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Over two thirds of patients with Cushing's disease suffer from hypertension. An analysis of 155 patients with Cushing's syndrome was undertaken to study its incidence and effects, and the biological profile and prognosis of the patients. The renin-angiotensin-aldosterone system was given particular attention in 5 patients. Serum angiotensin was raised and a positive correlation was observed with the serum cortisol. Serum aldosterone did not respond as normal to the usual stimuli and the normal plasma renin activity did not vary during the 24 hour period. The physiopathogenesis of hypertension in Cushing's disease is still not fully understood, especially with regard to the mode of action of the hypercortisolism, the essential factor. A mineralocorticoid type of behaviour, especially in the severe forms, may be associated with that of the ACTH-dependent precursors, a permissive action on certain pressor substances, the increase in secretion of angiotensin in parallel to that of the cortisol and finally, the increase in the risk factors probably play a role. The outcome of the hypertension after specific treatment of Cushing's disease is usually favourable. However, hypertension persists in a third of cases.

The renin aldosterone system was studied in 5 cases of Cushing's disease (bilateral benign hyperplasia) without medication. For a daily sodium intake of 120 mmol plasma angiotensinogen was abnormally increased, plasma renin activity (PRA) remained normal, but without significant diurnal variation. Plasma aldosterone (PA) was normal and its circadian rhythm was maintained. One hour active orthostatism and low sodium diet (20 mmol of sodium during 4 days) induced a normal PRA increase but an insufficient PA response. Positive significant correlations were found between PRA and PA and between plasma angiotensinogen and plasma cortisol. The mechanisms underlying this functional hypoaldosteronism were discussed.

To determine whether patients with hypothalamo-pituitary Cushing's disease (HPC-D) can be distinguished on psychological grounds from these presenting with adrenal Cushing's syndrome (AC-S) or with ectopic ACTH syndrome, an in-depth psychological study including full personal, family and socio-professional history and a psychological interview was carried out in 50 patients with endogenous hypercortisolism. The results showed that psychiatric symptoms, such as anxiety and depression, are virtually constant in patients with either HPC-D or AC-S. They are, however, more pronounced in patients with HPC-D, and the latter condition is more likely to develop in subjects with either "psychosomatic" or pre-morbid depressive neurotic personality.

A 31-year-old female diabetic in hyperthyroidism, after ketoacidosis leading to a hypoglycaemic coma showed diffuse and persistent abnormalities of ventricular repolarization. Arguments are given for myocardial ischemia of metabolic origin by hypersecretion of catecholamines.

Using radioimmunoassay of human melanotropic hormone (beta-MSH), were studied in one female patient with Nelson's syndrome the properties of the immunoreactive beta-MSH (beta-MSH-IR) secreted in the circulation in vitro by a pituitary adenoma. With Sephadex G-50 gel, beta-MSH-IR of plasma or from a culture mediium is eluted in greater part in a volume corresponding to a molecular weight of some 6,000 to 10,000. In the radioimmunological systems employed, the dilution curve of beta-MSH-IR in a culture medium is not parallel to that of synthetic human beta-MSH; by contrast, it is parallel to that a lipotropine, purified human beta-LPH.

In a group of 16 females and 2 males with hypogonadism and hyperprolactinemia, bromocriptine was found to suppress prolactin (PRL) high levels within one day without further significant lowering during a 3 weeks longitudinal survey. The usually effective dosage was 5 mg per day. On the contrary, sex hormones did not vary initially and increased secondarily only in those patients resuming gonadal activity. The changes were either cyclical or heterogenous when the first cycle was anovulatory. This latter situation could sometimes but not always be attributed to persistent hyperprolactinemia. Menstruation resumed in 11 patients. Persistance of hypogonadism in the remainder could be explained by incomplete PRL reduction in one case and probability of previous hypothalamo-pituitary damage in six. The latter hypothesis was based in part on impaired gonadotropins responses to LH RH which were not modified by the treatment.

The study is based upon 155 cases of Cushing's syndrome and shows the diagnostic value ognosis of the suprarenal lesion responsible was possible. Bilateral suprarenal hyperplasia was always recognised with accuracy. Pneumoretroperituneum is the technique of choice for the surveillance of the therapeutic effects of synthetic anti-cortisols (especially O.P.'D.D.D.).

beta-Endorphin, a pituitary morphino-mimetic peptide, was identified in a culture medium derived from a human corticotropic adenoma. Secretion products from cultured human cells derived from a small-cell carcinoma of the lung were shown to contain a high molecular weight precursor analagous to pro-opiocortin: this molecule is a polypeptide of the order of 28,000 daltons the enzymatic processing of which leads to the coordinated and simultaneous release of different peptide fragments: ACTH, beta- and gamma-lipotropins, beta-endorphin, fragment 16 K and gamma 3-MSH. All these peptides have been identified in human plasma, and pituitary and non-pituitary tumor extracts. Their plasma concentrations vary in a parallel manner, beta-endorphin and a peptide very similar to beta-MSH have been detected in human hypothalamus.

A case of ovarian androblastoma (arrhenoblastoma) of the intermediate differentiation type in a 5-year old girl is reported. The clinical features were precocious isosexual puberty with secondary masculinization. The tumour was removed but relapsed 26 months later, requiring ovariectomy and salpingectomy. The patient, who has now been followed up for 7 years and 6 months, is definitely cured. Biochemically, the androblastoma was accompanied by high plasma levels of oestrogens, androgens and, quite exceptionally, human chorionic ganodotropin, alpha HCG and beta HCG. Light and electron microscope examination failed to differentiale Sertoli cells from granulosa cells and Leyding cells from luteinized ovarian stroma cells. Areas resembling syncytiotrophoblastic cells were very limited and could not be seen under the electron microscope. Some cells looked like undifferentiated germ cells. The HCG secreted was biologically active on rabbit ovaries (Reiprich's reaction) but inactive on the girl's contralateral ovary, which was found on two biopsies to be unstimulated and prepubertal.

The authors report the results of the medical treatment in 46 cases of Cushing's disease. Long-term Op,DDD therapy apparently results in a drug-induced total adrenal suppression in 28 cases. In 12 cases it reduces the adrenal secretion down to the normal level. In only 6 cases of this series was the treatment unsuccessful. Accordingly the authors think that long-term medical treatment with Op,DDD deserves to be considered as a major total tool within the therapy of Cushing's disease. However regular and precise monitoring under therapy is necessary. The schema of the method used is described.

In the context of hyperandrogenism, the group of hyperandrogenism due to disturbances in hormon-synthesis of late onset is worthy of being considered separately, not by virtue of its prevalence but by the fact that its course may be one of isolate hirsutism (3 cases out of 11 in this study), or even sterility. The diagnosis may be of varying difficulty, because of the incomplete nature of the block. Eleven cases are reported, ten due to a partial deficit in 21 hydroxydation, and one due to a deficit in 11 hydroxydation. The presence of cortisone precursors is often more significant in stimulation tests. Estimation of blood testosterone levels may give somewhat high results in certain cases, but it must be emphasized that it may be diminished dexamethasone and the estimateion of delta 4 androstenedione is of value. In difficult cases, the diagnosis of a minor or incomplete disturbance is based upon a combination of biological, statistical and dynamic arguments. However this diagnosis is important since cortisone at low inhibitory doses are effective, in particular against menstrual disorders, sometimes making it possible to rapidly correct sterility.

The present study involved 143 patients with confirmed Cushing's syndrome, including 100 with Cushing's disease, 20 with adrenal adenoma and 23 with adrenal carcinoma. Out of 120 assessable patients 68% had arterial hypertension and the majority of these (78%) presented with adrenal carcinoma. Blood pressure returned to normal in 85% of hypertensive cases after Op'DDD therapy or adrenalectomy. Excessive cortisol production is probably the main cause of hypertension, but the precise pathophysiological mechanism is controverted. Serum lipids were studied in 88 patients, 40% of whom were found to have combined hyperlipoproteinaemia, this abnormality being particularly frequent in patients with malignant adrenal tumour. Serum cholesterol levels returned to normal after adrenalectomy. However, they were further increases during Op'DDD treatment (p less than 0.01) and only became normal after withdrawal of the drug. Cerebral vascular accidents were uncommon (6%) and might have been due to cobalt irradiation of the hypothalamus-pituitary region.

ACTH and lipotropins (beta- and gamma-LPH) are synthesized from a common precursor by the pituitary corticotropic cell. We have measured LPH plasma levels under physiological and pathological conditions and we have compared them with ACTH plasma levels in the same circumstances. Spontaneous variations (nycthemeral rhythm) in LPH, ACTH and cortisol plasma levels were parallel, while responses to Dexamethasone freination test and stress (Insulin induced hypoglycemia) or more specific stimulation (Metopirone, lysine-vasopressin) were parallel and superimposable. LPH levels were always higher than ACTH levels in two pathological circumstances: chronic renal failure and Cushing's syndromes with ectopic ACTH producing tumors. The determination of both ACTH and LPH levels assists the diagnosis of corticotropic insufficiency and etiologic investigation of Cushing's syndrome, after hypercorticolism had been established. Although unable to confirm the presence of corticotropic adenoma in patients with Cushing's disease, or the predict effectiveness of pituitary surgery, these determination bring good arguments for treated Cushing's diseases follow up.

Spirolactones (spironolactone, potassium canrenoate) may produce secundary sexual effects such as gynecomastia in man and menstrual disturbances in women. The mechanism of action of the antiandrogenic effects has been studied in man and rat. Acute i.v. injection of potassium canrenoate into man results in a decrease of plasma testosterone, without any change of gonadotropins. This decrease might be due to an impaired testicular steroidogenesis. On the other hand, spirolactones have an antiandrogenic effect at the target cells level. They do not modify the prostate 5alpha-reductase activity; however, they do inhibit the binding of androgens to their receptors. Thus the spirolactones interact with both biosynthesis and peripheral action of androgens.

Adrenoleukomyeloneuropathy (ALMN) is a rare neurological and endocrine disorder. It usually affects children, and consists of cortical disease and adrenal insufficiency (adrenoleukodystrophy: ALD). An adult form has recently been identified in which medullary disease is associated with an endocrine disorder (adrenomyeloneuropathy AMN). The authors describe the clinical, biological and physiopathological features of four cases of AMN.

During pregnancy the volume of prolactin-secreting pituitary adenomas tends to increase dangerously for surrounding structures, especially the optic chiasma. When rapid growth occurs, at least three therapeutic approaches are possible: resection of the adenoma, temporization under monitoring and administration of bromocriptine. The latter treatment, which seems to be of particular value, was applied to a female patient and was followed by prompt regression of optic chiasma compression. However, as bromocriptine was given concurrently with chlormadinone acetate, this excellent result cannot be ascribed to bromocriptine alone.

The case of a 34 years old patient, with an adrenal pheochromocytoma and a Cushing syndrome is reported. The Cushing syndrome was healed by removing the pheochromocytoma. The varied interrelations between adrenal cortex and medulla physiology or pathology are discussed. It seems that ectopic ACTH from pheochromocytoma is observed more often, unlike the proof has been rarely made.

Sipple's syndrome is a generally familial polyneoplastic affection associating a medullary thyroid cancer and a pheochromocytoma. The overall picture of the syndrome has, in fact, become larger now that it is known that there is previous hyperplasia of thyroid C cells and chromaffin cells in relation to neoplasms. Increase in plasma thyrocalcitonin levels is the best indicator of medullary cancer, and the discovery of this hormone in pheochromocytomas has shown the secretory origin of the two tumors, the cells of which have a common embryological origin in the neural crest. Sipple's syndrome is often associated with hyperparathyroidism, hyperplasia without adenoma (endocrine polyneoplasia type II a), or phacomatosis and a dystrophic condition (type II b or III). The authors discuss the nosology of the syndrome and its relation to the diffuse endocrine and APUD systems.

Ten cases of atypical pheochromocytomas are reported, and physiopathologic mechanisms of the multiple clinical manifestations of these tumors are discussed. The embryologic origin of pheochromocyte, derived from neural crest, and common metabolic properties of endocrine cells coming from this germ layer, elucidate the coupling of pheochromocytoma with neuroectodermic diseases (neurocristopathic syndromes), and the biosynthetic capacity of these tumors (synthesis of corticotropic activity and thyrocalcitonin are reported). Atypical peripheral effects of pheochromocytoma are discussed: catecholamines are responsible for an unstable hemodynamic state, always threatened by a spontaneous or induced release of amines: then, misleading clinical features occur, which are analysed. A screening and detecting procedure of pheochromocytoma is proposed for these particular forms, which are explained by the common multiple properties of the tumors derived from chromaffin cells.

The hypertension of Cushing's disease regresses in about two thirds of cases after specific treatment of this condition. The therapeutic possibilities available at present include the synthetic anticortisol drugs (OP'DDD, aminoglutethimide) adenomectomy and hypophyseal radiotherapy and, finally, bilateral adrenalectomy. The indications of one or the other forms of treatment depend on the presence of a patent hypophyseal tumour, the age of the patient and the stage of the disease. The hypertension requires treatment either because of its severity from the outset or its persistence after treatment of the Cushing's disease. Betablockers or central sympatholytic drugs like clonidine, are then used in monotherapy of first intention. Diuretics should be avoided whenever possible because of the risk of adrenal insufficiency after reduction of the hypercorticism.

In normal adult male, the intra-muscular hCG-test (5000 I.U. X 3) results in a progressive rise of plasma testosterone and dihydrotestosterone, and in a sharp increase of plasma estradiol followed by a decrease although th hCG stimulation is maintained. In testicular dysgenesis, the testosterone and estradiol responses are variable. In adult male gonadotropin deficiency, basal testosterone is always very low, and rises strongly, under hCG-test, only when previous and recent (less than 10 years) exposure to endogenous or exogenous gonadotropin had induced virilization ; by contrast the defective response of estradiol in all cases provides a reliable estimate of the actual gonadotropin deficiency.