| Adrenocorticotropic hormone (ACTH)
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| ACTH is synthesized as a 241-amino-acid precursor molecule pro-opiomelanocortin (POMC). POMC is cleaved at multiple sites to release several hormonally active peptides, including the endorphins and melanocyte stimulating hormones. In addition to the pituitary, POMC may also be produced in large quantities by certain malignancies giving rise to ectopic ACTH syndrome.
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ACTH itself is comprised of 39 amino acids with the biological activity residing in the N-terminal 24 moieties. It is secreted in stress-related bursts superimposed on a marked diurnal rhythm that shows a peak at 05.00 h. It is transported unbound in plasma and has a half-life of about 10 minutes. ACTH stimulates the synthesis and release of glucocorticoid hormones by interacting with cell-surface receptors on the adrenal cortex that stimulate the production of intracellular cAMP. Acute increases in the adrenal synthesis of cortisol occur within 3 minutes, principally by stimulating the activity of cholesterol esterase. Chronic effects of ACTH include induction of transcription of the genes that encode steroidogenic enzymes.
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| Negative feedback by cortisol occurs within two time frames, acting at both the hypothalamic and pituitary levels. Fast feedback alters the release of hypothalamic CRH and the CRH-mediated secretion of ACTH. Slow feedback results from reduced synthesis of CRH and AVP/ADH plus suppression of POMC gene transcription, which results in reduced ACTH synthesis.
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| A 35-year-old woman came to her physician complaining of palpitations, difficulty climbing stairs and general fatigue. She also said that she had lost 4 kg of weight recently despite a good appetite and no attempt at dieting. She reported occasional diarrhea. |
| Comment. On examination her skin was warm and moist and she had a fine tremor of outstretched hands. There was mild weakness of the thigh muscles. She had tachycardia (110/min). She also has a mild thyroid enlargement (goiter) and a bruit over the gland. Thyroid function tests show suppressed TSH level (<0.05; range 0.4-4 mU/L) (see Fig. 37.5) and increased thyroxine (T4 = 220; range: 55-144 nmol/L) and tri-iodothyronine (T3 = 4.0; range 0.9-2.8 nmol/L). Thyroid receptor antibodies were detected. |
| In hyperthyroidism, the TSH level tends to be suppressed by high circulating thyroid hormones. The low TSH level and high thyroid hormone concentrations suggest hyperthyroidism. The presence of thyroid receptor antibodies confirms that the cause is Graves disease, an autoimmune thyroid disorder. The antireceptor antibodies bind to the TSH receptors in the thyroid gland and mimic the effect of TSH, producing thyroid over-secretion. |
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