Studies on the low dose suppressible Cushing's disease.

Diagnosis of Cushing's disease in most cases can be established by the standard dexamethasone suppression test without difficulty. However, some cases were known to be normally suppressed by the standard low dose of dexamethasone (2 mg daily). The case we encountered recently was also normally suppressed by either the rapid (Nugent) or the standard (Liddle) method. This fact prompted us to study the usefulness of a single dose of 0.5 mg of dexamethasone to suppress the plasma cortisol in the normal. It was concluded that the single oral dose of 0.5 mg of dexamethasone given at 11 p.m. on the previous night suppressed the plasma cortisol efficiently the following morning in the normal, thus making the differentiation of particular cases of Cushing's disease from the normal possible. The disappearance of plasma dexamethasone did not differ significantly between the normal and the Cushing's disease.     

Treatment of Cushing's disease with low dose radiation therapy.

Nineteen patients with Cushing''s disease were treated with low dose external pituitary irradiation (20 Gy (2000 rad) in eight fractions over 10 days). While awaiting the effects of pituitary irradiation all patients were treated with metyrapone. Seven patients had a complete remission of their disease within six to 12 months of irradiation. They did not require any further treatment and were followed up for a mean of three and a half (range one to eight) years. Another patient had a complete remission after a second course of pituitary irradiation. A further two patients showed a significant biochemical improvement after irradiation, although they were not rendered eucorticoid. There were no complications after this dose of irradiation. These results compare favourably with those reported after pituitary irradiation at conventional doses (40-50 Gy (4000-5000 rad) over four or five weeks) but were not associated with any complications. It is therefore recommended that low dose external pituitary irradiation be used as definitive first line treatment for Cushing''s disease.     

Cortisol-suppressible dexamethasone-nonsuppressible cyclic Cushing's disease with evidence of clinical and biochemical remission with bromocriptine.

We report a rare case of a 57-year-old female patient with Cushing's disease who had clinically and biochemically proven cyclicity. There were periodic increases in plasma ACTH and cortisol and urinary free cortisol and 17-OHCS. Plasma CRH was undetectable and plasma ACTH responded to exogenous CRH when basal plasma cortisol was relatively low. Neither plasma ACTH nor cortisol responded to dexamethasone (oral and intravenous) but plasma ACTH was clearly suppressed by cortisol infusion. With 40 mg/day bromocriptine, the periodic hypercortisolemia disappeared and the patient was maintained on remission. The response of plasma cortisol to dexamethasone suppression test was also normalized.     

In vivo and in vitro studies in a patient with cyclical Cushing's disease showing some responsiveness to bromocriptine.

In vivo and in vitro studies were carried out in a 37-year old female with cyclical Cushing's disease. Preoperative studies revealed periodic secretions of urinary corticosteroids occurring with a cyclicity of 2-3 weeks. On transsphenoidal surgery, a microadenoma was visualized in the anteroinferior portion of the anterior pituitary. Gel filtration analyses of the adenoma and surrounding tissues revealed increased concentrations of beta-endorphin and an activated conversion of beta-lipotropin to beta-endorphin in the adenoma compared with the surrounding tissues. These findings were in agreement with the characteristics previously reported for corticotroph adenomas. However, unexpectedly, concentrations of ACTH and beta-lipotropin in the adenoma were only slightly higher than those in the surrounding tissues. Precise mechanisms underlying this unusual finding were elusive, but it may have been due to the periodic nature of her hypercortisolism. In addition, this patient was reproducibly responsive to bromocriptine (2.5 mg, per os) with a reduction of the plasma cortisol level. Although this may suggest an intermediate lobe subtype of Cushing's disease as proposed by Lamberts' group, our case did not have any other characteristic suggestive of this proposed variant. However, it is tempting to speculate that cyclical changes in the central dopaminergic tone may have been at least a partial trigger for the periodic hormonogenesis in this patient.     

Successful treatment of Cushing's disease using yttrium-90 rods.

Interstitial irradiation using yttrium-90 (90Y) rods implanted by needle into the pituitary gland was used as primary treatment in 16 patients with pituitary dependent Cushing''s disease. Clinical and biochemical remission was observed within three or six months in 13 and in the remaining three after a supplementary implant. There was no perioperative morbidity. Follow-up from the time of definitive operation ranged from six to 123 months (mean 39). No recurrence has been observed. The return of a normal diurnal cortisol rhythm has been observed in 10/12 patients studied after remission. Some form of long-term pituitary hormone replacement therapy was required in only the six patients who had received the largest irradiation dose. Implantation of 90Y is safe and effective treatment for patients with Cushing''s disease, comparing favourably with selective trans-sphenoidal pituitary surgery.     

Reduction of pituitary tumor size with clinical and biochemical improvement with bromocriptine in a normoprolactinemic Cushing's disease

We report a 37-year old Japanese female patient with Cushing's disease who was treated with a large daily dose of bromocriptine, which resulted in the reduction of the pituitary tumor size with clinical and biochemical improvements. On admission, the pituitary tumor size detected by magnetic resonance imaging (MRI) was 12.4 x 11.1 x 6.2 mm. Both the basal plasma prolactin level and its response to TRH test were normal. The patient was treated with bromocriptine at 5 to 35 mg/day. With 35 mg daily, 24-h urinary free cortisol started to decrease and eventually became normal. Four months after initiation of treatment with the drug, there was clinical remission with normalization of suppressibility of plasma cortisol with 1 mg dexamethasone. Repeated examination of the pituitary fossa by MRI showed a marked reduction in the tumor size (6.3 x 6.2 x 2.4 mm). This is a very rare case in which treatment with bromocriptine resulted in a reduction of the pituitary tumor size as well as clinical and biochemical improvements in a patient with normoprolactinemic Cushing's disease.     

Neurochemical and motor effects of high dose haloperidol treatment: exacerbation by tryptophan supplementation.

The neurochemical and motor effects of a high dose (25 mg/kg) of haloperidol were assessed in male Sprague-Dawley rats. In Experiment 1, this high dose of haloperidol caused dramatic increases in striatal dopaminergic and serotonergic turnover that only returned to control levels 100 hr after injection. In the second experiment, the same dose of haloperidol was administered twice over a 3-week interval in the presence or absence of a dietary tryptophan supplement added to the drinking water. Rats were assessed for disruption of locomotor behavior (using the rotorod) as well as the occurrence of spontaneous (dyskinetic-like) chewing and head twitching. It was observed that haloperidol impaired rotorod performance in a manner that paralleled the time course of the neurochemical changes in Experiment 1. In addition, the tryptophan (consumed at an average of 157 mg/kg/day) exacerbated the deficit in rotorod performance in haloperidol-treated rats after the first, but not after the second, haloperidol injection. Finally, the combination of haloperidol plus tryptophan was found to cause a long-lasting increase in spontaneous chewing movements that lasted 56 days after the first injection. These observations are interpreted in the context of tryptophan supplementation to antipsychotic therapy.     

Desferrioxamine B: reversible side effects of high daily doses.

16 patients with chronic liver or haematologic diseases were parenterally given various doses of Desferrioxamine B (DF). Each daily dose of DF (from 1 to 4 g) was given for a 7 days cycle. Liver, kidney and blood functions were investigated at the first and seventh day of each cycle, and 1 and 2 weeks after therapy was stopped. 1 g/day and 2 g/day had no side effects, with the exception of a fall of white blood cell (WBC) count in a single case on 2 g/day. 3 g/day (15 patients) were followed by rises of blood urea, creatinine, alkaline phosphatase and glutamyl-transpeptidase respectively in 4 cases, and by falls of WBC count in 3 cases. 4 g/day (9 patients) caused rises of creatinine, GPT and GOT (1 case) or LDH (1 case), while WBC count dropped in 4 cases. All changes were reversible within one-two weeks. These recorded changes were outside the range of pretreatment values as obtained over the previous four weeks.     

Beneficial effects of estrogen treatment in the HLA-B27 transgenic rat model of inflammatory bowel disease

A well-established model of bowel inflammation is the HLA-B27 transgenic rat that exhibits a spontaneous disease phenotype resulting in chronic diarrhea caused by immune cell activation. Estrogens have previously been shown to modulate the immune system, and both estrogen receptors (ERalpha and ERbeta) are present in the intestine and cells of the immune system. Therefore, the ability of estrogen to ameliorate disease progression in the HLA-B27 transgenic rat was determined. HLA-B27 transgenic rats with chronic diarrhea were treated with 17alpha-ethynyl-17beta-estradiol (EE) for 5 days. EE treatment dramatically improved stool scores after only 3 days. Histological scores of the degree of ulceration, inflammatory cell infiltration, fibrosis, and lesion depth of the colon were also improved by EE treatment. Because neutrophil infiltration into the colon is involved in the development and propagation of disease, myeloperoxidase (MPO) activity was measured. MPO levels were reduced by 80% by EE treatment. Cotreatment with the pure ER antagonist ICI-182780 (ICI) blocked the effects of EE on stool character, MPO activity, and histology scores, strongly suggesting that the activity of EE is mediated through ER. Mast cell proteases can promote neutrophil infiltration, and gene expression analysis demonstrated that mast cell protease 1, 3, and 4 mRNA were all decreased in colons from estrogen-treated rats. In addition, a direct effect of estrogen on bone marrow-derived mast cell activity was demonstrated, suggesting that ER-mediated inactivation of mast cells may contribute to the improvement in the clinical sign and histological scores in this model.     

Long-term treatment of acromegaly with bromocriptine.

Seventy-three patients with active acromegaly were treated for three to 25 months with bromocriptine 10-60 mg/day. Seventy-one patients showed symptomatic and objective clinical improvement. This included reduction in excessive sweating, hand and foot size, and the number of headaches; improved facial appearance; and increased energy and libido. Abnormal visual fields became normal in two patients, one of whom had concomitant radiotherapy. Mean circulating growth hormone levels, obtained by averaging serial samples through the day, fell by more than 7 microng/l or became undetectable in 58 patients (79%) but did not reach normal values: only 15 patients had mean levels on treatment of 5 microng/l or less. Twenty-three patients were diabetic before treatment, and glucose tolerance became normal in 15 and improved in a further five. Provided the drug was started slowly side effects were minor when compared with the considerable clinical benefit obtained.     

Metyrapone in long-term management of Cushing's disease.

Metyrapone was used in the long-term management of 13 patients with pituitary-dependent bilateral adrenal hyperplasia (Cushing''s disease). The total length of treatment ranged from two to 66 months, with a mean of 21 months. The clinical features of the disease rapidly improved on metyrapone and this improvement was maintained. Although plasma ACTH concentrations rose in all patients, the increase was insufficient to overcome the adrenal blockade induced by the drug. Eight of the 13 patients had additional external pituitary irradiation as definitive treatment of their disease and one underwent a transfrontal hypophysectomy. Radiotherapy cured one patient, and after three years metyrapone was withdrawn. Slight hirsuties was noted in four of the seven women who received the drug for six months or more. A fifth woman had more severe hirsuties and this led to bilateral adrenalectomy. Other than hirsuties, side effects were few and the routine use of metyrapone is recommended as an adjunct to more definitive treatment in all patients who present with Cushing''s syndrome, irrespective of aetiology.     

Regulation of glucocorticoid receptors in human mononuclear cells: effects of glucocorticoid treatment, Cushing's disease and ketoconazole

Glucocorticoid receptors (GcR) were determined by a whole cell assay in human mononulear leukocytes (hMNL) from control subjects, patients receiving glucocorticoid therapy for systemic diseases and Cushing's disease patients with or without ketoconazole therapy. Prolonged corticosteroid treatment resulted in down-regulation of GcR, while the mean level of GcR in Cushing's disease was normal. In this group, however, receptor levels and morning plasma cortisol values showed a negative correlation, indicating a subtle down-regulatory effect. Furthermore, GcR were unaltered after these patients received ketoconazole, in spite of a marked reduction in morning plasma cortisol and urinary free cortisol. We also observed that ketoconazole was a weak competitor of GcR in intact cells, although it significantly inhibited [3H] dexamethasone binding in cytosolic preparations from rat tissues. The results suggested that GcR in hMNL are down-regulated by synthetic steroids given in vivo, but they showed very mild down-regulation in hypercortisolemic patients suffering from Cushing's disease. Finally, we did not observed either up-regulation or antagonism of GcR by ketoconazole treatment, at the time that cortisol levels of patients with Cushing's disease were reduced. This indicates that the beneficial effects of ketoconazole in Cushing's disease are due to adrenal cortisol suppression and not to interaction with GcR of target cells, and that the process of GcR regulation in hMNL is a complex phenomenon awaiting further elucidation.     

Equivalent inhibition of in vivo platelet function by low dose and high dose aspirin treatment

In vitro platelet function was inhibited in healthy volunteers by two different doses of aspirin, as confirmed by measurement of maximum serum production of thromboxane B2 (TXB2) by platelets. 75 mg aspirin did not fully inhibit serum TXB2 production after 24 hours, whereas 300 mg aspirin did. Inhibition of platelet function in vitro was maintained by both 75 mg/day aspirin or 300 mg/alternate day aspirin. In contrast, in vivo production of TXB2, measured as urinary levels of the 11-keto-TXB2 metabolite, was inhibited similarly by both doses of aspirin throughout the study. These findings suggest that 75 mg/day aspirin may be sufficient adequately to inhibit platelet aggregation in vivo.     

Long-term bromocriptine treatment and somatostatin in acromegaly

9 active acromegalic patients were treated for 12 months with bromocriptine (Parlodel, Sandoz) in a daily dose of 10 mg, and at the end of this treatment a somatostatin infusion was administered. The glucose tolerance and the serum hGH level were determined, and the changes in the clinical symptoms were evaluated. 7 patients (responder group) reacted favourably to the treatment; the other 2 proved to be non-responders, the hGH increasing as a consequence of bromocriptine treatment. The non-responders were among those patients who reacted to hyperglycaemia with a hGH increase (paradox glucose response). The somatostatin infusion employed in the drug treatment caused a very drastic decrease in the hGH level. The biochemical and clinical changes were not synchronous. The results permit the conclusions that (1) a relatively small dose of bromocriptine has a very good effect in the large majority of acromegalic patients; (2) the behaviour of the glucose response is an important point in the differentiation of the non-responders; (3) with somatostatin infusion during bromocriptine treatment a further considerable hGH decrease may be induced (a role is presumably played in the effect by the substitution of the hypothalamically drug-inhibited somatostatin release by exogenous material); (4) there is not a close parallel between the hGH decrease on bromocriptine treatment and the clinical improvement, which indicates the significance of the peripheral effects of the drug.