An emerging thesis in such multipathway biological systems as the corticotropic, gonadotropic and somatotropic axes is that homeostasis is achieved by repeated incremental signaling among key components of the network.
Johannes D. Veldhuis, M.D., of the Division of Endocrinology, Diabetes, Metabolism, & Nutrition at Mayo Clinic in Rochester, Minn., says: "Direct sampling of hypothalamic-pituitary portal blood in the rat, sheep and horse establishes that corticotropin-releasing hormone (CRH), arginine vasopressin (AVP) and corticotropin (ACTH) are secreted in discrete bursts of varying frequency, amplitude and temporal concordance. Pulses of CRH and AVP drive bursts of ACTH secretion by activating cAMP-protein kinase A and protein kinase C, respectively. Pulses of ACTH, in turn, stimulate episodes of cortisol secretion by the adrenal zona fasciculata via parallel and convergent signaling cascades. Systemic cortisol acts through delayed and rapid negative feedback to oppose CRH and AVP secretion from the hypothalamus and their actions on corticotropes. According to this ensemble concept, regulatory interactions collectively — rather than any individual effector acting alone — maintain physiological glucocorticoid availability."
Impact of free and protein-bound cortisol
Cortisol acts on diverse target tissues, such as muscle, bone, brain, thymus and pituitary gland, through type I (mineralocorticoid, or MR) and type II (glucocorticoid, or GR) receptors. Human MR and GR have nominal dissociation constants for cortisol of 0.043 and 0.36 mcg/dL, respectively.
By comparison, diurnal peak and nadir-free cortisol concentrations average 1.2 and 0.3 mcg/dL, respectively. Critical illness, ACTH injection and major surgery elevate free cortisol levels to 2.2 to 8.7 mcg/dL. The importance of free cortisol as a negative-feedback signal is inferable in rare cases of patients with null mutations of the cortisol-binding globulin gene, who maintain normal ACTH concentrations despite a free cortisol concentration of 0.35 mcg/dL. This observation opens the possibility of using free cortisol measurements clinically.
The potency of glucocorticoids is specific to the target cell. Dr. Velhuis explains: "For example, in the rat, the one-half maximally inhibitory (ID50) serum corticosterone concentration is approximately 1 mcg/dL for the CRH gene, 2 mcg/dL for the thymus and 5 mcg/dL for the AVP gene. Differences in ID50 values putatively reflect the in vivo density of GR and MR, availability of coactivator and corepressor molecules, sequence characteristics of the targeted promoter, systemic and in situ CBG concentrations and activities of 11 b-hydroxysteroid dehydrogenase type I (activating cortisone to cortisol) and type II (inactivating cortisol)."
Dr. Velhuis continues: "Autoinhibition is a physiological hallmark of neuroendocrine systems. GR and MR mediate negative feedback by cortisol in the human because their respective antagonists, canrenoate/spironolactone and mifepristone (RU-486), increase mean cortisol concentrations. In the rat, corticosteroid feedback targets include the lateral septum, hippocampus, and bed nucleus of the stria terminalis (as mediated via both MR and GR) and parvocellular CRH and AVP neurons and corticotrope cells (transduced principally via GR). Sex steroids modulate the foregoing distinct pathways in animal models. Comparable details are not yet available in humans."
Circadian, hypothalamic-pituitary-adrenal (HPA) rhythms in animals arise from a combination of day-night variations in CRH and AVP gene expression, ACTH secretion, adrenal responsiveness to ACTH, and glucocorticoid feedback and clearance. In clinical studies, regulation of the mass (size) of ACTH and cortisol secretory bursts explain more than 95 percent and more than 85 percent of nyctohemeral rhythmicity, respectively. Thus, to obviate, confounding, clinical comparisons need to be conducted at a uniform time of day.
The time delays between successive ACTH secretory bursts are random about a mean probability with hormone-specific interpulse variability. This new model applies to other human neuroendocrine pulse generators also (for example, for gonadotropin-releasing hormone).
In animals, the HPA axis mediates adaptations to diverse physical (such as exercise), psychosocial (anxiety), and metabolic (fasting) stressors in a manner that depends on age, sex and sex steroids and the severity, persistence, novelty and type of stimulus.
Dr. Velhuis adds: "Aging in the human does not limit maximal ACTH or cortisol secretion induced by AVP, CRH or ACTH or by hypoglycemia, cortisol depletion, a cold pressor test or a 3.5-day fast. In 45 parallel-cohort studies involving 670 young and 625 older adults (mean [SD] age, 28  and 69  years, respectively), age accentuated stress-induced ACTH and cortisol secretion by a 2.4-fold increase and female sex did so by a 2.7-fold increase.
"Illustratively, young men often exhibit greater responses than premenopausal women to paradigms of competition stress. Young women as a group respond more prominently in the luteal, than follicular, phase of the menstrual cycle. And postmenopausal women manifest greater ACTH and cortisol responses than elderly men to challenges with ipsaparone (serotonin1A agonist), lumbar puncture, driving simulations, certain psychosocial stressors and physostigmine (indirect cholinergic agonist)."
Dr. Veldhuis summarizes: "Recent concepts in regulation of the corticotropic axis highlight the need for time of day, sex and sex steroid plus age-controlled clinical studies of stress-adaptive endocrine systems."