Search PubMed⌕ Search

Biomedical subjects

A D Rogol

Publications and source records attributed to A D Rogol.

At least 55 records · Page 3Linked to original sources
PubMed1997

A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty.

Leptin, the product of the ob gene, is an adipocyte-derived hormone that signals the amount of adipose tissue energy stores to the brain and exerts major effects on energy homeostasis and neuroendocrine function. Leptin has recently been shown to affect reproductive function in leptin-deficient and normal rodents. As puberty, the process of sexual maturation and acquisition of reproductive competence, has been proposed to be triggered by the attainment of a critical amount and/or distribution of fat, we examined whether changes in circulating leptin levels could represent the hormonal signal responsible for triggering the onset of puberty in humans. Eight prepubertal boys (Tanner genital stage 1 or early stage 2 at the initiation of the study) were evaluated longitudinally for 2.5-5.1 yr depending on when Tanner stage 5 of genital development was achieved. Sera for the determination of leptin, testosterone, and dehydroepiandrosterone sulfate were obtained every 4 months during the period of the study. Compared to baseline prepubertal levels (8 months before the onset of puberty, as defined by the initial rise in testosterone above the detection limit of the assay), leptin levels rose by approximately 50% just before the onset of puberty and decreased to approximately baseline values after the initiation of puberty (P < 0.01, by ANOVA), remaining stable for more than 2 yr. These changes occurred despite constantly increasing body mass index (P < 0.05, by ANOVA). No significant association between leptin and dehydroepiandrosterone sulfate concentrations was detected. In conclusion, the levels of circulating leptin are consistent with the hypothesis that this molecule is an important signal responsible for triggering the onset of puberty. The stimulus for a surge in leptin levels just before the onset of puberty is currently unknown.

Body Mass Index↗
PubMed1997

Comparison of pulsatile luteinizing hormone secretion between prepubertal children and young adults: evidence for a mass/amplitude-dependent difference without gender or day/night contrasts.

The assessment of pulsatile GnRH activity in children has become possible since the introduction of the sensitive third generation immunochemiluminescent assays, permitting detection of previously unmeasurable levels of LH and FSH. Despite this, however, studies differ with regard to pulse frequency and the presence of a diurnal variation in LH secretion in clinically prepubertal children. Discrepancies may reflect the limitations of relatively long intersampling intervals, less sensitive LH assays such as RIAs, and the use of algorithms to analyze pulsatile LH secretion, which do not account for endogenous production rates and metabolic clearance. To address this, we studied LH secretion in 10 prepubertal children (4 boys and 6 girls, age 8.5-10.8 y) and 12 young adults (7 men and 5 women in the early follicular phase, age 18.6-32.8 y). Blood was sampled every 5 min from 2000 h to 0200 h (nighttime) and from 0800 h to 1400 h (daytime) for LH determination, using an immunochemiluminescent assay. Deconvolution analysis revealed no difference between daytime and nighttime LH secretion, including LH secretory amplitude and pulse frequency, within any of the 4 groups, permitting pooling of the data from the 2 sampling intervals for analysis. In addition, there was no difference in LH secretion or half-life between genders. Comparison of pulsatile LH secretion between children and adults revealed a marked increase in the mass and amplitude of LH secreted per burst. LH secretory burst mass rose 9.5-fold in females, increasing the mean LH concentration by nearly 13-fold and the production rate by nearly 9-fold. The trend in males was similar although less remarkable, with a 4.2-fold rise in LH secretory burst mass from childhood to adulthood. No differences in pulse frequency, interburst interval, half-life, or approximate entropy were found between prepubertal children and adults. We conclude that the maturational change in LH secretion occurs via a highly specific mass/amplitude-dependent mechanism without significant gender or day/night differences.

Adolescent↗
PubMed1996

National Cooperative Growth Study substudy. II: Do growth hormone levels from serial sampling add important diagnostic information?

The National Cooperative Growth Study includes growth data on more the 24,000 children in the United States and Canada who have been treated with growth hormone (GH). To determine whether dysregulation of GH release causes growth failure in children, we initiated the National Cooperative Growth Study substudy II to evaluate the diagnostic utility of serially sampled GH levels and to determine whether those patterns were responsible for the low growth rates in certain subsets of short children and whether children in any of the diagnostic categories would respond to GH therapy. A total of 3744 subjects whose mean height standardized for their chronological age was -2.8 SD and whose pretreatment growth rate was 4.2 cm/yr had complete 12-hour data sets-- serial samples obtained in a 12-hour overnight period. Pulsatile characteristics of GH release were assessed with the cluster algorithm. There was a virtually complete overlap of the GH pulsatile characteristics between control subjects and short children, but the insulin-like growth factor I (IGF-I) levels were markedly lower in the short children, suggesting impairment in the GH-IGF-I axis. THe growth response to administered GH showed only very weak correlations with the various cluster-derived parameters. Our results indicate that one must look beyond the release of GH to find an explanation for the short statures and low IGF-I levels in the subsets of children with idiopathic short stature.

Activity Cycles↗
PubMed1996

Growth hormones and sex steroid interactions at puberty.

Puberty is a period of dynamic changes mediated by GH and the gonadal steroid hormones. Although these substances exert important independent effects, their interaction is vital to normal pubertal growth and development. This is supported by observations of blunted growth and diminished levels of GH and IGF-1 during adolescence in individuals with panhypopituitarism in whom adequate replacement with both hormones had not been achieved. The independent roles of androgens and estrogens in mediating the rise in GH secretion at puberty have been studied in individuals with complete androgen insensitivity and through the administration of nonaromatizable androgens and the use of selective androgen- or estrogen-receptor blockade. The preponderance of evidence from studies of nonaromatizable (pure) androgens suggests that GH secretion is not enhanced as it is under the influence of testosterone. In addition, studies have shown increased GH secretion following androgen-receptor blockade and diminished GH release after estrogen-receptor blockade. Together these studies suggest a facilitory role of estrogen receptor-mediated processes on GH secretion and IGF-1 production. If androgens influence the GH/IGF-1 axis, it is most likely by an inhibitory mechanism. Observations of delayed skeletal maturation and deficient bone mineralization in individuals with estrogen receptor defects or mutations of the aromatase gene demonstrate the essential role of estrogen in promoting normal bone maturation, the accrual and maintenance of BMD, and control of the rate of bone turnover.

Adolescent↗
PubMed1996

Apparent growth hormone deficiency in children with cerebral palsy.

Ten children with cerebral palsy (CP) and growth failure underwent assessment of the growth hormone (GH) axis, including spontaneous GH secretion, GH secretion in response to pharmacological stimulation, and circulating levels of insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3). Six of the children had subnormal GH secretion consistent with GH deficiency. Subnormal growth velocity was the best clinical predictor of GH deficiency. The large percentage of these children with apparent GH deficiency is surprising. Possible mechanisms include anatomic abnormalities of the hypothalamic-pituitary axis, psychosocial deprivation, and an interaction between suboptimal nutritional status and an abnormal central nervous system.

Adolescent↗
PubMed1996

Sex steroids, growth hormone, insulin-like growth factor-1: neuroendocrine and metabolic regulation in puberty.

UNLABELLED: The control of the onset of puberty involves the complex interaction of pituitary and gonadal hormones. At a preprogrammed time in a child's life there is an increase in the amplitude of GnRH pulses which triggers a cascade of events including increases in the amplitude of FSH and LH pulses, followed by marked increases in gonadal sex steroidal output, which in turn increases growth hormone (GH) and insulin-like growth factor-1 (IGF-1) production. Evidence suggests that there is an integral interaction between the endogenous opiate system and the hypothalamic-pituitary-gonadal axis, at least in the later stages of puberty in the male. Both androgenic and estrogenic hormones markedly increase GH production rates as measured by deconvolution models in the prepubertal human, and compelling data strongly suggest that it is indeed the estrogen which controls the feedback amplification of GH production during puberty even in the male. It appears that the prepubertal gonad is actively producing sex hormones which might be important in the control of GH production since early childhood. The translation of these neuroendocrine rhythms into distal metabolic actions is also reviewed. Utilizing isotopic tracer infusions of the essential amino acid leucine, studies clearly show a selective stimulation of whole body protein synthesis by both GH and IGF-1. GH, IGF-1 and androgenic hormones all increase in puberty, stimulating whole body protein anabolism during that period. However, we observed no protein-anabolic effect in the hypogonadal female given increasing doses of estrogen. The latter suggests that at least as it pertains to whole body protein effects, the action of androgens is probably mediated via the androgen and not the estrogen receptor, in clear distinction from the estrogen-mediated effects of androgens on the neuroendocrine axis. Calcium absorption and retention are also positively affected by the androgens as shown by significant increases in calcium absorption and retention after the administration of testosterone to the prepubertal male. This suggests an important role of sex steroidal hormones in the mineralization of the skeleton. IN CONCLUSION: GH, IGF-1 and sex steroids all markedly increase during puberty and their actions are amplified mutually as they control growth, increase muscle mass and affect the mineralization of the skeleton. The dichotomy of androgen and estrogen effects in the male and female may regulate the differential timing of the onset of puberty and final height in the two sexes. The synergistic actions of these anabolic hormones appear to be most significant during the finite years of puberty.

Adolescent↗
PubMed1996

A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. III. The neuroendocrine growth hormone axis during late prepuberty.

Cross-sectional studies demonstrating that physiological GH secretion varies widely among normally and slowly growing children as well as adults have created uncertainty over the definition of normal GH secretion. Furthermore, recent data indicate that the pattern of GH released under identical physiological conditions may be unique for each individual, and suggest that normality may be an individually defined condition. To investigate and develop further this concept and to avoid the confounding effects of fluctuating gonadal steroid hormone levels, we chose as a model normally growing prepubertal boys and performed a longitudinal assessment of spontaneous GH release characteristics (36 24-h GH secretion studies in 9 boys over 9-19 months). Assessment of serum GH pulse characteristics was accomplished using the Cluster pulse detection algorithm. Characteristics of underlying pituitary GH secretory events were estimated by multiple parameter deconvolution analysis. Approximate entropy was used to quantify the serial regularity or orderliness of GH release over 24 h. Among the group data, mean 24-h GH concentrations spanned a range of more than 4-fold (1.6-7.0 micrograms/L). The intersubject coefficient of variation (CV) was 41%. In contrast, values from individuals exhibited much less variability, not only for mean 24-h GH level (CV = 25 +/- 4%; P = < 0.02), but also for all assessed component GH pulse properties (P < 0.01) vs. intersubject values). Similarly, the estimated daily GH production rate, the calculated GH half-lives, and all parameters of GH secretory events varied much less for intraindividual compared to interindividual values. The sizes of the serum GH pulses gave rise to the greatest differences in overall serum GH level among individuals, as demonstrated by the large within-subject CV (50%). The most constant pulse characteristic among subjects was that of 24-h GH pulse frequency (intersubject CV = 30%). Approximate entropy estimates disclosed high within-subject consistency (mean CV = 15%). Several aspects of GH secretion and serum concentrations varied inversely with the subject's mean age-adjusted body mass index, including the 24-h GH production rate (r = -0.67; P < 0.05), the GH secretory burst amplitude (r = -0.73; P = 0.026), the mean serum GH pulse amplitude (r = -0.79; P = 0.011), and the sum of the GH pulse amplitudes (r = -0.66; P = 0.05). By contrast, no consistent pattern of increase or decrease in serum GH concentrations with advancing age was detectable during the prepubertal period. These data suggest that during prepuberty, 1) individual boys regulate daily GH secretion within relatively confined limits characteristic for that individual, much narrower than the range present in the larger population; 2) differences in mean 24-h GH levels among normally growing prepubertal boys arise primarily from differences in GH pulse size; 3) differences in body composition, as indicated by the body mass index, may influence the GH secretion range characteristic of each individual; and 4) there is no consistent change in mean 24-h GH concentrations or the orderliness (approximate entropy) of the GH release process ever time during late prepuberty as the onset of puberty approaches.

Adult↗
PubMed1996

A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. II. Estrogen levels as determined by an ultrasensitive bioassay.

A limited number of reports of estrogen levels in prepubertal and early pubertal boys have been published because previous estrogen assays have lacked adequate sensitivity to quantitate circulating estrogen concentrations. Development of a new ultrasensitive assay has permitted measurement of estrogen levels in 23 normally growing boys progressing through puberty. Concentrations were measured at approximately 4-month intervals over a 5- to 8-yr period. The levels increased with maturation in all and correlated directly with chronological age, bone age, weight, height, pubertal stage, and testosterone and insulin-like growth factor-I levels. Of these factors, the level of testosterone had the greatest influence on the estrogen concentration. The time from peak growth velocity also significantly correlated with estrogen level. The estrogen level correlated positively with growth velocity before the time of peak growth velocity and negatively after peak growth velocity. The estrogen levels first increased significantly an average of 3 yr after pubertal onset and reached a peak by 5 yr after pubertal onset. Peak growth velocity was attained an average of 3 yr after pubertal onset. The greatest increase in the rate of rise of the estrogen level was an 11-fold rise during the year in which puberty began. The next most significant increase was a 4.8-fold rise 3 yr after pubertal onset. With respect to pubertal stage, the greatest absolute change occurred from stage 4 to stage 5 and the greatest fold change occurred from stage 1 to stage 2. The estrogen level did not significantly correlate with the 24-h GH level. In conclusion, circulating estrogen levels are very low in all boys prepubertally and rise steadily during adolescent development. The estrogen level is closely related to testosterone concentration and to the time of peak growth velocity. These findings are consistent with the hypothesis that estrogen at low levels augments skeletal growth and maturation in boys (as well as girls). They are also consistent with the hypothesis that continued exposure to estrogen leads to epiphyseal fusion. Further studies are required to define the separate and combined roles of estrogen, GH, and testosterone, as well as other factors, on growth and sexual development at puberty.

Age Determination by Skeleton↗
PubMed1996

Mode of pulsatile follicle-stimulating hormone secretion in gonadal hormone-sufficient and -deficient women--a clinical research center study.

To test the hypothesis that FSH is secreted at least in part within discrete secretory bursts in women and that the characteristics of episodic FSH secretion are altered within differing gonadal hormone environments, we measured FSH by immunoradiometric assay every 10 min for 24 h in premenopausal women during the early follicular (EF), late follicular (LF), and midluteal (ML) phases of the menstrual cycle and in postmenopausal (PM) women (n = 8 in each group). Secretory events were evaluated using multiparameter deconvolution. FSH was secreted in an episodic manner, with the number of secretory bursts (per 24 h; mean +/- SEM) detected in LF (20 +/- 0.79) and PM (20 +/- 0.90) women being greater than that in EF (16 +/- 0.88) and ML (14 +/- 0.93) women. FSH secretory burst mass (milliinternational units per mL) was significantly higher in PM (12 +/- 1.6) than in EF (1.8 +/- 0.21), LF (3.1 +/- 1.3), or ML (0.8 +/- 0.11) women and primarily reflected a relative increase in the maximal secretory rate rather than increased burst half-duration. The estimated half-life (minutes) of endogenous FSH in LF women (155 +/- 18) was shorter than those calculated in EF (251 +/- 24), ML (277 +/- 38), and PM (231 +/- 18) women. Cross-correlation analysis showed strongly positive associations between successively paired serum FSH and LH concentrations in all four groups of women. Deconvolution of simultaneously obtained LH concentration-time series revealed statistically significant concordance (13-25%) between FSH and LH secretory episodes at a lag time of 0 min in EF, LF, and PM women and when LH secretory bursts led FSH secretory bursts by 10 min in ML phase women. However, as 75-87% of FSH and LH secretory pulses were discordant, we infer the operation of distinct control mechanisms in the generation of FSH and LH release episodes. In summary, these results suggest that FSH is secreted within discrete secretory bursts in women, that the mass and frequency of FSH secretory bursts differ in women exhibiting various gonadal hormone environments, and that FSH and LH secretory bursts occur coincidentally at a higher rate than expected on the basis of chance alone, but at such a low overall rate of concordance that distinct mechanisms probably operate to direct episodic FSH and LH secretory activity.

Adult↗
PubMed1996

Management of puberty in growth hormone deficient children.

At puberty there occur marked increases in gonadotropin, gonadal steroid and GH secretion. An important physiological synergism exists between the gonadal and somatotropic axes to permit the growth spurt and adolescent development; however, epiphyseal maturation is also accelerated leading to cessation of long-bone growth. GH deficiency may be absolute, but often is not and the diagnosis may be complicated by a constellation of physical and hormonal findings that are along a spectrum from low normal GH sufficiency to absent GH secretion. Growth hormone therapy not only accelerates the growth velocity, but also promotes the redistribution of adipose tissue stores to more peripheral sites. Given the remarkable physiological alterations in the activities of the GH and gonadotropin gonadal axes during adolescence in normal children, how should the therapeutic plan for the treatment of prepubertal GH deficiency be altered at puberty? Evidence for efficacy has been reported for each of the following for the treatment of GH deficiency at adolescence: 1) GH alone at the usual dosage (approximately 0.3 mg.kg-1.day-1); 2) Double or triple the amount of GH to mimic the finding of increased GH release at puberty. 3) GH at the usual or moderately increased dose and gonadotropin releasing hormone agonist analog to halt pubertal development. The latter two plans are at present hypotheses that must withstand the rigor of proper controlled trials. The end point is more than merely adult height, because of the significant psychological and skeletal system dysregulation that accompany decrements in the gonadal steroid hormones during adolescence.

Adolescent↗
PubMed1995

Absent pituitary gland in two brothers with an oral-facial-digital syndrome resembling OFDS II and VI: a new type of OFDS?

The oral-facial-digital syndromes (OFDS) comprise a group of heterogeneous genetic disorders. Considerable clinical overlap exists within the nine described types [Toriello, Clin Dysmorph 2:95-105, 1993], and with other entities such as Pallister-Hall (PH) syndrome and hydrolethalus syndrome, leading to difficulties in the classification of OFDS. We report on two brothers with findings overlapping OFDS II, VI, and Pallister-Hall syndrome who had congenital absence of the pituitary gland. This may represent a new type of OFDS or, alternatively, an example of phenotypic variability within the OFDS. It also emphasizes that agenesis of the pituitary gland can occur in a variety of syndromes with midline defects.

Face↗
PubMed1995

Physiology of growth and development. Its relationship to performance in the young athlete.

Proper grouping of children for sports is important for injury prevention and for fair competition. We have reviewed several of the classification systems presently used as well as the physiologic underpinnings of pubertal growth and development and the accrual of strength and power. It is during adolescence that the greatest physiologic differences exist mainly because of the wide variations in the timing and tempo of the pubertal growth spurt in normally growing boys and girls. Maturity-based categorization, especially in contact and collision sports, would heighten the competition and lessen rates of injury.

Adolescent↗
PubMed1994

Androgen-receptor blockade enhances pulsatile luteinizing hormone production in late pubertal males: evidence for a hypothalamic site of physiologic androgen feedback action.

To determine potential mechanisms by which androgens alter gonadotropin secretion and elimination in the pubertal male, we administered the potent nonsteroidal androgen receptor blocking agent, flutamide, to eight males with Tanner IV or V genital development. Venous blood samples were obtained every 10 min for 24 h and assayed for LH by a sensitive and high-precision fluorimmunoassay. Subjects were studied before and after the administration of flutamide. Deconvolution analysis was used to assess specific pulsatile LH secretory characteristics and estimate LH production and metabolic clearance rates quantitatively. After antagonism of endogenous androgen action, mean 24-h serum LH concentrations increased significantly. An increased mean 24-h LH production rate, without evident changes in serum LH half-life, accounted for the increase in average serum LH levels. The increased daily secretion rate of LH was in turn due to both an augmented mass of LH released per secretory episode and increased frequency of secretory events. There was no demonstrable change in the maximal rate of LH secretion attained within each secretory event. Serum concentrations of total testosterone, free-testosterone, and 17 beta-estradiol all increased during blockade of androgen action. Administration of the antiandrogen had no measurable effect on the pituitary response to a single maximally effective dose of exogenous gonadotropin releasing hormone (GnRH). These results indicate that, in the late pubertal male, endogenous androgen exerts negative feedback control of gonadotropin secretion primarily at a hypothalamic site reflected by regulation of the frequency of pulsatile LH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Relationship between age, percentage body fat, fitness, and 24-hour growth hormone release in healthy young adults: effects of gender.

We investigated whether gender affects the physiological relationships between the release of GH and age, body composition, and levels of physical fitness in humans. We studied 32 eumenorrheic females (age = 31 +/- 5 yr) and 12 males (age = 27 +/- 5 yr). Significant gender differences were found for peak oxygen consumption [VO2 peak = 40.5 +/- 6.9 (females) vs. 50.1 +/- 11.6 (males) ml/kg.min-1, P < 0.05] and body composition [hydrostatic weighing, percentage body fat = 28.7 +/- 5.4 (females) vs. 18.1 +/- 9.8 (males), P < 0.05] but not for body mass index [BMI = 23.7 +/- 3.1 (females) vs. 24.0 +/- 3.3 (males)]. Blood samples were drawn every 10 min for 24 h from 0800 h to determine integrated serum GH concentration [2350 +/- 1260 (females) vs. 3110 +/- 1760 (males) microgram/L x min]; females were studied during the early follicular phase (days 4-5) of the menstrual cycle. In females, a significant relationship existed between 24-h integrated serum GH concentration and age (r = -0.35, P = 0.05) but not BMI (r = -0.19, P = 0.29); the relationship between 24-h integrated serum GH concentration and VO2 peak (r = 0.31, P = 0.08) and percentage body fat (r = 0.29, P = 0.11) approached significance. In males, significant relationships existed between 24-h integrated serum GH concentration and age (r = -0.79, P = 0.002), percentage body fat (r = -0.75, P = 0.005), and VO2 peak (r = 0.58, P = 0.05) but not between 24-h integrated serum GH concentration and BMI (r = -0.53, P = 0.08). Standardized regression coefficients revealed that for each SD change in age, BMI, percentage body fat, or VO2 peak the associated change in 24-h integrated serum GH concentration was 1.9-2.6 times greater in males than in females. We conclude that age, percentage body fat (but not BMI), and fitness are related to 24-h GH release in young adults and that these relationships are considerably stronger in males than females.

Adipose Tissue↗
PubMed1994

An unusual presentation of McCune-Albright syndrome confirmed by an activating mutation of the Gs alpha-subunit from a bone lesion.

The McCune-Albright syndrome (MAS) is characterized clinically by polyostotic fibrous dysplasia, café-au-lait skin lesions, sexual precocity, and various other endocrinopathies. Recent investigations suggest an etiological role for embryonic somatic missense mutations that predict the substitution of a His or Cys for Arg at amino acid 201 of the Gs alpha-subunit (Gs alpha). Identification of these mutations in affected tissues is a sensitive assay that may help define a more complete clinical spectrum of the MAS. We investigated a woman who developed fibrous dysplasia 24 yr after premature menstruation. To determine if this was an unusual MAS variant, DNA and RNA were analyzed from affected and unaffected tissues. From samples of affected rib and normal rib DNA was extracted, amplified by polymerase chain reaction, subcloned, and sequenced. RNA was extracted from affected bone, reverse transcribed, amplified by polymerase chain reaction, subcloned, and sequenced. DNA sequence predicting a His for Arg substitution at Gs alpha amino acid 201 was found in 47% of the recombinant plasmids from DNA of affected bone and 17% of the plasmids from DNA of unaffected bone; a significant (P < 0.05) difference in frequency. The His201 substitution was found in 42% of the recombinant plasmids from RNA of affected bone. We conclude that this clinical variant is qualitatively indistinguishable from presentations of the complete MAS.

Adult↗
PubMed1994

Dexamethasone therapy for isosexual precocious pseudopuberty caused by generalized glucocorticoid resistance.

Generalized glucocorticoid resistance presents with clinical features secondary to excess production of mineralocorticoids and adrenal androgens. It is our hypothesis that these clinical and biochemical features will respond to glucocorticoid therapy. We tested this hypothesis in a boy with generalized glucocorticoid resistance and increased adrenal androgens. Dexamethasone was administered from age 7 6/12 yr until the onset of true puberty at 11 0/12 yr. Serum concentrations of cortisol and adrenal androgens decreased to the normal or near normal range. The accelerated precocity improved. Secondary sex characteristics did not progress; the difference between bone age and chronological age decreased from 3 1/2 yr to 2 yr, and the difference between height age and bone age decreased from 2 yr to 1/2 yr. We conclude that dexamethasone is effective and safe therapy for the sexual precocity of generalized glucocorticoid resistance.

Age Determination by Skeleton↗