Update on Managing Menopausal Symptoms

Update on Managing Disclosures Menopausal Symptoms

Dr. Meckstroth receives an honorarium from Danco, Inc. to serve as an expert for an FDA‐ mandated hotline for clinicians with questions regarding medical abortion.

Karen R. Meckstroth, MD, MPH Director, UCSF Women’s Options Center Clinical Professor, UCSF Dept. of Obstetrics, Gynecology & Reproductive Sciences Zuckerberg San Francisco General Acknowledgements to Michael Policar, MD & Risa Kagan, MD

Guidelines & Developments in Stages of Reproductive Aging Workshop Menopause Management (STRAW)

Nomenclature and criteria in reproductive aging FMP • 2012 STRAW +10 Reproductive phase Menopausal Post‐ Symptom management Transition Menopause • 2014 (2016) ACOG Pract Bulletin Mgt of Menopausal Sx AMH, 1 inhibin B • 2017 + earlier NAMS Position Statements – June 20th Y decline in R GSM late repro Perimenopause • 2014 ISSWSH‐NAMS Consensus Statement • 2015 Petition to remove black box < 40: Primary ovarian insufficiency (1%) 40‐45 yo or surgical: Early Menopause (5%) FSH IU/L Consequences of Estrogen Loss

• Vasomotor symptoms  hot flashes, night sweats • Neuro‐behavioral  sleep problems, memory loss • Genitourinary Syndrome of Menopause (GSM) – Vaginal dryness, painful sex

E2 pg/mL – Burning on urination; urge incontinence

• Bone loss  increased hip, vertebral fracture risk • Increased risk of MI, stroke (vs. premenopause) Figure 1 Adjusted population means (95% CI) for segmented mean profiles of follicle-stimulating hormone and estradiol across the final menstrual period in the Study of Women's Health Across the Nation (n =1,215). *, The y axis is unitless. The units of hormone are marked in the corresponding curves. Reproduced with permission from Randolph et al., J Clin Endocrinol Metab 2011;96:746–754

Published in: Siobán D. Harlow; Margery Gass; Janet E. Hall; Roger Lobo; Pauline Maki; Robert W. Rebar; Sherry Sherman; Patrick M. Sluss; Tobie J. de Villiers; Climacteric 2012, 15, 105-114.DOI: 10.3109/13697137.2011.650656 Copyright © 2012 International Menopause Society

Vasomotor Symptoms (VMS) Duration of Menopausal VMS

• Experienced by 75% of menopausal women • 3302 women 7 US sites; 1996‐ 2013, median 13 visits – May start during the peri‐menopause • Findings: – Cluster in 2‐year window before and after FMP – Duration 7.4 yrs (median) – 25% have hot flushes > 5 years after menopause – Persistence post‐FMP 4.5 yrs (median) • Smoking and obesity are risk factors – Both longer if premenopausal or early perimenopausal • Ethnic and racial differences when first reported frequent VMS Duration 11.8 yrs – More common in African‐American women Persistence post‐FMP 9.4 yrs – Less common in Chinese, Japanese FMP: final menstrual period Avis NE, et. al, for SWAN. JAMA Int Med. 2015 2017 NAMS Hormone Therapy Moderate‐Severe Hot Flashes CI: Contra‐ Position Statement (inadequate response to lifestyle modifications) Indication HT: Hormone therapy • Benefit‐risk ratio appears favorable for vasomotor No Yes symptoms (VMS) and elevated risk of bone loss or fracture if starting treatment: GSM sxs? Wants HT? No CI? – Younger than 60yo Yes No Yes No – Within 10 yrs of menopause Yrs since MP CV risk* <5Y 6‐10Y >10Y Wants SSRI? No CI? – No contraindications Free of Br/em ca? Avoid HT Low (5%) HT OK HT OK Avoid Mod (5‐10%) HT OK* HT OK* Avoid • Risks for above groups: CHD, stroke, DVT, dementia High (>10%) Avoid Avoid Avoid Yes No • Do NOT need to routinely D/C at any age Yes No •Prior hyst: E alone Try Try Try vaginal E or Intimate lubricants 2 2 •Intact uterus: E+P or • SSRI • GBP • Longer duration more favorable for estrogen alone ospemifene + moisturizers CEE + bazedoxifene • SNRI • Others * Consider transdermal hormone therapy Manson JE, Menopause 2015;22:247‐53 * CVriskcalculator.com

In addition to sleep hygiene and stimulus control, Case Study Would you recommend….. • Ms S is a 53 year old woman with moderate‐severe hot flashes and difficulty getting to sleep 1. a sleep/insomnia medication • Her menses were regular until two years ago, 2. a trial of SSRI or SNRI medication became irregular, and then stopped 16 months ago 3. lowest dose of estrogen and progestin • She has tried a number of herbal remedies, each of 4. a “mid‐range” dose of estrogen and progestin which helped for only a few months • Her medical history, BP, physical exam are normal 5. a consultation visit with an ObGyn • The hot flashes affect her work productivity and she wants to try something else Explaining HT Benefit and Risk Contraindications for Systemic HT HT risk is related to • Unexplained vaginal bleeding • A woman’s baseline disease risks • Severe active liver disease • Her age • Prior estrogen‐sensitive breast or endometrial ca • Age at menopause • CVD, stroke • Cause of menopause • Dementia • Time since menopause • History of or high risk for thromboembolic disease • • Prior use of any hormone Hypertriglyceridemia • HT types, route of administration, doses used Concerns: endometriosis or migraine may worsen, • Emerging medical conditions during treatment fibroids may grow

NAMS position statements. Menopause 2008, 2012, 2017.

Systemic HT & CV Risk (and All‐Cause Mortality) Systemic HT & Breast Cancer • Initiation <10 yrs after menopause and < 60yo • Effect of HT on breast cancer risk depends on – CVD lower and reduction in all‐cause mortality – Type of HT, regimen, dose, duration and route – Prior exposure and individual characteristics – Likely no increased risk of stroke • Nonsignificant reduction in risk w CEE alone – Increased risk VTE (RR=1.74) (in RCTs but not all obs studies. 7 fewer in 10,000) • Initiation > 10yrs or over 60yo • Increased risk with CEE+MPA. <1 more in 1000 – Increased stroke (RR=1.21) and VTE (RR=1.96) (in some RCTs and many obs studies) • Fewer breast changes w CEE+bazedoxifene • Across all ages: Stroke ↑6 per 10K, VTE ↑8 per 10K • Survivors: systemic generally not recommended; • Transdermal estrogen: lower risk in obs studies Local “may be considered” if fails non‐hormonal tx

NAMS 2017 NAMS 2017 Nonhormonal Management of Menopause‐associated VMS Recommend: Nonhormonal Management of Menopause‐associated Cognitive‐behavioral therapy (insomnia > hot flashes) Vasomotor Symptoms (VMS) Prescription Therapies • FDA‐approved low‐dose paroxetine salt (the only FDA‐approved non‐hormonal Rx) Key points from the • Gabapentin and pregabalin 2015 NAMS Position Statement • Other SSRIs and SNRIs yielding significant VMS reductions in large RCTs

NAMS. Menopause. 2015

VMS: Non‐Hormonal Therapies Recommend With Caution Level II evidence suggests these may be beneficial % treated patients % placebo patients • Weight loss with >50% ↓HF with >50% ↓HF • Mindfulness‐based stress reduction Venlafaxine 75 mg 54‐70% 30% (ok on tamoxifen) • S‐equol derivative of soy Paroxitine 10mg 50‐76% 35‐57% • Stellate ganglion block (SGB) Sertraline (Zoloft) 40‐56% 21‐41% (non signif) – Image‐guided anesthetic block at C‐6 level Escitalopram 55% 36% Gabapentin 46‐84% 27‐47% – 45‐90% HF reduction for 6 weeks‐3 months – No significant HF reduction at 6 months

• Over‐the‐counter supplements Level I evidence shows these are unlikely to • Herbal therapies alleviate VMS; may have other health benefits • Vitamins • Exercise • Relaxation • Yoga • Calibration of neural oscillations • Paced respiration • Chiropractic intervention • Acupuncture • Cooling techniques • Avoiding “triggers”

NAMS Recommendations For Clinical Care of Midlife Women Prescription HT Options: ET and EPT

• Hormone therapy is the most effective treatment for Oral Transdermal Intravaginal vasomotor symptoms ET • Micronized estradiol • Patches • Creams • “The benefits outweigh the risks for most healthy, • Conjugated equine • Gels • Intravaginal symptomatic women aged younger than 60 years or estrogens (CEE) • Emulsion tablet within 10 years of the final menstrual period” • Synthetic conjugated • Spray • Rings • Options include: estrogens – Estrogen alone (no uterus) • Esterified estrogens – Estrogen‐progestogen • Estropipate – Estrogen‐bazedoxifene • Estradiol acetate – Progestogen alone (300mg MP qhs, DMPA) EPT • CC‐EPT • E+P combo patch – Combined OCs in women requiring contraception • CS‐EPT

NAMS. Menopause 2014, 2017 Hormone Therapy Regimens Choice of HT Regimen Month 1Month 2 Estrogen Therapy (ET) • If no uterus: estrogen only Estrogen • If uterus present: estrogen + progestogen Continuous combined (CC) EPT – Goal is to avoid vaginal bleeding entirely, or, at Estrogen least, to make it predictable Progestin • Endometrial activity predicts bleeding pattern Continuous‐sequential (CS) EPT Estrogen – Recent spontaneous or induced bleeding: Progestin 14d Off for 14 dOff for 14 d • Use continuous sequential Continuous‐pulsed (CP) EPT – No bleeding for >2‐3 cycles:

3d • Use continuous combined

Hormone Therapy Dosages Choice of Estrogens

“Appropriate, often lowest” appropriate • Start low dose transdermal or oral estrogen • The lowest dose of HT should be used for the shortest • If suboptimal response, modify by: duration needed to manage menopausal symptoms – Change the estrogen dose (upward) • Lower doses better tolerated, may have more – Change the estrogen preparation favorable benefit‐risk ratio than standard doses – Change delivery systems (oral transdermal) • Additional local ET may be needed for persistent – Consider an estrogen + androgen (Covaryx)* vaginal symptoms • Injectable estrogen not recommended – Dosage equivalencies are not known – Estrogen cannot be discontinued easily

NAMS position statement. Menopause 2015 → 2017 *J.Shifrin & S.Davis. Androgens in postmenopausal women: a review. Jun 2017 Bazedoxifene 10 mg + CE 0.45 mg HT: Routes of Administration

• Tissue selective estrogen receptor modulator (SERM) • No clear benefit of one route of administration • Progestin‐free • Non‐oral systemic ET: • Reduces VMS frequency and severity – Lower DVT/PE risk • Prevents loss of bone mass – Less effect on SHBG (bioavailability of testosterone) • Treats GSM • With either route, progestogen required for • No increase in endometrial hyperplasia endometrial protection • Amenorrhea, breast tenderness adverse event rates and • Local ET preferred when solely vaginal symptoms overall safety similar to placebo

Taylor HS. Menopause; 2012 NAMS. Menopause 2008, 2017.

Systemic HT and Other Health Issues: Moderate‐Severe Hot Flashes CI: Contra‐ (inadequate response to lifestyle modifications) Indication Benefits HT: Hormone therapy • Indicated ONLY for: fracture prevention, VMS and premature No Yes hypoestrogenism • Improves chronic insomnia Wants HT? No CI? • Improves skin: thickness, collagen, elastin, moisture, Yes No fewer wrinkles. No change in hair found. Yrs since MP CV risk <5Y 6‐10Y >10Y Wants SSRI? No CI? • Sig decrease in diagnosis of type 2 DM (40%) Low (5%) HT OK HT OK Avoid • No change or decrease in weight Mod (5‐10%) HT OK* HT OK* Avoid High (>10%) Avoid Avoid Avoid Yes No • Decreases dizziness, vertigo (small trials) • May decrease cataracts and open‐angle glaucoma •Prior hyst: E2 alone Try Try •Intact uterus: E+P or • SSRI • GBP • Unclear effect on joint pain/osteoarthritis • CEE + bazedoxifene • SNRI • Others * Consider transdermal hormone therapy Manson JE, Menopause 2015;22:247‐53 NAMS 2017 Systemic HT and Other Health Issues: Systemic HT and Other Health Issues: AEs/Risks Dementia • CVD and breast cancer as discussed above • Timing of initiation likely significant determinant • AE’s: nausea, bloating, mood swings (prog), HA, breast • Initiated 65yo+: tenderness – Dementia risk doubled with EPT (23 per 10K) • Increased GSUI (vaginal ET improves incontinence) – No change with CEE alone • Cholelithiasis, cholecysitis (more w oral ET) ~50 per 10K • Initiated within 10 years: – Likely lowers Alzheimer’s risk • After surgical menopause: possibly beneficial • More favorable when initiated at the time of normal cognitive function. Does not improve function.

NAMS 2017 NAMS 2017

Physical Exam with No Evidence of: Case Study (Differential Diagnosis)

• Betty is a 53 year old G P Vietnamese American • Candidiasis • Vulvar intraepithelial 4 3 neoplasm with severe vulvovaginal irritation, burning, and • Bacterial vaginosis • Vulvar cancer watery yellow discharge • Desquamative inflammatory vaginitis • Other benign and malignant • Not sexually active for 10 years • Contact dermatitis (irritant tumors or allergic) • Other medical disorder (e.g., • Multiple courses of OTC topical antifungal drugs and • Lichen sclerosis diabetes, lupus) topical vulvar 1% cortisone with no relief • Lichen planus • Psychological causes • Lichen simplex chronicus • Trauma/Foreign body • “Vulvodynia”

MacBride MB, Rhodes DJ, Shuster LT Mayo Clin Proc 2010 Would you ….. Genitourinary Syndrome of Menopause (GSM)

• Vaginal changes Advise her that she has vulvar and vaginal signs of – Vaginal spotting or bleeding genitourinary syndrome of menopause (GSM) and – Vaginal dryness offer: – Dyspareunia: poor lubrication, less vaginal elasticity, skin 1. Prebiotics irritation, introital shrinkage – Negative impact on sexual function, relationships, QOL 2. Topical estrogen treatment • Bladder and urethra changes 3. Vaginal moisturizer – Urgency, frequency, dysuria, urge incontinence 4. Systemic low‐dose transdermal estrogen – Often misdiagnosed as bladder infection; tests negative – No effect on stress incontinence or pelvic organ prolapse

GSM Epidemiology

• 64 million postmenopausal women in the US1 • GSM symptoms will affect at least 50% of postmenopausal women at some point in their lives Expert consensus that vulvovaginal atrophy (VVA) – 4% during perimenopause and 47% 3 years post FMP 2 needed improved nomenclature • Atrophy has negative connotations – Chronic, progressive • Vagina: some patients consider inappropriate for discussion – Symptoms do not improve without treatment • Further, VVA does not encompass sx of lower genital tract • Many women unaware that changes can be a direct result of Precedent established for how medical lexicon has menopause changed and increased comfort in patient discussions: • Less than 1 in 10 symptomatic women are being treated3 “impotence” has fully transitioned to “ED”

1.Wysocki S, Clin Med Insights: Reprod Health 2014 53 2.Portman DJ, Gass ML Menopause 2014. 3. NAMS position statement Menopause 2013 Portman DJ, Gass MLS, on behalf of the Vulvovaginal Atrophy Terminology Consensus Conference Panel. Menopause 2014 21(10):1063-1068 “Estrogen therapy is the most effective GSM: Treatment treatment for GSM.” ‐NAMS 2017

• OTC lubricants • Estrogen lowers vaginal pH, increases subepithelial capillary growth, thickens epithelium – Water based: Astroglide®, KY Jelly®, Sliquid® • Raises level of vaginal secretions – Silicone based: K‐Y intrigue®, Astroglide X® • VMI increases reflecting higher percentage of – Oil based: Elegance®, olive oil, coconut oil superficial cells relative to parabasal cells • Vaginal moisturizers: Luvena®, Vagisil®, Replens® • Estrogen therapy alleviates subjective vaginal • Local estrogen therapy (preferred over systemic) symptoms • Systemic HT (when prescribed for VMS) – Dryness, soreness, irritation, pruritus, and dyspareunia • Oral ospemifene

Vaginal Histology Topical (Vaginal) Estrogen Composition Brand Name Dose and sig Vaginal cream Estrace® Vaginal Initial: 2.0‐4.0g/d for 1‐2 wk 17β‐Estradiol Cream Maint: 1.0g/d (0.1 mg/g) Vaginal cream Premarin® Vaginal 0.5‐2.0 g/d or twice/wk conj estrogens Cream (0.6 mg/g) Vaginal ring Estring® Ring contains 2 mg 17β‐estradiol releases 7.5 mcg/d for 90 d Vaginal ring Femring® (Systemic Systemic dose ring for 90 d E2 acetate dose and indication) 12.4mg releases 50mcg/d Premenopause Postmenopause 24.8mg releases 100mcg/d Vaginal tablet Vagifem® 10mcg Initial: 1 tablet/d for 2 wk Epithelium well-estrogenized,multi- Estrogen-deficiency atrophy with marked layered with good blood supply, thinning of epithelium, blood supply E2 hemihydrate Maintenance: 1 tab 2x /wk superficial cells rich in glycogen reduced, and loss of glycogen NAMS Position Statement Menopause. 2013 Onset of Action of Vaginal Estrogens GSM: Vaginal vs. Systemic Estrogen

• Improvements in VMI reported as early as • Topical therapy is preferred when vaginal symptoms are the 2 to 4 weeks after initiation of vaginal CEE cream or only complaint estradiol vaginal tablets • Topical more effective than systemic oral ET • Vaginal pH falls to lowest levels by 3rd week of vaginal • Presumed lower risk, progestin NOT needed for most estrogen treatment (number of superficial cells in the • 10%‐15% of women on systemic HT may also need local vagina has increased by that time) estrogen therapy • Superficial cells continue to increase during 12‐weeks of • Systemic ET may worsen or provoke stress incontinence therapy – Ultralow‐dose transdermal ET has no effect on incontinence • Atrophic vaginal epithelium absorbs locally applied • Only vaginal ET is effective for urinary tract infection estrogen faster than after the epithelium has been estrogenized • ACOG committee opinion and NAMS 2017 endorsed vaginal CEE, conjugated equine estrogen use in breast cancer survivors NAMS position statement. Menopause 2012, 2013. Santen RJ et al. Menopause 2002 Cody JD. Cochrane Database Syst Rev. 2009

Ospemifene Approved 2013 for Vulvovaginal Sx of Menopause Ospemifene • Daily 60mg oral tablet, administer with food • VMS: most common AE 7.2% vs 2% in placebo • Selective estrogen‐receptor modulator (SERM) • Prescribing information similar to estrogens and – Preclinical data: antiestrogen effects on breast tissue other SERMs and agonistic effects on bone • Improvement in… • Contraindicated in – Dyspareunia – Genital bleeding unknown etiology – Vaginal maturation index – Estrogen‐dependent neoplasia – Vaginal pH – DVT, PE, CVA, MI history or current – Vaginal dryness

Cui Y. Journal of Sexual Medicine. 2014; NAMS, Menopause. 2013 Vaginal Prasterone (DHEA/Dehydroepiandrosterone) Urinary Tract Symptoms: Vaginal Estrogen

• FDA Approved Nov 2016 • Provides greater benefit than non‐hormonal tx • 4 Phase 3 trials‐ 665 women, dyspareunia as MBS of VVA • Improves, may cure: • Prasterone ‐ 6.5 mg (0.5%) – Overactive bladder • Daily vaginal suppository – Urge incontinence • Slight increase in serum DHEA, estradiol, testosterone – Recurrent urinary tract infections secondary to aromatization –in PMP range – Urethritis (irritative) symptoms • No Box Warning • No effect on SUI (oral ET may worsen it!) • AEs: 5.7% discharge vs. • No HT product FDA approved for urinary health in US 3.66% placebo

, NAMS position statement. Menopause 2012

Day‐to Day Impact of Vaginal Aging HT & Sexual Function Questionnaire (DIVA)

• Treatment of moderate to severe vaginal atrophy with • Self‐report questionnaire: 23 items in 4 domains systemic ET/EPT or local ET can relieve dyspareunia 1. activities of daily living • One oral systemic ET product is FDA approved for 2. emotional well‐being dyspareunia 3. sexual functioning 4. self‐concept and body image • HT is not recommended as sole treatment of other sexual function problems (e.g., diminished libido) • Evaluation of the impact of GSM symptoms on QOL for women of diverse backgrounds • Valid for researchers and clinicians

NAMS position statement. Menopause 2008. Huang AJ, Gregorich SE, et al. Menopause 2015 Low‐Dose Vaginal Estrogen: Black Box Warning for Low–Dose Vaginal Estrogen Safe for Nearly All

“WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, BREAST CANCER AND PROBABLE DEMENTIA”

NAMS sponsored initiative- FDA scientific workshop November 2015

Citizen’s Petition supported by ACOG, AMWA, Endoc Soc. ++. Vulvar emojis from Risa Kagan, MD (past president of NAMS) Awaiting decision about label change.