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s*x differences of importance to health and human disease occur throughout the life span, although the specific expression of these differences varies at different stages of life. Some differences originate in events occurring in the intrauterine environment, where developmental processes differentially organize tissues for later activation in the male or female. In the prenatal period, s*x determination and differentiation occur in a series of sequential processes governed by genetic and environmental factors. During the pubertal period, behavioral and hormonal changes manifest the secondary s*xual characteristics that reinforce the s*xual identity of the individual through adolescence and into adulthood. Hormonal events occurring in puberty lay a framework for biological differences that persist through life and that contribute to variable onset and progression of disease in males and females. It is important to study s*x differences at all stages of the life cycle, relying on animal models of disease and including s*x as a variable in basic and clinical research designs.
All human individuals—whether they have an XX, an XY, or an atypical s*x chromosome combination—begin development from the same starting point. During early development the gonads of the fetus remain undifferentiated; that is, all fetal genitalia are the same and are phenotypically female. After approximately 6 to 7 weeks of gestation, however, the expression of a gene on the Y chromosome induces changes that result in the development of the testes. Thus, this gene is singularly important in inducing testis development. The production of testosterone at about 9 weeks of gestation results in the development of the reproductive tract and the masculinization (the normal development of male s*x characteristics) of the brain and genitalia. In contrast to the role of the fetal testis in differentiation of a male genital tract and external genitalia in utero, fetal ovarian secretions are not required for female s*x differentiation. As these details point out, the basic differences between the s*xes begin in the womb, and this chapter examines how s*x differences develop and change across the lifetime. The committee examined both normal and abnormal routes of development that lead individuals to become males and females and the changes during childhood, reproductive adulthood, and the later stages of life.
One of the basic goals of biologists is to explain observed variability among and within species. Why does one individual become infected when exposed to a microbiological agent when another individual does not? Why does one individual experience pain more acutely than another? s*x is a prime variable to which such differences can be ascribed. No one factor is responsible for variability, but rather, a blend of genetic, hormonal, and experiential factors operating at different times during development result in the phenotype called a human being.
As suggested by the reproductive processes of some species and punctuated by recent successful efforts at cloning of some species, s*xual reproduction is not necessary for species perpetuation. Debate exists on why s*xual reproduction has evolved. Most biologists agree that it increases the variability upon which evolutionary selection can operate; for example, variability would allow some offspring to escape pathogens and survive to reproduce. This theory is not without its critics (Barton and Charlesworth, 1998). The contribution of genetics to s*x differences has been described in Chapter 2. Here the focus is more on the endocrine and experiential bases for the development and expression of s*x as a phenotype.
Different species of vertebrate animals have evolved different pathways to determine s*x, but it is interesting that in all cases two s*xes emerge with distinctly different roles in the social and reproductive lives of the animals (Crews, 1993; Francis, 1992). In all vertebrates the genetic basis of s*x is determined by meiosis, a process by which paired chromosomes are separated, resulting in the formation of an egg or man-fluid, which are then joined at fertilization. Variations in the phenotypic characteristics of the different s*xes are determined during development by internal chemical signals. The process can be influenced by external factors such as maternal endocrine dysfunction or endocrine disrupters, as well as fetal endocrine disorders and exogenous medications (Grumbach and Conte, 1998).
Nongenomic s*xual Differentiation and s*xual Flexibility
Nongenomic s*xual differentiation has evolved in several species of fishes and reptiles. In these species, s*x results from external signals. For example, temperature during embryogenesis is the cue acting on autosomal genes to result in adult males and females in several species. In many species of flounder, for instance, elevated temperatures of the water in which the larval fish develop results in a higher proportion of males (Yamamoto, 1999). Similarly, in several turtle species the incubation temperature of the eggs influences the s*x ratio of the animals (Crews et al., 1989).
In some species, s*x determination can be delayed until well after birth or the s*x can even change after the birth of an organism. One fascinating study found that several species of fish develop s*xual phenotypes as a result of the fish's social rank in a group (Baroiller et al., 1999; Warner, 1984). The blue-headed wrasse is a polygynous coral reef fish with three phenotypes that vary in size, coloration, reproductive organs, physiology, and behavior (Godwin et al., 1996; Warner and Swearer, 1991). These phenotypes are females, initial-phase males, and terminal-phase males. As a result of changes in the social role, a fish can progress rapidly through these phenotypes. Upon the disappearance of a terminal-phase male, the behavior of the largest female in the group converts to male-like behavior in minutes and the fish shows full gonadal changes in days.
The belted sandfish (Sermnus subligarius) stands out as one of the most remarkable demonstrations of vertebrate s*xual flexibility. This coastal marine fish is a simultaneous hermaphrodite (Cheek et al., 2000). Its gonads produce both man-fluid and eggs, and each fish has the reproductive tract anatomies of both s*xes simultaneously. Within minutes each individual can show three alternative mating behaviors—that is, female, courting male, or streaker male—along with the appropriate external color changes (Cheek et al., 2000). A streaker male awaits the peak moment during the courtship of male and female morphs and then streaks in to release man-fluid at the moment of spawning. The man-fluid compete with the courting male's man-fluid. Partners can switch between male and female roles within seconds and may take turns fertilizing each other's eggs. The frequency with which an individual plays the female or male role is, in part, a function of size. Larger fish are more likely to play the male role more often.
In contrast, mammalian s*x determination is more directly under the control of a single internal event: fertilization. Under normal conditions, the direction of s*xual development is initiated and determined by the presence or absence of a Y chromosome.