Disclosure Menopause Webinar May 24, 2018 Gillian Graves Obs Gyn Dalhousie University Retired No Advisory Boards or other industry relations Guidelines Oversight Committee SOGC Royal College Subspecialty REI Exam Committee Accreditation Canada Surveyor for IVF Clinics Teach a few lectures for Department ObsGyn Surgical assists Plan Cases An update on newest guidelines 2017 Discuss any topic: eg hot flushes, window hypothesis for CV risk and HT, discontinuation, long term use Controversies: mortality, CVD protection Menopause Normal hormonal changes associated with cessation of periods at menopause cause menopausal symptoms Major cause of reduced quality of life Hot flushes and sweats: most important symptoms Others : changes in sexual interest and function, sleep disturbance, aching joints and muscles, insomnia and vaginal dryness Typical Situation 52 year old healthy female complains of severe flushes, feels that she is waking 12 times thru the night and is frequently drenched at work Has tried a supplement of clover and black cohosh, silken tofu, progesterone cream, phytoestrogens and meditation as well as acupuncture She exercises regularly and has read about layering her clothes, stopped hot drinks, spicy foods and wine Quality of Life Although ET or E/PT may improve a woman s quality of life, each woman has a unique risk profile which might lead to more or less benefit from HT Patient preferences and evidence from medical research influence decisions Consider benefits and risks Newly published research findings must be incorporated into patient care decisions 1
Quality of Life Health related quality of life improvement is a primary purpose of health promotion and health care Perception of Fears/Problems at Menopause Weight gain Osteoporosis Loss of sexuality Aging Loss of femininity/hair growth Heart disease No more children Breast cancer Death Financial insecurity Perceptions of Effective Therapy for Menopausal Symptoms Exercise Improving lifestyle and self care Education and Awareness Reducing stress Nutritional factors Natural therapies Calcium therapy Antidepressants Hormone therapy Remifemin (black cohosh) Increased soy in diet Local Therapy of UG Atrophy Very low circulating doses if vaginal route used 7.5-25 ug per day as cream, tablet or ring Minimal systemic effects and minimal endometrial stimulation- no need for progestin If bleeding occurs : need full evaluation including endometrial biopsy WHI Vaginal E Followup-Reassurance Menopause v25 no 1 2018p11-20 Between vaginal E users and nonusers in women with a uterus in WHI: Risks of stroke, invasive breast cancer, colorectal cancer, endometrial cancer, pulmonary embolism/dvt were not statistically different Risks of CHD, fracture, all cause mortality and global index event were lower in users than nonusers (adjusted hazard ratio 0.68 95%CI 0.7-1.26) Not different in hysterectomized population Key Message #1 Local low dose vaginal estrogen therapy does not need progestin protection of the endometrium Low dose does not change breast cancer risk Can be used indefinitely (ACOG) In selected cases can be used in survivors of breast cancer in consultation with patient, oncologist and other caregivers 2
Should She Start Hormonal Meds? 52 yo. White woman c/o severe hot flushes, interfering with sleep, daily activities No period for 7 months-previously always regular-g2 P2 Perfectly healthy, slim 105 lb, 5 1 Normal gynecologic exam, Br. Exam BP 110/70 Negative Family Hx, nonsmoker, nondrinker Decision Time She is agonizing over the information from the recent media reports about HRT and breast cancer Mammography- normal Putting Risks into Perspective The WHO Terminology for Adverse Event Rates Very common >1/10 Common 1 to 10/100 Uncommon 1 to 10/1,000 Rare 1 to 10/10,000 Very rare <1/10,000 Relevance By 2020 there will be 50 million US women older than 51 (mean age of menopause) ¾ of women report symptoms such as hot flushes or night sweats Women with moderate to severe vasomotor symptoms often experience them for more than a decade Council for International Organizations of Medical Sciences (CIOMS). Guidelines for preparing core clinical-safety information on drugs. 2 nd edition. Geneva:CIOMS: 1998 Hot Flushes Few women with hot flushes, sleep disruption, mood change, difficulty concentrating or short term memory impairment are evaluated or treated Untreated menopausal symptoms are associated with higher health care costs and loss of work productivity Questions Who should be treated? Who should not be treated? How long? When to stop? 3
Treatment Decisions For clinicians and patients considering treatment options ( including length of treatment) relevant information on VMS occurrence and duration is lacking Caution urged in initiating H many years from the menopause (British Medical Society, NAMS) NAMS 2017:occurrence of VMS is a primary consideration in a woman s benefit-risk ratio for HT use along with breast cancer and other diseases Natural Menopause-Freeman Study 2014 Only 10% of women had no VMS 90% had mean duration 4.6 yrs of moderatesevere after final menstrual period Rate in African Americans 2x that of whites Total duration including prior to final period 8.8yrs for any flushes, 10.2 yrs for moderate to severe NAMS v.21 2014 p924 Canadian Longitudinal Study on Aging Menopause v 25 no 1 2018, 2017 v25 no 3 p265 National estimate of age at natural menopause Median 51 yrs Having no partner, low SES, low education, current and former smoking, and CV disease all associated with earlier ANM Current employment, alcohol consumption and obesity associated with later Current use of HT in Canada 9.5%,21.9% past use Risk of Hot Flushes Modified by clinically evaluable risk factors including anxiety, race, obesity, and education levels Since natural duration of flushes can exceed the duration (3-5 yrs) recommended in the past for HT use, it is not surprising that women may experience a return of hot flushes after discontinuation of HT Need for individualizing treatment Effective Therapy Key Message 2 Systemic hormone therapy is the most effective treatment currently available for menopausal symptoms Should be recommended for women with moderate to severe vasomotor symptoms in the absence of contraindications 20 % of women in early menopause would fit these criteria (all women with premature menopause should be treated) Contraindications Excess risk of breast cancer or CV disease Not recently menopausal- debate Active uninvestigated PV bleeding Active liver disease Recent thrombus, CVA or MI or unstable angina or unstable hypertension, Migraine with complicated aura Hormone dependent cancer 4
NonHormonal Approaches For women with contraindications to systemic hormone therapy- tend to be less effective (58%) than HT (1 mg E2-80 %) Low dose paroxetine 7.5 mg Venlafaxine SNRI- 75 mg 47.6 % Gabapentin 6-900 mg/d Clonidine 0.1 mg/d Dixarit (Low dose 0.5mg E2=52.9%, placebo 28.6%) Nonprescription-Recommended Lifestyle changes-weight loss Mind-body techniques Dietary management and supplement-s-equol derivatives of soy isoflavone Cognitive behavioural therapy has been shown to be effective for VMS and to a lesser extent clinical hypnosis Stellate ganglion block NAMS v 22 Nov 2015 p 1155-74 Case 2 Nonhodgkins Lymphoma treated successfully 38 yo otherwise healthy Amenorrheic and having nasty hot flushes for 6 mo post chemo G2P2 tubal ligation hx Premature Menopause Age less than 40 Risks of premature E deficiency include osteoporosis, anxiety, depression, CV disease, cognitive impairment, Parkinsonism, and metabolic syndrome Usually symptomatic if abrupt onset after BSO or chemo Premature Menopause Generally recommended systemic HT until the median age of natural menopause(52) to negate some of the long term effects of premature estrogen deficiency If contraception is required, LNG IUS can be used as the progestin If Abnormal Bleeding on Standard HT After endometrial investigation; Bazedoxifene a novel third generation SERM is approved for hot flushes. It minimizes E effects on the endometrium and breast tissue Can be used with ET instead of progestogen. Long term safety data not yet available and no studies in women with BRCA mutation 5
WHI Legacy Women s decisions regarding therapy are surrounded by anxiety and confusion WHI results are now being used inappropriately in making decisions for women in their 40 s and 50 s who are menopausal and have distressing vasomotor symptoms WHI was designed to address risks and benefits of HT for prevention of chronic disease in postmenopausal women on average 63 years old 2017 NAMS HT Position Statement For women who are younger than 60 or within 10 years of menopause onset and have no contraindications Benefit risk ratio is most favourable for treatment of bothersome VMS and for those at elevated risk for bone loss or fracture NAMS 2017 For women who initiate HT > 10 or 20 years from menopause onset, or who are age 60 years or older : benefit risk ratio appears less favourable because of greater risks of coronary heart disease stroke, VTE and dementia NAMS 2017 Longer durations of therapy should be for documented indications : persistent VMS or bone loss with shared decision making and periodic re-evaluation For bothersome GSM symptoms not relieved by OTC therapy and without indications for systemic HT: low dose vaginal estrogen therapy or other therapies are recommended Explaining Risk Should understand the basic concepts of relative risk and absolute risk in order to communicate potential benefits and risks RR (risk ratio) is the ratio of event rates in the two groups Absolute risk (risk difference) is the difference in event rates between two groups Explaining Risk Odds ratios (ORs measure of association between exposure and outcome) or risk ratios of 2 or less in observational trials lack credibility and are difficult to interpret These smaller risk ratios can have little clinical or public health importance especially if outcomes are rare In properly performed RCT smaller risk ratios may be interpreted as having greater credibility but still can be bias, confounding etc 6
Formulations NAMS 2017 Estrogens-NAMS 2017 Meta analysis of FDA approved estrogen trials found no significant difference in effectiveness between estradiol and CEE in treating VMS Findings re adverse events were inconsistent despite more hepatic protein production with CEE There were differences in cognitive outcomes between types of estrogen and the brain serotonergic system with estradiol providing more robust anxiolytic and antidepressant effects CEE (estrone sulphate and mixtures of 10 minor components of different active forms of estrogen) Synthetic conjugated estrogens Micronized 17B estradiol Ethinyl estradiol CEE and estradiol are rapidly metabolized into weaker estrogens such as estrone Estrogen Dosing NAMS 2017 Therapeutic goal : use the most appropriate often lowest effective dose of systemic ET consistent with treatment goals and add progestin if uterus present No head to head RCT validates the supposition that non-oral routes have advantages Safety-NAMS 2017 Contraindications: Unexplained vaginal bleeding Active liver disease Prior estrogen sensitive breast or endometrial cancer Coronary heart disease, stroke Dementia Personal history or inherited high risk of VTE Porphyria cutanea tarda Hyper-triglyceridemia Concerns than endometriosis may reactivate, migraine headaches worsen or leiomyomas may grow Adverse Events NAMS 2017 Nausea Bloating, weight gain, fluid retention Mood swings (progestogen related) Breakthrough bleeding Headaches Breast tenderness FDA Approved-NAMS 2017 Genitourinary symptoms-in RCT effectively restores genitourinary tract anatomy, increasing superficial vaginal cells, reduces vaginal ph, and treats vulvo-vaginal atrophy 7
Extended Use-NAMS 2017 Fracture Prevention No general rules for stopping age 65 VMS - 50% chance of recurring when HT is discontinued independent of age and duration of use Bone loss and fracture risk continue to progress throughout aging as does untreated GSM No rebound fracture with discontinuation in WHI but virtually all women lost bone mass with increased risk of fracture and excess mortality from hip fracture Initiation of MHT after the age of 60 for the indication of fracture prevention is considered second line therapy Requires individually calculated benefit risk compared to other approved drugs If MHT is elected the lowest effective dose should be used Follow Up Women taking MHT- should have at least an annual consultation Include: a physical exam, update of medical and family history, relevant lab and imaging investigations, a discussion of lifestyle, and strategies to prevent or reduce chronic disease No current indication for increased mammographic or cervical smear screening, (unless increased breast density) IMS Climacteric 2016 v19,no2 109-150 After WHI-NAMS 2017 Elevated risk (rare absolute risk) of breast cancer persisted(hr 1.28 95%CI 1.11-1.48) with CEE+MPA during median 13 yr cumulative follow up (5.6yr intervention plus 8.2 yr post intervention observation) CEE alone-reduction in breast cancer risk HR 0.79 95% CI 0.65-0.97) 7.2 yr treatment and 6.6 yr post intervention follow up Most CVD risk became neutral During cumulative follow up: overall significant reduction in hip fracture risk persisted(hr 0.81,95% CI 0.68-0.97) and a reduction in endometrial cancer (HR 0.67 95% CI 0.49-0.91) OLD News? Again? Standard dose ET may decrease the risk of MI and all cause mortality when initiated in women younger than 60 or within 10 yrs of menopause Safety NAMS 2017 Potential risks for women younger than 60 or within 10 years of menopause onset include: rare risk of breast cancer with combined EPT, endometrial cancer or hyperplasia with inadequately opposed estrogen, VTE and biliary issues Additional risks across ages include MI, stroke and dementia 8
Combination EPT Initiated in women younger than age 60 or within 10 yrs of menopause showed less compelling mortality benefit And evidence of cardioprotection is inconsistent Global Consensus Statement on Menopausal Hormone Therapy IMS Climacteric 2016 v19 no4 p313-315 FDA Approved Indications-NAMS 2017 VMS-first line therapy for relief of menopausal symptoms in appropriate candidates Prevention of Bone Loss-shown in RCT to prevent bone loss and in WHI to reduce fractures in PM women Premature Hypoestrogenism-for hypogonadism, POI or premature surgical menopause without contraindications-with health benefits for VMS, prevention of bone loss, cognition and mood issues and in observational studies, heart disease Progestogen Indication NAMS 2017 Need for endometrial protection Chronic unopposed endometrial exposure to estrogen increases the risk for endometrial hyperplasia or cancer Commonly used: MPA, norethindrone acetate, and natural progesterone, LNG IUS If using bazedoxifene and estrogen, no need for progestogen Progestogen Dose and Duration NAMS 2017 In WHI use of oral MPA daily and CEE oral was associated with a risk of endometrial hyperplasia similar to placebo(hr 0.81 95% CI 0.48-1.36) Higher incidence of breast cancer was seen in WHI with CEE+MPA than placebo but a reduced incidence with CEE alone Observational studies suggest risk of breast cancer may be less with the use of micronized P compared to synthetic progestogens but bioavailability of oral and transdermal progesterone is poor Unscheduled Bleeding In women using EPT unscheduled bleeding occurring more than 6 months after initiation should be investigated NAMS 2017 Gaps in Training Core competencies in management of menopausal symptoms and prescription of HT have decreased in new graduates and in training programs for family medicine and obs gyn New markets of untested and unregulated alternative treatments including custom compounding of hormonal products have led to concerns about dose consistency, product contamination and problems with safety and efficacy claims 9
Safety of HT-NAMS 2017 Few medications have been as well studied for risk and benefit as HT For women in their 50 s the absolute risk of adverse outcomes is much lower than in older women Net effect on all cause mortality in younger women is neutral or even favourable New hormonal formulations with lower doses and transdermal delivery routes are now available For 50-59 Risk/Benefit 50-59 E Only Risk/Benefit Breast 2013 followup of WHI( Manson et al JAMA 353-68) Among users of E+P cumulative RR=1.28 Among users of E only RR=0.79 Confidence intervals did not include 1 E only may actually decrease risk E+P increases breast cancer incidence and death from breast cancer (after 5 yrs of use) Counselling Next series of slides address specific counselling points Tailor the discussion to individual and their concerns Generally should mention risks and benefits Breast/Cardiovascular(clot, stroke, CAD)/Bone/Gall Bladder/Symptoms?/other cancers Quality of Life Difference in CHD per 1000 Menopausal Women over 7.5 yrs Baseline pop risk in UK 26.3/1000 Women on E only-current users =6 fewer Women on EP-Current users=5 more >5 yrs since stopping E only= 6 fewer >5 yrs since stopping EP=4 more NICE Guideline Climacteric 2016 v 19 no 5 p426-29 10
Difference in Stroke Incidence per 1000 Menopausal Women over 7.5 yrs Baseline pop risk in UK over 7.5 yrs 11.3 per 1000 Women on E only current use no increase Women on EP current use = 6 more >5 yrs since discontinued E only= 1 more >5yrs since discontinued EP=4 more Difference in Br Cancer Incidence in 1000 Menopausal Women over 7.5 yrs Baseline population risk in UK over 7.5 yrs 22.48 per 1000 Women on current E only=4 fewer Women on Current EP =5 more >5 yrs since stopped E only=5 fewer >5 yrs since stopped EP=8 more Breast Risk Summary Cochrane 2012 In E only there are 7/10,000 Fewer invasive Br Ca per year In EPT >5 yrs attributable risk is 8/10,000 users per year by WHI data Increased risk of breast cancer with HT- Cochrane 2012 In WHI observational combined with EPT clinical trial there was an increased risk of breast cancer when HT was initiated within 5 years of menopause with an attributable risk of 39%over the first 5 years and 54% over the first ten years of use-ajepidem 2008 VTE In perimenopausal or recently menopausal VTE risk for 50-59= 1 more case per 1000 women /yr Doubles for 60-69, triples for 70-79 BMI 25-30 had double risk, >30 triple risk Smoking does not appear to increase risk of VTE but clearly increases CAD and CVA Air travel increases risk VTE 1/600 >4hr flight and 1/500 for flights over 12 hours if over 50 years old Menopausal Hormone Therapy doubles that risk in flyers (MHT) Stroke Risk In WHI Hemorrhagic CVA not increased by MHT (E+P) Ischemic stroke in EP for all ages= 0.9/1000 women years Ages 50-59 attributable stroke risk= 1/2500 women years for hormonal exposure E only all women= 1.1/1000 women years Age 50-59 no increase in risk 11
Stroke Risk Coronary Artery Disease Related to hormone dosage and possible route of delivery Evidence that transdermal as safer route BUT higher doses transdermal may still increase risk of stroke MHT may carry a small increase in coronary events if started after 60 or 10 years after menopause Absolute increase in mortality in older MHT users in WHI was small 1.6/1000 women years Comorbidities ( diabetes, hypertension, dyslipidemia, smoking and inactivity) should be addressed before initiating MHT in older women Endometrial Cancer Unopposed estrogen may lead to endometrial cancer even years after cessation When atypical hyperplasia the risk of progression to endometrial cancer may be as high as 30% Progestin co-therapy will generally protect against hyperplasia in appropriate dose and duration( LNG IUS or SERM bazidoxiphene) Colorectal Cancer Reduction in colorectal cancer incidence and mortality in current but not in former users In WHI: incidence of colorectal cancer was decreased in EPT women- no survival benefit due to more advanced stages of colon cancernot enough evidence to use for mainly cancer prevention Ovarian Cancer Slight increase in risk of endometrioid ovarian cancers and decrease in mucinous ovarian ca among users of hormone therapy Risk 1/8300 hormone users per year- also disappears within 2 years of cessation GB Disease Gallbladder disease consistently increased in current and former users (stones and cholecystectomy rates) E alone >EPT Oral> transdermal 1 additional GB disease per 200 women years of MHT use 12
Vulvovaginal Atrophy Genitourinary syndrome of menopause In up to 45% of women in midlife or later Adversely effects physical and sexual health, quality of life and progresses over the course of menopause Undertreated -compelling evidence that low dose vaginal estrogen is safe and effective(cost may be an issue or reluctance to discuss) Benefits of Systemic Treatment Reduces new onset somatic aches and pains and joint soreness Reduction of vasomotor symptoms and night sweats- relief peaks at 4 wks treatment Protection against accelerated bone loss of menopause and stabilizes BMD -50% protection against fracture Urogenital health-increased blood flow, sensation and enhances sexual satisfaction Improvement in insulin sensitivity and reduces(50%) new onset diabetes Benefit-Still... In healthy coronaries in newly menopausal women there is a reduction in death due to CAD 1 fewer death per 1000 women years When started in women who were older or had pre-existing CAD there is increased risk of adverse events Window of opportunity Challenges To help symptomatic menopausal women make appropriate decisions regarding treatment Given the greater safety of hormone therapy and its more favourable benefit risk in younger postmenopausal women and among women with lower baseline risk of CV disease and breast cancer, risk stratification and personalized risk assessment may be helpful The End Questions? Who should be treated? How Long? Who should not be treated? What are the other options? NAMS North American Menopause Society provides a free mobile app called MenoPro to facilitate counselling- it is a decision support tool with a mode for clinicians and for patients and includes non-hormonal options for menopause management NEJM 374:9 p803-5. JE Manson and AM Kaunitz- Menopause Management 13
Venlafaxine vs Estradiol for Hot Flushes Flushes and CVD Risk O+G 2014 (Aug)124(2) 233 Reed S, Mitchell C et al RCT to evaluate sexual function in midlife women taking low dose oral E2 or venlafaxine for flushes Overall sexual function in non-depressed women did not change over 8 wks in either group compared to placebo Subtle increase in desire and decrease in orgasm and pain in venlafaxine group Pro-inflammatory properties of adipose tissue may act directly on CNS with potential thermoregulatory effect to increase hot flushes Evidence shows increased atherosclerosis, poorer vascular endothelial function, a more prothrombotic profile, insulin resistance, elevated lipids, altered sympathovagal balance with hot flushes above and beyond obesity Pro-inflammatory profile is consistent with higher CVD risk Diabetes and Natural Menopause Hum Reprod. Mar 2015 p1491-98 J Brand et al Women with diabetes before 20 had an earlier age of menopause(10-20 years HR 1.43 ) compared to non-diabetic women adjusted for age smoking, reproductive and diabetic risk factors Women with diabetes at 50+ had a later menopause (HR 0.81) Chronic metabolic disease may affect earlier natural age of menopause( also smoking, nulliparity, low SES) ( OC use-later) Menopause Treatment History: in 1970 USA less than 0.5% of women used estrogen Peaked usage in 1999-13.5% for women aged 45-64 yrs old 2010- only 2.7% were using E and P in USA In Australia 2015 survey 14.3% of women with mod to severe flushes were using MHT but 0.9% using alternatives, and 4.5% were using vaginal E Menopause v23 no1, 2016 Discontinuation-O+G 2014 v.123 no1 Associated with recurrence of symptoms in 50% of women regardless of age and duration of use Abrupt vs tapering- insufficient evidence Decision to continue must be individualizedbased on woman s symptoms and risk benefit ratio regardless of age Since some women aged 65 and older may continue to need HT for the management of vasomotor symptoms ACOG recommends against discontinuation of systemic estrogen at age 65 After Stopping From data from Finland 2 million woman follow up years of 332,202 women Within first year of stopping HT women < 60 had 2-3x increased risk of CV mortality and stroke mortality compared with age standardized background population death rate Whether used < 5 yrs :standardized mortality ratio 1.52 (95% CI 1.13-2) >5 yrs SMR 2.08 CI 1.44-2.90 14
Stopping Options Absolute risk of additional CV deaths resulting from HT withdrawal estimated from the Finnish study is 4-5/10,000 woman years of HT exposure Rare risk Menopause 2018,25:375-79 Observational For endometrial protection alternate to progestin- new estrogen antagonist/agonist bazedoxifene combined with oral conjugated estrogen- approved by FDA for treatment of menopausal symptoms and to prevent osteoporosis in women with a uterus Significantly reduces number of vasomotor symptoms and significantly increase BMD compared to placebo Discontinuation Rates Many women are reluctant to take MHT and discontinue within 12 mo German analysis : 17020 patients receiving MHT 2004-2013 (1 or 2 mg combined) After 12 mo: 45%(1 mg)and 34% (2mg) were still on treatment at 12 mo Persistence rate: 40% on < 50 transdermal and 38% for > or=50 microgram Those starting in 2007-9 were more likely to discontinue than those starting 2010-13 (early post WHI years 2004-9) E+P :Incidence and Deaths from Breast Cancer-Climacteric 2015 18:336-8 With WHI cumulative intervention and post intervention mean follow-up 11 years in women in the E+P group there were more deaths from breast cancer(25/yr- 0.03%) vs (12/yr-0.01%) HR 1.96 95% CI 1.00-4.04 And more deaths from all causes after a breast cancer diagnosis 51(0.05%) vs 31(0.03%) HR 1.57 95% CI 1.02-2.48 E Alone In trial WHI- estrogen alone use for 5.9 years was associated with decreased invasive breast cancer incidence and breast cancer mortality over extended follow-up in PM women with prior hysterectomy 15