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Menopause and Hormone Replacement Therapy – an update Dr Vikram Talaulikar MD FRCOG PhD Associate Specialist, Reproductive Medicine Unit, University CollegeLondon Hospital Hon. AsUniversity CollegeLondonen’s Health, BMS certified MenopauseSpecialist Principal trainer for FSRH MenopauseSSM and BMS PPMC Stages during the journey towards menopause • Pre-menopause – before hormonal changes start Symptoms present – Can • Peri-menopause – hormonal fluctuations offerbothHRT andnon-HRT • (Usually for 2-5 years between 45-50) interventions forquality of life • Menopause – periods stop Symptoms (retrospective diagnosis 1 year after LMP) can last longerthen 10-15years • Post-menopause – 1 year since periods stopped till end forsome of life Timing of menopause Age of onset of Menopause • Medianage51 25 • 10%before45 20 • 1% of women< 40 t 15 c e • 0.1% ofwomen< 30 p 10 • Ethnicity important – average age 5 5 years earlier in Indian women (46.2) 0 0 10 20 30 40 50 60 Diagnosis of menopause • Clinicaldiagnosis(blood testsrarely needed) • No need to measure FSH in women >45 • May be of value age 40-45 • Useful in women<40 Diagnosing menopause Consider it in any woman – clinical history is the key! Blood tests not routinely needed • Vasomotor: 70% of women affected by hot flushes/night sweats/sleep issues • Psychological: Low mood, anxiety, irritability • Physical: Fatigue, joint pains, headaches, palpitations, dry skin, urinary symptoms, brain fogging, low libido • Vaginal: dryness, burning, itching, painful sex • Periods: more frequent, less frequent • (National Institute for Health and Care Excellence;Menopause; Clinical Guideline – methods, evidence and recommendations (NG23), 2015 www.nice.org.uk/guidance/ ng23)Symptoms overlap with other conditions • Some of the most reported symptoms - hot flushes/flashes, fatigue, headaches, irritability, insomnia, brain fogging, joint pains and depression overlap with other conditions • Chronic fatigue syndrome, fibromyalgia, rheumatological conditions, MS, depression, anxiety/panic disorders, viral illnesses (long-COVID), thyroid/adrenal dysfunction, vitamin deficiencies, migraines • Women with menopausal symptoms are nearly twice as likely to have chronic pain diagnoses Genitourinary Syndrome of Menopause • Often underdiagnosed and undertreated (about 60% of postmenopausal women who do not use systemic HRT will suffer from GSM) • Takes about three to five years for effects of oestrogen deficiency to become apparent • Women using systemic HRT may still experience symptoms of urogenital atrophy (25%) Genitourinary Syndrome of Menopause • In a healthy vagina, the superficial mucosal cells shed approximately every four hours, releasing large amounts of glycogen, which support lactobacilli • Oestrogen deficiency causes the mucosa to become thin, with a reduction in superficial cells, reduction in glycogen and lactobacilli and a rise in the pH of vaginal secretions (>5)Current conceptsabout management of symptomsand long-term health impact Addressing symptoms through • Lifestyle modification • Changes at workplace To improve • Nutritional/self-help interventions quality of life and/or • Alternative therapies healtherm • Non-HRT medications or • HRT What is available? (non-HRT options) Lifestyle interventions – reduce caffeine, alcohol, nutrition, exercise (yoga), a bone healthy and heart healthy lifestyle Practical tips at workplace - several layers of light clothing, natural fabrics, access to hydration, cooling Complementary therapies - acupuncture, homeopathy, hypnotherapy Psychological therapies – relaxation, CBT, mindfulness Herbal products including black cohosh What else is available? (non-HRT options) Non-hormonal pharmaceutical treatments: Can have some • SSRIs and SNRIs (e.g., Venlafaxine) sideeffects - mouth orss,dry • Gabapentin constipation, weightgain • Clonidine (generally mild and temporary) What is HRT? • Replacement of oestrogen, progesterone (and testosterone* to improve libido - off license) • Local or systemic • Systemic oestrogen replacement therapy is the most effective treatment for menopausal vasomotor symptoms follow relevantprofessionalguidance,taking full responsibilityforthe decision.Informed consentshould be obtained and documented Choice of HRT Choice of different hormones - >30 preparations • Oestrogen - 17 beta oestradiol preferredoestrogen (body-identical) • Progesterone - Natural progesterone (body-identical) and dydrogesterone(body- similar) are better tolerated than norethisterone, MPA or levonorgestrelbecause they are less androgenic (less thrombosis and impact on risk of breast cancer) • Progestogen sensitivity (in about 10%) – think about dose, route, changing the frequency MPA: medroxyprogesteroneacetate HRT routes • OralHRT preparations(tablet,capsule) • No risk factors for VTE (healthy women <60) • Patient preferenceand choice • Previously taken combined oral contraceptive (COCP) • Patient adherence: once-daily treatment • Aesthetics: non-visible • Transdermaloestrogenpreparations (gel,spray, implant or patches) • Taking a hepatic enzyme–inducing drug (for example an anticonvulsant drug) • Severe liver disorder • Bowel disorder which may affect absorption of oral treatment • History of migraine (when steadier hormone levelsmay be beneficial) • Lactose sensitivity (most HRT tablets contain lactose) • BMI>30, Age >60, multiple medical risks • Low-dosevaginaloestrogen(cream, pessary or vaginal ring) - For urogenital symptoms alone and can be used in conjunction with systemic HRTContraindicationsand caution (Individualise - in many situations HRT could be offered with specialist advice and counselling) • Do not prescribe HRT in womenwith: • Current, past,or suspectedbreastcancer • Known or suspectedoestrogen-dependentcancer • Undiagnosedvaginal bleeding • Untreatedendometrialhyperplasia • Previous idiopathic or currentvenous thromboembolism (deep vein thrombosis or pulmonary embolism), unless the woman is already on anticoagulanttreatment • Active or recent arterialthromboembolic disease(for example angina or myocardialinfarction) • Active liver disease with abnormalliver functiontests • Pregnancy • Prescribe HRT with cautionin womenwith: • Porphyria cutaneatarda • Diabeteswith complications,factorspredisposing to venous thromboembolism, history of endometrial hyperplasia • Migraine andmigraine-like headaches • Increasedrisk of breastcancer Bleed or bleed-free HRT • Cyclical HRT which causesbleeds – for women who are perimenopausalor who have justexperiencedmenopause • Bleed free continuousHRT - for women who are post-menopausal for at least a year or more(bleed-freecertainlypreferredafter5 years on combinedHRT) • Womenwith POI – prefer cyclical(especiallyifdesiringfertility) • Womenwith heavy withdrawalbleeds/endometriosis/PMS – no bleeds/Pill Treatment of GSM Vaginaloestrogen • Can be used for as long as needed • Enhances bloodflow which restores cell maturation,healthy bacterialflora and a pH below 5 • Helps with urinary symptomsincludingurgency,urge incontinence,frequency and nocturia • Oestradiol(E2) delivered as a small vaginal tablet or ring (90 days) or the weaker oestrogen, estriol (E3) delivered as a cream(either 0.1% or 0.01%), a pessary or an oily gel • A loadingdose followedby a maintenance dose for mostpreparations • BMS guidelines for use following breast cancer Vaginal dehydroepiandrosterone (DHEA) • The adrenal glands (80%) and ovaries (20%) secrete dehydroepiandrosterone (DHEA) • Prasterone/Intrarosa, 6.5 mg a pessary containing DHEA deliveredvaginally daily • Converted into oestrogens and androgens by enzymeswithin the epithelial cells of the vagina but not the endometrium • Maturation of the parabasal cells into superficial cells, with an associated increase in mucosal thickness and secretions. Increases collagen density in the lamina propria • Use in women with a history of breast cancer is contraindicated, although use may be agreed following a discussion with the breast care team Ospemifene • Ospemifene is a selective oestrogen receptor modulator (SERM), administered orally in a dose of 60mg once daily • Agonist in the vaginal mucosa, lowering vaginal pH and improving the Vaginal Maturation Index (VMI), and reduces symptoms including vaginal dryness and dyspareunia • There is an antagonist effect on the endometriumand breast tissue, • May be used in women with a history of breast and endometrial cancer, who have completedtreatment (no clinical trial data for patients with current breast cancer) • Hot flushes are the only consistent side effect associated with treatment with Ospemifene Body-identical and Bio-identical HRT • Body-identical or Bio-similar – oestrogen and progesterone types that are similar to their biological equivalents (WELL STUDIED AND REGULATED) • Bio-identical (compounded) – custom made preparation by clinics using plant-based hormones (NOT WELL REGULATED SO LONG-TERM SAFETY AND EFFICACY CANNOT BE GUARANTEED!) Hormone Replacement Therapy (HRT) – a guide for clinicians • Not all women need or wish to take HRT for menopause, Support but it should not be denied to anyone who couldbenefit women to fromit choose • HRT can be commencedforvasomotoras well as other when to stop symptomsduringperimenopauseor menopause HRT and • There should be no arbitrarylimits for duration of use of after 2 to 5 years or at the age of 60 are not backed up by arbitrary evidence - individualisebenefitsversusrisks limitsshould • Benefits for bones/heart/metabolism/symptomsand not be quality of life versus risks of thrombosis,breastand imposed endometrialcancers • Women with POI – at least until 50 (naturalage of menopause) Testosterone • The assessment and interpretation of testosterone blood levels is not straightforward • Indication – low libido (other possible causes ruled out) • There are no testosterone* products for female use licensed in the UK relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documenteder should follow Options • Gels, creams and implants (aim - 5 mg daily) • Total testosterone or Free androgen index as well as clinical response useful for monitoring relevantprofessionalguidance,takingfullresponsibilityforthedecision. InformedconsentshouldbeobtainedanddocumentedouldfollowSide effects - uncommon • Increased body hair • Generalised Hirsutism (uncommon) • Male pattern hair loss (uncommon) • Acne and greasy skin (uncommon) • Deepening of voice (rare) • Enlarged clitoris (rare)Risks of testosterone • Randomised controlled trials have not shown an increased risk of cardiovascular disease or breast cancer although longer term trials would be desirable Side effects of HRT – breakthrough bleeding • commonin first 3-6months ✓reassure (unless concerning features e.g., post- coital) • breakthrough on HRT ✓check compliance ✓? change dose/type of progestogen ✓ scan if persists > 6 months Chance of finding endometrial pathology lower when bleeding on HRT (unlike PMB)Other common side-effects on starting HRT • breasttenderness • bloating • nausea • headaches tend to wear off dose-dependent, consider reducing oestrogen and building up gradually HRT risks • Stroke/Thrombosis • Endometrial cancer • Breast cancer • Heart diseaseHRT & stroke/VTE ➢The absolute risk is very small in women < 60 ➢Taking oral oestrogen is associated with a small increase in the risk of stroke * ➢Transdermal oestrogen is not associated with risk increase NICE 2015 *MHRA estimate from 4 to 5 cases per 1000 women over 5 yearsRecent safety alert!NICE conclusionson HRT & breast cancerrisk ➢Oestrogen alone is associated with little or no change in the risk of breast cancer ➢Oestrogen plus progestogen can be associated with an increase in the risk of breast cancer ➢The risk of breast cancer is related to treatment duration and reduces after stopping HRT NICE GUIDELINE 2015 More recent analysesof HRT & breastcancerrisk ➢Lancet 2019: individual patient meta-analysis of worldwide epidemiological evidence ➢BC increased by all forms of systemic HRT ➢detectable before 5 years of use, and persisted after use for >10 years ➢detectable even in 40-50 age group ➢JAMA 2020: long-term follow-up of WHI randomized trial ➢Oestrogen alone after hysterectomy significantly lowered BC risk and mortality (HR 0.60) ➢Combined HRT significantly increased risk of BC (HR 1.28) but not mortality HRT & coronary heart disease ➢Not increased when HRT started in women < 60 ➢Associated with a more favourable benefit risk profile if started under the age of 60 or within 10 years of the menopause ➢Cardiovascular risk factors (BP, DM) are not a contraindication if optimally managed NICE GUIDELINE 2015• Since publication of the WHI study results and Million Women’s study results around 2003 – a lot has changed! • Every woman’s experience of menopause is unique – and individualising HRT recommendations is important Thank you