The cytological response to norethynodrel was investigated in 3 experiments the 1st using a high dose (1.5 mg/100 gm body weight/day) in intact rats the 2nd using a lower dose in previously ovariectomized rats and the 3rd using doses in the 5-150 mcg range to determine minimal effective dosage. Hypophyseal cells were studied by immunochemical staining. A nonsignificant tendency was observed in all groups toward pituitary enlargement. No significant changes were seen in growth hormone cells but high dose levels led to cellular and nuclear hypertrophy of prolactin cells which was less striking with the lower dose levels. High doses were associated with greatly reduces size and staining capacity of gonadotrophin cells (i.e. those cells delineated by anti-human chorionic gonadotropin with lesser size reductions with lower doses. It is hypothesized that the prolactin cell changes are probably due to the estrogenicity of norethynodrel of its metabolite and that this enhanced prolactin secretion may in turn foster mammary carcinoma. By comparison with other estrogens however norethynodrel was less potent in stimulating prolactin cells and did not accelerate mitotic activity in acidophils as other estrogens do