Abstract
Whereas it is well established that chronic stress induces female reproductive dysfunction, whether stress negatively impacts fertility and fecundity when applied prior to mating and pregnancy has not been explored. In this study, we show that stress that concludes 4 days prior to mating results in persistent and marked reproductive dysfunction, with fewer successful copulation events, fewer pregnancies in those that successfully mated, and increased embryo resorption. Chronic stress exposure led to elevated expression of the hypothalamic inhibitory peptide, RFamide-related peptide-3 (RFRP3), in regularly cycling females. Remarkably, genetic silencing of RFRP3 during stress using an inducible-targeted shRNA completely alleviates stress-induced infertility in female rats, resulting in mating and pregnancy success rates indistinguishable from non-stress controls. We show that chronic stress has long-term effects on pregnancy success, even post-stressor, that are mediated by RFRP3. This points to RFRP3 as a potential clinically relevant single target for stress-induced infertility.
Highlights
High psychological stress inhibits reproductive function when both occur concomitantly (Rivier and Rivest, 1991; Ferin, 1999; Tilbrook et al, 2000; Louis et al, 2011)
Stressed females exhibited fewer successful copulation events, fewer pregnancies in those that did successfully mate, and increased frequency of embryo resorption in the achieved pregnancies. These marked effects of stress on fertility were completely blocked by knockdown of RFamide-related peptide-3 (RFRP3), even though RFRP3 function was restored following stress cessation. These findings indicate that stress has lingering negative consequences for female reproductive function that are mediated by a transient rise in RFRP3
Selective knock-down of hypothalamic RFRP3 during stress exposure preserved all aspects of reproductive function that were otherwise reduced in stress-exposed animals
Summary
High psychological stress inhibits reproductive function when both occur concomitantly (Rivier and Rivest, 1991; Ferin, 1999; Tilbrook et al, 2000; Louis et al, 2011). Inhibition of reproductive function by acute stress may be adaptive, delaying reproduction in times of duress or resource scarcity (Wasser and Barash, 1983; Louis et al, 2011). After its cessation, can a prior, persistent stressor have long-term negative after-effects on reproductive health? A high-stress environment may be a significant barrier to sexual well-being and childbearing. A molecular framework to understand the longterm effects of stress on female reproduction, and its implications for human health, is currently lacking
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