Pituitary-adrenal response to the antiglucocorticoid action of RU 486 in Cushing's syndrome.

RU 486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)17 alpha-(prop-1-ynyl)estra-4,9-dien-3-one] is a steroid analog which antagonizes glucocorticoid action at the receptor level. The pituitary-adrenal response to RU 486 was evaluated in patients with Cushing's syndrome. The acute administration of 400 mg RU 486 at 0800 h in five patients with Cushing's disease induced no significant change in plasma cortisol during the next 10 h compared with the administration of placebo. However, prolonged administration (400 mg daily for 3 days) caused activation of the pituitary-adrenal axis; urinary cortisol increased the most from 727 to 5720, 830 to 8200, 610 to 1020, 110 to 570, and 300 to 990 micrograms/day. Plasma cortisol and lipotropins increased to a lesser extent. Hormone changes appeared on the second day of drug administration and lasted up to 3-4 days after the drug was discontinued. In two patients with nonpituitary-dependent Cushing's syndrome, RU 486 induced no significant change in steroid secretion. We conclude that RU 486 induced a delayed and prolonged pituitary-adrenal response in Cushing's disease; whether the resulting cortisol overproduction will overcome the peripheral effect of RU 486 remains to be determined.

Salivary cortisol measurement: a practical approach to assess pituitary-adrenal function.

The salivary cortisol concentration is an excellent indicator of the plasma free cortisol concentration. To establish its normal and pathological ranges, salivary cortisol concentrations were measured in 101 normal adults, 18 patients with Cushing's syndrome, and 21 patients with adrenal insufficiency. The normal subjects had a mean (+/- SEM) salivary cortisol concentration of 15.5 +/- 0.8 nmol/L (range, 10.2-27.3) at 0800 h and 3.9 +/- 0.2 nmol/L (range, 2.2-4.1) at 2000 h (n = 20). The mean value 60 min after ACTH administration in 58 normal subjects was 52.2 +/- 2.2 nmol/L (range, 23.5-99.4), and it was 1.4 +/- 1.1 nmol/L (range, 1.6-3) at 0800 h in 23 normal subjects given 1 mg dexamethasone 8 h earlier. In patients with primary or secondary adrenal insufficiency (n = 21) the mean salivary cortisol level was 7.5 +/- 0.4 nmol/L (range, 1.9-21.8) 60 min after ACTH. In patients with Cushing's syndrome (n = 7), the mean value after the 1-mg dexamethasone suppression test was 16.1 +/- 7.8 nmol/L (range, 5.8-66.8). No overlap was found between the values in the normal subjects and those in the patients during the dynamic tests. Discrepancies between salivary and total plasma cortisol were found in 8 patients with adrenal insufficiency, which may be explained by the effects of drugs such as thyroid hormones, Op'-dichlorodiphenyldichloroethane, and psychotropic agents. We conclude that salivary cortisol measurements are an excellent index of plasma free cortisol concentrations. They circumvent the physiological, pathological, and pharmacological changes due to corticosteroid-binding globulin alterations and offer a practical approach to assess pituitary-adrenal function.

True hermaphroditism: from female to male endocrine status.

True hermaphroditism was revealed by monthly intrascrotal bleeding in a 21-yr-old subject of male phenotype who had undergone surgical treatment for gonadal ectopy at the age of 7 yr. The presence of an ovary was demonstrated by the endocrine profile of an ovulatory menstrual cycle. Evidence for the presence of a testis was provided by a plasma testosterone increase after hCG administration (5000 IU/day for 3 days) and its spontaneous response to an endogenous preovulatory LH peak. Further endocrine studies revealed that both gonads were stimulated by endogenous gonadotropins. At surgery, a hemiuterus and an ovary with corpus luteum were found in the left hemiscrotum, and a testis and epididymis were found in the right hemiscrotum. After removal of the ovary, the subject passed from a predominantly female to a male endocrine status, which suggests that the endocrine secretion of the testis was inhibited by the negative feedback effect of ovarian steroids on gonadotropin secretion.

Transsphenoidal pituitary surgery for the treatment of Cushing's disease: results in 64 patients and long term follow-up studies.

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.

Effects of 10 days administration of percutaneous dihydrotestosterone on the pituitary-testicular axis in normal men.

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.

Insulin and growth hormone secretion in dialyzed children: influence of dietary manipulation.

The insulin and growth hormone responses to arginine and the growth hormone response to insulin were studied in 10 children undergoing chronic hemodialysis 1) under usual dietary prescription and 2) after 7 days of dietary manipulation (DM) decreasing mean carbohydrate intake from 48 to 36% and increasing lipid intake from 42 to 54% (percent of total energy) with the polyunsaturated/saturated fatty acids ratio being increased from 0.2 to 2. Mean fasting insulin and growth hormone were significantly decreased after DM: 10.3 +/- 3 muunits/ml and 19.9 +/- 3.5 ng/ml before and 4.3 +/- 0.8 muunits/ml and 9.3 +/- 2.4 ng/ml after DM. The mean arginine-induced insulin peak and the growth hormone peaks after arginine and insulin remained very high after DM. There was no decrease of mean plasma triglycerides: 214 +/- 30 mg/dl before and 237 +/- 26 mg/dl after DM. However, two children who had the greatest decrease in carbohydrate intake exhibited a decrease of triglycerides and of arginine-induced insulin secretion. The percent variation of insulin area after DM was significantly correlated with the percent variation of plasma triglycerides.

Characterization of specific low-density lipoprotein binding sites in human term placental microvillous membranes.

Purified microvillous membranes prepared from normal term human placenta were studied for their ability to bind specifically low-density lipoprotein (LDL). Electron microscopic examination of the membrane preparations revealed essentially microvilli-like structures, and the enzyme analyses a 14-17-fold enrichment in the membrane markers 5'-nucleotidase and alkaline phosphatase. The binding of [125I]LDL was dependent on time, temperature, pH and protein concentration; it was saturable with a low capacity (130.4 +/- 22.2 ng/mg of membrane protein) and presented a high affinity (apparent Ka 6.12 +/- 1.32 micrograms protein per ml). These high-affinity binding sites were specific for LDL (high-density lipoprotein induced less competition than unlabelled LDL) and were sensitive to pronase digestion. Unlike the binding of LDL to other tissues, the [125I]LDL binding to microvillous membranes did not require divalent cations. The presence of specific LDL receptors on the placental microvillous membranes, located at the effective site of exchange between the maternal blood and the placental tissue, supports the concept that human placenta utilizes LDL-cholesterol for its progesterone synthesis.

[Discordance between the short and standard metyrapone tests in isolated corticotropin insufficiency]. / Discordance entre les tests à la métopirone court et standard au cours d'une insuffisance corticotrope isolée.

A 71-year-old man presented with clinical and common biological features of secondary adrenal insufficiency. Basal ACTH level was in the normal range. As it has been previously reported in ACTH deficiency, cortisol response to ACTH-test was normal. A single-dose metyrapone test, performed to confirm the diagnosis of adrenal insufficiency, gave unexpectedly normal results. However 11-desoxycortisol (compound S) response to standard-metyrapone test was subnormal ascertaining the diagnosis of ACTH-deficiency. Thus normal responses to single-dose metyrapone test do not imperatively exclude secondary adrenal failure.

[Decreased number of insulin receptors in obesity: studies in the obese hyperglycemic mouse (author's transl)]. / Diminution de nombre des récepteurs de l'insuline dans l'obésité: Etudes chez la souris obèse hyperglycémique

The insulin-receptor interaction is impaired in liver, adipocyte and myocardium plasma membranes of the obese hyperglycemic (ob/ob) mouse. A decreased numer of receptors rather than an altered affinity for the hormone appears to be responsible for this defect. Some studies were conducted with respect to the specificity and the reversibility of the degect. 1) It involves the insulin receptor predominantly if not exclusively. 2) It is largely reversible. a) Fasting ob/ob mice for 40 hr or longer periods improved insulin binding significantly. b) Steptozotocin treatment of ob/ob mice also improved insulin binding in liver membranes. c) In fasting and in streptozotocin-treated mice, glucagon binding exhibited a shift opposite to that of insulin, i.e., it was decreased. These data suggest the possibility that the hormone may "down regulate" its own receptor. Although the mechanism(s) of such regulation, if it is verified, remain(s) to be established, similar observations reported with some other peptide hormones and with catecholamines suggest that this phenomenon may be of general interest in endocrine physiology and patho-physiology.

[The hormonal state of pregnancy: modification of cortisol and testosterone]. / Etat hormonal de la grossesse: modification du cortisol et de la testostérone.

The pattern of cortisol and testosterone levels during the normal pregnancy was investigated by measuring these hormones in the same 19 healthy pregnant women at 11th to 19th, 24th to 29th and 34th to 39th week post amenorrhea. We noted the well-known increase in total plasma cortisol and testosterone, due to the elevated concentration of their transport protein, i.e., Corticosteroid Binding Globulin (CBG) and Testosterone Estradiol Binding Globulin (TeBG), consecutive to the increase in plasma oestrogens. Morning (8h) and evening salivary cortisol (20 h) values, which are a good reflect of free plasma cortisol, were found increased since the second trimester of pregnancy, with a conserved circadian cycle. 24 h urinary free cortisol was slightly increased since the first trimester, yet remaining within the normal range; in the late pregnancy it reached sometimes higher levels. "Vesperal" urinary cortisol measured on a collected urine sample between 20 h and 24 h was higher in pregnant women since the beginning of pregnancy as compared to that of non pregnant women. Levels of salivary free testosterone measured in a few patients appeared similar to that of non-pregnant controls. We also report the data obtained in two pregnant women with Cushing's syndrome due to an adrenocortical carcinoma which showed a strong elevation of urinary and salivary free cortisol while a pregnant woman with a luteoma had a lower level as compared to normal pregnant. Moreover these three patients had a marked increase in free salivary testosterone opposite to normal pregnant women.

[Short term effects of ketoconazole in Cushing's syndrome]. / Effets à court terme du ketoconazole dans les syndromes de Cushing.

The effects of Ketoconazole (600 mg/day) were evaluated in 10 patients with Cushing's syndrome during a mean period of 4.5 weeks (range 1-12). The urinary free cortisol excretion (UFC) decreased by 21 +/- 15% (mean +/- SEM) (p less than 0.01) on day 1; 54 +/- 8% (p less than 0.0001) on day 2; 60 +/- 15% (p less than 0.0001) on day 3 and 87 +/- 3% (p less than 0.0001) on day 8 compared to baseline. Salivary cortisol at 0800 h decreased similarly. On day 3, 7 patients showed normal UFC values and on day 8, only 1 patient, with the ectopic ACTH syndrome, had persistent hypercortisolism. The cortisol decrease was associated with an increase in desoxycorticosterone values (p less than 0.01) and a decrease in dehydroepiandrosterone sulfate (p less than 0.001), delta 4 androstenedione (p less than 0.05) and testosterone (p less than 0.05). No significant variations were observed in ACTH, 11 desoxycortisol, aldosterone, plasma renin activity, corticosteroid-binding globulin and sex hormone-binding globulin. Side effects were few: mild clinical adrenal insufficiency (n = 5), oedema (n = 3) and reversible hepatic toxicity (n = 1). We conclude that Ketoconazole is an effective inhibitor of cortisol and androgens synthesis. It is well tolerated, rapidly effective and its efficacy persists unchanged for at least one month in all forms of Cushing's syndromes. For these reasons Ketoconazole may be a valuable drug for preoperative treatment of Cushing's syndrome.

[Study of corticotropic function: respective values of short tests using metropirone and exogenous ACTH regardless of the hour administered]. / Exploration de la fonction corticotrope: valeurs respectives des tests courts à la métopirone et à l'ACTH exogène quelle que soit l'heure de sa réalisation.

Basal plasma cortisol levels and adrenal responses to stimulation by endogenous and exogenous ACTH were compared between a group of controls and a group of patients with corticotrophic insufficiency. In addition, the adrenal response to the administration of exogenous ACTH was compared in each of these groups in relation to the timing of the test. There was a clear parallel between respective adrenal responses to exogenous ACTH and endogenous ACTH. Adrenal stimulation by exogenous ACTH may be used to investigate the residual secretion of endogenous ACTH and in the diagnosis or corticotrophic insufficiency, when a lesion interrupting functional hypothalamo-pituitary connections has been excluded. In the opposing case, use of a short test with metopirone is essential in order to confirm corticotrophic insufficiency. This test is better tolerated than the classical test and is not subject to sources of error due to urine collections.

[Male hypertestosteronemia]. / Hypertestostéronémie masculine.

Male hypogonadism is characterized by a lowering of plasma testosterone level below the lower limit of physiological variations. Conversely, some adult males, apparently eugonadic, have a plasma testosterone level much higher than normally. In most cases, male hypertestosteronaemia - defined by a plasma testosterone level above 13 ng/ml and due to various physiopathological mechanisms - is part of a wider pathological context. It betrays hyperandrogenism (elevated free testosterone) during treatment with androgens or chorionic gonadotropic hormone. In other cases, it seems to underlie a relative hypoandrogenism with rise of testosterone bound to transport proteins and/or excess of oestrogens. Hypertestosteronaemia therefore appears as a biochemical sign not to be ignored, but it also suggests that men with abnormally high testosterone levels present with new pathology and that aetiological investigations are necessary.

[Gynecomastia: effect of prolonged treatment with dihydrotestosterone by the percutaneous route]. / Gynécomasties: effet du traitement prolongé par la dihydrotestostérone par voie per-cutanée.

Gynaecomastia is a frequent disorder, sometimes painful or psychologically disturbing. Percutaneous dihydrotestosterone (DHT) was used to treat 30 patients with idiopathic gynaecomastia (IG) and 17 patients in whom the condition was associated with hypogonadism. All patients complaining of pain were relieved. Breast enlargement regressed or was substantially reduced in 22 of the IG patients and in all cases with hypogonadism, except those with gonadal dysgenesis. Plasma levels of testosterone and 17 beta-estradiol were significantly lowered in patients with IG as compared with controls. There was a significant increase in plasma DHT levels and in plasma androgen/estradiol ratio in all cases. The beneficial effects of the drug were manifest within 1 to 2 months in responsive patients. These effects may be due to a local and/or systemic activity. It is suggested that this medium-term treatment without side-effects should be tried in all cases of hypogonadism with gynaecomastia and in IG before considering more drastic therapeutic measures.

[Rapid beta 1-24-corticotropin test in the exploration of the corticotropic axis. 71 cases]. / Le test rapide à la beta 1-24 corticotrophine dans l'exploration de l'axe corticotrope. Soxiante et onze observations.

The reliability of the beta 1-24 corticotropin test, which is both cheap and safe, in the assessment of the hypothalamic-pituitary-adrenocortical function was re-evaluated by comparing its results with those of the metyrapone test in 71 subjects: 30 controls and 51 patients with suspected pituitary-adrenal dysfunction. Response to a 500 micrograms intramuscular injection of beta 1-24 corticotropin was evaluated by measuring the 60 min plasma cortisol levels; 4.5 g of metyrapone divided into 6 doses were then administered orally and response was evaluated by measuring plasma 11-desoxycortisol levels. A highly significant correlation (r = 0.79; p less than 0.001) was observed between plasma cortisol and plasma 11-desoxycortisol levels. The results were best interpreted by expressing the values obtained as plasma cortisol concentrations which, in normal subjects are at least 21 micrograms/100 ml. The rapid beta 1-24 corticotropin test was found to be very reliable (sensitivity 90%, specificity 100%) to detect adrenal insufficiency, irrespective of the organs affected on the hypothalamic-adrenocortical axis.

[Adrenal adenoma secreting exclusively estrogens in a woman during her reproductive period. 11-year follow-up]. / Adénome surrénalien sécréteur exclusif d'estrogènes chez une femme en période d'activité génitale. Recul de 11 ans.

Feminizing tumours are rare, most are malignant, and they are usually seen in children and male adults. We report an 11-year follow-up of a feminizing adrenal tumour which was unusual on three accounts: it was a benign adenoma, it secreted estrogens only and the patient was an female in her active reproductive years. To our knowledge, similar cases have not yet been published.