The present study surveyed 69 patients with aldosteronoma to study the clinical implications of renal cysts demonstrated in computed tomography. Patients who had cysts (n=16, 23.2%) were older and had a longer duration of hypertension and more severe hypokalemia than those without cysts (n=53). Patients with cysts therefore had longer-term, more severe hypokalemia than those without cysts. Endogeneous creatinine clearance (Ccr), measured in 61 patients, was significantly lower in patients with cysts (58.4±7.1ml/min, n=16) than in those without cysts (77.3±7.1ml/min, n=45, P=0.0039). This significant difference was observed even after adjusting for covariables (age, duration of hypertension, and serum potassium) between the two groups by analysis of covariance (ANCOVA). No significant difference was observed in gender, blood pressure, serum creatinine, plasma aldosterone, or PRA. Age, serum potassium levels, and systolic and diastolic blood pressure were the significant determinants in predicting Ccr in a backward stepwise multiple regression analysis (r=0.505, n=61, P=0.0025). Cysts were graded into four classes on the basis of number and size. Cyst grading correlated negatively with Ccr at a Spearman rank correlation (ρ=-0.33, n=61, P=0.0103). The incidence of chronic renal failure was significantly higher in patients with cysts (18.8%) than in patients without (0%) in a Fischer's exact probability test (P=0.0107). Thus, both renal cysts and dysfunction arose and/or developed from common roots, i.e., the duration and severity of hypokalemia, in primary aldosteronism. In addition, we surveyed 27 patients with pheochromocytoma. Patients with renal cysts (n=8) had a significantly longer duration of hypertension than those without cysts. No significant difference was observed in Ccr between patients with and those without cysts. Thus, a significant link between renal cysts and Ccr was a specific feature of primary aldosteronism, but not of pheochromocytoma. In summary, the renal cysts in primary aldosteronism should be recognized as a significant complication representing the extent of renal injury and dysfunction.
The cytologic localization and cellular levels of insulin-like growth factor binding protein-4 (IGFBP-4) in follicular and stromal compartments of normal and polycystic ovary syndrome (PCOS) ovaries during follicular growth and regression were investigated by the avidin/biotin immunoperoxidase method with a polyclonal antibody to human IGFBP-4, and a comparative assessment of IGFBP-4 expression in normal and PCOS ovaries was provided. In normal human ovaries, IGFBP-4 was immunolocalized to the oocyte throughout follicular growth, while the surrounding granulosa and theca cells were negligible for IGFBP-4 immunostaining in primordial, preantral and antral follicles. IGFBP-4 immunostaining became apparent, however, in the lutein cells of corpora lutea and the granulosa and theca cells of atretic follicles. In PCOS ovaries, prominent immunostaining for IGFBP-4 was apparent not only in the oocyte, but also in the surrounding granulosa cells in preantral follicles. In antral follicles from PCOS women without hyperinsulinemia, IGFBP-4 immunostaining was more prominent in the granulosa cells than the theca cells, whereas in antral follicles from PCOS women with hyperinsulinemia IGFBP-4 immunostaining was more prominent in the theca cells than the granulosa cells. Furthermore, in atretic follicles within PCOS ovaries IGFBP-4 immunostaining was prominent in the theca cells, regardless of the association of hyperinsulinemia. These results demonstrate for the first time that there is a great difference in cellular expression of IGFBP-4 between normal and PCOS human ovaries. In light of the high affinity of IGFBP-4 for IGF-I, the abundant expression of IGFBP-4 in granulosa and theca cells of preantral and antral follicles of PCOS ovaries may lead to decreases in the bioavailability of IGF-I in those follicles. The decrease in IGF-I-mediated stimulation of gonadotropin actions on granulosa and theca cells in preantral and antral follicles may impair the induction of aromatase activity, causing an androgenic microenvironment which is characteristic of atretic follicles and PCOS follicles.
Two patients with malignant pheochromocytoma were treated with a combination chemotherapy regimen consisting of cyclophosphamide, vincristine, and dacarbazine (CVD). With the first few cycles of the treatment, one patient, a 29-year-old man had a marked improvement of clinical symptoms and decreases in tumor size and catecholamine levels in plasma and urine. He had been in a clinically stable condition for 18 months but died 34 months after starting of this treatment because the CVD regimen became ineffective and rapid growth of the metastatic tumors occurred. The other patient, a 35-year-old man showed no significant change in tumor size but decreases in hormonal levels in response to CVD regimen. The patient has been in clinically stable condition in a follow-up of 24 months. The combined chemotherapy with CVD appears to be effective for advanced malignant pheochromocytoma.
Recent studies indicate that experimentally induced hyperinsulinemia may reduce serum dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEA-S). Serum DHEA and DHEA-S decrease in diabetic patients, but the mechanism by which hyperglycemia decreases DHEA and DHEA-S is unknown. In this study, we investigated the effect of hyperglycemia on DHEA and DHEA-S in impaired glucose tolerance (IGT) by means of the 75g-oral glucose tolerance test (OGTT). We selected 30 male IGT patients receiving diet therapy only, whose insulinogenic Index was under 0.3. Oral glucose challenge significantly reduced DHEA (P=0.0001) and DHEA-S (P<0.05) at 60 and 120min after OGTT. Setting the value of DHEA and DHEA-S at time zero as 100%, we calculated the DHEA and DHEA-S values at 60 and 120min after OGTT as %DHEA(-S) 60min and %DHEA(-S)120min, respectively. DHEA and DHEA-S at time zero showed no correlation with BMI, HbA1c, the sum of insulin values (∑IRI) or the area under the curve of plasma glucose (AUC). We found decreases in %DHEA 60min (r=-0.411, P<0.05), %DHEA-S 60min (r=-0.508, P<0.01) and %DHEA-S 120min (r=-0.393, P<0.05) as AUC increased, but ∑IRI showed no correlation with %DHEA(-S) 60min or %DHEA(-5)120min. We conclude that the depression of DHEA and DHEA-S after OGTT is attributable to hyperglycemia in male Japanese IGT with low insulin response.
This study was conducted to determine the effects of acute and chronic administration of GH-releasing peptide-2 (D-AIa-D-βNal-Ala-Trp-D-Phe-Lys-NH2, GHRP-2 or KP102) on GH responsiveness in male Holstein calves. In the dose response study of acute administration, six calves were injected iv with saline or 6.25, 12.5 and 25.0μg/kg body weight (BW) of KP102. The GH AUC (area under curve, ng/ml•min, mean±SEM) for 60min was significantly increased with 6.25 (676.3±125.6), 12.5 (1574.8± 318.0) and 25.0 (1578.7±214.6)μg/kgBW of KP102 than with saline (78.6±36.1) (P<0.01). GH responses were decreased by multiple injections of 12.5μg/kgBW KP102 at every 2h for 8h. The GH AUC for 60 min was decreased from the first injection (1162.9±313.3) to the second injection (604.7±131.9), but the response was significantly higher for the first and second injections than the third (304.4±173.1) and fourth injections (320.7±144.2) (P<0.05). In the chronic administration, 8 calves were implanted subcutaneously with osmotic pumps (Alzet pump®). Each of the 4 calves was given with 12.5μg/kgBW per hour KP102 and the other 4 calves served as the control. During the 14 day period, average daily gain was significantly increased (36.4%) over the control (P<0.05). Food efficiency was not significant, but numerically higher (29.4%) than the control. The plasma GH concentration was not increased by chronic administration of KP102, but IGF-I appeared to increase in KP102-treated calves more than the control. These results suggest that the synthetic KP102 can be used for enhancing the growth performance in domestic animals.
By an indirect immunofluorescence method with In-111 cells (hamster insulinoma cell line), circulating islet cell surface antibodies (ICSA) were detected in 7 (20%) out of 36 patients with non-insulin dependent diabetes mellitus (NIDDM), 9% of 68 chronic thyroiditis (CT) patients, or 16% of 19 NIDDM patients associated with CT, but not in 18 normal subjects. Sera from five out of nine ICSA-positive patients examined further also showed cell-surface immunofluorescence on TPC-1 cells (human thyroid papillary adenocarcinoma cell line), and prior absorption of the sera with In-111 cells abolished the immunofluorescence. The 64kDa protein from In-111 cells or human thyroid follicular cells was immunoprecipitated with ICSA-positive sera. In one case of NIDDM associated with CT, 64kDa protein was detected in both cells. The results indicate that some ICSA in NIDDM patients recognize the same or a very closely-related autoantigen(s) in both islet β-cells and thyroid follicular cells, suggesting an explanation, at least in part, for the autoimmune mechanism(s) in clinical association of NIDDM and CT.
The purpose of this study was to assess the effect of surgery on gonadal function in 42 male patients with pituitary adenomas. Gonadal functions were evaluated by measuring total serum testosterone concentrations pre- and postoperatively. The subjects of the study were 20 patients with GH secreting adenoma, 7 patients with prolactinoma and 15 patients with nonfunctioning (NF) adenoma. Their ages ranged from 18 to 60 years (mean±SEM, 41±1.9). The serum testosterone concentration was low at less than 300ng/dl preoperatively in 14 of 20 patients (70%) with GH producing adenoma, 6 of 7 patients (86%) with prolactinoma, and 7 of 15 patients (47%) with NF adenoma. Postoperatively, the total serum testosterone concentration was normalized in 9 of 14 patients (64%) with GH producing adenoma, one of 6 patients (17%) with prolactinoma, and 5 of 7 patients (71%) with NF adenoma. The normalization of serum GH and prolactin concentrations is indispensable for the restoration of gonadal function. It is very important to preserve the normal preoperative gonadotropin secretion by means of gentle surgery.
To assess the regulatory mechanism of insulin action on the biosynthesis of glycogen synthase under long-term control, we investigated post-transcriptional and post-translational regulation by insulin of glycogen synthase in rat hepatoma H4 cells. Glycogen synthase protein gradually increased in response to insulin and peaked at 6 h during a 24-h insulin incubation (185% of the control), corresponding with the second peak of glycogen synthase activation measured by the activity ratio (low glucose 6-P/high glucose 6-P). The effect of insulin on synthesis of glycogen synthase protein was assessed by measuring the incorporation of [35S]-methionine into the enzyme protein during a 6-h insulin incubation. The amount of [35S]-methionine incorporation into glycogen synthase was increased in response to insulin with time, and peaked at 4h (250% of the control). The degradation of glycogen synthase examined by measuring the rate of reduction of [35S]-methionine for 6h after the tracer incubation for 12h was not affected by insulin. The results indicate that (a) insulin induces glycogen synthase activity by accumulating the enzyme protein due to stimulation of protein synthesis rather than inhibition of protein degradation and (b) insulin-reduced stability of glycogen synthase mRNA is caused by acceleration of the translation rate.
We demonstrated the release of follistatin, an activin-binding protein, from cultured rat anterior pituitary cells by measuring immunoreactive (ir-) follistatin in a specific immunoradiometric assay. Ir-follistatin release gradually increased in cultures over 1-18 days and reached its maximal level at 12-15 days of incubation. The basal ir-follistatin levels in the culture media increased about 3- (P< 0.01) and 5-fold (P<0.001) in 2 and 10% fetal calf serum for 6 days, respectively. LHRH and activin A caused an approximately 2.0- (P<0.05) and 1.8-fold (P<0.05) rise in ir-follistatin release, respectively, in contrast to the lack of significant FSH effects. The culture medium condensed on sulfate-cellulofine gel was resolved by polyacrylamide gel electrophoresis and blotted with anti-follistatin polyclonal antibody, resulting in at least three protein bands ranging from 35 to 50kDa under non-reducing conditions. These results indicated that follistatin is produced in anterior pituitary cells and that its secretion is regulated at least in part by LHRH and activin, implying an autocrine/paracrine role of activin and follistatin in the pituitary.
It is well known that estrogen (E2) induces progesterone receptor (PR) in the uterus and the mammary gland. In MtT/F84, a pituitary tumor, which was established in our laboratory and has been maintained with in vivo passages, we investigated the PR regulation by E2 in relation to the host's thyroidal status. The PR level in the tumor had increased five fold 48h after an E2 injection. When the host rats were treated with propylthiouracil (PTU), an anti-thyroid drug, the induction of PR after an E2 injection was completely blocked. This result is consistent with our previous findings indicating that E2 responsiveness in the tumor may be under the control of thyroid hormones. The estrogen receptor (ER) level in the tumor treated with PTU was 15% of the control. This low ER level may account for the blocking of PR induction after an E2 injection. When the host animals were continuously treated with various doses of E2, the PR level in the tumor rose in correlation with the E2 doses. PTU administration, however, did not prevent long term induction of PR by continuous E2 treatment. Our findings suggest that PTU lower the ER level and suppresses the short term estrogenic actions such as PR induction after an E2 injection.
Human interferon β (IFN-β) has been used for the treatment of patients with benign and malignant astrocytomas. The effect of IFN-β on pituitary function, however, has not been precisely evaluated before. In this study the serum levels of various anterior pituitary hormones including GH, PRL, ACTH, and TSH were measured to determine the effects of IFN-β on pituitary endocrine function in 19 consecutive glioma patients receiving IFN-β. Daily doses of 3×106U of IFN-β were administered as a 30-min intravenous drip infusion beginning at 0800h every morning during the first week and then 4 times a week for additional 6 weeks. Blood samples were taken on the day prior to administration as controls (0900h and 1500h), and on the first day of administration (0900h and 1500h) and after 7 days of administration (0900h) in order to determine the acute and chronic or integrated effects of IFN-β on the above pituitary hormones. No significant change in serum concentrations of any of the pituitary hormones examined was observed, suggesting that human natural IFN-β used for the treatment of gliomas has no significant effect on the secretion of these hormones from the pituitary in these patients.
The onset of physical signs in infants with hypophosphatemic vitamin D resistant rickets (HDRR) has generally been considered to be at the age of 12 months, but the time of appearance of hypophosphatemia and rachitic signs on radiographs remains unclear. We report a prospective study in three neonates whose mothers were HDRR. At birth, despite a low maternal serum inorganic phosphorus (Pi) level, the serum Pi level was normal together with a negligible renal Pi leak in one neonate. At age 3 months, their serum Pi levels, percentages of tubular reabsorption of Pi, and renal tubular maximal rates of Pi reabsorption in relation to the glomerular filtration rate were low except for one infant. Radiographically, their rickets were not apparent at birth but at age 3 months in all. A premature born infant, born at 28 weeks' gestation weighing 1240g, was diagnosed as HDRR based on hypophosphatemia due to low renal tubular maximal rate of phosphorus reabsorption in relation to the glomerular filtration rate (TmP/GFR) and normal urine Ca excretion at age 5 months. They were initially treated with 1α-hydroxyvitamin D3 (1α OHD3) and later with 1α OHD3 in combination with Pi, which results in healing of the rickets and a normal increase in height. Thus, early detection and treatment of patients born from mothers with HDRR before physical signs of bow-leg and short stature is possible, but the outcome of early treatment requires further study.
To investigate how the visit-to-visit variation in serum lipids measurements affects the decision making concerning treatment according to the National Cholesterol Education Program (NCEP) guidelines in patients with clinically well controlled non-insulin-dependent diabetes mellitus (NIDDM) we have measured the biological variation (CVb) in serum total cholesterol (IC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) in 26 patients with NIDDM. We found the CVb as follows: TC, 5.1%; TG, 17.0%; HDL-C 4.4% and LDL-C, 8.3%. Confidence intervals (95%) were determined with total intra-individual variance values around the NCEP cut-off points to evaluate how well one, two and three lipid measurements provided reliable risk classification. A single TC measurements <177mg/dL or >263mg/dL allowed confident classification as “desirable” or “high risk” respectively. For LDL-C, one measurement was accurate only at below 106.3mg/dL or above 183.7mg/dL. The average of three measurements contracted these limits to <186.7mg/dL and >253.3mg/dL for TC, and <116.3mg/dL and >173.7 mg/dL for LDL-C. For HDL-C also, multiple measurements improved risk assignment in a similar fashion. There were no values which allowed assignment to the “borderline high” category with one TC measurement and with one and two LDL-C measurements. The mean of three TC and three LDL-C measurements allowed assignment to the “borderline high” category, if between 213.3 and 226.7mg/dL for TC, 143.7 and 146.3 mg/dL for LDL-C. Seven patients (26.9%) in this risk group based on the mean of two LDL-C estimates could be placed into a different category when the mean of three estimates was taken, even though the first two LDL-C test results did not differ by more than 30mg/dL. Our results suggest that repeated lipid measurement is important especially for the “borderline-high” risk group because big variations existed in some patients, and further that TC is the most reliable quantity.
Inhibin α and βA subunit messenger ribonucleic acid (mRNA) levels were measured quantitatively by reverse transcription-polymerase chain reaction (RT-PCR) in human pituitary adenomas. The inhibin α subunit mRNA levels were undetectably low in cultured adenoma tissues, but βA mRNA were 0.383±0.074 in 3 GH adenomas, 0.672±0.140 in 3 prolactinomas and 0.957±0.414 molecules/cell in 3 non-functioning adenomas. The addition of 10-8M activin A decreased the βA mRNA levels within 4h in 1 of 3 GH adenomas, 2 of 3 prolactinomas and 2 of 3 non-functioning adenomas, though the decreases were not statistically significant. The results showed an abundance of βA subunit mRNA compared with a subunit mRNA in all human pituitary adenomas and a local role for activin in its own production through inhibin βA mRNA subunit expression.