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Hormone Replacement Therapy ( HRT )

Hormone replacement therapy is the replacement of female sex 
hormones oestrogen and progesterone in women to control
 symptoms of the menopause 

( definition from the www.yourhormones.info )

HRT usage

About a million women in UK use treatment for menopausal symptoms An estimated 1.5 million women – around 80 % of those going through menopause experience some symptoms HRT is highly successful in treating common symptoms of menopause in the short term ( short-term is up to 5 yrs ) HRT is also been shown to reduce risk of CV disease , osteoporosis , type 2 diabetes , osteoarthritis and dementia Several studies have shown that if HRT if started within 10 yrs of menopause can provide the most benefits and reduce all cause mortality NICE recommends HRT for vasomotor symptoms after discussing with them short term and longer term benefits and risks NICE recommends HRT to consider HRT to alleviate low mood and anxiety that arises as a result of menopause British Menopause Society states that the safety of HRT largely depends upon age and healthy women younger than 60 should not be concerned about the safety profile of HRT In summary the benefits of HRT outweigh the risks for most women who start HRT < 60 yrs of age.

Women’s Health Initiative –this was a clinical trial of HRT rather than an observational study like the Million Women Study N American women in their mid-60s hence it is said that it cannot be used to determine the risks with HRT for women who are < 60 type of HRT used in WHI is not used any more women in this study had additional risk factors as obesity / over weight

Million Women Study- started in 1996 with an initial aim to obtain robust prospective information on the risk of breast cancer associated with different types of HRT recruited women in the UK between 1996-2001 born between 1935-1950 the women were 56 yrs on average the key findings were that the risk of cancers of the breast and endometrium vary substantially by the type of HRT used and that the hazards of smoking and also the benfits of stopping smoking in women are greater than previously thoughts in 2003 the 1st findings were published stating that women who were currently using HRT were at increased risk of developing breast cancer the study was questioned in 2012 when epidemiologists stated that the study doesn’t adequately satisfy several criteria for causality – including information bias , detection bias and biological plausibility

Collaborative Group on Hormonal Factors in Breast 
Cancer -Conducts pooled analyses of data on breast cancer Started in 1992 The latest MHRA evidence ( August 2019 ) comes from a meta-analysis by the group , published in the Lancet.

The two studies ( MWS and WHI ) led to widespread concern about breast cancer and HRT among prescribes and users. It led to a sharp fall in HRT prescribing by as much as 66 %. A generation of women have not used HRT as a result of the concerns raised by these 2 large studies.

Long term benefits and risks-does not increase CV risk when started in women aged < 60 yrs does not affect the risk of dying from CV disease presence of CV risk factors is not a contra-indication to HRT – manage the CV risks optimally NICE has produced a table for predicting the risk of CVD based upon
○ type of HRT used compared to placebo or no HRT use
○ duration of HRT use
○ time since stopping HRT

Based on above and using the table it can be advised that the 
○ risk of coronoary HD ( CHD ) & stroke varies based on presence of CV risk factors
○ oestrogen only HRT is associated with no , or reduced , risk of CHD
○ HRT with oestrogen & progesterone is associated with little or no increase in the risk pf CHD Women under 60- the baseline risk of stroke is very low Oral oestrogen ( not transdermal ) is associated with a small increase in risk of stroke.

Venous thromboembolism-risk of VTE is increased by oral HRT compared with baseline populations Risk is greater for oral than transdermal preparations Consider transdermal rather than oral HRT for menopausal ♀ who are at ↑ed risk of
 VTE ( including BMI of > 30 ) risk with transdermal HRT given at standard therapeutic dose is no greater than baseline population risk ie transdermal route does not increase the risk of VTE Since transdermal route is safer NICE recommends to consider transdermal route for menopausal women who are at increased risk of VTE including those with a BMI of over 30 Refer women at high risk of VTE to a haematologist for e.g
○ women with a strong family h/o VTE
○ hereditary thrombophilia.

Breast cancer – MHRA alert Aug 2019 -New data indicates that the risk of breast cancer is increased during use of all types of HRT-irrespective of the type of estrogen or progesterone or route ( oral or transdermal ) – other than vaginal oestrogens Risk falls after stopping HRT but the new analysis shows some excessive risk of breast cancer persists for more than 10 yrs after stopping HRT Less than 1 yr of use does not increase the risk but use longer than 1 yr increases the risk and this increases further with longer duration of use risk is higher for combined preparations than oestrogen only HRT At what age the HRT treatment is commenced (in 40s or 50s ) does not influence the outcome Low dose vaginal oestrogens do not appear to increase the risk of breast cancer Use the MHRA leaflet – HRT and breast cancer ( find it under links ) when discussing this topic

Type 2 diabetes – No increased risk of developing type 2 diabetes ( oral or transdermal )
○ ♀ with type 2 diabetes – HRT not generally associated with an adverse effect on blood glucose control
○ Women with type 2 diabetes- consider HRT after taking co-morbidities into
 account ( seek specialist adv if needed )

Osteoporosis –baseline population risk of fragility fracture for ♀ around menopause is low and varies from one woman to another
○ risk of fragility fracture decreased while taking HRT
○ benefit maintained during treatment but decreases once treatment stops
○ benefit may continue for longer in ♀ who take HRT for longer NICE has produced a table to assess the absolute rates of any fragility fracture for HRT

Loss of muscle strength –Limited evidence that HRT may improve muscle mass and strength
○ Advice daily activities and weight bearing exercises.

Dementia –NICE states that the likelihood of HRT affecting risk of dementia is unknown but a Cochrane review concludes that among women over 65 yrs of age taking continuous combined HRT the incidence of dementia was increased.

Contra-indications –current or suspected breast cancer previous h/o breast cancer h/o or suspected estrogen based cancer e.g uterine cancer undiagnosed abnormal PV bleeding untreated endometrial hyperplasia current VTE or h/o DVT h/o blood clotting disorders ( most common is Factor V Leiden mutation carriers ) active or recent arterial thromboembolism untreated hypertension chronic liver disease / dysfunction Dubin Johnson and Rotor syndrome porphyria pregnant status.

Individualized regimen-duration –Latest MHRA guidance suggests to use HRT for as short a time as possible to help reduce the overall risk Women with intact uterus need a combined preparation or contains and estrogen and a progestogen Studies have demonstrated that micronised progesterone poses a lower risk of breast cancer/ CVD/thromboembolic disease than androgenic progestogens Mode of delivery can be oral , transdermal , s/c , vaginal and intrauterine ( IUS progesterone only ) Most women can take continuous HRT but it commonly produces irregular breakthrough bleeding or spotting in the first 4-6 months of treatment


Still having periods
 or last period less than 12 months ago – Consider a cyclical HRT- also known as Sequential Combined Therapy-this mimics the normal menstrual cycle.

Last period more than 12 months ago-Continuous 
Combined Therapy-an oestrogen & a progestogen are given continuously to achieve period free HRT

Hysterectomy- oestrogen only HRT

Follow up-Consider a 3 months f/u to 
○ assess for benefits of therapy
○ side effects and bleeding pattern Reinforce lifestyle interventions Annual review after that.

Advice –Women with intact uterus should be advised that unscheduled vaginal bleeding is common SE of HRT within the 1st 3 months When stopping the HRT -it can be
○ stopped immediately- symptoms may return
○ gradual reduction- this may help limit the recurrence of symptoms in the short-term
○ there are no medical risks with stopping HRT

Long-run-no difference in symptoms whether stopped immediately or gradually.
 Advice that although HRT is considered effective in prevention of post-menopausal osteoporosis -it is generally recommended as an option for women who are at high risk of OP and cannot take non-oestrogen therapies Risk of other cancers 
○ Lung cancer – evidence is conflicting ( Jin Chao et 2019-reduced risk , Cochrane 2017-increased risk with long term use ) but NICE concludes that HRT has no effect on lung cancer
○ Gastro-intestinal including colorectal cancers – reduced risk
○ Ovarian , melanoma – increased risk
○ Non-Hodgkin’s Lymphoma – no effect Inform that HRT is not contraceptive That there is no clear evidence that HRT causes weight gain.

side effects –fluid retention breast tenderness bloating
nausea / dyspepsia headaches.fluid retention breast tenderness headaches mood swings PMT-like symptoms.

Referral-menopausal symptoms and contraindication to HRT uncertainty about the most suitable treatment option for control of menopausal symptoms persistent side effects of HRT poor symptoms control despite using HRT complex medical history /comorbidities previous h/o hormonal dependent cancers Bleeding problems-
○ sequential HRT -if there is an increase in heaviness or duration of bleeding or the bleeding is irregular
○ women on continuous combined therapy who have persistent breakthrough bleeding Suspected endometrial cancer ( follow NICE guidelines )

MHRA patient information on HRT and breast cancer 2019 https://assets.publishing.service.gov.uk/media/5d68d0e340f0b607c6dcb697/HRT-patient-sheet-3008.pdf

 

References

  1. Harper-Harrison G, Shanahan MM. Hormone Replacement Therapy. [Updated 2019 May 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK493191/
  2. HRT definition from https://www.yourhormones.info/topical-issues/what-is-hrt/
  3. Camden Clinical Commissioning Group- prescribing advice for the management of menopause in primary care https://gps.camdenccg.nhs.uk/cdn/serve/prescribing-guideline-downloads/1467294317-a074c4368ab4303917892e3596878421.pdf
  4. BMS response to Lancet paper on the link between different forms of HRT and breast cancer incidence British Menopause Society https://www.womens-health-concern.org/2019/08/bms-response-to-lancet-paper-on-the-link-between-different-forms-of-hrt-and-breast-cancer-incidence/
  5. CEU Hormonal Factors in Breast Cancer https://www.ceu.ox.ac.uk/research/hormonal-factors-in-breast-cancer
  6. Million Women Study Wrong , Group Says from Medpage Today https://www.medpagetoday.com/endocrinology/menopause/30698
  7. Women’s Health Concern HRT : Benefits and risks https://www.womens-health-concern.org/help-and-advice/factsheets/hrt-know-benefits-risks/
  8. One in a million- the story of the Million Women Study via https://www.ndph.ox.ac.uk/longer-reads/one-in-a-million-2013-the-story-of-the-million-women-study
  9. MHRA Alert-Hormone replacement therapy (HRT): further information on the known increased risk of breast cancer with HRT and its persistence after stopping DDLHRT August 2019 via https://www.gov.uk/drug-safety-update/hormone-replacement-therapy-hrt-further-information-on-the-known-increased-risk-of-breast-cancer-with-hrt-and-its-persistence-after-stopping
  10. Menopause: diagnosis and management
    NICE guideline Published: 12 November 2015 www.nice.org.uk/guidance/ng23
  11. Newson, Louise R. “Best practice for HRT: unpicking the evidence.” The British journal of general practice : the journal of the Royal College of General Practitioners vol. 66,653 (2016): 597-598. doi:10.3399/bjgp16X687097 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198659/
  12. Summary of evidence for 2019 surveillance of menopause (2015) NICE guideline NG23 https://www.nice.org.uk/consultations/672/10/long-term-benefits-and-risks-of-hormone-replacement-therapy
  13. Marjoribanks J, Farquhar C, Roberts H, Lethaby A, Lee J. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD004143. DOI: 10.1002/14651858.CD004143.pub5 https://www.cochrane.org/CD004143/MENSTR_long-term-hormone-therapy-perimenopausal-and-postmenopausal-women
  14. NICE Women with symptoms of menopause should not suffer in silence via https://www.nice.org.uk/news/article/women-with-symptoms-of-menopause-should-not-suffer-in-silence
  15. BMS HRT guide- Information for GPs and other health professionals https://thebms.org.uk/wp-content/uploads/2020/04/04-BMS-TfC-HRT-Guide-APR2020.pdf
  16. Jane Green, Gillian K Reeves, Sarah Floud, Isobel Barnes, Benjamin J Cairns, Toral Gathani, Kirstin Pirie, Siân Sweetland, TienYu Owen Yang, Valerie Beral, Cohort Profile: the Million Women Study, International Journal of Epidemiology, Volume 48, Issue 1, February 2019, Pages 28–29e, https://doi.org/10.1093/ije/dyy065
  17. HRT the history from Women’s Health Concern https://www.womens-health-concern.org/help-and-advice/factsheets/hrt-the-history/
  18. British Menopause Society Summary consensus statement https://thebms.org.uk/publications/consensus-statements/hormone-replacement-therapy/
  19. Easy HRT prescribing guide By: Dr Louise Newson BSc(Hons) MBChB(Hons) MRCP FRCGP via https://pcwhf.co.uk/wp-content/uploads/2019/03/PCWHF-Easy-HRT-prescribing-guide_March19-update.pdf
  20. RCGP Making sense of the HRT debate https://www.rcgp.org.uk/clinical-and-research/about/clinical-news/2019/march/making-sense-of-the-hrt-debate.aspx

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