The atrophic effects of a synthetic steroidal anti-androgen, TZP-4238, on the pituitary, prostate and adrenal gland of rats were investigated. Male Sprague-Dawley rats were divided into three experimental groups. Group 1 consisted of controls. Groups 2 and 3 received chlormadinone acetate (CMA) 50mg/kg/day and TZP-4238 10mg/kg/day p.o., respectively, for 3 weeks. CMA (Group 2) produced marked atrophy of the prostate. Furthermore, CMA caused marked atrophy of the adrenal gland. Histopathologically, the remarkable atrophy was observed in the adrenal cortical cells of zonae fasciculata and reticularis. The most striking ultrastructural alterations were noted in the mitochondria. In addition, intramitochondrial localization of glutathione-peroxidase (GSH-PO) which effectively reduces the lipid peroxides, was less than that in the controls. In the anterior pituitary gland, CMA induced a reduction in the size of ACTH cells. TZP-4238 (Group 3) produced marked atrophy of the prostate. However, TZP-4238 exerted no effect on the adrenal gland or anterior pituitary ACTH cells. In addition, the present histopathological study showed that TZP-4238 or CMA exerted no effect on the testes or anterior pituitary LH cells. Therefore, it is suggested that TZP-4238 causes atrophy of the prostate without any significant histopathological changes in the adrenal glands or anterior pituitary ACTH cells under the present experimental conditions. We further speculated that TZP-4238 had a more potent anti-prostatic effect than CMA and TZP-4238 had a less inhibitory influence than CMA on the pituitary-adrenal axis.

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This study was designed to examine how protein kinase C (PKC) regulates the release of endothelin-1 (ET-1) from cultured porcine aortic endothelial cells. We measured the release of immunoreactive (IR)-ET-1 from cells cultured for up to 72h in the presence or absence of a phorbol ester TPA. The release of IR-ET-1 from control cells (no TPA) increased according to time for up to 72 h. In the presence of TPA, the release of IR-ET-1 from the cells was higher than the control level for up to 8h, but was lower thereafter and reached a plateau after 48h. TPA dose-dependently stimulated IR-ET-1 release during incubation for 4h, but suppressed it after incubation for 72h. Stimulation of PKC by diacylglycerol mimicked the early (4h) action of TPA. On the other hand, pretreatment of cells with TPA to downregulate PKC significantly suppressed basal and thrombin- or FCS-stimulated IR-ET-1 release. These findings suggest that the activation of PKC is related to the stimulation of ET-1 release and that down-regulation of PKC leads to the suppression of ET-1 release from cultured endothelial cells.

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We present the unusual case of a 17-year-old female with insulin-resistant diabetes, acanthosis nigricans, hirsutism, amenorrhea, dental dysplasia and lipopexia on the extremities. She had been diagnosed as having border line diabetes with hyperinsulinemia at age 12 when she was not obese and diabetes mellitus at age 13. On admission, she was obese and had lipopexia only on the extremities. The presence of hyperinsulinemia and poor response to exogenous insulin suggested severe insulin resistance. Insulin binding to transformed B-lymphoblasts derived from her was extremely low compared to the normal control, showing decreased receptor affinity. Her parents and sister exhibited hypersecretion of insulin in response to a 75g oral glucose tolerance test. Her mother was diabetic, and her father and sister had border line diabetes, whereas her brother had a normal response. These findings support strongly the diagnosis of a type A syndrome with severe insulin resistance associated with lipopexia on the extremities. A genetic defect in the insulin receptor gene may be responsible.

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Plasma growth hormone (GH) responses to various stimuli were examined in 21 patients with GH-producing pituitary adenomas, classified into three types by the immunohistochemistry of cytokeratin and the glycoprotein hormone α-subunit distribution. Seven type 1 adenomas were exclusively composed of cells in which the cytokeratin formed a dot-like pattern; they were chromophobic to hematoxylin and eosin (H & E), occasionally positive for GH, and almost completely negative for the α-subunit. Thirteen type 2 adenomas were composed of cells with cytokeratin that had a perinuclear distribution; they were eosinophilic to H & E, and diffusely positive for both GH and the α-subunit. One patient had a type 3 adenoma which had a mixed pattern of intracellular cytokeratin distribution and was chromophobic and eosinophilic to H & E. Clinically, type 1 is characterized by earlier onset, larger tumor size, and more frequent aggressive extension. Paradoxical GH responses to TRH and OGTT were seen in 1 of 6 patients (16.7%) of type 1 and 8 of 9 patients (88.9%) of type 2, and 0% of type 1 and 62.5% of type 2, respectively. Type 2 cases showed higher plasma GH response to GH-releasing hormone, and a tendency to greater suppression of plasma GH by bromocriptine compared with type 1. Octreotide acetate administration revealed that the nadir/basal ratio of plasma GH levels was 42.9±6.6% in type 1 and 13.5±5.8% in type 2. These results suggest that there is a pathophysiological difference between these two distinct types of GH-producing pituitary adenomas.

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20α-Hydroxysteroid dehydrogenase (20α-HSD) in rat luteal tissue catalyzes the conversion of progesterone into a biologically inactive steroid, 20α-hydroxypregn-4-en-3-one (20α-OHP) and depletes the output of progesterone into the circulation. An increase in 20α-HSD activity in luteal tissue is therefore a prerequisite for the regression of functional corpora lutea in rats. We have reported that ovarian 20α-HSD is composed of two isoforms (HSD1 and HSD2). In this study, among batches of ovaries collected randomly during the estrous cycle, we selected two batches (batches A and B): the cytosol preparation from batch A contained both HSD1 and HSD2 activities, whereas that from batch B contained only HSD1 activity. From these 2 batches, we extracted mRNA, and each mRNA preparation was subjected to translation in Xenopus oocytes. The translation products of batch A exhibited both HSD1 and HSD2 activities, and those of batch B only HSD1 activity in accordance with the enzymatic activities observed in the respective cytosolic preparations. The results are compatible with the presence of two distinct mRNAs coding HSD1 and HSD2, and if so their transcription will be regulated separately according to the functional state of the ovary.

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The serum total T₃ level, evaluated in 687 patients with thyrotoxicosis diagnosed by an elevated serum free T₄ level and suppressed serum TSH level, was found to be high in 98.1% and normal in 1.9% of 592 patients with Graves' hyperthyroidism, and high in 75.8%, normal in 21.1% and low in 3.2% of 95 patients with destructive thyroiditis. Non-thyroidal illness was found in about a third of the patients with thyrotoxicosis and a normal serum total T₃ level. The serum total T₃ level was low with elevated serum thyroglobulin and reverse T₃ levels in three patients with severe non-thyroidal illness, in whom the thyroidal radioactive iodine uptake was suppressed and the thyrotoxicosis resolved spontaneously with a normalization of the serum total T₃ level after recovery from the destructive thyroiditis and non-thyroidal illness.
It is therefore concluded that thyrotoxicosis with a low serum total T₃ level, partially due to associated non-thyroidal illness, is more frequently found in patients with destructive thyroiditis than in those with Graves' hyperthyroidism.

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Our recent finding that ACTH increases c-fos mRNA in the adrenal gland of hypophysectomized rats indicates that the gene product FOS may play an important role (s) in mediating the action of ACTH. However, hypophysectomy employed in that study causes the disappearance of trophic hormones other than ACTH and may modify the effect of ACTH. Thus, in the present investigation, dexamethasone-treated rats were used. Since FOS functions only when it dimerizes with JUN (the product ofc-jun gene), the changes in the levels of c-fos and c-jun mRNAs were studied together with that of β-actin mRNA which is also affected by ACTH. Northern blot analysis was employed to determine the mRNA levels. It was demonstrated that ACTHincreases the mRNAs coding c-fos and c-jun in the adrenal glands of dexamethasone-treated, ACTH-suppressed rats. The c-fos mRNA was not detectable before ACTH administration. After ACTH administration, the mRNA levels were transiently increased, the maximum level being observed at 30min after ACTH. At 180min post ACTH, the level returned to the unstimulated level. The mRNA coding c-jun was detectable before ACTH administration and it also increased rapidly after ACTH with maximal stimulation at 30min. However, the mRNA level at 180min post ACTH was still higher than the unstimulated level. The changes in β-actin mRNA were approximately the same as those of c-jun mRNA. These results suggest that increased expression of c-fos, c-jun and β-actin genes by ACTH may play an important role in mediating its action on the adrenals.

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Treatment with a high daily dose bromocriptine was evaluated in 6 Cushing's disease patients (4 females and 2 males; aged 23 to 56 years). The highest doses administered were 40mg to patient 1, 55 mg to patient 2, 35mg to patient 3, 25mg topatient 4, 25mg to patient 5, and 17.5mg to patient 6. The former 3 cases, 2 (patients 1 and 2) of whom were previously reported and further followed up, showedclinical and biochemical improvement with the regimen. Patent 1 who obtained remission with 40mg/day has been on remission for further 14 months with a total of 36 months. Patient 2, who had a reduction in pituitary tumor size with 35mg daily, relapsed thereafter. The therapy, however, resolved the paradoxical responses of plasma ACTH and cortisol to arginine. Readministration of bromocriptine resulted into another clinical and biochemical improvement with 45 to 55mg/day. Patient 3, a relapsed case after a remission with reserpine plus pituitary irradiation, showed an improvement in the 24-h urinary free cortisol excretion with 35mg/day. Patient 4 was the only case who had a marked decrease in plasma cortisol (basal; 16.3, nadir; 1.9μg/dl) after a single-dose bromocriptine test among the5 cases tested. The patient had favorable response with 25mg/day for 2 months but the dose was not increased after an escape. Patient 5 received the drug in 4 occasions, 7.5 to 25mg/day, in combination with several agents, which failed to induce clinical remission. The last patient did not respond to a maximum dose of 17.5mg/day. These observations suggest that, regardless of the result of a single-dose bromocriptine test, treatment with a high daily dose of bromocriptine, 35mg or more, may be necessary to obtain a favorable clinical response and normal cortisol secretion.

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Renal failure was found in a five-year-old atient who had been treated with insulin since he was diagnosed as having insulin dependent diabetes mellitus (IDDM) at 3 years of age. Laboratory data showed that his renal failure was caused by a renal tubular dysfunction. The autopsy findings of his pancreas were compatible with those of IDDM. The kidneys were atrophied with an innumerable number of crystals in the proximal tubuli. Staining by Kossa indicated that the crystals contained calcium salt. The calcium content of his kidneys was significantly higher than that of control. The nephrocalcinosis seems to be caused by hypercalciuria associated with IDDM.

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We report the effectiveness of bromocriptine therapy in resolving the abnormal responses of plasma FSH and LH to TRH in a 70-year-old male with FSH-secreting pituitary macroadenoma who had unsuccessful transsphenoidal pituitary surgery. In the pre-treatment and post-operative periods, respectively, basal plasma levels of FSH were increased to 88.7 and 65.6mIU/ml (normal range; 8.5-32.4) but those of plasma LH were normal being 7.0 and 4.1mIU/ml;(normal range; 4.1 to 14.0). The responses of plasma FSH and LH to LHRH were exaggerated and their paradoxical responses to TRH were highly suggested. During the bromocriptine therapy, the basal level of plasma FSH was normalized and that of plasma LH remained normal. The magnitude of FSH and LH responses to LHRH decreased and their paradoxical responses to TRH were completely resolved.

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A 67-year-old man affected by prostate cancer was incidentally found to have a nodular enlargement of the left adrenal gland without apparent changes in hormonal status. The adrenal mass was found to be scintigraphically active, the radiolabelled compound being concentrated in its context with a consensual suppression of the contralateral uptake. The patient underwent a resection of the adrenal tumor. Histologically and biochemically, the adrenal mass was found to be a non-functioning adenoma. The radioisotopic uptake along with the non-hormonal activity prompted us to call this tumor “Pre -Cushing's syndrome” of the adrenal cortex.

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We report a 44-year-old male with a thyrotropin (TSH)-secreting pituitary adenoma. Basal serum free triiodothyronine (FT₃, 12.1pmol/l) and free thyroxine (FT₄, 28 pmol/l) were increased with normal basal TSH (3.1mU/l). There was impaired TSH response to thyrotropin releasing hormone (TRH) test. Serum TSH was suppressed to 59% of the basal level after oral administration of 1.4mg 3, 3'-5-triiodothyroacetic acid (triac), whereas no suppression was observed after 75 μg daily administration of triiodothyronine (T₃). Serum concentrations of a-subunit of TSH (TSH-α) and TSH-α/TSH molar ratio were high, being 1.95μg/l, and 4.4, respectively. Pituitary CT and MRI scan showed the presence of a macroadenoma in the anterior lobe of the pituitary gland. Histopathology of the excised pituitary confirmed the diagnosis of a TSH-producing adenoma. A positive correlation between TSH and FT₃ (r=0.66, P<0.01) or FT₄ (r=0.54, P<0.01) was observed in serial sera obtained before and after operation.

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