Key messages
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In women with a uterus (womb), estrogen therapy alone (without progestogen) probably increases the risk of endometrial hyperplasia (thickening of the womb lining that can progress to cancer) compared to placebo (dummy treatment) or continuous combined hormone therapy (where estrogen and progestogen are both taken daily). Estrogen therapy alone may increase the risk of endometrial hyperplasia compared to sequential combined therapy (where estrogen is taken every day but progestogen is taken only some days of the month).
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Women on sequential combined hormone therapy may have a higher risk of endometrial hyperplasia at one year compared to women on placebo. There may be little to no difference in the risk of endometrial hyperplasia at one year between women on continuous combined hormone therapy and women on placebo.
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We were unable to draw any meaningful conclusions about the risk of precancerous or cancerous changes of the womb lining in women using different dosage plans of combined hormone therapy.
What is hormone therapy?
Hormone therapy involves using hormones (usually estrogen, progestogen, or both) to manage troublesome menopausal symptoms. The recommended approach is for women to use the lowest effective dose and review the treatment regularly with their doctor. Previous studies have shown that treatment with estrogen alone can increase the risk of thickening of the womb lining (endometrial hyperplasia), which can develop into cancer. Adding the hormone progestogen reduces the risk of endometrial hyperplasia but can come with unwanted effects.
What did we want to find out?
We wanted to assess whether different hormone therapy combinations are sufficient for protecting against endometrial hyperplasia and endometrial cancer and then compare the dosing plans to see if any are better than the others. We wanted to know the lowest dose of progestogen that is safe to balance a specific estrogen dose (low, moderate, or high). We also wanted to include studies that assessed different ways of taking hormone therapy, not just tablets (such as patches, gels, nasal sprays, intrauterine systems, and vaginal inserts), as they are now more widely available and their use is increasing.
It is important to know which hormone therapy combinations are providing adequate protection of the womb lining. If we find that a lower dose of progestogen is adequate for a given estrogen dose, then it could help reduce unwanted effects.
What did we do?
We searched for and selected all studies that addressed our question. We used a checklist to make sure we included only studies with information we could verify. We assessed the quality of the studies, analyzed the results, and summarized our findings.
What did we find?
We included 72 studies involving 40,652 women in this review.
Estrogen therapy on its own probably increases the risk of endometrial hyperplasia at one year and later compared to placebo or continuous combined therapy (where estrogen and progestogen are both taken daily).
Sequential combined hormone therapy (where estrogen is taken every day but progestogen is taken only some days of the month) may increase the risk of endometrial hyperplasia compared to placebo at one year. Estrogen therapy on its own may increase the risk of endometrial hyperplasia when compared to sequential combined therapy (where estrogen is taken every day but progestogen is taken only some days of the month) at one year and later.
There may be little to no difference in the risk of endometrial hyperplasia with continuous combined therapy and with placebo at one year. Estrogen therapy on its own probably increases the risk of endometrial hyperplasia when compared to continuous combined therapy at one year and later.
We are unsure if any specific dose plans for combined hormone therapy reduce the risk of endometrial hyperplasia. We are unsure which types of hormone therapy reduce the risk of endometrial cancer. Further research should focus on different combined hormone therapy regimens that may reduce the risk of these outcomes.
What are the limitations of the evidence?
For most of the studies comparing different hormone therapy dosage plans, there were too few women diagnosed with endometrial hyperplasia or cancer to be able to draw meaningful conclusions.
How up to date is the evidence?
We searched all available evidence up to 22 July 2024.
Читать полную аннотацию (абстракт)
Reduced circulating estrogen levels around the time of the menopause can induce unacceptable symptoms that affect the health and well-being of women. Hormone therapy (both unopposed estrogen and estrogen/progestogen combinations) is an effective treatment for these symptoms, but is associated with risk of harms. Guidelines recommend that hormone therapy be given at the lowest effective dose and treatment should be reviewed regularly. The aim of this review is to identify the minimum dose(s) of progestogen required to be added to estrogen so that the rate of endometrial hyperplasia is not increased compared to placebo.
Задачи
• To assess the effects of hormone therapy regimens for protecting postmenopausal women against endometrial hyperplasia and endometrial cancer.
• To define the lowest effective dose(s) of progestogen used in combination with estrogen therapy for protecting the endometrium.
Методы поиска
We searched for trials in the Cochrane Gynaecology and Fertility Group specialized register, CENTRAL (containing output from two trial registers and CINAHL), MEDLINE, Embase, and PsycINFO to 22 July 2024. We also checked references and contacted study authors to identify additional studies.
Критерии отбора
Randomised comparisons of unopposed estrogen therapy, combined continuous estrogen-progestogen therapy, sequential estrogen-progestogen therapy with each other or placebo, administered over a minimum period of 12 months. Incidence of endometrial hyperplasia/carcinoma assessed by a biopsy at the end of treatment was a required outcome. Data on adherence to therapy, rates of additional interventions, and withdrawals owing to adverse events were also extracted.
Сбор и анализ данных
In this update, 46 studies were included. Odds ratios (ORs) were calculated for dichotomous outcomes. The small numbers of studies in each comparison and the clinical heterogeneity precluded meta-analysis for many outcomes.
Основные результаты
Unopposed estrogen is 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) is not significantly different from placebo at two years (1 mg NETA: OR 0.04; 95% confidence interval (CI) 0 to 2.8; 1.5 mg MPA: no hyperplasia events).
Выводы авторов
Unopposed estrogen probably increases the risk of endometrial hyperplasia versus placebo and continuous combined therapy at one year and later. Sequential combined therapy may increase the risk of endometrial hyperplasia at one year versus placebo. The evidence is less certain for continuous versus sequential combined regimens and dose comparisons of continuous and sequential combined regimens. The trials had few events, and long-term follow-up was challenging. For endometrial cancer, events were rare and trials were underpowered to draw meaningful conclusions.
Финансирование
This review had no dedicated funding.
Регистрация
Original review (1999) DOI: 10.1002/14651858.CD000402
Review update (2004) DOI: 10.1002/14651858.CD000402.pub2
Review update (2009) DOI: 10.1002/14651858.CD000402.pub3
Review update (2012) DOI: 10.1002/14651858.CD000402.pub4
