Androgen Insensitivity Syndrome

by Benjamin Bunting BA(Hons) PGCert

ben bunting BA(Hons) PgCert Sport & Exercise Nutriton  Written by Ben Bunting: BA(Hons), PGCert. Sport & Exercise Nutrition. L2 Strength & Conditioning Coach.

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Androgen insensitivity syndrome (AIS) is a rare genetic condition that affects males. It is characterized by the feminization of male genitals and an overall female-like appearance in people who are genetically male.

In this article we shall cover the following points:

  • Hormone disruption
  • What's AIS?
  • Causes
  • Symptoms
  • Complications
  • Diagnosis
  • Similar diseases
  • Control and treatment of AIS
  • Conclusion

Hormonal Disruption

AIS occurs due to impaired sensitivity to the male sex hormones or androgens like testosterone and dihydrotestosterone (DHT).

Normal tissues do not respond to these hormones, and therefore their physical manifestation tends to be that of a female.

AIS is a debilitating disease causing a range of problems for males, including infertility, ambiguous and non-functional genitalia, and increases the risk of complications like cancer.

In this article, we will highlight some important facts about androgen insensitivity syndrome and go over its management.

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What is Androgen Sensitivity Syndrome (AIS)?

As we mentioned earlier, AIS is a genetic disorder, i.e., it is a manifestation of a condition within the DNA of a person.

The kids affected by this disorder are genetically male and have the male 46, XY karyotype.

This disease presents as feminization of the external genital at birth and abnormal presentation of secondary sexual characteristics during puberty (adolescence).

Patients may present with varying characteristics as AIS often occurs in three broad phenotypes (observable traits).1 These comprise:

  • Complete androgen insensitivity syndrome (CAIS) – external genitals appear to be completely female-like.
  • Partial androgen insensitivity syndrome (PAIS) – can present as predominantly female, predominantly male, or mixed (ambiguous) external genitalia.
  • Mild androgen sensitivity syndrome (MAIS) – external genitalia usually appear male-like.

Androgen insensitivity syndrome is a very rare condition. Several studies quote the prevalence as 2-5 cases per 100,000 births.

A 10-year study in the Netherlands showed a prevalence of 1 case in 99,000 births. CAIS and PAIS are considered to be equally prevalent, and MAIS is seen less frequently than the former variants. 1,2

What causes AIS?

Partial or complete androgen insensitivity syndrome results from a genetic mutation inherited as an X-linked recessive disease.

Both these conditions occur due to problems in the androgen receptor gene or AR gene.

This gene is present on the X chromosome, one of the sex chromosomes (the other one being Y).

Women express two X chromosomes in the genetic makeup, and males have X and Y chromosomes.2–4

Suppose you have a mutated AR gene on the X chromosome. In that case, the process of manufacturing the androgen receptors on your body tissues gets defected, leading to either completely dysfunctional or partially functional receptors.

In the case of complete androgen insensitivity (CAIS), the AR gene fails to produce any functional androgen receptors leading to a complete absence response to androgens (testosterone) and severe symptoms.

People with PAIS (partial AIS) have some less severe mutations in the AR gene leading to some partially functional androgen receptors and a less severe disease course.1

Recessive genes

Since the disease is X-lined recessive, you might want to know that males are more likely to inherit androgen insensitivity syndrome by default.

For recessive disorders, a person must inherit two copies of the defective genes, i.e., one from their father and one from their mother.

If you have the only defective gene (inherited from one parent), you will not have the disease, as the correctly functioning gene (from the other parent) will do the job correctly.

Since males can only have one X-chromosome, a defective copy on the X-chromosome leads to disease presentation.

On the other hand, females require two copies of defective X-linked genes since they have two X chromosomes.4

Simply put, there is a 50% chance for a male to inherit androgen sensitivity syndrome and a 25% chance for a female to inherit AIS from their parents.

In reality, females are primarily the disease carriers (i.e., they carry the faulty gene but don't have symptoms) and don't show the phenotypic characteristics as males do. However, they can pass it on to their off-springs.

Symptoms of AIS

Androgen Insensitivity Syndrome

As described earlier, AIS can present in various phenotypes.

Depending on the severity of the mutation in the AR gene, the clinical presentation of AIS varies considerably.

As it affects the male-born kids, let's look at how a male newborn might present.

Having complete androgen insensitivity syndrome (CAIS), the males may have:

  • They have female-like genitals or 'testicular feminization.
  • Absent OR rudimentary epididymis, vas deferens, ejaculatory ducts, and seminal vesicle. This structure makes up the route for the sperms from the testes to the penis and is required for fertility.
  • Undescended testes – testes may be in the abdomen, or inguinal canal (groin)
  • Absence of pubic hair and/or auxillary hair
  • Vagina without cervix and uterus
  • Absence of menstruation during puberty (primary amenorrhea)
  • Normal breast development
  • Female sexual identity and heterosexual

In kids having PAIS, the disease can be divided into ambiguous genitalia and predominantly male presentations. Patients with ambiguous-genital-type may have:

  • A small phallus (micropenis), <1 cm, along with female-like genitals
  • Bifid scrotum (divided testes)
  • Descended or undescended testes – undescended testes may be present in the abdomen or groin
  • Hypospadias – a condition in which there is an abnormally located urethra (not on the tip of the penis)
  • Gynecomastia – enlargement of the breast during adolescence (puberty)
  • Absent or scant pubic hair
  • Absent or scant facial and body hair

Lastly, mild androgen insensitivity syndrome in males usually presents as:

  • Defected spermatogenesis
  • Impaired pubertal virilization – leads to small-sized genitals during adolescence
  • Gynecomastia during adolescence.
  • Impotence may be present
  • Scant facial and body hair
  • Infertility1,5

Complications of AIS

Commonly presenting complications include:

  • Infertility
  • Psychological problems
  • Social issues
  • Testicular cancer6

Diagnosis of AIS

As you might have speculated, it is often difficult to diagnose kids with AIS. In fact, many kids often go undiagnosed until childhood or after puberty.

In males with complete AIS, their external genitalia 1,2appear as females, and they develop as females.

Most patients with CAIS grow as females and present with the complaint of the absence of menstruation. Occasionally, testes are felt as abnormal masses in the abdomen.

People with PAIS or MAIS are diagnosed earlier as they have mixed or ambiguous genitals along with both male and female physical traits.

Further testing for AIS includes:

  • Blood levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) – the aim is to rule out other possible diseases causing similar features, e.g., androgen deficiency.
  • Pelvic or abdominal ultrasound

To confirm the diagnosis of AIS, genetic testing is required. Firstly, the patient's karyotype is obtained to determine the presence of male or female genetic makeup (XY or XX).

Following that, the geneticist will test for the mutations of the AR gene present on the X-chromosome of the affected person.

Genetic testing might not be conclusive a few times, and in that case, an androgen binding assay can be utilized.

This assay used antibodies to detect the presence of androgen receptors in the body.

Presence of AR receptor abnormalities and the symptomatic picture, the doctor will then confirm the diagnosis of AIS and the subtype. 1,6

Diseases similar to AIS

Symptoms of androgen insensitivity syndrome-like genital feminization, ambiguous genitalia, and pubertal-onset disorders (amenorrhea) are shared among certain other diseases as well.

Principally, these disorders revolve around the biochemistry of testosterone or similar hormones, that is, the androgens.

The androgens include 5-alpha dihydrotestosterone (5-DHT), androstenedione, and dehydroepiandrosterone (DHEA).

To have the symptoms, you would either have low androgen levels, or the androgen receptors in your body are likely non-functional.

The most common condition having a similar clinical picture to AIS is congenital adrenal hyperplasia.

This disorder is characterized by enlargement of the adrenal gland (hyperplasia) due to the deficiency of one of the enzymes.

Apart from the testes, the adrenal glands produce androgens constantly. Reduced production of androgens from the adrenal glands leads to similar symptoms as AIS.

The enzyme most commonly causing this problem is 17-alpha hydroxylase.

Next up, we have the enzyme 5-alpha reductase.

This enzyme is very important for the normal development of males in utero (during pregnancy) and also for the proper onset of puberty.

5-alpha reductase acts on testosterone produced by the Leydig cells in the testes to 5-DHT, a hormone that is much more potent than testosterone.

5-DHT is essential for the normal development of external genitals and gonads (testes).

During puberty or adolescence, 5-DHT promotes secondary sexual characteristics, e.g., deepening of voice and beard and hair growth.7

Are there any ways to control or treat AIS?

Since AIS is caused by genetic mutations and is an inherited problem, there are currently no ways to control or prevent it.

If carrier parents (people carrying the defective gene but not showing symptoms) are genetically tested for the mutations, they can undergo genetic counseling before they decide to have a baby.

Treatment

As far the treatment is concerned, the goal is to enhance the health standard of the individual affected by AIS. The doctors usually supplement the kids with either male or female sex hormones, depending on the type of AIS.

For complete AIS (CAIS), the undescended testes are surgically removed before the onset of puberty, and these patients are supplemented with estrogen (female sex hormone).

Hormones

Estrogen helps them retain their female-sexual secondary characteristics, e.g., proper breast growth and over feminization of the body.

The removal of testes is done to prevent malignancies in the future, as undescended testes are prone to undergo malignant transformation.

Surgery

In some cases, surgery might be required to enhance the cosmetic features of the vagina or dilate the vagina. Behavioral support and genetic counseling for the patients and their families are also provided.

Coming to partial AIS (PAIS), the main target is to assign the gender. Children often have ambiguous genitalia and mixed secondary sexual characteristics.

After diagnosing the patient, parents and the healthcare team work together and provide an informed consent about the gender assignment.

Subsequently, the child may go through reconstructive surgery with additional hormonal supplementation to maintain and develop the specific traits of either a male or female.

This decision often requires time and consultation, and gender assigning can be done at birth or after puberty.

Like CAIS, undescended testes warrant a surgical removal as there is a considerable risk of developing testicular cancer if the testes remain undescended.

Behavioral support and genetic counseling for the patients and their families are also provided.1–3

Lastly, males with mild androgen insensitivity syndrome (MAIS) require symptomatic treatment to correct the abnormal secondary sexual characteristics and improve virilization.

Genital reconstructive surgeries might be recommended along with breast procedures.

Moreover, androgen hormone replacement therapy is offered in an attempt to increase virilization (growth of male genitals). Genetic counseling and behavioral support are also offered frequently.

Conclusion

Androgen insensitivity syndrome is a genetic disorder that causes genetically male kids to have female-like genitals and/or appearance (feminization).

A defect in the androgen receptor causes the insensitivity, i.e., despite having adequate amounts of testosterone (androgen), the body tissues produce no response to it.

This disorder is inherited as X-linked recessive, leading to males being affected and females being carriers of the disease.

AIS presents in different forms depending on the severity of the mutation and functionality of the receptors.

Symptoms include genital feminization, ambiguous genitals at birth, and female-like characteristics (breast enlargement) during puberty.

Finally, treatment options available for AIS patients include gender assigning, reconstructive surgeries, hormone replacement therapy, and genetic counseling.

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References:

  1. Gottlieb B, Trifiro MA. Androgen Insensitivity Syndrome. GeneReviews®. Published online May 11, 2017. Accessed April 15, 2022. https://www.ncbi.nlm.nih.gov/books/NBK1429/
  2. Rare Disease Database. Partial Androgen Insensitivity Syndrome - NORD (National Organization for Rare Disorders). Accessed April 15, 2022. https://rarediseases.org/rare-diseases/androgen-insensitivity-syndrome-partial/
  3. What is complete androgen insensitivity syndrome (CAIS)? - ISSM. Accessed April 15, 2022. https://www.issm.info/sexual-health-qa/what-is-complete-androgen-insensitivity-syndrome-cais
  4. X-linked Recessive: Red-Green Color Blindness, Hemophilia A | Children’s Hospital of Philadelphia. Accessed April 15, 2022. https://www.chop.edu/conditions-diseases/x-linked-recessive-red-green-color-blindness-hemophilia
  5. Douglas G, Axelrad ME, Brandt ML, et al. Consensus in Guidelines for Evaluation of DSD by the Texas Children’s Hospital Multidisciplinary Gender Medicine Team. International Journal of Pediatric Endocrinology. 2010;2010:1-17. doi:10.1155/2010/919707
  6. Androgen insensitivity syndrome: MedlinePlus Medical Encyclopedia. Accessed April 15, 2022. https://medlineplus.gov/ency/article/001180.htm
  7. Halpern JA, Brannigan RE. Testosterone Deficiency. JAMA. 2019;322(11):1116-1116. doi:10.1001/JAMA.2019.9290