Effects of pre- and post-pubertal dihydrotestosterone treatment on penile length in 5α-reductase type 2 deficiency.

Steroid 5α-reductase type 2 deficiency (5αRD2) is a congenital disorder of sex development caused by impairment of conversion from testosterone (T) to 5α-dihydrotestosterone (DHT). DHT deficiency leads to various degrees of undervirilized external genitalia including micropenis, primarily correlated with mutations of the SRD5A2 gene that encodes 5α-reductase type 2. Four Japanese boys with isolated micropenis were diagnosed as 5αRD2 by elevated ratios of serum T/DHT, and decreased ratios of urinary 5α/5ß-reduced steroid metabolites. Genetic analyses for SRD5A2 identified that the four patients shared a hypomorphic mutation R227Q that has a residual activity related to the mild-form of 5αRD2. For prepubertal micropenis, DHT was transdermally applied to the four patients at the ages of 4-11 year, increasing a median of stretched penile lengths (SPLs) from 2.6 cm (-2.5 SD) to 4.4 cm (-0.2 SD). Nevertheless, the post-pubertal penile growth was apparently retarded, despite normal levels of T secreted from well-developed testes. The second course of DHT treatment underwent at ages of 12-18 year, but unable to normalize SPLs at a range of 6.0 to 7.0 cm (-3.4 to -2.4 SD). The prostate volumes of two patients were variable at 8.1 and 21 cm3, and a sperm cell count of one patient was normal as young adult. DHT treatment contributes to development of the penis and prostate, which are favorable for the potential fertility of 5αRD2 adults. Meanwhile, the retarded penile growth and a risk of prostate overgrowth may complicate the post-pubertal management with DHT for 5αRD2 males.

Oral Cholic Acid Is Efficacious and Well Tolerated in Patients With Bile Acid Synthesis and Zellweger Spectrum Disorders.

OBJECTIVES: Patients with bile acid synthesis disorders (BASDs) due to single enzyme defects (SEDs) or Zellweger spectrum disorders (ZSDs) accumulate hepatotoxic atypical bile acids resulting in potentially fatal progressive liver disease. We evaluated the efficacy and safety of oral cholic acid in patients with BASD. METHODS: In this phase 3, open-label, single-arm, nonrandomized, noncomparative study conducted over 18 years, patients were administered cholic acid orally 10 to 15 mg ·â€Škg ·â€Šday. The primary efficacy variables were changes from pre- to post-treatment in atypical urinary bile acids, liver chemistries (serum aspartate aminotransferase, alanine aminotransferase), and height and weight. Additional efficacy variables included changes in serum bilirubin and liver histology. RESULTS: Of the 85 enrolled patients (63 with SED and 22 with ZSD), 79 received at least 1 dose of study medication; 70 patients (50 with SED and 20 with ZSD) were included in the modified intent-to-treat dataset. Cholic acid significantly improved urine bile acid metabolite scores (P < 0.0001) and serum aspartate aminotransferase and alanine aminotransferase (P < 0.0001) in patients with SED and ZSD. Cholic acid also improved height and weight percentiles in both groups, but only the change in weight was significant (P < 0.05). Serum direct bilirubin decreased significantly post-treatment (P < 0.001) in the intent-to-treat population, and liver biopsies showed either stable findings or histologic improvement in all parameters except bridging fibrosis. The overall safety profile of cholic acid was favorable, with no study drug-related serious adverse events or drug-related deaths reported. CONCLUSIONS: Oral cholic acid is a safe, efficacious, and well-tolerated treatment for BASD due to SED and ZSD.

Treatment of Smith-Lemli-Opitz syndrome and other sterol disorders.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive genetic condition with a broad phenotype that results from deficiency of the final enzyme of the cholesterol synthesis pathway. This defect causes low or low-normal plasma cholesterol levels and increased 7- and 8-dehydrocholesterol (DHC) levels. Many therapies for SLOS and other disorders of sterol metabolism have been proposed, and a few of them have been undertaken in selected patients, but robust prospective clinical trials with validated outcome measures are lacking. We review the current literature and expert opinion on treatments for SLOS and other selected sterol disorders, including dietary cholesterol therapy, statin treatment, bile acid supplementation, medical therapies, and surgical interventions, as well as directions for future therapies and treatment research.

Titration of bile acid supplements in 3beta-hydroxy-Delta 5-C27-steroid dehydrogenase/isomerase deficiency.

OBJECTIVES: 3beta-Hydroxy-Delta 5-C27-steroid dehydrogenase/isomerase deficiency is a bile acid synthesis defect responsive to primary bile acids. We reviewed its clinical features and response to treatment with a mixture of ursodeoxycholic (UDCA) and chenodeoxycholic acid (CDCA) to titrate the dose of supplements required for disease control. PATIENTS AND METHODS: We studied our patients by liquid chromatography-tandem mass spectrometry, liver function tests, and histology. After diagnosis all of the patients received a balanced mixture of UDCA/CDCA and the dose was titrated according to urinary levels of 3beta,7 alpha-dihydroxy-5-cholenoic acid (u-3beta-D-OH-5C). RESULTS: Five patients presenting with giant cell hepatitis, biliary cirrhosis, and cryptogenic cirrhosis (1 each), and picked up by neonatal screening (2 patients) were diagnosed at a median age of 2.5 years (range 0.1-5.5). Normal levels of u-3beta-D-OH-5C were achieved after 4 months (range 3-28 months) from the start of the treatment. The minimum dose of UDCA/CDCA required to maintain normal u-3beta-D-OH-5C levels was 5/5 mg x kg(-1) x day(-1). A follow-up biopsy in 2 patients showed no progression of liver disease. CONCLUSIONS: A mixture of UDCA/CDCA can effectively control 3beta-hydroxy-Delta 5-C27-steroid dehydrogenase/isomerase deficiency. Dose titration by liquid chromatography-tandem mass spectrometry warrants the maintenance of negative feedback on the abnormal synthetic pathway and avoids disease progression.

Familial glucocorticoid deficiency type 1 due to a novel compound heterozygous MC2R mutation.

OBJECTIVE: Description of the clinical, biochemical and genetic features of a Polish patient with familial glucocorticoid deficiency. METHODS: Detailed clinical investigation, hormonal analysis and sequencing of the coding region of the melanocortin 2 receptor (MC2R) gene in this patient. RESULTS: We report on a 3-month-old boy with familial glucocorticoid deficiency who presented at the age of 3 months with skin hyperpigmentation, muscle weakness, mild jaundice and constipation. Hormonal analyses revealed high ACTH and TSH serum concentrations, low serum cortisol concentration along with normal blood electrolytes. On hydrocortisone supplementation, the disease symptoms disappeared and the child recovered completely. His physical and mental development progresses normally. Genetic analysis disclosed a novel compound heterozygous MC2R mutation p.Leu46fs and p.Val49Met. CONCLUSION: The heterozygous p.Leu46fs mutation adds to the small number of MC2R nonsense mutations and is the first frameshift mutation within the first transmembrane domain of the receptor. According to molecular modeling the Val49Met mutation results in a structural change of the first transmembrane domain and in a potential novel interaction of the transmembrane domains I and VII.

Infant cholestasis patient with a novel missense mutation in the AKR1D1 gene successfully treated by early adequate supplementation with chenodeoxycholic acid: A case report and review of the literature.

Steroid 5ß-reductase [aldo-keto reductase family 1 member D1 (AKR1D1)] is essential for bile acid biosynthesis. Bile acid deficiency caused by genetic defects in AKR1D1 leads to life-threatening neonatal hepatitis and cholestasis. There is still limited experience regarding the treatment of this disease. We describe an infant who presented with hyperbilirubinemia and coagulopathy but normal bile acid and γ-glutamyltransferase. Gene analysis was performed using genomic DNA from peripheral lymphocytes from the patient, his parents, and his elder brother. The patient was compound heterozygous for c.919C>T in exon 8 and exhibited a loss of heterozygosity of the AKR1D1 gene, which led to an amino acid substitution of arginine by cysteine at amino acid position 307 (p.R307C). Based on these mutations, the patient was confirmed to have primary 5ß-reductase deficiency. Ursodeoxycholic acid (UDCA) treatment did not have any effect on the patient. However, when we changed to chenodeoxycholic acid (CDCA) treatment, his symptoms and laboratory tests gradually improved. It is therefore crucial to supplement with an adequate dose of CDCA early to improve clinical symptoms and to normalize laboratory tests.

The genetics of ACTH resistance syndromes.

Inherited adrenocorticotropin (ACTH) resistance diseases are rare and include triple A syndrome and familial glucocorticoid deficiency (FGD). These conditions show genetic heterogeneity, i.e., the identical clinical phenotype may result from defects in more than one gene. Clinically, FGD is characterized only by ACTH resistance, while the triple A syndrome exhibits a variety of additional clinical features. FGD is caused by mutations in the ACTH receptor (melanocortin 2 receptor, MC2R) and the recently identified melanocortin 2 receptor accessory protein (MRAP) genes. In addition, linkage to a locus on chromosome 8 has been demonstrated. The identification of further genes in ACTH resistance syndromes may reveal novel aspects of MC2R signalling and trafficking. This review will summarize the clinical, biochemical and genetic aspects of these rare but informative diseases.

Safety of growth hormone treatment in pediatric patients with idiopathic short stature.

CONTEXT: Recombinant human GH was approved by the United States Food and Drug Administration in 2003 for the treatment of idiopathic short stature (ISS). However, to date, the safety of GH in this patient population has not been rigorously studied. OBJECTIVE: The objective of this study was to address the safety of GH treatment in children with ISS compared with GH safety in patient populations for which GH has been approved previously: Turner syndrome (TS) and GH deficiency (GHD). DESIGN/SETTING: The rates of serious adverse events (SAEs) and adverse events (AEs) of particular relevance to GH-treated populations were compared across the three patient populations among five multicenter GH registration studies. PATIENTS: Children with ISS, TS, or GHD were studied. INTERVENTION: Treatment consisted of GH doses ranging from 0.18-0.37 mg/kg.wk. MAIN OUTCOME MEASURES: The main outcome measures were rates of SAEs and AEs of special relevance to patients receiving GH. Laboratory measures of carbohydrate metabolism were used as outcome measures for the ISS studies. RESULTS: Within the ISS studies, comprising one double-blind, placebo-controlled study and one open-label, dose-response study, SAEs (mainly hospitalizations for accidental injury or acute illness unrelated to GH exposure) were reported for 13-14% of GH-treated patients. Overall AE rates (serious and nonserious) as well as rates of potentially GH-related AEs were similar in the GHD, TS, and ISS studies (for ISS studies combined: otitis media, 8%; scoliosis, 3%; hypothyroidism, 0.7%; changes in carbohydrate metabolism, 0.7%; hypertension, 0.4%). Measures of carbohydrate metabolism were not affected by GH treatment in patients with ISS. There was no significant GH effect on fasting blood glucose in either study (GH dose range, 0.22-0.37 mg/kg.wk) or on insulin sensitivity (placebo-controlled study only). CONCLUSION: GH appears safe in ISS; however, the studies were not powered to assess the frequency of rare GH-related events, and longer-term follow-up studies of GH-treated patients with ISS are warranted.

Efficacy of a long-acting growth hormone (GH) preparation in patients with adult GH deficiency.

CONTEXT: Treatment of adult GH deficiency (AGHD) with daily injections of GH results in decreased adipose mass, increased lean body mass (LBM), increased bone mineral density, and improved quality of life. OBJECTIVE: This study seeks to determine whether a depot preparation of GH given every 14 d would lead to comparable decreases in trunk adipose tissue as daily GH. DESIGN: This open-label, randomized study compares subjects receiving depot GH, daily GH, or no therapy. SETTING: The study was performed at 23 university or local referral endocrine centers. PATIENTS OR OTHER PARTICIPANTS: One hundred thirty-five adults with AGHD syndrome participated in the study. INTERVENTION: Subjects were randomized to receive depot GH (n = 51), daily GH (n = 53), or no treatment (n = 31) for 32 wk. The dose of GH was titrated so that IGF-I was less than or equal to +2 SD of the age-adjusted normal range. MAIN OUTCOME MEASURE: Trunk adipose tissue was the main outcome measure as measured by dual energy x-ray absorptiometry. RESULTS: The percentage of the trunk region that is fat increased by 0.4 in the no treatment group, but decreased by 3.2 (P = 0.001 vs. untreated) in the GH depot group and by 2.5 (P < 0.004 vs. untreated) in the daily GH group. Visceral adipose tissue area decreased by 9.1% in the GH depot group and by 6.8% in the daily GH group. LBM and high-density lipoprotein increased in both treatment groups. Side effect profiles were similar. Three subjects receiving GH experienced serious episodes of adrenal insufficiency. CONCLUSIONS: GH diminishes trunk and visceral adipose tissue and increases LBM in AGHD. A depot form of GH that is administered every 14 d is as safe and effective as daily GH injections.

Does a gender-related effect of growth hormone (GH) replacement exist on cardiovascular risk factors, cardiac morphology, and performance and atherosclerosis? Results of a two-year open, prospective study in young adult men and women with severe GH deficiency.

CONTEXT: GH secretion and response to GH replacement are gender-related. OBJECTIVE: The objective of this study was to investigate the effects of GH deficiency (GHD) and replacement on the cardiovascular system according to gender. DESIGN: The design was open and prospective. SETTING: The study was conducted at a university hospital. SUBJECTS: Subjects included 36 severe adult-onset GHD patients (18 men, 20 women, aged < 45 yr); 36 gender-, age-, and body mass index-matched healthy subjects served as controls. INTERVENTIONS: Subjects received GH replacement at a median dose of 6.5 microg/kg.d in men and 7.7 microg/kg.d in women for 2 yr. MAIN OUTCOME MEASURES: Homeostasis model assessment index, total to HDL cholesterol ratio, fibrinogen and C-reactive protein levels, left ventricular mass index, blood pressure, heart rate, diastolic filling, and systolic function at rest and at peak exercise and intima-media thickness (IMT) at common carotid arteries were measured. RESULTS: Basal prevalence and/or degree of insulin resistance, lipid alterations, compromised cardiac function, and IMT were similar in women and men. Diastolic dysfunction was more prevalent in men (61 vs. 25%, P = 0.036). After GH replacement, IGF-I levels normalized in all patients. Lipid profile, fibrinogen, and C-reactive protein levels normalized in all cases. The total to HDL ratio (P = 0.04) was higher in women than men. The homeostasis model assessment index persisted higher in GHD patients than controls and decreased only in GHD men (P = 0.017). Left ventricular mass index normalized during treatment in both women and men, abnormal diastolic function persisted in three women (P = 0.031), and abnormal systolic performance persisted in six women and one man (P = 0.13). IMT decreased similarly in women and men, persisting higher than in controls. Exercise performance normalized in all. CONCLUSIONS: Two-year GH replacement has similar beneficial effects on cardiac and exercise performance and atherosclerosis in women and men with severe GHD.

Interdependence of lean body mass and total body water, but not quality of life measures, during low dose GH replacement in GH-deficient adults.

Lean body mass (LBM) and total body water (TBW) are reduced in GH-deficient (GHD) adults and alter with GH replacement. Whether these parameters are interdependent and whether alterations in their homeostasis contribute to the perceived quality of life (QOL) deficit in GHD remains unclear. In this study, IGF-I, body composition by whole-body dual-energy X-ray absorptiometry, TBW by deuterium dilution (D(2)O) and two validated QOL instruments - psychological general well-being schedule (PGWB, generic, 6 domains; lower score worse QOL) and assessment of GH deficiency in adults (AGHDA, disease orientated; higher score worse QOL) were studied at baseline and after 3 and 6 months of GH replacement in thirty GHD adults. Patients with diabetes insipidus, and cardiac and renal failure were excluded. Median age-adjusted IGF-I standard deviation score increased from -3.40 (-6.40 to -1.60) to -0.2 (-1.88 to 0.78) (P < 0.0001) at a median daily GH dose of 0.4 mg. During treatment, LBM increased from 47.4 +/- 10.7 kg at baseline to 49.5 +/- 10.8 kg at 6 months (P = 0.0008), and fat mass decreased from 28.0 +/- 12.1 kg at baseline to 27.2 +/- 12.6 kg at 6 months (P = 0.0004). A non-significant trend towards an increase in TBW was observed (mean 1.7 kg, P = 0.08). The PGWB score increased from 62.9 +/- 20.6 to 73.7 +/- 21.7 (P = 0.0006). The AGHDA score decreased from 13.7 +/- 7.3 to 8.75 +/- 7.75 (P = 0.0002). At each time point, a linear correlation between LBM and TBW was demonstrated, defined by TBW = (0.972 x LBM)-10.6. However, only a weakly positive correlation existed between the percentage changes in these variables (R = 0.40, P = 0.04). No correlations were demonstrated between QOL measures and body composition. The change in LBM with physiological GH replacement correlates weakly with change in TBW, therefore factors other than TBW may also contribute to the LBM changes. Improved QOL with GH replacement is not explained by favourable changes in body composition.

Effects of GH replacement therapy in adults on serum levels of leptin and ghrelin: the role of lipolysis.

OBJECTIVE: The regulation and function of systemic ghrelin levels appear to be associated with food intake and energy balance rather than GH. Since GH, in turn, acutely induces lipolysis and insulin resistance in skeletal muscle, we aimed to study the isolated and combined effects of GH, free fatty acids (FFAs) and insulin sensitivity on circulating ghrelin levels in human subjects. DESIGN: Seven GH-deficient patients (aged 37 +/- 4 years (mean +/- s.e.)) were studied on four occasions in a 2 x 2 factorial design with and without GH substitution and with and without administration of acipimox, which lowers FFA levels by inhibition of the hormone-sensitive lipase, in the basal state and during a hyperinsulinemic euglycemic clamp. RESULTS: Serum FFA levels decreased with acipimox administration irrespective of GH status. The GH-induced reduction in insulin sensitivity was countered by acipimox. Fasting ghrelin levels decreased insignificantly during GH administration alone, but were reduced by 33% during co-administration of GH and acipimox (Aci) (in ng/l): 860 +/- 120 (-GH - Aci), 711 +/- 130 (-GH + Aci), 806 +/- 130 (+GH - Aci), 574 +/- 129 (+GH + Aci), P < 0.01. The clamp was associated with a further, moderate lowering of ghrelin. GH and acipimox induced a reciprocal 25% increase in serum leptin levels (microg/l): 11.2 +/- 4.4 (-GH - Aci), 11.7 +/- 4.4 (-GH + Aci), 11.5 +/- 4.4 (+GH - Aci), 13.9 +/- 4.2 (+GH + Aci), P = 0.005. CONCLUSION: Our data suggest that antilipolysis via suppression of the hormone-sensitive lipase in combination with GH administration is associated with significant and reciprocal changes in ghrelin and leptin.

Estrogens are essential for male pubertal periosteal bone expansion.

The skeletal response to estrogen therapy was studied in a 17-yr-old boy with congenital aromatase deficiency. As expected, estrogen therapy (1 mg estradiol valeriate/d from age 17 until 20 yr) normalized total and free testosterone and reduced the rate of bone remodeling. Dual-energy x-ray absorptiometry-assessed areal bone mineral density (BMD) of the lumbar spine and femoral neck increased significantly (by 23% and 14%, respectively), but peripheral quantitative computed tomography at the ultradistal radius revealed no gain of either trabecular or cortical volumetric BMD. The increase in areal BMD was thus driven by an increase in bone size. Indeed, longitudinal bone growth (height, +8.5%) and especially cross-sectional area of the radius (+46%) and cortical thickness (+12%), as measured by peripheral quantitative computed tomography, increased markedly during estrogen treatment. These findings demonstrate that androgens alone are insufficient, whereas estrogens are essential for the process of pubertal periosteal bone expansion typically associated with the male bone phenotype.

Growth hormone deficiency in patients with sickle cell disease and growth failure.

BACKGROUND: Growth disorders are common in children with sickle cell disease (SCD). The etiology for growth disturbances in this population appears to be multifactorial. Recent evidence suggests abnormalities in the growth hormone (GH)/insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) axis may play a role. OBJECTIVE: To measure GH levels through provocative stimulation in a group of patients with SCD with growth failure, and to evaluate response to treatment. PATIENTS AND METHODS: Growth records were reviewed of 79 children with sickle cell hemoglobinopathies to identify children with growth failure. GH levels were measured in patients with SCD with and without growth failure using arginine and L-Dopa as provocative stimulation tests. Treatment with GH was offered to GH-deficient children with SCD and these patients were followed longitudinally over 5 years. RESULTS: Of the 79 patients, 13 (16.5%, all SS) had heights less than -2 SD below the mean or a growth velocity < -2 SD below the mean for age. Seven of the 13 children with growth failure participated in this study. Five patients received GH for 3 or more years and demonstrated significant improvement in their height SDS. One of the two who declined treatment was lost to follow-up and the other had significant worsening of height SDS score. CONCLUSION: GH deficiency may be associated with growth failure in some patients with SCD. These patients may benefit from treatment with GH.

Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials).

Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited treatment options. This analysis evaluated the effect of a monoclonal antibody to proprotein convertase subtilisin/kexin 9, alirocumab 150 mg every 2 weeks (Q2W), on Lp(a) levels in pooled data from 3 double-blind, randomized, placebo-controlled, phase 2 studies of 8 or 12 weeks' duration conducted in patients with hypercholesterolemia on background lipid-lowering therapy (NCT01266876, NCT01288469, and NCT01288443). Data were available for 102 of 108 patients who received alirocumab 150 mg Q2W and 74 of 77 patients who received placebo. Alirocumab resulted in a significant reduction in Lp(a) from baseline compared with placebo (-30.3% vs -0.3%, p <0.0001). Median percentage Lp(a) reductions in the alirocumab group were of a similar magnitude across a range of baseline Lp(a) levels, resulting in greater absolute reductions in Lp(a) in patients with higher baseline levels. Regression analysis indicated that <5% of the variance in the reduction of Lp(a) was explained by the effect of alirocumab on low-density lipoprotein cholesterol. In conclusion, pooled data from 3 phase 2 trials demonstrate substantive reduction in Lp(a) with alirocumab 150 mg Q2W, including patients with baseline Lp(a) >50 mg/dl. Reductions in Lp(a) only weakly correlated with the magnitude of low-density lipoprotein cholesterol lowering.

A novel mutation in the MC2R gene causing familial glucocorticoid deficiency type 1.

Familial glucocorticoid deficiency (FGD) or hereditary unresponsiveness to adrenocorticotropin (ACTH) is an autosomal recessive disorder characterized by isolated glucocorticoid deficiency associated with normal mineralocorticoid secretion. Mutations in genes encoding either ACTH receptor or melanocortin 2 receptor accessory protein are responsible for the disease in about 50% of cases, named FGD type 1 and type 2, respectively. Patients may present with hyperpigmentation, recurrent infections, failure to thrive, hypoglycemic seizures, and coma in infancy or early childhood. Here we report the case of a 17-day-old newborn diagnosed with FGD type 1 who presented with hyperbilirubinemia and hyperpigmentation, a sign which was erroneously assumed to be due to prolonged phototherapy by the referring physician. Hormone analysis showed low cortisol and high ACTH levels with normal serum electrolytes and renin-aldosterone axis. Genetic analysis revealed a novel homozygous melanocortin 2 receptor mutation p.Leu225Arg in the patient. The healthy parents were heterozygous for the mutation.

Adult height in patients treated for isolated growth hormone deficiency: role of birth weight.

To evaluate the effect of growth hormone (GH) administration on adult height (AH) in two groups of isolated GH-deficient (IGHD) children born either small (birth weight below -2 SD) or appropriate (birth weight above -2 SD) for gestational age (GA). Out of 35 prepubertal IGHD children, 14 small for GA (SGA, group A) and 21 appropriate for GA (AGA, group B) were examined. All patients received continuous GH treatment at a median dose of 0.028 mg/kg/day (range 0.023-0.032) in group A and 0.024 (range 0.023-0.028) in group B. GH treatment was administered for a period of 67.0 months (range 42.37-96.05) in group A and 54.31 months (range 47.14-69.31) in group B. All children were measured using a Harpenden stadiometer every 6 months until they reached AH (growth velocity <1 cm/year). The patients underwent a retesting a few months after stopping GH therapy. A significant difference was found between group A and B as expected for birth weight SD, -2.70 (range -2.87 to -2.29) and -0.73 (range -1.30 to 0.14) respectively (p < 0.000001) and interestingly also for body mass index SDS (BMI SDS) at retesting, 0.08 (range 0.30 to -1.51) and 0.61 (range 0.73 to -1.10) respectively (p < 0.04). We observed no significant differences between groups A and B in height (expressed as the SDS for chronological age, height SDS) at diagnosis (p = 0.75), height SDS at start of puberty (p = 0.51), height SDS at retesting (p = 0.50), target height SDS (TH SDS) (p = 0.47), AH SDS (p = 0.92), corrected height SDS (height SDS - TH SDS) (p = 0.60), BMI SDS at diagnosis (p = 0.25), GH dosage (p = 0.34) and therapy duration (p = 0.52). GH treatment with a standard dose in short IGHD children leads to a normalization of AH without any significant difference between SGA and AGA patients.

Advances in growth hormone therapy: a new registry tool.

Growth hormone (GH) deficiency is a rare condition, and physicians may lack clinical experience of its treatment. Despite evidence for the efficacy and tolerability of GH therapy, a substantial proportion of patients remain untreated. Registries and other large-scale databases are an important tool for expanding the evidence base for GH treatment. Since the mid-1980s, registries have provided data on important aspects of the safety and efficacy of GH treatment. Registries have also allowed pooling of data from patients with rare conditions that could otherwise not be recruited in sufficient numbers for clinical trials. Importantly for patients and their relatives, use of registry data has allowed the development of prediction models that indicate the likely outcomes of treatment. MEGHA (Metabolic Endocrinology and Growth Hormone Assessment) is a recently developed, observational database with a number of features not found in existing registries, including its use as a day-to-day clinical management tool, the ability to create individual sub-studies, direct comparison of personal data against the full database, and a particular focus on the transition from childhood to adulthood. This creative registry is a promising instrument for further research into GH-related disorders that will improve GH therapy and thus provide benefits for patients.

Bridging regional and global perspectives.

In recent years, medical practice has evolved towards greater reliance on evidence-based medicine. Societies and reimbursement agencies often publish recommendations for treatment based on literature review and trial data. Despite this, growth hormone (GH) replacement therapy in adults varies substantially from region to region. The reasons for this include differing beliefs in quality of life benefits, the cost-effectiveness of GH and the role of GH in reducing cardiovascular mortality. Reimbursement varies from almost complete take-up in Sweden and Germany, to strict guidelines in the UK, while in some countries GH is not reimbursable for adults with GH deficiency, leaving patients open to the short- and long-term consequences of the condition. Clearly, there is a need for further evidence regarding the overall value of GH replacement. Randomized, controlled trials are the foundation of evidence-based medicine, but long-term treatment is difficult to assess in such trials. Thus, there is an important role for large-scale registries in gathering evidence. For example, the MEGHA (Metabolic Endocrinology and Growth Hormone Assessment) database provides participants with a sub- studies function, allowing them to create and design collective, observational studies to investigate areas of GH medicine that are of particular interest or concern to them and their patients.