The Million Women Study found that HT containing estrogen alone increased the risk of endometrial cancer (compared to women who had never taken HT) [4]. Progestogens, however, counteract the adverse effect of estrogens. The effect of continuous combined preparations was a reduction in risk, while there was no significant risk (or protection) from use of cyclical preparations.

The Women’s Health Initiative and the Heart and Estrogen/Progestin Therapy trials observed a reduced risk of endometrial cancer associated with use of continuous-combined EPT [5, 13]. Both trials were limited by small case numbers (N = 58 and N = 10, respectively) and a shorter duration of exposure than has been examined in most observational studies.

Brinton et al., in a recent review published in 2014, reported that numerous epidemiologic studies have shown substantial risk of endometrial cancers with use of unopposed estrogens, especially among thin women [14]. This risk, however, can be reduced if progestins are added to the therapy. The manner in which progestins are prescribed is a critical determinant of risk. Most studies show that women who have ever used progestins continuously (>25 days/months) are at somewhat reduced risk relative to nonusers (metaanalysis relative risk, RR, based on observational studies = 0.78, 95 confidence intervals, CI, 0.72–0.86). The reduced risk in greatest among heavy women. In contrast, women who have ever used progestins sequentially for <10 days each month are at increased risk, with metaanalysis results showing on overall RR of 1.76 (1.51–2.05); in contrast, progestins given for 10–24 days/month appear unrelated to risk (RR = 1.07, 0.92–1.24). These risks were based on varying patterns of usage, with little information available regarding how endometrial cancer risk is affected by duration of use, type, and/or dose of estrogen or progestin, or mode of administration. Effects may also vary by clinical characteristics (e.g., differences for type I vs. II tumors).

Another study reported that approximately 20 % of women given unopposed estrogen for 1 year develop endometrial hyperplasia [15].The relative risk of endometrial carcinoma is 2–3. This is dramatically reduced by the addition of progestogen to the regimen, but cyclical progestogen as part of a sequential HT regimen does not completely eliminate the risk of carcinoma. The prevalence of endometrial hyperplasia associated with sequential HT is 5.4 %, and that of atypical hyperplasia (endometrial intraepithelial neoplasia) is 0.7 %. Continuous combined HT is not associated with the development of hyperplasia or carcinoma, and may normalize the endometrium of women who have developed complex hyperplasia on sequential HT.

There are several other observational studies which have explored the possible association between use of continuous-combined EPT and endometrial cancer, with varying results. While several studies have reported either no increased risk or a modest decreased risk of endometrial cancer associated with use of continuous-combined EPT, three studies have reported an increased risk [16–21].

Grady et al. conducted a metaanalysis of 30 studies conducted after 1970 and reported that the protective effect is seen if progestogen is administered for a minimum of 10 days, or even better, i.e., 12–14 days (Evidence level II) [22]. However, increased risk has also been demonstrated with addition of monthly sequential progestogen (SCEPT), in contrast to CCEPT (Evidence level II) [23]. Indeed, the question of whether the risk with CCEPT is lower than with no treatment is to be investigated in further clinical trials, because, in the present studies, only a relatively small number of patients are represented. It is certain that with estrogen monotherapy, after metaanalysis of over 30 studies a two- to fourfold risk with short term and 10-fold relative risk with long-term therapy (10 years) is calculated (Evidence level II). The elevated risk also remains for at least 5 years after stopping estrogen therapy [24]. Table 40.2 depicts the relative risk (95 % confidence interval) of endometrial cancer in patients on hormone therapy with or without progestogen in various studies.

Some women developing endometrial cancer have already gone through menopause. However, younger women with endometrial cancer, undergo premature menopause after surgical treatment. A recent study based on gynecologists’ experience reported that although HRT is not actively recommended, HRT given posttherapy to endometrial cancer patients is considered acceptable [25].

For survivors of endometrial cancer, the concern is that endometrial cancer is an estrogen-linked cancer, and estrogen used in HT may increase the risk of endometrial cancer recurrence. Only limited research has been done on this HT risk. Guidelines on treating uterine cancers from the National Comprehensive Cancer Network (NCCN) state that studies have not conclusively proved that estrogen therapy causes a higher relapse rate (Table 40.3 ).

Global Consensus Statement on Menopausal Hormone Therapy, 2013, by International Menopause Society labels breast carcinoma survivors as a contraindication to hormone therapy but endometrial carcinoma survivors are not labeled as a contraindication [27].

The Hormone Therapy Position Statement of the North American Menopause Society gives its recommendations as stated in Table 40.4.

According to the latest official statements of the North American Menopause Society (2012), the treatment of moderate to severe menopause symptoms (vasomotor symptoms and sleep disruption from vasomotor symptoms) remains the primary indication for systemic ET and EPT. In women who have been treated previously for endometrial cancer, these benefits must be weighed against the risk of stimulating tumor growth and recurrence. There is no available evidence based from randomized clinical trials. For a definite conclusion that HT after endometrial cancer is not deleterious, large randomized trials are required.

According to the ACOG committee opinion, in the absence of HT a well-differentiated neoplasm of endometrioid cell type with superficial invasion would entail an approximate 5 % risk of recurrent disease, and a moderately differentiated neoplasm with up to one-half myometrial invasion entails a 10–15 % risk [29].

The essential outcomes of some nonrandomized controlled studies are listed in Tables 40.5. All studies are retrospective, nonrandomized case–control studies (evidence level II). These studies produced no data showing that a higher risk exists with HT after treated endometrial carcinoma.

Since estrogen therapy may be associated with increased risks of endometrial carcinoma and safety profile of systemic estrogen therapy on endometrial carcinoma survivors is not known, alternative therapies have evolved. These therapies can be hormonal or nonhormonal.