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1.
Intern Med ; 61(3): 365-371, 2022 Feb 01.
Article in English | MEDLINE | ID: mdl-34373377

ABSTRACT

A 21-year-old Japanese man without known diabetes mellitus had abdominal pain. The diagnosis was ketoacidosis and hypertriglyceridemia-induced acute pancreatitis. He had polydipsia and polyuria and had habitually drunk several soft drinks every day for two years. After hospitalization, despite adequate liquid intake, dehydration remained with hypotonic polyuria. Further examinations revealed the coexistence of central diabetes insipidus (CDI), possibly caused by lymphocytic infundibulo-neurohypophysitis, based on anti-rabphilin-3A antibody positivity. Although CDI had been undiagnosed for two years, over-consumption of sugar-rich soft drinks to ease thirst caused ketoacidosis, hypertriglyceridemia, and acute pancreatitis. There are no previous reports of this three-part combination of symptoms caused by CDI.


Subject(s)
Diabetes Insipidus, Neurogenic , Diabetes Insipidus , Diabetes Mellitus , Hypertriglyceridemia , Ketosis , Pancreatitis , Acute Disease , Adult , Carbonated Beverages/adverse effects , Humans , Hypertriglyceridemia/complications , Hypertriglyceridemia/diagnosis , Male , Pancreatitis/complications , Pancreatitis/diagnosis , Polydipsia/diagnosis , Polydipsia/etiology , Young Adult
2.
J Endocr Soc ; 5(6): bvab055, 2021 Jun 01.
Article in English | MEDLINE | ID: mdl-34061117

ABSTRACT

CONTEXT: Paradoxical increases in serum cortisol in the dexamethasone suppression test (DST) have been rarely observed in Cushing disease (CD). Its pathophysiology and prevalence remain unclear. CASE DESCRIPTION: A 62-year-old woman with suspected CD showed paradoxical increases in cortisol after both 1-mg and 8-mg DST (1.95-fold and 2.52-fold, respectively). The initiation of metyrapone paradoxically decreased plasma adrenocorticotropic hormone (ACTH) levels and suppressed cortisol levels. Moreover, the pituitary tumor considerably shrank during metyrapone treatment. EX VIVO EXPERIMENTS: The resected tumor tissue was enzymatically digested, dispersed, and embedded into Matrigel as 3D cultured cells. ACTH levels in the media were measured. In this tumor culture, ACTH levels increased 1.3-fold after dexamethasone treatment (P < 0.01) while control tumor cultures exhibited no increase in ACTH levels, but rather a 20% to 40% suppression (P < 0.05). CLINICAL STUDY: A cross-sectional, retrospective, multicenter study that included 92 patients with CD who underwent both low-dose and high-dose DST from 2014 to 2020 was performed. Eight cases (8.7%) showed an increase in serum cortisol after both low-dose and high-dose DST. CONCLUSION: This is the first report of a patient with glucocorticoid (GC)-driven positive feedback CD who showed both ACTH suppression and tumor shrinkage by metyrapone. Our cohort study revealed that 8.7% of patients with CD patients possibly possess GC-driven positive-feedback systems, thereby suggesting the presence of a new subtype of CD that is different from the majority of CD cases. The mechanisms exhibiting GC positive feedback in CD and the therapeutic approach for these patients remain to be investigated.

3.
J Clin Endocrinol Metab ; 106(3): 718-723, 2021 03 08.
Article in English | MEDLINE | ID: mdl-33248444

ABSTRACT

CONTEXT: Luscan-Lumish syndrome (LLS) is characterized by postnatal overgrowth, obesity, Chiari I malformation, seizures, and intellectual disability. SET domain-containing protein 2 (SETD2) is a histone methyltransferase, where mutations in the gene are associated with the development of LLS. However, mechanisms underlying LLS remain unclear. CASE DESCRIPTION: A 20-year-old man was referred to our hospital because of tall stature. His body height was 188.2 cm (+3.18 SD) and he showed obesity with a body mass index of 28.4 kg/m2. He exhibited acral overgrowth, jaw malocclusion, and prognathism, but no history of seizures, intellectual disability, or speech delay. Serum growth hormone (GH), insulin-like growth factor 1 (IGF-1), and nadir GH levels after administration of 75 g oral glucose were within normal range. Pituitary magnetic resonance imaging showed no pituitary adenoma, but Chiari I malformation. Whole exome sequencing analysis of the proband revealed a de novo heterozygous germline mutation in SETD2 (c.236T>A, p.L79H). Skin fibroblasts derived from the patient grew faster than those from his father and the control subject. In addition, these cells showed enhanced tyrosine phosphorylation and transcriptional activity of signal transducer and activator of transcription 5b (STAT5b) and increased IGF-1 expression induced by GH. CONCLUSION: This is a mild case of LLS with a novel mutation in SETD2 without neurological symptoms. LLS should be differentiated in a patient with gigantism without pituitary tumors. Although further investigation is necessary, this is the first study to suggest the involvement of aberrant GH signaling in the development of LLS.


Subject(s)
Gigantism/genetics , Gigantism/metabolism , Histone-Lysine N-Methyltransferase/genetics , Human Growth Hormone/metabolism , Arnold-Chiari Malformation/complications , Arnold-Chiari Malformation/diagnosis , Arnold-Chiari Malformation/genetics , Gigantism/diagnosis , Heterozygote , Histone-Lysine N-Methyltransferase/metabolism , Humans , Intellectual Disability/complications , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Male , Mutation, Missense , Obesity/complications , Obesity/diagnosis , Obesity/genetics , Pedigree , Seizures/complications , Seizures/diagnosis , Seizures/genetics , Signal Transduction/physiology , Syndrome , Up-Regulation/genetics , Young Adult
4.
J Clin Endocrinol Metab ; 105(6)2020 06 01.
Article in English | MEDLINE | ID: mdl-32249909

ABSTRACT

CONTEXT: Germline mutations in fumarate hydratase (FH) gene are known to cause hereditary leiomyomatosis and renal cell carcinoma (HLRCC) and are occasionally accompanied with cutaneous and uterine leiomyoma or cortisol-producing adrenocortical hyperplasia. However, the association between FH mutations and cardiac or adrenocortical tumors has remained unknown. Here, we identified a novel deletion in FH, exhibiting cardiac myxoma and subclinical Cushing syndrome due to adrenocortical tumor. CASE DESCRIPTION: A 44-year-old man was referred to our hospital for cardiac and adrenal tumor evaluation. He had a history of multiple painful, dermal papules and nodules diagnosed as cutaneous leiomyoma. The surgically resected cardiac tumor was diagnosed as myxoma. The adrenal tumor was clinically diagnosed as subclinical Cushing syndrome. Laparoscopically resected adrenal tumor was pathologically diagnosed as adrenocortical adenoma harboring unique histological findings similar to primary pigmented nodular adrenocortical disease (PPNAD). DNA analysis revealed a germline deletion in FH c0.737delT (p. Phe225Leufs*31) and loss of heterozygosity (LOH) in cardiac myxoma. As a functional analysis of FH in cardiac myxoma, low FH protein expression with elevated 2-succinocysteine (2SC), a marker of FH dysfunction, was immunohistochemically detected. However, in adrenocortical tumor, LOH of FH was not detected, and FH or 2SC expression was not altered. CONCLUSIONS: This is the first case of HLRCC complicated by cardiac myxoma. LOH of FH deletion and its dysfunction were identified in cardiac myxoma. The association between FH deletion and adrenocortical lesion, however, needs to be further clarified.


Subject(s)
Adrenal Cortex Neoplasms/complications , Adrenocortical Adenoma/complications , Fumarate Hydratase/genetics , Gene Deletion , Heart Neoplasms/etiology , Hydrocortisone/metabolism , Myxoma/etiology , Adrenal Cortex Neoplasms/genetics , Adrenal Cortex Neoplasms/metabolism , Adrenal Cortex Neoplasms/pathology , Adrenocortical Adenoma/genetics , Adrenocortical Adenoma/metabolism , Adrenocortical Adenoma/pathology , Adult , Heart Neoplasms/pathology , Humans , Male , Myxoma/pathology , Prognosis
7.
Clin Pediatr Endocrinol ; 26(4): 229-241, 2017.
Article in English | MEDLINE | ID: mdl-29026272

ABSTRACT

The primary goal of the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) was to assess the safety and effectiveness of Humatrope®, a GH preparation, in the treatment of pediatric patients with short stature. We report our findings in the GH-treated Japanese pediatric population focusing on the incidence of type 2 diabetes (T2D) and occurrence of neoplasms. A total of 2,345 Japanese patients were assessed for safety. During a mean observation period of 3.2 yr, T2D occurred in 3 patients (0.13%) and slowly progressive insulin-dependent diabetes mellitus (SPIDDM) related to underlying mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in 1 patient (0.04%). Neoplasms were reported in 13 patients (0.56%), including 1 patient with brain tumor (germinoma) and 5 with craniopharyngiomas (4 recurrences); the remainder were benign, typically dermatological, neoplasms. The incidence of diabetes mellitus determined in the study did not differ from previous reports in GH-treated pediatric patients, and there was no apparent increase in the risk of new neoplastic lesions or malignant tumors.

8.
Growth Horm IGF Res ; 36: 36-43, 2017 10.
Article in English | MEDLINE | ID: mdl-28923784

ABSTRACT

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.


Subject(s)
Growth Disorders/drug therapy , Hormone Replacement Therapy , Human Growth Hormone/administration & dosage , Quality of Life , Recombinant Proteins/administration & dosage , Adult , Female , Humans , Male , Middle Aged , Product Surveillance, Postmarketing
9.
Endocr J ; 64(7): 651-662, 2017 Jul 28.
Article in English | MEDLINE | ID: mdl-28529275

ABSTRACT

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.


Subject(s)
Congenital Hypothyroidism/drug therapy , Dwarfism, Pituitary/drug therapy , Hormone Replacement Therapy/adverse effects , Human Growth Hormone/adverse effects , Recombinant Proteins/adverse effects , Adult , Biomarkers/blood , Congenital Hypothyroidism/blood , Congenital Hypothyroidism/ethnology , Drug Monitoring , Dwarfism, Pituitary/blood , Dwarfism, Pituitary/ethnology , Female , Follow-Up Studies , Human Growth Hormone/administration & dosage , Human Growth Hormone/genetics , Human Growth Hormone/therapeutic use , Humans , Japan , Lost to Follow-Up , Male , Medical Records , Middle Aged , Patient Dropouts , Product Surveillance, Postmarketing , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use , Sex Characteristics , Young Adult
10.
Endocr J ; 63(4): 337-47, 2016 Apr 25.
Article in English | MEDLINE | ID: mdl-26796763

ABSTRACT

Pegvisomant is a GH receptor antagonist and strong inhibitor of insulin-like growth factor I (IGF-I) production. The treatment goal for acromegaly is to normalize serum IGF-I levels and attenuate associated symptoms. The efficacy and safety of pegvisomant as treatment for acromegaly have been reported in Caucasians, but not in Japanese. Here we report the clinical experience of using pegvisomant in Japanese patients with acromegaly. The efficacy and safety data for pegvisomant from two open-labeled clinical studies in Japan, conducted from 2004 to 2007, were re-analyzed using the new Japanese age- and sex-matched normative ranges for IGF-I. Eighteen patients with active acromegaly were enrolled in an initial pivotal study, and 16 of them were moved to a long-term (max 168 weeks) extension study. The dose of pegvisomant in the extension study was adjusted to 10-30 mg per day according to IGF-I levels. IGF-I normalization was observed in 81.3% (13/16 patients) during the extension study. The mean percentage decrease from baseline in serum IGF-I level was 64.7% at the time of last observation. The clinical symptoms and overall health status were improved, and the ring size was reduced over time until Week 12 and maintained. For safety, no clinically significant changes were observed both in the pituitary tumor size and the anti-GH antibody level. Three subjects were withdrawn from the studies due to an abnormal elevation of liver enzymes which resolved after discontinuation. Pegvisomant demonstrated excellent clinical efficacy and was well tolerated in Japanese patients with acromegaly.


Subject(s)
Acromegaly/drug therapy , Hormone Antagonists/administration & dosage , Hormone Antagonists/adverse effects , Human Growth Hormone/analogs & derivatives , Acromegaly/blood , Adult , Aged , Female , Human Growth Hormone/administration & dosage , Human Growth Hormone/adverse effects , Human Growth Hormone/blood , Humans , Insulin-Like Growth Factor I/analysis , Japan , Male , Matched-Pair Analysis , Middle Aged , Retrospective Studies , Treatment Outcome
12.
Endocr J ; 62(8): 749-56, 2015.
Article in English | MEDLINE | ID: mdl-26073867

ABSTRACT

In addition to impaired physical activity, adult GH deficiency (GHD) can decrease quality of life (QOL). Hence, assessment of QOL is important to evaluate the efficacy of GH replacement therapy. This study aimed to identify factors that may be predictive of long-term improvement in QOL among clinical/laboratory variables during GH replacement therapy. The analysis included 83 Japanese adults with GHD who participated in the Hypopituitary Control and Complications Study (HypoCCS). Correlations between the change from baseline in clinical/laboratory variables at 6 months and the change from baseline in Quality of life (Short-Form 36 [SF-36] component scores) at 12 months were examined. Unexpectedly, all component scores were negatively correlated with the change in fasting plasma glucose concentration (FPG) (physical component summary [PCS], r = -0.456; mental component summary [MCS], r = -0.523; role/social component summary [RCS], r = -0.433). The change in MCS was positively correlated with the change in insulin-like growth factor-1 standard deviation score (IGF-1 SDS) (r = 0.417). The change in PCS was positively correlated with the change in body fat (r = 0.551). The change in RCS was positively correlated with the change in waist circumference (r = 0.528). Short-term changes in several clinical/laboratory variables, most notably FPG and IGF-1 SDS, were correlated with long-term changes in QOL. The clinical importance of these correlations for predicting GH replacement treatment efficacy warrants further investigation.


Subject(s)
Hormone Replacement Therapy/psychology , Human Growth Hormone/therapeutic use , Hypopituitarism/drug therapy , Quality of Life/psychology , Adult , Human Growth Hormone/deficiency , Humans , Hypopituitarism/psychology , Treatment Outcome
13.
Clin Pediatr Endocrinol ; 23(3): 83-92, 2014 Jul.
Article in English | MEDLINE | ID: mdl-25110392

ABSTRACT

The aim of this study was to assess changes in quality of life (QoL) in Japanese children with GH deficiency (GHD) after 12 mo of GH treatment or with idiopathic short stature (ISS) after 12 mo without treatment. Children with GHD were treated with GH after enrollment. Outcome measures included the parent-rated Child Behavior Checklist (CBCL), the Youth Self-Report Form (YSR), and height standard deviation scores (SDS). Total CBCL scores significantly decreased in children with GHD (n = 152, mean change (standard deviation [SD]) = -3.42 [11.21]) and ISS (n = 129, mean change = -4.82 [10.09]) after 12 mo (p < 0.001). Total YSR scores (mean change = -9.21 [14.07]) and height SDS (mean change = 0.35 [0.38]) significantly decreased in children with GHD (p < 0.001), but were unchanged in children with ISS. The change in total YSR score was significantly correlated with the change in height SDS in children with GHD (r = -0.516, p = 0.003). Our findings demonstrate that GH treatment can improve QoL in Japanese children with GHD. The correlation between the changes in total YSR score and height SDS demonstrated that increased height resulted in improved QoL.

15.
Endocr J ; 60(10): 1131-44, 2013.
Article in English | MEDLINE | ID: mdl-23823978

ABSTRACT

This large-scale observational study examined the long-term effectiveness and safety of growth hormone (GH) replacement therapy for adult GH deficiency (GHD) in Japanese clinical practice using the Hypopituitary Control and Complications Study database. The study included 402 GHD patients for safety analyses and a subset of 209 patients (149 adult-onset and 60 childhood-onset GHD patients) who had not previously received GH replacement therapy for the efficacy analyses. Data on clinical, metabolic, quality of life (QoL) characteristics, and all adverse events (AEs) were collected at baseline (start of GH treatment), 6 months, 1 year and 2 years. Over the observation period, there were improvements from baseline in insulin-like growth factor-I standard deviation scores (P<0.001), although the changes in metabolic parameters were minimal. QoL (Short Form-36) Z-scores significantly increased from baseline in both onset-type groups for several subscale domains (P<0.05). A total of 145 (36.1%) patients experienced ≥1 AE. Common AEs were hyperlipidaemia (2.7%) and hyperinsulinaemia (2.2%). Some patients experienced recurrent hypothalamic/pituitary tumour (events per 1000 patient-years: 2.78), new benign (0.93), malignant tumour (10.28) or other new tumour (0.93), new diabetes mellitus (7.45), and new stroke (3.71). Seven patients died during the observation period. Our safety findings are inconclusive about the associations between GH replacement and AEs, although the incidence of diabetes mellitus and cardiovascular events are similar to those reported in the Japanese general population. In conclusion, the key beneficial effects of GH replacement therapy for GHD are observed in routine clinical practice in Japan.


Subject(s)
Human Growth Hormone/therapeutic use , Adolescent , Adult , Cardiovascular Diseases/chemically induced , Diabetes Mellitus/chemically induced , Female , Hormone Replacement Therapy/adverse effects , Human Growth Hormone/adverse effects , Human Growth Hormone/deficiency , Humans , Insulin-Like Growth Factor I/metabolism , Japan , Male , Middle Aged , Neoplasms/chemically induced , Quality of Life
16.
Mol Cell Endocrinol ; 376(1-2): 93-8, 2013 Aug 25.
Article in English | MEDLINE | ID: mdl-23732115

ABSTRACT

PROP1 mutation causes combined pituitary hormone deficiency (CPHD). Several mutations are located in a transactivation domain (TAD) of Prop1, and the loss of TAD binding to cofactors is likely the cause of CPHD. PROP1 cofactors have not yet been identified. In the present study, we aimed to identify the PROP1-interacting proteins from the human brain cDNA library. Using a yeast two-hybrid assay, we cloned nine candidate proteins that may bind to PROP1. Of those nine candidates, amino-terminal enhancer of split (AES) was the most abundant, and we analyzed the AES function. AES dose-dependently decreased the PROP1-induced Pit-1 reporter gene expression. An immunoprecipitation assay revealed the relationship between AES and PROP1. In a mammalian two-hybrid assay, a leucine zipper-like motif of the AES Q domain was identified as a region that interacted with TAD. These results indicated that AES was a corepressor of PROP1.


Subject(s)
Homeodomain Proteins/genetics , Hypopituitarism/genetics , Mutation , Pituitary Gland/metabolism , Repressor Proteins/genetics , Transcription Factor Pit-1/genetics , Binding Sites , Brain/metabolism , Cell Line, Tumor , Co-Repressor Proteins , Gene Expression Regulation , Gene Library , Genes, Reporter , Homeodomain Proteins/metabolism , Humans , Hypopituitarism/metabolism , Hypopituitarism/pathology , Pituitary Gland/cytology , Protein Binding , Protein Interaction Domains and Motifs , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Repressor Proteins/metabolism , Transcription Factor Pit-1/metabolism , Two-Hybrid System Techniques
17.
Endocr J ; 60(5): 651-63, 2013.
Article in English | MEDLINE | ID: mdl-23337477

ABSTRACT

The somatostatin analog lanreotide Autogel has proven to be efficacious for treating acromegaly in international studies and in clinical practices around the world. However, its efficacy in Japanese patients has not been extensively evaluated. We examined the dose-response relationship and long-term efficacy and safety in Japanese patients with acromegaly or pituitary gigantism. In an open-label, parallel-group, dose-response study, 32 patients (29 with acromegaly, 3 with pituitary gigantism) received 5 injections of 60, 90, or 120 mg of lanreotide Autogel over 24 weeks. Four weeks after the first injection, 41% of patients achieved serum GH level of <2.5 ng/mL and insulin-like growth factor-I (IGF-I) level was normalized in 31%. Values at Week 24 were 53% for GH and 44% for IGF-I. Dose-dependent decreases in serum GH and IGF-I levels were observed with dose-related changes in pharmacokinetic parameters. In an open-label, long-term study, 32 patients (30 with acromegaly, 2 with pituitary gigantism) received lanreotide Autogel once every 4 weeks for a total of 13 injections. Dosing was initiated with 90 mg and adjusted according to clinical responses at Weeks 16 and/or 32. At Week 52, 47% of patients had serum GH levels of <2.5 ng/mL and 53% had normalized IGF-I level. In both studies, acromegaly symptoms improved and treatment was generally well tolerated although gastrointestinal symptoms and injection site induration were reported. In conclusion, lanreotide Autogel provided early and sustained control of elevated GH and IGF-I levels, improved acromegaly symptoms, and was well tolerated in Japanese patients with acromegaly or pituitary gigantism.


Subject(s)
Acromegaly/prevention & control , Adenoma/drug therapy , Antineoplastic Agents/administration & dosage , Gigantism/drug therapy , Growth Hormone-Secreting Pituitary Adenoma/drug therapy , Peptides, Cyclic/administration & dosage , Pituitary Gland/drug effects , Somatostatin/analogs & derivatives , Acromegaly/etiology , Adenoma/blood , Adenoma/physiopathology , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/adverse effects , Delayed-Action Preparations/pharmacokinetics , Delayed-Action Preparations/therapeutic use , Dose-Response Relationship, Drug , Down-Regulation/drug effects , Drug Monitoring , Female , Gastrointestinal Diseases/chemically induced , Gels , Gigantism/blood , Growth Hormone-Secreting Pituitary Adenoma/blood , Growth Hormone-Secreting Pituitary Adenoma/physiopathology , Human Growth Hormone/blood , Humans , Insulin-Like Growth Factor I/analysis , Japan , Male , Middle Aged , Peptides, Cyclic/adverse effects , Peptides, Cyclic/pharmacokinetics , Peptides, Cyclic/therapeutic use , Somatostatin/administration & dosage , Somatostatin/adverse effects , Somatostatin/pharmacokinetics , Somatostatin/therapeutic use
18.
Endocr J ; 60(1): 57-64, 2013.
Article in English | MEDLINE | ID: mdl-23001148

ABSTRACT

This study assessed the effectiveness and safety of growth hormone (GH; Humatrope(®)) therapy in Japanese children with GH deficiency (GHD) or Turner syndrome (TS) enrolled in the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). GeNeSIS is an open-label, multinational, multicenter, observational study conducted in 30 countries. In this interim report, there were 1129 GH treatment-naïve children with GHD, with a mean chronological age (± standard deviation) of 8.75 (3.32) years, and 90 girls with TS, with a mean chronological age of 8.93 (3.67) years. The mean height standard deviation score (SDS) increased from -2.73 (0.63) SD and -2.71 (0.63) SD at study entry to -2.22 (0.68) SD and -2.20 (0.60) SD after 1 year of treatment in the GHD and TS groups, respectively. In both groups, mean height SDS increased further with each year of treatment to 4 years; however, the magnitude of change in height SDS declined with time. The mean insulin-like growth factor-I SDS increased from below the mean of the reference population at study entry to a level similar to (GHD group) or higher than (TS group) the mean of the reference population during the 4-year treatment period. The incidence of serious adverse events (AEs), treatment-related AEs, and AEs related to glucose intolerance was low in both groups (0.1% to 3.0%). In conclusion, GH treatment in Japanese children with GHD or TS resulted in increased growth over a 4-year treatment period with a favorable safety profile; however, the improvements in growth declined with time.


Subject(s)
Hormone Replacement Therapy , Human Growth Hormone/therapeutic use , Hypopituitarism/drug therapy , Turner Syndrome/drug therapy , Asian People , Body Height , Child , Child, Preschool , Female , Human Growth Hormone/adverse effects , Human Growth Hormone/deficiency , Humans , Infant , Male , Treatment Outcome
20.
Nutr Res ; 32(9): 676-83, 2012 Sep.
Article in English | MEDLINE | ID: mdl-23084640

ABSTRACT

Atrogin-1 and MuRF1, muscle-specific ubiquitin ligases, and autophagy play a role in protein degradation in muscles. We hypothesized that branched-chain amino acids (BCAAs) may decrease atrogin-1, MuRF1, and autophagy, and may have a protective effect on disuse muscle atrophy. To test this hypothesis, we selected hindlimb suspension (HS)-induced muscle atrophy as a model of disuse muscle atrophy because it is an established model to investigate the effects of decreased muscle activity. Sprague-Dawley male rats were assigned to 4 groups: control, HS (14 days), oral BCAA administration (600 mg/[kg day], 22.9% L-isoleucine, 45.8% L-leucine, and 27.6% L-valine), and HS and BCAA administration. After 14 days of the treatment, muscle weights and protein concentrations, cross-sectional area (CSA) of the muscle fibers, atrogin-1 and MuRF1 proteins, and microtubule-associated protein 1 light chain 3 II/I (ratio of LC3 II/I) were measured. Hindlimb suspension significantly reduced soleus muscle weight and CSA of the muscle fibers. Branched-chain amino acid administration partly but significantly reversed the HS-induced decrease in CSA. Hindlimb suspension increased atrogin-1 and MuRF1 proteins, which play a pivotal role in various muscle atrophies. Branched-chain amino acid attenuated the increase in atrogin-1 and MuRF1 in soleus muscles. Hindlimb suspension significantly increased the ratio of LC3 II/I, an indicator of autophagy, whereas BCAA did not attenuate the increase in the ratio of LC3 II/I. These results indicate the possibility that BCAA inhibits HS-induced muscle atrophy, at least in part, via the inhibition of the ubiquitin-proteasome pathway. Oral BCAA administration appears to have the potential to prevent disuse muscle atrophy.


Subject(s)
Amino Acids, Branched-Chain/pharmacology , Hindlimb Suspension/adverse effects , Muscle Proteins/metabolism , Muscular Atrophy/prevention & control , SKP Cullin F-Box Protein Ligases/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Blotting, Western , Isoleucine/pharmacology , Leucine/pharmacology , Male , Muscle Proteins/genetics , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscular Atrophy/pathology , Muscular Disorders, Atrophic/pathology , Muscular Disorders, Atrophic/prevention & control , Organ Size/drug effects , Rats , Rats, Sprague-Dawley , SKP Cullin F-Box Protein Ligases/genetics , Tripartite Motif Proteins , Ubiquitin-Protein Ligases/genetics , Valine/pharmacology
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