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Pros and cons of hormone replacement therapy

Margaret Rees
MA DPhil FRCOG
Honorary Senior Clinical Lecturer
Obstetrics and Gynaecology

Janet Brockie
SRN
Clinical Nurse Specialist
Women's Centre
John Radcliffe Hospital, Oxford

The frequency of hormone replacement therapy (HRT) use in different populations varies greatly. In Western Europe rates vary from 3% to 44%. In the UK it is 17% with a lower uptake in minority non-Caucasian groups.(1,2) Over 50% of women will have stopped therapy within 1 year, even women with a low bone-mineral density who are advised to take HRT.
The majority of women take HRT for the relief of vasomotor symptoms, with only 10% indicating concern for osteoporosis prevention. Women receive much of their information from the media, resulting in an incomplete understanding.(1) Some women decline HRT as they consider it unnatural; others receive insufficient knowledge; and others with few symptoms or risk factors for osteoporosis feel it offers them limited benefits.
Compliance is greater in female gynaecologists, GPs or the spouses of their male counterparts, suggesting that good information and a positive attitude to therapy are important.(3) A major reason for taking HRT is a positive attitude and recommendation by the practitioner. Gender is also significant, with non-compliance being greater with male than female practitioners. 
Concordance is greater in women following hysterectomy and bilateral oophorectomy, but symptomatology is often more severe in this group. These women will require oestrogen-only HRT and will not experience vaginal bleeding or progestogenic side-effects, both common reasons for discontinuing therapy. Other reasons cited in studies for discontinuing therapy include lack of efficacy, side-effects and concern about long-term risk.

HRT preparations

There has been a dramatic increase in the number of licensed HRT preparations, with over 50 now available in the UK.(4) The essential component is oestrogen, which is combined with a progestogen to prevent endometrial hyperplasia in women whose uterus is intact. HRT can be delivered by a variety of routes: oral, transdermal, subcutaneous, vaginal and intranasal. Tibolone is a synthetic compound with mixed oestrogenic, progestogenic and androgenic actions, and is used in postmenopausal women who wish to have amenorrhoea. Androgens, currently available as testosterone implants, may be used to improve libido, but are not successful in all women since factors such as marital problems may be involved.
The oral route is the usual first-line treatment unless there is a pre-existing medical condition. Transdermal oestradiol and progestogens can penetrate the skin. Two transdermal systems are now available: patch and gel. There are two patch technologies: alcohol-based reservoir patches with an adhesive outer ring and matrix patches where the hormone is evenly distributed throughout the adhesive. Skin reactions are less common with matrix than with reservoir patches. Only norethisterone and levonorgestrel are delivered transdermally in patches. Currently only oestradiol is delivered in a gel.
Oestradiol implants are crystalline pellets of oestradiol that are inserted subcutaneously under local anaesthetic, releasing oestradiol over many months. Implants have the advantage that the patient does not have to remember to take medication. A significant concern is tachyphylaxis, defined as recurrence of menopausal symptoms while the implant is still releasing adequate levels of oestradiol. Oestradiol and progestogens can also be absorbed from the vagina and nasal mucosa, leading to the development of vaginal rings and nasal sprays.
Intrauterine levonorgestrel can provide the progestogen component of HRT. The oestrogen can then be given orally or transdermally. It also provides a solution to the problem of contraception in the perimenopause, and it is the only way in which a "no-bleed" regimen can be achieved in perimenopausal women.

Long-term risks of HRT

Breast cancer is the most common reason given for not taking long-term HRT. In North America and Europe the cumulative incidence of breast cancer between the ages of 50 and 70 in those who never use HRT is about 45 per 1,000 women. A reanalysis undertaken in 1997 of 51 epidemiological studies, including 52,705 women with and 108,411 without breast cancer, found that HRT increases the risk by 2.3% per year of use when it is started in the above-50 age group, roughly equivalent to the rise in relative risk of breast cancer associated with each year the menopause is delayed after the age of 50.(5) Such an effect is not seen in young women with a premature menopause who take HRT until 50 years, indicating that it is the duration of lifetime oestrogen exposure that is relevant. After cessation of HRT, the effect on breast cancer disappears within five years. 
The link between unopposed postmenopausal oestrogen replacement therapy and endometrial hyperplasia and cancer was first reported in the 1970s. In a meta-analysis of 30 studies, the relative risk (RR) was 2.3 for oestrogen users compared with 2.1-2.5 for non-users with a 95% confidence interval (CI). The RR increased with prolonged duration of use (9.5 for ten or more years).(7) The risk of endometrial cancer remains elevated for 5 or more years after discontinuation of unopposed oestrogen therapy (RR 2.3).   
A recent series of case control studies and one randomised controlled trial provide clear evidence linking HRT and venous thromboembolic disease (VTE), with an RR of 2-4 and an absolute risk of around three per 10,000 users per year compared with one per 10,000 in non-users.(8) So for 10,000 women-years of use, HRT would be responsible for two extra cases of VTE that would otherwise not have occurred. The mortality of VTE is 1-2%. One study suggested the increased risk was restricted to the first year of use.

Managing the side-effects

Side-effects account for almost 35% of HRT discontinuation and can be oestrogen and/or progestogen related. Bleeding and fear of weight gain are also common. Oestrogenic- related side-effects include fluid retention, bloating, breast tenderness/enlargement, nausea, headaches, leg cramps and dyspepsia. They occur continuously or randomly throughout the cycle. In most cases they are transient and resolve with continued use. Patients should be encouraged to persist with therapy for at least 12 weeks to await resolution. 
Progestogen-related side-effects include fluid retention, breast tenderness, headaches/migraine, mood swings, depression, acne, lower abdominal pain and backache. They occur during the progestogen phase. The options to consider are reduction in dose or frequency, and change of route of delivery or type of progestogen administered. Continuous combined therapy may reduce progestogenic side-effects but is only suitable for postmenopausal women.
Many women decline or stop HRT because of a fear of weight gain. Irrespective of HRT, women at or near the menopause tend to gain weight with age. A recent Cochrane systematic review evaluated all randomised, placebo or no-treatment controlled trials that detailed the effect of HRT on weight or bodyfat distribution. No statistically significant difference was found in mean weight gain between those using unopposed oestrogen and non-HRT users (0.66kg, 95% CI: -0.62, 1.93).(9)
Bleeding is a common reason for stopping HRT, and it is not surprising that there is an increased use of HRT in hysterectomised women. For monthly sequential regimens if withdrawal bleeding is heavy or prolonged, or there is breakthrough bleeding, the dose and type of progestogen needs to be altered. Pelvic pathology will need exclusion if the problem is persistent or does not respond to treatment. For long-cycle HRT regimens breakthrough bleeding is common in the first 3-6 months of therapy, but thereafter needs assessment.
In the case of "no-bleed" therapy, with continuous combined therapies or tibolone it is not unusual for women to bleed during the first 6 months of therapy; in most cases it is light bleeding or spotting. Investigation needs to be undertaken if bleeding persists beyond 6 months or occurs after many months of amenorrhoea.

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References

  1. Hope S, et al. Survey of British women's views on the menopause and HRT. J Br Meno Soc 1998;4:33-6.
  2. Hill DA, Weiss NS, LaCroix AZ. Adherence to post-menopausal hormone therapy during the year after the initial prescription: a population-based study. Am J Obstet Gynecol 2000;182:270-6.
  3. Brockie J. Compliance or concordance? J Br Meno Soc 2000;6:23-6.
  4. Rees M, Purdie D, editors. Management of the menopause. The handbook of the British Menopause Society. Oxford: BMS Publications; 1999.
  5. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and HRT: collaborative re-analysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047-59.
  6. Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: oestrogen versus oestrogen plus progestin. J Natl Cancer Inst 2000;92:328-32.
  7. Grady D, Gebretsadik T, Kerlikowske K, et al. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol 1995;85:304-13.
  8. RCOG. Hormone replacement therapy and venous thrombo-embolism. London: RCOG; 1999.
  9. Norman RJ, Flight IH, Rees MC. Oestrogen and progestogen hormone replacement therapy for peri-menopausal and post-menopausal women: weight and body fat distribution. Cochrane Database Syst Rev 2000;2:CD001018.

Resources
British Menopause Society
T:01628 890199
W:www.the-bms.org

HRT Resource Centre
W:www.hrtinfo.co.uk

Further reading
Rees M, Purdie DW, editors. Management of the menopause. The handbook of the British Menopause Society. Oxford: BMS Publications; 1999

Hope S, Rees M,  Brockie J, editors. Hormone replacement therapy - a guide for primary care. Oxford: Oxford University Press; 1999

Contact
Lactacyd Femina website: ­comprehensive and practical advice on the product range, together with the role of lactic acid
www.lactacydfemina.co.uk
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