Background: As a person begins to experience ovarian hormone disruption (perimenopause) through to and beyond their final menstrual period (post menopause) they may be affected by a variety of symptoms.
The most commonly mentioned symptoms include vasomotor flushing and/or sweating, mood changes (low mood, irritability, feeling overwhelmed), joint aches & pains, fatigue, etc. Urogenital symptoms like vaginal dryness; which might in turn cause discomfort (particularly during exercise or intercourse) can be a problem at this time. Some (peri) menopausal people suffer a worsening in their pre-existing GU problems such as frequency of urination or more frequent UTI’s. These and the more than 50 additional complaints attributed to menopause may have a severe impact on the patients’ quality of life, conversely there are some lucky people who notice very little disruption at this time. It is very hard to predict who will have a rough time in menopause and who won’t but as clinicians we are trained to offer a sympathetic ear and try to help where we can.
For many decades offering menopause support in the form of Hormone Replacement Therapy (HRT) tablets was common practice. But, in 2002, after the publication of an editorial discussing early results of the Women’s Health Initiative (WHI) trial in the USA, concerns were raised about that trial’s use of equine estrogen tablets blended with the synthetic progestagen ‘medroxy provera acetate’ (MPA) and raised risk of breast cancer as well as thrombotic events including CVA and MI.
During the following 10-15 years many clinicians feared prescribing HRT and a lot of patients weren’t too keen on having to use it. Demand fell, interest in training in menopause waned and patients were left with very few options. Things did slowly improve after the shock waves of the WHI subsided a little. It was known back then but subsequent studies have now affirmed that not all HRT is the same.
Concerns that were raised about the connection with HRT use and breast cancer were somewhat offset by analysis of the absolute risk vs the relative risk. The WHI data showed an increased risk of breast cancer diagnosis with use of oral equine estrogen +MPA HRT use in the order of 1.27. This is about the same risk attached to drinking 2 units of alcohol a day and much lower than the risk attached to being overweight/ obese. So this does not dismiss risk – there is an association – but helps put risk into perspective. Roehm E. A Reappraisal of Women’s Health Initiative Estrogen-Alone Trial: Long-Term Outcomes in Women 50-59 Years of Age. Obstet Gynecol Int. 2015; 2015:713295. doi: 10.1155/2015/713295. Epub 2015 Jan 1. PMID: 25685151; PMCID: PMC4313058
Other information from more recent trials on HRT use and breast cancer risk data examined the effect of the choice of HRT progestagen on risk. It is thought that more modern, less androgenic progestagens particularly micronised progesterone and dydrogesterone, seem to have less of an impact on breast cancer risk than the powerful MPA used exclusively in the WHI study. Fournier A, Berrino F, ClavelChapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008;107(1):103-111. doi:10.1007/s10549-007-9523-x
Concerns we had about orally ingested estrogen (e.g. the COCP or oral HRT) do not appear to apply to the low dose, transdermal 17 beta estradiol – the type typically used in modern transdermal HRT. Orally administered estrogen affects the thrombin system and can increase the risk of VTE but modest doses of TD 17 beta estradiol have a neutral effect on clotting.
So in recent years, not only is the fear of HRT use abating, we are seeing the demand for menopause consultations and HRT products outstripping supply. Hamoda H, Panay N, Pedder H, Arya R, Savvas M. The British Menopause Society & Women’s Health Concern 2020 recommendations on hormone replacement therapy in menopausal women. Post Reprod Health. 2020;26(4):181-209. doi:10.1177/2053369120957514
This has been challenging. Clinicians have not always kept up their confidence surrounding menopause guidelines so may be worried about offering up to date advice. Even for general practitioners with expertise, advising on menopause management options and prescribing HRT (and alternatives) is not really supported in primary care. There are no special considerations for what can be a lengthy and nuanced consultation and perhaps ‘first menopause/ perimenopause visit’ should be added to the chronic disease payment schedule. Added frustration for prescribers is ongoing as the demand for high quality TD estrogens and the more ‘breast friendly’ progestagens has been so high, many patients find that they cannot reliably access their HRT in Irish pharmacies. www.hse.ie/eng/about/who/cspd/ ncps/medicines-management/ guidance-on-shortages/mmpguidance-for-prescribers-on-hrtshortages-september-2022.pdf
Typical Menopause vs ‘Complex’ Menopause
When a person develops symptoms that may be attributable to (peri) menopause there are many well established therapies available. There is no single, best answer when it comes to maintaining wellbeing and improving symptoms in menopause, but the fact remains HRT has been proven most effective for vasomotor symptoms caused by hormonal fluctuations at this transitional time. Maclennan AH. Evidence-based review of therapies at the menopause. Int J Evid Based Health. 2009 Jun;7(2):112-23. doi: 10.1111/ j.1744-1609.2009.00133. x. PMID: 21631851
But what about prescribing HRT to people with underlying medical conditions? What are the rules?
Well, that’s a little tricky.
Research on (peri) menopause and HRT and their impact on serious medical conditions is staggeringly poor. We are only beginning to see female biological variables being taken into consideration as part of mainstream health research & pharmaceutical studies. Yakerson, A. Women in clinical trials: a review of policy development and health equity in the Canadian context. Int J Equity Health 18, 56 (2019). https://doi.org/10.1186/s12939019-0954-x
Studies on using HRT in groups of people with serious underlying medical conditions are very few and far between. In the absence of actual data, experts look to see what (if any) impact menstruation, pregnancy and use of hormonal contraceptives might have on specific medical conditions then try to work out what impact menopausal changes and HRT use might be gleaned from this information. Not ideal and often unhelpful.
So what do we know about use of HRT for females with menopausal symptoms who have background medical issues? There are some guidelines when it comes to chronic manageable conditions as well as the more serious situations where if at all possible referral to a colleague with specific menopause training is advised. The British Menopause Society is generally regarded as the ‘go-to’ resource for up to date guidance and advice in Ireland. They have been enormously supportive of colleagues both in Britain and Ireland. www.bms.org.uk
They advise that expert advice should be sought in a variety of situations including women with complex medical backgrounds (such as women with breast cancer, personal history of venous thrombosis or personal history of stroke, ischemic heart disease, etc.).
Menopause itself is often triggered by medical intervention for serious disease and its treatments. People with female hormonesensitive cancers may undergo oophorectomy on medical advice which can cause sometimes very troublesome menopausal symptoms and if done before 40 yrs. of age could go on the undermine future health outcomes. ESHRE guideline group. ESHRE Guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016 May;31(5):926–37
Pelvic radiotherapy and certain forms of chemotherapy can cause temporary or even permanent ovarian failure. Anti-endocrine therapies are often prescribed for females with estrogen sensitive malignancies – most commonly but not exclusively, breast cancer. These medicines improve cancer outcomes but (depending on the patient) the side effects and the menopausal symptoms they can trigger disimprove quality of life and often limit compliance with the prescribed therapy. Meade E, et.al. Survivorship care for postmenopausal breast cancer women in Ireland: What do women want? Eur J Oncol Nurs. 2017 Jun;28:69–76.
Being diagnosed with cancer when already using HRT may become a problem and oncologists might sometimes advise discontinuation of the HRT leading to a rapid return of menopausal symptoms.
Menopausal symptoms can be managed with hormonal, nonhormonal and non-pharmacological therapies. MHT is the most effective method of managing menopausal symptoms but may not be suitable for all after a cancer diagnosis as the role of hormone receptors in many types of cancer and their treatment may complicate the discussion about when MHT should or should not be used.
There is a growing list of therapies and medications that have been shown to be useful in relieving some of the symptoms of menopause for women who are either on anti- estrogen therapies or who have been advised to avoid standard HRT. The British Menopause Society offers guidelines on their “Tools for Clinicians” webpage. Interestingly one of the management options with the best range of meno symptoms relief is Cognitive Behavioural Therapy which has been shown to be effective over placebo in helping with vasomotor flushing and sweating, fatigue, weight gain, musculoskeletal (MSK) pain and sexual function Franzoi MA, et al Evidence-based approaches for the management of side-effects of adjuvant endocrine therapy in patients with breast cancer. Lancet Oncol. 2021 July but access to one on one CBT is limited and so some people may be directed to on online therapy and/ or smart phone apps to seek relief. Other strategies that have been shown to be helpful include:
– SSRI’s & SNRI’s which may help some people with vasomotor symptoms, mood and MSK issues
– Anticonvulsants like gabapentin may help with vasomotor flushing
– Antispasmodics like Oxybutynin can also help with both vasomotor flushing and urinary issues
– Antihistamines with sedating properties may help with sleep disruption
Other options that have shown benefit include yoga and acupuncture, gently physical activity and exercise and hypnosis. Franzoi MA, et al Evidence-based approaches for the management of side-effects of adjuvant endocrine therapy in patients with breast cancer
New medical therapies designed to reduce vasomotor flushing specifically for people with a breast cancer diagnosis are being launched to market in Europe in 2024. The root cause of VMS appears to be linked to heightened signalling of certain neurotransmitters (particularly neurokinin B & its receptor (neurokinin 3 & 4 receptors) – these affect the autonomic thermoregulatory pathway. A group of drugs known as the NK3R antagonists can block NK3R related VMS seemingly as effectively as HRT. The Oasis 4 trial is helping to explore one of these NK antagonist drugs. They are recruiting here in Ireland at time of writing. https://findoasisnow.com/ gb-en/hcp
Applying the research
In our Complex Menopause Clinic at The National Maternity Hospital we aim to offer patients time to discuss the symptoms of menopause that are affecting people with comorbidities or a past diagnosis that might limit typical menopause options. This is a new service funded by the HSE’s National Infant and Women’s Health Program. We are one of six clinics operating around the republic of Ireland.
We try to validate the patients’ individual experience (as some people sadly seem to have been given little forewarning about what the menopausal effects of procedures and treatments for cancers). We explore lifestyle issues and offer support there where we can. We take them through the varied non-HRT strategies that could bring them some relief and allow them improve their QoL. We prescribe where appropriate and review them after 3 months to see if there is any improvement – if they are still struggling we try something else. Some of our patients never really regain their optimal QoL- some we barely help at all I worry – but most patients have expressed a gratitude for having been given a safe space to be listened to, to discuss their symptoms and worries and to be offered treatments wherever we have them.
Written by Dr Deirdre Lundy Specialist in Women’s Health and Menopause at The National Maternity Hospital
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