Testicular changes in gonadotropin-independent familial male sexual precocity. Familial testotoxicosis.

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.

Somatomedin-C in normal puberty and in true precocious puberty before and after treatment with a potent luteinizing hormone-releasing hormone agonist.

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.

Treatment of true precocious puberty with a potent luteinizing hormone-releasing factor agonist: effect on growth, sexual maturation, pelvic sonography, and the hypothalamic-pituitary-gonadal axis.

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.

Hormone ontogeny in the ovine fetus. XVIII. The effect of an opioid antagonist on luteinizing hormone secretion.

Endogenous opioid-like peptides influence gonadotropin release in adult animals and man; however, the role of these peptides in the regulation of fetal LH secretion is not known. We administered naloxone hydrochloride (1.3 mg/kg iv), a specific opioid receptor antagonist, to 22 chronically catheterized ovine fetuses of gestational ages 94-143 days (term = 147 days). As a control, each fetus also received the vehicle on a separate occasion, the sequence of the studies being randomized. After the administration of naloxone, LH secretion increased from 38.6 +/- 5.8 to 114 +/- 21 ng/h ml-1 (P less than 0.001); LH release was not affected by administration of the vehicle. Morphine (13 mg/kg) and naloxone (1.3 mg/kg) were administered together to three fetuses (gestational age 94-105 days); LH secretion was sharply reduced from 411 +/- 14.3 ng/h ml-1 after naloxone alone to 53 +/- 17.5 ng/h ml-1 after the administration of both naloxone and morphine (P less than 0.01). The response to naloxone varied with gestational age. Fetuses of 94-115 days showed a significantly higher increment in LH secretion when given naloxone (112.3 +/- 30.7 ng/h ml-1) than did older fetuses of gestational age 126-143 days (64.8 +/- 20.8 ng/h ml-1) (P less than 0.02). These findings indicate that, in the ovine fetus endogenous opioid-like peptides exert a tonic suppressive effect on LH secretion at least as early as 94 days gestation. Moreover, the effectiveness of naloxone in augmenting LH release decreases with advancing gestational age. This latter observation supports the concept that, in the ovine fetus, endogenous opioid tone is not the sole factor involved in the dampened fetal LH secretion which is characteristic of late gestation.

Pituitary gonadotropin-independent male-limited autosomal dominant sexual precocity in nine generations: familial testotoxicosis.

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.