Computer generated transcript

Warning!
The following transcript was generated automatically from the content and has not been checked or corrected manually.

Managing Hormone Replacement Therapy Dr Vikram T alaulikar MD FRCOG PhD Associate Specialist, Reproductive Medicine Unit, University College London Hospital Hon. AssUniversity College London’s Health, BMS certified Menopause Specialist Principal trainer for FSRH Menopause SSM and BMS PPMC Stages during the journey towards menopause • Pre-menopause – before hormonal changes start Symptoms • Peri-menopause – hormonal fluctuations present–Canoffer bothHRTandnon- (Usually for 2-5 years between 45-50) HRTinterventions forqualityof life • Menopause – periods stop Symptoms can last longer (retrospective diagnosis 1 year after LMP) then 10-15 years for some • Post-menopause – 1 year since periods stopped till end of life Timing of menopause Age of onset of Menopause • Median age 51 25 • 10% 40 - 45 20 • 1% of women < 40 t e 15 r • 0.1% of women < 30 p 10 5 • Ethnicity important – average age 5 years earlier in Indian women (46.2) 0 0 10 20 30 40 50 60 What is HRT? • Replacement of oestrogen, progesterone (and for some testosterone* to improve libido - off license) • Systemic or Local • Systemic oestrogen replacement therapy is the most effective treatment for menopausal vasomotor symptoms Choice of HRT Choice of different hormones - >35 preparations • Oestrogen - 17 beta oestradiol preferred oestrogen (body-identical) • Progesterone - Natural progesterone (body-identical) and dydrogesterone (body- similar) are better tolerated than norethisterone, MPA or levonorgestrel because they are less androgenic (less thrombosis and impact on risk of breast cancer) • Progestogen sensitivity (in about 10%) – think about type, dose, route, changing the frequency Body-identical and body-similar HRT Both micronised progesterone (body-identical) and dydrogesterone (body- similar) are derived from the natural wild yam plant extracts Same starting material Micronised UV light Micronised progesterone Dydrogesterone Both chemically modified (body-identical) (body-similar) CH 3 CH3 CH3 C O Highly comparable C O structures CH3 CH3 CH3 H H O O An additional double bond between carbons 6 and 7 creates a rigid curved structure Anti-Mineralo- Progestogen Progestogenic Estrogenic Androgenic Anti-Androgenic Glucocorticoid corticoid Progesterone + - - * + + Dydrogesterone + - - * - * Drospirenone + - - + - + MPA + - * - + - Norethisterone + + + - - - Levonorgestrel + - + - - - - Not effective Weakly * effective Effective + Receptors Common side effects by stimulation of receptors Estrogenic Breast tenderness, enlargement, leg cramps, bloating, nausea, headache Progestogenic PMS type symptoms, mood changes Androgenic Oily skin, acne, hirsutism Glucocorticoid Dosage and duration dependent: Oedema, fluid retention, weight gain Mineralcorticoid Oedema, weight gain, bloating and migraine HRT routes - preference • Oral HRT preparations (oestrogen in tablet form) • No risk factors for VTE (healthy women <60) • Patient preference and choice • Patient adherence: once-daily treatment and fixed dose combinations with progestogens • Aesthetics: non-visible • Transdermal oestrogen preparations (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 levels may be beneficial) • Lactose sensitivity (most HRT tablets contain lactose) • Patient preference and choice • BMI>30, Age >60, medical risks • Low-dose vaginal oestrogen (cream, gel, pessary or vaginal ring) - For urogenital symptoms alone and can be used in conjunction with systemic HRTContraindications and caution – Not absolute Individualise! • Do not prescribe HRT in women with: • Current, past, or suspected breast cancer • Known or suspected oestrogen-dependent cancer • Undiagnosed vaginal bleeding • Untreated endometrial hyperplasia • Previous or current venous thromboembolism (deep vein thrombosis or pulmonary embolism) unless the woman has had haematology input or is already on anticoagulant treatment • Active or recent arterial thromboembolic disease • Active liver disease with abnormal liver function tests • Pregnancy • Prescribe HRT with caution in women with: • Porphyria cutanea tarda • Diabetes, factors predisposing to venous thromboembolism, history of endometrial hyperplasia • Migraine and migraine-like headaches • Increased risk of breast cancerSome prescribing tips • One size fits all approach does not work • Aim to prescribe at lowest dose that treats symptoms and increase dose based on symptoms/side effects (as far as possible, avoid off-license prescribing) • Blood tests may help if poor absorption is suspected • Women with Premature Ovarian Insufficiency often need more oestrogen • ‘Pill versus HRT’ for Premature Ovarian Insufficiency – HRT preferred (think POISE trial) Bleed or bleed-free HRT • Cyclical HRT which causes bleeds – for women who are perimenopausal or who have just experienced menopause in the last year • Bleed free continuous HRT - for women who are post-menopausal for at least a year or more (bleed-free certainly preferred after 5 years on combined HRT) • Women with POI – prefer cyclical (especially if desiring fertility) • Women with heavy withdrawal bleeds/endometriosis/PMS – no bleeds/Pill Vaginal oestrogens • Very effective for vulvovaginal dryness, irritation and painful sex • Can help reduce urinary frequency, incontinence and UTIs • Help with pelvic muscle health • In suitable women, can be used as long as required and have little/no absorption into the body 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 DATA NOT AVAILABLE!) Hormone Replacement Therapy (HRT) – a guide for clinicians • but it should not be denied to anyone who could benefit When to from it start and stop HRT • symptoms during perimenopause or menopause as other • There should be no arbitrary limits for duration of use of (arbitrary after 2 to 5 years or at the age of 60 are not backed up by limits should evidence - individualise benefits versus risks not be • of life versus risks of thrombosis, breast and endometrial imposed) cancers • menopause) POI – at least until 50 (natural age of T estosterone • The assessment and interpretation of testosterone blood levels is not straightforward • Indication – low libido (other possible causes considered) • There are no testosterone* products for female use licensed in the UK Options • Gels, creams and implants (aim - 5 mg daily) • Total testosterone or Free androgen index as well as clinical response useful for monitoring • Tibolone – unique place in HRT (has some androgen effect) Side 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 • common in first 3-6 months üreassure (unless concerning features e.g., post-coital) • persistent breakthrough on HRT ücheck compliance üAssess risk factors ü? change dose/type of progestogen ü scan if persists > 6 months Chance of finding endometrial pathology lower when bleeding on HRT (unlike PMB)Other common side-effects on starting HRT • breast tenderness • 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 disease HRT & stroke ØThe absolute risk is very small in women < 60 ØTaking oral oestrogen is associated with a small increase in the risk of stroke * ØTransdermal oestrogen is not associated with risk increase NICE 2015 *MHRA estimate from 4 to 5 cases per 1000 women over 5 years VTE risk with HRT in healthy women Type of HRT odds ratio (95% CI) 26770 cases, 82672 controls. UK general practices. BMJ 2019;364:k4810 Role and effect of progestogen in HRT In women with a uterus (or post endometrial ablation or within first few years of hysterectomy for endometriosis or subtotal hysterectomy with some remaining endometrium) Progestogen is required with exogenous oestrogen to reduce the risk of endometrial hyperplasia and endometrial cancer LNG IUS; levorgesterol-releasing intrauterine system Role & effect of progestogen in HRT Unopposed estrogen Non-hysterectomised Up to 5 years of use Long term use of sequential replacement women combined (> 5 years) Associated with significant Required daily in a Progestogen intake in increased risk of continuous combined recommended doses May be associated with a endometrial hyperplasia small increase in risk of regimen for 12–14 days a endometrial hyperplasia month and endometrial cancer Both dose and duration Require progestogen Does not appear to be dependent with exposure administered for 12-14 days associated with a Risk is dose and duration between 1-3 years in a sequential regimen significant increase in risk dependent in relation to progestogen intake of endometrial hyperplasia Women taking sequential HRT with <10 days of Only when progestogen progestogen are at compliance is assured increased risk of endometrial hyperplasia and cancerRecent safety alert! NICE conclusions on HRT & breast cancer risk ØOestrogen alone is associated with little or no change in the risk of breast cancer ØOestrogen plus progestogen can be associated with an increase in the risk of breast cancer ØThe risk of breast cancer is related to treatment duration and reduces after stopping HRT NICE GUIDELINE 2015Pictorial explanation of risk based on observational data Climent-Palmer Post-Reproductive Health 2019; 25:175-8 based on Lancet 2019; 394:1159-68 Other life-style factors: impact on risk of breast cancer comparator + 4 - 4 + 4 + 5 + 3 + 24 - 7 More recent analyses of HRT & breast cancer risk ØLancet 2019: individual patient meta-analysis of worldwide epidemiological evidence ØBC increased by all forms of systemic HRT Ødetectable before 5 years of use, and persisted after use for >10 years Ødetectable even in 40-50 age group ØJAMA 2020: long-term follow-up of WHI randomized trial ØOestrogen alone after hysterectomy significantly lowered BC risk and mortality (HR 0.60) ØCombined HRT significantly increased risk of BC (HR 1.28) but not mortality HRT & coronary heart disease ØAssociated with a more favourable benefit risk profile if started under the age of 60 or within 10 years of the menopause ØCardiovascular risk factors (BP, DM) are not a contraindication if optimally managed ØCan be considered after 60 – benefits may not apply but no increased morbidity so individualise! Treatment of GSM Vaginal oestrogen • Can be used for as long as needed • Enhances blood flow which restores cell maturation, healthy bacterial flora and a pH below 5 • Oestradiol (E2) delivered as a small vaginal tablet or ring (90 days) or the weaker oestrogen, Oestriol (E3) delivered as a cream (either 0.1% or 0.01%), a pessary or an oily gel • A loading dose followed by a maintenance dose for most preparations • BMS guidelines for use following breast cancer Treatment of GSM Vaginal dehydroepiandrosterone (DHEA) • The adrenal glands (80%) and ovaries (20%) secrete dehydroepiandrosterone (DHEA) • Prasterone/Intrarosa, 6.5 mg a pessary containing DHEA delivered vaginally daily • Converted into oestrogens and androgens by enzymes within the epithelial cells of the vagina but not the endometrium • Use in women with a history of breast cancer is contraindicated, although use may be agreed following a discussion with the breast care team Treatment of GSM 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 endometrium and breast tissue, • May be used in women with a history of breast and endometrial cancer, who have completed treatment (no clinical trial data for patients with current breast cancer) • Hot flushes are the only consistent side effect associated with treatment with Ospemifene, risk of DVT applies Conclusion • Since publication of the WHI study results and Million Women’s study results around 2003 – a lot has changed! • Body-identical HRT and transdermal preparations have been a gamechanger • Every woman’s experience of menopause is unique – and individualising HRT recommendations is important Thank you