Clinical effects of ethynyl estrogens, used with and without progestational agents, on bleeding patterns, weight, and blood pressure

Abstract

Although there is still controversy regarding the relative clinical potency of ethynylestradiol and mestranol, no studies have been carried out to compare their effects on the menstrual cycle of normal individuals. A total of 184 normal volunteers were enrolled randomly in a study consisting of six consecutive cycles of estrogen treatment for 21 days (ethynylestradiol at .05 or .08 mg/day, or mestranol at .05, .08, or 0.1 mg/day) with the usual 7-day rest period, followed by an additional six cycles of the same estrogen regimen accompanied daily by norethindrone acetate, dl -norgestrel, or megestrol acetate. A total of 1677 treatment cycles was accumulated and compared with 342 cycles observed simultaneously in a group of 30 women using an IUD. Substantial differences in cycle regularity (i.e., onset of withdrawal bleeding or amenorrhea) were observed between the two estrogens; these differences were dose-independent but changed with successive cycles. The differences largely disappeared with the concomitant administration of a progestin, although the variability of cycle length was consistently less with mestranol combinations. The chief difference in cycle length between the two types of estrogens was attributable to the frequency of amenorrhea, which was disproportionately high in the early mestranol cycles. In addition, the duration of withdrawal bleeding was greater with the earlier mestranol cycles, although the difference disappeared by the time estrogen/progestin treatments were instituted. Intermenstrual bleeding diminished as the estrogen dose was increased. There was no consistent superiority of one estrogen over the other. Due to the insensitivity of small sample size, differences between the progestins were difficult to detect; however, with norgestrel the incidence was lowest. On this basis, studies relying on occasional biopsy examinations of the endometrium cannot provide adequate information regarding the qualitative and quantitative effects of these estrogens, particularly on repeated cyclic administration. Cyclic estrogen therapy, at any dose, failed to have a significant effect on body weight over a 6-month period. Some of the estrogen/progestin combinations were associated with statistically significant weight gain by one method of analysis but not by another. In any event, there was no consistency among the various combinations. No significant alterations in systolic or diastolic blood pressure were observed; if a 2% incidence of drug-induced hypertension (i.e., 140/90 or more) had been induced, the probability of its detection in at least one individual would have exceeded 95%.