Corticosterone Blocks Ovarian Cyclicity and the LH Surge via Decreased Kisspeptin Neuron Activation in Female Mice

Abstract

Stress elicits activation of the hypothalamic-pituitary-adrenal axis, which leads to enhanced circulating glucocorticoids, as well as impaired gonadotropin secretion and ovarian cyclicity. Here, we tested the hypothesis that elevated, stress-levels of glucocorticoids disrupt ovarian cyclicity by interfering with the preovulatory sequence of endocrine events necessary for the LH surge. Ovarian cyclicity was monitored in female mice implanted with a cholesterol or corticosterone (Cort) pellet. Cort, but not cholesterol, arrested cyclicity in diestrus. Subsequent studies focused on the mechanism whereby Cort stalled the preovulatory sequence by assessing responsiveness to the positive feedback estradiol signal. Ovariectomized mice were treated with an LH surge-inducing estradiol implant, as well as Cort or cholesterol, and assessed several days later for LH levels on the evening of the anticipated surge. All cholesterol females showed a clear LH surge. At the time of the anticipated surge, LH levels were undetectable in Cort-treated females. In situ hybridization analyses the anteroventral periventricular nucleus revealed that Cort robustly suppressed the percentage of Kiss1 cells coexpressing cfos, as well as reduced the number of Kiss1 cells and amount of Kiss1 mRNA per cell, compared with expression in control brains. In addition, Cort blunted pituitary expression of the genes encoding the GnRH receptor and LHβ, indicating inhibition of gonadotropes during the blockage of the LH surge. Collectively, our findings support the hypothesis that physiological stress-levels of Cort disrupts ovarian cyclicity, in part, through disruption of positive feedback mechanisms at both the hypothalamic and pituitary levels which are necessary for generation of the preovulatory LH surge.

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

“…After 10 days, blood samples from the tail vein were collected with a pipette every 6 min for two 90-min intervals, pre: -1.5 to 0 h or post: 46.5-48 h, relative to the subcutaneous implantation of a pellet containing either cholesterol or corticosterone (n = 3/ group) while briefly exposed to isoflurane anesthesia. Cholesterol or corticosterone-releasing pellets were manufactured in our laboratory as described previously [4], by coating siliconefilled (Liquid Nails, Butler County, PA, USA) Silastic tubing of 1.0 cm length (0.040 in. I.D.…”

“…Evidence that a glucocorticoid receptor (GR) antagonist prevents the inhibition of gonadotropin secretion during stress in intact male rats and ovariectomized (OVX) female sheep treated with estradiol, supports a mediatory role of elevated glucocorticoids [1][2][3]. We have previously demonstrated that a chronic elevation of a stress-like level of corticosterone, the natural glucocorticoid in rodents, disrupts the ovulatory cycle of the female mouse [4]. Female mice exposed to elevated corticosterone remain in diestrus, a stage comparable to the early follicular phase in humans, suggesting that a suppression in luteinizing hormone (LH) secretion contributes to ovulatory cycle disruption.…”

Glucocorticoids and Reproduction: Traffic Control on the Road to Reproduction

“…KISS1 neurons in the anteroventral periventricular nucleus and periventricular nucleus continuum of the preoptic area of the hypothalamus express GR, suggesting that glucocorticoids can directly act in these neurons [8]. In mice, corticosterone treatment diminished hypothalamic expression of KISS1 during the estradiol-induced LH surge and decreased the activation of KISS1 neurons [9]. Impairment of KISS1 neurons represents a newly discovered mechanism by which glucocorticoids are able to suppress the HPG axis.…”

“…In addition to the effects on ovarian cyclicity mediated through the hypothalamus and pituitary, glucocorticoids impact ovarian physiology through regulating the functions of granulosa cells, oocytes, cumulus cells, and luteal cells [9]. Glucocorticoids differentially induce and repress steroidogenesis in the ovary.…”

The roles of kisspeptin and gonadotropin inhibitory hormone in stress-induced reproductive disorders

“…Some studies have also evaluated the intermediate factors that transfer stress signals to kisspeptin neurons. As a result, it was found that both the central administration of CRH and the peripheral administration of corticosterone reduced hypothalamic Kiss1 mRNA expression and kisspeptin neuron activity in female rats and mice, indicating that activation of the HPA axis is involved in the stressinduced suppression of the kisspeptin system [77,80]. Interestingly, relatively severe stress protocols were used in these studies; i.e., high-dose LPS (1-5 mg/kg) or repeated LPS administration protocols (three consecutive injections at 24-h intervals), to evaluate the effects of immune stress [75,76,81,82], and chronic (once per day for four weeks) or combined (restraint and isolation) protocols were used to evaluate the effects of unpredictable and psychosocial stress [78,79].…”