Complete reversal of adult-onset isolated hypogonadotropic hypogonadism with clomiphene citrate.

OBJECTIVE

Inhibition of pituitary gonadotropin secretion in men by T is principally mediated by aromatization to estrogen (E), which inhibits hypothalamic secretion of GnRH. We hypothesized that adult-onset isolated hypogonadotropic hypogonadism (IHH) might result from an altered central set-point for E-mediated negative feedback.

DESIGN AND SETTING

Longitudinal clinical investigation unit-based evaluation of the clinical and biochemical response to E-receptor blockade.

PATIENT(S): A 31-year-old man presenting with an 18-month history of sexual dysfunction resulting from severe adult-onset IHH (LH 1.7 U/L, FSH 2.0 U/L, T 3.5 nmol/L).

INTERVENTION(S): Initial therapy with 50 mg of clomiphene citrate (CC) three times a day for 7 days, with overnight LH pulse profiling and 9 am T levels evaluated at baseline and on completion. A 2-month washout period, followed by low-dose maintenance therapy (25-50 mg/d) for 4 months.

MAIN OUTCOME MEASURE(S): Baseline and stimulated T levels and LH pulsatility; effect on sexual function.

RESULT(S): Clomiphene therapy resulted in complete normalization of pulsatile gonadotropin secretion, serum T level, and sexual function.

CONCLUSION(S): Isolated hypogonadotropic hypogonadism may result from an acquired defect of enhanced hypothalamic sensitivity to E-mediated negative feedback. Whereas direct T replacement therapy can further suppress endogenous gonadotropin secretion, treating IHH men with gonadotropins can stimulate endogenous T secretion and enhance fertility potential. On theoretical grounds, reversal of gonadotropin deficiency with CC might be expected to have a similar biological effect.