ReviewGonadal steroid hormones and the hypothalamo–pituitary–adrenal axis
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.
Section snippets
An overview of the HPA axis
Animals respond to real or perceived threats to their welfare by activating neurons that control neuroendocrine responses (e.g. the HPA axis) and the sympathetic autonomic response. For HPA axis activation, the net response is the secretion of glucocorticoids from the adrenal cortex into the general circulation. In humans and many mammals, the main adrenal glucocorticoid is cortisol, whereas corticosterone is the primary glucocorticoid in most rodents. Circulating corticosteroids act on a
Mineralocorticoid and glucocorticoid receptors
Following secretion from the adrenal cortex, corticosteroids regulate numerous functions throughout the body, including those of the central nervous system. The actions of glucocorticoids are mediated by two receptors, the type I corticosteroid receptor or mineralocorticoid receptor (MR; also designated NR3C2), and the type II corticosteroid receptor or glucocorticoid receptor (GR, also designated NR3C1). Both of these receptor types are expressed in multiple regions of the mature and
Overview of the hypothalamo–pituitary–gonadal (HPG) axis
Reproduction, the physiological process that is all-important for the survival of the species, is regulated by a neuroendocrine axis that is parallel to the HPA axis and involves the hypothalamus, anterior pituitary gland and gonads. This hypothalamo–pituitary–gonadal (HPG) axis is comprised, at its most fundamental element, of GnRH expressing neurons that, in the rodent, are located in the rostral forebrain (medial septum, diagonal band of broca, medial preoptic area, anteroventral preoptic (
Gonadal steroid receptors
Classical gonadal steroid receptors belong to a “superfamily” of intracellular receptors that act as ligand-activated transcription factors (Evans, 1988). The steroid/thyroid hormone receptor superfamily consists of three main classes (for reviews see Evans, 1988, Mangelsdorf et al., 1995). Class 3 comprises the estrogen receptor (ER), androgen receptor (AR), progesterone receptor (PR), GR, and MR. In addition, gonadal steroids have rapid effects through classic and non-classic receptors at the
Sex difference in HPA axis function
Numerous reports have indicated that the function of the HPA axis is different between the sexes, although the direction of this difference is sometimes dependent upon the species being examined. In rodents, basal and stress-induced adrenal glucocorticoid secretion has been reported to be greater in females than in males (Critchlow et al., 1963, Handa et al., 1994a, Kitay, 1963). Activation of the stress response and of PVN neurons is reported to be higher in females than males (Larkin et al.,
Molecular mechanism for gonadal steroids in controlling the HPA Axis
The subfamily of nuclear receptors that contain the steroid hormone receptors are characterized by their ability to regulate transcription by interacting with select DNA response elements. The classically described DNA element is the inverted repeat, a nucleotide sequence that is the reversed complement of another downstream sequence, in which both sequences are separated by a variable number of nucleotides. Alternatively, steroid hormone receptors can act via composite elements, which consist
Effects of estrogens on anxiety and depressive-like behaviors
Studies examining anxiety and depressive-like behaviors in ERα and ERβ knockout (βERKO) mice have generally concluded that ERβ is involved in dampening anxiety and stress related behaviors. The initial clue that ERβ might be involved in regulating anxiety-like behaviors came from studies by Krezel et al. (2001) who demonstrated elevated anxiety-like behaviors in female ERβ null mutant mice in the open field arena and the elevated plus maze. Correspondingly ERβ null mice show increased
Summary and conclusions
It is becoming apparent that the ability of the hypothalamus to oversee normal physiology and make rapid adjustments in response to shifts in the environment is swayed by the reproductive status of the animal. Hence, the hypothalamus monitors reproductive state through neurons that express receptors for gonadal steroid hormones. The identification and function of these androgen and estrogen receptor containing neurons and the neuroanatomical and molecular pathways that they utilize to influence
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