Studies on testosterone metabolism in subjects with testicular feminization syndrome.

The metabolism of radioactive testosterone simultaneously administered intravenously and either orally or percutaneously has been studied in seven patients with the syndrome of testicular feminization and compared with that of normal males and females. This investigation was carried out in order to determine the relative contribution to urinary 17-oxo and 17beta-hydroxy androstane steroids of labeled testosterone, according to its mode of administration. In normal males the yields of urinary 5alpha-androstane-3alpha,17beta-diol (androstanediol) originating from either an intravenous or a percutaneous dose of testosterone were respectively 3 and 6 times higher than those arising from an oral dose which perfuses the liver directly. These data indicate that in normal males, testosterone might be 5alpha-hydrogenated outside the liver. By contrast in patient with feminizing testes, because the contribution to androstanediol of radioactive testosterone is identical whatever its mode of administration, the extrahepatic 5alpha-reduction of this substrate seems very unlikely. The metabolic abnormalities observed in patients with testicular feminization syndrome may be reproduced in normal males by estrogen treatment. Nevertheless, the sensitivity of the patients to estrogen seems to be 10 times greater than that of normal males. This sensitivity was appreciated from the reduction of radioactive testosterone intravenously injected to urinary 17beta-hydroxy-5alpha-androstan-3-one and androstanediol and also from the level of plasma binding for testosterone. This level was significantly higher (P < 0.05) in patients with feminizing testes than in normal males. The level increased dramatically after administration of a low dose of estrogen whereas this effect was not observed in normal males under the same experimental conditions. In light of these results the defect of extrahepatic 5alpha-reduction of testosterone observed in patients with feminizing testes does not necessarily reflect an enzymatic impairment but might be related to an abnormal synthesis of plasma binding protein(s) under the effect of circulating estrogens so that an abnormally small amount of unbound testosterone may be available in target cells for 5alpha-reduction.

Leydig cell tumor with gynecomastia: further studies--the recovery after unilateral orchidectomy.

The recovery of exocrine and endocrine testicular function was studied in six patients orchidectomized for an estrogen-producing Leydig cell tumor. Gynecomastia disappeared in four patients. The contralateral testis, whose volume was reduced, returned to normal size after 30 days. Sperm density returned to normal in only one of the four patients in whom the preoperative sperm count was reduced. One day after unilateral orchidectomy, plasma estradiol decreased to normal and testosterone (T) fell about 50%. On the 10th postoperative day, plasma T [5.60 +/- 1.20 ng/ml (SD)] was normal. On day 120, T was higher than on day 10 (6.83 +/- 1.20 ng/ml). There was no significant increase of T after a single injection of hCG (5000 IU) on day 10, and the T response was similar to that of normal men on day 120. Plasma FSH and LH were increased on the 10th postoperative day; they then decreased between 60 and 120 days after the operation but were still above the normal values on day 120. The FSH/LH ratio, which was 0.43 +/- 0.17 preoperatively returned to normal (1.60 +/- 0.25) 10 days postoperatively. In conclusion, after hemicastration for an estrogen-secreting tumor, testicular hormonal secretion returns to normal within 120 days but spermatogenesis may still be impaired at this time.

Increase in H-Y antigen-positive lymphocytes in hirsute women: effects of cyproterone acetate and estradiol treatment.

To investigate a possible relationship between lymphocyte H-Y antigen expression and plasma androgen concentrations in hirsute women, 27 hirsute women were studied. A significant increase in the percentage of H-Y-positive lymphocytes was found in both hirsute women with idiopathic hirsutism [13.4 +/- 2.9% (+/- SD); n = 15] and hirsute women with the polycystic ovary syndrome (13.0 +/- 2.8%; n = 12) compared to that in normal women (10.0 +/- 1.9%; n = 30; P less than 0.0005). Plasma testosterone and androstenedione concentrations, % H-Y+ lymphocytes, and hirsutism scores diminished during oral cyproterone acetate (50 mg/day) and percutaneous estradiol (3 mg/day) treatment. Significant correlations between % H-Y+ lymphocytes and hirsutism scores (P less than 0.001), % H-Y+ lymphocytes and plasma T concentrations (P less than 0.01) were found. We conclude that 1) women can produce H-Y antigen in the same way as men; 2) hirsutism is associated with an increase in H-Y antigen; and 3) the antiandrogen cyproterone acetate reduces H-Y antigen expression on lymphocytes.

Leydig cell tumor with gynecomastia: hormonal effects of an estrogen-producing tumor.

A patient with a testicular interstitial cell tumor and gynecomastia is reported. The testicular tumor was capable of aromatizing 8.3% testosterone. Spermatic venous samples taken from the tumor-bearing side had marked elevations of 17 beta-estradiol (E2), progesterone, and 17-hydroxyprogesterone (170 HP). The progesterone to 17OHP and 17OHP to androstene-dione ratios suggested an enzymatic block of 17 alpha-hydroxylase and 17-20 lyase possibly secondary to locally produced E2. The E2 produced by the tumor appeared to suppress gonadotropin secretion. The plasma testosterone and gonadotropin levels rose within 7 days after the removal of tumor, and the gynecomastia began to decrease.

Hormonal profile of Leydig cell tumors with gynecomastia.

The hormonal profile of estrogen-secreting Leydig cell tumors was studied in four patients. Plasma testosterone (T) and estradiol (E2) levels varied from day-to-day whereas the T/E2 ratios were decreased (22:85, normal 170 to 440). hCG administration induced a higher estrogen response in the patients than in normal men. The finding in the spermatic venous blood of the tumor-bearing testis of a particular biochemical profile, including a low T/E2 ratio (12:27), associated with high progesterone/17-hydroxyprogesterone ratios (0.13:0.26) and high 17-hydroxyprogesterone-androstenedione ratios (26:44), allowed localization of a small testicular tumor when no testicular abnormality was found clinically. Also, the E2 level was moderately elevated in the spermatic vein of one patient compared with normal men. Spermatic venous blood also was obtained after hCG administration in two patients. Increased estrogen and reduced T responses were found in the tumoral testis in comparison with the contralateral testis. In conclusion, the hormone content of spermatic venous effluent from testes containing an interstitial cell tumor is abnormal in several respects and such abnormalities allow detection of the tumor when it is not recognizable clinically.

Nature of cytochromes P450 involved in the 2-/4-hydroxylations of estradiol in human liver microsomes.

Kinetics of the 2- and 4-hydroxylations of estradiol (E2) by human liver microsomal samples were studied to determine the major P450 isoform involved in these endogenous reactions. Thirty human liver microsomal samples were analysed. Metabolism of 25 microM [14C]E2 produced 2-hydroxy and 4-hydroxy derivatives with a ratio of 3.2 +/- 1.5 and a great inter-individual variation. Kinetic analysis of the 2- and 4-hydroxylations of E2 exhibited a curvilinear double reciprocal plot with an apparent Km of 15 microM. Further experiments demonstrated that alpha-naphthoflavone, testosterone and progesterone increased the 2-hydroxylation activity, suggesting the involvement of a substrate activation mechanism. These two hydroxylations of E2 were shown to be catalysed by cytochrome P450 with an apparent dissociation constant Ks of 0.8 microM. These 2- and 4-hydroxylations inter-correlated significantly (r = 0.93; N = 30). The 2-hydroxylation of E2 correlated with four monooxygenase activities known to be supported by P450 3A4/3A5, namely nifedipine oxidation (r = 0.78; N = 29); erythromycin N-demethylation (r = 0.69; N = 27), testosterone 6 beta-hydroxylation (r = 0.66; N = 25) and tamoxifen N-demethylation (r = 0.64; N = 29). On the other hand, E2-hydroxylations did not correlate with activities supported by P450 1A2 and P450 2E1. Furthermore, drugs as cyclosporin, diltiazem, triacetyl-oleandomycin and 17 alpha-ethynylestradiol inhibited more than 90% of the E2-hydroxylations at concentrations < 250 microM, while weak inhibition was shown with 500 microM cimetidine and no significant inhibition with caffeine, phenacetin and omeprazole. Finally, 2- and 4-hydroxylations of E2 correlated significantly with the content of P450 3A4/3A5 immunodetected by a monoclonal antibody anti-human P450-nifedipine (r = 0.84; N = 28). E2-hydroxylation activities were inhibited by more than 80% with polyclonal anti-human anti-P450-nifedipine. Preincubation of human liver microsomes with 100 microM gestodene (a suicide substrate of P450 3A4) inactivated this P450 isoform and accordingly allowed evaluation of the contribution of other P450 isoforms to the E2 metabolism to about 21% (+/- 17%, N = 29). All these results taken together suggest that P450 3A4/3A5 are the major forms involved in the formation of catecholestrogens in the human liver microsomes.

Circulating immune complexes containing bovine insulin in a patient with systemic allergic manifestations.

A woman treated for 15 days with bovine insulin for gestational diabetes presented with severe urticaria of the chest and back, distant from the injection site. She had neither local reaction nor general manifestations. Replacement of bovine NPH insulin by biosynthetic human NPH was followed by regression of urticaria. We isolated the circulating immune complex (CIC), mainly of IgG class, from the patient's serum. It disappeared when bovine insulin administration had been ceased for 48 h. There were no specific IgE-insulin-antibodies. The IgG-CIC were dissociated. Insulin was identified by RIA in the CIC. Insulin characterization was carried out by high-performance liquid chromatography (HPLC), which showed that the insulin in the complexes was injected bovine insulin.

[Kinetics of prolactinemia after withdrawal of dopamine perfusion and during the administration of domperidone. Normal and hyperprolactinemic subjects (prolactinomas and suprahypophyseal lesions)]. / Cinétique de la prolactinémie aprés arrêt de la dopamine perfusée et lors de l'administration orale de dompéridone. Sujets normaux et hyper-prolactinémiques (prolactinomes et lésions supra-hypophysaires).

Fifteen normal menstruating women in the early follicular phase of their menstrual cycle, fifteen patients with prolactin secreting adenomas, two patients with a suprahypophysial lesion and an hyperprolactinemia, underwent a dopamine infusion (4 micrograms/kg/mn for four hours and an orally administration of domperidone (40 mg). Prolactin rebound after the arrest of dopamine infusion and during domperidone are + 400% and + 2,300% in normal subjects. These same studies are followed by similar and reduced prolactin response in suprahypophyseal lesion and prolactinomas. Such results suggest an abnormality of central dopaminergic control and/or a primary abnormality of lactotropes in prolactinomas. In two prolactinomas the normalization of both prolactin level and prolactin responses during the same tests is in favor of a primary abnormality of adenomatous lactotrope. These data justify neuro-surgical adenomectomy.

[Long-term effects of treatment with SMS 201-995 on sleep apnea syndrome associated with acromegaly]. / Effets à long terme du traitement par SMS 201-995 sur un syndrome d'apnées du sommeil associé à une acromégalie.

A 60-year-old woman with acromegaly associated with sleep apnea was treated with the somatostatin analogue SMS 201-995 (Sandoz) for several months. Growth hormone levels were normalized and a rapid improvement in sleep apnea was controlled with polygraphic nocturnal monitoring. Hypophysectomy seems to have variable effects on sleep apnea in acromegaly. The origin of obstructive apnea in acromegaly is therefore unclear.

[Adrenoleukodystrophy in the child and adrenomyeloneuropathy. Study of 2 families]. / Adrénoleucodystrophie de l'enfant et adrénomyéloneuropathie. Etude de deux familles.

Ten subjects from 2 families with adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN), hereditary X-linked diseases, were systematically explored. We performed endocrinological, biochemical assays and neurophysiological tests; the latter consisted of nerve conductions (CNV), Hoffmann's reflex and multimodal evoked potentials: visual (flash and pattern, VEP), brainstem auditory (BAEP) and somesthetic (SEP) using median nerve stimulation at the wrist. We only considered values above 2 SD. The purpose of our study was to determine the correlation between neurophysiological and endocrinological perturbations and the presence of pathological traits. Our results suggest that the correlation is high in diseased male patients, lower for the ALD carriers (BAEP, SEP and CNV were more frequently abnormal) and very low for the AMN carriers. Only the biochemical assays appeared to have any value for the characterization of female carriers of ALD and AMN.

[Receptiveness to sexual steroids. Physiopathological aspects]. / La réceptivité aux stéroïdes sexuels. Aspects physiopathologiques.

Each hormonal signal is specifically related to a cellular receptor. However, the same receptor may bind several hormones. Oestradiol which binds to the oestrogenic receptor with a Kd of 0,1 nM, may also bind with the prostatic androgen receptor with a Kd of 3 nM. Progesterone is another example of binding pluralism as it binds not only to the progesterone receptor but also to the androgenic (anti-androgenic effect), mineralocorticoid receptors (anti-aldosterone effect) and the gluco-corticoid (anti-inflammatory effect. As different receptors may bind the same steroid, reciprocally, a given receptor may bind different steroids. What applies to natural hormones, also applies to synthetic hormones. Each new molecule has a specificity of biological action which can be predicted from pharmacological screening tests. This specificity is expressed by the affinity of relative binding to a given receptor compared with a reference steroid. In vitro studies do not take endogenic metabolism which may alter the concentration of the tested substances at the receptor site into account. The modes of receptivity to steroid hormones are complex and other factors than the receptor proteins are involved. The change in uterine blood flow induced by oestradiol cannot be explained by these mechanisms. Similarly, progesterone acts at the cell membrane level of the amphibian egg. The receptivity to sexual steroids is therefore a complex phenomenon, the first elements of which are beginning to be understood.

[An introduction to synthetic progestogens pharmacology (author's transl)]. / Introduction â la pharmacologie des progestatifs de synthése.

Synthetic progestins differ in their progestomimetic and other endocrine effects. Their affinities for different steroid hormone receptors have been measured and their pharmacological activities (progestomimetic, uterotrophic, anti-estrogenic, androgen and anti-gonadotrophic) have been evaluated concomitantly. Derivatives of the pregnane series are basically progestomimetic only, whereas derivatives of the norandrostane series have distinctly androgenic and anti-estrogenic properties. A knowledge of these various activities facilitates the choice of an appropriate therapy.

[Physiology and physiopathology of breast development in men]. / Physiologie et physiopathologie du développement mammaire chez l'homme.

Development of breasts in male subjects is a characteristic feature of gynecomastia, a not infrequent condition as it may be a physiological feature present at birth or developing during puberty and old age. The possibility of an underlying pathological process has always to be considered. Male breast enlargement may result from voluntary or involuntary ingestion of estrogens or medication possessing anti-androgenic activity. Pathological gynecomastia is due to either an excessive production of estrogens or a drop in the plasma T/E2 ratio, medical treatment is unsatisfactory, and mammectomy is required when esthetic considerations are of primary importance, after investigations to establish the etiology of the gynecomastia.

[Recurrent hyperaldosteronism and hypertension post adrenalectomy (author's transl)]. / Problèmes posés par l'hyper-aldostéronisme primaire récidivant et l'hyper-tension artérielle post-surrénalectomie

Primary Aldosteronism may be due to adenoma or hyperplastic adrenals. Such a distinction can be obtained from biochemical studies. In our observation, a man with recurrent aldosteronism after right adrenalectomy was studied. Radiological and surgical data might indicate an adenoma. This opinion was modified by pathological studies. This absence of capsule and the presence of microadenomatous hyperplastic lesions indicated pseudo-adenomatous hyperplastic glands. On the other hand, high blood pressure remained after adrenalectomy. A treatment with beta-blocking substances corrected this hypertension.

[Adrenal reactivity to prolonged-action ACTH in hirsute women treated with 50 mg of cyproterone acetate combined with percutaneous estradiol]. / Réactivité surrénalienne à l'ACTH retard chez les femmes hirsutes traitées par l'acétate de cyprotérone 50 mg associé à l'estradiol percutané.

A prolonged-action Synacthen (R) test (1 mg.i.m. was performed in 14 hirsute women before and 6 months after instituting combined treatment with cyproterone acetate (50 mg/day/21 days) and percutaneous estradiol (3 mg during the last 10 days of cyproterone acetate administration). Determination of blood cortisol and precursors of cortisol--plasma androgens--was carried out to evaluate possible modification of adrenal enzymatic activity. At the used doses, cyproterone acetate failed to influence adrenal reactivity to synthetic ACTH or the enzymatic activities of 21-hydroxylase and 17-beta-reductase in vivo.

[Mid-term and long-term outcome in Leydig cell estrogen tumors]. / Devenir à moyen et à long terme des tumeurs estrogéniques à cellules de Leydig.

A study has been realized in six patients with estrogen secreting Leydig cell tumors from 18 to 120 months after hemicastration. Testicular contralateral volume is normalized, gynecomastia can be completely reduced, sex steroids are normalized while gonadotropins can be temporary increased. Spermogram which is abnormal can be normalized. These results confirm the heterogeneity of these tumors.

[Inappropriate secretion of antidiuretic hormone and diabetes insipidus after surgery for pituitary adenoma]. / Sécrétion inappropriée d'hormone anti-diurétique et diabète insipide dans les suites opératoires de l'adénomectomie hypophysaire.

The purpose of our study was to evaluate the incidence and risk factors of SIADH (syndrome of inappropriate antidiuretic hormone) and diabetes insipidus after pituitary adenoma surgery in patients and report follow-up data collected in our department of endocrinology. This retrospective study included 78 patients seen in the last 5 years. Possible risk factors of SIADH and diabetes insipidus were studies: patient age and gender, type of secretion, tumor volume, surgical approach, presence of postoperative pituitary failure. The incidence of SIADH and diabetes insipidus were similar: 12.8%. We did not find any risk factor for SIADH associated with postoperative anterior pituitary failure. This study illustrates the importance of postoperative follow-up after pituitary adenoma surgery.

[Intracardiac ectopic thyroid]. / Ectopie thyroïdienne intracardiaque.

Intracardiac ectopic thyroid tissue was removed in a 51 years old woman, after echography has discovered a tumor in the right ventricle. There was a normal thyroid gland in the neck and thyroid function tests were normal. Intra-cardiac ectopic thyroid tissue is very rare; it is due to an abnormality of embryological development, when thyroid anlage is in close contact with the embryonic heart.

[Polycystic ovary and diazoxide. In vivo study]. / Ovaires polykystiques et diazoxide. Etude in vivo.

The suppression of hyperinsulinism with diazoxide (300 mg/d during 30 days) in a young woman with PCOS and hirsutism, hyperinsulinism and insulinoresistance was followed by a modification of plasma androgens. Testosterone (T) and free testosterone (fT) were reduced after ten days and then increased but always remained below the baseline level. DHEAS had increased 200% by day 10, and 3 alpha-adiol G to three times its basal value by day 20. These modifications were constant during the treatment. fT decrease was secondary to reduction of hyperinsulinism which was followed by an increase of TeBG and a modest and transient reduction of androgen theca cells production. DHEAS increase was due to hyperinsulinism suppression which stimulated adrenal 17-20 lyase activity. 3 alpha-adiol G increase was concomittant, and can be considered as an index of adrenal androgen secretion.

[Pregnancy in diabetic women. Apropos of 9 pregnancies. Management]. / La grossesse chez la femme diabétique. A propos de neuf grossesses. Conduite à tenir

Pregnancy in a diabetic woman carries with it a risk of intra-uterine death for the foetus. In this paper the authors report on 9 cases of pregnancy in diabetic women and the results obtained when a systematic management of the condition involving delivery before term, always by caesarean section, is carried out. It is absolutely vital to have perfect stabilisation of the diabetic state during the pregnancy, in order to do this the patient must be seen very often and brought into hospital early, soon after the 28th week. It would appear to us that caesarean delivery is the delivery of choice because it allows the extraction of a foetus in good condition, at a chosen time when a trained team is ready. It is essential to end the pregnancy somewhere between the 36th and 37th week of the pregnancy and sometimes even earlier if there is associated pathology such as toxaemia. This systematic method implies a constant check on the fetal well-being by oestriol estimations, although we realise that the levels are still low between the 7th and 8th month and that watching a graph that is steadily climbing allows the team to wait until the calculated date for bringing the pregnancy to its conclusion. In two cases the pregnancy was interrupted early because of variations in the graph; in one early delivery was justified by the development of toxaemia and in the other a moderate drop in the oestriol levels led us to intervene early. When there is a drop in the levels is it very important to ensure that is is due to fetal distress and not to daily physiological changes because the risk is of excessive prematurity if induction is carried out too soon.