Androgen+Insensitivity

Androgen Insensitivity Syndrome

(AIS)

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An outline What is AIS? Classification History of AIS What happens in AIS? Testing Treatment Psychological Issues

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What is AIS? Genetic condition where affected people have male chromosomes and male

gonads with complete or partial feminization of the external genitals An inherited X-linked recessive disease with a mutation in the Androgen

Receptor (AR) gene resulting in:Functioning Y sex chromosomeAbnormality on X sex chromosome

Types

CAIS (completely insensitive to AR gene)External female genitalia Lacking female internal organs

PAIS (partially sensitive-varying degrees)External genitalia appearance on a spectrum (male to female)

MAIS (mildly sensitive, rare)Impaired sperm development and/or impaired masculinization

Also called Testicular Feminization

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Androgen Insensitivity Visuals

Image 1 : A woman with an XY chromosome pattern but insensitivity to androgens

Image 2 : A newborn genetic male (46XY) with complete androgen insensitivity syndrome and female external genitalia

Image 1

Image 2

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Classification of AIS form Exists along continuum depending on degree of mutation in AR gene (Quigley

and French)

Grade 1: PAISMale genitals, infertile

Grade 2: PAISMale genitals but mildly ‘under-masculinized’

Grade 3: PAISMale genitals more severely ‘under-masculinized’

Grade 4: PAISAmbiguous genitals

Grade 5: PAISEssentially female genitalia, with enlarged clitoris

Grade 6: PAISFemale genitalia with pubic/underarm hair

Grade 7: CAISFemale genitalia with little to no pubic/underarm hair

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History Possibly first mentioned in the Talmud (400 BC) Speculation of whether Joan of Arc (1412) and Queen Elizabeth I

(1533-1603) had AIS First reported 1817

Steglehner described apparently normal woman with undescended testes

Dieffeneach (American geneticist) 1906Hereditary Pattern

Petterson and Bonnier 1937Concluded that affected persons are genetically male

Wilkins, 1957Found tissue unresponsiveness to androgens

Androgen receptor gene cloned and sequenced in 1988

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Statistics Affects 1 in 20,400 people

2/3 of cases inherited from mother1/3 of cases come from a spontaneous mutation in the egg

No effect on life expectancy

For a carrier woman, there is a 1 in 4 chance in each pregnancy that the child will have AIS and a 1 in 2 chance if the fetus is male

No racial differences

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Normal Sexual Development

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MALE Sex Chromosome = XY

Gonads = Testes

External Genitalia = Male

FEMALE Sex Chromosome = XX

Gonads = Ovaries

Normally chromosome sex determines gonad sex which determines phenotypic sex

WHAT HAPPENS IN AIS?

External Genitalia = Female

Androgen Receptor Gene AIS results from mutations in the androgen receptor gene,

located on the long arm of the X chromosome (Xq11-q12). The AR gene provides instructions to make the protein

called androgen receptor, which allows cells to respond to androgens, such as testosterone, and directs male sexual development.

Androgens also regulate hair growth and sex drive Mutations include complete or partial gene deletions, point

mutations and small insertions or deletions.

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The Process of Sexual Development In AIS the chromosome sex and gonad sex do not agree with the

phenotypic sex

Phenotypic sex results from secretions of hormones from the testicles

The two main hormones secreted from the testicles are testosterone and mullerian duct inhibitor

Testosterone is converted into dyhydrotestosteroneMullerian duct inhibitor suppresses the mullerian ducts and

prevents the development of internal female sex organs in males

Wolffian ducts help develop the rest of the internal male reproductive system and suppress the Mullerian ducts

Defective androgen receptors cause the wolffian ducts and genitals to be unable to respond to the androgens testosterone and dihydrotestosterone.

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AIS Fetus Development Each fetus has non-specific genitalia for the first 8 weeks after conception

When a Y-bearing sperm fertilizes an egg an XY embryo is produced and the male reproductive system begins to develop Normally the testes will develop first and the Mullerian ducts will be

suppressed and testosterone will be produced

Due to the inefficient AR gene cells do not respond to testosterone and female genitalia begin to form

The amount of external feminization depends on the severity of the androgen receptor defect CAIS: complete female external genitalia PAIS: partial female external genitalia MAIS: Mild female external genitalia, essentially male

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Testing for AIS Tests

During PregnancyChorionic Villus Sampling (9-12 weeks)Ultrasound and Amniocentesis (after 16 weeks)

After BirthPresence of XY Chromosomes

Buccal Mouth SmearBlood Test

Pelvic Ultrasound

Histological Examination of Testes

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Biochemical Testing for Carriers Tests

1960-70s: Skin biopsies-evaluate androgen binding capacity

Carries: 50% androgen binding Problem: some cases skipped because mutation did not

always take place in the binding region of the gene

1990s: DNA Testing blood or mouth cavity smears

Now: Measure length of base pair repeat region in first exon of

gene and compare it to a female relative’s repeat region to determine if they are a carrier

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Non-Biochemical Testing Maternal relatives affected by AIS

In an XX femaleDelayed puberty Reduced pubic-auxiliary hairAsymmetric pubic-auxiliary hairReduced bone density

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Treatments Surgery Orchidectomy or gonadectomy

Removal of the testes Vaginal lengthening Genital plastic surgery

Reconstructive surgery on the female genitalia if masculinization occurs

Phalloplasty Vaginoplasty

Pressure dilation Clitorectomy

DebateWhat age? Who decides?

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Treatments Hormone Replacement Therapy (HRT) Types

Female: EstrogenProgesterone (sometimes take to reduce risk of breast

or uterine cancer)postorchidectomy

Male: Testosterone and DHT

FormOral, transdermal, implant, injection, vaginally

Prevents osteoporosis (age 10 or 11)Body responds as if it is post-menopausal, thus body

density decreases and osteoporosis occurs

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Psychological Issues Medical Care Services (geneticist and a pediatric endocrinologist)

Criticisms Lack of emotional and psychological support

Family When to tell their children about their disorder Knowledge of if they are a carrier and if so guidance on whether

they should have children or not

Patients Therapy

Isolation Registration desk of a doctor’s office Group examination

Androgen Insensitivity Syndrome Support Group (AISSG)

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Thank You

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