Premature adrenarche.

Adrenarche is the puberty of the adrenal gland. The descriptive term "pubarche" indicates the appearance of pubic hair, which may be accompanied by axillary hair. This process is considered premature if it occurs before age 8 yr in girls and 9 yr in boys. The chief hormonal products of adrenarche are DHEA and DHEAS. The well-documented evolution of adrenarche in primates and men is incompatible with either a neutral or harmful role for DHEA and implies most likely a positive role for some aspects of young adult pubertal maturation and developmental maturation. Premature adrenarche has no adverse effects on the onset and progression of gonadarche and/or final height. Mechanisms for initiation of adrenal androgen secretion at adrenarche are still not well understood. Maturational increases in 17-hydroxylase and 17,20-lyase are seen together with a lower activity of 3beta-hydroxysteroid dehydrogenase (3beta-HSD). There is good evidence that the zona reticularis is the source of adrenal androgens. Adrenarche and gonadarche are regulated differently. Although premature adrenarche has been thought to be a benign, normal variant of puberty, our findings indicate that, for certain girls, premature adrenarche represents an early clinical feature of syndrome X (obesity, hypertension, dyslipidemia, insulin resistance). Perhaps the early identification of these patients will permit early therapy, such as lifestyle changes, including dietary and activity level intervention. As insulin resistance is an underlying feature of premature adrenarche, it seems rational to assess the efficacy and safety of using insulin-sensitizing agents to treat these individuals. In the absence of controlled longitudinal studies, the cross-sectional data available from our studies suggest that premature pubarche driven by premature adrenarche and hyperinsulinemia may precede the development of ovarian hyperandrogenism, and this sequence may have an early origin with low birth weight serving as a marker. Premature adrenarche may thus be a forerunner of syndrome X in some girls.

Fasting glucose insulin ratio: a useful measure of insulin resistance in girls with premature adrenarche.

The purpose of this study was to determine whether the fasting glucose/insulin ratio is a useful screening test for insulin resistance in prepubertal girls with premature adrenarche. The glucose/insulin ratio was compared with the insulin sensitivity index calculated from the frequently sampled iv glucose tolerance test with tolbutamide using the minimal model computer program. Thirty-three prepubertal girls (22 Caribbean Hispanic and 11 African American; mean age, 6.8 yr; bone age, 8 yr) were studied. All underwent a 60-min ACTH stimulation test. The fasting glucose/insulin ratio was also compared with IGF-binding protein-1 and ACTH-stimulated androgen levels. Insulin sensitivity correlated significantly with the glucose/insulin ratio (0.76; P < 0.001), fasting insulin (0.75; P < 0.001), and IGF-binding protein-1 (0.59; P < 0.005). Stepwise regression analysis with the insulin sensitivity index as the dependent variable showed that the fasting glucose/insulin ratio was significantly predictive of the insulin sensitivity index (P < 0.002). When viewed as a screening test, setting a value of the fasting glucose/insulin ratio of less than 7 as abnormal and of less than 5.7 x 10(-4) min/microU.ml for the insulin sensitivity index as evidence of insulin resistance (normal prepubertal insulin sensitivity index, >5.7 x 10(-4) min/microU.ml), the sensitivity of the fasting glucose/insulin ratio was 87%, and the specificity was 89%. Furthermore, those girls with a low glucose/insulin ratio (<7) had higher body mass index, fasting insulin, free T, and ACTH-stimulated 17-hydroxypregnenolone and lower fasting IGF-binding protein-1 and SHBG than those girls with a glucose/insulin ratio greater than 7. The fasting glucose/insulin ratio is a useful screening test for insulin resistance in prepubertal Caribbean Hispanic and African American girls with premature adrenarche.

Pre- and postpuberal findings in premature adrenarche.

The complications of hyperinsulinism and insulin resistance are becoming more common in pediatrics (including type 2 diabetes mellitus, dyslipidemia and polycystic ovary syndrome) because of the increased occurrence of obesity in children. We report the occurrence of insulin resistance and marked hyperandrogenism in prepubertal minority group girls (African-American and Caribbean Hispanic) with premature adrenarche. Approximately one-third of our prepubertal patients with premature adrenarche evaluated have been noted to have marked hyperandrogenism with ACTH stimulated levels of 17-hydroxypregnenolone and the ratio of 17-hydroxypregnenolone/17-hydroxyprogesterone more than two standard deviations above the mean of normal early pubertal girls (Tanner II-III). Furthermore, those girls with the more marked hyperandrogenism have been noted to have insulin resistance as assessed by the frequently sampled intravenous glucose tolerance test. A preliminary evaluation of adolescent girls previously evaluated for premature adrenarche has revealed that those girls with hyperandrogenism and insulin resistance when evaluated in the prepubertal period continue to have obesity, insulin resistance, hyperandrogenism and symptoms of hyperandrogenism (irregular menses, hirsutism and acne). Hence, the early identification of children at risk for insulin resistance should permit early intervention in order to avoid complications.

Three-year follow-up of borderline congenital hypothyroidism.

The purpose of this study was to determine whether children with borderline hypothyroidism in the neonatal period had persistent hypothyroidism after 3 years of levothyroxine replacement therapy. Fourteen term infants with slightly abnormal newborn screening results (thyroxine <10th percentile, thyroid stimulating hormone ¿TSH <40 microU/mL) were identified. The subsequent serum confirmatory TSH results of 12 subjects were modestly elevated (5.3 to 18.8 microU/mL, normal 0.6 to 4.6), whereas 2 subjects who had borderline confirmatory TSH (4.6 and 4.7 microU/mL) had abnormal TSH responses to thyrotropin releasing hormone testing. After 3 years of therapy, levothyroxine was discontinued in 13 patients, and repeat thyroid function tests were obtained 1 month later. Levothyroxine was not discontinued in one patient because he had an elevated random TSH (10 microU/mL) while receiving therapy. At 3 years of age, 13 patients had persistently abnormal thyroid function tests (TSH >4.6 microU/mL or a thyroid releasing hormone test result consistent with primary hypothyroidism), and levothyroxine was reinitiated. Only one patient had normal thyroid function studies. Although prospective studies are still lacking, we recommend levothyroxine replacement in newborns with borderline hypothyroidism.

Premature adrenarche--normal variant or forerunner of adult disease?

Adrenarche is the puberty of the adrenal gland. The descriptive term pubarche indicates the appearance of pubic hair, which may be accompanied by axillary hair. This process is considered premature if it occurs before age 8 yr in girls and 9 yr in boys. The chief hormonal product of adrenarche is dehydroepiandrosterone (DHEA) and its sulfated product DHEA-S. The well documented evolution of adrenarche in primates and man is incompatible with either a neutral or harmful role for DHEA and implies most likely a positive role for some aspect of young adult pubertal maturation and developmental maturation. Premature adrenarche has no adverse effects on the onset and progression of gonadarche in final height. Both extra- and intraadrenal factors regulate adrenal androgen secretion. Recent studies have shown that premature adrenarche in childhood may have consequences such as functional ovarian hyperandrogenism, polycystic ovarian syndrome, and insulin resistance in later life, sometimes already recognizable in childhood or adolescence. Premature adrenarche may thus be a forerunner of syndrome X in some children. The association of these endocrine-metabolic abnormalities with reduced fetal growth and their genetic basis remain to be elucidated.

The roles of insulin sensitivity, insulin-like growth factor I (IGF-I), and IGF-binding protein-1 and -3 in the hyperandrogenism of African-American and Caribbean Hispanic girls with premature adrenarche.

Recent reports indicate that girls with premature adrenarche are at risk of developing functional ovarian hyperandrogenism and polycystic ovarian syndrome (PCOS). As insulin and insulin-like growth factors (IGFs) have been implicated in the pathogenesis of PCOS, we hypothesize that they may also have a role in the hyperandrogenism of premature adrenarche. Thirty-five prepubertal girls (23 Caribbean Hispanics and 12 Black African-Americans) underwent a 60-min ACTH and LH-releasing hormone test. Insulin sensitivity (S(I)) was assessed using the frequently sampled i.v. glucose tolerance test with tolbutamide. Fasting levels of IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, sex hormone-binding globulin, and free testosterone (T) were also obtained. The mean age of the patients was 6.8 yr, and bone age was 8.0 yr. Twenty-five patients had a family history of noninsulin-dependent diabetes mellitus and 19 patients had acanthosis nigricans. The mean S(I) for the entire group was 6.78 +/- 5.21 x 10(-4) min/microU x mL (normal prepubertal S(I), 6.5 +/- 0.54 x 10(-4) min(-1) x microU(-1) x mL(-1)). However, 15 of the 35 girls had an S(I) that was more than 2 SD below the mean reported for normal prepubertal children. Of these 15 patients, 13 were obese, and 14 had acanthosis nigricans. For the entire group of girls, the mean ACTH-stimulated levels of 17-hydroxypregnenolone (17OHPreg), dehydroepiandrosterone (DHEA), androstenedione (AS), 17-hydroxyprogesterone (17OHP), and T and the ACTH-stimulated ratios of 17OHPreg/17OHP, 17OHPreg/DHEA, 17OHP/AS, and DHEA/AS did not differ from the levels reported for Tanner stage II-III pubertal girls. The girls were divided into two groups based on their S(I) (group I, S(I) >2 SD below the mean for age; group II, normal S(I)). The group I girls with a reduced S(I) had significantly higher ACTH-stimulated levels of 17OHPreg (group I, 760 +/- 87.84 ng/dL; group II, 428.9 +/- 46.28 ng/dL; P = 0.002), 17OHPreg/17OHP ratio (group I, 3.95 +/- 0.36; group II, 2.96 +/- 0.35; P = 0.05), 17OHPreg/DHEA (group I, 2.06 +/- 0.21; group II, 1.4 +/- 0.13; P = 0.01), and free T (group I, 1 +/- 0.23 ng/dL; group II, 0.49 +/- 0.19 ng/dL; P = 0.014). Levels of sex hormone-binding globulin were lower in the group I girls. Furthermore, for the entire group of girls, the S(I) correlated inversely with ACTH-stimulated levels of 17OHPreg, DHEA, and AS and the ACTH-stimulated ratio of 17OHPreg/17OHP. IGF-I correlated inversely with S(I) (r = -0.94; P < 0.001) and correlated directly with the ACTH-stimulated levels of 17OHPreg (r = 0.8; P < 0.001) and AS (r = 0.63; P < 0.05). IGF-I also correlated with the ACTH-stimulated ratios of 17OHPreg/17OHP (r = 0.61; P < 0.05), 17OHPreg/DHEA (r = 0.9; P < 0.001), 17OHP/AS (r = 0.79; P < 0.001), and DHEA/AS (r = 0.96; P < 0.001). IGFBP-1 correlated inversely with the ACTH-stimulated levels of 17OHPreg (r = -0.38; P < 0.05) and DHEA (r = -0.36; P < 0.05). To summarize, the ACTH-stimulated delta5-steroid levels were higher in prepubertal girls with premature adrenarche and reduced S(I). There was a significant inverse correlation among ACTH-stimulated hormone levels, S(I), and IGFBP-1, whereas IGF-I correlated directly with ACTH-stimulated androgens. These findings support the hypothesis that insulin and IGFs may have a role in the hyperandrogenism of premature adrenarche just as they do in PCOS. Hence, in certain girls with premature adrenarche, hyperandrogenism may be the first presentation of PCOS and/or insulin resistance.

Premature adrenarche: findings in prepubertal African-American and Caribbean-Hispanic girls.

Premature adrenarche was previously thought to be a benign condition. However, the authors and several other research groups have noted hyperinsulinism and insulin resistance in many girls with premature adrenarche. African-American and Caribbean-Hispanic girls with premature adrenarche are frequently obese with marked hyperandrogenism, signs which correlate with the degree of insulin resistance (i.e., those girls who are obese and insulin resistant tend to have higher levels of adrenocorticotropic hormone-stimulated androgens). Also, girls with premature adrenarche and reduced insulin sensitivity can have subtle decreases in their high-density lipoprotein (HDL) profile. Many of these girls have a strong family history of type 2 diabetes mellitus. Preliminary data regarding long-term follow-up of girls with premature adrenarche indicate that those girls who remain obese are at risk of developing polycystic ovary syndrome (PCOS). The term 'syndrome X' refers to the constellation of laboratory and clinical findings associated with hyperinsulinism stemming from insulin resistance. These findings include obesity, acanthosis nigricans, glucose intolerance, type 2 diabetes mellitus, dyslipidaemia with reduced HDL and elevated low-density lipoprotein, cardiovascular disease and PCOS. Hence, for certain girls, premature adrenarche may be a part of the clinical spectrum of syndrome X.

Metabolic consequences of 5-year growth hormone (GH) therapy in children treated with GH for idiopathic short stature. Genentech Collaborative Study Group.

In a multicenter study the metabolic effects of 5 yr of GH therapy in children with idiopathic short stature were evaluated. Patients received 0.3 mg/kg.week recombinant human GH. Of the 121 patients who entered the study, data for 62 were analyzed at the final 5 yr point. Routine laboratory determinations were available for all 62 subjects at the 5 yr point. Special laboratory determinations, such as postprandial glucose and insulin, were available for only a subset of patients. Mean insulin-like growth factor I levels rose to 283 +/- 101 micrograms/L, within the normal range using age-appropriate reference standards. T4, cholesterol, triglycerides, blood chemistries, and blood pressure showed no significant changes during the 5-yr period. Mean baseline and 2-h postprandial glucose levels remained unchanged. Both fasting and postprandial insulin levels rose substantively from low normal levels to the normal range (median, 4.9-43 mU/L). Mean hemoglobin A1c levels remained within the normal range throughout the study. In summary, careful monitoring has not revealed any currently discernible metabolic side-effects of clinical significance after GH therapy in this 5-yr study of children with idiopathic short stature.

Hormonal findings in African-American and Caribbean Hispanic girls with premature adrenarche: implications for polycystic ovarian syndrome.

BACKGROUND: Premature adrenarche refers to the early maturation of the adrenal zona reticularis such that the resultant modest hyperandrogenism causes the early appearance of pubic hair before the age of 8 years in girls and 9 years in boys. The precise etiology of premature adrenarche is not known. However, recent studies indicate that certain girls with premature adrenarche are at risk of developing functional ovarian hyperandrogenism, polycystic ovarian syndrome, and hyperinsulinism. Caribbean Hispanic women in general are at increased risk of developing polycystic ovarian syndrome, and African-Americans are at increased risk of developing the complications of hyperinsulinism. Previously, girls with premature adrenarche were reported to have androgens in the range found in normal children in the early stages of puberty. We noted that many of our African-American and Caribbean Hispanic patients with premature adrenarche had androgens that were much higher than what has been reported previously. OBJECTIVE: This retrospective study was performed to characterize the adrenocorticotropin-stimulated androgen response in an African-American and Caribbean Hispanic population of girls with premature adrenarche. METHODOLOGY: The androgen response to adrenocorticotropin stimulation in 72 African-American and Caribbean Hispanic girls with premature adrenarche was compared with those reported for normal girls in early puberty (Tanner stages II and III). The mean age was 6.8 +/- 0.8 years, bone age was 8 +/- 1.5 years, pubic hair was Tanner stages II and III, and body mass index was 18.6 +/- 4. RESULTS: Of the girls, 28% were found to have elevated stimulated 17OHPregnenolone (17OHPreg) levels that were >2 SD units above the mean for normal early pubertal children. The stimulated ratio of 17OHPreg/17OHProgesterone also was elevated in 18% of the girls and showed a modest correlation with body mass index. CONCLUSION: In contrast to previous studies of girls of mixed ethnic backgrounds with premature adrenarche, 28% of the 72 African-American and Caribbean Hispanic girls with premature adrenarche had adrenocorticotropin-stimulated 17OHPreg levels that were significantly higher than those seen in early pubertal girls. Because 17OHPreg hyperresponsiveness has been described previously in women with hirsutism or polycystic ovarian syndrome, the similar finding in many African-American and Caribbean Hispanic girls with premature adrenarche suggests that the two conditions may share a common mechanism for their hyperandrogenism. Therefore, the hyperandrogenism in certain African-American and Caribbean Hispanic girls with premature adrenarche may not be benign and may be the first presentation of polycystic ovarian syndrome.

Insulin resistance in prepubertal African-American and Hispanic girls with premature adrenarche: a risk factor for polycystic ovary syndrome.

Recently, the modest hyperandrogenism of premature adrenarche has been linked to the more severe hyperandrogenism of polycystic ovary syndrome (PCOS). The presence of hyperandrogenism, obesity, acanthosis nigricans, hyperinsulinism and reduced insulin sensitivity in girls with premature adrenarche and in women with PCOS suggests that the two conditions might have a common mechanism. As the early appearance of pubic hair might be the first presentation of hyperandrogenism and insulin resistance, these girls should have continued.

Pseudotumor cerebri in an infant after L-thyroxine therapy for transient neonatal hypothyroidism.

Pseudotumor cerebri is generally a benign disorder. It has been reported to occur in hypothyroidism, particularly after the initiation of L-thyroxine replacement therapy. Previous case reports have involved children primarily in the peripubertal age range (approximately 8 to 13 years). We report here the development of pseudotumor cerebri in an infant who required treatment with L-thyroxine for transient neonatal hypothyroidism as a result of maternal thyroid-stimulating hormone receptor-blocking antibodies.

Carbohydrate metabolism in children receiving growth hormone for 5 years. Chronic renal insufficiency compared with growth hormone deficiency, Turner syndrome, and idiopathic short stature. Genentech Collaborative Group.

Carbohydrate metabolism was evaluated by fasting and postprandial glucose, insulin, and hemoglobin (Hb)Alc levels in children with chronic renal insufficiency and various other growth disorders treated with growth hormone. Mean fasting and postprandial glucose remained unchanged throughout the 5-year study period in all four study groups. Median fasting insulin levels rose from low-normal levels into the normal range after 5 years of growth hormone. Average fasting insulin level after 5 years was 10 mU/l. Median postprandial insulin values also rose, yet remained within the normal range at the 5-year mark. Mean Hb Alc levels remained within low to middle end of the normal range in the patients with growth hormone deficiency, Turner syndrome, and idiopathic short stature. Mean Hb Alc levels at the 5 years were slightly elevated to 6.3% for the patients with chronic renal insufficiency.

Transient congenital hypoparathyroidism: resolution and recurrence in chromosome 22q11 deletion.

Transient congenital hypoparathyroidism (TCHP), with spontaneous resolution in infancy and subsequent recurrence in childhood, has not been associated with a specific cause. We report three patients with TCHP, initially with severe but transient neonatal hypocalcemia. During childhood, recurrence of hypoparathyroidism and recognition of phenotypic features suggested a diagnosis of velocardiofacial syndrome (VCFS). Features specific for the DiGeorge syndrome, with known clinical and genetic overlap with VCFS, were not present except for hypoparathyroidism. Genetic analysis confirmed chromosome 22q11 deletion in each patient. TCHP may be the earliest specific finding in 22q11 deletion/VCFS subgroup, with other diagnostic features emerging in later childhood. Infants with resolved TCHP need continued observation of parathyroid sufficiency, genetic analysis, and examination for anomalies associated with chromosome 22q11 deletion.

Bayley-Pinneau method of height prediction in girls with central precocious puberty: correlation with adult height.

One of the sequelae of idiopathic central precocious puberty (ICPP) can be short adult stature. In this retrospective study adult height was normal in 90% of girls with untreated ICPP (mean, 161.4 +/- 7.7 cm). The height prediction made at the time of initial examination and the height age correlated with adult height. Therefore the initial height prediction can be useful in identifying those girls with ICPP at risk for short stature.

Decreased insulin sensitivity in prepubertal girls with premature adrenarche and acanthosis nigricans.

Benign premature adrenarche (PA) is the term used to refer to girls with the early development of pubic hair before the age of 8 yr and is characterized by mild hyperandrogenism. Hyperandrogenism in adult women is often not as benign and has been associated with insulin resistance, acanthosis nigricans (AN), and the polycystic ovary syndrome. We have seen a group of young girls with PA who have also been found to have AN. The purpose of this study was to determine whether there are any clinical and biochemical differences in those girls with PA with and without AN. Twelve girls with PA were divided into two groups at the time of evaluation: group I, those without AN (n = 5); and group II, those with AN (n = 7). Adrenal androgen levels were determined in all subjects by a 60-min ACTH stimulation test. Insulin sensitivity was measured by the frequently sampled iv glucose tolerance test with tolbutamide and was assessed using the modified minimal model. Mean chronological age, bone age, and weight for length index were similar in the two groups. The baseline and stimulated levels of adrenal androgens were also not significantly different between the two groups. The group I girls (without AN) had an insulin sensitivity index of 6.75 +/- 1.31, which was in the normal prepubertal range. This was significantly different from that in group II (with AN), who had an insulin sensitivity index of 3.69 +/- 1.29. Therefore, many girls with premature adrenarche can have AN and decreased insulin sensitivity. Whether these girls have a truly benign course or are at risk of ovarian dysfunction or carbohydrate intolerance needs to be assessed.

The effect of luteinizing hormone-releasing hormone analog for central precocious puberty on growth hormone (GH) and GH-binding protein.

The pubertal growth spurt is characterized by a marked increase in the amplitude of GH secretory pulses. The high affinity GH-binding protein (GHBP) reportedly has an important role in enhancing the growth-promoting action of GH. Levels of GHBP are characteristic for an individual and increase only slightly as puberty progresses. It has been hypothesized that each individual adjusts GH production to a level appropriate for his GHBP environment. The withdrawal of gonadal steroids that occurs in children with central precocious puberty (CPP) treated with LH-releasing hormone agonist (LHRHa) therapy results in a decrease in growth velocity (GV) and GH secretion. This study was performed to determine the effect of treatment of CPP with the LHRHa leuprolide acetate for depot suspension on GH secretion and levels of GHBP. Six girls and one boy with CPP were studied before and 6 months after treatment was initiated. Within 6 months of initiation of therapy, there was a significant decline in GV, from 8.9 +/- 3.2 to 5.4 +/- 2.0 cm/yr (P < 0.05). Twelve-hour mean nocturnal GH levels decreased significantly from 8.6 +/- 3.5 to 5.1 +/- 2.3 micrograms/L (P < 0.05). This occurred via a decrease in the amplitude of GH pulses as the number of peaks remained 4.6 and 4.1/12 h. Individual levels of GHBP were variable and reflect the wide range of levels observed in normal children. Although GV and GH levels decreased substantially, mean GHBP levels remained unchanged at 139.9 +/- 46.0 and 152 +/- 39.8 pmol/L. In children with CPP, within 6 months of LHRHa therapy, the decrease in GV occurs via a decrease in nocturnal GH secretion as levels of GHBP remain unchanged. In children with CPP, the withdrawal of gonadal steroids may inhibit the child's ability to secrete the GH appropriate for his/her GH/GHBP milieu.

Lack of clinical evidence of sodium retention in children with idiopathic short stature treated with recombinant growth hormone.

In adults patients, administration of human growth hormone and growth hormone synthesized by recombinant DNA technology (rGH) results in sodium and fluid retention and weight gain. This study was performed to determine whether rGH administration in children with idiopathic short stature (ISS) caused any clinical evidence of sodium retention. The parameters assessed included blood pressure, height, weight, plasma renin activity (PRA), aldosterone, and atrial natriuretic peptide (ANP). These were measured in nine treated children after 0, 3, 6, 9, and 12 months of growth hormone therapy; seven untreated children served as controls. After 12 months, the treated children had no significant increases in measurements of blood pressure, PRA, aldosterone, and ANP. Although treated children gained more weight than control patients, they also grew faster. Therefore, there was no significant difference in weight for height percentile for treated children when compared with normal controls. After 1 year of therapy, the administration of rGH to children with ISS does not result in any clinically significant evidence of sodium retention.

Normative data for the steroidogenic response of mineralocorticoids and their precursors to adrenocorticotropin in a healthy pediatric population.

The responses of mineralocorticoids and their precursors 1 h after a 0.25-mg bolus of ACTH has not previously been established in infancy or childhood. We report the steroidogenic responses of pregnenolone, progesterone (Prog), deoxycorticosterone (DOC), corticosterone (B), 18-hydroxycorticosterone (18OHB), and aldosterone (A) measured 1 h after a 0.25-mg bolus of ACTH in 102 healthy children who were divided into 5 age groups: group 1 (< 1 yr; n = 22), group 2 (1-5 yr; n = 22), group 3 (6-12 yr; n = 15), group 4 (early to midpuberty; n = 21), and group 5 (late puberty; n = 22). Baseline pregnenolone levels were constant throughout childhood; however, there was a significant fall in the stimulated level after the first year of life (group 1 vs. 2, P < 0.0125). Baseline Prog levels rose significantly with the onset of puberty (group 3 vs. 4, P < 0.0125), but levels did not increase after ACTH stimulation during puberty. Both baseline and stimulated levels of Prog, DOC, and 18OHB were significantly higher in group 3 males than in group 3 females (P < 0.05). Stimulated levels of DOC and corticosterone were constant during childhood, the only exception being the fall in the stimulated level of both steroids with the onset of puberty in males (group 3 vs. 4, P < 0.0125). The baseline level of 18OHB also fell with the onset of puberty in males (P < 0.0125), but a similar fall was not seen in females or in the stimulated level of 18OHB in either sex. The stimulated aldosterone level was higher in group 1 males than in group 2 males (P < 0.0125); a similar difference was not observed in females. The differences that we observed confirm the importance of specific age- and sex-related reference data when patients with possible abnormalities of mineralocorticoid synthesis are evaluated.

The effect of long-acting analog of luteinizing hormone-releasing hormone on growth hormone secretory dynamics in children with precocious puberty.

Long-acting preparations of LHRH (LHRHa), such as leuprolide acetate, have been shown to selectively and reversibly suppress the clinical and biochemical features of central precocious puberty (CPP). The withdrawal of gonadal sex steroids results in a decline of growth velocity and a decrease in the rate of bone age maturation, with resultant improvement in predicted adult stature. The purpose of this study was to define GH secretory dynamics in children treated with leuprolide acetate. Twelve-hour nocturnal GH studies were performed in five children (four girls and one boy) with CPP before and after 6 months of treatment with leuprolide acetate. Mean GH levels, GH secretory rate, and number of GH secretory episodes were determined. Secretory profiles were analyzed using the Cluster program. Growth velocity, somatomedin-C, and dehydroepiandrosterone sulfate were measured before and after 6 months of therapy. By 6 months of therapy, there was a significant decrease in mean growth velocity from 10.5 +/- 3.3 to 6.7 +/- 1.6 cm/yr. Somatomedin-C levels remained the same at 46.90 +/- 9.51 and 52.5 +/- 12.40 nmol/L. Levels of dehydroepiandrosterone sulfate remained unchanged at 118.6 +/- 71.4 and 139.0 +/- 61.3 mumol/L at 0 and 6 months of the study. By 6 months, there was a significant decrease in mean GH levels from 13.6 +/- 5.3 to 6.4 +/- 3.4 micrograms/L (P less than 0.05). Total GH levels decreased from 1367.9 +/- 687.3 to 447.0 +/- 186.5 ng/12 h. The number of GH secretory episodes remained the same at 5.4 +/- 1.5 and 4.8 +/- 1.0/12 h at 0 and 6 months of study. Therefore, the decrease in GH that occurs during the withdrawal of gonadal sex steroids with LHRHa in children with CPP is an amplitude-modulated phenomenon, as the number of secretory peaks remains unchanged.

Preservation of physiological growth hormone (GH) secretion in idiopathic short stature after recombinant GH therapy.

This study was undertaken to assess the recovery of spontaneous GH secretion 48 h after the cessation of GH therapy in children with idiopathic short stature treated with recombinant DNA-generated human GH (rhGH-M). Eleven prepubertal children with GH responses of 10.0 ng/mL or more after provocation were divided into therapeutic (n = 7) and control (n = 4) groups. GH was sampled every 20 min for 24 h in six treated and three control patients. One treated and one control patient had 12-h overnight studies because of their weight. The sampling studies were carried out before GH therapy was initiated and 48 h after rhGH was discontinued after 12 months of therapy. Three patients in the treated group also underwent a 24-h study at the 6 month time point. The treated group started treatment with rhGH (0.1 mg/kg), given three times a week. The results showed that pre- and posttreatment GH secretory profiles were comparable with respect to the number of peaks, mean concentrations, peak amplitude, and secretory rate. At the 6 month point, the mean GH and peak GH amplitude (n = 3) were greater than the means of the treatment group (n = 7) at the 0 and 12 month points, but the difference was not statistically significant. Somatomedin-C rose in the treated group from 0.42 +/- 0.1 to 1.25 +/- 0.3 U/mL (mean +/- SD; P less than 0.01). In the control group it rose from 0.56 +/- 0.1 to 1.16 +/- 0.8 U/mL (mean +/- SD; P greater than 0.05) because one patient entered puberty in the 12-month period of observation; his somatomedin-C level rose from 0.72 to 2.5 U/mL. We conclude that exogenous GH therapy does not interfere with the maintenance of endogenous pulsatile secretion of GH. These data show that exogenous GH therapy does not interfere with the maintenance of endogenous pulsatile secretion of GH and provide evidence for the resilience of the GH secretory system in the growing child.