9-fluorocortisone and Adrenal-Hyperplasia--Congenital

Topics: Adrenal Hyperplasia, Congenital; Cortisone; Cytochrome P-450 CYP11B2; Desoxycorticosterone; Humans; Mutation; Sodium

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency is characterized by a defect in cortisol and aldosterone secretion and adrenal hyperandrogenism. Current treatment is to provide adequate glucocorticoid and mineralocorticoid substitution to prevent adrenal crises and to suppress excess adrenal androgen secretion. Satisfactory adrenocortical suppression often requires supraphysiological doses of hydrocortisone, which may produce an unacceptable degree of hypercortisolism. A new four-drug treatment regimen of flutamide, testolactone, reduced hydrocortisone dose, and 9alpha-fludrocortisone has been shown to achieve normal growth and development after 2 yr of therapy and may, therefore, represent a potential alternative approach to the treatment of children with classic congenital adrenal hyperplasia. We investigated the effect of flutamide and testolactone, and flutamide alone, on cortisol clearance by performing clearance studies twice in 13 children (6 males and 7 females; age range, 7.0-14.5 yr) with classic 21-hydroxylase deficiency. All studies were conducted at least 3 months after institution of the four-drug treatment regimen. In eight patients (group 1), the first cortisol clearance study was performed on the four-drug regimen, and the second study was performed after a 48-h washout period off flutamide and testolactone. In five patients (group 2), the first study was conducted 1 wk after discontinuation of testolactone and while patients were receiving flutamide, hydrocortisone and 9alpha-fludrocortisone, and the second study was performed after a 48-h washout period off flutamide. Oral hydrocortisone was held on the day of the clearance studies, and all patients received a continuous infusion of hydrocortisone (0.6 mg/m(2).h) from 1800 h to 0200 h, with cortisol concentrations measured once hourly. In addition, an in vitro study was conducted to exclude the possibility of an analytical interference of flutamide, 2-hydroxyflutamide, and testolactone with the serum cortisol immunoassay. Total body cortisol clearance was significantly lower during treatment with the four-drug regimen than during treatment with hydrocortisone and 9alpha-fludrocortisone (153.5 +/- 26.8 vs.355.4 +/- 65.8 ml/min; P = 0.001). Similar results were obtained comparing flutamide, hydrocortisone, and 9alpha-fludrocortisone therapy to hydrocortisone and 9alpha-fludrocortisone therapy (155.8 +/- 26.5 vs. 281.8 +/- 96.2 ml/min; P = 0.037). The in vitro study

Topics: Adrenal Hyperplasia, Congenital; Androgen Antagonists; Child; Cortisone; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Flutamide; Humans; Hydrocortisone; Male; Metabolism, Inborn Errors; Testolactone

A normal gonadal maturation with normal fertility are some of the major goals of long-term replacement therapy in adult males with Congenital Adrenal Hyperplasia (CAH). We describe here two young men, G.O. (case A, 23 years old) and S.S.(case B, 24 years old), both with a well defined diagnosis of CAH due to 21-hydroxylase deficiency classic homozygote form (21-CAH). In case A the diagnosis of the 21-CAH classic virilizing form was made at 3 years of age. The patient has undergone glucocorticoid therapy and is now 170 cm tall; all his hormonal findings are within the normal range. The semen analysis has shown a good fertility potential, with a slight modification when the patient decided to discontinue the therapy. In case B the diagnosis of the 21-CAH salt wasting form was performed at 9 days of age. The patient was initially treated with i.v. normal saline solution and a daily i.m. injection of hydrocortisone and, subsequently, with mineral and glucocorticoid replacement therapy po. A satisfactory adult stature (165 cm) was attained. The patient is still on therapy, with a good hormonal profile. The semen analysis has shown an apparently normal fertility. In conclusion, our experience in adult males with 21-CAH, who have been administered prompt and adequate replacement therapy, shows that these patients can attain normal quality of life, satisfactory growth and development, normal sexual maturation and activity, and adequate sperm fertilizing ability, thereby supporting the usefulness of continuing this therapy during adult age.

Topics: Adrenal Hyperplasia, Congenital; Adult; Cortisone; Dexamethasone; Drug Therapy, Combination; Follicle Stimulating Hormone; Follow-Up Studies; Glucocorticoids; Homozygote; Humans; Hydrocortisone; Infertility, Male; Luteinizing Hormone; Male; Prednisone

Topics: Adrenal Hyperplasia, Congenital; Child; Child, Preschool; Cortisone; Drug Therapy, Combination; Female; Growth; Humans; Hydrocortisone; Infant; Male

The conventional treatment of CAH with hydrocortisone (16-19 mg/m2 per day) and 9 alpha-F-cortisol (just enough to normalise renin concentrations, started at 07:00 h) was ineffective in suppressing the early morning rise of 17-OH-progesterone and in turn androgens in about 20% of our patients. The present work explored the effect of a modified dosage regimen of the drug in five patients. The schedule was: 03:00 h F 33% + 9 alpha-F-F 33%; 07:00 h F 30%; 12:00 h F 22% + 9 alpha-F-F 33%; 17:30 h F 15% + 9 alpha-F-F 33%. Monitored levels of circulating 17-OH-progesterone, testosterone, and individual urinary 17-ketosteroids showed significant improvement, which was not achieved by giving higher or later evening doses. Menarche was induced in two girls (bone age 15 years). The modified dosage schedule offers on the one hand the possibility of better management of CAH, and on the other, cuts down the risk of enhanced Cushing-like effects, which in animal models have been related frequently to dosage schedules not corresponding to the circadian rhythm. The difficulty of administering the drugs at 03:00 h should be overcome by the development of a late-releasing preparation.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adrenal Hyperplasia, Congenital; Child; Circadian Rhythm; Cortisone; Drug Administration Schedule; Female; Humans; Hydrocortisone; Hydroxyprogesterones; Male

Topics: Adrenal Hyperplasia, Congenital; Child; Cortisone; Dwarfism; Female; Growth Plate; Humans; Hydrocortisone; Steroid Hydroxylases