# Mild chronic stress promotes female fertility via the ovarian CRF receptor

## TL;DR

Mild chronic stress in female mice improves fertility by activating a stress-related receptor in the ovaries, leading to increased ovulation and litter size.

## Contribution

This study reveals a novel mechanism by which mild chronic stress enhances female fertility through ovarian CRF receptor activation.

## Key findings

- Mild chronic variable stress increased ovulation rate and litter size in female mice.
- Stressed mice showed lower estrogen levels and reduced ovarian 17β-HSD3 expression.
- CRFR1 knockout mice and mice treated with a CRF receptor antagonist had reduced ovulation and higher estrogen levels.

## Abstract

In many species, including human, stress is accompanied by disruption of reproductive functions. The endocrine stress-response is activated and regulated by members of the corticotropin releasing factor (CRF) protein family. Stress stimuli may affect reproductive functions locally, recruiting autocrine/paracrine strategies. Yet, the molecular mechanisms mediating these effects are not fully understood.

To explore the molecular mechanism mediating the ovarian stress response, we used three different models: (1) ICR mice subjected to chronic variable stress (CVS) procedure for 4 weeks. The stress procedure consisted of 9 different stressors per week, approximately 2 stressors per day both in the dark and the light phases. (2) wild-type mice undergoing intraovarian injection of the CRF receptor antagonist, β-asstressin, and (3) CRF-R1 knockout mice.

We report herein that ovulation rate was significantly elevated, and the litter size was substantially increased, in the following estrous cycle of female mice subjected to mild chronic variable stress (CVS). These females exhibited lower serum estrogen levels associated with reduced ovarian 17β-HSD3 expression. Exploration of the involvement of a neuroregulatory mechanism in this event revealed upregulation of the corticotropin releasing factor type 1 receptor (CRFR1) in the theca-interstitial cells of large ovarian follicles. In agreement, CRFR1 knockout mice, as well as wild-type females undergoing intraovarian injection of the CRF receptor antagonist, β-asstressin, displayed reduced ovulation rate, enhanced estrogen secretion and an increase in 17β-HSD3 expression.

Our findings show a direct gonadal response to neuroendocrine and central stress-response regulators. The mechanism of this unexpected beneficial effect of CVS on reproduction may provide a neuro-endocrine background to the well-known “Baby Boom” phenomenon.

The online version contains supplementary material available at 10.1186/s12964-025-02371-0.