Leuprolide Acetate Therapy in Luteinizing Hormone–Dependent Cushing's Syndrome

Abstract

ORTICOTROPIN-INDEPENDENT Cush-ing's syndrome is usually caused by cortisol-secreting adrenal adenomas, carcinomas, or (rarely) bilateral adrenal hyperplasia. In some patients with this syndrome, the excess secretion of cortisol is caused by abnormal adrenal expression and function of receptors for various hormones, including gastric inhibitory polypeptide, 1-6 vasopressin, 7-9 b-adrenergic agonists, 10 and interleukin-1. 11 These findings suggest that diverse other hormone receptors could be implicated in other patients. 12 We describe a woman with bilateral adrenal hyper-plasia and corticotropin-independent Cushing's syndrome that was clinically manifested transiently during her pregnancies and became constant only after menopause. The patient's cortisol secretion was stimulated by luteinizing hormone and chorionic gonado-tropin and by drugs that activate serotonin 5-hydroxy-tryptamine (HT 4) receptors. Long-term suppression of luteinizing hormone secretion by the administration of leuprolide acetate every four weeks led to complete reversal of Cushing's syndrome in the patient. CASE REPORT A 63-year-old woman presented with a 12-month history of hy-pertension, numbness and proximal-muscle weakness of the lower extremities, hot flashes, and a decrease in concentration and memory. Her usual weight was 45 to 50 kg until menopause at 52 years of age; it then increased progressively to 73 kg. She had gained between 18 and 22 kg during each of four full-term pregnancies , at which time she had a cushingoid distribution of fat but no hypertension, purple skin striae, or hirsutism; all her children were normal. Post partum, her weight had rapidly returned to base line, and she had anorexia, nausea, and fatigue, all of which subsided within two to three months. She had undergone hysterectomy and bilateral oophorectomy at 61 years of age because of uterine prolapse. There was no family history of adrenal disease. Her height was 1.59 m, her blood pressure was 198/102 mm Hg, C and her heart rate was 80 beats per minute. The patient had central obesity, mild facial plethora and hirsutism, supraclavicular fat pads, proximal muscle weakness, and decreased vibratory sensation in the lower legs, but no abdominal striae. She was taking an an-giotensin-converting-enzyme inhibitor, a thiazide diuretic, and estrogen-replacement therapy; these medications were discontinued three days before the studies described below. The initial evaluation, which took place in March and April 1997, revealed a urinary cortisol excretion of 279 µg per day (770 nmol per day; normal, 20 to 90 µg per day [55 to 248 nmol per day]). The patient's morning plasma corticotropin concentration was less than 5 pg per milliliter (1 pmol per liter; normal, 9 to 52 pg per milliliter [2 to 11 pmol per liter]). Her plasma cortisol concentration was 28.4 µg per deciliter (784 nmol per liter) at 8 a.m. and 18.4 µg per deciliter (508 nmol per liter) at 8 p.m.; it was 24.7 µg per deciliter (681 nmol per liter) in the morning after the oral administration of 1 mg of dexamethasone at midnight and was not suppressed by 4 mg of dexamethasone administered intravenously. Plasma aldosterone and renin values obtained with the patient su-pine and upright were normal. An abdominal computed tomo-graphic scan revealed bilateral macronodular adrenal hyperplasia, with nodules measuring up to 4 by 3.5 cm on the right and 2.5 by 4 cm on the left.