Real-World Clinical Efficacy of Antifibrotic Agents for Idiopathic Pulmonary Fibrosis: A Single-Center Retrospective Study in Japan.

BACKGROUND: The antifibrotic drugs, nintedanib and pirfenidone, inhibit the decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF). Nintedanib also inhibits the onset of acute exacerbation and reduces the risk of all-cause mortality. However, their effectiveness in real-world practice remains unclear. Our study aimed to investigate the changes in forced vital capacity, survival period, causes of death, and risk factors for mortality in patients with IPF receiving antifibrotic drugs. METHODS: This retrospective study enrolled Japanese patients who visited Toho University Sakura Medical Center who were diagnosed with IPF and received antifibrotic drugs. RESULTS: We included 102 patients [mean age ± standard deviation (SD): 71.8 ± 7.5 years], of whom 76 were males. The decline in forced vital capacity (mean ± SD) during the antifibrotic therapy period was - 154 ± 259 mL/year, which was significantly lower than before the antifibrotic therapy period (- 484 ± 589 mL/year; n = 80, p = 0.003). Altogether, 52 deaths were confirmed, and the median survival time from antifibrotic therapy initiation was 38.0 months (95% confidence interval: 25.9-50.1 months). Acute exacerbation accounted for 9.6% of all deaths (95% confidence interval: 1.6-17.6). The decline in forced vital capacity during antifibrotic therapy was a risk factor for mortality. CONCLUSIONS: In actual clinical practice in Japan, antifibrotic drugs suppressed the gradual decline in forced vital capacity, which is a risk factor for mortality. However, the median survival period remained poor at 38 months.

Summary of the clinical practice manual for late-onset hypogonadism.

Testosterone plays an important role in maintaining both physical and mental function. Age-related testosterone depletion contributes to the development of angina, arteriosclerosis, obesity, metabolic syndrome, dementia, frailty, and a range of other conditions. A condition involving age-related testosterone depletion and the associated clinical symptoms is defined as late-onset hypogonadism (LOH). LOH is treated by testosterone replacement therapy. Indications for testosterone replacement therapy are determined by evaluating symptoms and signs.

A nationwide survey of adrenal incidentalomas in Japan: the first report of clinical and epidemiological features.

The aim of this study was to reveal clear epidemiologic and clinical characteristics of incidentally discovered adrenal masses, termed adrenal incidentalomas (AIs), and to establish appropriate managemental and therapeutic regimens in Japan. This study had been originally carried out as a project of a research proposed on behalf of the Japanese Ministry of Health, Labour and Welfare, from 1999 to 2004. This nationwide multicenter study on AIs included 3,672 cases with clinically diagnosed AIs, involving 1,874 males and 1,738 females, with mean age 58.1 ± 13.0 years (mean ± SD). In the present study, we focused on the investigation of the real prevalence of various adrenal disorders with AI. The mean nodule size of AI based on computed tomography was 3.0 ± 2.0 cm. Compared to non-functioning adenomas (NFAs), tumor diameters were significantly larger in adrenocortical carcinomas (ACCs), pheochromocytomas, cortisol-producing adenomas (CPAs), myelolipomas, metastatic tumors, cysts, and ganglioneuromas (p < 0.01). Endocrinological evaluations demonstrated that 50.8% of total AIs were non-functioning adenomas, while 10.5%, including 3.6% with subclinical Cushing's syndrome, were reported as CPAs, 8.5% as pheochromocytomas, and 5.1% as aldosterone-producing adenomas. ACCs were accounted for 1.4% (50 cases) among our series of AIs. In conclusion, while almost 50 % of AIs are non-functional adenomas, we must be particularly careful as AIs include pheochromocytomas or adrenal carcinomas, because they may be asymptomatic. To our knowledge, this is the first and the largest investigation of AI, thus providing basic information for the establishment of clinical guidelines for the management of AI.

Prognosis of primary aldosteronism in Japan: results from a nationwide epidemiological study.

The Research Committee of Disorders of Adrenal Hormones, Japan, undertook a nationwide epidemiological study of primary aldosteronism (PA). The present study was undertaken as a part of this study to reveal the relationship between type of treatment and the prognosis of PA. In the primary survey, 4161 patients with PA during the period January 1, 2003-December 31, 2007 were reported from 3252 departments of internal medicine, pediatrics and urology. In the secondary survey, a questionnaire that requested detailed clinical information on individual patients was sent to those departments reporting patients in the primary survey. In total, data on 1706 patients with PA were available in the present study. Among patients with bilateral or unilateral aldosterone-producing adenoma, after adjustment for age at which prognosis was examined, sex, surgical treatment and medical treatment, surgical treatment was significantly associated with amelioration of hypertension (adjusted odds ratio [OR]: 0.47 [95% confidence interval (CI): 0.29-0.77]) and hypokalemia (adjusted OR: 0.17 [95% CI: 0.11-0.29]). No significant relationship was observed between medical treatment and such prognosis in this group of patients. Among patients with bilateral or unilateral adrenal hyperplasia, surgical, but not medical, treatment was significantly associated with amelioration of hypokalemia (adjusted OR: 0.23 [95% CI: 0.06-0.74]), while there was no relationship between surgical or medical treatment and the prognosis of hypertension. In conclusion, surgery offered a better prognosis of PA than medication with regards to hypertension and hypokalemia, with the limitation that a new anti-aldosterone drug, eplerenone, was not available during the study period.

Establishment and characterization of a novel cell line derived from a human small cell lung carcinoma that secretes parathyroid hormone, parathyroid hormone-related protein, and pro-opiomelanocortin.

There are few case reports describing small cell lung carcinoma (SCLC), which secrete parathyroid hormone (PTH)-related protein (PTHrP) and result in hypercalcemia. We have established a novel cell line, derived from a 37-year-old woman with SCLC, which produced PTH, PTH-rP, and a part of proopiomelanocortin (POMC), and led to hypercalcemia. The cell line, named SS-1, was grown as floating cell clusters in DMEM/F12 medium supplemented with 10% fetal bovine serum and had a population doubling time of 72 h. The modal chromosome number was 47 (88%); marker chromosomes were not observed. The SS-1 cell line secreted not only PTHrP but also PTH, and both were decreased by CaCl(2) administration. Decreasing the concentration of Ca(++) in the growth medium stimulated the secretion of both PTHrP and PTH. The cell line had calcium sensing receptor (Cas-R). Since PTHrP and PTH secretion from the SS-1 cells was related to Ca(++) concentration in the growth medium, the cell line might be useful for the study of PTH-rP and PTH regulation as well as for SCLC analysis. In addition, the cells secreted N terminal POMC, the precursor of adrenocorticotropic hormone, in response to stimulation with corticotropin releasing hormone. In summary, we established a novel cell line, SS-1 from SCLC, which produced PTHrP, PTH and N terminal POMC.

The relation of initial methimazole dose to the incidence of methimazole-induced agranulocytosis in patients with Graves' disease.

The relation between the incidence of methimazole (methylmercaptoimidazole; MMI)-induced agranulocytosis and initial MMI dose was evaluated in a group of 514 patients with Graves' disease who were treated between 1995 and 2005. One hundred and forty-six (28.40%) patients had received an initial dose of 30 mg MMI and 277 (53.89%) patients had been treated with 15 mg MMI. Nine patients (1.75%) developed agranulocytosis due to MMI treatment. Six (4.11%) of 146 patients who received an initial dose of 30 mg MMI, two (4.54%) of 44 patients given an initial dose of 20 mg MMI, and one (0.36%) of 277 patients given an initial dose of 15 mg MMI developed agranulocytosis. There was a statistically significant difference in agranulocytosis incidence between patients receiving an initial dose of 30 mg MMI and those who received an initial dose of 15 mg. Although 8 (4.10%) of 195 patients in the high-dose group (20 mg or higher) developed agranulocytosis, only 1 (0.31%) of 319 patients in the low-dose group (15 mg or lower) did. In conclusion, the incidence of agranulocytosis with low-dose MMI therapy was ten times lower than that of the high-dose regimen.

Changes in serum sex hormone profiles after short-term low-dose administration of dehydroepiandrosterone (DHEA) to young and elderly persons.

In man, serum concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease with age after the twenties. For this reason, the decline in DHEA and DHEAS concentrations may be related to the development of some chronic diseases that are prevalent in the older age population. In this study, we evaluate the benefit and safety level of DHEA administration to men as a hormone replacement therapy. Twenty-two healthy Japanese males (age 26-63; mean +/- SD, 41.0 +/- 10.0 yrs.) received 25 mg DHEA once a day orally in the morning for two weeks. Serum concentrations of steroid hormones and cytokines were measured before and after the DHEA administration. Glucose tolerance and insulin resistance were also assessed before and after the DHEA administration using a 75 g oral glucose tolerance test and homeostasis model assessment (HOMA-R), respectively. Serum DHEA and DHEAS levels were significantly elevated after the DHEA administration for all ages of test subjects. In subjects who were older than 41 yrs. (older group) serum androstenedione and estradiol levels were elevated after the DHEA administration. Significant negative correlations were observed between the serum DHEA concentration and the serum concentration of fasting insulin, HOMA-R, leptin, and high-sensitivity C-reactive protein for all subjects. Daily administration of 25 mg DHEA increased the serum DHEA, DHEAS, androstenedione, and estradiol levels of the subjects of the older group to the same level as that of younger subjects.

Effects of valsartan on inflammatory and oxidative stress markers in hypertensive, hyperglycemic patients: an open-label, prospective study.

BACKGROUND: Diabetes mellitus and hypertension are aggravated by activation of the renin-angiotensin system caused by increased oxygen stress and local inflammatory responses. Several studies have suggested that angiotensin II type 1 receptors can reduce inflammatory markers (high-sensitivity C-reactive protein [hs-CRP], interleukin [IL]-6, IL-18, soluble vascular cell adhesion molecule [VCAM]-I, and l-selectin) and oxidative stress markers (urinary 8-hydroxy-7,8-dihydro-2'-deoxyguanosine [8-OHdG] and 8-epi-prostaglandin F2α [8-isoprostane]) in hypertensive patients. OBJECTIVE: The aim of this study was to assess the effects of valsartan, an angiotensin II receptor blocker, on inflammatory and oxidative stress markers in hypertensive patients with mild diabetes or impaired glucose tolerance. METHODS: In this open-label, prospective study, hypertensive patients aged >20 years with mild diabetes (requiring treatment by diet alone or an oral hypoglycemic), seen on an outpatient basis at the Division of Diabetes, Metabolism, and Endocrinology, Omori Hospital, Toyko, Japan, who were receiving a therapeutic dietary regimen for ≥1 month in the treatment of diabetes or hypertension, were eligible for enrollment. Blood pressure, inflammatory markers (hs-CRP, IL-6, IL-18, VCAM-1, and L-selectin), and oxidative stress markers (urinary 8-OHdG and 8-isoprostane) were monitored before treatment commencement with valsartan (40-80 mg/d) and after 3 months of treatment. RESULTS: A total of 26 patients (18 men, 8 women; mean [SD] age, 57.7 [11.3] years; mean [SD] weight, 65.3 [13.1] kg) were enrolled in the study. After 3 months of treatment, patients' mean (SD) blood pressure had significantly decreased from 153.1 (11.2)/88.3 (11.4) to 143.7 (13.7)/85.2 (9.0) mm Hg (P < 0.05). Among the inflammatory and oxidative stress markers, hs-CRP, VCAM-1, and urinary 8-OHdG concentrations decreased significantly from 0.231 (0.199) to 0.134 (0.111) mg/dL (P = 0.043), 471.1 (193.9) to 403.2 (135.2) ng/mL (P = 0.012), and 12.12 (5.99) to 8.07 (3.36) ng/mg · creatinine (P = 0.001), respectively. The reductions in these markers were observed in patients regardless of whether or not their glycosylated hemoglobin (HbA1c) concentration improved (defined as a decrease of ≥1% in HbA1c). CONCLUSION: This small, open-label, prospective study found that a 3-month treatment with valsartan was associated with a significant reduction of hs-CRP, VCAM-1, and urinary 8-OHdG concentrations independent of improvement in HbA1c concentration in these hypertensive patients with hyperglycemia.

Effects of the long-acting calcium channel blockers, amlodipine, manidipine and cilnidipine on steroid hormones and insulin resistance in hypertensive obese patients.

OBJECTIVE: To demonstrate that calcium channel blockers can improve insulin resistance clinically, we investigated the effects of the calcium channel blockers, amlodipine, manidipine and cilnidipine on serum levels of steroid hormones and insulin. SUBJECTS AND METHODS: Thirty hypertensive obese patients [15 men and 15 women; mean age 55.9 years, mean body mass index (BMI) 27.6] were divided into three groups and treated with either 5 mg of amlodipine, 20 mg of manidipine or 10 mg of cilnidipine. Blood pressure (BP), fasting plasma glucose (FPG), HbA1c, fasting serum immunoreactive insulin (F-IRI), insulin resistance index [as assessed by the homeostasis model assessment (HOMA-R)], serum DHEA, serum DHEA-S, plasma ACTH, serum cortisol, plasma renin activity (PRA), and serum aldosterone, were measured before and after 1, 2, 3 and 6 months of treatment. RESULTS: In all three groups, BP decreased significantly after 1 month and F-IRI and HOMA-R decreased significantly after 2-3 months. A concurrent rise in serum DHEA and DHEA-S levels was also observed, however, the differences were not significant. No changes in FPG, HbA1c, ACTH, cortisol, PRA or aldosterone levels were observed during treatment. CONCLUSIONS: We conclude that amlodipine, manidipine and cilnidipine all improve insulin resistance and consequently increase serum levels of DHEA and DHEA-S.

Transient hyper-17-OHPnemia unrelated to cross-reactions with residual fetal adrenal cortex products.

OBJECTIVE: To clarify the pathogenesis of transient hyper-17alpha-hydroxyprogesteronemia, we initiated a laboratory investigation in a pre-term infant with persistently high serum 17alpha-hydroxyprogesterone (17-OHP) until 2 months of age. METHODS: Serum 17-OHP level was measured by high-performance liquid chromatography and radioimmunoassay, and gene analysis of CYP21A2 (21-hydroxylase) was performed. RESULT: Serum 17-OHP level on the 29th day of life was 25.4 ng/ml, and the urinary steroid profile showed low pregnanetriolone. Gene analysis of 21-hydroxylase disclosed no mutation, and 17-OHP normalized by 3 months of age without specific treatment. CONCLUSION: Transient elevations in 17-OHP, which do not appear related to cross-reactions with products of a residual fetal adrenal cortex, may occur in the first few months of life.

Comment: the corticotropin-releasing hormone stimulation test in white coat hypertension.

This study was undertaken to clarify the status of the ACTH and cortisol responses to CRH in patients with white coat hypertension. White coat hypertension was defined as a difference between clinic blood pressure and ambulatory blood pressure of at least 20 mm Hg for systolic blood pressure and/or 10 mm Hg for diastolic blood pressure. CRH stimulation tests were performed between 1400 and 1700 h in 11 patients with white coat hypertension (4 males and 7 females) and 11 normal subjects (4 males and 7 females). Blood pressure and heart rate were measured 15 min before, at time zero, and 15, 30, 60, and 120 min after initiation of the CRH stimulation tests. In white coat hypertension, both the mean systolic blood pressure (162 +/- 15 mm Hg) and diastolic blood pressure (97 +/- 10 mm Hg) were higher than in controls (P < 0.01) on 3 occasions. The mean ambulatory blood pressure for the 24-h period of the test did not differ between patients with white coat hypertension and normal subjects. Basal levels of ACTH and cortisol did not differ between patients with white coat hypertension and control subjects. However, challenge with CRH elevated ACTH (30 min) and cortisol (30, 60, and 120 min) to levels higher than those in controls, with the net increase in both ACTH and cortisol being higher than that in controls over the study period (P < 0.01). These significant responses suggest that white coat hypertension is associated with hypothalamic-pituitary-adrenal hypersensitivity to stressors.

Intranasal administration of adrenocorticotropin-(1-24) stimulates adrenocortical hormone secretion.

To determine the efficiency of transmucosal absorption of ACTH, we measured serum cortisol, aldosterone, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEA-S) levels after intranasal (in) vs. iv administration of ACTH-(1-24) (250 microg) in 12 healthy adult men (mean age, 24.3 +/- 3.2 yr; range, 21-31 yr), who had received no prior medication and had no symptoms of rhinitis. Blood was collected at 0, 30, 60, 120, and 180 min after administration of ACTH-(1-24), and the levels of adrenocortical steroids were measured by specific RIAs. There were no side-effects associated with in or iv ACTH administration. After in administration, serum cortisol and aldosterone increased rapidly by 224.7 +/- 39.2% and 147.2 +/- 50.5%, respectively, peaking 30 min after ACTH-(1-24) administration, and decreasing to basal levels within 120 min. These increases in serum cortisol and aldosterone were lower than those obtained after iv administration. Thirty minutes after in or iv administration of ACTH-(1-24), DHEA increased by 49.1 +/- 27.2% and 81.6 +/- 17.1%, respectively, and remained elevated for 180 min. Serum DHEA-S levels did not change after in administration of ACTH-(1-24) and increased only slightly after iv injection. Adrenocortical steroid levels did not increase after in administration of saline. These data demonstrate that adrenocortical steroids are stimulated by in administration of ACTH-(1-24). We suggest that intranasal administration of ACTH offers both a diagnostic approach as an adrenal function test and a therapeutic approach as ACTH replacement therapy in patients with ACTH deficiency. The latter may be more physiological than glucocorticoid replacement.

Decreased steroidogenic enzyme 17,20-lyase and increased 17-hydroxylase activities in type 2 diabetes mellitus.

OBJECTIVE: To analyze activities of adrenal steroidogenic enzymes in type 2 diabetes mellitus, serum levels of 11 steroid hormones were measured simultaneously. SUBJECTS: We studied 130 patients with type 2 diabetes mellitus (74 men and 56 women between the ages of 40 and 69 years), whose blood glucose control had been poor (more than 10% in HbA(1c)). Age-matched normal subjects served as the control group. METHODS: Serum levels of steroid hormones (pregnenolone (Preg), progesterone (Prog), deoxycorticosterone (DOC), corticosterone (B), 17-hydroxypregnenolone (17-OH-Preg), 17-hydroxyprogesterone (17-OHP), 11-deoxycortisol (S), cortisol (F), dehydroepiandrosterone (DHEA) and Delta4-androstenedione (Delta4A)) were measured by HPLC/RIA methods. Fasting plasma glucose (FPG), HbA(1c), ACTH, serum immunoreactive insulin (IRI) and DHEA sulfate (DHEA-S) were also measured. We analyzed product/precursor ratios to assess relative activities of adrenal steroidogenic enzymes. RESULTS: Serum levels of ACTH and F were high and DHEA and DHEA-S were low in both male and female patients under poor blood glucose control. Following 6-months treatment with diet only or with sulfonylurea, FPG and HbA(1c) improved, and blood concentrations of ACTH and F decreased while DHEA and DHEA-S levels increased to within the normal range. DHEA/17-OH-Preg and Delta4A/17-OHP ratios, reflecting 17,20-lyase activity, were low before treatment and recovered to the normal range after treatment, and 17-OH-Preg/Preg and 17-OHP/Prog ratios, reflecting 17-hydroxylase activity, were high before treatment, and fell within the normal range after treatment. 3beta-Hydroxysteroid dehydrogenase, 21-hydroxylase and 11beta-hydroxylase activities remained within the normal range both before and after treatment. CONCLUSIONS: These data suggest that the decrease in DHEA and DHEA-S concentrations together with the high F levels that occur in patients with type 2 diabetes mellitus is associated with low 17,20-lyase and high 17-hydroxylase activity in the adrenal steroidogenic enzymes. High insulin concentrations may further lower DHEA and DHEA-S levels.