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Publisher Summary The hormones play an essential role, in all species, in the development and function of ovaries and testes, but in most species with Y-determined sexual differentiation, administration of androgens or estrogens does not cause sex reversal. This chapter explains the mechanism by which genetic sex is ultimately translated into phenotypic sex because the mechanisms are different in the two types of mammals. In the marsupial, chromosomal directly dictates major aspects of the sexual phenotype. There is some evidence that genetic factors may control directly at least one sexually dimorphic trait in the eutherian mammal: one or more Y-linked traits appear to influence height and tooth size independent of endocrine function. The human Y chromosome has been mapped by YAC cloning, but the specific gene(s) responsible for these growth phenomena has not been identified. The mechanisms by which the sexual phenotypes form in man and marsupial may not be totally dissimilar. In both, major components are controlled by testicular hormones and there is a direct genetic component, the difference being that the direct genetic sex contribution to the male phenotype is less important in the eutherian mammal.

The cholesterol-fed rat subjected to cannulation of the intestinal lymph duct and injected with acetate-2-(14)C has been utilized for a study of the mechanism by which cholesterol synthesized in the intestinal wall gains access to the circulation. It has been concluded that locally synthesized cholesterol is excreted bidirectionally, approximately half going into the lymph and half into the lumen. Furthermore, under the conditions of these experiments, little of the luminal cholesterol appears to be reabsorbed, which suggests that direct transfer from wall to lymph is the principal route for the entry of this endogenously derived cholesterol pool into the lymph and ultimately into the blood stream. Finally, it has been demonstrated that bile is required for this transfer of cholesterol from wall to lymph as well as for the absorption of dietary cholesterol.

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.

Publisher Summary This chapter discusses whether animal models of sexual behavior are applicable to the understanding of human sexual behavior. Development of reproductive capacity involves diverse activities—such as the formation of the male and female phenotypes during embryogenesis, sexual maturation, and the onset of gametogenesis at the time of puberty—and the acquisition of specific behavioral patterns, such as sexual drive and capacity for intercourse as well as patterned behavior. In all species including man, gonadal steroid hormones are involved in the conversion of the sexually indifferent embryo into the male phenotype, in sexual maturation of males and females during postnatal life, and in the development of a basic sexual drive at the time of sexual maturation. In many animal species, gonadal steroids also play a critical role in the development of the specific actions that characterize male and female reproductive behavior. It has been documented that a portion of the action of gonadal hormones in this regard is because of direct effects on the central nervous system. Steroid hormones act via a common intracellular molecular machinery involving a high-affinity receptor protein and the genetic machinery to exert their effects in such diverse tissues as external genitalia and brain.

Publisher Summary The 5α-reduction of radioactive Δ4-3-ketosteroids, which do not contain substitutions on carbon-11 of the steroid molecule, is followed in the presence of an excess of NADPH by measuring the appearance of the radioactive 5α-reduced metabolites, utilizing a rapid thin-layer chromatographic separation. The assay in this chapter has been developed because the low activity of the enzyme in most tissues precludes the measurement of NADPH disappearance spectrophotometrically. The enzyme exhibits distinctive tissue localization in that most activity is found in the organs of accessory reproduction and in liver.

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.

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.

Since dihydrotestosterone rather than testosterone is the principal intracellular androgen in the prostate and since dihydrotestosterone concentration is increased in hypertrophic prostate of dog and man, long term studies were undertaken to test the possibility that unregulated production of dihydrotestosterone is the cause of prostatic hypertrophy. Control and castrated two year-old dogs were given triolein or pharmacological doses of testosterone or dihydrotestosterone (75 mg/week) for 18–24 months. Although two control dogs developed prostatic hypertrophy (15·5 and 19?·4 g in weight), none of the castrated animals developed prostatic hypertrophy, despite the fact that prostate dihydrotestosterone content was as high in testosterone and dihydrotestosterone-treated dogs (1·0 and 0·7 μg dihydrotestosterone/100 g tissue) as in the controls with benign prostatic hypertrophy (0·6 μg/100g tissue). This suggested that mode of delivery of the hormone to the gland was critical or that some testicular hormone other than testosterone or dihydrotestosterone is required for the development of prostatic hypertrophy. Therefore, six aged male dogs with prostatic hypertrophy were subjected to vas duct ligation and followed for six months. No change occurred in prostate weight or the tissue content of testosterone and dihydrotestosterone. Thus, some testicular hormone other than testosterone or dihydrotestosterone is required for the development of prostatic hypertrophy.

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.