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Sexuality and Our Diversity: Integrating Culture with the Biopsychosocial, v. 1.0

by Marcus Tye

4.2 Biological Sex: Becoming Female or Male [Ch Part A: Sexual Differentiation]

Learning Objectives

  1. Outline how biological sex includes chromosomes, gonads, hormones, internal reproductive structures, external genitalia, and sexual differentiation of nervous system tissue, including the brain.
  2. Understand the special function of sex chromosomes.
  3. Follow typical female-male development in the womb.
  4. Describe the ways that individuals may differ in the development of biological sex.
  5. Understand potential conflicts between the medical profession’s guidelines for disorders of sex development and the recommendations of intersex adults.

“Is she really a HE? Women’s 800m runner shrugs off gender storm to take gold”MacLean, S. (2009, August 19). Is she really a HE? Women’s 800m runner shrugs off gender storm to take gold. Daily Mail. Retrieved from http://www.dailymail.co.uk/news/worldnews/article-1207653/Womens-800m-gold-medal-favourite-Caster-Semenya-takes-gender-test-hours -World-Championship-race.html. Read more: http://www.dailymail.co.uk/news/worldnews/article-1207653/Womens-800m-gold-medal-favourite-Caster-Semenya-takes-gender-test-hours -World-Championship-race.html#ixzz1AwQ0bkAB

MacLean (2009)

This sensationalist headline from a British news tabloid referred to South African world medalist Caster Semenya, who had to take a “gender test” to determine her biological sex. The results were kept confidential, but the world athletic organization for her sport indicated that she could continue to compete as a female, which was the sex shown on her birth certificate, even though newspapers at the time alleged that she had no womb or ovaries and that her gonads were internal testes.

How can there be ambiguous cases if our species has two sexes? How do world athletics and the Olympics perform “gender verification”? What are biological sex differences in most people? These are some of the questions we answer in this section.

When a baby is born, “it’s a girl” or “it’s a boy” is one of the first things that a parent hears, with the pronouncement being based not on a sophisticated medical test but on a cursory visual inspection of an infant’s external genitalia. Although this anatomy has individual differences, most babies are clearly female or male in appearance. Nonetheless, variations are common enough that many medical personnel who deliver infants have a third alternative ready—variations on “here’s your baby”—for when the genitalia do not appear clearly male or female.

If we study the typical development of most females and males, we can see that biological sex actually includes six discrete aspects of biology, several of which have multiple components: sex chromosomes, gonads, internal reproductive structures, hormonal sex, external genitalia, and the nervous system. This includes the brain and spinal column (central nervous system) and the peripheral nervous system. Each of these components has some sexual differentiation or distinctive difference in type between the sexes. Each aspect of biological difference in the sexes can vary in degree of sex differentiation; while in most individuals they vary in the same direction, even that can differ in approximately 1 out of 1,000 individuals.

Sexual differentiationThe biological differences between the sexes and how these differences develop, including differences in structure and organization at the level of tissues as well as differences in activation of tissues. describes both the biological differences between the sexes and how these differences develop. This involves average differences in structure and organization at the level of tissues, such as reproductive organs and areas of the brain. Such physical differences are also referred to as sexual dimorphismsAnother term for sexual differentiation; a physical or anatomical average difference between the sexes., and they become fairly fixed during fetal development and again at puberty. Sexual differentiation also involves average differences in activation of some tissues, such as sites in the brain that have ranges of functioning that depend on levels of sex hormones, which typically differ between the sexes.

Sex Chromosomes

You may remember that we have 22 pairs of autosomes and one pair of sex chromosomes. The description of meiosis referred to the chromosomes “blending,” but what about the sex chromosomes during meiosis, which leads to the production of a single sex chromosome in each gamete that is either an X or a Y?

In a typical female, sex chromosomes in her cells are XX, and meiosis results in her gametes containing a single X, which is indeed a new remix of genes from the original pair of X chromosomes, much as the autosomes recombine. Thus every egg cell contains a unique X sex chromosome.

In a typical male, sex chromosomes in his cells are XY. Because the X and Y sex chromosomes are literally different lengths, during meiosis they don’t line up well, and for the most part, the X chromosome or Y chromosome remains intact, with approximately half of the gametes receiving an entire X chromosome and half receiving an entire Y chromosome. There are a small number of regions, referred to as pseudoautosomes, on the X and Y that do align and exchange, so each gamete receives a slightly different X or Y sex chromosome than the original XY but with substantially less remixing than the autosomes. Because an egg cell (which has two X chromosomes) must pass an X chromosome to the future fetus, it is thus the sperm cell (which has an X chromosome and a Y chromosome) that determines the sex of the future fetus. We say “future fetus” because after fertilization, the developing organism is referred to as a conceptusA fertilized egg, prior to development as an implanted embryo. until it has implanted in the womb. Since the egg always has an X, if the sperm carried an X sex chromosome, the resultant conceptus will have XX for the sex chromosome pair and be female. If the sperm has a Y chromosome, the conceptus will have XY for the sex chromosome pair and be male.

The sexual differentiation of females and males begins in embryonic development with a chain of events. The sex chromosomes, and especially certain genes on these chromosomes, cause precursor cells to develop along one of two pathways. These two different pathways cause initially undifferentiated gonads to develop into either ovaries or testes. The ovaries or testes then secrete hormones at different levels, which in turn leads to other tissues in the body developing differently, such as neurological tissue in both the spinal column and the brain, as well as the external genitalia and internal reproductive structures. The sex chromosomes also direct the production of other signaling chemicals that affect physiological development.

The default pathway of most fetal tissues in mammals is to develop in the female direction. This was first discovered by Alfred Jost in the 1940s (Jost, 1953)Jost, A. (1953). Problems of fetal endocrinology: The gonadal and hypophyseal hormones. Recent Progress in Hormone Research, 8, 379–418. in the now-classic studies in which he removed the ovaries and testes from fetal rabbits. Provided the gonads were removed early enough in development, he found that both sexes of rabbits were born with the genitalia of females and grew into outwardly female adults (albeit infertile).

Specific regions on the two sex chromosomes are of particular importance on a molecular level in directing sexual differentiation, both of the gonads and of other tissues. These regions include the SRY gene, the DAX-1 gene, and the DSS region of the X chromosome. When it was discovered in 1990, the SRY gene was called the sex-determining region of the Y chromosome, because it was thought to be the exclusive genetic determinant of biological maleness, as otherwise, genetically XY individuals who inherited a Y chromosome lacking SRY develop as females and, likewise, genetically XX individuals who inherit an X chromosome that carried a mislocated SRY develop as males. The SRY plays such a key role in this biological chain of events because its presence has been found to create a transcription factor (a protein that regulates gene expression) that causes precursor cells in genital ridges within the embryo to develop into Sertoli cells. Sertoli cells then cause the gonads to develop into testes as the fetus grows. In the absence of SRY, the precursor cells in the genital ridges develop into granulosa cells, which cause the gonads to develop into ovaries.

Another key sex-determining region is DSS, named for being a dosage-sensitive sex reversal region. The X chromosome typically has one copy of this region, so most females inherit two copies (one on each X) and most males inherit a single copy (on their one X chromosome). In most males, SRY appears to override the one DSS region. However, genetically XY individuals who inherit a typical Y chromosome with one SRY, but who inherit an X chromosome with two copies of the DSS region, typically develop as females. For this reason, DSS is called the femaleness gene by some authors. “Femaleness gene” or “maleness gene” are, however, misleading, as other specific sex-determining regions are being discovered, such as DAX-1, a specific gene within the DSS region on the X chromosome, which also facilitates the normal development of granulosa cells and ovaries (Rowland & Incrocci, 2008).Rowland, D. L., & Incrocci, L. (2008). Handbook of sexual and gender identity disorders. Hoboken, NJ: John Wiley & Sons. The function of most human genes remains unknown, so it is likely that researchers have yet to discover numerous interactions among these sex-determining genes that may affect other aspects of development.

The incidence of sex-linked genetic anomalies and disorders are more common in males than in females, simply because females inherit two X chromosomes, so if one chromosome has a recessive defective allele or missing gene, this may be compensated for by the other X chromosome. Since the Y chromosome is so short, it has few “mirror” genes, so any defects on the X chromosome are much more likely to manifest themselves in males.

Sexual Development of the Gonads and Other Internal Reproductive Structures

After fertilization, the conceptus continues to divide (reproducing through mitosis) into identical cells, eventually forming a blastocyst, which, in as many as 50% of fertilizations, implants in the uterus and begins to develop into an embryo. These cells continue to reproduce, forming what are referred to as embryonic stem cellsCells that have the potential to become different types of tissue.. Although all the cells in the body have identical DNA, embryonic stem cells have the potential to become different types of tissue as well as to reproduce into additional stem cells. Once most other types of cells have become specialized types of tissue, they generally can only reproduce as the same type of tissue. By 2 weeks after conception, the stems cells have already organized into three distinct layers from which even more specialized tissues and organs will eventually form. These three embryonic layers are on the embryo (beginning with the outermost layer): the ectoderm, which will eventually form the skin and nervous system; the mesoderm, which will form the muscles, skeleton, and cardiovascular system; and the endoderm, which will later form the digestive system and lungs. Sexually differentiated structures in females and males develop in tissues originating in all three embryonic layers. In adults, physiological differences occur in neural tissue, internal reproductive structures and organs, and external skin and anatomy.

By 6 weeks of fetal development, many organ systems can be seen in early form, as shown in Figure 4.2 "Reproductive Structures". However, at this point they are still precursors and are similar in both females and males. There are two preliminary sets of ducts running parallel to the gonads—the Wolffian ducts and the Müllerian ducts—and two small regions of tissue near the lower part of these ducts. One of these will develop into Skene’s ducts in females or the prostate gland in males; the other will develop into Bartholin’s glands in females or Cowper’s glands in males. The ureters (which descend from the kidneys) merge into a urethra (the urethra forms from a urethral fold, which is initially on the external part of the fetus’s skin). By 8 weeks, sex differences start to develop in these structures, eventually resulting in complete differentiation of internal female and male reproductive structures by 12 weeks (Rowland & Incrocci, 2008).Rowland, D. L., & Incrocci, L. (2008). Handbook of sexual and gender identity disorders. Hoboken, NJ: John Wiley & Sons.

In the female, by 8 weeks, the gonads have developed into the ovaries, which are located higher in the abdomen, and are absent of the strong presence of androgens, the Wolffian ducts atrophy and disappear. The upper portion of the Müllerian ducts form into the fallopian tubes, the midportion of these ducts merge to form the uterus and later the cervix, and the lower part of the ducts merge to form what will become the inner portion of the upper vaginal walls. The two regions of tissue mentioned previously have developed, one into Skene’s ducts and the other into Bartholin’s glands, whose function was described in Chapter 3 "Sexual Bodies: Anatomy and Physiology".

In the male, the gonads have developed into testes and have moved to a lower position in the pelvic region. The testes secrete androgens in higher levels than in the female fetus, which causes the Wolffian ducts to continue to develop and grow into the vas deferens, seminal vesicles, and ejaculatory ducts. If for some reason androgens are not present (as we discuss in further detail shortly), the Wolffian ducts will spontaneously disappear as they do in a female—even in a genetic male. The vas deferens loop up from the testes, over the ureters, and back down. The Sertoli cells in the testes secrete anti-Müllerian hormone (also called Müllerian-inhibiting substance), which causes the Müllerian ducts to atrophy and disappear. The two regions of tissue mentioned before have developed distinctly, one into the prostate gland and the other into Cowper’s glands, whose functioning was described earlier.

Thus the sex chromosomes and specific genes on these chromosomes affect the development of the precursor gonads into ovaries or testes. All fetuses start with both female and male precursor reproductive structures. The development of one and disappearance of the other are regulated by the sex hormones and control substances secreted by the newly forming ovaries or testes.

Figure 4.2 Reproductive StructuresAdapted from Jonathan Marcus. (2010). Human sexual differentiation. Retrieved February 7, 2013, from Wikimedia Commons: http://commons.wikimedia.org/wiki/File:Human_sexual_differentiation.gif.

The illustration on the top shows reproductive structures at approximately 6 weeks of fetal development, undifferentiated in the fetus. The illustrations on the bottom show reproductive structures by approximately 12 weeks, which have mostly differentiated in males, shown on the left, and in females, shown on the right.

Sex Hormones

The primary sex hormones are present in both females and males and are made in the body by a series of chemical enzyme reactions from a common chemical precursor: cholesterol. The body converts this into progesterone, and further chemical steps convert this into testosterone, one of the two main androgens. Testosterone is sometimes converted into 5α-dihydrotestosterone (DHT), the other main androgen. It is also converted in the body into estradiol-17β, the principal estrogen. Although estrogen is often referred to popularly as female and testosterone as male, in reality the ovaries and testes produce both estrogen and testosterone, and both sexes have both types of sex hormone; estrogen levels are higher in females, and testosterone levels are higher in males.

Testosterone is also produced in a region of the adrenal glands, and DHT synthesis occurs in the skin and other parts of the body. Later in life, the gonads and other tissues synthesize other sex hormones, affecting the menstrual cycle, pregnancy, and lactation in females and puberty in both sexes. Other hormones, such as oxytocin, are influential in pair-bonding (also known as love). The main sex hormones active during fetal development are androgens and estrogen, which affect the development of precursor external genitalia into female or male types as well as influence the development of neurological tissue.

Sexual Development of the Genitalia

The external genitalia are undifferentiated at around 6 weeks of fetal development, as shown in Figure 4.3 "External Genital Structures". Differentiation starts in the 7th and 8th weeks and is fully complete by the 12th week. In both females and males, at 6 weeks, five distinct external genital structures can be seen: a genital tubercle, a urethral fold, a urethral groove, a genital fold, and an anal pit. The genital tubercle develops into two structures: a glans, which becomes the head of the clitoris or the head of the penis, and a prepuce, or fold of skin that covers the glans in both females and males. The prepuce is referred to as the clitoral hood in the female and the foreskin in the male. (Recall the discussion in Chapter 3 "Sexual Bodies: Anatomy and Physiology" contrasting the cultural practices of male circumcision and female genital mutilation.) Until puberty, the clitoral hood or foreskin typically cannot be pulled back without causing injury, but at puberty, as the glans further develops, the hood can be retracted. The amount of retraction varies depending on the person. In male infants, occasionally the foreskin interferes with even passage of urine, which is a condition referred to as phimosisAn abnormal development of the foreskin, which for an infant creates problems with urination and in an older male creates problems with erectile functioning, as it does not retract sufficiently.. Some physicians may recommend circumcision, while others argue that it is only rarely that surgery is medically required. One study examining several hundred referrals made by physicians found that circumcision was only indicated in 15% of cases and that in 75% of cases, although the foreskin did not retract, this was cosmetic and not pathological (McGregor, Pike, & Leonard, 2005).McGregor, T. B., Pike, J. G., & Leonard, M. P. (2005). Phimosis—a diagnostic dilemma? Canadian Journal of Urology, 12, 2598–2602.

The clitoris and penis, even though clearly differentiated in most adults, are homologous structuresAnatomical structures that, although different in outer appearance and size, have the same origin and similar internal physiology., because they are anatomical structures that have the same origin and similar internal physiology in both females and males. They are also sexually dimorphic structures, differing in average size and typical appearance between the sexes.

Starting at 7 to 8 weeks, it is the higher levels of androgens (testosterone and testosterone converting into DHT) that cause these structures to develop into typical male anatomy. Absent of these higher levels (e.g., in genetic females or in individuals who lack a gene for androgen receptors), these external structures develop in the female direction. As described in Chapter 3 "Sexual Bodies: Anatomy and Physiology", the glans of the clitoris or penis has a high concentration of special nerve endings, as does the prepuce. As the surface area of the clitoris is smaller, the density of nerve cells is more concentrated, but the type of nerve cells is similar. In females, the glans remains shorter, and by 12 weeks most of the shaft stays inside the body along on the frontal wall of the vagina, with only the head of the glans and clitoral hood external to the body. In both sexes, the head and shaft of the glans contain erectile tissues. In males, the glans lengthens into the shaft of the penis, and by 12 weeks most of the shaft extends beyond the body.

The other external genital structures are also formed from a common precursor. By 12 weeks of fetal development, the urethral fold and urogenital groove develop into the urethra. In females, the end of the urethra, the urethral meatus, exits in the vagina, above the vaginal opening, while the genital fold develops into the labia minora, which remains separated, creating an opening into the vagina. Another part of the genital fold develops into the labioscrotal swelling, which becomes the labia majora in females.

Figure 4.3 External Genital Structures

This illustration shows external genital structures in males and females as they differentiate during fetal development. It also shows the typical appearance at birth, although there are many possible variations.

In males, the genital fold surrounds the lengthening urethra, and the skin of the genital fold develops external to the body, surrounding the shaft of the penis and merging with the glans. The other part of the genital fold, the labioscrotal swelling, becomes the scrotum. The area where the genital fold wraps back around on itself can still be seen in some adult males on the underside of the penile shaft and/or scrotum, appearing as a line or ridge. In males, the urethral meatus exits in the middle of the lower portion of the glans of the penis. It is common for there to be slight variations in the exact location on the glans of the urethral meatus. If the urethral meatus is far removed from the glans, on the shaft of the penis, this is referred to as a hypospadiaAn abnormal development of the location of the urethral meatus in such a way that it exits on the shaft of the penis., which occurs in about 1 out of 350 births. Surgery during infancy is often recommended, as urine and semen will exit from an unusual location; however, physicians debate whether surgery is actually necessary, as urination and adult sexual functioning is possible even when the urethral meatus is located on the shaft of the penis (Fichtner, Filipas, Mottrie, Voges, & Hohenfellner, 1995).Fichtner, J., Filipas, D., Mottrie, A. M., Voges, G. E. & Hohenfellner, R. (1995). Analysis of meatal location in 500 men: Wide variation questions need for meatal advancement in all pediatric anterior hypospadias cases. Journal of Urology, 154, 833–834. Hypospadia can also occur in females, although a mildly atypical location in the vagina of the urethral exit is not as likely to be noticed.

The sex hormones create additional physical changes during puberty, which will be covered in a later chapter when we consider the development of sexuality in childhood.

Sexual Development of the Nervous System and the Brain

Sexual dimorphisms (differences between females and males) are also observed in the nervous system, such as the greater density of genital nerve endings in the clitoris than the glans of the penis, as previously noted. Another difference is Onuf’s nucleus, an area of neurons in the spinal column that controls some of the muscles in the pelvic floor, which is larger in males.

There are numerous studies showing average sex differences in the brain—that is to say, an average difference between a group of females and a group of males. Study of brain differences in humans are particularly controversial, both because of the long philosophical and political controversy about environment and biology mentioned in Chapter 1 "Perspectives on Sexuality in a Cultural and Historical Context" and because of technical difficulties in research. Many confounds exist when studying the origin of brain differences in humans, as experience is known to influence physical brain structure. For example, an individual exposed to repeated traumas will have measurable changes in the size and function of the amygdala, a brain structure associated with fear and anxiety. London taxi cab drivers must memorize every single one of the 25,000 byzantine streets of that city, and this learning causes measurable changes in their hippocampus, a brain structure associated with memory. The sex-based brain differences we describe in this section are real, although controversy exists in terms of identifying how much of the difference is attributable to experience, how much is innate, and how much is based on a G × E interaction, given that biological sex predisposes an individual to different experiences in most cultures. Animal studies are particularly helpful where controversies exist, because while animals also have social and biological environments, these can be carefully controlled.

A forward part of the hypothalamus, the medial preoptic area, is larger on average in males than in females. This is sufficiently different in many species of mammals that it has been called the sexually dimorphic nucleus of the preoptic area (SDN-POA). In rats, females and males have very specific sexual behaviors, which are instinctive rather than learned. Females arch their back in a characteristic behavior, referred to as lordosis, and males mount, copulate, and pause copulation (referred to as intromission) before ejaculating. These species-specific, sex-specific behaviors are known to be controlled by the medial preoptic area in rats, as damage to this area results in both female and male rats engaging in female-patterned behavior. Differentiation is known to occur during early development, because administering testosterone at the right stage, known as a sensitive period, can cause a female rat to have both the SDN-POA of a male rat and the behavior of a male rat. In rats, the sensitive period is just after birth, when the rat brain is still maturing. This area also affects mate choice in rats.

Humans have a much larger cerebral cortex, of course, but many underlying brain structures are similar in all mammals. One difference is that a much greater portion of human brain development occurs prior to birth, as the fetus has 9 months to mature. A sexually dimorphic region of the medial preoptic area has also been found in humans, which is referred to as the interstitial nucleus of the anterior hypothalamus, or INAH3. This area is associated with multiple roles in human sexual behavior. The significance of the sex difference in behavior is less clear in humans; for example, humans do not have sex-specific mating positions, and the positions that humans take during copulation are influenced by cultural traditions and individual learning. The INAH3 region has also been associated with sexual orientation in humans.

Another hypothalamic region with a sex difference in humans is the bed nucleus of the stria terminalis (BST), with two areas of it being larger in males than in females. Broad differences in brain anatomy also exist. Adult females have a larger right hemisphere, and adult males have a larger left hemisphere. The corpus callosum, which connects the two hemispheres, is on average thinner in males, possibly indicating less communication between the two brain hemispheres. There are also numerous differences in neurotransmitter activity within specific brain regions (Resnick & Driscoll, 2008).Resnick, S., & Driscoll, I. (2008). Sex differences in brain aging and Alzheimer’s disorders. In J. B. Becker, K. J. Berkley, E. Hampson, J. Herman, & E. A. Young (Eds.), Sex differences in the brain: From genes to behavior (pp. 427–454). New York, NY: Oxford University Press.

The differences being studied are often so small that they do not show up reliably with brain scanning on a living person and require dissection and analysis of the brain tissue itself after death. Most dissection is of the brains of adults who have died and donated their bodies for medical research. Since it is rare for parents who have lost an infant or child to make a whole-body donation for research, a confound exists in most studies in the literature, as the brains being dissected come only from adults, who have had decades of experiential differences.

This confound has been partially addressed by research on other mammals, particularly rats and primates. Although some advocates of animal welfare object to such research, current ethical standards permit raising these mammals in controlled environments and subjecting both sexes to hormonal alteration, providing that steps are taken to ensure that the animals do not experience pain.

The results of such experiments show that many of the neurological differences in mammals do appear to be innate and due to exposure to different levels of androgens, particularly during sensitive periods in early development. Controlled studies on monkeys—which, like humans, have long gestational periods and complex cerebral cortexes—show multiple periods of sensitivity during fetal development (Pomerantz, Goy, & Roy, 1986).Pomerantz, S. M., Goy, R. W. & Roy, M. M. (1986). Expression of male typical behavior in adult female pseudohermaphroditic rhesus: Comparisons with normal males and neonatallygonadectomized males and females. Hormones and Behavior, 20, 483–500. Some areas of the brain also differ in activation in response to different levels of sex hormones. For example, Xu et al. (2012)Xu, X., Coats, J. K., Yang, C. F., Wang, A., Ahmed, O. M., Alvarado, M.,…Shah, N. M. (2012). Modular genetic control of sexually dimorphic behaviors. Cell, 148, 596–607. doi:10.1016/j.cell.2011.12.018 identified sexually dimorphic genes in mice that regulate the functioning of neurons in the amygdala and hypothalamus. These genes activate quite different patterns of behavior in the presence of female-typical or male-typical levels of hormones, and by deactivating single genes, specific deficits can be observed in sexual aggression and sexual behavior in both sexes, and so can maternal behavior in females, showing discrete “switches” in the brain that are activated by sex hormones.

Most children spontaneously identify with a particular biological sex—that is to say, express their gender identity—around 2 to 3 years of age. A parsimonious interpretation of sex differences in humans is that a substantial amount of sexual differentiation in the brain occurs prior to birth, serving as a foundation that substantially affects many aspects of sexuality, including sexual orientation and gender identity. This biological foundation in turn interacts with environmental experiences, which, in humans, include social environment and culture. This results in gendered behavior with more varied and malleable outcomes as we move to those aspects of gender roles that are more clearly culturally bound.

Variations in Sexual Development

Now that we’ve explored the biological basis of sex for most females and males, we consider variations that occur in human sexual development due to genetic anomalies, which used to be referred to as intersexA term for variations in the development of biological sex that is preferred by some individuals who are intersex; also used by some people who have variations in biological sex to describe their gender identity. and are presently referred to by medical professionals as disorders of sex development (DSDs)A term for variations in the development of biological sex that is preferred by physicians and some people with DSDs.. In ancient Greece, some people with DSDs, such as those that resulted in people having an outward appearance of breasts and a penis, were referred to as hermaphrodites. This term appears in older medical literature and is still used by some physicians. Today we realize that there are numerous disorders of sex development with unique patterns of difference in chromosomes, hormones, internal reproductive structures, and/or external genitalia.

In most individuals, the various components of biological sex align. So, for example, a typical person with an XX chromosome also has the DSS region and DAX-1 genes, does not have the SRY gene, has ovaries and a uterus, has external genitalia that appear typically female, and from an early age identifies as female. A similar alignment occurs for most males in the various aspects of biological sex. However, in approximately 1 out of 1,000 births, variations occur in one or more of the biological components of sex.

Some individuals who have these variations prefer to describe themselves as having a DSD, while others prefer to describe themselves as having an intersex condition. It is respectful to use either term professionally and, when referring to an individual, to use the term that person prefers. Of the many components of biological sex, none perfectly predicts gender identity and whether someone feels female or male. Some people with DSDs do feel female or male and have a clear gender identity of one sex. Others prefer the term intersex to refer to their gender identity.

In the discussion that follows, we use the term DSD when referring to a specific condition and the term intersex when referring to people with a condition; again, many individuals with DSDs do identify as female or male. Table 4.1 "Disorders of Sex Development: Preferred Medical Terms" shows some of the more common variations that can occur in chromosomal sex and sexual development, and Table 4.2 "Examples of Sex Differentiation in Six DSDs" lists the effects of some of the more common disorders of sex development (sexual orientation is not listed, as there is insufficient data on DSDs and sexual orientation).

Table 4.1 Disorders of Sex Development: Preferred Medical TermsHutcheson, J., & Snyder, H. M. III. (2009). Ambiguous genitalia and intersexuality. Retrieved from http://emedicine.medscape.com/article/1015520-overview.

There are many different types of DSDs. Here are a few of the more common ones, listed with their preferred medical grouping (by chromosome):
Sex chromosome disorders of sex development (DSDs)
  • 45,X (Turner syndrome and variants)
  • 47,XXY (Klinefelter syndrome and variants)
  • 45,X/46,XY (mixed gonadal dysgenesis, ovotesticular DSD)
  • 46,XX/46,XY (chimeric, ovotesticular DSD)
46,XY DSD 46,XX DSD
  • Disorders of testicular development (complete and partial gonadal dysgenesis)
  • Disorders of androgen synthesis

    • Complete and partial androgen insensitivity
    • Disorders of antimüllerian hormone (AMH)/receptor
    • Androgen biosynthesis defect
  • Other: severe hypospadias
  • Ovotesticular DSD, testicular DSD, gonadal dysgenesis
  • Androgen excess

    • Fetal—for example, congenital adrenal hyperplasia (CAH)
    • Fetoplacental, maternal
  • Other: vaginal atresia, cloacal exstrophy

Table 4.2 Examples of Sex Differentiation in Six DSDsHutcheson, J., & Snyder, H. M. III. (2009). Ambiguous genitalia and intersexuality. Retrieved from http://emedicine.medscape.com/article/1015520-overview; Rowland, D. L., & Incrocci, L. (2008). Handbook of sexual and gender identity disorders. Hoboken, NJ: John Wiley & Sons.

DSD*/Effects AIS (androgen insensitivity syndrome) CAH (congential adrenal hyperplasia, or fetally androgenized females, or adrenogential syndrome) DHT-deficient males Klinefelter syndrome Ovary and testis, or ovotestes Turner syndrome
Chromosomes/causes 46, XY/missing genes for androgen receptors 46, XX/decreased cortisol production leads to excess ACTH, leading to excess androgen production 46, XY/testosterone not converted into dihydrotestosterone 47, XXY/additional X chromosome (sometimes more: XXXY) Varied/some body cells are XX, some are XY 45, XO/only one sex chromosome
Gonadal sex Testes never descend Ovaries Testes undescended at birth Small testes Both testicular and ovarian tissues Streaks of ovarian tissue, no ovaries
Internal reproductive structures & fertility Lacking; usually sterile Fallopian tubes, uterus, vagina; usually fertile Vas deferens, seminal vesicles, no prostate, partial vagina; usually sterile Typical male but usually sterile Varied Uterus, fallopian tubes; usually sterile
External genitalia Clitoris, shallow vagina Ambiguous, more male than female, although urethra may exit into vagina Ambiguous, more female than male at birth Small penis Varied Typical female
Secondary sex characteristics at puberty Breasts, female (no menstruation) Female (may masculinize at puberty without medical intervention) Masculinizes at puberty Some feminization Varied Undeveloped
Typical gender identity** Female Female but often many male-typical interests Female prior to puberty, usually male after puberty Male but often many female-typical interests Varied Female
Common medical issues*** If labial folds fuse into a scrotum-like sac, will require corrective surgery so that urine and menstrual blood can exit the body Specific learning disorders Increased risk of cancer in testicular tissue Nonverbal learning disorders; renal and cardiac issues

*Many DSDs, such as AIS, vary in degree and likewise vary in extent of changes in sex differentiation.

**Gender identity is something that can vary in any person regardless of biological sex differentiation. This row shows the most common gender identity reported by people with a particular DSD, although there is wider variation than in people without DSDs.

***This row notes which (if any) medical conditions have a higher incidence in people with that DSD (conditions do not always occur).

An individual with androgen insensitivity syndrome (AIS)Typically, a chromosomally XY individual whose genes result in few or no receptor sites for testosterone and DHT, with many aspects of biological sex developing as characteristically female. has typical sex chromosomes but lacks genes for receptor sites for testosterone and DHT. Without receptors, the cells are not sensitive to the usual effects of androgens. AIS can vary in degree, from partial to complete insensitivity to androgens. A chromosomally female individual might have some effects, but usually these would not be noticeable; while androgens occur in females as well, they are far more critical in male biological sex development. A chromosomally male individual with AIS would have very noticeable effects. Because of being XY, the SRY gene will be active in the differentiation of the gonads, and the person will have testes. Because testes produce Müllerian-inhibiting substance, there will be no uterus or fallopian tubes. However, because of the missing androgen receptors, most other aspects of biological sex will develop along the typical female pathway, so the person with AIS will have external genitalia that look typically female—a vagina (which may be shorter than normal length) and a clitoris. At puberty, the person will develop breasts. The person’s gender identity is usually female, suggesting that neurological development also occurs along the female pathway in most humans absent higher fetal androgen levels. Some individuals with AIS are not aware that they have any anomalies until puberty, when they develop breasts but do not menstruate.

Web Link

Androgen Insensitivity Syndrome

Go to http://intersexual.wordpress.com/about/androgen-insensitivity-syndrome/ to learn more about AIS including images of the external genitalia of an adult with AIS.

Then, visit http://www.aisdsd.org/just-learned/ to learn about Katie Baratz, a physician who has AIS. She works to educate the public about the condition.

Congenital adrenal hyperplasia (CAH)Typically, a chromosomally XX individual whose genes result in excess androgen production, with many aspects of biological sex developing as characteristically male., also referred to as fetally androgenized females, or adrenogenital syndrome, occurs in chromosomally XX individuals who have excess androgen production; a genetic anomaly actually results in lower levels of cortisol, and a feedback loop in the body attempts to compensate by producing higher levels of androgens). The person has ovaries and internal reproductive structures of a female, with a urethral meatus that exits in the vagina; however, the person’s external genitalia either are ambiguous or develop male in appearance. Without medical intervention androgen, production will continue at higher levels, and the person would continue to masculinize at puberty but may also menstruate. With medical treatment, the person would undergo menarche, menstruate, and develop breasts. The labial folds may merge into a scrotum-like sac, in which case surgery would be necessary to ensure that urine (and later menses) can exit the body. The person’s gender identity is usually female; however, often the person has many interests that are more typical of males in the culture. This suggests the possibility that gender role conformity in most people may have a biological component. A controversial treatment for pregnant women known to be at risk of carrying a female fetus with CAH involves administering dexamethasone during pregnancy to prevent the development of CAH by blocking fetal androgens. Dreger, Feder, and Tamar-Mattis (2012)Dreger, A., Feder, E., & Tamar-Mattis, A. (2012). Prenatal dexamethasone for congenital adrenal hyperplasia. Journal of Bioethical Inquiry, 9, 277–294. doi:10.1007/s11673-012-9384-9 argue that this is unethical, as the complications of dexamethasone can be serious, including intellectual impairment, and the variations of CAH are mostly harmless and involve primarily gender-nonconforming behavioral differences.

Web Link

Congenital Adrenal Hyperplasia

View Figure 2 at http://radiographics.rsna.org/content/28/7/1891.figures-only to see an image of an infant with CAH.

Then, visit http://www.isna.org/about/thea_hillman to read about Thea Hillman, a poet who has borderline CAH and writes on her experiences.

DHT-deficient males Typically, a chromosomally XY individual whose genes results in lower levels of androgens during fetal development and a more female biological appearance but who at puberty become more masculinized.have a genetic condition that, during fetal development, interferes with conversion of testosterone to 5α-dihydrotestosterone. Thus although they have testes, their external genitalia are ambiguous or more female at birth, and persons who have DHT deficiency typically identify as girls during childhood. However, due to the surge of androgens at puberty, sufficient testosterone is produced so that many people with DHT deficiency masculinize at puberty, with the external genitalia developing into a penis (sometimes smaller than average), and with the person typically identifying as male as an adult. This change from childhood to postpubescent gender identity is not typical of other DSDs. A person who has DHT deficiency usually is sterile and, while having testes that descend at puberty, has no internal reproductive structures (neither womb nor vas deferens or prostate). However, with medical assistance, viable sperm may be collected should he wish to conceive. Although rare in large populations, in a genetically isolated village of Salinas in the Dominican Republic, a cluster of children were born with DHT deficiency, sufficient for the village to consider this a normal variation, and the infants were called “balls at twelve” (the literal translation of the Spanish guevedoce, or “eggs at twelve,” with eggs in this context being a slang term for testicles; Fausto-Sterling, 1992; Zucker, 2006).Fausto-Sterling, A. (1992). Myths of gender (2nd ed.). New York, NY: BasicBooks.Zucker, K. (2006). Gender identity and intersexuality. In S. E. Sytsma (Ed.), International library of ethics, law, and the new medicine: Volume 29, Ethics and Intersex. Dordrecht, The Netherlands: Springer. doi:10.1007/1-4220-4314-7

Other common DSDs include Klinefelter syndrome, ovotestes (both ovarian and testicular tissue in the body), and Turner syndrome. All together, the incidence of chromosomal DSDs is about 0.1% of births. If one includes hypospadias, which relate to sexual development and are sometimes also classified as DSDs, the incidence is somewhat higher. The specific extent and effects of DSDs vary considerably not only by disorder but also within disorder depending on the person. Rather than detailing further specifics of each DSD, it may be more useful to consider some of the common issues that occur for people who have DSDs and their parents.

Medical and Other Issues for Intersex Individuals

Biological sex has a legal meaning in modern industrialized societies. Identity documents require picking female or male (a few governments include intersex); toilet facilities, locker rooms and showers in athletic facilities are usually designated as female or male; and most sports have separate teams and contests for females and males. Although chromosomal, gonadal, outward appearance of the genitalia and other aspects of biological sex match for 99.9% of people, this is not the case with intersex individuals, between 4,000 and 5,000 of whom are born each year in the United States.

When a person with a DSD competes in an international athletic competition, there is not yet any consensus as to the criteria for whether the person should compete as female or male, but complications exist, as most international sports require competitors to be classified as female or male. Each sport handles the classification differently, and the variations reflect that there is no single biological criterion that makes someone male or female. In reality, there are multiple factors. While most people are in alignment on all those factors, people with DSDs possess some biological traits of both sexes and may not be aware of this until someone challenges whether they really are female (because the concern is most often about male muscle mass giving unfair advantage, scrutiny typically falls on athletes competing in women’s events—not on those competing in men’s events).

For example, in the 1990s, the International Olympics Committee (IOC) used to test for the presence or absence of XY sex chromosomes and, later, the SRY gene. As we’ve seen, a person with that gene who has AIS may be in almost every other respect biologically female yet still have an SRY gene. The IOC in the 2000s moved to a case-by-case approach, as did many other sports at the international level, often keeping the specific details of an evaluation confidential, disclosing only the decision as to whether the person should compete with women or with men. In the 2012 Olympics, the IOC adopted a test that focused on circulating blood levels of testosterone, holding that sex chromosomes were irrelevant but that if blood levels of testosterone are in the range typical for males, an athlete must compete as a male. This again will create issues for people with AIS, and it raises issues of fairness for people with partial AIS versus those with complete AIS.

Figure 4.4 "Caster Semenya" shows Caster Semenya, who has always identified as female. She expressed surprise that her sex was being questioned after winning the women’s 800-m world competition in 2009. The International Association of Athletics Federations required her to take extensive medical tests. They did not disclose the results, but after several months of deliberation, they determined that she would keep her medal and continue to compete as female. A DSD is consistent with the portions of her medical history that have been made public, but she has not indicated that she has a DSD. While having a DSD is not necessarily psychologically damaging, she was reportedly quite traumatized by the experience of publicly having to prove she was a woman.

Figure 4.4 Caster SemenyaTab59. (2012). Caster Semenya London 2012. Retrieved February 7, 2013, from Wikimedia Commons: http://commons.wikimedia.org/wiki/File:Caster_Semenya_London_2012.jpg.

This photograph shows Caster Semenya, who won a world competition in the women’s 800 m in 2009. Competitors raised questions as to whether she was intersex and should have competed as a male. The International Association of Athletics Federations required her to take extensive medical tests. The results were not disclosed, but the decision, after several months, was that she would continue to compete as a female.

Of course, most people who have a DSD won’t have to undergo public scrutiny of their biological makeup, but some do have a committee of medical professionals who decide whether they will be female or male and assign a gender in infancy through surgery and hormones. For others, the identification as female, male, or intersex is left up to the individual and how they feel as they grow up.

Some people with DSDs naturally express a gender identity of female or male, while others may feel that neither fits and may prefer intersex as their adult gender identity. People with DSDs may experience issues with the reactions of others, as the person’s external genitalia may appear different than is typical for her or his gender identity, and there may be additional issues involving fertility or other biological conditions that require treatment. Others with DSDs may have typically appearing genitalia and may not know that they have a DSD unless told by physicians. In the past, parents were encouraged to hide the presence of a DSD from their children, and many adult intersex individuals have expressed distress upon learning that they had been lied to throughout their childhoods.

The detailed history of medical practices with DSDs shows a path that, in retrospect, has caused significant harm to hundreds of thousands of people worldwide. The first surgical assignment of gender for children with visible DSDs began in the mid-19th century, long before the discovery of DNA and any understanding of biological sex development (Reis, 2009).Reis, E. (2009). Bodies in doubt: An American history of intersex. Baltimore, MD: The Johns Hopkins University Press. The selection of gender was guided by gonadal sex for much of the 20th century. By the mid-20th century, assignment was often to female, as surgeons found it easier to remove an enlarged clitoris and create the appearance of typical female genitalia than to create the appearance of typical male genitalia. Medical focus was on the cosmetic appearance of genitalia—not sexual functioning. By the 1960s, and continuing for several decades, surgical and hormonal techniques became more advanced and were routinely applied to children with DSDs, most commonly involving reduction or removal of the glans, leaving the person unable to experience an orgasm and giving sex hormones at puberty to develop the secondary sexual characteristics typical of the assigned sex (e.g., estrogen for someone being raised as female).

To understand why this became commonplace, one must understand the role that cultural traditions and values play in shaping people’s perceptions. Philosophically, in psychology, behaviorism was the prevailing paradigm, and experts such as John Money at Johns Hopkins University incorrectly believed that gender identity was learned in the second and third years of life. This was based on poorly conducted experiments, which we illustrate in Chapter 4, Section 3 "Identity and Roles: Feeling and Being [Ch Part B: Gender Identity]". Physicians recommended limited disclosure to patients, believing that it would be less emotionally traumatizing, so parents were encouraged to lie to children, telling them they required hormone treatments for unspecified medical conditions. Culturally, there was significant pressure on conformity and little skepticism about the limits of science, so parents usually accepted without question the recommendations of physicians, who felt that early assignment would be least traumatizing to both children and parents.

As genetic testing became available in the 1990s, it became possible to identify specific genetic anomalies and to map the typical adult gender identification for a given DSD. Assignment of gender in infancy continued but was now guided by the identity commonly manifested by adults with that DSD. In addition, many of the individuals who were reassigned when infants in the 1960s and 1970s had grown up, and more careful long-term collection of data revealed that while some people were satisfied with their sexual functioning and assigned gender identity, many intersex individuals were not. Some expressed a gender identity different from that which had been assigned, and many expressed dissatisfaction with sexual functioning due to side effects of surgery. Many also reported a feeling of betrayal and distrust of both parents and medical professionals, and significant psychological trauma was attributed to the medical interventions themselves, which did not appear to have any benefit for patient or family.

The Intersex Society of North America (ISNA) was founded in 1993 by Cheryl Chase, a person with a DSD, to help address these issues. Many intersex adults argue that the medical profession’s approach of offering surgery on infants and having parents decide is inappropriate, leading to needless psychological and physical trauma. Only a subset of individuals with DSDs requires medically necessary surgery for health reasons, such as labial fusing in CAH. The ISNA’s work culminated in 2006 with a change in recommended medical guidelines in the United States, and the ISNA closed in 2008 (although their website remains online).

Today, these guidelines encourage educating parents about the DSD and typical biological sex differentiation, informing children with DSDs as they grow up about their condition, and encouraging parents to delay nonessential surgery until the person with the DSD is old enough to express a gender identity and participate in medical decisions (Consortium on the Management of Disorders of Sex Development, 2006).Consortium on the Management of Disorders of Sex Development. (2006). Clinical guidelines for the management of disorders of sex development in childhood. Rohnert Park, CA: Intersex Society of North America. In most medical centers, pediatric urological surgeons and endocrinologists are involved, and sometimes a psychologist is also involved in the treatment team, but the ultimate decision continues to be left with parents. In Europe, current guidelines are broadly similar but have more emphasis on early gender assignment. Some intersex advocacy organizations argue that parents and physicians should never be allowed to perform nonessential genital surgery. For the author’s personal opinion on this conflict between some medical professionals and adult intersex advocates, see the “Our POV” sidebar.

Our POV

Surgery and DSDs

A modern goal of medicine is to restore and maintain normal functioning based on rigorous scientific evidence, in the manner that is least invasive, while respecting the patient’s autonomy for deciding which treatments to accept and reject. An ancient goal of medicine, going back to Hippocrates, is “to do no harm.” It seems obvious to me that physicians should follow the recommendations of intersex advocacy organizations and let children with DSDs grow to express their natural gender identity and make their own decisions about surgery (if any). By understanding the continuing desire of physicians and parents to assign a sex early, I think we can understand how pervasive gender role conformity remains in our culture. This is something that ultimately affects most people—not just those with DSDs.

For example, pediatric guidelines in Europe, published in 2009, continue to encourage gender assignment, including surgery “as quickly as a thorough diagnostic evaluation permits,” even while stating elsewhere in the report that there is a lack of scientific data to support such treatment (Tekgul et al., 2009, p. 69).Tekgul, S., Riedmiller, H., Gerharz, E., Hoebeke, P., Kocvara, R., Nijman, R.,…Stein, R. (2009). Disorders of sex development. Guidelines on paediatric urology, 62–72. Arnhem, The Netherlands: European Association of Urology. “Clitoral surgery has been reported to have an adverse outcome on sexual function and clitoral surgery should therefore be limited to severely enlarged clitorises” (p. 70). No medical rationale is given for why a severely enlarged clitoris should be reduced: while inconsistent with the appearance of an average female, a penis-sized clitoris does not necessarily create any functional impairment or reduction in normal physiological functioning for a person, and a hypospadia, if present, can be corrected without the surgical reduction of the “severely enlarged” clitoris. Yet the report recommends it anyway! Likewise, some people who have a shortened vaginal canal who want coitus will experience discomfort and elect to have surgery or vaginal dilation to stretch the vaginal canal, but any physical discomfort can also be addressed by varying positions during sex and engaging in sexual behaviors other than coitus. It seems to this author that many physicians, like other people, are influenced not by a rational consideration of the data but by traditional cultural discomfort with ambiguity and the idea that biological sex and gender identity should conform neatly with one of two familiar categories. Perhaps intersex activist Kiira Treia (1951–2012) put it best with her humorous Phall-O-Meter, shown in Figure 4.5 "Phall-O-Meter", which mocks the historically male surgical community’s fixation on making infant genital appearance conform to typical expectations.

Figure 4.5 Phall-O-MeterKiira Triea, adapted by Alice Dreger; with permission of Kiira Triea and Alice Dreger.

Key Takeaways

  • Biological sex includes chromosomes, gonads, hormones, internal reproductive structures, external genitalia, and differences in the brain and other parts of the nervous system.
  • Chromosomal sex is XX in females and XY in males.
  • Many structures that are sexually differentiated at birth come from common fetal precursors.
  • The default path for the development of many of these structures is in the female direction, regulated by special regions on the sex chromosomes. These genes include SRY on the Y chromosome and, on the X chromosome, DAX-1 and the DSS region.
  • The special genes on the sex chromosomes cause the gonads to differentiate into ovaries or testes, which in turn secrete other sex hormones at different levels.
  • Two sets of precursor internal reproductive structures exist in all fetuses (both a female and a male system), one of which develops and the other of which atrophies, due to hormones and inhibiting substances secreted by the gonads.
  • The external genitalia develop from one set of fetal precursor structures, under the influence of gonadal hormones.
  • Fetal hormones also affect neurological development. Multiple structures in the central nervous system have been identified that have average differences in relative size in females and males. These include Onuf’s nucleus in the spine, two different regions of the hypothalamus in the brain, the left and right hemispheres of the cerebral cortex, and the thickness of the corpus callosum connecting the hemispheres.
  • In rats and primates, the hypothalamus is strongly associated with female-male typical sexual behavior.
  • Animal studies, normal development, and atypical development suggest that brain differences likely create a strong biological foundation for gender identity in humans and that infants do not learn their biological sex.
  • Both rats and humans also show an influence of social environment on certain aspects of sex-typical behavior.
  • About 1 out of 1,000 births have variations from typical sexual development due to chromosomal, hormonal, or genetic anomalies. These are collectively referred to as disorders of sex development.
  • Some people with DSDs prefer to be referred to as intersex. Adult gender identity correlates with the type of DSD to some degree, but there are considerable individual variations.
  • Medical doctors used to recommend infant assignment to a likely gender identity based on genes and gonadal development, often accompanied by surgery to make the genitalia resemble the assigned gender. Such surgery is usually not medically necessary and may impair adult sexual functioning.
  • Increasingly, both medical doctors and intersex advocates recommend not assigning a gender identity in infancy but instead waiting and allowing children to express their innate gender identity, and then having them participate in their own decisions about surgery when they are older.

Exercises and Discussion

  1. Share experiences in a group of students about having cats, dogs, or other mammals as pets. Who had their pets spayed or neutered? What behavioral differences might have been associated with the removal of the gonads as compared with what is reported by people who have unneutered pets of the same species?
  2. Get a group of students together with families of various origins. Did you, or someone you know, grow up in a family with siblings of the same sex (all boys or all girls)? Did you, or someone you know, grow up with siblings of both sexes? How about a twin sibling (or a sibling very close in age) of the other sex? Can you identify any social experiences that may have influenced your own gendered behaviors?
  3. In a group, role-play. Some of you are on the IOC and are considering an athlete with a DSD. How would you determine if the athlete should compete as a female or male? Several in the group should take the role of the athlete. Assume you had always felt the gender identity that you have now; how would you feel about being tested and having your competition possibly be based on some aspect of your biology other than your own identity? Would you believe that certain aspects of the testing should be kept private? Would it be fair if all people competed against each other, rather than having separate women’s and men’s competitions?
  4. In a group, role-play. Imagine that some of you have a baby and are told that the child has a DSD with ambiguously differentiated genitalia and that children with this disorder typically (but not always) have a gender identity that does not match your child’s current genital appearance. Would you wait or request surgery? Do you think your choices would depend on the specific DSD and whether your baby’s genitalia are feminized or masculinized? For others in the group, imagine you were that infant and have grown up. What decisions would you have wanted made for you when you were an infant? What decisions would you want to have been able to make for yourself? If you were not told but later discovered your biological condition as an adult, would you feel betrayed? If you were told as a child growing up, how might this have altered your experience of childhood? If doing this exercise alone, try to switch roles and consider both perspectives.