Transsphenoidal adenomectomy is currently the first choice for treatment of patients with pituitary ACTH-dependent ushing's syndrome. However, pharmacotherapy is prescribed for some patients, e.g., unsuccessful surgery. We treated a woman in whom pituitary Cushing's syndrome was improved while she was on antimuscarinic cholinergic agents, atropine sulphate and pirenzepine hydrochloride. The diminished effect of anticholinergics on ACTH and cortisol was incidentally identified in an inferior petrosal sinus sampling procedure. A single intramuscular injection of atropine significantly decreased both ACTH (43.9pg/ml to less than 12.0; normal, 12.0-40.0pg/ml) and cortisol (29.9μg/dl to 13.6; normal, 7.6-23.6μg/dl). An M1-muscarinic receptor specific antagonist, pirenzepine hydrochloride, also had a diminishing effect on these hormones and this inhibiting effect was partially blocked by the simultaneous administration of an anticholinesterase agent, pyridostigmine bromide. Chronic oral ingestion of these agents led to improvement in clinical symptoms, and urinary 17-hydroxycorticosteroid and 17-ketosteroid levels were at normal to upper-normal levels. This is the first documentation of involvement of the cholinergic system in the pathogenesis of pituitary Cushing's syndrome.
We describe a type 2 diabetic patient who showed immediate-type allergy against human insulin associated with marked eosinophilia at initial insulin therapy. Three months after initiation of insulin therapy, he noticed itchy skin wheals at the site of the insulin injection. Laboratory data at that time showed marked eosinophilia (2512/mm3) and progression of renal dysfunction. Skin test with semisynthetic human insulin and protamine sulfate resulted in local immediate skin reactions such as itchy erythema and wheals. Histopathology of the biopsy specimen from skin showed perivascular infiltration of lymphocytes and numerous eosinophils in the dermis and subcutaneous fat. Although the titer of total IgE antibody was within normal range, that of insulin-specific IgE antibody was high. Insulin administration was discontinued to preserve his insulin secretion, and stable control of his hyperglycemia was obtained by initiating nateglinide treatment (360mg/day). His itchy skin lesions disappeared within two weeks after cessation of the insulin therapy and both eosinophilia and renal dysfunction gradually improved. Although the widespread use of human insulin in diabetic patients has greatly reduced the incidence of insulin allergy, the possibility of human insulin allergy should be kept in mind when initiating such therapy.
We report on GH (0.5IU or 0.17mg/kg/week) and GnRH analog (GnRHa, 60μg/kg, every 4 weeks) therapy in SHOX haploinsufficiency. Case 1 was a 46, XY boy with microdeletion of the Y chromosomal pseudoautosomal region. At 7 years of age, he exhibited short stature (-3.9SD) with a reduced growth rate (3.8cm/year), short 4th metacarpals, and mild Madelung deformity. GH therapy resulted in a marked increase in height velocity (10.7cm/year in the first year). Case 2 was a 46, XX girl with a heterozygous nonsense mutation of SHOX (C674T). At 6 years of age, she presented with short stature (-3.3SD) with a low height velocity (4.0cm/year). GH therapy caused a moderate increase in height velocity (6.6cm/year in the first year and 6.0cm/year in the second year) before puberty. Because of breast development, she received GnRHa from 9 8/12 years of age. At 10 10/12 years of age, she had mild shortening and borderline curvature of radius. Case 3 was a girl with a 46, X, der(X)t(X;2)(p22.3;p21) karyotype. She was treated with GH from 6 to 14 years of age, and also with GnRHa from 12 to 15 years of age. Her height remained around mean -4SD, with no discernible alteration of height velocity. At 17 years of age, she had short stature (-4.1SD), bilateral cubitus valgus, Madelung deformity, and full breast development. The results suggest that GH therapy may have variable statural effects in SHOX haploinsufficiency as in most disorders including Turner syndrome, and that GnRHa therapy after pubertal entry may be insufficient to prevent the development of skeletal lesions such as Madelung deformity
We report the case of a 64-year-old woman with rheumatoid arthritis (RA) associated with high grade fever, malaise, and painless swelling of thyroid gland. Laboratory findings showed severe systemic inflammatory reactions, including increases in various cytokines such as IL-6. Gallium-67 citrate imaging revealed intense uptake in the painlessly enlarged thyroid gland. Histologically, biopsied specimens of thyroid showed diffuse amyloid infiltrations, which included amyloid A (AA) protein. Biopsies of rectum and stomach revealed similar amyloid depositions, indicating that the amyloid had a secondary origin, potentially due to RA. All clinical symptoms were relieved by intravenous pulsatile administration of methylprednisolone followed by oral prednisone, resulting in prolonged hypothyroid status. To our knowledge, this is the first case report in Japan describing painless thyroiditis with severe inflammatory reactions in amyloid goiter.
Secretion of aldosterone from aldosterone-producing adenoma (APA) is to some degree under the control of ACTH and the suppressible effect of glucocorticoid on plasma aldosterone concentration (PAC) and blood pressure has been reported to be transient. We report a rare case of aldosteronism due to APA in which PAC and blood pressure were well controlled with small dose dexamethasone for over one year. No chimeric gene of glucocorticoid-remediable aldosteronism (GRA) was found in DNA of APA and leukocytes from peripheral blood and 17α-hydroxylase deficiency (17-OH-D) was ruled out by endocrinological examinations, this case indicates the possibility of an unknown mechanism of ACTH-dependent APA.
To study the effects of hydroxyl radicals on the sensitivity of the ATP-sensitive K+ (K+ATP) channel to tolbutamide, we used patch clamp and microfluorometric techniques in pancreatic β-cells isolated from rats. In cell-attached membrane patches, exposure of the cells to 0.3mM H2O2 increased the probability of opening of K+ATP channels in the presence of 2.8mM glucose. Tolbutamide dose-dependently inhibited the K+ATP channel with half-maximal inhibition (IC50) at 0.8μM before and immediately after exposure to H2O2. After prolonged exposure (>20min) to H2O2, the IC50 was increased to 15μM. The presence of both ATP and ADP at concentrations ranging from 0.01 to 0.1mM in the inside-out bath solution significantly enhanced the inhibition of the channels by 10μM tolbutamide. Addition of 0.3mM H2O2 induced a transient minute increase in the cytoplasmic Ca2+ concentration ([Ca2+]i) within 10min, followed by a sustained pronounced increase in [Ca2+]i. After more than 20min of exposure of cells to 0.3mM H2O2, [Ca2+]i was increased to above 2μM. Treatment of the cytoplasmic face of inside-out membrane patches with 1μM Ca2+ attenuated the tolbutamide-sensitivity of the K+ATP channel, but not the ATP-sensitivity of the channel. These findings indicate that H2O2 reduces tolbutamide sensitivity by inducing a sustained increase in [Ca2+]i.
Androstenediol (5-androsten-3β, 17β-diol, ADIOL) and androstenediol 3-sulfate (ADIOLS) are active metabolites of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS), respectively, and have estrogenic activity and immunoregulatory function. We examined serum concentrations of ADIOL, ADIOLS, DHEA, DHEAS and pregnenolone sulfate (5-pregnen-3β-ol-20-one sulfate, PREGS) in patients with Graves' thyrotoxicosis (male/female 9/14), hypothyroidism (11/20) and in normal controls (14/29). In hypothyroidism serum levels of all these steroids were significantly decreased in both genders. In hyperthyroidism, in contrast, serum levels of ADIOLS (male 1.49±0.69, female 0.64±0.31μmol/l), DHEAS (male 7.43±3.91, female 5.13±2.03μmol/l), and PREGS (male 1.13±0.58, female 1.07±0.85μmol/l) were markedly increased, but serum concentrations of ADIOL and DEHA were not significantly different from controls (ADIOLS male 0.36±0.33, female 0.14±0.09μmol/l; DHEAS male 2.88±1.70, female 1.86±1.03μmol/l; PREGS male 0.18±0.12, female 0.11±0.08μmol/l; ADIOL male 3.76±1.35, female 1.91±1.17nmol/l; DHEA male 9.23±3.49, female 13.5±10.8nmol/l). Serum concentrations of all these steroids correlated with the serum concentration of the thyroid hormones in these patients. Serum albumin and sex hormone-binding globulin concentrations were not related to these changes in the concentrations of steroids. These findings indicate that serum concentrations of ADIOLS, ADIOL, DHEAS, DHEA and PREGS were decreased in hypothyroidism, whereas serum ADIOLS, DHEAS and PREGS concentrations were increased but ADIOL and DHEA were normal in hyperthyroidism. Thyroid hormone may stimulate the synthesis of these steroids and sulfotransferase is speculated to be increased in hyperthyroidism. Increased ADIOLS might contribute to menstrual disturbances and gynecomastia in hyperthyroidism.
A gradual loss of anterior pituitary hormones is suspected in patients treated with irradiation due to brain tumors. Development of growth hormone deficiency (GHD) with age has been documented in patients with idiopathic GHD. A gradual loss of adrenocorticotropic hormone (ACTH) secretion has been also shown in a patient with severe GHD and an invisible pituitary stalk on magnetic resonance imaging (MRI). The purpose of this longitudinal and cross-sectional study was to evaluate the gradual loss of growth hormone (GH) and ACTH in a homogeneous group of patients with hypopituitarism. Twenty-eight patients (23 males, 5 females) from four hospitals were diagnosed as having prenatal or perinatal-onset hypothalamic hypopituitarism. They had an abnormal pituitary stalk on MRI (invisible in 18 patients, thin in 10 patients) without any other organic disease of the brain. Each patient had GHD upon initial evaluation. Height (n=20) was analyzed as standard deviation score (SDS). Longitudinal (n=8) and cross-sectional (n=28) GH secretion capacity was evaluated by GH peaks, in response to insulin tolerance test (ITT) and growth hormone releasing factor test (GRF test). Longitudinal (n=10) and cross- sectional (n=28) ACTH secretion capacity was evaluated by cortisol peaks in response to ITT. Height SDS decreased each year in all the untreated patients after birth. GH peaks decreased gradually with age. Longitudinal data showed decreased GH peaks with age in seven out of eight patients using ITT and in all four patients using GRF tests. Cortisol peaks also decreased gradually together with signs and symptoms for adrenal deficiency such as general fatigue. Cortisol peaks of less than 414nmol/L (15μg/dl) in response to ITT were seen in 24% of the tests before age 10 and 56% before age 25. In conclusion, GHD and ACTH deficiency developed gradually in patients with prenatal or perinatal-onset hypothalamic hypopituitarism who had invisible or thin pituitary stalks examined by MRI.
We report a case of an ectopic ACTH-producing carcinoid in the lung. Typical Cushingoid appearance, elevated plasma ACTH and serum cortisol, bilateral enlargement of the adrenal glands, absence of pituitary adenoma and negativity in petrosus sinus venous sampling indicated the ectopic ACTH syndrome. Venous samplings from a lung tumor which was detected by the chest X-ray, did not show any step-up of ACTH. However, ACTH concentration in the bronchoscopic lavage was as high as that in the peripheral blood. Removal of the tumor, which was an ACTH producing carcinoid, resulted in normalization of ACTH and cortisol concentrations. Measurement of ACTH in the bronchoscopic lavage was useful for the diagnosis of ectopic ACTH-producing tumor.
Several lines of evidence suggest that ATP-sensitive potassium (KATP) channels are involved in glucose uptake by insulin target tissues. The aim of the present study was to prove directly the effect of KATP channel activity on glucose transport into cultured human skeletal muscle cells. We used potassium channel openers PCO-400 and nicorandil alone or in combination with channel blockers glibenclamide and gliclazide to examine their effects on insulin- or high glucose concentration-induced glucose uptake using 2-deoxy-D-3H-glucose or 3-O-methyl-D-3H- glucose as tracer, respectively. PCO-400 inhibited the basal (non-stimulated) uptake of 2-DG or 3-OMG at the glucose concentration of 5mM. PCO-400 and nicorandil dose-dependently inhibited insulin-stimulated glucose uptake, and their inhibitory effects were reversed by glibenclamide or gliclazide. In addition, PCO-400 inhibited high glucose concentration-facilitated glucose transport in the absence of insulin, and this effect was also antagonized by both sulfonylurea drugs. Regarding the mechanism by which KATP channels modulate glucose transport, we focused on protein kinase C (PKC), because PKC has been supposed to participate in both insulin- and high glucose concentration -stimulated glucose transport. PMA (phorbol 12-myristate 13-acetate) dose-dependently reversed the PCO-400-induced suppression of insulin-stimulated glucose uptake. On the other hand, PCO-400 at the concentration that inhibited glucose uptake caused no alteration of membrane-associated PKC activity in the presence of insulin or PMA. From these results we conclude that KATP channels modulate the basal and insulin-or high glucose level-stimulated glucose transport in skeletal muscle through a mechanism independent of PKC.
The aim of this study was to assess the effect of the long-term different diabetic therapies on the plasma leptin level in type 2 diabetic subjects. We measured plasma leptin, body fat and fasting plasma insulin in 96 type 2 diabetic male subjects. They had received the same treatment regimen for more than one year (3.5±2.3 years, mean±SD) and were weight-stable over the previous three months. The distribution was as follows: diet control group: 32, oral hypoglycemic agent (OHA) group: 32, and insulin group: 32. The results showed that the plasma leptin level of the different therapy groups was all positively correlated with body fat. The fasting insulin levels were significantly higher (p<0.0001) in the insulin group than those in the other two groups. The fasting insulin of the OHA group was also greater than that of the diet group but was not statistically significant. The leptin concentrations were significantly higher in the insulin group (p<0.001) and OHA group (p=0.0082) than that in the diet group. The leptin concentrations of insulin group were also significantly higher (p=0.0021) than that of the OHA group. Stepwise multiple regression analysis revealed that the significant differences in the leptin level of whole group was mainly affected by fasting insulin (p<0.0001), followed by fat percentage (p=0.001), fat distribution (p=0.009) and fasting sugar (p=0.02), whereas there was no association of leptin with age, height, glycosylated hemoglobin A1c, lipid, or blood pressure. We concluded that long-term different diabetic therapies may affect the plasma leptin level, which is mediated mainly by insulin changes. This insulin effect is independent of body fat and may be superior to the fat effect on plasma leptin in the type 2 diabetic patients.
We report a 49-year-old man with primary hyperthyroidism who presented with pancytopenia. The patient presented with leg edema, sinus tachycardia, cardiomegaly, and pleural effusions, all from congestive heart failure. Laboratory data showed pancytopenia and primary hyperthyroidism; echocardiogram showed diffuse hyperkinesis of the left ventricular wall and right ventricular overloading. The bone marrow was moderately hypercellular and compatible with arrested hematopoiesis. Pancytopenia and heart failure improved after administration of methimazole and diuretics. However, high levels of thyroid hormone recurred with pancytopenia 4 months after admission. Therefore, subtotal thyroidectomy was performed, and the levels of thyroid hormones and peripheral blood cell counts have remained normal. Pancytopenia may be caused by hyperthyroidism.
Insulinotropic action of glucose can be categorized as 1) triggering of release, 2) augmentation of exocytosis elicited by Ca2+, and 3) time-dependent potentiation (TDP) of the exocytotic machinery. Glucose-induced closure of ATP-sensitive K+ (K+ATP) channel is required for the first but not for the latter two. We examined the egitimacy of a novel hypothesis that glutamate is a conveyer of the K+ATP channel-independent glucose action, using intact rat pancreatic islets. To this end, we compared glucose and cell permeable glutamate donors such as dimethylglutamate and glutamine for their potency of augmentation and TDP in the presence of diazoxide (250μmol/l), a K+ATP channel opener. One millimolar leucine was employed as an activator of glutamate dehydrogenase (GDH) as needed. A high concentration (16.7mmol/l) of glucose applied simultaneously with a depolarizing concentration (50mmol/l) of K+ augmented (5.80 fold) insulin release elicited by the latter. Pretreatment of the islets with 16.7mmol/l glucose caused TDP so that insulin release subsequently elicited by 50mmol/l K+ alone was enhanced (4.70 fold). The augmentation and TDP caused by dimethylglutamate and glutamine (10mmol/l each), respectively, were very weak (12% of the glucose effect utmost), and dramatically enhanced upon activation of GDH by leucine. Insulinotropic effect of the glutamate donors, but not that of 50mmol/l K+, was eliminated by 2mmol/l NaN3, a mitochondrial poison. Glutamate per se serves as a weakly metabolizable mitochondrial fuel, but not a direct conveyer of the K+ATP channel-independent glucose action in the islet β cell.
The aims of this study were to determine whether the human placenta and decidua express PRL-releasing peptide (PrRP) mRNA and whether PrRP regulates PRL secretion from cultured human decidual cells. PrRP gene expression was analyzed by reverse transcription (RT)-PCR, and the level of the gene expression was quantified by a ribonuclease protection assay. PrRP gene expression was detected in both the placenta and decidua. These tissues expressed PrRP mRNA throughout pregnancy and the level of PrRP mRNA expression somewhat increased during midpregnancy. Placental and decidual cells also expressed PrRP mRNA, in vitro. To determine whether PrRP affects decidual PRL secretion, human endometrial stromal cells and decidual cells were cultured and treated with or without 1μM PrRP31. PrRP31 did not affect PRL secretion in either short or long term incubation. Moreover, the RT-PCR analysis indicated that human decidua does not express the PrRP receptor, hGR3, mRNA. These findings suggest that PrRP produced by the human placenta and decidua does not affect decidual PRL secretion due to a lack of the receptor, and that it may play other roles during pregnancy.