Jean D. Wilson

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...

The induction of prostatic hypertrophy in the dog with androstanediol.

The effects of androstanediol and estradiol on prostatic growth were investigated in castrate dogs. Estrogens along resulted in no significant change in prostatic weight, whereas androstanediol produced growth comparable to that in uncastrated controls. Androstanediol plus estradiol resulted in an even more striking increase in prostate growth. Approximately half the animals receiving androstanediol alone and all of those receiving androstanediol plus estradiol fulfill the weight and histological criteria for prostatic hypertrophy in the dog. Since both these steroid hormones are presumed to be normal secretory products of the testis, it is possible that they are involved in the pathogenesis of prostatic hypertrophy in the dog.

Dihydrotestosterone in prostatic hypertrophy: I. The formation and content of dihydrotestosterone in the hypertrophic prostate of man

To explore the relation between androgens and prostatic hypertrophy in man, the concentrations of testosterone, dihydrotestosterone, and androstenedione and the rate of conversion of testosterone to dihydrotestosterone have been measured in normal and hypertrophic prostate tissue. First, a double isotope derivative technique was adapted for the measurement of tissue androgen content in 15 normal and 10 hypertrophic prostates. Although there was no significant difference in the content of androstenedione and testosterone between the two types of tissue, the content of dihydrotestosterone was significantly greater in the hypertrophic tissue (0.60 +/-0.10 mug/100 g) than in the normal glands (0.13 +/-0.05 mug/100 g). Second, a regional study was performed in three normal prostates and four glands with early hypertrophy, and it was demonstrated that the dihydrotestosterone content was two and three fold greater in the periurethral area where prostatic hypertrophy usually commences than in the outer regions of the gland. Finally, the rate of conversion of testosterone to dihydrotestosterone has been measured under standardized conditions in tissue slices from 4 normal and 20 hypertrophic prostates. There was no significant difference in the rate of dihydrotestosterone formation between the two types of gland (6.0 +/-0.8 and 7.8 +/-0.5 mumumoles/15 mg of tissue per hr). While the mechanism by which dihydrotestosterone accumulation occurs remains unexplained, it is possible that the local accumulation of dihydrotestosterone may be involved in the pathogenesis of prostatic hypertrophy in man.

Regulation of Cholesterol Metabolism

Absorption of Cholesterol Mechanisms of cholesterol absorption. The second source of cholesterol entering the miscible pools is dietary or exogenous cholesterol. The essential features of the proce...

Genetic and pharmacological evidence for more than one human steroid 5 alpha-reductase.

The enzyme steroid 5 alpha-reductase catalyzes the conversion of testosterone into the more potent androgen, dihydrotestosterone, and impairment of this reaction causes a form of male pseudohermaphroditism in which genetic males differentiate predominantly as phenotypic females. We previously isolated cDNA clones that encode a human steroid 5 alpha-reductase enzyme. Here, we report molecular and genetic studies demonstrating that the gene encoding this cDNA is normal in subjects with the genetic disease steroid 5 alpha-reductase deficiency. We further show that in contrast to the major steroid 5 alpha-reductase in the prostate and cultured skin fibroblasts, the cDNA-encoded enzyme exhibits a neutral to basic pH optima and is much less sensitive to inhibition by the 4-aza steroid, finasteride (MK-906). The results provide genetic, biochemical, and pharmacological support for the existence of at least two steroid 5 alpha-reductase isozymes in man.

Molecular genetics of steroid 5 alpha-reductase 2 deficiency.

Two isozymes of steroid 5 alpha-reductase encoded by separate loci catalyze the conversion of testosterone to dihydrotestosterone. Inherited defects in the type 2 isozyme lead to male pseudohermaphroditism in which affected males have a normal internal urogenital tract but external genitalia resembling those of a female. The 5 alpha-reductase type 2 gene (gene symbol SRD5A2) was cloned and shown to contain five exons and four introns. The gene was localized to chromosome 2 band p23 by somatic cell hybrid mapping and chromosomal in situ hybridization. Molecular analysis of the SRD5A2 gene resulted in the identification of 18 mutations in 11 homozygotes, 6 compound heterozygotes, and 4 inferred compound heterozygotes from 23 families with 5 alpha-reductase deficiency. 6 apparent recurrent mutations were detected in 19 different ethnic backgrounds. In two patients, the catalytic efficiency of the mutant enzymes correlated with the severity of the disease. The high proportion of compound heterozygotes suggests that the carrier frequency of mutations in the 5 alpha-reductase type 2 gene may be higher than previously thought.

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 syndromes of androgen resistance

The concept that endocrine disease can result from resistance to hormone action was elaborated in 1942 by Albright et al., who deduced that pseudohypoparathyroidism resulted from peripheral resista...

The use and misuse of androgens

Because testosterone is rapidly metabolized by the liver, it is necessary either to administer androgens by injection in the form of testosterone esters that are absorbed slowly into the circulation or to administer by mouth derivatives that are slowly metabolized by the liver. The later derivatives, however, have deleterious side effects that limit their usefulness. Long-acting parenteral androgen esters are the treatment of choice in the replacement therapy of male hypogonadism. Because these esters must be hydrolyzed to the free hormone prior to exerting their cellular actions the effectiveness of therapy can be monitored by following plasma testosterone levels. All known effects of the endogenous hormone can be duplicated except for the induction and maintenance of normal spermatogenesis. Androgens have been tried in a variety of clinical situations other than male hypogonadism in the hopes that the nonvirilizing actions would outweigh any detectable side effects. The only disorders in which a salutary effect has been documented are hereditary angioneurotic edema and some patients with anemia due to failure off the bone marrow.

The Intranuclear Metabolism of Testosterone in the Accessory Organs of Reproduction

Publisher Summary This chapter discusses the intranuclear metabolism of testosterone in the accessory organs of reproduction. Testosterone is taken up by nuclei of the accessory organs of male reproduction. Within these nuclei, testosterone may undergo at least two fates; it may either be bound to a protein of the chromatin or it may be reduced to dihydrotestosterone prior to or as a step in the binding process. The implications of these events in regard to the mechanism of action of the hormone are unclear. On the one hand, it is possible that specific testosterone metabolites may have different effects within a single target tissue. It seems more likely, however, that the various metabolites have different binding affinities for the same binding site(s) and that any differences in the effects of different metabolites can, as a consequence, be explained in qualitative terms. The physiological meaning of dihydrotestosterone formation is also uncertain. On the basis of the remarkable growth-promoting effects of dihydrotestosterone on prostate both in vivo and in organ culture, the correlation between the rate of dihydrotestosterone formation in skin of man and the known growth response of the skin to testosterone, and the striking relation between prostatic growth in different species and the rate of this conversion, it is tempting to speculate that dihydrotestosterone formation may have some special relation to the growth-promoting effects of testosterone.