Hormone Replacement Therapy (including Risks and Benefits)

oPatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.

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

  • Vasomotor symptoms affect around 80% of women during the menopause transition and are severe in about 20% of these women.
  • The duration of these symptoms varies, with a median of four years, but may continue for as many as 12 years in about 10% of women.[1] 

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.

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.

Current evidence-based guidelines advise consideration of HRT for troublesome vasomotor symptoms in perimenopausal and early postmenopausal women without contra-indications and after individualised discussion of likely risks and benefits.

Starting HRT in women over the age of 60 years is generally not recommended.

For women with premature (age <40 years) or early (<45 years) menopause, current guidelines recommend HRT until the age of 51 years for the treatment of vasomotor symptoms and bone preservation.

Current indications for the use of HRT are:

  • For the treatment of menopausal symptoms where the risk:benefit ratio is favourable, in fully informed women.
  • For women with early menopause until the age of natural menopause (around 51 years).

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For most symptomatic women, use of HRT for five years or less is safe and effective. Benefits of HRT include:

Reduction in vasomotor symptoms

  • HRT is the most effective treatment at reducing vasomotor symptoms.
  • Vasomotor symptoms are usually improved within four weeks of starting treatment and maximal benefit gained by three months.
  • There has been shown to be a significant mean reduction in the frequency of hot flushes by around 18 a week and in the severity of hot flushes by 87% compared with placebo[1]

Improvement in quality of life

  • HRT may also improve sleep, muscle aches and pains and quality of life in symptomatic women.[3]
  • Short-term HRT may improve mood and also depressive symptoms.

Improvement of urogenital symptoms

  • Various studies have shown that HRT significantly improves vaginal dryness and sexual function.
  • HRT is effective in improving the symptoms related to vaginal atrophy.[4] 
  • HRT may also relieve the symptoms of urinary frequency, as it has a proliferative effect on the bladder and urethral epithelium.[2] 
  • Topical oestrogen is very effective in improving urinary symptoms in menopausal women.[5]
  • Vaginal symptoms are improved, vaginal atrophy and pH decrease and there is improved epithelial maturation with topical oestrogen preparations compared to placebo or non-hormonal gels.[6] 

Reduction in osteoporosis risk

  • HRT is effective in preserving bone mineral density.
  • Taking HRT leads to a reduction in osteoporosis in the spine and hip[7] 
  • Women taking HRT have a significantly decreased incidence of fractures with long-term use[8] .
  • HRT is the first-line treatment for the prevention and management of osteoporosis in women with menopausal symptoms who are under the age of 50 years.
  • HRT should be considered in those women at high risk of fracture if there are no contra-indications to HRT.[1] 
  • The bone protection qualities of HRT are dose-related.
  • Although bone density declines after discontinuation of HRT, some studies have demonstrated that women who take HRT for a few years around the time of the menopause may have a long-term protective effect for many years after stopping HRT.[9]

Reduction in cardiovascular disease

  • The relation between HRT and cardiovascular disease is controversial, but the timing and duration of HRT, as well as pre-existing cardiovascular disease, are likely to affect outcomes.[1].
  • The Women's Health Initiative (WHI) trial demonstrated that there was a small increase in the incidence of coronary heart disease in the first year after starting HRT (women in this trial were taking conjugated equine oestrogens with or without medroxyprogesterone acetate).[10] 
  • Women who start HRT when they are aged over 60 years have an increased risk of coronary heart disease.
  • A recent study has shown that HRT reduces the incidence of coronary heart disease by around 50% if it is started within ten years of the menopause.[11]
  • This study also demonstrated that women receiving HRT early after menopause had a significantly reduced risk of mortality without any apparent increase in risk of cancer, venous thromboembolism (VTE) or stroke.
  • Another RCT showed that there is a neutral impact on cardiovascular disease risk markers (eg, coronary calcium scores and intima thickness) in women who were given low-dose HRT within three years of their last period.[12]

Other benefits

  • HRT has a protective effect against connective tissue loss and may even reverse this process.[13]
  • Some studies have shown an improvement in cognition in women who started HRT in early menopause; others have not shown this benefit.[14] 
  • There is a possible reduction in the long-term risk of Alzheimer's disease and all-cause dementia in those women who take HRT.
  • However, further studies are needed to be undertaken in this area[15] .

The principal risks of HRT are thromboembolic disease (VTE and pulmonary embolism), stroke, cardiovascular disease, breast and endometrial cancer, and gallbladder disease.[1]

Large studies, including the WHI and the Million Women Study (MWS), in the past cast concerns and controversy over the use of HRT.[10][16] 

However, data accumulated from the WHI and other studies over the past decade have shown that, in women with symptoms or other indications, initiating HRT near menopause will probably provide a favorable benefit:risk ratio. [17] 

Venous thromboembolism (VTE)

  • Oral HRT (combined oestrogen and progestogen, and oestrogen-only) increases the risk of VTE, pulmonary embolism, and stroke.[18] 
  • The risk of VTE is increased two to three times with oral HRT.
  • These risks increase with age and with other risk factors, such as obesity, previous thromboembolic disease, smoking, and immobility.
  • In healthy women aged under 60 years, the absolute risk of thromboembolic disease is low and mortality risks from VTE are low.
  • The type, dose and delivery system of both oestrogen and progestogen influence the risk of thromboembolic disease.
  • The VTE risk appears to be higher among users of oestrogens plus progestogens than among users of oestrogens alone. In addition, there is evidence for a deleterious effect of medroxyprogesterone acetate on VTE risk.[19] 
  • Current use of oral oestrogens increases the risk of VTE, especially during the first year of treatment, but past users of hormone therapy have a similar risk as never-users. However, transdermal oestrogens are thought to be safe with respect to thrombotic risk.[20]

Stroke

The risk of ischaemic (but not haemorrhagic) stroke is unclear. However, the risk:

  • Appears to be increased in women taking oestrogen-only or combined HRT.
  • Does not appear to be increased in women under 60 years old.
  • Tibolone increases the risk of stroke (doubled) in women aged over 60 years.
  • Transdermal oestrogen appears to be associated with a lower risk of stroke.
  • The effects of HRT on stroke may be dose-related and so the lowest effective dose should be prescribed in women who have signficant risk factors for stroke.

Breast cancer

Combined HRT increases the risk of breast cancer. However, the absolute risk is small at around one extra case of breast cancer per 1,000 women per annum. The risk:

  • Is greatest in lean women (BMI <25).
  • Is similar in magnitude to the risk associated with late menopause, early menarche, nulliparity, and obesity.
  • Is also similar in magnitude to drinking two to three units of alcohol daily.
  • Returns to that of a non-user within five years of stopping HRT.
  • In respect of mortality, is not significantly increased in an HRT user.

The risk of breast cancer with oestrogen-only HRT is far less than with combined HRT:

  • Most observational studies do not demonstrate an increased risk of breast cancer in women taking oestrogen-only HRT for up to five years.[21]
  • The incidence of breast cancer may not be increased with oestrogen alone, in hysterectomised women.
  • There is no evidence of an increased risk of breast cancer in women on HRT under the age of 50 compared with menstruating women of the same age.
  • Combined HRT also increases breast density and the risk of having an abnormal mammogram.[22] It is important that women are informed about this.

Data regarding the true effect of HRT on the incidence of breast cancer are still contentious.

Endometrial cancer

  • Oestrogen-only HRT substantially increases the risk of endometrial cancer in women with a uterus.
  • The use of cyclical progestogen for at least ten days per 28-day cycle eliminates this risk.
  • Tibolone does not increase the risk of either endometrial hyperplasia or endometrial cancer.[23]

Ovarian cancer

  • Current data on the role of HRT and the risk of ovarian cancer are still currently conflicting.
  • There is some evidence that there is an increased risk of ovarian cancer with the use of HRT[24].
  • The WHI study has been the only RCT studying the incidence of ovarian cancer and HRT and it concluded there was no increased risk.[10] 

Colorectal cancer

  • The WHI trial showed that colorectal cancer risk was reduced in women taking combined conjugated equine oestrogens and medroxyprogesterone acetate.[10] 
  • However, some experts feel that their results do not actually support a clinically meaningful benefit for combined hormone therapy on colorectal cancer.[25] 
  • Other studies have demonstrated a reduction in risk of colorectal cancer with use of oral combined HRT.[26] 
  • 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 LFTs.
  • Uncontrolled hypertension.

Women who would like HRT but have a contra-indication to it (eg, 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 National Institute for Health and Care Excellence (NICE) guidance on familial breast cancer.[27]
  • The woman has arterial disease or risk factors for arterial disease - consider checking lipid profile.

The dose, regimen and duration of HRT need to be individualised. There is no maximum duration of time for women to take HRT; for the women who continue to have symptoms, their benefits from HRT usually outweigh any risks.

Micronised progesterones are natural, 'body-identical' progesterones, devoid of any androgenic as well as glucocorticoid activities but being slightly hypotensive due to their anti-mineralocorticoid activity. These appear to be the optimal progestogen in terms of cardiovascular effects, blood pressure, VTE, probably stroke and even breast cancer.[28] Utrogestan® is the only one currently available to prescribe in the UK.

As transdermal oestrogen is associated with fewer risks than oral HRT, a transdermal route may be preferable for many women. This route is also advantageous for women with diabetes, hypertension and other cardiovascular risk factors, and also especially with advancing age.[29] 

Which preparation - cyclical or continuous systemic or local?

  • Women should be prescribed sequential combined HRT if:
    • their last menstrual period was less than one year ago.
  • Women can be prescribed continuous combined HRT if:
    • they have received sequential combined HRT for at least one year; or
    • it has been at least one year since their last menstrual period; or
    • it has been at least two years since their last menstrual period if they had a premature menopause.
  • If bleeding is heavy or irregular on sequential combined HRT then the dose of progestogen can be doubled or increased in duration to 21 days.
  • Erratic bleeding can be common in the first 3-6 months after starting HRT.
  • Women with persistent vaginal bleeding after six months of starting HRT need to have further investigations.
  • Women with progestogen side-effects (eg, fluid retention, mood swings, weight gain) can have the progestogen dose halved or the duration of taking progestogen reduced to 7-10 days.
  • Fewer progesteronic side-effects occur with progesterone and dydrogesterone.
  • The Mirena® intrauterine system (IUS) can be used as an alternative for endometrial protection. Its licence for this use is four years.
  • Drospirenone has anti-androgenic and anti-mineralocorticoid properties.
  • Topical oestrogen is advisable as first-line for women with vaginal atrophy.
  • However, around 10-25% of women still have symptoms with topical oestrogen so will require HRT in addition.

Which delivery route?

Delivery routes include:

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

The choice of delivery route depends partly on patient preference but there are also other advantages to certain delivery routes.

By avoiding the first pass metabolism through the liver, non-oral preparations (ie patches or gels):

  • Have less effect on clotting factors.
  • Reduce triglycerides.
  • Are are often more suitable for:
    • Women who experience side-effects such as nausea with oral preparations.
    • Women with liver disease or gallstones.
    • Women with a history of malabsorption.
    • Women who are at risk of thrombosis.
    • Women with diabetes.
    • Women taking enzyme-inducing drugs.
    • Those women with a history of migraines (the bolus effects of oral medication can trigger migraines in some women).

Other considerations

  • Low-dose vaginal oestrogen (tablet, cream, pessary, or vaginal ring) may be preferred if symptoms are primarily urogenital.
  • The levonorgestrel-releasing IUS (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.
  • The progesterone component of HRT may be progesterone or a progestogen (which binds to the progesterone receptor).
  • Some observational studies have shown that HRT containing micronised progestogens or dydrogesterone may be associated with a lower risk of breast cancer, cardiovascular disease and thromboembolic events.[1] 

Tibolone

  • Tibolone is a selective oestrogen receptor modulator (SERM) which combines oestrogenic and progestogenic activity with weak androgenic activity.
  • 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 progestogen.
  • Randomised controlled trials suggest it may be helpful in improving sexual function and vasomotor symptoms. It may also reduce the risk of spinal fractures.
  • There may be a small increased risk of stroke, endometrial and breast cancer (including breast cancer recurrence) with tibolone.
  • Tibolone is less effective than combined HRT in alleviating menopausal symptoms.[30] .
  • 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.

See separate article HRT - Follow-up Assessments for a discussion of how to manage these side-effects.

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

  • 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. 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.
  • HRT is not a contraceptive and a woman is considered potentially fertile for two years after her last menstrual period if she is under 50 years and for one year if she is over 50 years.
  • A woman who is under 50 years and free of all risk factors for venous and arterial disease can use a low-oestrogen combined oral contraceptive pill to provide both relief of menopausal symptoms, and the protection of contraception.
  • Women aged 50 years and over should not be prescribed the combined oral contraceptive pill. See separate article Contraception and the Mature Woman for more information. 

Further reading & references

  1. Hickey M, Elliott J, Davison SL; Hormone replacement therapy. BMJ. 2012 Feb 16;344:e763. doi: 10.1136/bmj.e763.
  2. Panay N, Hamoda H, Arya R, et al; The 2013 British Menopause Society & Women's Health Concern recommendations on hormone replacement therapy. Menopause Int. 2013 Jun;19(2):59-68. doi: 10.1177/1754045313489645. Epub 2013 May 23.
  3. de Villiers TJ, Pines A, Panay N, et al; Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climacteric. 2013 Jun;16(3):316-37. doi: 10.3109/13697137.2013.795683.
  4. Sturdee DW, Panay N; Recommendations for the management of postmenopausal vaginal atrophy. Climacteric. 2010 Dec;13(6):509-22. doi: 10.3109/13697137.2010.522875. Epub 2010 Sep 30.
  5. Tan O, Bradshaw K, Carr BR; Management of vulvovaginal atrophy-related sexual dysfunction in postmenopausal women: an up-to-date review. Menopause. 2012 Jan;19(1):109-17. doi: 10.1097/gme.0b013e31821f92df.
  6. Goldstein I; Recognizing and treating urogenital atrophy in postmenopausal women. J Womens Health (Larchmt). 2010 Mar;19(3):425-32. doi: 10.1089/jwh.2009.1384.
  7. Stevenson JC; HRT, osteoporosis and regulatory authorities Quis custodiet ipsos custodes? Hum Reprod. 2006 Jul;21(7):1668-71. Epub 2006 Mar 23.
  8. Marjoribanks J, Farquhar C, Roberts H, et al; Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2012 Jul 11;7:CD004143. doi: 10.1002/14651858.CD004143.pub4.
  9. Bagger YZ, Tanko LB, Alexandersen P, et al; Two to three years of hormone replacement treatment in healthy women have long-term preventive effects on bone mass and osteoporotic fractures: the PERF study. Bone. 2004 Apr;34(4):728-35.
  10. 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.
  11. Schierbeck LL, Rejnmark L, Tofteng CL, et al; Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ. 2012 Oct 9;345:e6409. doi: 10.1136/bmj.e6409.
  12. Harman SM, Brinton EA, Cedars M, et al; KEEPS: The Kronos Early Estrogen Prevention Study. Climacteric. 2005 Mar;8(1):3-12.
  13. Calleja-Agius J, Muscat-Baron Y, Brincat MP; Estrogens and the intervertebral disc. Menopause Int. 2009 Sep;15(3):127-30. doi: 10.1258/mi.2009.009016.
  14. Lethaby A, Hogervorst E, Richards M, et al; Hormone replacement therapy for cognitive function in postmenopausal women. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD003122.
  15. Maki PM, Henderson VW; Hormone therapy, dementia, and cognition: the Women's Health Initiative 10 years on. Climacteric. 2012 Jun;15(3):256-62. doi: 10.3109/13697137.2012.660613.
  16. Beral V; Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003 Aug 9;362(9382):419-27.
  17. Langer RD, Manson JE, Allison MA; Have we come full circle - or moved forward? The Women's Health Initiative 10 years on. Climacteric. 2012 Jun;15(3):206-12. doi: 10.3109/13697137.2012.666916.
  18. Sare GM, Gray LJ, Bath PM; Association between hormone replacement therapy and subsequent arterial and venous vascular events: a meta-analysis. Eur Heart J. 2008 Aug;29(16):2031-41. doi: 10.1093/eurheartj/ehn299. Epub 2008 Jul 3.
  19. Canonico M, Plu-Bureau G, Scarabin PY; Progestogens and venous thromboembolism among postmenopausal women using hormone therapy. Maturitas. 2011 Dec;70(4):354-60. doi: 10.1016/j.maturitas.2011.10.002. Epub 2011 Oct 22.
  20. Canonico M, Scarabin PY; Hormone therapy and risk of venous thromboembolism among postmenopausal women. Climacteric. 2009;12 Suppl 1:76-80.
  21. Santen RJ, Allred DC, Ardoin SP, et al; Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2010 Jul;95(7 Suppl 1):s1-s66. doi: 10.1210/jc.2009-2509. Epub 2010 Jun 21.
  22. Chlebowski RT, Hendrix SL, Langer RD, et al; Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA. 2003 Jun 25;289(24):3243-53.
  23. Archer DF, Hendrix S, Gallagher JC, et al; Endometrial effects of tibolone. J Clin Endocrinol Metab. 2007 Mar;92(3):911-8. Epub 2006 Dec 27.
  24. Morch LS, Lokkegaard E, Andreasen AH, et al; Hormone therapy and different ovarian cancers: a national cohort study. Am J Epidemiol. 2012 Jun 15;175(12):1234-42. doi: 10.1093/aje/kwr446. Epub 2012 Apr 19.
  25. Simon MS, Chlebowski RT, Wactawski-Wende J, et al; Estrogen plus progestin and colorectal cancer incidence and mortality. J Clin Oncol. 2012 Nov 10;30(32):3983-90. doi: 10.1200/JCO.2012.42.7732. Epub 2012 Sep 24.
  26. Barzi A, Lenz A, Labonte MJ, et al; Molecular Pathways: Estrogen Pathway in Colorectal Cancer. Clin Cancer Res. 2013 Aug 21.
  27. Familial breast cancer: Classification and care of people at risk of familial breast cancer and management of breast cancer and related risks in people with a family history of breast cancer; NICE (June 2013)
  28. L'Hermite M; HRT optimization, using transdermal estradiol plus micronized progesterone, a safer HRT. Climacteric. 2013 Aug;16 Suppl 1:44-53. doi: 10.3109/13697137.2013.808563.
  29. Simon JA; What's new in hormone replacement therapy: focus on transdermal estradiol and micronized progesterone. Climacteric. 2012 Apr;15 Suppl 1:3-10. doi: 10.3109/13697137.2012.669332.
  30. Formoso G, Perrone E, Maltoni S, et al; Short and long term effects of tibolone in postmenopausal women. Cochrane Database Syst Rev. 2012 Feb 15;2:CD008536. doi: 10.1002/14651858.CD008536.pub2.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Hayley Willacy
Current Version:
Peer Reviewer:
Prof Cathy Jackson
Document ID:
485 (v8)
Last Checked:
21/10/2013
Next Review:
20/10/2018