PIP: In this discussion of estrogens in oral contraceptives (OCs) information is reviewed on the historical background, clinical developments, the use of estrogens for contraception, and the question of the safety of OCs. Ludwig Haberlandt is the 1st great name in hormonal contraception. As early as 1919 he was conducting studies which showed that transplants of tissues or extracts of these tissues (now known to contain progesterone) could produce infertility in rabbits and mice. In 1930 Reiprich of Breslau suggested that the antifertility action of estrogen might be the result of pituitary inhibition. In 1938 ethinyl estradiol was synthesized and 1 year later Dodds and his group reported the synthesis of a series of nonsteroidal estrogens (stilbestrol, hexestrol, and dienestrol). None of the clinical trials conducted in the 1940s could have demonstrated the superiority of 1 estrogen over another with respect to ovulation inhibition at equivalent estrogenic dosage. Studies of this aspect lagged until the 1960s. At that time it was clearly demonstrated that the ethinyl side-chain imparted an augmented pituitary inhibiting potency to estradiol as compared either to other natural estrogens or to other synthetics. It was a fortunate accident that the early clinical preparations of contraceptive progestins contained about 1% contamination with mestranol from the process of manufacture. While this quantity appeared trivial to the chemists, the presence of about 150 mcg of mestranol in the original 10 mg doses of the 19-norprogestins could have accounted totally for their contraceptive efficacy. It was not until several years later than estrogen-free norprogestins were prepared and their intrinsic antiovulatory action proven. When these purified progestins were used for contraceptive therapy, an increased incidence of menstrual irregularities appeared. One standardized quantity of ethinyl estrogen was reincorporated into contraceptive preparations for the control of menstrual regularity, but without any idea that a contribution was being made to contraceptive effectiveness. Clinical studies with continuous low-dose progestin only formulations have demonstrated that their effectiveness in inhibiting ovulation is substantially lower than that of sequential or combination type preparations. A progestational agent added to a baseline estrogen dose appears to produce a greater suppression of plasma gonadotropins than estrogen by itself. While cyclic estrogen administration is capable of inhibiting ovulation with a high degree of efficiency, such a therapeutic regimen is impractical from the point of view of menstrual regularity. The entire matter of cardiovascular hazards related to OC use has been called into question by studies of mortality statistics in the U.S., Great Britain, and Taiwan. In none of these studies is the predicted mortality from cardiovascular disease in OC users confirmed.