Effect of growth hormone and oxandrolone treatment on glucose metabolism in Turner syndrome. A longitudinal study

In 18 girls with Turner syndrome, glucose tolerance was studied before treatment and after 6 and 24 months of growth-promoting treatment with recombinant human growth hormone (24 IU/m(2)/week; 8 mg/m(2)/week) and oxandrolone (0.06 mg/kg/day), as well as after termination of the treatment. One girl developed an overt non-ketotic diabetes mellitus 50 months after termination of treatment. The results of the remaining 17 girls in whom the effect of treatment on glucose metabolism was reversible are presented as a group. Their median age at the beginning of the treatment was 10.4 years (range 6.9-15.9), and 15.0 years (range 12.1-19.9) at the final assessment. There was a moderate, but not significant rise in fasting glucose throughout the course of the longitudinal study. At oral glucose tolerance testing (oGTT), the area under the curve for glucose rose significantly (p = 0.013) during the period of treatment and returned to the basic value thereafter. Fasting insulin and especially the integrated insulin values (AUCi; area under the curve for insulin) during oGTT increased continuously during treatment, declined after termination of treatment but were still significantly (p = 0.04) higher than before treatment. Considering the fact that in untreated girls with Turner syndrome the fasting insulin and the AUCi increase with age, one can conclude that the insulinaemia returned to age-specific norm after termination of treatment. Thus the effect of a combined growth hormone and oxandrolone growth-promoting treatment on glucose metabolism was fully reversible in these 17 girls with Turner syndrome.     

Psychosocial functioning after discontinuation of long-term growth hormone treatment in girls with Turner syndrome

It is common practice in the case of Turner syndrome (TS) to treat short stature with GH treatment and to induce puberty with estrogens at an age as close to normal puberty as possible. This approach in most cases leads to a height in the normal range in childhood, adolescence, and adulthood in TS. Little data is available, however, on its effect on psychosocial functioning. In the present study, we evaluated psychosocial functioning in a group of 50 women with TS, after reaching final height in two multicenter GH trials. Thirty-six girls participated in a randomized dose-response study from mean (SEM) age 6.8 (0.4) years, and 14 girls participated in a frequency-response study from age 13.2 (0.4) years. After discontinuation of long-term GH treatment, these 50 girls were evaluated for psychosocial functioning at a mean age of 18.8 (0.3) years. GH was given in a dosage of 4 IU/m2/day (approximately 0.045 mg/kg/day), 6 IU/m2/day, or 8 IU/m2/day. After a mean GH treatment duration of 7.1 (0.4) years, mean final height (ref. normal girls) was FH1.2 (0.2) SD score. Behavioral problem scores (Achenbach) of the TS women were comparable to normal Dutch peers. Although self-perception (Harter total scale: p < 0.01), and bodily attitude (Baardman: p < 0.05) was significantly less positive than for their normal Dutch peers, we found no evidence of depression. TS women rated their family functioning higher than their Dutch peers (p < 0.0001), and had a slightly different coping pattern. These results show that even after reaching a height in most cases within the normal range and puberty induction at a pubertal age, some women with TS still experience psychosocial problems. It is likely, however, that GH and estrogen treatment improved psychosocial functioning. Long-term follow-up of these GH-treated patients will allow an evaluation of their life achievements.     

The effect of the weak androgen oxandrolone on psychological and behavioral characteristics in growth hormone-treated girls with Turner syndrome

The weak androgen oxandrolone (Ox) increases height gain in growth-hormone (GH) treated girls with Turner syndrome (TS), but may also give rise to virilizing side effects. To assess the effect of Ox, at a conventional and low dosage, on behavior, aggression, romantic and sexual interest, mood, and gender role in GH-treated girls with TS, a randomized, placebo-controlled, double-blind study was conducted. 133 patients were treated with GH (1.33 mg/m²/d) from baseline, combined with placebo (Pl), Ox 0.03 mg/kg/d, or Ox 0.06 mg/kg/d from the age of eight, and with estrogens from the age of 12. The child behavior checklist (CBCL), Junior Dutch Personality Questionnaire (DPQ-J), State-subscale of the Spielberger's State-Trait Anger Scale, Romantic and Sexual Interest Questionnaire, Mood Questionnaire, and Gender Role Questionnaire were filled out before, during, and after discontinuing Ox/Pl. The changes during Ox/Pl therapy were not significantly different between the dosage groups. In untreated patients, the mean CBCL total (P = 0.002) and internalizing (P = 0.003) T scores, as well as the mean DPQ-J social inadequacy SD score (SDS) (P = 0.004) were higher than in reference girls, but decreased during GH + Ox/Pl therapy (P < 0.001, P = 0.05, P < 0.001, respectively). Whereas the mean total (P = 0.01) and internalizing (P < 0.001) T score remained relatively high, the mean social inadequacy SDS became comparable with reference values. We conclude that in GH-treated girls with TS, Ox 0.03 mg/kg/d or 0.06 mg/kg/d does not cause evident psychological virilizing side effects. Problem behavior, frequently present in untreated girls with TS, decreases during therapy, but total and internalizing problem behavior remain increased.     

Turner syndrome, insulin sensitivity and growth hormone treatment

Mild insulin resistance appears to be an early metabolic defect in girls with Turner syndrome (TS). Impaired glucose tolerance has been reported in 10-34% of patients with TS, and type 2 diabetes mellitus is 2-4 times more common and occurs at a younger age in girls with TS than in the general population. In a mixed longitudinal and cross-sectional study, we analysed carbohydrate tolerance and insulin sensitivity in 46 children and adolescents with TS who reached their final height after long-term treatment (mean 6.3 +/- 2.5 years) with growth hormone (GH: 0.33 mg/kg/week [0.05 mg/kg/day]), and in 36 of these patients who were followed-up after the cessation of GH therapy (mean follow-up, 2.6 +/- 2.5 years; range, 1-9.5 years). Patients with TS were compared with an age-matched female control group. Insulin sensitivity appeared to be lower in patients with TS than in controls, even before the start of GH therapy. As in controls, insulin sensitivity decreased with age in patients with TS, and levels were lower in those aged >12 years than in those aged <12 years. GH therapy resulted in good catch-up growth in patients with TS, with final height significantly higher than projected height evaluated before the initiation of GH therapy. Insulin sensitivity increased after 7-8 years of therapy and, on the cessation of GH therapy, returned to pre-treatment levels. The increase in insulin sensitivity seen on the cessation of GH therapy appeared to be influenced negatively by body mass index and triglyceride levels, and correlated positively with the number of years since cessation of GH therapy. As in the general population, excess weight and an abnormal lipid profile, in particular excess triglyceride levels, worsened insulin sensitivity. In conclusion, our study confirms that GH therapy reduces insulin sensitivity, but at its cessation there is a return to pre-therapy values. We therefore report a progressive improvement in carbohydrate tolerance and insulin function in patients with TS, despite an increase in age.     

Effect of recombinant human growth hormone on urinary 15N-nitrogen balance in girls with Turner syndrome as compared to children with growth hormone deficiency

15N-nitrogen balances before and on human growth hormone (hGH) were studied in 13 girls with Turner syndrome (TS) aged 4.4-16 (median 13.2) years (45,X0 or equivalent, no X0/XX mosaicism, no estrogen replacement). The results were compared with those reported from 9 patients with growth hormone deficiency (GHD). The TS patients received subcutaneous hGH doses of 2 x 3 (group A, n = 6), 3 x 2 (group B, n = 3), or 2 x 6 (group C, n = 4) IU/m2 on consecutive days. The mean 15N dose given to the patients of groups A and C was higher (13.6 mg/kg) than that given to those of group B (2.7 mg/kg). The lower hGH doses in the first two groups induced small positive mean 15N balance changes (+0.6 +/- 0.6 mg/kg 15N, group A; +0.03 mg/kg, group B). The higher hGH dose in group C caused a more marked mean balance change (+3.0 mg/kg 15N) comparable to that in GHD patients (+3.2 mg/kg). Individual variation of response, however, was larger in patients with TS than in those with GHD. With low and high hGH doses, there were responders and nonresponders. It is concluded from this pilot study in a small number of cases that 15N balance studies might be potentially useful to choose the appropriate hGH dose for long-term treatment in TS patients.     

Differences in infantile growth patterns in Turner syndrome girls with and without spontaneous puberty.

OBJECTIVE: The role of prepubertal estrogen in child growth was modeled using Turner's syndrome, comparing growth patterns of girls who later did or did not enter puberty spontaneously. The hypothesis was that TS patients with normal prepubertal estrogen levels would have a different growth pattern from those with subnormal estrogen levels. STUDY DESIGN: Growth data from 78 full-term patients with Turner's syndrome were collected retrospectively. 24/78 later developed spontaneous puberty, (+Pub), and their growth data were compared to TS patients without spontaneous puberty (-Pub). A nonlinear mixed model was fitted using the bi-exponential model. RESULTS: The growth velocity difference between the -Pub and +Pub groups suggests an early infantile growth advantage in the -Pub group, which disappears before the end of the first year of life; growth velocity remains similar (+/- 1 cm/y) for the next 6 years and declines at age 7-8 years in the +Pub group faster than it does in the -Pub group. Bi-exponential analysis showed that both the 1st (restrictive) and 2nd exponent (forward) were different (p = 0.0003). CONCLUSIONS: Comparison of girls with or without spontaneous puberty suggests a role for estrogen in child growth. Estrogens restrict infantile growth, as well as growth during the mid-childhood spurt.     

GH assessment and three years' hGH therapy in girls with Turner syndrome.

Fifteen girls with Turner syndrome (TS) were submitted to GH secretion assessment before undergoing hGH therapy. In the first 9 months, hGH was given at a dose of 0.5 IU/kg/week s.c. daily; afterward, the dose was increased to 1 IU/kg/week s.c. daily. The girls were prepubertal, with a mean (SD) chronological age (CA) of 12.5 (2.6) years, and a mean (SD) bone age of 10.5 (1.8) years. A clonidine stimulation test, 1-29 GHRH test and GH spontaneous nocturnal secretion assessment were performed in all patients. Results showed a variable pattern of GH secretion in 10 patients, in only 2 did we find all values definitely normal, and in 3 we found a total GH deficiency. Height velocity, expressed as standard deviation scores (SDS) for CA according to Turner references, during the first year of treatment increased significantly: 0.36 (1.15) -3.30 (2.87) (p < 0.001), and the increment remained quite unchanged during both the second and third years: 3.16 (2.96) and 2.55 (3.87), respectively (n.s.). Height, expressed in SDS for CA for Turner references, increased significantly throughout the whole period of treatment and reached the highest value at the end of the third year of therapy. GH secretion parameters poorly correlated with pretreatment auxological data or response to treatment. Our long-term study confirms that in TS GH measurement is not useful in indicating hGH therapy or in predicting the response.     

The physical phenotype of girls and women with Turner syndrome is not X-imprinted

Certain behavioral and metabolic aspects of Turner syndrome (TS) are attributed to X-chromosome genomic imprinting. To investigate the possible contribution of imprinting to the physical features of the TS phenotype in live-born individuals, we genotyped the single normal X-chromosome in subjects with TS who all underwent a comprehensive evaluation as part of the NIH genotype–phenotype protocol. All had physical examinations, auxological measurements and imaging of the renal and cardiovascular systems. Absolute height and height as a percent of predicted height was the same in X^M (n = 56) and X^P (n = 23) subjects that had reached final height and were not growth hormone treated. Interestingly, adult height was significantly correlated with maternal but not paternal heights in both X^M and X^P groups. Neck webbing was found in 35% of the X^M (n = 133) and 22% of the X^P (n = 50) groups (P = 0.11). Renal anomalies were present in 24% of X^M and 25% of X^P groups (P = 0.9). Bicuspid aortic valve was found in 26% of X^M and 24% of X^P groups (P = 0.83), and any cardiovascular anomaly (abnormal aortic valve, aortic coarctation, elongated transverse aortic arch, anomalous pulmonary venous connection, left superior vena cava) affected 55% of X^M and 52% of X^P groups. Thus, we found no evidence for X-linked genomic imprinting effects on stature or lymphatic, renal or cardiovascular development in TS. Our sample size was sufficient to exclude such effects within 95% confidence limits. We did demonstrate a selective maternal effect on final stature that was independent of X-chromosome origin, suggesting potential autosomal imprinting effects on growth revealed by X monosomy.     

Long-term treatment of growth hormone insensitivity syndrome with IGF-I. Results of the European Multicentre Study. The Working Group on Growth Hormone Insensitivity Syndromes.

A total of 33 patients (17 female, 16 male) with Laron syndrome (n = 31) or hGH-1 gene (n = 2, type IA deletion) from 22 centres in 12 countries were enrolled in a study conducted by Pharmacia & Upjohn, Stockholm, which was designed to test the efficacy, in terms of growth promotion and safety, of IGF-I (Igef(TM)). The patients were treated with 40-120 microg/kg IGF-I s.c. twice daily after meals. After the study ended, the patients continued to be treated on an individual basis. The results of 17 patients, who were treated for 48 months or longer were available for the present analysis. Six patients were treated for up to 72 months. When treatment started, the mean age of these patients (8 female, 9 male) was 9.1 (3.7-13.5) years and mean height was -6.5 +/- 1.3 SDS. At the end of the observation period, the mean age of the 17 patients was 14.2 (9.1-17. 7) years and mean height was -4.9 +/- 1.9 SDS. All patients showed a significant increase in growth during the final year on IGF-I, with two of them reaching the age-corresponding 3rd centile. The total gain in height (DeltaHT) was 1.7 +/- 1.2 SDS. DeltaHT SDS correlated negatively with age at onset of treatment (R(2) = -0.78, p < 0.02). BMI was 0.6 +/- 1.8 SDS at start of treatment and 1.8 +/- 1.5 SDS at the end of observation. Total DeltaHT SDS correlated positively with total DeltaBMI SDS (R(2) = 0.59, p < 0.01). Long-term treatment of patients with GHIS thus proved to be effective in promoting growth. If treatment is started at an early age, there is considerable potential for achieving height normalisation. The treatment modalities need to be optimized with respect to the growth-promoting and metabolic effects of IFG-I.     

Comparison of four computerized models to estimate 24-hour growth hormone secretion in girls with Turner's syndrome.

Daily pituitary growth hormone (GH) secretion can be estimated from a 24-hour GH profile by various methods. We have used four methods to assess GH secretion in 36 girls with Turner's syndrome: the method described by Thompson et al., the Pulsar algorithm combined with the method of Hellman et al. and two deconvolution techniques. The number of detected peaks varied considerably among the methods. The mean (+/- SD) total daily secretion per square meter body surface was 0.53 (0.19) U/m2.day by deconvolution, in contrast to 0.31 (0.17) with the Hellman method and 1.06 (0.37) according to Thompson. The differences are explained by different assumptions about the metabolic clearance rate and various methodological aspects. Assuming a degradation rate of 50%, the growth hormone substitution dosage would be 1-2 IU/m2.day in GH-deficient children. The usual dosage in girls with Turner's syndrome is expected to lead to serum GH levels approximately 4 times higher than in the untreated state.     

Oestrogen deficiency and growth hormone treatment in childhood are not associated with hearing in adults with turner syndrome

BACKGROUND/AIMS: Women with Turner syndrome (TS) have an increased prevalence of hearing loss, with conductive (CHL) and sensorineural (SNHL) components. The association between hearing loss and clinical parameters, particularly oestrogen and previous growth hormone (GH) treatment, was investigated. METHODS: A cross-sectional study of pure tone audiometry tests in an adult TS population. Previous ENT history, karyotype, anthropomorphic measurements and the impact of oestrogen and childhood GH therapy were assessed. One hundred and thirty-eight women (median age 29, range 16-67 years) completed the study. RESULTS: Normal hearing was found in 20.3% of women, CHL in 18.8%, SNHL in 57.2% and confounding factors in 3.6%. Neither CHL nor SNHL were associated with oestrogen deficiency or GH treatment independent of age. CHL but not SNHL was more common in those with a history of recurrent otitis media (p < 0.01) and monosomy 45,X (p < 0.01). CONCLUSIONS: Current regimens of oestrogen and GH therapy have no impact on adult hearing loss in TS, independent of age. The prevalence of SNHL increases with age. CHL but not SNHL is associated with ENT history and karyotype. According to present evidence, the only possible intervention to reduce hearing loss in women with TS remains assiduous treatment of ENT problems in childhood.     

Validity of height velocity as a diagnostic criterion for idiopathic growth hormone deficiency and Turner syndrome.

A deflecting growth curve over several years is sometimes the only indication for the possible presence of a growth disorder. In this study we looked at the potential diagnostic role of long-term downward deflection of the growth curve. It reports on the diagnostic validity of height velocity over 1, 2 or 3 years for isolated idiopathic growth hormone deficiency and for Turner syndrome in prepubertal children with a height that is still above -2.5 standard deviation scores (SDS). 1-year height velocity was found to have no diagnostic value because of an almost complete overlap of height velocity distributions with normal prepubertal children. However, height velocity over 3 years was found to have an acceptable validity in children 5-12 years old. In this age range a change in height SDS of -0.75 can be used as a valid criterion for further examination of karyotype and GH secretion capacity even if there are no other clear signs of a particular growth disorder.     

Thyroid hormone dysregulation in intrauterine growth retardation associated with maternal malnutrition and/or anemia.

Data on the effect of maternal malnutrition and/or anemia on thyroid hormone regulation in human fetuses are scarce, and would be of great importance in examining the relevance of Barker's hypothesis, which proposes adaptation of fetuses to undernutrition leading to permanent metabolic and endocrine changes that form the basis of adult diseases. To examine the quantitative variations in thyroid hormone profile of neonates born to malnourished and/or anemic mothers, we quantitated the T3, T4, rT3 and TSH levels in cord blood of neonates and maternal blood of their corresponding mothers that are malnourished and/or anemic. Further, we classified neonates born to each of these groups of mothers into Small for Gestational Age (SGA) or Appropriate for Gestational Age (AGA) based on the intrauterine growth curve for our population, and examined the thyroid hormone profile in these neonates. Our results show that firstly, the effects of malnutrition or anemia on thyroid hormone profile are distinct, secondly, significantly higher levels of cord blood T4 and correspondingly lower levels of T3 and rT3 are observed in the neonates born to anemic and malnourished mothers and thirdly, decreases in cord blood T3 levels were observed in Small for Gestational Age neonates born to anemic mothers. These observations lead us to speculate that alterations in the pituitary-thyroid function result in beneficial adaptations to the hostile intrauterine environment in malnutrition related growth retardation and anemia.     

Lower growth hormone and higher cortisol are associated with greater visceral adiposity, intramyocellular lipids, and insulin resistance in overweight girls

Although body composition, insulin sensitivity, and lipids are markedly altered in overweight adolescents, hormonal associations with these parameters have not been well characterized. Growth hormone (GH) deficiency and hypercortisolemia predispose to abdominal adiposity and insulin resistance, and GH secretion is decreased in obese adults. We hypothesized that low-peak GH on the GH-releasing hormone (GHRH)-arginine stimulation test and high cortisol in overweight adolescents would be associated with higher regional fat, insulin resistance, and lipids. We examined the following parameters in 15 overweight and 15 bone age-matched control 12- to 18-yr-old girls: 1) body composition using dual-energy X-ray absorptiometry and MR [visceral and subcutaneous adipose tissue at L(4)-L(5) and soleus intramyocellular lipid ((1)H-MR spectroscopy)], 2) peak GH on the GHRH-arginine stimulation test, 3) mean overnight GH and cortisol, 4) 24-h urinary free cortisol (UFC), 5) fasting lipids, and 6) an oral glucose tolerance test. Stepwise regression was the major tool employed to determine relationships between measured parameters. Log peak GH on the GHRH-arginine test was lower (P = 0.03) and log UFC was higher (P = 0.02) in overweight girls. Log mean cortisol (overnight sampling) was associated positively with subcutaneous adipose tissue and, with body mass index standard deviation score, accounted for 92% of its variability, whereas log peak GH and body mass index standard deviation score accounted for 88% of visceral adipose tissue variability and log peak GH for 34% of the intramyocellular lipid variability. Log mean cortisol was independently associated with log homeostasis model assessment of insulin resistance, LDL, and HDL and explained 49-59% of the variability. Our data indicate that lower peak GH and higher UFC in overweight girls are associated with visceral adiposity, insulin resistance, and lipids.     

Effects of interleukin-1-beta,interleukin-6 and tumor necrosis factor-alpha,alone or in association with hexarelin or galanin,on growth hormone gene expression and growth hormone release from pig pituitary cells

OBJECTIVE: We studied the effects of IL-1beta, IL-6 and TNF-alpha on GH gene expression and secretion with or without galanin and hexarelin. METHODS: Pituitary cells from adult pigs were treated with IL-1beta, IL-6 or TNF-alpha (1, 10 and 100 ng/ml), alone or in association with galanin or hexarelin (10(-8) M): GH mRNA was measured by RT-PCR and GH secretion by ELISA. RESULTS: IL-1beta (1, 10 and 100 ng/ml) and IL-6 (1 and 10 ng/ml) significantly (p < 0.05) enhanced GH output. IL-1beta and TNF-alpha (1 and 10 ng/ml) reduced (p < 0.05) the galanin-induced GH secretion and IL-6 (10 ng/ml) potentiated the effect of both GH releasers (p < 0.05). GH gene expression was increased only by IL-6 at the concentrations of 1 and 10 ng/ml, either alone or in association with both galanin and hexarelin. CONCLUSIONS: We hypothesize that cytokines may play a paracrine/autocrine role in GH regulation in the pituitary independently from the intracellular pathways of the GH secretagogues.     

Psychosocial functioning, self-perception and body image and their auxologic correlates in growth hormone and oestrogen-treated young adult women with Turner syndrome

BACKGROUND: Few data are available on the psychosocial status of growth hormone (GH) and oestrogen treated women with Turner syndrome (TS). In this study, we evaluated psychosocial functioning, self-concept and body image in GH and oestrogen treated young adult women with TS and we studied the relationship with auxological parameters. PATIENTS AND METHODS: Thirty women with TS (mean +/- SD age: 22.1 +/- 2.4 years), all treated with GH and oestrogens if indicated, and an age-matched reference group of 44 non-Turner female students (age: 20.5 +/- 2.1 years) completed 3 questionnaires evaluating, respectively, behavioural and emotional problems (Young Adult Self Report), self-concept (Self Perception Profile for College Students) and body-image (Body Attitude Scale). RESULTS: TS patients did not report more behavioural and emotional problems compared to the non-TS females except for attention problems; they even reported fewer problems on some subscales (somatic complaints, thought problems, delinquent behaviour). TS patients did not differ from the non-TS female group in their bodily satisfaction. TS patients, particularly patients with a 45,X karyotype, perceived themselves as less socially competent. BMI was significantly related to the appraisal score of the Body Attitude Scale, whereas height was not related to any of the evaluated psychosocial parameters. CONCLUSION: The psychosocial adaptation of young adult women with TS, diagnosed at an early age and treated during childhood with GH and oestrogens if indicated, appears to be quite satisfactory. Follow-up of adult TS patients should not neglect the problem of overweight and associated psychosocial consequences.