Final height gain by GH therapy in children with idiopathic short stature is dose dependent.

Recombinant human GH therapy to children with idiopathic short stature (ISS) increases growth velocity, but its effect on final height (FH) is still uncertain. The aim of this study was to investigate the effect of recombinant human GH on FH of patients with ISS who were treated according to two protocols in comparison to untreated historical controls. In study 1 (n = 24), all patients were treated with 14 IU (4.6 mg)/m(2) body surface x wk in the first year; thereafter the dosage was doubled if the growth response was insufficient. In study 2 (n = 34), patients were randomized into three arms: 18 IU (6 mg)/m(2) x wk; 27 IU (9 mg)/m(2) x wk; and 18 IU/m(2) x wk in the first year, followed by 27 IU/m(2) x wk thereafter. Observed or estimated FH was available for 53 patients. Thirty-four untreated controls from the same centers were available for comparison. Mean FH SD score in GH-treated children was -2.1, vs. -2.4 in controls (-2.4) (NS), but height SD score gain (1.3 vs. 0.7) and the difference between FH and predicted adult height (4.0 vs. 0.8 cm) were significantly greater. The growth response on an initial dosage of 27 IU/m(2) x wk (6.9 cm) was significantly better than on other regimens (2.8 cm). We conclude that a GH dosage of 27 IU (9 mg)/m(2) x wk to prepubertal children with ISS leads to a mean FH gain of approximately 7 cm, whereas regimens starting on lower dosages are less efficacious.

The rise of estradiol and inhibin B after acute stimulation with follicle-stimulating hormone predict the follicle cohort size in women with polycystic ovary syndrome, regularly menstruating women with polycystic ovaries, and regularly menstruating women with normal ovaries.

Polycystic ovaries contain a larger number of antral follicles than control ovaries. The aim of this study was to test whether the increase in estradiol (E(2)) and inhibin B after stimulation with 300 IU recombinant FSH in the early follicular phase and the ovarian volume can predict the size of the follicle cohort in polycystic ovary syndrome (PCOS) patients (n = 10), patients with polycystic ovaries detected by ultrasound but with regular menstrual cycles (PCO; n = 10), and regularly menstruating patients with normal ovaries (n = 10). The follicle cohort size was measured as the FSH-sensitive follicles growing during a standardized in vitro fertilization stimulation. Linear regression analysis showed that the slopes of the regression lines of the E(2) increment and the inhibin B increment in relation to the number of follicles were not significantly different among the three groups, meaning that an increased sensitivity for FSH of the granulosa cells of polycystic ovaries was not found. For the total group (n = 30) we calculated that an E(2) increment of 100 pmol/L predicts 5.5 follicles (95% confidence interval, 2.8--8.2; r = 0.617; P < 0.001), and an inhibin B increment of 100 ng/L predicts 6.2 follicles (95% confidence interval, 3.5--9.0; r = 0.665; P < 0.001). The ovarian volume could not be used in a prediction model because the association with the number of follicles was different in the PCO group compared with the PCOS and the control group. Women with PCO and women with PCOS both had a follicle cohort twice as big as the cohort in control women (P < 0.01). The differences in menstrual cycle pattern between the PCO and PCOS groups cannot be explained by differences in cohort size.

Corticosteroids do not influence ovarian responsiveness to gonadotropins in patients with premature ovarian failure: a randomized, placebo-controlled trial.

OBJECTIVE: To determine the effect of corticosteroids on ovarian responsiveness to exogenous gonadotropins in patients with idiopathic premature ovarian failure (POF). DESIGN: Placebo-controlled, randomized, double-blind, multicenter study. SETTING: Two tertiary care academic centers for reproductive endocrinology and fertility and two general teaching hospitals. PATIENT(S): One hundred patients with idiopathic POF intended to enter the study. The study was discontinued after 36 patients failed to ovulate. INTERVENTION(S): Endocrine and immune parameters were tested on days 1 and 15. On day 1, subjects were randomized to receive either 9 mg of dexamethasone daily or placebo. From day 5 onward, 300 IU of hMG daily was added for 10 days in both groups. The dosage of dexamethasone was decreased stepwise in the second week and discontinued after day 15. Patients were monitored by transvaginal ultrasonography and by determining serum E2 levels. MAIN OUTCOME MEASURE(S): Ovulation rate. Fifty patients would have to be included in each study group to detect a statistically significant difference of 20% in the ovulation rate between the two groups with alpha = 0.05 and beta = 0.1 (one-tailed test). RESULT(S): No ovulation was recorded in the first 36 patients. Interim analysis showed that the 95% confidence intervals of an ovulation rate of 0 were 0-17% for the dexamethasone arm (n = 19) and 0-19% for the placebo arm (n = 17). Because the preset objective (a difference of 20%) would never be reached, the study was discontinued. CONCLUSION(S): Corticosteroids do not influence ovarian responsiveness to gonadotropins in patients with idiopathic POF.

Influence of growth hormone treatment on pubertal timing and pubertal growth in children with idiopathic short stature. Dutch Growth Hormone Working Group.

We studied the influence of recombinant human growth hormone (rhGH) on pubertal timing and pubertal growth in children with idiopathic short stature (ISS), and evaluated whether this was different between children with and without intra-uterine growth retardation (IUGR). Twenty-six (18 M, 6 IUGR; 'treated') subjects were treated with rhGH (6-7 days/week, dosage: 14-28 IU/m2 per week [i.e. 0.2-0.3 mg/kg per week]). Fifty-eight subjects (31 M, 9 IUGR; 'controls') were not treated. All subjects attained final height. Prepubertal height gain was significantly larger in the treated children compared to control children (M: 0.66 SDS, 95% confidence interval [CI] 0.41 to 0.92; F. 0.92 SDS, CI 0.58 to 1.26). Pubertal height gain, peak height velocity and duration of puberty were similar for the treated and control subjects. rhGH advanced the age at peak height velocity by 0.7 years (CI 0.3 to 1.0) in boys, and the age at onset of puberty by 1.1 years (CI 0.3 to 1.9) in girls. The gain in final height was 2-3 cm. Age and height SDS at start were the most important predictors for pubertal height gain, total height gain and final height in a multivariate regression analysis. Total height gain of treated subjects with IUGR was less than that of treated subjects without IUGR. In conclusion, rhGH did not affect pubertal growth in children with ISS, and slightly improved their final height. rhGH treatment should be started early to improve height as much as possible before the onset of puberty.

Changes in body composition during 12 months after discontinuation of growth hormone therapy in young adults with growth hormone deficiency from childhood.

Little is known about the velocity of changes in body composition after discontinuation of GH therapy at final height. The aim of this study was to describe the changes of fat distribution in male and female GH deficient young adults during the first year after discontinuation of GH therapy. Ten Dutch GH deficient young adults who had reached final height were retested and confirmed to be still GH deficient. These preliminary results demonstrate that the greatest gain in subcutaneous fat, measured by skinfold thickness, was observed in the first 3 months after GH withdrawal. Intra-abdominal fat was measured by CT scan at 0 and 12 months study time. The mean gain in intra-abdominal fat after 12 months was dramatically high (48%). We conclude that the subcutaneous and intra-abdominal fat mass increased dramatically in young GH deficient Dutch adults with GH deficiency, after discontinuation of therapy, especially in the first three months. This indicates that GH therapy should be restarted as soon as possible, after reconfirming the diagnosis of GH deficiency in adults. This will reduce the risk for these patients of diseases associated with overweight, such as cardiovascular diseases.

Immunologic studies in children with idiopathic short stature before and during growth hormone therapy. Dutch Growth Hormone Working Group.

In 34 children with idiopathic short stature (ISS) we studied parameters of humoral and cellular immunity before and during growth hormone (GH) therapy. The patients were treated with recombinant human GH 3.0 or 4.5 IU/m2 body surface/day, 6 times/week. Leucocyte and lymphocyte counts, percentages of neutrophils, eosinophils, basophils and monocytes were available up to 4 years of therapy (n = 34) and lymphocyte subsets and serum immunoglobulins during the first year of treatment (n = 16). Differences between the measurements at the start and during therapy were tested by a mixed model ANOVA to repeated measurements. Before the start of GH therapy all parameters of immunity were within the normal range in these children. During the first months of treatment the leucocyte and lymphocyte counts decreased and at 6 months were significantly lower than at the start (p = 0.003 and p = 0.006, respectively). Thereafter leucocyte numbers no longer differed from baseline. Lymphocytes were again lower at 36 months (p = 0.001). The percentages of neutrophils, eosinophils, basophils, monocytes and lymphocyte subsets did not change during therapy. Serum IgA concentrations showed a transient decrease at 3 and 6 months of GH therapy (p = 0.01 and p = 0.02). The observed changes were not related to GH dosage or height velocity. We conclude that GH treatment in children with ISS induced a small decrease in leucocyte and lymphocyte counts and serum IgA concentrations.

Women with polycystic ovary syndrome gain regular menstrual cycles when ageing.

The aim of this study was to investigate if previously oligo- or amenorrhoeic polycystic ovary syndrome (PCOS) patients gain regular menstrual cycles when ageing. Women registered as having PCOS, based on the combination of oligo- or amenorrhoea and an increased LH concentration, were invited by letter to participate in a questionnaire by telephone. In this questionnaire we asked for the prevalent menstrual cycle pattern, which we scored in regular cycles (persistently shorter than 6 weeks) or irregular cycles (longer than 6 weeks). We interviewed 346 patients of 30 years and older, and excluded 141 from analysis mainly because of the use of oral contraceptives. The remaining 205 patients showed a highly significant linear trend (P < 0.001) for a shorter menstrual cycle length with increasing age. Logistic regression analysis for body mass index, weight loss, hirsutism, previous treatment with clomiphene citrate or gonadotrophins, previous pregnancy, ethnic origin and smoking showed no influence on the effect of age on the regularity of the menstrual cycle. We conclude that the development of a new balance in the polycystic ovary, solely caused by follicle loss through the process of ovarian ageing, can explain the occurrence of regular cycles in older patients with PCOS.

Longitudinal analysis of growth in children with idiopathic short stature.

In this study the growth curves of 229 children (145 boys, 84 girls ) with idiopathic short stature (ISS) were analysed in three ways: (1) we compared the results of longitudinal modelling by means of Karlberg's ICP model with those of a cross-sectional analysis; (2) we studied to what extent an individual changes his/her height standard deviation score (SDS) position during childhood; and (3) we constructed height velocity curves for children with ISS using Cole's LMS method, and compared these with the British references. During childhood the difference between the average longitudinal and the cross-sectional height curves was less than 1 cm and the spread was almost identical. The average change in height SDS during childhood was not different from zero, indicating that in general growth of children with ISS was well canalized. The individual change in height SDS position during childhood was within 0.6 SDS for a follow-up of 1 year, increasing to 1.9 SDS for a follow-up of 7 years. During childhood mean height velocity was about 1 cm/year lower than that of the British reference. With respect to the pubertal growth spurt the maximum height velocity took place 1 year later, and was 0.6 cm/year lower than the British reference in boys as well as girls. We conclude that spontaneous growth of children with ISS adequately described by a cross-sectional curve.

Quality of life of young adults with idiopathic short stature: effect of growth hormone treatment. Dutch Growth Hormone Working Group.

The aim of the study was to evaluate whether treatment with recombinant human growth hormone (rhGH) affects the quality of life of young adults who were diagnosed as idiopathic short stature (ISS) during childhood, and whether their quality of life and aspects of the personality are different from normal. Experiences and expectations concerning rhGH treatment of the subjects and their parents were also investigated. Eighty-nine subjects were included into the study: 24 subjects (16M, 8F) were treated with rhGH from childhood, whereas 65 subjects (40M, 25F) were never treated. At the time of the interview all subjects had attained final height [mean (SD) -2.3 (0.9) SDS for Dutch references], and the age of the treated subjects was 20.5 (1.0) y, and 25.7 (3.5) y of the control subjects (p < 0.001). The level of education was similar, but the treated subjects had less often a partner compared to the control subjects (adjusted for age and gender, p < 0.001). The Nottingham Health Profile and Short Form 36 Health Survey showed no difference in general health state between treated and control subjects, and the healthy Dutch age-specific references (norm group). Although 74% of the subjects reported one or more negative events related to their height, and 61% would like to be taller, only 22% and 11% were willing to trade-off at Time Trade-Off and Standard Gamble, respectively. The personality of the subjects, which was measured by the Minnesota Multiphasic Personality Inventory, was not different from the norm group. The satisfaction with the rhGH treatment was high, as it had caused 12 (8) cm and 13 (7) cm gain in final height according to the subjects and parents, respectively. Based on initial predicted adult height (Bayley & Pinneau), this gain was only 3.3 (5.6) cm. We concluded that although the treated subjects had a partner less often when compared to the control subjects, the quality of life of subjects with ISS at adult age is normal and appears not to be affected by rhGH therapy, The treated subjects were very satisfied with the treatment, probably by overestimation of the final height gain.

Birth weight corrected for gestational age is related to the incidence of Down's syndrome pregnancies.

Three recent studies reported that early depletion of the primordial follicle pool is likely to be an independent risk factor for Down's syndrome pregnancies. The size of the primordial follicle pool at birth is determined by oogenesis and by the rate of follicle atresia during the intra uterine period. Since intra uterine growth retardation was reported to be associated with a significantly reduced primordial follicle pool at birth, we investigated the possibility of a relation between low birth weight for gestational age and the risk of a Down's syndrome pregnancy. In a case control study, 95 women with a history of a Down's syndrome pregnancy and 85 controls provided information on their own birth weight and length of gestation. Birth weight standard deviation scores, indicating the difference in birth weight from a reference group, were significantly lower in Down's syndrome mothers than in controls. These findings illustrate that the risk of a Down's syndrome pregnancy is related to a low birth weight corrected for gestational age, possibly by a causal relation between intra uterine growth retardation and the size of the primordial follicle pool.

Ligation of the uterine artery and early postnatal food restriction - animal models for growth retardation.

Intrauterine growth restriction (IUGR) is one of the major causes of short stature in child- and adulthood. The cause of IUGR is unknown, however, an impaired uteroplacental function during the second half of human pregnancy might be an important factor, by affecting the programming of somatotropic axis and leading to postnatal growth failure into adulthood. Two rat models with perinatally induced growth retardation were used to examine the long-term effects of perinatal insults on growth. IUGR rats were prepared from pregnant dams, with a bilateral uterine artery ligation at day 17 of their pregnancy. Since the rat is relatively immature at birth, an early postnatal food restriction model was included as another model to broaden the time window of sensitive period of organogenesis. An individual growth curve was calculated of each animal (n = 813). From these individual growth curves the predicted growth curve for each experimental group was calculated by multilevel analysis. The proposed mathematical model allows us to estimate the growth potentials of these rat models with precision and could provide basic information to investigate the relationships among a number of other variables in future studies. Furthermore, we concluded that both pre- and early postnatal malnutrition leads to irreversible slowing down of postnatal growth.

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.

Dose-finding study of triptorelin acetate for prevention of a premature LH surge in IVF: a prospective, randomized, double-blind, placebo-controlled study.

Gonadotrophin-releasing hormone agonists (GnRHa) are routinely used in IVF programmes to prevent an unwanted LH surge and consequent ovulation. Despite its widespread use in IVF, a convincing dose recommendation for GnRHa in IVF does not exist. In our opinion, the lowest possible dose of GnRHa should be used. Thus, we performed a prospective, randomized, double-blind, placebo-controlled study to determine the minimal daily dose of triptorelin acetate needed to suppress a premature LH surge during IVF treatment in a long protocol. A total of 240 women (60 in each group) was randomized to either placebo or to one of three doses of triptorelin, i.e. 15, 50 or 100 microg daily. Ovarian stimulation was performed with two or three ampoules of FSH daily. A premature LH surge occurred in 23% of placebo-treated patients, but in none of the triptorelin acetate-treated patients. There were significantly more oocytes and embryos in the 50 and 100 microg triptorelin groups. There was no dose relationship in rates of either implantation, pregnancy, ongoing pregnancy, live birth or baby take-home. In this study we showed that daily administration of 15 microg triptorelin is sufficient to prevent a premature LH surge, and that 50 microg is equivalent to 100 microg in terms of IVF results.

Adult height in patients with early onset of Crohn's disease.

BACKGROUND: Growth impairment during childhood and adolescence is a common problem faced by patients with an early onset of Crohn's disease. AIMS: To establish how the final adult height is affected in patients with early onset of symptoms of Crohn's disease. METHODS: Information on height, parental height, and disease history was obtained from 135 patients with Crohn's disease who reached their adult height (men 22-40 years, women 18-40 years) using a questionnaire and by outpatient measurement of height where possible. Subsequently, adult heights were expressed as standard deviation scores, with and without correction for the expected target height. RESULTS: Patients with onset of disease before puberty were shorter compared with patients with onset in adulthood (p<0.01). This difference was not statistically significant when adult heights were corrected for parental height. Also, height standard deviation scores for those patients with onset of disease before puberty were significantly lower than those with onset of disease during puberty (p<0.05) but after correction for parental height the difference was not significant. The site of disease had no influence on adult height. Patients who had used corticosteroids during puberty were significantly shorter than patients who had not (p=0.005). This was also true when corrected for target height (p=0.007). CONCLUSIONS: Although there was a trend indicating a deficit in adult height in patients with an early onset of Crohn's disease, once adjustment was made for parental height, this difference was not significant. Use of corticosteroids in puberty resulted in lower adult height.

Progressively motile human spermatozoa are well protected against in vitro lipid peroxidation imposed by induced oxidative stress.

Semen samples of 24 patients were analysed. Volumes were measured and the numbers of progressively motile (PMS), motile (MS) and nonmotile spermatozoa (NMS) were determined. These 24 samples appeared to show a large variation in motility percentages and numbers. Spermatozoa of these semen samples were isolated from the seminal plasma and exposed to induced radical oxygen stress imposed by iron/ascorbate. Lipid peroxidation (LPO) was quantified as thiobarbituric acid reactive material. The contributions of PMS, MS and NMS were also estimated. It was found that the PMS did not contribute to the formation of lipid peroxides. The cellular radical defence system of PMS may offer them adequate protection against the harsh conditions of radical oxygen stress. Stepwise regression analyses showed that only the population of NMS contributed significantly to the explanation of the variance in LPO production (R2 = 0.56, P < 0.001). Pre-existing membrane lipid peroxides were not detected in spermatozoa. It is therefore suggested that LPO takes place only after radical oxygen stress has exhausted the cellular defence system. LPO is not the initial, but one of the later, events leading to the death of spermatozoa. It is concluded that the population of progressively motile spermatozoa in semen samples does not contribute to the production of thiobarbituric acid reactive substances as induced by in vitro radical oxygen stress.

Growth hormone therapy with three dosage regimens in children with idiopathic short stature. European Study Group Participating Investigators.

OBJECTIVE: In children with idiopathic short stature (ISS) we studied the growth-promoting effect at 4 years of recombinant human growth hormone (rhGH) therapy in three dose regimens and evaluated whether increasing the dosage after the first year could prevent a decline in height velocity (HV). DESIGN: Included were 223 patients who were treated with subcutaneous administrations of rhGH 6 days per week. They were randomized to three groups: 3 IU/m2 body surface/day, 4.5 IU/m2/day, and 3 IU/m2/day during the first year and 4.5 IU/m2/day thereafter, corresponding with dosages of 0.2 and 0.3 mg/kg body weight/week, respectively. Growth was compared with a standard of 229 untreated children with ISS [ISS standard]. RESULTS: During the first year of treatment HV almost doubled and was higher with 4.5 IU/m2 than with 3 IU/m2. In the second year HV no longer differed among the groups, but increasing the dosage slowed the rate of the fall of HV. During 4 years of therapy the height SD score for age increased by a mean (SD) of 2.5 (1.0) [ISS standards], or 1.2 (0.7) (British standards), bone age increased by 4.8 (1.3) years, and predicted adult height SD score increased by 1.5 (0.7). After 4 years the results of the group with 4.5 IU/m2 were slightly better than those of the other groups. When dropouts were included in the analysis (assuming a stable height SD score after discontinuation of rhGH therapy), height gain was still significant. CONCLUSIONS: During 4 years of rhGH therapy, growth and final height prognosis improved, slightly more with 4.5 IU/m2 than with 3 IU/m2 or 3 to 4.5 IU/m2. However, bone age advanced on average 4.8 years during this period; therefore, any effect on final height will probably be modest.