Biomedical subjects
J D Wilson
Publications and source records attributed to J D Wilson.
Peer review and publication. Presidential address before the 70th annual meeting of the American Society for Clinical Investigation, San Francisco, California, 30 April 1978.
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Hereditary male pseudohermaphroditism associated with an unstable form of 5 alpha-reductase.
The properties of 5alpha-reductase have been compared in genital skin fibroblasts cultured from five patients from three families (Los Angeles, Dallas, and Dominican Republic) in which hereditary male pseudohermaphroditism has been established to result from deficient conversion of testosterone to dihydrotestosterone. Despite the fact that 5alpha-reductase was immeasurable in a homogenate of epididymis removed from one of the Los Angeles patients, 5alpha-reductase activity was normal in intact fibroblasts and fibroblast extracts from both patients from the Los Angeles family. Although the apparent K(m) for testosterone was also near normal, the apparent K(m) for NADPH in these mutants is elevated some 40-fold above normal. Furthermore, the enzyme is not protected against denaturation at 45 degrees C by concentrations of NADPH that stabilize normal 5alpha-reductase, and in intact fibroblasts from these patients (but not from controls), enzyme activity decreases promptly when protein synthesis is inhibited. We conclude that the mutation in this family results in an unstable enzyme. In contrast 5alpha-reductase activity in fibroblast extracts from a patient from the Dominican Republic family is similar to that previously described in two members of the Dallas family, namely total enzyme activity is low at the optimal pH for the normal reaction, and the apparent K(m) for testosterone is some 20-fold higher than that of the controls. We conclude that the mutations in the Dallas and Dominican Republic families are similar and result in low activity of the enzyme as the result of a decreased affinity for testosterone.Thus, two distinct types of mutations can produce male pseudohermaphroditism due to deficient dihydrotestosterone formation.
Aromatase activity in the developing rabbit brain.
The formation of 17beta-[3H]estradiol from [1,2,6,7-3H]testosterone was assessed in placenta and central nervous system tissues from rabbit embryos that varied in age from 13-28 days of gestation. In the fetal brain, significant rates of aromatase activity were limited exclusively to the forebrain, and the highest rates of activity (approximately 0.5 pmol/h/mg protein) were found in the diencephalon both male and female embryos between days 19 and 25 of gestation. These rates of aromatase activity are second only to the fetal ovary when expressed per mg protein; moreover, forebrain is the only tissue in the male embryo capable of synthesizing significant amounts of estrogens in vitro. When projected to the whole organ, the capacity of the diencephalon for aromatization exceeds the capacity of the fetal ovary approximately 9-fold. Placental aromatase activity was high (2.1 pmol/h/mg protein) on day 13 but fell to a level approximately 20-fold lower by day 19 of gestation. These findings indicate the potential importance of the forebrain as a source of estrogens during embryogenesis.
Studies on the regulation of testosterone synthesis in the fetal rabbit testis.
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Studies on the mechanism of 3 alpha-androstanediol-induced growth of the dog prostate.
The conditions under which dihydrotestosterone and 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-androstanediol) induce prostatic growth in the castrate dog have been investigated in animals in which the initial size of the prostate was either normal or large. When androgen replacement was commenced immediately after castration of dogs with preexisting prostatic hypertrophy, dihydrotestosterone was as effective as 3 alpha-androstanediol in maintaining prostate weight. Under all other conditions examined (replacement commenced immediately after castration in dogs with small prostates or 2 weeks after castration in dogs with large prostates), 3 alpha-androstanediol but not dihydrotestosterone induced significant prostatic growth. The maximal effect of 3 alpha-androstanediol in inducing prostatic growth was observed in 12 weeks. The administration of 17 beta-estradiol enhanced the growth-promoting action of 3 alpha-androstanediol, but did not affect the action of dihydrotestosterone or influence 3 alpha-hydroxysteroid dehydrogenase activity in prostate. Thus, the synergistic effect of 17 beta-estradiol and 3 alpha-androstanediol seems to be independent of any effect on the interconversion of the two androgens. The activity of the 3 alpha-hydroxysteroid dehydrogenase in dog prostate was high under all conditions of accelerated prostatic growth and appeared to be under androgenic control.
Intranuclear binding of [3H]dihydrotestosterone by cultured human fibroblasts.
The uptake of [1,2,4,5,6,7-3H]dihydrotestosterone into whole cells and nuclei has been assessed in fibroblasts grown from genital skin of 10 controls and 9 subjects with hereditary male pseudohermaphroditism due to androgen resistance. The cells were exposed to hypotonic buffer and ruptured by passage through a 25-gauge needle, and the nuclei were purified by sedimentation through 2.1 M sucrose. Uptake of the hormone into nuclei reached an apparent plateau in 45 min, was saturable at 1 nM dihydrotestosterone, and was not detectable in the presence of excess nonradioactive hormones. Over a wide range of uptake by intact cells from control subjects and from subjects with androgen resistance due to 5alpha-reductase deficiency or receptor deficiency, nuclear uptake averaged about half of the total cell uptake. Furthermore, in cells from two unrelated 46,XY phenotypic females with androgen resistance but normal 5alpha-reductase activity and normal whole cell dihydrotestosterone binding, uptake into the nucleus was also normal. In these subjects, the defect in androgen action must be at some terminal phase of androgen action.
Conversion of androgen to estrogen by the human fetal ovary.
The conversion of radiolabeled androgen to estrone and 17 beta-estradiol was assessed in tissues of human embryos that varied from phenotypically indifferent stages (1-3 cm crownrump length) to midgestation (15. 1-20 cm crownrump length). Significant rates of estrogen synthesis were demonstrated only in ovaries, liver, and brain. Estrogen synthesis was undetectable in gonads from 1-3 cm fetuses, but by the 3.1-5-cm stage it had reached an average rate of 1.9 pmol . h-1 . mg protein -1 in ovaries and remained at this level of activity through the latest stages examined. Estrogen formation was undetectable in testes at all stages examined, but the time of appearance of the capacity to form estrogens in the fetal ovary is similar to the onset of the capacity of the fetal testis to synthesize testosterone. The capacity of the fetal ovary to form estrogen develops before histological differentiation of the tissue.
Clinical, endocrinological, and enzymatic characterization of two patients with 5 alpha-reductase deficiency: evidence that a single enzyme is responsible for the 5 alpha-reduction of cortisol and testosterone.
Two siblings with 46,XY male pseudohermapthroditism were demonstrated to have the phenotype characteristic of 5 alpha-reductase deficiency, namely normal testes and male Wolffian duct derivatives (epididymis, vas deferens, and seminal vesicle) terminating in a blind-ending vagina. Clitoromegaly was present at birth and increased further at the time of expected puberty. The diagnosis of 5 alpha-reductase deficiency was confirmed by demonstration of male levels of testosterone and testosterone precursors before and after hCG administration, elevated plasma testosterone to dihydrotestosterone and urinary etiocholanolone to androsterone ratios, and by in vitro studies indicating 5 alpha-reductase enzyme deficiency in the epididymis of one patient. Studies of control and mutant epididymal microsomes indicated that a single enzyme is responsible in the normal person for the 5 alpha-reduction of testosterone and cortisol (and probably other delta 4-3-ketosteroids as well) and that 5 alpha-reductase activity is undetectable for all substrates examined in the mutant. This finding explains why the formation of 5 alpha-reduced glucocorticoids is also defective in the disorder.
Hereditary male pseudohermaphroditism.
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Different rosette assays for detecting Fc receptor-bearing lymphocytes measure different subpopulations.
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Clinical experience with the new insulins.
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Roosters, Reifenstein's syndrome and hormone resistance.
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Skin testing in the assessment of cell-mediated immunity.
Cell-mediated immunity may be assessed by measuring the response to subcutaneous injection of a battery of recall antigens. The finding of cutaneous anergy (the failure to respond to testing) is strong evidence of either major pathology or a significant immunosuppressive event. A protocol for skin testing is presented together with some preliminary results, including normal values for a New Zealand population. Consideration of its adoption is urged.
Transfer factor therapy: clinical experience and the role of the E rosette assay.
Transfer factor has been administered to 17 patients, most with infectious diseases of various kinds. In 12 patients the therapy was followed by a definite clinical improvement although in most cases conventional chemotherapy was given concomitantly. In all cases where clinical improvement followed the sheep red cell or E rosette assay showed low values initially, with an improvement following therapy. This test of T lymphocyte function may be useful both in predicting patients likely to respond to transfer factor, and in monitoring response to treatment. As no specific assay of transfer factor activity is available, an in vivo rise in E rosette formation following transfer factor administration serves as a crude indicator that the injected material has some biological activity.
Characterization of the 3alpha-hydroxysteroid dehydrogenase of dog prostate.
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Autoantibodies following vasectomy.
The incidence of 7 different autoantibodies was determined in 904 men 3 months to 6 years after vasectomy operations and in 700 control subjects. There was no clinically significant increase in autoantibodies in the vasectomized group nor was any autoimmune disease detected that could be related to the vasectomies.
Genetic control of renin activity in the submaxillary gland of the mouse.
Administration of androgen to female mice is known to increase the level of several proteins in the submaxillary gland, including nerve growth factor, epidermal growth factor, esteroproteolytic activity, and renin. In the present study, renin activity has been assessed in extracts of submaxillary gland of female mice from two inbred strains (SWR/J and C57BL/10J), from F1 and F2 hybrids, and from backcrosses between F1 and parental strains. In both uninduced and induced mice, renin activity of submaxillary gland was more than 100-fold greater in SWR/J than in C57BL/10J mice as measured by either an enzymatic assay or an immunodiffusion method. This difference was not due to differences in plasma testosterone levels between the strains, and the enzymes from the two strains had similar pH optima, substrate specificities, heat stabilities, and apparent Michaelis constants. In the submaxillary gland the difference was relatively specific for renin because increases in esteroproteolytic activity, nerve growth factor, and epidermal growth factor after androgen treatment appeared to be similar in both strains. Studies with the various hybrids indicate that the difference in renin activity between the two strains is apparently due to a single regulatory gene.