10/2/2015

Current Management of Menopausal Symptoms Vanessa M. Barnabei, MD, PhD Professor and Chair Department of Obstetrics and Gynecology University at Buffalo

NO DISCLOSURES

Objectives • Review current management of menopausal symptoms • Discuss safety issues for use of systemic and local estrogen therapy

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Scope of the Problem • 75% of perimenopausal and menopausal women will experience vasomotor symptoms (hot flashes and/or night sweats) • In 15% of women, symptoms are moderate-severe and may warrant treatment • Symptoms are common in women who are still menstruating • Symptoms are common in women with normal estrogen levels

Timing Hypothesis • “Critical Window” for benefit of HT • Helps explain discrepancy between observational studies and RCTs • Component 1: HT initiated early in menopausal transition will slow progression of early atherosclerosis • Component 2: Beneficial effects of HT will be lost in later menopause when atherosclerosis is more advanced

Timing Hypothesis • Nurses Health Study RR 0.61 for major coronary event (observational) in HT users • HERS no differences between groups in CAD or plaque progression (secondary intervention) • WHI no difference in CAD except in youngest women

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Animal Studies • Clarkson et al, cynomolgus monkeys, showed beneficial effect of estrogen on atherosclerosis progression • Decrease in estrogen receptors (ER) in endothelium affected by atherosclerosis • Estrogen may be anti-inflammatory with more ER and pro-inflammatory with fewer ER • Pro-inflammatory effect leads to activation of MMPs (matrix metalloproteinases) and plaque disruption

Pathogenesis of Coronary Artery Atherosclerosis of North American Human Females Stage of Reproductive Life

Premenopause

Perimenopause

Postmenopause MMP-9

~5%

~15%

15-25 yrs

25-35 yrs

Benefits of Endogenous E 2

35-45 yrs

45-55 yrs

Primary Benefits of ERT/HRT

55-65 yrs

65 yrs

Deleterious Effects of ERT/HRT

Relation Relation of Age Distribution Distribution in WHI WHI to Stage of Progression of of Coronary Artery Atherosclerosis 70%

0% yrs

10%

20%

45%

25%

50-54

55-59

60-69

70-79

Adventitia

MMP-9

Media Internal Elastic Lamina

Fibrous Cap Plaque

Fibrous Cap

Fatty Streak/Plaque

35-45 yrs

Plaque

45-55 yrs

Fibrous Cap Plaque

Necrotic Core

55-65 yrs

Necrotic Core

65 yrs

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Rossouw JE et al, 2007; Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause

Age

All

CEE

CEE+ MPA

50-59

0.93

0.63

1.29*

60-69

0.98

0.94

1.03

Years since LMP

70-79

1.26

1.13

1.48*

20

1.28

All

CEE

CEE+ MPA

0.76

0.48

0.88

1.10

0.96

1.23

1.12

1.66*

Mortality Toll, Natural Menopause • Li S et al; 2013; Maturitas • Prospective, cohort study, Black Women’s Health Study • All-cause mortality in women with menopause age < 40 years significantly greater relative to women with LMP age 50-54 • Mortality Rate Ratio (MRR) 1.34 • Mortality ameliorated if women used HT • MMR 1.97 in never users • Authors suggest “accelerated or premature somatic aging” in women with LMP prior to age 40

Effect Modifiers • Progestogen • WHI data suggest deleterious effect; other data conflicting; micronized P4 may be safer than synthetic progestogens • Metabolic Disorder • Wild et al, 2013; nested case-control study within WHI in women without prior CHD • HR 2.26 for HT vs. placebo in women with MetS • HR 0.97 for HT vs. placebo in women without MetS • Dose • CHD benefit seen with even low doses • High doses may increase other risks

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HT and Health Outcomes, WHI 2013 • • • • • •

Manson JE et al; JAMA 2013;310:1353-1368 Extended outcomes data, 13y cumulative follow up CHD: RR 1.18 for EPT; 0.94 for ET Breast Cancer: 1.24 for EPT; 0.79 for ET Age affected risk for CHD and stroke Neither regimen affected all-cause mortality

Transdermal Better than Oral • • • • • • • •

VTE risk Migraine headache Mammographic breast density Sexual function (libido) Growth hormone and IGF-1 Triglyceride response Gallbladder disease Bile acid secretion and Biliary cholesterol saturation

Transdermal Estrogen • Absorption of estrogen through the skin is very high • Avoids first pass effect • No change in SHBG or other binding globulins • No change in E2:E1 ratio • Allows for more convenient dose titration and weaning

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Transdermal vs. Oral Estrogen • Data emerging that thromboembolism risk is modified by method of administration • Non-oral administration avoids first-pass effect • ESTHER study 2007 • Synthetic progestogens may also increase VTE risk • ACOG Committee Opinion April 2013: “When prescribing estrogen therapy, the gynecologist should take into consideration the possible thrombosissparing properties of transdermal forms of estrogen therapy.”

VTE and CVD Risk-A Matched Control Study • Simon JA et al, 2013 NAMS abstract • 7558 women using t-ET matched with 7552 women using oral estrogen from health insurance claims • Mean age 50y • 718 t-ET users and 828 oral estrogen users developed VTE or CVD (adjusted IRR = 0.79, 0.700.89 CI) • Healthcare and event-associated costs also lower in t-ET users

Progesterone and Progestins • Progestin is recommended for all women with a uterus who are receiving systemic estrogen therapy. Includes women s/p endometrial ablation. • Transdermal, intravaginal, intrauterine • Risk for breast cancer, VTE and CVD vary with type of progestin • Bioidentical P4 lowest risk • WHI: combined therapy (CEE with MPA) showed increased risk for CVD and breast cancer vs. CEE alone

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HT Alternatives SSRI/SSNI: many studies support benefit, off-label Low-dose mesylate salt of paroxetine 7.5 mg (+FDA) Gabapentin and Pregabalin, off-label SERMS “estrogen agonist/antagonist with tissue selective effects”: • Ospemifene: approved for VVA, may make VMS worse; probable breast/endometrial safety • CEE+bazedoxifene, may relieve need for progestogen but still has risks of oral estrogen • Tibolone: endorsed by Spanish Menopause Society for VVA and VMS • Clonidine: still effective, still off-label

• • • •

HT Alternatives • Behavioral and lifestyle interventions are probably as or more effective than over-the-counter, complementary and alternative therapies

FIG. 1

Menopause Decision-Support Algorithm

FIG. 1 . Algorithm for menopausal symptom  management and hormonal/non‐hormonal  therapy decision making. Algorithm footnotes  appear at the end of the article.

Algorithm and mobile app for menopausal  symptom management and hormonal/non‐ hormonal therapy decision making:  a clinical  decision‐support tool from The North American  Menopause Society. Manson, JoAnn;  MD, DrPH; Ames, Jeffrey;  BS,  MEng; Shapiro, Marla; MD, NCMP; Gass, Margery;   MD, NCMP; Shifren, Jan;  MD, NCMP; Stuenkel,  Cynthia;  MD, NCMP; Pinkerton, JoAnn;  MD,  NCMP; Kaunitz, Andrew;  MD, NCMP; Pace, Diane;   PhD, FNP‐BC; Kagan, Risa; MD, NCMP; Schnatz,  Peter;  DO, NCMP; Kingsberg, Sheryl; Liu, James;  Joffe, Hadine; MD, MSc; Richard‐Davis, Gloria;  Goldstein, Steven;  MD, NCMP; Schiff, Isaac; Utian,  Wulf;  MB, Bch;  PhD, DSc Menopause. 22(3):247‐253, March 2015. DOI: 10.1097/GME.0000000000000373

© 2015 by The North American Menopause Society.  Published by Lippincott Williams & Wilkins, Inc.

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…and App (of course) • MenoPro iPhone/iPad app (free) • Designed to help clinicians and patients decide who are appropriate candidates for hormone therapy and/or other pharmacologic interventions for symptom relief • Based on a risk stratification model plus patient preferences

Management of Vulvovaginal Atrophy (VVA), aka Genitourinary Syndrome of Menopause (GSM) • Up to 45-50% of PMP women symptomatic from VVA • 75% report negative consequences on sex life • Symptoms and Treatment options often not discussed by PCPs and gynecologists • Delay in recognition and treatment can lead to loss of structure and function

Management of VVA • Very few absolute contraindications for vaginal estrogen use • Most effective therapy for urogenital atrophy • Estradiol works better than estriol • Minimal absorption once vagina is reepithelialized • Absorption: cream > tablet > ring • Ring has highest acceptability and fewest side effects

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Management of VVA • Minimal change in serum E2 with vaginal administration: • Vaginal ring: 5-10 pg/ml (may be higher during first week of use) • Vaginal tablets: 3-11 pg/ml • Vaginal E2 cream: up to 80 pg/ml! • CEE cream: no change in E2 but may still have estrogenic effect • Use in breast cancer patients still controversial; consult with patient’s oncologist before prescribing

Summary • Estrogen increases the risk of stroke in all women; risk is age-related • Systemic estrogen can be used safely in most perimenopausal and early menopausal women (benefits may outweigh risks) • Transdermal estrogen has better safety profile than oral estrogen • Progestogen compromises some of the benefits of estrogen and may have risks; P4 has lowest impact • Local estrogen use is safe for most postmenopausal women when appropriately prescribed

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