The effects of surgery on pituitary-gonadal function were investigated in women with pituitary adenomas other than prolactinomas. The subjects were 46 women of premenopausal age with a pituitary adenoma. Twenty tumors were GH producing, 19 were nonfunctioning, and 7 were adrenocorticotropin producing adenomas. The surgery was performed mainly via the transsphenoidal route, with the aim of eradicating the tumor and preserving pituitary function. The menstrual cycle was preserved postoperatively in 9 out of 10 (90%) patients with regular preoperative menstruation. Menstrual disturbance was seen in 36 (78.3%) cases preoperatively. The causative factors for menstrual disturbance were gonadotropin impairment and hyperprolactinemia in GH producing and nonfunctioning adenoma. Excessive hormonal secretion itself is a major causative factor for menstrual disturbance in GH and ACTH producing adenoma. Regular menstruation was restored following surgery in 20 out of 36 (55.6%) patients with menstrual problems. The predicting factors for postoperative recovery of menstruation are: size of adenoma less than 40mm, period of amenorrhea less than 5 years, and preoperatively preserved gonadotropin secretion. In addition, preoperative hyperprolactinemia was also a predicting factor in women with nonfunctioning adenoma. Thus, even in patients with pituitary adenomas other than prolactinoma, the restoration of menstruation is highly achievable when surgery is performed with attention to preserving pituitary function.

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The amount of gonadotropin releasing hormone receptor (GnRH-R) in the anterior pituitary changes during the rat estrous cycle; in addition, it is chronically increased for several weeks in response to ovariectomy. The present study was undertaken to investigate these changes in relation to the concentrations of GnRH-R mRNA, gonadotropins and luteinizing hormone-β (LH-β) subunit in serum and the pituitary gland, as well as hypothalamic GnRH. GnRH-R concentrations on the day of estrus were significantly lower than that at diestrus (30% lower during 2d), its mRNA decreased even further (by 60%), but there were no significant changes in gonadotropin. Ovariectomy increased GnRH-R significantly (by 30% during 2wk) in parallel with receptor mRNA and with pituitary LH and LH-β, but induced an earlier increase in serum gonadotropins. Our results suggest that transcriptional activity is more intimately linked to the number of GnRH-R in the long-term increase after ovariectomy than in the short-term change during the estrous cycle, and that the increased GnRH-R is not a major factor in ovariectomy-stimulated gonadotropin release.

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The purpose of the present study was to examine the responses of plasma growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels to intravenous injection of xylazine in female dairy calves. Xylazine (0.05, 0.15 and 0.30mg/kg body wt., iv) injections induced a significant dose-dependent increase in plasma GH level within 30min. After plasma GH levels reached peaks, GH concentrations began to decrease immediately and they returned to control levels 1h after xylazine injection. Plasma IGF-I concentration tended to be suppressed by xylazine treatment. Xylazine induced a significant dose-dependent increase in plasma glucose for 3.5 to 5.5h after the treatments. Xylazine also induced a significant decrease in plasma insulin level within 30min after treatments. The present data suggested that xylazine stimulates GH release in cattle.

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The present study demonstrated the change in interleukin-1 (IL-1) production of peritoneal macrophages during the estrous cycle in golden hamsters and discussed its possible roles in ovarian function. Macrophages were collected from the peritoneal cavity at 0900h on various days of the estrous cycle and incubated for 6h in the presence of ovine pituitary LH (500ng/ml). The IL-1 concentration in the media was measured by bioassay with the A375S2 human melanoma cell line. The number of macrophages significantly (P<0.01) increased on estrus and proestrus compared with diestrus 1 or diestrus 2. LH-induced production of IL-1 was also greater (P<0.01) on proestrus (292±36pg/10⁶cells/ml) and estrus (222±30pg/10⁶cells/ml) than on diestrus 1 (34±15pg/10⁶cells/ml) or diestrus 2 (117± 16pg/10⁶cells/ml). To clarify the factor inducing the changes in peritoneal macrophages, hamsters were ovariectomized on diestrus 1, and 3 weeks later the animals were treated with sc injections of progesterone (200μg/day), testosterone (100μg/day), estradiol (10μg/day) or sesame oil for three days. The hamsters were killed 24h after the last injection, and the number and IL-1 producing capacity of macrophages were determined. The number of macrophages and their response to LH to produce IL-1 were increased significantly (P<0.01) by estradiol treatment but not by progesterone or testosterone treatment. It was concluded that the peritoneal macrophages became more sensitive to LH to produce IL-1 on proestrus and estrus in cyclic hamsters, and that these changes in macrophages, probably induced by estradiol, would play important roles in ovarian function.

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The synthesis of nitric oxide (NO) has been demonstrated in the vascular endothelial cells and other tissues including in rat and bovine adrenal gland. To determine whether NO mediates aldosterone production in the adrenals, we evaluated the basal production of aldosterone, and the ACTH or angiotensin II (A II)-stimulated aldosterone in the presence of LN^G monomethyl arginine (L-NMMA) or L-arginine or L-NMMA + L-arginine in isolated rat adrenal capsular tissue by an ex vivo perfusion technique. ACTH increased the release of aldosterone by 40%. Such release of aldosterone was inhibited by L-NMMA, but not by a mixture of L-NMMA and L-arginine. A II stimulated aldosterone release by 40%. The increase in aldosterone release in response to A II was inhibited by L-NMMA or L-arginine. The increase in aldosterone release stimulated by A II was also inhibited by L-NMMA with L-arginine. L-glutamine did not inhibit the A II stimulated aldosterone release. In conclusion, the inhibition of NO synthesis prevented the release of aldosterone stimulated by ACTH, suggesting NO is required for the action of ACTH on aldosterone production.

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A 50-year-old Korean man with repeated episodes of temporary loss of consciousness was diagnosed as having hyperinsulinemic hypoglycemia. Under the tentative diagnosis of insulinoma, localization procedures were carried out but no tumor was found. By percutaneous transhepatic portal venous sampling, no definite gradient in insulin concentration was found. During exploratory laparotomy no tumor was palpable in the pancreas, and intraoperative ultrasonography showed low echogenicity in the pancreatic head. Whipple's operation was performed and 70% of the proximal pancreas was removed. Histomorphometric examination of the resected specimen revealed graded hyperplasia of the islet cells. The most profuse hyperplasia was noted in the head with progressive decrease in the degree of hyperplasia to the body and tail. The patient remains euglycemic and tolerates 24h fasting without any medication until 15 months after operation.

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Surgical strategies for pheochromocytomas in patients with multiple endocrine neoplasia (MEN) type 2 syndrome have been controversial. The purpose of this study is to review the current status of patients with MEN 2 who underwent adrenalectomy with or without adrenal autotransplantation. We studied 15 patients with MEN 2A who underwent adrenal surgery between 1981 and 1992. The follow-up survey included physical examination and biochemical determinations. The median period from initial surgery to follow-up was 54 months (range, 0-145 months). Initial bilateral total adrenalectomy was performed on seven patients, and subtotal adrenalectomy was carried out on two. Among six patients who initially underwent unilateral adrenalectomy, four had remained normotensive (median follow-up, 61 months), whereas the other two patients had to undergo reoperation on the contralateral side because of recurrent symptoms. Two patients were suspected of having had a relapse of the disease after total adrenalectomy. Seven patients underwent adrenal autotransplantation; however, none of them were able to discontinue glucocorticoid replacement therapy. In MEN 2A patients having large pheochromocytomas on only one side, unilateral adrenalectomy can be a suitable alternative to bilateral adrenalectomy in terms of blood pressure control and preservation of adrenocortical function. The attempt to preserve adrenocortical function by autotransplantation is discouraged.

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We studied the effects of short term replacement with human GH at three doses (0.124, 0.250 and 0.375IU/kgBW/week) in 12 adult patients with GH deficiency (GHD). The patients were divided at random into three goups of 4 patients (groups A, B and C) and each group was treated with three doses of GH and placebo for 10 weeks in shifts of two weeks each. The replacement was started with one of three doses of GH given sc daily at 2100h for 2 weeks, which was followed by placebo treatment for 2 weeks. The various doses of GH and placebo were then given alternately. GH treatment increased serum IGF-I and IGF-BP3 levels in all the patients examined although the responses were partly influenced by the order of GH treatment. When the data obtained with the same doses of GH in the three groups were combined, a dose-response was demonstrated. There was a close correlation (r=0.726) between serum IGF-I and IGFBP-3. Serum triiodothyronine as well as non-esterified fatty acid (NEFA) levels also increased after GH replacement. Adverse side effects included edema in two cases and sleep distress in one case during the GH treatment at the highest dose of 0.375IU/kgBW/week. These findings indicate that short term replacement with GH at the doses of 0.125 and 0.250IU/kgBW/week is safe and effective in adult patients with GHD.

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A 43-year-old female showing signs and symptoms of subacute thyroiditis was referred to our hospital for further evaluation of her thyroid function because TSH-binding inhibitor immunoglobulins (TBII) were detected in her serum. A diagnosis of subacute thyroiditis was made based on high levels of thyroid hormones with suppressed TSH level, suppressed radioactive iodine uptake (RAIU), and positive inflammatory findings and ultrasonogram results. She was at first thyrotoxic, then transiently hypothyroid, and finally became euthyroid. The assay results for TBII and thyroid-stimulation blocking antibodies (TSBAb) were positive in the thyrotoxic phase, and the TBII and TSBAb activities were decreased and finally became undetectable during the course of her illness. In contrast, the assay results for thyroid-stimulating antibodies (TSAb) were negative throughout the investigation period. The presence of TSBAb may have induced the development of hypothyroidism because she became euthyroid after the disappearance of TSBAb from the serum, but the duration of the hypothyroid phase was the same as that in typical cases of subacute thyroiditis. Inflammatory or destructive changes in the thyroid gland are thought to be involved in the production of the TSH-receptor antibodies in the patient.

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Measurement was made of the serum carboxyl-terminal propeptide of type I procollagen (PICP), carboxyl terminal cross-linked telopeptide of type I collagen (ICTP) and osteocalcin in 17 full-term mother-infant pairs and 17 age-matched nonpregnant women. Serum PICP and ICTP of term women at the time of delivery were significantly higher (P<0.025, P<0.01, respectively) and serum osteocalcin was significantly lower (P<0.001) than in nonpregnant women. The ratio of PICP to ICTP was essentially the same for term and nonpregnant women. Serum PICP, ICTP, and osteocalcin were virtually the same in the umbilical arteries and vein. PICP, ICTP and osteocalcin were much higher in fetal than maternal circulation (P<0.001). The fetal levels of these proteins were not correlated with maternal levels, nor with birth weight. Thus, during pregnancy, either osteoclastic or osteoblastic activity would appear to increase slightly, but the balance between bone formation and resorption is maintained. During fetal life, bone turnover may be greatly accelerated and bone metabolism may occur independently of maternal bone metabolism.

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In order to determine what and how many test items are necessary for the initial tests when examining patients with thyroid disorders, a questionnaire was sent to the council members of the Japan Thyroid Association. Thyroid disorders were divided into 4 categories; hyperthyroidism, hypothyroidism, diffuse goiter, and nodular goiter. The questionnaire was designed to assess: 1) tests routinely ordered at the initial examination; 2) minimum test battery necessary; 3) the 5 most important tests in order; and 4) selection of only 2 tests at most. The data on 112 completed questionnaires were collected and analyzed. When the choice was limited to only 2 tests, TSH and fT₄ were commonly selected for hyperthyroidism, hypothyroidism and diffuse goiter, but these 2 tests would be insufficient for the differentiation of disorders. In the case of nodular goiter, ultrasonogram and fine needle aspiration biopsy (FNA) were selected. The mean number of routinely ordered tests was 6.62±2.00 (S.D.) for hypothyroidism and 8.06±2.48 for nodular goiter, but many fewer tests were cited as absolutely necessary. In hyperthyroidism, 4.56±1.92 tests were required, in hypothyroidism 4.39±1.92, in diffuse goiter 4.93±1.75, and in nodular goiter 5.15±2.13. Most of the function-related tests, ultrasonogram and autoantibodies were commonly selected, while TBII and thyroid ¹²³I or ^99mTcO₄^- uptake in hyperthyroidism, and FNA, Tg and scintigram in nodular goiter were considered to be for specific purposes. Summarizing all these, the authors propose 5 or 6 tests to be necessary as the initial tests when examining patients with 4 individual thyroid disorders.

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Ventricular natriuretic peptide (VNP), a possibly new type of natriuretic peptide with an extended C-terminal tail, has been isolated from eel cardiac ventricles. We investigated the effects of eel VNP on the kidney and cardiovascular system and compared these results with those of mammalian peptides in dogs. Eel VNP, human (dog) ANP, human and dog BNPs were infused into the renal artery at non-hypotensive doses. All peptides produced similar diuresis and natriuresis, but cardiac output and the left and right ventricular stroke work were decreased by BNPs, but ANP and eel VNP did not change these parameters. Systemic vascular resistance was increased by BNPs, but unaffected by other peptides. These results show that eel VNP has renal effects similar to ANP and BNP, but it elicits responses in the heart different from those of BNPs in anesthetized dogs.

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A two-year double-blind study monitored and evaluated the effects of 1α-hydroxy vitamin D₃ (1α(OH)D₃) on the lumbar (L_2-4BMD) and total body bone mineral densities (TBBMD) and occurrence of fracture in 113 female osteoporotic patients receiving 0.75μg/day of 1α(OH)D₃ (n=57) or a placebo (n=56) with calcium supplementation in both groups. L_2-4BMD increased 1.81% and 2.32% after one and 2 years in the 1α(OH)D₃ group, but decreased 1.89% (P<0.05) and 0.28% in the placebo group. A significant difference (P<0.01) existed between the two groups after one year. TBBMD decreased significantly in the placebo group by 3.34% (P<0.01) and 3.52% after one and 2 years. Six new fractures occurred in the control group, but only two in the 1α(OH)D₃ group (Odd's ratio=0.343, 95% confidence range; 0.0648-1.815). There were no serious adverse effects of the 1α(OH)D₃ treatment. It was concluded that two-year treatment with 1α(OH)D₃ increased the lumbar BMD and inhibited the decrease in TBBMD. Altough it was not significant, new fracture occurrence in the 1α(OH)D₃ group was around 1/3 of that in the control group.

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To evaluate the role of insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) in exessive fetal growth (macrosomia) in diabetic pregnancy, 84 insulin-treated diabetic mothers and their infants were tested for serum concentrations of IGF-I, IFG-II, and IGFBP-1, -2 and -3. These parameters were correlated with the birth weight of neonates and placental weight. IGF-I and II levels were determined by specific radioimmunoassays (RIAs) after serum samples were extracted with aid-ethanol. IGFBPs were measured by Western immunoblot with specific antibodies to the respective IGFBP species. Serum concentrations of both IGF-I and IGF-II in mothers with either IDDM or NIDDM increased with the gestational period, reached a plateau at the third trimester, and returned to non-pregnant levels within 7 days after delivery. These values were not different from those in normal mothers before and throughout pregnancy. As previously reported, IGF-I concentrations in cord serum of neonates born to diabetic mothers were (P<0.01) higher than those of newborns of normal mothers. Likewise, cord blood IGF-II levels were 2-fold higher in babies of diabetic mothers (P<0.001). Fetal IGF-I and IGF-II correlated with each other and with maternal HbA_1C, and they positively correlated with either birth weight or placental weight. Cord IGFBP-3 concentrations were significantly higher in diabetic pregnancy, but IGFBP-2 concentrations were not different from those in normal pregnancy. Cord IGFBP-1 concentrations were significantly higher only in babies of mothers with IDDM. None of these cord IGFBP concentrations correlated with birth weight or placental weight. The data suggest that fetal IGF-II, like IGF-I, is involved in fetal and placental growth in diabetic pregnancy. The role of IGFBPs remained to be determined.

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In an attempt to define the hypothalamic-pituitary-adrenal (HPA) axis in non-insulin dependent diabetic rats (WBN/Kob), we measured plasma corticotropin releasing factor (CRF), as well as arginine vasopressin (AVP), ACTH, and corticosterone (B), CRF concentrations in the median eminence (ME), the remainder of the hypothalamus (rHY) and the neurointermediate lobe of the pituitary (NIL). We also measured Iodine-125-labeled ovine CRF ([¹²⁵I]oCRF) binding in the brain and peripheral tissues. Body and thymus weight in WBN/Kob rats were significantly lower than in control Wistar rats, but adrenal weight was higher in WBN/Kob rats. Plasma ACTH levels were significantly higher in WBN/Kob rats than in the control rats. However, plasma CRF, AVP and B levels in WBN/Kob rats were not different from those in the control rats. The CRF concentration was significantly decreased in the ME of the diabetic rats, compared with control rats, but CRF concentrations in the rHY and NIL were unchanged in the two groups. A significant reduction in [¹²⁵I]oCRF binding in the anterior pituitary was demonstrated in WBN/Kob rats, but no significant difference between the diabetic and control rats in CRF binding was observed in the frontal cortex, spleen or adrenal gland. These findings suggest that the HPA axis is chronically stimulated in the non-insulin dependent diabetic rats.

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Corticotropin releasing hormone (CRH) and ACTH concentrations in plasma and CRH and IL-6 concentrations in synovial fluid in patients with rheumatoid arthritis (RA) were examined to clarify the relationship between cytokines and the hypothalamic-pituitary-adrenal axis (HPA axis). Concentrations of serum amyloid A protein (SAA), one of the acute phase proteins, were also measured as an indicator of inflammation. CRH and IL-6 concentrations in synovial fluid were higher in RA patients than in control patients (osteoarthritis, OA). Plasma ACTH and CRH levels were significantly lower in RA patients than in OA patients. This suggests that CRH secretion in synovial fluid is regulated differently from plasma CRH secretion, as CRH levels in synovial fluid and plasma showed opposite changes in RA patients. SAA levels were positively correlated with the levels of CRH or IL-6 in synovial fluid, whereas there was no correlation between CRH and IL-6 levels. The results suggest that CRH and IL-6 play important independent roles in producing SAA in synovial fluid.

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