Recent evidence suggests that a group of children exists in whom premature sexual maturation occurs in the absence of pubertal levels of gonadotropins; that is, they have gonadotropin-independent precocious puberty. We compared six boys and one girl with this disorder with four boys and five girls with central precocious puberty, in which there is a pubertal pattern of gonadotropin release. The two groups were similar in age of onset, degree of sexual development, growth velocity, and rate of skeletal maturation. A family history of precocity was noted in four of the boys with gonadotropin-independent precocity, and the girl had McCune-Albright syndrome. Children with central precocious puberty demonstrated a pulsatile release of gonadotropins, pubertal responses to luteinizing hormone-releasing hormone, and complete suppression of gonadarche after exposure to an analogue of luteinizing hormone-releasing hormone (LHRHa). In contrast, children with gonadotropin-independent precocity demonstrated an absence of gonadotropin pulsations, variable responses to luteinizing hormone-releasing hormone, lack of suppression of puberty in response to LHRHa, and cyclic steroidogenesis. Tissue from testicular biopsies performed in five of six boys with gonadotropin-independent precocity showed a range from incipient pubertal development of the tubules with proliferation of Leydig cells to the appearance of normal adult testes. We conclude that gonadotropin-independent precocious puberty is a distinct syndrome, of unknown cause, that may be familial and may have been responsible for many previously reported cases of precocious puberty.

LHRHa suppresses gonadarche in girls with CPP, but little information is available regarding the response of males to this therapy. Four boys with CPP received LHRHa for 12 consecutive months. Prior to therapy, the patients had Tanner stage II-IV pubertal development, a mean testicular volume of 16±3 (SE) ml, a chronologic age of 7.7±0.6 years and a bone age of 12.9±0.4 years. Following therapy, 3/4 boys demonstrated regression of secondary sex characteristics and all had a marked decrease in testicular size to 7±1 ml. Bone age advanced 4.5±0.5 months during 12 months of exposure to LHRHa. The pretreatment pubertal growth velocity of 13.5±2.7 cm/yr fell significantly to 5.5±.13 cm/yr over the year of therapy. Predicted height was increased to 3.84±2.24 cm. Endocrinologic parameters are summarized below:1=plasma testosterone (ng%) in a PM pool; 2=mean of 8h pulsation study (mIU/ml LER 907); 3=ΔFSH or ΔLH after LHRH (2.5 mcg/kg sc).In boys with CPP, LHRHa is capable of: 1) reversing the clinical features of precocity, 2) abolishing the pulsatile release of gonadotropins with subsequent suppression of testosterone production, and 3) retarding skeletal maturation, slowing growth velocity, and improving predicted adult stature.

During puberty the effect of adrenal androgens on skeletal maturation and growth is obscured by the influence of gonadal steroids. Suppression of gonadarche with an LHRHa affords an opportunity to explore the association between adrenarche, skeletal development and adult stature. In 16 girls with central precocious puberty (CPP), gonadarche was suppressed by LHRHa administration for 12 to 36 months. During treatment dehydroepiandrosterone sulfate (DS) levels, an index of adrenarche, were constant or increased in an age expected fashion. Rate of bone maturation (ΔBA) for change in chronologic advancement (ΔCA) decreased as shown by ΔBA/ΔCA < 1 in all subjects. DS levels were positively correlated with ΔBA/ΔCA (R = 0.07, p < 0.002). Statural growth also decreased but less than bone maturation so that predicted mature height (Bayley and Pinneau) was increased in all but one subject. A significant negative linear regression of DS levels with increase in predicted height was observed (R = 0.70, P < 0.003). Conclusions: 1) In girls with CPP, adrenarche progressed during LHRHa suppression of gonadarche. 2) In preadrenarchal girls, LHRHa administration was associated with a more striking slowing of bone maturation with relatively lesser effects on height velocity. In those girls with the onset or progression of adrenarche in the absence of gonadal steroids, therapy was associated with less evidence of restraint on bone maturation. 3) These data are compatible with a direct effect of adrenal androgens upon skeletal maturation and growth.