Regulation by ACTH

Cortisol synthesis and secretion are regulated physiologically by ACTH synthesized in the anterior pituitary. ACTH is synthesized in the corticotrope cells of the anterior pituitary as part of the large precursor molecule proopiomelanocorticotropin (POMC), which is proteolytically cleaved to form ACTH, β-endorphin, and melanocyte-stimulating hormone (MSH). β-Endorphin has opioid effects that reduce pain perception (see Chapter 36), whereas MSH acts on the melanocytes that confer skin pigmentation. The hyperpigmentation that is associated with overproduction of ACTH is thought to be associated with overproduction of MSH. The POMC gene is also transcribed in the posterior pituitary, where the POMC precursor is differentially cleaved into endorphins and MSH, but not ACTH. ACTH is secreted episodically from the anterior pituitary, and these pulses can contribute to the larger ACTH fluctuations regulated by circadian rhythms. Generally, the ACTH pulses exhibit greater frequency and magnitude in the early morning compared with the early afternoon. There is a close correlation of ACTH and cortisol secretion, which is characterized by a sharp rise in plasma concentrations followed by a slower decline, with approximately 8 to 10 major bursts of cortisol secretion occurring daily (Fig. 39-1).

FIGURE 39–1 Serum cortisol concentrations in a healthy man. Serial blood samples collected at 10-minute intervals were assayed for cortisol. A, Concentrations plotted, with the continuous line calculated using a multiple parameter model of combined secretion and clearance of cortisol. B, Calculated rates of cortisol secretion as a function of time. Zero time represents 8 am, the beginning of the experimental period.

Modified from Veldhuis JD, Iranmanesh A, Lizarralde G, et al: Am J Physiol 1989; 257:E6.

ACTH acts through membrane receptors, leading to activation of adenylyl cyclase, enhanced formation of intracellular 3’-5’ cyclic adenosine monophosphate (cAMP), and increased phosphorylation by protein kinase type A, which ultimately stimulates cortisol synthesis and secretion. Cholesterol is stored esterified to long-chain fatty acids, which must be cleaved and transported to the inner mitochondrial membrane, where the enzymatic processes leading to steroid synthesis reside. This transport step through the outer mitochondrial membrane is the actual rate-limiting process in overall steroid synthesis and requires the participation of the steroidogenic acute regulatory protein (StAR). ACTH rapidly stimulates StAR synthesis in the adrenals (as the gonadotropins do in the testes and ovaries), which facilitates cholesterol transport through the mitochondria, leading to initiation of steroid synthesis. Mutations in StAR have been associated with congenital lipoid adrenal hyperplasia, an autosomal recessive disorder that leads to deficiencies of adrenal and gonadal hormones and life-compromising pathology associated with salt loss, hyperkalemic acidosis, and dehydration, unless treated with adrenal steroids.

The rate-limiting enzyme in steroid synthesis converts cholesterol to pregnenolone by the P450 cholesterol side-chain cleavage enzyme (see Fig. 38-1), desmolase, located on the inner mitochondrial membrane. ACTH-stimulated increases in cAMP accelerate transcription rates of the gene coding for this enzyme and most other enzymes in the cortisol biosynthetic pathway.

In addition to its role in stimulating adrenocorticosteroid metabolism, ACTH is a tropic hormone that directly controls the size of the adrenal cortex in a concentration-dependent manner. Specifically, low plasma ACTH concentrations lead to adrenal cortex atrophy, whereas elevated levels, such as occur during primary adrenal insufficiency, promote adrenal cortex hyperplasia.

Modulation of ACTH Release

Serum concentrations of ACTH are modulated by integrated stimulatory signals from hypothalamic releasing peptides and by inhibitory feedback from circulating cortisol (Fig. 39-2). Physiologically, serum ACTH concentrations are increased in response to metabolic stresses such as severe trauma, illness, burns, hypoglycemia, hemorrhage, fever, exercise, and psychological stresses such as anxiety and depression. These stresses are believed to induce physiological changes by altering the release of hypothalamic factors. Two hypothalamic peptides, corticotropin-releasing hormone (CRH) and to a lesser extent arginine vasopressin (AVP or antidiuretic hormone), both act to stimulate ACTH release. These peptides bind to distinct membrane receptors on the corticotrope. CRH exerts its effect primarily via cAMP-dependent pathways, whereas AVP stimulates phosphatidylinositol hydrolysis and activates protein kinase C. CRH is the most important physiological stimulating factor and can be used pharmacologically to screen for appropriate corticotrope function. CRH may also increase POMC gene transcription and processing, thus increasing available peptide stores for subsequent release.

FIGURE 39–2 Regulatory feedback mechanisms in the HPA. ACTH, Adrenocorticotrophic hormone; AVP, arginine vasopressin; CRH, corticotropin-releasing hormone.

Feedback Control Mechanisms

Pituitary production of ACTH is extremely sensitive to suppression by cortisol at both the pituitary and hypothalamus. Cortisol acts directly on the pituitary to decrease POMC gene transcription and ACTH secretion and to suppress the pituitary response to CRH. It also acts on the hypothalamus to suppress CRH release. Results of this negative feedback can endure for weeks after cessation of glucocorticoid therapy. Thus glucocorticoid therapy and its cessation must be approached cautiously. High concentrations of ACTH may also suppress CRH release from the hypothalamus.

Receptors

All natural and synthetic glucocorticoids act by binding to specific receptors that are members of the nuclear receptor superfamily. Glucocorticoids bind to both glucocorticoid receptors (GR, also known as NR3C1) and mineralocorticoid receptors (MR, also known as NR3C2). These receptors are closely related in their overall DNA sequence but differ considerably in the N-terminal antigenic region of the ligand-binding domains. Both receptors have similar binding affinities for glucocorticoids and are expressed in many cell types including liver, muscle, adipose tissue, bone, lymphocytes, and pituitary. The receptors are proteins consisting of approximately 800 amino acids, which can be divided into functional domains similar to those for other steroid receptors (see Chapter 1). The structure of the steroid receptor is characterized by zinc finger domains formed by stabilization of protein folds by zinc interaction with cysteine residues. In the cytoplasm the inactive steroid receptor exists as a heteromer associated with cytoplasmic proteins (e.g., heat shock protein 90). The interaction of this complex with a steroid leads to dissociation of the accessory protein-receptor complex. This sequence of events is generally called glucocorticoid receptor activation. Phosphorylation of the receptor stabilizes a configuration, the nuclear location signal that interacts with importin at nuclear pores and initiates translocation of the hormone-receptor complex across the nuclear membrane. Once inside the nuclear membrane, the steroid-receptor complex interacts at specific palindromic sites on deoxyribonucleic acid (DNA), termed glucocorticoid-responsive elements. The binding to DNA is stabilized by the interaction of the zinc finger structures with the major groove of DNA, and specificity is partially conferred by the sequence of the palindromic sites. Specificity among different steroids appears to be conferred by the structure of the steroid-occupied receptor, amino acid sequence of the DNA binding region of the receptor protein, especially the Zn fingers, nucleotide sequence of the DNA binding motif and space between half sites, and chromatin architecture of the gene promoter at sites of interaction of bound receptor protein and DNA. The presence of the specific glucocorticoid response elements in the promoter region of specific genes allows steroids to alter transcription (see Chapter 1).

Metabolic Effects

Glucocorticoids have several metabolic effects including increased hepatic gluconeogenesis as a consequence of stimulating the synthesis of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, and increased amino acid degradation as a consequence of stimulating the synthesis of tyrosine aminotransferase and tryptophan oxygenase. In striated muscle, glucocorticoids act in concert with other hormones to influence protein synthesis and degradation. Cortisol has little or no effect on protein turnover in the presence of insulin and in well-fed people. However, during fasting or when the insulin concentration is low, cortisol stimulates the breakdown of muscle protein and decreases the uptake of amino acids. Thus the presence of high concentrations of circulating glucocorticoids for long periods can lead to muscle wasting. In adipose tissue, cortisol stimulates lipolysis, resulting in the release of free fatty acids and glycerol. Other lipogenic hormones are required for the full lipolytic response to occur. Overall, cortisol stimulates both protein and lipid catabolism. Glucocorticoids also regulate growth and development, particularly in fetal tissues. One critical action on the fetus is induction of surfactant synthesis in the lungs before birth. Cortisol can be administered to lessen the severity of respiratory distress syndrome resulting from a failure of sufficient surfactant secretion.