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

Fertil Steril. 2006 Nov;86(5):1513.e5-9. doi: 10.1016/j.fertnstert.2006.03.065.


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.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Clomiphene / therapeutic use*
  • Estrogen Antagonists / therapeutic use
  • Humans
  • Hypogonadism / complications*
  • Hypogonadism / drug therapy*
  • Male
  • Recovery of Function / drug effects
  • Sexual Dysfunction, Physiological / etiology
  • Sexual Dysfunction, Physiological / prevention & control*
  • Treatment Outcome


  • Estrogen Antagonists
  • Clomiphene