Morning versus evening administration of estradiol to girls with turner syndrome receiving growth hormone: impact on growth hormone and metabolism. A randomized placebo-controlled crossover study.

UNLABELLED: Timing of 17beta-estradiol (E2) administration in relation to that of GH could influence the "first pass effect" of E2 on hepatic IGF-I secretion. In order to test this hypothesis, a randomized double-blind placebo-controlled crossover study was conducted. Nine Turner girls (12.8-20.0y) were treated for 2 mo periods with GH 0.1 IU/kg/d sc at bedtime, and oral E2 6-11 microg/kg/d in the morning and placebo in the evening in one 2-mo period and vice versa in the other period. After each period, 24-h blood sampling was performed. IGF-I and mean 24-h integrated GH were comparable. However, the IGF-I/IGFBP-3 ratio was higher (p = 0.05) and insulin levels were lower after evening administration of E2 (24 h: p = 0.03). During an oral glucose tolerance test in the morning, glucagon and insulin were lower following evening E2 administration (ANOVA: glucagon, p = 0.03; insulin, p = 0.04), as well as insulin resistance tended to be lower (p = 0.09). CONCLUSION: The timing of oral E2 supplementation modulates the IGF-I/IGFBP-3 ratio, insulin and glucagon levels in Turner syndrome during GH treatment, Evening administration of oral estrogen together with evening injections of GH may be preferable.

Occurrence of gonadoblastoma in females with Turner syndrome and Y chromosome material: a population study.

The presence of Y chromosome material in patients with Turner syndrome is a risk factor for the development of gonadoblastoma. However, no cases with gonadoblastoma or other ovarian malignancies have been found in epidemiological studies of cancer, morbidity, or mortality in Turner syndrome. We examined 114 females with Turner syndrome for the presence of Y chromosome material by PCR. Initially, five different primer sets were used. Y Chromosome-positive individuals were further examined with an additional four primer sets. We found 14 (12.2%; 95% confidence interval, 6.9-19.7%) patients who had Y chromosome material. The karyotype in 7 of these patients did not suggest the presence of Y chromosome material. Seven of the patients had been ovariectomized before entering the study due to verified Y chromosome material, whereas three patients were operated upon after the DNA analysis. The histopathological evaluations showed that 1 of the 10 ovariectomized patients actually had a gonadoblastoma. The rest of the patients did not have gonadoblastoma or carcinoma in situ on histopathological evaluation. Three patients (age, >50 yr) positive for Y chromosome material chose not to have ovariectomy performed, and detailed ultrasonographies did not suggest the presence of gonadoblastoma. The frequency of Y chromosome material is high in Turner syndrome (12.2%), but the occurrence of gonadoblastoma among Y-positive patients seems to be low (7-10%), and the risk may have been overestimated in previous studies, perhaps due to problems with selection bias. This study emphasizes the need for prospective unbiased studies.

Glucose metabolism, lipid metabolism, and cardiovascular risk factors in adult Turner's syndrome. The impact of sex hormone replacement.

OBJECTIVE: To examine glucose metabolism, blood pressure, physical fitness, and lipid metabolism in adult untreated women with Turner's syndrome compared with a group of normal women and to examine the effects of female sex hormone substitution on these factors. RESEARCH DESIGN AND METHODS: A total of 26 patients with Turner's syndrome were examined before and during sex hormone replacement with 17 beta-estradiol and norethisterone, and an age-matched control group (n = 24) was examined once. A frequently sampled intravenous glucose tolerance test was applied with minimal model assessment. We also performed an oral glucose tolerance test, measurement of 24-h ambulatory blood pressure, and assessment of physical fitness and lipid metabolism. RESULTS: Insulin sensitivity (SI) and glucose effectiveness (SG) were similar in Turner's syndrome patients and control subjects, whereas the acute insulin response (P = 0.03) was lower in Turner's syndrome patients, and no change was seen during sex hormone treatment. Abnormal glucose tolerance was found in 50% of Turner's syndrome patients before and 78% during treatment with sex hormones. Fat-free mass (FFM; P = 0.0005) and physical fitness (P = 0.002) were lower in Turner's syndrome subjects compared with control subjects. During treatment, an increase in FFM (P = 0.001) and physical fitness (P = 0.02) was seen in Turner's syndrome patients. Blood pressure was increased in Turner's syndrome, and a decrease was seen in diastolic blood pressure during treatment with sex hormones. CONCLUSIONS: Turner's syndrome is associated with glucose intolerance, diminished first-phase insulin response, elevated blood pressure, reduced FFM, and physical fitness. Sex hormone administration causes a deterioration in glucose tolerance, increases FFM and physical fitness, and has beneficial effects on blood pressure. The deleterious effect on glucose tolerance may be mediated by norethisterone, a gestagen known to have androgenic effects.

Morbidity in Turner syndrome.

Turner syndrome afflicts approximately 50 per 100,000 females and is characterized by retarded growth, gonadal dysgenesis, and infertility. Much attention has been focused on growth and growth promoting therapies, while less is known about the natural course of the syndrome, especially in adulthood. We undertook this study to assess the incidence of diseases relevant in the study of Turner syndrome. The study period was from January 1, 1984 to December 31, 1993, and the study base was all women living in Denmark during the study period. We used data from the Danish Cytogenetic Central Register and the Danish National Registry of Patients to assess morbidity. This study supports several earlier studies reporting increased morbidity and confirms results of a recent study on cancer in Turner syndrome. Women with Turner syndrome seem to have an increased incidence of fractures, osteoporotic fractures in adulthood, and non-osteoporotic fractures in childhood. Furthermore, diabetes mellitus, both NIDDM and IDDM, was found with a markedly increased incidence in Turner syndrome, as well as ischemic heart disease, hypertension, and stroke. The risk of cancer, except cancer of the large bowel, does not seem to be elevated in Turner syndrome. Our data suggest that patients with Turner syndrome are extraordinarily prone to abnormalities constituting the metabolic syndrome (e.g., hypertension, dyslipidaemia, NIDDM, obesity, hyperinsulinemia and hyperuricemia). The present data may help to explain the decreased life span found in patients with Turner syndrome.

Reference values for height, height velocity and weight in Turner's syndrome. Swedish Study Group for GH treatment.

As Northern Europeans are currently the tallest people in the world, specific growth charts for girls with Turner's Syndrome from this area are needed. Based on height and weight measurements from 598 girls with Turner's Syndrome (372 from the Netherlands, 108 from Denmark, 118 from Sweden) not treated with growth-promoting substances and without signs of spontaneous puberty, we constructed growth charts for height-for-age, height-velocity-for-age, weight-for-age, weight-for-height and Body Mass Index for age. Reference tables and regression equations for mean and standard deviation are provided allowing calculation of Standard Deviation Scores. The height and height velocity curves show a low birth length, gradual deviation from the normal percentile curves without pubertal growth spurt, and a prolonged growth until the early 20s. Mean adult height was 146.9 +/- 7.8 cm. Mean weight-for-age was lower than in normal reference children but height-adjusted weight was higher, except in infancy and early childhood. Further studies are required on the factors influencing the weight-height relationship in Turner's Syndrome.

Body composition and physical fitness are major determinants of the growth hormone-insulin-like growth factor axis aberrations in adult Turner's syndrome, with important modulations by treatment with 17 beta-estradiol.

The objectives of this study were to 1) study the GH-insulin-like growth factor (IGF) axis in adult untreated Turner's syndrome compared to that in age-matched controls; 2) examine the effects of sex hormone substitution on this axis, 3) study the effects of route of administration of 17 beta-estradiol on the measured variables, and 4) examine the effects of sex steroids on hepatic function in Turner patients. Twenty-seven patients with Turner's syndrome were evaluated before and during sex hormone replacement, and an age-matched control group (n = 24) was evaluated once. Main outcome variables were GH and other measures of the GH-IGF axis, body composition, maximal oxygen uptake, sex hormone-binding globulin, and hepatic enzymes and proteins. The integrated 24-h GH concentration (IC-GH; micrograms per L/24 h) was reduced in women with Turner's syndrome (T) compared to controls [C; mean +/- SD, 18.3 +/- 12.0 (T) vs. 37.2 +/- 29.7 (C); P = 0.007]. However, multiple regression revealed that fat-free mass (FFM) and maximal oxygen uptake were significant explanatory variables (joint r = 0.77; P < 0.0005), accounting for 60% of the variance in the 24-h IC-GH. This association was also present in controls. After adjustment for these two variables, any difference in GH concentration between Turner patients and controls disappeared. Serum IGF-I and IGF-II were identical in Turner patients and controls despite the difference in 24-h IC-GH. The level of GH-binding protein (GHBP; nanomoles per L) was higher in Turner women [1.87 +/- 0.72 (T) vs. 1.22 +/- 0.33 (C); P = 0.0005]; after adjustment for FFM, the difference in GHBP levels disappeared between Turner patients and controls. During sex hormone treatment a significant increase was seen in the 24-h IC-GH (P = 0.02), FFM (percentage of weight; P < 0.0005) and maximal oxygen uptake (milliliters of O2 per kg/min; P = 0.02). Serum IGF-I was unchanged, whereas serum IGF-II (micrograms per L) decreased significantly [Turner, basal (TB), vs. Turner, treatment (TT), 860 +/- 135 vs. 823 +/- 150; P = 0.04]. Alanine aminotransferase (units per L), gamma-glutamyl transferase (units per L), and alkaline phosphatase (units per L) were significantly elevated during the basal study period, and all decreased during treatment [alanine amino-transferase, 55 +/- 55 (TB) vs. 30 +/- 20 (TT; P = 0.006); gamma-glutamyl transferase, 92 +/- 98 (TB) vs. 43 +/- 65 (TT; P = 0.003); alkaline phosphatase, 211 +/- 113 (TB) vs. 175 +/- 54 (TT); P = 0.06]. The route of administration of 17 beta-estradiol did not affect its actions. In conclusion, we found the GH-IGF axis in Turner's syndrome to be normal, with body composition and physical fitness exerting the same modifying effects on this axis as seen in the normal population. Sex hormone replacement in Turner's syndrome is associated with normalizing effects on the GH-IGF axis, body composition, physical fitness, and hepatic function. The lowering of hepatic enzymes is a surprising and hitherto undiscovered action of sex steroids. Finally, the route of administration of 17 beta-estradiol is of minor importance in Turner's syndrome.

[Prenatal and postnatal prevalence of Turner syndrome. A registry-based study]. / Praenatal og postnatal praevalens af Turners syndrom. Et register-studie.

The prevalence of Turner's syndrome in Denmark 1970-1993 was studied and the validity of prenatal diagnosis was assessed. The study was conducted on prenatal and postnatal Turner's syndrome in the Danish Cytogenetic Central Register. All registered Turner's syndrome karyotypes (100 prenatal cases and 215 postnatal cases) at the Danish Cytogenetic Central Register were included. The main outcome measures were prevalence of Turner's syndrome karyotypes among prenatally tested fetuses and Turner's syndrome among liveborn infants. The results showed that among infant girls, prevalence of Turner's syndrome was 32/100,000. Among female fetuses tested by amniocentesis, prevalence of Turner's syndrome karyotypes was 176/100,000 (relative risk of syndrome, 6.74 compared with prevalence among untested pregnancies). Among female fetuses tested by chorion villus sampling, prevalence of syndrome karyotypes was 392/100,000 (relative risk, 16.8). We excluded prenatal tests referred because of results of ultrasound scanning: among fetuses tested by amniocentesis revised relative risk was 5.68, while revised relative risk among fetuses tested by chorion villus sampling was 13.3. For 29 fetuses with prenatal diagnosis of possible Turner's syndrome, pregnancy was allowed to continue and 24 of the children were live born. Thirteen of the liveborn children were karyotyped postnatally, and the diagnosis of Turner's syndrome had to be revised for eight, seven being normal girls and one boy. This gives a tentative predictive value of amniocentesis in the diagnosis of Turner's syndrome between 21% and 67%. There was no significant relation between mother's age and risk of Turner's syndrome. In conclusion, a discrepancy between prenatal and postnatal prevalence of Turner's syndrome challenges the specificity of prenatal examination in diagnosing Turner's syndrome.

A regression method including chronological and bone age for predicting final height in Turner's syndrome, with a comparison of existing methods.

A total of 235 measurement points of 57 Dutch women with Turner's syndrome (TS), including women with spontaneous menarche and oestrogen treatment, served to develop a new Turner-specific final height (FH) prediction method (PTS). Analogous to the Tanner and Whitehouse mark 2 method (TW) for normal children, smoothed regression coefficients are tabulated for PTS for height (H), chronological age (CA) and bone age (BA), both TW RUS and Greulich and Pyle (GP). Comparison between all methods on 40 measurement points of 21 Danish TS women showed small mean prediction errors (predicted minus observed FH) and corresponding standard deviation (ESD) of both PTSRUS and PTSGP, in particular at the "younger" ages. Comparison between existing methods on the Dutch data indicated a tendency to overpredict FH. Before the CA of 9 years the mean prediction errors of the Bayley and Pinneau and TW methods were markedly higher compared with the other methods. Overall, the simplest methods--projected height (PAH) and its modification (mPAH)--were remarkably good at most ages. Although the validity of PTSRUS and PTSGP remains to be tested below the age of 6 years, both gave small mean prediction errors and a high accuracy. FH prediction in TS is important in the consideration of growth-promoting therapy or in the evaluation of its effects.

Prenatal and postnatal prevalence of Turner's syndrome: a registry study.

OBJECTIVE: To study prevalence of Turner's syndrome in Denmark and to assess validity of prenatal diagnosis. DESIGN: Study of data on prenatal and postnatal Turner's syndrome in Danish Cytogenetic Central Register. SUBJECTS: All registered Turner's syndrome karyotypes (100 prenatal cases and 215 postnatal cases) during 1970-93. MAIN OUTCOME MEASURES: Prevalence of Turner's syndrome karyotypes among prenatally tested fetuses and Turner's syndrome among liveborn infants. RESULTS: Among infant girls, prevalence of Turner's syndrome was 32/100,000. Among female fetuses tested by amniocentesis, prevalence of Turner's syndrome karyotypes was 176/100,000 (relative risk of syndrome, 6.74 compared with prevalence among untested pregnancies). Among female fetuses tested by chorion villus sampling, prevalence of syndrome karyotypes was 392/100,000 (relative risk, 16.8). We excluded prenatal tests referred because of results of ultrasound scanning: among fetuses tested by amniocentesis revised relative risk was 5.68, while revised relative risk among fetuses tested by chorion villus sampling was 13.3. For 29 fetuses with prenatal diagnosis of possible Turner's syndrome, pregnancy was allowed to continue and 24 children were live born. Thirteen of these children were karyotyped postnatally, and diagnosis of Turner's syndrome had to be revised for eight, seven being normal girls and one boy. This gives tentative predictive value of amniocentesis in diagnosing Turner's syndrome of between 21% and 67%. There was no significant relation between mother's age and risk of Turner's syndrome. CONCLUSIONS: Discrepancy between prenatal and postnatal prevalence of Turner's syndrome challenges specificity of prenatal examination in diagnosing Turner's syndrome.

Growth hormone and 17 beta-oestradiol treatment of Turner girls--2-year results.

Girls with Turner syndrome are mainly characterized by growth retardation and gonadal insufficiency. In order to evaluate the effect of growth hormone (GH) and/or low dose 17 beta-oestradiol (E2) on growth and pubertal development, 39 Turner girls with a chronological age (CA) of 7.6-18.1 years were divided into three groups depending on pretreatment bone age (BA). They were treated with either GH 0.1 IE/kg per day (n = 13, BA 7.1-10.2), peroral E2 0.01 mg/kg per day (n = 8, BA 8.5-12.7) or both (n = 18, BA 10.5-15.3). In the 2nd year the E2 group also received GH, while the E2 dose was reduced 30%. In the 1st year height velocity (HV) expressed as standard deviation scores (SDS) increased in all groups (mean): from -0.4 to 3.3 (P < 0.01) in the GH group, -0.5 to 2.7 (P < 0.01) in the E2 group, and -0.8 to 4.6 (P < 0.001) in the GH+E2 group. A possible synergistic effect from combination therapy was seen, as HV increase was higher in group 3 than groups 1 and 2 (P < 0.05). In the 2nd year HV was unchanged in groups 1 and 2, while a clear decrease was seen in the GH+E2 group (P < 0.001). In the 1st year BA progression in the E2 group was rapid (1.9 BA/CA year) and higher than in the other groups (P < 0.05). In the 2nd year progression slowed down--particularly in the E2 group (0.7 BA/CA year, P = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

Growth hormone dose regimens in adult GH deficiency: effects on biochemical growth markers and metabolic parameters.

OBJECTIVE: We examined the effects of different doses of GH on insulin-like growth factor I (IGF-I), IGF binding protein 3 (IGFBP-3), body composition, energy expenditure, and various metabolites in GH deficient adults, in order to approach a metabolically appropriate GH dosage in young GH deficient adults. DESIGN: Ten GH deficient patients (age 21-43) were studied after 4 weeks without GH followed by three consecutive 4-week periods, where the patients received in a fixed order GH 1, 2 and 4 IU/m2 s.c. per day. At the end of each period the patients were hospitalized for a 24-hour examination. RESULTS: Mean 24-hour levels of GH (mIU/l) were 2.7 +/- 0.3 (0 GH), 7.2 +/- 0.9 (1), 10.8 +/- 1.5 (2) and 18.9 +/- 2.7 (4 IU/m2) (mean +/- SEM) (P < 0.01). Likewise, IGF-I levels increased dose dependently from 61 +/- 21 to 206 +/- 65, 260 +/- 70 and 468 +/- 171 micrograms/l (P < 0.05); serum IGF-I in an age and sex matched control group was 248 +/- 25 micrograms/l. Corresponding serum IGFBP-3 levels also increased from 1860 +/- 239 to 3261 +/- 379, 3762 +/- 434 and 4384 +/- 652 micrograms/l (P = 0.01) respectively. Significant increases in diurnal serum insulin levels after 4 IU/m2 were recorded, whereas plasma glucose levels remained unchanged. Lipid intermediates increased dose independently during GH administration. GH caused a significant increase in resting energy expenditure, whereas the respiratory exchange ratio was unaltered. Fat mass was increased without GH therapy and decreased during the study. Four patients made complaints during 4 IU/m2 GH administration, probably related to GH induced fluid retention. CONCLUSION: Based primarily on IGF-I and IGFBP-3 levels our data suggest that a GH replacement dose in young GH deficient adults in the order of 1-2 IU/m2 per day is adequate. This is a relatively low dose as compared to dose regimens in children and adolescents.

[Treatment of girls with Turner's syndrome with growth hormone and estrogen--1-year experiences]. / Vaeksthormon- og østrogenbehandling af piger med Turner's syndrom--et års erfaringer.

Girls with Turner's syndrome are characterized by growth retardation and defective pubertal development, among other features. In this investigation, 40 girls with Turner's syndrome were treated with growth hormone in doses of 0.1 IU/kg/day (group 1, n = 14), oral oestradiol in doses of 0.01 mg/kg/day (group 2, n = 8) or a combination of these (group 3, n = 18), depending on the bone age. All three forms of treatment increased the height velocity significantly. The combined treatment increased the height velocity more than the growth hormone of oestradiol alone (p less than 0.05). In group 2, a pronounced progression of bone age leading to a decrease in the prognosis of final height was observed. The serum insulin-like growth factor I was unchanged in group 2 while this rose in groups 1 and 3. Pubertal development was, by and large, satisfactory. No serious side effects were observed. Treatment of girls with Turner's syndrome with growth hormone should not be supplemented with oestrogen prior to the bone age of 11 years. The initial dosage of oestradiol should be less than 0.01 mg/kg/day, but the subsequent increase should be adjusted individually.

Skeletal size and bone mineral content in Turner's syndrome: relation to karyotype, estrogen treatment, physical fitness, and bone turnover.

Bone mineral content (BMC), bone mineral density, and metacarpal dimensions were studied in 50 women with Turner's syndrome aged 21-45 years in relation to karyotype, estrogen treatment, physical fitness, and biochemical markers of bone turnover. No differences were found between the 25 women with karyotype 45.X and women with other karyotypes. Forty-six women had received estrogen. Significant partial correlations were found between bone mineral density of the forearm and duration of estrogen treatment and physical fitness. BMC of the lumbar spine corrected for vertebral height (BMC(C)spine) was directly correlated with duration of estrogen treatment and height, marginally correlated with physical fitness, and inversely correlated with age. Outer metacarpal width was positively correlated with duration of estrogen treatment, age at initiation of therapy, and body weight. The diameter of medullary space showed negative correlation with physical fitness and height, and positive correlation with age at initiation of estrogen treatment. Cortical thickness was positively correlated with duration of estrogen treatment, physical fitness, and height. No convincing effects of estrogen could be demonstrated in women below the age of 30. Above the age of 30, all bone mineral measurements were markedly elevated in women treated for longer than the average of this age group. BMC(C)spine was inversely correlated with biochemical markers of bone formation. Our results demonstrate that estrogen treatment and physical fitness are important determinants of bone mineral status in Turner's syndrome and add to the evidence that estrogen treatment increases BMC in Turner's syndrome.

Prediction of final height in Turner's syndrome. A comparative study.

Various methods are used for prediction of final height in girls with Turner's syndrome (TS), but their accuracy has not been systematically investigated or compared. We have compared predictions of final height made with the most commonly used methods in 20 Turner girls at ages 9.5-18 years. Growth standards based on growth and final height of 78 Danish Turner women were used for calculation of standard deviation scores (SDS). In order to provide the necessary basis for "index of potential height" (IPH) method, bone age development was determined from 74 X-rays of 38 untreated Turner girls aged 5.2-19 years. This method was further modified and improved for use in TS. Prediction methods based only on height and chronological age (CA) showed little difference from methods including bone age. The IPH method in our modification was more accurate than those of Bayley-Pinneau and Tanner. At younger ages the IPH method showed better results when using Tanner-Whitehouse 2 (TW2) bone age than when using Greulich-Pyle bone age. Accuracy of predictions were considerably improved by combining methods with and without allowance for bone age. Combinations including the IPH method based on TW2 bone age appeared to be the most accurate. Predictions of final height in Turner's syndrome should therefore be made by combining the IPH method and one of the methods based on height and CA.

Effect of oxandrolone on growth and final height in Turner's syndrome.

Thirty-two girls with Turner's syndrome aged 11.5-16.7 years were treated with oxandrolone (0.125 mg/kg/day). The treatment period was scheduled to 2 years. Height velocity (HV) was expressed in Standard Deviation Scores (SDS), calculated by growth standards for untreated Danish Turner-girls. For girls with initial bone age below 13 years HV increased significantly from a mean pretreatment value of -0.2 SDS (3.1 cm/year) to +3.5 SDS (5.6 cm/year) in the 1st year of treatment and +2.1 SDS (4.1 cm/year) in the 2nd year. Mean bone age velocity during treatment was 0.9 year/year. Twenty-two girls have reached final height. Predictions of their final height were made by three different methods and compared to observed final height. A significant (p less than 0.001) improvement in the order of 3-4 cm was found for girls with initial bone age below 13 years, while girls with higher initial bone age had no height gain (p greater than 0.3). Side effects were seen in 16% of the girls.

Standards for growth and final height in Turner's syndrome.

Data on birth, growth and final height were collected retrospectively for 78 women with Turner's syndrome born 1955-66. Seventy-one had received estrogen treatment from a mean age of 17.7 years (SD = 2.0 years), while 7 were spontaneously menstruating. At birth Turner girls were 440 g lighter (p less than 0.001) and 1.4 cm shorter (p less than 0.001) than 46,XX girls. Standards for untreated growth were established for the age period 6.5-17.5 years, while growth after 17.5 years was described in both untreated and estrogen treated women. Analysis of growth pattern showed that though no pubertal growth spurt was present, the steady decrease of height velocity (HV) was interrupted at the age of 9 years. HV was then constant until 12 years of age, whereafter it slowly decreased. Mean final height (FH) was 146.8 cm (SD = 5.8 cm, n = 76) compared to 166.8 cm in the general female population. No difference was found between 45,X women and women with other karyotypes (p greater than 0.7). Correlations between FH and parental heights, birthweight and birthlength were similar to those reported for normal women (19). FH varied with age at diagnosis. Those diagnosed after 17 years of age had a mean FH = 151.3 cm, while those diagnosed before had a mean FH = 145.8 cm (p less than 0.001).