The metabolic clearance rate and origin of plasma dihydrotestosterone in man and its conversion to the 5-alpha-androstanediols.

Dihydrotestosterone metabolism was studied with a constant infusion technique in three men, three women, five hirsute women, and four estrogen-treated hirsute women. The mean dihydrotestosterone metabolic clearance rate was higher in men (336 liters/24 hr per m(2) [range, 239-448]) than in women (153 liters/24 hr per m(2) [range, 108-184]). The metabolic clearance rates in hirsute patients were intermediate between those men and women and were decreased by estrogen treatment. These observations demonstrate similarities in the metabolic rates of testosterone and dihydrotestosterone. The conversion of plasma testosterone and androstenedione to dihydrotestosterone was studied in men and hirsute women. Approximately 4 and 2% of plasma testosterone and androstenedione, respectively, were converted to plasma dihydrotestosterone in both groups. From these observations it was determined that a major fraction of plasma dihydrotestosterone was derived from these plasma precursors rather than from glandular secretion. Both 5alpha-androstan-3alpha,17beta-diol (3alpha-diol) and 5alpha-androstan-3beta,17beta-diol (3beta-diol) were identified in plasma during dihydrotestosterone and testosterone infusions. The conversion ratio of dihydrotestosterone to 3alpha-diol (C(BB) (DHT-3alpha)) was greater than the conversion ratio to the 3beta-isomer (C(BB) (DTH-3beta)) in all the patients studied. Both C(BB) (DHT-3alpha) and C(BB) (DHT-3beta) were higher in men (mean values of 0.151 [range, 0.110-0.222] and 0..031 [range, 0.022-0.042]) than in women (means of 0.044 [range, 0.037-0.048] and 0.012 [range 0.010-0.013]). A smaller fraction of testosterone was converted to 3alpha-diol and 3beta-diol.

Antiandrogenic effect of spirolactones: mechanism of action.

Spirolactones are aldosterone antagonists which inhibit the binding of aldosterone to the renal mineralocorticoid receptor. These molecules also possess an antiandrogenic effect which could be due, among other possibilities, to a peripheral antagonism of androgens. This hypothesis has been tested in the present study. From in vivo experiments, spironolactone K+ canrenoate appear to inhibit the binding of [3H]5alpha-dihydrotestosterone [3H]DHT to the cytosolic and nuclear receptor of the rat ventral prostate. The doses used are in the same range as those used for demonstrating the antimineralocorticoid effect of these molecules. In vitro incubations and in vitro displacement studies show that spironolactone and K+ canrenoate are respectively about 20 and 100 times less effective than DHT in displacing 50 percent of 5 times 10- minus 10 M [3H]DHT from its receptor. Spirolactones are also able to compete with [3H]DHT for the specific 8 S cytosolic receptor. Neither spironolactone nor K+ canrenoate decreases prostatic 5alpha-reductase activity, even at a concentration as high as 10- minus 5 M. It seems likely that spirolactones, besides their action on testosterone biosynthesis, exert their antiandrogenic activity via a peripheral androgen antagonism.

Dissociated responses of plasma testosterone and estradiol to human chorionic gonadotropin in adult 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.

Urinary nandrolone metabolites of endogenous origin in man: a confirmation by output regulation under human chorionic gonadotropin stimulation.

19-Nortestosterone (nandrolone) is an anabolic steroid compound widely used as a doping agent by athletes. The analysis of its urinary metabolites, 19-norandrosterone (NA) and 19-noretiocholanolone (NE) glucuronides, allows the detection of surreptitious administration of nandrolone in sport. A threshold concentration at 2 microgram/L urinary nandrolone metabolites is advocated by the International Olympic Committee for the detection of doping, but some controversy concerning the validity of this threshold arose from the demonstration of endogenous production of nandrolone in mammals, including humans. The regulation of human nandrolone production and its contribution in vivo to the process of aromatization remain unknown. In the present study 10 healthy men were successively submitted to insulinic stress and gonadal stimulation by hCG administration. Urinary NA and NE concentrations were quantified by gas chromatography-mass spectrometry. NA was detected in basal urine samples from all subjects, with a mean urinary excretion rate (UER) of 3.17 +/- 0.35 ng/h, whereas NE was detected in 4 of 10 (UER range, 0.8-4.7 ng/h). Insulinic hypoglycemia did not significantly modify mean NA UER despite random intraindividual variations between timed urine collections. After hCG administration, NA UER increased by 250% (P < 0.01) and estradiol (E(2)) UER by 260% (P < 0.001). The maximum NA concentration obtained after stimulation was 0.43 microgram/L. NA UER, plasma E(2), and E(2)/T ratio peaked on day 1 after hCG administration, whereas plasma T peaked later on day 3. NA UER correlated with plasma E(2) (r = 0.61; P < 0.001) and E(2)/T (r = 0.51; P < 0.001), but not with plasma T. In conclusion, insulinic stress did not significantly alter nandrolone metabolism, whereas the effect of hCG was a stimulation of NA excretion in all subjects, which constitutes strong support for the endogenous origin of low basal NA excretion. The comparative kinetics of NA UER, plasma E(2), and E(2)/T ratio suggest a contribution of the aromatase process to nandrolone biosynthesis in man.

Hormonal changes induced by bromocriptine (CB-154) at the early stage of treatment.

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.

Testicular steroidogenesis in adult men with human chorionic gonadotropin-producing tumors.

There are few critical studies on plasma testosterone (T) and 17 beta-estradiol (E2) levels in men with hCG-producing tumors, and the results are contradictory. Plasma E2 levels are most often elevated, whereas plasma T values are high or in the normal range. We studied the plasma levels of such steroids and of delta 4 and delta 5 T precursors in adult men with intact hCG-producing tumors to evaluate the relationship between hCG and steroid hormone levels or steroidogenic enzyme activities. Ten adult men with hCG-producing tumors and 25 normal adult men were investigated. Seven men with testicular tumors were studied before and after hemicastration. The 2 patients with extratesticular tumors were investigated before and during chemotherapy. The remaining patient was studied every 2 months for 1 yr during the spontaneous course of the disease. Plasma progesterone (P), 17 alpha-hydroxyprogesterone (17-OHP), androstenedione (A), 17-hydroxy-delta 5-pregnenolone (17-OH delta 5-P), dehydroepiandrosterone (DHEA), T, E2, and hCG were measured, and ratios of steroid levels were also calculated. In patients with increased hCG values (i.e. > 5 IU/L), the mean plasma P, 17-OHP, A, 17-OH delta 5-P, DHEA, T, and E2 levels were higher (P < 0.01 at least) than those in patients whose hCG values were normalized or in controls. The patterns of these steroids were very different according to plasma hCG levels. Indeed, for hCG levels between more than 5 and 3.5 x 10(3) IU/L, positive correlations (P < 0.05 at least) were found between hCG levels and delta 4 T precursor, delta 5 T precursor, T, or E2 values. Conversely, for hCG values greater than 3.5 x 10(3) IU/L, hCG levels were negatively correlated (P < 0.05 at least) to all steroid values. Furthermore, in patients with increased hCG levels, the mean plasma P to 17-OHP ratio, 17-OHP to A ratio, A to T ratio, 17-OHP to T ratio, and 17-OH delta 5-P to DHEA ratio were similar to those in patients with normalized hCG values or in controls. In contrast, in patients with increased hCG levels, the mean plasma T to E2 ratio value was lower (P < 0.001) than that in patients with normalized hCG levels or in controls.(ABSTRACT TRUNCATED AT 400 WORDS)

Reversible gonadotropin deficiency in male Cushing's disease.

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.

Elevated plasma level of lipotropin revealing an occult carcinoid tumor with normal plasma adrenocorticotropin.

The increases in the level of plasma lipotropin (LPH) and in the LPH/ACTH ratio are considered diagnostic tools in ectopic ACTH syndrome. However, plasma ACTH is also elevated in this syndrome. We report a case of a small carcinoid tumor with an increase in both ACTH and LPH in plasma before surgery. Eight months after the tumoral resection, plasma LPH alone was increased again, whereas plasma ACTH and plasma and urinary cortisol remained normal in this apparently cured patient. This repeated abnormality was the only available feature that allowed successful removal of the occult tumoral residue.

Food-dependent Cushing's syndrome: characterization and functional role of gastric inhibitory polypeptide receptor in the adrenals of three patients.

In the present work, the presence of gastric inhibitory polypeptide (GIP) receptors and their functional role in the adrenal cells of three patients with food-dependent Cushing's syndrome were studied. RT-PCR and in situ hybridization studies demonstrated the presence of GIP receptor in the adrenals of the three patients. The presence of this receptor was also demonstrated in two human fetal adrenals, but not in two normal adult human adrenals or in the adrenals of one patient with nonfood-dependent Cushing's syndrome. Freshly isolated cells from patient adrenals responded in a dose-dependent manner to the steroidogenic action of both ACTH and GIP, whereas cells from normal adrenals responded only to ACTH. Treatment of cultured normal adrenal cells with ACTH, but not with GIP, increased the messenger ribonucleic acid (mRNA) levels of cholesterol side-chain cleavage cytochrome P-450, P450c17, and 3beta-hydroxysteroid dehydrogenase, whereas both hormones enhanced these mRNAs in patients' adrenal cells, although the effects of ACTH were greater than those of GIP. Moreover, pretreatment with ACTH enhanced the steroidogenic responsiveness of both normal and patient adrenal cells, whereas GIP caused homologous desensitization, and this was associated with a marked reduction of GIP receptor mRNA levels, as demonstrated by RT-PCR and in situ hybridization. Finally, both ACTH and GIP inhibited DNA synthesis in one patient's adrenal cells, whereas in normal adrenal cells only ACTH had this effect. In conclusion, the present data demonstrate that ectopic expression of functional GIP receptors is the main cause of food-dependent Cushing's syndrome.

Postprandial lipoprotein metabolism in normotriglyceridemic non-insulin-dependent diabetic patients: influence of apolipoprotein E polymorphism.

Non-insulin-dependent diabetes mellitus (NIDDM) is associated with postprandial lipoprotein clearance defects that are correlated with the fasting hypertriglyceridemia widely observed in NIDDM patients. The aim of this study was to determine if such postprandial disturbances are found in NIDDM patients strictly normotriglyceridemic in the fasting state, and if the apolipoprotein E (apo E) polymorphism influences postprandial metabolism of intestinally derived lipoproteins. The vitamin A-fat loading test was used in 18 normotriglyceridemic NIDDM patients and seven normotriglyceridemic obese controls, and postprandial triglyceride (TG) and retinyl palmitate (RP) concentrations were evaluated in total plasma, and in the chylomicron (Sf > 1,000) and nonchylomicron (Sf < 1,000) fractions isolated by ultracentrifugation. NIDDM patients exhibited an amplified response of both TG and RP as compared with obese controls in the three fractions. Incremental TG response to the oral fat load was strongly correlated with fasting TG level (r = .80, P < .0001) in the whole study population. Postprandial lipoprotein profiles were distinguished in NIDDM patients according to apo E phenotype: despite normal fasting TG levels in E3/3 (n = 6), E2/3 (n = 6), and E3/4 (n = 6), postprandial RP response was twofold to threefold higher in E2/3 and E3/4 patients than in the common E3/3 phenotype. Contrasting lower postprandial TG increment and lower fasting and postprandial high-density lipoprotein (HDL) and HDL3 cholesterol levels were observed in E3/4 versus E3/3 patients, possibly reflecting modifications in lipid content of the postprandial lipoproteins driven by a differential lipid transfer activity depending on apo E isoform. These data indicate an enhanced postprandial lipemia in normotriglyceridemic NIDDM patients, and demonstrate the influence of apo E polymorphism on their lipoprotein clearance. Postprandial alterations of lipoprotein remnants may thus accelerate atherogenesis even in normotriglyceridemic NIDDM patients.

High frequency of IgG antagonizing follicle-stimulating hormone-stimulated steroidogenesis in infertile women with a good response to exogenous gonadotropins.

OBJECTIVE: To investigate the presence of FSH-blocking IgG in infertile women. DESIGN: Retrospective study. Sera from patients and controls were processed for IgG purification, and purified IgG were tested at various concentrations for their ability to inhibit the recombinant human FSH-induced P production in vitro by human granulosa cells. SETTING: Departments of Endocrinology, and Obstetrics and Gynecology, University of Caen. PATIENT(S): Fifty-seven infertile women including 14 women with premature ovarian failure (POF), 29 women with a poor response to IVF-ET, and 14 women with a good response to IVF-ET. Controls consisted of 22 healthy age-matched women. INTERVENTION(S): IVF-ET allowed human granulosa cell pooling and culture for FSH bioassay. MAIN OUTCOME MEASURE(S): Inhibition by purified IgG of the in vitro recombinant human FSH-induced P production by human granulosa cells. RESULT(S): Blocking IgG were identified in only 3 of 14 POF and in 2 of 29 women with a poor response to IVF-ET. In contrast, IgG from women with a good response to IVF-ET inhibited significantly P production, and blocking IgG were detected in 85% women with a good response to IVF-ET. CONCLUSION(S): This study identified FSH-blocking IgG in a high proportion of women with a good response to IVF-ET. The significance of this remains questionable.

[Cleidocranial dysostosis. Contribution to its study apropos of 2 personal cases (an isolated and a familial form)]. / La dysostose cléido-crânienne. Contribution à son étude à propos de deux cas personnels (une forme isolée et une forme familiale).

Cleidocranial dysostosis is a rare embryopathy affecting the whole osseous system. Anomalies predominate on skull, chest and dentition but the whole skeleton can be affected especially pelvic girdle and spine. An autosomal transmission is often demonstrable; isolated forms are very uncommon. We present two cases fortuitously diagnosed in our ward: a familial cleidocraniopelvic major form and an incomplete isolated form. The treatment must be especially oriented towards dental malformations.

[Study of Leydig cells and gonadotropin activity in 14-18 days old fetal mouse (author's transl)]. / Etude de l'activité leydigienne et gonadotrope chez l'embryon de souris mâle en fin de gestation.

An organ culture system has been developed for mouse embryo testes and pituitaries at 14-18 days of gestation. The testosterone (T) production by fetal testes has been measured by RIA in the culture medium: it increases from day 14 to day 18 and may be specifically stimulated by ovine LH and hCG. Fetal pituitaries in culture release a gonadotropin activity at 16 and 18 days (not found at 14 days), which is detectable by an heterologous RIA of LH and by a significant increase in T production from age-matched testes in co-culture. The 18-days old pituitaries respond to synthetic LH-RH by an enhanced production of immunologically and biologically active LH.

[Gonadotropic function in female Cushing syndrome (author's transl)]. / Etude de la fonction gonadotrope dans le syndrome de Cushing chez la femme.

A study of 38 female Cushing syndromes showed decreased levels of FSH and LH, with normal LH-RH stimulation in most adrenal hyperplasia and benign adenoma, and absent stimulation in carcinoma. The levels were normalized by suppression of hypercorticism. This suggests a blunted gonadotropic function, in female Cushing syndrome, probably at the hypothalamic level. The predominant respective roles of hyperandrogeny in carcinoma and of hypercortisolism in adrenal hyperplasia and benign adenoma seem probable.

[Gonadotropic function in female Cushing's syndrome (author's transl)]. / La fonction gonadotrope dans le syndrome de Cushing chez la femme.

Gonadotropic function has been studied without selection in 38 female patients with Cushing's syndrome followed during four years. The level of gonadotropins FSH and LH was low in all etiologies of the syndrome. LH-RH stimulation is normal in adrenal hyperplasia and adenoma, and very low in carcinoma. These abnormalities are cured after reduction of hypercorticism. The share of either cortisol or androgens is discussed. A predominant hypercortisolism blunting action on gonadotropic function is possible, cortisol being the common factor of Cushing's syndrome.

[Antiandrogenic effect of spirolactones: different mechanisms of action (author's transl)]. / Effets anti-androgéniques des spirolactones: différents modes d'action

The spirolactones decrease the plasma testosterone levels in men. They also inhibit the specific dihydrotestosterone binding to rat prostate, and have no effect on 5 alpha-reductase. The spirolactones are antiandrogenic drugs, acting at several levels.

[Reappraisal of the water test in adrenocortical exploration]. / Réévaluation du test à l'eau dans l'exploration corticosurrénale.

The water-loading test (Robinson's test) has been used since 1941 to evaluate the adrenocortical function. Due to this technique, impaired water excretion has become a classical feature of adrenal deficiency. The purpose of this study was to assess the reliability of this test when compared with modern procedures for adrenal exploration. Water excretion was decreased in 23 cortisol-deficient patients but also in 16 out of 58 subjects (27%) with normal adrenal biological tests. We consider that this simple test, although old-fashioned, remains useful since normal diuresis after 2 hours is sufficient to rule out a cortisol deficiency.

[Monilial granuloma treated successfully with ketoconazole over a period of 30 months]. / Granulome moniliasique traité avec succès par kétoconazole depuis 30 mois.

A case of monilial granuloma of 12 years duration is being successfully treated with ketoconazole administered orally in doses of 200 mg per day. Trush, onyxis and keratotic granulomatous lesions of the face and hands have dramatically regressed. In view of persistent anomalies of cellular immunity and complete deficiency in serum and salivary IgA, treatment with ketoconazole at the same dosage level has now been continuously pursued for 30 months without any evidence of toxicity.

[Gonadal function in primary apparent male osteoporosis. 12 cases]. / Etude de la fonction gonadique au cours de l'ostéoporose masculine en apparence primitive. Douze cas.

The testicular endocrine function was studied in 12 patients aged from 33 to 76 years (mean: 56.3 +/- 11.5 years) presenting with an apparently primary vertebral osteoporosis and in 14 age-matched controls (mean: 52.6 +/- 12.8 years). The mean bone mineral content, measured in the vertebral column by biphoton absorptiometry, was lower in patients than in control (P +/- 0.01). Plasma levels of testosterone, oestradiol, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were the same in both groups. In two patients of each group, a rise of LH with normal testosteronaemia was suggestive of compensated Leydig's cell deficiency. There was no correlation between bone mineral content, plasma testosterone, LH, FSH level and the subjects' weight and height. However, a positive correlation was found between plasma oestradiol level and bone mineral contents in patients with osteoporosis (P +/- 0.01) ans in all subjects under study (P +/- 0.05). This study shows that primary osteoporosis is not due to testicular deficiency and suggests a possible action of oestradiol on male bone.

[Topographical diagnosis of insulinoma of the pancreas. Value of the test of intra-arterial calcium infusion]. / Diagnostic topographique d'insulinome du pancréas. Intérêt du test de perfusion calcique intra-artérielle.

OBJECTIVE: The localization of insulinomas is a central problem, because none of the imaging techniques has proved sufficiently reliable for the diagnosis of tumors smaller than 2 cms. PATIENTS AND METHODS: Calcium stimulation test was performed during selective pancreatic angiogram with calcium gluconate injection in the pancreatic arteries, e.g. gastroduodenal, superior mesenteric and splenic. A simultaneous catheterization of hepatic veins through the femoral vein allowed measurement of insulin level increment after calcium stimulation. RESULTS: In our experience, this test allowed a positive location of an insulinoma in three consecutive patients presenting with organic hypoglycemia, and was useful for surgeons while non-invasive imaging techniques failed to locate the tumor in any of the three patients. DISCUSSION: The calcium stimulation test is a reliable preoperative procedure, particularly when other imaging techniques fail to locate the tumor. However it remains invasive, and our data are still too preliminary to clearly define its place within imaging techniques.