Complete, mild, or partial androgen insensitivity syndrome (CAIS, MAIS, PAIS)

Complete androgen insensitivity syndrome (CAIS) is a condition whereby cells are unable to respond to androgens (testosterone). Genital tissue that would ordinarily become masculinised through the action of testosterone in a developing 46, XY foetus remains the default feminine. ^​1​

Additionally, at puberty, secondary male characteristics (pubic hair, voice drop, genital growth, etc.) do not occur.

People with CAIS are genetically male – 46, XY (instead of 46, XX) – but in every other way, they are female. 

When an egg is fertilised, the sperm determines the gender of the child, so this is already decided by the time we start growing in the womb. All babies are by default female.

CAIS is an interruption in the growing process when the foetus would ordinarily be changing from the default girl into a boy. What you end up with in CAIS, for all intents and purposes, is a woman.

Women who have 46, XY chromosomes are almost always heterosexual with female gender identity. It is not thought to be related to transgenderism, though it is an understudied population.

The other variants of CAIS – partial or mild androgen insensitivity (PAIS and MAIS) – can result in variations in bodies, including the full spectrum of genital appearance. CAIS, MAIS and PAIS affect genital appearance only.

Terms to know when talking CAIS

46, XY – genetic male

46, XX – genetic female

DSD – Differences in Sexual Development

Phenotypical – characteristics of, in this case, body shape, voice, and general body features CAIS can occur in genetic females (46, XX), but the genitals and sexual development are not significantly affected, since genetic females don’t have the same androgen dependency.

The incidence of CAIS is not known, but one estimate puts it at one in every 20,400 live 46, XY births. That is, one in every 20,400 genetically male live births. This process occurs due to the SRY gene’s influence on the Y chromosome.

Types of androgen insensitivity syndrome

There are three types of androgen insensitivity syndrome that are split up depending on the degree of genital masculinisation. AIS is the largest single cause leading to 46,XY under-masculinisation.

1. Complete androgen insensitivity syndrome (CAIS) – external genitalia is that of a typical female, with no signs of masculinity
2. Mild androgen insensitivity syndrome (MAIS) – external genitalia is that of a typical male
3. Partial androgen insensitivity syndrome (PAIS) – external genitalia is partially, but not fully, masculinised, including male appearance, but small penis, micropenis, large clitoris, and other flesh development differences

Diagnosis of CAIS

CAIS is not suspected unless periods don’t arrive, or an inguinal hernia (a hernia in the soft large V space that surrounds the pubic mound) presents itself prior to puberty.^​2,3​

Up to two per cent of girls with inguinal hernias have CAIS. CAIS can be diagnosed in utero using a karyotype from the foetus and comparing it to the external genitalia of the foetus during a prenatal ultrasound.

CAIS – what it looks like in real life

These genetic males are born as a 46,XY karyotype, but appear completely female. Symptoms do not appear until puberty, which could be somewhat delayed, though appear quite typical except for the conspicuous absence of menstrual periods (primary amenorrhoea).^​4​

This means girls don’t find out until they are between 15 and 18 years old – a confusing time to find out you should have, technically, been a boy. Pubic hair may also be less or absent.

A third of all people with CAIS do not develop armpit hair. The labia and clitoris can be somewhat underdeveloped. Vaginal depth is variable, and generally appears typical, but could be on the short side.^​5​

These women do not have ovaries, uterus, fallopian tubes or a cervix, but testes, since the testes do not need androgens to develop. This means that no eggs exist, and therefore biological children are an impossibility.

The fallopian tubes, uterus and the upper portion of the vagina (the Müllerian system) most often regress due to a hormone that stems from the testes, anti-Müllerian hormone (from the Sertoli cells).^​6​ This means those affected by CAIS most often do not have fallopian tubes, a cervix, or a uterus, and the vagina ends in a sort of pouch that goes nowhere.

Sometimes this process does not complete (in a third of cases), and there will be remnants of these organs. From time to time, a person with fully developed Müllerian structures is reported. Each case is reasonably unique in this respect. 

The testes are often found in different locations, which could spark the discovery of this condition. Testes found in affected people are found to be atrophic (wasting away) once removed.^​7​

The testosterone produced by these testes isn’t able to be utilised directly, since the mutant androgen receptor that caused the condition in the first place is a characteristic of this state, and isn’t usable to a great degree.

Instead, the testosterone is converted into oestrogen, causing the feminisation of the body and resulting in the typical female appearance.^​8​

The testes produce immature sperm, however, they don’t get an opportunity to mature – spermatogenesis relies on androgens.

The epididymides, vas deferens and seminal vesicles don’t exist, but in 30 per cent of cases, these structures can partially develop. This development depends on the mutant causing the CAIS.

The prostate never develops and remains in the female form (Skene’s glands).

The whole body is affected by CAIS and here’s how

Other differences in people with CAIS are slightly longer limbs, and larger hands, feet, and teeth, due to greater stature than those unaffected. People with CAIS usually never suffer from acne (often caused by androgens), have well-developed breasts, and more dysfunction of moisture-producing glands (meibomian gland) – dry eyes, light sensitivity, etc.

Tissues throughout the body are affected, including the bones. Bone mineral density can decrease, with some suggesting the late timing of the gonadectomy (removal of the testes) and a lack of oestrogen supplementation are the culprit, however recent research has not supported this. New hypotheses suggest that androgens play more of a role in bone mineralisation than previously thought.^​9​

CAIS is associated with increased gonadal tumours if the testes are left in the body. This risk increases with age – 33 per cent at age 50, compared with just 3.6 per cent at age 25.^​10​

Childhood gonadal tumour incidence is low. Longevity is not thought to be associated with CAIS, meaning anyone with CAIS, PAIS or MAIS can expect to live a long and healthy life, all other things being equal.

Fertility outcomes in CAIS

Most people with CAIS are infertile, however in mild and partial forms, this isn’t always true.^​11,12​

Psychological outcomes in CAIS

CAIS is associated with psychological difficulties, at least partially due to parents not understanding how to manage their child’s very particular situation.^​13​

Long-term counselling for parents and kids is recommended. It can be really challenging to find out that you aren’t ‘normal’, you may never have your own biological children, ‘ordinary’ sex may be difficult, and that your genitals (and insides) may look different to everyone else’s.

Feelings are intense, and the grieving process must be respected. Acceptance is the goal, and learning self-love is critical, and while easy to say and not easy to do, counselling can help to redirect your mental and emotional energies into things that help you feel good.

Support is critical, and there are forums and forums full of people with CAIS, PAIS and MAIS. Find them. Dance.

What else could it be?

Swyer syndrome or Müllerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome or MRKH) may be suspected. CAIS and Swyer syndrome are both associated with the same 46, XY karyotype, so it is easy enough to rule out MRKH. MRKH means a genetic female who looks like a genetic female.

Management strategies for CAIS outcomes

Management is the only real option, and that means controlling any negative symptoms. Management may include sex assignment, genitoplasty, gonadectomy, hormone replacement therapy, vaginal dilation, and genetic and psychological counselling.

Gender assignment and identification in CAIS

People with CAIS are raised as girls – they almost always have a heterosexual female gender identity, and the incidence of homosexuality in those with CAIS is understood to be less than in women without CAIS. Rarely, male gender identity has been reported.

Splitting the concept of gender and sex is critical – sex is usually about physical attributes, whereas gender is based on our self-concept and identification, and the role we play in our lives.^​14​

There are currently no predictors of someone’s eventual gender identity, with PAIS being more complex for gender identity than the CAIS or MAIS.

Sexual activity for people with CAIS

An improperly formed or shallow vagina (vaginal hypoplasia) or a missing vagina (vaginal agenesis) is common, and can cause painful sexual problems (dyspareunia) and issues with penetration.^​15​

Dilation can be used to help stretch out the vaginal tissue even in the most severe cases. Dilation can be uncomfortable or painful so compliance is an issue.

Typically the Vecchietti procedure has been used, but new, less invasive techniques are now more popular. Dilation should not be used prior to puberty.

Hormone replacement therapies in CAIS

Androgen replacement has been found to increase a sense of wellbeing in women who have had their testes removed, and women taking oestrogen therapies experience less bone loss.^​16​

The neovagina in CAIS

A neovagina is an imperfect surgical procedure using skin grafts, a segment of bowel, and other tissues to create a vagina for sexual function. It is a big operation, but is of late becoming more and more successful and satisfying.

Psychological challenges of CAIS

The psychological consequences can be hefty, since infertility and sexual problems can be heavy burdens to carry. With solid psychological and physical support, however, people with CAIS can be perfectly content.^​17​

References

1. 1.

   Tyutyusheva N, Mancini I, Baroncelli GI, et al. Complete Androgen Insensitivity Syndrome: From Bench to Bed. IJMS. Published online January 27, 2021:1264. doi:10.3390/ijms22031264
2. 2.

   Guo M, Huang JC, Li CF, Liu YY. Complete androgen insensitivity syndrome: a case report and literature review. J Int Med Res. Published online February 2023:030006052311544. doi:10.1177/03000605231154413
3. 3.

   Fulare S, Deshmukh S, Gupta J. Androgen Insensitivity Syndrome: A rare genetic disorder. International Journal of Surgery Case Reports. Published online 2020:371-373. doi:10.1016/j.ijscr.2020.01.032
4. 4.

   Farah S, El Masri D, Hirbli K. Complete androgen insensitivity syndrome in a 13-year-old Lebanese child, reared as female, with bilateral inguinal hernia: a case report. J Med Case Reports. Published online April 17, 2021. doi:10.1186/s13256-021-02738-0
5. 5.

   Lanciotti L, Cofini M, Leonardi A, Bertozzi M, Penta L, Esposito S. Different Clinical Presentations and Management in Complete Androgen Insensitivity Syndrome (CAIS). IJERPH. Published online April 9, 2019:1268. doi:10.3390/ijerph16071268
6. 6.

   Rasheed MW, Idowu NA, Adekunle AA, et al. Complete androgen insensitivity syndrome with Sertoli cell tumour in a 27-year-old married woman: a case report. Afr J Urol. Published online May 9, 2023. doi:10.1186/s12301-023-00358-2
7. 7.

   Souhail R, Amine S, Nadia A, et al. Complete androgen insensitivity syndrome or testicular feminization: review of literature based on a case report. Pan Afr Med J. Published online 2016. doi:10.11604/pamj.2016.25.199.10758
8. 8.

   Hughes IA, Davies JD, Bunch TI, Pasterski V, Mastroyannopoulou K, MacDougall J. Androgen insensitivity syndrome. The Lancet. Published online October 2012:1419-1428. doi:10.1016/s0140-6736(12)60071-3
9. 9.

   Bauer EM, Hoang TD. Complete Androgen Insensitivity and Decreased Bone Mineral Density. Journal of the Endocrine Society. Published online May 1, 2021:A778-A779. doi:10.1210/jendso/bvab048.1584
10. 10.

    Barros BA, Oliveira LR de, Surur CRC, Barros-Filho A de A, Maciel-Guerra AT, Guerra-Junior G. Complete androgen insensitivity syndrome and risk of gonadal malignancy: systematic review. Ann Pediatr Endocrinol Metab. Published online March 31, 2021:19-23. doi:10.6065/apem.2040170.085
11. 11.

    Hiort O, Holterhus P ‐M. Androgen insensitivity and male infertility¹. Int J of Andrology. Published online January 10, 2003:16-20. doi:10.1046/j.1365-2605.2003.00369.x
12. 12.

    Giwercman A, Kledal T, Schwartz M, et al. Preserved Male Fertility Despite Decreased Androgen Sensitivity Caused by a Mutation in the Ligand-Binding Domain of the Androgen Receptor Gene1. The Journal of Clinical Endocrinology & Metabolism. Published online June 1, 2000:2253-2259. doi:10.1210/jcem.85.6.6626
13. 13.

    Wisniewski AB, Migeon CJ, Meyer-Bahlburg HFL, et al. Complete Androgen Insensitivity Syndrome: Long-Term Medical, Surgical, and Psychosexual Outcome¹. The Journal of Clinical Endocrinology & Metabolism. Published online August 2000:2664-2669. doi:10.1210/jcem.85.8.6742
14. 14.

    Hou L, Zhao M, Fan L, et al. One hundred twelve cases of 46, XY DSD patients after initial gender assignment: a short-term survey of gender role and gender dysphoria. Orphanet J Rare Dis. Published online October 9, 2021. doi:10.1186/s13023-021-02039-1
15. 15.

    Minto CL, Liao KLM, Conway GS, Creighton SM. Sexual function in women with complete androgen insensitivity syndrome. Fertility and Sterility. Published online July 2003:157-164. doi:10.1016/s0015-0282(03)00501-6
16. 16.

    Ko JKY, King TFJ, Williams L, Creighton SM, Conway GS. Hormone replacement treatment choices in complete androgen insensitivity syndrome: an audit of an adult clinic. Endocrine Connections. Published online August 2017:375-379. doi:10.1530/ec-17-0083
17. 17.

    Engberg H, Strandqvist A, Nordenström A, et al. Increased psychiatric morbidity in women with complete androgen insensitivity syndrome or complete gonadal dysgenesis. Journal of Psychosomatic Research. Published online October 2017:122-127. doi:10.1016/j.jpsychores.2017.08.009