Addition of progestogens along with oestrogen is recommended for the treatment of menopausal symptoms for women with intact uterus.
The recommendation is strong because of moderate or large effect size for reducing the risk of endometrial cancer (a patient important adverse outcome), with no significant reduction in beneficial outcomes with combination treatment compared to oestrogen alone.
A Cochrane review [Abstract] 1 included 46 studies with over 38 000 subjects. Unopposed estrogen was associated with increased risk of endometrial hyperplasia at all doses, and durations of therapy between one and three years. For women with a uterus the risk of endometrial hyperplasia with hormone therapy comprising low dose estrogen continuously combined with a minimum of 1 mg norethisterone acetate (NETA) or 1.5 mg medroxyprogesterone acetate (MPA) was not significantly different from placebo (1 mg NETA: OR 0.04 (0 to 2.8); 1.5 mg MPA: no hyperplasia events).
In six trials, rates of endometrial hyperplasia after 1 year of therapy were significantly higher for the group receiving low or moderate dose unopposed estrogen therapy, compared with the group receiving continuous combined low or moderate dose estrogen + progestogen treatment, for all of the 13 regimens compared, with odds ratios for the individual comparisons ranging between 3.8 and 9.4. There were statistically significant differences in the odds of developing endometrial hyperplasia at one year between the groups taking unopposed estrogen and the groups taking sequential estrogen plus progestogen in all of the regimens compared, favouring the sequential group (4 studies).
The WHI poststopping phases trials 2 assessed the risk of endometrial cancer. Women in the CEE+MPA compared to placebo group had a HR of 0.83 (0.49-1.40). Post-intervention and cumulative follow-up showed a reduced risk of endometrial cancer with CEE+MPA emerged post-intervention (HR=0.58, 95% CI 0.40 to 0.86) and for cumulative follow up (HR=0.67, 95% CI 0.49 to 0.91).
Another Cochrane review [Abstract] 3 included 13 studies with over 1657 subjects. The levonorgestrel-intrauterine system (LNG-IUS) improved regression of endometrial hyperplasia (EH) compared with non-intrauterine progestogens at short-term follow-up (up to 6 months) (OR 2.94, 95% CI 2.10 to 4.13; I² = 0%; 10 RCTs, n=1108). This suggests that if regression of EH following treatment with a non-intrauterine progestogen is assumed to be 72%, regression of EH following treatment with LNG-IUS would be between 85% and 92%. Regression of EH was improved by LNG-IUS compared with non-intrauterine progestogens at 12 months (OR 3.80, 95% CI 1.75 to 8.23; 1 RCT, n=138). The LNG-IUS was associated with fewer hysterectomies, fewer withdrawals from treatment due to hormone-related adverse effects, and improved patient satisfaction compared to non-intrauterine progestogens.
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