Estradiol Enables Chronic Corticosterone to Inhibit Pulsatile Luteinizing Hormone Secretion and Suppress Kiss1 Neuronal Activation in Female Mice

Abstract

Introduction: Two common responses to stress include elevated circulating glucocorticoids and impaired luteinizing hormone (LH) secretion. We have previously shown that a chronic stress level of corticosterone can impair ovarian cyclicity in intact mice by preventing follicular-phase endocrine events. Objective: This study is aimed at investigating if corticosterone can disrupt LH pulses and whether estradiol is necessary for this inhibition. Methods: Our approach was to measure LH pulses prior to and following the administration of chronic corticosterone or cholesterol in ovariectomized (OVX) mice treated with or without estradiol, as well as assess changes in arcuate kisspeptin (Kiss1) neuronal activation, as determined by co-expression with c-Fos. Results: In OVX mice, a chronic 48 h elevation in corticosterone did not alter the pulsatile pattern of LH. In contrast, corticosterone induced a robust suppression of pulsatile LH secretion in mice treated with estradiol. This suppression represented a decrease in pulse frequency without a change in amplitude. We show that the majority of arcuate Kiss1 neurons contain glucocorticoid receptor, revealing a potential site of corticosterone action. Although arcuate Kiss1 and Tac2 gene expression did not change in response to corticosterone, arcuate Kiss1 neuronal activation was significantly reduced by chronic corticosterone, but only in mice treated with estradiol. Conclusions: Collectively, these data demonstrate that chronic corticosterone inhibits LH pulse frequency and reduces Kiss1 neuronal activation in female mice, both in an estradiol-dependent manner. Our findings support the possibility that enhanced sensitivity to glucocorticoids, due to ovarian steroid milieu, may contribute to reproductive impairment associated with stress or pathophysiologic conditions of elevated glucocorticoids.

Dynamic hormone control of stress and fertility

“…The model reproduced the effects of ovarian hormone removal (OVX) and restitution (E 2 ) on the HPA and HPG axes dynamics, both under physiological conditions [12] (Fig. 3) and under exogenous CORT excess [8] (Fig. 4).…”

“…In a recent study, Kreisman and co-workers [8] investigated the effect of chronic CORT administration on LH pulsatility and demonstrated the importance of gonadal steroid hormones in mediating the inhibitory effect of CORT on the HPG axis. The study showed that a pellet delivering a high dose of CORT over 48 hrs in OVX mice has no effect on LH pulsatility, whereas a significant reduction of LH pulse frequency is observed in OVX animals treated with a 17β-estradiol silastic implant (OVX+E 2 ).…”

“…The study showed that a pellet delivering a high dose of CORT over 48 hrs in OVX mice has no effect on LH pulsatility, whereas a significant reduction of LH pulse frequency is observed in OVX animals treated with a 17β-estradiol silastic implant (OVX+E 2 ). In our model, we accounted for the OVX and OVX+E 2 scenarios as described in the previous section, while the constantly high CORT levels were achieved by replacing the effective CORT levels modulating the KNDy network by a constant high value estimated from [8] (see Supplementary Material). Figure 4 illustrates the differential effect of chronically elevated CORT levels on the GnRH pulse generator frequency in OVX versus OVX+E 2 animals.…”

“…In recent years, animal models have greatly enhanced our understanding of how specific perturbations in the HPA axis dynamics affect the HPG axis [8,9,10,11], as well as how the activity of the HPG axis can in turn modulate the dynamics of the HPA axis [12,13,14,15]. Furthermore, human studies have shown how glucocorticoid excess can have profound effects on the menstrual cycle [16,17,18].…”

“…Second, we consider the evidence on stress-induced suppression of GnRH pulse generator activity dependent of estradiol, and use the model to understand the role of estradiol-dependent effects on the HPA axis [12,25]. We also explore the simultaneous effect of exogenous estradiol and glucocorticoids on the dynamics of the GnRH pulse generator [8]. Third, we use the model to explore how perturbations such as stressors and chronic changes in gonadal steroids and glucocorticoid levels can disrupt normal rhythmicity and lead to dysregulations that propagate from one neuroendocrine system to the other.…”