A case of acromegaly accompanied by adrenal preclinical Cushing's syndrome.

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.

A hypopituitary patient who attained tall stature without growth hormone.

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.

Evidence that a fast, rate-sensitive negative feedback effect of corticosterone is not a principal mechanism underlying the indomethacin inhibition of interleukin-1 beta-induced adrenocorticotropin secretion in the rat.

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.

A comparative study of adrenocorticotropin-releasing activity of prostaglandins E1, E2, F2 alpha and D2 in the rat.

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.

A study on the role of circulating prostaglandin E2 in the adrenocorticotropin response to intravenous administration of interleukin-1beta in the rat.

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.

A case of cyclical Cushing's disease associated with corticosteroid-binding globulin deficiency: a rare pitfall in the diagnosis of Cushing's disease.

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.

Lack of involvement of the cholinergic mechanism in vasoactive intestinal peptide- and peptide-histidine methionine-induced growth hormone (GH) responses in acromegaly: comparison with the GH responses to thyrotropin-releasing hormone and GH-releasing hormone.

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.

Neuropeptide Y potentiates the luteinizing hormone (LH) response to LH-releasing hormone in men.

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.