R. Corda

Reduced growth hormone response to growth hormone-releasing hormone in children with simple obesity: evidence for somatomedin-C mediated inhibition.

We have evaluated the plasma GH response to a single injection of 1μg/kg of GH‐releasing hormone (GHRH)‐40 in 15 obese children and 15 age‐matched control children. Most of the obese children showed a subnormal plasma GH response to GHRH and the mean plasma GH integrated area (IC‐GH) following stimulation was significantly smaller in obese than control children. Plasma somatomedin‐C (SM‐C) levels were significantly higher in obese than control children, and were negatively correlated with the peak plasma GH levels (r=−0.616, P<001) and the IC‐GH (r=−0.554, P<0.02) after GHRH. Non‐esterified fatty acids (NEFA) and fasting plasma insulin levels were also elevated in obese children, but did not correlate with the extent of plasma GH response to GHRH. These data confirm previous observations on the refractoriness of obese children to release GH after GHRH, and imply that it may be due to the feedback inhibition operated by the elevated plasma levels of SM‐C.

CLONIDINE TREATMENT FOR SHORT STATURE

34 pubertal children with constitutional growth delay (CGD) were treated with clonidine orally twice a day. In 25 of the children the height velocity rose on clonidine treatment, and in 21 of them by more than 2 cm/yr during the first 6 months of treatment (mean [SD] growth increment 4.4 [0.5] cm/yr). Of the 22 who were treated for 12 months the increment in height velocity was maintained in 13 (3.4[0.4] cm/yr). Withdrawal of clonidine for 6 months did not stop the stimulatory effect of the drug on linear growth in 6 children, but in the other 8 children height velocities fell to pretreatment levels or below. In a few children reinstitution of clonidine for 2-4 months resulted in a new increment in height velocity. A high height standard deviation score and low growth velocity before treatment were predictive of a good growth response to clonidine. Clonidine did not induce noticeable side-effects. It may be a useful form of therapy for children with CGD.

ADRENAL AND GONADAL STEROIDS IN GIRLS DURING SEXUAL MATURATION

The peripheral venous plasma concentrations of gonadotrophins (LH and FSH), prolactin (Prl), cortisol, dehydroepiandrosterone (DHA), dehydroepiandrosterone‐sulphate (DHA‐S), pregnenolone (Δ5P), progesterone (P), 17‐hydroxyprogesterone (17P), androstenedione (A), testosterone (T), dihydrotestosterone (DHT) and oestradiol (E2) were measured in girls at different stages of sexual development (from P1 to P4–5 according to Tanner, 1962). Both gonadotrophins increase progressively during sexual maturation, to reach the highest concentrations in P4–5. However, the FSH values were significantly lower in these P4–5 pre‐menarchal girls than those found in adult women in the early follicular phase. No significant changes were found in plasma Prl, cortisol and 17P levels during pubertal development; in contrast, plasma concentrations of DHA tripled from P1 to P4–5, reaching adult levels. A progressive rise was also found in DHA‐S plasma levels. A significant, but less evident increase was found in Δ5P and P plasma concentrations, from group P1 to P4–5. A, T and DHT levels rose progressively and significantly from P1–2 to the end of sexual maturation. In the case of E2, only a moderate increase was found during pubertal development.

Synthetic hpGRF 1–40 stimulates growth hormone and inhibits prolactin secretion in normal children and children with isolated growth hormone deficiency

Intravenously administered synthetic hpGRF 1-40 at doses of 0.1, 0.33 and 1.0 microgram/kg increased plasma GH in a dose-dependent fashion in 4 normal prepubertal children. hpGRF 1-40 at the dose of 1.0 microgram/kg stimulated GH release, though to a lesser extent than in normals, in 7 children with isolated GH-deficiency (IGHD) but failed to do so in a patient with craniopharyngioma. In all normal children and 6/7 patients with IGHD, hpGRF 1-40 at all doses used induced a clear and sustained lowering of plasma prolactin levels; this effect was lacking in the patient with craniopharyngioma. hpGRF 1-40 had no effect on plasma FSH, LH, TSH or glucose levels nor did it influence pulse rate, blood pressure, or body temperature. These results indicate that hpGRF 1-40 is a potent stimulus to GH release in normal prepubertal children and holds promise for treatment of GH-deficient children. In addition, in both normal children and children with IGHD, hpGRF 1-40 is a potent suppressor of prolactin levels.

Correlations between plasma levels of opioid peptides and adrenal androgens in prepuberty and puberty.

In 139 prepubertal children and in 38 pubertal adolescents plasma levels of ACTH, cortisol, beta-lipotropin (BLPH), beta-endorphin (BEP) and dehydroepiandrosterone sulphate (DHAS) were determined by specific radioimmunoassays directly (steroids) or after plasma purification (peptides). ACTH and cortisol concentrations remain stable during both prepuberty and puberty, while DHAS levels constantly increased from 5 to 16 years. Both BLPH and BEP increase from early infancy to late prepuberty when they reach adult values. During puberty both opioids remain constantly within the adult range. BLPH and BEP concentrations were significantly correlated to those of DHAS throughout prepuberty. These data suggest a possible role of BLPH and BEP in and/or other proopiocortin-related peptides in the development of adrenarche, while the lack of particular changes in these peptide levels during sexual maturation seems to exclude their role in gonadarche and pubertal development.

THE EFFECT OF GALANIN ON BASELINE AND GHRH-INDUCED GROWTH HORMONE SECRETION IN OBESE CHILDREN

We have evaluated the effect of the administration of galanin (Gal), a newly identified hypothalamic peptide, on baseline and GHRH‐induced GH rise in five obese children and in seven controls. The GH response to GHRH (hpGRF(1–29), 1 μg/kg i. v.), and to Gal (15 μg/kg/h for 1 h), evaluated both as the maximum GH peak and as integrated area under the curve (AUC), was significantly lower in the obese children than in the controls. Simultaneous administration of Gal plus GHRH significantly increased the GH response to GHRH in all the obese subjects, so that their mean peak GH levels and AUC after Gal plus GHRH were similar to those of the control children after GHRH. Also, in control children Gal caused a significant augmentation of the GH response to GHRH. Mean peak GH levels and mean AUC after Gal plus GHRH were significantly higher in the controls than in the obese children given the same treatment. Our data indicate that obese children have a blunted GH response to Gal, which, however, is able to enhance the GH response to GHRH. This observation strengthens the view that the mechanism of action of Gal involves modulation of endogenous somatostatin (SRIH) release. In addition, similarity between the effects of Gal and pyridostigmine on baseline and GHRH‐stimulated GH release in obese children may indicate the existence of a cholinergic link in the action of Gal.

THE EFFECT OF OXANDROLONE ON THE GROWTH HORMONE RESPONSE TO GROWTH HORMONE RELEASING HORMONE IN CHILDREN WITH CONSTITUTIONAL GROWTH DELAY

The effect of treatment with oxandrolone, an anabolic steroid, on GH response to GH‐releasing hormone (GHRH) has been evaluated in children with constitutional growth delay. Five subjects, four males and one female, aged 11·0–17·1 years were given oxandrolone 0·1 mg/kg p.o. daily for 2 months, and underwent acute administration of GHRH (GRF 1–40, 1 μg/kg i.v.) before and after withdrawal of oxandrolone therapy. GHRH administration induced a much greater GH response, evaluated either as a peak plasma GH levels or plasma GH integrated area, after than it did before oxandrolone treatment. These findings indicate that in children with constitutional growth delay oxandrolone increases the sensitivity of somatotrophs to exogenous GHRH and, likely, to the endogenously‐released neurohormone.

Growth hormone response to growth hormone releasing hormone 1-40 in Turner's syndrome.

The response of growth hormone (GH) to acute administration of GH-releasing hormone 1-40 (GHRH) was evaluated in 12 patients with Turners syndrome and in 12 prepubertal or early pubertal girls. In 7 of 12 patients GHRH induced a definite increase (greater than 10 ng/ml) of plasma GH levels. In 5 patients there was a poor GH rise after GHRH administration (less than 10 ng/ml). Overall, the mean GH response of patients was significantly lower than that of normal girls. Five out of 7 patients with a 45 X,O karyotype had a reduced GH rise after GHRH, while all patients with non X,O karyotype (mosaicism and/or 46 X,iX) had a normal GH response to GHRH. Although the cause of short stature in patients with Turners syndrome is most likely multifactorial, a reduced pituitary GH reserve, as documented by the reduced GH response to GHRH in some of our patients, may contribute to the growth impairment in this disorder.

The effect of short-term growth hormone or low-dose oxandrolone treatment in boys with constitutional growth delay.

We evaluated the effect of six-month treatment with growth hormone (GH) or low-dose oxandrolone in a group of boys with constitutional growth delay (CGD). Sixteen boys were randomly assigned to two treatment groups. Group 1 received GH (0.6 U/kg/week sc 5–6 times/week) and Group 2 received oxandrolone (0.07 mg/kg po). The boys of the two groups were closely matched for age (13.7 ± 0.5 and 12.8 ± 0.4 years) (mean ± SE), chronologic age/bone age ratio (1.15 ± 0.04 and 1.16 ± 0.02), height standard deviation score (SDS; −2.7 ± 0.4 and −2.5 ± 0.3) and pretreatment height velocity (HV) (3.7 ± 0.8 and 4.0 ± 0.4 cm/year). Other known causes of short stature were excluded in all subjects, and none had taken long-term medication prior to the study. After 6 months of treatment HV increased to 7.5 ± 0.4 and to 8.1 ± 0.5 cm/year in group 1 and 2, respectively. Plasma IGF-I concentrations rose significantly after treatment in both groups. Predicted adult height was not significantly affected by either GH or oxandrolone treatment. We conclude that a short-term course of low-dose oxandrolone is as effective as GH to accelerate growth in boys with CGD. Low-dose oxandrolone represents an effective, cheap, and convenient therapeutic approach in boys with CGD.

Adrenal and testicular function in boys affected by thalassemia

The adrenal androgen secretion and testicular function were studied in 6 thalassemic boys aged between 16 and 20 years. Six normal boys of the same age and 6 at the same pubertal stage (P1 according to Tanner) were also studied as controls. Plasma testosterone levels were found significantly lower (p < 0.001) in the thalassemic boys (0.8 ± 0.1 ng/ml) than in healthy boys of the same age (3.4 ± 1.01 ng/ml), but within the range of the healthy boys at the same pubertal stage (0.69 ± 0.1 ng/ml). DHA-S, a marker of adrenal maturation, showed a similar pattern. The hCG test showed a significant (p < 0.001) testosterone response in all 3 groups. The response of thalassemic boys (1.5 ± 0.18 ng/ml) was similar to that of normal boys at stage P1 (1.8 ± 0.31 ng/ml), but significantly lower (p < 0.001) than the group of normal boys of the same age (12.5 ± 3.2 ng/ml). The impaired adrenal and testicular activity is probably due to iron deposits in the endocrine glands.