The Case of CAIS: Understanding the Complexity of Sex Reversal
Complete Androgen Insensitivity Syndrome is a complex developmental disorder and its details are often misunderstood. The biological phenomenon of sex reversal provides insight.
Illustration by Cynthia (@PTElephant).
There has been a lot of debate about how sex is defined and determined, particularly when it comes to two groups: transgender individuals who have undergone what is referred to as "bottom surgery", and individuals with disorders of sex development (DSD). While trans rights activists (TRAs) like to equate transgender individuals with those who have DSDs, they are far from being the same. However, the complexity of DSDs and how sex is determined has led to confusion by most, particularly those who are not in the fields of evolutionary biology or medicine.
It's time to clear up the confusion.
Sex determination and development
To understand the complexity of DSDs, we must first understand how sex is determined genetically and how the reproductive system develops for that vast majority of the population.
All humans go through a process called sexual differentiation, the process where the body develops the organs that make us either male or female. This process starts at approximately week 5-6 of development. Prior to this process, we all have undifferentiated anatomy, including a gonadal ridge, Wolffian ducts, Müllerian ducts, genital tubercle, urogenital folds, and labioscrotal folds.[1] These structures are bipotential, meaning that they can develop down two potential pathways.
Sex is an inherited trait, one that is regulated through many genes.[2] For the vast majority of the population, sex is determined by the combination of sex chromosomes. Normally, everyone receives one X chromosome from their mother and either an X or a Y chromosome from their father. The SRY gene on the Y chromosome is the primary gene that determines sex development. Those who get the SRY on the Y chromosome follow the male developmental pathway, and those who do not receive the Y chromosome follow the female developmental pathway.
What do I mean by pathway?
The process of sex development in humans is mutually antagonistic.[3] This means that differentiation of one sex trait automatically prevents the development of the opposite sex trait. This is why humans can only be either male or female. This is also called gonochorism, meaning that humans never change sex in their lifetime.[4]
The actual process of development of the human reproductive system involves a complex series of signals, each starting a cascade of interactions involving multiple genes and initiation of hormones prompting development of specific structures. But, at very specific points in development, the process reaches a fork in the road. One path leads to development of female structures, and the other leads to the development of male structures.[5]
In the (XY) male pathway the SRY gene signals for the development of testes. As the testes differentiate, they begin to produce testosterone. The testosterone signals to the Wolffian ducts to develop into the "upper" portions of the male reproductive system, such as the seminal vesicles and vas deferens. In addition, the testes begin producing anti-Müllerian hormone (AMH). This causes the Müllerian ducts to disintegrate, preventing female reproductive organs from developing. Then, testosterone is converted into dihydrotestosterone (DHT) and begins to influence the genital tubercle, urogenital folds, and labioscrotal folds to form into the scrotum and penis.
In the (XX) female pathway, the absence of the SRY allows for genes like WNT4 and FOXL2 to differentiate the gonadal ridge into ovaries.[6] Because ovaries develop and not testes, there is no testosterone or AMH being produced. As a result, the Wolffian ducts disintegrate and the Müllerian ducts begin to develop into the upper portion of the female reproductive system including fallopian tubes and uterus. Finally, in absence of testosterone, the genital tubercle, urogenital folds, and labioscrotal folds are molded into the lower female reproductive organs: vulva, labia, and vagina.[7]
What is special about CAIS?
Complete Androgen Insensitivity Syndrome (CAIS) is a type of DSD. More accurately, CAIS is a type of DSD called sex reversal. Sex reversal refers to a change in the sex developmental path, causing an embryo to develop sex characteristics opposite of what is expected from their sex chromosomes.[8]
How does this happen? Well, it's different for every condition, but let's take a deeper look at CAIS.
An individual with CAIS has XY chromosomes, which means they have the SRY gene. The SRY gene results in the development of testes just like it does in normal male development. This is where the problem happens. Individuals with CAIS are unable to use androgens like testosterone. This is the result of a mutation in the genes that develop androgen receptors.
The male pathway of development requires testosterone in order to continue, so now what happens in CAIS? During embryonic development, they take a detour down the female path of development.
While the testes of a person with CAIS do not function normally, in that they cannot produce any sperm cells, the testes still produce AMH, which means that the embryo’s Müllerian structures disintegrate. Without the ability to use testosterone, however, the Wolffian structures also disintegrate. Similarly, the lack of ability to utilize testosterone results in the development of female external genitalia.[9]
The result is an individual with internal testes, a vulva, labia, and vagina.
In addition, at puberty, the testosterone is converted into estrogen through a process called aromatization.[10] The estrogen then allows for female typical structures to develop, such as female typical fat distribution and normal female breast tissue.[11]
Are individuals with CAIS male or female?
The answer is complicated, even for the most educated in the field, and often depends on the level of analysis.
For evolutionary biologists, who base sex on reproductive role (universally defined by the gonad / gamete type and what genes can be passed on) the answer is male. This puts more importance on sex chromosomes and gonads as the major influences on sexual reproduction. Therefore, because their genetics triggered gonadal differentiation into testes, individuals with CAIS are male, and their developmental disorder resulted in a dead end for their lineage.
From a medical standpoint, are individuals with CAIS male?
In 2021, the Endocrine Society describes sex as being firstly defined by the gonad / gamete type, but when someone is not producing gametes, has no gonads, or a mismatch of sex characteristics, non-gonadal traits like the internal and external genitalia are used as the secondary definition. They explain that the development of the internal genital ducts (such as Müllerian or Wolffian structures) and the external genitalia (such as the vulva and penis) are tightly linked to gonadal function, and that these primary sex characteristics can be used as an operational definition. The paper then states:
For individuals that possess a combination of male- and female-typical characteristics, these clusters of traits are sufficient to classify most individuals as either biologically male or female.[12]
Where does that leave CAIS? As we saw in the development of a person with CAIS, they begin on a male pathway and then have to divert to the female developmental pathway. This leaves them with primarily female characteristics with the exception of internal testes.
In addition, individuals with CAIS are not diagnosed at birth. Instead, they are diagnosed when they fail to menstruate during puberty. This is because their external genitalia are unambiguously female.
In addition, as described by the Spanish Association of Pediatrics, individuals with CAIS are incapable of developing male sex characteristics beyond the internal gonadal tissue because of their inability to respond to androgens.[13] Thus, when it comes to medical consensus, individuals with CAIS are treated as female.
One of the most commonly debated points in defining the sex of a person with CAIS is that if not for the androgen insensitivity, these individuals would develop as normal, fertile males. Although this is true, it is not logical to define sex as what happened prior to the sex reversal.
Let's explain this in a different way. We have an individual who gets into an accident. As a result of the accident the person loses a leg. Medically we call this person an amputee. Prior to the accident, the person had no issues with their leg. Should we classify this person as having normal legs because they were normal prior to the accident? Or do we classify them as an amputee because the accident happened?
In the same way, should we consider a person with CAIS male because if not for the sex reversal, they would have developed as male? Or should we consider CAIS as female because the sex reversal happened?
Is sex reversal the same as changing sex?
No. The two processes are very different. Sex reversal is a change in the developmental path during sex development. This change can only take place during very specific and critical windows of gonadal and genital development in the embryonic stage of development. Once the structures have developed, these changes are set and cannot be changed.
On the other hand, changing sex is an adaptation of a very few and specific species that allows them to change sex to fit the reproductive needs of the group of organisms and to changes in environment. For instance, in clownfish, if there is an absence of females in a group then the most dominant male will undergo a change in gamete production switching from the production of sperm to the production ova. This happens to adults of a species, whereas sex reversal happens during embryonic development.
Aren't people with CAIS male just like transwomen?
No. Women with CAIS and transwomen have several key differences and should not be conflated:
Phenotype: at birth, transwomen are unambiguously male with normal male genitalia. Individuals with CAIS are born with unambiguously female genitalia.
Hormones and transition: Transwomen transition through exogenous (meaning it came from outside the body) hormones and/or surgery. These traits are not part of their natural development and are acquired traits, meaning they are not inherited traits. Women with CAIS do not transition, nor would they be able to be supplemented with male hormones because of their androgen insensitivity.
Fertility: Transwomen are fertile males, meaning that they can produce sperm and father children. The transition process can make a transwoman infertile, but this infertility is an acquired trait, not an inherited one. Women with CAIS are infertile.
Dysphoria: Transwomen have gender dysphoria that leads them to change their body to appear more female. Gender dysphoria is rare in women with CAIS.
Congenital conditions: A congenital condition is a condition that one has from birth. The vast majority of transwomen are born with no congenital conditions. CAIS, by definition, is a congenital condition.
It really comes down to this: a person with CAIS has a case of sex reversal, a very specific case of DSD. During development, they began on a male path of development and had to detour (or reverse) towards the female path of development. Women with CAIS are not the same as males with gender dysphoria (aka transwomen), nor is CAIS an example of changing sex.
Because of these reasons, a person with CAIS is functionally, for medical and practical purposes, considered to be female.
Sex development chart of CAIS. See all charts here.
We are 100% independently funded. If you like our work, consider making a donation.
[1] Rey, R., Josso, N., Racine, C. (2020). Sexual differentiation. In: Endotext. South Dartmouth, MDText, Inc.
[2] Eggers, S., Sinclair, A. (2012). Mammalian sex determination: insights from humans and mice. Chromosome Res, 20.
[3] Warr, N., et al. (2012). The molecular and cellular basis of gonadal sex reversal in mice and humans. WIREs Dev Bio, 1.
[4] Holub, A., Shackelford, T. (2021). Gonochorism. Encyclopedia of Animal Cognition and Behavior. Springer.
[5] Aatsha, P.A., Arbor, T.C., Krishan, K. (2022). Sexual development. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing.
[6] Biason-Lauber, A. (2012). WNT4, RSPO1, and FOXL2 in sex development. Seminars in Reproductive Medicine, 30(5).
[7] Rey, R., Josso, N., Racine, C. (2020).
[8] Weber, C. & Capel, B. (2018). Sex reversal. Current Biology, 28(21), R1234-R1236.
[9] Oakes, M., et al. (2008). Complete androgen insensitivity syndrome: a review. Journal of Pediatric and Adolescent Gynecology, 21(6).
[10] Hussain, A., Gilloteaux, J. (2020). The human testes: Estrogen and ageing outlooks. Translational Research in Anatomy, 20.
[11] Singh, S., Illyayeva, S. (2023). Androgen insensitivity syndrome. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing.
[12] Bhargava, A., et al. (2021). Considering sex as a biological variable in basic and clinical studies. Endocrine Reviews, 20(20).
[13] Guerrero-Fernández, J., et al. (2018). Management guidelines for disorders/different sex development (DSD). Anales de Pediatría, 89(5).
