stress and female reproductive system

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Journal of Reproductive Immunology 62 (2004) 61–68 Review Stress and the female reproductive system S.N. Kalantaridou a , A. Makrigiannakis b , E. Zoumakis c , G.P. Chrousos c,d,a Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Ioannina, School of Medicine, Panepistimiou Avenue, 45500 Ioannina, Greece b Department of Obstetrics and Gynecology, University of Crete, School of Medicine, 7110 Heraklion, Greece c Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 9D42, Bethesda, MD 20892-1583, USA d 1st Department of Pediatrics, University of Athens, School of Medicine, Athens, Greece Received in revised form 25 September 2003; accepted 25 September 2003 Abstract The hypothalamic–pituitary–adrenal (HPA) axis, when activated by stress, exerts an inhibitory effect on the female reproductive system. Corticotropin-releasing hormone (CRH) inhibits hypothalamic gonadotropin-releasing hormone (GnRH) secretion, and glucocorticoids inhibit pituitary luteiniz- ing hormone and ovarian estrogen and progesterone secretion. These effects are responsible for the “hypothalamic” amenorrhea of stress, which is observed in anxiety and depression, malnutrition, eating disorders and chronic excessive exercise, and the hypogonadism of the Cushing syndrome. In addition, corticotropin-releasing hormone and its receptors have been identified in most female reproductive tissues, including the ovary, uterus, and placenta. Furthermore, corticotropin-releasing hormone is secreted in peripheral inflammatory sites where it exerts inflammatory actions. Repro- ductive corticotropin-releasing hormone is regulating reproductive functions with an inflammatory component, such as ovulation, luteolysis, decidualization, implantation, and early maternal toler- ance. Placental CRH participates in the physiology of pregnancy and the onset of labor. Circulating placental CRH is responsible for the physiologic hypercortisolism of the latter half of pregnancy. Postpartum, this hypercortisolism is followed by a transient adrenal suppression, which may explain the blues/depression and increased autoimmune phenomena observed during this period. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Decidualization; Implantation; Luteolysis; Maternal tolerance; Ovulation; Parturition; Reproductive corticotropin-releasing hormone; Stress Corresponding author. Tel.: +1-301-496-5800; fax: +1-301-402-0884. E-mail address: [email protected] (G.P. Chrousos). 0165-0378/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jri.2003.09.004

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Stress and Female Reproductive System

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Page 1: Stress and Female Reproductive System

Journal of Reproductive Immunology62 (2004) 61–68

Review

Stress and the female reproductive system

S.N. Kalantaridoua, A. Makrigiannakisb,E. Zoumakisc, G.P. Chrousosc,d,∗

a Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Ioannina,School of Medicine, Panepistimiou Avenue, 45500 Ioannina, Greece

b Department of Obstetrics and Gynecology, University of Crete, School of Medicine, 7110 Heraklion, Greecec Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human

Development, National Institutes of Health, Building 10, Room 9D42, Bethesda, MD 20892-1583, USAd 1st Department of Pediatrics, University of Athens, School of Medicine, Athens, Greece

Received in revised form 25 September 2003; accepted 25 September 2003

Abstract

The hypothalamic–pituitary–adrenal (HPA) axis, when activated by stress, exerts an inhibitory effecton the female reproductive system. Corticotropin-releasing hormone (CRH) inhibits hypothalamicgonadotropin-releasing hormone (GnRH) secretion, and glucocorticoids inhibit pituitary luteiniz-ing hormone and ovarian estrogen and progesterone secretion. These effects are responsible for the“hypothalamic” amenorrhea of stress, which is observed in anxiety and depression, malnutrition,eating disorders and chronic excessive exercise, and the hypogonadism of the Cushing syndrome.In addition, corticotropin-releasing hormone and its receptors have been identified in most femalereproductive tissues, including the ovary, uterus, and placenta. Furthermore, corticotropin-releasinghormone is secreted in peripheral inflammatory sites where it exerts inflammatory actions. Repro-ductive corticotropin-releasing hormone is regulating reproductive functions with an inflammatorycomponent, such as ovulation, luteolysis, decidualization, implantation, and early maternal toler-ance. Placental CRH participates in the physiology of pregnancy and the onset of labor. Circulatingplacental CRH is responsible for the physiologic hypercortisolism of the latter half of pregnancy.Postpartum, this hypercortisolism is followed by a transient adrenal suppression, which may explainthe blues/depression and increased autoimmune phenomena observed during this period.© 2004 Elsevier Ireland Ltd. All rights reserved.

Keywords: Decidualization; Implantation; Luteolysis; Maternal tolerance; Ovulation; Parturition; Reproductivecorticotropin-releasing hormone; Stress

∗ Corresponding author. Tel.:+1-301-496-5800; fax:+1-301-402-0884.E-mail address: [email protected] (G.P. Chrousos).

0165-0378/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.jri.2003.09.004

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1. Introduction

The hypothalamic–pituitary–adrenal (HPA) axis exerts an inhibitory effect on the femalereproductive system (Chrousos et al., 1998). In addition, the hypothalamic neuropeptidecorticotropin-releasing hormone (CRH) and its receptors have been identified in most fe-male reproductive tissues, including the ovary, uterus, and placenta. Furthermore, CRHis secreted in peripheral inflammatory sites where it exerts strong inflammatory actions.Thus, “reproductive” CRH is a form of “tissue” CRH (CRH found in peripheral tissues),analogous to the “immune” CRH (Chrousos, 1995). “Reproductive” CRH is regulatingkey reproductive functions with an inflammatory component, such as ovulation, luteolysis,implantation, and parturition.

2. Interactions between the hypothalamic–pituitary–adrenal axis and the femalereproductive system

The hypothalamic–pituitary–adrenal axis along with the arousal and autonomic nervoussystems constitute the stress system. Activation of the stress system leads to behavioraland peripheral changes that improve the ability of the organism to adjust homeostasis, andincreases its chance for survival (Chrousos and Gold, 1992).

The principal regulators of the HPA axis are CRH and arginine–vasopressin (AVP), bothproduced by parvicellular neurons of the paraventricular nucleus of the hypothalamus intothe hypophyseal portal system (Chrousos and Gold, 1992). CRH and AVP synergisticallystimulate pituitary adrenocorticotropic hormone (ACTH) secretion and, subsequently, cor-tisol secretion by the adrenal cortex.

The female reproductive system is regulated by the hypothalamic–pituitary–ovarian axis.The principal regulator of the hypothalamic–pituitary–ovarian axis is gonadotropin-releasinghormone (GnRH), produced by neurons of the preoptic and arcuate nucleus of the hypotha-lamus into the hypophyseal portal system (Ferin, 1996). GnRH stimulates pituitary folliclestimulating and luteinizing hormone secretion and, subsequently, estradiol and progesteronesecretion by the ovary.

The HPA axis, when activated by stress, exerts an inhibitory effect on the female repro-ductive system (Table 1). Corticotropin-releasing hormone and CRH-induced proopiome-lanocortin peptides, such as�-endorphin, inhibit hypothalamic GnRH secretion (Chen et al.,1992). In addition, glucocorticoids suppress gonadal axis function at the hypothalamic, pi-tuitary and uterine level (Sakakura et al., 1975; Rabin et al., 1990). Indeed, glucocorticoid

Table 1Effect of the hypothalamic–pituitary–adrenal axis on the female reproductive system

Hypothalamic–pituitary–adrenal axis Effect on the female reproductive system

CRH Inhibition of GnRH secretion�-Endorphin Inhibition of GnRH secretionCortisol Inhibition of GnRH and LH secretion, inhibition of ovarian estrogen

and progesterone biosynthesis, inhibition of estrogen actions

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administration significantly reduces the peak luteinizing hormone response to intravenousGnRH, suggesting an inhibitory effect of glucocorticoids on the pituitary gonadotroph(Sakakura et al., 1975). Furthermore, glucocorticoids inhibit estradiol-stimulated uterinegrowth (Rabin et al., 1990).

These effects of the HPA axis are responsible for the “hypothalamic” amenorrhea ofstress, which is observed in anxiety and depression, malnutrition, eating disorders andchronic excessive exercise, and the hypogonadism of the Cushing syndrome (Chrousoset al., 1998).

On the other hand, estrogen directly stimulates the CRH gene promoter and the centralnoradrenergic system (Vamvakopoulos and Chrousos, 1993), which may explain women’smood cycles and manifestations of autoimmune/allergic and inflammatory diseases thatfollow estradiol fluctuations. Indeed, suicide attempts and allergic bronchial asthma attackssignificantly increase when the plasma estradiol level reaches its lowest level, i.e. duringthe late luteal and early follicular phases of the menstrual cycle (Fourestie et al., 1986;Skobeloff et al., 1996).

3. “Reproductive” corticotropin-releasing hormone

CRH and its receptors have been identified in several female reproductive organs, in-cluding the ovaries, the endometrial glands, decidualized endometrial stroma, placental tro-phoblast, syncytiotrophoblast and decidua (Mastorakos et al., 1994, 1996; Makrigiannakiset al., 1995a; Grino et al., 1987; Clifton et al., 1998; Frim et al., 1988; Petraglia et al., 1992;Jones et al., 1989; Grammatopoulos and Chrousos, 2002). “Reproductive” CRH partici-pates in various reproductive functions with an “aseptic” inflammatory component, such asovulation, luteolysis, implantation and parturition (Table 2).

Ovarian CRH is primarily found in the theca and stroma and also in the cytoplasm of theovum (Mastorakos et al., 1993, 1994). Corticotropin-releasing hormone type 1 (CRHR-1)

Table 2Reproductive corticotropin-releasing hormone, potential physiologic roles and potential pathogenic effects

Reproductive CRH Potential physiologic roles Potential pathogenic effects

Ovarian CRH Follicular maturation Premature ovarian failure (↑ secretion)Ovulation Anovulation (↓ secretion)Luteolysis Corpus luteum dysfunction (↓ secretion)Suppression of female sexsteroid production

Ovarian dysfunction (↓ secretion)

Uterine CRH Decidualization Infertility (↓ secretion)Blastocyst implantation Recurrent spontaneous abortion (↓ secretion)Early maternal tolerance

Placental CRH Labor Premature labor (↑ secretion)Maternal hypercortisolism Delayed labor (↓ secretion)Fetoplacental circulation Preeclampsia and eclampsia (↑ secretion)Fetal adrenal steroidogenesis

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receptors (similar to those of the anterior pituitary) are also detected in the ovarian stromaand theca and in the cumulus oophorus of the graafian follicle. In vitro experiments haveshown that CRH exerts an inhibitory effect on ovarian steroidogenesis in a dose-dependent,interleukin (IL)-1-mediated manner (Calogero et al., 1996; Ghizzoni et al., 1997). Thisfinding suggests that ovarian CRH has anti-reproductive actions that might be related to theearlier ovarian failure observed in women exposed to high psychosocial stress (Brombergeret al., 1997). Interestingly, CRH and its receptors have also been identified in Leydig cellsof the testis, where CRH exerts inhibitory actions on testosterone biosynthesis (Fabri et al.,1990).

There is no detectable CRH in oocytes of primordial follicles in human ovaries, whereasthere is abundant expression of the CRH and CRHR-1 genes in mature follicles, suggestingthat CRH may play auto/paracrine roles in follicular maturation (Mastorakos et al., 1993,1994; Asakura et al., 1997). However, polycystic ovaries present diminished amounts ofCRH immunoreactivity, suggesting that decreased ovarian CRH might be related to theanovulation of polycystic ovarian syndrome (Mastorakos et al., 1994). Finally, the concen-tration of CRH is higher in the premenopausal than the postmenopausal ovaries, indicatingthat ovarian CRH may be related to normal ovarian function during the reproductive lifespan (Zoumakis et al., 2001).

The human endometrium also contains CRH (Mastorakos et al., 1996; Makrigiannakiset al., 1995a). Epithelial cells are the main source of endometrial CRH, while stroma doesnot express it, unless it differentiates to decidua (Mastorakos et al., 1996;Makrigiannakiset al., 1995a,b;Ferrari et al., 1995). In addition, CRH receptors type 1 are present in bothepithelial and stroma cells of human endometrium (Di Blasio et al., 1997) and in humanmyometrium (Hillhouse et al., 1993), suggesting a local effect of endometrial CRH. Estro-gens and glucocorticoids inhibit and prostaglandin E2 stimulates the promoter of humanCRH gene in transfected human endometrial cells, suggesting that the endometrial CRHgene is under the control of these agents (Makrigiannakis et al., 1996). The endometrialglands are full of CRH during both the proliferative and the secretory phases of the cycle(Mastorakos et al., 1996; Makrigiannakis et al., 1995a). However, the concentration of CRHis significantly higher in the secretory phase, associating endometrial CRH with intrauter-ine phenomena of the secretory phase of the menstrual cycle, such as decidualization andimplantation (Zoumakis et al., 2001).

Early in pregnancy, the implantation sites in rat endometrium contain 3.5-fold higherconcentrations of CRH compared to the interimplantation regions (Makrigiannakis et al.,1995b). Furthermore, human trophoblast and decidualized endometrial cells express Fasligand (FasL), a pro-apoptotic molecule. These findings suggest that intrauterine CRHmay participate in blastocyst implantation, while FasL may assist with maternal immunetolerance to the semi-allograft embryo. A nonpeptidic CRH receptor type 1-specific an-tagonist (antalarmin) decreased the expression of FasL by human trophoblasts, suggestingthat CRH regulates the pro-apoptotic potential of these cells in an auto/paracrine fash-ion (Makrigiannakis et al., 2001). Invasive trophoblasts promoted apoptosis of activatedFas-expressing human T-lymphocytes, an effect potentiated by CRH and inhibited byCRH antagonist. In support of these findings, female rats treated with the CRH antag-onist in the first 6 days of gestation had a dose-dependent decrease of endometrial im-plantation sites and markedly diminished endometrial FasL expression (Makrigiannakis

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et al., 2001). Thus, locally produced CRH promotes implantation and maintenance of earlypregnancy.

The human placenta contains CRH as well. Placental CRH is produced in syncytiotro-phoblast cells, in placental decidua and fetal membranes (Riley et al., 1991; Jones et al.,1989). Placental CRH expression increases as much as 100 times during the last 6–8 weeksof pregnancy (Frim et al., 1988). The biologic activity of CRH in maternal plasma is at-tenuated by the presence of a circulating CRH binding protein (CRH-BP), produced bythe liver and placenta (Challis et al., 1995; Linton et al., 1993). Nevertheless, CRH-BPconcentrations decrease during the last 6 weeks of pregnancy, leading to elevations of freeCRH (Challis et al., 1995; Linton et al., 1993). Thus, placental CRH is responsible forthe hypercortisolism observed during the latter half of pregnancy. This hypercortisolismis followed by a transient suppression of hypothalamic CRH secretion in the postpartumperiod, which may explain the blues/depression and autoimmune phenomena seen duringthis period (Chrousos et al., 1998; Magiakou et al., 1996; Elenkov et al., 2001).

Placental CRH induces dilation of uterine and fetal placental vessels through nitric oxidesynthetase activation, and stimulation of smooth muscle contractions through prostaglandinF2alpha and E2 production by fetal membranes and placental decidua (Chrousos, 1999;Grammatopoulos and Hillhouse, 1999). Placental CRH secretion is stimulated by glucocor-ticoids, inflammatory cytokines, and anoxic conditions, including the stress of preeclampsiaor eclampsia (Chrousos et al., 1998; Robinson et al., 1988; Goland et al., 1995), whereas itis repressed by estrogens (Ni et al., 2002).

CRH may be the placental clock triggering the onset of parturition (McLean et al., 1995;Challis et al., 2000; Majzoub and Karalis, 1999). Of note, experimental data have shownthat CRH receptor type 1 antagonism in the sheep fetus, using antalarmin, can delay theonset of parturition (Cheng-Chan et al., 1998).

4. Conclusions

The HPA axis exerts an inhibitory effect on the female reproductive system. CRH inhibitshypothalamic GnRH secretion, whereas glucocorticoids suppress pituitary LH and ovarianestrogen and progesterone secretion and render target tissues resistant to estradiol (Chrousoset al., 1998). The HPA axis is responsible for the “hypothalamic” amenorrhea of stress, whichis observed in anxiety and depression, malnutrition, eating disorders and chronic excessiveexercise, and the hypogonadism of the Cushing syndrome (Chrousos et al., 1998).

In addition, CRH and its receptors have been identified in female reproductive organs,including the ovaries, the endometrium and the placenta. “Reproductive” CRH partici-pates in various reproductive functions with an inflammatory component (Chrousos et al.,1998). Ovarian CRH participates in the regulation of steroidogenesis, follicular maturation,ovulation and luteolysis. Endometrial CRH participates in the decidualization, blastocystimplantation, and early maternal tolerance. Placental CRH, which is secreted mostly duringthe latter half of pregnancy, may be responsible for the onset of labor and the physiologic hy-percortisolism seen during this period. This hypercorticolism causes a transient postpartumadrenal suppression, which may explain the blues/depression and autoimmune phenomenaof the postpartum period (Magiakou et al., 1996; Elenkov et al., 2001).

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