Andrea F. Attanasio

Final height after long-term growth hormone treatment in Turner syndrome

OBJECTIVES To study final height after long-term growth hormone (GH) treatment in girls with Turner syndrome (TS). PATIENTS One hundred fifty three patients with TS, participating in five European trials, were included. They started GH treatment in 1987-1989 at an age of 10 years or older. Mean age at start of treatment ranged between 11.7 and 14.6 years among countries and mean bone age between 9.4 and 11.8 years. Fourteen girls were lost to follow-up, leaving 139 for analysis. Most girls have now attained final height (FH), defined as a linear growth velocity (GV) of 4 mm/yr or less, measured over at least 6 months (group 1, n = 56), or near-FH, defined as a GV of 5 to 9 mm/yr (group 2, n = 22). Sixty-one girls were still growing 10 mm/yr or more. METHODS AND MAIN RESULTS At the last measurement, mean (SD) height was 150.7 (4.9) cm in group 1 and 148.5 (5.1) cm in group 2. The differences between FH and projected final height based on extrapolation of the initial height-standard deviation score on Turner syndrome reference values, were 2.9 (3.8) and 3.0 (3.3) cm, respectively. The mean gain over the Bayley-Pinneau prediction of FH was 3.3 (3.9) cm in both groups. No significant differences between countries were found. The range of gains over projected height (-4.7 to 12.1 cm) was large, and 25% of gains were 5 cm or more. Gain over initial projection was strongly related to initial growth delay and to growth response during the first 2 years of treatment. A logistic regression model is presented that predicts gain of more than 5 cm with a positive predictive value of 62% and a negative predictive value of 84%. CONCLUSIONS Long-term GH treatment in girls with TS, starting treatment at a relatively advanced age ( > 10 years) resulted in a modest mean gain in FH of 3 cm, with wide interindividual variation.

The safety profile of GH replacement therapy in adults

OBJECTIVE The benefits of GH replacement in GH‐deficient adult patients are becoming accepted but the safety profile continues to be defined. The GH deficiency in adults may have arisen in either childhood or during adult life and these two groups differ with regard to history of disease. The aim of the present report was to study differences in safety profile between these two groups during long‐term replacement therapy with recombinant human GH (hGH). Possible factors which placed a patient at risk of experiencing an adverse event were also examined.

Prevalence of metabolic syndrome in adult hypopituitary growth hormone (GH)-deficient patients before and after GH replacement.

CONTEXT AND OBJECTIVE Metabolic and body compositional consequences of GH deficiency (GHD) in adults are associated with a phenotype similar to the metabolic syndrome (MetS). PATIENTS We assessed MetS prevalence in adult GHD patients (n = 2531) enrolled in the Hypopituitary Control and Complications Study. Prevalence was assessed at baseline and after 3 yr of GH replacement in a subset of 346 adult-onset patients. RESULTS Baseline MetS crude prevalence was 42.3%; age-adjusted prevalence in the United States and Europe was 51.8 and 28.6% (P < 0.001), respectively. In the United States, age-adjusted prevalence was significantly higher (P < 0.001) than in a general population survey. Increased MetS risk at baseline was observed for age 40 yr or older (adjusted relative risk 1.34, 95% confidence interval 1.17-1.53, P < 0.001), females (1.15, 1.05-1.25, P = 0.002), and adult onset (1.77, 1.44-2.18, P < 0.001). In GH-treated adult-onset patients, MetS prevalence was not changed after 3 yr (42.5-45.7%, P = 0.172), but significant changes were seen for waist circumference (62.1-56.9%, P = 0.008), fasting glucose (26.0-32.4%, P < 0.001), and blood pressure (59.8-69.7%, P < 0.001). Significantly increased risk of MetS at yr 3 was associated with baseline MetS (adjusted relative risk 4.09, 95% confidence interval 3.02-5.53, P < 0.001) and body mass index 30 kg/m(2) or greater (1.53, 1.17-1.99, P = 0.002) and increased risk (with a P value < 0.1) for GH dose 600 microg/d or greater (1.18, 95% confidence interval 0.98-1.44, P = 0.088). CONCLUSION MetS prevalence in GHD patients was higher than in the general population in the United States and higher in the United States than Europe. Prevalence was unaffected by GH replacement, but baseline MetS status and obesity were strong predictors of MetS after GH treatment.

Changing Patterns of the Adult Growth Hormone Deficiency Diagnosis Documented in a Decade-Long Global Surveillance Database

BACKGROUND GH therapy in adult patients with GH deficiency (GHD) was approved over 10 yr ago, and the indication has subsequently gained broad acceptance. The HypoCCS surveillance database is a suitable means to examine the evolution of diagnostic patterns since 1996. METHODS Baseline demographics, reported cause of GHD, and diagnostic tests were available from 5893 GH-treated patients. Trends for change over time in diagnosis, GH stimulation test data, and IGF-I measurements were analyzed at 2-yr intervals by linear regression models, with entry year as the predictive variable. RESULTS Over the decade, there was a decrease in patients enrolled with diagnoses of pituitary adenoma (50.2 to 38.6%; P < 0.001), craniopharyngioma (13.3 to 8.4%; P = 0.005) and pituitary hemorrhage (5.8 to 2.8%; P = 0.001); increases in idiopathic GHD (13.9 to 19.3%; P < 0.001), less common diagnoses (7.4 to 15.8%; P < 0.001), and undefined/unknown diagnoses (1.3 to 8.6%; P < 0.001) were observed. Use of arginine, clonidine, and L-dopa tests declined, whereas use of the GHRH-arginine test increased. Median values for peak GH from all tests except GHRH-arginine and for IGF-I SD scores increased significantly (P < 0.001). Over the decade (1996--2005), idiopathic GHD was reported for 16.7% of patients, and more than half of these had adult onset GHD. In the idiopathic adult onset group, 40.2% had isolated GHD; 18.3 and 4.4% had a stimulation test GH peak of at least 3.0 and 5.0 microg/liter, respectively. CONCLUSIONS Significant shifts in diagnostic patterns have occurred since approval of the adult GHD indication, with a trend to less severe forms of GHD.

Prevalence and Incidence of Diabetes Mellitus in Adult Patients on Growth Hormone Replacement for Growth Hormone Deficiency: A Surveillance Database Analysis

CONTEXT GH replacement in adult GH-deficient patients may cause insulin resistance, raising concerns of potential increased risk of developing diabetes mellitus (DM). OBJECTIVE Our objective was to assess DM prevalence and incidence in the international Hypopituitary Control and Complications Study (HypoCCS) surveillance database. DESIGN AND PARTICIPANTS GH-treated patients enrolled into HypoCCS (2922 U.S. and 3709 European patients) were assessed for DM, defined as recorded on the clinical report form, reported as adverse events, fasting glucose at least 7 mmol/liter recorded at least twice, or insulin treatment reported. RESULTS DM prevalence was 8.2% [95% confidence interval (CI) = 7.6-8.9] overall, 11.3% in the United States and 5.7% in Europe. Incidence (n/1000 patient-years) was 9.7 (95% CI = 8.4-10.9) overall, 14.1 (11.5-16.7) in the United States, and 7.0 (5.6-8.3) in Europe. Overall incidence was 2.1 (0.9-3.3) for patients with body mass index (BMI) below 25 kg/m(2) increasing to 16.4 (13.7-19.1) for BMI over 30 kg/m(2). Obesity (BMI > 30 kg/m(2)) prevalence was higher in the United States than Europe and higher in U.S. patients than a U.S. reference population. After age, gender, and BMI adjustment, U.S. HypoCCS DM incidence was 10.6 (8.1-13.0), compared with 7.1 (6.0-8.1) in the National Health Interview Survey. In Europe, incidence for French and German patients was comparable to reference populations; for Sweden, the point estimate was higher than the reference population, but 95% CI overlapped. GH dose was not correlated with DM incidence. CONCLUSIONS The present analysis showed no evidence for increased DM incidence in GH-treated adult hypopituitary patients. However, those more prone to develop DM exhibited a higher than normal prevalence of obesity.

Confirmation of severe GH deficiency after final height in patients diagnosed as GH deficient during childhood

objective Human GH treatment of patients with childhood‐onset (CO) growth hormone deficiency (GHD) ceases when they reach final height; this provides an opportunity to retest GH status in all patients before determining whether GH therapy will be required in adult life. At present, the diagnostic approach to these patients is not fully standardized. This study aimed to characterize a large group of previously GH‐treated CO GHD patients and establish their GH status.

Plasma Adrenocorticotropin, Cortisol, and Dehydroepiandrosterone Response to Corticotropin-Releasing Factor in Normal Children during Pubertal Development

ABSTRACT: The adrenocorticotropin (ACTH), Cortisol, and dehydroepiandrosterone responses to synthetic human corticotropin-releasing factor (CRF) were studied in 28 endocrinologically healthy children (age 1–16 yr) and in six adult volunteers (age 24–42 yr). CRF was given as an intravenous bolus (1 μg/kg body weight) between 0900 and 1000 hr. Significant increments in ACTH and Cortisol levels after CRF were observed in all subjects, with an ACTH peak value of 48.2 ± 3.4 pg/ml at 10 min (p < 0.001). The ACTH and Cortisol response patterns after CRF did not change with age or pubertal maturation and did not differ in children and in adults. In contrast, the dehydroepiandrosterone response to CRF clearly was related to the stage of pubertal development. The peak value after CRF significantly increased from puberty stage 1 to puberty stage 5 (164 ± 18 versus 779 ± 86 ng/100 ml, p < 0.001). In adults, the mean dehydroepiandrosterone peak value after CRF did not differ from that of P5 children. These results show that CRF can be given safely to children. The absence of age-dependent ACTH and Cortisol responses and a dehydroepiandrosterone response changing with pubertal maturation points to the existence of factors involved in the control of adrenal androgen production other than ACTH.

Rhythm development in pineal and circulating serotonin, N-acetylserotonin, and melatonin in Syrian hamsters.

The ontogeny of diurnal rhythm patterns in the pineal and serum levels of melatonin, serotonin, and N‐acetylserotonin was studied in Syrian hamsters (Mesocricetus auratus) from birth to adulthood. The pineal and blood specimens were collected at 1100 h and 0200 h, and the compounds were measured by radioimmunoassay (RIA) procedures. Pineal melatonin and serotonin did not show any circadian rhythm at day 5 of postnatal age. At this age N‐acetylserotonin was undetectable in the light phase but became manifest at night. By 10 days of age pineal serotonin registered an established rhythm pattern, with a higher level during the day. The occurrence of circadian rhythm in pineal melatonin was delayed and manifested first at 25 days of age. At this age, the first detectable daytime level of N‐acetylserotonin also occurred. Circadian rhythm in serum melatonin was also established at this age. The serum serotonin did not evince any rhythm pattern throughout the observation period, except at day 17 of postnatal age. The massive concentration of daytime serotonin in the pineal was not reflected in the circulatory system. For serum N‐acetylserotonin there was no discernable day‐night rhythm in all age groups, except at 25 days of age. The results show that the timing of the appearance of various compounds in the neonatal pineal is variable; the release of the substances does not always reflect their synthesis; the ontogenesis of circadian rhythm is a part of the maturational process; and 25 days of age is a rather critical time in development.

Skeletal requirements for optimal growth hormone replacement in the transitional years.

In addition to its well-established effects on linear growth in childhood and adolescence, growth hormone (GH) has both direct and indirect actions on bone remodelling and homeostasis. In this review, the discussion begins with the influence of childhood-onset growth hormone deficiency (CO-GHD) on bone mineral accretion. The limitations of methods of assessing bone mineral density (BMD) are highlighted and specific influential factors, which affect peak bone mass achievement and therefore skeletal health in later life, are evaluated.

Estrogens promote growth: Experimental and clinical evidence

Although increasing estradiol levels accompany the pubertal growth spurt in girls our understanding of the effects of estrogens on growth has been dominated by the experience with high doses in tall girls. - In male Wistar rats castrated on age day 27 and treated with ethinylestradiol (EE)(250-25-2.5-1-0.25 μg/kg BW d s.c.) until age day 45 the three highest doses showed to be inhibiting body growth, GH, SM and gonado tropins. The lowest dose however enhanced body growth. The effects on bone maturity were inversely related to dose. In girls with multiple pituitary hormone deficiencies (MPHD) treated with low doses of EE (5μg/d p.o.) corresponding observations were made. In 5 patients (CA:[xmacr ]=18.0 yrs.; BA:[xmacr ]=12.3 yrs) treated for 6-12 mo. with EE(-and constance of other medication-) height velocity increased from [xmacr ]=3.4 to 4.5 cm/yr. without unduely advancing BA, but inducing signs of puberty. Preliminary observations suggest positive effects on growth with EE doses suboptimal in respect to the induction of the female sex characteristics.