Role of cigarette smoking on the postmenopausal endometrium during sequential estrogen and progestogen therapy

To study the effect of cigarette smoking on the endometrial response to sequentially combined hormone replacement therapy.

Healthy, early postmenopausal women were randomly assigned to three treatment groups: estradiol (E2) sequentially combined with 75 micrograms of levonorgestrel (19), or 150 micrograms of desogestrel (20), or 10 mg of medroxyprogesterone acetate (18). After 2 years of therapy, the hormone effects on the endometrium were assessed by endometrial histology; effects were also analyzed on biochemical markers of secretion, specifically, secretory endometrial protein (placental protein 14) in serum, and E2 dehydrogenase and isocitrate dehydrogenase in endometrial tissue. Information on smoking habits was elicited by questionnaire.

Smokers numbered relatively more women with an atrophic endometrium (50 versus 22%) and proportionally fewer with secretory endometrium (50 versus 78%) (P < .05). The level of serum placental protein 14 was correspondingly almost halved in the smokers (P < .001). The influence of smoking was in part caused by a reduced level of serum E2, but primarily by a non-E2-mediated effect. The E2 effect accounted for 38% of the decrease in serum placental protein 14, and the non-E2-mediated smoking effect for 62%. Endometrial E2 and isocitrate dehydrogenase tended to be lower in smokers, but not after adjustment for the reduced serum E2 level.

We suggest that smokers may benefit from a hormone combination with a higher dose of E2, even higher than expected as seen from the measurement of serum E2.