Stress CRasHes into fertility command center

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Science Translational Medicine  08 Nov 2017:
Vol. 9, Issue 415, eaaq1232
DOI: 10.1126/scitranslmed.aaq1232


Corticotropin-releasing hormone alters activity of gonadotropin-releasing hormone neurons in an estradiol-dependent manner.

Metabolic and psychosocial stressors can lead to functional hypothalamic amenorrhea (FHA), a contributor to anovulation and infertility in women. Although hyperactivation of the stress axis in women with FHA results in increased corticotropin-releasing hormone (CRH) concentrations in cerebrospinal fluid (CSF), it remains unclear whether and how CRH impacts firing of hypothalamic gonadotropin-releasing hormone (GnRH) neurons, the central regulators of the reproductive axis.

Investigators Phumsatitpong and Moenter designed an in vitro slice electrophysiology study to characterize the effects of CRH and estradiol on the electrical activity of GnRH neurons in ovariectomized female mice. Data showed that at low concentrations CRH increased GnRH firing, whereas high concentrations of CRH decreased GnRH activity. These dose-dependent effects of CRH were only seen when estradiol was present. Additionally, administration of CRH receptor 1 (CRHR1) and 2 (CRHR2) agonists reproduced the effects of low and high CRH concentration, respectively. Overall, the data indicate that CRH alters activity of GnRH neurons in an estradiol- and CRH receptor–dependent manner. These results suggest that increased CSF concentration of CRH in women with FHA might contribute to stress-induced reproductive impairments by inhibiting GnRH neuronal activity via activation of CRHR2. The results of this study also showed that at low concentration, CRH might act via CRHR1 to activate GnRH neurons, providing mechanistic insights for previous clinical and preclinical reports indicating that acute stress exposure can induce ovulation. Although these findings suggest that CRH receptor on hypothalamic GnRH neurons may serve as pharmacological target for reproductive dysfunction, CRH receptor antagonists developed for treatment of psychiatry conditions associated with hyperactivation of the stress axis (i.e., depression) have failed in transitioning from preclinical studies to clinical trials. Future studies are necessary to translate these findings from rodents to nonhuman primates that have similar 28-day ovarian cycles as women and to identify other signals that may serve as air bags to lessen CRH’s adverse effects on reproductive function.

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