Evaluating the possible risks or benefits of hormone replacement therapy use for an individual patient is quite complex and, as many experts on this topic have already stated, individual assessment of each woman is necessary to appropriately evaluate the most suitable course of treatment. The available data from research studies can guide the decision, but an assessment of the age of the woman, her individual risk profile, the type of hormone replacement therapy under consideration, the proposed dose and the duration of use of replacement hormones, and an assessment of her concurrent drug use will provide the most important information. Some of this information is lacking — for example, it is still not clear what role if any progestogens play in breast cancer risk. This may become clearer after the release of findings from the oestrogen-only arm of the WHI trial.
Age is an important consideration in the decision-making process. The risk of osteoporosis for women less than 50 who have premature or surgical menopause increases in tandem with the number of years without ovarian hormones. Replacement hormones may be an appropriate option for these women and the usually low risk of heart disease and smaller risk of breast cancer needs to be weighed against the considerable risk of developing osteoporosis. The issues for women between 50 and 60 who have sufficient indications for hormone replacement therapy were not necessarily clarified by the WHI study, because the cohort were primarily older women with a different risk profile to this age group. Again, it will likely be the other features of the woman’s history that are critical to the prescribing doctor in making a decision.
Dose of hormone replacement therapy may need to be altered, depending on the type of condition to be treated. There is an increasing trend to suggest the lowest effective dose, especially when hormone replacement therapy is prescribed for hot flushes. This may not be possible, however, when the primary aim is to manage osteoporosis, because effective doses for maintaining or improving bone density may be higher than those needed for symptom control.
The type of hormone replacement therapy may be selected to moderate the degree of risk. For example, topical oestrogens have a lower overall risk profile and should be suggested instead of oral hormone replacement therapy for urogenital symptoms. Synthetic oestrogens may increase the tendency to thromboembolic disease and natural oestrogens can be prescribed instead. The selection of the type of progestogen needs to be assessed in the light of the knowledge that some types used long term have been associated with abnormal blood lipid profiles.
The duration of use is emerging as the primary feature in breast cancer risk and even when hormone replacement therapy is used to improve bone density, another form of medication may need to be considered after five years of continued hormone replacement therapy use. Many medications, such as corticosteroids or high doses of thyroxine reduce bone density, and a range of bone-protective medications including hormone replacement therapy will need to be considered for women on these types of medication. Finally, each woman’s individual risk profile for heart disease, breast cancer and osteoporosis will be critical factors in the decision-making process to evaluate the need or otherwise for hormone replacement therapy as well as deciding on which type to use.
The evidence for adverse effects on breast cancer risk with long-term use of hormone replacement therapy has been increasing for the past ten years. Oestrogen replacement alone has been estimated to increase breast cancer risk amongst post-menopausal women by 2 per cent, and oestrogen with a progestogen by 4 per cent, in one large multi-centre population study. Other estimates suggest that the overall risk is 2.3 per cent each year for current use and recent use (Hormone Replacement Therapy during the past four years). A number of investigations have confirmed that breast cancer risk increases with increasing duration of use. Once hormone replacement therapy has been stopped for more than five years, the risk diminishes to the same rate as in women who have not used Hormone Replacement Therapy.
In view of the knowledge that breast cancer risk in the general population increases with age, older women have a greater background risk of breast cancer, which amplifies their drug-related risk when taking replacement hormones. The recent WHI trial, for instance, identified a 26 per cent increase of invasive breast cancer compared to placebo, which equated to 38 cases per 10 000 person-years compared to 30 cases per 10 000 person-years with placebo. There was no increase in risk in the rate of development of in situ breast cancers.
Table Factors associated with increased breast cancer risk
• Never having been pregnant and not having breastfed (or pregnancy and breastfeeding later in life)
• Family history of breast cancer
• hormone replacement therapy for more than five years
• Increased breast density on mammogram before starting Hormone Replacement Therapy
Endometrial cancer can occur when oestrogen is given without a progestogen to a woman who has not had a hysterectomy. The risk increases the longer the woman stays on the oestrogen replacement therapy, and remains elevated for five or more years after stopping the treatment. This risk is reduced when progestogens are given for a short period of time and then withdrawn, causing a ‘period’; or when a low dose of progestogen is given continuously which leads to endometrial ‘shrinkage’ with eventual cessation of uterine bleeding after several cycles.
Osteopaenia and osteoporosis
Women with osteopaenia are not routinely prescribed hormone replacement therapy and should improve their bone density by taking supplemental calcium or other nutrients, starting an exercise regime, staying a healthy weight, retaining agility and muscle strength, and eating a balanced diet. Hormone replacement is one option for women with osteoporosis, as oestrogens, including the oral contraceptive pill, have a positive effect on bone density. Women with substantial fracture risk are often prescribed hormone replacement therapy (HRT), but any positive effect will be lost within a few years at a rate similar to that seen in the immediate postmenopausal years when hormone replacement therapy is stopped.
Hormone Replacement Therapy and oestrogen replacement therapy (ERT) reduce the rate of bone turnover and resorption. Progestogens to protect against increased risk of endometrial cancer (from unopposed oestrogen) do not reduce the bone-preserving effects. There are more than fifty randomised, placebo controlled clinical trials that show that ERT/Hormone Replacement Therapy increases spine bone mineral density (BMD) by 4-6 per cent and hip BMD by 23 per cent, and maintains those increases after three years of treatment. To date there is little consistent and conclusive research on the efficacy of hormone replacement therapy on fracture prevention from randomised clinical trials. Observational studies (which are considered less valid) indicate a significant reduction in fracture with ERT/Hormone Replacement Therapy (HRT), ranging from a 25 per cent reduction in hip fracture amongst women who had ever used ERT/Hormone Replacement Therapy (HRT), to a 35 per cent reduction in risk of non-spine fractures in current long-term users compared to never users. ERT/Hormone Replacement Therapy was more effective if started within five years of menopause and if used longer than ten years.
Until recently, hormone replacement therapy was the first choice for doctors in the prevention of bone loss. After the findings of the WHI study, an Australian expert committee convened by the Therapeutic Goods Administration recommended against long-term use of hormone replacement therapy (HRT), but stated that continued use for women with osteoporosis could be considered as an option for some women after discussion of the risks and benefits between patient and doctor. WHI examined the long-term effects of hormone replacement therapy and demonstrated a decreased risk of hip fracture over 5.2 years, with five fewer hip fractures in the hormone replacement therapy group (10 versus 15) than in the group not on hormone replacement therapy (equivalent to a 34 per cent risk reduction).
Women are likely to be reluctant to embark on long-term hormone replacement therapy for prevention of osteoporosis, especially when there is little data to support a reduction in fracture risk but evidence of an increased breast cancer risk as shown in the WHI study. However, even before these results were published, about 75 per cent of women who begin ERT/Hormone Replacement Therapy discontinue after six months, probably because of breast cancer concerns.
It has been observed that endogenous oestrogens exert cardio-protective effects in pre-menopausal women which led to the expectation that hormone replacement therapy given to menopausal women would have the same protective effects. However, the findings of the WHI trial which resulted in the termination of the oestrogen/ progestogen arm of the trial, coupled with the recent Heart Estrogen/Progestin Replacement Study (HERS), suggest that hormone replacement therapy does not confer any benefit in the prevention of stroke or heart disease in otherwise healthy women. Two recent meta-analyses support this position, which has also been endorsed by the American Heart Association. The positive effects from preventative strategies that incorporate dietary changes such as consuming more oily fish and omega-3 essential fatty acids, soy and vitamin E-containing foods is increasingly being verified in the literature.
Table Factors associated with increased risk of cardiovascular disease
• Cigarette smoking
• Elevated triglycerides, total cholesterol and low HDL cholesterol
• Poor physical fitness
• Inadequate diet, including a low omega-3 fatty acid intake
• Hormonal medication including hormone replacement therapy and the Pill, especially when taken by women over 35
Gall bladder disease
Oestrogen changes the composition of bile and increases the amount of cholesterol in bile more than a dietary increase in cholesterol. Because high levels of cholesterol in the bile are prone to precipitate out and form gall stones, women on the Pill and hormone replacement therapy are more prone to gall bladder disease than other women. To prevent this complication, an oestrogen patch is often suggested because transdermal oestrogens do not cause the rapid increase in oestrogens and the subsequent changes to the consistency of the bile.
Evidence is accumulating that the use of hormone replacement therapy reduces the risk of colorectal cancers in post-menopausal women. The Nurses Health Study showed an apparent protective effect amongst current users of hormone replacement therapy (HRT), and the WHI study found a 37 per cent reduction in the incidence of colon cancer.