Cortisol disrupts the ability of estradiol-17β to induce the LH surge in ovariectomized ewes

Abstract

Stress disrupts the preovulatory luteinizing hormone (LH) surge in females, but the mechanisms are unknown. We tested the hypothesis that cortisol compromises the ability of estrogen to induce a preovulatory-like LH surge in ovariectomized ewes in both the breeding and nonbreeding season. Luteinizing hormone surges were induced in ovariectomized ewes by treatment with progesterone followed by a surge-inducing estradiol-17β (E2) stimulus using a crossover design. The experiment was replicated in the breeding and nonbreeding seasons. Cortisol reduced the incidence of LH surges irrespective of season. Cortisol increased the latency from E2 stimulus to the onset of the surge in the breeding season only and suppressed the LH surge amplitude during both seasons (P < 0.01). We conclude that cortisol can interfere with the LH surge in several ways: delay, blunt, and in extreme cases prevent the E2-induced LH surge. Furthermore, the effect of cortisol to delay the E2-induced LH surge is more pronounced in the breeding season. These results show that cortisol disrupts the positive feedback effect of E2 to trigger an LH surge and suggest the involvement of multiple mechanisms.

Introduction

Stress can impair various aspects of reproduction, including gonadotropin secretion, estrus, and ovulation. In females, stress has been shown to disrupt the natural follicular phase of the ovarian cycle in various species, including the cow [1], rat [2], [3], monkey [4], and sheep [5], [6], [7], [8]. Female reproductive cycles depend upon a series of synchronized endocrine events that allow cyclic generation of ovulation and estrus, and this finely tuned sequence of events is clearly susceptible to perturbation by stress [9], [10]. Stressors, such as transportation [7] and endotoxins [11], have been shown to delay or inhibit the preovulatory luteinizing hormone (LH) surge in cyclic ewes. The actions of estradiol-17β (E2) are critical for the generation of the LH surge, and the extent to which stress influences these actions is not well understood.

During the early follicular phase of the estrous cycle in sheep, E2 exerts a negative feedback effect on gonadotropin-releasing hormone (GnRH)/LH secretion, but as plasma E2 concentrations rise, a hypothetical “threshold” is reached and a “positive feedback” on GnRH/LH secretion is activated. This process involves a train of events that initiate the preovulatory surge in GnRH and LH secretion [12], [13], [14], [15], [16]. Within the brain, E2 causes a surge in GnRH [16], which is complemented by increased responsiveness of the pituitary gonadotropes to GnRH [17]. This ability of E2 to have a transient positive feedback effect is demonstrated in the ovariectomized ewe administered a single injection of E2 benzoate [18], [19], [20].

Cortisol could mediate the effect of stress to influence the cyclic preovulatory GnRH/LH surge. A universal response to stress is the activation of the hypothalamo–pituitary–adrenal axis, which is characterized by elevation in the plasma concentrations of cortisol [21], [22], [23], [24] and reduction in pulsatile LH secretion [28]. In sheep, this is typified in the responses to endotoxin challenge [5], [25] and isolation and restraint stress [26]. Cortisol reduces pulsatile secretion of LH during the follicular phase of the estrous cycle, which leads to a delay in the preovulatory LH surge in normally cycling ewes [27], [28]. Cortisol may act at the level of the brain to reduce GnRH secretion [29] and at the level of the pituitary to reduce pituitary responsiveness to GnRH [30], [31], [32]. Cortisol may activate systems within the brain or the pituitary gland to reduce pulsatile GnRH and gonadotropin secretion, respectively, thereby reducing the output of E2 by the follicle and compromising the ovarian “signal” for positive feedback [28]. It is also feasible that cortisol could impair the positive feedback mechanisms per se, reducing the ability of an E2 stimulus to induce the GnRH and LH surges [27], but this hypothesis has not been fully tested. Reproductive events in sheep vary with the circannual breeding season. It has been found that season does not affect the inhibitory actions of cortisol on the pulsatile secretion of LH in ovariectomized ewes [33] or on the interaction between E2 and cortisol in ovariectomized ewes that have undergone hypothalamo–pituitary disconnection and have been treated with fixed injections of GnRH [31], but the effect of season has not been investigated with respect to the actions of cortisol to influence the E2-induced LH surge. In this study we tested the hypothesis that a sustained elevation in plasma cortisol can block the positive feedback action of E2 to induce a preovulatory-like LH surge in ovariectomized ewes in both the breeding and nonbreeding seasons.