This study is a continuation of two previous studies conducted at the NIH. The first study
, "Treatment of True Precocious Puberty with a Long-Acting Lutenizing Hormone Releasing
Hormone Analog (D-Trp(6)-Pro(9)-Net-LHRH)" had less than optimal results. Some patients, all
of whom were diagnosed with familial isosexual precocious puberty, had an inadequate
response to the medication and were observed to have high levels of testosterone, advanced
bone aging, and other complications of the disease. As a result these patients were
enrolled in a second study
In the second study, "Spironolactone Treatment for Boys with Familial Isosexual Precocious
Puberty", - the patients received another medication, spironolactone (Aldactone). The drug
blocked the effects of testosterone, -but bone age advancement did not improve. Some
patients began experiencing gynecomastia (an abnormal growth of the male breasts).
Researchers believe these may be the effects of elevated levels of estrodiol (a form of the
female hormone, estrogen).
In the present study, testolactone is added to the drug regimen to block the production of
estrogen. The study therefore uses spironolactone to prevent the action of the male
hormones (androgen) and testolactone to block the production of female hormones (estrogen).
Deslorelin, an LHRH analog which works by turning off true (central) puberty, is added to
the drug regimen once true puberty begins. This is because it is know that boys with
familial male precocious puberty go into true puberty too early (despite treatment with
spironolactone and testolactone), and when that happens, the spironolactone and testolactone
are no longer as effective. The goal of the treatment is to delay sexual development until
a more appropriate age and prevent short adult stature (height).
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
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.
Patients with familial male precocious puberty will be admitted to the Clinical Center.
In order to be eligible for the study, the following criteria will be met:
Boys 10 years of age or less.
Tanner II to IV pubertal development.
Unfused epiphyses by bone films.
Evidence that precocious puberty is not secondary to another recognized cause of
1. We will exclude congenital adrenal hyperplasia, and document pretreatment androgen
levels, by a 1-hour ACTH test, which will include measurement of 11-deoxycortisol and
17-OH-progesterone at 0 and 60 minutes.
2. We will exclude tumor of adrenal or testes by physical exam, ultrasound, and
measurement of adrenal androgens (DHA, DHAS, androstenedione).
Elevated testosterone levels measured at 10 am, 2pm, 10 pm and 2 am over a 24 hour period.