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Purpose: Recent studies in the rat suggest that early exposure to exogenous testosterone accelerates the loss of androgen receptors and compromises eventual penile length. To determine whether this is true in men we measured adult penile length of patients treated in childhood for sexual precocity., Materials and Methods: We examined 21 men with sexual precocity due to true precocious puberty (12) or congenital adrenal hyperplasia (9) who had been followed at our institution since childhood. Penile lengths were compared with data from normal men., Results: Mean stretched penile length plus or minus standard deviation was 12.7 +/- 2.6 cm. in all patients, 12.1 +/- 2.6 cm. in those with true precocious puberty and 13.6 +/- 1.6 cm. in those with congenital adrenal hyperplasia. These lengths were not significantly different from those of normal men (12.4 +/- 2.7 cm.)., Conclusions: In contrast to findings in rats, exposure to endogenous testosterone during gestation and/or childhood does not reduce adult penile length in men. Thus, the use of testosterone to treat childhood genitourinary anomalies would likely not compromise mature penile size.

We report a long term study on the effectiveness of chronic GnRH agonist treatment on final or near-final height in 26 patients (20 females and six males) with true precocious puberty (TPP). This study differs from other treatment studies in that the median age at onset of therapy was 4.7 yr for females and 6.2 yr for males, the youngest cohort of treated patients reported to date. We compared patients treated with GnRH agonists who attained final or near-final height with a historical control group of untreated children with TPP (n = 116) matched for mean age of pubertal onset, etiology of TPP (idiopathic or neurogenic), rate of progression, and sex ratio. The current mean height of GnRH agonist-treated females who began therapy at more than 5 yr of age (157.6 +/- 6.6 cm) is already significantly greater than the mean final height of untreated females (152.7 +/- 8.6 cm). The current mean predicted height of the treated females is 164.6 +/- 9.7 cm. The current mean height of females whose treatment was started before 5 yr of age is greater (164.1 +/- 7.7 cm) than that of females whose treatment began after 5 yr of age (157.6 +/- 6.6 cm). The final height of untreated children whose age of sexual precocity was less than 5 yr at diagnosis is significantly less than that of treated patients who were less than 5 yr when they developed TPP (P = 0.0006). The current mean height of GnRH agonist-treated males is 166.3 +/- 12.2 cm, and the current mean predicted height is 170.8 +/- 11.3 cm. This is in sharp contrast to the mean final height of untreated males (155.6 +/- 7.7 cm). The current predicted height correlates negatively with the age at initiation of treatment and the initial bone age and positively with height SD for bone age in the agonist-treated children. The current mean height deviation from target height is significantly less in the 20 treated females (-1 SD) than in 93 untreated females (-2.4 SD; P = 0.006). The mean final height deviation from target height in 23 untreated males (-3.7 SD) is significantly greater than the current height deviation from target height in 6 treated males (-1.7 SD; P = 0.03). The salutary effects of long term GnRH agonist therapy on stature are more clear-cut in the younger treated children. Young untreated children may have the worst outcome with respect to final height.(ABSTRACT TRUNCATED AT 400 WORDS)

The LHRH-secreting hypothalamic hamartoma (HH), a congenital malformation consisting of a heterotopic mass of nervous tissue that contains LHRH neurosecretory neurons attached to the tuber cinereum or the floor of the third ventricle, can cause true or central precocious puberty (TPP). We have suggested that it functions as an ectopic LHRH pulse generator independent of the central nervous system inhibitory mechanism that normally restrains the hypothalamic LHRH pulse generator. TPP associated with a hamartoma has all of the hormonal hallmarks of puberty, including a pubertal pattern of pulsatile LH and a pubertal plasma LH response to LHRH administration. Little is known about the natural history of HH. We present long term data on 10 children (5 females and 5 males) with TPP due to HH. Physical signs of puberty were observed at a mean age of 2.2 +/- 1.6 yr (range, 0.5-5.1). Two of 10 had a pedunculated mass, and 8 of 10 had a sessile mass. The hamartoma varied in diameter from 4-25 mm and did not change with time (3.5-8.7 yr). Four patients have a seizure disorder, 3 with gelastic seizures (1 with mental retardation) and 1 with tonic-clonic seizures. The shape of the hamartoma, sessile or pedunculated, did not correlate with the occurrence of seizures. At presentation with sexual precocity, the mean height SD for chronological age was +3.5 +/- 0.4, the mean height SD for bone age was -1.9 +/- 0.4, and the mean bone age SD for chronological age was +6.8 +/- 0.7. Baseline data were comparable to those of 10 females with idiopathic TPP. Nine of 10 HH patients and all idiopathic TPP patients were treated with a LHRH agonist. The response to therapy was excellent in both groups and indistinguishable. Nine of 10 HH children attend school regularly and, aside from those with seizures, have no neurological handicap. While surgical resection of the hamartoma has been recommended, it carries an increased risk of morbidity and mortality and, if removal is incomplete, does not arrest the sexual precocity. In our experience, LHRH agonist therapy for TPP due to HH is the preferable approach.

The relative contributions of GH, insulin-like growth factor-I (IGF-I), estradiol, and testosterone to the pubertal growth spurt are incompletely understood. We studied 8 patients (5 girls and 3 boys) with true precocious puberty and GH deficiency due to CNS lesions to assess the role of sex steroids in pubertal growth independent of an increase in circulating GH. Included is 1 patient with an unusual hypothalamic lesion due to head trauma. A control group of 17 GH-sufficient patients with true precocious puberty (13 girls and 4 boys) was matched for chronological age. The GH-deficient girls grew at a mean velocity of 9.2 cm/yr (range, 7.2-14.4), and the boy's mean height velocity was 7.9 cm/yr (6.1-9.9). Mean bone age was advanced in the GH-deficient group (girls, +2.7 SD; boys, +2.6 SD), but not as much as the GH-sufficient controls (girls, +5.4 SD; boys, +4.3 SD). The mean concentration of plasma IGF-I was lower in the GH-deficient group than in the control group, but was greater than the mean concentration in age-matched prepubertal GH-deficient patients. Four GH-deficient patients were treated with a potent agonist of LRF. This caused suppression of gonadal sex steroid concentrations and a fall in mean height velocity from 9.1 to 4.3 cm/yr after 1 yr of therapy; however, circulating GH and IGF-I values were not uniformly altered. We conclude that a substantial pubertal growth spurt can occur in patients with true precocious puberty and GH deficiency that is dependent on gonadal sex steroids yet unaccompanied by normal pubertal levels of circulating GH or IGF-I. Reversal of this growth acceleration is possible with sex steroid suppression. The results, in light of previous in vivo and in vitro studies, suggest that the normal pubertal growth spurt is mediated in part by direct effects of sex steroids at the growth plate.

A recently described form of male sexual precocity characterized by active Leydig cell differentiation and premature onset of spermatogenesis in the absence of pituitary gonadotropin stimulation has been termed familial testotoxicosis. The clinical and endocrine findings in the condition are consistent with an inherited intratesticular defect rather than central or true precocious puberty. In this report, testicular changes in biopsy specimens from a series of affected patients are presented. In all of the cases, Leydig cells demonstrated nuclear and cytoplasmic features characteristic of fully differentiated steroidogenic cells. Reinke crystals were absent. Germ cells at all stages of spermatogenesis were present, but there was evident disorganization of maturation. Spermatids exhibited a variety of structural abnormalities. Sertoli cells were characterized by complex cytoplasmic differentiation, Charcot-Böttcher crystals, and tight junction formation. The morphologic changes indicate premature differentiation of all of the major testicular cell types and are consistent with a distinctive type of intratesticular abnormality.

To explore further the relationship of gonadal sex steroids to the rise in somatomedin-C (Sm-C) during puberty, we studied a group of children with true precocious puberty before and after treatment which suppressed sex steroid output. Plasma estradiol and testosterone and serum acid-ethanol-extractable Sm-C were determined by specific RIAs in 7 boys and 12 girls with true precocious puberty before and at regular intervals during treatment with a potent LHRH-agonist (LHRH-A), D-Trp6-Pro9-NEt-LHRH. For comparison, Sm-C and sex steroid concentrations were determined in 266 normal adolescents and 37 normal prepubertal children, 1-9 yr of age. The mean +/- SEM Sm-C levels in normal male individuals peaked at 15 yr (2.46 +/- 0.23 U/ml) and at pubertal (genital) stage III (2.29 +/- 0.19 U/ml), and those in normal females reached their highest concentration at 12-15 yr of age and at pubertal (breast) stage III (2.47 +/- 0.15 U/ml). Sm-C concentrations correlated better with pubertal (genital or breast) stage than with chronological age for both sexes and better with testosterone levels in males than with estradiol levels in females. The mean +/- SEM Sm-C concentrations in both males and females with true precocious puberty were 2.07 +/- 0.16 U/ml before therapy and decreased significantly to 1.52 +/- 0.13 U/ml after 6 months of therapy. The mean Sm-C level of the patients remained significantly elevated for chronological age, but decreased into the normal range for bone age after 6-12 months of therapy. Sm-C correlated significantly with testosterone and estradiol levels, but not with growth rate. Mean nighttime GH secretion decreased significantly after 6 months of LHRH-A therapy. In summary, children with true precocious puberty have Sm-C elevations typical of normal puberty. The decrease in Sm-C levels after suppression of gonadal sex steroid output with LHRH-A is evidence that sex steroids are necessary to induce this elevation in Sm-C concentration. The decrease in GH secretion during LHRH-A therapy suggests that the effect of sex steroids on Sm-C levels during normal puberty is mediated, at least in part, through stimulation of GH secretion.

We used the LHRH agonist D-Trp6-Pro6-N-ethylamide LHRH (LHRH-A) to treat 19 children (12 girls and 7 boys) with true precocious puberty. Fourteen patients had idiopathic true precocious puberty, 4 had a hamartoma of the tuber cinereum, and 1 had a hypothalamic astrocytoma. Basal gonadotropin secretion and responses to native LHRH decreased within 1 week of initiation LHRH-A therapy, and sex steroid secretion decreased within 2 weeks to or within the prepubertal range. Ultrasonographic evaluation of the uterus indicated a postmenarchal size and shape in all 11 girls studied before treatment, which reverted to prepubertal size and configuration in 5 girls during LHRH-A therapy. The enlarged ovaries decreased in size and the multiple ovarian follicular cysts regressed. Sexual characteristics ceased advancing or reverted toward the prepubertal state in all patients receiving therapy for 6-36 months. All 5 girls with menarche before therapy had no further menses. Three girls had hot flashes after LHRH-A-induced reduction of the plasma estradiol concentration. Height velocity, SDs above the mean height velocity for age, and SDs above the mean height for age decreased during LHRH-A therapy; the velocity of skeletal maturation decreased after 12 months of LHRH-A therapy and was sustained during continued therapy over 18-36 months. In 4 patients, a subnormal growth rate (less than 4.5 cm/yr) occurred during LHRH-A therapy. Six patients had cutaneous reactions of LHRH-A, but no demonstrable circulating antibodies to LHRH-A. In 2 patients in whom LHRH-A therapy was discontinued because of skin reactions, precocious sexual maturation resumed at the previous rate for the ensuing 6-12 months; subsequently, they were desensitized to LHRH-A, and during a second course of therapy, their secondary sexual development and sex steroid levels again quickly decreased. LHRH-A proved an effective and safe treatment for true precocious puberty in boys as well as girls with central precocious puberty whether of the idiopathic type or secondary to a hamartoma of the tuber cinereum or a hypothalamic neoplasm.

One hundred micrograms synthetic luteinizing hormone-releasing factor (LRF) were administered to 13 girls and 2 boys with idiopathic precocious puberty, 3 girls with precocious thelarche, 2 girls with precocious adrenarche, and 5 children treated with medroxyprogesterone acetate (MPA). Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex steroid responses were assessed. The mean readily releasable LH rose to a peak of 8.4 plus or minus 1. 8 ng/ml (LER 960) in the children with idiopathic precocious puberty and was significantly greater than in normal prepubertal (1.8 plus or minus 0.14) or pubertal children (4.9 ng/ml) (LER 869) was higher in precocious puberty but not significantly greater than in normal prepubertal (5.3 plus or minus 1.9) or pubertal girls (6.0 plus or minus 1.2). The mean concentration of plasma estradiol rose significantly above resting levels after LRF in the girls with idiopathic precocious puberty. The LH response in girls with precocious the larche was in the prepubertal range. In 4 of 5 children with sexual precocity treated with MPA, the LH release evoked by LRF was diminished.

A recently described, distinct form of male sexual precocity is characterized by premature Leydig and germinal cell maturation in the absence of pituitary gonadotropin stimulation. Analysis of a nine-generation kindred with at least 28 affected males supports sex-limited autosomal dominant transmission. Three boys, with precocious sexual development at 1 to 4 years of age, had low basal plasma gonadotropin values without pubertal-type pulsatility and a minimal rise in luteinizing hormone after acute stimulation with luteinizing hormone releasing factor or its potent analog D-Trp6-Pro9-NEt-LRF, distinguishing them from boys with true precocious puberty. Two affected adults had a mature luteinizing hormone response to LRF. Testicular biopsies showed a progression of abnormalities in the seminiferous tubules from childhood to maturity; in one adult this disorder was associated with marked oligospermia and selective elevation of plasma follicle-stimulating hormone. The findings are consistent with an inherited intratesticular defect. Furthermore, the majority of cases of familial male sexual precocity seem to be examples of this disorder rather than central or true precocious puberty.

Four boys with sexual precocity are described in whom pubertal concentrations of plasma testosterone were associated with premature Leydig and germinal cell maturation without activation of the hypothalamic-pituitary gonadotropin unit. Extensive laboratory evaluation localized the source of testosterone secretion to the testes, and testicular biopsy revealed maturation of Leydig cells and spermatogenic elements. These events appear to be nongonadotropin-dependent in view of the absence of a pubertal pattern of pulsatile LH secretion, persistence of a prepubertal LH response to LRF even after long standing sexual precocity, prepubertal basal levels of LH and undetectable hCG, and the absence of biologically active LH-hCG by bioassay. Indirect immunofluorescence studies failed to demonstrate an immunoglobulin in the patients' sera that bound to Leydig cells or seminiferous tubules of normal adult human testes. The potent LRF analog D-Trp6-Pro9-NEt-LRF did not result in suppression of plasma testosterone or Leydig cell function even after 3 months of daily treatment in two patients which provides additional support of pituitary gonadotropin independence and of the lack of a direct effect of the analog on Leydig cell function. Oral medroxyprogesterone acetate treatment in two patients was associated with a striking decrease in both plasma testosterone concentration and height velocity. In the only patient in whom a complete family history could be obtained (three of four patients were adopted), sexual precocity was noted in the maternal grandfather. As this familial syndrome is characterized by a prepubertal hypothalamic-pituitary gonadotropin unit and apparent gonadotropin-independent maturation of Leydig cells and germinal epithelium, possibly due to an intratesticular inborn error, we propose the term "familial testotoxicosis" to describe this group of sexually precocious boys.