I’ve just described XY Complete Androgen Insensitivity Syndrome, or CAIS, a genetic condition in which there is a defect in the androgen (testosterone) receptor gene – located, ironically, on the X-chromosome.*
Describing CAIS
XY (genetically male) individuals with CAIS have gonads (testes) that manufacture testosterone, but their body’s cells cannot see the testosterone. As a result, their internal and external genitalia develop as female, but the vagina is shortened and smaller than normal. The testes are either located in the groin or in the abdomen.
At puberty, individuals with AIS develop breasts due to the body’s conversion of testosterone to estrogen. Pubic and underarm hair is scant, since this hair growth requires androgen receptors. With dilation of the vagina, AIS individuals can have sexual intercourse, but they cannot bear children.
As to gender identity, although CAIS individuals are viewed as female and until now, treated that way, it may not be as simple as that. (Huge “Duh” from the AIS community on this one, I’m sure…) Some interesting brain imaging studies do suggest the brain sexual response in CAIS aligns to female, not male. But gender identity is too individual an issue to address here. It could be linked to specific gene defects, and I suspect will be teased out over time as the medical community wakes up to the psycho-sexual needs of this community.
One way in which we are already waking up is in how we are managing the risks of cancer of the gonads in individuals with CAIS.
Cancer Risks in the Gonads of XY individuals with CAIS
Until recently, based mostly on case reports and anecdotal evidence, it had been accepted that there was an increased risk of cancer in the testes of individuals with AIS – a risk as high as 22% in one early published series. Therefore, for many years, one of the tenets of caring for individuals with AIS has been removal of the gonads in childhood, followed by the induction of puberty with estrogen and lifelong estrogen replacement therapy.
All of this has changed over the past few decades. A growing scientific literature finds that the actual incidence of gonadal cancers in CAIS is as low as 5 to 10%, with few to no malignancies prior to puberty. This led to the current standard of care for AIS, which is to delay gonad removal till after puberty is complete – usually between ages 16-18. This allows for a smooth, natural pubertal transition (nature always does it better than pharma), and for the more mature patient to be involved in management decisions going forward.
Rethinking Gonad Removal for Cancer Prevention
Now, the needle is shifting even further, as genetic sequencing allows us to stratify cancer risks in individuals with AIS according to their genetic defect. For those with complete androgen insensitivity, at lowest risk of cancer, the chance of retaining the gonads indefinitely is now being considered, along with various surveillance regimens to help catch cancer if and when it develops in the retained gonads. Proposed surveillance options include gonad biopsy, ultrasound and serum tumor markers in individuals whose testes can be easily seen on sonogram. For those whose gonads are hard to image, laparoscopic surgery called gonadopexy can move the testes closer to the abdominal wall to allow for biopsy and sonographic surveillance.
(Note that this option of surveillance is only appropriate for those with CAIS. Individuals with Partial Androgen Insensitivity Syndrome or PAIS have a cancer risk as high as 50%. For these individuals, standard of care is to remove the testes, usually before puberty.)
We don’t know yet just what, if any, advantage there is in retaining the gonads past puberty in CAIS, other than the obvious one of avoiding surgery and hormone replacement therapy. Proposed gonadal surveillance strategies have not yet been tested prospectively, and ideally would be done in an IRB-approved clinical trial, which may not be randomized for ethical reasons, but could certainly be matched to individuals choosing to have their gonads removed at puberty.
Paramount to moving forward on any path towards surveillance, research or otherwise, is a well-informed patient. The good news on that front is that there is a lot of information out there now for patients and their families to help them learn about and participate in management decisions around CAIS. And as we move forward, let’s never forget – Prima non nocere.
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SUGGESTED READING
Patel V, Kastl Casey R, Gomez-Lobo, V. Timing of Gonadectomy in Patients with Complete Androgen Insensitivity Syndrome – Current Recommendations and Future Directions, J Pediatr Adol Gynecology 29 (2016) 320-325. This blog post was written in response to this well-written state of the art mini-review and its accompanying editorial by Joseph Sanfilippo, MD.
RESOURCES FOR AIS INDIVIDUALS AND THOSE WHO LOVE THEM
- AIS Support Group
- ACCORD Alliance – support for parents of children with disorders of sexual development
*Note – there are XX individuals with CAIS who carry a gene defect of the androgen receptor on both X chromosomes. These individuals are genetically female and develop as a female, but are minimally affected, though they may be tall, have scant pubic and underarm hair and delayed puberty. This blog post is not about them.
