Glucocorticoids

ACTH, a peptide hormone synthesized and secreted by the corticotrophs (basophilic cells) of the anterior pituitary gland, controls the rate of corticosteroid synthesis. The three zones of the adrenal cortex are regulated by ACTH to varying extents. Elevated ACTH can result in adrenocortical hypertrophy and sustained high output of cortisol and corticosterone, whereas ACTH deficiency results in adrenocortical atrophy and reduced secretion of glucocorticoids. In contrast, aldosterone levels are not significantly affected by ACTH, because the zona glomerulosa is the least ACTH-responsive region of the adrenal cortex. ACTH functions via a classical peptide hormone mechanism of action: binding of ACTH to cognate G-protein-coupled receptors in the adrenal cell membrane results in activation of the receptors and the subsequent upregulation of intracellular cyclic adenosine monophosphate (cAMP) and other secondary messengers.¹⁰ ACTH stimulates the adrenal cortex to increase synthesis and secretion of steroids by increasing the rate conversion of cholesterol to pregnenolone. ACTH regulates this first step in the steroid biosynthetic pathway by increasing both the synthesis of the cyp 450 side chain cleavage enzyme^11,12 and the availability of cholesterol substrate via an increase in the number of low-density lipoprotein (LDL) receptors.¹³

ACTH secretion from the pituitary is positively regulated by corticotropin-releasing factor (CRF), secreted by the median eminence of the hypothalamus in response to neural signals. CRF reaches the pituitary via a vascular connection with the hypothalamus. In the pituitary, CRF causes the synthesis and release of the polyprotein ACTH precursor molecule proopiomelanocortin (POMC), which is then cleaved into ACTH and other bioactive peptides including β-endorphin and β-lipotropin before secretion by the corticotrophs. Glucocorticoids negatively feed back on ACTH levels both at the level of the hypothalamus and the pituitary¹⁴: they suppress the synthesis of POMC, decrease stores of ACTH in secretory granules, and at high levels cause degeneration of the corticotrophs. In adrenalectomized or Addison disease patients, glucocorticoid levels are low and ACTH remains high. However, ACTH levels can still be increased by CRF, demonstrating that ACTH remains under nervous control in the absence of negative feedback. In addition to endocrine feedback loops, the hypothalamic-pituitary-adrenal (HPA) axis is subject to immune regulation via the action of cytokines (eg, interleukins 1β and 6, tumor necrosis factor α, and interferons α and γ), which regulate POMC expression, CRF secretion and function, and the function of the adrenal cortex.¹⁵

Plasma cortisol levels fluctuate, with spontaneous increases in the rate of cortisol secretion occurring 7 to 13 times each day.¹⁶ Although irregular, these changes occur in a reproducible pattern, with a consistent slope of rise in secretion rate, for any given person. The average slope of rise in secretion is 50 mg/min, and the decay of cortisol peaks occurs in a semilog fashion, indicating that the spontaneous secretion occurs in an “on/off” manner. The total amount of cortisol secreted each day is determined by the number of episodes of high secretion, rather than by changes in the rate of cortisol secretion. The spontaneous rhythm of cortisol secretion results in minimal plasma cortisol levels 1 to 2 h after the onset of sleep followed by a rise to maximal levels at the time of awakening and a fall in plasma cortisol over the course of the day. This pattern of secretion is due to the intrinsic function of the hypothalamus and does not appear to be subject to negative feedback by glucocorticoids. While the mechanism of this rhythm is unclear, the major factors influencing the pattern appear to be the timing of sleep, feeding and light exposure.

Stress (physical or psychological) is a key regulator of ACTH production and adrenal steroid secretion,¹⁷ and there is a quantitative relationship between intensity of stressful stimuli and the magnitude of the adrenal response.¹⁸ If the sensory connections that mediate stressful stimuli are blocked, adrenal stimulation does not occur,¹⁹ and pretreatment with glucocorticoids can dampen the magnitude of stress responses in the adrenal by negative feedback on the HPA axis.²⁰

Mineralocorticoids

The major physiologic regulator of aldosterone levels is the renin-angiotensin system.²¹ Renin, synthesized in the kidney, converts angiotensinogen to angiotensin I (AT I). The AT I peptide is subsequently converted to the active peptide angiotensin II (AT II) and its bioactive degradation products AT III and AT IV, by the action of angiotensin-converting enzymes (ACE). AT II (and probably AT III and AT IV) stimulates aldosterone biosynthesis through interaction with G-protein coupled receptors in the zona glomerulosa. This process is regulated by a variety of factors including plasma potassium level, intracellular calcium, and release of nitric oxide (NO) and atrial natriuretic peptide.²² AT II also increases peripheral arterial resistance, which results in increased blood pressure.²³ Changes in blood pressure then feed back on the secretion of renin, a process regulated by the interaction of kidney baroreceptors, renal nerves, NO synthesis, and the balance of calcium, potassium, and sodium in the serum.²⁴

Sodium and potassium levels are another modulator of mineralocorticoid synthesis. Increased serum potassium directly impacts the adrenal gland, upregulating early steps in adrenal steroid biosynthesis and resulting in increased aldosterone secretion. Low serum sodium can also increase aldosterone secretion, but this mechanism does not appear to be a major regulator of mineralocorticoid secretion, because serum sodium concentration changes little with changes in total blood volume.