Module 5 – CaseSTRESS EFFECTS ON THE EXCRETORY AND REPRODUCTIVE SYSTEMSNote: If you have trouble viewing some of the course materials, install Quicktime and the Adobe Shockwave Player, both of which can be downloaded free from the Internet.

STOP!!! YOU MUST HAVE COMPLETED THE TUTORIALS AND VIEWED ALL LINKS ON THE MODULE 5 HOME PAGE IN ORDER TO COMPLETE THIS CASE ASSIGNMENT!!!!Case Assignment

Now that you have reviewed the anatomy and physiology of reproduction, let’s continue to investigate the influence of the stress response on human reproductive function. We will begin by investigating the interactions between hormones responsible for regulating female reproductive cycles and the stress hormones.

First read some background on stress and reproduction in the article, “Stress puts double whammy on reproductive system,” By Robert Sanders, UC Berkeley News. 15 June 2009.

Next read the review by Kalantaridou, N.S., et al. Stress and the female reproductive system. Journal of Reproductive Immunology. 2004.62:61–68, and address the following questions in paragraph format:What term is used in this article to describe the regulatory axis of the reproductive system? What is the principle regulatory hormone for this axis?What effects does the HPA axis have on the female reproductive system? What two hormones are described in this article and what are the general effects of these hormones on female reproductive organs?Which female reproductive organs normally respond to CRH? What effect does this hormone have on these organs? What is the role of this hormonal signal in regulating reproduction? Use Table 2 and do a little outside research to look up any unfamiliar terms.Recall the information that you have reviewed in previous modules about unregulated cortisol and stress hormone release on the other systems of the body. What are the implications of dysregulation of CRH and glucocorticoids for human reproduction? Describe the physiological and psychological effects that these hormones can have relative to female reproduction.Assignment Expectations

Organize this assignment by answering the questions above in four paragraphs that align with the numbering above. Answer each question using complete sentences that relate back to the question. Be sure to include a references section at the end of your assignment that lists the websites and articles used above and any additional resources you used to research your answers. Follow the format provided in the Background page.

 Stress puts double whammy on reproductive system

By Robert Sanders, Media Relations  | 15 June 2009

BERKELEY —  University of California, Berkeley, researchers have found what they think is a critical and, until now, missing piece of the puzzle about how stress causes sexual dysfunction and infertility.

Scientists know that stress boosts levels of stress hormones – glucocorticoids such as cortisol – that inhibit the body’s main sex hormone, gonadotropin releasing hormone (GnRH), and subsequently suppresses sperm count, ovulation and sexual activity.

 In the reproductive system, the brain’s hypothalamus (blue oval) produces GnRH, which stimulates the pituitary gland to produce the peripheral hormones luteinizing hormone and follicle-stimulating hormone which in turn stimulate production of testosterone and estradiol and affect sexual behavior. Stress (right) makes the adrenal gland produce glucocorticoids, which act directly on the hypothalamus to suppress GnRH production (red X). UC Berkeley researchers have now found that glucocorticoids also boost hypothalamic GnIH production (red star), which acts to reduce GnRH production as well as to directly lower pituitary secretion of sex hormones (red arrow), thereby suppressing the entire reproductive system.  (Elizabeth Kirby/UC Berkeley)

The new research shows that stress also increases brain levels of a reproductive hormone named gonadotropin-inhibitory hormone, or GnIH, discovered nine years ago in birds and known to be present in humans and other mammals. This small protein hormone, a so-called RFamide-related peptide (RFRP), puts the brakes on reproduction by directly inhibiting GnRH.

 

The common thread appears to be the glucocorticoid stress hormones, which not only suppress GnRH but boost the suppressor GnIH – a double whammy for the reproductive system.

“We know stress affects the top-tier reproductive hormone, GnRH, but we show, in fact, that stress also affects another high-level hormone, GnIH, to cause reproductive dysfunction,” said lead author Elizabeth Kirby, a graduate student at UC Berkeley’s Helen Wills Neuroscience Institute. “This work provides a new target for researchers, a new way to think about infertility and dysfunction. The more we know, the more we can look for ways to treat it.”

The results will be published the week of June 15 in the Online Early Edition of the journal Proceedings of the National Academy of Sciences (PNAS)

The conclusions are based on experiments in rats and inferences from the effects of the hormone in birds. But if this new reproductive hormone acts the same way in all mammals, researchers say the finding could not only change the way physicians look at human reproductive problems, but also affect how breeders approach animal husbandry and captive breeding programs for endangered species.

“There is a growing body of work that points to GnIH as being a big player in the inhibition of reproduction in mammals,” said co-author George Bentley, UC Berkeley assistant professor of integrative biology. “We didn’t have any hint of this stress effect nine years ago, when GnIH was first discovered.”

In humans, chronic stress can lead to a drop in sex drive as well as a drop in fertility. Even the stress of infertility treatments can block their effectiveness, as evidenced by many anecdotes about couples conceiving children after the failure of assisted reproduction.

Animal breeding also is affected by stress. Zoos, in particular, have difficulty getting some animals to reproduce in captivity, Bentley said.

Based on animal experiments, researchers attribute much of this stress effect on sexual function to an increase in glucocorticoids – stress hormones – produced by the adrenal gland. In the brain, these glucocorticoids suppress the main reproductive hormone, GnRH, which in turn causes a shut-down of the release of the gonadotropins luteinizing hormone and follicle-stimulating hormone by the pituitary, and then a suppression of testosterone, estradiol and sexual behavior.

In 2000, however, a new reproductive hormone was discovered in birds and dubbed gonadotropin-inhibitory hormone (GnIH) because it had the opposite effect of GnRH – it inhibited release of gonadotropins, thereby suppressing reproduction.

“It’s very adaptive to not be wasting resources on reproduction during times of acute stress, to just shut down reproduction for 24 hours or so until the stress is gone,” said co-author Daniela Kaufer, a UC Berkeley assistant professor of integrative biology who looks at how stress affects molecular processes in the brain. “These functions go back in evolution a long way.”

Because of the negative effects of GnIH on reproduction, Bentley, who helped establish the critical role played by GnIH in birds, teamed up with Kaufer and Kirby to explore whether stress might affect GnIH levels in the brain. The homologous hormones in mammals have been dubbed RFamide-related peptides, or RFRPs.

Kirby showed that acutely stressed rats showed increased RFRP levels for several hours, but that levels returned to normal by the next day. Chronically stressed rats, however, were left with longer-term elevations of RFRP levels in the dorsomedial hypothalamus area of the brain, and suppression of activity in the reproductive axis – the hypothalamus-pituitary-gonadal hormone cascade – that is associated with lowered sexual activity.

“With chronic stress, glucocorticoids went sky high,” Kirby said.

To determine the role of glucocorticoids, Kirby removed the adrenal glands of male rats, eliminating the source of the hormone. Without adrenals, stress no longer affected RFRP levels in the brain. The researchers also showed that the cells that produce RFRP have receptors for glucocorticoids, a clear indication that these stress hormones can directly affect the cells that produce RFRP.

“Critically, we show that RFRP neurons express the receptors for glucocorticoids, which are released from the adrenal glands in response to stress, and that removal of the adrenal glands prevents the stress-induced, up-regulation of RFRP,” Bentley said. “Thus, we believe we have identified an entirely novel pathway for stress-induced reproductive dysfunction.”

Kirby noted that adrenal hormones are critical to survival, so removing the gland and thus glucocorticoids is not a solution to chronic stress.

However, Kaufer said, it may be possible to block GnIH to reduce some of the effects of stress on reproduction.

The researchers plan to confirm the results in female rats and investigate further the role of GnIH in reproduction.

The work was supported by the National Science Foundation. Other coauthors of the PNAS paper are graduate students Anna C. Geraghty and Takayoshi Ubuka of UC Berkeley’s Department of Integrative Biology. Kaufer, Kirby and Bentley are all members of the Helen Wills Neuroscience Institute.

 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: [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 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 S.N. Kalantaridou et al. / Journal of Reproductive Immunology 62 (2004) 61–68 63

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

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 E 2 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 S.N. Kalantaridou et al. / Journal of Reproductive Immunology 62 (2004) 61–68 65

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 F 2alpha and E 2 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 ). 66 S.N. Kalantaridou et al. / Journal of Reproductive Immunology 62 (2004) 61–68

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