Fredrick W. George

The Role of Gonadal Steroids in Sexual Differentiation

Publisher Summary The embryos of both sexes develop in an identical fashion for the first two months of gestation. Only thereafter does anatomical and physiological development diverge to result in the formation of the male and female phenotypes. Gonadal steroids play an important role in sexual differentiation. This chapter discusses this particular role. Male development is induced in the embryo only in the presence of specific hormonal signals arising from the fetal testis. According to the Jost formulation, sexual differentiation is a sequential, ordered, and relatively simple process. Chromosomal sex, established at the time of conception, directs the development of either ovaries or testes. If testes develop, their hormonal secretions elicit the development of the male secondary sex characteristics, collectively known as the male phenotype. If an ovary develops—or if no gonad is present—anatomical development is female in character. Thus, it is the action of the gonads as endocrine organs that is responsible for the development of the sexual phenotypes. The chapter describes current concepts of the processes by which the fetal gonads acquire the capacity to function as endocrine organs and of the mechanisms by which the endocrine secretions of the fetal testis modulate male development. It also gives an overview of the anatomical events involved in the formation of the sexual phenotypes and the factors that mediate this development.

Role of Gonadal Hormones in Development of the Sexual Phenotypes

SummaryMale and female embryos develop in an identical fashion during the initial portion of gestation. If the indifferent gonad differentiates into an ovary (or if no gonad is present), a female phenotype is formed. Male phenotypic differentiation, however, requires the presence of an endocrinologically active testis. Two secretion of the fetal testis, Müllerian inhibiting substance and testosterone, are responsible for male development. Studies of single gene mutations that interfere with androgen action indicate that testosterone itself is responsible for virilization of the Wolffian duct system into the epididymis, vas deferens, and seminal vesicle, whereas the testosterone metabolite dihydrotestosterone induces development of the prostate and male external genitalia. Thus, impairment of dihydrotestosterone formation results in a characteristic phenotype consisting of predominantly female external genitalia but normally virilized Wolffian ducts. The molecular mechanisms by which testosterone and dihydrotestosterone act during fetal development appear to involve the same high affinity receptor, a protein that transports both testosterone and dihydrotestosterone to the nucleus of target cells. When this receptor is either absent, deficient, or structurally abnormal, the actions of both testosterone and dihydrotestosterone are impaired, and the resulting developmental anomalies involve both internal and external genital structures.

The androgen receptor of the urogenital tract of the fetal rat is regulated by androgen

To provide insight into androgen-mediated virilization, we measured the androgen receptor in tissues of male and female rat fetuses prior to and during the period of phenotypic sex differentiation. Western immunoblotting was performed utilizing an antibody directed against the 21 amino-terminal segment of the androgen receptor. In immunoblots prepared from urogenital tract tissues of day 17 male and female fetal rats, this antibody specifically recognizes a 110K protein band characteristic of the androgen receptor. Androgen receptor levels were low to undetectable in a variety of non-urogenital tract tissues. After day 18 of fetal development, the amount of androgen receptor decreased in female urogenital tissues, and by day 22 the amount of immunoreactive androgen receptor was higher in the male urogenital sinus and tubercle than in the corresponding tissues of the female. Administration of 5 alpha-dihydrotestosterone to pregnant rats at a dose of 50 mg/kg body weight per day from day 12 to day 22 caused an increase in immunoreactive androgen receptor in the female urogenital sinus and tubercle to levels approaching those in male tissues. Administration of the androgen antagonist flutamide (100 mg/kg body weight per day) during the same interval caused a reduction in androgen receptor level in the urogenital sinus and tubercle of the male. These findings suggest that androgens modulate the amount of androgen receptor in the embryonic urogenital tract either by inducing the proliferation of androgen-responsive cells or by increasing androgen receptor levels in individual cells.

Androgen Metabolism in the Prostate of the Finasteride-Treated, Adult Rat: A Possible Explanation for the Differential Action of Testosterone and 5α-Dihydrotestosterone during Development of the Male Urogenital Tract1

Previous work has clearly demonstrated that inhibition of 5α-dihydrotestosterone (DHT) formation in vivo is not as effective as total androgen ablation (castration) in causing involution of the prostate. It is likely that this is due to the fact that testosterone is partially effective in maintaining androgen action. To provide insight into this observation, the androgenic metabolites of testosterone, androstenedione, and 5α-DHT, were measured in prostate tissue and in blood of 5α-reductase inhibitor (finasteride)-treated adult male rats. Finasteride treatment caused a significant decrease in prostatic DHT levels and a profound increase in prostatic testosterone and androstenedione levels. Similarly, circulating DHT levels were decreased in finasteride-treated rats (0.02 ng/ml compared with 0.05 ng/ml seen in control rats), and circulating androstenedione and testosterone levels were significantly elevated in finasteride-treated animals compared with controls. The in vitro effects of finasteride were asse...

The Fetal Rat Gubernaculum Contains Higher Levels of Androgen Receptor than Does the Postnatal Gubernaculum

The androgen receptor of the rat gubernaculum was measured by a sensitive immunoblotting technique from day 19 of fetal development to day 20 of postnatal development. In relative terms (densitometric units/microgram. protein), it was found that the amount of the gubernacular androgen receptor decreased dramatically from fetal to postnatal development, coincident with the transition of the gubernaculum from a tissue primarily composed of undifferentiated mesenchymal cells in the fetus to a tissue that is primarily made up of muscle during postnatal development. We conclude that the undifferentiated mesenchyme of the fetal gubernaculum is a primary target of androgen action.

ENDOCRINE CONTROL OF SEXUAL DIFFERENTIATION IN THE HUMAN

Publisher Summary This chapter discusses the endocrine control of sexual differentiation in the human. It describes sexual differentiation as an ordered and sequential process. Chromosomal sex, established during fertilization, directs the development of gonadal sex. Hormonal secretions from the fetal testes then transform the phenotypically indifferent embryonic urogenital tract into that of the male. Despite the difference in chromosomal constitution, the gonads and the urogenital tracts of male and female embryos develop initially in an identical manner. The first evidence of sexual dimorphism in the human embryo is the appearance of the spermatogenic cords in the fetal testes between week 6 and week 7 of gestation. The factors involved in the differentiation of the ovaries and testes are not fully understood, but the characterization of the male-specific histocompatibility antigen (HY antigen) has provided a working model to explain the mechanisms by which the Y chromosome directs testicular development. During the indifferent stage of sexual development, the urogenital tract of the embyro consists of two components: (1) two duct systems (wolffian and mullerian), derived from the mesonephros, and (2) the urogenital sinus and genital tubercle. The development of the internal urogenital tract of the male involves regression and ultimate disappearance of the mullerian ducts as well as the growth and differentiation of the wolffian ducts into the epididymides, vasa deferentia, and seminal vesicles. In females, the mullerian ducts persist to form the fallopian tubes, the uterus, and the upper portion of the vagina, and the wolffian ducts degenerate. Thus, the internal genital tracts develop from different anlagen in the two sexes.

Characterization of the increased estrogen synthesis in skin fibroblasts from the Sebright bantam.

We have utilized the Sebright bantam chicken as a model system to explore the regulation of estrogen formation in peripheral tissues. As the result of a gene mutation, Sebright males develop a female feathering pattern associated with an increase in estrogen synthesis in skin and in fibroblasts cultured from skin. To provide insight into the mechanisms by which estrogen synthesis is increased we examined several parameters of the aromatase reaction in homogenates from control ovaries, Sebright ovaries and fibroblasts grown from Sebright skin: the pH optima; the apparent Kms for testosterone, 19-nortestosterone, androstenedione, 16-hydroxyandrostenedione, and NADPH; the apparent Kis for 4-hydroxyandrostenedione, aminoglutethimide, dehydroepiandrosterone, and 19-hydroxytestosterone; and the inactivation of the reaction by heating. No qualitative differences were identified in the enzyme from Sebright and control birds.

The androgen receptor in the fetal epididymis is similar to that in the mature rabbit.

Abstract To provide insight into the mechanism of wolffian duct virilization the androgen receptor has been characterized in pooled epididymal tissue from Day 27 rabbit embryos. Although the receptor is present at levels about a tenth that of other androgen target tissues in rabbit embryos, it appears to be a typical androgen receptor in regard to sedimentation characteristics and preferential binding of 5α-dihydrotestosterone over testosterone. Thus, the mechanism by which testosterone virilizes the wolffian duct cannot be explained by unique binding characteristics of the androgen receptor in tissues derived from the wolffian ducts.

Genetic control of extraglandular aromatase activity in the chicken

Feminization of feathers in the Sebright cock is the result of increase in the activity of skin aromatase. This increased estrogen synthesis is the consequence of an autosomal dominant mutation that causes an increase in the specific androgen-binding cytochrome P450 oxidase involved in the reaction. Since this oxidase appears to be kinetically indistinguishable from the activity in control ovary we believe that the mutation causes an increased steady-state level of normal enzyme. The mechanism by which the mutation acts is unknown, but its presence implies that in normal birds an allele of the mutation limits the activity of the enzyme in all tissues other than ovary.

2 – Sexual Differentiation

Publisher Summary This chapter focuses on the subject of sexual differentiation. Although the genetic blueprint for mammalian sexual differentiation is established at the time of fertilization, the initial development of male and female embryos is identical. Sexual differentiation is an ordered and sequential process: Chromosomal sex, established at the time of fertilization, directs the development of the indifferent gonad into a testis or ovary; the differentiated gonad then determines phenotypic sexual development. The presence of the Y chromosome in the male dictates the development of a testis, and the secretions of the testis impose male development on the phenotypically indifferent fetus. Absence of a Y chromosome results in development of an ovary and a female phenotype. Thus, a central concept in mammalian sexual differentiation is that the male is the induced phenotype, whereas the female develops as the passive consequence of the lack of male determinants. The chapter describes the anatomic events in male and female development and summarizes the current understanding of the mechanisms by which this development is regulated.