Adult growth hormone deficiency (AGHD) increases the prevalence of complications, including metabolic disorder, leading to increased cardiovascular mortality from cardiovascular diseases. However, no large database studies have evaluated AGHD patients without GH replacement therapy (GHRT). We investigated the prevalence of AGHD-related complications in patients without GHRT.

Patients with AGHD and associated complications were identified from the Medical Data Vision claims database using Japanese local disease codes mapped to ICD-10 codes. The prevalence of AGHD-related complications in 2020 was estimated to compare with the prevalence in the Japanese general population in the latest available year 2020. Risk factors for complications were evaluated by Kaplan-Meier curves and a Cox proportional hazard model.

We identified 8,809 untreated patients with AGHD from April 2008 to September 2022, including 3,430 in 2020. In 2020, the prevalence of complications was higher in the AGHD population adjusted for sex and age than in the Japanese general population, e.g., diabetes mellitus, 9.3% vs. 3.6%; osteoporosis, 4.8% vs. 1.3%; and dyslipidemia, 22.0% vs. 3.9%. Age was a significant risk factor for most complications, and female sex for osteoporosis. Diabetes mellitus was a significant risk factor for dyslipidemia, ischemic heart disease, cerebrovascular disease, and all-cause death.

Untreated patients with AGHD have a higher prevalence of metabolic complications than the general population despite no difference in their related risk factors. Given the low use of GHRT in this study, comprehensive treatment approaches that include GHRT need to be considered to alleviate the risk of complications.

Blast brain injury (bBI) is a combination of several forces of pressure, rotation, penetration of sharp objects and chemical exposure causing laceration, perforation and tissue losses in the brain. The bBI is quite prevalent in military personnel during combat operations. However, no suitable therapeutic strategies are available so far to minimize bBI pathology. Combat stress induces profound cardiovascular and endocrine dysfunction leading to psychosomatic disorders including diabetes mellitus (DM). This is still unclear whether brain pathology in bBI could exacerbate in DM. In present review influence of DM on pathophysiology of bBI is discussed based on our own investigations. In addition, treatment with cerebrolysin (a multimodal drug comprising neurotrophic factors and active peptide fragments) or H-290/51 (a chain-breaking antioxidant) using nanowired delivery of for superior neuroprotection on brain pathology in bBI in DM is explored. Our observations are the first to show that pathophysiology of bBI is exacerbated in DM and TiO₂-nanowired delivery of cerebrolysin induces profound neuroprotection in bBI in DM, not reported earlier. The clinical significance of our findings with regard to military medicine is discussed.

Non-functioning pituitary adenoma (NFPA) is one common cause of adult growth hormone deficiency (AGHD). In Japan, a GH-releasing peptide (GHRP)-2 test is used to evaluate GH secretion. Although the cut-off for peak GH during a GHRP-2 test for severe AGHD is ≤9 ng/mL, severe AGHD may further diminish responses (range, nearly no-response to ≤9 ng/mL). We studied whether the peak GH responses during a GHRP-2 test could be predicted based on clinical characteristics of patients with NFPA. We compared patients with almost no-response during a GHRP-2 test with other patients considered as severe AGHD. Among the 76 patients with NFPA who were admitted to our institution, 36 patients (mean age, 61 years; male/female, n = 23/n = 13) were diagnosed with severe AGHD based on a preoperative GHRP-2 test. Based on the preoperative median peak GH concentration (2.83 ng/mL), patients were divided into two groups (<median = low or group L, n = 18; ≥median = moderate or group M, n = 18). Clinical manifestations, body mass index, severity of hypopituitarism and tumor size, volume, and extension were analyzed retrospectively. Compared with group M, group L patients were significantly older and more gonadotropin and ACTH deficient. A lower peak GH release during a GHRP-2 test was associated with a higher number of anterior pituitary hormone deficiencies across all 76 patients. Postoperatively, seven in group M and no patient in group L were assessed as having no longer severe AGHD, respectively. Preoperative peak GH concentrations assessed during a GHRP-2 test reflected the severity of hypopituitarism and the recovery of postoperative GH secretion.

Growth hormone (GH) affects body composition and atherogenic risk factors. Severe hyperlipidemia may develop in GH-deficient adults as a consequence of continuous GH deficiency. We investigated changes in lipid profiles in 158 Japanese children (103 boys and 55 girls) with GH deficiency who had been enrolled in the Pfizer International Growth Database Japan during 3 yr of GH replacement therapy to evaluate whether GH treatment has beneficial effects on atherogenic risk factors. Total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC) and atherogenic index were evaluated before treatment and then once a year during treatment. The mean baseline TC was within the normal range in both boys and girls. Seventeen (16.5%) of the 103 boys and 18 (32.7%) of the 55 girls, however, had a TC level over 200 mg/dl before treatment. The mean TC level showed a significant decrease in girls. In a separate analysis, patients of both sexes with a TC level > 200 mg/dl showed significantly decreased TC. LDLC decreased significantly only in girls, while HDLC showed no change in either sex. The atherogenic index decreased significantly in girls. GH replacement therapy in children with GH deficiency had beneficial effects on lipid metabolism and atherogenic risk in both sexes. Early GH treatment would produce lipid metabolism benefits in these patients.

The clinical characteristics of Caucasian adults with growth hormone (GH) deficiency (GHD) have been well defined. However, no large-scale clinical practice study has examined the clinical characteristics of Japanese adults with GHD. The aim of our study was to describe the clinical characteristics of Japanese adults with GHD by reviewing the records of participants who were GH-naive at the time of enrollment in the Hypopituitary Control and Complications Study (N = 349). The majority of participants (280 of 349; 80.2%) had adult-onset rather than childhood-onset GHD. Hypothalamo-pituitary tumors were the most common cause of GHD in Japanese adults (247 of 349; 70.8%); these tumors were primarily pituitary adenomas in participants with adult-onset GHD (156 of 243; 64.2%), and germ cell tumors (19 of 40; 47.5%) and craniopharyngiomas (18 of 40; 45.0%) in participants with childhood-onset GHD. Most participants (310 of 349; 88.8%) had multiple pituitary hormone deficiencies. Dyslipidemia (195 of 349; 55.9%), visual field loss (67 of 349; 19.2%), hypertension (59 of 349; 16.9%), and liver disease (54 of 349; 15.5%) were the most common pre-existing conditions in Japanese adults with GHD. Quality of life was decreased in seven of the eight short form-36 domains in participants with GHD compared with age- and sex-matched healthy Japanese individuals. Our findings confirm that the clinical characteristics of Japanese adults with GHD are similar to those of Caucasian adults with GHD. Confirmation of these clinical characteristics will enhance the ability of clinicians to identify and treat Japanese adults with GHD.

The possibility that diabetes influences the outcome of heat stress-induced brain pathology was examined in our experimental rat model. Because growth hormone (GH) deficiency is an important factor in diabetes, the possible neuroprotective role of GH supplements was also examined in diabetic rats following heat stress. Rats receiving streptozotocine once daily for three days (50 mg/kg, i.p.) and allowed to survive four weeks resulted in diabetes (blood glucose level 18 and 20 mMol/L) compared to controls (blood glucose 4-6 mMol/L). Control or diabetic rats when subjected to four hours' heat stress at 38 degrees C in a biological oxygen demand incubator (BOD) showed profound disruption of the blood-brain barrier (BBB), reduction in cerebral blood flow (CBF), brain edema formation, and cell injury. These effects were most pronounced in diabetic rats. Pretreatment with GH (50 microg/kg/min for 10 min before heat stress) significantly attenuated brain pathology in normal animals subjected to hyperthermia. On the other hand, almost a double dose of the growth hormone (80 to 120 microg/g/min for 10 min) is needed in diabetic rats to induce considerable neuroprotection following heat stress. These observations are the first to suggest that diabetic rats are more vulnerable to heat stress-induced brain pathology and further show that the efficacy of neuroprotective drugs is also severely reduced in diabetic rats. Taken together, our results demonstrate that the dosage of neuroprotective drugs requires adjustment to enhance neuroprotection depending on the patient's endocrine or metabolic status, for example, diabetes mellitus, a finding not reported earlier.

The aim of the study was to evaluate the efficacy and safety of growth hormone (GH) treatment in Japanese adult patients with GH-deficiency. In the extension of the efficacy study, the effect of individualized-dosing (ID), based on insulin-like growth factor-I (IGF-I) levels, and fixed-dose (FD) GH regimens on body composition, were compared in Japanese GH-deficient adults.

Randomized, double-blind (DB), placebo-controlled, 24-week treatment period followed by 48-week, open-label study in 43 endocrinology clinics in Japan. Patients received DB treatment with GH (0.012 mg/kg/day; n=57) or placebo (n=60) followed by open-label GH in an ID (n=75) or FD (0.012 mg/kg/day; n=38) regimen.

Adult Japanese GH-deficient patients (peak GH<3 ng/mL).

Trunk and total body fat (BF), lean body mass (LBM), and adverse events were determined.

Percentage trunk fat was reduced significantly more in GH- than in placebo-treated patients at 24 weeks (-16.2 vs. 1.7%, p<0.0001). Open-label treatment with an ID or FD GH regimen provided similar reductions in percentage trunk fat (-8.12 vs. -9.35%), and total BF (-0.92 vs. -0.70 kg) and a comparable increase in LBM (1.032 vs. 0.97 kg). Mean+/-SD GH doses (mg/kg/day) at 48 weeks were significantly lower with the ID GH regimen (ID, 0.0082+/-0.0050; FD, 0.0095+/-0.0033; p<0.05). The safety profile was comparable between ID and FD groups.

Treatment with GH was associated with a significant reduction in trunk fat and improvement in serum lipid profile in Japanese adult GH-deficient patients. The improvement in body composition and tolerability were comparable between ID and FD GH regimens despite a significantly lower daily GH dose with the ID regimen.

Adult patients with hypopituitarism are treated by the replacement of deficient hormones, although GH has not been substituted until March 2006 in Japan except for clinical trial. This study examines which hormonal status influences the prevalence of vascular risk disorders in hypopituitary adults. A sample of 263 adult patients with hypopituitarism was studied, among whom there were various hormonal status such as no deficiency, treated or untreated deficiency of each pituitary hormone. Analysis of adult patients with hypopituitarism showed that hypertension was more prevalent in the older than in younger patients and in male than in female patients. Hypercholesterolemia and hypertriglyceridemia were more prevalent in patients with TSH deficiency even with thyroxine substitution than those without TSH deficiency. Both obesity and hypertension were less prevalent in patients with treated ACTH deficiency than those without ACTH deficiency. Obesity was more prevalent in patients with treated vasopressin deficiency than those without vasopressin deficiency. These results provide evidence that glucocorticoid substitution in ACTH deficient adults was favorable to prevent obesity and hypertension but that the thyroxine substitution in TSH deficient adults appeared rather insufficient to prevent hyperlipidemia.

Both Japanese and Caucasian adults with GH deficiency (GHD) have pronounced abdominal obesity, which is associated with increased risk of cardiovascular complications. We investigated the effects of GH treatment in 27 adult Japanese GHD patients, 15 with adult onset (AO) and 12 with childhood onset (CO) GHD. Patients initially received GH titrated to 0.012 mg/kg/day for 24 weeks in a double-blind design and the dose was then individualized for each patient according to IGF-I for a further 24 weeks. Dual-energy x-ray absorptiometry (DXA) data were evaluated for percentages of trunk fat, total body fat and lean body mass. Serum IGF-I and lipid concentrations were determined at a central laboratory. There were 25 patients who completed 48 weeks of treatment, with 7, 6 and 12 patients then receiving GH at 0.003, 0.006 and 0.012 mg/kg/day, respectively. With the reductions in dose when individualized between weeks 24 and 48, mean serum IGF-I level was reduced and excessively high values, observed in AO patients on the fixed GH dose, were no longer seen. The decrease from baseline in trunk fat was similar at week 24 (-3.8 +/- 3.3%, p<0.001) and week 48 (-3.1 +/- 3.7%, p<0.001), and the difference between changes was not significant. Total cholesterol was decreased from baseline by -24 +/- 28 mg/dl (p<0.001) at week 24 and -17 +/- 28 mg/dl (p = 0.007) at week 48. Two patients had elevated HbA1c levels: one continued GH treatment after a dose reduction and the other discontinued due to persistent impaired glucose tolerance. Therefore, excessively high IGF-I levels can be avoided by individualized dosing during long-term GH treatment. Individualized dosing maintains the decrease in abdominal fat in adult Japanese GHD patients and should reduce the cardiovascular risk.

Patients with growth hormone deficiency (GHD), both Japanese and Caucasian, have an abnormal body composition with pronounced abdominal obesity. This study aimed to evaluate changes in trunk fat with GH treatment.

Double-blind, placebo-controlled study.

Sixty-one Japanese adult GH deficient patients (mean age 37 years) were randomised to either GH, titrated to 0.012 mg/kg/day, (n = 30) or placebo (n = 31) for 24 weeks. Body composition, by dual-energy X-ray absorptiometry (DXA), was evaluated at a central laboratory for trunk fat, total body fat and lean body mass. Serum lipid levels were also determined centrally.

At baseline, 26 (42.6%) patients had a body mass index (BMI) > or = 25 kg/m(2), the threshold for obesity-related complications for Japanese subjects. Median trunk fat mass (FM) was > or = 9.0 kg for each treatment and gender group, higher than the cut-off for increased age-adjusted risk for cardiovascular complications reported in the normal Japanese population. After 24 weeks of GH treatment, the change in percentage trunk FM was -3.4 +/- 0.6%, versus 0.4 +/- 0.6% with placebo (p < 0.001). Change in total body FM was -2.8 +/- 0.5% with GH and 0.0 +/- 0.5% with placebo, indicating that the decrease in trunk fat was more pronounced than for total body fat. Total and low density lipoprotein (LDL)-cholesterol were both significantly (p < 0.001) decreased compared with placebo. One patient discontinued due to a subdural haematoma and one had GH dose reduced due to hyperglycaemia.

Japanese patients with GHD have abnormal central fat accumulation, which is reduced by GH treatment over 24 weeks. This may reduce cardiovascular risk but the GH dose should be individualised to maintain IGF-I in the normal range.

The aim of this study was to assess the effect of growth hormone (GH) replacement therapy on lean body mass (LBM) and other variables including body fat mass, serum lipids and quality of life measures in GH-deficient Japanese adults.

This was a multicentre, double-blind, placebo-controlled, parallel group study. Following initial screening, patients were randomly assigned to GH treatment (n=37) or placebo (n=36). GH treatment was started at an initial dose 0.003 mg/kg/day s.c. each day for the first 4 weeks after which the dose was increased to 0.006 mg/kg/day for 4 weeks and then to 0.012 mg/kg/day for the last 16 weeks (n=37). Body composition, serum lipids, serum IGF-I and IGFBP-3 levels were measured during the 24-week study. Short Form-36 and Quality of Life Assessment of GH Deficiency in Adults scores were also determined.

LBM was significantly increased from baseline at 24 weeks in GH-treated patients, with a mean (+/-SD) increase of 4.7% (+/-5.3%) compared with an increase of 1.0% (+/-4.4%) in the placebo group (p<0.0001 versus baseline, p=0.0003 versus placebo). Percentage body fat decreased significantly from baseline in GH-treated patients (9.3%, p<0.0001), compared with a non-significant 0.2% increase in the placebo group (p<0.0004 for difference between treatment groups). In addition, significantly increased serum IGF-I and IGFBP-3 levels and improvements in the patients' serum lipid profiles were observed in patients who received GH therapy. Changes in quality of life measures did not differ between treatments, probably because of the small number of patients studied. GH therapy was well tolerated, with adverse events of any cause reported in 86.5% of the GH treatment group and 83.3% of the placebo group.

GH treatment significantly improved body composition and serum lipid profiles in adult Japanese patients with GH deficiency compared with placebo and had no clinically relevant adverse effects.

An increased prevalence of both hypertension and cerebrovascular stroke is apparent in growth hormone (GH) deficiency whilst hypertension is a frequent complication in acromegaly. This has suggested a possible link between GH, stature and arterial function. Since the risk of both hypertension and stroke also appears to be inversely correlated with adult height, we have instigated an exploratory study to assess whether inter-individual variation in the genes encoding human growth hormone (GH1) and the GH receptor (GHR) might be associated with an increased risk of hypertension and stroke. GH1 promoter haplotypes were found to differ significantly not only between hypertensive patients (n = 111) and controls (n = 121) but also between stroke patients (n = 155) and controls (n = 158). Intriguingly, the association between GH1 promoter haplotype and risk of hypertension was much greater in females than in males. An inverse correlation between height and central systolic blood pressure was apparent in both hypertensive patients and normal controls but was much stronger in individuals carrying at least one GH1 promoter risk haplotype. The GH1 genotype therefore constitutes a risk factor for hypertension that interacts with stature. A strong association was found between the presence of at least one GH1 risk haplotype and a family history of stroke at an early age (odds ratio: 9.07, 95% confidence interval: 1.14-72.22). Three novel GH variants (Arg16His, Phe176Cys, Cys189Arg) were identified during the course of this study. Although two exhibited markedly reduced biological activity in vitro, their clinical significance remains unclear. No association was found between GHR genotype and either hypertension or stroke, nor was any interaction noted between GHR and GH1 genotypes in terms of a disease association. However, an association between GHRd3 genotype and hypertension was observed among stroke patients, particularly females. Elevated HDL was found to be a risk factor for hypertension in individuals lacking a copy of the GHRd3 allele. Weak associations with GHR genotype were also noted for peripheral systolic and diastolic blood pressure in hypertensive patients. Although the underlying mechanisms are still unclear, our findings are consistent with a complex relationship between height, hypertension, GH1 promoter haplotype, GHR polymorphism and the risk of stroke.