Biomedical subjects

M Haji

Publications and source records attributed to M Haji.

At least 19 recordsLinked to original sources

PubMed1996

Androgen insensitivity syndrome due to new mutations in the DNA-binding domain of the androgen receptor.

Androgen insensitivity syndrome (AIS) is associated with a wide range of quantitative or qualitative defects in the androgen receptor (AR). In some patients with AIS, however, no defects are detectable in the ligand-binding properties of the AR. We have analyzed the ARs of two unrelated patients with this category (termed 'receptor-positive type') of AIS. Sequence analysis of these patients' AR gene revealed single amino acid substitutions (579Cys(TGC)-->Phe(TTC) and 582Phe(TTC)-->Tyr(TAC)) in exon B encoding the first zinc finger of the DNA-binding domain of the AR. These mutations have not been previously reported. Moreover, cotransfection assays and mobility shift assays revealed that these patients' mutant ARs had defective transcriptional activity of the target gene because of impaired DNA-binding ability to the androgen-responsive element. These findings strongly indicate that these mutations are responsible for the pathogenesis of AIS in these patients.

Adult↗

PubMed1996

1,25-Dihydroxyvitamin D3 enhances the enzymatic activity and expression of the messenger ribonucleic acid for aromatase cytochrome P450 synergistically with dexamethasone depending on the vitamin D receptor level in cultured human osteoblasts.

Not every postmenopausal woman with a low level of estrogen suffers from osteoporosis, and no correlation of bone density with serum estrogen level, but a significant correlation with adrenal androgens is often noted. Vitamin D3 has been reported to be osteoclastic in vitro, whereas the effectiveness of vitamin D3 for the treatment of osteoporosis is clinically relevant. To study the roles of these factors in the development of osteoporosis, we characterized aromatase activity converting androgens to estrogens in human osteoblasts, because postmenopausal women maintain considerable levels of adrenal androgens. Glucocorticoids at 10(-9)-10(-7) M transiently induced the expression and enzymatic activity of aromatase cytochrome P450 (P450AROM) in primary cultured osteoblasts, and the Km value for androstenedione (4.7 +/- 2.9 nM) was lower than that in adipose tissue and skin. Human osteoblasts showed a promoter specificity different from that found in other tissues. 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] alone did not induce aromatase activity, but enhanced and maintained glucocorticoid-induced P450AROM gene expression. This synergistic effect was not observed by other sex steroids or retinoic acids. The enhancement of P450AROM activity by 1,25-(OH)2D3 varied from 0.94-fold (no enhancement) to 2.40-fold (maximal enhancement) among the individual human osteoblasts examined, but the magnitude of the enhancement was significantly correlated with the level of vitamin D receptor messenger RNA (P < 0.05). Cycloheximide did not abolish the synergistic effect of 1,25-(OH)2D3, suggesting that de novo protein synthesis is not required for the synergism with 1,25-(OH)2D3. These results suggest that bone tissue can synthesize estrogen from adrenal androgens by a unique aromatase activity depending on the level of vitamin D receptor expressed.

Adolescent↗

PubMed1996

Serum dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) in Alzheimer's disease and in cerebrovascular dementia.

A decreased concentration of dehydroepiandrosterone sulfate (DHEA-S) in patients with Alzheimer's disease (AD) has been reported but is still controversial. In the present study, serum concentrations of DHEA and DHEA-S were determined in 19 patients with AD, 21 patients with cerebrovascular dementia (CVD) and 45 age- and gender matched elderly control individuals from the Japanese community at large. Serum concentration of DHEA among controls, patients with AD and patients with CVD did not significantly differ from one another. However, patients with AD and patients with CVD were found to have lower concentration of serum DHEA-S and a lower DHEA-S/DHEA ration compared to normal control individuals. No significant difference was observed in the concentration of serum DHEA-S or the DHEA-S/DHEA ratio between patients with AD and those with CVD. These results suggest that reduced concentrations of serum DHEA-S may not be unique to AD, but instead reflect a common phenomenon in dementing diseases. However, since serum concentration of DHEA in these patients remained unchanged, the significance of DHEA in dementia remains unclear.

Aged↗

PubMed1995

cDNA cloning of a NGFI-B/nur77-related transcription factor from an apoptotic human T cell line.

A human T lymphoid cell line, PEER, dies by apoptosis in the presence of PMA and calcium ionophore. A new gene, TINUR, was cloned from apoptotic PEER cells. The expression of the TINUR gene is induced within 1 h after the cross-linking of the T cell Ag receptor complex. TINUR belongs to the NGFI-B/nur77 family of the steroid receptor superfamily and is an orphan receptor. TINUR binds to the same DNA sequence as NGFI-B/nur77. We also propose that the NGFI-B/nur77 family can be classified into two subtypes.

Amino Acid Sequence↗

PubMed1995

[A case of primary hypothyroidism with pituitary enlargement and abnormal secretion of growth hormone and prolactin].

A case of primary hypothyroidism accompanied by pituitary enlargement and pituitary dysfunction is documented. A 27-year-old woman was admitted to our hospital for further examination of pituitary enlargement. Endocrinological examination revealed that she had primary hypothyroidism. Her TSH level in serum was elevated to more than 300 microU/ml. She also had pituitary dysfunction such as hypersecretion of prolactin in response to TRH and paradoxical rise of GH to glucose load. Serum antibodies against the pituitary gland were negative. Magnetic resonance imaging (MRI) examination showed an enlarged pituitary gland extending to supraseller cistern, which was homogeneously enhanced after Gadolinium-DTPA treatment. Treatment with 50-100 micrograms of levothyroxine sodium normalized her thyroid function and secretion of GH and prolactin. In addition, periodic MRI examination demonstrated a gradual decrease in the size of the pituitary gland after the treatment. The above clinical course indicates that pituitary enlargement in this patient occurred as a result of primary hypothyroidism. The mechanism of the abnormal secretion of TSH, GH and prolactin secondary to primary hypothyroidism was discussed.

Adult↗

PubMed1995

The antiobesity effect of dehydroepiandrosterone in castrated or noncastrated obese Zucker male rats.

Although antiobesity effect of dehydroepiandrosterone (DHEA) has been reported in rats, it remains unclear whether the effect is brought about by itself or mediated by sex steroids converted from DHEA in gonads. In the present study, to clarify this point, the effect of DHEA on growth in obese Zucker male rats was reevaluated under two conditions: with or without castration. Castration did not affect the pattern of growth curve of obese Zucker male rats. Three-months treatment of castrated Zucker rats with 0.3% DHEA in the diet resulted in dramatic decrease of body weight gain in comparison to DHEA-untreated and castrated rats. The degree of antiobesity effect of DHEA in castrated rats was almost same as that observed in non-castrated rats. These results suggest that DHEA exerted its antiobesity effect by itself rather than through conversion to testosterone in testis.

Animals↗

PubMed1995

Effect of dehydroepiandrosterone on glucose uptake in cultured human fibroblasts.

Dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S) reportedly have antidiabetic and antiobesity effects. The effect of DHEA on glucose uptake in cultured human fibroblasts was examined. Incubation of cells with supraphysiologic concentrations of DHEA (10(-5) mol/L) for > or = 10 hours enhanced 2-deoxyglucose (2-DG) uptake significantly (P < .05). Supraphysiologic concentrations of insulin (10(-7) mol/L) increased the sensitivity of glucose uptake to DHEA. Conversely, the sensitivity of glucose uptake to insulin was increased by incubating cells with 10(-6) mol/L DHEA. Both the abundance of transcripts encoding glucose transporter-1 (Glut-1) and the maximal velocity (Vmax) of 2-DG transport were increased in cultured fibroblasts incubated with DHEA. Cultured fibroblasts expressed a specific binding factor with low affinity for [3H]DHEA (maximal number of binding sites, 18,496 sites per cell; Kd, 298 nmol/L). Other androgen hormones exerted a less-marked effect on glucose uptake; DHEA-S had no effect. These results suggested that DHEA increases Glut-1 mRNA through binding to a specific factor in cultured human fibroblasts and thereby stimulates glucose uptake in these cells.

Adult↗

PubMed1995

Aromatase in bone cell: association with osteoporosis in postmenopausal women.

To clarify the possible action of adrenal androgen on bone cell, the existence, characteristics and regulation of aromatase in human osteoblast-like osteosarcoma cells (HOS) and primary cultured osteoblast-like cells from normal human bones (HO) were examined in this study. Significant positive correlation between bone mineral density (BMD) and serum dehydroepiandrosterone sulfate (DHEA-S) was found in 120 postmenopausal women (51-99 years old) but no correlation was seen between BMD and serum estradiol (E2). In subset analysis, strongly positive correlation of serum DHEA-S and estrone (E1) with BMD was observed in postmenopausal women aged less than 69 years old. Administration of DHEA to ovariectomized rat significantly increased BMD and decreased relative osteoid volume in femur. These in vivo findings strongly suggested that serum adrenal androgen may be converted to estrogen in peripheral organ, especially, osteoblast and be important steroids to maintain BMD. [3H]DHEA was converted to [3H]androstenedione and [3H]androstenedione to [3H]estrone in primary cultured human osteoblast. Osteoblast-like cells showed aromatase activity, and an apparent Km and the Vmax were 4.74 +/- 0.78 nM (mean +/- SD, n = 3) and 0.83 +/- 0.79 fmol/mg protein/h for HOS, and 4.6 +/- 2.9 nM and 279 +/- 299 fmol/mg protein/h (mean +/- SD, n = 19) for HO, respectively. The aromatase activity was significantly increased by dexamethasone in a dose-dependent manner. Reverse transcription-polymerase chain reaction analysis revealed that dexamethasone increased the transcript of P450AROM gene. Osteoblast-specific promoters were also determined. Dexamethasone and 1 alpha,25-dihydroxyvitamin D3 synergistically enhanced aromatase activity and P450AROM mRNA expression. These results demonstrate that adrenal androgen, DHEA, is converted to E1 in osteoblast by P450AROM which is positively regulated by glucocorticoid and 1 alpha,25-dihydroxyvitamin D3 and important to maintain BMD in the 6 to 7th decade, after menopause.

Aged↗

PubMed1995

Effect of dehydroepiandrosterone on glucose uptake in cultured rat myoblasts.

The effects of dehydroepiandrosterone (DHEA) on glucose uptake and on insulin sensitivity were studied in cultured rat myoblasts (L6 cells). Preincubation with supraphysiological doses of DHEA (10(-5) M approximately significantly enhanced (p < 0.05) the cellular uptake of [3H]-2-deoxyglucose. Glucose uptake was significantly increased in cells exposed to 10(-4)M DHEA for 10 hours (p < 0.005), and for 24 hours (p < 0.001), but not for 3 hours. An increase in DHEA sensitivity with an enhanced glucose uptake was observed in cells exposed to 10(-7)M of human insulin. Insulin sensitivity was increased by preincubating the cells with 10(-6)M of DHEA. Other androgens enhanced the effect on glucose uptake to a lesser extent. DHEA sulfate had no effect on L6 cells, suggesting that the effect may be specific for DHEA, not common to androgens, Sulfation of DHEA may negate the effect. In reciprocal plot analysis, the Km value for glucose transport was decreased by preincubation with DHEA (from 0.67 mM without DHEA, 0.56mM with 10(-5)M DHEA, and 0.25mM with 10(-4) M DHEA), although Vmax was unchanged, We conclude that DHEA increases the affinity of glucose transport in the plasma membrane of cultured rat myoblasts, leading to an enhanced glucose uptake and an increase in insulin sensitivity.

Animals↗

PubMed1995

Up-regulation of high-affinity dehydroepiandrosterone binding activity by dehydroepiandrosterone in activated human T lymphocytes.

Although evidence indicates that dehydroepiandrosterone (DHEA) exerts direct physiological effects, its mechanism of action remains unknown. DHEA binding sites were examined using a whole-cell binding assay in a human T lymphoid cell line, PEER, revealing that a single class of high-affinity binding sites for DHEA (dissociation constant = 7.4 +/- 0.53 nmol/L, mean +/- SE, n = 4) was greatly increased when treated with DHEA, phorbol-12-myristate-13-acetate, and the Ca2+ ionophore A23187. Bound [3H]DHEA was displaced sensitively by DHEA and secondarily by dihydrotestosterone, but not effectively by other steroids, including DHEA sulfate. These results not only indicate the existence of a DHEA receptor, but also suggest that T cells become susceptible to regulation by DHEA during the process of signal-induced activation.

Binding Sites↗

PubMed1995

In vivo and in vitro evidence for the production of inhibin-like immunoreactivity in human adrenocortical adenomas and normal adrenal glands: relatively high secretion from adenomas manifesting Cushing's syndrome.

To clarify whether adrenal gland secretes inhibin in vivo in physiological or pathological conditions, we measured the levels of inhibin-like immunoreactivity (inhibin-LI) in adrenal veins (A-vein) and compared them with those in inferior vena cava (IVC) using blood samples obtained at catheterization of adrenal vein in the patients with adrenal adenoma manifesting Cushing's syndrome (Cs), aldosterone-producing adenoma, clinically non-functioning adenoma and normal adrenal gland. The tumor sides of A-veins in the patients with adenomas and also both sides of A-veins in subjects with normal adrenal glands showed significantly higher contents of inhibin-LI than their IVC. When the inhibin-LI secretion rate from adrenal gland was estimated by the difference between the levels of A-vein (tumor side) and IVC, Cs adenomas showed the highest secretion rate. Similarly, the tissue inhibin-LI content and the basal secretion rate of inhibit-LI from primary cultured cells were the highest in Cs adenomas. These findings indicated that normal adrenal glands and adrenocortical adenomas produced and secreted inhibin-LI into the general circulation in vivo and Cs adenomas have relatively high capacity for secreting inhibin-LI, and the present study provided the first in vivo evidence for adrenal inhibin-LI production in pathological conditions.

Adrenal Cortex Neoplasms↗

PubMed1995

Cushing's disease preceding sarcoidosis.

We present a 32-year-old-woman with Cushing's disease and sarcoidosis. She had been diagnosed as having Cushing's disease in 1985. She had transsphenoidal surgery followed by pituitary radiation. Subsequently her plasma cortisol level gradually decreased to normal range. In 1991, she manifested bilateral hilar lymphadenopathy on chest X-ray, erythema nodosum, subcutaneous nodules and granulomatous uveitis. From the histological findings of the skin lesions, the patient was diagnosed as having sarcoidosis. Interestingly, an inverse relationship between the disease activity of sarcoidosis and the level of serum cortisol in Cushing's disease was observed in the clinical course of this patient. Co-existence of Cushing's disease and sarcoidosis is very rare. Since the therapeutic significance of steroids in sarcoidosis has been well established, this case provides insight to the relationship between sarcoidosis and steroids.

Adrenocorticotropic Hormone↗

PubMed1994

[A case of Rathke's cleft cyst with panhypopituitarism].

A 41-year-old man was admitted to our hospital because of general fatigue, sexual debility and finger stiffness. Endocrinological examinations revealed that he had panhypopituitarism, resulting in secondary adrenal insufficiency, hypothyroidism and gonadal failure. Computed tomography (CT) of the head demonstrated a low density intrasellar mass, while brain magnetic resonance imaging (MRI) showed a high intensity mass extending from the intrasellar to suprasellar region in both T1WI and T2WI. The mass was removed by transsphenoidal surgery and histologically diagnosed as Rathke's cleft cyst. Replacement with hydrocortisone and levothyroxine sodium greatly improved the clinical symptoms. Rathke's cleft cyst causing panhypopituitarism is relatively rare. The clinical and endocrinological characteristics of Rathke's cleft cyst were discussed based on the findings in 49 Japanese cases including this case and two other cases we have experienced.

Adult↗

PubMed1994

Pancreastatin-like immunoreactivity of cerebrospinal fluid in patients with Alzheimer type dementia: evidence of aberrant processing of pancreastatin in Alzheimer type dementia.

The concentrations of pancreastatin-like immunoreactivity (PST-LI) of the cerebrospinal fluid (CSF) were measured in the patients with Alzheimer type dementia (ATD) and in age-matched normal subjects. The mean PST-LI concentration in the CSF of ATD patients was significantly lower than that of normal subjects. Gel chromatographic analysis revealed that the main PST-LI peak of ATD's CSF eluted at molecular weight (MW) 13.5 kDa. However, the age-related change of the molecular forms of PST-LI in CSF was observed in normal subjects as following; PST-LI in neonatal CSF showed one peak at MW 13.5 kDa, that of 16-64-year-old showed two peaks at MW 13.5 and 5.4 kDa, however, only one main peak was shown at MW 5.4 kDa in the CSFs of 72-85-year-old. These findings suggest that the production of PST-LI was decreased and the proteolytic cleavage, which should process big PST to PST (1-52) in normal subjects, was altered to that of neonatal type in the CNS of the patients with ATD.

Aged↗

PubMed1994

Unique change of pancreastatin-like immunoreactivity in cerebrospinal fluid by aging.

Using a specific antiserum for the C-terminal glycine amide region of human pancreastatin (PST), pancreastatin-like immunoreactivity (PST-LI) was measured in cerebrospinal fluid (CSF) from 447 subjects (368 +/- 10.8 pmol/l, mean +/- S.E.M.) free from endocrine diseases. The CSF contents of PST-LI showed a mountain-shape type change which peaked at 40 years of age. The highest concentration was found in the group of ages 40-49 years old (412 +/- 22.9 pmol/l) and the lowest concentration was found in the group of ages 80-89 years old (293.2 +/- 45.2 pmol/l) among various age groups. Gel chromatographic examination revealed the presence of two major forms (MW 13,500 and 5,400) of PST-LI in CSF. Because of the character of this antibody, the large molecular form is possibly an N-terminally elongated PST and the other may be PST-52. This may be the first report on the unique age-related change of PST concentration in CSF.

Adolescent↗

PubMed1994

Sertoli cell function declines earlier than Leydig cell function in aging Japanese men.

In order to evaluate the age-related changes in Leydig cell and Sertoli cell function, we measured serum levels of total testosterone (TT), free testosterone (FT), inhibin, LH and FSH in 116 healthy Japanese men, aged 24-92 years. Serum TT remained constant up to the age of 80 years and decreased thereafter. Serum FT declined linearly with aging and was significantly lower in men in their forties than in younger men (24-39 years old). Serum inhibin levels also declined with aging, with serum concentrations significantly lower in men older than 40 and markedly lower in men over 80 years old. LH and FSH were elevated in men over 60 and 40 years old, respectively. We also examined relationships between gonadotropins and gonadal hormones in these men divided into three age groups, young (24-39 years old), middle aged (40-59 years old) and aged (60-92 years old) men. Although there was a significant inverse correlation between LH and TT or FT for the entire population, subset analysis demonstrated that this inverse correlation was confined to men over 60 years old. In fact, in young men, TT and FT were positively correlated with LH. Overall, there was also an inverse correlation between FSH and inhibin. In subset analysis this relationship was present in both middle aged and aged men. These findings suggest that in Japanese men testicular endocrine functions decline after the fourth decade of life, and that Sertoli cell function declines earlier than Leydig cell function.

Adult↗

PubMed1994

In-vitro evidence for the regulation of 17,20-lyase activity by cytochrome b5 in adrenocortical adenomas from patients with Cushing's syndrome.

OBJECTIVE: The electron transfer system molecules, NADPH-cytochrome P450 reductase (Red) and cytochrome b5 (b5) are known to increase the relative activity of 17,20-lyase to 17 alpha-hydroxylase in vitro. Consistent with this hypothesis, we have reported recently that adrenocortical adenomas from patients with Cushing's syndrome that produced exceptionally high concentrations of androgens also contained more b5 mRNA as well as greater 17,20-lyase activity than adenomas that produced low concentrations of androgens. This finding was suggestive but inconclusive in linking b5 functionally to this difference in adenoma 17,20-lyase activity. In the present study, we have extended this finding by examining the effect of b5 on microsomal 17,20-lyase activity using an antibody against cytochrome b5. DESIGN: Biochemical quantitation of the content of b5 and Red activity in the microsomal fraction of the tumours and determination of 17,20-lyase activity in the microsomes in the presence or absence of an antibody against b5. PATIENTS: Seven patients with a clinical diagnosis of Cushing's syndrome secondary to benign adrenocortical adenoma were studied. MEASUREMENTS: The microsomal activities of 17 alpha-hydroxylase, 17,20-lyase and 3 beta-hydroxysteroid dehydrogenase were measured by in-vitro enzyme assay with thin layer chromatography. Microsomal Red activity was assayed by measuring NADPH-dependent cytochrome c reduction reaction. Cytochrome b5 concentration was determined by spectrophotometric analysis. RESULTS: An in-vitro enzyme assay of microsomal fractions from the adenoma showed that the 17,20-lyase activities of two adenomas that produced high concentrations of adrenal androgen were threefold greater than those of five other adenomas that produced low concentrations of androgens. Cytochrome b5 concentrations were greater in the two adenomas with high 17,20-lyase activity than in the other adenomas, while no significant difference in Red activity was observed among all the adenomas. The increased 17,20-lyase activity in the two adenomas was partially but significantly antagonized by an antibody against b5. CONCLUSIONS: These results suggest that differences in tissue b5 are functionally associated with differences in 17,20-lyase activity in adrenocortical adenomas in Cushing's syndrome, resulting in a dissociated secretion of cortisol and androgens in some patients.

Adenoma↗

PubMed1994

Mechanism of abnormal production of adrenal androgens in patients with adrenocortical adenomas and carcinomas.

The production of adrenal androgens can be modulated by the activities of steroidogenic enzymes and by the electron transfer system, NADPH-cytochrome P450 reductase (Red) and cytochrome b5 (b5), both of which have been shown to increase 17,20-lyase activity in vitro. To clarify the mechanism of diminished secretion of adrenal androgens in patients with adrenocortical adenoma and Cushing's syndrome and of excess secretion in patients with adrenocortical carcinoma, we investigated the enzymatic activities of cytochrome P45017 alpha, 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), and Red as well as the content of b5 in five adenomas, three carcinomas, and two normal adrenal glands. An in vitro enzyme assay using a microsomal fraction of the tissues indicated that all the tumors had almost the same degree of 17 alpha-hydroxylase activities as the normal adrenals. However, the relative activity ratio of 17,20-lyase to 17 alpha-hydroxylase of the three adenomas was markedly diminished, and 3 beta-HSD activity was apparently lower in the three carcinomas. The messenger RNA concentrations of P45017 alpha were similar in all tumors, whereas those of 3 beta-HSD were markedly lower in the carcinomas than in other tissues. Both the content of b5 and the activity of Red were significantly lower in the adenomas. These results suggest that low concentrations of adrenal androgens in patients with adrenocortical adenomas are mainly due to low 17,20-lyase activity, which may be explained in part by a lower content of b5 and Red. In addition, high concentrations of adrenal androgens in patients with adrenocortical carcinoma are mainly due to the diminished activity of 3 beta-HSD.

3-Hydroxysteroid Dehydrogenases↗