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Abstract
There is increasing interest in and tolerance of the lay public for variations in human sexuality. In contrast, the molecular biology that underlies gender identity, the development of gonadal and genital anatomy, and the factors that define sexual behavior is proving unexpectedly complex and is still incompletely understood. It is now evident that humans cannot be characterized as member of 1 of 2 clearly defined units: male or female. In fact, individuals exist on a continuum: those who do not conform unequivocally to the dyadic view of human sex in terms of anatomy, gender identity, and/or sexual behavior should be characterized as having variations in rather than disorders of sexual development. Such individuals can no longer be regarded as anomalies to be rejected, condemned, and, if possible, “corrected” either psychologically or anatomically.
Societal changes are increasingly moving the conceptualization of gender from a set of binary categories towards a bimodal continuum.
Meyer-Bahlburg et al1
Most humans enjoy the seamless congruence of their gonadal and genital anatomy. Furthermore, their gender identity (the sense of themselves as male or female) coincides with that anatomy, as does their choice of sexual partners. Departures from the usual constellation of these features of human sexuality have always been said to be relatively rare. But 21st-century society’s increasing openness and acceptance of variations in human sexual identity and behavior continues to expand. Children with anomalous genitalia are no longer routinely surgically “corrected” at birth. Transgender and homosexual persons are elected to public office.2 Same-sex marriages are legal in many states. The reality of gender dysphoria is increasingly accepted3; well-informed parents accept the fact that children who believe they are not the sex their anatomy suggests that the conviction is genuine and may either disappear at puberty or persist into adult life. We now make room for the opinion and inclination of the child himself in the decisions made about managing the issues involved.
Traditionally and simplistically, we have categorized humans as either male or female: In fact, this rigid dyadic view does not allow for nor explain the whole spectrum of variations in gender identity, sexual differentiation, and patterns of sexual activity—all of which are the consequence of still incompletely understood variations in the molecular biology of sex. Arguably, one of the most competent and accomplished investigators concentrating on the biologic underpinnings of intersex, which he defines as “the impossibility of distinguishing whether the individual is male or female” is Eric Vilain.4 He estimates the incidence of intersex births as 1 in 4500 and stresses the tremendous genetic heterogeneity of intersex individuals:
The biological mechanisms of intersexuality are complex and for the most part understanding them is still a work in progress.…many intersex babies are born without a clear biological explanation.
Vilain4
In contrast to the progress the lay community has made in accepting intersexuality and homosexuality, the ability of molecular biologists to explain their biological underpinnings is far behind. Nevertheless, the perhaps unanticipated complexity of sexual biology notwithstanding, we are making important advances. The character of the debate about the origins of sexual behavior (is it nature, ie, biology or nurture, ie, the postnatal environment) is fundamentally changing. It is now generally accepted that neither gender identity nor homosexuality can be reversed by postnatal environmental conditions and experiences; they are biologically determined during intrauterine life and are irreversible.5
Another significant advance has been the development of a new science, epigenetics, in which the addition of chemical tags to the genome regulates gene activity: gene function, far from being set in stone, is modified by a complex array of factors that turn them on or off. Not only parental alleles, but the epigenetic pattern of gene activation and/or suppression can be inherited and links experiences of previous generations to offspring, sometimes to a third generation.6,7 The epigenetic changes induced by environmental experiences can be inherited, and the experiences of grandparents can impact the phenotype of a developing grandchild in a sex-specific manner.
Despite its complexity, defining the molecular biology of normal sexual development and explaining the mechanisms of variations from the process have been the subject of extensive investigation, particularly since the description of the structure of the human genome 2 decades ago. Although the impact of hormones on sexual development is fundamentally important, the genomic scaffolding that underlies the establishment and elaboration of all aspects of biological sex is of particular interest: it is conceivable that we will have the ability to alter genomic structure and/ or epigenetic modifications of gene expression to correct variations from the norm. To quote only one example of the potential of such manipulations, Minajigi et al point out that if one could unlock the epigenetic state of the inactivated X chromosome, it could be used as “a reservoir of functional genes that could be tapped to replace expression of a disease allele on the active X (Xa).”8
Given the expanding interest and increasing social acceptance of variations in gender identity, gonadal and genital anatomy, and sexual behavior, it is useful to summarize some of what we know and what is still to be investigated about the biology of sex in humans.
X and Y: The Consequences of Mismatch
Some aspects of the biology of sex are well understood and solidly documented. The role of the X and Y chromosomes is probably the best example of what we know, because we have been able to chronicle the consequences of variations in the combinations of those chromosomes in living patients. Errors in sex chromosome pairing, that is, XO (Turner syndrome), XXY (Kleinfelter syndrome), and so on, can and do occur with profoundly important and permanent phenotypic modification, not only on sexual features but on a whole spectrum of body systems and tissues.
Even when XX or XY pairing is flawless, it is evident that collaboration between the chromosomes is multifactorial: while the presence of the Y chromosome is enough to create a male, the absence of one of the X chromosomes produces characteristic anatomic and functional abnormalities in the female.9 Nevertheless, we do not know what particular genes on the paired set of X’s are needed to generate the complete female phenotype. Similarly, male biological sex is the consequence of a still incompletely understood sequence of events of which the SRY gene is only the initiator: for example, the genesis of an intact, fertile male requires multiple genes on the Y chromosome paired with one (and only one) X.10 Mittwoch10 writes,
The dominant effect of the Y chromosome on male sexual development is attenuated in the presence of supernumerary X chromosomes, resulting in sterility…. In virtually all cases, the germ cells die and the genetic function is zero.
The genomic cause of sex reversal can be exquisitely rare and elude detection, certainly by the majority of clinical laboratories: Guellaen et al report the incidence of single copy Y fragments in the genome of 4 human XX males (which occurs once in 20 000-30 000 newborn males), possibly due to a translocation of the Y fragment to another chromosome, probably the X.11
Variations in the Sexual Phenotype
Disturbances of the complex sequence of genomic events initiating, developing, and maintaining the sexual phenotype produce what is now termed “disorders of sexual development (DSD).” These conditions include outright sex reversal and/or ambiguity of gonadal anatomy and external genitalia. Some are due to mosaicism or chimerism. Berger-Zaslaw et al reported an individual with ambiguous genitalia and a 46XX/46XY karyotype.12 Not all are confined to the X or Y chromosome: some are located on the autosomes. The human chromosome 9, for example, contains 2 genes that are essential for testis differentiation.13 Ledig et al discuss ovotesticular disorders that occur in patients with normal karyotypes but who have autosomal abnormalities.14 Even the rare occurrence of males with an XX chromosomal compliment is explained by their having a small piece of DNA from the Y chromosome accidentally transferred during meiosis to the X chromosome; that fragment contained the testis-determining factor SRY.15
Developing the Male or Female Gonad
The establishment of biological sex launches the trajectory of sex determination, that is, the creation of an ovum or a testis. The process, which depends exclusively on genetics, is complex and multifactorial. Anomalies are rare (estimated by some authorities as 1 in 20 00016). The nascent gonad is neutral, that is, neither male nor female, and has the unique property of being capable of differentiating into either a male or female lineage.17 DiNapoli and Capel point out that the path to male or female sex is not always direct, complete, or inevitable and discuss some of the many components of gonadogenesis that are involved in setting and stabilizing gonadal sex.18
That “fate decision” is under genetic control. Many of the genes involved are still unknown; sex reversal cannot be explained in 75% of individuals.19 The balance between the agents that produce a male gonad and those that fashion the ovum is multifactorial, delicate, and precarious; it has been termed by many investigators as “the battle of the sexes.” At least 2 opposing sets of genes are involved in the signaling pathway; SOX9 and FGF9 promote testicular development; WNT4 and possibly RSPO1 foster that of the ovary. DiNapoli18 comments,
These observations paint a picture that is markedly different from the classic male-active/female passive model. It now appears that the bipotential gonad is the battleground between two active and opposing signaling pathways…
By the 7- to 8-week of development in humans, the gonad is sexed. In the case of the testis, the process is well delineated: the testis-determining factor is the SRY gene (sex-determining region of the Y). It is expressed in the supporting cell lineage precursors in the XY gonad and the Sertoli cell differentiates from the bipotential primordium. Other genes are involved downstream; the first is SOX9. Mutations or deletions in the male-determining sequence can abort testicular formation: mutations in SRY produce 10% of sex reversal, while deletion of the SOX9 gene produces male to female reversal in humans.20,21 Conversely, duplication or overexpression of SOX9 can cause female-to-male sex reversal.22
The details of ovarian formation are less well understood than those that produce the testis, but it is clear that the process is also actively controlled by genetic forces: the old view that the ovary develops by default if no SRY is present is defunct. DiNapoli18 comments,
Whether there is a parallel transcription factor regulating the initiation of ovary development (i.d., a female-determining gene) is unknown, but not theoretically required. Regardless of whether or not one is found, it is clear that initiation of the ovarian pathway involves the active regulation of many genes and is not simply a passive/default developmental process.
Tevosian and Manulov summarized the current view of ovarian development and make an excellent case for the fact that it depends on a complex active pathway that emerges at the same time the testis develops in males.23 They cite the pivotal role of the signaling pathway, WNT/β-catenin signaling.
The initiation and maintenance of gonadal differentiation does not only involve the earliest stages in the canalized trajectory of the establishment of sex; Miura et al affirm that the action of the genes involved must continue to operate as “maintenance factors” throughout the postnatal and adult stages of development. They remind us that the loss of key genes can result in a sex-reversal phenotype.24
Veitia’s review reinforces this view of gonadal differentiation. He uses the term “battle of the sexes,” pointing out that far from being a passive agent in the differentiation of the gonad, the ovary actively represses male-specific genes not only during development but continues to do so into adult life.25 If the ovarian transcription factor FOXL2 is absent, the male-specific genes that initiate testis development (SOX9 and the gonad-specific enhancer mediating its expression, TESCO) are not repressed. Thus, the ovary must act to maintain its differentiated state throughout life. Koopman emphasizes the delicate balance between the male and female gonadal development pathways. He too endorses an active role for genetic determination not only of the testis, but for the ovary.26 In particular, he emphasis the vulnerability of the gonadal choice to disruption by, for example, environmental factors.
Disorders (Variations) in Sexual Development
While sex determination is accomplished when the gonad differentiates into a testis or an ovary, sex differentiation is the consequence of hormones, which promote the formation of internal and external genitalia. Fleming and Vilain point out that genital anomalies occur in about 1 in 100 births.16 These are established by the first 2 months of pregnancy. The 2 are not always consistent: chromosomal sex and phenotypic sex may be at variance in the same person. Vilain’s group studied forty 46,XY patients with DSD and identified the genetic cause in 35%, pointing out that only 10% to 15% of DSDs could be attributed to SRY or NR5A1 (the gene encoding steroidogenic factor-1) abnormalities.27 The authors comment that the more precisely physicians can identify the variation in the genome of individuals with DSD, the more useful genetic counseling and the better selection of treatment modalities can become.
Chromosomal females with congenital adrenal hyperplasia are born with male genitalia; traditionally, these patients were identified as female because of the XX chromosomal complement even in the presence of fully virilized genitalia; Lee and Houk studied such individuals and challenged what they called a dogmatic approach to gender assignment based on the presence of ovaries, recommending that clinicians consider categorizing such patients, particularly those with completely masculinized genitalia, as males.28 They reviewed the available reports concerning 20 fully masculinized 46,XX adult individuals and added 10 of their own, all of whom in spite of the presence of ovaries, retained a sense of themselves as males.
Gender Identity: The Sexed Brain
Despite their existential role, our knowledge about the neurobiological underpinnings of sexual orientation and gender identity is very limited.
Manzouri29
The next frontier in the field of sex determination is to understand the biology gender identity, i.e. one’s own perception of one’s sex.
Vilain4
Human sexuality is not only defined by gonadal and genital anatomy. The sense of whether one is male or female resides in the brain. The factors that create the gendered brain and gender identity are not clearly defined; indeed, even the concept of gender-specific brain structure and function is being challenged.30 The incidence of gender dysphoria or transsexualism is reported as 0.005% to 0.014% in natal males and from 0.002% to 0.0003% in natal females.31 But estimates are probably too low and vary considerably geographically.
Current science continues to reinforce the concept of a spectrum of brain sex rather than a dyadic, clear-cut separation between men and women. Joel et al30 comment that rather than 2 distinct, consistently characterized male and female brains, there is significant overlap between the 2:
The high degree of overlap in the form of brain features between females and males combined with the prevalence of mosaicism within brains are at variance with the assumption that sex divides human brains into two separate populations…. Sex affects the brain, but the prevalence of mosaicism does not support the view that sex effects on the brain produce two distinct types of brains.…human brains do not belong to one of two distinct categories: ‘male brain’/female brain’.
Glezerman, however, reflects the view of most biologists, in that the brain is sexually dimorphic.32 He points out that the instrument Joel et al used was magnetic resonance imaging-essentially still images, which do not reflect the sex-specific differences in brain functionality. He writes, “Functionally, brains of women and men are indeed different. Not better, not worse, neither more nor less sophisticated, just different. The very brain cells differ chromosomally.”
Some facts, however, are clear: genes play a critical role in determining brain sex. The genetic impact is irreversible: it cannot be reversed by gonadal hormones, although hormones also play a crucial role in neurobehavioral development.33
The first evidence of the role of genes in sexing the brain was data from the zebra finch whose sex-specific courtship behavior could not be changed or modified by hormonal/gonadal manipulation.34,35 More recently, Dewin and Vilain observed that sexual differences were apparent in the mouse brain before gonadal differentiation and before differentiation of the adrenal glands.36 Both genes localized to the sex chromosomes and autosomal genes are involved. These investigators found that male and female mouse brains had different levels of more than 50 genes. Bao and Swaab point out that genes play an essential role in sexing the brain, opining that SRY and ZRY are possible candidates for that role.37 It is entirely probable that the trajectory for the eventual sense of being male or female is irreversibly programmed at this very early time in development. Coolidge et al studied 157 pairs of twins and found that the prevalence of clinically significant gender dysphoria was 2.3%. Fully, 62% of the variance was due to a significant additive genetic component.38
In spite of the intriguing idea that genes are probably an essential part of irreversibly programming gender identity, the impact of hormones on neurobiological morphology and gendered behavior is well established. Indeed, it is generally held that the fetal brain develops into a male brain under the influence of testosterone and the female brain “by default” in the absence of the male hormone. The process is thought to occur or at least to be completed later in development rather than genital differentiation. Other investigators point out that hormones reinforce gender identity: Hines et al point out that exposure to high levels of androgens in utero increases the likelihood of the establishment of male gender identity, even when the subject is reared as a female.33 They cite the impact of postnatal testosterone that occurs in boys from 1 to 6 months of postnatal life, predicting that it will be a more valuable period to study the impact of hormones on gender identity because studies of hormone concentrations before birth have not been done on the developing individual, but on maternal blood and/or amniotic fluid. On the other hand, Jordan-Young points out that in females with congenital adrenal hyperplasia (CAH) “the vast majority of genetic females with CAH reared as females have a female gender identity.”39 Dessens et al reviewed gender dysphoria in CAH females and commented that “the underlying mechanisms establishing gender behavior and gender identity are not quite the same.”40 They found that the majority (94.8%) of chromosomal females with CAH had a female gender identity.
Vilain’s group discusses the data concerning the biological basis of gender identity and points out that studying transsexuals might yield insights into how this is accomplished.4 These investigators opine that the data concerning the genetic basis of transsexualism are “extremely limited” and it is apparent that we will have to wait for further studies to establish the mechanisms involved in producing the contradiction between the sense of being male and female and an anatomy that does not correspond to that sense. Bao and Swaab emphasize the difference in timing between genital development which is finished earlier in pregnancy than the sexed brain and point out that since the 2 processes are separated in time, they may develop “in opposite directions.”30
Seeking the Sexual Partner
The Biological Basis of Homosexuality
Gender identity does not inevitably determine sexual preference. Gender dysphoria should not be interchangeable with homosexuality; one does not predict the other. Hines et al comment, “Certainly, transsexual individuals can be hetero, bi-or homosexual, with sexual orientation defined according to their natal sex.”33
Estimates of the incidence of homosexuality are approximately 1% to 10% of the population and are in general lower for females than for males. The evidence for the impact of heredity on the occurrence of homosexuality is strong: Zietsch et al studied a community-based sample of 4904 Australian twins and found that gender dysphoria is not predictive of homosexual behavior and that homosexuality is partly due to inherited genes.41 Coolidge et al summarized the evidence for the hereditability studies of at least male homosexuals (there are much fewer studies of female homosexuals), including the fact that male homosexuality appears to be familial and has a genetic component although it is not linked to the X chromosome or controlled by a single major gene.33
Deamater and Friedrich describe the stages in human sexual development and point out that there are distinct sexual orientations for different times in the life span: infants are capable of sexual response from birth. The sexuality of the preadolescent phase is likely to focus on same-gender children while sexual interest becomes heterosexual at puberty.42
Like all authorities in the field of sexuality, Savic admits that “the neurobiological underpinnings of sexual orientation and gender identity is very limited.”29 She does remark that homosexuality and bisexuality are greater in persons with gender dysphoria (about 50% compared with <10%) and believes, along with Wallen et al, that childhood behavior is a better predictor of sexual orientation than any other factor.43 She reviews the confusion in the literature about whether or not the brains of persons with gender dysphoria have consistent characteristic features. On the other hand, she maintains, sexual orientation may have a characteristic neurobiology. Essentially, she holds that the cerebral sexual dimorphism that characterizes the cis gender brain is less pronounced in homosexuals, particularly among men. Gender dysphoria, on the other hand, she suggests, is related to the cerebral networks mediating self-body perception which are formed early in development and finally become permanent.
One of the most interesting recent developments in the science of human sexual behavior has been the proposal that epigenetics underlies the basis of sexual orientation. In a recent review, Ngun and Vilain advance the concept of homosexuality being the consequence of epigenetic modification of genomic activity.44 They write,
The preponderance of evidence from sexual orientation research strongly suggests that human sexual orientation has biological underpinnings and that it is tightly regulated at the molecular level…. However, much work remains to be done on both fronts (gene studies and epigenetics) to identify which genes are involved in the control of sexual orientation.44
They cite evidence that differences in DNA methylation patterns exist in monozygotic (MZ) twins at the time of birth and postulate that the intrauterine environment may produce differences in the epigenetic pattern of MZ twins that account for differences in many traits. They propose that homosexuality is one of them. It is important to note that these investigators suggest that specific patterns of DNA methylation are responsible for the establishment of sexual orientation and that this is achieved in utero. The epigenetic changes postulated to be responsible for homosexuality are not the result of environmental factors like parental attitudes/behavior or societal disapproval but rather from the impact of epigenetic inheritance and/or the intrauterine environment on gene expression.
These same investigators also suggest that the biologic mechanism of homosexuality might be different in men and women. For example, the linkage to Xq28 for sexual orientation, which is true for men, does not hold for women. The high levels of testosterone to which CAH females are exposed may in fact be related to the higher incidence of homosexuality in these individuals compared to unaffected women. They cite work that points out the difference in the higher percentage of homosexual women who are attracted to both sexes compared with homosexual men, for whom the preference is more frequently focused only on males.
Summary
The description of the human genome structure only 20 years ago has accelerated our ability to understand the genetic components of human sexuality and to assess their interaction with hormones in the establishment of phenotypic sex. The view that the world’s population can be separated into a clearly defined dyadic unit of male and female is defunct; not only clinical observations, but molecular biology has established that sexual identity is on a continuum, with an enormous potential for variance. The search for the specific biological factors that determine a sense of being male or female, the anatomy of the reproductive system, and whether sexual inclination is homosexual or heterosexual is accelerating, but the data are still far from complete. The interest of the lay public in neutralizing the prejudice and distaste for variations in human sexual identity and behavior is intense. It is our responsibility to continue to delineate the molecular biology of what makes us male or female and to explore the many, heretofore largely concealed and often subtle variations that place an individual on a continuum. Those who do not fit into the dyadic view of human sex as either male or female can no longer be regarded as an anomaly to be rejected, condemned, and, if possible, “corrected,” either psychologically or anatomically.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
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