Urinary 17-OHCS Excretion Research Articles

1,111 Patients with Adrenal Incidentalomas Observed at a Single Endocrinological Center

A majority of incidentally found adrenal tumors derive from the adrenal cortex. The aim of our study was evaluation of the incidence of chromaffin tumors in a group of 1,111 patients with adrenal incidentalomas. In this group there were 803 women and 308 men, aged 10-87 years. Clinical examination, imaging studies (ultrasound scans, CT, and MRI if necessary), and hormonal determinations (cortisol, ACTH and androgens in the blood, dexamethasone suppression test, urinary excretion of 17-OHCS, aldosterone and 17-KS, as well as PRA/aldosterone stimulation test and metanephrines in hypertensive patients and those with density in CT over 20 HU) were used. In 380 patients treated by surgery (mainly by laparoscopic approach), histological and immunocytochemical examinations were performed. Clinical examination revealed hypertension in 25% of the patients under study. Chromaffin tumors were detected in 43 patients, 33 women, and 10 men aged 20-75 years: pheochromocytoma in 36 (malignant in 3); chromaffin cells hyperplasia in 2; paraganglioma in 3; ganglioneuroblastoma in 1; ganglioneuroma in 1; and schwannoma in 2. The tumors' diameter ranged between 1.1 and 20.0 cm, density=25 Hounsfield units (HU) or more before contrast medium injection. Hypertension was present in 53% of these patients. The urinary metanephrines excretion was elevated in 31 of 38 patients, in whom the determinations were done. Chromaffin tumors were detected in 4% (pheochromocytomas in 3%) of 1,111 patients with adrenal incidentalomas. Malignancy was present in 9% of 43 patients with chromaffin tumors. High density in CT was a very important diagnostic finding in the incidentally found medullary tumors.

Autoimmune Hypophysitis Treated with Intravenous Glucocorticoid Therapy

A 46-year-old man presented with frontal headache, a visual field defect and general fatigue. Magnetic resonance imaging (MRI) of the brain showed symmetrical enlargement of the pituitary gland and stalk due to the presence of a mass lesion extending toward the optic chiasm. Gadolinium injection further revealed homogeneous strong enhancement with involvement of the adjacent dura (dural tail). Basal plasma levels of ACTH, free thyroxine and gonadotropins were decreased, and 24-h urinary 17-OHCS excretion was reduced. An elevated anti-thyroglobulin antibody titer indicated the presence of autoimmune thyroiditis. Under the suspicion of autoimmune hypophysitis, 60 mg/day prednisolone sodium succinate was intravenously administered for two weeks followed by a decreasing dose of oral prednisolone. Clinical symptoms and pituitary dysfunction recovered during steroid treatment and MRI showed marked shrinkage of the pituitary mass. Early initiation of an intravenous dose of glucocorticoid followed by oral steroid administration therefore seems to be an efficient treatment for autoimmune hypophysitis even in patients with visual dysfunction.

Urinary 17-KS and 17-OHCS as markers of endocrine disruption by air pollution in primary school children.

The present study was undertaken to determine the effects of air pollution on urinary excretion of 17-ketosteroids (17-KS) and 17-hydroxycorticosteroids (17-OHCS), which are markers of adrenal cortex functions, in primary school children from five schools with different levels of air pollution. One hundred and twentynine fourth-grade children were included in the study. Urinary excretion of 17-KS and 17-OHCS were significantly lower in male children living in polluted areas than in children living in clean areas. We conclude that adrenal cortex functions before puberty can serve as practical markers of endocrine disruption by environmental factors in epidemiological studies.

Effects of repeated exposures to severely cold environments on thermal responses of humans.

This study was conducted to investigate the effects of different exposure rates on thermal responses with the total cold exposure time the same under each of the conditions. After resting in a warm room (25 degrees C) for 10 minutes, six male students wearing standard cold protective clothing entered an adjoining cold room (-25 degrees C). Each 5-, 10- and 20-minute cold exposure was repeated 12, 6 and 3 times, respectively. Each cold exposure was followed by a similar duration of rest at 25 degrees C. Total cold exposure time was the same under the three conditions. Rectal temperature, skin temperatures, blood pressure, 17-hydroxycoyticoids (OHCS), counting task and subjective responses were measured. At the end of the cold exposure skin temperatures in the shorter exposures were higher than those in the other conditions, except on the foot. Discomfort due to cold was less in the shorter exposures and manifestation of discomfort was delayed. However, there were no differences among the three conditions in the fall of rectal temperature and urinary excretion of 17-OHCS, which are good indices of cold stress. Moreover, increase in blood pressure and decrease in counting task due to cold were not different among the three conditions. Even though the cold exposure time for each stay was short, when cold exposures were repeated frequently, cold stress of the whole body and decrease in manual task performance were the same as in the longer cold exposure.

Possible pre-Cushing's syndrome due to an adrenal adenoma incidentally discovered.

We demonstrated the functional evaluation of adrenal incidentaloma in 8 patients who had no abnormal finding associated with Cushing's syndrome. Adrenal tumors were incidentally discovered by abdominal echogram in 5 patients and by computed tomography (CT) in 3 patients. Serum cortisol levels and urinary excretion of 17-hydroxycorticosteroids (17-OHCS) were within normal limits in four of 8 patients. Urinary excretion of free cortisol was also within normal limits except for patient 8. Urinary excretion of 17-OHCS, however, was not suppressed by dexamethasone administration in five of 8 patients. Excretion of urinary 17-OHCS did not increase in response to metyrapone in 3 of 4 dexamethasone-insuppressible patients, but increased in 3 dexamethasone-suppressible ones. Serum cortisol increased in response to exogenous ACTH in all 6 patients examined. 131I-Adosterol accumulation was found in only the tumor side in 7 patients and bilaterally in one patient. Adrenalectomy was done in 7 patients, and microscopic findings showed adrenocortical adenoma. Serum cortisol was significantly suppressed in response to dexamethasone in the post-operative stage in all 7 patients examined. These results indicate that these adrenal incidentalomas seem to have a cortisol over-production which is dexamethasone-insuppressible and ACTH-dependent, and that they can be classified as "Pre-Cushing's Syndrome."

CUSHING'S SYNDROME IN INFANCY CAUSED BY ADRENOCORTICAL CARCINOMA-CASE REPORT-

Adrenocortical tumors, usually adrenocortical carcinoma, producing hormonal symptoms are very rare in children. A 4-year-old girl with acne, general obesity, moon face and hypertrichosis was admitted to our hospital. Hormonal studies demonstrate high urinary excretion of 17-OHCS and 17-KS, and a high serum testosterone concentration. The serum ACTH concentration low was and the cortisol level was within the normal range. A right adrenal tumor was detected by CT scan, MRI and ultrasound. Complete extripation of the tumor, weighing 126g, was carried out successfully. Pathologically a diagnosis of adrenocortical car-cinoma was made because of the presence of venous and capsular invasion by the tumor cells. It is very difficult to make a pathological diagnosis in this tumor. Although prognosis of adrenocor-tical carcinoma is poor, the patients is doing well with no signs of postoperative recurrence.

ＲＡ患者の術前ＡＣＴＨテストの検討，その意義 第２報 手術における副腎皮質機能について

This report evaluates the use of steroid hormore cover during for rheumatoid arthritis patients, and offers guidelines for such use. We measured the daily urinary excretion of 17OHCS and 17KS in patients undergoing surgery for osteoarthritis of the hip. Preoperative mean values of 17OHCS and 17KS were 4.96mg/day and 4.46mg/day, respectively. The mean values of 17OHCS and 17KS on the day of surgery were 9.81mg/day and 9.14mg/day, respectively. If these mean values in RA patients for three days after ACTH injection are higher than the mean values on the day of surgery, we think that steroid cover is not necessary.

異所性ACTH産生症候群を呈した前立腺癌の1例

A 67-year-old man was admitted to the orthopedic ward, complaining of severe pain in his right greater trochanter. He was diagnosed as spinal cord tumor and underwent laminectomy for extirpation of the tumor. Histological examination revealed bone metastasis of unknown origin. Laboratory data revealed hypokalemia and hyperglycemia. Endocrinological data showed elevation of plasma cortisol and ACTH, and increased excretion of urinary 17-OHCS. Ten specimens needle biopsy of the prostate showed poorly differentiated adenocarcinoma, thus patient was diagnosed as prostate cancer with bone metastasis (stage D2) and perhaps ectopic ACTH production. Castration was performed, however 2 days after the surgery he died suddenly. We suspected that cerebral hemorrhage was the cause of his death. On autopsy ectopic ACTH production in the prostate was confirmed.

An ACTH and FSH Producing Invasive Pituitary Adenoma with Crooke's Hyalinization

We report on a patient with ACTH and FSH producing invasive pituitary adenoma complaining of cutaneous pigmentation. Elevations in plasma ACTH, beta-endorphin and cortisol levels as well as urinary 17-OHCS and cortisol excretion were found. Serum FSH concentration was just within the upper limit of the normal range, whereas serum LH level was reduced and alpha-subunit level was normal. Roentogenographic examination showed an almost complete loss of sellar floor and destruction of the posterior clinoids and dorsum sella. CT scan and MRI demonstrated an enlarged tumor invasion of the clivus and its extension to the sphenoid sinus. After subtotal removal of the large pituitary tumor, serum cortisol and plasma beta-endorphin levels as well as plasma ACTH concentrations returned to normal and serum FSH levels also remarkably decreased. Histologically, the tumor corresponded to a chromophobe, slightly PAS positive adenoma. These tumor cells exhibited positive immunostaining with antibody to ACTH (1-24), beta-LPH, beta-endorphin and FSH, while immunostaining of the adenoma cells was negative for LH, TSH, GH and prolactin. The immunogold technique also demonstrated ACTH and FSH particles in the secretory granules in the cytoplasm of the adenoma cells. Some of the tumor cells disclosed Crooke's hyalinization and type I microfilament occupied most of the cytoplasm. In the present study, a very rare case of ACTH and FSH producing invasive pituitary adenoma is reported.

Presidential Lecture delivered on the 63th Autumn Congress of Japan Endocrine Society

We followed up 21 Cushing's disease patients (16 females and 5 males) aged 15 to 46 years, treated with reserpine (R) plus pituitary irradiation (PI). Mean duration of R administration and mean dose of PI were 24.5 +/- 10.8 (mean +/- SD) months and 54.0 +/- 9.8 Gy, respectively. Of them, four patients did not respond, one who received 66 Gy had brain necrosis and panhypopituitarism, and the other 16 patients (78%, 16/21) achieved initial remission. Of these 16 patients, there were 10 (aged 15 to 46 years) who were irradiated with 50 Gy or less (mean, 45.5 +/- 6.9 Gy), and 7 of them had initial response. As previously demonstrated effectiveness of the present regimen (R plus PI) could be evaluated by subjecting the patients to R-test, higher rate of remission was obtained among R-test responders (J. Clin. Endocrinol. Metab. 41:511, 1975). Eleven of our R-test responders in the present study showed an early onset of remission (6.9 +/- 5.7 months) as compared with 5 R-test non-responders (17.0 +/- 9.1, p less than 0.05). In addition, the response time positively correlated with the ratio of the difference between basal plasma cortisol (11-OHCS) levels before and after midnight administration of 8 mg dexamethasone (delta D8) divided by the difference between 24-h urinary excretion of 17-OHCS for 3 successive days before, during metyrapone (3.0 g/day, 6 divided dose, 2 days) administration and one day after (delta M). The sixteen patients were followed up until 1990 for a mean of 12.4 years (2.2 to 25.2 years). Among them, one died of unrelated illness with this regimen 4 years after achieving remission, 4 relapsed between 5 to 7 years follow-up, and the remaining 11 (52%, 11/21) had long-term remission for a mean of 15.7 +/- 9.0 years (2.2 to 25.2 years). Of them, there were 5 patients who were treated with PI with 50 Gy or less, and had long-term remission (5.8 to 24.4 with a mean of 17.6 +/- 7.6 years). During the long-term follow-up period of these 11 patients, endocrine assessment was carried out while off therapy. Basal urinary excretion of cortisol or 17-OHCS were were normal in all of the 11 patients, and 8 of 9 showed normal diurnal rhythm of plasma cortisol. Nine of 10 patients tested showed normal suppressibility by overnight 1 mg dexamethasone test and 6 of 9 showed normal response to CRH.(ABSTRACT TRUNCATED AT 400 WORDS)

The Unusual Association of Transient Resolving Thyrotoxicosis due to Painless Thyroiditis, Hypopituitarism and Central Diabetes Insipidus Associated with Spontaneous Pituitary Apoplexy

Pituitary apoplexy is characterized by a wide spectrum of clinical features. A quite rare case of painless thyroiditis, hypopituitarism and central diabetes insipidus (DI) followed by pituitary apoplexy was presented. A 61-year-old woman was admitted to our hospital in May, 1986 because of marked general malaise, polydipsia and weight loss which became progressively worse. Four months earlier she had experienced episodes of abrupt onset of severe headache associated with nausea and blurring vision. Physical examinations revealed a fine tremor, dry skin and nervousness. The thyroid gland was not palpable. Visual fields were intact. Her blood pressure was 105/64 mmHg with variable tachycardia. The routine laboratory studies were normal or negative except for hypoalbuminemia, hypocholesterolemia and hypernatremia. Erythrocyte sedimentation rate was 12 mm/hr. An impairment in corticotropin secretion was suspected from the low plasma cortisol and the low urinary excretion of 17-OHCS and the sufficient response to ACTH. Basal levels of GH and gonadotropin were also low, and responses to the stimulation tests (Insulin-stress, L-DOPA, and LH-RH) were all blunted. Brain computed tomographic scan and magnetic resonance imaging demonstrated a suprasellar mass that, after infusion, developed peripheral ring-like enhancement and large hyperintense pituitary mass, respectively. A diagnosis of pituitary apoplexy with anterior pituitary failure was made. However, the initial levels of thyroid hormones showed elevated as follows: Free T3 7.6 pg/ml, Free T4 3.3 ng/dl and T3-resin uptake 41.1%. TSH responses to TRH were all suppressed. TSH receptor antibody (TBII) was negative. Both antithyroglobulin and antimicrosomal antibodies were repeatedly positive. A thyroid scan with 99mTc revealed no uptake in the thyroid area. These findings led us to the diagnosis of "painless autoimmune thyroiditis". She had become hypothyroid without any medication. At that time radioactive 99mTc and 123I uptakes increased significantly. When hydrocortisone was substituted, daily urine output abruptly increased to about 10 liters with low osmolality, and the presence of DI was suspected. This diagnosis was confirmed by water deprivation and hypertonic saline infusion tests and subsequent pitressin test. She is currently quite well on L-thyroxine, hydrocortisone and desmopressin (1988). This association with pituitary apoplexy must be a rare occurrence, as a literature search has failed to find a similar case. The pathogenetic trigger of "painless thyroiditis" in this case may be responsible for some immunological change due to secondary adrenal insufficiency after pituitary apoplexy.

A study on the effects of the physical load of instructors during ice skating camp

The present study was conducted to estimate the effects of the physical load of instructors during ice skating camp. The subjects were 9 instructors aged from 20 to 24. To discover measures to relieve the physical load, we measured 1) urinary excretion of catecholamine (noradrenaline; NA, adrenaline; A), 17-OHCS, creatinine and nitrogen; N each day, 2) subjective symptoms of fatigue three time a day (morning, after skating, and at night), 3) nutrient intakes, 4) performed a time study and 5) measured the heart rate during skating instruction. The main results obtained were as follows: 1) The mean heart rate during skating instruction was 98.4-113.1 beats/min. 2) Urinary excretions of NA, A, and 17-OHCS were observed to have increased gradually during skating camp. The values of NA, A and 17-OHCS in the skating camp period were significantly higher than those of daily life. Subjective symptoms of fatigue were also increased gradually. The construction of symptom clusters was of the I-dominant type (I greater than III greater than II) at each point. 3) Intakes of energy, carbohydrate, protein and fat during the skating camp period were higher in comparison with those of daily life. 4) Urinary-N and creatinine levels during the skating camp period showed no changes. N-intake/urinary-N of the skating camp period tended to be higher than that of daily life. 5) In the time study, mean energy consumption was 3300-3400 kcal/day. The mean time of skating instruction was 218-227 min. The sleeping time was observed to have decreased gradually.(ABSTRACT TRUNCATED AT 250 WORDS)

Normal and abnormal function of the hypothalamic-pituitary-adrenocortical system in man.

The first half of this manuscript is devoted to a review of the methods used and the results obtained in the published measurements of the normal responses to tests of the three main types of hypothalamic-pituitary-adrenocortical (HPA) activity in man. These are, I, basal, unstressed activity leading to appropriate levels of total daily production of cortisol in the characteristic circadian pattern; II, responses to feedback stimulation of HPA activity by metyrapone administration; and III, responses to tests of the effects of stress on the HPA system including the effects of hypoglycemia, induced fever, vasopressin administration, and ACTH injections and infusions. The advantages and shortcomings of each type of procedure are discussed. The second half of this paper describes the authors' attempts to establish the limits of normality of standard and modified methods of evaluating the HPA system. The defined limits of normality have been used to assess the HPA function in 158 patients with known or suspected disorders of the HPA system. In normal controls, halfhourly plasma cortisol determinations established the normality of circadian and postprandial fluctuations and of mean plasma cortisol concentration, 6.2 +/- 0.3 (SEM) micrograms/dl, which were closely approximated by determinations every 6 h. Metyrapone, given in a dose of 500 mg every 2 h for 24 h increased urinary 17-OHCS excretion to 10.5-32.6 mg/day or to 1.7-7.8 times basal excretion rate. Increasing rates of insulin infusion disclosed significant relationships between resulting plasma glucose and cortisol concentrations. The slopes of the delta cortisol/delta glucose responses were similar after insulin infusions (0.46 +/- 0.05) and after insulin injections, 0.15 U/kg (0.43 +/- 0.09), and were always greater than 0.20 micrograms/mg. This index provides a useful objective measure of the normality of responses to hypoglycemic stress, 0.20-0.87 micrograms/mg. Adrenocortical responses to iv infusions of ACTH (cosyntropin 0.25 mg) may be equivocal at 2 h but are clear cut at 4, 6 and 8 h. Of 158 patients in whom hypopituitarism was known or suspected because of the presence of a pituitary tumor, acromegaly, hyperprolactinemia, or clinical features, HPA function was found to be entirely normal in 88 patients and partially or severely abnormal in the remaining 70 patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Application of ACTH Stimulation to Adrenal Imaging with Radioiodocholesterol

ACTH-stimulation adrenal imaging (ACTH-I) was performed in 14 patients after baseline imaging (B-I) was performed. In six patients with no adrenal diseases in whom the findings of B-I were equivocal, morphologic normality of the adrenals was confirmed by ACTH-I because of increased adrenal uptake of radioiodocholesterol. In three patients with cortisol-producing tumors, visualization of contralateral glands by ACTH-I provided indirect evidence for autonomous cortisol secretion of the tumors. In three patients with pheochromocytoma or cyst, ACTH-I increased adjacent cortical radioactivity to more clearly delineate the lesions. In two patients with primary adrenocortical insufficiency, exogenous ACTH had no effect on adrenal uptake of the tracer. Correlation was observed between response of the adrenal net counts and urinary excretion of 17-OHCS and 17-KS. ACTH-I is useful when B-I does not provide sufficient diagnostic information or further information is needed due to low or absent radioiodocholesterol uptake by the adrenal gland(s).

43 HYPOTHALAMO-HYPOPHYSO-ADRENAL SYSTEM IN ASTHMATIC CHILDREN UNDER BECLOMETHASONE TREATMENT

In order to study a possible action of beclomethasone spray, a corticosteroid drug used succesfully in treatment of bronchial asthma, on the hypothalamo-hypophyso-adrenal cortex system, 8 chronic asthmatic children 8 to 14 years old, free of corticosteroid treatment for at least 6 months prior to analysis were evaluated before and after 3 months on 300ug of beclomethasone spray daily. Urinary excretion of 17OHCS and THS, and serum concentrations of F and S, in basal conditions (B), during and one day after metopirone (M) were measured. 17-OHCS excretions before and after treatment were B: 3.81 ± 0.47 and 2.89 ± 0.43, post M 9.15 ± 0.63 and 6.63 ± 1.31, THS excretion B undetectable and post M 2.95 ± 0.73mg/d,. Serum concentrations of F, B: 9.09 ± 0.54 and 7.16 ± 0.68, M 3.90 ± 0.62 and 4.05 ± 0.34 and S, B: 0.51 ± 0.17 and 0.39 ± 0.16, post M 10.50 ± 2.09 and 8.39 ± 1.61 ug/100ml (X ± SE). No significative differences were observed under beclomethasone. It is concluded that the beclomethasone spray in the used doses, didn't inhibit the hypothalamo-hypophyso-adrenal axis in these children.

Inverse correlation between urinary 17-hydroxycorticosteroid (17-OHCS) excretion and thyrotropin-releasing hormone (TRH)-induced thyrotropin (TSH) response in disorders of adrenocorticotropic hormone (ACTH) and adrenal secretion.

A TRH test was performed in patients with Cushing's syndrome and isolated ACTH deficiency, and serum TSH was measured. A TRH-induced TSH showed low response in patients with Cushing's syndrome but showed excessive response in patients with isolated ACTH deficiency. However, in both diseases TRH-induced TSH response showed a tendency to normalize after the treatment. Urinary 17-OHCS excretion was measured in patients with Cushing's syndrome and isolated ACTH deficiency before and after the treatment. There was a definite inverse correlation between ;the logarithm for urinary 17-OHCS excretion and the peak TSH response to TRH. These results suggested that glucocorticoids regulate not only ACTH but also TSH secretion.

Periodic ACTH discharge

A 9 1/2-year-old girl is presented who had cyclical attacks of abdominal pain, vomiting, emotional disturbance, and marked weight change for two years. Associated findings were facial plethora, hypertension, transient hyperglycemia and glycosuria, elevated plasma ACTH, cortisol, and urinary 17-OHCS excretion, and low plasma osmolality with hyponatremia. Urinary excretion of catecholamines and porphyrin metabolites was not increased. Between episodes, she showed no abnormal clinical signs or laboratory data. The attacks were effectively suppressed with the administration of chlorpromazine. The disorder appears to be due to the periodic release of excessive ACTH; the cause remains unknown.

Urinary excretion of adrenaline, noradrenaline, 17-OHCS, 5-hydroxytryptamine and certain electrolytes in 24-hour shift workers taking a 4-hour night nap.

Urinary excretion of adrenaline, noradrenaline, 17-OHCS, 5-hydroxytryptamine and certain electrolytes was measured in 15 male guards engaged in 24-hour shift work containing a 4-hour night nap. In the night nap, it was found that the urinary output of adrenaline had a significant negative correlation to a self-rated value of feeling about depth of sleep. Based on this finding, it is considered that adrenaline output may be useful as a sleep index. The urinary level of adrenaline during the night nap was as low as the level during usual normal night sleep. However, the level of adrenaline during a daytime nap after the night work was considerably high compared to those in the night nap and in the normal night sleep. This suggests that the daytime nap was possibly not so deep as night sleep.

Studies on the Hypothalamic-Pituitary-Adrenal Function in a State of Malnutrition

The hypothalamic-pituitary-adrenal axis was investigated in 33 patients with various psychosomatic diseases treated with fasting therapy for 11 days, and a comparative study was made between this group and 13 young women with anorexia nervosa. The results obtained were as follows : 1) The administration of dexamethasone failed to suppress cortisol levels to a normal range in 14 out of 33 patients during fasting 2) The normal circadian rhythm of plasma cortisol was abolished in 9 out of 21 patients during fasting. Plasma cortisol concentrations were significantly elevated at any given time of the day, especially in the dexamethasone nonsuppressive patients. 3) The excretion of urinary 17-OHCS and 17-KS in the 24-hr samples after the oral administration of metopirone was significantly higher in fasting patients as compared with non-fasting patients. The response of plasma ACTH to metopirone showed a non-significant increase. 4) The circadian rhythm of ACTH responsiveness to metopirone administration was normal in patients during fasting. 5) The plasma cortisol response to β1-24 ACTH 0.25 mg im was significantly higher in fasting patients as compared with non-fasting patients. 6) The basal urinary 17-OHCS and 17-KS in the 24-hr sample displayed a biphasic fluctuation with the peaks at 3 and 6 days after the initiation of fasting, 7) The cortisol metabolic clearance rate in fasting patients was prolonged as compared with that in non-fasting patients. 8) After refeeding, pituitary adrenal functions returned to normal in all patients. 9) Anorexia nervosa patients, non-suppressive to dexamethasone, demonstrated elevated plasma cortisol levels, normal responses to metopirone and ACTH, with a decreased excretion of urinary 17-OHCS and 17-KS. It is concluded that high levels of plasma cortisol in both fasting and anorexia nervosa were caused by abnormalities of the negative feedback mechanism and prolongation of cortisol metabolic clearance rate. In addition, it was noted that patients exposed to fasting revealed an adrenocortical hyperfunction.

Treatment of Cushing's disease by transsphenoidal microsurgery (author's transl)

Six patients of ACTH dependant Cushing's disease were treated by transsphenoidal resection of pituitary adenomas. Preoperative endocrinological results showed that both plasma ACTH and cortisol were maintained at higher levels and their normal diurnal rhythms were lost. Urinary 17-OHCS excretion was partially suppressed by larger doses of dexamethasone (8 mg). These data was suggestive of pituitary dependent Cushing's disease, rather than ectopic ACTH-producing tumors. The sella volume was measured by Di Chiro's method and in 3 cases it exceeded minimally above the upper limit of the normal value, but the other 3 showed completely normal sella. Localized bulging of the sella floor was found in 2 cases by midline lateral tomography. In the A-P tomogram asymmetry of the sella floor was found in one case and localized bulging in other 2 cases. Minimal suprasellar expansion of the tumor was found only in one case by midline pneumotomography. Magnified cerebral angiography with subtraction method or computed tomography was not diagnostic to verify pituitary microadenomas. The indication of pituitary surgery had to be decided mainly by endocrinological findings. In only one case the adenoma occupied most of the intrasellar space, but in the other 5 they were microadenomas and 3 of them were buried in the normal glands. Complete resection of the adenoma was attempted, but macroscopically normal tissue was tried to be left as much as possible. Typical Crooke's hyaline changes were found in the normal adenohypophysis in one case and immunohistochemical studies using anti-ACTH serum revealed that the Crooke's cells are still reactive. After surgery most patients showed decreased plasma ACTH and cortisol levels and substitution therapy of adrenocortical hormones was necessary for the first one or two months. Rapid clinical remission of Cushing's syndrome was observed in all but one, who might have residual tumor cells due to technical incompleteness. Successive endocrinological reevaluation showed that pituitary-adrenal function has been normal or subnormal in 5 cases. One showed no significant improvement. None had pan-hypopituitarism nor any serious side effects, such as liquorrhea and continuous diabetes insipidus. Overall results suggest that transsphenoidal resection of pituitary adenomas in Cushing's disease should be located in the center of the treatment.