Estrogens and Tibolone ( Livial ) increase the risk of endometrial cancer.

Many postmenopausal women, who have not had a hysterectomy, use combined hormone-replacement therapy ( HRT ), containing progestagen and estrogen, or Tibolone, synthetic HRT, because estrogen-only preparations are known to increase the risk of endometrial cancer. But little information exists on the incidence of endometrial cancer in users of these other therapies.

A total of 717 000 postmenopausal women from the UK, aged 50-64 years, who had no previous history of cancer and had not had a hysterectomy, were enrolled into the Million Women Study, between 1996 and 2001.

The women filled in questionnaires about their use of HRT and other personal details and were followed up for an average of 3•4 years.

During the follow-up, 1320 endometrial cancers were diagnosed.

The 45% of women reported at recruitment that they had used HRT, among whom the 22% last used continuous combined therapy ( progestagen added daily to estrogen ), the 45% last used cyclic combined therapy ( progestagen added to estrogen, usually for 10–14 days per month ), the 9% last used Tibolone, and the 4% last used estrogen-only HRT.

The investigators found that, compared with women who had never used HRT, women who last used estrogen-only HRT or Tibolone had a higher risk of endometrial cancer overall and that the risk increased with longer use of Tibolone.

By contrast, use of combined HRT did not increase the overall incidence of endometrial cancer.

The researchers also found that among hormone-replacement therapy users the risk of endometrial cancer varied according to bodyweight when compared with women who had never used HRT.
The adverse effects of Tibolone and estrogen-only HRT were greatest in non-obese women, and the beneficial effects of combined HRT were greatest in obese women.

Professor Valerie Beral concludes: “ These new results create a dilemma for women who haven't had a hysterectomy and want to use HRT. On one hand, oestrogen-only HRT and Tibolone increase the risk of endometrial cancer but, on the other hand, HRT containing both oestrogen and progesterone causes the greatest increase in breast cancer.

Since breast cancer is much more common than endometrial cancer, combined HRT poses the greatest overall cancer risk.”

In an accompanying comment Louise Brinton and colleagues from National Cancer Institute: “ The important clinical question is how hormones can be prescribed in a fashion that will allow women to receive the greatest benefits without commensurate risks. To minimise cancer and other risks, clinicians should prescribe the lowest possible dose of oestrogen for short periods of time.
Fortunately, recent evaluations support the idea that oestrogens prescribed at low doses are generally effective in controlling menopausal symptoms as the traditional higher doses. Although the benefits of short-term use of hormones during the early stages of menopause appear to outweigh the risks, we need other approaches for symptom relief and disease prevention as the menopause progresses. ”

Tibolone, a synthetic steroid with estrogenic, progestagenic, and androgenic properties, has not been licensed in the USA, but is prescribed as HRT in many countries.

Source: The Lancet, 2005


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