Androgen Insensitivity Syndrome

Lynae M. Brayboy
Learning Objectives

• You will review complete and partial androgen

insensitivity sydrome.

• You will be able to discuss luteinizing hormone

receptor defects.

• You will recognize disorders of anti-mullerian

hormone and anti-mullerian hormone receptor.
Androgen Insensitivity Syndrome: Complete vs. Partial Definition

These patients have normal gonads and steroid biosynthesis

however mutations in the receptors can mute the effect of
steroids on specific tissues.
Target Organs of Testosterone Definition

Skin Brain
Hair growth, balding, sebum Libido, mood
production
Muscle
Liver Increase in strength and
Synthesis of serum proteins volume
Kidney
Male sexual organs
Stimulation of erythropoietin
Penile growth, production
spermatogenesis, prostate
growth and function Bone
Accelerated linear growth,
Bone marrow closure of epiphyses
Stimulation of stem cells
Androgen Insensitivity Syndrome (AIS) Epidemiology

1:20,400 live-born XY individuals will have

1 of 300 mutations of the androgen receptor.
The gene for the androgen receptor is located
on the X chromosome and therefore follows an
X-linked pattern of inheritance.
40 % of patients with complete AIS
have a de novo mutation.
The majority of mutations result in XY
single-amino acid substitutions.
Androgen Insensitivity Syndrome: Complete vs. Partial Definition

Complete AIS (CAIS) are unambiguous XY

females who typically present with
amenorrhea and infertility.

E. Goljan, Rapid Review Pathology E-Book, 4th Edition, 2013, p. 148, Fig. 6-27, Mosby (Elsevier)
Androgen Insensitivity Syndrome: Complete vs. Partial Definition

CAIS is generally associated with complete absence of androgen

binding and androgen receptor activation.
Androgen Insensitivity Syndrome: Complete vs. Partial Definition

Partial AIS (PAIS)

• Male phenotype with:

• Gynecomastia
• Hypospadias
• Infertility

• PAIS is very heterogenous and can

present with the following:
• Micropenis
• Cryptoorchidism
• Perineoscrotal hypospadias
(Reifenstein syndrome: bifid scrotum
and perineoscrotal hypospadias)
Gynecomastia: what the surgeon needs to know, Singer-Granick CJ, Granick MS - Eplasty (2009), https://openi.nlm.nih.gov/detailedresult.ph
p?img=PMC2632162_eplasty09e06_fig6&query=Gynecomastia&lic=by&req=4&npos=8, resized, CC BY 2.0
Androgen Insensitivity Syndrome: Complete vs. Partial Definition

Partial AIS (PAIS)

• Male phenotype with:

• Gynecomastia
• Hypospadias
• Infertility

• PAIS is very heterogenous and can

present with the following:
• Micropenis
• Cryptoorchidism
• Perineoscrotal hypospadias
(Reifenstein syndrome: bifid scrotum
and perineoscrotal hypospadias)
Hypospadias By Buddy I Con, PD
Androgen Insensitivity Syndrome: Complete vs. Partial Definition

Partial AIS (PAIS)

• Male phenotype with:

• Gynecomastia
• Hypospadias
• Infertility

• PAIS is very heterogenous and can

present with the following:
• Micropenis
• Cryptoorchidism
• Perineoscrotal hypospadias
(Reifenstein syndrome: bifid scrotum
and perineoscrotal hypospadias)
Micropenis: etiology, diagnosis and treatment approaches., N, S - J Clin Res Pediatr Endocrinol (2013),
https://openi.nlm.nih.gov/detailedresult.php?img=PMC3890219_JCRPE-5-217-g5&query=Micropenis&lic=by&req=4&npos=1, CC BY 2.5
Androgen Insensitivity Syndrome: Complete vs. Partial Definition

Partial AIS (PAIS)

• Infants and children may present with

unilateral or bilateral hernias.

• Could also present as phenotypic

virilized female with fused labioscrotal
folds +/- clitoromegaly.

• PAIS patients have normal pubic and

axillary hair, but little or no face or chest
hair.

Cliteromegaly (By Copcu, E, Aktas, A, Sivrioglu, N, Copcu, O, Oztan, Y. - Copcu, E, Aktas, A, Sivrioglu, N, Copcu, O, Oztan, Y. Idiopathic
isolated clitoromegaly: Reproductive Health. 1, 4. 2004. https://commons.wikimedia.org/w/index.php?curid=2528076), resized, CC BY 2.0
Laboratory Findings with CAIS Examination

Serum testosterone concentrations are

normal or moderately increased in male
ranges.

Clinical pearl

Normal Production of Testosterone by

intact Testis
Remember that androgen insensitivity
means normal production, but the
Diagnosis of Androgen Insensitivity Syndrome Diagnosis

The most reliable method for

diagnosis of androgen insensitivity is
to sequence the androgen receptor
using DNA obtained from blood or
tissue and then cross reference to a
database of mutations.
The karyotype should also be
checked and it will be 46, XY.
Complete Androgen Insensitivity Syndrome Examination

• Overall body habitus is female but height and

weight is greater than that of average for
women.

• Breast development is female.

• The external genitalia are clearly female, the

vagina is either blind or shortened.

• Axillary and pubic hair are scant or absent.

Androgen Insensitivity Management Management

Gonadectomy Undervirilized male Plastic surgery Psychological

phenotype counseling and
support
Performed to For example It can correct
eliminate the risk of Reifenstein gynecomastia, and if
tumors developing in syndrome (PAIS) the patient wishes to
the cryptorchid could benefit from identify as a female,
testes  then HRT is high doses of DHT or vaginal dilation with
initiated depending testosterone. dilators or surgical is
on what gender the possible.
patient prefers.
Conclusion

CAIS looks phenotypically female.

PAIS has a range presentations  virilized female to

undervirilized male.

Testosterone levels are the same as normal males.

Gonadectomy of testis is critical to decrease cancer risk

with cryptoorchidism.

X-linked inheritance so prenatal screening of relatives is

possible.
Case Study
15-year-old G0 presents for consultation due to primary amenorrhea. You
astutely observe her tall stature, Tanner Stage V breasts, but Tanner
Stage I pubic hair. You send sequencing of her androgen receptor and
find she indeed has complete AIS (CAIS).

What is your next step? How can she start a family one day?
• Refer for gonadectomy and psychological support.

• Explain that gender has nothing to do with karyotype or anatomy.

Reassure her that she is a woman if she chooses to be one.

• Explain that she does not have a uterus, therefore she cannot carry a
fetus. Explain that she has testis so she does not produce eggs. Her
options include adoption, oocyte donor with gestational surrogate.

• If a PAIS patient identifies as male, a sperm donor is another option.

E. Goljan, Rapid Review Pathology E-Book, 4th Edition, 2013, p. 148, Mosby (Elsevier)
Learning Outcomes

 You can identify CAIS vs. PAIS.

 You understand the pathophysiology.

 You are able to recognize risk of cancer in

crytoorchid testes.

 You can discuss management after

diagnosis.