Moris Angulo

Growth hormone secretion and effects of growth hormone therapy on growth velocity and weight gain in children with Prader-Willi syndrome.

Obesity, short stature, decreased growth rate and delayed skeletal maturation are common features of children with Prader-Willi syndrome (PWS). In contrast to PWS, children with simple exogenous obesity have normal or increased growth rate and normal or advanced skeletal maturation. Decreased growth hormone (GH) secretion evaluated by pharmacological or physiological testing associated with increased plasma insulin-like growth factor (IGF-I) and GH-binding protein (GH-BP) levels are also characteristic of simple obesity. In order to understand whether the suboptimal GH secretion in PWS is an artifact of the obesity, we studied 33 obese and 11 non-obese PWS children, aged 2-16 years.GH secretion was evaluated with three pharmacological stimuli (insulin, clonidine and L-dopa) and by spontaneous 24-hour GH secretion. Skeletal maturation was delayed in 70% whereas plasma IGF-I and GH-BP were either low or normal. Forty subjects, including ten non-obese children, had GH deficiency by standard testing (failure to respond to two pharmacological stimuli), and all but one had blunted spontaneous 24-h GH secretion. No significant correlation between body mass index (wt/ht2) and spontaneous 24-h GH secretion (r = 0.145), p > 0.06) or GH-BP levels (r = 0.19, p > 0.07) was found. Thirty documented GH deficient children have completed at least two years of GH therapy. With treatment the overall mean height SD and weight SD changed from -2.2 to -0.8 and from 3.5 to 2.4 respectively (p < 0.0001). No patient has developed diabetes mellitus. In conclusion, growth velocity, skeletal maturation, GH secretion and GH dependent proteins in PWS resemble GH deficiency more than simple obesity. Our ongoing study suggests that GH deficiency in PWS is not an artifact of obesity. Although it is unlikely that GH deficiency is the only cause of decreased growth velocity and increased adiposity in PWS, it is a common feature and significant contributory factor. Long term observation will be required until achievement of adult height to determine whether GH therapy actually improves final height.

Final adult height in children with Prader-Willi syndrome with and without human growth hormone treatment.

Short stature is characteristic of children with Prader–Willi syndrome (PWS). While previous studies have demonstrated acceleration of linear height velocity with growth hormone (GH) treatment, the long‐term benefit on final adult height (AH) has not been reported. The objective of this study was to compare AH attained in PWS subjects with and without GH treatment. We reviewed the records of 21 children (aged 8.3 ± 2.7 years) with PWS and confirmed GH deficiency that attained AH after receiving human GH treatment (0.25 ± 0.06 mg/kg/week) for a period of 7.9 ± 1.7 years. A group of 39 non‐GH‐treated adults with matched initial height standard deviation score (SDS) at age 6.8 ± 1.3 years was used as control. In the GH‐treated group the mean initial height and AH‐SDS was −1.9 ± 1.7 and −0.3 ± 1.2 respectively (P < 0.0001), whereas the mean initial and AH‐SDS in the control group was −1.9 ± 1.3 and −3.1 ± 1 respectively (P < 0.0001). Scoliosis was seen in 43% and 39% in the GH‐treated and control group respectively. Premature adrenarche (PA) was noticed in 57% of GH‐treated group. Six subjects in the control group but none of the GH‐treated subjects developed type 2 diabetes mellitus. Our data show that administration of GH to children with PWS restores linear growth and final AH without significant adverse effects other than PA. Further studies will be necessary to determine related morbidity and mortality in individuals with PWS that reached final AH with or without GH treatment.

Pituitary Evaluation and Growth Hormone Treatment in Prader-Willi Syndrome

Short stature, obesity, hypogonadism and intellectual impairment are the main characteristics of children with Prader-Willi syndrome. We evaluated the spontaneous 24hour growth hormone (GH) secretion and the GH responses to three pharmacological stimuli with Clonidine, L-dopa and insulin-induced hypoglycemia in 11 obese and 4 non-obese Prader-Willi syndrome children, aged 1 to 15.5 years. Although the response to provocative stimuli varied from impaired to normal, all participants had blunted spontaneous GH secretion regardless of their body weight. Ten of these children were treated with conventional doses of recombinant human growth hormone, 0.1 mg/kg body weight three times a week intramuscularly, for a period of six months. Interval growth increased from 2.0 ± 0.23 cm to 5.3 ± 1.5 cm after therapy without advancing bone age more than chronological age. Weight gain during the same period decreased from 3.6 ± 0.9 kg to 1.3 ± 0.7 kg. Somatomedin-C levels increased significantly from 0.6 ± 0.3 U/ml to 1.5 ± 0.2 U/ml. Our results suggest growth hormone neurosecretory irregularities in Prader-Willi syndrome and potential benefits of GH therapy in these children. Reprint address: Moris Angulo, M.D. Director, Genetics Winthrop-University Hospital 222 Station Plaza North, #611 Mineola, New York 11501, USA

Male hypogonadism with gynecomastia caused by late-onset deficiency of testicular 17-ketosteroid reductase.

BACKGROUND 17-Ketosteroid reductase deficiency results in male pseudohermaphroditism because conversion of the weak androgen androstenedione to the more potent androgen testosterone is impaired. If a late-onset form exists, hypogonadism and gynecomastia caused by decreased testosterone production and increased estrogen production, respectively, would be expected as the major clinical manifestations in men. METHODS We studied 48 male subjects, ranging from 14 to 26 years of age, who had idiopathic pubertal gynecomastia. Serum concentrations of gonadal and adrenal steroid hormones were measured before and after the administration of corticotropin and after the combined administration of chorionic gonadotropin and dexamethasone for three days. RESULTS We identified three unrelated subjects (ages, 16, 17, and 26 years) with results indicative of a partial deficiency of testicular 17-ketosteroid reductase. The three subjects had gynecomastia as well as decreased libido and impotence. Their mean (+/- SD) base-line serum androstenedione and estrone concentrations were elevated as compared with the levels in the 45 subjects without this enzyme deficiency (androstenedione, 380 +/- 70 vs. 110 +/- 70 ng per deciliter [13 +/- 2 vs. 4 +/- 2 nmol per liter]; estrone, 138 +/- 12 vs. 46 +/- 9 pg per milliliter [511 +/- 44 vs. 170 +/- 33 pmol per liter]). After the administration of chorionic gonadotropin, the mean serum androstenedione concentration in these three subjects was 910 +/- 48 ng per deciliter (32 +/- 2 nmol per liter) and the mean serum estrone concentration was 260 +/- 16 pg per milliliter (962 +/- 59 pmol per liter). The mean serum testosterone concentration at base line was 210 +/- 80 ng per deciliter (7.4 +/- 2.8 nmol per liter) in the 3 subjects, as compared with a value of 410 +/- 12 ng per deciliter (14.4 +/- 0.42 nmol per liter) in the 45 other subjects, and it did not increase in response to the administration of chorionic gonadotropin. The concentrations of androstenedione and estrone in spermatic venous serum were 19 times higher and 73 times higher, respectively, than in normal men. The serum concentrations of follicle-stimulating hormone and luteinizing hormone in these three subjects were inappropriately low, suggesting the presence of hypogonadotropic hypogonadism. CONCLUSIONS A late-onset form of testicular 17-ketosteroid reductase deficiency can cause gynecomastia and hypogonadism in men.

Effect of prolonged clonidine administration on growth hormone concentrations and rate of linear growth in children with constitutional growth delay

Sixteen prepubertal children with constitutional growth delay (10 boys and six girls, mean age 7.2 +/- 2.1 years) were administered a daily dose of clonidine (0.15 mg/m2) for a period of 1 year. Growth hormone levels, plasma somatomedin C, and linear growth rate were significantly increased at the end of the treatment. Six of the children maintained the higher growth rate even 6 months after treatment. These and other studies suggest that prolonged stimulation of the hypothalamus by clonidine may ameliorate the impairment of growth hormone release seen in some children with constitutional growth delay. Because of the low cost and the convenience of the oral route, administration of clonidine could be a mode of treatment in some children with poor growth.

Paradoxical Association of Central Precocious Puberty and Hypergonadotropic Hypogonadism in 3 Patients with Klinefelter, Down, and Turner Syndrome

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MACROTESTES ASSOCIATED WITH HYPERPROLACTINEMIA

Prolactin secreting pituitary adenomas are a rare finding in prepubertal children /1/. As in adults, their incidence is higher in girls than in boys; however, the macroadenomas are predominant in boys /20-16/. Two prepubertal boys who presented with short stature and linear growth deceleration were diagnosed to have prolactin secreting pituitary macroadenoma associated with growth hormone (GH) deficiency. They were treated with bromocryptine and exogenous recombinant hGH. They achieved a normal adult stature, full sexual maturation and tumor regression on the therapy. In addition, both boys developed macrotestes. Further evaluation ruled out other etiologies for macrotestes. We presume that the elevated prolactin caused local testicular growth factors to induce testicular cell division and/or hypertrophy resulting in an increased testicular volume.

Characterization of zona glomerulosa function in patients with classic and non-classic forms of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency.

The function of the adrenal zona glomerulosa was studied in 18 patients with 11-hydroxylase deficiency confirmed by elevated plasma levels of 11-deoxycortisol. Patients were divided into two groups. Group I (4 males, 7 females; aged 1.2-2.8 yrs) had symptoms at birth or shortly after (classic form), and Group II (4 males, 3 females; aged 7.3-20.1 yrs) had their first clinical manifestation during childhood (non-classic form). To study zona glomerulosa function, patients were given dexamethasone p.o. 2 mg/m2/day x6 days, thus suppressing the zona fasciculata. Six hours after the last dose of dexamethasone, the zona glomerulosa was stimulated by i.v. administration of furosemide 1.0 mg/kg as a single dose. Blood was drawn 2 h later. In the untreated state, all patients had striking elevation of ACTH (Group I: 1,070 +/- 380 pg/ml; Group II: 764 +/- 180 pg/ml), 11-deoxycortisol (Group I: 63,000 +/- 22,000 ng/dl; Group II: 17,200 +/- 5,200 ng/dl) and deoxycorticosterone (Group I: 1,100 +/- 67 ng/dl; Group II: 499 +/- 27 ng%) while plasma renin activity (< 0.5 ng/ml/h in both groups) and aldosterone (Group I: 3.0 +/- 1.8 ng/dl; Group II: 2.3 +/- 1.8 ng/dl) were markedly suppressed. After the administration of furosemide 4 patients in Group I were unable to increase aldosterone (2.8 +/- 0.9 ng/dl) secretion in spite of marked elevation of plasma renin activity (28 +/- 7 ng/ml/h), suggesting an impairment of 11-hydroxylase in the zona glomerulosa.(ABSTRACT TRUNCATED AT 250 WORDS)

FAILURE OF CLONIDINE TO IMPROVE THE GROWTH HORMONE RESPONSE TO L-DOPA ADMINISTRATION

We have previously shown that oral administration of clonidine (C) during one year period increases plasma somatomedin C (SM-C) levels, growth velocity and growth hormone (GH) response to C in prepubertal short children. We have now studied the effect of chronic administration of C on SM-C level and GH response to L-Dopa (DA) administration in three short children (aged 13.8 ± 1.8 yrs) with blunted GH response to DA administration but normal GH response to insulin-induced hypoglycemia and C.C was administered orally in a single dose (0.15 mg/m2/body surface area) daily at night during a 3-month period. The GH response to DA (250 mg) administration was determined before and one week after the treatment with C was terminated.Our results suggest that the increase in SM-C levels seen after long term administration is not mediated by Dopaminergic pathway.

433 EFFECT OF CHRONIC ADMINISTRATION OF CLONIDINE IN NORMAL CHILDREN WITH SHORT STATURE: RATE OF GROWTH AND SOMATOMEDIN LEVELS

The oral administration of Clonidine, (C) a selective Alpha-Adrenergic agonist has been shown to increase growth hormone(GH) secretion in children and has been proposed as one of the reliable tests of GH reserve. The effects of chronic administra tion of C on growth have not yet been reported. We have now evaluated the effects of C administration on the rate of growth (RG) and somatomedin C (SM-C) levels in normal prepubertal children with short stature. Ten children (4-9y) with normal RG and normal GH reserve as assessed by the C test and SM-C determination were the subjects of this study. C was administer ed orally to these children as a single dose (0.15mg/m2/body surface area) every night during a 6-month period. Height, weight and blood pressure were measured. Plasma SM-C was determined before and one week after the last C dose. No side effects were observed during the 6-month period.The administration of C during that period produced a significant increase in the RG and SM-C levels.We conclude that C-administration could be used as an alternative treatment modality for normal children with short stature