Complete Androgen Insensitivity Syndrome (CAIS)

Difference of Sex Development (DSD) is a term used to describe many different conditions where the development of the body’s reproductive or sexual organs do not follow typical patterns. 

People with DSD conditions may have: 

• Differences in how their sexual and reproductive body parts have formed. 
• Variations in the hormones which are used for puberty and reproduction.  
• This includes how their hormones are made or how their hormone signals are received. 

These variations may, or may not, be related to differences in their genetics.   

Having a DSD condition may affect someone’s: 

• Puberty. 
• How they have sex. 
• Options to become a parent. 
• Wider physical and emotional health. 
• Having a DSD can feel less easy to talk about than other health conditions. 

Our team at University College London Hospital provide a specialist service to support people with Difference of Sex Development (DSD) conditions. Please see our welcome pack.  

People with CAIS have a difference in the DNA that codes for their Androgen Receptor gene and they have 46XY chromosomes.   

Understanding the science behind this can help some people feel better about living with CAIS.  

CAIS and a 46XY karyotype

DNA is the genetic blueprint for our bodies. Our DNA code is found in every cell of the body and sections of DNA (genes) provide the code for all the different parts of our bodies. 

DNA is organized into chromosomes which are paired.   

Typically, humans have 23 pairs of chromosomes: 46 chromosomes in total. One pair are referred to as the sex chromosomes (this is because they include a lot of DNA coding for the bodies sexual and reproductive organs).  

Sex chromosomes can be X or a Y chromosome. A ‘karyotype’ describes what someone’s chromosomes are. Usually, but not always, women will have 46XX karyotype and men will have 46XY karyotype.

However, some women will have an 46XY karyotype and some men 46XX (and there are further variations beyond these different karyotypes (e.g. 45X, 47XXY). 
 
The X chromosome is quite a bit bigger than the Y chromosome and includes DNA code for other important parts of the body beyond sex and reproductive system development. Therefore, everyone needs to have at least one X chromosome (so it’s not possible to have a 46YY karyotype).   

CAIS and Androgen Receptor gene

In CAIS, the DNA for the androgen receptor is coded differently.  

This means that body cells are unable to receive androgen hormone signals as the androgen receptors are not coded to receive androgen hormones.  

There are different ways that the androgen receptor gene can be coded. In some people their androgen receptors may be able to partially receive androgen receptor signals and will have a different DSD condition: Partial Androgen Insensitivity Syndrome (PAIS).  

The androgen receptor gene is located on the X chromosome. This means that CAIS only affects people if they have one X chromosome (‘X-linked recessive’). This means that CAIS is only seen with 46XY chromosomes - and is recognised as a 46XY DSD condition. 

People with this genetic difference who have a 46XX karyotype will not have CAIS. This is because they have another unaffected androgen receptor gene on their other X chromosome and their gonads developed into ovaries.   

They will be a carrier of the androgen receptor gene difference which means they could pass on this genetic variation to their children. 

Two out of every three people with CAIS will have received their Androgen Receptor gene difference from their mother, and in 1 out of 3 it will be a new change just in them. 

If you haven’t yet had a genetic test to look at your androgen receptor DNA your doctor will talk to you about the option of having this test at your appointments. 

CAIS and genetic testing

If you haven’t yet had a genetic test to look at your androgen receptor DNA the DSD team at UCLH will talk to you about the option of having this test at your appointments.   

Genetic testing can identify the type of genetic difference in the androgen receptor gene.  
 
This is helpful to: 

• Confirm a diagnosis of CAIS.   
• A small proportion of people may have a different type of DSD condition and genetic testing helps identify this. 
• Some people find having a confirmed genetic diagnosis helpful for understanding their CAIS.  
• It can allow family testing (but only if you give permission for this). Two in three people with CAIS will have received their Androgen Receptor gene difference from their mother, and this means that other members of their family may be affected. 

The UCLH DSD team can arrange this genetic test for you and will go through your results. You will have the option for onward referral to your local clinical genetics service for more detailed genetic counselling which would include the option for family testing.

Usually, adolescents and adults with CAIS will have blood tests which show very high levels of testosterone, but they will not have any of the effects of having high testosterone.   

Testosterone is a type of androgen hormone which is mainly made by the gonads.   

The gonads are the organs that develop into either ovaries or testes- this happens in early pregnancy. Gonad can also be used as a wider term to describe either ovaries or testes.   

The effects of testosterone include body and facial hair, change in the fat and muscle distribution in the body, a deeper voice, and vulva changes - specifically an increase in the size of someone’s clitoris. 

This means that someone with CAIS is not born with any of the body structures that need androgens to develop before birth (penis, scrotum and internal structures such as the prostate).  

People with CAIS will be born with a typically appearing vulva. This means that CAIS doesn’t tend to be recognised at birth unless there’s been a reason to check karyotype during pregnancy.  

Before birth the gonads also make a different type of hormone: AMH (anti-Mullerian Hormone). This is not an androgen and therefore its action is not affected by androgen resistance.   

AMH stops the development of the Mullerian ducts. The Mullerian ducts develop before birth into the uterus (womb) and upper vagina.  

This means that someone with CAIS will not have a uterus and so will not have periods or be able to carry a pregnancy.

Puberty is the hormone driven change our bodies and minds go through as we develop from children into adults.  

In CAIS puberty is expected to start at a typical age (from around 9 years of age). Hormone messages from the brain stimulate the gonads to turn on and start making hormones for puberty.   

In CAIS the gonads start making androgens. Usually, adolescents and adults with CAIS will have blood tests which show very high levels of testosterone. However, because of androgen resistance there aren’t any androgen changes seen. For example, there are no changes in body or facial hair, voice deepening, or increase in clitoral size.  

In CAIS as the cells are resistant to androgens the testosterone is instead changed into Oestrogen.   

Oestrogen is a different type of sex hormone to testosterone and is typically produced by ovaries.    

Blood tests will often have lower levels of oestrogen on blood tests because the conversion from to oestrogen happens at a cellular level (i.e., the testosterone travels in the blood and is then turned into oestrogen). 

This means that there will be puberty changes that happen because of oestrogen. 

Breast development is the most easily recognised of these changes. Other oestrogen puberty changes include changes in fat distribution with hips becoming wider. 

Most people with CAIS will be diagnosed as an adolescent when they do not start having periods as they do not have a uterus (womb).

The gonads in CAIS can be either inside in the pelvis (lower tummy) or in someone’s groin. Sometimes CAIS is recognised in younger children when the gonads in the groin are investigated as possible hernias.   

CAIS and gonadal risk

There is a risk of the gonads in people with CAIS becoming cancerous. Previously there were concerns that the risk of gonadal cancer in CAIS was very high with a recommendation to remove someone’s gonads as soon as possible. We know now that the risk of cancer in the gonads is lower than previously thought but as CAIS is a rare condition we don’t fully understand what the risk is.   

It’s recognised that the risk of gonadal cancer changes in childhood is rare and that puberty with someone’s own gonadal hormones is better than hormone treatment. 

Therefore it’s not generally recommended to remove the gonads for someone with CAIS until they have completed puberty.  

From adolescence the risk of pre-cancer changes in gonads with CAIS is felt to be around 5-10%. We don’t understand what proportion of these pre-cancers become invasive (malignant) cancers but it’s felt to be a small proportion.  

A malignant cancer would typically require chemotherapy treatment after surgery to remove the gonads. On the whole survival figures are high but because the condition is rare we don’t have much evidence to be sure about this risk.  

Some people with CAIS prefer to have their gonads removed to lower their cancer risk. This means that they would then need to have an operation to remove their gonads -‘gonadectomy’- and they would then need to use Hormone Replacement Treatment (HRT).  

If someone with CAIS chooses to have surgery to remove their gonads the type of operation will depend on the location of their gonads. If they are inside their pelvis (internal) then they would have a laparoscopic (key-hole) procedure. If they are in their groin then they would have surgery through small incisions either side.  

UCLH information on Laparoscopic gonadectomy 

UCLH information on Inguinal gonadectomy  

Some people with CAIS prefer to avoid or delay surgery and the need for HRT. This means that they will instead have follow-up with gonadal surveillance.    

We recognise that this isn’t an easy choice, and our team are here to support you with deciding that’s right for you.

Currently there are no tests that can help us identify pre-cancer changes in someone’s gonads. This means that generally scans and blood tests will only identify healthy appearing gonads or cancer of the gonads.  

At UCLH if someone with CAIS chooses to not have surgery to remove their gonads (gonadectomy) or delay this until they are older then we currently recommend annual MRI scans with blood tests.   

MRI stands for magnetic resonance imaging. It's a type of scan which uses magnets (rather than X-rays or ultrasound) to generate pictures of the inside of the body. You can find out more information about MRI scans here. 

We check bloods for tumour markers that can increase when there is cancer of the gonads (although these tests are also not reliably able to identify cancer).   

We will also monitor how well the gonads are functioning. We do this by checking hormone levels, bone density scans and checking in with how some is generally feeling.  

A bone density scan is a special type of X-ray (also called a DEXA scan). The scan uses low dose X-rays to see how dense (or strong) your bones are. The scan works by measuring how much of the X-ray beams pass through the bones. 

Hormone replacement treatment (HRT) is essential to keep someone healthy and well if they have had surgery to remove their gonads (gonadectomy). 

HRT helps support the bones, heart and brain’s health, as well as how someone feels in terms of energy levels, skin and hair health.  

Without these hormones they’ll be at increased future risk of osteoporosis (weak bones that can easily break) and heart disease. People with low oestrogen levels often describe brain fog (not being able to think clearly or concentrate), poor sleep, and hot flushes (where they suddenly feel very hot and sweaty).   

Typically after gonadectomy oestrogen HRT would be started. This can either be as a tablet taken daily, a gel applied daily, or a patch (which is like a plaster) changed twice weekly. 

The patch and gel are not associated with an increased risk of blood clots that can form in the legs and lungs (venous thromboembolism). Therefore, we recommend this option to people over the age of 45years old as the risk of blood clots increases with age.  

It can take some time to settle on a dose of oestrogen that suits after a gonadectomy.  
Some people with CAIS prefer to use testosterone with their oestrogen, or instead of oestrogen. Testosterone HRT comes in a gel.     

It can take some time with different hormone treatment combinations for someone to feel well, and themselves, with their HRT.

We check on how HRT is suiting that person by thinking about how they are feeling and checking their bones every 3-5 years with bone density scans.

HRT is recommended until someone is at least 50 years old. HRT products are mostly made for older people (over 50 years old) and therefore the information leaflet with HRT describes risks for this group. HRT use has not been found to raise the risk of breast cancer in people younger people (less than 50 years old).

As well as your HRT medications you can keep your bones healthy by having enough calcium in your diet, staying active (specifically with weight bearing exercise) and having enough Vitamin D. Your doctor will provide you with more detail about this during your appointments.

Usually people with CAIS will have a short vagina (this can be a few cm in length) or vaginal dimple (a small depression where the vaginal entrance would be).  

This means that CAIS can affect how someone can have sex; specifically, whether they can have vaginal sex.  

If you would like more information about your vaginal differences, then you have the option to be examined in clinic, but this is only if, and when, you choose to be examined.  

Vaginal dilation can be used to help increase the length of someone’s vagina to allow them the option of vaginal sex. It’s unusual for surgery to be needed.   

Vaginal dilatation describes where someone uses vaginal dilators to increase the length of their vagina. This is using vaginal dilators with them applying pressure on the vaginal dimple to gradually increase the length of their vagina.   

Not everyone wants to be able to have the option of having vaginal sex and there's no expectation that someone with CAIS should (or when they should) use vaginal dilators. 

Regardless of whether you want, or do not want, to have vaginal sex the UCLH team will support you with achieving a fulfilling sex and romantic life. 

There are few factors that can affect how long, or how ‘easy’ someone finds vaginal dilation: 

• The starting length of their vaginal dimple.  
• Their hormone status. 
• Their vulval skin health. 
• How busy they are. 
• Whether someone has a quiet, private space to perform vaginal dilation. 
• How someone feels about using vaginal dilators. 
• How they feel about having CAIS and how it affects them. 
• How they are feeling about things in life in general.  
• Whether someone is single, or a relationship can affect how someone finds vaginal dilation.  You do not need to be in (or starting) a relationship to be able to do vaginal dilatation. 

Our Clinical Nurse Specialist runs our dilatation service and will support you with how, when and if to start and continue with vaginal dilatation.   

For more information on vaginal dilatation please see the DSD families Top Tips for dilation.

Our psychology team can support you in thinking about what CAIS means to you and living with CAIS.

CAIS can be hard to understand (look at the size of this page!) and it can be a long and difficult journey to a getting a diagnosis.  

This support can vary between people and at different stages of their life.  

The psychology team can support you with: 

• How you feel about having CAIS.  
• Sharing information about your CAIS with other people. 
• Exploring your thoughts and feelings around having future romantic relationships. 
• Starting and continuing with vaginal dilatation. 
• Enjoying intimacy. 
• Exploring your options for managing the risk of gonadal cancer. 
• Exploring your thoughts, feelings, and options to become a parent. 

Our DSD psychology team can offer both short term individual therapy and support group sessions online. The psychology team see you in person or online.

If you want to link in with our psychology team ahead of your next clinic appointment you can contact our team via email (uclh.pag.queries@nhs.net).

Having CAIS means that there are different routes to become a parent.  

Someone with CAIS is born without a womb and therefore they cannot carry a pregnancy.  

Their gonads are not able to produce mature gametes (sex cells needed for pregnancy; sperm or eggs are gametes). There is currently not the technology to take gametes from someone with CAIS’s gonads and mature these into sperm that could be used for a pregnancy.  

This means that people with CAIS can currently become parents by either through adoption or surrogacy (this is where someone else carries an IVF pregnancy in their uterus (womb) and would need to involve a donor gamete).  

You can find more information about adoption here.  

You can find more information about surrogacy here. 

This video from Fertility Initiate Education shows how fertility treatments help different people become parents (this is not specific to CAIS).

During your appointments at the clinic, you may have your blood pressure recorded, as well as other markers of general health including your height and weight. If at any point you do not wish for this to be recorded, just let the nursing staff know in the clinic. 

We may also recommend blood tests at your appointment which can check for blood sugar levels (a test that you don’t need to fast for), lipid levels and other markers of general health, such as kidney and liver function tests. You will usually receive these results in your clinic letter, with an explanation of what they mean for you and your general health, as well as any specific requests that we may pass on to your GP.  

Someone with CAIS doesn’t need contraception as they are not able to fall pregnant. Barrier contraception (eg. Condoms) are still recommended to reduce the risk of sexually transmitted infections.

The UCLH team will write to your GP to request that the invitation for cervical screening (smear test) is not automatically sent out to you. Someone with CAIS doesn’t need this as they do not have a cervix (the opening of a womb into a vagina).

Our clinic is currently based in gynaecology outpatients. This is on the lower ground floor (one floor down from where you come in) in the Elizabeth Garrett Anderson Wing.    

You can access the clinic via the Elizabeth Garrett Anderson Wing main entrance on Grafton Way. There is both lift and stair access to the lower ground floor, and there is a reception team available to help direct you.

We hope that this has been helpful to read. It may have raised some questions and patients to our service can contact our team with these. 

Louise Perry Clinical Nurse Specialist 

Email: uclh.pag.queries@nhs.net 

Website: www.uclh.nhs.uk