Transgender identity has been in the news lately—and unsurprisingly so. The charged political climate of this month has yielded many contentious issues about gender and LGBT rights to use public restrooms—and it’s clear that these discussions are long overdue. But before we delve and expound on whether transgender individuals like Gretchen Diez should be allowed to use the ladies’ bathroom, it is important for us to set aside our eons-old assumptions about sex and gender. We must first assess our knowledge on the topic because there are so many misconceptions being peddled by netizens about their biological underpinnings. It’s a complicated subject, to say the least, because the science of sex and gender occurs at the intersection of many biological disciplines, including molecular biology, genetics, neurobiology, endocrinology and evolutionary biology.
First, let’s talk about sex. The word “sex” is perhaps one of the most complex words in science and it has a broad range of meanings defined by biology. I am not here to talk about sexual intercourse but more about the science of sexual determination system, sexual differentiation, or how biological sex is coded or programmed during development. Another point to consider is what it means to be male or female. Is gender determined by chromosomal sex, genetics, anatomical features, or behavior? What about sexual orientation and transgender identity? Is sexual orientation determined by experience in childhood or neuroanatomical features and genetic makeup? Does gender live in the brain? These are challenging questions and I will try to answer them all by looking first at the basic biology of sex and gender.
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The ABC’s of XX, XY, and SRY
The science of sex and gender is provisional at some level. We thought that gender was static; now we know it’s dynamic and complex. We were all taught in school that sex is supposed to be simple and immutable—at least at the cellular or molecular level—and an examination of the venerable XY determination system is instructive. As virtually everyone learned in grade school or high school biology, the explanations that appear in our textbooks is that, within the nucleus of every human cell, DNA provides a person’s blueprint—all the information needed to build an individual. And the classic recipe was simple: Females have two X chromosomes, an X chromosome from mom and an X chromosome from dad, while an X chromosome from mom and a Y chromosome from dad will yield a genetic male. When eggs meet sperm, each parent contributes 22 non-sex chromosomes and one-sex chromosome—always an X from the mother, and either an X or Y from the father. Thus, the contribution from the father determines the sex of the baby because the defining gene for male genotypic and phenotypic sex is found on the Y chromosome: a single gene that is commonly called SRY (an acronym for sex-determining region of the Y chromosome, which codes for a protein called testis-determining factor (TDF). The TDF/SRY gene product is the sole determinant for establishing male gonadal tissues that yields a male phenotypic sex.
It seems like a pretty simple and straightforward system—but it wouldn’t be biological science without exceptions and extra rules muddying the waters. Now we know that it becomes increasingly crystal clear that a pair of chromosomes do not always suffice to distinguish girl/boy—either from the standpoint of sex (refers to the biological traits male and female) or of gender (social and cultural attributes traditionally attached to sex). It’s well established in science that, in most instances the XX genotype leads to the development of female sex organs such as uterus, ovaries, fallopian tube, cervix, clitoris, labia and vagina; the XY genotype typically leads to the development of testicles, vas deferens, seminal vesicles, penis and scrotum. In few instances, however, the XX determination system follows an atypical trajectory that muddles the waters i.e., XX yields to the development of male phenotype and XY leads to the development of female phenotype.
Mismatches Between Chromosomal Sex and Hormones
Humans are conditioned by society to view sex and gender as binary attributes or linear spectrum. Before most infants are named, they are assigned a sex based on the appearance of their external genitalia by a third party and we are definitely labeled “boy” or “girl”. Yet the modern science of sex and gender points to a much more ambiguous reality. Determination of biological sex is now getting enormously complex and intricate, involving not only anatomy but a combination of genetic, enzymatic and hormonal factors that unfolds over time. For example, intersex individuals like the guevedoces or colloquially referred to as “testes-at-12” in Dominican Republic and Haiti—those for whom sexual development follows an atypical trajectory because of consanguineous pedigrees—are characterized by a diverse range of conditions, such as 5-alpha reductase deficiency in the embryonic genitalia and maintenance of another in the brain yields . These conditions and the pathways they follow add additional layer of complexity on the gender with which a person identifies does not always align with the sex they are assigned at birth, and they may not be wholly with male or female. As infants and children, the genitalia of these individuals resemble those of females more than males because of the enzyme deficiency. At puberty, the surge of androgens the clitoris enlarges to a penis and the testes descend, changing these individuals into phenotypic males.
The case of guevedoces is proof that chromosomal sex, phenotypic sex, and gender are not always aligned, and genetic differences in humans challenge the usual definitions of female and male. Because hormones, not chromosomal sex, largely determine the sexual characteristics of the nervous system, it is possible to have genetic males with female brains and genetic females with male brains. It is also possible to have female phenotypes despite having XY genotype or male phenotypes with XX genotype.
There are also various conditions in which normal sex differentiation does not occur. For example, in androgen sensitivity syndrome (also called testicular feminization), the genotype is XY and testes are present, but the phenotype (external genitalia and vagina) is female. It is caused by a mutation in the androgen receptor gene. Hence, genetic males (XY) who carry a defective androgen receptor gene may have profound androgen insensitivity because the androgen receptor gene is on the X chromosomes; males thus have only one copy of it, and males with the defective gene cannot produce functioning androgen receptors. In a nutshell, the person with androgen insensitivity syndrome is missing the androgen receptors and without these receptors the physical features will be adversely affected. The testosterone will not be detected by the pituitary gland and thereby can’t detect the negative feedback. Luteinizing hormone (LH) will go up and testosterone will continuously go up which causes increased production of estrogen due to the negative feedback mechanism. These individuals develop normal and functional testes and produce ample testosterone, but they appear outwardly female because their tissues cannot respond to androgen; they have a vagina, a clitoris and labia, and at puberty they develop breasts and a female body shape. They do not menstruate, however, and remain infertile. Androgen-insensitive genetic males not only look like females, but they also behave like them. Even when they are aware of their biological conditions, they prefer to call themselves women; they dress like women, act like women, and they choose men as their partners.
On the other hand, some people have a condition called congenital adrenal hyperplasia (CAH), which literally means overgrown adrenal glands present at birth. The majority of CAH cases are the result of mutations in the gene encoding 21-hydroxylase, an enzyme responsible for synthesis of two additional steroids secreted by the adrenals: cortisol and aldosterone. In XX genotype, CAH leads to overactive secretion of testosterone during development Although they are genetically female, because their adrenal glands secrete unusually large amounts of androgen, CAH females are exposed to abnormally high levels of circulating androgens early in their development. CAH girls often exhibit behavioral traits more often associated with boys than girls; they are more likely to describe their behavior as aggressive or tomboyish. As adults, these women may be more likely to form sexual relationships with female partners.
Gender is neither binary nor linear spectrum
Mounting evidence from clinical studies shows that sex is not an immutable condition determined at birth because there are multifarious factors that play a role into whether someone is male or female, or somewhere in between. But where does the feeling of gender come from in the first place? The science is still far from conclusive because the neuroscience or genetics of gender identity is still in its infancy. Little is known about the causes of transgender phenomenon but scientists have made great strides in recent years in unlocking the biological basis of several factors by looking for genetic and neuroanatomical signs in transgender people. Clinical studies of transgendered individuals show that they report deeply held identities that oppose their genotypic and phenotypic sex. Their experiences, usually thoroughly assessed in rigorous diagnostic evaluation, often lead to hormonal or surgical reassignment of phenotypic sex. Current understanding of transgendered men and women thus reinforces a sense that their perception of sex and sexuality has biological underpinnings.
Scientists often look at twins in studying the genetics of transgender individuals. A major difference between identical and fraternal twins is that the former share more of their genetic material than the latter. If researchers find more agreement in transgender identity among identical twins than in fraternal twins, they infer that genetics play some role. And, in fact, this is exactly what early studies are finding. For example, in one 2012 review of the literature, Ghunter Heylens of Ghent University in Belgium and his colleagues looked at 44 sets of same-sex twins in which at least one twin identified as transgender. They found that in nine of the 23 identical twin pairs, both siblings were transgender, whereas in no case among the same-sex fraternal twin pairs were both twin transgender, suggesting transgender identity has some genetic underpinnings.
Similarly, some neuroscience studies have shown that trans people appear to be born with brain structures that resemble those of the individuals with the same gender identity, rather than people with the same sex at birth. In 1995 and 2000, two clinical studies by independent teams of researchers decided to examine a region of the brain called the bed nucleus of the stria terminalis (BSTc) in trans- and cisgender men and women. The purpose of these two studies sought to look closer into the brains of transgender individuals to figure out if their brains better were similar in neuroanatomical structures to their assigned or chosen sex. Both teams discovered that male-to-female transgender women had a BSTc more closely resembling that of cisgender women than men in both size and cell density, and that female-to-male transgender men had BSTcs resembling cisgender men. What was also astounding was that these differences remained even after the scientists took into consideration the fact that many transgender men and women in their study were taking estrogen and testosterone during their transition by including cisgender men and women who were also on hormones not corresponding to their assigned biological sex (for a variety of medical reasons). These findings have since been confirmed and corroborated in other studies and other regions of the brain, including a region of the brain called the sexually dimorphic nucleus, that is believed to affect sexual behavior in animals.
These findings suggest that gender is certainly neither binary nor linear spectrum. Like many other facets of identity, it can operate on a broad range of levels and operate outside of many definitions. It also appears that gender may not be as static as we assume. At the forefront of this, transgender identity is enormously complex with multicausal causes – it’s unlikely we’ll ever be able to attribute it to one neat, contained set of causes, and there is still much to be learned in the future. But we know now that several of those causes are biological. Most of these individuals are not “choosing” a different identity on a whim. The transgender identity is multi-dimensional – but it deserves no less recognition or respect than any other facet of humankind. Nobel Prize-winning Steven Weinberg once said that the spread of scientific spirit during the Enlightenment in the late seventeenth and early eighteenth centuries was one of the reasons that stopped the burning of witches. Learning the new science of sex and gender may not end mankind’s persistent superstitions and misconceptions but it might help stem the surge of homophobia and transphobia in the country. Lastly, being knowledgeable about sex and gender holds the prospect of helping shape public opinion and policy making to acknowledge this reality.
[Parts of this article were culled from Neuroscience: Exploring the Brain by Bear, et al. and Neuroscience by Purves, D., et al].