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

∗ Correspondingauthor.Tel.:+1-301-496-5800;fax:+1-301-402-0884. E-mail address: chrousog@mail.nih.gov (G.P. Chrousos).

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

62 S.N. Kalantaridou et al. / Journal of Reproductive Immunology 62 (2004) 61–68

1. Introduction

The hypothalamic–pituitary–adrenal (HPA) axis exerts an inhibitory effect on the female reproductive system (Chrousos et al., 1998). In addition, the hypothalamic neuropeptide corticotropin-releasing hormone (CRH) and its receptors have been identified in most fe- male reproductive tissues, including the ovary, uterus, and placenta. Furthermore, CRH is 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 regulating key reproductive functions with an inflammatory component, such as ovulation, luteolysis, implantation, and parturition.

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

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

The principal regulators of the HPA axis are CRH and arginine–vasopressin (AVP), both produced by parvicellular neurons of the paraventricular nucleus of the hypothalamus into the hypophyseal portal system (Chrousos and Gold, 1992). CRH and AVP synergistically stimulate 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-releasing hormone (GnRH), produced by neurons of the preoptic and arcuate nucleus of the hypotha- lamus into the hypophyseal portal system (Ferin, 1996). GnRH stimulates pituitary follicle stimulating and luteinizing hormone secretion and, subsequently, estradiol and progesterone secretion 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 1
Effect of the hypothalamic–pituitary–adrenal axis on the female reproductive system

Hypothalamic–pituitary–adrenal axis

CRH -Endorphin Cortisol

Effect on the female reproductive system

Inhibition of GnRH secretion
Inhibition of GnRH secretion
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 intravenous GnRH, suggesting an inhibitory effect of glucocorticoids on the pituitary gonadotroph (Sakakura et al., 1975). Furthermore, glucocorticoids inhibit estradiol-stimulated uterine growth (Rabin et al., 1990).

These effects of the HPA axis 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 (Chrousos et al., 1998).

On the other hand, estrogen directly stimulates the CRH gene promoter and the central noradrenergic system (Vamvakopoulos and Chrousos, 1993), which may explain women’s mood cycles and manifestations of autoimmune/allergic and inflammatory diseases that follow estradiol fluctuations. Indeed, suicide attempts and allergic bronchial asthma attacks significantly increase when the plasma estradiol level reaches its lowest level, i.e. during the 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; Makrigiannakis et 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 as ovulation, luteolysis, implantation and parturition (Table 2).

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

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

Reproductive CRH Ovarian CRH

Uterine CRH

Placental CRH

Potential physiologic roles

Follicular maturation Ovulation
Luteolysis
Suppression of female sex steroid production

Decidualization Blastocyst implantation Early maternal tolerance

Labor
Maternal hypercortisolism Fetoplacental circulation Fetal adrenal steroidogenesis

Potential pathogenic effects

Premature ovarian failure (↑ secretion) Anovulation (↓ secretion)
Corpus luteum dysfunction (↓ secretion) Ovarian dysfunction (↓ secretion)

Infertility (↓ secretion)
Recurrent spontaneous abortion (↓ secretion)

Premature labor (↑ secretion)
Delayed labor (↓ secretion)
Preeclampsia and eclampsia (↑ secretion)

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receptors (similar to those of the anterior pituitary) are also detected in the ovarian stroma and theca and in the cumulus oophorus of the graafian follicle. In vitro experiments have shown 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). This finding suggests that ovarian CRH has anti-reproductive actions that might be related to the earlier ovarian failure observed in women exposed to high psychosocial stress (Bromberger et al., 1997). Interestingly, CRH and its receptors have also been identified in Leydig cells of 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, whereas there is abundant expression of the CRH and CRHR-1 genes in mature follicles, suggesting that CRH may play auto/paracrine roles in follicular maturation (Mastorakos et al., 1993, 1994; Asakura et al., 1997). However, polycystic ovaries present diminished amounts of CRH immunoreactivity, suggesting that decreased ovarian CRH might be related to the anovulation of polycystic ovarian syndrome (Mastorakos et al., 1994). Finally, the concen- tration of CRH is higher in the premenopausal than the postmenopausal ovaries, indicating that ovarian CRH may be related to normal ovarian function during the reproductive life span (Zoumakis et al., 2001).

The human endometrium also contains CRH (Mastorakos et al., 1996; Makrigiannakis et al., 1995a). Epithelial cells are the main source of endometrial CRH, while stroma does not express it, unless it differentiates to decidua (Mastorakos et al., 1996;Makrigiannakis et al., 1995a,b;Ferrari et al., 1995). In addition, CRH receptors type 1 are present in both epithelial and stroma cells of human endometrium (Di Blasio et al., 1997) and in human myometrium (Hillhouse et al., 1993), suggesting a local effect of endometrial CRH. Estro- gens and glucocorticoids inhibit and prostaglandin E2 stimulates the promoter of human CRH gene in transfected human endometrial cells, suggesting that the endometrial CRH gene is under the control of these agents (Makrigiannakis et al., 1996). The endometrial glands 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 CRH is significantly higher in the secretory phase, associating endometrial CRH with intrauter- ine phenomena of the secretory phase of the menstrual cycle, such as decidualization and implantation (Zoumakis et al., 2001).

Early in pregnancy, the implantation sites in rat endometrium contain 3.5-fold higher concentrations of CRH compared to the interimplantation regions (Makrigiannakis et al., 1995b). Furthermore, human trophoblast and decidualized endometrial cells express Fas ligand (FasL), a pro-apoptotic molecule. These findings suggest that intrauterine CRH may participate in blastocyst implantation, while FasL may assist with maternal immune tolerance to the semi-allograft embryo. A nonpeptidic CRH receptor type 1-specific an- tagonist (antalarmin) decreased the expression of FasL by human trophoblasts, suggesting that CRH regulates the pro-apoptotic potential of these cells in an auto/paracrine fash- ion (Makrigiannakis et al., 2001). Invasive trophoblasts promoted apoptosis of activated Fas-expressing human T-lymphocytes, an effect potentiated by CRH and inhibited by CRH 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 early pregnancy.

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 weeks of 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 by the liver and placenta (Challis et al., 1995; Linton et al., 1993). Nevertheless, CRH-BP concentrations decrease during the last 6 weeks of pregnancy, leading to elevations of free CRH (Challis et al., 1995; Linton et al., 1993). Thus, placental CRH is responsible for the hypercortisolism observed during the latter half of pregnancy. This hypercortisolism is followed by a transient suppression of hypothalamic CRH secretion in the postpartum period, which may explain the blues/depression and autoimmune phenomena seen during this 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 oxide synthetase activation, and stimulation of smooth muscle contractions through prostaglandin F2alpha 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 preeclampsia or eclampsia (Chrousos et al., 1998; Robinson et al., 1988; Goland et al., 1995), whereas it is 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 shown that CRH receptor type 1 antagonism in the sheep fetus, using antalarmin, can delay the onset of parturition (Cheng-Chan et al., 1998).

4. Conclusions

The HPA axis exerts an inhibitory effect on the female reproductive system. CRH inhibits hypothalamic GnRH secretion, whereas glucocorticoids suppress pituitary LH and ovarian estrogen and progesterone secretion and render target tissues resistant to estradiol (Chrousos et al., 1998). The HPA axis is 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 (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, blastocyst implantation, and early maternal tolerance. Placental CRH, which is secreted mostly during the 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 postpartum adrenal suppression, which may explain the blues/depression and autoimmune phenomena of the postpartum period (Magiakou et al., 1996; Elenkov et al., 2001).

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