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Long Term Treatment of Male and Female Precocious Puberty by Periodic Administration of a Long-Acting Preparation of D-Trp⁶-Luteinizing Hormone-Releasing Hormone Microcapsules

Fondation de Recherche en Hormonologie Paris
Hôpital Saint Vincent de Paul Paris
U.E.R. Alexis Carrel Lyon
Centre Hospitaller Uniuersitaire Grenoble
Centre Hospitaller Régional Bordeaux
Hôpital Saint Charles Montpellier
Hôpital Debrousse Lyon, France
The Tulane University Medical Center and Veterans Administration Hospital New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Dr. M. Roger, Fondation de Recherche en Hormonologie, B.P. 110, 94268 Fresnes Cedex, France.

The efficacy and safety of a delayed release formulation of the LHRH agonist D-Trp⁶-LHRH (LHRH-A; im microcapsules) were tested in 16 girls, 6.9–8.8 yr old, and 10 boys, 2.0–10.5 yr old, with precocious puberty. All children had advanced bone age, breast or testis enlargement, and a pubertal LH response to LHRH. Precocious puberty was idiopathic in 19 subjects and secondary to a brain tumor or other central nervous system abnormality in 7. Nine girls and 6 boys had been previously treated unsuccessfully with medroxyprogesterone and/or cyp rote rone acetate. The microcapsules were made of 2% LHRH-A dispersed in a biocompatible biodegradable polymeric matrix of DL-lactide-coglycolide. Sixty micrograms of LHRHA/kg BW were given im on days 1 and 21 and thereafter every 4 weeks for 10–27 months. Plasma LHRH-A levels were measured in 13 children by means of a specific RIA. On days 3, 7, 14, and 21, mean concentrations (±SEM) were 295 ± 44, 218 ± 31, 215 ± 45, and 224 ± 39 pg/ml, respectively. In girls, breast enlargement disappeared, and mean uterus size decreased from 44.4 ± 2.5 to 38.1 ± 3.1 mm (mean ± SEM; P < 0.02) within 6 months. Mean ovary length decreased from 23.0 ± 1.5 to 16.2 ± 1.5 mm (P < 0.01). In boys, mean testis volume decreased from 8.1 ± 1.2 to 6.7 ± 1.2 ml (P < 0.02) within 6 months. In both sexes, growth velocity decreased significantly, and bone maturation was generally reduced. Plasma levels of estradiol or testosterone and FSH levels decreased significantly within 3 weeks. The LH response to LHRH was reduced to normal prepubertal values after 7 weeks. No secondary clinical or biochemical escape occurred. In 1 boy, all biological features of puberty recurred within 1 month after omission of the fifth injection. No sideeffects occurred, except for transient vaginal bleeding in girls after the first or second injection. No antibodies to LHRH-A were detected in the patients' sera. This study demonstrates the ability of a delayed release formulation of LHRH-A to achieve stable levels of the drug in plasma for at least 21 days after a single im injection and to suppress pituitary and gonadal secretion and pituitary response to LHRH for as long as 2 yr after therapy. This treatment appears to be more efficient in treating both clinical and biochemical abnormalities than does treatment with inhibitory steroids. Additionally, the method of administration is more practical and ensures better patient compliance.

Received August 14, 1985.

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