MENOPAUSE AND HORMONE REPLACEMENT THERAPY (HRT): CANCER RISK AND THE OESTROGENS USED IN HRT
The association of HRT with cancer risk in the main target sites of oestrogen and progestogen (such as the breast, endometrium, cervix and ovaries) needs careful examination. Much research has been carried out in this area, but for accurate interpretation the findings must always be related to individual medical histories.
The evidence that oestrogen therapy may increase the likelihood of cancer is small, but uncertainties are still present. The interpretation of research data needs great care, because the percentage of risk depends on whether the menopause was natural or surgical and, in the latter case, whether the ovaries were removed or conserved. Previous benign (non-cancerous) breast disease, an early menarche or a late menopause can all influence risk and alter study results. For example, it is reasonably well established that late onset of menopause and an early menarche increases breast cancer risk. Regular periods after the age of 54 may increase the risk of uterine cancer. An early childbirth and an early or surgical menopause reduce breast cancer risk. Risk is increased by late first births (over the age of 25) and by childlessness. Smokers tend to have a reduced breast risk, while women who are overweight post-menopausally are at greater risk. Alcohol consumption slightly increases risk of breast cancer.
A study carried out in Sweden (see references at end of chapter) in 1989 involving 23,000 women showed a slightly increased risk of breast cancer with HRT usage. It also indicated that taking any form of oestrogen over a period of time was associated with increased risk. The risk, however, is small and starts to show with combined oestrogen/progestogen usage beyond six years.
The International Consensus Conference on Progestogens in 1988 concluded that there was not enough evidence to suggest that progestogens have a protective effect on breast tissue when they are part of opposed HRT therapy.
A study undertaken in 1986 by the American National Cancer Institute found that oestrogen use does not produce an overall increase in breast cancer; however, if oestrogen use is extended beyond 10 years the risk increases in the order of 1.5-3 times. It also suggested that women with previous benign breast disease are at risk of breast cancer if the diagnosis preceded oestrogen use. Moreover, no evidence exists to suggest that women with a strong family history of breast cancer and, therefore, already at increased risk of developing breast cancer, will be at any greater risk as a result of post-menopausal oestrogen use.
The Seventh Day Adventist Women Study in California of 1989, involving 20,000 participants, concluded that there was a three-fold increase in breast cancer occurrence in users of conjugated oestrogens after a duration of six to ten years.
To summarise, recent studies, although to some extent contradictory, indicate:
there is a moderate increase in breast cancer risk with long-term (over 10 years) oestrogen usage, of the order of 1.5-3 times.
certain women may be more at risk than others: for example, those with benign breast disease or whose mothers have had breast cancer.
added progestogens may not affect the increased risk that results from long-term oestrogen use.
In the USA in the 1960s and 1970s unopposed high doses of mainly conjugated oestrogen were used to treat menopausal symptoms. In the mid-1970s the first studies were published which linked endometrial hyperplasia and increased risk of endometrial cancer to cyclical oestrogen use. In the late 1970s it became clear that by adding a progestogen to the cyclical oestrogen therapy hyperplasia of the endometrium could be prevented.
Studies published in 1986 and 1989 confirm the protective effect given by the addition of a progestogen. It has been shown that the incidence of hyperplasia can be reduced to zero if a progestogen is added for 12-13 days of each cycle. Without added progestogens there is a duration-dependent increased risk of developing endometrial cancer which may be as high as 10-fold after 10-15 years, as indicated in two studies published in 1982 and 1980.
To summarise, the addition of a progestogen to oestrogen cyclical therapy for 12 days during each cycle, at an appropriate dosage, greatly reduces the likelihood of endometrial cancer.
Cancer of the ovary is more common than endometrial cancer, with an incidence of 177 cases annually per million, and accounts for 6 per cent of all cancer deaths. Some 5-10 per cent of all ovarian cancer may be hereditary, and the condition is most common in white Caucasian women of higher socio-economic groups.
There is also a link between ovarian and breast cancer. A women with the latter has twice the normal risk of developing the former.
Studies published in 1989 and 1988 suggest that HRT appears to have no adverse effect on the ovaries. However, further studies are required before this conclusion can be confirmed.
The peak occurrence of both cervical dysplasia and cervical cancer is before the menopause.
Studies published in 1987 and 1989 found no evidence of an increase in cervical cancer with HRT. It is thought that HRT can be used safely both in women who have never been treated for cervical dysplasia and those who have.
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