What are the causes of high Follicle-Stimulating Hormone (FSH) levels in men apart from testicular failure?

Causes of High FSH in Men Beyond Testicular Failure

High FSH levels in men can be caused by several conditions beyond primary testicular failure, including pituitary adenomas, thyroid dysfunction, and certain medications, with each requiring specific diagnostic evaluation and management approaches. 1

Primary Causes of Elevated FSH

1. FSH-Secreting Pituitary Adenomas

• Rare but important cause of elevated FSH without testicular failure
• Clinical presentation:
  • Testicular enlargement (rather than atrophy seen in primary testicular failure) 2, 3
  • May have normal or even high testosterone levels despite hypogonadal symptoms 2
  • Visual field defects and headaches if macroadenoma is present 2
  • Normal sexual function and fertility may be preserved 3
• Diagnostic findings:
  • Elevated FSH with normal/high-normal LH
  • Normal or elevated testosterone levels
  • Increased inhibin levels (unlike primary testicular failure) 3
  • Pituitary imaging shows adenoma

2. Thyroid Dysfunction

• Hyperthyroidism:
  • Causes hyperresponsiveness of LH to GnRH
  • Elevated testosterone and SHBG
  • Elevated estradiol (may cause gynecomastia)
  • Subnormal response to hCG 4
• Hypothyroidism:
  • Can cause hypogonadotropic hypogonadism (typically low FSH)
  • However, in male children, FSH can be elevated with testicular enlargement 4

3. Recovery Phase of Hypogonadotropic Hypogonadism

• During treatment of hypogonadotropic hypogonadism
• FSH may transiently rise above normal before stabilizing

Iatrogenic Causes

1. Post-Radioactive Iodine Therapy

• Radioactive iodine (RAI) treatment for thyroid cancer
• Causes dose-dependent impairment of spermatogenesis
• Elevates FSH for up to 2 years post-treatment
• May cause permanent testicular germ cell damage with high doses 4
• Typically increases both FSH and LH while reducing inhibin B levels

2. Medications

• Certain medications can affect the hypothalamic-pituitary-gonadal axis
• Selective estrogen receptor modulators (SERMs) like clomiphene citrate
• Aromatase inhibitors
• GnRH agonists during initial administration

Diagnostic Considerations

Initial Evaluation

• Complete hormonal panel should include:
  • FSH, LH, total and free testosterone
  • Inhibin B and MIS/AMH (helps distinguish causes)
  • Prolactin (if testosterone is low with low/normal LH)
  • Thyroid function tests (TSH, free T4) 1

Imaging

• Pituitary MRI if:
  • FSH is disproportionately elevated compared to LH
  • Prolactin is elevated
  • Very low testosterone (<150 ng/dL) with low/normal LH
  • Visual symptoms are present 1
• Scrotal ultrasonography to assess testicular size and structure

Clinical Pearls

• FSH values above 4.5 IU/L may be associated with abnormal semen parameters, even though the traditional normal range extends to 18.1 IU/L 5
• Men with FSH levels >7.5 IU/L have a five to thirteen times higher risk of abnormal semen quality 5
• Testicular enlargement with elevated FSH suggests a pituitary gonadotrophinoma rather than primary testicular failure 3
• The combination of high FSH with normal/high testosterone is particularly suggestive of an FSH-secreting pituitary adenoma 2, 6

Management Approach

• For FSH-secreting adenomas: surgical resection is typically required
• For thyroid dysfunction: treat the underlying thyroid condition
• For medication-induced elevations: consider medication adjustment if possible
• For post-RAI therapy: monitoring with potential recovery within 18-24 months

Remember that while primary testicular failure remains the most common cause of elevated FSH in men, these alternative etiologies should be considered, especially when clinical presentation includes unusual features like testicular enlargement or normal/high testosterone levels.