Post Reproductive Health

A reduction in bone mass is observed in a high percentage of patients following organ or marrow transplantation, with the prevalence of osteopenia or osteoporosis reported to be as high as 80%. Between 4 and 65% of transplant recipients will experience an osteoporosis-related fracture and the likelihood of such a serious outcome is dependent on pre-existing disease and immunosuppressive therapy. End-stage pulmonary disease is commonly associated with a reduction in BMD; chronic liver disease with osteomalacia and osteoporosis; and renal patients are often recognised to have osteodystrophy, osteopaenia or osteoporosis at the time of transplantation. Post-transplant glucocorticoid therapy plays a major role in the further reduction in bone mass observed in these patients. Glucocorticoids have several effects deleterious to the skeleton, transiently increasing bone resorption then subsequently inhibiting both osteoclast and osteoblast activity. They also interfere with calcium, vitamin D and PTH metabolism. The additional role of other immunosuppressant treatments in bone loss is less clear but there is some evidence to suggest that cyclosporin A (CsA) and tacrolimus (FK506) result in high bone turnover osteopenia. CsA can also result in hypogonadism when used in high doses and hypomagnesaemia which can contribute to a reduction in bone mass. Comparative studies in renal transplant patients have suggested that CsA monotherapy has less of an effect on BMD than combination therapy with glucocorticoids. Newer immunosuppressants such as rapamycin are believed to have minimal effects on bone metabolism compared to CsA or FK506. Although some variability exists in the studies reporting bone related outcomes following transplant, current evidence suggests that the cumulative dose of glucocorticoid, male gender, increasing age and development of an early menopause as a result of treatment are the factors associated with severe bone disease. Since the greatest loss of bone is observed in the first 3-6 months following transplant, coincident with glucocorticoid therapy, strategies to prevent bone loss should be directed at the peri-operative period. Reduction in the use of glucocorticoids by using steroid-sparing combination therapy has been effective and in cardiac transplant patients the use of vitamin D or its analogues in combination with calcium has also proved beneficial. Early reports of the use of intravenous pamidronate are encouraging with improved BMD and significant reductions in fractures reported.

The exact incidence of new breast symptoms with hormone replacement therapy (HRT) and its trophic effects on benign breast disorders is not well quantified and remains relatively understudied. This is a rapidly growing clinical issue as the rate of HRT use is increasing. Significant mastalgia with breast tenderness, mammographic changes and benign and premalignant breast proliferative epithelial diseases with and without atypia are common with HRT. Mammographic sensitivity and specificity are decreased by the increased focal and diffuse mammographic density caused by oestrogen and/or progestogen. There is a widely perceived but incorrect belief that progestogens are beneficial for the breast in terms of symptoms and breast cancer risk; however, the opposite now appears to be the case. The small but significant risk of the diagnosis of invasive breast cancer with HRT has diverted attention in the medical literature away from the actual increase in the incidence of benign breast disease. This is well and truly counter-balanced by the many proven important health benefits of therapy in postmenopausal women including prevention of osteoporosis and improved quality of life.

Antioestrogens are among the most widely used agents in the treatment of breast cancer. There has been a recent surge of interest in these compounds because of their potential breast cancer chemopreventive properties. The newer generation of antioestrogens, with increased selectivity and better toxicity profiles, have the potential to increase the effectiveness of hormonal treatment of breast cancer. The selective oestrogen receptor modulators (SERMs) hold the promise of revolutionising the care of healthy postmenopausal women with their beneficial effects on bone and lipids in addition to the chemoprevention of breast cancer.

This review summarises current evidence for therapeutic options for hyperlipidaemia in post menopausal women. The two situations in which treatment is recommended are:

1. Primary prevention, which requires assessment of total risk factors for coronary heart disease.

a) Statins. AFCAPS/TEXCAPS is the only randomised controlled trial (RCT) to include women. Fewer coronary heart disease (CHD) events, but no difference in mortality was found.

b) Hormone replacement therapy (HRT). While there are numerous reports of positive observational epidemiological studies for HRT, there are no completed RCTs. There is little evidence for statin use in women except for familial hypercholesterolaemia. HRT is therefore not only appropriate for its multiple effects on lipoproteins, vascular function and insulin sensitivity but also for prevention of osteoporosis.

2. Secondary prevention, to achieve target total and low density lipoprotein (LDL) cholesterol.

a) Statins. The major measurable effect of these drugs is to reduce total and LDL cholesterol. In the RCTs 4S, CARE and LIPID, where 20% of subjects were female, CHD events, but neither CHD mortality nor total mortality were significantly reduced in women.

b) HRT. Data available from two RCTs using conjugated equine oestrogens and medroxyprogesterone acetate show no benefit. Other studies of HRT have been observational and positive. The effects of treatment on lipoproteins with statins, HRT and the combination have been investigated. In secondary prevention for hyperlipidaemic women to achieve cholesterol <5 and LDL<3 mmol/L statins will be first choice, with HRT a possible addition for its other benefits on cardiovascular risk factors.

Choice of HRT medication. The route of administration will affect specific risk factors, eg, oral oestrogen reduces Lp(a) and LDL, increases HDL, while the transdermal route is less effective at reducing Lp(a) and LDL but does not increase triglyceride. Both routes reduce fibrinogen, factor VII and adhesion molecules and improve blood flow. The choice of progestogen will also affect cardiovascular risk factors. The most important lipid risk factors in women are HDL, triglyceride and Lp(a). The risk associated with raised triglyceride and LDL is offset by high HDL. Thus, in women with risk factors in primary prevention, theoretically oral HRT with a non-androgenic progestogen is likely to be of most benefit. However, since long-term adherence to therapy is important in reducing cardiovascular risk, the individual's choice of route and type of HRT is paramount.

Coronary artery disease (CAD) is the number one cause of death and disability in the Western world. Its incidence increases with age and women present with symptomatic CAD on average about ten years later than men. Rationale for using hormone replacement therapy (HRT) is based on its effects on vasoreactivity, progression of atherosclerosis, lipids and lipoproteins, effects on the haemostatic system and impaired glucose tolerance. However, unopposed oestrogen might be related to an increased risk of endometrial cancer. The overall beneficial effect of HRT on cardiovascular diseases is derived from prospective cohort studies. The Heart and Estrogen/progestin Replacement Study showed no beneficial effect of HRT on cardiovascular morbidity and mortality. However, there are uncertainties about the duration and optimal type of HRT regimen. Ongoing trials addressing similar questions are not expected to be published within the next five years. The Women's Hormone Intervention Secondary Prevention (WHISP) pilot study addresses the effect of a novel HRT regimen on lipid and haemostatic risk markers of heart disease and may pave the way for a large trial evaluating the effect of HRT on morbidity and mortality.