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‘Premature menopause and Surgical menopause’ Dr Vikram Talaulikar MD FRCOG PhD Associate Specialist in Reproductive Medicine, University College London Hospital Hon. Associate Professor, University College London BMS certified Menopause Specialist Principal trainer for FSRH Menopause SSM Trainer for BMS principles and practice of menopause care How is POI defined? What are the symptoms and signs? How is it confirmed? What tests are relevant? Surgical menopause Key concepts What are the implications for fertility and long- term health? How to suppress unpleasant symptoms and protect long-term health?Stages during the journey towards menopause • Pre-menopause – before hormonal changes start • Peri-menopause – hormonal fluctuations (Usually for few months to years) • Menopause – periods stop (always retrospective diagnosis 1 year Symptoms present after the last menstrual period) • Post-menopause – 1 year since periods have stopped and thereafter Age at Menopause • Average age at menopause – 51 (range 45-55) • Early menopause – 40-45 (10%) • Premature ovarian insufficiency - <40 (1-2% - varies in different ethnicities and populations) Loss of ovarian activity prior to 40 (1-2% of women) Also termed ‘primary OI’, ‘POF, Premature ‘premature menopause’ Ovarian ‘Premature Ovarian Insufficiency’ Insufficiency covers both natural and iatrogenic Guidelines from BMS, IMS, ESHRE • 1/100 <40 (two standard deviations below the age of natural menopause) Prevalence • 1/1000 <30 • 1/10000 <20 • Potentially life changing – physical and emotional consequences Diagnosis • Chronic hypooestrogenic state can cause short- with term menopausal symptoms AND long-term effects on bone, cardiovascular health, cognition significant and fertility consequences • About 25% women will demonstrate intermittent ovulations and conception) hormonal symptoms, • Unknown in about 80% (unexplained) • Other causes – genetic, autoimmune, Causes infections, metabolic, toxin-related and iatrogenic (chemotherapy/radiation/embolisation/ surgery)s 10000 n s Ovulations o 1000 1,000,000 between ages ( 250,000 15 – 45 r 100 v o e 10 a v O 1 25,000 0.1 -10 0 10 20 30 40 50 Age Depletion of ovarian follicles/eggs throughout life 700,000 to 1 million oocytes (eggs) in primordial follicles at birth This pool determines reproductive lifespan (400 ovulations)What could cause POI? • POI could be due to reduction in primordial follicle pool in recruitment/maturationlicular destruction or problems • Epigenetic aging (part of aging syndrome – can begin few weeks post conception in fetal tissues) • Overall, between 10—20% of POI • 30% of unexplained POI – family history positive • Mainly X chromosome or autosomal genetic variations Genetic causes • Several genetic mutations have been discovered recently • Chromosomal karyotyping and Fragile X screening are the tests offered Genetic • Turner syndrome – 1 in 2500 births, complete or partial loss of X chromosome (deletions, translocations, inversions, isochromosomes and sometimes mosaicisms) • Women with TS should be offered care in multidisciplinary clinics • Long-term health issues include - hearing and learning difficulties, diabetes, loss of bone density, coeliac disease, hypothyroidism, cardiovascular disease, hepatic dysfunction, dyslipidaemia, and potential pregnancy risks Oocyte cryopreservation in women with Turner syndrome • Talaulikar VS, Conway GS, Pimblett A, Davies MC. Outcome of ovarian stimulation for oocyte cryopreservation in women with Turner syndrome. Fertil Steril. 2019 Mar;111(3):505-509 Genetic • Fragile X syndrome - A premutation in the fragile X mental retardation I gene (FMR-I) carried in 1 in 250 women affects the copies of the CGG trinucleotide repeat in this gene in the 5’ area of chromosome X • Genetic screening including family members is male offspring as well as for affected female family members who might consider egg storage or pregnancy planning Autoimmune • Spontaneous POI has been associated with autoimmune diseases in 4–30% of cases (Hashimoto’s thyroiditis, type I diabetes, adrenal insufficiency, Sjögren’s syndrome, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, celiac disease, myasthenia gravis and alopecia) • and Adrenal antibodiesclude - Ovarian antibodies, Coeliac screen, Thyroid antibodies • Surgical menopause can be more severe • Damage to ovaries varies with chemotherapeutic agents • More common with alkylating agents (POI in 40% of treated cases) Iatrogenic • Risk is influenced by the dose of medications or radiotherapy used and the age of the woman at the time of treatment • Risk reducing surgery for BRCA Individual clinical situations can vary but typically – Lack of periods for >4 months Confirmed by two elevated FSH blood tests, 4–6 weeks apart (>25) What are the signs/symptoms? Subfertility Oestrogen deficiency symptoms How to diagnose (Symptoms sudden and tend to be severe with POI? surgical menopause – so planning beforehand important) Low AMH levels suggest low egg store but not a diagnostic test • osteoporosisOI are at increased risk of • Comprehensive risk evaluation, education (lifestyle) and HRT (gold standard) – mainly prospective studies and observational data Bone health • Calcium 1,000 mg (usually through diet) and vitamin D of 1,000 IU daily intake, weight bearing exercises • monitoringty scans every 4 years helpful for • Specialist advice when HRT is contraindicated or if fragility fractures • Increased risk of heart disease and cardiovascular mortality (observational data) • (stopping smoking, regulating body weight,s Cardiometabolic moderating alcohol, etc.) health • Oestrogen deficiency, lipid and insulin resistance – diagnose and treat • HRT lowers the long-term risk and is strongly menopauseed at least until the average age of • Observational studies have shown an increased risk of cognitive impairment and dementia Cognitive with POI health/dementia • A window of opportunity for cognitive benefit menopause transitionted early in the process of No proven treatments to increase the rate of pregnancy with autologous oocytes 5-10% spontaneous pregnancy rate (20% miscarriage rate) HRT is not contraceptive!! Fertility Oocyte donation (Higher risk of preeclampsia, PPH, preterm birth and low birth weight) Stem cell therapies, platelet-rich plasma and primordial follicle activation all require further research Symptoms and quality of life • >80% of women experience some unpleasant menopausal symptoms • About 30% or more - severe symptoms which affect quality of life > 30 symptoms • Irregular bleeding • Hot flushes, night sweats, disturbed sleep • Dry hair/eyes/skin/mouth • Low energy, low libido, body and joint pains • Emotional fluctuations, low mood, heightened anxiety • Brain fogging, poor concentration • Vaginal dryness, painful sex and bladder symptoms • SubfertilityPsychological support and specialist care • Psychological support crucial! (often missed) • Please seek help, counselling • Life planning! • Care best offered through specialist healthisciplinary clinics – annual reviews of Addressing symptoms through • Lifestyle modification • Changes at workplace Aim - improved • Nutritional/self-help interventions quality of life and long-term • Alternative therapies health • Non-HRT medications and • Hormone Replacement Therapy (HRT) – The Gold Standard What is available? (yoga), several layers of light clothinge, avoid excess alcohol, nutrition, exercise Complementary therapies - acupuncture, homeopathy Psychological therapies – relaxation, CBT, mindfulness Herbal products including black cohosh and red clover What else is available? (non-HRT options) Non-hormonal pharmaceutical treatments (mainly for women who cannot have HRT for medical reasons) • SSRIs and SNRIs (Venlafaxine) • Gabapentin • Clonidine • Can have some side effects - drowsiness, dry mouth or constipation (generally mild and temporary) Oestrogen – the key hormone! • Gets rid of unpleasant symptoms and improves energy levels • Protects bones, heart, skin, joints, muscles and improves memory/cognition • Protects against high cholesterol and diabetes • Minor and usually temporary side effects – headaches, breast tenderness, nausea Combined pill or HRT? • Replacement can be with the COC pill if contraception is required but in the long-term HRT is recommended to optimise bone and metabolic health • Pill has the cost advantage and could be preferred to avoid heavy withdrawal bleeds • POISE STUDY COMPARES PILL WITH HRT Progesterone – the necessary hormone • Mainly needed to protect womb lining as you can’t take oestrogen alone (unless hysterectomy) • Helps a little with hot flushes and sleep • Can have side effects such as bloating, mood changes, PMS-like (although uncommon) – can be minimised using natural progesterone or Mirena coil or modifying the HRT regimenTestosterone • Improves libido and sexual function in women who have persistent symptoms (especially surgical menopause!)Vaginal • problems and painful sexal dryness, bladder oestrogen • Can be used as long as required and have creams or in women with history of breast cancer)afe (even pessaries Risks associated with HRT use Blood clotting and Breast cancer For young women, risk of blood clotting from HRT is minimal so oral HRT is safe unless there are additional risks blood clotslas compared to oral tabletscoil are associated with no increased risk of No increase in risk of breast cancer for women with POI! Benefits for symptoms, heart, bone, brain and metabolism far outweigh any risks! 33HRT – recommendations Oestrogen • The aim - to achieve physiological levels of oestradiol • 2mg a day of oral oestradiol first line • If risk factors for thrombosis - 75-100 micrograms a day of transdermal oestradiol patches or 2-4 pumps of oestradiol gelHow long to take HRT? • (standard advice)e until 50 • Is there an upper age limit? NO (Every individual is unique) • As long as benefits from HRT outweigh risks – individual choice 35 Summary • POI and surgical menopause care should include specialist input from both medical and psychological teams • Early diagnosis and quick referrals are key to avoiding problems and ensuring quality of life (pre- op planning for surgical menopause) • HRT – recommended at least until age of 50 for long-term health protection • has started recruiting), much more research needed specific to surgical menopause! (POISE trial Thank you for your time today!