Gonadal steroid hormones and the hypothalamo–pituitary–adrenal axis

Highlights

• The HPA axis is a complex neuroendocrine loop that integrates stressor-related information.

• Sex differences in the HPA axis arise through effects of gonadal steroid hormones.

• Estrogen can alter HPA function though divergent actions mediated by ERalpha and ERbeta.

• Androgens inhibit HPA function through actions at the androgen receptor or ERbeta.

Abstract

The hypothalamo–pituitary–adrenal (HPA) axis represents a complex neuroendocrine feedback loop controlling the secretion of adrenal glucocorticoid hormones. Central to its function is the paraventricular nucleus of the hypothalamus (PVN) where neurons expressing corticotropin releasing factor reside. These HPA motor neurons are a primary site of integration leading to graded endocrine responses to physical and psychological stressors. An important regulatory factor that must be considered, prior to generating an appropriate response is the animal’s reproductive status. Thus, PVN neurons express androgen and estrogen receptors and receive input from sites that also express these receptors. Consequently, changes in reproduction and gonadal steroid levels modulate the stress response and this underlies sex differences in HPA axis function. This review examines the make up of the HPA axis and hypothalamo–pituitary–gonadal (HPG) axis and the interactions between the two that should be considered when exploring normal and pathological responses to environmental stressors.

Introduction

The origins of the study of stress physiology are rooted in the contributions of the early physiologists, Walter Cannon and Hans Selye. It was Cannon who originally coined the term, “fight or flight”, when referring to the physiological responses to acute stressors (Cannon, 1915). He later described the concept of homeostasis as a steady state condition that requires active mechanisms to maintain (Cannon, 1932). These pioneering concepts were further explored by Hans Selye who examined the effect of chronic stressors on an organism’s physiology. Selye’s studies into the body’s reactions to chronic stressors led to his development of the general adaptation syndrome (GAS), a set of nonspecific responses to a stressor which could give rise to pathology after continuous, unrelieved stress.

The pioneering work of Cannon and Selye were closely followed by studies focused on teasing out the biological mechanisms underlying the stress response. These included the demonstration that an anterior pituitary hormone (i.e. adrenocorticotropic hormone; ACTH) can stimulate adrenal glucocorticoid release (Sayers, 1950) and the development of the postulate that pituitary gland function was under neural control (Harris, 1951a, Harris, 1951b). The latter hypothesis was based on Harris’ observations of the capillary system that existed connecting the ventral hypothalamus with the anterior lobe of the pituitary. In these pioneering studies, Harris demonstrated that disrupting blood flow from the hypothalamus to the pituitary by pituitary stalk section would impair ACTH release (Fortier et al., 1957), whereas electrical stimulation of the rabbit hypothalamus triggered the release of ACTH into the general circulation (De Groot and Harris, 1950). Harris also showed that pituitary explants were non-functional, yet viable (Harris and Jacobsohn, 1952). Such studies confirmed the importance of the hypothalamus in controlling anterior pituitary function and helped establish the field of neuroendocrinology as a discipline. Further studies by McCann (1953) and Porter (1953) demonstrated that hypothalamic lesions prevented ACTH release thereby establishing the hypothalamus as the source of the alleged ‘releasing factors’ that affected pituitary function.

The initial attempts to isolate the putative corticotropin releasing factor (CRF) proved difficult, although initially, the ability of an alternate “CRF”, vasopressin, to induce ACTH release was described (McCann and Brobeck, 1954). Hypothalamic releasing factors, such as thyrotropin releasing hormone (TRH), and luteinizing hormone releasing hormone (LHRH, or gonadotropin releasing hormone, GnRH, Schally et al., 1971a) were initially isolated in the late ‘60s and early ‘70s (Amoss et al., 1971, Burgus et al., 1970, Nair et al., 1970, Schally et al., 1971b, Schally et al., 1971c), yet, it was a decade later when Vale et al. (1981) isolated, characterized, and described the biological activity of a hypothalamic peptide that caused the release of ACTH from the anterior pituitary gland. Since then, the 41 amino acid CRF, has been shown to be expressed in many brain areas and has been implicated in a wide variety of behaviors and neurobiological functions (Bale and Vale, 2004). We now know that CRF and vasopressin can be co-localized in some neurons of the paraventricular nucleus of the hypothalamus (Sawchenko et al., 1984, Whitnall and Gainer, 1988), that they can be co-released, and that vasopressin acts to enhance the secretogogue properties of CRF at the anterior pituitary gland (Bilezikjian and Vale, 1987, Gillies et al., 1982, Rivier and Vale, 1983).

Of importance for this discussion are the findings that a number of human neuropsychiatric disorders are accompanied by a dysregulation of the HPA axis and that many of these disorders exhibit profound sex differences in risk implicating a modulatory role for gonadal steroid hormones (Kessler et al., 1993, Kessler, 2003). For example, the incidence of major depressive disorder is at least two fold greater in women than in men (Angold and Worthman, 1993, Kessler et al., 1993, Weissman et al., 1993) and this is associated with enhanced HPA activity associated with a reduced ability to feedback regulate the system (Ising et al., 2007, Strohle and Holsboer, 2003). In this review, we first examine the HPA axis and its regulatory elements and follow with a discussion of pre-clinical studies showing sex differences in the function of the HPA axis and the well-described role of gonadal steroid hormones in modulating HPA axis responsivity to stress and stress-related behaviors in adulthood.