Safety and effectiveness of long-term growth hormone therapy in Japanese patients with adult growth hormone deficiency: a postmarketing, multicenter, observational study.

We aimed to evaluate the long-term safety and effectiveness of growth hormone (GH) therapy in Japanese patients with adult growth hormone deficiency (AGHD). In this observational, multicenter study, Norditropin® (Novo Nordisk A/S, Bagsvaerd, Denmark) was administered as injections of 0.021 mg/kg/week as a starting dose divided into 6-7 doses/week. The dose was increased according to clinical response. Patients' data were obtained from medical records. Measurements (lipids, glucose metabolism, and body composition) taken at baseline; 3, 6, and 12 months; and yearly until the end of the study were collected. Adverse drug reactions (ADRs), serious ADRs, and serious adverse events (SAEs) were evaluated. Of 387 registered patients, 334 were eligible for safety. After GH treatment initiation, a marked decrease in total cholesterol was observed earlier in the child-onset group than in the adult-onset group. LDL-cholesterol also decreased, but no significant differences in changes in LDL-cholesterol between adult-onset and child-onset groups were found. A significant increase in HDL-cholesterol starting 1 year after GH treatment initiation was found in the adult-onset group. There was no effect of GH treatment on glucose metabolism. Because of the small number of dual-energy X-ray absorptiometry data, the overall assessment of changes of body composition was difficult. Fifty-six (16.8%), 12 (3.6%), and 35 (10.5%) patients experienced ADRs, serious ADRs, and SAEs, respectively. This study demonstrated a favorable long-term safety and effectiveness profile of GH therapy in AGHD patients in the real-life Japanese clinical practice setting.

The long-term safety and effectiveness of growth hormone treatment in Japanese children with short stature born small for gestational age.

This study aimed to characterize the safety and effectiveness of GH treatments, in usual clinical practice, in children with short stature born small for gestational age (SGA). This was a multicenter, open-label, non-interventional study (NCT01110928) conducted at 150 sites in Japan (2009-2018). The primary objective was to assess the type and frequency of serious adverse drug reactions (SADRs) associated with long-term GH use. Overall, 452 naïve and 46 non-naïve (previously treated) children were enrolled. GH treatment was well­tolerated, with SADRs occurring in 1.3% (6/452) and 0% (0/46) of naïve and non-naïve children, respectively. No new safety concerns or notable changes in glucose metabolism were identified during long-term treatment. Altogether, 57 children (32 naïve and 25 non-naïve) reached near adult height (NAH). In naïve and non-naïve children, mean ± standard deviation (SD) height standard deviation score (SDS) at NAH were -2.03 ± 0.77 and -1.53 ± 0.81, respectively, representing a change of +0.85 ± 0.72 and +1.24 ± 0.66 from baseline height SDS, respectively. Mean treatment duration to NAH was 4.29 (naïve) and 7.26 (non-naïve) yr. Thus, long-term GH treatment for short stature in children born SGA was confirmed to have a good safety profile and was effective for improving adult height.

Assessment of quality of life on 4-year growth hormone therapy in Japanese patients with adult growth hormone deficiency: A post-marketing, multicenter, observational study.

OBJECTIVE: Improvement of quality of life (QOL) by growth hormone (GH) therapy was not demonstrated in Japanese adult growth hormone deficiency (AGHD) patients by either the QOL Assessment of Growth Hormone Deficiency in Adults or the Questions on Life Satisfaction-Hypopituitarism, which are widely used to evaluate QOL in Western AGHD patients. We therefore evaluated QOL in Japanese AGHD patients receiving recombinant GH, Norditropin® (Novo Nordisk A/S, Denmark), using the newly developed Adult Hypopituitarism Questionnaire (AHQ). DESIGN: This multicenter, non-interventional, observational study in Japanese patients with severe AGHD was conducted from 1 October 2009 to 30 September 2014. Patients with severe AGHD already receiving somatropin and somatropin-naïve patients were included. GH therapy (Norditropin®) was initiated as injections of 0.021mg/kg/week divided into 6-7 doses/week, and was adjusted according to clinical responses. Demographic/clinical data were obtained from medical records or by patient recall. QOL was assessed using the AHQ at baseline; 3, 6, and 12months; and annually up to 4years. RESULTS: Of 387 registered patients, 161 were eligible for QOL analysis. AHQ scores significantly improved after 3months of treatment. Improvements in the psycho-social and physical domains were statistically significant throughout the 4-year study period. Although the GH dose was increased in females such that insulin-like growth factor-1 levels reached those of males, QOL improvements in females did not reach those of males. Despite the greater GH dose in child-onset patients, limited QOL improvements were observed in child-onset vs adult-onset cases. CONCLUSIONS: Four-year GH treatment in Japanese AGHD patients elicits sustained improvement in QOL as assessed by AHQ scores.

Evaluation of growth hormone treatment efficacy in short Japanese children born small for gestational age: Five-year treatment outcome and impact on puberty.

Some children born small for gestational age (SGA) have short stature and are at an increased risk of developing psychosocial or behavioral problems. Here we evaluated the efficacy of GH and its effects on the timing of pubertal onset in a 3-yr extension of our previous 2-yr (total 5 yr) multicenter, randomized, double-blind, parallel-group clinical trial of 65 short Japanese children born SGA. Patients received low or high doses of GH (0.033 or 0.067 mg/kg/day, respectively). Age at onset of puberty was not statistically different for male and female patients receiving high- or low-dose GH. After the onset of puberty, no difference in height gain was observed between the two GH dose groups. At the onset of puberty, height standard deviation scores for chronological age of boys and girls improved significantly in both dose groups with evidence of a dose-response effect. Mean bone age/chronological age ratios in the low- and high-dose groups were significantly increased compared with baseline, being significantly greater in the high-dose group at 5 yr after treatment initiation. Delayed bone age at baseline was close to chronological age following GH treatment. GH treatment, especially high-dose GH, induced advanced bone age in short children born SGA.

The influence of a long-term growth hormone treatment on lipid and glucose metabolism: a randomized trial in short Japanese children born small for gestational age.

BACKGROUND: Long-term growth hormone (GH) treatments in short children born small for gestational age (SGA) restore lipid metabolism, but also increase insulin resistance. The aim of this study was to evaluate the influence of long-term GH therapy on lipid and glucose metabolism as well as its dose dependency in short Japanese children born SGA. METHODS: Eighty Japanese children with a short stature who were born SGA participated in this study; 65 were treated with fixed GH doses of 0.033 (low) or 0.067 (high) mg/kg/day for 260 weeks; 15 were untreated controls in the first year and were randomized to one of the two treatment groups at week 52. Serum cholesterol, glucose and insulin levels were regularly measured. An oral glucose tolerance test (OGTT) was conducted annually. RESULTS: The mean age at the start of GH therapy was approximately 5.3 years. Serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in the high dose group significantly decreased over time during GH therapy. In both dose groups for TC, and in the high dose group for LDL-C, the higher the baseline values, the greater the decrease after 260 weeks. The rate of the decrease observed after 260 weeks in patients with high LDL-C levels was greater in the high dose group. Based on the results of OGTT, no patient was classified as being diabetic; however, annual increases were observed in post-OGTT insulin levels. After 260 weeks, the homeostasis model assessment as an index of insulin resistance (HOMA-IR) increased, suggesting that insulin resistance developed over time with the GH treatment, while 36.6 % of the subjects entered puberty. CONCLUSIONS: Long-term continuous GH treatment for children born SGA may have a potentially beneficial effect on several parameters in lipid metabolism and does not adversely affect glucose metabolism. TRIAL REGISTRATION: GHLIQUID-1516, GHLIQUID-1517, Japan Pharmaceutical Information Center Clinical trial registration: JapicCTI-050132. Registered 13 September 2005. Retrospectively registered. JapicCTI-050137. Registered 13 September 2005. Retrospectively registered. ClinicalTrials.gov trial registration: NCT00184717. Registered 13 September 2005. Retrospectively registered.

Expression profiles of genes in DJ-1-knockdown and L 166 P DJ-1 mutant cells.

DJ-1 is a novel oncogene and a causative gene for the familial form of Parkinson's disease (PD). DJ-1 has been shown to play roles in anti-oxidative stress by eliminating reactive oxygen species and in transcriptional regulation of genes. Loss of these functions of DJ-1 is thought to trigger the onset of PD. In this study, to identify genes for which expressions are regulated by DJ-1, DNA microarray analyses were carried out using two mouse NIH3T3 cell lines, DJ-1-knockdown cells and cells harboring an exogenously added L 166 P DJ-1 mutant found in PD patients. In both cell lines, drastic changes in expressions of genes, including genes related to stress, apoptosis, oxidative stress and neurotoxicity, were observed and changes in expressions were confirmed by RT-PCR. Of the genes identified, expression level of the extracellular superoxide dismutase (SOD 3) gene was found to decrease in DJ-1-knockdown cells, while expressions of SOD 1 and SOD 2 genes did not change. Furthermore, expression of the tau gene, a gene whose product gives cells neurotoxicity by aggregation, was found to increase at its promoter level in L 166 P DJ-1 cells. These findings suggest that DJ-1 regulates expressions of genes for which functions are thought to be related to cell death or neurodegeneration.

Circadian expression of the Na+/H+ exchanger NHE3 in the mouse renal medulla.

Renal tubular NHE3, the Na+/H+ exchanger, is a critical enzyme for electrolyte and acid-base homeostasis in the kidney. We previously demonstrated that the expression of this gene in the kidney followed a circadian rhythm directly regulated by clock genes acting on E-box elements present on its promoter region. In the present study, we further characterize the circadian expression of NHE3 in the mice kidney by in situ hybridization, and refine quantification of gene expression using real-time PCR combined with laser capture micro-dissection. We show NHE3 mRNA was strongly expressed in the inner stripe of the outer medulla and weakly in the cortex. Further realtime PCR data from dissected medullary nephron demonstrated clear circadian oscillations in the thick ascending limbs and the thin descending limbs, but not in the collecting ducts. The circadian changes of this molecule in the renal medulla may partially contribute to the circadian change of urinary electrolyte secretion.

Circadian expression of 86- and 84-kDa heat shock proteins in the mouse suprachiasmatic nucleus.

Circadian rhythm pervades in many aspects of the biological processes including basic cellular functions. Here we examined the circadian gene expression of two forms of 90 kDa heat shock proteins referred to HSP86 and HSP84 in the mouse suprachiasmatic nucleus, the circadian center. In both light-dark, and constant dark conditions, Hsp86 mRNA showed an overt circadian rhythm showing a peak at (subjective) night and a trough at (subjective) day. Hsp84 mRNA also showed the similar expression profile, but the amplitude was weaker. These results indicate that gene expression of molecular chaperone such as Hsp86 and Hsp84 are regulated by the circadian clock.