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Lymphocytic hypophysitis usually occurs in the antepartum or postpartum period and recovery of pituitary dysfunction has not been documented in most cases reported previously. We present a 50-year-old woman with lymphocytic hypophysitis who spontaneously recovered from panhypopituitarism over 18 months with the disappearance of an intrasellar mass. Although lymphocytic hypophysitis is thought to be an autoimmune disease, the clinical and pathogenetic significance of circulating antipituitary autoantibodies has not been clarified. Antipituitary antibodies were studied by immunofluorescence in blood samples obtained during the whole clinical course in this particular patient. Antibodies against rat pituitary cytosol were positive during the period of hypopituitarism and became negative when pituitary function recovered. Antibodies reacting with intact prolactin-secreting rat GH3 and corticotropin-secreting mouse AtT-20 cells were also positive during her period of hypopituitarism. They remained positive for several years after the recovery of pituitary function. We conclude that circulating antibodies against rat pituitary cytosol are good markers of pituitary inflammation in this patient. The other point to be emphasized in this case is the simultaneous development of painless thyroiditis and lymphocytic hypophysitis. We have discussed the pathogenic relationship of these two diseases on the basis of similar cases reported previously.

Four post-menopausal women had Cushing's syndrome due to adrenal cortical carcinomas. Comprehensive analyses of blood and urinary steroids showed that although the steroid profiles differed between patients, the pattern in each patient remained almost constant as the disease progressed, or remitted due to therapy. Elevations of serum testosterone and oestradiol were commensurate with the extent of virilisation, and the urinary output of aldosterone was associated with the severity of hypertension. A new finding was that all had substantially increased urinary free deoxycorticosterone. Complete surgical removal of the primary tumours was impossible but when most of the tumour tissue was removed, full clinical and biochemical remissions were obtained for a short time in 2 patients. One patient obtained a clinical and biochemical remission from op'DDD. In another patient the drug caused reduction both in blood pressure and in urinary aldosterone excretion, but there were unpleasant side effects. A third patient could not tolerate op'DDD. Metyrapone therapy produced neither clinical nor biochemical improvement in 3 patients. The mean duration of survival was 17 months after the first symptoms and 10 months from the date of operation. Despite advances in drug therapy, adrenal cortical carcinoma remains a lethal disease. Biochemical screening of multiple steroids offers a means of early diagnosis and disease monitoring. Extensive surgical removal of the tumour offers the best chance of a clinical and biochemical remission.

Cushing's syndrome was diagnosed in a 14 year old girl and, 5 years later, in her nephew (sister's son) also when he was 14 years of age. Administration of tetracosactid (Synacthen) did not stimulate adrenocortical function in either patient, nor did dexamethasone suppress the elevated urinary steroids in the girl, and only partially suppressed them in the boy. Both patients were adrenalectomized and made an uneventful recovery. The surgical specimens were identical both on gross inspection and histologically, showing the typ ical morphological features of pigmented multinodular adrenocortical dysplasia. We believe that this lesion represents an inherited adrenocortical maldevelopment (rather than true neoplasia) leading to an autonomous adrenocortical hyperfunction which typically manifests itself clinically during adrenarche (i.e. functional adrenocortical maturation) at the beginning of puberty. Family Cushing's syndrome, caused by pigmented multinodular adrenocortical dysplasia, represents a disease entity.

Recent reports of patients with Cushing's disease who have been explored via the transsphenoidal route indicate that the great majority has pituitary adenomas. We report a patient with biochemically documented pituitary-based hypercortisolism who had a clinical and biochemical remission following hypophysectomy. Serial sections of the pituitary tissue removed showed hyperplasia of corticotroph cells but no adenoma. Hypophysectomy was complete as documented by serum levels of FSH, LH, TSH, prolactin, hGH and ACTH at the lower limits of the respective assays, with no response to appropriate stimuli. This case demonstrates that a minority of patients with Cushing's disease has corticotroph cell hyperplasia without a pituitary adenoma.

Pituitary adenoma was suspected in a woman of 74 with hypercorticism,hypokalaemic alkalosis and radiographically enlarged sella turcica. However, non-suppressibility of steroid excretion by high-dose dexamethasone and low plasma concentration of ACTH suggested adrenal tumour. Detailed analysis of urinary steroid excretions demonstrated unusually large amounts of corticosterone metabolites, 14.6 mg/24 h compared to a mean normal value of 0.5 mg. The basal levels of the remaining pituitary hormones were unremarkable. The patient died incidentally before a planned adrenalectomy. The autopsy disclosed an adrenal carcinoma and an empty sella turcica. The enlarged pituitary fossa was lined by a narrow rim of histological normal pituitary tissue.

Cushing's syndrome was found in 2 of 4 siblings all of which also had other malformations. After bilateral adrenalectomy no hyperpigmentation was noted. Morphologically the adrenals of both siblings with Cushing's syndrome showed the typical lesions of the so-called microadenomatosis or primary adrenocortical nodular dysplasia with foci of eosinophilic giant cells. This is a new form of Cushing's syndrome due to an inborn error of the adrenals and no hypothalamic-pituitary dysfunction.

The excretion of 7 individual 17-oxosteroids and 7 individual corticosteroids in 24 h urine samples from 62 normal infants, children and adolescents, based on an accurate and specific paper chromatographic method for their separation and quantitation, is reported. The excretion of the 11-deoxy-17-oxosteroids gradually increases from 7 years of age and the increase becomes more rapid 2 or 3 years before the clinical signs of puberty appear. The rise continues throughout puberty and beyond it until the adult level is reached. The increase far exceeds that which would be accounted for by the growth of the individual. The increase in the excretion of the 11-oxy-17-oxosteroids with age is much more gradual. Androgens favour the formation of 5alpha metabolites and the 5alpha:5beta ratio of the total 5alpha 17-oxosteroids and the total 5beta 17-oxosteroids shows a statistically significant increase with age. In addition, a relatively high 5alpha:5beta ratio is noted in male infants, which is likely to be related to their relatively high plasma testosterone levels. The excretion of the 17-hydroxycorticosteroids and the alpha-ketolic metabolites of cortisol gradually rises with age and correlates with body weight. The alpha-ketolic metabolites of corticosterone are relatively high in infancy, but after the age of 4 years their excretion also correlates with body weight. An increase in the 5alpha:5beta ratio of allo-THF to THF is noted at puberty similar to that found with the 5alpha:5beta ratios of the 17-oxosteroids.

A virilizing adrenocortical adenoma was demonstrated in a yound female. Urinary 17-ketosteroid excretion and subfractions, plasma testosterone level and urinary 17-ketogenic steroid excretion were markedly increased. Dehydroepiandrosterone was the main constituent of the androgen excess. Otherwise the adrenocortical function was found to be normal as evaluated from measurements of cortisol, corticosterone and their metabolites under basal conditions and during dynamic tests. The androgen excess showed an unexpected response to trophic hormones. Human chorionic gonadotrophin stimulation resulted in a pronounced increase in androgen production, whereas no gonadotrophin-dependency could be demonstrated by means of the oestrogen suppression test. Similarly, no corticotrophin-dependency could be demonstrated by corticotrophin stimulation and suppression tests. Removal of the tumour resulted in normalization of the androgen production and no abnormal response upon human chorionic gonadotrophin administration could now be found. The inappropriate response of tumours to trophic hormones is discussed. It is concluded that the reliability of stimulation and suppression tests in determining the site of excessive androgen production should be accepted with reservation.

Three otherwise healthy relatives of patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency and salt-wasting presented with clinical and/or biochemical findings, which exceeded those usually seen in heterozygotes: Two females (1 mother and 1 prepubertal sister of a patient with CAH) had marked hypertrichosis and hirsutism and excreted pregnanetriolone in their urine. The mother had increased basal plasma 17alpha-OH-progesterone (296 ng/100 ml), which increased to 7170 ng/100 ml after ACTH as in homozygotes of CAH. One adult male (brother of a patient with CAH) was clinically normal, but also excreted pregnanetriolone and had a high plasma 17alpha-OH-progesterone (1905 ng/100 ml), which increased further to 6352 ng/100 ml after ACTH. It is concluded that these subjects represent unusually marked heterozygotes of CAH rather than mild homozygotes. In females, this condition should be included in the differential diagnosis of idiopathic hirsutism, in males, it will pass unnoticed, unless relatives of patients with CAH are systematically tested.

A 52 year old man is described in whom the simultaneous occurrence of isolated adrenocorticotrophin (ACTH) deficiency and primary hypothyroidism was documented by the determination of six anterior pituitary hormones by specific radioimmunoassays after suitable stimulations. The urinary 17-hydroxycorticosteroids excretion was persistently reduced and was increased by repeated ACTH injections. The low basal metabolic rate, reduced serum thyroid hormones and elevated serum thyrotrophic hormone were consistent with primary hypothyroidism. After resumption of euthyroidism, secretory reserves of growth hormone and ACTH were assessed. The growth hormone reponse to insulin-induced hypoglycaemic was normal. No rise in plasma cortisol and ACTH was observed following insulin-induced hypoglycaemia. Plasma ACTH was not augmented by iv infusion of metyrapone. The pathogenesis of two co-existent endocrine deficiencies was discussed.

Urinary excretion of 17-ketosteroids was measured during dexamethasone substitution followed by ACTH (Synacthen Depot, 1 mg daily) in 10 non-virilized adrenalectomized women. No significant changes could be demonstrated indicating ovarian androgenic dependence of ACTH in non-virilized females.

In a series of 146 school girls and nurses in the serum levels of growth hormone (GH), follicle stimulating hormone (FSH), and luteinizing hormone (LH) were determined in the afternoon after 4-5 hours' fast. Blood specimens of the menstruating girls were taken on the 7th to 10th day from the beginning of the preceding menstrual bleeding. From the 24-hour urines collected on the previous day the excretion of total oestrogens, 17-ketosteroids and 17-hydrocorticosteroids was determined. The series was grouped according to skeletal age which varied from 8.0 years to the adult stage. In the girls aged 11-13 years the GH curve showed a significant rise parallel with the mean height curve. The FSH values at the early age of 8-9 years corresponded to the follicular phase of adult women. The LH level increased syteeply up to the 15th year of bone age and mean values of adults were found to be about three times those of childhood. The excretion of total oestrogens and 17-ketosteroids increased steadily up to the full maturity of skeletal age. In the oldest group of girls the excretion was about four times that of the group aged 8-9 years. The hormonal maturation seems to continue until late puberty. The 17-OHCS, on the other hand, reached the adult level in the group with a bone age of 13 years. The excretion of 17-OHCS shows a steep rise from the age of 11 to 12 years and this acceleration of excretion perhaps exceeds the increase in surface area.

Plasma testosterone levels were suppressed in 6 of 8 mature male patients with Cushing's disease, all of whom complained of loss of libido and decreased sexual potency. Gonadotrophin levels, both under basal conditions and in response to LH-RH, were generally normal. The testicular response to stimulation with hCG was brisk in the 2 patients examined. Oestradiol levels were slightly elevated in 2 patients and prolactin levels were normal in all patients. Thus, male patients with Cushing's disease demonstrated normal gonadotrophin levels in the presence of suppressed testosterone, or, viewed from a slightly different prospect, low testosterone levels despite normal gonadotrophins. Neither oestradiol nor prolactin excess appeared to account for the observations. Possible explanations for these findings include (a) a combination of impaired hypothalamic and testicular function, and (b) a resetting downwards of the level of testosterone that is seen as appropriate by the disordered bypothalamic-pituitary unit. Following correction of cortisol excess in Cushing's disease, testosterone levels rose into the normal range.

The endocrine effects of ketoconazole (400 mg orally every 8 h) were studied in 9 previously untreated patients with advanced prostatic cancer. Five of these patients were followed for 12 months. A rapid fall in the serum concentration of testosterone was noted in all patients studied. Minimal values were observed on day 4 of treatment but thereafter serum testosterone increased slowly. The effect of the drug on unbound testosterone was relatively more important, since sex hormone binding globulin increased markedly during treatment. An increase in progesterone and LH was observed in all patients. This suggests that ketoconazole limits the conversion of C21-precursors into androgens. This block is compensated in part by activation of the hypothalamo-hypophyseal feedback system. Urinary 17-ketosteroids were decreased but 17-hydroxysteroids were unaffected by the treatment. In 5 patients followed monthly over a period of 12 months the mean testosterone concentration ranged from 69 ng/100 ml in one patient to 428 ng/100 ml in another. An excellent inverse correlation could be demonstrated between the mean serum concentration of testosterone and the mean concentration of ketoconazole. The change of serum dehydroepiandrosterone sulphate also correlated inversely with the mean ketoconazole level. Increased concentrations of oestradiol were noted in 2 patients with slight gynaecomastia. It is concluded that long-term suppression of androgen production can be realized by high-dose ketoconazole treatment and that the degree of suppression is proportional to the serum levels of the drug.

To determine endocrine activity of adrenal tumours incidentally discovered on C.T., we examined 20 consecutive patients. They underwent thorough hormonal assessment and scintigraphic scanning with radioactive cholesterol under dexamethasone suppression (19 patients). Biochemical findings compatible with cortisol hypersecretion were detected in 5 patients. One patient had reduced reserves of cortisol secretion and one had hyporeninemic hypoaldosteronism. The scintigraphy showed no uptake in 10, unilateral uptake in 4, and bilateral uptake in 5 patients. In 3 patients the finding was unilateral on CT. but bilateral on scintigraphy. Signs of autonomous cortisol production were more common among patients who had uptake on scintigraphy. At the operation of 8 patients only benign lesions were found. During the follow-up (9 to 49 months) of the 12 unoperated patients, the tumour disappeared in one and remained unchanged in the others. No changes occurred in the biochemical findings except in one patient whose cortisol response to 1 mg of dexamethasone became abnormal. Since slight hypercortisolism or a bilateral disease often exists behind an incidentally discovered adrenal tumour, we emphasize the importance of careful assessment of cortisol metabolism and a scintigraphic scanning under dexamethasone suppression in the examination of these patients.

Significantly decreased levels of serum testosterone from the pre-anaesthesia level were found during and up to 7 days following major surgery under general anaesthesia (nitrous oxide, oxygen and halothane following induction with thiopental and succinylcholine chloride) in 18 male patients. On the other hand in the same patients, the serum lutenizing hormone (LH) increased significantly from the pre-anaesthesia level 30 min and 1 h after the beginning of anaesthesia. A slight increase in LH level was also noted on the 7th post-operative day. The determinations of serum testosterone and LH in fiberoptic bronchoscopy under the same general anaesthesia as that used in surgery or local anaesthesia in 26 male patients, revealed that the change in the serum LH during and following surgery seemed to be mainly induced by the general anaesthesia and that the rate of decrease in the serum testosterone may be related to the severity of surgical stress including the anaesthesia. The rate of increase in serum testosterone following the injection of gonadotrophin in 20 males on the 6th post-operative day was similar to that in 10 pre-operative males. The effects of pulmonary lobectomy on serum testosterone and urinary steroids were also studied in 6 males under adrenal suppression with dexamethasone. On the 6th post-operative day, the urinary aetiocholanolone plus androsterone and serum testosterone were found to be half the level of those on the pre-operative day, while the urinary 5beta-pregnane-3alpha, 17alpha, 20alpha-triol remained unchanged. These observations in human are not inconsistent with the report of Tcholakian and Eik-Nes (1971) in dogs namely that a shift in androgen biosynthetic pathway is present in the testis under surgical stress.

Plasma and urinary corticosteroids were measured in 13 obese subjects before and after high and low protein diets, and after fasting. During isocaloric high and low protein diets, urinary 17-oxogenic steroids and to a lesser extent urinary free cortisol excretion rose and fell in parallel with protein intake. Plasma unbound cortisol levels were not much changed by high or low protein intake. However, during 7 to 11 days total fasting, there was a highly significant rise in plasma unbound cortisol at 24.00. A smaller rise occurred at 09.00. The overall effect was a considerable diminution of the day-night variation of plasma unbound coritsol levels during fasting, and a rise in prevailing unbound cortisol levels and urinary free cortisol excretion. In 3 subjects tested these changes were reversed immediately by glucose re-feeding.

Congenital stenosis of the aqueduct of Sylvius is reported to be associated with sella turcia enlargement and clinical and laboratory abnormalities of the hypothalamic-pituitary-target-organ axis. It is a surgically reversible lesion. In the present report, 3 female patients with this lesion were studied with tests of basal endocrine function, as well as insulin tolerance tests, response to metyrapone and determination of circadian periodicity of plasma cortisol levels. In one patient all testing was normal and no surgery was performed. In 2 other patients the insulin tolerance test revealed either abnormal cortisol or growth hormone responses and in one patient urinary gonadotrophins were absent. All tests became normal post-operatively although in one instance not completely so until 5 years after surgery.

Unlabelled: We determined glucocorticoid receptors in human mononuclear leukocytes in 9 patients with Cushing's disease, in order to correlate them with laboratory data. Receptors were measured by a whole-cell assay method, after incubation with [3H]-dexamethasone in the presence or absence of excess unlabelled hormone. In Cushing's disease, there were 4425 +/- 364 sites/cell (N = 9), similar to in the controls: 4473 +/- 476 (N = 10); average Kd was 2.42 +/- 0.52 nmol/l (N = 3) similar to in the controls: 2.0 +/- 0.20 nmol/l (N = 3). In Cushing's patients we found significant negative correlations between basal glucocorticoid receptors and: 1) morning blood cortisol (r = -0.67, P less than 0.05), and 2) 17-ketogenic steroids after 2 mg of dexamethasone (r = -0.85, P less than 0.01). No correlations were observed with afternoon blood cortisol, free urinary cortisol, basal and post-8-mg dexamethasone 17-ketogenic steroids, TRH-TSH area, urinary calcium, plasma glucose, or systolic blood pressure., Conclusions: In Cushing's disease, a subtle receptor down-regulation may exist, as suggested by the inverse relationship between glucocorticoid receptors and morning blood cortisol. Secondly, the relationship between basal receptors and 17-ketogenic steroids after 2 mg of dexamethasone suggests that glucocorticoid receptors in human mononuclear leukocytes could reflect the sensitivity of the nervous system-pituitary-adrenal axis to dexamethasone inhibition.

A patient with a thymic carcinoid tumour causing ectopic ACTH syndrome is presented. The case illustrates the rapid development of the clinical and laboratory findings often associated with ectopic secretion of ACTH, including severe proximal myopathy, emotional lability, and hypokalaemic alkalosis. Interpretation of conventional tests of pituitary-adrenal function was complicated by intermittent secretion of ACTH by the tumour. The results of selective venous sampling for ACTH ruled out pituitary ACTH hypersecretion and were suggestive of a thymic source; computerized tomography of the chest localized the tumour. In vivo and in vitro investigations confirmed excessive ACTH production by the tumour, and surgical resection plus radiotherapy has resulted in resolution of the syndrome. The diagnostic problems created by intermittent secretion of ACTH by these tumours and the pre-operative and post-operative medical management of these patients are discussed.

Serum concentrations of LH, FSH and testosterone, and urinary excretion of individual 17-ketosteroids, oestrogenic substances and free cortisol was investigated in 12 normal men after a daily administration of 50 mg clomiphene citrate for 14 days. A significant increase in the serum concentrations of LH, FSH and testosterone was seen after 8 days with a further increase when measured a week later. The percentual increase in urinary excretion of oestrogens and dehydroepiandrosterone was of the same order as the increase in serum testosterone concentrations whereas the increase in androsterone and a aetiocholanolone was significantly lower. The excretion of free cortisol was unaltered. The study that measurements of oestrogens in the urine might be used as a parameter of the stimulatory effect of clomiphene on the hypothalamic - pituitary - gonadal axis in man. In addition, of the results support the hypothesis of an independent effect of clomiphene on adrenal steroidogenesis, not related to the production of glucocorticoids.

Oral testosterone undecanoate (TU) in arachis oil has been evaluated with a view to its possible use as a means of androgen replacement therapy. A single 100 mg dose was found to elevate plasma androgen levels and urinary 17-ketosteroid excretion in 6 normal men. Ninety mg/day and 60 mg/day doses taken by a hypogonadal man resulted in sustained levels of androgen which appeared physiological when measured by radioimmunoassay without chromatography. However, upon separation of the steroids by chromatography it was found that much of the androgen present was in fact dihydrotestosterone not testosterone. Both TU and dihydrotestosterone undecanoate were detected in plasma by gas chromatography and it is suggested that the ester is absorbed as such from the intestine and the unesterified steroid subsequently released by hydrolysis. The convenience of oral administration, the resulting prolonged elevated plasma androgen levels and the probable lack of deleterious effects on the liver may render oral TU of value where androgen replacement therapy is indicated.

Unlabelled: A 12 year old child (46,XY) with 17-ketosteroid reductase deficiency was investigated. The patient, reared as a female, was first noted to have clitoromegaly at 10 years of age. Increased facial hair, deepening of the voice, acne, increased body hair and minimal breast development were noted at 12 years. delta4-Androstenedione (delta4) in peripheral blood was markedly elevated (1913 ng/100 ml) whereas testosterone (T) was in the male range of Tanner III puberty (240 ng/100 ml). Thus, delta4/T in this patient was 9.4, compared to a normal ration of 0.15 to 0.25. T/DHT was normal (10.5). Oestrone (Oe1) level was slightly elevated (6 ng/100 ml, normal: 2.5-4.5 ng/100 ml). Oestradiol (Oe2) was normal (1.7 ng/100 ml, normal: 1.5-3 ng/100 ml. Oe1/Oe2 was slightly elevated (3.6, normal: 1-2). At laparotomy, testes were found and spermatic vein blood was obtained prior to castration. Androgen determinations of spermatic vein blood demonstrated extremely high delta4 levels (283 microgram/100 ml) and low levels of T (16 microgram/100 ml). delta4/T in spermatic vein was 17, higher than in the peripheral blood, suggesting intact peripheral conversion of delta4 to T. Incubation of testes slices with delta4 demonstrated severely impaired conversion to T. Conversion of Oe1 to Oe2 was impaired to a lesser degree., Conclusion: 17-ketosteroid reductase deficiency was documented in vivo by impaired conversion of precursor hormones resulting in higher than normal delta4T and Oe1/Oe2 ratios in blood. In vitro studies with testes slices confirmed the enzymatic defect.

Two cases of 17 alpha-hydroxylase deficiency are described. Both patients had primary amenorrhoea, total lack of female secondary sexual characteristics, slight hypertension and hypokalaemia. One patient was of male genotype (male pseudohermaphrodite), and in addition this patient had complete gonadal agenesis. The other patient was of female genotype. In both patients the level of plasma corticosterone was markedly increased, whereas the concentration of plasma cortisol was very low and plasma aldosterone low within the normal range. Furthermore, the plasma ACTH level was significantly increased and the plasma renin activity around the lower normal limit. The urinary excretion of corticosterone metabolites was markedly increased, whereas the excretion of both cortisol metabolites and tetrahydroaldosterone was decreased. The patients had no symptoms of glucocorticoid deficiency. Treatment with dexamethasone 0.5 mg daily completely suppressed the abnormal corticosterone production and normalized both blood pressure and serum potassium. In addition, the patient of male genotype has received sequential therapy with oestrogen and gestagen for 3 years, but so far no development of the secondary sexual characteristics has occurred.

The increase in serum concentrations of LH and FSH after intramuscular administration of LH/FSH-RH was investigated in normal and hypogonadotrophic hypogonadal males. LH and FSH were measured by specific radio-immunoassays. To evaluate the appropriate dose of LH/FSH-RH for intramuscular administration different doses were administered and with 200 mu g an increase in LH and FSH was found comparable to the results obtained by other investigators using intravenous administration. After the initial studies a simple test including two determinations before LH/FSH-RH administration and one 60 min and 120 min after administration was developed and used in all cases. In 12 normal males a significant increase in the serum concentration of both LH and FSH was found averaging 381% and 148% respectively 60 min after 200 mu g LH/FSH-RH with a slight decrease in LH but not in FSH after 120 min. A positive response similar to that in normal men was observed in 11 hypogonadotrophic hypogonadal patients presenting different clinical pictures. This indicates that in all these patients the hypogonadotrophic state was due to a hypothalamic defect and not to a hypophyseal disorder.

The mean basal plasma testosterone level in 28 patients with chromatin positive Klinefelter's syndrome was significantly lower than in 58 healthy male controls. In 12 of the patients the hormone levels were in the normal range. In both the eugonadal males and the Klinefelter patients the plasma testosterone levels spontaneously decreased throughout the day, the relative decrease in both groups being of the same order of magnitude. Short term ACTH infusion and the administration of dexamethasone did not significantly influence the plasma testosterone concentration in the Klinefelter patients. These findings do not support the view that the adrenal cortex plays a major role in contributing to the circulating plasma testosterone levels in this syndrome.