Pubertal Maturation of the Lh Stimulatory Response to Clomiphene Citrate in Congenital Virilizing Adrenal Hyperplasia*

Abstract

To determine the LH release response to clomiphene citrate in children with virilizing congenital adrenal hyperplasia (CAH), we examined six patients with glucocorticoid-treated virilizing CAH, five girls and one boy, chonological age (CA) 4 years 2 months-15 years 9 months and bone age (BA) range 8-18 years. All the patients but one, were treated with nocturnal dexamethasone. Their ages at the onset of treatment ranged from 2 years 6 months to 13 years 8 months. An additional boy (CA = 4 years 3 months and BA = 7-8 years) was studied 10 days after removal of a virilizing adrenal adenoma. Clomiphene citrate (3mg/kg/day) was administered orally in two doses/day for 8 days. Venous blood was collected on days 0, 4, 6 and 8. Two patients were also studied in consecutive years. In three patients no increase was noted over the basal levels of LH, but in the others LH rose during clomiphene administration. In two patients studied in consecutive years, there was detectable shift of LH release pattern. The basal LH levels and the sum of responses (day 4, 6 and 8) to clomiphene citrate and particularly their decimal logarithms were statistically significantly correlated with their respective BA. These results confirm that previous prolonged exposure to elevated concentrations of adrenal sex steroids, in children with treated virilizing CAH, may induce precocious maturation of the hypothalamic pubertal mechanism of LH secretion. This maturation was closely correlated with the degree of skeletal maturation.

Recovery of persistent hypogonadism by clomiphene in males with prolactinomas under dopamine agonist treatment

“…At low doses (25-50 mg/day), clomiphene is reportedly ineffective in prepubertal boys, but stimulates gonadotropin secretion in pubertal and adult males. At high doses (500 mg/day), clomiphene suppresses gonadotropin secretion even in normal adult males (25,26). In our study, a relatively low dose of clomiphene (50 mg/day) was able to increase and sustain serum gonadotropins and testosterone levels even in face of raising estradiol levels, which indicates an anti-estrogenic effect at the hypothalamus and/or pituitary.…”

Luteinizing hormone response to clomiphene citrate in central precocious puberty

“…There is a demonstrable change from their unaltered or negative response to a positive one when the bone age is around 8-9 years. This pattern of LH release during the clomiphene citrate test is similar to those observed in normal children (Kulin el al., 1971(Kulin el al., , 1972Nankin et af., 1971) and late treated virilizing congenital adrenal hyperplasia (Moreira et al, 1982) in which a change in the prepubertal LH release is observed in mid to late puberty, when the bone age is around 13-14 years. Since clomiphene citrate may act predominantly as an anti-oestrogen at the hypothalamic level (Adashi, 1984), our data indicate that the activation of the hypothalamic pubertal mechanism in CPP usually progresses in a sequence similar to that described for normal puberty, but occurs at a much earlier age.…”

“…In addition, the LH response to clomiphene citrate increases in the late pubertal stages of normal children (Kulin etal., 1971(Kulin etal., ,1972Nankinetal., 1971)whobecomecapableof responding in an adult fashion, probably reflecting the maturation of the hypothalamic pubertal mechanism. We have previously documented the LH responses to clomiphene citrate in children with combined precocious puberty due to late treatment of congenital adrenal hyperplasia (Moreira et al, 1982). This study indicated that secondary precocious hypothalamic maturation may occur in response to one of the forms of peripheral precocious puberty.…”

“…The changes in plasma LH during the clomiphene test were compared with those determined for normal postpubertal young adults, five women and five men (Moreira, 1978;Moreira et al, 1982). We consider the LH response to clomiphene to be adult post-pubertal in character when an absolute LH level of more than 5 IU/I is obtained during the test, together with a relative increment of more than 50% of the basal level.…”

Clomiphene fails to revert hypogonadism in most male patients with conventionally treated nonfunctioning pituitary adenomas

“…In the hypothalamus-pituitary axis, at low doses (25 to 50 mg/day), clomiphene is reportedly ineffective in prepubertal boys, but stimulates gonadotropin secretion in pubertal and adult males. At high doses (500 mg/day), clomiphene suppresses gonadotropin secretion even in normal adult males (22,23).…”