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Conflict of Interest HRT: New Evidence on a Old Topic • Conflict of Interest – None

• Off –label drug use – Mirena IUD

Marcelle I. Cedars, M.D. – Gabapentin Professor and Director – Effexor Division of Reproductive Endocrinology and Infertility – Clonidine UCSF

Problems in Peri- Postmenopausal Women

• Abnormal uterine bleeding • Vasomotor symptoms • Genital atrophy • Decrease in skin collagen • Rapid bone loss • Increase in coronary heart disease • Increase in Alzheimer’s disease

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1966 2002 “Feminine Forever” WHI – E+P 1992 – American College of Physicians WHI vs. Observational studies Recommends MHT to prevent CHD

Menopausal Hormone Therapy (MHT) over the decades

1980’s – cohort and case/control Studies – support MHT reduces CHD and osteoporosis

1995 PEPI trial 2004 2015 WHI - ERT ELITE Manson JE, et al. 2006; 13:139

Patient Characteristics: Age Danish Osteoporosis the “timing” hypothesis Prevention Study (DOPS) • Grodstein et al. J Womens Health 2006 • 1006 women – Nurse’s Health Study: evaluating time from menopause – women near menopause reduced CV • Randomized 45-58 years, last vaginal risk (RR 0.66 CI: 0.54-0.80) bleeding 3-24 months prior to enrollment • Manson et al. NEJM 2007 and increased FSH – WHI: coronary calcium – women 50-59, coronary • Randomized, open-label, trial of estrogen calcium score lower in women on ET vs. placebo (2mg daily), triphasic estradiol + (OR 0.69 CI: 0.48-0.98) norethisterone (uterus) vs. no treatment • ELITE Trial – Hodus HN 2015 – Protection from CIMT changes in younger women Schierbeck LL, BMJ 2012

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DOPS - 2012 DOPS - 2012

• At 10 years, reduced overall mortality • Reduced heart failure, MI

• No “apparent” increased risk cancer, VTE

Schierbeck LL, BMJ 2012

Breast Cancer Breast Cancer Risk Factors Risk Factors • Was there truly a “protective” effect of • Low body weight estrogen in the E-only arm – WHI? • High mammographic breast density • Late menopause • Estrogen – Role of estrogen deprivation • Whether natural or via anti-estrogens (tamoxifen/aromatase inhibitors) – Estrogen as a pro-apoptotic

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Breast Cancer Breast Cancer The ‘Gap’ Hypothesis Risk Factors • Starting estrogen remote from menopause • Low body weight decreases risk while treatment within 2 years increases breast cancer risk • High mammographic breast density • Late menopause • The ‘gap hypothesis’ and the ‘timing • Starting close to menopause hypothesis’ are thus in conflict • 2 years after stopping HRT – risk equivalent to never users

The “Menopausal Syndrome” Role of Progestational Agents • Epidemiological Studies: proximity to • Gompel, Climacteric 2018 menopause, not associated with aging, – Estrogen alone lowest risk relieved with estrogen • Not indicated with uterus in situ – Vasomotor Symptoms – Synthetic progestins higher risk – Vaginal dryness/dyspareunia • Higher affinity for glucocorticoid receptor • Also androgen receptor and mineralocorticoid – Difficulty sleeping/insomnia – Natural progesterone risk lowest – Mood and depression – Changes in cognitive function

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Trouble Sleeping by Cycle Day Hot Flashes worsen Sleep

• 20 healthy premenopausal women receiving GnRHa • 80% concordance between subjective/objective VMS (sVMS/oVMS) • Sleep efficiency (actigraphy) worse with oVMS, quality worse with sVMS (questionnaire)

Kravitz, H. M. et al. Arch Intern Med Joffe H, Menopause 2013 PMID 23481119

Verbal Duration of VMS Memory

Decrement in immediate (A) and delayed (B) verbal recall

Epperson JCEM 2013

Avis, NE: JAMA Int Med 2015

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Adjusted OR for CES-D > 16 Estradiol and Depressive Disorders Across Menopausal Transition (Soares et al., Arch Gen Psychiatry 2001;58:529) • 50 perimenopausal women aged 40-55 with irregular Pre Early Peri Late Peri Post HT Users menstrual periods and FSH > 25 IU/L meeting criteria for major depressive, dysthymic, or minor 1.8 depressive disorder by DSM-IV blindly randomized 1.6 to transdermal estradiol (0.1 mg) or placebo for 12 1.4 wks 1.2 1 • Remission of depression observed in 17 of 25 (68%) 0.8 on E2 and 5% on placebo 0.6 • Regardless of DSM-IV diagnosis, subjects responded 0.4 similarly to E 0.2 2 0

Bromberger, J Affect Disord 2007

Estrogen for Depression Estrogen and the Brain Prevention • Direct effects – Enhances synaptic plasticity, neurite growth, hippocampal neurogenesis and long-term potentiation (memory) – Protects against apoptosis and neural injury Gordon, J JAMA Psychiatry – Stimulates aceytlcholine (memory), serotonin, 2018 noradrenalin – Decrease deposition of b-amyloid – Promotes morphological and electrophysiological correlates of learning and memory • Indirect effects – Vasculature – Immune system NIA – Frontiers proposal – Bench to Bedside Estrogen as a case-study (2009)

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Estrogen and the Brain Estrogen and the Brain Alzheimer Disease

• Alzheimer Disease • Observational studies suggest protection • Meta-analyses suggest risk reduction of – Early and consistent symptom – loss of approximately 1/3 episodic memory (failing to recall • Contradicted by the WHIMS trial (ages 65-79) appointments and events) – Risk of dementia increased two-fold with combined – In the laboratory: estrogen reduces the HRT – Impact noted within a few years, suggesting impact formation of b-amyloid formation and primarily on the vasculature diminishes hyperphosphorylation of tau – Past history of use associated with lowered incident protein risk of dementia (including Alzheimer Disease) • Initiation in older women WITH disease is not beneficial

U.S Preventative Task Force Long-term risk/benefit Holm M, BJOG 2018

Gartlehner, JAMA 2017 Gross D, JAMA 2017

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Endocrine Society 2010 Endocrine Society 2010

Current Thinking Current Thinking • Best treatment population • Estrogen most effective treatment – Young women < 60 years of age • Bio-identical hormones – < 10 years from menopause – no more effective • Individualization – no evidence for improved safety – Personal preference • BZA/CE comparative efficacy – Baseline risk – Thromboembolic risk comparative – Characteristics of MHT (route, type, dose) – Long-term data lacking

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“Lowest Dose” Route/Type

• Start low • Blood pressure – impaired endothelial function – Decreased stroke risk – Small impact of oral; no impact for transdermal – beneficial impact suggested with estradiol and – Positive effects on symptoms drospirenone • May take longer to document benefit – Positive effects on bone • Metabolic syndrome – menopause diabetogenic – Safety re: endometrial protection when – Reduced DM and insulin resistance with estrogen unopposed not confirmed – Advantage of natural progesterone/non-androgenic – Safety re: CVD not confirmed progestins (drospeirenone, dydrogesterone)

Route/Type Route/Type

• CVD • Neuroprotection – CRP – increased with oral and not transdermal; worsening affect with MPA – No differences available between oral and – MMP-9 – increased by oral and not by transdermal transdermal – “first pass” effect on the liver (lipids) – endothelial function - improved with both • Breast cancer (inhibited by MPA and NET) – No differences available between oral and transdermal • Thromboembolic events (case-control study) – Increased risk with oral – Increased risk with combined progestational – No increase with transdermal agent

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Route Type

• Transdermal • Progestogen – Less negative effect on surrogate markers – Daily combined vs. cyclical • Clotting factors, TG, CRP • Improved protection re: endometrial cancer – Decrease stroke risk • Increased breast cancer risk – Decreased CV risk – not well documented – MPA vs. progesterone • Vaginal • Stroke risk: Progesterone < MPA – For local symptoms

Mirena for Uterine Protection Duration • 3-5 years • Stopping guidelines – Breast cancer risk after combined continuous for 7 years – Bone loss will resume – Vasomotor and vaginal symptoms may return • Long-term treatment Jareid M, Gynecol Oncol 2018

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Impact of Stopping HT Impact of Stopping HT

MikolaTS 2015 JCEM MikolaTS 2015 JCEM

Venetkoski M 2017 Menopause

Vaginal Relief – new Non-hormonal Alternatives alternatives • SSRI and SNRI have modest effect • Ospemifene – Avoid paroxetine with tamoxifen – SERM – local effect on vaginal tissue • Gabapentin equally effective to estrogen – Minimal increase endometrial thickness – no – ER may have less side effects histological changes – Neutral breast • Clonidine – Possible positive bone effect (bone markers) – No comparative trials with estrogen – Possible increased stroke risk – High side effect profile

Archer DF, Menopause 2014

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Behavioral therapy Individualization

• Yoga appears in early studies to have • Risk profile some benefit • Symptom profile • Mindfulness, avoidance of triggers and • Patient preferences relaxation may offer benefit to some • New studies evaluating cognitive behavioral therapy with reduction in sleep disturbances and depression

Assess Risk Assess Risk

• CV Risk • Osteoporosis Risk – http://my.americanheart.org/cvriskcalculator – http://www.shef.ac.uk/FRAX/tool.aspx?country=9 • Stroke Risk • NAMS decision support tool – Bushnell, Annals Int Med 2014 – Menopause 22(3): 247-253, 2014 • Breast Cancer Risk – MenoPro App – http://www.cancer.gov/bcrisktool/ – Discuss SERM if 5-year risk > 3% – First degree relative, BRCA+, personal history of biopsy with atypia

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Type – new alternatives

• Combination – estrogen + SERM – CEE 0.45mg + Bazedoxifene (BZA) 20mg – Vasomotor symptom relief – Vaginal symptom relief – Bone protection – albeit < MHT – Favorable lipid profiles – No adverse risk to bone/endometrium – No long-term studies of events Lobo RA, Fertil Steril Pinkerton JV, J Women’s Health 2014 Pinkerton JV, JCEM 2014

Type – New combination therapies

• Activella: E2 1mg + NETA 0.5mg daily • Femhrt: EE 5 mcg + NET 1mg daily • Ortho-prefest: E2 1mg + norgestimate 0.09mg – Alternate 3 days unopposed E2 with combination • Combi-patch – E2 with LVG or NETA

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