First Consensus Meeting on Menopause in the East Asian Region
Hormone replacement therapy and gynaecological cancers
Nik Mohd Nasri Ismail
Department of Obstetrics and Gynaecology, National University of Malaysia, Kuala Lumpur, Malaysia
The benefits of hormone replacement therapy (HRT), both for the short-term relief of menopausal symptoms and long-term protection against coronary heart disease and osteoporosis, are well documented [1–4]. However, the relationship between HRT and some gynaecological cancers remains controversial, especially with regard to breast cancer. The many studies carried out over the last 20 years to examine the relationship between HRT and breast cancer have produced conflicting results. Concern about the relationship between HRT and breast cancer is due to the presence of receptors for sex hormones in the breast. The rates of breast, endometrial and ovarian cancer are generally lower in Asia than in the West; for example, the rate of endometrial cancer in Singapore and Japan is about 2 per 100,000 women compared with 25 per 100,000 women in parts of the USA. Currently, most scientists believe that for the majority of women, the benefits of HRT (such as prevention of osteoporosis and reduction of cardiovascular disease) clearly outweigh the possible cancer risks.
Endometrial epithelium contains sex steroid receptors, and risk factors for endometrial carcinoma are closely related to the presence of both endogenous and exogenous female sex hormones . Oestrogens promote proliferation of the endometrium and stimulate formation of oestrogen receptors, while progestogens protect against endometrial hyperplasia by promoting endometrial shedding, inhibiting DNA synthesis in the endometrium, increasing production of the enzyme that promotes conversion of oestradiol to oestrone, and by reducing the number of oestrogen receptors in the endometrium. Endometrial hyperplasia can and does develop in women not exposed to any exogenous hormones, but it can also develop in women receiving HRT or oestrogen replacement therapy (ERT). Endometrial carcinoma occurs almost exclusively after the menopause. Administration of unopposed ERT to postmenopausal women increases the risk of endometrial cancer . Estimates of the relative risk range from two to eight, depending on the dose of the formulation and the duration of therapy. It has been shown, for example, that after receiving conjugated oestrogens for about 18 months, more than 30% of women develop hyperplasia. In many cases, this progresses to adenomatous or complex hyperplasia with atypia, and some women may even go on to develop endometrial cancer. Using a combination of oestrogen and progestogen for 10–13 days of each cycle appears to decrease the risk linked to the use of oestrogen alone. Voight et al.  reported an increased relative risk of 2.0 with cyclic addition of progestogens for a period of less than 10 days, but a decreased relative risk of 0.9 with cyclic addition of progestogens for a period of 10 or more days. In fact an unpublished Norwegian study found the incidence of endometrial cancer to be more common in women not receiving HRT than in those taking combined therapy. Hence, for women with an intact uterus, a combination of oestrogen and progestogen should be prescribed for HRT, whether as a cyclic or a continuous regimen.
The effects of continuous daily low-dose oestrogen and progestogen replacement therapy are not known yet because this regimen has only recently become popular. Neither has the risk of endometrial carcinoma in oestrogen users switching to combined therapy been adequately studied.
After total abdominal hysterectomy and bilateral salpingo-oophorectomy for endometrial carcinoma, women should be prescribed the combined regimen even though they no longer have a uterus. In three retrospective studies on women operated for stage-I endometrial cancer, fewer cases of recurrent disease were found among women who had been treated with combination HRT than among women who were not undergoing HRT [8–10]. Currently, however, it is the practice to prescribe oestrogen-only replacement therapy to women who have undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy and adjuvant radiotherapy for the treatment of endometrial cancer.
About 190,000 cases of ovarian cancer occur each year, with slightly more in the developing than in the developed world. There has been a recent trend towards a decrease in countries which previously had high rates, and an increase in countries previously at low risk . Cancer of the ovary is influenced by hormones and reproductive factors. Risk is slightly increased in women who have never given birth and in those with a personal or family history of breast or ovarian cancer.
The ovaries produce oestrogens and progesterone and thus contain sex hormone receptors. However, it is still not clear whether there is a connection between ovarian cancer and sex hormones. Pregnancy and the use of oral combined contraceptive pills decrease the risk of ovarian cancer . The incidence of ovarian cancer increases after the menopause until the age of 65 . The hypothesis for this is either the decreased number of ovulations (during pregnancy) or the decline in serum gonadotropin levels [7, 13].
Although it is certain that the use of oral contraceptives reduces the risk of ovarian cancer, there is still no consensus on the effect of HRT. Thus most doctors would be reluctant to prescribe ERT to women who have been treated for ovarian cancer, as 60% of ovarian cancer cells contain oestrogen and progestogen receptors and the increased risk of ovarian cancer due to ERT cannot be excluded. HRT/ERT should be prescribed cautiously in women in clinical remission from ovarian cancer. Prescription should only be for serious climacteric symptoms, osteoporosis or reduction of cardiovascular disease.
Although the cervical epithelium contains sex hormone receptors and undergoes changes under their influence, no relationship has ever been demonstrated between sex hormones and cervical cancer. A study of 120 women who had been treated for stage-I and -II cervical cancer and then prescribed HRT/ERT did not show any negative influence on the rate of recurrence or on 5-year survival . Sadan et al.  showed that the concentration of oestrogen receptors did not differ in women with normal or abnormal cervices. They therefore concluded that HRT may be prescribed to women with cervical cancer if indicated.
Cancer of the vulva and vagina
Vulval and vaginal cancers can also be influenced by exogenous hormones. They generally occur at an advanced age, although younger women can occasionally be affected. Sex hormone receptors are present in the vulva and vagina. No relevant information is available about any correlation between HRT and these types of cancer, which are almost exclusively of the squamous cell type.
Breast cancer is the most common malignant disease in women throughout the developed world except in Japan. The incidence rates are increasing everywhere, particularly in areas of previously low incidence such as Asia. If the present trend continues, the incidence of breast cancer may reach one million cases annually by the year 2000 .
Breast cancer is an emotive subject for most women. However, it is important to keep the relative risk of this disease in perspective. More women are dying from breast cancer than previously, but this could be attributed to the longer life span of women. It is reported that breast cancer causes 376,000 deaths a year worldwide . It is hoped that screening with mammography will identify tumours earlier when they are more amenable to therapy and thus improve survival.
The association between breast cancer and HRT remains controversial despite mounting evidence that postmenopausal HRT protects against osteoporosis and cardiovascular disease. Indeed many patients and even some physicians hesitate to use HRT because of the fear of breast cancer. Breast tissue contains sex steroid receptors and there is a correlation between endogenous hormone metabolism and the origin of breast cancer. The exact mechanisms of action of oestrogens and progesterone in breast tissue are not yet completely understood. It is assumed that oestrogens make the breast tissue more sensitive to carcinogenic influences . It is suggested that progestogens in combination with oestrogens increase the risk of breast cancer more than oestrogens alone .
The risk factors for breast cancer are:
— age, which is a very strong risk factor since more than 50% of cases occur after the menopause,
— early menarche,
— late age at first birth,
— late menopause,
— strong family history of breast cancer,
— exposure to radiation at the time of breast development,
— use of oral contraceptive pills at an early age,
Since 1970 there have been more than 50 studies on HRT and a possible connection with breast cancer. Analyses have shown a relative risk of generally about 1.08, but there are almost as many studies indicating non-significantly decreased risks of breast cancer with HRT as there are those indicating non-significantly increased risks. Currently, there seems to be some broad, though by no means universal, agreement that giving HRT for a period of less than 5 years does not increase the risk of breast cancer. However, a meta-analysis has suggested that using HRT for 8 years seems to increase the relative risk by 25% , and by 15–30% after 10 years , although this is not universally accepted. It is possible that this increased risk is confined to certain subgroups of women such as those with a strong family history of breast cancer, or to older women.
The prospective cohort study of Colditz et al.  has caused some concern among the public and some uncertainty among the medical profession. The authors conclude from their data, extracted from questionnaires posted to 121,700 nurses (95% return rate), that nurses who have used oestrogens in the past are not at increased risk of breast cancer, irrespective of their duration of intake. However, the authors suggest that there might be a small but substantial increase in statistical risk of developing breast cancer in the group of postmenopausal nurses currently receiving oestrogen or oestrogen-progestogen therapy, especially when the period of use exceeds 5 years and if the users are more than 60 years of age. They further state that the addition of a progestogen to the oestrogen therapy does not reduce the risk of breast cancer.
On the other hand, a recent study by Stanford et al.  found that middle-aged women who take oestrogen or a combination of oestrogen and progestogen as HRT apparently do not face an increased risk of breast cancer. The authors studied the medical histories of 1029 women aged 50–64 years. More than half (537) had been diagnosed with breast cancer, listed as the case group, while the remaining 492 women did not have a history of breast cancer and were listed as controls. The researchers write: ‘In this large population-based case-control study of middle-aged women, we found no overall association between breast cancer risk and the use of either oestrogen alone or oestrogen with progestogen hormone replacement regimens. Long-term use (8 years and more) of the combined oestrogen-progestogen HRT regimen was associated with, if anything, a reduction in risk of breast cancer. We found no association between breast cancer risk and extended duration (20 years or more) of use of oestrogen replacement therapy.’
In a 22-year prospective and follow-up study , there were six cases of breast cancer in 52 never-users of HRT, whereas none of the 116 women who had used ERT at any time developed breast cancer (p = 0.01). This is strong evidence that adding progestogen to ERT reduces the risk of breast cancer.
In women treated for breast cancer, HRT is widely considered unsuitable because of the fear that exposure to female sex hormones can increase the risk of cancer recurrence. Wren  showed that women with stage-I breast cancer who took continuous oestrogen and medium-dosage progestogen replacement therapy had a much reduced risk of recurrence or death compared with matched controls.
Progesterone also has a role to play in the management of breast cancer. Performing mastectomy during the luteal phase of the menstrual cycle — when the serum progesterone levels are higher — improves the overall survival and recurrence-free interval of breast cancer patients. In one study , the 10-year survival from breast cancer was 84% when surgery was performed during the luteal phase, compared with 54% when the procedure was performed 3–12 days after the last menstrual period (p < 0.001). In another study, a higher recurrence rate (43%) was observed when surgery occurred before ovulation than when mastectomy was performed later in the cycle (29%) . A third study observed that 79% of women who underwent surgery at least 13 days after the last menstrual period were still alive 10 years later, compared with 40% of women who underwent surgery 1–12 days after the last menstrual period .
Lastly, for those women in whom oestrogens are completely contraindicated, i.e those with metastatic or active breast cancer, yet who are complaining of climacteric symptoms, a herbal extract therapy has been shown to be a simple and natural way of treating symptoms to improve their quality of life. However, this extract of the rhizome Cimicifuga racemosa cannot prevent osteoporosis or reduce cardiovascular disease.
Screening programmes can enable breast cancer to be detected at an early stage when adequate and effective treatment is possible. However, young women will continue to undergo premature menopause as a result of chemotherapy. According to the World Health Report , the only effective prevention strategy is currently mammography with routine breast examination which can reduce by one-third the risk of death from breast cancer among women over the age of 55 years. In the developing world, detection by breast examination may lead to a reduction in the disease. The decision to use HRT to improve quality of life should be carefully considered by both the patient and the doctor.
Despite the increasing evidence of cardiovascular protection and prevention of osteoporosis with HRT, there is still concern about its relationship with endometrial and breast cancer. It can be concluded that HRT (oestrogen plus progestogen) can be prescribed to women with an intact uterus. This would significantly reduce the risk of endometrial carcinoma. This regimen has also been shown to significantly decrease the risk of breast cancer, and thus should also be prescribed to women who have undergone hysterectomy. Together with regular screening with mammography and annual breast examination, HRT can be considered safe with regard to breast cancer risk.
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