhibin could be of overriding importance during preovulatory follicular development. Among many locally produced factors capable of modulating this action of LH. This family of growth factors is presently known to include NGF and TGFbs. VEGF and several bone morphogenetic proteins. 1996).. 1993). they exist as homo. 1991). LH and TSH). 1998b).

Segaloff. Hum.J.L. Mol. The ovaries do however express 11bHSD isoforms (Tetsuka et al. Estrogens Estrogen production is the hallmark of preovulatory follicular development. Conti et al. 1997. The IGF family and folliculogenesis. possibly through inhibition of cAMP metabolism (Hillier and de Zwart.T. R. 1997.A. reflecting FSH induced expression of cytochrome P450arom (CYP19) that converts androgen to estrogen in granulosa cells (Hillier et al. Adashi.J.S. 1405 – 1417. However... Classic ER (ERa) may not fully explain estrogen action at this level since granulosa cells more abundantly express a second ER isoform. J. Metab. E.. T.. Endocrinol. 1991.N. 1997... serving to amplify overall actions of FSH (Richards. as a natural anti-inflammatory agent it is an obvious potential participant in the ovulation associated injury-repair process (Hillier and Tetsuka.E.W.E.. G. 1993.A.. D. Progesterone Progesterone is produced in increasing amounts by differentiated granulosa cells through FSH induction of cytochrome P450scc (CYP11A). Rosenfeld. Glucocorticoids Ovarian cells do not express cytochromes P450c21 (CYP21B) or P45011b.. Cellular localization and hormonal regulation of follicle-stimulating hormone and luteinizing hormone receptor messenger RNAs in the rat ovary. Clin.. the pattern of 11bHSD isoform expression induced by the ovulation-inducing gonadotropin surge favors cortisol accumulation and hence activation of GR in the preovulatory follicle (Harlow et al.Y.Y. 172 – 182. 1998b... Hormonally regulated phosphodiesterase 4A (PDE4A.Y.L.3. Tetsuka et al.3.W. which are necessary for corticosteroid synthesis (Omura and Morohashi. 1998a. Sar and Welsch. Mayo. 5. 1996). 1991. 1857 –1869. E. Clemens. 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Amplification of FSH-induced PKA signalling by androgen appears to a means of sensitising granulosa cells to tonic stimulation by FSH.. Certain activating mutations within helix 6 of the human luteinizing hormone receptor may be explained by alterations that allow transmembrane regions to activate Gs. Gustafsson. Endocrinol. A. However. R. References Abell. Immunol. Progesterone receptors (PR) do not appear in granulosa cells until onset of the gonadotrophin surge (Natraj and Richards. J. 6. 1998) is a potential candidate for regulation by AR but this remains to be tested. Tetsuka and Hillier 1996.... Endocrinol.. A. During late preovulatory development. 140. W. 1994. 1995). 1201 – 1214. Daniels.3. Female ERa knockout mice are infertile (Korach et al.. Developmental regulation of ER is not well studied but both isoforms are down-regulated by the ovulation inducing gonadotropin surge (Byers et al. J. Cell Endocrinol. 39.. 1994).S. C. Estrogen receptor-beta mRNA expression in rat ovary: down-regulation by gonadotropins. Kistner. the inducible form of prostaglandin synthase that is also essential to ovulation (Lim et al. 1997. Baumann. Yding-Andersen et al. Ryan. C. R. D. 4. whereas ERb − /− females are fertile and exhibit normal sexual behaviour. . 62. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. Robker.. Reprod. 1995).L. 904 –910.. Barbieri. Mol.. K. K. Mol. A. Katzenellenbogen. Hillier / Molecular and Cellular Endocrinology 179 (2001) 39–46 early antral development. Endocrinol... Makris. R.. As discussed above. Camp. The role of the granu- 43 losa cell PR in ovarian function is uncertain. 1997). J. Tetsuka and Hillier. G. Expression of PR is temporally to expression of COX-2. 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