Treatment of Cushing's syndrome with large doses of reserpine

The effectiveness of high doses of reserpine was studied in two groups of patients, suffering from Icenko-Cushing's disease. The patients of the first group received gamma-beam therapy combined with high doses of reserpine. The patients of the second group were treated with gamma-beam radiation associated with unilateral adrenalectomy plus high doses of reserpine. The controls were treated as described above, but without reserpine use. The results obtained have shown that reserpine monotherapy is not recommended in Icenko-Cushing's disease. High doses of reserpine combined with gamma-beam radiation alone or coupled with unilateral adrenalectomy shortened the period of the appearance of remission. The arterial blood pressure was significantly lower in patients treated with high doses of reserpine.     

Evaluation and treatment of Cushing's syndrome

Cushing’s syndrome results from sustained pathologic hypercortisolism caused by excessive corticotropin (ACTH) secretion by tumors in the pituitary gland (Cushing’s disease, 70%) or elsewhere (15%), or by ACTH-independent cortisol secretion from adrenal tumors (15%). The clinical features are variable, and no single pattern is seen in all patients. Those features most specific for Cushing’s syndrome include abnormal fat distribution, particularly in the supraclavicular and temporal fossae, proximal muscle weakness, wide purple striae, and decreased linear growth with continued weight gain in a child. Patients with characteristics of glucocorticoid excess should be screened with measurements of saliva or urine cortisol or dexamethasone suppression testing. The diagnosis of Cushing’s syndrome should be followed by the measurement of plasma ACTH concentration to determine whether the hypercortisolism is ACTH-independent. In ACTH-dependent patients, bilateral inferior petrosal sinus sampling with measurement of ACTH before and after administration of ACTH-releasing hormone most accurately distinguishes pituitary from ectopic ACTH secretion. Surgical resection of tumor is the optimal treatment for all forms of Cushing’s syndrome; bilateral adrenalectomy, medical treatment, or radiotherapy are sought in inoperable or recurrent cases. The medical treatment of choice is ketoconazole. The prognosis is better for Cushing’s disease and benign adrenal causes of Cushing’s syndrome than adrenocortical cancer and malignant ACTH-producing tumors.     

Treatment of Cushing's disease with reserpine and pituitary irradiation.

Eighteen patients with Cushing's disease were treated with reserpine and pituitary irradiation. Complete remission was obtained in 9 out of 18 patients after reserpine treatment of 1-2 mg per day for a mean period of 20.4 months, and pituitary irradiation with a mean of 5,865 rads. In another 9 patients, reserpine 0.8-2 mg per day for a mean period of 22.5 months, and pituitary irradiation with a mean of 6,650 rads, were employed. Of these 9 patients, an additional subtotal adrenalectomy was carried out in 6 patients who are now in complete remission. Because of severe psychic symptoms resulted from the original disease in 2 of the remaining 3 patients, subtotal adrenalectomy was performed first and pituitary irradiation and reserpine treatment followed. Remission was eventually obtained in these 2 cases. One patient refused the operation, and thus had little clinical remission. All of the 17 cases in remission were followed up for periods of 6 months to 10 yr. During this time, only one case which had responded to reserpine and pituitary irradiation relapsed, but regained remission following resumption of therapy. Another died of cerebral glioblastoma 4 yr after remission of the disease. It was noteworthy that endocrinologic data including: plasma levels of ACTH and 11-OHCS, suppressibility by dexamethasone, responses of plasma GH to arginine and to insulin loads, and diurnal rhythm of plasma 11-OHCS were nearly normal in a considerable number of the cases in remission. Effectiveness of the combined therapy with reserpine and pituitary irradiation for treating Cushing's disease may support a working hypothesis that reserpine acts through some as yet unknown mechanism to correct a presumed central nervous disorder, while suitable pituitary irradiation probably corrects the pituitary dysfunction directly.     

Long-term treatment of central Cushing's syndrome with rosiglitazone.

CONTEXT: Central Cushing's syndrome is not always curable by surgery or radiation of the pituitary. Medical treatment is often not possible or effective. Some studies revealed beneficial effects of the PPARgamma (Peroxisome-Proliferator-Activator- Receptor-gamma)-agonist rosiglitazone (RG) in in vitro studies, animal models and short term clinical studies. OBJECTIVE: of this study was to observe the long-term effects of RG-treatment on cortisol- and ACTH -secretion, clinical outcomes and morphological changes of the pituitary in patients with persistent ACTH-overproduction despite previous operation and radiation. DESIGN, SETTING AND PATIENTS: 14 patients with persistent central ACTH -production were included and monitored over a period up to 12 months. RG was administered daily and increased to a maximum dosage of 24 mg daily, according to the response of ACTH and cortisol secretion. ACTH and cortisol were measured at least every 4 weeks during RG treatment. RESULTS: Patients were treated between 4 and 12 months with RG (mean 6.8 months). Compared to baseline, ACTH- and cortisol levels dropped significantly (p<0.01) after 12, 16, 20, 24 and 28 weeks but thereafter rose again during the study period, despite continuous RG- treatment and dose increase up to the maximum dosage. This was paralleled by reocurrence of clinical symptoms. MRI-scans were performed in 6 patients because of persisting visible adenoma, but showed no morphological changes. CONCLUSION: RG seems not to be a long-term treatment option for patients with persistent central ACTH-evcess. Though, in order to reduce perioperative complications, short term treatment of patients could be an alternative.     

The treatment of Cushing's syndrome and adrenal cancer.

Cushing's syndrome can be classified as either ACTH-dependent or ACTH-independent, and appropriate treatment depends on an accurate differential diagnosis as the treatment modality is different for each category. This article details the therapies now being used and their success rates.     

Long term follow-up of Cushing's disease treated with reserpine and pituitary irradiation.

Twenty adult patients with Cushing's disease treated with long term reserpine administration in combination with a single course of external pituitary irradiation were followed. Eleven patients experienced long term remissions of 15.5 +/- 8.9 (mean +/- SD) yr (55%) after a mean irradiation dose of 53.9 +/- 11.4 Gy and a mean duration of reserpine administration of 24.3 +/- 9.3 months. The long term remission rates of the patients irradiated with 50 Gy or less (n = 9; 45.0 +/- 7.1 Gy) and those with more than 50 Gy (n = 10; 61.3 +/- 3.3 Gy; excluding 1 irradiated with 66 Gy who developed brain necrosis) were 56% (5 of 9) and 60% (6 of 10), respectively, and did not differ significantly. There were no significant differences between the 2 groups with regard to the duration of reserpine administration or pretreatment clinical features. At the latest examination, regardless of the irradiation dose, all 9 patients with long term remission showed a higher level of plasma cortisol or 11-hydroxycorticosteroids in the morning than in the evening, normal suppressibility of plasma cortisol with overnight 1 mg dexamethasone (9 of 10), and well preserved responses of other pituitary hormones to various loading tests: normal responses of plasma ACTH to CRH (6 of 9), TSH (7 of 8), and PRL (5 of 8) to TRH and age-related normal responses of GH to GRH (4 of 8), LH (6 of 8), and FSH (6 of 8) to GnRH. These findings suggest that long term reserpine administration in combination with a conventional dose of pituitary irradiation is useful in the treatment of Cushing's disease.     

Successful treatment of Cushing's syndrome with the glucocorticoid antagonist RU 486

A patient with Cushing's syndrome due to ectopic ACTH secretion was treated successfully with the new glucocorticoid antagonist RU 486 [17 beta-hydroxy-11 beta-(4-dimethylamino phenyl) 17 alpha-(1-propynyl)estra-4,9-dien-3-one]. This compound is a 19-nor steroid with substitutions at positions C11 and C17 which antagonizes cortisol action competitively at the receptor level. Oral RU 486 was given in increasing doses of 5, 10, 15, and 20 mg/kg . day for a 9-week period. Treatment efficacy was monitored by assessment of clinical status and by measuring several glucocorticoid-sensitive variables, including fasting blood sugar, blood sugar 120 min after oral glucose administration, and plasma concentrations of TSH, corticosteroid-binding globulin, LH, testosterone-estradiol-binding globulin, and total and free testosterone. With therapy, the somatic features of Cushing's syndrome (buffalo hump, central obesity, and moon facies) ameliorated, mean arterial blood pressure normalized, suicidal depression resolved, and libido returned. All biochemical glucocorticoid-sensitive parameters normalized. No side-effects of drug toxicity were observed. We conclude that RU 486 may provide a safe, well tolerated, and effective medical treatment for hypercortisolism.     

Recurrent ACTH-independent Cushing's syndrome in multiple pregnancies and its treatment with metyrapone

A 17-year-old primigravid woman presented with Cushing's syndrome. Typical clinical symptoms and signs developed at the beginning of pregnancy. By week 17 of gestation, plasma cortisol diurnal rhythm was absent and there was a paradoxical increase in plasma cortisol after a 1-mg dexamethasone overnight suppression test. Basal urinary free cortisol was 10 times above the upper limit (in pregnancy) and ACTH levels were suppressed. The diagnosis of ACTH--independent Cushing's syndrome was established. MRI scans revealed normal adrenal and pituitary glands. To control hypercortisolism, the patient was treated with metyrapone. At 34 weeks of gestation, the patient developed preeclampsia and underwent caesarean section. A female infant weighing 1070 g was delivered. No apparent metyrapone-induced teratogenic effects were observed. Cushing's syndrome in the patient resolved within three weeks of delivery. No corticosteroid replacement therapy either for child or mother was needed. Eight months after delivery the patient became pregnant again and rapidly developed Cushing's syndrome with typical clinical symptoms and signs and laboratory results (urinary free cortisol 6464 nmol/24 h). This second pregnancy was unwanted and terminated by artificial abortion that was followed by rapid resolution of hypercortisolism. A third pregnancy, 12 months after delivery was also accompanied by the rapid development of hypercortisolism which recovered after artificial termination. The mechanisms by which pregnancy-induced Cushing's syndrome occurred in this patient are unclear. Aberrant responsiveness or hyperresponsiveness of adrenocortical cells to a non-ACTH and non-CRH substance produced in excess in pregnancy should be considered. Metyrapone suppression of hypercortisolism currently represents the best treatment for these rare cases.     

Leucine metabolism in patients with Cushing's syndrome before and after successful treatment

OBJECTIVE Results from studies on the effect of glucocor-ticosteroids on protein turnover in both rat and man have been conflicting. The aim of this study was to investigate the primary cause of muscle wasting in patients with Cushing's syndrome. DESIGN Studies of whole body 1-¹⁴C-leucine turnover in patients with Cushing's syndrome before and after successful treatment, and in control subjects. PATIENTS Eleven patients with Cushing's syndrome before and after (n= 5) treatment and 11 control subjects. MEASUREMENTS Whole body 1-¹⁴C-leucine turnover to determine leucine metabolic clearance rate, leucine production rate, leucine oxidation rate and leucine incorporation into protein. RESULTS Plasma leucine concentration (mean ± SEM 100 ± 6 μ mol/l), leucine metabolic clearance rate (9.97 ± 0.11 μ mol/min/kg), leucine turnover (0.98 ± 0.11 μ mol/min/kg) and leucine incorporation into protein (0.71 ± 0.09 μ mol/min/kg) were all significantly reduced in patients with Cushing's syndrome compared with control subjects (122 ± 6 μ mol/l, P < 0.05; 13.61 ± 1.27 μ mol/min/kg, P < 0.05; 1.65 ± 0.12 μ mol/min/kg, P < 0.05; 1.46 ± 0.10 μ mol/min/kg, P < 0.001, respectively). Leucine oxidation rate was similar in the patients with Cushing's syndrome and control subjects. When leucine metabolism was expressed in terms of lean body mass (LBM) in five patients with Cushing's syndrome and 11 control subjects, leucine MCR, leucine turnover and leucine oxidation were not significantly different in the two groups. However, leucine incorporation into protein was significantly reduced (P< 0.001) in the patients with Cushing's syndrome (1.07 ± 0.20 μ mol/min kg LBM) compared with control subjects (1.95 ± 0.11 μ mol/min/kg LBM). CONCLUSION We conclude from these studies that the muscle wasting associated with Cushing's syndrome is primarily due to a reduction in protein synthesis.     

Circadian blood pressure profile in patients with Cushing's syndrome before and after treatment

The aim of the study was to evaluate the circadian blood pressure (BP) profiles in patients with two forms of Cushing's syndrome, and to compare them to those in patients with essential hypertension. The study included 100 patients with Cushing's syndrome (80 with pituitary adenomas and 20 with adrenal adenomas) and 40 with essential hypertension. Twenty-four-h ambulatory BP monitoring was performed before and after therapy. All 3 groups had similar office-, 24-h-, awake-, and sleep BP mean values. The awake-sleep differences between the patients with two forms of Cushing's syndrome were similar. The night-time BP decline in the patients with Cushing's disease, as well as in those with adrenal adenomas, was significantly lower than that in the patients with essential hypertension. In the patients with both forms of Cushing's syndrome, there was a highly significant decline in the office and ambulatory BP levels after the treatment, and the awake-sleep systolic BP difference became significantly higher. The night-time diastolic BP decline was significantly higher after treatment in patients with adrenal adenomas and not-significantly higher in patients with Cushing's disease. In the patients with Cushing's disease, the duration of hypertension was greater, and lower percentage of normalized BP after treatment was observed in comparison with the patients with adrenal adenomas. The significant negative correlation between duration of the disease and extent of the night-time BP decline suggests that the 'non-dipping' profile is related not only to hypercortisolism itself but also to the severity of hypertension and duration of the disease.     

Use of ketoconazole in the treatment of Cushing's syndrome

The therapeutic value of ketoconazole for long term treatment of patients with Cushing's syndrome was studied. Seven patients with Cushing's disease and one with an adrenal adenoma received 600-800 mg/day ketoconazole for 3-13 months. Plasma ACTH, cortisol, and dehydroepiandrosterone sulfate levels and urinary cortisol, 17-ketosteroid, and tetrahydro-11-deoxycortisol excretion were determined periodically during the treatment period. Plasma ACTH and cortisol responses to CRH stimulation were determined before and during treatment. Rapid and subsequently persistent clinical improvement occurred in each patient; plasma dehydroepiandrosterone sulfate and urinary 17-ketosteroid and cortisol excretion decreased soon after the initiation of treatment, subsequently remaining normal or nearly so throughout the treatment period. Urinary tetrahydro-11-deoxycortisol excretion increased significantly. Plasma cortisol levels decreased. Plasma ACTH levels did not change, and individual plasma ACTH and cortisol increments in response to CRH were comparable before and during treatment. The cortisol response to insulin-induced hypoglycemia improved in one patient and was restored to normal in another. The seven patients tested recovered normal adrenal suppressibility in response to a low dose of dexamethasone during ketoconazole treatment. Ketoconazole is effective for long term control of hypercortisolism of either pituitary or adrenal origin. Its effect appears to be mediated by inhibition of adrenal 11 beta-hydroxylase and 17,20-lyase, and it, in some unknown way, prevents the expected rise in ACTH secretion in patients with Cushing's disease.     

Effect of surgical treatment on hypertension in Cushing's syndrome

The effect of a surgical cure of hypercortisolism on hypertension in 54 patients with Cushing's syndrome was assessed. The correlation between preoperative duration of hypertension and posttreatment blood pressure was significant (P < .01). Restoration of normal cortisol was associated with blood pressure normalization in 39 out of 54 cases. Duration of hypertension of patients with normalized blood pressure was significantly shorter than that of patients with persistent hypertension post-operatively (P < .0001). Duration of hypertension, ie, long-lasting exposure to increased cortisol, appears to be the determinant of persistent hypertension following successful surgery in Cushing's syndrome.