REVIEW ARTICLE published: 20 February 2013 doi: 10.3389/fendo.2013.00012 Regulation of gonadotropins by corticotropin-releasing factor and urocortin

Kazunori Kageyama* Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan

Edited by: While stress activates the hypothalamic–pituitary–adrenal (HPA) axis, it suppresses the Hubert Vaudry, University of Rouen, hypothalamic–pituitary–gonadal (HPG) axis. Corticotropin-releasing factor (CRF) is a major France regulatory peptide in the HPA axis during stress. Urocortin 1 (Ucn1), a member of the Reviewed by: CRF family of peptides, has a variety of physiological functions and both CRF and Ucn1 David Lovejoy, University of Toronto, Canada contribute to the stress response via G protein-coupled seven transmembrane receptors. Jae Young Seong, Korea University, Ucn2 and Ucn3, which belong to a separate paralogous lineage from CRF, are highly South Korea selective for the CRF type 2 receptor (CRF2 receptor). The HPA and HPG axes interact *Correspondence: with each other, and gonadal function and reproduction are suppressed in response to Kazunori Kageyama, Department of various stressors. In this review, we focus on the regulation of gonadotropins by CRF Endocrinology and Metabolism, Hirosaki University Graduate School and Ucn2 in pituitary gonadotrophs and of gonadotropin-releasing hormone (GnRH) via of Medicine, 5 Zaifu-cho, Hirosaki, CRF receptors in the hypothalamus. In corticotrophs, stress-induced increases in CRF Aomori 036-8562, Japan. stimulate Ucn2 production, which leads to the inhibition of gonadotropin secretion via the e-mail: [email protected] CRF2 receptor in the pituitary. GnRH in the hypothalamus is regulated by a variety of stress conditions. CRF is also involved in the suppression of the HPG axis, especially the GnRH pulse generator, via CRF receptors in the hypothalamus. Thus, complicated regulation of GnRH in the hypothalamus and gonadotropins in the pituitary via CRF receptors contributes to stress responses and adaptation of gonadal functions.

Keywords: corticotropin-releasing factor, urocortin, stress, gonadotropin

INTRODUCTION a large population of GnIH/RFamide-related peptide-expressing A variety of stressors have been shown to suppress gonadal func- cells (Kirby et al., 2009). Glucocorticoids increase the inhibitory tion (Chand and Lovejoy, 2011). Proteins that play key roles in actions of GnIH on GnRH secretion (Kirby et al., 2009), while the vertebrate reproduction include the neuropeptides gonadotropin- regulation of GnIH via the CRF receptor remains to be determined. releasing hormone (GnRH) and kisspeptin and their receptors Corticotropin-releasing factor activates and regulates the (Kim et al., 2012): kisspeptin stimulates GnRH release from hypothalamic–pituitary–adrenal (HPA) axis during stress (Vale hypothalamic GnRH neurons via Gpr54, a G protein-coupled et al., 1981, 1997). Stress-induced CRF synthesis and secretion receptor (Messager et al., 2005), while the gonadal steroid estro- from the hypothalamic paraventricular nucleus (PVN) stimulates gen mediates its inhibitory effect on GnRH secretion by acting adrenocorticotropic hormone (ACTH) release from pituitary cor- on kisspeptin-expressing neurons of the arcuate nucleus (Oakley ticotrophs (Gillies et al., 1982; Mouri et al., 1993), which, in turn, et al., 2009; Ohkura et al., 2009). The expression of kisspeptin and stimulates the release of glucocorticoids from the adrenal glands kisspeptin receptor mRNA is downregulated by stressors including (Whitnall, 1993). These glucocorticoids then moderate the stress restraint, hypoglycemia, and lipopolysaccharide, which suggests response by inhibiting hypothalamic PVN production of CRF that kisspeptin/kisspeptin receptor signaling plays a critical role and pituitary production of ACTH (Whitnall, 1993). Urocortin in the transduction of stress-induced suppression of reproduction 1 (Ucn1), a 40-amino acid peptide originally cloned from the (Kinsey-Jones et al., 2009). In fact, kisspeptin–GPR54 signaling Edinger–Westphal nucleus, is a member of the CRF family of pep- in the arcuate nucleus of the mediobasal hypothalamus is a criti- tides (Vaughan et al., 1995). Both CRF and Ucn1 contribute to cal neural component of the hypothalamic GnRH pulse generator stress responses and cardiovascular and gonadal functions via G (Li et al., 2009). protein-coupled seven transmembrane receptors (Vale et al., 1997; Gonadotropin-inhibitory hormone (GnIH), an RFamide- Kageyama et al., 1999a; Suda et al., 2004). CRF exhibits high affin- related peptide, can also modulate the reproduction of vertebrates ity for CRF type 1 receptor (CRF1 receptor; IC50 = 1.6 nM) but not (Ubuka et al., 2008). GnIH neurons interact directly with GnRH for CRF type 2b receptor (CRF2b receptor; IC50 = 42 nM), while neurons, and the action of GnIH is mediated by a novel G Ucn1 exhibits similar affinity for CRF1 receptor (IC50 = 0.16 nM) protein-coupled receptor, Gpr147 (Ubuka et al., 2008). In mice, and CRF2b receptor (IC50 = 0.86 nM; Jahn et al., 2004). CRF1 higher concentrations of GnIH-like substances are expressed in the receptor is predominately expressed in the brain and pituitary hypothalamus and GnIH reduces GnRH release from the mouse gland (Chang et al., 1993; Chen et al., 1993; Vita et al., 1993; Potter hypothalamus (Bentley et al., 2010). The glucocorticoid and et al., 1994). In the pituitary, the CRF1 receptor is mainly expressed corticotropin-releasing factor (CRF) receptors are expressed in by corticotrophs and is responsible for mediating the effects of

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hypothalamic CRF on ACTH secretion in response to stress (Wynn RNase protection assays of anterior pituitary mRNA show that et al., 1985; Antoni, 1986). the dominant receptor type is the CRF type 2a receptor (CRF2a) Ucn2 and Ucn3 prohormones were identified in the human receptor and not the CRF2b receptor (Lovenberg et al., 1995a; genome database and in mouse genomic DNA, respectively (Hsu Kageyama et al., 2003). Rat CRF2a receptor, linked to various roles and Hsueh, 2001; Lewis et al., 2001; Reyes et al., 2001), from in the brain, is expressed primarily in several discrete brain regions, which the identity and existence of endogenous peptides were including the hypothalamus, lateral septum, and raphe nuclei predicted (Fekete and Zorrilla, 2007). Ucn2 and Ucn3 are more (Lovenberg et al., 1995b), whereas the CRF2b receptor is found similar to each other than to CRF with regard to receptor bind- predominately in peripheral tissues such as the heart, gastrointesti- ing (Kishimoto et al., 1995; Lovenberg et al., 1995a; Perrin et al., nal tract, arterioles, and muscles (Kageyama et al., 1999b). These 1995; Stenzel et al., 1995). Ucn2 exhibits high affinity for CRF2b data suggest that the CRF2a receptor in pituitary gonadotrophs receptor (IC50 = 0.25 nM) but low affinity for CRF1 receptor is involved in the modulation of gonadotropin secretion and/or (IC50 > 350 nM; Jahn et al., 2004). Similarly, Ucn3 binds with gonadal function. moderate affinity to CRF2b receptor (IC50 = 14 nM), but its spe- Activation of the stress system could potentially influence cific binding to CRF1 receptor is not detectable (IC50 > 2000 nM; reproduction at any level of the HPG axis (Tilbrook et al., 2002). Jahn et al., 2004). It is hypothesized that an ancient gene duplica- The stress-induced decreases in LH/follicle-stimulating hormone tion event is behind why Ucn1 belongs to the CRF lineage and why (FSH) secretion influence gonadal functions such as sex steroido- Ucn2 and Ucn3 represent a separate paralogous lineage (Fekete genesis and sperm production (Demura et al.,1989; Tilbrook et al., and Zorrilla, 2007). 2002). Ucn2 is expressed mainly in corticotrophs of rat pituitary The CRF1 receptor is primarily involved in stress responses and (Yamauchi et al., 2005), and its secretion and expression levels depression, while the CRF2 receptor is believed to mediate “stress- are increased by CRF and suppressed by glucocorticoids (Nemoto coping” responses in the brain, such as anxiolysis (Suda et al., et al., 2007). 2004), because mice deficient in the CRF2 receptor or treated with a The CRF2 receptor-selective ligand Ucn2 suppresses both CRF2 receptor antagonist display increased anxiety-like behaviors expression and secretion of gonadotropins in rats, while a CRF2 and hypersensitive stress responses (Bale et al., 2000). Further- receptor antagonist increases the secretion of gonadotropins more, both Ucn2 and Ucn3 act as anorexigenic neuropeptides via (Nemoto et al., 2009). In addition, an anti-CRF antibody blocks the CRF2 receptor (Fekete et al., 2011; Chao et al., 2012) and Ucn3 stress-induced increases in plasma ACTH and corticosterone, and regulates glucose-stimulated insulin secretion and energy home- an anti-Ucn2 antibody blocks stress-induced suppression of LH ostasis (Li et al., 2007). Ucn3 signaling through the CRF2 receptor secretion without affecting stress-induced ACTH and corticos- is also a critical molecular mediator in the ventromedial nucleus terone release (Nemoto et al., 2010). Stress-induced increases in of the hypothalamus in regulating feeding and peripheral energy microRNA-325-3p also suppress gonadotropin secretion (Nemoto metabolism (Chao et al., 2012). et al., 2012). Although the presence and/or secretion of mature Corticotropin-releasing factor is involved in the suppression Ucn2 has not been determined in the pituitary or other tissues, of the hypothalamic–pituitary–gonadal (HPG) axis (Rivier et al., it is possible that stress-induced increases in CRF stimulate Ucn2 1986), especially the GnRH pulse generator in the hypothala- in corticotrophs, which inhibits gonadotropin secretion via CRF2 mus (Knobil, 1992). Stress profoundly inhibits the reproductive receptors in the pituitary. function by suppressing the pulsatile release of GnRH and con- sequently luteinizing hormone (LH), at least in part via the REGULATION OF GnRH BY CRF AND Ucn VIA CRF RECEPTORS CRF system as well as through the GABAergic system (Lin et al., IN THE HYPOTHALAMUS 2012). Although CRF and Ucn clearly have potent effects on Although peripheral administration of CRF fails to affect LH secre- the HPG system, their possible roles and how they are regu- tion (D’Agata et al., 1984; Rivier and Vale, 1984), central injection lated have yet to be fully determined. In this review, we focus on of CRF inhibits secretion of gonadotropins (Rivier et al., 1986). the regulation and the roles of Ucn2 in pituitary gonadotrophs These effects of CRF probably reflect a central mechanism that and discuss the regulation of GnRH via CRF receptors in the involves modulation of the activity of GnRH neurons in the hypothalamus. hypothalamus (Petraglia et al., 1987; Li et al., 2010). Indeed, in monkeys, a CRF antagonist attenuates suppression of the GnRH REGULATION OF GONADOTROPINS BY CRF AND Ucn2 IN THE pulse generator in response to hypoglycemic stress (Chen et al., PITUITARY 1996). Furthermore, a recent in vivo rat study indicated that CRF Changes in CRF1 receptor expression and desensitization of the innervation of the dorsolateral bed nucleus of the stria terminalis receptor in pituitary corticotrophs play a major role in modulating plays a central role in stress-induced suppression of the GnRH adaptive responses to stressors (Kageyama et al., 2006). CRF, vaso- pulse generator (Li et al., 2011). pressin, lipopolysaccharides, cytokines, and glucocorticoids can Corticotropin-releasing factor also suppresses GnRH gene negatively modulate the levels of pituitary CRF1 receptor mRNA expression levels in murine GnRH GT1-7 cells (Kinsey-Jones et al., (Pozzoli et al., 1996; Sakai et al., 1996; Aubry et al., 1997). However, 2006). In fact, GT1-7 GnRH-producing cells have been used CRF2 receptor mRNA is also found in the anterior pituitary and extensively in studies of the basic control mechanisms involved combined immunohistochemistry and in situ hybridization have in GnRH neuronal function. Belsham and colleagues have man- demonstrated that CRF2 receptor mRNA colocalizes mainly with aged to develop cell lines that are representative of the enormous gonadotrophs, not corticotrophs (Figure 1). range of cell types of the hypothalamus (Dalvi et al., 2011). N39,

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FIGURE 1 | Localization of CRF2 receptor mRNA in the rat anterior immunostaining for LH and in situ hybridization for CRF2 receptor pituitary gland. Representative dark-field photomicrographs showing mRNA are indicated by arrows. Inset: High-power magnification of the anterior pituitary sections probed with either antisense (A) or sense boxed area of panel (D) to illustrate a LH-positive cell that shows a (B) in situ hybridization probes for CRF2 receptor mRNA. Positive signals positive signal for CRF2 receptor mRNA (scattered black silver grains). (E) (indicated by silver grain clusters) were found only in the tissues probed Representative bright-field photomicrograph of the anterior pituitary showing with antisense probes; no signals were found in the sense control. ACTH-immunoreactive cells (brown DAB precipitate). (F) Dark-field image of (C) Bright-field photomicrograph showing LH-immunoreactive cells in the same area as panel (E) showing CRF2 receptor mRNA signals (silver grain the rat anterior pituitary. Gonadotrophs (visualized by the brown DAB clusters). Only a few ACTH-immunoreactive and CRF2 receptor mRNA precipitate) represent LH-immunoreactive cells. (D) Dark-field image double-labeled cells (arrow) were observed. Scale bar,50μm. Reproduction of the same area as panel (C) showing CRF2 receptor mRNA-positive from Kageyama et al. (2003) with permission of the publisher. Copyright 2003, cells (silver grain clusters). Some of the cells that are double-labeled by The Endocrine Society.

developed from primary mouse fetal hypothalamic culture, is one these cells that a CRF1 receptor antagonist, antalarmin, inhibits of these homologous neuronal cell lines. To further understand CRF-induced decreases in GnRH mRNA levels, which suggests the possible function of Ucn and the regulation of GnRH by that CRF decreases GnRH mRNA levels via the CRF1 receptor CRF receptors in the hypothalamus, hypothalamic N39 cells have (Figure 2). been studied because they express both CRF1 and CRF2 receptor The CRF2 receptor may also be involved in the regulation of mRNA and protein (Kageyama et al., 2012). It has been shown in GnRH gene expression. It has been reported that CRF regulates

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whether glucocorticoid-induced changes in CRF and Ucn are involved in the regulation of GnRH and gonadotropins.

RELATION BETWEEN SEXUAL DIFFERENCES AND THE CRF SYSTEM IN THE HYPOTHALAMUS Sexual dimorphism is associated with stress sensitivity and inter- action of the HPA and HPG axes (Chand and Lovejoy, 2011). Estrogens are implicated in the differing stress responses between the sexes and modulate activation of the HPA axis; females, but not males, generally have slight hypercortisolism (Magiakou et al., 1997). Estrogen replacement increases the basal levels of ACTH in ovariectomized rats (Ochedalski et al., 2007) and in post- menopausal women (Fonseca et al., 2001). Moreover, women in the midluteal phase, when both progesterone and estrogen levels are relatively high, show enhanced ACTH levels in response to a stressor (Altemus et al., 2001). Estrogens acting centrally, including in the pituitary corti- cotrophs and the hypothalamus, are able to modulate the stress responses (Nakano et al., 1991), and direct estrogenic regulation of CRF gene expression has also been demonstrated in various tissues (Vamvakopoulos and Chrousos, 1993; Dibbs et al., 1997). As high levels of estrogen replacement increase the basal levels of FIGURE 2 | Effects of a CRF receptor antagonist on the effects of CRF CRF mRNA in the PVN of ovariectomized rats (Ochedalski et al., and Ucn2 on GnRH mRNA levels in N39 cells. Cells were pre-incubated 2007), estrogen would regulate the HPA axis in vivo by stimulating with medium containing 1 μM antalarmin (ANT), antisauvagine-30 (AS), or CRF gene expression in the hypothalamus. CRF mRNA levels in vehicle for 30 min, and then incubated for 6 h with medium containing 100 nM CRF,100 nM Ucn2, or vehicle. Reproduction from Kageyama et al. the PVN are not affected by estrogen treatment in either gonadec- (2012) with permission of the publisher. Copyright 2012, Elsevier. tomized estrogen receptor (ER) type β (ERβ) knockout mice or wild-type male mice (Nomura et al., 2002). Therefore, it is likely that estrogen modulates CRF gene expression in a sex-dependent GnRH mRNA levels via, at least in part, the CRF2 receptor manner. in GT1-7 cells (Kinsey-Jones et al., 2006). In N39 cells, Ucn2 Hypothalamic 4B cells show characteristics of the parvocellular increases GnRH mRNA levels, and these Ucn2-induced increases neurons of the PVN because these cells express CRF, vasopressin, in GnRH mRNA levels are blocked by the CRF2 receptor antagonist CRF1 receptor, and glucocorticoid receptors. Estrogen directly antisauvagine-30 (Figure 2). These results suggest that Ucn2 stim- stimulates CRF gene expression in hypothalamic 4B cells (Ogura ulates GnRH mRNA levels via the CRF2 receptor in hypothalamic et al.,2008), suggesting that estrogen is involved in the positive reg- cells. In an in vivo study, hypoglycemia- and lipopolysaccharide- ulation of CRF gene expression in the parvocellular region of the induced suppression of LH involves activation of CRF2 receptor PVN in vitro. Neurons expressing both CRF and ERβ are found in while restraint stress-induced inhibition of LH pulses involves the medial parvocellular division (Miller et al., 2004) and project both CRF1 and CRF2 receptors (Li et al., 2006). On the other hand, to the median eminence, and CRF in parvocellular PVN neu- amorerecentin vivo study showed that a CRF1 receptor antagonist rons exerts effects on corticotroph ACTH secretion (Gillies et al., blocks the acute stress-induced increases in gonadotropin secre- 1982; Mouri et al., 1993). Therefore, estrogen and ERβ would con- tion on the morning of proestrus while a CRF2 receptor antagonist tribute to the enhancement of stress responses through stimulation weakly blocks the increase in FSH secretion (Traslaviña and Franci, of CRF neurons of the hypothalamus, and may constitute the 2012). Although GnRH production and secretion may be differ- basis of sexual dimorphism in the regulation of the CRF gene entially modulated via CRF receptors under different stressors, (Straub, 2007). In addition, estrogen also enhances CRF- and further study will be required to elucidate the involvement of CRF stress-induced suppression of pulsatile LH secretion (Cates et al., receptors. 2004), and upregulation of the CRF2 receptor may contribute Glucocorticoids were recently shown to increase CRF2a recep- to the sensitizing influence of estradiol on the CRF- and stress- tor expression while simultaneously inhibiting CRF1 receptor induced suppression of the GnRH pulse generator (Kinsey-Jones expression in pancreatic β cell-derived insulinoma MIN6 cells et al., 2006). expressing glucocorticoid receptors (Huising et al., 2011). The dif- Meanwhile, Ucn1 in the non-preganglionic Edinger–Westphal ferential effects of the glucocorticoids on the expression of these nucleus plays an important role in stress adaptation. Estro- receptors in the endocrine pancreas represent a mechanism of gens exert a differential transcriptional regulation of the Ucn1 shifting sensitivity from CRF1 to CRF2 receptor ligands (Huis- gene through either ER type α (ERα)orERβ receptors (Haeger ing et al., 2011). In the hypothalamus, glucocorticoids, released in et al., 2006). Ucn1 mRNA levels in the non-preganglionic response to stress, inhibit GnRH and gonadotropins through acti- Edinger–Westphal nucleus of male rats are much higher than vation of GnIH (Kirby et al., 2009). It has yet to be determined those of females (Derks et al., 2010), and estrogens may

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FIGURE 3 |A schematic model of the regulation of gonadotropins by CRF CRF inhibits the stress-induced suppression of the GnRH pulse generator and and Ucn. Stress-induced increases in CRF stimulate Ucn2 in corticotrophs, decreases GnRH mRNA levels via the CRF1 receptor in the hypothalamus. which inhibits gonadotropin secretion via the CRF2 receptor in the pituitary. The CRF2 receptor may also be involved in the regulation of GnRH. contribute to stress adaptation through modulation of Ucn1 of GnRH production and secretion. GnRH production and secre- production. tion may be differentially modulated via CRF receptors in response to different stressors. Thus, complicated regulation of GnRH CONCLUSION and gonadotropins via the CRF receptors contributes to stress In summary, Ucn2, mainly produced in corticotrophs in response responses and adaptation in gonadal functions. to CRF, acts on gonadotrophs expressing the CRF2 receptor and inhibits the production of gonadotropins in the pituitary ACKNOWLEDGMENT (Figure 3). CRF is involved in the suppression of the HPG This work was supported in part by Health and Labour Sci- axis, especially the GnRH pulse generator in the hypothalamus, ences Research Grants (Research on Measures for Intractable and also decreases GnRH mRNA levels via the CRF1 receptor Diseases) from the Ministry of Health, Labour, and Welfare of (Figure 3). The CRF2 receptor may be involved in the regulation Japan.

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