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

Subtotal adrenalectomy was given to 10 adult patients with Cushing's disease, concurrently with or following therapeutic regimen by long term reserpine administration and pituitary irradiation. In the present study, we describe long term follow-up results. Two patients died after the operation due to acute adrenal crisis and pneumonia, respectively. The other 8 patients achieved clinical and biochemical remissions and were followed for long term. Three patients relapsed 9, 14 or 17 years after achieving remission, two patients developed hypopituitarism 12 or 20 years after and one died of cerebral vascular accident at 64 years, 5 years after the remission. The remaining 2 patients maintained remission for 10 or 18 years, respectively. During the remission periods of 0.5 to 20 years with a mean of 10.1 +/- 6.7 years, 6 of 7 patients examined by 1 mg overnight dexamethasone test showed normal suppressibility of plasma cortisol. Provocative tests of plasma GH by l-arginine infusion and/or insulin-induced hypoglycemia were performed in 6 patients in the early remission period. All of 5 patients in the arginine infusion test and 3 of 5 in the insulin-induced hypoglycemia test showed normal responses. Furthermore, to facilitate prediction of long term response or failure to our therapeutic regimen, long term reserpine administration and pituitary irradiation, pretreatment clinical and biochemical characteristics were analyzed retrospectively in 3 divided groups; the present 10 patients treated with reserpine and pituitary irradiation followed by subtotal adrenalectomy, 11 patients achieving long term remission treated by our regimen alone, and 7 patients failed with our regimen alone. There were no significant factors predictive of response to our regimen. These findings suggest that subtotal adrenalectomy does not lead favorable outcome, however, reserpine administration shows usefulness to improve pituitary functions in treating Cushing's disease.

Effects of reserpine treatment on pituitary-adrenocortical axis in patients with Cushing's disease.

Effects of reserpine treatment, not associated with pituitary irradiation, on the pituitary-adrenocortical axis in a total of 37 untreated patients with Cushing's disease were evaluated. With short-term treatment (2 mg daily for 2 weeks, n = 36), basal excretion of urinary 17-OHCS significantly decreased from 11.2 +/- 5.2 mg/day/m2 (body surface area) (mean +/- SD) to 9.6 +/- 4.4 mg/day/m2 (P < 0.01), and metyrapone-induced incremental responses of urinary 17-OHCS decreased from 58.4 +/- 41.4 mg/3 days/m2 to 45.9 +/- 29.8 mg/3 days/m2 (P < 0.05). Long-term treatment (1.7 +/- 0.3 mg/day for a mean of 15.8 +/- 19.9 weeks) induced a marked reduction in plasma cortisol, and 24-h urinary 17-OHCS and/or free cortisol in 4 of 8 patients examined. Long-term reserpine administration caused normal suppression of plasma cortisol (or 11-OHCS) in 3 of 9 patients with 1 mg, and in all of 5 patients with an 8 mg overnight dexamethasone suppression test. Plasma ACTH response to CRH was evidently decreased in one patient evaluated one month after the initiation of reserpine. The circadian rhythm of plasma cortisol was normal in one patient when the basal glucocorticoid level became normal with reserpine treatment. The present findings suggest that reserpine itself contributes in a causal fashion to the effectiveness of our regimen, reserpine and pituitary irradiation, for some Cushing's disease patients in whom it is effective.

Medial longitudinal fasciculus syndrome associated with a subdural hygroma and an arachnoid cyst in the middle cranial fossa.

A 60-year-old man complaining of diplopia and vertigo showed bilateral medial longitudinal fasciculus (MLF) syndrome. The CT scan revealed a space-occupying lesion with watery fluid in the left cranial fossa, which was divided into two parts by a thin septum. Surgical trepanation was performed followed by 4 weeks of prednisolone therapy. He was completely cured 5 months later. The plausible causes of MLF syndrome relevant to preexisting space-occupying lesions are discussed.

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.

[Pharmacokinetics of prednisolone (PSL) during PSL treatment. II. PSL pharmacokinetics during intermittent treatment with PSL administration 4 consecutive days a week].

Pharmacokinetics of prednisolone (PSL) was investigated in 10 patients treated with long-term intermittent regimen of PSL administration, 4 consecutive days administration a week. In 8 patients (group I; 3 of nephrotic syndrome, 2 of SLE, and each of Crohn's disease, aortitis syndrome, and hemolytic anemia), PSL was initially administered daily until the therapeutic effects were achieved (daily period), and this was followed by consecutive 4 days administration (on-day) and consecutive 3 days discontinuation (off-day) of PSL every week (intermittent period), keeping the weekly dose of PSL in the preceding daily regimen. In 2 patients (group II) with multiple myeloma and idiopathic thromocytopenic purpura, respectively, PSL was started with the intermittent regimen of PSL without preceding daily period. In group I, pharmacokinetic studies by respective oral and i.v. administrations of 40mg PSL and of 25.6mg PSL hemisuccinate (equivalent to 20mg of PSL) were performed before treatment, in daily period and both on on-day and off-day within the same week during intermittent period. In one patient of group II, study only by intravenous PSL administration was performed before treatment and in intermittent period. In another patient of group II, studies by oral and intravenous PSL administration were performed only in an intermittent period. PSL was measured by radioimmunoassay. Paired t-test was used for the comparison. In each case of group I, there was no difference in Cmax, Tmax, or AUCp.o. after oral administration of PSL among 4 periods tested, before treatment, daily period, on-day and off-day during intermittent period. On the intravenous PSL administration, increase in AUCi.v., prolongation of half-life, and decreases in MCR and bioavailability on on-day of intermittent period were observed in comparison with those before treatment, respectively. Only bioavailability among these parameters on on-day was increased compared with that in daily period. On the other hand, on off-day of intermittent period, decrease in AUCi.v. and increase in MCR were observed compared with those on on-day within the same week. When each parameter on off-day was compared with that of daily period, decrease in AUCi.v. and increases in MCR and bioavailability on off-day were observed. Vd did not differ each other among these 4 periods. Remarkable finding was the fact that MCR fluctuated regularly in 4 periods of this therapy regimen, i.e., significant decrease in daily period compared with before treatment, no significant difference between on-day and daily period, and the increase on off-day compared with that on on-day or in daily period.(ABSTRACT TRUNCATED AT 400 WORDS)

[Pharmacokinetics of prednisolone (PSL) during PSL treatment. I. PSL pharmacokinetics during daily PSL treatment].

We studied the pharmacokinetics of prednisolone (PSL) in eight patients (two each with subacute thyroiditis, systemic lupus erythematosus, and nephrotic syndrome: and one each of Crohn's disease and aortitis syndrome) before and during the daily treatment with PSL(duration of 0.5-4.0 months with the mean of 1.9 months; total amount of 0.3-8.0 g with the mean of 2.8 g). PSL was measured by radioimmunoassay. Cmax, Tmax and AUCp.o. were calculated on the single oral administration of 40 mg PSL, and T1/2 beta, Vd and MCR were calculated when 25.6 mg of PSL sodium succinate (equivalent to 20 mg of PSL) was injected intravenously. Bioavailability was calculated by the ratio of AUCp.o. X PSL i.v. dose to AUCi.v. X PSL p.o. dose. With the oral administration, there was no difference in Cmax, Tmax and AUCp.o. between before and during the treatment, respectively. With the intravenous PSL administration, significant increase of AUCi.v. (p less than 0.01), significant decrease of MCR (p less than 0.01), significant elongation of T1/2 beta (p less than 0.05), and significant decrease of the bioavailability (p less than 0.001) were found in the PSL treatment period compared with before the treatment, but no significance was found in Vd between, before, and during the treatment. There was no difference in these changes in parameters among the diseases. Nor were any correlations found between the changes in these parameters of T1/2 beta, MCR or bioavailability and the duration or the total amount of PSL administered, respectively. These results indicate that the decreased MCR, elongated T1/2 beta and the decreased bioavailability of PSL were brought about by daily administration of PSL, regardless of the kind of diseases, or the total amount or the duration of PSL administration.

Comparative assessment of ultrasonography and computed tomography in adrenal disorders.

Comparative diagnostic assessment by ultrasonography (US) and computed tomography (CT) was performed in each of 17 patients with adrenal disorders. US is better than CT for demonstrating the intratumorous characteristics, the relationship between the tumor and the surrounding organs, and the organ from which large tumors arise, such as pheochromocytoma. On the other hand, CT is better able to detect small adrenal tumors in primary aldosteronism, although US with a sector or linear scanner can also detect small tumors in some cases. Adrenal hyperplasia in both Cushing's disease and congenital adrenogenital syndrome was more easily demonstrated by CT than by US. Of the two US instruments, a sector scanner was more useful in the delineation of the enlarged right nontumorous adrenal by scanning from the right intercostal region, but both scanners were of no use in the delineation of the enlarged nontumorous left adrenal in patients with obesity.

[Image diagnosis of adrenal disorders. III. "Nonfunctioning" adrenal adenoma, weak mineralocorticoids producing adrenal carcinoma, congenital adrenogenital syndrome due to 21-hydroxylase deficiency--simple virilizing form, and pheochromocytoma].

The image diagnoses of a case of so-called "nonfunctioning" adrenal adenoma, weak mineralocorticoids producing adrenal carcinoma, congenital adrenogenital syndrome due to 21-hydroxylase deficiency--simple virilizing form--, and 5 cases of pheochromocytoma were studied. In a patient with so-called "nonfunctioning" adrenal adenoma (2.3 X 3.0 X 3.3 cm), in which steroids biosynthesis was confirmed, computed tomography (CT) delineated the tumor shadow with extremely low density, and ultrasonography (US) demonstrated the round tumor echo with homogenous and low echogenicity at the superior region of the right renal pole. Adrenal scintigraphy also showed the tumor image. A weak mineralocorticoids-producing left adrenal carcinoma (3.5 X 3.5 X 3.0 cm) was shown as a heterogenous round tumor at the left lateral portion of the vertebra by CT. On adrenal scintigraphy under dexamethasone pretreatment, there was good uptake in the tumor and disappearance of the contralateral. Both bilateral adrenal images on CT in a patient with congenital adrenogenital syndrome were linear-shaped and markedly enlarged. The enlarged right adrenal was clearly demonstrated by US with an electronic sector scanner but not with an electronic linear scanner, although the left one was hardly shown by either US instruments. Three of 4 patients with pheochromocytomas examined by US were correctly detected, while in the remaining one the tumor image was judged to be a retroperitoneal tumor. CT also correctly demonstrated the former 3 pheochromocytomas, but misjudged the latter one as a pancreatic cancer. Good uptake of Adosterol by bilateral adrenals was shown in a case of extra-adrenal pheochromocytoma. Three of 4 cases of adrenal pheochromocytoma showed the isotope uptake of the contralateral normal adrenal alone. In another case of right adrenal pheochromocytoma, isotope accumulation in the colon obscured whether the isotope uptake in the right adrenal was shown or not.

[Image diagnosis of adrenal disorders--II. Cushing's syndrome].

Comparative study of image diagnosis of ultrasonography (US) by linear electronic scanner, computed tomography (CT), and adrenal scintigraphy was performed in 14 patients with Cushing's syndrome. Adrenal imaging by scintigraphy was performed at the 5th and 6th day or further 7th day following the injection of 1 mCi of Adosterol. Cushing's disease (11 cases) US failed to detect the adrenals in 4 cases examined. Measurement of the adrenals on CT film demonstrated the enlargement of adrenals (greater than mean + 2SD) in 6 of 7 cases (85.7%). Scintiscanning showed the increased uptake of bilateral adrenals in 4 of 10 cases (40%). Adrenal scintigraphy with dexamethasone pretreatment (DP) still demonstrated the isotope uptake of bilateral adrenals in all of those 4 cases tested, although the other 6 cases were not studied with DP. From these findings, it was suggested that the measurement of adrenal size by CT was useful for the additional image diagnosis of Cushing's disease, and the adrenal scintigraphy with DP was also available for complementary study of Cushing's disease. Cushing's syndrome due to adrenocortical adenoma (3 cases) In one case examined by US, which had the smallest adenoma (0.6 X 1.0 X 2.0 cm) in this syndrome, the adenoma was not detected. All of 3 adrenal adenomas (2.6 X 2.6 X 2.2 cm to 0.6 X 1.0 X 2.0 cm) were detected by CT. Adrenal scintigraphy demonstrated good uptake by adrenal adenoma but no visualization of the contralateral adrenal in every case.

[Image diagnosis of adrenal disorders--I. CT images of control subjects and image diagnosis of primary aldosteronism].

The shape and size of the adrenals in control subjects without adrenal disorders were studied by computed tomography (CT), and a comparative assessment of diagnostic values of ultrasonography (US) by electronic linear scanner, CT, and adrenal scintigraphy was made on 9 patients with primary aldosteronism. Adrenal imaging by scintigraphy was performed on the 5th and 6th day, or further on the 7th day after the injection of 1 mCi of Adosterol. CT findings of the adrenals in control subjects: Eighty-two % of 100 control right adrenals, and 89% of 100 control left adrenals were detected by CT. Seventy-seven % of the right adrenals were in linear-shape, and the others were in V-shape. The shape of the left adrenals could be classified into triangular-shape (54%), Y-shape (28%) and V-shape (18%). The mean width and thickness of the right adrenals were 28.6 +/- 7.5 mm (M +/- SD) and 3.8 +/- 1.4 mm, respectively. Those of the left ones were 19.4 +/- 5.5 mm and 5.3 +/- 1.8 mm. Image diagnosis of primary aldosteronism: In 2 out of 3 patients examined by US, aldosteronomas were detected. In these 2 patients, one had 2 adenomas 2.8 X 1.7 X 1.2 cm and 1.0 X 1.0 X 2.0 cm in size, and the other had one adenoma 0.8 X 1.0 X 2.0 cm in size. On adrenal scintiscanning under dexamethasone pretreatment (DP), the isotope uptake of aldosteronoma was still seen with the disappearance of the contralateral adrenal in 7 out of 9 cases. In these 7 cases, the laterality of the tumor was confirmed. In one of the remaining 2 cases, the bilateral adrenal images were obtained regardless of DP. In the other case, of which aldosteronoma was the smallest (0.6 X 0.6 X 0.8 cm), the image of the affected adrenal with adenoma as well as the contralateral adrenal disappeared under DP. CT delineated all aldosteronomas in 8 cases examined including 2 cases in which adrenal scintiscanning failed to elucidate the localization of aldosteronoma. These results indicated that the combination of these 3 new image diagnostic methods was available for the detection of aldosteronomas of various sizes.

Serum thyroglobulin (Tg) concentration in healthy subjects: absence of age- and sex-related differences.

Serum concentrations of thyroglobulin in healthy subjects were measured by a solid-phase immunoradiometric assay. The mean concentration of serum thyroglobulin in 53 healthy males was 5.0 ng/ml (1.0-25.9 ng/ml) and that of 57 healthy females was 5.2 ng/ml (1.0-27.7 ng/ml). Neither sex-related nor age-related change in the serum thyroglobulin level was observed.