R Nasushita

Hirosaki University, Khirosaki, Aomori, Japan

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Publications (12)32.08 Total impact

  • [Show abstract] [Hide abstract] ABSTRACT: We encountered a 58-year-old woman with acromegaly accompanied by a cortisol-secreting adrenal tumor without clinical features of hypercortisolism. The simultaneous occurrence of these two endocrinopathies in one individual is extremely rare. She was diagnosed as having diabetes mellitus 8 years ago. Afterwards, in spite of insulin therapy, her hyperglycemia could not be well controlled. Her acromegaly and preclinical Cushing's syndrome were histopathologically proven to be due to a pituitary adenoma and an adrenocortical adenoma, respectively. Successful treatment for these endocrinopathies resulted in greatly improved blood sugar control because of a reduction in insulin resistance. In this case of preclinical Cushing's syndrome, replacement therapy with glucocorticoid was able to be discontinued at only 8 weeks after adrenalectomy, so that the period of necessary replacement was much shorter than that for overt Cushing's syndrome. This is the first report describing insulin resistance before and after treatment in a case of acromegaly accompanied by adrenal preclinical Cushing's syndrome.
    No preview · Article · Mar 1999 · Endocrine Journal
  • [Show abstract] [Hide abstract] ABSTRACT: A number of previous studies have concluded that prostaglandins (PGs) play a crucial role in mediating the corticotropin-releasing hormone and adrenocorticotropin (ACTH) secretion induced by interleukin (IL) 1 beta in the rat. This is mainly based on a significant inhibitory effect of indomethacin, a cyclooxygenase inhibitor, on the hormonal response. However, there is one previous study which reported that such an inhibitory action of indomethacin on ACTH secretion is mediated principally by a fast, rate-sensitive negative feedback effect of corticosterone which increases after indomethacin injection, rather than by a decrease in PG production. In order to have a better understanding of this unresolved issue, in the present study the authors compared the effects of two different time intervals (10 or 20 min) between the intravenous injections of indomethacin (10 mg/kg body weight) and of recombinant human IL-1 beta (3 micrograms/kg body weight) on the cytokine-induced ACTH secretion in male rats. Although IL-1 beta-induced ACTH response was significantly suppressed by indomethacin given either 10 or 20 min before, the latter protocol led to a significantly greater inhibition of the hormonal response than the former. However, between the two groups, the rising slope of corticosterone from -20 or -10 min to time zero and that from time zero to 10 min after IL-1 beta injection were statistically indistinguishable. There results strongly suggest that the fast, rate-sensitive negative feedback effect of corticosterone may not be a principal mechanism whereby indomethacin inhibits IL-1 beta-induced ACTH secretion in the rat. It was concluded that such an action of indomethacin is primarily mediated by its inherent pharmacological action, i.e. the inhibition of endogenous PG production.
    No preview · Article · Jun 1998 · Cytokine
  • [Show abstract] [Hide abstract] ABSTRACT: We describe an unusual patient with hypopituitarism who attained tall stature even without growth hormone (GH). A 37-year-old man was devoid of secondary sexual characteristics, but manifested tall stature with a eunuchoidal feature. Serum levels of GH, insulin-like growth factor-I, gonadotropins and testosterone were all below normal. GH secretion was not enhanced by any provocative stimulus. Adrenocorticotropic hormone increased after administration of corticotropin releasing hormone, but not after insulin-induced hypoglycemia. Thyrotropin increased in response to thyrotropin releasing hormone, but both free T3 and T4 did not rise. Magnetic resonance imaging disclosed a transected pituitary stalk. The present patient had hypopituitarism due to perinatal problems but had grown with the aid of non-GH growth-promoting factors, which suggests that man may be able to achieve statural growth even without GH.
    No preview · Article · Jun 1998 · Internal Medicine
  • R Nasushita · H Watanobe · K Takebe
    [Show abstract] [Hide abstract] ABSTRACT: There is substantial evidence to indicate that prostaglandin (PG) E2 exerts a stimulatory effect on the hypothalamo-pituitary-adrenal axis in rodents. However, little is known regarding the possibility that other PGs play a similar role in regulating the endocrine axis. Therefore, in this study we compared the effects of intravenous administration of PGs E1, E2, F2 alpha and D2 on adrenocorticotropin (ACTH) secretion in conscious male rats. Each PG was administered at two doses of 0.1 and 1.0 mg/kg body weight, and blood samples were collected sequentially up to 120 min postinjection. Although PGD2 was without effect on ACTH secretion at either dose, PGs E1, E2 and F2 alpha all significantly stimulated the hormonal response at both doses. Interestingly, PGs E1, E2 and F2 alpha were largely equipotent in stimulating ACTH release. To the best of our knowledge, this is the first study to demonstrate significant ACTH-releasing activity of intravenously administered PGs E1 and F2 alpha in the rat. These results suggest that PGE2 might not be the only prostanoid playing a role in regulating the hypothalamo-pituitary-adrenal axis and, thus, multiple PGs may be involved in the endocrine axis.
    No preview · Article · Mar 1997 · Prostaglandins Leukotrienes and Essential Fatty Acids
  • R. Nasushita · H. Watanobe · K. Takebe
    [Show abstract] [Hide abstract] ABSTRACT: There is substantial evidence to indicate that prostaglandin (PG) E2 exerts a stimulatory effect on the hypothalamo-pituitary-adrenal axis in rodents. However, little is known regarding the possibility that other PGs play a similar role in regulating the endocrine axis. Therefore, in this study we compared the effects of intravenous administration of PGs E1, E2, F2α and D2 on adrenocorticotropin (ACTH) secretion in conscious male rats. Each PG was administered at two doses of 0.1 and 1.0 mg/kg body weight, and blood samples were collected sequentially up to 120 min postinjection. Although PGD2 was without effect on ACTH secretion at either dose, PGs E1, E2 and F2α all significantly stimulated the hormonal response at both doses. Interestingly, PGs E1, E2 and F2α were largely equipotent in stimulating ACTH release. To the best of our knowledge, this is the first study to demonstrate significant ACTH-releasing activity of intravenously administered PGs E1 and F2α in the rat. These results suggest that PGE2 might not be the only prostanoid playing a role in regulating the hypothalamo-pituitary-adrenal axis and, thus, multiple PGs may be involved in the endocrine axis.
    No preview · Article · Feb 1997 · Prostaglandins Leukotrienes and Essential Fatty Acids
  • H Watanobe · R Nasushita · K Takebe
    [Show abstract] [Hide abstract] ABSTRACT: It is almost generally agreed that prostaglandins (PGs), especially PGE2, may play a significant role in mediating corticotropin-releasing hormone (CRH) and adrenocorticotropin (ACTH) secretion by interleukin (IL)-1. The origin and site of action of PGE2 involved in this response appear to be within the brain, but the possibility has yet to be excluded that circulating PGE2, which increases after a systemic administration of IL-1, enters the brain to stimulate CRH and ACTH release. In this study, we attempted to answer the question utilizing in vivo experimental paradigms in conscious male rats. Intravenous bolus injection of recombinant human IL-1beta (3 mu g/kg) caused a prompt and robust rise in plasma ACTH (peak, 748 +/- 183 (-x +/- SE) pg/ml at 20 min), but this was not associated with a significant change in plasma PGE2 up to 120 min postadministration. Intravenous bolus injection of PGE2 at doses of 0.1 mg and 1.0 mg/kg BW resulted in dose-dependent significant elevations of the plasma ACTH with peak levels being 155 +/- 27 pg/ml (at 10 min) and 343 +/- 35 pg/ml (at 20 min), respectively. Peak PGE2 levels in the plasma which occurred 10 min after injecting either dose of PGE2 were 13,245 +/- 5,093 and 57,150 +/- 350 pg/ml, respectively. Thus the ACTH response which followed the plasma PGE2 levels of 13,000-57,000 pg/ml was even lower than the ACTH response to IL-1beta which did not cause a significant rise in the plasma PGE2. We conclude from these results that circulating PGE2 is not involved in the ACTH response to intravenous administration of IL-1beta. It is thus very likely that the source and site of action of PGE2 mediating the hormonal response are in the brain. However, this study does not exclude a possible role for other circulating PGs in the IL-1beta stimulation of ACTH secretion in the rat.
    No preview · Article · Jan 1996 · Neuroendocrinology
  • R. Nasushita · H. Watanobe · S. Sasaki · K. Takebe · T. Suda · H. Kudo
    [Show abstract] [Hide abstract] ABSTRACT: It is well established that interleukin (IL)-1 can activate the hypothalamo-pituitary-adrenal axis in the rat. It has been reported that the IL-1-induced adrenocorticotropin (ACTH) response was abolished or markedly suppressed by pretreatment with indomethacin, a cyclooxygenase inhibitor, and this effect of indomethacin has been ascribed to a reduced synthesis of prostaglandin (PG). However, Rivier and Vale have reported in 1991 that this inhibition by indomethacin may be mediated principally by a fast negative feedback effect of corticosterone, a hormone which rises after indomethacin, rather than by indomethacin-induced decrease in PG synthesis. Therefore, in this study, we attempted to examine this hypothesis. In addition, we examined a possible role of circulating PGE2 in the IL-1β-induced ACTH secretion, and also a possible ACTH-releasing activity of other PGs. Recombinant human IL-1β (3 μg/kg) was administered intravenously to the rats 10 or 20 min after giving indomethacin (10 mg/kg). The pretreatment with indomethacin was suppressive on the IL-1β-induced ACTH response regardless of the time interval between the indomethacin and IL-1β injections, but the effect of indomethacin was more marked when it was given 20 min before IL-1β than 10 min before. Even so, the initial rising slope of corticosterone after IL-1β injection was almost the same between the two protocols. Circulating levels of PGE2 did not change significantly after IL-1β injection. Among 4 kinds of PG comprising PGD2, PGE1, PGE2, and PGF(2α) for all of which we tested an ACTH-releasing activity, PGD2 was without effect, but all the remaining PGs were able to significantly stimulate ACTH secretion. These results suggest the following: The inhibitory effect of indomethacin on IL-1β-induced ACTH secretion may be mediated primarily via a reduced synthesis of endogenous PG rather than via a negative feedback effect of indomethacin-induced corticosterone on ACTH secretion. The principal sites of action and synthesis of PGE2 involved in the IL-1β-induced ACTH secretion are in the brain but not in the general circulation, and not only PGE2 but also PGE1 and PGF(2α) are potent stimulators of ACTH secretion.
    No preview · Article · Jan 1996
  • Hajime Watanobe · Ryo Nasushita · Kazuo Takebe
    [Show abstract] [Hide abstract] ABSTRACT: It is almost generally agreed that prostaglandins (PGs), especially PGE2, may play a significant role in mediating corticotropin-releasing hormone (CRH) and adrenocorticotropin (ACTH) secretion by interleukin (IL)-l. The origin and site of action of PGE2 involved in this response appear to be within the brain, but the possibility has yet to be excluded that circulating PGE2, which increases after a systemic administration of IL-1, enters the brain to stimulate CRH and ACTH release. In this study, we attempted to answer the question utilizing in vivo experimental paradigms in conscious male rats. Intravenous bolus injection of recombinant human IL-1β (3 μg/kg) caused a prompt and robust rise in plasma ACTH (peak, 748 ± 183 (x ± SE) pg/ml at 20 min), but this was not associated with a significant change in plasma PGE2 up to 120 min postadministration. Intravenous bolus injection of PGE2 at doses of 0.1 mg and 1.0 mg/kg BW resulted in dose-dependent significant elevations of the plasma ACTH with peak levels being 155 ± 27 pg/ml (at 10 min) and 343 ± 35 pg/ml (at 20 min), respectively. Peak PGE2 levels in the plasma which occurred 10 min after injecting either dose of PGE2 were 13,245 ± 5,093 and 57,150 ± 350 pg/ml, respectively. Thus, the ACTH response which followed the plasma PGE2 levels of 13,000-57,000 pg/ml was even lower than the ACTH response to IL-1β which did not cause a significant rise in the plasma PGE2. We conclude from these results that circulating PGE2 is not involved in the ACTH response to intravenous administration of IL-1β. It is thus very likely that the source and site of action of PGE2 mediating the hormonal response are in the brain. However, this study does not exclude a possible role for other circulating PGs in the IL-1β stimulation of ACTH secretion in the rat.Copyright © 1995 S. Karger AG, Basel
    No preview · Article · Dec 1995 · Neuroendocrinology
  • H Watanobe · T Nigawara · R Nasushita · S Sasaki · K Takebe
    [Show abstract] [Hide abstract] ABSTRACT: We experienced an extremely unusual combination of Cushing's disease and corticosteroid-binding globulin (CBG) deficiency that has been reported in only one similar case to date. A 53-year-old woman presented at a medical clinic with clinical Cushing's disease. However, her plasma levels of adrenocorticotropin (ACTH) and cortisol were in the normal range. Six months later, during a second visit, a high urinary excretion of 17-hydroxycorticosteroids was found, but plasma ACTH and cortisol levels were normal again. Further investigation revealed a decreased CBG concentration. Free plasma cortisol levels were clearly elevated. Furthermore, the Cushing's disease of our patient was complicated by periodic secretion of ACTH and cortisol, with high or normal outputs of corticosteroids occurring alternately every 1-3 days, which explained the occasionally normal plasma ACTH and cortisol levels. A combination of a decreased serum CBG concentration and periodic secretion of ACTH can be an important pitfall in the diagnosis of Cushing's disease.
    No preview · Article · Oct 1995 · European Journal of Endocrinology
  • H. Watanobe · T. Nigawara · R. Nasushita · S. Sasaki · K. Takebe
    No preview · Article · Sep 1995 · European Journal of Endocrinology
  • H Watanobe · S Habu · R Nasushita · K Takebe
    [Show abstract] [Hide abstract] ABSTRACT: We examined whether the cholinergic mechanism is involved in the paradoxical GH responses to vasoactive intestinal peptide (VIP) and peptide histidine methionine (PHM) in acromegaly. 28 patients with active acromegaly underwent i.v. bolus injections of thyrotropin-releasing hormone (TRH, 500 micrograms), GH-releasing hormone (GHRH, 100 micrograms), VIP (100 micrograms), and PHM (100 micrograms) with or without a prior atropine treatment (1 mg, i.m., 30 min before). Blood samples were collected before and at intervals up to 120 min after the injection, and plasma GH levels were measured. In response to TRH, GHRH, VIP and PHM, 23 (82%), 24 (86%), 13 (46%) and 7 (25%) patients, respectively, responded with a significant GH increase (> 50% and 6 micrograms/l above the basal level). The effect of atropine pretreatment was examined in only these responders to the respective peptides. When the GH responses were estimated by the area under the response curve, the atropine pretreatment was able to significantly suppress the GH response to GHRH, but not to TRH, VIP, or PHM. Although the lack of cholinergic involvement in the TRH-induced GH release in acromegaly is confirmatory to previous reports, the same results with the VIP- and PHM-induced GH release are novel. The present study may suggest that in acromegaly the physiological GH response is mediated by the cholinergic mechanism, but the paradoxical ones are not.
    No preview · Article · Aug 1994 · Neuropeptides
  • [Show abstract] [Hide abstract] ABSTRACT: It has been demonstrated in several animal species that neuropeptide Y (NPY) exerts a modulatory effect on luteinizing hormone (LH) secretion. However, whether NPY plays a similar role also in humans has yet to be determined. Therefore, in this study we examined the effect of human NPY on the anterior pituitary hormone secretion in 6 normal men. Intravenous bolus injection of 100 micrograms of human NPY alone did not affect the secretion of any anterior pituitary hormone or cortisol. However, when NPY (100 micrograms) was administered simultaneously with LH-releasing hormone (LHRH, 100 micrograms), a significant potentiation was observed for LHRH-induced LH secretion. Similarly, follicle-stimulating hormone (FSH) response to LHRH was slightly potentiated by the coadministration of NPY, although this effect was not statistically significant. This is the first study to demonstrate that NPY can augment the LHRH-induced LH secretion in humans.
    No preview · Article · May 1994 · Biochemical and Biophysical Research Communications