Hormone Replacement Therapy

Around the time of the menopause, declining levels of oestrogen and progesterone can bring about many symptomatic changes for women.

• 80% of menopausal women experience symptoms, such as hot flushes and night sweats.
• 45% find these symptoms distressing.¹
• Most symptoms are usually short-lived over a period of 2-5 years, but they may persist longer in a small proportion of women.

Hormone replacement therapy (HRT) can be an effective treatment for the typical menopause-related symptoms. There are also other long-term health problems associated with the menopause: the risk of osteoporosis, cardiovascular disease and stroke all increase after the menopause. HRT may also have an influence on these health problems, though it should be noted that it does not necessarily reduce their risk for all women.

Large studies, including the Women's Health Initiative (WHI)² and the Million Women Study (MWS),³ have cast concerns and controversy over the use of HRT, with evidence of increased risk of breast cancer, cardiovascular disease and thromboembolic disease and little evidence for supposed benefits, such as maintained protection against osteoporosis and cognitive decline.⁴

However, many women still have significant and disabling symptoms associated with the menopause, and HRT continues to have an important clinical role in improving quality of life in symptomatic menopausal women, with many opting to remain on HRT despite the research findings.⁵

This article discusses HRT in detail. A separate article Menopause and its Management discusses menopausal symptoms, differential diagnosis and possible investigations (although the diagnosis is usually clinically based on the typical symptoms). It also discusses health problems associated with the menopause and gives an overview of management. See separate related articles: HRT- Topical, Combined Hormone Contraception and HRT (Risks vs Benefits) and HRT - Alternatives.

Current indications for the use of HRT are more limited than previously:^1,4

• For the treatment of menopausal symptoms where the risk-benefit ratio* is favourable, in fully informed women, in the lowest possible dose to control symptoms and for the shortest duration possible.
• For women with early menopause (<45 years) until the age of natural menopause (taken as 50 years).
• HRT should only be used for the prevention of osteoporosis in women unable to use other medicines licensed for this use.

HRT can help:¹

• Vasomotor symptoms (including sleep or mood disturbance caused by these symptoms; when compared with alternatives, HRT is the most effective way to control these symptoms^7,8)
• Urogenital symptoms⁹
• Prevent osteoporosis (though HRT should not be used as a first-line treatment except in women who have premature menopause because the risks outweigh the benefits)
• Reduce the risk of colorectal cancer (but HRT should not be used just for this purpose)
• Women with premature menopause for prevention and treatment of cardiovascular disease and osteoporosis until 50 years (taken as the age of natural menopause)

Reduced libido and sexual function will not be directly affected by HRT. Loss of libido after surgical menopause has been assisted by testosterone therapy. But there are potential adverse effects and advice on dosing should be sought from a specialist. Tibolone (see below) may be helpful in relieving vaginal dryness and also for increasing libido.¹⁰

• Venous thromboembolism (VTE)^4,11,12
  • HRT (combined or oestrogen-alone) increases the risk of a deep vein thrombosis or pulmonary embolism, especially in the first year of treatment. The risk is more pronounced in women with pre-existing risk factors for VTE.
  • The baseline risk of VTE increases with age, and use of HRT further adds to this risk.
  • Approximate risks:
    • 5 in 1,000 non HRT-using women aged 50-59 years will have a VTE over five years, increasing to 8 in 1,000 in the 60-69 year age bracket.
    • In women using oestrogen-only HRT, 7 per 1,000 of the 50-59 year-olds (i.e. an extra two cases) and 10 per 1,000 in the 60-69 year olds (again an extra two cases) will experience a VTE in a five-year period.
    • In women using combined HRT, 12 women aged 50-59 years (i.e. an extra seven cases) and 18 women aged 60-69 years (an extra ten cases) will experience a VTE in five years.
  • A recent meta-analysis suggests that transdermal oestrogens may be a safer option - as regards risk of VTE - than oral oestrogens for HRT.¹³ This requires clarification but may offer a means of improving risk-benefit ratios in women with pre-existing risk factors for VTE who nonetheless require HRT.
• Coronary heart disease (CHD)⁴
  • There is not the same evidence of cardioprotection from HRT as was originally thought.
  • There is an increased risk of CHD in women starting combined HRT more than ten years after menopause.¹⁴ There are fewer data assessing the risk of younger, newly menopausal women, whose overall risk (baseline and that attributable to HRT) is likely to be low.
  • No increased risk of heart disease was found in the oestrogen-only arm of WHI after seven years.
  • Assess all women's risk of CHD prior to starting HRT.
• Stroke
  • Risk of stroke is increased in those taking HRT (both combined and oestrogen-only):⁴
    • There is a small increase in overall rate of stroke in women taking either combined or oestrogen-only HRT from 4 (in non-users) up to 5 strokes per 1,000 women aged 50-59, taking HRT for five years.
    • In older women, the stroke risk in non-users is higher. So, older women taking either combined or oestrogen-only HRT have a higher absolute risk: 5 years' HRT use increases the risk of stroke from 9 up to 12 per 1,000 women aged 60-69.
• Dementia
  • If HRT is started after the age of 65, it is not thought to protect against dementia.
  • Also, combined HRT may increase the risk of dementia in women over the age of 75 years. The WHI Memory Study trials suggest that HRT (pooled combined and oestrogen-only) increases the risk of dementia from 12 to 20 cases per 1,000 women using HRT for five years.¹⁵
• Breast cancer⁴
  • HRT used for several years increases the risk of breast cancer but the additional breast cancer risk due to HRT for an individual is relatively small and multiple other risk factors also contribute, e.g. alcohol intake, obesity and lack of exercise.
  • Combined HRT is associated with a higher risk than oestrogen-alone. The MWS suggested a small increase in risk of breast cancer with oestrogen-only HRT compared with combined HRT.³ This increase in breast cancer with unopposed oestrogen was not found in the WHI study when oestrogen-only HRT was used for up to seven years.¹⁶
  • The increased breast cancer risk is proportional to the duration of HRT but not the age at which treatment is started (but the baseline risk of breast cancer also increases with age):
    • Using combined HRT for five years, in women aged 50-59, there are 6 additional cases of breast cancer per 1,000 women on a baseline incidence of about 10 per 1,000 women. For oestrogen-only HRT, there are about 2 extra cases per 1,000 women.
    • Using combined HRT for five years in women aged 60-69, there are 9 extra cases per 1,000 women on a baseline incidence of 15 per 1,000 women. For oestrogen-only HRT, there are 3 extra cases.
    • If duration of use increases to 10 years, in women aged 50-59 taking combined HRT, there are 24 additional cases of breast cancer per 1,000 women on a baseline incidence of 20 per 1,000 women. For oestrogen-only HRT, there are 6 extra cases.
    • For women aged 60-69 with 10 years' use, combined HRT increases cases of breast cancer by 36 per 1,000 on a baseline of 30 per 1,000 women and oestrogen-only by 9 cases.
  • The excess breast cancer risk subsides within five years of stopping.
  • The invasive breast cancers diagnosed in the combined HRT group of WHI were larger and more advanced than the placebo group.² Previously it had been thought that breast tumours found in HRT users had a better prognosis.
  • HRT, especially certain regimes (e.g. conjugated equine oestrogens +/- medroxyprogesterone), can increase mammographic density and may increase the likelihood of having an abnormal mammogram that needs further investigation.
• Endometrial cancer⁴
  • Oestrogen-only HRT substantially increases the risk of endometrial cancer in women with a uterus.
  • The use of cyclical progestogen for at least 10 days per 28-day cycle eliminates the risk.
• Ovarian cancer^4,17
  • There is a small increased risk of ovarian cancer developing in current, or recent, users of HRT, which increases with duration of use, and is seen whichever preparation, constituents or mode of administration is used.
  • It amounts to one extra ovarian cancer in women aged 50-59 using HRT for 10 years (baseline 4 per 1,000 women) and two extra cases in women aged 60-69 (baseline 6 per 1,000 women).

A recent post-hoc analysis of the WHI study has shown that, although treatment with oestrogen plus progestogen in postmenopausal women did not increase the incidence of lung cancer, it did increase the number of deaths from lung cancer, in particular deaths from non-small cell lung cancer. The analysis concluded that these findings should be incorporated into risk-benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer.¹⁸

• Pregnancy and breast-feeding
• Undiagnosed abnormal vaginal bleeding
• Venous thromboembolic disease
• Active or recent angina or myocardial infarction
• Suspected, current or past breast cancer
• Endometrial cancer or other oestrogen-dependent cancer
• Active liver disease with abnormal liver function tests

Women who would like HRT but have a contra-indication to it (e.g. current or past breast or endometrial cancer) should be referred for specialist advice.

Investigations are not usually necessary before starting HRT unless:

• There is sudden change in menstrual pattern, intermenstrual bleeding, postcoital bleeding, or postmenopausal bleeding - refer for endometrial assessment.
• There is a personal or family history of VTE - a thrombophilia screen may be helpful.
• There is a high risk of breast cancer - consider mammography or MRI scan; refer to NICE guidance on familial breast cancer (see link below).
• The woman has arterial disease or risk factors for arterial disease - consider checking lipid profile.

Which preparation - systemic or local; cyclical or continuous?

• Women with an intact uterus
  • Vasomotor symptoms
    • Perimenopausal: systemic cyclical combined HRT (a 3-monthly regimen can be used for women with infrequent periods or who cannot tolerate progestogens).
    • Postmenopausal: systemic continuous combined HRT or tibolone.
  • Urogenital symptoms
    • Perimenopausal: low-dose vaginal oestrogen or systemic cyclical combined HRT.
    • Postmenopausal: low-dose vaginal oestrogen or systemic continuous combined HRT.
• Women who have had a hysterectomy
  • Vasomotor symptoms: systemic oestrogen-only HRT.
  • Urogenital symptoms: low-dose vaginal oestrogen or systemic oestrogen-only HRT.

Which delivery route?¹

Delivery routes include:

• Continuous or cyclical oral therapy
• Patches
• Creams or gels
• Nasal sprays
• Local devices such as the progesterone-releasing Mirena® coil
• The oestrogen-releasing vaginal ring
• Subcutaneous implants

The choice of delivery route depends partly on patient preference but there may also be other advantages to certain delivery routes:

• Transdermal patches may be preferred to oral administration in some situations:
  • If there is poor control of symptoms with oral treatment.
  • If there are side-effects such as nausea.
  • There may be a lower risk of VTE with patches.
  • If the woman is taking a liver enzyme-inducing drug.
  • If the woman has a bowel disorder which may affect oral absorption.
  • Steadier hormone levels with patches may be beneficial if there is a history of migraine.
  • Most HRT tablets contain lactose, so patches are preferred if there is lactose sensitivity.
• Low-dose vaginal oestrogen (tablet, cream, pessary, or vaginal ring) may be preferred if symptoms are primarily urogenital.
• Estradiol implants are sometimes used after hysterectomy if symptoms cannot be controlled using other delivery routes.
• Levonorgestrel-releasing intrauterine system (Mirena®) plus oestrogen component may be used if:
  • Progestogen side-effects are experienced with other progestogen preparations and delivery routes.
  • Contraception is still needed.
  • There is persistent heavy bleeding on cyclical combined HRT and normal investigations.

Tibolone

• Tibolone is a selective oestrogen receptor modulator (SERM) which has oestrogenic, progestogenic and androgenic properties.
• It can be used in women with an intact uterus who have had no bleeding for more than one year, without the need for cyclical progesterone.
• Randomised controlled trials suggest it may be helpful in improving sexual function and vasomotor symptoms.^19,20 It may also reduce the risk of spinal fractures.¹
• There may be a small increased risk of stroke, endometrial and breast cancer (including breast cancer recurrence) with tibolone.
• Tibolone probably has a similar risk profile to combined HRT in younger women. However, in women over the age of 60 years, the increased stroke risk means that the risks outweigh the benefits.¹

• Oestrogen: breast tenderness, leg cramps, bloating, nausea, headaches.
• Progestogen: premenstrual syndrome-like symptoms, breast tenderness, backache, depression, pelvic pain.
• Bleeding: monthly sequential preparations should produce regular, predictable and acceptable bleeds starting towards the end, or soon after, the progestogen phase. Breakthrough bleeding is common in the first 3-6 months of continuous combined and long-cycle HRT regimens.

There is a discussion of how to manage these side-effects in the separate article HRT - Follow-up Assessments.

A separate article HRT - Initial Consultation gives advice about starting HRT.

• A separate article HRT - Follow-up Assessments gives advice about following up women taking HRT and when to stop HRT.
• Initial follow-up after starting HRT should occur at about three months.^1,7 Most symptoms are likely to have responded to oestrogen in this time period and any residual problems may require alternative management.
• Frequency of follow-up thereafter is controversial and not evidence-based. Drug manufacturers vary in their recommendations but consensus appears to be a minimum of annual checks.¹

• HRT does not suppress ovulation.
• In those with an intact uterus, contraception should be used:¹
  • For one year after the last menstrual period in woman >50.
  • For two years after the last menstrual period in woman <50.

1. Menopause, Clinical Knowledge Summaries (January 2008)
2. Rossouw JE, Anderson GL, Prentice RL, et al; Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33. [abstract]
3. Beral V; Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003 Aug 9;362(9382):419-27. [abstract]
4. CSM Drug Safety Update Vol 1, Issue 2, Sept 2007
5. Rymer J, Sturdee DW; Hormone replacement therapy after the menopause--where are we now? Br J Gen Pract. 2005 Mar;55(512):172-4.
6. Hormone-replacement therapy: safety update - UK Public Assessment Report; MHRA July 2007.
7. Rees M, Stevenson J, Hope S, Rozenberg S, Palacios S. Management of the Menopause, 5th edition. May 2009.
8. Maclennan AH, Broadbent JL, Lester S, et al; Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD002978. [abstract]
9. Robinson D, Cardozo L; The menopause and HRT. Urogenital effects of hormone therapy.; Best Pract Res Clin Endocrinol Metab. 2003 Mar;17(1):91-104. [abstract]
10. Modelska K, Cummings S; Tibolone for postmenopausal women: systematic review of randomized trials.; J Clin Endocrinol Metab. 2002 Jan;87(1):16-23.
11. British National Formulary; 58th Edition (September 2009) British Medical Association and Royal Pharmaceutical Society of Great Britain, London (link to current BNF).
12. MeReC Bulletin; Hormone replacement therapy: an update. Volume 15. Number 4. March 2005.
13. Canonico M, Plu-Bureau G, Lowe GD, et al; Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ. 2008 May 20;. [abstract]
14. Rossouw JE, Prentice RL, Manson JE, et al; Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007 Apr 4;297(13):1465-77. [abstract]
15. Espeland MA, Rapp SR, Shumaker SA, et al; Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24):2959-68. [abstract]
16. Anderson GL, Limacher M, Assaf AR, et al; Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004 Apr 14;291(14):1701-12. [abstract]
17. Beral V, Bull D, Green J, et al; Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet. 2007 May 19;369(9574):1703-10. [abstract]
18. Chlebowski RT, Schwartz AG, Wakelee H, et al; Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial. Lancet. 2009 Sep 18. [abstract]
19. Nathorst-Boos J, Hammar M; Effect on sexual life--a comparison between tibolone and a continuous estradiol-norethisterone acetate regimen. Maturitas. 1997 Jan;26(1):15-20. [abstract]
20. Al-Azzawi F, Wahab M, Habiba M, et al; Continuous combined hormone replacement therapy compared with tibolone. Obstet Gynecol. 1999 Feb;93(2):258-64. [abstract]

• International Menopause Society
• Familial breast cancer, NICE Clinical Guideline (October 2006); the classification and care of women at risk of familial breast cancer in primary, secondary and tertiary care