Effect of growth hormone treatment on craniofacial growth in Turner's syndrome

A cephalometric study was performed in 19 patients with Turner's syndrome, aged 8.7–16.5 years. A lateral roentgencephalogram was taken before and after two years of treatment with biosynthetic growth hormone in a dose of 24 IU/m²/week. During two years of growth hormone treatment, the mandibular length increased mainly due to vertical growth. The initially posteriorly rotated mandible showed an anterior rotation, although the normal position was not reached. The other linear measurements and angles did not change during treatment. No indications were found for an increase in the disproportionate growth or for excessive chin growth as a sign of acromegaly during growth hormone treatment. In conclusion, growth hormone treatment in patients with Turner's syndrome resulted in an increase in mandibular length, mainly due to vertical growth of the ramus and in the anterior rotation of the mandible.     

Methionyl human growth hormone in Turner's syndrome.

Sixteen girls with Turner''s syndrome aged 7.9-15.2 years (bone ages 7.0-11.8 years) were given methionyl growth hormone (somatrem) 4 IU/m2 body surface daily, corresponding to 0.9 IU/kg/week. During one year of treatment their mean (SD) height velocity increased from 3.4 (0.9) to 7.2 (1.7) cm/year and height prediction from 148.2 (4.4) to 150.0 (4.4) cm. All the girls except one had a height velocity increment of more than 2 cm/year and these velocities are above the age references for girls with Turner''s syndrome. The girl with a low growth response had antibodies against growth hormone with high binding capacity (3.7 U/l). The height velocity increment was inversely correlated with age and bone age, but this might be partly due to the somewhat higher dosage/m2 body surface and kg body weight that the younger patients were given because of the rounding off of the dose. The better results of our study compared with those of other workers who used similar dosages but did not give the drug as often suggest that giving it daily might have increased the growth response as it does in children deficient in growth hormone.     

Endogenous growth hormone secretion does not correlate with growth in patients with Turner's syndrome. Italian Study Group for Turner Syndrome

We investigated in Turner's syndrome patients whether the decrease in growth hormone (GH) secretion is frequent or sporadic, whether or not reduced GH secretion contributes to insufficient growth, and whether age, spontaneous presence of telarche and/or pubarche, karyotype and weight influence GH secretion decrease. We evaluated GH reserve in 301 patients by classical stimulation tests and in 68 of these patients mean nocturnal spontaneous secretion was also measured. Spontaneous telarche and/or pubarche were present in 33% of girls aged > 9 years. In 11% of patients, weight was more than 20% above levels appropriate for height. In 36.2% of patients (low-responders), we observed a reduction of the GH reserve (peak < or = 10 micrograms/l during two stimulation tests). Moreover, we noted reduced mean nocturnal spontaneous secretion (< or = 3.3 micrograms/l) in 61.8% of patients. Karyotype and the presence/absence of spontaneous telarche and/or pubarche did not influence either GH reserve or mean nocturnal spontaneous secretion. GH secretion (both GH reserve and mean nocturnal spontaneous secretion) did not influence height, yet low-responders had a significantly higher chronological age than normal-responders. Obese Turner's girls were low-responders and showed reduced mean nocturnal spontaneous secretion more frequently than normal weight girls; body mass index was significantly higher in patients with reduced GH secretion when compared to patients with normal GH secretion. We conclude that impairment of GH secretion is frequent in Turner's syndrome patients, especially if obese; that GH secretion impairment is not related to karyotype or spontaneous telarche and/or pubarche; that GH secretion is irrelevant to growth in these, patients and, therefore, its evaluation is unnecessary.     

The effects of long-term growth hormone treatment on cardiac left ventricular dimensions and blood pressure in girls with Turner's syndrome. Dutch Working Group on Growth Hormone.

OBJECTIVE: To assess the effects of long-term growth hormone (GH) treatment for short stature on left ventricular (LV) dimensions and systemic blood pressure (BP) in girls with Turner's syndrome without clinically relevant cardiac abnormalities. STUDY DESIGN: LV dimensions measured by echocardiography and systemic BP were assessed before and during 7 years of GH treatment in 68 girls with Turner's syndrome participating in a randomized dose-response study. These previously untreated girls, age 2 to 11 years, were randomly assigned to 1 of 3 GH dosage groups: group A, 4 IU/m(2)/d; group B, first year 4 IU/m(2)/d, thereafter 6 IU/m(2)/d; group C, first year 4 IU/m(2)/d, second year 6 IU/m(2)/d, thereafter 8 IU/m(2)/d. After the first 4 years, girls >/=12 years of age began receiving 17beta-estradiol, 5 microg/kg body weight per day, for induction of puberty. RESULTS: At baseline the LV dimensions of almost every girl were within the normal range, and the mean SD scores were close to zero. During 7 years of GH treatment, the growth of the left ventricle was comparable to that of healthy girls. No signs of LV hypertrophy were found. Before the start of GH treatment, mean BP was within the normal range but significantly higher than in healthy control subjects. Diastolic BP and systolic BP were above the 90th percentile in 23% and 28% of the girls, respectively. After 7 years of treatment, these percentages were 14% and 36%, respectively (not significantly different from baseline). The SD score of the diastolic BP showed a small decrease after 7 years of treatment. The growth of the left ventricle and the development of BP were not different between the GH dosage groups. CONCLUSIONS: Long-term GH treatment, even at dosages up to 8 IU/m(2)/d, does not result in LV hypertrophy or hypertension in girls with Turner's syndrome. Continued observation into adulthood is recommended to monitor the further development of the relatively high BP and to ensure that GH treatment has no long-term negative effect on the heart.     

Effect of obesity on endogenous secretion of growth hormone in Turner's syndrome.

Nocturnal growth hormone secretion over a 12 hour period was assessed at 20 minute intervals in 25 prepubertal subjects with Turner''s syndrome and 11 normal prepubertal girls of short stature to try and elucidate the relationship between body weight and endogenous secretion of growth hormone in Turner''s syndrome. There were no differences in mean growth hormone concentration, age, height, or growth velocity between the two groups. There was an age related decline in mean growth hormone concentration in patient''s with Turner''s syndrome in contrast to the age related increase in controls. Mean percentage of ideal body weight was significantly higher in the Turner''s syndrome group than among controls and it increased with age. There was a strong inverse relationship between mean growth hormone concentration and percentage of ideal body weight in those with Turner''s syndrome. Covariate analysis of the multiple linear regression of mean growth hormone concentration on age and percentage of ideal body weight in Turner''s syndrome indicated that percentage of ideal body weight had a significant effect on endogenous secretion of growth hormone when age was held constant, but not the other way round. We conclude that the age related decline in endogenous secretion of growth hormone in Turner''s syndrome is partly the result of increasing body weight with age. The significant influences of biological variables such as age and body weight in the interpretation of measurements of endogenous secretion of growth hormone in Turner''s syndrome should be emphasised.     

Reduced spontaneous growth hormone secretion in patients with Turner's syndrome

We evaluated growth hormone (GH) secretion in 81 patients with Turner's syndrome (TS) (mean age 10.7+/-3.6 y) with respect to karyotype, auxological characteristics and growth response to GH treatment (1 IU/kg/wk). None of the patients had spontaneous puberty or had started replacement therapy with estrogens. Thirty-nine patients (48%) had monosomia 45X, 29 (36%) structural abnormalities of the X chromosome and 13 (16%) X mosaicism. Before the start of GH therapy, each patient underwent an evaluation of mean nocturnal GH concentration (MGHC) and 75 patients also underwent 2 pharmacological tests. MGHC of the TS patients did not differ from that of 29 prepubertal GH-deficient girls (GH peaks < 8 microg/l after pharmacological tests) and both groups were lower (p < 0.0001 and p < 0.0005, respectively) than MGHCs of 27 short normal girls (GH peak > 8 microg/l). MGHC of the patients with TS was negatively correlated (p < 0.001) with bodyweight excess (BWE) at multiple regression analysis. MGHC of the TS patients with BWE < 20% was significantly higher (p < 0.02) than that of the TS patients with BWE > 20%, but again did not differ from that of the GH-deficient patients and was lower (p < 0.001) than that of the short normal girls. MGHC did not significantly differ between the 3 groups subdivided according to karyotype. Forty-four percent of the TS patients showed GH responses to pharmacological tests < 8 microg/l. Height velocity SDS at first and second year of therapy was not influenced by MGHC levels, chronological or bone age, target height or BWE. In conclusion, spontaneous secretion in our patients with TS was lower than that of the short normal prepubertal girls and did not differ from that of GH-deficient subjects, even if we excluded overweight patients. The level of GH secretion was unable to predict GH response to treatment.     

Thyroid autoantibodies, Turner's syndrome and growth hormone therapy

The prevalence of thyroid autoantibodies, i.e. thyroglobulin antibodies and antibodies to thyroid peroxidase, was analyzed in 89 girls, aged 3-16 years (mean age 10 years), with Turner's syndrome. The analyses were performed before the start of growth-promoting treatment and during a follow-up period of 1-5 years. The patients were divided into four groups according to karyotype as follows: group 1, 45, X (n = 63); group 2 with structural abnormalities of the X chromosome (n = 4); group 3 with mosaicism but no structural abnormalities of the X chromosome (n = 10); and group 4, with isochromosome X of the long arm (n = 12): 199 healthy girls aged 12 years, served as controls. Thyroid autoantibodies were demonstrated in 46 of 89 (52%) patients with Turner's syndrome compared with 34 of 199 (17%) age-matched control girls (p < 0.001), thus confirming the relationship between thyroid abnormalities and Turner's syndrome. There was also an increase in the prevalence of thyroid antibodies with age. Simultaneous presence of both autoantibodies was significantly more frequent in group 1 (45, X) and group 4 (isochromosome X of the long arm) than in group 3 (mosaicism) (p = 0.04 and p < 0.002, respectively) and significantly more frequent in group 4 than in group 1 (p < 0.05). During 12-60 months of growth-promoting treatment, no increase in the prevalence of thyroid antibodies was observed. The findings demonstrate the importance of continuous monitoring of thyroid function in girls with Turner's syndrome.     

Does growth hormone treatment of patients with Turner's syndrome cause an abnormal body shape?

The effect of human growth hormone on the body shape of 51 patients with Turner's syndrome (aged 6-19 years) was evaluated. Biosynthetic growth hormone was given in a dose of 24 IU/m2 body surface/week for two years. Karyotype analysis on peripheral blood was performed. Patients older than 12 years also received 0.1 microgram ethinyl oestradiol/kg body weight/day orally. Body shape was characterized by studying pairs of measurements expressed as SD scores (z scores). As reference data, our own locally obtained data from normal children were used. After two years of growth hormone therapy, height, sitting height, bi-acromial and bi-iliac diameter increased from -3.7, -2.9, -1.7 and -1.2 to -1.3, -2.5, -0.6 and +0.5 z scores, respectively. The shape of the patients, expressed as height/bi-iliac diameter and also as sitting height/bi-iliac diameter became more abnormal. As no difference could be noted between the prepubertal and pubertal groups or between the XO and mosaic groups, it is suggested that growth hormone treatment causes a relatively wide pelvis in patients with Turner's syndrome.     

Improved final height with long-term growth hormone treatment in Noonan syndrome

Aim: To assess whether children with Noonan syndrome on long-term growth hormone (GH) therapy improve their final height to near mid-parental height. Methods: Twenty-five prepubertal children (13 girls) with Noonan syndrome (NS) were studied. A single clinician made the diagnosis based on clinical criteria. GH treatment started at an age ranging from 3.1 to 13.8 y and was continued for at least 2 y. Improvement or “gain” in final height (FH) was defined as either the difference between adult height SD scores (SDS) and pre-treatment height SDS (the childhood component of the Swedish reference) or height SDS compared to the Noonan reference. Results: Ten children received a GH dose of 33 μg/kg/d (mean age at start 7.7±2.1 y, mean age at stop 17.6±1.7 y) and 15 received a dose of 66 μg/kg/d (mean age at start 8.6±3.3 y, mean age at stop 18.4±2.1 y). Eighteen out of 25 patients reached FH. A substantial improvement in FH of 1.7 SDS, equivalent to 10.4 cm compared to pre-treatment height, was observed. No significant difference was seen between the two GH doses. Females gained a mean height of 9.8 cm and males 1-13 cm (FH 174.5±7.8 cm vs mean adult height of 162.5±5.4 cm for males with NS) at final height. Moreover, 60% reached a mid-parental height of±1 SD.

Conclusion: GH treatment improves final height in patients with Noonan syndrome, with a mean gain of 1.7 SDS. The prepubertal height gain is maintained to final height and the children achieve a height close to their mid-parental height.     

Growth hormone treatment in girls with Turner's syndrome. A review of the literature

Most girls with Turner's syndrome seemed to increase their growth rate during the first year of growth hormone treatment. The gain is rarely more than 3 cm/year. In 3 studies the combination of growth hormone and an anabolic steroid resulted in higher growth rates compared to those with each individual compound. The results of long-term treatment (more than one year) also appear to be positive. The impact of growth hormone therapy on final height has not yet been established, however.     

Spontaneous growth in Turner's syndrome

The natural course of growth in Turner's syndrome is demonstrated on the basis of growth data from untreated patients. The mean adult height was found to be 145.5 cm (range 136-166 cm), the growth curve was similar to that in comparable studies. A decreased growth potency of skeletal (and other) cell populations seems to be the causal defect, beginning with intrauterine growth retardation. Special other causes like metabolic or endocrine changes could be excluded.     

Final height in girls with Turner's syndrome treated with once or twice daily growth hormone injections. Dutch Advisory Group on Growth Hormone.

OBJECTIVES: To study final height in girls with Turner's syndrome treated with once or twice daily injections of growth hormone (GH) in combination with low dose ethinyl oestradiol. DESIGN: Until final height was reached, the effect of fractionated subcutaneous injections given twice daily was compared with once daily injections of a total GH dose of 6 IU/m2/day. Twice daily injections were given as one third in the morning and two thirds at bedtime. All girls concurrently received low dose oestradiol (0.05 microgram ethinyl oestradiol/kg/day, increased to 0.10 microgram/kg/day after 2.25 years). PATIENTS: Nineteen girls with Turner's syndrome aged > or = 11 years (mean (SD) 13.6 (1.7) years). MEASUREMENTS: To determine final height gain, we assessed the difference between the attained final height and the final height predictions at the start of treatment. These final height predictions were calculated using the Bayley-Pinneau (BP) prediction method, the modified projected adult height (mPAH), the modified index of potential height (mIPHRUS), and the Turner's specific prediction method (PTSRUS). RESULTS: The gain in final height (mean (SD)) was not significantly different between the once daily and the twice daily regimens (7.6 (2.3) v 5.1 (3.2) cm). All girls exceeded their adult height prediction (range, 1.6-12.3 cm). Thirteen of the 19 girls had a final height gain > 5.0 cm. Mean (SD) attained final height was 155.5 (5.4) cm. A "younger bone age" at baseline and a higher increase in height standard deviation score for chronological age (Dutch-Swedish-Danish references) in the first year of GH treatment predicted a higher final height gain after GH treatment. CONCLUSIONS: Division of the total daily GH dose (6 IU/m2/day) into two thirds in the evening and one third in the morning is not advantageous over the once daily GH regimen with respect to final height gain. Treatment with a GH dose of 6 IU/m2/day in combination with low dose oestrogens can result in a significant increase in adult height in girls with Turner's syndrome, even if they start GH treatment at a relatively late age.     

Robinow syndrome with growth hormone deficiency: treatment with growth hormone.

We describe a 5 years and nine months old boy who presented with facial features, vertebral anomalies and dwarfism consistent with Robinow syndrome. Investigations revealed growth hormone (GH) deficiency to be the cause of his dwarfism. We reviewed data on four other patients with Robinow syndrome from the Genentech National Cooperative Growth Study (NCGS). Results of GH testing on three out of four were available and showed GH deficiency. Recombinant human GH therapy in our patient and the three patients from the NCGS resulted in a significant increase in the growth rate per year. The cause of dwarfism in children with Robinow syndrome has hitherto not been studied. We propose its association with GH deficiency and that treatment with rhGH can result in a significant increase in the growth rate of these children.     

Bone mineral density assessed by phalangeal radiographic absorptiometry before and during long-term growth hormone treatment in girls with Turner's syndrome participating in a randomized dose-response study

Immunosuppressive effects of carrageenan, a high-molecular-weight polysaccharide, on antibody and T cell responses have been previously demonstrated. However, its effect on anaphylaxis is unknown. Our objectives were to test carrageenan-mediated oral tolerance induction in young mice subsequently sensitized to a common cow's milk antigen. C3H/HeJ mice were fed or not lambda-carrageenan (0.5 g/L) and/or 0.01 mg/mL beta-lactoglobulin (BLG) for 5 d before oral sensitization with BLG and cholera toxin. Subsequently, the mice were challenged with BLG and symptom scores of anaphylaxis were recorded. Mesenteric lymph node cells, spleen cells, Peyer's patches cells, intraepithelial lymphocytes, and lamina propria lymphocytes were isolated and stimulated in vitro with BLG, IL-2, or left unstimulated. BLG-specific IgG, IgG(1), and IgG(2a) antibodies were measured. Pretreatment with carrageenan and BLG, but not pretreatment with either carrageenan or BLG alone or omission of pretreatment, diminished significantly the number of anaphylactic mice after BLG challenge (6.3 % versus 53 % in mice without pretreatment, p = 0.006). Mesenteric lymph nodes and spleen cells from pretreated mice proliferated less in presence of BLG or IL-2 than cells from sensitized control mice. Antigen-specific antibody production and passive cutaneous anaphylaxis was not suppressed by carrageenan and BLG pretreatment. In conclusion, carrageenan administered to young mice in conjunction with low doses of allergen before sensitization efficiently prevents anaphylaxis.     

Optimization of treatment in Turner's syndrome

We discuss treatment for short stature and hypogonadism in patients with Turner's syndrome, using recombinant human growth hormone (GH) and estrogen. We discuss the starting dose of GH, age at start of treatment, and association with oxandrolone or low dose estrogen therapy before 12 years old. We provide recommendations for optimization of therapy for best final height and induction of puberty with estrogen therapy. Our experience in the Children's Endocrinology Clinic in "La Paz" University Hospital, Madrid, is that 83% of our patients need estrogen therapy and only 17% had spontaneous menarche. The average age for puberty induction was 12.2 years, and the average duration of estrogen treatment was 2.1 years. The average final height obtained using GH treatment was 151.3 cm with a gain related to predicted height of 6.8 cm.     

Spontaneous growth in idiopathic short stature. European Study Group.

Documenting the spontaneous growth pattern of children with idiopathic short stature (ISS) should be helpful in evaluating the effects of growth promoting treatments. Growth curves for children with ISS were constructed, based on 229 untreated children (145 boys and 84 girls) from nine European countries. The children were subdivided according to target range and onset of puberty, and the growth of these subgroups was evaluated from standard deviation scores (SDS). At birth, children with ISS were already shorter than normal (means; boys -0.8 SDS, girls -1.3 SDS). Height slowly decreased from -1.7 SDS at the age of 2 years to -2.7 SDS at the age of 16 years in boys and 13 years in girls. Final height was -1.5 SDS in boys and -1.6 SDS in girls (mean (SD): boys 164.8 (6.1) cm, girls 152.7 (5.3) cm)), which was 5-6 cm below their target height. The onset of puberty was delayed (boys 13.8 (1.3) years, girls 12.9 (1.1) years). Subclassification resulted in similar growth curves. These specific growth data may be more suitable for evaluating the effects of growth promoting treatments than population based references.     

Spontaneous growth in idiopathic short stature. European Study Group

Documenting the spontaneous growth pattern of children with idiopathic short stature (ISS) should be helpful in evaluating the effects of growth promoting treatments. Growth curves for children with ISS were constructed, based on 229 untreated children (145 boys and 84 girls) from nine European countries. The children were subdivided according to target range and onset of puberty, and the growth of these subgroups was evaluated from standard deviation scores (SDS). At birth, children with ISS were already shorter than normal (means; boys -0.8 SDS, girls -1.3 SDS). Height slowly decreased from -1.7 SDS at the age of 2 years to -2.7 SDS at the age of 16 years in boys and 13 years in girls. Final height was -1.5 SDS in boys and -1.6 SDS in girls (mean (SD): boys 164.8 (6.1) cm, girls 152.7 (5.3) cm)), which was 5-6 cm below their target height. The onset of puberty was delayed (boys 13.8 (1.3) years, girls 12.9 (1.1) years). Subclassification resulted in similar growth curves. These specific growth data may be more suitable for evaluating the effects of growth promoting treatments than population based references.     

Demography, auxology and response to recombinant human growth hormone treatment in girls with Turner's syndrome in the Kabi Pharmacia International Growth Study

Demographic and auxological data were analysed from 818 girls with Turner's syndrome treated with recombinant human growth hormone (GH) and entered into the Kabi Pharmacia International Growth Study. Size at birth was low and correlated with the heights of both parents. The median age at start of GH treatment was 11.4 years and the parents had a median height SDS of -2.9. Height SDS at the start of treatment correlated with parental heights. Height velocities conformed to Turner-specific standards. The weight-for-height index increased sharply above 9 years of age. The frequency of spontaneous appearance of Tanner breast stage 2 was high (34.1% of girls > 10 years of age). Bone age (Greulich and Pyle) data were described by the equation: bone age = 1.61 (chronological age) -0.04(chronological age)² - 3.61. This equation was used to correct adult height predictions. The median initial dose of GH was 0.8 IUkglweek and was maintained during the first 3 years of treatment. The median frequency of injections was six/week. Height velocity increased from 4.1 to 6.8 cm/year in the first year, and height velocity SDS for chronological age remained positive for 4 years. The height prediction corrected for bone age increased over the first 2 years only. Differences in demography and auxology were described according to karyotype and country of origin. A greater height velocity SDS was observed at higher GH doses and when oxandrolone was used concomitantly.     

Variable effect of growth hormone on growth and final adult height in Scottish patients with Turner's syndrome

The aim of this work was to assess the outcome of recombinant growth hormone (rGH) therapy in a large unselected group (72) of patients with Turner's syndrome (TS), 26 of whom have reached final height. Growth data were collected from Scottish patients with TS and outcome was assessed in three ways: response to therapy in the first year, response in subsequent years and final height. Phenotypic, auxological, genetic and biochemical factors, all of which may have affected the first-year response, were investigated. Fifty-one percent of the cohort had a clinically "good" first-year response to therapy and 49% had a "poor" response; a "good" response was defined as a change in the TS standard deviation score (SDS) of +0.5 or more and a "poor" response as a change in the TS SDS of less than +0.5. The percentage of children showing a positive change in TS SDS after 2, 3 and 4 years of therapy declined (88%, 78%, 41%). Mean (range) final height was 142.6 (133.4–153.6) cm, mean (range) pretreatment TS SDS was -0.27 (-2.1 to +1.09) and mean (range) final TS SDS was -0.05 (-1.4 to +1.59). Thirteen (50%) patients attained a final height that was greater than projected, eleven did not attain their projected final height and two achieved their exact projected final height. Short girls with TS appear to benefit more from rGH supplementation than tall girls, but otherwise there was no significant correlation between any of the parameters studied and the response to treatment. It is concluded that large-scale prospective studies are still required to assess the impact of rGH on final height in TS and to identify factors responsible for the variability in response.