Glucocorticoids, stress, and fertility

Abstract

Modifications of the hypothalamo-pituitary-adrenal axis and associated changes in circulating levels of glucocorticoids form a key component of the response of an organism to stressful challenges. Increased levels of glucocorticoids promote gluconeogenesis, mobilization of amino acids, and stimulation of fat breakdown to maintain circulating levels of glucose necessary to mount a stress response. In addition to profound changes in the physiology and function of multiple tissues, stress and elevated glucocorticoids can also inhibit reproduction, a logical effect for the survival of self. Precise levels of glucocorticoids are required for proper gonadal function; where the balance is disrupted, so is fertility. Glucocorticoids affect gonadal function at multiple levels in hypothalamo-pituitary-gonadal axis: 1) the hypothalamus (to decrease the synthesis and release of gonadotropin-releasing hormone [GnRH]); 2) the pituitary gland (to inhibit the synthesis and release of luteinizing hormone [LH] and follicle stimulating hormone [FSH]); 3) the testis/ovary (to modulate steroidogenesis and/or gametogenesis directly). Furthermore, maternal exposure to prenatal stress or exogenous glucocorticoids can lead to permanent modification of hypothalamo-pituitary-adrenal function and stress-related behaviors in offspring. Glucocorticoids are vital to many aspects of normal brain development, but fetal exposure to superabundant glucocorticoids can result in life-long effects on neuroendocrine function. This review focuses on the molecular mechanisms believed to mediate glucocorticoid inhibition of reproductive functions and the anatomical sites at which these effects take place.

Figure I

The Hypothalamo-Pituitary-Gonadal Axis. The Hypothalamo-Pituitary-Gonadal axis includes the effects of the hypothalamus, pituitary, and gonads as a feed forward/back entity. The hypothalamus produces gonadotropin-releasing hormone, which signals through the anterior portion of the pituitary gland to produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In females, FSH and LH act primarily to activate the ovaries to produce estrogen and inhibin. In males, LH stimulates the Leydig cells of the testes to produce testosterone and FSH signals through the Sertoli cells to support spermatogenesis. The sex steroids hormones, testosterone and estrogen, and FSH-stimulated inhibin feed back to inhibit the release of GnRH and pituitary secretion of LH and FSH.

Figure II

Glucocorticoid Action in the Brain. In the reproductive system, the brain's hypothalamus produces GnRH, which stimulates the pituitary gland to produce LH and FSH, which in turn stimulate production of testosterone, estradiol and sexual behavior. Stress induces elevated circulating levels of glucocorticoids, which act directly on the hypothalamus to suppress GnRH production. Glucocorticoids also stimulate expression of RFRP, a gonadotropin-inhibitory hormone, which also acts to reduce GnRH production as well as to directly lower pituitary secretion of LH and FSH. Glucocorticoids may also play a protective role in maintaining the HPG axis during acute stress through suppression of PGs.

Figure III

Glucocorticoid Regulation in the Testis. The Leydig cell is the primary target of glucocorticoid regulation in the testis. The direct inhibitory effect of glucocorticoids involves multiple mechanisms: (1) inhibition of testosterone biosynthesis, (2) reduction in steroidogenic enzymes CYP17, P450 SCC, and StAR, (3) induction of Leydig cell apoptosis, and (4) stimulation of MIF expression. Glucocorticoids can regulate other cell types within the testis. Germ cells are susceptible to glucocorticoid-induced apoptosis possibly through BAX regulation.

Figure IV

Prenatal Exposure to Excess Glucocorticoids Predispose Offspring to Fetal Programming. Excessive fetal glucocorticoid exposure may result from a stressful maternal environment, reduced fetoplacental 11β-HSD2 activity, or exogenously administered glucocorticoids. A modified fetal environment can directly affect development of the brain and neuroendocrine structures, likely involving epigenetic modifications. These changes can predispose offspring to various metabolic, cardiovascular, and neurobiological pathophysiologies.