The term ‘gender’ can be subjective. It is often seen as a social construct that each individual has their own interpretation of, or connotations that they associate with it. For the scientific community, gender is usually associated with one’s sex and therefore the presence of X and Y chromosomes. However, XX and XY chromosomes are not that simple. There are cases where neither sex organs nor the presence of sex chromosomes dictate sex.
Intersex individuals are born with sex characteristics that do not fit the binary notions of male or female. Due to these differences, intersex individuals are often stigmatised and subjected to multiple human rights violations. Unfortunately, there are few countries that protect the intersex community from discrimination.
People often argue that if you are genetically XX or XY then that’s what your gender is. However, intersex individuals have genetics that do not fit this paradigm. In this blog we delve into the genetics of intersex traits, and also explore some of the social and ethical issues that exist and will continue to arise as societal awareness increases.
Intersex individuals were previously referred to as hermaphrodites. Then, in 1917, Richard Goldschmidt created the term ‘intersexuality’ to refer to a variety of physical sex ambiguities. In the clinical setting, the term ‘disorders of sex development’ (DSD) has been used since 2006. However, this shift has caused some controversy.
Generally, intersex is considered an umbrella term for differences in sex traits or reproductive anatomy. There can be many differences, including genitalia, hormone, internal anatomy or chromosome. Estimates indicate that 1.7% of the population are born with intersex traits, which is comparable to the number of people born with red hair. While some intersex traits are noticed at birth, others do not appear until puberty or later life.
Some people with intersex traits self-identify as intersex, while others do not. A study, published in 2016, found that 60% of respondents used the term ‘intersex’ to self-describe their sex characteristics. Most participants (75%) also self-described as male or female. However, a study conducted this year found that 43% of participants thought the term intersex was bad. In fact, most participants preferred terms that were specific to their somatic condition. It is therefore essential that further research and clinician evaluation for patient preference is considered.
The biological differences between men and women result from two processes: sex determination and differentiation. Variation in these processes can result in intersexuality. In other words, there is a range of chromosome complement, hormone balance and phenotypic variations that can determine an individual’s sex. Here, we explore some of these variations and their genetic basis.
Sex chromosomes aneuploidies
More than 95% of the Y chromosome is male-specific. The Y chromosome acts as a dominant inducer of male phenotype. When a Y chromosome is present, early embryonic testes develop around the tenth week of pregnancy. When the Y chromosome and testis-determining factor are absent, ovaries develop. There are several conditions where sex chromosome copy number is altered.
Klinefelter Syndrome (47XXY or XY/XXY mosaic) with male phenotype is the most prevalent sex chromosome anomaly. It was first identified by Harry Klinefelter in the 1940s. It affects approximately 1:600 males. Males carry two or more X chromosomes, which results in abnormal development of the testes. This leads to hypogonadism and infertility. The testes are small and quite firm. While those born with Klinefelter usually develop male genitals at puberty, these individuals may not virilise very strongly. Individuals also produce relatively small amounts of testosterone, impacting development of secondary male sex characteristics. If requested, doctors can prescribe testosterone to help virilisation.
Turner Syndrome (45X or 45X0), also known as monosomy X, was first described by Henry Turner in 1938. It occurs in individuals that inherit one X chromosome and are phenotypically female. It has a live-birth frequency of 1:3000. Individuals with Turner Syndrome usually have female sex characteristics, but they are underdeveloped. They experience abnormal growth patterns, are short in stature, generally lack prominent female secondary sexual characteristics and are also sterile. Hormonal therapy can be given to help individuals develop menstrual periods and breasts. Modern reproductive technologies can also be used to help women become pregnant if they desire.
Other chromosomal abnormalities
Women with three X chromosomes (47XXX) experience normal development of sexual traits and are fertile. Individuals are typically taller and have slender builds. The frequency of women obtaining an extra X chromosome is approximately 1:1000. There are no known severe phenotypes associated with having three X chromosomes.
Men who inherit an additional Y chromosome (47XYY) are usually taller and are prone to acne because they produce higher levels of testosterone. Affected males are generally fertile and mostly unaware that they have a chromosomal abnormality. The frequency of men obtaining an extra Y chromosome is approximately 1:1000.
There are several inherited conditions that can impact hormone balance and therefore sex determination and differentiation processes.
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia (CAH) is a group of inherited autosomal recessive conditions that can affect both sexes. They are characterised by impaired cortisol synthesis due to the deficiency of a key enzyme required for cortisol synthesis in the adrenal cortex. Each form of CAH is associated with a specific defective gene. The most common type (95% of cases) involves the gene for 21-hydroxylase. Deficiency of this enzyme results in incomplete female sex differentiation and increased androgenic effects. The disorder occurs with a frequency of 1:5000. Children with CAH need to take replacement cortisol and aldosterone daily for the rest of their lives.
Androgen insensitivity syndrome
Androgen insensitivity syndrome (AIS) is an X-linked recessive disorder. Affected individuals have external female genitalia and breast development despite being genetically male (46XY). It results in the partial or complete inability of cells to respond to androgen. Moreover, it can be divided into three categories: complete, mild or partial AIS – CAIS, MAIS and PAIS, respectively. It is caused by mutations in the gene encoding human androgen receptor and is currently limited to symptomatic management. CAIS affects 2 to 5 per 100,000 people who are genetically male. PAIS is thought to be less common.
5-Alpha Reductase Deficiency
5-Alpha Reductase Deficiency is an autosomal recessive condition that impacts genetically male (46XY) individuals. It is caused by mutations in SRD5A2, a gene encoding the enzyme 5-Alpha reductase type 2. As a result, individuals do not produce enough of a hormone called dihydrotestosterone (DHT) which is critical in male sexual development. Deficiency of this hormone impacts virilisation and leads to external genitalia that appear phenotypically between male and female. While the exact incidence of this condition is unknown, large families with affected members have been found in several countries, including Papua New Guinea and Egypt.
Intersex in society
Sex assignment to individuals with intersex traits usually aligns with a child’s anatomical sex and phenotype. Some intersex individuals are assigned and then raised male or female but identify as another gender later in life, while most continue to identify with their assigned sex. An ongoing issue is the performance of early surgical or medical interventions made on an individual’s behalf by their parents.
In 2011, Christiane Völling became the first intersex individual to sue for damages in a case brought for non-consensual surgical intervention. Völling was born in 1959 with XX sex chromosomes yet had ambiguous genitalia and therefore was assigned and raised male. During an appendectomy when she was 14, she was informed of the presence of female organs. At age 18, her reproductive organs were removed. Völling continued to live as a man for some time but later transitioned to live as a woman. In 2006, Völling obtained her medical records and discovered the concealment of her chromosomal diagnosis, and the nature of her surgery in 1977. She later argued that she was unable to consent fully to her surgery in 1977 and was later awarded €100,000 by the Regional Court of Cologne.
Timing, individual choice and surgical irreversibility remain topics of concern, with no consensual attitude regarding this. Unfortunately, there is still an unclear standard of care and broad disagreement among practitioners concerning the human rights of their patients. While certain surgical interventions are medically necessary, some surgeries continue to be performed that are unnecessary and potentially considered more cosmetic. Most importantly, some of these procedures can also be sterilising. These procedures not only have physical consequences but can also result in long-term psychological effects. In 2015, Malta became the first country to outlaw non-consensual medical intervention to modify sex anatomy. Interestingly, according to the The Times, NHS England have also drafted proposals that will prevent genital or gonadal surgery being performed until children are able to consent for themselves.
Other societal issues
Intersex individuals often experience prejudice and discrimination because their bodies do not conform to sex and gender stereotypes. In some countries, individuals with visible intersex traits are subject to abandonment and violence. Intersex infanticide remains a major problem in southern and eastern Africa, South Asia, Brazil and China. Unfortunately, some individuals have had their intersex status deliberately withheld from them. Not only this, intersex individuals also face discrimination at school, work or within the community. As a result, intersex people are often reluctant to seek care.
Controversy recently hit when two-time Olympic 800m gold medal winner Caster Semenya lost her appeal to Switzerland’s Federal Supreme Court against the restriction of testosterone levels in female runners. This meant Semenya was denied the opportunity to defend her title at the Tokyo 2020 Olympics. Semenya is an intersex cisgender woman, assigned female at birth. She is genetically XY but has elevated testosterone levels due to a 5-Alpha reductase deficiency. This instance has catalysed important conversations and debate that is likely to grow in the coming years, particularly as notions of gender continue to change.
Gender is the subject of a lot of debate and reform. The construct is not only important on a societal level but also on a scientific one. As a genetics community, it is our responsibility to research intersex traits and educate the public to raise awareness and end stigmatisation. We must work with intersex communities to ensure that their voices are heard and reflected within medical practice.
Life is complex and so are our genetics. We must acknowledge our differences and ensure every life is valued equally.
Image credit: By itakdalee – canva.com