Height, bone mineral density and bone markers in congenital adrenal hyperplasia.

AIM: To evaluate height, bone growth, areal bone mineral density (aBMD), volumetric bone mineral density (vBMD) and markers of bone turnover in a group of patients affected by congenital adrenal hyperplasia (CAH). PATIENTS: There were 50 patients (23 males, 27 females), aged 1-28 years, affected by CAH due to 21-hydroxylase deficiency: 27 with the salt-wasting (SW); 14 with the simple virilizing (SV), and 9 with the nonclassical (NC) forms. METHODS: Bone morphometry was evaluated with the metacarpal index (MI) and lumbar aBMD and vBMD (L2-L4) by dual energy X-ray absorptiometry. Serum osteocalcin was used as a marker of bone formation, while urinary cross-linked N-telopeptides of type-I collagen and free deoxypyridinoline levels were evaluated as indexes of bone resorption. RESULTS: The height standard deviation score (SDS) was -0.41 +/- 1.4 in SW patients, -0.01 +/- 1.9 in SV patients, and -0.01 +/- 2.3 in NC patients. There was no significant difference among groups and against zero. The MI SDS was also not different between groups and against zero. aBMD was significantly lower in the pubertal patients compared with normal values, but only when patients with the SW and SV forms were considered together (p < 0.05). vBMD was significantly reduced in all patients with the classical form. Bone markers were not different in patients and controls. CONCLUSION: Our study shows that normal height can be attained in CAH patients; however, an impairment in bone growth and mineralization may be found in adolescents and young adults affected by the classical form.     

Effect of puberty on the relationship between bone markers of turnover and bone mineral density in Turner's syndrome

It has been suggested that the appropriate timing of puberty is necessary for normal bone mineral acquisition which may not be achieved amongst patients with Turner's syndrome (TS). The aim of this study was to assess bone mineral density (BMD) and bone turnover in 34 patients with TS (age range 2.2-39.0 years). The areal BMD (aBMD) was determined by dual-energy X-ray absorptiometry, and the volumetric BMD was calculated. Blood and second voided urine samples were taken the morning after an overnight fast for evaluation of the biochemical markers of bone turnover: bone-specific alkaline phosphatase (BAP) and N-telopeptides of type I collagen (NTX), respectively. Both were determined by enzyme-linked immunosorbent assay. The patients were divided into three groups: group 1 (n = 13; prepubertal; age range 2.2-19.0 years), group 2 (n = 10; teenagers; age range 12.4-19.0 years), and group 3 (n = 11; adults; chronological age >20 years). They were also grouped by breast development according to Tanner stage into B1 (n = 12), B2-3 (n = 9), and B4-5 (n = 13). The aBMD was significantly lower in group 1 and was higher at Tanner stages 4 and 5 as compared with patients at Tanner stage 1. The bone turnover markers were significantly higher in group 1 (NTX: p = 0.002; BAP: p = 0.0005) and declined, as puberty progressed. A negative correlation was observed between aBMD and biochemical bone markers at the lumbar spine (NTX: r = -0.54, p = 0.05; BAP: r = -0.44, p = 0.01) and in the whole body (NTX: r = -0.60, p = 0.0008; BAP: r = -0.19, p = 0.002). We conclude that the negative relationships between aBMD and biochemical markers suggest a high bone turnover, mainly in prepubertal patients and that the results observed in relation to aBMD and puberty are imputed to the delayed puberty which occurs amongst TS patients.     

Auxological and endocrine evolution of 28 children with Prader-Willi syndrome: effect of GH therapy in 14 children

We report on the auxological and endocrine evolution of 28 patients presenting with Prader-Willi syndrome. Half of them received growth hormone (GH) therapy (group 2). The spontaneous auxological evolution was analyzed in the two groups from 2 to 8 years; the mean SDS for height remained stable (-0.6 +/- 0.6) in group 1 and decreased (from -2.0 +/- 0.9 to -2.7 +/- 0.6) in group 2. Magnetic resonance imaging showed marked pituitary hypoplasia in the two groups. In group 2, the mean GH peak after two provocative tests was 3.8 +/- 2.4 microg/l, the mean SDS values for insulin-like growth factor I levels were -2.0 +/- 1.5 (range from -0.5 to -5.0). The mean duration of GH treatment was 3.6 +/- 2.9 (range 1-9.3) years. 14 children completed 1 year of treatment. The two groups had opposite evolutions in Delta SDS for height (-0.8 +/- 0.8 vs. +1.1 +/- 0.8), for growth velocity (-1.9 +/- 2.2 vs. +2.9 +/- 2.7), and for Z score of the body mass index (+0.37 +/- 1.3 vs. -0.14 +/- 0.76; group 1 vs. group 2). This retrospective study shows that, in children with Prader-Willi syndrome and true GH deficiency, long-term GH therapy is effective in increasing growth velocity and in maintaining body mass index.     

Effect of growth hormone therapy on IGF-I, bone GLA-protein and bone mineral content in short children with and without chronic renal failure.

Chronic renal failure (CRF) in the young is complicated by, among other conditions, growth retardation, hyperparathyroidism and uremic osteodystrophy. Many children with CRF are now being treated with growth hormone (GH). Since GH has a direct mitogenic effect on osteoblasts in culture, we studied the effects of GH therapy on osteoblastic activity, such as serum alkaline phosphatase (AP), bone GLA-protein (BGP) and bone mass density (BMD) in poorly growing children with and without CRF. Fifteen (4 girls, 11 boys) healthy children with short stature (SS) and 10 (3 girls, 7 boys) children with end-stage renal failure (CRF) 4.5-12.4 years of age were treated with daily subcutaneous injections of GH in a dose of 0.1-0.125 IU/kg/day for 1 year. IGF-I, BGP and BMD of the spine were determined before and after the year of treatment. During GH therapy, a similar increase in height velocity and IGF-I were noted in SS and CRF groups: 3.8 +/- 0.77 to 8.38 +/- 1.25 (p < 0.001) vs. 4.0 +/- 0.6 to 7.14 +/- 1.3 cm/year (p < 0.001) and 7.8 +/- 2.6 to 21.8 +/- 7.5 (p < 0.01) vs. 7.9 +/- 1.3 to 21.5 +/- 5.6 nmol/l (p < 0.01), respectively. AP increased from 205 +/- 27 to 274 +/- 50 IU/l (p < 0.01) in the SS group but not in CRF patients (223 +/- 58 pre- 218 +/- 51 IU/l post-GH therapy).(ABSTRACT TRUNCATED AT 250 WORDS)     

IGF-I and IGF binding protein-3 levels during initial GH dosage step-up are indicators of GH sensitivity in GH-deficient children and short children born small for gestational age

BACKGROUND: A stepwise increment of the GH dose is an approach aimed at avoiding adverse events. We investigated GH sensitivity by studying IGF-I and IGFBP-3 concentrations during the initial phase of GH treatment. METHODS: Our investigation was part of the regular follow-up of prepubertal children with GH deficiency (GHD) (n = 31) and small for gestational age (SGA) (n = 23). Dosage was increased in three steps: one-third at the start, two-thirds after 14 days, and the full dose after 28 days (full dose: GHD = 28 microg/kg body weight (BW)/day; SGA = 60 microg/kg BW/day). Blood samples were taken on days 0, 14 and 28, as well as in conjunction with anthropometrical examinations after 3, 6 and 12 months. IGF-I and IGFBP-3 were measured by means of published in-house RIAs and age-related references were used to calculate standard deviation scores (SDS). Height velocity (cm/year) and Delta HT SDS were taken as growth response parameters. RESULTS: Before GH treatment (GHD vs. SGA; median and p values): age (years) (6.6 vs. 6.0; n.s.), HT SDS (-2.6 vs. -3.2; p < 0.05); GH amount after stepping up (mug/kg BW/day) (28 vs. 60; p < 0.01); BW SDS (-0.5 vs. -2.9; p < 0.01); max. GH stimulated (microg/l) (5.6 vs. 10.8; p < 0.01); IGF-I SDS (-3.5 vs. -1.8; p < 0.01); IGFBP-3 SDS (-2.0 vs. 0.8; p < 0.01). After 1 year of GH therapy: HT velocity (cm/year) (9.8 vs. 9.6; n.s.), Delta HT SDS (0.9 vs. 0.9; n.s.); WT velocity (kg/year) (3.3 vs. 3.5; n.s.). Our results show that changes in growth similar to GHD could be induced in SGA by a dosage that was twice as high as the replacement dose given in GHD. GH dose and HT velocity did not correlate in both groups. IGF-I and IGFBP-3 increased as follows in GHD and SGA during stepping up of the dosage (ng/ml, GHD vs. SGA): at start, 54 vs. 89; at day 14, 78 vs. 132; at day 28, 90 vs. 167; at 3 months, 118 vs. 218. There was the same relationship between dose levels and absolute IGF-I concentrations in both groups. In terms of IGF-I SDS, the dose-response curve in SGA showed a shift to the right in comparison to GHD, thus indicating lower sensitivity to GH. The dynamics of IGF-I and IGFBP-3 differed, as IGFBP-3 peaked earlier (on day 28). In GHD, IGF-I SDS at 3 months was -0.7 vs. +0.9 in SGA. Near-identical levels were found for Delta IGF-I SDS and IGFBP-3 SDS above basal levels for each time-point investigated. First year HT velocity in GHD correlated negatively with basal IGF-I SDS (R(2) = 0.33; p <0.001) and basal IGFBP-3 (R(2) = 0.17; p <0.05) but did not correlate with the IGF-I increment during the 0- to 3-month period. Conversely, first year HT velocity correlated (+) in SGA with the IGF SDS increment during the 0- to 3-month period (R(2) = 0.26; p = <0.05). Height velocity in SGA, however, correlated neither with basal IGF-I and IGFBP-3 nor with the 0- to 3-month increments of IGFBP-3 SDS. CONCLUSIONS: IGFs increase during initial GH therapy, thus raising questions about short-term IGF generation tests. (I) In terms of IGF generation, substantially lower sensitivity to GH was observable in SGA. (II) Higher GH sensitivity during first year catch-up growth is associated with GHD, but in SGA it is attributable to increases in IGF. A wider range of GH dosages needs to be explored in order to gain further insight into the relationship between GH dose, IGF levels, and growth. Monitoring IGFs is a practical means for exploring GH sensitivity during dosage stepping up.     

Growth hormone therapy for patients with Turner's syndrome

The linear growth of 8 patients with Turner's syndrome during human growth hormone (GH) administration was documented. Mean growth velocity was significantly greater during GH treatment (4.9 +/- 0.8 cm/year) than before treatment (3.3 +/- 0.8 cm/year, p less than 0.001). Growth velocity was related to dosage but not correlated with chronologic age, skeletal age or weight.     

Final height after growth hormone therapy in peripubertal boys with a subnormal integrated concentration of growth hormone.

The aim of this study was to test the effect of growth hormone (GH) therapy on final height in peripubertal boys with idiopathic short stature in whom a subnormal integrated concentration of GH (< 3.2 micrograms/l) was found. Twenty-eight peripubertal children were studied. Height was below 2 SD for age, growth velocity was < 4.5 cm/year, bone age was more than 2 SD below mean for age and GH response to provocative tests was more than 10 micrograms/l. Eleven subjects (group B) were treated with recombinant GH 0.75 unit/kg/week, divided into 3 weekly doses for 2 years, and then the same weekly dose divided into daily injections was administered until final height was attained. Seventeen untreated children (group A) who were followed until cessation of growth served as controls. The GH-treated patients reached their target heights (-2.1 +/- 0.5, mean +/- SD in SDS) and predicted heights (-1.8 +/- 0.8) determined by the Bayley and Pinneau method, while the final heights of the untreated patients were significantly lower than their target heights and their predicted final heights (-2.7 +/- 0.7, -1.8 +/- 1.0 and -2.7 +/- 0.7, respectively). The main effect of GH was observed during the 1st year of treatment when height velocity was significantly higher in the GH-treated group than in the untreated one (9.3 +/- 2.1 vs. 5.3 +/- 1.1, respectively, p < 0.001). The high cost of the treatment in this specific age group should be weighed against the results.     

Plasma growth hormone (GH) response to GH-releasing factor (SM-8144) in children of short stature and patients with GH deficiency

Synthetic human GRF (hGRF (1-44) NH2; SM-8144) was administered as an iv bolus to 141 normal children of short stature (NSC), 73 patients with severe idiopathic GH deficiency (IGD; group A), 30 patients with mild idiopathic GH deficiency (IGD; group B), 29 patients with secondary GH deficiency, 3 patients with primary hypothyroidism, 21 patients with Turner's syndrome and 25 patients with various other disease. Their height was below normal for their age and sex, and they were all below 25 years old without obesity. The maximal GH responses (M+SEM) were 39.5 +/- 2.2, 7.2 +/- 0.9, 27.2 +/- 3.7, 5.2 +/- 0.8, 9.7 +/- 4.4, 25.1 +/- 2.8 and 32.3 +/- 4.8 ng/ml, respectively (significance from the NSC, ; p less than 0.05, ; p less than 0.001). The GH responses to hGRF were greater than those elicited by standard pharmacological tests. There was a negative correlation between bone age and peak plasma GH response to hGRF in patients with idiopathic GH deficiency (IGD) but not in normal children (NSC). In twenty-two percent of the patients with IGD in group A the response was above 10 ng/ml and in 57% of the patients with IGD in group B the response was above 20 ng/ml, suggesting that a large percentage of patients with idiopathic GH deficiency lack hypothalamic GRF. The side effect of flushing was observed in 15.2% of all subjects. These results indicate the potential usefulness of hGRF (1-44) NH2 (SM-8144) in inducing GH release from the pituitary.     

Effects of a combination of recombinant human growth hormone with metformin on glucose metabolism and body composition in patients with metabolic syndrome.

Abdominal obesity and insulin resistance are central findings in metabolic syndrome. Since treatment with recombinant human growth hormone (rhGH) can reduce body fat mass in patients with organic GH deficiency, rhGH therapy may also have favourable effects on patients with metabolic syndrome. However, due to the highly increased risk for type 2 diabetes in these patients, strategies are needed to reduce the antagonistic effect of rhGH against insulin. We conducted a 18-month randomised, double-blind, placebo-controlled study to assess the effect of rhGH in combination with metformin (Met) in patients with metabolic syndrome. 25 obese men (55 +/- 6 years, BMI 33.4 +/- 2.9 kg/m (2)) with mildly elevated fasting plasma glucose (FPG) levels at screening (6.1-8.0 mmol/l) were included. All patients received metformin (850 mg twice daily) either alone or in combination with rhGH (daily dose 9.5 microg/kg body weight). An oGTT was performed at baseline, after 6 weeks, and after 3, 6, 12, and 18 months of therapy. Glucose disposal rate (GDR) was measured by euglycemic hyperinsulinemic clamp at 0 and 18 months and body composition was measured by DEXA every 6 months. In the Met + GH group, IGF-I increased from 146 +/- 56 microg/l to 373 +/- 111 microg/l (mean +/- SD) after 3 months and remained stable after that. BMI did not change significantly in either group during the study. Total body fat decreased by -4.3 +/- 5.4 kg in the Met + GH group and by -2.7 +/- 2.9 kg in the Met + Placebo group (differences between the two groups: p = n. s.). Waist circumference decreased in both groups (Met + GH: 118 +/- 8 cm at baseline, 112 +/- 10 cm after 18 months; Met + Placebo: 114 +/- 7 cm vs. 109 +/- 8 cm; differences between the two groups: p = 0.096). In the Met + GH group, FPG increased significantly after 6 months (5.9 +/- 0.7 vs. 6.7 +/- 0.4 mmol/l; p = 0.005), but subsequently decreased to baseline levels (18 months: 5.8 +/- 0.2 mmol/l). FPG remained stable in the Met + Placebo group until 12 months had elapsed, and then slightly decreased (baseline: 6.2 +/- 0.3, 18 months: 5.5 +/- 0.6 mmol/l, p = 0.02). No significant changes were seen in either group regarding glucose and insulin AUC during oGTT or HbA (1c) levels. GDR at 18 months increased by 20 +/- 39% in Met + GH-group and decreased by -11 +/- 25% in the Met + Placebo group (differences between the two groups: p = 0.07). In conclusion, treatment of patients with metabolic syndrome and elevated FPG levels did not cause sustained negative effects on glucose metabolism or insulin sensitivity if given in combination with metformin. However, since our data did not show significant differences between the two treatment groups with respect to body composition or lipid metabolism, future studies including larger numbers of patients will have to clarify whether the positive effects of rhGH on cardiovascular risk factors that have been shown in patients with GH deficiency are also present in patients with metabolic syndrome, and are additive to the effects of metformin.     

Comparison between quantitative X-ray imaging,dual energy X-ray absorptiometry and microCT in the assessment of bone mineral density in disuse-induced bone loss

Objectives:

We recently introduced a new methodology called quantitative X-ray imaging (qXRI) to investigate bone mineral density in isolated rodent bones. The aims of the present study were to compare DXA and microCT with qXRI in a rat model of disuse osteoporosis.

Methods:

Fourteen Copenhagen rats were injected with a single dose of botulinum toxin (BTX - 2 UI) in the right Mus quadriceps femoris. The left hindlimb serves as control. Areal BMD and vBMD were determined with a Hologic Discovery-W device and a Skyscan 1172 microcomputed tomograph (microCT). Absorbing material density (AMD) was determined on digitized X-ray images obtained with a Faxitron M020 device.

Results:

All three methods highlighted significant lower values for aBMD, vBMD and AMD in trabecular and cortical bone in the BTX-injected side. In trabecular bone, aBMD, vBMD and AMD were significantly correlated with BV/TV. In cortical bone, only aBMD and vBMD were significantly correlated with cortical bone mass On the other hand, only AMD was significantly correlated with the mechanical parameters bending strength and bending modulus.

Conclusions:

qXRI is a rapid and cheap method to assess trabecular bone mass in isolated rodent bones and can be used as a surrogate for the densitometry of small animals.     

Effectiveness of slow-release lanreotide in previously operated and untreated patients with GH-secreting pituitary macroadenoma.

The aim of this study was to verify whether treatment with slow-release lanreotide (SRL) before surgery is useful in the management of patients with GH-secreting pituitary macroadenoma. Twenty untreated acromegalics were enrolled randomly in two groups. Ten patients (group 1: 2 males and 8 females aged 44.5 +/- 4.3 years) underwent surgery via transsphenoidal access. Only one of them was cured by surgery, whereas the other nine were treated with SRL. In the other ten patients (group 2: 3 males and 7 females aged 43.2 +/- 12.3 years), transsphenoidal surgery followed SRL treatment. Surgery induced the normalization of GH and IGF-1 levels in four group 2 patients - three of them had shown an evident shrinkage of the tumor after SRL treatment. After surgery, group 1 showed a significant decrease of mean IGF-1 (580 +/- 63 vs. 789 +/- 64 ng/ml, p < 0.02), but not of GH values (26.1 +/- 9.8 vs. 44.8 +/- 19.3 ng/ml, NS); the cured patient was excluded from the following evaluations. Group 2 showed an evident, but not significant, decrease of both GH and IGF-1 values compared to values measured at the end of medical treatment (GH: 22.4 +/- 9.7 vs. 7.7 +/- 4.7 ng/ml, NS. IGF-1: 570 +/- 69 vs. 402 +/- 58 ng/ml, NS). Gonadal, thyroid and adrenal impairment was evident in six, four and no patients in group 1 and in three, two and one patients in group 2, respectively. SRL 30 mg was administered every 14 days for three months and then every 10 days until the 6th month. Before SRL treatment, mean GH and IGF-1 levels did not differ significantly in group 1 vs. group 2 (GH: 29.3 +/- 10.5 vs. 43.4 +/- 22.0 ng/ml; IGF-1: 633 +/- 38 vs. 778 +/- 83 ng/ml). In group 1, a significant decrease of serum GH, but not of IGF-1 levels, was achieved at the end of 1st trimester of SRL (GH: 17.6 +/- 5.4 ng/ml, p < 0.05. IGF-1: 540 +/- 48 ng/ml, NS), whereas a significant decrease in both GH and IGF-1 values was evident during the 2nd trimester (GH: 6.1 +/- 3.0 ng/ml, p < 0.05. IGF-1: 433 +/- 74 ng/ml, p < 0.02). Serum GH levels, measured during the 2nd trimester of SRL therapy, were also significantly lower than levels measured at the end of the 1st trimester (p < 0.05). Group 2 serum GH and IGF-1 levels were not significantly decreased at the end of the 1st trimester (GH: 27.2 +/- 12.1 ng/ml, NS. IGF-1: 698 +/- 74 ng/ml, NS), whereas only serum IGF-1 (570 +/- 69 ng/ml, p < 0.05) was significantly reduced during the 2nd trimester of SRL (GH: 22.4 +/- 9.7 ng/ml, NS). Serum GH and IGF-I fell in the normal range in 4 patients in group 1 and one in group 2 at the end of the second trimester of SRL therapy. Independently of the trial applied, the mean clinical score level ameliorated significantly in both groups (group 1: p < 0.0005; group 2: p < 0.0001). In both groups, the proportion of patients complaining of headache and tissue swelling and the score level of headache, tissue swelling and excessive sweating decreased significantly. In group 1 the score level of fatigue and arthralgia also decreased significantly. In conclusion, this study proves that in patients with GH-secreting pituitary macroadenoma: (i) surgery followed by SRL induces a better clinical and biochemical status than SRL alone; (ii) SRL treatment before surgery ameliorates the clinical and biochemical outcome and reduces the prevalence of hypopituitarism due to surgery.     

Final height of growth hormone-treated GH-deficient children and girls with Turner's syndrome: the Dutch experience. The Dutch Advisory Group on Growth Hormone

In the Dutch growth hormone (GH) registration database there are currently 552 GH-deficient children being treated, subcutaneously, with recombinant human GH six to seven times per week. Of those, 112 who have been treated for at least 2 years have reached final height. Mean age at start of therapy was 11.70 years. Mean GH dose was 15.5 IU/m(2) body surface per week. Mean final height was 173.2 cm (boys) and 159.7 cm (girls) and -1.36 SD of the population mean. Of the patients, 73.2% and 63.4%, respectively, reached a final height above -2 SD of the population or within target limits. FH-SDS was higher compared with the results of earlier cohorts with different treatment regimens. Target height, GH peak value at diagnosis, age at start of GH therapy, height SDS (HSDS) at start of puberty, and duration of GH therapy were significantly correlated with final height. These results, combined with those of a prospective GH dose-response study, suggest that better long-term results can be obtained with early and prolonged treatment and if the GH dose is individually adapted to the short-term growth response. In an ongoing dose-response study, 68 girls with Turner's syndrome, aged 2-11 years, were randomized into three dosage groups with a daily GH dose of: (group A) 4 IU/m(2) body surface; (group B) 4 IU/m(2) in the first year of therapy and 6 IU/m(2) thereafter; (group C) 4 IU/m(2) in the first year, 6 IU/m(2) in the second year, and 8 IU/m(2) thereafter. After 4 years of GH therapy, girls aged 12 years or older started low-dose oestrogen therapy. After 7 years of GH therapy, mean HSDS in all three groups had increased to values above the third percentile for healthy girls. Mean final height and final height gain of 25 girls was 159.1 and 12.5 cm, 161.8 and 14.6 cm, and 162.7 and 16.0 cm in groups A, B and C respectively. These long-term and final height results are more favourable than the results of earlier Dutch Turner's syndrome studies. Possible explanations are the higher GH doses and/or the younger age at start of GH therapy.     

Low areal bone mineral density values in adolescents and young adult turner syndrome patients increase after long-term transdermal estradiol therapy

OBJECTIVE: To study the effects of long-term estradiol therapy on areal bone mineral density (aBMD) values in young adult Turner syndrome patients. METHODS: The effects of 2-year transdermal estradiol administration on lumbar, L2-L4, aBMD values were evaluated in 12 Turner syndrome patients, 15.41-21.85 years old, who had reached adult height and had low aBMD values. Puberty was induced in all at a chronological age above 12 years and menarche appeared between 13.82 and 15.40 years. The patients were on oral estrogen/gestagen therapy from then until the start of the study. Adhesive patches of 17-beta-estradiol designed to be worn for 72 h and deliver 100 microg of estradiol per day, which results in a steady mean serum estradiol level of 75 pg/ml, were used for 21 days. From day 11 to day 21, 10 mg of oral didrogesterone were also added. Nutritional and physical activity habits were evaluated at the beginning, after 1 year and at the end of the study. RESULTS: aBMD values significantly increased from 0.910 +/- 0.065 to 1.005 +/- 0.086 g/cm2 (10.06 +/- 3.37%) and the z-score from -2.38 +/- 0.63 to -1.54 +/- 0.71 (0.81 +/- 0.30 z-score). No significant differences were observed in body mass index, calcium intake and physical activity habits at the start, during and at the end of the study. CONCLUSION: In summary, our results underline the importance of estrogens for bone mass peaking and suggest that this therapeutic protocol may be useful in the therapy of Turner syndrome patients with low bone mass.     

Long-term evolution of endocrine disorders and effect of GH therapy in 35 patients with pituitary stalk interruption syndrome

We report long-term evolution of endocrine functions and the results of GH treatment in 35 patients (26 male and 9 female) with pituitary stalk interruption. At diagnosis, mean chronological age was 4.8 +/- 2.7 years, mean SDS for height -3.1 +/- 0.8 with a bone age retardation of 2.3 +/- 1.3 years and a mean SDS for growth velocity of -0.5 +/- 1.1; 80% presented complete GH deficiency (GHD) and 20% partial GHD; thyroid deficiency was present in 47.1% of children with complete GHD but absent in all partial GHD. Diagnosis was made during the first months of life in only 2 patients while 23% presented with severe neonatal distress; neonatal signs were only observed in the group with pituitary height below 2 mm (45.7% of patients). GHD was isolated in 40.6% of patients below 10 years while multiple hormone deficiencies was consistent at completion of growth in all patients. Height gain was significantly higher in patients who started GH treatment before 4 years (p = 0.002). GH treatment is very effective: in 13 patients, final height was -0.4 +/- 1.0, total height gain 3.2 +/- 1.2 and distance to target height -0.3 +/- 1.6 SDS.     

Effect of low-repetition jump training on bone mineral density in young women.

The hypothesis of the present study was that low-repetition and high-impact training of 10 maximum vertical jumps/day, 3 times/wk would be effective for improving bone mineral density (BMD) in ordinary young women. Thirty-six female college students, with mean age, height, and weight of 20.7+/-0.7 yr, 158.9+/-4.6 cm, and 50.4+/-5.5 kg, respectively, were randomly divided into two groups: jump training and a control group. After the 6 mo of maximum vertical jumping exercise intervention, BMD in the femoral neck region significantly increased in the jump group from the baseline (0.984+/-0.081 vs. 1.010+/-0.080 mg/cm2; P<0.01), although there was no significant change in the control group (0.985+/-0.0143 vs. 0.974+/-0.134 mg/cm2). And also lumbar spine (L2-4) BMD significantly increased in the jump training group from the baseline (0.991+/-0.115 vs. 1.015+/-0.113 mg/cm2; P<0.01), whereas no significant change was observed in the control group (1.007+/-0.113 vs. 1.013+/-0.110 mg/cm2). No significant interactions were observed at other measurement sites, Ward's triangle, greater trochanter, and total hip BMD. Calcium intakes and accelometry-determined physical daily activity showed no significant difference between the two groups. From the results of the present study, low-repetition and high-impact jumps enhanced BMD at the specific bone sites in young women who had almost reached the age of peak bone mass.     

The effect of primary lack of estrogens and the influence of the age at the beginning of estrogen therapy on bone mineral density in patients with Turner's syndrome

Lumbar spine bone mineral density (BMD) values were measured in women with Turner's syndrome (TS) and the influence of primary ovarian failure as well as the age at the start of estroprogestins (EP) therapy were considered. EP treatment with 2mg of estradiol (E2) and BMD monitoring were started in 72 and finally continued for 5 years in 34 patients with TS, aged 12-38 years, previously not treated with growth hormone or anabolic steroids. The mean total BMD gain (deltaBMD) was 20% and the most significant increase was observed after the first (7.5%) and the second (6.6%) year of the therapy. Before the start and during EP treatment E2 levels were evaluated: they increased from 9.2pg/ml to the values observed in the controls (C) but positive correlation with BMD was not observed. Analysis of TS patients in age brackets (<15 years, 15-20 years, 21-25 years, >25 years) showed that only in the group that started EP treatment before the age of 15 every year significant deltaBMD was observed. The group that started EP therapy after the age of 20 didn't achieve significant deltaBMD. Patients wit TS had significantly higher levels of bone metabolism markers (Ntx and BALP) than the controls and in both groups negative correlation with age was found. On the basis of the results the conclusion was made that in hypoestrogenic women, not exclusively TS, the age when estrogen therapy is started may determine the effects in relation to bone mass. The administered E2 doses may also be important.     

Calcium supplementation increases bone mass in GH-deficient prepubertal children during GH replacement

BACKGROUND/AIMS: Since GH plays an important role in bone mineralization, and several studies demonstrated the positive influence of a higher calcium intake on bone mass, we studied the effect of calcium supplementation in GHD children during GH therapy. METHODS: 28 prepubertal GHD children, 5.0-9.9 years old, were assigned to two groups: group A (n = 14; 7 females) treated with GH, and group B (n = 14; 7 females) treated with GH + calcium gluconolactate and carbonate (1 g calcium/day per os). Auxological parameters, total bone mineral content (TBMC) and density (TBMD), leg BMC and BMD, lumbar BMD, fat mass (FM) and lean tissue mass (LTM), blood 25-hydroxyvitamin D (25-OHD), parathyroid hormone (PTH), osteocalcin (OC) and urinary N-terminal telopeptide of type I collagen (NTx) were determined at the start of therapy and after 1 and 2 years of treatment. RESULTS: During the 2 years of the study, TBMC, TBMD, leg BMC and BMD (but not lumbar BMD) increased in both groups of patients, however after 2 years of treatment they were significantly higher in the calcium-supplemented group B than in group A (p < 0.05, for all parameters). At the start of therapy, in both groups of patients percentage FM was higher and total and leg LTM lower than in controls (p < 0.05 for each parameter). Thereafter, FM decreased and LTM increased and after 2 years they were both different from baseline (p < 0.05). After 2 years of treatment, leg BMC and BMD were more positively correlated with regional leg LTM in patients of group B (r = 0.834 and r = 0.827, respectively; p < 0.001) than in patients of group A (r = 0.617 and r = 0.637, respectively; p < 0.05). 25-OHD and PTH levels were in the normal range in all patients at the start and during treatment. OC levels were lower and urinary NTx levels higher in patients than in controls (p < 0.05 for both parameters), either at the start and after 1 year of treatment. After 2 years of treatment, OC levels were significantly higher than at the start of the study (p < 0.05) in both groups of patients, but they were higher in group B than in group A (p < 0.05); on the contrary, urinary Ntx levels were lower in group B than in group A (p < 0.05). CONCLUSION: In GHD children, treated with GH, calcium supplementation improved bone mass; it may aid in reaching better peak bone mass and in protecting weight-bearing bones, usually completed in childhood to maximum levels, from risk of osteoporosis and fractures later in life.     

Increased bone mineral density and serum leptin in non-obese girls with precocious pubarche: relation to low birthweight and hyperinsulinism.

BACKGROUND: Hyperinsulinism and hyperandrogenism have the capacity to increase bone mineral density (BMD) and serum leptin, independently of body fat mass. We therefore assessed lumbar BMD and serum leptin in girls with the sequence of a low birthweight and precocious pubarche (PP) in childhood, in whom hyperinsulinism and hyperandrogenism have been described. METHODS: Fifty-two non-obese PP girls were studied (age range 6.9-14.9 years). Serum leptin was also measured in 42 control girls, matched for age, body mass index and pubertal stage. RESULTS: BMD SDS, measured by dual-energy X-ray absorptiometry, was elevated in PP girls compared to the population reference (0.39 +/- 0.18 SDS; p = 0.03) and bone age, assessed from hand radiographs, was significantly advanced compared to chronological age (1.2 +/- 0.1 years; p < 0.0005). CONCLUSION: Compared to control girls, PP girls had higher leptin levels for degree of body mass index (PP girls: 9.4 +/- 0.6 ng/ml; controls: 7.8 +/- 0.6 ng/ml; p = 0.01). In PP girls, serum leptin was inversely related to birthweight (r = -0.32, p = 0.01) and positively related to free androgen index (FAI) (r = 0.71, p < 0.0005). BMD SDS was also inversely related to birthweight (r = -0.26, p < 0.05) and positively related to serum leptin (r = 0.42, p < 0.05), FAI (r = 0.45, p < 0.05) and mean serum insulin during oral glucose tolerance testing (MSI) (r = 0.59, p < 0.0005). In multiple regression, MSI was the strongest determinant of BMD SDS (beta = 0.50, p = 0.002). In conclusion, elevated BMD and serum leptin in non-obese PP girls were related to degrees of low birthweight, hyperinsulinism and hyperandrogenism. The characteristic hyperinsulinism of PP girls is proposed to be the key variable in this constellation.     

Final height in children with idiopathic growth hormone deficiency treated with recombinant human growth hormone: the Belgian experience

BACKGROUND: The growth response to recombinant hGH (rhGH) treatment and final height of 61 Belgian children (32 boys) with idiopathic growth hormone deficiency (GHD) were studied. PATIENTS/METHODS: Two patient groups were compared: Group 1 with spontaneous puberty (n = 49), Group 2 with induced puberty (n = 12). The patients were treated with daily subcutaneous injections of rhGH in a dose of 0.5-0.7 IU/kg/week (0.17-0.23 mg/kg/week) from the mean +/- SD age of 11.9 +/- 3.1 years during 5.1 +/- 2.1 years. RESULTS: rhGH treatment induced a doubling of the height velocity during the first year and resulted in a normalisation of height in 53 (87%) patients. Final height was -0.7 +/- 1.1 SDS, being 170.4 +/- 7.2 cm in boys and 158.0 +/- 6.4 cm in girls. Corrected for mid-parental height, final height was 0.0 +/- 1.1 SDS. Ninety-two percent of the patients attained an adult height within the genetically determined target height range. Although height gain during puberty was smaller in the patients with induced puberty (boys: 17.1 +/- 7.0 cm vs. 27.5 +/- 6.6 cm (p < 0.005); girls: 9.6 +/- 7.4 cm vs. 22.2 +/- 6.1 cm (p < 0.005)), no differences in final height after adjustment for mid-parental height were found between patients with spontaneous or induced puberty. CONCLUSIONS: We conclude that patients with idiopathic GHD treated with rhGH administered as daily subcutaneous injections in a dose of 0.5-0.7 IU/kg/week reach their genetic growth potential, resulting in a normalisation of height in the majority of them, irrespective of spontaneous or induced puberty.     

Effects of long-term treatment with GH in the bone mineral density of adults with hypopituitarism and GH deficiency and after discontinuation of GH replacement.

BACKGROUND: Only few previous studies have assessed the effects of long-term growth hormone (GH) replacement therapy on bone mineral density (BMD) in adult patients with GH deficiency. The aim of this study was to investigate the effects of long-term GH therapy on bone metabolism and BMD. MATERIAL AND METHODS: At the start of the study, 20 adults with GH deficiency were randomized to receive either GH, 0.25 IU x kg per week, or placebo. After 6 months, patients in the placebo group were switched to GH therapy, and they received GH for a further 18 months. Of the 20 patients, 14 were male and 6 female with GH deficiency of adult-onset. The mean age of the patients at the start of the study was 40.3+/-10.9 years and the duration of GH deficiency was 10.6+/-6.4 years. Patients deficient in pituitary hormones other than GH had been receiving stable replacement doses of appropriate hormones for at least 6 months before the start of the study. Rates of bone metabolism were assessed by measuring calcium, phosphate, alkaline phosphatase, calciuria, phosphaturia and osteocalcin. BMD was measured by dual X-ray absorptiometry. Body composition was calculated from measurements of bioelectrical impedance. RESULTS: Before GH treatment, BMD in the femoral neck was lower in patients than in controls. The rate of bone resorption markers increased significantly after 6 months and remained stable during the whole treatment period. BMD significantly increased in L2-L4 after 12 months of treatment with an increase of Z-score. The total BMD increase was 4.5+/-6.5%. BMD in the femoral neck increased after 12 months with an increase of Z-score after 18 months. The total increase was 10.4+/-18%. The total BMD increase was not different among patients with or without basal osteopenia. In both groups BMD in L2-L4 and in the femoral neck remained stable after 12 months without GH treatment. Sex, age, BMI and the time in which GH deficiency started, before or after the end of the peak of BMD, did not correlate with BMD. The BMD values and their response to GH treatment did not correlate with other associated deficiencies, and we did not find differences among BMD increase and GH dose, levels of insulin-growth factor-I, insulin growth factor binding protein-3, and parameters of body composition. CONCLUSIONS: The results of the study support previous ones that BMD is subnormal in adults with GH deficiency; that GH replacement therapy stimulates bone turnover with initial biochemical changes; and that in the long term, this stimulation results in a significant augmentation in BMD that continues to increase after 2 years and remains stable after 12 months of GH withdrawal.