Most males with precocious puberty who have been referred to NIH have been successfully treated under protocol 79-CH-0112 "Treatment of True Precocious Puberty with a Long-Acting Luteinizing Hormone Releasing Hormone Analog (D-Trp6-Pro9-Net-LHRH)." A subset of these patients, however, all of whom had familial male isosexual precocity, had an inadequate response to LHRH analog as demonstrated by high serum testosterone levels, rapid advancement in bone age, testicular growth, sperm production, and lack of regression of secondary sex characteristics. These patients had low baseline gonadotropin levels and lacked a pubertal response to LHRH, whereas the patients who had responded to LHRH analog all had clear evidence of central precocious puberty.

As an alternative approach to treatment, the patients with familial male precocious puberty were enrolled in protocol 83-CH-0028, "Spironolactone Treatment of Boys with Familial Isosexual Precocious Puberty". Spironolactone (Aldactone) is an antiandrogen that also reduced testosterone synthesis by inhibiting the enzyme 17-hydroxylase. This treatment decreased the plasma testosterone level and inhibited the peripheral effect of testosterone on target tissues. This was apparent through a decrease in acne and in the frequency of spontaneous erections.

Bone age advancement, however, was not slowed by spironolactone and gynecomastia had begun to occur in a number of patients. Both of these processes may be the result of persisting elevated estradiol levels. To attempt to reduce elevated estrogen levels in these patients to normal prepubertal levels, we plan to use testolactone (Teslac) to inhibit aromatase, the last step of estrogen biosynthesis. Testolactone has previously been used for a similar purpose in girls with gonadotropin-independent precocious puberty (McCune-Albright Syndrome) under protocol 82-CH-0165, "Testolactone treatment of girls with LHRH analog-resistant precocious puberty due to autonomous non-neoplastic ovarian estrogen secretion."

We plan to administer combined spironolactone and testolactone treatment-spironolactone to inhibit the action of androgen, and testolactone to block the formation of estrogen. The goal of this treatment is to delay sexual maturation and to prevent early closure of the epiphyses and adult short stature. These goals are being partially met with spironolactone and we postulate that the addition of testolactone will improve response by slowing bone growth and preventing gynecomastia. Preliminary results using this regimen demonstrate that blockade of both androgen action and estrogen synthesis is an effective treatment for familial male precocious puberty. Throughout the therapy, patients will receive frequent clinical, hormonal, and toxicological monitoring.