Management of bleeding problems with hormone replacement therapy.

It is well established that all non-hysterectomised women taking oestrogen replacement therapy should receive additional progestogen to reduce the incidence of endometrial hyperplasia1–3 and cancer.4 Progestogens are either added cyclically on a monthly (sequential), or 3monthly basis (tricyclic) or continuously (period-free or no bleed). Alternative combinations such as bimonthly,5 6monthly6 and intermittent where the progestogen is added for 3 days every 3 days have been tried.7 However, data on these preparations are limited, and there are no licensed products in the UK utilising these schedules. Choosing the appropriate combination is a key factor in minimising the likelihood of unscheduled bleeding with hormone replacement therapy (HRT). The introduction of period-free HRT in perimenopausal women, often in the hope that it will stop their bleeding, is probably one of the biggest causes of bleeding problems with HRT. Continuous progestogen addition should be reserved for women who are clearly postmenopausal. This is often taken to be over 54 years, as by this stage over 80% of women will be postmenopausal, but there is no reason why younger women cannot commence it if they are clearly postmenopausal. Unscheduled bleeding on HRT is a common problem and is one of the biggest causes of dissatisfaction with HRT. With advancing age the potential for underlying pathology increases, thus the two main strategies in managing irregular bleeding on HRT are first to exclude pathology and second to correct the irregular bleeding. Bleeding problems are not only inconvenient and a cause of anxiety, they are also costly. Ettinger et al. reported that over 38% of women on sequential and 41% on period-free HRT attended his clinic with bleeding irregularities in a 12-month period, and 12% and 20%, respectively, required endometrial biopsies.8 Various types and routes of progestogens are used in HRT. The most widely used are the testosterone derivatives, norethisterone acetate (NETA) and levonorgestrel, and the C21 derivatives, medroxyprogesterone acetate (MPA) and dydrogesterone. Other progestogens that are used with HRT include trimegestone,9 cyproterone acetate,10 nomegestrol11 and norgestimate.12 The third-generation levonorgestrel derivatives, desogestrel and gestodene, were being actively looked at as part of HRT combinations but since their possible association with an increased thrombosis risk in the combined pill, little progress has been made. Natural progesterone is available in the UK as either vaginal pessaries or sustained-release vaginal gel13 and can be used as an alternative for progestogen intolerant women. This should not be confused with ‘natural’ progesterone cream, which is available as a natural health product but has no proven efficacy on the endometrium.14. Oral micronised progesterone may also be used but is not readily available in the UK. NETA and levonorgestrel are available transdermally as part of an oestrogen combination patch. The levonorgestrel intrauterine system (IUS) is increasingly being used for the progestogen component of HRT. Whilst it appears to be effective in opposing the oestrogenic effects on the endometrium and it also solves the vexing problem of contraception in perimenopausal women, it is not currently licensed for use with HRT, and the few published studies have very small numbers.15 Further trials are ongoing. Choosing the progestogen for a particular woman is an individual decision. Side effects are common with all progestogens and may be improved by changing the type or dose of the progestogen. Whilst there are some differences between the metabolic effects of the various progestogens, the clinical relevance of these is unclear and caution should be exercised in interpreting data on surrogate markers of disease end points such as cardiovascular disease and thrombosis. As far as cycle control is concerned there are no clear data to indicate that one progestogen is superior to another. The recommended doses for cyclical administration are well known16 and commercial preparations incorporate these. When particular difficulties arise, the progestogens can be prescribed individually as part of a tailor-made combination.