Oestrogen treatment and endometrial carcinoma

As it is unlikely that retrospective studies will be able definitively to establis: the relationship of oestrogens to endometrial carcinoma prospective surveys to elucidate this problem fully are urgently needed. In our prospective studies we have performed pretreatment curettage and then monitored the endometrial response to unopposed oestrogen and combined oestrogen/progestogen regimens, curettage being repeated at intervals during therapy. In a double-blind, randomised, placebocontrolled crossover study endometr.al hyperplasia was diagnosed in 23 00 of patients after unopposed oestrogens but in no patient after placebo."1 In further longitudinal studies12 13 extending for nearly three years dose-dependent hyperplasia was diagnosed in 13-36 0. of patients during unopposed cyclical oestrogen therapy, atypical hyperplasia developing later than, and perhaps from, cystic glandular hyperplasia. The urinary and plasma oestrogen levels during therapy13 were in and above the range associated with the mid-cycle ovulatory peak (indicating that the term "hormone replacement therapy," much used in your article, is inappropriate). The development of both cystic glandular and atypical hyperplasia, in view of the oestrogen levels, is not illogical and we find that, in order effectively to relieve menopausal symptoms oestrogens have to be given at dosages which promote endometrial hyperplasia. Our final disagreement with your article relates to the value of progestogens in preventing endometrial hyper-stimulation. Although endometrial carcinoma has been reported during sequential therapy,'4 such anecdotal reports should not be included in a serious debate. Combination oestrogen/progestogen therapy (as in oral contraception) has not resulted in an epidemic of endometrial cancer, and progestogens per se are destructive to endometrial cancer.15 16 In our studies'2 13 the subsequent addition of a progestogen for five or seven days each calendar month not only reversed oestrogen-induced hyperplasia to normal endometrium in all cases but also reversed pretreatment hyperplasia. Furthermore, hyperplasia was diagnosed in only one (2 0,) of patients solely given sequential therapy. Progestogens therefore act in a protective role. It is probable that this protective effect is exerted in at least two ways. Progestogens induce regular endometrial shedding and in our studies the absence of vaginal bleeding during unopposed oestrogen therapy was associated with a higher incidence of endometrial hyperplasia. In the premenopausal woman progesterone lowers the endometrial levels of both oestradiol and progesterone receptors'7 and increases the oestradiol dehydrogenase levels.'8 19 Oestrogenic stimulation of the endometrium which is mediated through the receptor mechanism is therefore depressed. Also, the enzymatic conversion of the more active intrauterine oestrogen, oestradiol, to the less active oestrone is accelerated and these actions of progesterone may be synergistic. Our preliminary data suggest that similar mechanisms operate in the postmenopausal woman given progestogens.2 .