Introduction

The use of unopposed estrogen in postmenopausal women is associated with an increased risk of developing endometrial adenocarcinoma, the size of which increases with increasing duration of use (1). Epidemiologic studies have verified that progestogen administration assists in diminishing the stimulatory effect of estrogen on the endometrium, thereby decreasing the risk of endometrial cancer (ECA) associated with unopposed estrogen. The association of ECA with postmenopausal combined hormone therapy has been examined in several large case control studies performed by groups in Seattle, Los Angeles, and Stockholm,

Sweden (2-5). These studies have provided information about different patterns of progestogen delivery (cyclical for less than 10 days, cyclical for 10-24 days, and continuous); and duration ofuse. In addition, the Swedish study5 evaluatedthe risk ofECA by type ofprogestogen, comparing risks among women using C-21 derived progestogens, [principally medroxyprogesterone acetate (MPA)] to non-users and the nor-testosterone derived progestogens to non-users. There are no large studies that have reported on the dose of progestogen as it relates to the risk of ECA.

Progestogen dose becomes relevant because the balance between decreasing ECA risk with an adequate progestogen dose must be weighed against potential progestogen side effects seen with higher dosing regimens. Progestogen side effects lead to non-compliance with postmenopausal combined hormone therapy in at least one third of patients (6, 7). In addition, and potentially most importantly, the addition of a progestogen to postmenopausal estrogen therapy appears to decrease the favorable lipid benefits of estrogen (8, 9) and increase the risk of breast cancer (9-12). It is unknown whether progestogen has a major contribution to the increased risk of stroke and cardiovascular events observed with combined continuous hormone therapy (9). Identification of the dose of progestogen for use in combined postmenopausal hormone therapy that maximizes efficacy but also has a low rate of adverse consequences is therefore desirable.

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