Treatment of Boys With Precocious Puberty

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00001202
First received: November 3, 1999
Last updated: March 3, 2008
Last verified: January 2004
  Purpose

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).


Condition Intervention Phase
Precocious Puberty
Drug: Spironolactone
Drug: Testolactone
Drug: Deslorelin
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Primary Purpose: Treatment
Official Title: Spironolactone and Testolactone Treatment of Boys With Familial Isosexual Precocious Puberty

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Estimated Enrollment: 80
Study Start Date: January 1985
Estimated Study Completion Date: January 2004
Detailed Description:

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.

  Eligibility

Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA:

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 pseudopuberty:

  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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00001202

Locations
United States, Maryland
National Institute of Child Health and Human Development (NICHD)
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT00001202     History of Changes
Other Study ID Numbers: 850016, 85-CH-0016
Study First Received: November 3, 1999
Last Updated: March 3, 2008
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Luteinizing Hormone
High Serum Testosterone Levels
Low Baseline Gonadotropin
LHRH
Precocious Puberty
Familial Isosexual Precocious Puberty

Additional relevant MeSH terms:
Puberty, Precocious
Gonadal Disorders
Endocrine System Diseases
Spironolactone
Testolactone
Deslorelin
Aldosterone Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Diuretics
Natriuretic Agents
Cardiovascular Agents
Therapeutic Uses
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 22, 2014