Endometrial Cancer in Postmenopausal Women Using Estradiol-Progestin Therapy

Well-known risk factors of endometrial cancer are nulliparity, obesity, endogenous hyperestrogenism, hereditary nonpolyposis colon cancer syndrome, history of breast cancer, tamoxifen use, unopposed estrogen use, and inadequate progestin addition to estrogen. A large international variation in incidence rates of endometrial cancer indicates that many of those risk factors may be modifiable.

It is known that approximately 80% of the endometrial cancers are preceded with endometrial hyperplasia. These type I tumors are mostly low-grade adenocarcinomas with a fairly good prognosis. In contrast, type II tumors, such as serous papillary carcinomas, clear cell adenocarcinomas or squamous carcinomas, originate from polyps or other nonhyperplastic endometrial lesions. They are more malignant and usually diagnosed at a more advanced stage than type I tumors. Except for advanced age, no other confirmed risk factors exist for type II tumors, although estrogen may also be involved.

Previous data uniformly show that unopposed estrogen therapies or an inadequate progestin complement to estrogen is accompanied by an elevation in the risk for endometrial cancer. In these studies, progestins as part of hormone therapy (HT) have mainly been given orally, and the role of long-term use of transdermal progestin in endometrial protection is open.

Moreover, various progestins used in commercial combined HT preparations show large differences in their capacity to bind progesterone and other receptors and therefore differences in endometrial safety between various progestins as part of HT are possible. There are no long-term follow-up data on this issue so far.

Due to the large national differences in the use and content of HT its effect on endometrial cancer burden should ideally be studied in each country separately. The objective of our study was to estimate the risk of endometrial cancer in all Finnish postmenopausal women using various forms of estradiol-progestin therapy.

DISCUSSION

Taken as a whole, the use of estradiol-progestin therapy for at least 6 months was associated with a 54% elevation in the risk of endometrial cancer in the Finnish postmenopausal female population. However, only monthly and long-cycle sequential estradiol-progestin regimen use for more than 5 years were associated with significant elevation (69% and 276%, respectively) in the risk of endometrial cancer, whereas the use of continuous estradiol-progestin therapy showed a protective efficacy (approximately 70%) against endometrial cancer. Transdermal sequential estradiol-progestin therapy did not differ from oral therapy, and norethistoterone acetate, medroxyprogesterone acetate, and dydrogesterone did not differ from each other in endometrial safety.

We compared the incidence of endometrial cancer in estradiol-progestin therapy users with that in the entire same-aged female population, also including those using any type of postmenopausal hormone therapy. About 11% of postmenopausal women use estradiol-progestin therapy for more than 5 years. Such a small proportion of women with a partly elevated and partly decreased risk for endometrial cancer in the reference background population should not markedly alter the risk estimates and certainly should not invalidate the conclusions. It is acknowledged that our present study cannot control important confounding factors, such as parity, weight, or the use of oral contraceptives, but lack of major differences between HT users and nonusers in these factors in Finland is reassuring.