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Twelve adult males with documented active Cushing's disease were studied. Mean plasma testosterone (T) was significantly decreased: 1.8 +/- 0.3 (SEM) ng/ml (N=6.8 +/- 0.5); gonadotropin measurements in 8 patients, in basal conditions and under LH-RH iv, showed a significant decrease in both FSH and LH. A further study of 11 patients in remission of Cushing's disease indicated a significant increase in plasma T and gonadotropins up to the normal range. One patient with an initial low T value had a normalized T while in remission, then a dramatic decrease when the disease relapsed. We conclude: a hypogonadotropic hypogonadism is found in male Cushing's disease; it disappears as early as hypercortisolism is suppressed. Some possible mechanisms are discussed.

Serum somatomedin/insulin-like growth factor (IGF) levels in 92 acromegalic patients were measured, after gel filtration in acetic acid, by means of a competitive proteinbinding assay using specific binding proteins produced by rat liver in culture and human IGF-I as tracer. Results are expressed in comparison with a pool of normal adult serum arbitrarily assigned a value of 1 U/ml. In 37 untreated patients, the mean IGF level was 2.64 ± 0.13 (SEM) U/ml, whereas in 34 normal subjects, it was 1.06 ± 0.03 U/ml. In all patients, IGF levels were above the mean + 2 SD of control values. Among the patients studied after treatment, two thirds of the 43 patients in whom removal of the pituitary tumor was complete had normal or subnormal IGF levels, while the remaining third had values above normal, and 34 patients in whom removal of the pituitary tumor was incomplete had IGF values close to those in untreated patients. In these subjects, cobalt therapy reduced the IGF levels, which, nevertheless, remained higher ...

We studied the electrophoretic pattern of hemoglobin (Hb) and red blood cell indices in 128 women divided into four groups: group I, 36 nonanemic hyperthyroid women, divided in two subgroups: 36 with untreated hyperthyroidism (subgroup IA) and 9 made euthyroid by antithyroid drug therapy (subgroup IB); group II, 12 nonanemic women with untreated hypothyroidism; group III, 30 women known to be heterozygous for beta-thalassemia; and group IV, 50 healthy women. The mean (+/- SEM) HbA2 level was higher (P less than 0.001) in subgroup IA (3.21 +/- 0.06%) than in subgroup IB (2.42 +/- 0.09%) and group IV (2.48 +/- 0.04%), but lower (P less than 0.001) than in group III (5.26 +/- 0.12%). The mean HbA2 level was lower (P less than 0.001) in group II (1.99 +/- 0.08%) than in group IV. Hb fetal was detectable in eight patients of subgroup IA and undetectable in subgroup IB and groups II and IV. The mean cellular volume was lower (P less than 0.001) in subgroup IA than in other nonanemic groups. The mean cellular volume was higher (P less than 0.001) in group II than in group IV. Follow-up of nine patients who became euthyroid with treatment showed the normalization of these erythrocyte parameters. These results suggest that thyroid hormones can modulate the synthesis of delta- and gamma-globin chains.

Dihydrotestosterone (DHT) was administered percutaneously in a dose of 125 mg twice daily for 10 days to 12 normal men. Basal plasma levels of testosterone (T), 17 beta-estradiol (E2), and LH were measured every 2 days in these men and every 5 days in subjects from a control group receiving placebo. The daytime course of plasma hormone levels between two DHT applications was studied in six men. LRH tests were performed in nine men before and on day 10 of DHT administration. Plasma levels of free T and free E2, and T - E-binding globulin capacity and affinity were measured in six men before and on days 5 and 10 of DHT administration. Before DHT administration, there was no difference in basal plasma levels of T, DHT, E2, and LH between the control and the DHT-treated group. In the latter group, plasma DHT levels increased sharply from 0.52 +/- (+/- SE) to 3.70 +/- 0.92 ng/ml on day 2 (P less than 0.001) during DHT treatment. Plasma T, E2, and LH levels decreased significantly from 7.33 +/- 0.74 to 1.33 +/- 0.54 ng/ml (P less than 0.001), from 46 +/- 5 to 20 +/- 3 pg/ml (P less than 0.01), and from 7.8 +/- 1 to 4.2 mIU/ml (P less than 0.05), respectively. Except for a small decrease in plasma DHT (P less than 0.05) 12 h after the previous DHT application, hormone levels were stable during the time between the two DHT treatments. The responses of LH and FSH to LRH were not different before and on day 10 of DHT administration. Plasma levels of free T and free E2 as well as those of total T and E2 decreased; however, the percentages of unbound T and E2 were not different before and during DHT administration. T - E-binding globulin capacity and affinity were not modified by DHT administration. Changes in plasma DHT levels were negatively correlated with those in The results of this study demonstrate that 10-days DHT administration has an inhibitory effect on the hypothalamo-pituitary-testicular axis in normal men.

Plasma testosterone (T), dihydrotestosterone (DHT) and estradiol (E2) were determined by radioimmunoassay in 10 normal males receiving hCG im 5000 IU on days 1, 2 and 3. The mean increase of plasma steroid on days 2, 3 and 1, respectively, was: 1.42, 1.79 and 1.87 times for T; 1.17, 1.56 and 1.49 times for DHT; 4.04, 3.29 and 2.33 times for E2. While T was still significantly increasing from day 2 to day 4, E2 significantly decreased. A positive correlation (P less than 0.01) was found between the basal T and the E2 peak after hCG, suggesting a release of E2 from a storage compartment in the testis. No significant change of either steroid was detected 4 h after the first hCG injection. In 6 cases of primary male hypogonadism, the mean basal values of T to hCG was defective, despite considerable individual variations. In 14 males with gonadotropin deficiency, basal values of T and E2 were very low; the T response to hCG ranged from undetectable to dramatic, and was correlated with the degree and duration of previous exposure to gonadotropin; and impaired response of E2 in all cases porvides a better estimate of the actual gonadotropin deficiency.

SummaryAfter an analysis of the consequences of hypercorticism, the three causes of Cushing syndrome ate considered : adrenal tumour, paramoplasic syndrome and Cushing disease (hypereorticism of central origin).The Characteristics of hypereorticism in Cushing disease are described, as well as the changes in ACTH secretion, the anomalies of the feed-back ACTH-Cortisol system, the frequency, type and initial symptomatology of pituitary tumours. A physiopathologic concept is proposed : Cushing disease could be due to hypothalamic disturbance and primary central hypertonia of undetermined origin, responsible of pituitary stimulation, leading to adrenal hyperplasia.The created pituitary disturbance could be the site of single overactivity of micro-adenomas or of a single tumour which could make its appearance after adrenalectomy; the adrenals would show single diffuse or micro-adenomatous hyperplasia. The different histologic pictures of the pituitary or of the adrenals would constitute successive steps of a s...

Fifteen female patients with amenorrhea and hyperprolactinemia were studied 1 to 3 times daily during the first 4 days of treatment with bromocriptine (2.5 mg b.i.d.). Normal PRL levels were reached within one day in 12 while the mean value for the whole group showed no further significant decrease. Estradiol, LH and FSH levels did not vary significantly at this stage even in those 10 patients who subsequently resumed menstruation.

We have studied clinical and endocrine parameters in a group (group A) of forth men referred to us because of persistent idiopathic gynaecomastia (of more than 18 months duration), before and during the administration of percutaneous dihydrotestosterone (DHT). The endocrine parameters (testosterone (T), 17 beta-oestradiol (E2), DHT, gonadotrophins (FSH and LH) and prolactin (PRL), were compared to those of control groups of 12 healthy men on DHT therapy (group B) and 10 on placebo (group C). Local administration of DHT was followed by the complete disappearance of gynaecomastia in 10 patients, partial regression in 19 and no change in 11 patients after 4 to 20 weeks of percutaneous DHT (125 mg twice daily). Before treatment the T + DHT/E2 ratio was significantly (P less than 0.001) lower in group A 244 +/- 21 (SEM) than in groups B and C (361 +/- 21) while T, DHT and E2 concentrations were all within the normal range. During DHT treatment plasma hormone levels were measured in 26 patients from group A: DHT levels increases significantly (day 0: 1.63 +/- 0.14 nmol/l; day 15: 12.8 +/- 1.6 nmol/l, P less than 0.001) while T and E2 levels fell significantly (T: day 0: 22.6 +/- 1.2 nmol/l; day 15: 11.0 +/- 1.5 nmol/l, P less than 0.001; E2: day 0: 110.5 +/- 7.12 pmol/l; day 15: 86.79 +/- 9.4 pmol/l, P less than 0.01). The T/E2 ratio decreased from 231 +/- 20 to 164 +/- 27 (P less than 0.05) while the T + DHT/E2 ratio increased significantly (P less than 0.02) to a normal mean value (day 15: 354 +/- 57).(ABSTRACT TRUNCATED AT 250 WORDS)

In a study of nonsurgical therapy of Cushing's disease, 62 patients received O,p'-dichlorodiphenyldichloroethane (O,p'DDD), 16 of whom also received cobalt irradiation of the pituitary. After an initial treatment period averaging eight months, a remission of the disease was obtained in 38 of the 46 patients given O,p'DDD alone and in all patients who received drug combined with radiation. Although 60 per cent of these patients subsequently relapsed, additional courses of drug or radiation therapy were usually effective, and 63 per cent of the entire group of patients have so far been kept under control without adrenalectomy. (Forty patients have been followed for at least two years after the initial course of treatment.). O,p'DDD produced little gastrointestinal discomfort; an increased serum cholesterol was the main side effect. This drug allows long-term medical management of Cushings disease in most cases. Whether the combination of O'p'DDD with pituitary radiation is the best therapy has not been established.

Transsphenoidal pituitary surgery was performed in 64 patients with Cushing's disease in search of a corticotroph adenoma. In 4 patients, profuse local bleeding prevented completion of the exploration. Of the 60 patients who had an adequate exploration, 4 could not be followed after surgery. Short term assessment of the surgical outcome (3-6 months postoperatively) was performed on 60 patients, including the 4 who had incomplete pituitary exploration. Forty-two patients (70%) were judged as immediate successes [urinary cortisol excretion, less than 90 micrograms (less than 248 nmol)/day]; the mean urinary cortisol excretion and plasma ACTH level fell from 463 +/- 70 (+/- SE) to 26.7 +/- 3.6 micrograms/day (1277 +/- 193 to 74 +/- 10 nmol/day; n = 33) and from 111 +/- 33 to 36 +/- 14 pg/mL (24 +/- 7 to 8 +/- 3 pmol/L; n = 23) in patients who had both measurements pre- and postoperatively. Eighteen patients (30%) were judged as immediate failures; neither urinary cortisol excretion nor plasma ACTH levels changed significantly in patients who had both measurements pre- and postoperatively. The preoperative epidemiological, clinical, hormonal, and radiological characteristics of the 2 groups were similar. Histological examination of pituitary fragments removed in 58 of the 60 patients evaluated postoperatively revealed the presence of tumoral tissue in a higher percentage of patients in the immediate success group (72%) than in the immediate failure group (24%; P less than 0.01). The 42 patients in the immediate success group were followed from 6 months to 7 yr (median, 2 yr); 6 patients had recurrences from 2-3 yr after operation. Actuarial analysis indicates that the probability of a patient remaining well 6 yr after surgery is 72 +/- 20% (95% confidence limit). Most of the patients in the immediate success group had transient ACTH deficiency preceding a progressive return to normal pituitary-adrenal function.

A human pituitary adenoma responsible for a case of Nelson's syndrome was maintained in organ culture and the incubation medium was examined with four different RIAs; human corticotropin (ACTH), beta-MSH, lipotropin (LPH), and beta-endorphin (beta-End). All four immunoreactivites (IRs) were present in the medium obtained after 24 h of incubation. Gel exclusion chromatography under denaturing conditions (6 m guanidine HCl) revealed several immunoreactive components. Two components having both human beta-MSH (beta-hMSH) and human LPH (hLPH) IR coeluted with beta-hLPH and gamma-hLPH; a component with beta-hMSH IR but no hLPH IR coeluted with [125I]beta-hMSH; a component with human ACTH (hACTH) IR eluted at the position of hACTH. Sephadex G-50 gel exclusion chromatography revealed that approximately 80% and 20% of human beta-End (beta-hEnd) IR were accounted for by components coeluting with beta-hLPH and beta-hEnd, respectively. These data demonstrate the presence in this incubation medium of materials similar to if not identical with beta-hLPH, gamma-hLPH, hACTH, beta-hMSH, and beta-hEnd; they suggest that all of these peptides may be secreted in the circulation of patients with Nelson's syndrome.

A radioimmunoassay directed toward the NH2-terminal region of mouse pro-ACTH/endorphin (called 16K fragment) was used to examine human samples. Culture media from two corticotropic adenomas and plasmas from 11 patients with various ACTH hypersecretory syndromes gave parallel displacement curves; displacement curves for human samples were not parallel to purified mouse 16K fragment. Following sodium dodecyl sulfate polyacrylamide gel electrophoresis of culture medium from one adenoma, a major peak of 16K fragment immunoreactivity with an apparent molecular weight of ca. 16,000 was detected. A significant correlation (r = 0.963 ; p less than 0.001) was found between immunoreactive 16K fragment and ACTH in the patients' plasmas. These data indicate that a peptide similar to 16K fragment exists in man ; that human and mouse 16K fragment are immunologically distinguishable and that human 16K fragment appears to be secreted concomitantly with ACTH.

The effect of synthetic MIF (H-Pro-Leu-Gly-NH2) on beta-MSH secretion was studied in five patients with Nelson's syndrome and in one patient with Addison's disease. Two milligrams of the tripetide were injected intravenously (1 mg in an acute injection, followed by a 30-minute-infusion of 1 mg in 20 ml of saline solution). No consistent effect could be observed during the 90-minute period after the beginning of the infusion. In the same patients, LVP stimulation and dexamethasone suppression tests brought about significant changes in the plasma beta-MSH and ACTH levels.

Tissue concentrations of immunoreactive lipotrophin, β-endorphin, and met-enkephalin were determined in 10 phaeochromocytomas, 3 of which were responsible for the ectopic ACTH syndrome. Lipotrophin and β-endorphin immunoreactivities could be detected in all cases, whether or not Cushing's syndrome was present, and their tissue concentrations were significantly correlated (r = 0.95, P < 0.001). Chromatographic studies showed tha γ-lipotrophin and β-endorphin were the main peptides in the tumours. Met-enkephalin immunoreactivity was also found in all tumours examined, at much higher concentration and showing no correlation with either lipotrophin or β-endorphin immunoreactivity. Although β-endorphin and met-enkephalin are thought to originate from different precursor molecules, these data show that the two opioid peptides may be secreted by the same tumour. The evidence for excess secretion of opioid peptides and their pathological significance in phaeochromocytomas remain to be established.

We evaluated the usefulness of measurement of urinary free corticoids (UFC) in the diagnosis of hypercorticism. One hundred and thirty patients with features suggestive of Cushing's syndrome were examined. Twenty-six patients were proved to have Cushing's syndrome. The remaining 104 patients were considered not to have this disease on the basis of other investigations, and were designated as 'suspected patients'. UFC and 17-hydroxycorticosteroids were measured in all these patients in the basal state and on the 5th day of a low-dose-dexamethasone suppression test (3 mg/day for 5 days). UFC values of patients with Cushing's syndrome were well above 125 μg/24 h in the basal state and higher than 10 μg/24 h during the suppression test. UFC values of 'suspected patients' were between 20 and 125 μg/24 h in the basal state and below 10 μg/24 h during the suppression test. It can be concluded that the measurement of UFC in the basal state and on the 5th day of a suppression test is not only a very sensitive but also a specific method for the diagnosis of Cushing's syndrome.

A new 17α-hydroxylase deficiency associated with male pseudohermaphroditism without evidence of puberty and severe hypertension due to hypermineralocorticism is reported. The defect was proven by low excretions of 17aα-hydroxysteroids associated with hyperproduction of progesterone, pregnenolone, corticosterone and desoxycorticosterone. Correction of hypertension and of hypokalemic alkalosis was obtained with dexamethasone therapy. Before dexamethasone, aldosterone excretion was low and it remained low after one yr of this treatment. The secretion of 18-hydroxycorticosterone was 6 times increased before dexamethasone therapy and returned to normal after one yr of treatment. Data strongly suggest another defect: 18ol-dehydrogenase deficiency.