The hypothalamo-neurohypophyseal system as well as the autonomic nervous system is involved in homeostatic responses associated with changes in head position and orthostatic reflex. The responses induced by body tilt on earth are thought to be attributed to changes in inputs from baroreceptors, vestibular organs and proprioreceptors that are normally required for postural control. The information from these organs is sent to the hypothalamus which thereby influences both neuroendocrine and autonomic systems as well as various kinds of emotional behavior. Our findings showing the fastigial input to the hypothalamus suggested that the FN plays a significant role in these homeostatic responses through its connections with the brain stem and the hypothalamus. Figure 4 shows the input-output organization among the hypothalamus, cerebellum and brain stem, described in detail in sections III to V. This hypothesis may help to account for the autonomic and endocrine disorders often observed in weightlessness.

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To elucidate the short-term effects of octreotide, a somatostatin analogue, on glucose tolerance in acromegaly, the plasma glucose and insulin responses to a 75-g oral glucose tolerance test (75-g OGTT) were examined in 6 patients. The glucose disposal rate (GDR) was also measured by the hyperinsulinemic euglycemic clamp method before and after the administration of octreotide. Before octreotide therapy, 2 patients had normal responses of plasma glucose and insulin to 75-g OGTT (normal glucose tolerance: NGT) and 4 showed hyperinsulinemia or glucose intolerance (glucose intolerance: GIT). GDR-insulin dose-response curves showed a normal pattern in patients with NGT and pattern of insulin resistance in patients with GIT. After 2-3 weeks of octreotide administration, plasma growth hormone (GH) levels decreased in all of the patients. The plasma glucose response to 75-g OGTT was not changed in any patient. In contrast, the plasma insulin response to 75-g OGTT was enhanced in patients with NGT but lessened in patients with CIT. Patients with NGT showed no significant change in GDR-insulin dose-response curves. Patients with GIT showed improvement in GDR at low levels of plasma insulin, but did not show complete improvement at high levels. These results indicate that octreotide improves insulin resistance at the insulin receptor site by lowering plasma levels of CH and insulin in acromegalic patients with glucose intolerance.

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The aims of this study were to determine the change in the rate of insulin-stimulated glucose disposal (insulin sensitivity) and the ability of insulin to inhibit its own secretion in four pancreas-kidney transplant recipients with insulin-dependent diabetes mellitus. Insulin sensitivity (glucose infusion rate, GIR) was measured by a euglycemic hyperinsulinemic clamp technique before and 2, 6 and 12 months after transplantation. The GIR values in the four recipients were normalized within 2 months and remained normal for 12 months after transplantation, despite long-term steroid therapy for immunosuppression. Physiological hyperinsulinemia (50-70 μU/ml) suppressed plasma C-peptide, but its nadirs were still higher than the basal levels in normal controls. Taking into account evidence of a minimal increase in the concentration of circulating insulin that inhibits insulin secretion in healthy subjects and evidence of increased insulin secretion in pancreas recipients, the authors speculate that defective feedback inhibition of insulin secretion could contribute, at least in part, to the disproportionate basal hyperinsulinemia in patients with a denervated, transplanted pancreas in the absence of insulin resistance.

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The kinetics of type III iodothyronine deiodinase (5-D) in rat placenta and brain and the role of phospholipids in enzyme activity were determined. Pregnant Sprague-Dawley rats were given either vehicle (control group) or T₄ (15μg/100g bw/day; hyperthyroid group) from the 14th to the 21st day of gestation. Mitochondrial-microsomal fractions of the placenta and brain were used as the source of T₄ 5-D. Placental T₄ 5-D activity in the hyperthyroid group was increased when determined at 13nM T₄, but it was not significantly different from the control value when assayed at 1.3μM T₄. In contrast, T₄ 5-D in the brain was significantly increased in the hyperthyroid group regardless of the substrate concentration. Hyperthyroid rats showed decreased Km for placental 5-D and increased Vmax for brain 5-D. CM-Sephadex chromatography of solubilized placental microsomes was performed to determine whether phospholipids cause a reduction in the Km of placental 5-D in hyperthyroid rats. T₃ 5-D activity was undetectable unless protein-containing fractions were combined with phospholipid-containing fractions in the reaction mixture. Kinetic studies revealed that phospholipids had no effects on either Km or Vmax of placental T₃ 5-D. These data indicate that 5-D activity in the rat placenta is increased in hyperthyroidism with different kinetic changes from those in the brain, and that phospholipids have no effects on the kinetic parameters of placental 5-D whereas they are essential for the enzyme activity.

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It has been reported that tumor necrosis factor-α (TNF-α) derived from luteal macrophage is concerned with luteolysis. In the present study, to evaluate the correlation between TNF-α and regression of luteal blood vessels, recombinant human TNF-α (rh-TNF) was injected into the parenchyma of pseudopregnant rabbit ovaries. These injections were performed on day 7 of pseudopregnancy (functional luteal phase). Only Mg⁺⁺ and Ca⁺⁺ free phosphate buffer saline (PBS-) as the solvent was injected in the control group. Estimations of conditions in the luteal vessels after the injections was performed by observations of luteal vascular corrosion casts under a scanning electron microscope. Concentrations of serum progesterone before or after the injection were also assayed. In the control group, no change in the structure of luteal vessels was observed after PBS- injection, but regressing blood vessels with strictures, obstructions and rugged surfaces on the vessels were observed, and also concentrations of serum progesterone decreased noticeably after rh-TNF injection. These findings suggest that TNF-α plays a role in angiolysis through luteolysis in the rabbit corpus luteum.

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To evaluate surgical and medical treatment of GH-producing pituitary tumors and GH supplement to GH-deficient patients, we determined the reference values for serum IGF-I in Japanese adults. The serum IGF-I concentration in 454 apparently healthy subjects (246 men aged 21-70 years and 208 women aged 21-72 years) was measured with a commercial RIA kit after acid-ethanol extraction. The concentration of serum IGF-I decreased with age in both sexes. The IGF-I in females was significantly higher than that in males in the group aged 21-30 years and lower in the group aged 61-72 years. We conclude that an age- or sex-related standard is necessary for comparing IGF-I values in patients.

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The cytologic localization and cellular levels of tumor necrosis factor-α (TNFα) in the human ovary during follicular growth and regression were examined by the avidin/biotin immunoperoxidase method with a specific antibody to human recombinant TNFα. In the infant ovary, TNFα immunostaining was present only in the oocyte within the primordial follicles. TNFα immunostaining was also present within the oocyte in primordial follicles of the adult ovary. Positive immunostaining for TNFα in granulosa cells became apparent in preantral follicles, while that in theca interna cells began to appear at the antral follicle stage. The staining intensity of the oocyte increased as the oocyte reached the preovulatory stage. The intensity of immunostaining for TNFα in the granulosa and thecal cells increased as the follicle became larger and matured. In corpora lutea, the immunostaining for TNFα persisted in the granulosa lutein and theca lutein cells and intensified in the mid luteal phase. In the regressing corpora lutea, TNFct immunostaining in the luteal cells decreased as the regression advanced. Regressed corpora lutea with a central core of scar tissue were bordered by macrophage-like cells which exhibited intense immunostaining for TNFα. In the cortex region, the corpus albicans was negative for TNFα immunostaining, whereas macrophage-like cells peripheral to the corpus albicans exhibited intense immunostaining for TNFα. In the medullary region, the corpus albicans and surrounding stromal cells were totally negative for TNFα. By contrast, in the early atretic stage, the degenerating oocyte showed weak immunostaining for TNFα, while the granulosa and theca interna cells showed moderate immunostaining for TNFα. In the late atretic stage, the immunostaining for TNFα in the scattered granulosa cells became negligible, whereas the theca interna cells showed intense immunostaining for TNFα. The results obtained indicate that the oocyte is the primary intrafollicular site of TNFα localization within the ovary and that TNFα may participate in regulating follicular growth, regression and aresia.

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Sixty-four patients with acromegaly were retrospectively analyzed to study the incidence and cause of hypertension in acromegaly. WHO criteria indicate that 37.5% patients with acromegaly have hypertension. The blood pressure was positively correlated with age, the insulin-like growth factor I (IGF-I) and serum sodium (Na) concentration. In addition, IGF-I and Na were significantly different in hypertensive and normotensive groups. Seventy-five percent of hypertensive patients had a family history of hypertension. IGF-I, Na and blood pressure were significantly higher in patients with a family history of hypertension than in those without it. In patients with a family history of hypertension, blood pressure was positively correlated with IGF-I and serum Na, but IGF-I was not correlated with serum Na. In patients without such a family history, blood pressure had a good correlation only with age, and IGF-I was not significantly correlated with blood pressure. In addition, the incidence of hypertension in this group was the same as or lower than that in the general population. The above results suggest that the genetic factor produces hypertension in acromegaly by two ways, by increasing Na and enhancing IGF-I production by GH.

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Expression of gonadotropin-releasing hormone (GnRH) gene in the hypothalamus of female rats was studied by the quantitative reverse transcription-polymerase chain reaction (RT-PCR) method. During the estrous cycle, the GnRH mRNA level did not change from diestrus I to II, and then increased with a peak at 1100h on proestrus. In the afternoon of proestrus, GnRH mRNA decreased rapidly with a nadir at 1600h, and thereafter increased again and reached a peak at 1100h on estrus. Since hypothalamic GnRH mRNA was found to be increased by subcutaneous implantation of estradiolcontaining silastic tubing in ovariectomized rats, the peak of GnRH gene expression in the proestrous morning might be due to an increase in circulating estrogen in this phase of the estrous cycle. The surge of luteinizing hormone in the proestrous afternoon and the subsequent increase in GnRH mRNA were completely blocked by the injection of MK801, an antagonist for NMDA receptors, suggesting that the excitation of GnRH neurons leads to an increase in GnRH gene expression. This was further supported by the in vitro observation that high K⁺-induced membrane depolarization markedly increased GnRH mRNA in hypothalamic slices. This increase in GnRH mRNA due to neuronal excitation does not seem to require newly synthesized proteins because anisomycin, a protein synthesis inhibitor at the level of translation, did not affect GnRH gene expression. These results suggest that the hypothalamic GnRH mRNA level reached two peaks during the rat estrous cycle, i.e., in proestrous morning and estrous morning, and that estrogen and GnRH neuronal excitation play pivotal roles in regulating GnRH gene expression.

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We have examined healthy women (51 premenopausal women and 30 postmenopausal women; age 28-59) for lumbar bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) and assessed metabolic bone markers, such as type I procollagen carboxy-terminal propeptide (P1CP), pyridinoline (PYR), deoxypyridinoline (DPYR), osteocalcin (BGP) and alkaline phosphatase (ALP). BMD was assessed once a year in three consecutive years. Correlations among the BMD, BMD changes and levels of bone markers in samples at the first DXA assessment were studied. In pre-menopausal women, none of the biochemical markers were correlated with the BMD or changes in BMD. In contrast, BMD in post-menopausal women correlated (negatively) well with levels of P1CP, DPYR, PYR and ALP declining in this order, and a significant positive correlation was observed between the rate of bone loss in postmenopausal women and the P1CP concentration. PYR and DPYR also had a tendency to correlate. Combinations of several bone markers improved the correlation. These results show that by measuring several bone specific biochemical markers in postmenopausal women, one can estimate their rates of bone loss as well as their present BMDs. The measurement of biochemical bone markers will therefore be very useful in evaluating bone status and would be applicable in screening postmenopausal osteopenia.

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A 68-year-old woman was admitted to our hospital for severe normochromic and normocytic anemia. She had a history of prolonged postpartum hemorrhage at the age of 20yr. Her menses were resumed thereafter and she gave birth to two other children, but her lactation was poor. She had no subjective symptom until the age of 63yr when she complained of weakness and cold intolerance. Laboratory examination at admission revealed severe anemia (Hb 7.2 g/dl) with relatively low serum erythropoietin (EPO 20.4mIU/ml) and panhypopituitarism. Empty sella was also found by magnetic resonance imaging (MRI). Hb levels were corrected by replacement with levothyroxine (75μg/day) and hydrocortisone (10mg/day), which was accompanied by an increase in serum EPO levels. These findings indicate that this is a very rare case of Sheehan's syndrome with severe anemia and empty sella proved at the longest reported interval of 48yr after the provoking delivery, and that serum EPO levels are increased by replacement with glucocorticoid and thyroxin in panhypopituitarism.

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The case of a 55-year-old woman with inappropriate secretion of anti-diuretic hormone (ADH) is reported. Her pituitary-adrenocortical function test showed normal values on admission, but when she recovered from hyponatremia, severe panhypopituitarism became overt. Her adrenal insufficiency was considered to have been “masked” by endogenous stimulation of the hypothalamus-pituitary-adrenal axis under severe stress. One should be cautious in estimating the pituitary-adrenal function of severely ill patients.

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Present study was planned to clarify the effects of GH and insulin-like growth factor I (IGF-I) on testosterone secretion using premature male rats. Forty rats were divided four groups. GH, IGF-I, both of them or normal saline solution as control were subcutaneously administered to the rats of each group for seven days from 3-week to 4-week of age. After the treatment, six of each group were used to human chorionic gonadotropin (hCG) loading and four to Leydig cell preparation. Serum testosterone responses to hCG loading were significantly higher in 4-week-old rats treated with GH and/or IGF-I for 1 week than in control rats. However, the responses were similar among three treated groups (GH, IGF-I and both). After one-week treatment with GH and/or IGF-I, isolated Leydig cells were prepared from testes of 4-week-old rats and testosterone production by the stimulation of hCG was examined. Amounts of testosterone production stimulated by hCG were significantly greater in the treated rats than in control rats. These findings suggest that GH mediated by IGF-I promotes the testicular responsiveness to gonadotropin on testosterone production in premature rats.

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A fifty-year-old woman was admitted to our hospital because of palpitation and general fatigue. She had received hemithyroidectomy for thyroid papillary adenocarcinoma at 28 years of age. She had experienced episodes of repeated painless thyroiditis five times over the last 12 years. At her sixth episode of thyrotoxicosis, she was suspected to have Graves' disease and admitted to our hospital. Laboratory findings revealed thyrotoxicosis with positive thyroid stimulating antibody and high radioactive iodine uptake, i.e. Graves' disease. Painless thyroiditis often relapses but rarely develops into Graves' disease. This is a rare case in which repeated painless thyroiditis was followed by Graves' disease. The relation between painless thyroiditis and Graves' disease is discussed.

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