1386
13.
14.
15. 16.
COMMENTS
hydroxytryptophan (5-HPT) on plasma prolactin levels in man, J Clin Endocrinol Metab 38: 695, 1974. Beretta, C , A. H. Glasser, M. B. Nobili, and R. Silvestri, Antagonism of 5-hydroxytryptamineinduced broncospasm in guinea-pig by 8-betacarbobenzoy loxy-aminomethy 1-1-me thy 1-10alpha-ergoline,/ Pharm Pharmacol 17: 423, 1965. Molinatti, G. M., F. Massara, E. Strumia, F. Pennisi, G. A. Scassellati, and L. Vancheri, Radioimmunoassay of human growth hormone, J Nucl Biol Med 13: 26, 1969. McNeilly, A. S., Radioimmunoassay of human prolactin, Proc R Soc Med 66: 863, 1973. Bivens, C. H., H. E. Lebovitz, and J. M. Feldman,
JCE & M 1976 Vol 43 ( No 6
Inhibition of hypoglicaemia-induced growth hormone secretion by the serotonin antagonists cyproheptadine and methysergide, N Engl J Med 289: 236, 1973. 17. Delitala, G., A. Masala, S. Alagna, and L. Devilla, Effect de la cyproheptadine sur les variations spontanees diurnes de ACTH-cortisol plasmatiques et sur la secretion de ACTH-GH determinee par L-Dopa, Biomedicine 23: 406, 1975. 18. Bivens, C. H., H. E. Lebovitz, and J. M. Feldman, Growth hormone and serotonin antagonist, N Engl J Med 289: 871, 1973. 19. Beretta, C., R. Ferrini, and A. H. Glasser, 1-methyl8 - beta - carbobenzyloxy - aminomethyl - 10alpha-ergoline: a potent and long-acting 5-hydroxytryptamine antagonist, Nature 207: 421, 1965.
Spironolactone Stimulation of Gonadotropiri Secretion in Boys with Delayed Adolescence R. J. SANTEN,1 H. E. KULIN,1 D. L. LORIAUX,2 AND J. FRIEND 1 l Division of Endocrinology, Departments of Medicine and Pediatrics, The Milton S. Hershey Medical Center of The Pennsylvania State University, Hershey, Pennsylvania 17033; and Reproduction Research Branch, National Institute of Child Health and Human Development, Bethesda, Maryland
ABSTRACT. Spironolactone (Aldactone®) acts as an antiandrogen by blocking testosterone synthesis and competing with testosterone for the androgen receptor. These properties of the mineralocorticoid antagonist were used in an attempt to interrupt the gonadal-pituitary-hypothalamic negative feedback axis and thereby stimulate LH and FSH in 7 boys with delayed puberty. Following administration of aldactone (5 mg/kg) daily for one week, there was a significant (P < .01) mean increase in serum LH of 60%. In all 7 boys an absolute rise in LH was observed, but these changes were statistically significant in only 5 individuals. While mean FSH levels increased by 60% in this group of boys, the individual responses were variable. No rise in
T
H E REGULATION of gonadotropin secretion in adult men involves complex negative feedback interactions between hypothalamus,
Received September 30, 1975. Supported in part by a grant from the Human Growth Foundation. Presented in part at an NIH Combined Clinical Staff Conference. "Spironolactone and Endocrine Dysfunction," September 11, 1975, and the Sixth Brook Lodge Workshop on Problems of Reproductive Biology, Kalamazoo, Mich., Oct. 8-10, 1975. 1 Division of Endocrinology, Departments of Medicine and Pediatrics, The Milton S. Hershey Medical
gonadotropin levels occurred in 2 patients with Kallmann's syndrome, who also received 5 mg/kg of spironolactone daily for 1 week. Large doses of the drug appeared necessary to stimulate gonadotropin secretion since a dose of 3 mg/kg per day did not cause LH or FSH increments in 2 additional patients with delayed puberty. Progesterone and 17a-hydroxyprogesterone levels increased to a greater extent than LH and FSH in response to spironolactone, reflecting either adrenal or testicular enzyme inhibition. Spironolactone is the first drug shown to be capable of stimulating gonadotropin secretion by interrupting negative feedback inhibition in boys with delayed puberty. (/ Clin Endocrinol Metab 43: 1386, 1976)
pituitary, and gonadal steroids. Data obtained from children suggest that this negative feedback loop is also intact prior to puberty, but set at a lower level of sensitivity (1). This feedback axis has not been interrupted by pharmacologic means in children with consequent effects on gonadotropin secretion. Spironolactone (Aldactone®) seemed ideal for this purpose since Center of The Pennsylvania State University, Hershey, Pennsylvania 17033; and Reproduction Research Branch, National Institute of Child Health and Human Development, Bethesda, Maryland.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 October 2015. at 12:24 For personal use only. No other uses without permission. . All rights reserved.
COMMENTS
1387
TABLE 1. Clinical data and hormone levels
Chronologic age
Case
(yr)
no.
Bone
Genital 1 develop-
Testis
Testos-
age (yr)
ment (stage)
size (cm)
terone (ng/dl)
Delayed puberty: aldactonei 5 mg/kg 1 15-6712 14 III 2 14 I 15-0/12 14 III 3 16-10/12 II 4 14 16-6/12 15-9/12 5 II 14 14-6/12 6 II 13Vi 7 III 14-0/12 Delayed puberty: aldactone: 3 mg/kg 8 III 13& 16-0/12 9 15-0/12 14 II
2x3 IVix 2x 2x 1x
1& 3 3 2
88
13.
14.
15. 16.
COMMENTS
hydroxytryptophan (5-HPT) on plasma prolactin levels in man, J Clin Endocrinol Metab 38: 695, 1974. Beretta, C , A. H. Glasser, M. B. Nobili, and R. Silvestri, Antagonism of 5-hydroxytryptamineinduced broncospasm in guinea-pig by 8-betacarbobenzoy loxy-aminomethy 1-1-me thy 1-10alpha-ergoline,/ Pharm Pharmacol 17: 423, 1965. Molinatti, G. M., F. Massara, E. Strumia, F. Pennisi, G. A. Scassellati, and L. Vancheri, Radioimmunoassay of human growth hormone, J Nucl Biol Med 13: 26, 1969. McNeilly, A. S., Radioimmunoassay of human prolactin, Proc R Soc Med 66: 863, 1973. Bivens, C. H., H. E. Lebovitz, and J. M. Feldman,
JCE & M 1976 Vol 43 ( No 6
Inhibition of hypoglicaemia-induced growth hormone secretion by the serotonin antagonists cyproheptadine and methysergide, N Engl J Med 289: 236, 1973. 17. Delitala, G., A. Masala, S. Alagna, and L. Devilla, Effect de la cyproheptadine sur les variations spontanees diurnes de ACTH-cortisol plasmatiques et sur la secretion de ACTH-GH determinee par L-Dopa, Biomedicine 23: 406, 1975. 18. Bivens, C. H., H. E. Lebovitz, and J. M. Feldman, Growth hormone and serotonin antagonist, N Engl J Med 289: 871, 1973. 19. Beretta, C., R. Ferrini, and A. H. Glasser, 1-methyl8 - beta - carbobenzyloxy - aminomethyl - 10alpha-ergoline: a potent and long-acting 5-hydroxytryptamine antagonist, Nature 207: 421, 1965.
Spironolactone Stimulation of Gonadotropiri Secretion in Boys with Delayed Adolescence R. J. SANTEN,1 H. E. KULIN,1 D. L. LORIAUX,2 AND J. FRIEND 1 l Division of Endocrinology, Departments of Medicine and Pediatrics, The Milton S. Hershey Medical Center of The Pennsylvania State University, Hershey, Pennsylvania 17033; and Reproduction Research Branch, National Institute of Child Health and Human Development, Bethesda, Maryland
ABSTRACT. Spironolactone (Aldactone®) acts as an antiandrogen by blocking testosterone synthesis and competing with testosterone for the androgen receptor. These properties of the mineralocorticoid antagonist were used in an attempt to interrupt the gonadal-pituitary-hypothalamic negative feedback axis and thereby stimulate LH and FSH in 7 boys with delayed puberty. Following administration of aldactone (5 mg/kg) daily for one week, there was a significant (P < .01) mean increase in serum LH of 60%. In all 7 boys an absolute rise in LH was observed, but these changes were statistically significant in only 5 individuals. While mean FSH levels increased by 60% in this group of boys, the individual responses were variable. No rise in
T
H E REGULATION of gonadotropin secretion in adult men involves complex negative feedback interactions between hypothalamus,
Received September 30, 1975. Supported in part by a grant from the Human Growth Foundation. Presented in part at an NIH Combined Clinical Staff Conference. "Spironolactone and Endocrine Dysfunction," September 11, 1975, and the Sixth Brook Lodge Workshop on Problems of Reproductive Biology, Kalamazoo, Mich., Oct. 8-10, 1975. 1 Division of Endocrinology, Departments of Medicine and Pediatrics, The Milton S. Hershey Medical
gonadotropin levels occurred in 2 patients with Kallmann's syndrome, who also received 5 mg/kg of spironolactone daily for 1 week. Large doses of the drug appeared necessary to stimulate gonadotropin secretion since a dose of 3 mg/kg per day did not cause LH or FSH increments in 2 additional patients with delayed puberty. Progesterone and 17a-hydroxyprogesterone levels increased to a greater extent than LH and FSH in response to spironolactone, reflecting either adrenal or testicular enzyme inhibition. Spironolactone is the first drug shown to be capable of stimulating gonadotropin secretion by interrupting negative feedback inhibition in boys with delayed puberty. (/ Clin Endocrinol Metab 43: 1386, 1976)
pituitary, and gonadal steroids. Data obtained from children suggest that this negative feedback loop is also intact prior to puberty, but set at a lower level of sensitivity (1). This feedback axis has not been interrupted by pharmacologic means in children with consequent effects on gonadotropin secretion. Spironolactone (Aldactone®) seemed ideal for this purpose since Center of The Pennsylvania State University, Hershey, Pennsylvania 17033; and Reproduction Research Branch, National Institute of Child Health and Human Development, Bethesda, Maryland.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 October 2015. at 12:24 For personal use only. No other uses without permission. . All rights reserved.
COMMENTS
1387
TABLE 1. Clinical data and hormone levels
Chronologic age
Case
(yr)
no.
Bone
Genital 1 develop-
Testis
Testos-
age (yr)
ment (stage)
size (cm)
terone (ng/dl)
Delayed puberty: aldactonei 5 mg/kg 1 15-6712 14 III 2 14 I 15-0/12 14 III 3 16-10/12 II 4 14 16-6/12 15-9/12 5 II 14 14-6/12 6 II 13Vi 7 III 14-0/12 Delayed puberty: aldactone: 3 mg/kg 8 III 13& 16-0/12 9 15-0/12 14 II
2x3 IVix 2x 2x 1x
1& 3 3 2
88
