Chronic restraint stress induces excessive activation of primordial follicles in mice ovaries

Abstract

Chronic stress is an important factor influencing people’s health. It usually causes endocrinal disorders and a decline in reproduction in females. Although studies of both human and animals suggest a detrimental effect of stress on reproduction, the influence of chronic stress on the ovarian reservation and follicular development is still not clear. In this study, a chronic restraint stress (CRS) mouse model was used to investigate the effect of stress on ovarian reservation and follicular development and explore the underlying mechanism. In this study, after 8 weeks of CRS, primordial follicles were excessively activated in the ovaries of the CRS group compared with the control group. Further results showed that the activation of primordial follicles induced by CRS was involved in the increasing expression level of Kit ligand and its receptor Kit and the activation of phosphatidylinositol 3-kinase (PI3K)/phosphatase and tensin homolog deleted on chromosome 10 (PTEN)/protein kinase B (Akt) pathway. The corticotropin-releasing hormone (CRH) is a neuropeptide released due to stress, which plays an important role in regulating follicle development. A high level of serum CRH was detected in the CRS mouse model, and the real-time polymerase chain reaction assay showed that the mRNA level of its main receptor CRHR1increased in the ovaries of the CRS mouse group. Moreover, 100nM CRH significantly improved the activation of primordial follicles in newborn mouse ovaries in vitro. These results demonstrated that CRS could induce immoderate activation of primordial follicles accompanied by the activation of Kit-PI3K signaling, in which CRH might be an important endocrine factor.

Chronic restraint stress impairs cognition via modulating HDAC2 expression

“…In this experiment, a restraining tube was used as a way to induce chronic stress in mice [ 5 ]. All procedures involving animals were reviewed and approved by Institute of Laboratory Animals Science for ensuring animal care.…”

“…In modern society, with the accelerating pace of life, chronic stress has become a common problem that cannot be ignored and has become an important risk factor for the onset of many diseases including Alzheimer’s disease (AD) [ 1 , 2 , 3 ]. Two important stress response systems include the hypothalamic-pituitary-adrenal axis (HPA axis) and the sympathetic nervous system [ 4 , 5 ]. The sympathetic nervous system is involved in the acute stress response, whereas for chronic stress stimuli, the HPA axis is activated with increased glucocorticoid released [ 6 , 7 ].…”

Implications of Nonphysiological Ovarian Primordial Follicle Activation for Fertility Preservation

“…Similarly, female mice exposed to chronic restraint stress for 8 weeks developed estrous cycle and ovulation disorders as well as excessive recruitment of PFs, compared to non-exposed mice. This phenomenon has been correlated with increased expression of KL and c-KIT and overactivation of the PI3K/PTEN/Akt pathway (91). Oxygen supply is also of concern, especially during in vitro culture.…”

Primordial follicle activation as new treatment for primary ovarian insufficiency

“…On the contrary, inhibition of PTEN and activation of PI3K may cause activation of dormant follicles, since PTEN is a negative regulator of the PI3K/AKT signaling pathway. In addition, accumulating evidence shows that the PTEN/PI3K/AKT/FOXO3 pathway is responsible for chemotherapy-induced POI [25] and that chronic stress and bisphenol A are related to pathway modulation [26,27]. Numerous inhibitors and activators directed against either individual or multiple components of this pathway have already been developed, based on the primary importance of modulating this pathway for cancer treatment (Figure 1) [28].…”