Induction of puberty in boys with delayed adolescence by methandrostenolone

Methandrostenolone administration at a daily dose of 0.03 mg/kg for 3 months was successful in inducing puberty in 9 boys (aged 14 6/12±6/12 years, m±SD) with delayed puberty and studied in the prepubertal stage. One year after initiation of treatment they reached a mid-pubertal stage (testicular volume m±SD 6±2 ml and pubic hair development Tanner stage 3–4). At the same time growth velocity accelerated from 5.3±1.5 to 8.5±3.4 cm/yr and bone age advanced from 10 9/12±9/12 to 13±6/12 years (m±SD).During treatment there was suppression of basal plasma LH and FSH (m±SD) from 1.3±0.3 to 0.5±0.2 mIU/ml (P<0.001) and from 1.4±0.8 to 0.8±0.3 mIU/ml (P<0.05) respectively, and of the LH response to LRH (50 mcg/m², i.v.) from 5.2±1.0 to 1.9±0.6 mIU/ml (P<0.001). After discontinuation of methandrostenolone there was a significant and prolonged elevation of the basal plasma LH (2.0±0.4 mIU/ml) and testosterone levels (from 24±7.7 to 175.6±67.5 ng/dl, P<0.01) and an enhanced LH response to LRH (8.3±2.4 mIU/ml, P<0.05), compared to the pre-treatment levels.Eleven prepubertal boys with constitutional short stature (aged 9 3/12±9/12 years, m±SD) maintained their prepubertal state one year following the same therapeutic regime with methandrostenolone. No significant changes in the basal plasma testosterone and gonadotropin levels, or the responses to LRH, were noted in this group.During treatment a significant increase in growth velocity was noted (from 4.1±1.7 to 9.7±3.0 cm/year, P<0.02), with a subsequent decrease to 5.4±2.9 cm/year (m±SD) which was not significantly different to the pre-treatment value. Bone age advanced from 6 3/12±1 before treatment to 8±1 6/12 years 12 months following methandrostenolone administration.It is concluded that methandrostenolone can induce puberty in boys with delayed puberty if administered in the prepubertal stage, but not in younger prepubertal boys with short stature. The concomitant changes in the basal plasma testosterone and gonadotropin levels, and their response to LRH stimulation, which were found in the boys with delayed puberty indicate that a certain degree of maturation of the hypothalamic pituitary gonadal axis is probably needed to permit induction of puberty by methandrostenolone. The effect of this drug is due in part to its androgenic potency and probably also to its modulation of negative feedback in the hypothalamic-pituitary-gonadal axis, causing a rebound phenomenon following brief suppression.Supported in part by the Harry C. Bernard Fund     

The LH and FSH responses to LH-releasing hormone (LH-RH) in girls with true precocious puberty treated with cyproterone acetate

Ten girls with precocious puberty ranging in age from 7 to 10 7/12 years who were treated with oral cyproterone acetate on a long term basis, were subjected to LH-RH tests, prior to and 3 to 16 months after the institution of therapy. Cyproterone acetate was given in doses from 60 to 153 mg/m², which proved to be clinically effective, as evidenced by the slowing down of sexual maturation.The basal levels of LH were found to be unaffected by therapy and corresponded to the pubertal stages of the individual girls. The peak increment of LH after LH-RH stimulation was markedly suppressed by the therapy. FSH secretion and its responsiveness to LH-RH was not affected by cyproterone acetate. The basal levels of FSH were higher during therapy than before, but the peak FSH increment remained the same. An escape phenomenon in the LH peak response was evident in 2 patients upon retesting after prolonged therapy. It is possible that the antigonadotrophic action of cyproterone acetate is due to its progestational nature.Supported in part by a Grant from the Harry C. Bernard Fund     

Pubertal development in the Prader-Labhart-Willi syndrome.

The sexual maturation in the Prader-Labhart-Willi (PLW) syndrome was investigated in 14 patients, 10 females and 4 males. A wide variability in the pattern of pubertal development was found including delayed puberty in 5 patients and normal puberty in 4 patients; sexual precocity was also observed in 5 patients, true precocious puberty in one patient and incomplete sexual precocity in the form of precocious pubarche in 4 patients. In 5 patients, 3 of them with precocious pubarche, the appearance of the pubertal signs was followed by a delay or arrest in their future development. An LH-RH stimulation test was performed in 11 patients. In the 6 patients who eventually developed normal puberty, the basal levels and the peak responses of both LH and FSH were within the range of those observed in normal controls of the same pubertal stage. In 4 patients showing marked delay or arrest of puberty, the basal levels were normal or low and the responses of LH and FSH to LH-RH were blunted. Priming with repeated LH-RH stimulation in one of the male patients led to an augmented LH response, suggesting a hypothalamic hypogonadotrophism. It is concluded that the lack of uniformity in the pattern of sexual maturation in the PLW syndrome is due to a variability in the location and extent of a hypothalamic lesion, which may comprise an active process continuing beyond the perinatal period.     

The plasma FSH and LH response to synthetic LH-RH in normal pre-pubertal and early pubertal girls--a re-evaluation.

A standard LH-RH test (50 microgram/m2) given iv was carried out in 65 normal girls, 42 of them pre-pubertal aged from 4 7/12 to 11 years and 23 in the early stage of puberty, aged from 9 to 12 9/12 years. The results indicate that in pre-pubertal girls the basal levels of the plasma gonadotrophins remain steady (LH 0.6 +/- 0.1 mIU/ml; FSH 0.8 +/- 0.1 mIU/ml, m +/- SD) and that there is a small but significant response of LH to LH-RH (1.6 +/- 0.2 mIU/ml). During this period the FSH response to LH-RH is very marked (8.0 +/- 1.0 mIU/ml) with a gradual, significant decrease seen towards the onset of puberty (6.5 +/- 0.9 mIU/ml, P less than 0.001). These results support earlier reports that the LH-RH test is a useful tool to evaluate the secretion of pituitary LH and FSH in early childhood.     

Plasma LH and FSH response to LRH in boys with compensatory testicular hypertrophy.

The plasma LH, FSH and testosterone response to LRH was studied in 12 boys with compensatory testicular hypertrophy (CTH) and normal puberty and in a matched control group with normal testicular development. It was found, that the boys with CTH had normal basal plasma testosterone and LH concentrations; at the same time the basal plasma FSH level were significantly higher than in the control group. The response of plasma LH and FSH to LRH was markedly greater in the CTH group than it was in the control group. It is concluded, that the contralateral testicular hypertrophy which enables a normal pubertal process is the result of increased secretion of gonadotropins, mainly FSH.     

Gonadal dysfunction in patients with ataxia telangiectasia.

Two males and three females with ataxia telangiectasia aged from 4 6/12 to 23 years were subjected to an i.v. LH-RH test. All were found to have elevated basal levels of FSH and three had elevated levels of LH. In all the response of FSH to LH-RH was supranormal. In the pubertal and adult females the basal levels of estradiol were low. The laboratory and clinical findings in these patients as well as data reported by others indicated that the primary gonadal failure is an integral part of AT.     

Response to LH-RH and HCG in two brothers with the Reifenstein syndrome.

Two brothers with Reifenstein syndrome underwent LH-RH and HCG tests at various ages ranging from 13 to 17 years. We found that at age 13 the plasma LH and FSH response to one LH-RH injection was normal. After the age of 14, the basal plasma concentration of LH and FSH and their response to LH-RH became elevated. Concomitantly the plasma testosterone levels rose to abnormal levels. These findings are compatible with progressive development of primary gonadal dysfunction and with peripheral insensitivity to testosterone.     

XY gonadal dysgenesis associated with hGH and gonadotrophin deficiencies

A girl of remarkably short stature, referred for investigation with the diagnosis of gonadal dysgenesis and the finding of a male karyotype, proved to be deficient in growth hormone and gonadotrophin secretion, and was treated with growth and sex hormones. It was concluded that this case demonstrates an apparently casual coincidence of pituitary insufficiency with XY gonadal dysgenesis, evidently the first to be reported.     

Cyproterone acetate in treatment of precocious puberty

Twenty-nine children (23 girls, 6 boys) with precocious puberty were treated with cyproterone acetate for various periods of time ranging from 6 months to 3 years 4 months. They received an oral dose ranging from 70-150 mg/m2 per day, or an intramuscular depot injection once a fortnight or once a month at a dose ranging from 107-230 mg/m2. Both forms of therapy were found to suppress the signs of sexual maturation, but the oral form proved to be superior. Only the younger patients with a bone age under 11 years showed a beneficial effect upon linear growth and bone maturation. No side effects were noted, but additional advantageous effects upon behaviour and sociability were. It is concluded that at present cyproterone acetate by mouth is the drug of choice in the treatment of precocious puberty. The treatment should be initiated as early as possible to attain maximum benefit.