A comparison of different definitions of growth response in short prepubertal children treated with growth hormone.

BACKGROUND: How to define poor growth response in the management of short growth hormone (GH)-treated children is controversial. AIM: Assess various criteria of poor response. SUBJECTS AND METHODS: Short GH-treated prepubertal children [n = 456; height (Ht) SD score (SDS) ≤-2] with idiopathic GH deficiency (IGHD, n = 173), idiopathic short stature (ISS, n = 37), small for gestational age (SGA, n = 54), organic GHD (OGHD, n = 40), Turner syndrome (TS, n = 43), skeletal dysplasia (n = 15), other diseases (n = 46) or syndromes (n = 48) were evaluated in this retrospective multicenter study. Median age at GH start was 6.3 years and Ht SDS -3.2. RESULTS: Median [25-75 percentile] first-year gain in Ht SDS was 0.65 (0.40-0.90) and height velocity (HtV) 8.67 (7.51-9.90) cm/year. Almost 50% of IGHD children fulfilled at least one criterion for poor responders. In 28% of IGHD children, Ht SDS gain was <0.5 and they had lower increases in median IGF-I SDS than those with Ht SDS >0.5. Only IGHD patients with peak stimulated growth hormone level <3 µg/l responded better than those with ISS. A higher proportion of children with TS, skeletal dysplasia or born SGA had Ht SDS gain <0.5. CONCLUSION: Many children respond poorly to GH therapy. Recommendations defining a criterion may help in managing short stature patients.

Management of polycystic ovary syndrome in childhood and adolescence.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women. It may manifest as early as in the first decade of life. Most often it becomes clinically apparent during adolescence with maturation of the hypothalamic-pituitary-ovarian axis. CLINICAL FEATURES: Typical features in adolescence include irregular menstrual cycles, acne, hirsutism, obesity and signs of insulin resistance such as acanthosis nigricans. Biochemical hyperandrogenism and polycystic ovaries are often present. However, some adolescents have no evidence of clinical and biochemical hyperandrogenism despite dysfunctional polycystic ovaries. PATHOGENESIS: The pathogenesis of PCOS is uncertain, however, both genetic and environmental factors play a role, resulting in key features of the syndrome; disordered gonadotropin release, dysregulated steroidogenesis, ovarian and adrenal hyperandrogenism and hyperinsulinism. PCOS is often accompanied by metabolic syndrome, with abnormalities in lipid and glucose metabolism. TREATMENT: Treatment of PCOS is symptomatic. Lifestyle changes are a first-line intervention, however, increasing evidence suggests that metformin and estrogen-progestin combination pill may be beneficial. CONCLUSIONS: PCOS is a lifelong condition that carries long-term health risks. Several risk factors for PCOS have been identified and clinicians should be alert for this condition already in childhood and adolescence. Early intervention and counseling might be the key for prevention of co-morbidities of PCOS.

Growth in children with poor-risk neuroblastoma after regimens with or without total body irradiation in preparation for autologous bone marrow transplantation.

Impaired growth after TBI prior to BMT has been a constant finding in children with leukemia. The growth of poor-risk neuroblastoma (NBL) survivors treated with myeloablative preparative regimens and ABMT at the Hospital for Children and Adolescents, University of Helsinki, since 1982 is reported. Two separate groups were analyzed: (1) The TBI- patients (n = 15) were conditioned with high-dose chemotherapy only. They had been treated at the age of 1.0-6.3 (mean 3.0) years and the post-ABMT follow-up time was 1.5-14.5 (mean 7.7) years. (2) The TBI+ patients (n = 16) had received TBI in addition to high-dose chemotherapy. They had been treated at the age of 1.3-4. 8 (mean 3.0) years, and the post-ABMT follow-up time was 1.5-8.0 (mean 4.7) years. The height standard deviation score (SDS) was similar for the two groups at the time of diagnosis, -0.3 +/- 1.2 (mean +/- s.d.), and at the time of ABMT, -0.7 +/- 1.1. After transplantation, the height SDS continued to decrease in the TBI+ group, the mean being -2.0 SDS at 5 years after ABMT. In the TBI-group, the mean height SDS remained within -0.7 to -0.9 to the 10 years of follow-up. Five patients received growth hormone (GH) therapy starting 2-6 years after ABMT. They all had low GH secretion in provocative tests. All showed some response to GH therapy. The mean height SDS increased 0.4 SDS during the 3 years following the start of GH therapy, while in the untreated patients a decrease of 0. 8 SDS during the corresponding time (P = 0.009) was observed. We conclude that NBL patients grow poorly following ABMT when TBI is included in the conditioning regimen, but close to normally when treated without TBI. The need for GH therapy should be evaluated early to avoid an unnecessary decrease in final height.

Plasma tacrine concentrations are significantly increased by concomitant hormone replacement therapy.

BACKGROUND: In vitro results suggest that the synthetic hormones used in postmenopausal hormone replacement therapy (HRT) may be significant inhibitors of oxidative drug metabolism. Moreover, HRT has been reported to enhance response to tacrine in postmenopausal patients with Alzheimer's disease, but the mechanism of this interaction remains unclear. OBJECTIVE: To examine the effect of HRT with 2 mg estradiol valerate and 0.25 mg levonorgestrel once daily on the pharmacokinetics of tacrine. METHODS: Ten healthy female volunteers received treatment for 10 days with once-daily HRT or placebo in a randomized, double-blind crossover study. One hour after the last HRT or placebo capsule on day 10, the subjects received a single 40-mg dose of tacrine. Plasma samples were collected for 30 hours and urine samples were collected for 24 hours after tacrine intake for the measurement of tacrine and 1-hydroxytacrine concentrations. RESULTS: HRT increased the mean plasma concentration-time curve calculated from zero to infinity (AUC) of tacrine by 60% (P = .009); the greatest individual increase in the AUC was about threefold. Similarly, the mean peak concentration in plasma of tacrine was 46% (P = .031) higher in the HRT phase compared with the placebo phase. HRT reduced the mean apparent oral clearance of tacrine by 31% (P = .014), but no significant difference was found in the elimination half-life or the renal clearance of tacrine between the HRT phase and the placebo phase. The metabolic ratio (1-hydroxytacrine AUC/tacrine AUC) was significantly (mean, 26%; P < .001) reduced in all 10 subjects. CONCLUSIONS: HRT with estradiol and levonorgestrel significantly increased plasma tacrine concentrations. This interaction between tacrine and HRT involves reduced metabolic conversion of tacrine to its main metabolite 1-hydroxytacrine by CYP1A2 during the first-pass phase. The interaction may be clinically important with regard to both enhanced efficacy and increased likelihood of concentration-dependent adverse effects of tacrine in the long-term treatment of patients with Alzheimer's disease. Accordingly, smaller doses of tacrine may be appropriate when coadministered with HRT.

Reduced bone mineral density in long-term survivors of childhood acute lymphoblastic leukemia.

PURPOSE: Osteoporosis and pathologic fractures are occasionally found in patients with childhood acute lymphoblastic leukemia (ALL). This study was performed to determine the degree of possible osteopenia in long-term survivors of childhood ALL. PATIENTS AND METHODS: Lumbar spine (L2-L4) and femoral neck bone mineral densities (BMDs) (g/cm2) were measured in 29 survivors (aged 12 to 30 years, median 17) of childhood ALL 2 to 20 (median 8) years after discontinuation of chemotherapy. These results were compared with those from 273 healthy controls and expressed as a percentage of the age- and sex-matched control values (mean +/- standard deviation). RESULTS: Lumbar and femoral BMDs were significantly reduced in survivors of childhood ALL. Particularly, male gender (lumbar: 91.7 +/- 10.4%, p = 0.008; femoral: 91.9 +/- 11.3%, p = 0.005) and a history of cranial irradiation (lumbar: 93.0 +/- 8.9%, p = 0.005; femoral: 94.4 +/- 13.3%, p = 0.03) were associated with low lumbar and femoral BMDs. CONCLUSIONS: The detected deficit in bone density in survivors of childhood ALL may predispose these patients to osteoporotic fractures later in adulthood. A follow-up of BMD in survivors of childhood ALL should facilitate the identification of patients who would require specific therapeutic interventions to prevent further decrease of their skeletal mass and preserve their BMD.

Impaired androgen production in female adolescents and young adults after total body irradiation prior to BMT in childhood.

Pubertal development and androgen production were evaluated 1-10 years after bone marrow transplantation (BMT) in 15 females aged 14-23 (mean 17) years. Before BMT, these patients had received combination chemotherapy for hematologic malignancy, and all had had a transplant program including total body irradiation (TBI). Of the nine patients who were pre-menarcheal at BMT, two had subsequently experienced spontaneous menarche at 11.5 and 13.3 years of age. Six were post-menarcheal, but became amenorrheic after BMT. Menstruation subsequently started spontaneously in one of them 6 years after BMT. At the time of the study, three patients were early to mid-pubertal and 12 late pubertal or post-pubertal. Twelve patients were receiving sex steroid substitution therapy. Serum concentrations of testosterone, androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) were determined. Androgen levels of late pubertal and post-pubertal transplanted patients were compared with 19 post-menarcheal patients aged 14-21 (mean 17) years who had been treated for hematologic malignancy with conventional chemotherapy. Testosterone levels of 52 healthy post-menarcheal females aged 14-29 (mean 19) years were measured as controls. Androgen levels of the BMT patients were lower than those of the conventionally treated patients. Differences in testosterone, androstenedione and DHEA levels were significant. Three spontaneously menstruating BMT patients had normal androgen levels. Testosterone levels of the conventionally treated patients and healthy controls were similar. Subnormal androgen production might be one factor behind the problems in pubertal development and sex life experienced by females after BMT. The use of these hormone levels for follow-up purposes and the potential value of androgen replacement therapy in females after TBI merit further study.

Long-term survivors of childhood cancer have an increased risk of manifesting the metabolic syndrome.

Survivors of childhood cancer have been reported to have a severalfold increased risk of death from cardiovascular disease. A cluster of metabolic abnormalities, including obesity, insulin resistance, hyperinsulinemia, glucose intolerance, hypertension, and dyslipidemia, have been designated as forming a metabolic syndrome that is associated with increased cardiovascular mortality. We studied 50 survivors (23 males) of childhood cancer, aged 10.5-31.2 yr, an average of 12.6 yr (range, 7.9-21.3 yr) after their diagnosis and compared them with 50 age- and sex-matched controls for signs of the metabolic syndrome by examining clinical and anthropometric measures, serum lipid profile, and fasting plasma insulin and glucose concentrations. Spontaneous nocturnal GH secretion was also evaluated in the cancer survivors. The patients had increased relative weight (P = 0.03) and body fat mass (P < 0.001), decreased serum high density lipoprotein (HDL) cholesterol (P < 0.001), and a reduced ratio of HDL to total cholesterol (P = 0.01). Fasting plasma glucose and insulin levels were higher (P < 0.001 and P = 0.003, respectively) in the cancer survivors than in the controls. The patients had an increased risk [odds ratio (OR), 4.5; 95% confidence interval (CI), 1.3-15.8; P = 0.01] of obesity (relative weight, > 120%), fasting hyperinsulinemia ( > 111 pmol/L; OR, 3.0; 95% CI, 1.0-8.6; P = 0.04), and reduced HDL cholesterol ( < 1.07 mmol/L; OR, 7.9; 95% CI, 2.2 to 29.6; P < 0.001). A combination of obesity, hyperinsulinemia, and low HDL cholesterol was seen in eight cancer survivors (16%), but in none of the controls (P = 0.01). This high risk group was characterized by reduced spontaneous GH secretion (P = 0.02). Long term survivors of childhood cancer appear to have an increased risk of manifestations of the metabolic syndrome. Decreased GH secretion may contribute to these metabolic abnormalities.

Insulin-like growth factor binding protein production in human follicular thyroid carcinoma cells.

IGFs and IGF binding proteins (IGFBPs) appear to serve as regulators of non-malignant thyroid cells from several species, but little is known about their role in thyroid malignancy. We have examined IGFBP production and hormonal regulation in two human thyroid follicular carcinoma cell lines; FTC-133 line derived from a local tumor recurrence and FTC-236 cells from a tumor metastasis. Under basal conditions these cell lines produced IGFBP-3, IGFBP-4 and IGFBP-2. In both cell lines, EGF or TPA stimulated IGFBP-3 production while TSH or forskolin inhibited IGFBP-3 production and reduced the stimulation of IGFBP-3 seen with EGF or TPA. IGFBP-4 production was increased in the presence of TSH, forskolin, and EGF and was reduced by TPA. mRNA assessment revealed that IGFBP-3 mRNA, more abundant in FTC-236 than FTC-133 cells, increased in the presence of EGF or TPA, while IGFBP-4 mRNA content was increased in the presence of TSH, EGF, and forskolin. These results indicate that IGFBP production in human thyroid follicular carcinoma clones is under specific hormonal regulation. IGFBP-3 production is increased by dedifferentiation factors such as EGF and TPA and inhibited by TSH and forskolin, which enhance differentiated function. The highly specific regulation of IGFBP-3 and IGFBP-4 suggests a potential role for these peptides in modulating malignant thyroid growth.

Pituitary size assessed with magnetic resonance imaging as a measure of growth hormone secretion in long term survivors of childhood cancer.

We investigated 37 long term survivors of childhood cancer to study the relationship among growth, GH secretion, and pituitary size. The median follow-up time after diagnosis was 13.2 yr. The pituitary gland was visualized with magnetic resonance imaging. Radiated patients (n = 25) had a reduced relative height and showed a greater reduction in relative height after diagnosis than nonradiated patients (n = 12). The patients had lower spontaneous nocturnal GH secretion than controls due to a reduced peak amplitude. Spontaneous GH secretion was lower in radiated patients than in nonradiated subjects. The patients had lower plasma insulin-like growth factor-I (IGF-I) and serum IGF-binding protein-3 (IGFBP-3) concentrations than the controls. Radiated subjects had decreased IGF-I and IGFBP-3 concentrations compared to nonradiated subjects. Half of the patients (20 of 37) evaluated with magnetic resonance imaging had a reduced pituitary size (pituitary height, < -2 SD score). Radiated subjects had smaller pituitary glands than nonradiated ones. Seventeen of 20 patients (85%) with reduced pituitary size had decreased nocturnal GH release. There was a positive correlation between nocturnal GH secretion, plasma IGF-I, and serum IGFBP-3 levels, on the one hand, and pituitary height, on the other. These results indicate that cranial radiation may result in tissue damage, leading to decreased pituitary size, reduced spontaneous GH secretion, and impaired linear growth. The finding of reduced IGF-I levels in both radiated and nonradiated patients combined with decreased IGFBP-3 concentrations in radiated patients, indicates that cytotoxic chemotherapy may induce hepatic damage resulting in decreased IGF-I synthesis.

Regulation of human granulosa-luteal cell progesterone production and proliferation by gonadotropins and growth factors.

The effects of human chorionic gonadotropin (hCG), follicle-stimulating hormone (FSH), fibroblast growth factor (FGF), and epidermal growth factor (EGF) on human granulosa-luteal cell proliferation and progesterone (P) production were studied in vitro. The cells were obtained from an in vitro fertilization protocol and were cultured for 2 to 12 days on plastic culture dishes or on dishes coated with extracellular matrix (ECM). During the first 2 to 4 days of culture, basal P production was high and could not be further stimulated with gonadotropins. Thereafter, basal P production decreased and could be stimulated by both hCG and FSH. The cells growing on ECM produced less P than the cells growing on plastic. EGF and FGF significantly increased cell proliferation on both substrates. FGF did not influence P production, while EGF clearly increased basal P production of the cells cultured on plastic. The high P production in cultured human granulosa cells obtained from follicles stimulated in vivo indicates that at least some of the cells were luteinized. The present data also demonstrate that EGF and FGF are mitogenic for human granulosa-luteal cells, and EGF regulates their biosynthesis in vitro. These results suggest that growth factors may also regulate granulosa cell function in vivo.