4 Biology and Sexual Minority Status William Byne 1 Introduction The purpose of this chapter is to provide clinicians with an overview of current knowledge pertaining to the biology of sexual minority status. Under the umbrella of sexual minority are included homosexu- als, bisexuals, transgenders and intersexes. The most developed bio- logic theory pertaining to sexual minority status is the prenatal hormonal hypothesis. According to this hypothesis, prenatal hormones act (pri- marily during embryonic and fetal development) to mediate the sexual differentiation not only of the internal and external genitalia but also of the brain. The sexually differentiated state of the brain then influ- ences the subsequent expression of gender identity and sexual orien- tation. Intersexuality results from variation in the normative course of somatic sexual differentiation, and homosexuality and bisexuality have been proposed to reflect variant sexual differentiation of hypothetical neural substrates that mediate sexual orientation. Similarly, transgen- derism has been conjectured to reflect variant differentiation of hypo- thetical neural substrates that mediate gender identity. Some of the same hormones and hormonal receptors mediate the sexual differenti- ation of both the brain and the genitalia. Thus, the brains, as well as the genitalia, of intersexes may exhibit sexual differentiation that is intermediate between that of normatively developed males and females. The chapter begins with clarification of terminology and then an overview of the genetics and neuroendocrinology of sexual differenti- ation. The prenatal hormonal hypothesis is then elaborated and evalu- ated in light of current evidence. Genetic and other salient biologic evidence is then summarized. Models are examined for considering how biologic factors, in concert with experiential factors, might influ- ence sexual minority status. 2 Terminology In this chapter, sex refers to the status of biologic variables that can be described as either male-typical or female-typical in normatively developed individuals (e.g., genes, chromosomes, gonads, internal and 66 W. Byne external genital structures, hormonal profiles). Particular features of the human brain also appear to be sexually dimorphic, at least in a statis- tical sense, and should perhaps also be considered among the variables of sex (Collaer et al., 2003). Gender refers to social categories (e.g., man or woman, boy or girl) or to factors related to living in the social role of a man or a woman. Gender identity refers to one’s sense of belong- ing to the male or female gender category, whereas gender role refers to behaviors (e.g., mannerisms, style of dress, activities) that convey to others one’s membership in one of those categories (Money & Ehrhardt, 1972). Sexual orientation refers to one’s pattern of erotic responsiveness and is described here as androphylic (attracted to men), gynephilic (attracted to women), or bisexual (attracted to both). The course of normative development culminates in full concor- dance among all of the biologic variables of sex (i.e., either all male or all female). In intersexed individuals, however, one or more of those variables is discordant with the others, or its differentiation is inter- mediate between male and female norms. The fact that gender identity and role may be discordant with one or more of the biologic variables of sex underscores the social basis of gender categories. Intersex has become the preferred term to encompass a variety of syndromes previously classified on the basis of gonadal histology as true hermaphroditism, in which both testicular and ovarian tissue are present in a single individual, and pseudohermaphroditism, in which only one type of gonadal tissue is present. In that system of taxonomy, prece- dence was given to gonadal histology as the arbiter of “true sex” upon which gender assignment should be based. With the advent of kary- otype analysis, chromosomal sex became viewed as the arbiter of “true sex” (Zucker, 1999). When the sexual variables are not fully concordant in a given individual, there is no reason to insist that one variable should hold precedence over the others. Instead, the status of each vari- able must be stated to describe accurately the sex of the individual. In the Diagnostic and Statistical Manual of Mental Disorders (4th edition), the presence of an intersex disorder excludes the diagnosis of a gender identity disorder (American Psychiatric Association, 1994). 3 Overview of Sexual Differentiation The mammalian embryo is initially sexually bipotential (Collaer et al., 2003; Arnold et al., 2004). During the usual course of male differentia- tion a testis determining gene, SRY, which is normally on the Y chro- mosome, directs the development of testes from the fetal gonadal precursor. Subsequently, testicular secretions orchestrate differentia- tion of the male genitalia and brain. Initially, both male and female embryos possess two sets of primordial internal genital duct systems: one (the müllerian, or paramesonephric, duct system) is capable of developing into female internal genital structures and another (the woffian, or mesonephric, duct system) is capable of developing into the male internal genitalia. A secretion from the testis, müllerian inhibitory substance, induces regression of the müllerian (i.e., female) 4 Biology and Sexual Minority Status 67 duct system, and the 5α-reduced derivative of testosterone, 5α- dihydrotestosterone (DHT), stimulates the development of male inter- nal genital structures. DHT also stimulates both the growth and dif- ferentiation of the embryonic phallus into a penis and fusion of the labioscrotal folds to form the scrotum into which the testes later descend. In the absence of testes or müllerian inhibitory factor, the internal female genital system fails to regress. In the complete absence of testosterone, the 5α-reductase enzyme that converts it to DHT, or functional androgen receptors, the male internal genital structures fail to develop, the phallic rudiment develops into a clitoris rather than a penis, and the labioscrotal folds develop into labia instead of a scrotum. Intermediate levels of androgenic exposure result in intermediate development of internal male genital structures and differentiation of the external genital structures that are intermediate between those of normatively developed males and females. Work in laboratory animals suggests that sexual differentiation of the brain is analogous to sexual differentiation of the internal genitalia, where separate male and female primordia are involved, and thus fully developed male and female structures can theoretically exist in the same individual. Extending this analogy, sexual differentiation can be conceptualized as involving processes of defeminization (i.e., sup- pression of female characteristics—analogous to regression of the müllerian ducts) and masculinization (i.e. the development of male characteristics—analogous to development of the male internal geni- talia). In rats, the most studied aspects of brain defeminization include suppression of the brain’s potential to mediate a stereotypically female mating posture called lordosis, and its ability to orchestrate the neuroendocrine response necessary for normal ovarian function. Both defeminization and masculinization of the rodent brain are brought about by testosterone and its derivatives. Testosterone acts on the brain by two primary pathways: (1) an androgen pathway in which either testosterone or DHT interacts with androgen receptors on target cells and (2) an estrogen pathway in which testosterone is converted to estrogen by aromatase enzymes in the brain. In the latter pathway the brain-derived estrogen interacts with estrogen receptors. In laboratory rodents, the androgen pathway contributes to masculinization of the brain, and the estrogen pathway contributes to both defeminization and masculinization (Goy & McEwen, 1980; Olsen, 1983). In addition to having different hormonal requirements, animal work suggests that the various aspects of somatic and brain sexual differentiation occur during different periods of development in a sequence of temporally overlapping steps (Goy & McEwen, 1980; Byne & Kemether, 2000). In the absence of the cascade set in motion by the testis-determining gene, female development ensues, at least to a first approximation. 3.1 Timing of Sexual Differentiation in the Human Human testes begin to secrete androgens by the seventh or eighth week of gestation (Siiteri & Wilson, 1974), a process initially regulated by human chorionic gonadotropin secreted by the placenta (Moore, 1982). 68 W. Byne By the 15th week of gestation the regulation of androgen secretion is taken over by gonadotropin from the fetal pituitary, which is regulated by the fetal hypothalamus. Genital differentiation occurs largely during the period when androgen secretion is regulated by the placenta rather than by the fetal pituitary. Gonadotropin secretion decreases toward the end of gestation presumably due to the development of inhibitory inputs to the hypothalamus in addition to the onset of negative feed- back of androgen on gonadotropin release. Thus, fetal androgen in males is elevated between weeks 8 to 24 of gestation, with peak levels occurring between weeks 14 and 16 (Smail et al., 1981). In males, the level of testosterone increases from birth to a peak at 1 to 3 months and then decreases to prepubertal levels by ages 4 to 6 months (Hrabovsky & Hutson, 2002). The