Can Keytruda Cause Low Testosterone in Women?
Keytruda (pembrolizumab) can cause hypogonadism, including low testosterone in women, through immune-related hypophysitis that disrupts the hypothalamic-pituitary-gonadal axis. This is a recognized immune-related adverse event (irAE) of immune checkpoint inhibitors.
Mechanism and Clinical Presentation
- Pembrolizumab and other immune checkpoint inhibitors can cause inflammation of the pituitary gland (hypophysitis), which leads to multiple endocrine deficiencies including hypogonadism 1
- Hypophysitis presents with low testosterone or estradiol levels accompanied by low luteinizing hormone (LH) and follicle-stimulating hormone (FSH), indicating central (secondary) hypogonadism 1
- In premenopausal women, this manifests as fatigue, loss of libido, mood changes, and menstrual irregularities 1
Diagnostic Workup
When hypophysitis is suspected in women on Keytruda, the following evaluation should be performed:
- Measure LH, FSH, and estradiol levels in premenopausal females with fatigue, loss of libido, and mood changes 1
- Check morning ACTH and cortisol levels, as adrenal insufficiency commonly coexists with hypophysitis 1
- Evaluate TSH and free T4, since central hypothyroidism frequently accompanies pituitary dysfunction 1
- Consider MRI of the brain with pituitary/sellar cuts in patients with multiple endocrine abnormalities, especially if new severe headaches or vision changes are present 1
Management Approach
The primary treatment is hormone replacement therapy, not corticosteroids alone:
- Testosterone or estrogen therapy should be provided to affected women without contraindications 1
- For mild symptoms (Grade 1), consider holding Keytruda until the patient is stabilized on replacement hormones 1
- For moderate to severe symptoms (Grade 2-4), hold Keytruda until stabilization occurs 1
- Endocrine consultation is essential for all grades of hypophysitis 1
Critical Pitfall
When multiple hormone deficiencies exist, always start corticosteroids several days before thyroid hormone replacement to prevent precipitating adrenal crisis 1. This is a life-threatening complication that occurs when thyroid hormone increases metabolic demand in the setting of untreated adrenal insufficiency.
Monitoring Considerations
- Follow free T4 (not TSH) for thyroid hormone replacement titration, as TSH is unreliable in central hypothyroidism 1
- All patients with adrenal insufficiency need education on stress dosing and should wear a medical alert bracelet 1
- The hypogonadism from checkpoint inhibitor-induced hypophysitis is typically permanent and requires lifelong hormone replacement 1