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 longterm 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 17 alpha -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 3 beta -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.

Concern has been raised that children with central precocious puberty (CPP) are prone to the development of obesity. Here we report longitudinal height, weight, and body mass index (BMI) data from 96 girls and 14 boys with CPP before, during, and after GnRH agonist (GnRHa) administration. Skinfold thickness (n = 46) and percent body fat by dual energy x-ray absorptiometry (n = 21) were determined in subsets for more accurate assessment of body composition and to validate the use of the BMI SD score as an index of body fatness in our subjects. Before the initiation of therapy (PRE), the girls with CPP had a mean BMI SD score for chronological age (CA) of 1.1+/-0.1 and for bone age (BA) of 0.1+/-0.1. By the end of the study, 12-24 months after the discontinuation of GnRHa, the mean BMI SD score was 0.9+/-0.1 for CA and 0.6+/-0.1 for BA. At the visit when GnRHa was discontinued, 41% and 22% of the girls had a BMI SD score for CA more than the 85th and 95th percentiles, respectively, indicating that obesity was present at a high rate among our subjects; the BMI SD score for CA at the PRE visit was its strongest predictor. Indeed, 86% of the girls with BMI SD score for CA above the 85th percentile when GnRHa was discontinued also had BMI SD score for CA above the 85th percentile at the PRE visit. The proportion of boys with elevated BMI SD score for CA was also high. Fifty-four percent and 31% of the SD scores were greater than the 85th and 95th percentiles after 36 months of GnRHa therapy; the BMI SD score for CA PRE had been above the 85th percentile in 71% of these overweight subjects. Obesity occurs at a high rate among children with CPP, but does not appear to be related to long term pituitary-gonadal suppression induced by GnRHa administration. Children with CPP should have a baseline BMI SD score calculated, and those at risk for obesity should be counseled appropriately.

UNCOOKED CORNSTARCH (UCS) REGIMENS FOR NOCTURNAL TREATMENT OF YOUNG ADULTS WITH TYPE 1 GLYCOGEN STORAGE DISEASE (GSD-1). † 588

In our ongoing studies, 60 girls with CPP have been evaluated at 6-12m intervals for ≥ 12 months following the discontinuation of GnRHa. All received daily sc injections of either deslorelin or histrelin for 3.8 ± 0.2 years (range 2.0-7.7). Of these 60 girls, 36 have attained their final height (at FHT; GV < 2 cm/year, TW BA = 16 years), while the remainder have some residual growth potential (near FHT). In both subsets, the latest measured HT, while remaining 7.1 ± 1.0 cm below the genetic target HT, significantly exceeded the Bayley-Pinneau prediction prior to GnRHa administration (*, p = 0.0001). A single girl with a pre-GnRHa BA < 10 yrs has reached her FHT, while such patients comprise 34% of our total CPP female population. Since changes in predicted HT during GnRHa administration correlate significantly with pretherapy CA and BA, we must still await the FHT outcomes in young patients enrolled early in puberty to judge comprehensively the impact of gonadal sex steroid suppression on FHT in patients with CPP.

Intact LH and free alpha-subunit (FAS) are differentially regulated during GnRH agonist (GnRHa)-induced pituitary desensitization; circulating levels of FAS rise, while LH levels decline. Increased steady state alpha and decreased LH-beta mRNA levels in desensitized rat pituitaries suggest that differential regulation occurs at the level of subunit transcription. We assessed a renal contribution to these changes in serum hormone concentrations by studying LH and FAS levels in serum and urine in 15 pubertal children before and during long term GnRHa administration. Before GnRHa, serum LH and FAS were secreted in concordant pulses, and both responded briskly to exogenous GnRH. During GnRHa-induced pituitary desensitization, mean (+/- SEM) serum and urinary LH levels fell [11 +/- 3 vs. 2 +/- 0.2 IU/L (P < 0.01) and 39 +/- 15 vs. 5 +/- 1 IU/g creatinine (P < 0.05), respectively), and the LH response to exogenous GnRH was ablated (117 +/- 20 vs. 1 +/- 0.3 IU/L; P < 0.01). In contrast, despite suppression of FAS pulsatility, mean serum FAS levels rose during GnRHa treatment (204 +/- 23 vs. 405 +/- 50 ng/L; P < 0.01), and responsiveness to exogenous GnRH was maintained. Paradoxically, urinary FAS levels fell (3.2 +/- 0.9 vs. 1.7 +/- 0.4-mu-g/g creatinine; P < 0.05) as did it renal clearance (3.1 +/- 0.5 vs. 1.3 +/- 0.1 mL/min.m2; P < 0.05).We conclude that during GnRHa-induced pituitary desensitization, the gonadotrope maintains the ability to respond to GnRH with FAS release, and the rise in serum FAS is due in part to its diminished renal clearance.

ABSTRACT: To assess sleep-associated changes in gonadotropin-releasing hormone secretion during sexual maturation, we studied nighttime and daytime patterns of LH and FSH secretion in two groups with qualitatively similar sex steroid levels: girls with central precocious puberty and young adult women in the early follicular phase of an ovulatory menstrual cycle. In the girls with central precocious puberty, all indices of LH secretion were significantly higher at night than during the day (mean LH levels, 12 ± 2 versus 5 ± 1 IU/L, p ≤ 0.01; LH pulse amplitude 16 ± 2 versus 7 ± 1 IU/L, p ≤ 0.01; and LH pulse frequency 0.70 ± 0.05 versus 0.35 ± 0.08 pulse/patient-h, p ≤ 0.01). Girls with a history of menses, who were presumably the most mature, lacked this diurnal variability. Mean nocturnal FSH levels were only slightly higher than daytime levels (7.6 ± 0.5 versus 7.2 ± 0.5 IU/L, p ≤ 0.05) resulting in alternating periods of LH (nighttime) and FSH (daytime) predominance in this pubertal population. In contrast, the adult women had lower mean gonadotropin levels and LH pulse frequencies at night than during the day (mean LH 7 ± 1 versus 10 + 1 IU/L, p ≤ 0.05; mean FSH 9 ± 1 versus 10 ± 1 IU/L, p ≤ 0.05; LH pulse frequency 0.40 ± 0.08 versus 0.70 ± 0.10 pulse/patient-h, p ≤ 0.05) and often (six of eight) demonstrated striking suspension of gonadotropin-releasing hormone secretion during sleep. The smaller changes in FSH again resulted in periods of relative LH (daytime) and FSH (nighttime) predominance. When between-group comparisons were made, the girls with central precocious puberty differed significantly from the women in the early follicular phase with respect to each index of gonadotropin secretion except for daytime LH pulse amplitude. Thus, neuroendocrine maturation in the human female appears to be characterized by changes in both the pattern of gonadotropin-releasing hormone secretion and the daily alternating periods of relative LH and FSH predominance in response to sleep.

Forty girls with central precocious puberty (CPP) were studied before and during 1-3 yr of luteinizing hormone-releasing factor (LHRH) agonist (LHRHa) administration to examine the impact of gonadal steroid secretion and its suppression on skeletal growth and maturation. Pubertal growth velocity (GV) was 10.1 +/- 0.7 (SE) cm/yr and, when normalized for chronological age (CA) and bone age (BA), demonstrated that the effects of sex steroids were most profound in patients with the youngest CA and BA. GV decreased significantly to 5.8 +/- 0.3 (n = 40), 4.6 +/- 0.3 (n = 30), and 3.2 +/- 0.6 cm/yr (n = 12) during 3 yr of gonadal suppression and correlated negatively with starting BA. Skeletal maturation was markedly accelerated by premature sex steroid secretion (BA/CA = 1.8 +/- 0.1), was slowed significantly with gonadal suppression (mean delta BA/delta CA less than 1), and also was negatively correlated with the starting BA. Cumulative increases in predicted adult height were observed regardless of starting BA and averaged +2.0 +/- 0.4, +5.2 +/- 0.5, and +6.7 +/- 1.2 cm after 1, 2, and 3 yr of gonadal suppression. The comparable changes in height predictions across all BAs despite highly variable GVs underscore the need for use of developmental (i.e., BA-based) rather than CA-based standards in the analysis of growth during gonadal steroid exposure and suppression in childhood.

Suppression of gonadal sex steroid secretion in children with central precocious puberty (CPP) by LHRH analogs affords an opportunity to study sex steroid modulation of GH and somatomedin-C (Sm-C) secretion and to examine the role of GH and Sm-C in pubertal and prepubertal statural growth. Nocturnal serum GH and plasma Sm-C levels were measured in 10 preadrenarchal girls [mean age, 3.0 +/- 0.6] ( +/- SEM) yr with CPP before and during 2 yr of LHRH analog-induced gonadal suppression. Their mean height velocity, initially 4.6 +/- 0.6 ( +/- SEM) SD above the mean for chronological age, decreased to -0.1 +/- 0.4 SD during 12-24 months of ovarian suppression (P less than 0.00005). The mean peak nocturnal plasma GH level was 22.5 +/- 5.4 ( +/- SEM) micrograms/L during puberty, and it decreased to 10.2 +/- 2.1 micrograms/L after 3 months of suppression of gonadarche. This decrease persisted throughout the 2 yr of gonadal suppression (P less than 0.05). The reduction in GH secretion was accompanied by a decrease in mean plasma Sm-C levels from 3.5 +/- 0.7 to 1.5 +/- 0.2 U/mL after 3 months of suppression of gonadal sex steroids, which persisted during 2 yr of gonadal suppression (P less than 0.01). Suppression of ovarian function in girls with CPP results in decreased height velocity. This slowing of growth occurs in association with decreased nocturnal serum GH and plasma Sm-C levels, suggesting that acceleration of growth during puberty is partially mediated by sex steroid-induced augmentation of GH secretion.

During puberty the effects of adrenal androgens upon skeletal maturation are obscured by the influence of gonadal steroids. Suppression of gonadarche with an analogue of luteinizing hormone releasing hormone (LHRHa) affords an opportunity to examine the onset and progression of adrenarche in the absence of pubertal levels of gonadal steroids in a controlled fashion and to explore the relationship between adrenal androgens and the rate of epiphyseal maturation. In 29 children with central precocious puberty, gonadarche was suppressed with LHRHa administration for 1-4 yr. During LHRHa exposure, dehydroepiandrosterone sulfate (DHAS) levels, as an index of adrenal maturation, were constant or increased in an age-expected manner. The change in bone age for change in chronologic age decreased from 1.7 +/- 0.1 to 0.49 +/- 0.05 (P = 0.00005), indicating that the LHRHa-induced return to a prepubertal gonadal steroid environment was associated with a slowing of skeletal maturation. DHAS levels were correlated with the rate of skeletal advancement before (r = 0.57, P = 0.001) and during 12 to 48 mo of exposure to LHRHa (r = 0.52, P = 0.003). A negative correlation of DHAS values with subsequent increases in predicted mature height was observed (r = -0.49, P = 0.007). Thus, in children with central precocious puberty, adrenarche progressed normally during LHRHa suppression of gonadarche. In children with the onset of progression of adrenarche during maintenance of a prepubertal gonadal steroid milieu, there was less evidence than in preadrenarchal children of a restraint upon skeletal maturation. These data suggest that adrenal androgens contribute importantly to epiphyseal advancement during childhood.

Bromocriptine (1.25 mg BID) was administered orally to a 23 year old asymptomatic female with accelerated growth and a parasellar tumor (tissue type unknown). Other forms of therapy were refused. Length increased from 76 to 95 cm (22 cm/yr) and weight increased from 10 to 16.25 kg between ages 13 and 23 months. Bone age was 2 years at a chronological age of 18 months. Somatomedin C level was 4.3 U/ml (n=2: normal 0.8 to 2.2 U/ml). Thirteen growth hormone values during overnight monitoring averaged 4.7 ng/ml, range 1.8 to 7.9 ng/ml. Suppression to 5.0 ng/ml was seen during an OGTT. Other neuroendocrine functions were normal. No evidence of isosexual precocity was noted. Somatomedin C levels were 3.2, 2.6, 2.5, 2.4, and 2.2 U/ml on days 1 to 5 of therapy, 2.5 U/ml at 14 days and 2.7 U/ml at 56 days. Length increased from 95 to 97 cm (4.8 cm/yr) during the first 5 months of therapy. CT scan at 5 months shows no change in tumor size. The patient remains asymptomatic. The decrease in levels of somatomedin C associated with a reduction in the growth rate may have resulted from decreased GH production; however, other effects of bromocriptine, such as blocking the peripheral action of somatomedins may be involved.

Article Diazoxide Treatment of Neonatal and Infant Hypoglycemia: A Review and Reassessment was published on January 1, 1985 in the journal Journal of Pediatric Endocrinology and Metabolism (volume 1, issue 1).

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.

Bromocriptine (1.25 mg BID) was administered orally to a 23 year old asymptomatic female with accelerated growth and a parasellar tumor (tissue type unknown). Other forms of therapy were refused. Length increased from 76 to 95 cm (22 cm/yr) and weight increased from 10 to 16.25 kg between ages 13 and 23 months. Bone age was 2 years at a chronological age of 18 months. Somatomedin C level was 4.3 U/ml (n=2: normal 0.8 to 2.2 U/ml). Thirteen growth hormone values during overnight monitoring averaged 4.7 ng/ml, range 1.8 to 7.9 ng/ml. Suppression to 5.0 ng/ml was seen during an OGTT. Other neuroendocrine functions were normal. No evidence of isosexual precocity was noted. Somatomedin C levels were 3.2, 2.6, 2.5, 2.4, and 2.2 U/ml on days 1 to 5 of therapy, 2.5 U/ml at 14 days and 2.7 U/ml at 56 days. Length increased from 95 to 97 cm (4.8 cm/yr) during the first 5 months of therapy. CT scan at 5 months shows no change in tumor size. The patient remains asymptomatic.

Annals of the New York Academy of SciencesVolume 458, Issue 1 p. 28-35 Extended MHC Haplotypes in Salt-Losing 21-Hydroxylase Deficiencya CHESTER A. ALPER, CHESTER A. ALPER Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Children's Hospital, Boston, Massachusetts 02115Search for more papers by this authorELLEN FLEISCHNICK, ELLEN FLEISCHNICK Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Children's Hospital, Boston, Massachusetts 02115Search for more papers by this authorZUHEIR AWDEH, ZUHEIR AWDEH Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115Search for more papers by this authorDONALD RAUM, DONALD RAUM Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Beth Israel Hospital, Boston, Massachusetts 02115Search for more papers by this authorJOHN F. CRIGLER JR., JOHN F. CRIGLER JR. Center for Blood Research, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Children's Hospital, Boston, Massachusetts 02115Search for more papers by this authorPARK S. GERALD, PARK S. GERALD Center for Blood Research, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Children's Hospital, Boston, Massachusetts 02115Search for more papers by this authorEDMOND J. YUNIS, EDMOND J. YUNIS Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Dana-Farber Cancer Institute, Boston, Massachusetts 02115Search for more papers by this author CHESTER A. ALPER, CHESTER A. ALPER Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Children's Hospital, Boston, Massachusetts 02115Search for more papers by this authorELLEN FLEISCHNICK, ELLEN FLEISCHNICK Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Children's Hospital, Boston, Massachusetts 02115Search for more papers by this authorZUHEIR AWDEH, ZUHEIR AWDEH Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115Search for more papers by this authorDONALD RAUM, DONALD RAUM Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Beth Israel Hospital, Boston, Massachusetts 02115Search for more papers by this authorJOHN F. CRIGLER JR., JOHN F. CRIGLER JR. Center for Blood Research, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Children's Hospital, Boston, Massachusetts 02115Search for more papers by this authorPARK S. GERALD, PARK S. GERALD Center for Blood Research, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Children's Hospital, Boston, Massachusetts 02115Search for more papers by this authorEDMOND J. YUNIS, EDMOND J. YUNIS Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115 Center for Blood Research, Dana-Farber Cancer Institute, Boston, Massachusetts 02115Search for more papers by this author First published: November 1985 https://doi.org/10.1111/j.1749-6632.1985.tb14586.xCitations: 4 a These studies were supported by NIH grant nos. AM–26844, HL–29583, CA–19589, CA–20531, CA–06516, and HD–17461. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume458, Issue1Congenital Adrenal HyperplasiaNovember 1985Pages 28-35 RelatedInformation

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.