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Context: Adrenarche refers to the rise of dehydroepiandrosterone sulfate (DHEA-S) associated with the development of a functional adrenal zona reticularis. Clinical features of adrenarche include onset of body odor, axillary hair, and pubic hair, which reflect increased androgen action. An early rise in adrenal androgens, or premature adrenarche (PremA), is a risk factor for adverse metabolic profiles in adolescence and adulthood. The bioactive androgens associated with adrenarche and PremA remain poorly understood. The adrenal gland is a potential source of testosterone (T) and the 11-oxygenated derivatives 11β-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT)., Objective: The objective of this study was to characterize the adrenal androgen biome contributing to adrenarche and PremA., Participants and Methods: With the use of mass spectrometry, 19 steroids including the 11-oxygenated derivatives of T were measured in sera obtained from girls with PremA (n = 37; 4 to 7 years) and age-matched girls (n = 83; 4 to 10 years)., Results: In reference population girls, dehydroepiandrosterone, DHEA-S, androstenediol-3-sulfate, T, and 11KT all increased at the onset of adrenarche (6 to 8 years) and beyond (9 to 10 years) (P < 0.05 vs younger subjects 4 to 5 years). T, 11OHT, and 11KT were further elevated in PremA vs age-matched girls (P < 0.001). Circulating concentrations of 11KT during adrenarche and PremA exceeded those of T and 11OHT (11KT > T ≥ 11OHT). Androgen receptor activity and nuclear translocation studies demonstrated that 11KT is a potent androgen similar to T., Conclusions: Our findings suggest that 11KT is the dominant bioactive androgen in children during adrenarche and PremA. Its androgenic capacity suggests that it may be responsible for the phenotypic changes seen in these phenomena.

Context: Adrenal production of dehydroepiandrosterone sulfate (DHEA-S) increases throughout childhood owing to expansion of the zona reticularis (ZR). ZR features cells with a steroidogenic phenotype distinct from that of the adjacent zona fasciculata, with higher expression of cytochrome b 5 type A (CYB5A) and steroid sulfotransferase type 2A1 but decreased 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2). In addition to DHEA-S, three adrenal Δ5-steroid sulfates could provide additional tools to define adrenal maturation., Objective: This study sought to simultaneously measure serum levels of four adrenal Δ5-steroid sulfates, pregnenolone sulfate (Preg-S), 17α-hydroxypregnenolone sulfate (17OHPreg-S), DHEA-S, and 5-androstenediol-3-sulfate (Adiol-S) as a function of age and relate their production to the age-dependent adrenal localization of CYB5A., Participants and Methods: Δ5-steroid sulfates were quantified by liquid chromatography-tandem mass spectrometry in sera from 247 normal children (129 males,118 females) age 1.5-18 y and 42 adults (20 males, 22 females). Immunofluorescence localized HSD3B2 and CYB5A in normal adrenal glands from subjects age 2-35 y. Finally, HAC15 adrenocortical cells were transduced with lentiviral short hairpin RNA to suppress CYB5A expression., Results: Of the Δ5-steroid sulfates quantified, DHEA-S was most abundant. Adiol-S increased in parallel with DHEA-S. Steroid ratios (17OHPreg-S/DHEA-S) suggested increases in 17,20-lyase activity during childhood. Immunofluorescence analysis showed age-related increases in ZR CYB5A immunoreactivity. Furthermore, silencing CYB5A in HAC15 adrenocortical cells significantly reduced DHEA-S and Adiol-S production., Conclusion: Adiol-S shows a similar age-related increase to that of DHEA-S. This likely results from the childhood expansion of CYB5A-expressing ZR, which enhances 17,20-lyase activity and the production of DHEA-S and Adiol-S.

Context: Denosumab is a humanized monoclonal antibody to receptor activator of nuclear factor-κB ligand used primarily for postmenopausal osteoporosis and skeletal-related events from metastatic cancer. Its safety in children has not been established., Objective: The objective of the study was to investigate the effects of denosumab treatment on skeletal growth and histology., Design: This was an observational case report with radiological and histopathological analyses., Setting: The study was conducted at a clinical research center., Patients: A 9-year-old boy with fibrous dysplasia treated with a 7-month course of denosumab participated in the study., Intervention: Histological analyses were performed and compared on growth plates from limbs that had been amputated before and 17 months after denosumab treatment., Main Outcome Measures: Skeletal radiographs and bone histopathology from before and after treatment were measured., Results: After initiating denosumab, sclerotic metaphyseal bands appeared on radiographs. Posttreatment radiographs revealed migration of the bands away from the growth plates, consistent with continued linear growth. Histologically, the bands were composed of horizontally arranged trabeculae containing calcified cartilage. This cartilage appeared to derive from unresorbed primary spongiosa as a result of osteoclast inhibition by denosumab, similar to what has been observed with bisphosphonates. By 17 months after treatment, active bone resorption and formation had returned, as evidenced by the presence of active osteoclasts in resorption pits and osteoid surfaces., Conclusions: Further studies are needed to determine the safety of denosumab on the growing skeleton. However, in this child there was continued epiphyseal activity both during and after treatment and reversal of bone turnover suppression after treatment discontinuation, suggesting that denosumab did not have significant adverse effects on growth.

Fibrous dysplasia (FD) is a skeletal disease caused by somatic activating mutations of the cyclic adenosine monophosphate (cAMP)-regulating protein, α-subunit of the Gs stimulatory protein (G(s) α). These mutations lead to replacement of normal bone by proliferative osteogenic precursors, resulting in deformity, fracture, and pain. Medical treatment has been ineffective in altering the disease course. Receptor activator of NF-κB ligand (RANKL) is a cell-surface protein involved in many cellular processes, including osteoclastogenesis, and is reported to be overexpressed in FD-like bone cells. Denosumab is a humanized monoclonal antibody to RANKL approved for treatment of osteoporosis and prevention of skeletal-related events from bone metastases. We present the case of a 9-year-old boy with severe FD who was treated with denosumab for a rapidly expanding femoral lesion. Immunohistochemical staining on a pretreatment bone biopsy specimen revealed marked RANKL expression. He was started on monthly denosumab, with an initial starting dose of 1 mg/kg and planned 0.25 mg/kg dose escalations every 3 months. Over 7 months of treatment he showed marked reduction in pain, bone turnover markers (BTMs), and tumor growth rate. Denosumab did not appear to impair healing of a femoral fracture that occurred while on treatment. With initiation of treatment he developed hypophosphatemia and secondary hyperparathyroidism, necessitating supplementation with phosphorus, calcium, and calcitriol. BTMs showed rapid and sustained suppression. With discontinuation there was rapid and dramatic rebound of BTMs with cross-linked C-telopeptide (reflecting osteoclast activity) exceeding pretreatment levels, accompanied by severe hypercalcemia. In this child, denosumab lead to dramatic reduction of FD expansion and FD-related bone pain. Denosumab was associated with clinically significant disturbances of mineral metabolism both while on treatment and after discontinuation. Denosumab treatment of FD warrants further study to confirm efficacy and determine potential morbidity, as well as to determine the mechanism of RANKL in the pathogenesis of FD and related bone marrow stromal cell diseases., (Copyright © 2012 American Society for Bone and Mineral Research.)

Aim: The aim of this study was to determine and compare the effect of treatment with transdermal oestrogen and phytoestrogen on insulin sensitivity and sex hormone-binding globulin (SHBG) levels in healthy postmenopausal women., Methods: Forty-three healthy postmenopausal women aged 68 ± 7 (mean ± SD) years who were not receiving hormonal replacement therapy completed a 3 month randomized drug therapy study. The participants were randomized to one of four groups: 0.05 mg or 0.1 mg transdermal oestrogen/day, or 40 or 80 mg oral phytoestrogen (Promensil)/day insulin sensitivity was indirectly measured using the quantitative insulin sensitivity check index (QUICKI). SHBG, total testosterone, oestradiol, and fasting glucose and insulin levels for calculation of insulin sensitivity were obtained at baseline and at monthly intervals during the 3 months of therapy., Results: In healthy nondiabetic postmenopausal women, the rate of change in QUICKI was significantly different between the red clover based phytoestrogen and transdermal oestrogen groups, so that after three months of therapy, QUICKI with red clover based phytoestrogen therapy was lower than that in the transdermal oestrogen group, p = 0.01. Red clover based phytoestrogen therapy was not associated with any changes in SHBG levels whereas transdermal estrogen therapy significantly increased SHBG levels, p = 0.05., Conclusions: In contrast to transdermal oestrogen therapy, oral phytoestrogen therapy does not decrease androgenicity and is associated with a decrease in insulin sensitivity. These effects are similar to those of raloxifene and consistent with phytoestrogen's selective oestrogen receptor modulator properties., (Published 2011. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: To study the link between fatness and gonadotropin secretion. Overweight status is linked to polycystic ovary syndrome (PCOS) in adolescents. We postulated that heavier adolescents without symptoms would secrete LH with: [1] increased pulse frequency (LHPF) and [2] exaggerated integrated concentrations (LHAUC)., Design: Cross-sectional., Setting: General clinical research center., Patient(s): Eighty-seven postmenarcheal cyclic adolescents from lean to overweight recruited during the follicular phase., Intervention(s): Luteinizing hormone sampling: [1] every 10 minutes/24 hours; [2] at 20-minute intervals after a GnRH challenge., Main Outcome Measure(s): The LHPF and LHAUC (calculated by the CLUSTER algorithm). Hormonal and metabolic covariates included percent body fat (PercentBF), insulin-like growth factor-I (IGF-I), fasting insulin, and the insulin resistance index HOMA-IR. The SAS software was used for analyses., Result(s): The PercentBF and younger gynecological age predicted faster LHPF. Fatness was negatively linked to LHAUC, which was best predicted by PercentBF and IGF-1 in multivariate modeling (R(2) = 0.25). The PercentBF and insulin predicted a lower 20-minute LH response to GnRH., Conclusion(s): [1] Higher adiposity and younger gynecological age predict rapid LHPF. [2] The early years after menarche represent a vulnerable window for an exaggerated LHPF with weight gain. [3] In healthy adolescents, higher adiposity is linked to lower LHAUC, thereby preserving pituitary stores., (Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Permanent neonatal diabetes mellitus is a rare disorder known to be caused by activating mutations in KCNJ11 or ABCC8, inactivating mutations in INS, or very rarely in GCK or insulin promotor factor-1 (IPF-1) genes. We report a patient with permanent neonatal diabetes mellitus and severe exocrine pancreatic insufficiency. Ultrasound examination revealed pancreatic agenesis with a suggestion of a small amount of tissue in the head of the pancreas. Genetic testing revealed that the neonate had a homozygous Pro63fsX60 IPF-1 mutation. This is the second reported case of neonatal diabetes mellitus secondary to a homozygous mutation in the IPF-1 gene and supports the previously proposed biological role of IPF-1 in the pancreatic development in human.

Study Objective: Oligomenorrhea in active adolescent females of normal weight is presumed to be related to hypoestrogenism secondary to physical activity and decreased fat mass. We hypothesized that active adolescents with oligomenorrhea would have lower estrogen levels than normal controls with similar levels of cardiovascular fitness., Design/participants: Twenty healthy participants between the ages of 16 and 20 years were recruited at least 2 years postmenarche. Adolescents reporting fewer than 9 cycles a year (n = 6) were compared to 14 controls with monthly menstrual cycles. Histories of eating disorder, hirsutism, severe acne, depression, or amenorrhea were cause for exclusion., Main Outcome Measures: Body composition and bone density were measured by total body dual x-ray absorpitometry. Cardiovascular fitness was evaluated by measuring oxygen consumption during exercise. Control subjects were matched by age, body mass index (BMI), and fitness level. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, progesterone, and estradiol were obtained. Statistical analysis was performed using SAS 9.1., Results: Cardiovascular fitness in both groups was within normal limits for age. No significant differences in BMI, estradiol concentrations, or bone density were found, but trunk fat mass was lower in adolescents with oligomenorrhea who also reported more frequent exercise. Testosterone concentrations and LH/FSH ratios were significantly higher in participants with irregular menstrual cycles (P = 0.0018 and <0.001, respectively)., Conclusion: Adolescents with oligomenorrhea were leaner, yet they had higher testosterone levels and a greater LH/FSH ratio than their BMI-matched, cyclic counterparts. We hypothesize that, in active adolescents of normal weight, elevated androgen and LH concentrations are linked to ovarian dysfunction, which can masquerade as exercise-induced oligomenorrhea.

Ghrelin stimulates both appetite and secretion of growth hormone (GH). We hypothesized that fasting should increase ghrelin, thereby increasing GH concentrations in obesity. Eight obese girls underwent a 48-h fast, receiving 25% of calories for ideal body weight. Blood was obtained every 15 min for the last 24 h of the fast. Four months later, six obese girls had blood obtained in the fed state. Two additional obese and five lean girls had blood obtained in the fed state. Ghrelin was determined in 3-h pools. Mean ghrelin concentrations were 0.41 +/- 0.03 ng/mL for lean girls and 0.16 +/- 0.01 ng/mL in obese fed girls (p < 0.0001). Lean fed girls had diurnal variation of ghrelin whereas obese fed girls did not. Fasting neither increased ghrelin (0.18 +/- 0.01 ng/mL) nor restored diurnal variation. Ghrelin concentrations were related to the body mass index (BMI) SD score (SDS) (r = 0.45, p = 0.005). For the six obese girls who participated in both fasting and fed studies, change in mean ghrelin concentration between studies was related to change in BMI SDS but not fed or fasting state. Ghrelin concentrations are, thus, a function of BMI rather than feeding status in obese girls.

Objective: We sought to determine whether, in a specialty referral clinic, parental perceptions of their child's obesity were commensurate with the child's body mass index z score. Secondarily, we examined the impact of birth weight and parental body mass index on their child's body mass index z score and review results of an intake questionnaire., Design: Cross-sectional study, Setting: University of Michigan from March 21, 2003 through June 30, 2004, Participants: Eighty-two children ages 1-20.2 years of age, Intervention: Body mass index z score for all participants was calculated. An intake questionnaire was completed by caregivers in which they were asked to describe their child as little overweight, overweight, very overweight or obese., Outcome Measures: Mean body mass index z score was compared to each parental descriptor. Regression analysis related body mass index z score to birthweight and parental body mass index., Results: Body mass index z score was not related to parental descriptors. Maternal body mass index and child birthweight were predictors of the child's body mass index z score (r2=0.15, p<0.05; and r2=0.11, p<0.05, respectively). Both together produced a better model than either alone (r2=0.23, p<0.05). There was no relationship between paternal and child body mass index z score (p>0.05)., Conclusions: There is a divergence between the parental perception of childhood obesity and the clinical definition that persists even in the context of an explicit referral. Given the significant impact of maternal weight on childhood overweight, education for prevention of overweight youth should encompass prenatal, early childhood and adolescent health maintenance.

Context: Ghrelin is related to energy balance that regulates food intake., Objective: The aim was to explore whether ghrelin would be linked to differences in fitness in adolescent girls, whose menstrual cycles are sensitive to changes in energy balance., Methods: A total of 72 girls, ages 14-21 yr, including five with amenorrhea, were studied in the follicular phase. LH was sampled every 10 min over 24-h, and ghrelin was measured hourly between 2300 and 0300 h. Body composition was measured by dual x-ray absorptiometry. Fitness was characterized by reported frequency of exercise per week and by maximal oxygen consumption with "high" vs. "low" fitness groups defined from maximal oxygen consumption norms for this population. Data were analyzed with SAS software (SAS Institute Inc., Cary, NC)., Results: Ghrelin was related to percent body fat (P = 0.038; R(2) 0.07), weekly exercise (P = 0.032; R(2) 0.07), and 24-h mean LH (P = 0.002; R(2) 0.13). The ghrelin relationship with LH was more pronounced in the low-fitness group. In multiple regression models, 24-h LH was an independent predictor of ghrelin after adjusting for percent body fat, fitness, exercise, or age. Ghrelin was higher in Caucasian girls than in African-American girls after adjusting for covariates at 0200 h (P = 0.017)., Conclusions: Twenty-four-hour LH is an independent predictor of nighttime ghrelin concentrations in postpubertal adolescent girls. Diverging patterns in ghrelin may reflect differences in exercise patterns and/or may be influenced by ethnicity. These data introduce ghrelin as a biomarker of individual differences in energy balance during the menstrual cycle and across ethnicities.

Background: Our aim was to describe the incidence of quality assurance events between overweight/obese and normal weight children., Methods: This is a retrospective review of the quality assurance database of the Mott Children's Hospital, University of Michigan for the period January 2000 to December 2004. Using directly measured height and weight, we computed the body mass index (BMI) in 6094 children. Overweight and obesity were defined using age and gender-specific cut off according to the National Center for Health Statistics (NCHS)/Centers for Disease Control and Prevention (CDC) (2000) growth charts. Frequency of quality assurance events were compared between normal weight, overweight, and obese children., Results: There were 3359 males (55.1%) and 2735 females (44.9%). The mean age for the entire population was 11.9 +/- 5.2 while the mean BMI was 21.6 +/- 6.7 kg x m(-2). The overall prevalence of overweight and obesity was 31.6%. Obesity was more prevalent in boys than girls (P = 0.016). Preoperative diagnoses of hypertension, type II diabetes, and bronchial asthma were more common in overweight and obese than normal weight children (P = 0.0001 for hypertension, P = 0.001 for diabetes and P = 0.014 for bronchial asthma). Difficult airway, upper airway obstruction in the postanesthesia care unit (PACU) and PACU stay longer than 3 h and need for two or more antiemetics were more common in overweight and obese than normal weight children (P = 0.001). There was no significant difference in the incidence of unplanned hospital admission following an outpatient surgical procedure between normal weight and overweight/obese children., Discussion: Studies on perioperative aspects of childhood overweight and obesity are rare. Our report shows a high prevalence of overweight and obesity in this cohort of pediatric surgical patients. Certain perioperative morbidities are more common in overweight and obese than in normal weight children. There is a need for prospective studies of the impact of childhood overweight and obesity on anesthesia and surgical outcome.

Objective: To describe the prevalence of overweight and obesity in a pediatric surgical population from a large teaching hospital in the United States., Methods and Procedures: We carried out a retrospective review of the perioperative database for the period January 2000 to December 2004 at the University of Michigan. Using directly measured height and weight, we computed body mass index (BMI) on 6,017 children. Overweight and obesity were defined using age- and gender-specific cut-off according to the National Center for Health Statistics (NCHS)/Centers for Disease Control and Prevention (CDC) (2000) growth charts. We also examined the type of surgical procedures most commonly performed on overweight and obese children, and the distribution of overweight and obese patients by preoperative American Society of Anesthesiologist (ASA) classification., Results: We found a somewhat "heavy" pediatric population with a mean BMI of 21.6kg/m(2). The mean BMI in males was 21.7 kg/m(2) and 21.6 kg/m(2) in females. BMI showed a positive correlation with age overall (r=0.48, p < 0.01), and in both males and females. The overall prevalence of overweight and obesity using age-specific criteria was 14.4% and 17.2%, respectively. Approximately 10% of the children met adult criterion for obesity (BMI > or =30 kg/m(2)). Orthopedic and otolaryngological procedures were the most common surgeries in this cohort of overweight and obese children. We further found that 35.3% of obese and 20.6% of morbidly obese children were classified as ASA I., Conclusion: The prevalence of overweight and obesity is high in this pediatric surgical population. Follow-up studies examining the impact of overweight and obesity on perioperative outcome are needed.

Context: GH is strongly related to body composition, physical activity, and pubertal progression. Adolescent girls decrease physical activity during puberty, whereas their weight increases. Because leptin is a good index of energy balance in active young women, we hypothesized that leptin is related to GH secretion in this population while taking into account fitness, fatness, and age at menarche., Methods: We measured body composition and maximal oxygen consumption (VO(2)max) in 37 postpubertal adolescent girls aged 16-21 yr. GH was sampled every 10 min and leptin hourly for 24 h. We first analyzed 6-h time blocks by repeated measures for GH and leptin, with body mass index (BMI), percent body fat, and VO(2)max as covariates for the entire group and a lean subgroup. The deconvolution method was used to characterize GH pulsatility from individual time points., Results: GH varied through the day (P < 0.0001), with the highest concentrations overnight. BMI, percent body fat, and VO(2)max were related to GH concentrations in the entire group, whereas leptin predicted GH in the entire group as well as the lean subgroup of girls. Higher leptin was related to lower GH concentrations (P = 0.011), regardless of time. A log leptin level increase by 1 unit decreased GH by 27%. Pulsatility characteristics showed a 1-yr increase of age at menarche increasing total GH input by 20% (P = 0.0035) independently from BMI., Conclusion: In postpubertal adolescent girls, leptin is related to GH concentration across the lean to overweight BMI spectrum. GH pulsatile secretion was greater in girls with later age at menarche.

Objective: Major depression is associated to altered hypothalamic-pituitary function. Stress is linked to elevated cortisol as well as menstrual cycle disturbance; however, there is no known relationship between depression and menstrual cycle disruption. The aim of this study was to investigate changes of growth hormone (GH) secretion during the menstrual cycle in normal and depressed women., Design: Case-control study., Patients and Methods: Nineteen women affected with depression and 24 normal controls were included. The two groups had comparable body mass index (BMI), and age (29.4 +/- 9.8 vs. 28.6 +/- 9.7 years). Nine depressed and 10 controls were studied in the follicular phase, while 10 depressed and 14 controls were studied in the luteal phase of the cycle. GH was sampled every 10 min for 24 h, and the data were analysed by the cluster pulse detection method., Results: There was no difference in 24-h mean GH concentrations between depressed and control subjects (P = 0.93), even after accounting for menstrual cycle phase (P = 0.38). GH pulse frequency was higher during the follicular phase of the cycle (P = 0.032), and nocturnal GH was higher in the follicular phase of the cycle (P = 0.05, and after adjusting for 24-h GH, P = 0.0138) regardless of whether the subjects were depressed or healthy., Conclusions: In studies of GH secretion in women with or without depression, it is necessary to control for the phase of menstrual cycle.

In obese adolescents, body mass index (BMI) is a poor predictor of insulin resistance, and the potential role of diminished physical activity has not been quantitated. We measured possible determinants of sensitivity to insulin in 53 adolescent females with a BMI between the 10th and the 95th percentile. We hypothesized that across weight and fitness spectra, relative fat mass, rather than BMI, and cardiovascular fitness would be predictors of insulin resistance. We measured body composition by total-body dual x-ray absorptiometry. Self-reported weekly frequency of aerobic exercise for 1 h (RDE) was recorded, and maximal oxygen consumption (VO(2)max) was measured. Insulin sensitivity was estimated by homeostasis model assessment index (HOMA(IR)) derived from fasting glucose and insulin concentrations. BMI was not related to HOMA(IR) (P = 0.20), RDE showed a marginal relationship (P = 0.049), whereas percent body fat and VO(2)max were significantly related to HOMA(IR) (P = 0.01 and 0.0008, respectively). In a multiple regression model, VO(2)max was a more critical determinant of insulin resistance than percent body fat (P = 0.03 vs. P = 0.67) or RDE (P = 0.01 vs. 0.51). For prevention strategies in youth, physical inactivity may represent a greater metabolic risk than obesity alone.

Objective: To relate endocrine and nutritional correlates of fitness in postpubertal physically active females across the normal weight spectrum to identify markers and how these might serve as associations of exercise-related endocrine disruption., Design: Cross-sectional study analyzed by repeated-measures analysis of variance for frequent blood sampling., Setting: A general clinical research center., Subjects: Twenty-two healthy postpubertal female subjects recruited 2 years or more after menarche., Main Outcome Measures: Maximum oxygen consumption was determined as an index of fitness and daily caloric intake was calculated from a 3-day food diary. During the follicular phase of the cycle, luteinizing hormone was sampled every 10 minutes during a 24-hour period, while follicle-stimulating hormone and cortisol were sampled hourly., Results: For every 1-unit increase in maximum oxygen consumption, cortisol concentration increased by 2% (P =.005; 95% confidence interval, 1%-3%). However, there was no association between mean gonadotropin concentrations and fitness. Hormone concentrations were not significantly associated with body mass index or percentage of body fat. Higher mean caloric intake from a 3-day summary was inversely related to mean luteinizing hormone concentration, which decreased by 5.5% for every 100-kcal increase (P =.03; 95% confidence interval, 1%-10%). With every 1-year increase in age at menarche, follicle-stimulating hormone concentration decreased by 12% (P =.01; 95% confidence interval, 4%-19%) and cortisol concentration increased by 7% (P =.03; 95% confidence interval, 1%-12%)., Conclusions: In active adolescents, increased cortisol concentration may represent an adaptive change to exercise that may precede gonadotropin changes seen with higher levels of fitness.

An increase in androgenicity may contribute to the development of insulin resistance in postmenopausal women. Increased androgenicity in women has been found to be associated with the development of type 2 diabetes. In addition, obesity and central obesity are associated with greater androgenicity. Insulin sensitivity, androgenicity, and body composition were characterized in 34 nondiabetic postmenopausal women age 72 +/- 1 years (mean +/- SEM) to test the hypothesis that androgenicity is a predictor of insulin sensitivity independent of measures of obesity. Androgenicity was measured using levels of sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and free androgen index (FAI). Insulin sensitivity (S(I)) was determined from a frequently sampled intravenous glucose tolerance test. Body composition measures included body mass index (BMI) and dual energy x-ray absorptiometry measurements of total and central fat mass. S(I) was found to be associated with total fat mass (r = -.51, P =.002), central fat mass (r = -.62, P =.0001), BMI (r = -.55, P =.0008), SHBG levels (r =.65, P =.0001), and FAI (r = -.41, P =.01). SHBG levels were inversely correlated with central fat mass (r = -.59, P =.0002). Using multiple regression, SHBG and central fat mass were the only significant independent predictors of S(I), accounting for 50% of its variance (r =.71, P =.0001); total fat mass, BMI, total and free testosterone, DHEA-S, androstenedione, and FAI did not enter the model. We conclude that there is a significant association between insulin sensitivity and androgenicity in postmenopausal women that is independent of obesity. Interventions to decrease androgenicity may therefore be useful in improving insulin sensitivity in postmenopausal women.

Objectives: To test the hypothesis that both raloxifene and estrogen would improve insulin sensitivity in postmenopausal women and that the magnitude of the effect would be similar for both drugs., Design: Placebo-controlled, double-blind, randomized study., Setting: The General Clinical Research Center of the University of Michigan Medical Center, a university hospital., Participants: Forty-four healthy postmenopausal women 73 +/- 7 years old (mean age +/- standard deviation) who were not receiving hormone replacement therapy., Intervention: Eight weeks of drug therapy with randomization to raloxifene (n = 16), estrogen (n = 14), or placebo (n = 14)., Measurements: These subjects underwent a frequently sampled intravenous glucose tolerance test to determine insulin sensitivity (SI) and total and regional (central) body composition measurements by dual-energy x-ray absorptiometry at baseline and after 8 weeks of drug therapy., Results: There were no statistically significant differences in age, body mass index, total or central fat mass, or SI between the three groups at baseline. The major outcome variable was SI. After 8 weeks of drug therapy, there was no significant change in SI in the placebo group or in the estrogen group and a significant decrease in SI in the raloxifene group, P =.003., Conclusion: In contrast to estrogen's ability to maintain insulin sensitivity, raloxifene decreases insulin sensitivity in healthy nondiabetic postmenopausal women. The clinical significance of this effect of raloxifene to impair insulin sensitivity in postmenopausal women warrants further evaluation in future studies.

We studied nutrition and GH in eight obese girls, aged 6-11 yr. Blood was sampled every 15 min for 24 h. A 48-h diet providing 25% of assumed caloric needs was imposed, with repeat sampling during the last 24 h. Six nonfasting lean girls were also studied, and their mean GH was 3 times that of the obese girls in the fed state (P = 0.024). Dieting increased mean GH by 60% (P = 0.0028). There was no difference in pulse number for either group, but total secretion for lean girls was 3.9 times greater than that in obese girls during the fed state. With dieting, obese girls increased their total GH secretion by 60% (P = 0.010), but maintained lower total secretion, approximately 40% that of lean girls (P = 0.014). Mean leptin in obese girls in the fed state was 6.2 times greater than mean leptin in lean girls (P = 0.0001), with higher concentrations at night (P < 0.05) and lowering of total mean leptin while dieting. We conclude that in early pubertal obese girls, short-term caloric restriction partially reverses the low GH state that is characteristic of obesity. The change is concomitant with a decrease in leptin and a lessening of circadian differences.

The enzyme 3beta-hydroxysteroid dehydrogenase (3beta-HSD) is a key enzyme in the biosynthesis of steroid hormones. To date, this laboratory has isolated and characterized five distinct 3beta-HSD complementary DNAs (cDNAs) in the mouse (3beta-HSD I through V). These different forms are expressed in a tissue- and developmentally-specific manner and fall into two functionally distinct enzymes. 3beta-HSD I and III, and most likely II, function as dehydrogenase/isomerases, whereas 3beta-HSD IV and V function as 3-ketosteroid reductases. This study describes the isolation, characterization, and tissue-specific expression of a sixth member of this gene family, 3beta-HSD VI. This new isoform functions as an NAD+-dependent dehydrogenase/isomerase exhibiting very low Michaelis-Menten constant (Km) values for pregnenolone (approximately 0.035 microM) and dehydroepiandrosterone (approximately 0.12 microM). 3beta-HSD VI is the earliest isoform to be expressed during embryogenesis in cells of embryonic origin at 7 and 9.5 days postcoitum (pc), and is the major isoform expressed in uterine tissue at the time of implantation (4.5 days pc) and continues to be expressed in uterine tissue at 6.5, 7.5, and 9.5 days pc. 3beta-HSD VI is expressed in giant trophoblasts at 9.5 days pc and is expressed in the placenta through day 15.5 pc. In the adult mouse, 3beta-HSD VI appears to be the only isoform expressed in the skin and also is expressed in the testis, but to a lesser extent than 3beta-HSD I. Mouse 3beta-HSD VI cDNA is orthologous to human 3beta-HSD I cDNA. Human type I 3beta-HSD has been shown to be the only isoform expressed in the placenta and skin. The demonstration that mouse 3beta-HSD VI functions as a dehydrogenase/isomerase and is the predominant isoform expressed during the first half of pregnancy in uterine tissue and in embryonic cells suggests that this isoform may be involved in local production of progesterone, which is needed for successful implantation of the blastocyst and/or maintenance of early pregnancy.

To investigate whether pituitary-dependent hormones may regulate galanin (GAL) content, synthesis and distribution in the hypothalamus, female hypophysectomized Wistar rats were treated for 2 weeks with subcutaneous injections of thyroxine (T4, 2 x 1 microgram), bovine growth hormone (GH, 2 x 125 micrograms), cortisol (C, 50 micrograms), subcutaneous implants of beta-estradiol (E2, 5-mm implant, dilution 1:1), or with the combinations [T4+GH], [T4+GH+C+E2] or [T4+GH+C+E2 + rat PRL, 2 x 125 micrograms] (doses/100 g BW/day). Concentrations of GAL in the hypothalamus were measured by radioimmunoassay (RIA) and GAL mRNA abundance was quantified by Northern blot (6 rats/group); 2 rats/group were used for immunohistochemistry. Hypophysectomy caused decreases of hypothalamic GAL peptide and mRNA concentrations (by 70 and 50%, respectively; p < 0.05 vs. intact rats). GAL immunoreactivity disappeared in the median eminence (ME), but increased in the neurohypophyseal magnocellular neurons of hypophysectomized rats. Substitution with T4, GH, [T4+GH], C or E2 had no significant effect on total hypothalamic GAL peptide and GAL mRNA concentrations. A treatment combining [T4+GH+C+E2] increased hypothalamic GAL (1.9 +/- 0.1 vs. 1.2 +/- 0.1 ng/mg protein in untreated hypophysectomized rats; p < 0.01) and GAL mRNA concentrations (127 +/- 19 vs. 59 +/- 2 densitometric units in untreated rats, p < 0.001). Addition of PRL to this combined treatment had no further effect. Treatment with T4, GH, [T4+GH] or E2 enhanced GAL labeling in the ME of hypophysectomized rats. The effect of estrogens was restricted to the GnRH-rich lateral regions of the ME. The combined treatment with [T4+GH+C+E2] restored the ME GAL immunoreactivity to levels observed in intact rats. In contrast, the increased GAL labeling observed in magnocellular neurons after hypophysectomy was not influenced by any hormonal treatment. In conclusion, hypophysectomy leads to marked reductions of hypothalamic GAL and GAL mRNA concentrations, and of GAL immunoreactivity in the ME. These reductions are prevented in part by a combined hormonal treatment associating T4, GH, C and E2, but not by any hormone given alone. This suggests specific pituitary hormone-dependent regulation of the hypophysiotropic GAL neurons. In contrast, the increased GAL labeling in magnocellular neurons of hypophysectomized rats persists despite hormonal treatment and likely represents a lesional effect on the neurohypophyseal GAL system.

FSH plays an essential role in folliculogenesis and ovarian growth. However, cross-sectional studies have not shown an increase in bioactive FSH (B-FSH) during puberty. To eliminate intersubject variability, we used a longitudinal design and tested the hypothesis that B-FSH increases during puberty. Thirty normal, healthy girls were enrolled in a longitudinal study from pubertal stages I to IV. The subjects were evaluated at 6-mo intervals; each visit consisted of pubertal staging, bone age determination by x-ray, measurements of serum immunoreactive FSH (I-FSH) and B-FSH (n = 14) or immunoreactive LH (I-LH) and bioactive LH (B-LH) (n = 18), and adrenal and ovarian steroids. All girls had clinical and hormonal characteristics of puberty. Both I-FSH and B-FSH levels were relatively elevated before puberty, whereas serum I-LH and B-LH were low. From pubertal stages I to III, there was a modest yet significant rise in serum I-FSH (p < 0.001) and serum B-FSH (p < 0.01). Serum I-LH and B-LH concentrations showed the expected increases with puberty (p < 0.001), with serum B-LH concentrations exhibiting a greater rise than I-LH (p < 0.001). Our results demonstrate that serum B-FSH and I-FSH increase during puberty. Relatively elevated B-FSH concentrations from early to midpuberty may be an important factor for ovarian growth while circulating LH and estrogen are still low. As puberty progresses, the continued and selective increase in LH induces a rise in estradiol and ultimately leads to ovulation.

To understand better the relationship between hypothalamic galaninergic neurons and the pituitary gland, we studied the effects of hypophysectomy on hypothalamic galanin (GAL) content and distribution by radioimmunoassay and immunohistochemistry, and on GAL mRNA by Northern blot analysis. Three weeks after hypophysectomy, performed at 5 or 8 weeks of age, the hypothalamic concentrations of GAL and GAL mRNA were reduced by 30-50% in both male and female rats, compared to age- and sex-matched controls. Similar reverse-phase HPLC retention times of hypothalamic GAL were observed in intact and hypophysectomized rats. The reduction of hypothalamic GAL concentration following hypophysectomy was time-dependent, as peptide levels were unaffected one week after surgery. Immunohistochemistry showed regional differences in the effect of hypophysectomy on galaninergic neurons. In the hypophysiotropic hypothalamus, the scarce GAL immunoreactivity normally observed in the arcuate nuclei was no longer detectable in hypophysectomized rats, and the intense GAL immunoreactivity of the external zone of the median eminence progressively decreased and completely disappeared 3 and 6 weeks after hypophysectomy. In contrast, in the neurohypophyseal system, there was an increase of GAL labelling of the perikarya and emerging axons in the supraoptic and lateral-paraventricular nuclei, 1 and 3 weeks after hypophysectomy, that disappeared 6 weeks after hypophysectomy. An increase of GAL immunoreactivity was also observed in the internal zone of the median eminence 1 week but not 3 weeks after hypophysectomy. We conclude that hypophysectomy reduces the content of GAL and GAL mRNA in the rat hypothalamus. These changes are time-dependent and clearly detected after 3 weeks. The neurohypophyseal and hypophysiotropic galaninergic systems respond differently to hypophysectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Previous studies indicate an elevation of circulating progesterone blocks the positive feedback effect of a rise in circulating estradiol. This explains the absence of gonadotropin surges in the luteal phase of the menstrual or estrous cycle despite occasional rises in circulating estradiol to a concentration sufficient for surge induction. Recent studies demonstrate estradiol initiates the LH surge in sheep by inducing a large surge of GnRH secretion, measurable in the hypophyseal portal vasculature. We tested the hypothesis that progesterone blocks the estradiol-induced surge of LH and FSH in sheep by preventing this GnRH surge. Adult Suffolk ewes were ovariectomized, treated with Silastic implants to produce and maintain midluteal phase concentrations of circulating estradiol and progesterone, and an apparatus was surgically installed for sampling of pituitary portal blood. One week later the ewes were allocated to two groups: a surge-induction group (n = 5) in which the progesterone implants were removed to simulate luteolysis, and a surge-block group (n = 5) subjected to a sham implant removal such that the elevation in progesterone was maintained. Sixteen hours after progesterone-implant removal (or sham removal), all animals were treated with additional estradiol implants to produce a rise in circulating estradiol as seen in the follicular phase of the estrous cycle. Hourly samples of pituitary portal and jugular blood were obtained for 24 h, spanning the time of the expected hormone surges, after which an iv bolus of GnRH was injected to test for pituitary responsiveness to the releasing hormone. All animals in the surge-induction group exhibited vigorous surges of GnRH, LH, and FSH, but failed to show a rise in gonadotropin secretion in response to the GnRH challenge given within hours of termination of the gonadotropin surges. The surges of GnRH, LH, and FSH were blocked in all animals in which elevated levels of progesterone were maintained. These animals in the surge-block group, however, did secrete LH in response to the GnRH challenge. We conclude progesterone blocks the estradiol-induced gonadotropin discharge in the ewe by acting centrally to inhibit the surge of GnRH secreted into the hypophyseal portal vasculature.