Disorders of Sex Development / Intersex

 

Written by Dr. Daniel Shumer

Introduction

This article provides an overview of disorders of sex development (DSD), a phrase used for conditions where a person is born with reproductive or sexual anatomy that doesn’t fit the typical definitions of male or female. The term intersex is also sometimes used to describe these conditions.

When a newborn baby is born, the delivering midwife, nurse or physician will often exclaim, “It’s a boy!” or “It’s a girl”. Of course, we are all attuned to the fact that the infant’s gender identity is unknowable at this stage. Rather, we understand that what this exclamation is actually describing is that the newborn has external genitalia in either a male or female appearance – the health professional is labeling the infant’s anatomic sex.

Sex is a term that, on its face, seems straightforward: male or female. We use sex to separate people into these two seemingly binary categories. However, sex development is actually quite complicated, involving complex fetal choreography between chromosomes, genes, developing gonads, and hormones.

Sex Determination and Differentiation

Most often, a fetus has 23 pairs of chromosomes, with one of those pairs referred to has sex chromosomes. Typically, the fetus receives an X chromosome from the egg and either an X or a Y chromosome from the sperm in fertilization. Those sex chromosomes then provide a blueprint for development of the developing gonad.

In all fetuses there is a gonadal ridge, which in the first 6-7 weeks of gestation is identical regardless of sex chromosomes. This gonadal ridge has the potential to become the testes or ovaries, and it is the sex chromosomes that guide this change. The medical term for the sex chromosomes providing instructions for the development of testes or ovaries is sex determination.

After this stage, the testes and ovaries act differently; they produce different hormones. These hormones act on structures which have the potential to become familiar anatomic structures. The genital tubercle has the potential to become the penis or the clitoris. The labio-scrotal folds have the potential to become the labia or scrotum. The typical development of these structures in either a male or female direction is guided by the testes or ovaries. The medical term for this process is sex differentiation.

In this complex biological process starting with the sex chromosomes and ending with genital development, there can be deviations from typical at any step along the way. This may result in a newborn having genitals which do not match the typical binary male or female appearance. It may also result in a newborn with a typical male or female genital appearance, who subsequently will have atypical sexual development. When a newborn is born with genitalia not matching the typical binary male or female appearance, the term ambiguous genitalia is sometimes used. It is estimated that 1 in 2,000 to 4,500 infants are born with some degree of genital ambiguity.

Newborn Considerations

In situations where an infant is born with atypical genitalia, a multidisciplinary team of providers is called upon to provide assessment of the infant and support for the family. This team often involves providers from the fields of pediatric endocrinology, genetics, urology, gynecology, and psychology. An immediate task for the team is to assess for life threatening emergencies. Some DSD conditions, such as congenital adrenal hyperplasia, require immediate medical attention and are life-threatening if untreated. The team also works to understand the infant’s anatomy and eventually make a diagnosis.

One of the most important roles of the DSD team is to support new parents. Becoming a new parent is stressful; genital ambiguity can add to this stress and uncertainty. A supportive health provider will simultaneously congratulate the new parents on the addition to their family, validate the feelings and experience of the parents, explain the process of assessment and diagnosis, and often counsel parents to delay decision making on sex-of-rearing until more information is gathered.

Sex-of-rearing refers to the decision to assign a male or female sex to the infant. This decision is a shared decision between parents and medical providers, based on what is known about the infant’s diagnosis, factors such as anatomy and fertility potential, and perhaps most importantly, what is known about other individuals with the same condition with respect to gender identity development.

A Note on Sex and Gender

Gender identity is, of course, unknowable in all infants. Even infants with typical appearing genitals may grow to have a gender identity different from the sex assigned at birth. In infants with a DSD, a sex-of-rearing decision is made with best intentions to match the infant’s future gender identity. It is not recommended and extremely uncommon to delay a sex-of-rearing decision until later childhood (i.e. to rear a child without assigning a sex during infancy), however, parents should be counseled to love and support their child as they grow and develop a sense of self, and be open to the normal exploration of gender and sexual identity as the infant becomes a child, and the child becomes an adolescent. The growing and developing child should be provided age-appropriate information about their body, and offered accurate and truthful answers to questions. Providers may also provide information to parents around the term intersex, the fact that some individuals identify with this term while others do not, and the values that members of the intersex community may share and advocate for.

Terminology Focus: DSD and Intersex

The 2006 Consensus Statement on Management of Intersex Disorders published by the Pediatric Endocrine Society and the European Society for Paediatric Endocrinology, states, “Terms such as ‘intersex,’ ‘pseudohermaphroditism,’ ‘hermaphroditism,’ ‘sex reversal,’ and gender-based diagnostic labels are particularly controversial. These terms are perceived as potentially pejorative by patients and can be confusing to practitioners and parents alike. We propose the term ‘disorders of sex development’ (DSD), as defined by congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical.”

In general, parents of newborns are provided accurate medical information about their child’s sexual development with a goal of providing a medical diagnosis. In my experience as a pediatric endocrinologist, this is extremely helpful to parents. For example, it is current best practice to explain to parents that they have a female infant with congenital adrenal hyperplasia rather than labeling the infant as intersex. That said, it is also important for parents to understand that some individuals with the same

condition grow up to identify as intersex. If you think of intersex as an identity, you can imagine that an infant cannot identify as intersex, but they may in the future. Furthermore, understanding the values and positions of those who do identify as intersex is critical in understanding DSD.

InterACT is an advocacy organization whose mission is to “work to empower intersex youth and advance the rights of all people with innate variations in their physical sex characteristics through advocacy, public engagement and community connection.” According to the InterACT website, “the word intersex…invokes a community.” In regard to terminology InterACT states, “many intersex people reject the term ‘DSD’ because it supports the idea that their bodies are wrong, or up to doctors to ‘fix.’

The Critical Role of Intersex Advocacy in Highlighting the Value of Patient Autonomy

It is worth repeating that not all individuals with a DSD identify as intersex, and intersex advocacy groups do not speak for, or represent the beliefs and values of, all individuals with DSD. That said, intersex advocacy has played a critical role in how DSD conditions are managed today and how parents are counselled. In past decades, upon identifying a diagnosis, DSD teams would often advocate for surgical interventions to make atypical appearing genitals more typical. This could include reducing the size of a clitoris or creating a vagina or penis during infancy in situations where there is no medical necessity to perform the surgery in infancy. Parents and providers would choose to proceed with these surgeries in order to make the genitals as typical appearing as possible for the sex-of-rearing at an age where the infant would not remember the surgery. Intersex advocates point out that while some individuals “may grow up and want to change their bodies, or be glad that their bodies were changed,” others will not. By making the decision in infancy we are substituting provider and parental autonomy for patient autonomy. While parents choosing these interventions certainly have best intentions in mind, individuals who later do not identify with the sex-of-rearing chosen, or who identify with the term intersex, may hold resentments about these decisions.

Today, some large children’s hospitals such as Lurie Children’s Hospital at Northwestern University and Boston Children’s Hospital have explicit statements outlining restrictions on certain surgeries in infancy such as clitoral reduction or the creation of a vagina.

As with anything, it is important to understand that while sometimes painted as a black and white issue, medical decision making is often more complex. For example, a patient born with a DSD and non-functioning gonads, who is at high risk of cancer if the gonads remain in place, may benefit from gonadectomy. These types of decisions should be made with parents while having an honest conversation about medical risk, patient autonomy, and parental values.

DSD Diagnosed Outside of the Neonatal Period

While many DSD are diagnosed after an infant is born with genital ambiguity, others are not diagnosed until later in childhood, adolescence, or even adulthood. For example, young women with complete androgen insensitivity syndrome (CAIS) may present to care with a concern of lack of menses. Upon evaluation the individual may be found to have no uterus, testicles in the abdomen, and XY chromosomes. This specific condition is caused by a complete lack of response to testosterone on the body due to a mutation in the androgen receptor. This condition is a helpful reminder that sex has many different components which may or may not align. A woman with CAIS has a male chromosomal sex, a male gonadal sex, a male hormone profile, but female external genitalia and a female sex-of-rearing. The

vast majority of individuals with CAIS have a female gender identity. While different individuals may respond to the diagnosis with different feelings and emotions, validating to a patient with CAIS that she is no less valid as female now that prior to the diagnosis is likely to be helpful. While the majority of women with CAIS do not identify as intersex, if that identity fits with her sex-concept upon receiving this diagnosis, that identity should be honored and validated as well.

All that said, this topic brings up a larger philosophical question related to biological diversity and sex, i.e. with the wide variability of biological variation, what actually constitutes an intersex condition, and who is it to say?

An individual with polycystic ovarian syndrome (PCOS) is typically a person assigned female at birth, with typical XX female chromosomes and ovaries, whose ovaries happen to produce slightly higher amounts of testosterone compared to women without PCOS. The vast majority of individuals with PCOS identify as cisgender women, however there is conflicting evidence suggesting possible increase in transgender identity in individuals with PCOS. While PCOS is not typically included under the umbrella of DSD diagnoses, some individuals with PCOS do identify as intersex. According to Sam Sharpe writing on the InterACT website, “Is PCOS an intersex variation? Again, there is no one size fits all answer. Intersex variations are 1) present from birth 2) result in sex traits which differ from typical binary understandings of human biological sex. How much do they have to differ? There isn’t a clear-cut answer to this question…for people who know they have PCOS who are wondering about this, I think the question of whether you experience your body in the world in a way that is better understood as having an intersex variation rather than as having a female endocrine disorder is relevant.”

Transgender and DSD/Intersex

As a provider caring for both transgender patients and patients with DSD, I am sometimes asked by transgender patients whether they should be tested for a DSD. First, it is critical to be mindful that for some transgender individuals, their gender identity difference is so profound that it would make sense to that individual, and perhaps even be helpful, if the gender identity difference were to be explained with a biological answer. That said, it is clear that the vast majority of transgender individuals do not have a DSD/intersex condition. There is consensus that a transgender individual presenting to a gender clinic does not require a workup for an intersex condition unless there are specific signs or symptoms suggestive of such a condition. These signs or symptoms could include a history of genital ambiguity at birth, lack of menses in someone with a female assigned sex, atypically robust masculinization at puberty in someone assigned female at birth, lack of typical masculinization at puberty in someone assigned male at birth, or other differences in pubertal development.

Above, we discussed that PCOS is a condition generally classified as a female endocrine condition, not a DSD. However, as Sam Sharpe so beautifully outlined, an individual with PCOS who experiences the world in a way that is better described as intersex, that is valid.

The vast majority of transgender individuals have no measurable difference in any biological parameters compared to cisgender individuals. Also, there is no blood test or x-ray available to measure someone’s gender identity. That said, scientific research and medical literature across disciplines demonstrates that gender identity, like other components of sex, has a biological foundation. For example, there are numerous studies detailing the similarities in the brain structures of transgender and non-transgender people with the same gender identity. In one such study, the volume of the bed nucleus of the stria

terminalis (a collection of cells in the central brain) in transgender women was equivalent to the volume found in non-transgender women.

There are also studies highlighting the genetic components of gender identity. Studies of twins are a helpful way to understand genetic influences on human diversity. Identical twins share the same DNA, while fraternal twins share roughly 50% of the same DNA; however, both types of twins share the same environment. Therefore, studies comparing differences between identical and fraternal twin pairs can help isolate the genetic contribution of human characteristics. Twin studies have shown that if one identical twin is transgender, the other twin is much more likely to be transgender compared to fraternal twins, a finding which points to genetic underpinnings to gender identity development.

It is within this context that the concept of “brain sex” emerges. In addition to chromosomal sex, gonadal sex, hormonal sex, anatomic sex, our “brain sex” or gender identity can be considered the one element of sex that can’t be measured, but which is no less rooted in biology. Taking this thought experiment further, could a transgender individual with a “brain sex” discordant from the other elements of sex be described as having a DSD or as intersex? I would propose that, similar to the point made by Sam Sharpe above, it may depend on whether an individual experiences their body in the world that is better understood as having an intersex variation or a difference in gender identity. In other words, telling a transgender individual that they are not intersex may be dubious scientifically, but more importantly unhelpful if this identity is incorporated into the individual’s self-concept.

Classification of DSD’s by Category

There are various methods of categorization of DSD, but the most commonly used classification schema uses the sex chromosome as a starting point.

46,XX DSD

Individuals with 46,XX chromosomes are most typically female. Individuals with a 46,XX DSD typically have overproduction of androgen hormones in utero. The most common example is congenital adrenal hyperplasia (CAH). In many types of CAH, the adrenal glands are unable to make the hormone cortisol. In the absence of enough cortisol, the adrenal gland over-produces androgens causing virilization of the genitals. Deficiency of the enzyme 21-hydroxylase accounts for over 90% of individuals with CAH. The vast majority of individuals with 21-hydroxylase deficiency CAH are reared female, and later identify as girls and women.

46,XY DSD

Individuals with 46,XY chromosomes are most typically male. Those with a 46,XY DSD have underproduction of testosterone, or a defect of testosterone action at the androgen receptor. For example individuals with 17-beta hydroxysteroid dehydrogenase deficiency have an impairment in converting the precursor of testosterone (androstenedione) to testosterone. Individuals with 5-alpha reductase deficiency have an impairment in conversion of testosterone to its more active form, dihydrotestosterone (DHT). DHT acts on the tissues of the body to cause virilization, but can’t perform this function without a normally functioning androgen receptor. Individuals with partial androgen insensitivity syndrome (PAIS) or complete androgen insensitivity syndrome (CAIS) have dysfunction of the androgen receptor. In all of these conditions there will be varying degrees of under-virilization. Decisions on sex-of-rearing may be made based on the degree of virilization and what is known about

the specific condition with regards to future fertility and gender identity outcomes. Individuals with CAIS are a special case, whereby the external genitals are the same as a typical female, sex-of-rearing is always female, and the expectation for future gender identity is female with no known increase rate of gender identity difference compared with other women, despite a 46,XY chromosomal makeup. Many girls with CAIS are diagnosed in adolescents due to the absence of the first menstrual cycle due to absence of a uterus.

Sex Chromosome DSD

Despite the fact that the majority of individuals have either 46,XX chromosomes or 46,XY chromosomes, some individuals have other sex chromosome makeups. Girls and women with Turner Syndrome have 45,X chromosomes (missing an X chromosome). They have normal female external anatomy, tend to be short in stature, and often require estrogen supplementation in adolescence and adulthood. Boys and men with Klinefelter Syndrome have 47,XXY chromosomes (an additional X chromosome). They have normal male external anatomy, tend to be tall in stature, and often require testosterone supplementation in adolescence and adulthood. Sex chromosome mosaicism refers to individuals with different chromosomal makeups in different cells in their bodies. For example, an individual may have some cells with 45,X chromosomes and some with 46,XY chromosomes (45,X/46,XY mosaicism). This may result in external anatomy along a spectrum from typical female, to typical male, and the spectrum in-between.

Conclusion

Sex is often considered a straightforward term used to categorize individuals as male or female. However, sex is more complicated and less binary when viewed through the lens of the diversity of human biology. Chromosomes, genes, and hormones act on the developing fetus to organize the reproductive organs. This complex biological action can act differently in different individuals leading to a source of human diversity. When an infant is born with a DSD, a multidisciplinary team approach is used to support the infant and family through a journey of discovery and decision making. Children, adolescents and adults with DSD are a diverse group of individuals with different life experiences, attitudes, and opinions with respect to their bodies and identities. These individuals may or may not identify as intersex. Intersex individuals and intersex advocacy organizations have contributed to the modern-day understanding of importance of personal autonomy in medical decision making.

References

Witchel SF. Disorders of Sex Development. Best Pract Res Clin Obstet Gynaecol. 2018 Apr; 48: 90-102.

Lee PA, Houk CP, Ahmed SF, Hughes IA. Consensus Statement on Management of Intersex Disorders. Pediatrics. 2006 Aug; 118 (2): e488-e500.

InterACT Advocates for Intersex Youth. (2024, October 3). https://interactadvocates.org/

Sharpe, S. (2024, October 2). No one-size-fits all: Myths and misconceptions about PCOS. interACT. https://interactadvocates.org/no-one-size-fits-all-myths-and-misconceptions-about-pcos/

Chung WC, De Vries GJ, Swaab DF. Sexual differentiation of the bed nucleus of the stria terminalis in humans may extend into adulthood. J Neurosci. 2002;22:1027–1033.

Heylens G, De Cuypere G, Zucker KJ, et al. Gender identity disorder in twins: a review of the case report literature. J Sex Med. 2012;9: 751–757.