What causes androgen resistance characterized by hypergonadotropic hypogonadism (high Follicle-Stimulating Hormone (FSH), high Luteinizing Hormone (LH)), hyperandrogenism (high serum testosterone), and elevated Sex Hormone-Binding Globulin (SHBG), and how is it treated?

Androgen Resistance: Causes and Treatment

Androgen resistance syndrome is caused by mutations in the androgen receptor gene on the X chromosome, resulting in varying degrees of receptor dysfunction, and treatment should focus on appropriate hormone replacement therapy based on the clinical presentation and fertility goals. 1

Causes of Androgen Resistance

Pathophysiology

• Androgen resistance occurs when there is dysfunction in the androgen receptor, preventing normal androgen action despite normal or elevated androgen levels
• Characterized by hypergonadotropic hypogonadism (elevated FSH, LH) with high testosterone and SHBG levels 1
• The biological actions of androgens are mediated by a single intracellular androgen receptor encoded by a gene on the X chromosome
• Mutations in this gene result in varying degrees of receptor dysfunction 1

Clinical Presentation

• Complete androgen insensitivity: XY sex reversal with female phenotype
• Partial androgen insensitivity: ambiguous genitalia or mild undervirilization
• Mild androgen insensitivity: infertility with otherwise normal male phenotype
• Laboratory findings typically show:
  • Elevated LH and FSH (hypergonadotropic)
  • High serum testosterone
  • Elevated SHBG levels 2

Diagnostic Approach

Laboratory Assessment

• Morning total and free testosterone levels
• SHBG levels (typically elevated)
• LH and FSH levels (typically elevated)
• Prolactin levels to rule out hyperprolactinemia 3
• Consider genetic testing for androgen receptor mutations 1

Differential Diagnosis

• Polycystic ovary syndrome (PCOS) - typically has high LH:FSH ratio >2 3
• Hyperprolactinemia
• Congenital adrenal hyperplasia
• Adrenal/ovarian tumors 3
• Other causes of hypergonadotropic hypogonadism 4

Treatment Approaches

For Fertility Goals

1. Gonadotropin Therapy:

   • For patients with hypogonadotropic hypogonadism (not androgen resistance), human chorionic gonadotropin (hCG) combined with FSH has shown better outcomes than single compounds 5
   • In androgen resistance, gonadotropin therapy is generally ineffective due to receptor dysfunction 1

2. Assisted Reproductive Technologies:

   • For men with idiopathic infertility or androgen resistance, assisted reproductive technologies (ART) are often necessary 3
   • Intracytoplasmic sperm injection (ICSI) during IVF can overcome sperm quality issues as long as viable sperm are present 3

For Symptom Management

1. Hormone Replacement:

   • In complete androgen insensitivity syndrome (CAIS), estrogen replacement after gonadectomy is recommended
   • In partial androgen insensitivity syndrome (PAIS), sex hormone replacement depends on gender assignment 1

2. Management of Hyperandrogenism:

   • Combined oral contraceptives (COCs) to suppress ovarian androgen production and increase SHBG in female patients 2
   • Antiandrogens such as spironolactone (50-200 mg daily) or finasteride (2.5-5 mg daily) can be used as second-line therapy 2

3. Surgical Management:

   • Gonadectomy is recommended in complete androgen insensitivity syndrome due to risk of gonadal tumors
   • Timing of gonadectomy should consider tumor risk versus benefits of endogenous hormone production 1

Special Considerations

Monitoring

• Regular monitoring of hormone levels every 3-6 months initially, then annually 2
• Assessment of clinical symptoms and response to therapy
• Monitoring for side effects of hormone therapy

Psychological Support

• Genetic and psychological counseling is essential 1
• Gender identity issues may arise in cases of partial androgen insensitivity

Treatment Pitfalls to Avoid

• Treating with testosterone in androgen resistance is ineffective due to receptor dysfunction
• Failure to consider gonadal malignancy risk in patients with androgen insensitivity
• Overlooking psychological impact of the diagnosis
• Treating isolated laboratory abnormalities without considering clinical symptoms 2

Prognosis

• Prognosis depends on the severity of androgen resistance
• Complete androgen insensitivity has good outcomes with appropriate hormone replacement after gonadectomy
• Partial androgen insensitivity has variable outcomes depending on degree of resistance and appropriateness of gender assignment
• Fertility prognosis is generally poor without assisted reproductive technologies

Androgen resistance represents a spectrum of disorders requiring individualized management based on the degree of receptor dysfunction, gender identity, and fertility goals. Genetic testing and comprehensive hormonal evaluation are essential for accurate diagnosis and appropriate treatment planning.