Case 8: Awat Khali

Androgen Receptors (ARs)

Intracellular transcription factors

Androgen binding = Confirmation change + bind androgen response elements in DNA = Regulate androgen-responsive genes

ARs: Hormones

DHT: Higher binding affinity = Increase action potency

Testosterone: Lower binding affinity = Decrease action potency

ARs: Hormone Effects

DHT:

• Stimulate male external genitalia and prostate growth

Testosterone:

• Stimulate male internal genitalia (Wolffian ducts) growth

• Negative feedback = Inhibit GnRH and gonadotropin secretion

ARs: Mutation Effects

Androgen insensitivity syndrome = Sexual differentiation issues

Androgen Insensitivity Syndrome: Description

Congenital disorder causing atypical sexual differentiation

Complete: Female external genitalia

Partial: Predominant female/male or ambiguous external genitalia

Mild: Male external genitalia

Androgen Insensitivity Syndrome: Etiology

X-linked recessive AR gene mutations

• Inherited or de novo

• Karyotype: 46,XY

Heterozygous (carrier) mother = 25% risk of offspring…

• 46,XY + affected

• 46,XY + unaffected

• 46,XX + carrier

• 46,XX + non-carrier

Androgen Insensitivity Syndrome: Pathophysiology

Androgen receptor defect = Decrease end-organ (gonad) response to androgens

• Increased androgens → Estrogens = Feminization

• Testicles secrete antimullarian hormone = Incomplete female internal genitalia development

Androgen Insensitivity Syndrome: Clinical Presentation

Complete

• Female external genitalia (testicular feminization + breast development)

• Cryptorchidism: Undescended testes*

  • No other male internal genitalia

• Underdeveloped female internal genitalia

• Decreased/no pubic hair

• Primary amenorrhea + infertility

Partial: depend on degree of androgen insensitivity

Androgen Insensitivity Syndrome: Investigations

Genetic testing

Sex hormone testing

Androgen Insensitivity Syndrome: Sex Hormone Testing

Before Puberty: Increased testosterone

After Puberty:

• Increased LH

• Increased estrogen

• Normal/increased testosterone

Androgen Insensitivity Syndrome: Treatment

Hormone replacement therapy

Gonadectomy

Androgen Insensitivity Syndrome Treatment: Hormone Replacement Therapy

Complete: Estrogen

Partial: High-dose androgen for male-identifying patients

Androgen Insensitivity Syndrome Treatment: Gonadectomy

Elective

• Indication: Intraabdominal/intralabial testes

After puberty

Prevent malignant transformation

Androgen Insensitivity Syndrome: Complications

Testicular malignancy

Infertility

Gynecomastia: Benign breast enlargement in males

Androgen Insensitivity Syndrome vs Congenital Adrenal Hyperplasia

Androgen Insensitivity Syndrome: Non-sick

• Female external genitalia + primary amenorrhea

• No systemic illnesses/metabolic disorders

Congenital Adrenal Hyperplasia: Sick neonate

• Adrenal insufficiency = Crisis

  • Poor feeding

  • Vomiting

  • Dehydration

  • Hyponatremia

  • Hyperkalemia

  • Hypovolemia

  • Shock