A 60-year-old woman is being evaluated for chronic weakness and fatigue. She has no other medical problems and takes no medications. After performing initial laboratory studies, the physician decides to proceed with a metyrapone stimulation test. The changes in urinary 17-hydroxycorticosteroid (17-OHS) excretion following metyrapone administration are shown in the graph below. Which of the following mechanisms is most likely responsible for the findings seen in the graph?

Question

A 60-year-old woman is being evaluated for chronic weakness and fatigue.  She has no other medical problems and takes no medications.  After performing initial laboratory studies, the physician decides to proceed with a metyrapone stimulation test.  The changes in urinary 17-hydroxycorticosteroid (17-OHS) excretion following metyrapone administration are shown in the graph below.  Which of the following mechanisms is most likely responsible for the findings seen in the graph?

Quizplus · Accepted Answer

11ec160b_3aad_e9e3_9249_4f0db3b34080_MD0001_00 Like most hormones, secretion of cortisol is regulated via a negative feedback loop. Corticotropin-releasing hormone (CRH) is secreted by the hypothalamus in response to stress and circadian signals received from other parts of the central nervous system. CRH stimulates ACTH release by the pituitary, which in turn increases cortisol secretion by the adrenal cortex. High cortisol levels suppress secretion of ACTH and CRH, and low cortisol levels cause an increase in ACTH and CRH secretion. Although not commonly used, the metyrapone stimulation test is a sensitive indicator of hypothalamic-pituitary-adrenal (HPA) axis integrity. Metyrapone blocks cortisol synthesis by inhibiting 11-β-hydroxylase, which converts 11-deoxycortisol to cortisol in the zona fasciculata. Because 11-deoxycortisol lacks glucocorticoid activity, it does not inhibit pituitary ACTH secretion. As a result, the reduction in cortisol levels following metyrapone administration cause an increase in pituitary ACTH secretion. This leads to increased production of 11-deoxycortisol, which is further metabolized by the liver to 17-hydroxycorticosteroids that accumulate in the urine. Serum 11-deoxycortisol and urinary 17-hydroxycorticosteroid levels will normally rise in response to metyrapone, indicating an intact HPA axis. Failure of these steroid levels to increase implies primary or secondary adrenal insufficiency, which can be distinguished based on plasma ACTH levels. (Choices B and D) The renin-angiotensin-aldosterone system regulates aldosterone synthesis by the zona glomerulosa. Because metyrapone inhibits 11-β-hydroxylase, aldosterone synthesis will decrease. However, accumulation of the aldosterone precursor 11-deoxycorticosterone (a weak mineralocorticoid) prevents the development of mineralocorticoid deficiency, so renin levels will not change significantly. (Choice C) The inhibition of 11-β-hydroxylase by metyrapone would lead to a decrease in cortisol, not an increase. (Choice E) Vasopressin is a hormone secreted by the posterior pituitary that is responsible for regulating water balance. Additionally, vasopressin acts as a potentiator for CRH, enhancing the release of ACTH. However, there is no clear feedback loop between cortisol and vasopressin; therefore, metyrapone administration is unlikely to lead to vasopressin overproduction. Educational objective: Administration of metyrapone will cause a decrease in cortisol synthesis via inhibition of 11-β-hydroxylase. In patients with an intact hypothalamic-pituitary-adrenal axis, this will cause a reactive increase in ACTH, 11-deoxycortisol, and urinary 17-hydroxycorticosteroid levels.

A 60-Year-Old Woman Is Being Evaluated for Chronic Weakness and Fatigue