In children a progressive decrease in nocturnal serum melatonin (MT) has been shown with advancing age, suggesting a reduction in the amplitude of the circadian MT curve with maturation. Whether this alteration of MT levels is related to human sexual maturation or occurs independently remains to be elucidated. Also, the impact of gonadal steroids on the MT rhythm remains an open question. We examined 56 patients (51 females and 5 males) with central precocious puberty (52 idiopathic and 4 neurogenic). Patients were studied before and 3, 6, and 12 months after initiation of GnRH analog treatment. Three hundred and thirty-seven endocrinologically normal subjects (190 males and 147 females) served as controls. In all subjects nocturnal serum MT (blood collection between 2300 and 0100 h) was measured with a highly specific RIA. In young patients, aged 1-5 yr, we found significantly lower MT levels than in age-matched controls. Pubertal patients, aged 5-9 yr, displayed nocturnal MT levels in the same range as control subjects approaching normal pubertal age. In contrast to endocrinologically normal children, there was no age-dependent decrease in nocturnal MT in untreated precocious puberty; rather, it appeared that serum MT had already declined in association with the onset of sexual maturation. Although there was a significant difference in weight between patients and age-matched controls, the low MT values in patients 1-5 yr old were only partly explained by the weight difference (P less than 0.0009); their pubertal status also contributed significantly (P less than 0.006). Pituitary-gonadal suppression induced by long term GnRH analog treatment did not result in a return to prepubertal MT levels; rather, nocturnal MT decreased during therapy. The collected data indicate that nocturnal serum MT levels are related to sexual maturation, since serum MT is similar in precocious puberty and normal pubertal children. Since suppression of the pituitary-gonadal axis did not result in increases in nocturnal MT levels in young patients with precocity (i.e. return to age-appropriate levels), the reduction of nocturnal MT with normal puberty is not likely to be dependent on pubertal gonadotropin or sex steroid milieu.
The physical changes that herald the onset of puberty result from the combination of adrenarche and gonadarche. To examine adrenal maturation and associated changes in growth without the confounding effects of changes in the gonadal steroid milieu, we performed a longitudinal study in 14 young girls with idiopathic central precocious puberty during long-term pituitary-gonadal suppression. Beginning at the mean age of 2.9 yr, dehydroepiandrosterone sulfate levels, linear growth, skeletal maturation, body mass index, and secondary sexual development were evaluated at 3- to 6-month intervals for up to 12.3 yr. In 12 of the girls, levels of dehydroepiandrosterone, androstenedione, 17-hydroxypregnenolone, and 17alpha-hydroxyprogesterone were determined before and after acute ACTH stimulation every 6 months to investigate the maturation of adrenal steroidogenic enzyme activity. Serum dehydroepiandrosterone sulfate levels rose progressively throughout the study. An exponential model fit the longitudinal datasets well and indicated that dehydroepiandrosterone sulfate levels increased approximately 22%/yr from the youngest age onward. Increasing activity of 17-20 lyase (CYP17) and decreasing activity of 3beta-hydroxysteroid dehydrogenase were also evident in preadrenarchal subjects. When controlled for chronological age, no significant associations were noted between weight, body mass index, or body surface area and dehydroepiandrosterone sulfate levels. However, similar analyses revealed modest correlations of both height and growth velocity with dehydroepiandrosterone sulfate levels. Our results suggest that adrenarche is not the result of sudden rapid changes in adrenal enzyme activities or adrenal androgen concentrations; rather, adrenarche may be a gradual maturational process that begins in early childhood.
Studies utilizing the administration of GnRH in various GnRH-deficient models have revealed the critical importance of the dose and mode of delivery of this releasing factor in determining the subsequent pituitary response. Chronic administration of long acting GnRH agonists (GnRHa), like continuous infusion of high doses of the native peptide, results in suppression of pituitary gonadotropin secretion. This selective and reversible suppression of gonadotropin secretion suggested several therapeutic applications for these analogs, particularly in the treatment of central precocious puberty (CPP), a disorder for which the previously available therapies lacked uniform efficacy and were associated with potential side effects. In our series, 74 children with CPP have been treated during the last 5 yr with the potent GnRH agonist, [D-Trp6, Pro9-ethylamide(NEt)]GnRH. Having selected a dose and route of administration that produced uniform suppression of spontaneous and stimulated pituitary gonadotropin secretion, GnRHa therapy resulted in a fall of gonadal sex steroid levels into the prepubertal range, a halting or regression of secondary sexual development, and a complete cessation of menses. Growth velocity slowed during therapy, with this slowing more pronounced during prolonged treatment periods and among those patients with more advanced chronological and skeletal ages. Skeletal maturation was retarded to a greater degree than linear growth, with resultant increases in the predictions for adult stature. Moreover, these benefits have been achieved in the absence of significant side effects. Complete reversal of the suppression of gonadarche has followed discontinuation of therapy; however, patterns of growth and skeletal maturation after discontinuation of GnRHa administration remain to be characterized. Thus, the impact of GnRHa therapy on final height must await further longitudinal study. The selective nature of GnRHa suppression of gonadarche also permits an investigation of the natural history of adrenarche and its discrete influences upon skeletal growth and maturation. In addition, GnRHa therapy of CPP provides a unique opportunity to study the effects of gonadal sex steroids on GH secretion and somatomedin-C (Sm-C) generation during sexual maturation. Finally, the detailed characterization of children with precocious puberty has helped to define more precisely a subset of patients whose precocity occurs in the absence of demonstrable gonadotropin secretion.(ABSTRACT TRUNCATED AT 400 WORDS)
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.