James D. Madden

Familial incomplete male pseudohermaphroditism, type 2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias

Abstract Two 46 XY siblings with familial incomplete male pseudohermaphroditism, Type 2, inherited as an apparent autosomal recessive trait, were investigated. The phenotype was distinctive in that male wolffian-duct structures (epididymis, vas deferens and seminal vesicles) were present whereas tissues derived from the urogenital sinus and from the anlage of the external genitalia were female in character. Studies of estrogen and androgen dynamics revealed normal male blood testosterone and estrogen levels, production rates and interconversions. The normal blood luteinizing hormone level and normal estrogen production rate suggest that androgen resistance in this syndrome is different from that in other androgen-resistant states. The demonstration of markedly deficient dihydrotestosterone formation in slices of perineal skin, epididymis and phallus, considered with the fact that dihydrotestosterone is the fetal hormone responsible for male differentiation of the external genitalia, is compatible with the...

Congenital Absence of the Vagina: The Mayer-Rokitansky-Kuster-Hauser Syndrome

We describe 14 patients with congenital absence of the vagina associated with a variable abnormality of the uterus and review the literature. Associated developmental anomalies of the urinary tract and skeleton are common. As a result of the analysis of two affected families, we believe that the disorder may represent the variable manifestation of a single underlying genetic defect that can be expressed alone or in any combination of vertebral, renal, and genital abnormalities. Some affected persons may have lethal manifestations such as absence of both kidneys, and some cases may result from multifactoral causes rather than a single gene defect. Whatever the cause, the defect involves mesodermal development and the mesonephric kidney, the latter resulting in abnormalities in the paramesonephros (uterus and vagina) and in the metanephric kidney. Both nonoperative and surgical treatments are generally successful in repairing the vaginal abnormality.

The Endocrinology of Human Chorionic Gonadotropin-Secreting Testicular Tumors: New Methods in Diagnosis

Serum from 59 men with testicular masses was examined for the presence of human chorionic gonadotropin-beta. Results indicate: 1) In patients with testicular tumor human chorionic gonadotropin-beta serves as a sensitive and specific marker of tumor activity with an incidence of 28%. 2) Because human chorionic gonadotropin-beta levels correlate with response to therapy this test will be useful in selecting men for adjunctive irradiation or chemotherapy. 3) Radioimmunoassay for human chorionic gonadotropin-beta is far more sensitive and specific than conventional methods for detecting human chorionic gonadotropin production. 4) After unilateral orchiectomy for carcinoma of the testis elevated serum luteinizing hormone levels are common and may be unrelated to the presence or activity of residual tumor. 5) Human chorionic gonadotropin-beta-producing tumors were associated with increased estradiol and testosterone levels and significantly depressed serum follicle stimulating hormone levels in this series. 6) The prognostic implications of the presence of human chorionic gonadotropin-beta are not yet fully understood. The importance of this study is the fact that men with testicular tumors have a high incidence of human chorionic gonadotropin-beta secretion and this fact provides the physician with a powerful new tool for examining the various aspects of tumor activity. It also shows the feasibility for prospective screening of patients with a wide variety of neoplasms of differing histologic types.

The metabolic clearance rate of dehydroisoandrosterone sulfate

In the present study, the metabolic clearance rate of dehydroisoandrosterone sulfate (MCRDS) decreased in normotensive gravidas during short-term studies utilizing angiotensin II-induced elevation of blood pressure. Therapy with hydralazine hydrochloride in chronic hypertensive gravidas resulted in a decrease in blood pressure and an accompanying decrease in the MCRDS. A variable response was observed in the apparent volume of distribution of DS (AVDDS) during therapy with hydralazine hydrochloride. Decreases in MCRDS also occurred in chronic hypertensive gravidas following therapy with 40 mg. of intravenously administered furosemide despite a failure of blood pressure to be altered. The AVDDS increased in four of five patients receiving furosemide, suggesting a possible direct action of furosemide upon vascular smooth muscle.

Clinical and endocrinological evaluation of patients with congenital microphallus

Eight patients with congenital microphallus were investigated. Plasma luteinizing hormone, follicle-stimulating hormone, testosterone and androstenedione levels were obtained in all cases. In addition, the response to the administration of human chorionic gonadotropin, luteinizing horomone-releasing hormone and adrenocorticotropic hormone, the assessment of testicular histology by electron microscopy and the measurement of dihydrotestosterone formation by preputial skin were determined in some patients. The results of these studies were compared to similar studies in 6 normal prepubertal boys, 4 boys with bilateral cryptorchidism, 1 male infant with anorchia and 1 adult with hypogonadotropic hypogonadism. The clinical and endocrinological findings in the 8 patients with microphallus can be divided into 2 distinct categories. In 5 patients the disorder is familial, gonadotropin levels are low and there is a normal response to stimulation with chorionic gonadotropin. The data are compatible with the possibility that 3 (possibly 5) of the 8 patients with microphallus have hypogonadotropic hypogonadism. In the other group the cases are sporadic, serum luteinizing hormone and follicle-stimulating hormone levels are elevated and plasma testosterone failed to increase after short-term treatment with chorionic gonadotropin. In these patients a primary testicular disorder appears to be responsible. Experimental and clinical evidence suggests that microphallus results from defective testicular function during the second and third trimesters of pregnancy, either as the result of defective gonadotropin secretion or defective androgen synthesis.

The pattern and rates of metabolism of maternal plasma dehydroisoandrosterone sulfate in human pregnancy

The present study was done to map the metabolic pathways and rates of maternal plasma clearance of dehydroisoandrosterone sulfate (MCRDS) in pregnancy. In the present study, maternal plasma dehydroisoandrosterone sulfate (DS) metabolism was largely accounted for by two major pathways not present or not prominent in the nonpregnant woman. The first major pathway was clearance of maternal plasma DS by placental aromatization of DS to form estradiol (E2). This pathway accounted for approximately 35 per cent of the total clearance. The second major pathway of metabolism of maternal plasma DS was by 16 alpha-hydroxylation within the maternal compartment. This pathway accounted for approximately 32 per cent of maternal plasma DS clearance. Two other minor pathways of DS metabolism, that is, loss to the fetus and excretion as unaltered DS into urine, accounted for less than 1 per cent of total metabolism in each instance. The final pathway of DS metabolism was excretion as neutral steroids such as urinary 17-ketosteroids and other undefined losses. By combining the rate of DS clearance (MCRDS) from maternal plasma via all pathways with that fraction of DS removed uniquely by placental conversion of DS to estradiol (DS leads to E2), the placental clearance of DS leads to E2 (PCDSE2) may be measured. The measurement of PCDSE2 may be expected to reflect uteroplacental perfusion and as such may provide an investigative tool capable of assessing the dynamics of uteroplacental function in a variety of clinical conditions.

The metabolic clearance rate of dehydroisoandrosterone sulfate: III. The effect of thiazide diuretics in normal and future pre-eclamptic pregnancies☆

The present study reports that the metabolic clearance rate of dehydroisoandrosterone sulfate (MCRDS) is decreased by thiazide diuretics during normal and future pre-eclamptic pregnancies. This observation supports the thesis that diuretics represent a potential hazard to the fetus by decreasing placental perfusion.

Dehydroisoandrosterone sulfate in peripheral blood of premenopausal, pregnant and postmenopausal women and men

Abstract A radioimmunoassay specific for the direct measurement of dehydroisoandrosterone sulfate in 0.5 or 1 μl of human serum was developed using an antibody directed against dehydroisoandrosterone hemisuccinate coupled to thyroglobulin. Dehydroisoandrosterone sulfate levels were measured in pregnant women throughout gestation starting with the 6th week of pregnancy, and in young ovulatory women, postmenopausal women and in men. During pregnancy the concentrations of dehydroisoandrosterone sulfate in maternal serum decreased steadily with advancing gestation [1825 ± 68 ng/ml (mean and S.E.) at 6–8 weeks gestation vs 706 ± 141 ng/ml at 36–41 weeks gestation], and the most striking decrease was observed between 14 and 16 weeks of gestation. The mean concentrations of dehydroiso-androsterone sulfate were higher in men than in young nonpregnant women (2679 ±196 ng/ml vs 2020 ± 108 ng/ml respectively). In postmenopausal women, mean serum dehydroisoandrosterone sulfate concentrations (764 ± 28 ng/ml) were considerably lower than those in young premenopausal women P

The effect of oral contraceptive treatment on the serum concentration of dehydroisoandrosterone sulfate

Dehydroisoandrosterone sulfate (DS), the major C19-steroid in the human circulation, was measured in serum obtained from blood samples collected daily (8 to 10 A.M.) throughout the menstrual cycles of eight normal, presumably ovulatory women and daily throughout the treatment cycles in four women taking an oral contraceptive (norethindrone, 1 mg., plus mestranol, 80 mcg.). The serum concentrations of DS in the ovulatory women ranged from 1,025 to 4,200 ng. per milliliter; mean, 2,062 +/- 137 ng. per milliliter (mean and standard error; n = 213). Serum DS concentrations during the follicular and luteal phases of the menstrual cycles of these women were similar. In women taking the oral contraceptive, the plasma DS concentrations ranged from 475 to 1,400 ng. per milliliter (mean, 895 +/- 83; n = 119). The 24 hour secretory pattern of DS was evaluated in one subject during a nontreatment cycle and again after 20 days of oral contraceptive treatment. In this subject, the mean serum DS level was 34 per cent lower during oral contraceptive treatment than the level before treatment. The decrease in the serum concentration of DS during oral contraceptive treatment likely results from a reduction in adrenal DS secretion since DS secretion by the normal human ovary is negligible and ovarian dehydroisoandrosterone secretion is small. Therefore, it is likely that the reduced serum DS levels in women taking oral contraceptives are the consequence of reduced adrenal secretion of DS resulting from reduced release of adrenocorticotropic hormone.

Study of the kinetics of conversion of maternal plasma dehydroisoandrosterone sulfate to 16α-hydroxydehydroisoandrosterone sulfate, estradiol, and estriol☆☆☆

The transfer constants of conversion of maternal plasma dehydroisoandrosterone sulfate to estradiol ([rho]DS-E2BU) and to 16alphaOH-dehydroisoandrosterone sulfate ([rho]DS-160HDS BU) and of maternal plasma 16alphaOH-dehydroisoandrosterone sulfate to estriol ([rho]160HDS-E3 BU) were measured in women late in pregnancy. The mean [rho]160HDS-E3 BU, 0.17, was considerably less than the mean [rho]DS-E2 BU, 0.29. However, the extent of 16alpha-hydroxylation of maternal plasma dehydroisoandrosterone sulfate was great, the mean [rho]DS-160HDS BU being 0.36.