Pituitary adenoma developed in a 33-year-old male-to-female transsexual patient who was given estrogen, starting at 16 years of age; the pituitary adenoma was surgically removed and studied by light microscopy, immunocytochemistry, and in situ hybridization. The adenoma cells were immunoreactive for prolactin, and exhibited a strong signal for prolactin and estrogen receptor messenger RNAs and a weak signal for dopamine receptor messenger RNA. The question of whether the development of an adenoma was incidental or was the direct effect of estrogen or whether it was mediated via other mechanisms, such as activation of growth factors or oncogenes or inhibition of tumor-suppressing genes or other genetic abnormalities, remained unresolved. The present case, which, to our knowledge, is the first to describe structural findings of a pituitary adenoma in a transsexual patient who was given estrogen, reinforces the view that protracted stimulation may play a role in the genesis of endocrine tumors.