Simon 2015

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The Post Menopausal Woman:Hormone Therapy

In the Era of WHI, KEEPS, and ELITE

James A. Simon, MD, CCD, NCMP, IF, FACOGClinical Professor

Department of Ob/GynGeorge Washington University

Washington, DC

Medical DirectorWomen’s Health & Research Consultants®

1850 M Street, NWWashington, DC

www.JamesASimonMD.com

The Post Menopausal Woman:Hormone Therapy

In the Era of WHI, KEEPS, and ELITE

James A. Simon, MD, CCD, NCMP, IF, FACOGClinical Professor

Department of Ob/GynGeorge Washington University

Washington, DC

Medical DirectorWomen’s Health & Research Consultants®

1850 M Street, NWWashington, DC

www.JamesASimonMD.com

@JamesASimonMD

Disclosures 2015Dr. James A. Simon has served (within the last year) or is currently serving as a consultant to or on the advisory boards of: AbbVie, Inc. (North Chicago, IL), Actavis, PLC. (Dublin, Ireland), Amgen Inc. (Thousand Oaks, CA), Amneal Pharmaceuticals (Bridgewater, NJ), Apotex, Inc. (Toronto, Canada), Ascend Therapeutics (Herndon, VA), Dr. Reddy Laboratories, Ltd. (Hyderabad, India), Everett Laboratories, Inc. (West Orange, NJ), JDS Therapeutics, LLC (Purchase, NY), Merck & Co., Inc. (Whitehouse Station, NJ), Noven Pharmaceuticals, Inc. (New York, NY), Novo Nordisk (Bagsvrerd, Denmark), Nuelle, Inc. (Mountain View, CA), Perrigo Company, PLC (Dublin, Ireland), Radius Health, Inc. (Waltham, MA), Regeneron Pharmaceuticals, Inc. (Tarrytown, NY), Sanofi S.A. (Paris, France), Sermonix Pharmaceuticals, Inc. (Columbus, OH), Shionogi Inc. (Florham Park, NJ), Sprout Pharmaceuticals (Raleigh, NC), TherapeuticsMD (Boca Raton, FL).

In the last year he has received or is currently receiving grant/research support from: AbbVie, Inc. (North Chicago, IL), Actavis, PLC. (Dublin, Ireland), Agile Therapeutics (Princeton, NJ), Bayer Healthcare LLC., (Tarrytown, NY), New England Research Institute, Inc. (Watertown, MA), Novo Nordisk (Bagsvrerd, Denmark), Palatin Technologies (Cranbury, NJ), and TherapeuticsMD (Boca Raton, FL).

He has also served or is currently serving on the speaker’s bureaus of: Amgen Inc. (Thousand Oaks, CA), Eisai, Inc. (Woodcliff Lake, NJ), Merck (Whitehouse Station, NJ), Noven Pharmaceuticals, Inc. (New York, NY), Novo Nordisk (Bagsvrerd, Denmark), Shionogi Inc. (Florham Park, NJ).

Dr. Simon served as chief medical officer (CMO) of Sprout Pharmaceuticals until April 2013.

10/01/15

Learning Objectives:

Upon completion of this lecture, participants will be able to:

Describe the current status/outcomes of the WHI, KEEPS, ELITE and other current hormone therapy (HT) and estrogen therapy (ET) trials, and have a contextual understanding of their clinical implications to date.

Understand the tenets of the “gap hypothesis” and how it applies differentially to cardiovascular disease vs. breast cancer.

Have a working knowledge of how route of administration could impact the overall risk/benefit ratio for postmenopausal systemic HT or ET, and how these differences have been incorporated into treatment guidelines.

Have You and Your Patients Been Getting Mixed Signals about Hormone Therapy?

Menopause Prevalence and Duration• More than 50 million women in the United States are beyond 50 years of age1

− The average age of natural menopause is 51.3 years2

− 75% of women between the ages of 50 and 55 are postmenopausal3

• Premature or early menopause– 1% of women under the age of 40 experience premature menopause3

– 5% of women between 40-45 years of age experience early menopause3

• Surgical Menopause– 267,000 US women age 45 and over undergo hysterectomies each year– Ovaries are removed in more than 80% of these women4

• Among women who have hot flashes (HFs):– 25% report that these symptoms remain for longer than 5 years1 and 10% report that they remain

for longer than 10 years5-7

– Vasomotor symptoms (VMS) may last for up to 10 years or longer in some women6,7

1. US Census Bureau. The 2012 Statistical Abstract: The National Data Book. http://www.census.gov/compendia/statab/cats/population.html. Accessed November 19, 2012. 2. McKinlay SM, Brambilla DJ, Posner JG. Maturitas. 2008; 61(1-2):4-16. 3. NAMS. A clinicians guide. 4th ed. Mayfield Height, OH: North American Menopause Society; 2010. 4. Hall MJ, et al. National health statistics reports; no 29. Hyattsville, MD: National Center for Health Statistics. 2010:1-24. 5..Jenkins MR et al. Cleve Clin J Med. 2008;75:S17-S24. 6.The North American Menopause Society. Menopause Practice: A Clinician’s Guide, 4th ed. Mayfield Heights, OH: The North American Menopause Society; 2010.7.Berecki-Gisolf J et al. Menopause. 2009;16:1021-1029.

Background, Update & Perspective

“Estrogen is Dangerous and Harmful”

As a result of all these factors, an idea became deeply rooted world-wide- the idea that estrogen is dangerous and harmful.

This idea persists among doctors, other health care providers and the public in spite of the plethora of evidence to the contrary

Information and evidence has so far been unable to kill off the idea – it walks among us – like a zombie-seemingly impervious to our best efforts

Advancing Health After Hysterectomy: (AHAH)

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Zombie Idea

“An idea that should have been killed by evidence, but refuses to die”

Paul Krugman. Nobel Prize in Economics, 2008 NYT. March 30, 2014

Slide by Voelker EE and Sarrel PM

N.B.: “Zombies” tap into deep‐rooted, irrational human fears 

Decline in the Use of Postmenopausal HT In the US 1999‐2010*

HT Use in Women > 40 years (%) 1999‐2000 2009‐2010

Any formulation 22.4 4.7

Estrogen only 13.3 2.7

Estrogen + Progestogen 8.3 1.7

p< 0.01 for all comparisons 1999-2000 vs 2009-2010

*Source: Sprague BL et al. Obstet Gynecol. 2012;120:595-603

99

0

5

10

15

20

25

30

35

40

1999- 2000 2001- 2002 2003-2004 2005-2006 2007-2008 2009-2010

Use of Estrogen and Estrogen/Progestin Has Dropped Since the WHI: Results From NHANES

Pro

po

rtio

n R

ep

ort

ing

O

ral H

orm

on

eU

se

(%

)

Hormone Usage in Women Without a Uterus

Hormone Usage in Women With a Uterus

Data from 10,107 women aged ≥40 years in the National Health and Nutrition Examination Survey (NHANES).Sprague BL, et al. Obstet Gynecol. 2012;120:596-603.

Vasomotor Symptoms and Related PsychosocialImpairment During the Menopausal Transition

• Hot flushes

• Night sweats

• Sleep disturbances– Insomnia

– Sleep apnea

• Mood swings– Irritability

– Sadness

– Tension

• Cognitive deficits– Poor concentration

– Verbal memory problems

• Social Impairment– Disruption of family relationships

– Social Isolation

• Work Related Difficulties– Reduced Productivity

• Other Quality-of-life Impairment– Embarrassment

– Anxiety

– Fatigue

Utian WH. Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review. Health Qual Life Outcomes. 2005 Aug 5;3:47.

Simon JA and Reape KZ. Understanding the menopausal experiences of professional women. Menopause 2009; 16 (1): 73-76.

1111

Impact and Costs of Untreated Vasomotor Symptoms

*P<0.0001. †Costs are expressed in US$2011.N = 252,273 women with untreated VMS (mean age, 56 y) matched to 252,274 controls.Sarrel P, et al. Menopause. 2014;22(3):epub.

0

2

4

6

8

10

12

14

16

Inci

den

ce

(per

pat

ien

t p

er y

ear)

Untreated VMS

Controls**

*

*

Pharmacy claims

Outpatientvisits

All-causework loss

Absenteeism0

1000

2000

3000

4000

5000

6000

Mea

n C

ost

s†

(per

pat

ien

t p

er y

ear)

Untreated VMS

Controls

*

*

**

All-causecosts

Outpatientcosts

All-causecosts

Absenteeism

Direct Costs

Indirect Costs

Causes of Death Among U.S. Women

Source: Ten Leading Causes of Death 2011-2012 (National Vital Statistics System/NCHS/CDC)

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Observational Studies of CVD Risk: ET Compared with HT

Grodstein et al, 1999Swedish cohort

Grodstein et al, 2000Nurses Health Study (NHS)

Varas-Lorenzo et al, 2000

0.25 0.50 1.0 2.0 4.0

Relative Risk (95% CI)

ET

HT

Rosenberg et al, 1993

Mann et al, 1994

Psaty et al, 1994

Sidney et al, 1997

ET = unopposed estrogenHT = sequential estrogen + progestin

The Woman’s Health Initiative(Randomized Clinical Trial Data)

(July 2002 WHI Press Conference RE: E+P)

WHI received enormous media coverage – more than 400 newspaper stories and 2500 television-radio stories…

Annals of Internal Medicine, V0l. 140(3), pp:226

The Truth About Hormones –Hormone Replacement Therapy is Riskier Than Advertised: What’s a woman to do?

July 22, 2002

The End of the Age of EstrogenJuly 22, 2002

Hormone Therapy: The Danger Assessed May 27, 2003

Another Study Slams Hormone Pills; The Replacement Regimen Doesn’t Help Improve Women’s Memory or Mood, Researchers Said March 18, 2003

Hormone HazardsJuly 29, 2002

Study Dismissed HRT As Clinically UselessMarch 18, 2003

A New Blow to Hormone Therapy, June 24, 2003

Bad to Worse: Major Findings by a Government Study of Hormone Therapy for Women August 7, 2003

Hormone Therapy’s Use Knocked Again

August 7, 2003

And what about the embargo?

WHI-E+P: Relative and Absolute RiskWomen 50 to 79 (mean 63.5) Years of Age at Baseline

Breast cancer

Strokes

VTE

Colorectal cancer

Hip fractures

Total fractures

New onset diabetes

OverallHazardRatio

Absolute Riskper 10,000

Women/YearHealth Event

1.26

1.31

2.11

0.56

0.67

0.76

0.79

8

7

187

5

47

15

Absolute Benefitper 10,000

Women/YearNominal

95%

1.00–1.59

1.02–1.68

1.58–2.82

0.38–0.81

0.47–0.96

0.69–0.85

0.67–0.93

Adjusted95%

0.83–1.92

0.93–1.84

1.26–3.55

0.33–0.94

0.41–1.10

0.63–0.92

Confidence Interval

Cauley JA, et al. JAMA 2003;290:1729-38; Chlebowski RT, et al. N Engl J Med 2004;350:991-1004; Chlebowski RT, et al. JAMA 2003;289:3243-53; Manson JE, et al. N Engl J Med 2003;349:523-534; Wassertheil-Smoller S, et al. JAMA 2003; 289:2673-84; Margolis KL, et al. Diabetologia 2004;47:1176-87; Writing Group for the Women's Health Initiative Investigators. JAMA 2002;288:321-33.

CHD 1.29 1.02–1.63 0.85–1.97 7

CHD-Revised 1.24 1.00–1.54 0.97–1.60 6

Breast cancer 1.24 1.01–1.54 0.97–1.59 8

30.70–2.550.87–2.061.34PE

560.59–0.830.63–0.790.70Total fractures

60.33–1.110.41–0.910.61Hip fractures

10.63–1.860.75–1.551.08Colorectal cancer

70.86–2.080.99–1.791.33VTE

120.97–1.991.10–1.771.39Strokes

70.57–1.060.59–1.010.77Breast cancer

50.72–1.150.75–1.120.91CHD

Absolute Benefitper 10,000

Women/Year

Absolute Riskper 10,000

Women/Year95%

Adjusted95%

NominalOverall

HREvent

Confidence Intervals

Women's Health Initiative Steering Committee. JAMA. 2004;291:1701-1712.

WHI-E: Relative and Absolute RiskWomen 50 to 79 (mean 64) Years of Age at Baseline

140.77–1.01New onset diabetes 0.88

WHI E+P SubstudyRisk by Age

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-1-0.4

1

-0.8-0.2

0

1.91.4

0.20.8

1.2

-0.5 -0.3

1.7

0.3

-0.7

-2-1

-5

-3

-1

1

3

5

CHD Invasive breast cancerStroke VTEColorectal cancer Hip fracture

WHI E‐Alone SubstudyRisk by Age

Absolute (attributable) risk per 1,000 women  

Age 50‐59 Age 60‐69 Age 70‐79

Placebo (baseline risk)

Num

ber o

f Eve

nts

*

*Final, centrally adjudicated data as reported in The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women’s Health Initiative Randomized Controlled Trial. JAMA. 2004;291:1701‐1712.

†Significance by hazard ra o and 95% confidence interval.

†

†

†

Rates for Everyday Life Events and Adverse Drug Reactions

Event (United States)

Rate (per 100,000 population) Same as: Translates to:

Traffic Death Rate (2009)1 11.0 0.011% 1.1 in 10,000

Maternal death during pregnancy and childbirth (2010)2 21 0.021% 2.1 in 10,000

Identify Theft (2010)3 81.2 0.0812% 8.12 in 10,000

Total Violent Crime (2009)4 1,690 1.69% 169 in 10,000

1. http://www.census.gov/compendia/statab/2012/tables/12s1103. pdf. 2. http://data.worldbank.org/indicator/SH.STA.MMRT3. http://www.census.gov/compendia/statab/2012/tables/12s0337.pdf. 4. http://bjs.ojp.usdoj.gov/content/glance/tables/viortrdtab.cfm. 5. Guidelines for preparing core clinical safety information on drugs. 2nd Ed. Report of CIOMS Working Groups III and IV.CIOMS Geneva 1999.

Frequency of Adverse Drug Reactions (CIOMS)5 Same as: Translates to:

Very common ≥1/10 ≥ 10% More than 1,000 in 10,000

Common (frequent) ≥1/100 and < 1/10 ≥ 1% to < 10% Between 100 and 999 in 10,000

Uncommon (infrequent) ≥1/1,000 and < 1/100 ≥ 0.1% to < 1% Between 10 and 99 in 10,000

Rare ≥1/10,000 and < 1/1,000 ≥0.01% to < 0.1% Between 1 and 9 in 10,000

Very rare <1/10,000 < 0.01% 1 or less in 10,000

CIOMS= Council for International Organizations of Medical Sciences

WHI – CACCoronary Artery Calcium Score in Women on ERT alone in WHI aged 50-59

1,064 women aged 50-59 with hysterectomy on ERT alone who had screening for coronary calcium

CAC reflects progression from simple fatty streak to complex plaque

Mean CAC/ERT, 83.1 vs placebo CAC/placebo, 123.1 (P=0.02)

Among women with 80% adherence

– CAC of 0 OR .64

– CAC 10-99 OR .55

– CAC >100 OR .46

Manson JE et al. N Engl J Med 356: 2591, 2007

CEE and Coronary Artery Calcium at Age 50‐59 Years

CAC Score Odds Ratio Conf. Interval

<10 1

10-100 0.82 0.57-1.18

100-300 0.72 0.44-1.17>300 0.58 0.35-0.95 P=.03

Subjects with ≥80% compliance)

<10 110-100 0.67 0.44-1.02

100-300 0.43 0.23-0.80

>300 0.39 0.21-0.73 P=.04

Manson JE et al. N Engl J Med. 2007;356(25):2591‐2602.

Estrogen        Placebo         Ratio

WHI : Estrogen AloneCardiovascular Outcomes Ages 50‐59

Clinical Trial Observational Study

Placebo CEE+ Ratio Nonusers E+P RatioMPA E+P

No. of Women 8,102 8,506 35,551 17,503

CHDNo. of Events 147 188 615 158Annual Incidence(%) 0.33 0.39 1.18 0.32 0.20 0.50

StrokeNo of Events 107 151 490 123Annual Incidence(%) 0.24 0.32 1.29 0.25 0.13 0.52

VTENo. of Events 76 167 336 153Annual Incidence(%) 0.17 0.35 2.10 0.17 0.15 0.94

WHI-EP Trial and WHI Observational Study of Estrogen and Progestin

Prentice RL, et al. Am J Epidemiol 2005;162:404-414.

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WHI Post‐Intervention Reports:ET+P 20101 and ET 20112

1. Chlebowski et al. JAMA. 2010;304 (15):1684-1692.2. LaCroix AZ et al. JAMA. 2011;305 (13):1305-1314. .

1. Rossouw JE et al. JAMA. 2002;288(3):321-333. 2. Anderson GL et al. JAMA. 2004;291(14):1701-1712. 3. LaCroix AZ et al. JAMA. 2011;305 (13):1305-1314. 4. Chlebowski RT et al. JAMA. 2010;304 (15):1684-1692.

Results of the WHI After More Than a Decade of Follow-up

Enrolled More Than 27,000 Menopausal Women, Aged 50 to 79 Years1,2

Women who had a hysterectomy

Placebo (n= 5429)CEE (n=5310)

CEE (vs placebo): No significant change in risk of coronary heart disease (CHD)

Persistence of decreased risk of breast cancer3

CEE + MPA (vs placebo): Increased risk of breast cancer and breast

cancer mortality4

Major outcomes after 11.0 years(mean intervention 5.6 years)4

Women with an intact uterus

Major outcomes after 10.7 years(mean intervention 7.1 years)3

Placebo (n= 8102)CEE + MPA (n=8506)

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HRT and CV Risk by Age: WHI Second Arm (Estrogen Alone after Hysterectomy)

Age

50-59 60-69 70-79

.59 1.0 1.06

.54 1.05 1.26

.73 1.04 .81

.80 .73 .81

CHD

MI

Mortality

Breast Ca

LaCroix AZ et al. JAMA. 2011;305(13):1305-14

ET and HT vs. Placebo and Breast Cancer in The WHI

Anderson G Lancet Oncology Mar 2012 (Slide Courtesy of Dr. Lila Nachtigall)

E

E+P

WHI E‐alone post‐intervention study

WHI Post‐Intervention Reports:ET+ P and ET 20131

1. Manson JE, Chlebowski RT, Stefanick MI, et. al. JAMA 2013; 310(13):1353‐1368.30

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Estrogen + Progestin Therapy and Risk of MI in WHI: Results According to Age# and Time Since Menopause#

Age HR

50‐59 1.32^

60‐69 1.05

70‐79 1.46*

Time Since 

Menopause Onset HR

<10 yrs 0.91

10‐19 yrs 1.16

> 20 yrs 1.99*

P, interaction 0.55                     P, interaction 0.01+

^based on 5 events#At enrollment*P‐value <0.05+ P‐value for trend by age group

Manson JE, Chlebowski RT, Stefanick MI, et. al. JAMA 2013; 310(13):1353‐1368.

Women’s Health Initiative (WHI) Estrogen‐Alone Trial: MI, CABG/PCI Results According to Age at Randomization

Total MI CABG/PCI

Age Group HR (95% CI) HR (95% CI)

50‐59 0.55 (0.31‐1.00) 0.56 (0.35‐0.88)

60‐69 0.95 (0.69‐1.30) 1.13 (0.88‐1.46)

70‐79 1.24 (0.88‐1.75) 1.07 (0.79‐1.43)

P, interaction = 0.02+ P, interaction = 0.06+

MI = myocardial infarction. CABG = coronary artery bypass grafting. PCI = percutaneous coronary intervention

+p, trend by age group

Other Miscellaneous Findings From WHI 2013 (1)

• For CEE alone, younger women(aged 50‐59 years) had more favorable results for all‐cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age).

• Following stopping of the interventions, fewer than 4% of women reported personal use of hormone therapy.

• RE: Breast cancer—– women assigned to CEE alone had an HR of 0.79 (95% CI, 0.61‐1.02) compared with 

placebo and the HRs did not differ by time since randomization.

– The HR for invasive breast cancer with CEE plus MPA remained statistically significantly elevated during the post‐intervention and cumulative follow‐up compared with placebo (HR for cumulative follow‐up, 1.28 (95% CI, 1.11‐1.48); a detailed time dependent analyses identified risk attenuation with time since cessation of hormone therapy use.

Other Miscellaneous Findings From WHI 2013 (2)

• A reduced risk of endometrial cancer with CEE plus MPA emerged post‐intervention. HR of 0.58 (95% CI, 0.40‐0.86) compared with placebo.

• Women in both the CEE + MPA and CEE alone groups had statistically significant 33% reductions in hip fracture compared to placebo.

• In both trials, women assigned hormone therapy had significantly lower rates of treated diabetes than women assigned to placebo. HR, 0.81 (95%CI, 0.70‐0.94) for CEE plus MPA and 0.86 (95% CI, 0.76‐0.98) for CEE alone; these reductions in diabetes dissipated post‐intervention in both trials.

• Rates of gallbladder disease were approximately 50% higher among women assigned to hormone therapy in both trials; HRs for gallbladder disease were attenuated, but still elevated for CEE plus MPA and became neutral for CEE alone.

• Health‐related quality of life (RAND 36‐Item Short Form Health Survey) with CEE plus MPA compared with placebo was associated with a small but statistically significant benefit for physical functioning, role physical, bodily pain, and general health, and neutral results for the other subscales.

Kronos Early Estrogen Prevention Study (KEEPS): Design

• N=727 menopausal women aged 42‐59 (mean age, 52.7, within 3 years of LMP)• Trial Duration: 48 months• Design: Multicenter double blind, placebo controlled RCT• Treatment Arms:

• Oral conjugated equine estrogens (o‐CEE) given as Premarin®, 0.45 mg/d (lower dose than WHI)

• Transdermal estradiol (t‐E2) given by Climara® patch, 0.05 mg/d• Placebo

(active arms received cyclical micronized progesterone [Prometrium®] 200 mg/d x 12 d/mo; placebo arm received placebo Prometrium®)

Wharton W, Gleason CE, Miller VM, Asthana S. Rationale and Design of the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS Cognitive and Affective Sub‐Study (KEEPS Cog). Brain Res. 2013 June 13; 1514: 12–17.

KEEPS: Directions of Changes in CHD* Risk Factors

Factor O‐CEE T‐E2

Systolic BP Neutral Neutral

Diastolic BP Neutral Neutral

LDL Cholesterol Favorable Neutral

Triglycerides Adverse Neutral

HDL Cholesterol Favorable Neutral

Fasting Glucose Neutral Favorable

HOMA‐IR* Neutral Favorable

*CHD: Coronary Heart Disease; HOMA‐IR: homeostasis model assessment‐estimated insulin resistance

o‐CEE is Premarin 0.45mg/dt‐E2 is Climara 0.05 mcg/d

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Harman SM, Black DM, Naftolin F, et. al. Arterial imaging outcomes and cardiovascular risk factorsin recently menopausal women: a randomized trial. Ann Intern Med. 2014 Aug 19;161(4):249-60.

KEEPS KEEPS Overall Summary & Conclusions+

• Similarities: Both o‐CEE and t‐E2 had: – neutral     favorable effects on CVD biomarkers (differences related to first‐pass liver metabolism).

– neutral effects on CIMT and CAC (ns trend for CAC benefit).– neutral effects on cognition; favorable effects on VMS.

• Differences: – o‐CEE improved mood– t‐E2 improved HOMA‐IR and some advantages on sexual function.

• Conclusions:– KEEPS highlights the need for individualized decision making about HT, by treatment priorities and risk factor status.

– Additional research on HT in newly menopausal women (i.e. formulations/doses/routes of delivery) is needed.

+ Presented by JoAnn E. Manson, MD, Dr.PH, NCMP at NAMS Annual Meeting October 11, 2013 

Conclusion: Four years of treatment with o‐CEE at a lower dose than that studied in the WHI with cyclic m‐P or transdermal E2 with cyclic m‐P did not increase breast pain in healthy, recently menopausal women.

Early vs. Late Intervention Trial with Estradiol (ELITE)

The “timing hypothesis” posits that there is a differential effect on atherosclerosis and clinical events according to when postmenopausal HRT is initiated in relation to menopause.

Timing Hypothesis

Hodis HN, et al. J Am Geriatr Soc 2013;61:1005-1010.Hodis HN, et al. J Am Geriatr Soc 2013;61:1011-1018. Slide Courtesy of Dr. Cynthia Stuenkel

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Pathogenic Sequence of Vascular AgingNo HRT Adventitia

Media

Fatty Streak/Plaque

InternalElasticLamina

Necrotic Core

Plaque

FibrousCap

FibrousCap

Plaque Necrotic Core

Plaque

FibrousCap

MMP-9

EPAT = HRT Early & Continued

WELL-HART = HRT Late

HRT

Age 35-45 years Age 45-55 years Age 55-65 years Age >65 years

HRT

Mural Thrombus

Hodis HN, et al. N Eng J Med 2003;349:535–545.

All Ages

>10 years since menopause,

>60 years old

<10 years since menopause,

<60 years old

0.25 0.50 1.0 1.5 2.0

Relative Risk (95% CI)

0.99 (0.88-1.11)

0.68 (0.48-0.96)

1.03 (0.91-1.16)

CHD Events Associated with HRT inYounger and Older Women:

Meta-analysis of 23 Randomized Controlled Trials (191,340 patient-years)

Salpeter S, et al. J Gen Intern Med 2006;21:363-366.

Risk of Cognitive Decline in PreviousHT Trial Participants

OR = Odds ratio

Bagger YZ, et al. Menopause 2005;12:12-17.

Mean Age at Treatment, 54 YearsMean Follow-up Period, 10 Years

0.01 0.1 1 10

Adjusted Relative Hazard (95% CI)

1.0Never user (n = 107)

Long-term or current HT (n = 82)(mean duration, 6.2 years)

OR (95% CI, P-value)

0.36 (0.111.15, 0.083)

0.33 (0.130.84, 0.021) Short-term HT (n = 146) (during randomized clinical trial-2-3 years)

ELITE - Design

Study design: Single-center, randomized, double-blinded, placebo-controlled trial with a 2 x 2 factorial design

Subjects: 643 healthy recently postmenopausal (<6 years) and remotely postmenopausal women (>10 years) without preexisting CVD and diabetes mellitus

Intervention: Oral micronized 17β-estradiol 1 mg/d (+ vaginal micronized progesterone gel x 12 days every month in women with a uterus) Or Matching Placebos

Follow-up: Every month for the first 6 months and then every 2 months for 5-6 years

Funding: NIH – National Institute on Aging (R01AG-024154)

The Early versus Late Intervention Trial with Estradiol (ELITE)

•643 healthy postmenopausal women– no clinical evidence of CVD or diabetes mellitus

•Stratified by time since menopause–<6 years, n=271 (median, 3.5 years)

–>10years, n=372 (median 14.3 years)

•Primary end point: progression of carotid artery intima media thickness (CIMT).

•Women randomized to oral 17β‐estradiol 1 mg daily with or without vaginal micronized progesterone gel 4% (45 mg) 10 days per month or to placebo

The rate of CIMT progression was significantly reduced with HT relative to placebo (approx 40%) in the early postmenopausal group but not in the late postmenopausal group (p= 0.007). 

When HT is initiated at  or within 6 years of menopause:  significant reduction in CVD 

When initiated >10 years after menopause, no change. 

Hodis H et al, Am Heart Assoc 2014

Are Transdermal Preparations Safer?CHD• In a Danish national registry, significantly lower risk of MI was found with

the transdermal route than with oral unopposed estrogen (P=0.04)2. STROKE• In a nested case-control study from the UK General Practice Research

database (n=15,710), the risk of stroke was not increased with low-dose transdermal estrogen (50 mcg) but did increase with higher transdermal doses and oral therapies.3

VTE• In a French systematic review and meta-analysis, the risk of first-time

VTE was increased in oral estrogen users, but not in transdermal estrogen users (OR 2.5 [1.9–3.4] for oral; 1.2 [0.9–1.7] for transdermal)1

1. Canonico et al. BMJ 2008; 336 (7655): 1227‐1231.   2. Løkkegaard E, Andreasen AH, Jacobsen RK, et al. Eur Heart J. 2008; 29: 2660-8.3. Renoux C, et al. BMJ. 2010;340:c2519.

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Transdermal estrogen and change in body weight or BMI

• “One crossover study noted greater fat gain with oral vs. transdermal estrogen, results that are supported by clinical data.”

Santen RJ. Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement. JCEM.2010:95,S1:S1-S66

Transdermal Estradiol Absorption From Hydroacholic Gels (i.e. Estrogel® 0.06%, Elestrin® 0.06%, Divigel® 0.1%)

Impact From Other Transdermals Repeated daily application of moisturizer placed on the skin 1 hour after application of

0.06% estradiol gel (Estrogel®), increased the mean AUC 0-24h and Cmax of estradiol by 38% and 73%, respectively.

Repeated daily application of sunscreen for 7 days placed on the skin 1 hour after application of 0.06% estradiol gel (Estrogel®), decreased the mean AUC 0-24h and Cmax of estradiol by 16%.

If the application site is washed 1 hour after application, there is a 22% decrease in average 24-hour serum concentrations of estradiol.

There have been no studies to assess the impact of moisturizer, or sunscreen if applied before the application of 0.06% estradiol gel (Estrogel®).

0.06% estradiol gel=Estrogel®, prescribing information.

Sunscreen application 10 minutes before application of 0.06% estradiol gel (Elestrin®), increased the exposure to estradiol by approximately 55%.

No significant change in estradiol exposure was observed when sunscreen was applied 25 minutes after application of 0.06% estradiol gel (Elestrin®).

Prolonged (7 days) concomitant application of sunscreen to the site of 0.06% estradiol gel (Elestrin®) application increased exposure to estradiol by about 2-fold.

0.06% estradiol gel=Elestrin®, prescribing information.

The effect of sunscreens and other topical lotions on the systemic exposure of 0.1% estradiol gel (Divigel®) has not been evaluated in clinical trials.

0.1% estradiol gel=Divigel®, prescribing information.

How Might You Explain the Cardiovascular and Breast Cancer Results of the WHI (The Gap or Timing Hypothesis), and keep them in clinical perspective?

The Gap or Timing Hypothesis (earlier “better”, later “worse”)

This Gap Hypothesis also seems to apply to:Mood1

Dementia2

Ischemic Stroke3

Mild cognitive impairment4

Parkinson’s Disease5

1Soares, CN, Maki PM, Menopausal transition, mood, and cognition: an integrated view to close the gaps. Menopause. 2010: 17 (4), 812-814.2Rocca WA, Grossardt BR, Shuster LT, Stewart EA. Hysterectomy, Oophorectomy, Estrogen, and the Risk of Dementia. Neurodegener Dis. 2012 Jan 21. [Epub ahead of print]3Rocca WA, Grossardt BR, Miller VM, Shuster LT, Brown RD Jr. Premature menopause or early menopause and risk of ischemic stroke. Menopause. 2012 Mar;19(3):272-7.4Rocca WA, Grossardt BR, Shuster LT. Oophorectomy, menopause, estrogen treatment, and cognitive aging: clinical evidence for a window of opportunity. Brain Res.

2011 Mar 16;1379:188-98. Epub 2010 Oct 18. Review.5Rocca WA, Bower JH, Maraganore DM, Ahlskog JE, Grossardt BR, de Andrade M, Melton LJ 3rd. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology. 2008 Jan 15;70(3):200-9. Epub 2007 Aug 29.

Breast Cancer

The Headlines:The Women’s Health Initiative Results (E + P)

41% Increase in Strokes 29% Increase in Heart Attacks 100% Increase in Venous Thromboembolism 22% Increase in Total CV Disease26% Increase in Breast Cancer (3.3/1000

increased to 4.1/1000 for each year) 37% Decrease in Colorectal Cancer 33% Decrease in Hip Fracture 24% Decrease in Total Fractures No Difference in All Cause Mortality

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None 12304 114 vs 102 1.06 0.81-1.38

<5 yrs 3005 32 vs 15 2.13 1.15-3.94

5-10 yrs 783 11 vs 2 4.61 1.01-21.02

>10 yrs 515 9 vs 5 1.81 0.60-5.43

YRS N HT vs PBO HR 95% CI

WHI Breast Cancer by Years of Prior Use (E + P)

Writing Group for Women’s Health Initiative Investigators. JAMA. 2002; 288

HT and Breast Cancer Risk

Initial WHI data suggested that CEE + medroxyprogesterone acetate (MPA) was associated with increased breast cancer risk

Adjusting for breast cancer risk factors at baseline, there was no statistically significant increase in breast cancer risk in the combined arm vs placebo (RR=1.20; 95% CI, 0.94-1.53) at 5+ years of treatment

Tremendously good news for women

Anderson GL, et al. Maturitas. 2006;55:103-115.Hodis HN, Mack WJ. Menopause. 2007;14:944-957.

The Other Gap or Timing Hypothesis (earlier “worse”, later “better”)

This Gap Hypothesis also seems to apply to:

Breast Cancer

James Ingle 1981 Tamoxifen versus Diethylstilbestrol

Event DES N=74 TAM N=69

Emesis 18 (25%) 8 (12%)

Edema 39 (53%) 8 (12%)

Phlebitis 2 (3%) 0

Vag bleed 11 (15%) 1 (1%)

CCF 2 (4%) 0

Hot flashes 2 (3%) 20 (29%)

Ingle et al NEJM 304:16-21 1981

0

0.01

0.02

0.03

0.04

0 1 2 3 4 5 6 7

WHI E+P Trial: No Effect of E+P on Risk of In Situ Breast Cancer

Cu

mu

lati

ve P

rop

orti

on

Time (years)

Chlebowski RT et al. JAMA. 2003;289(24):3243-3253.

Placebo

EP

HR = 1.18

95% CI = 0.77–1.82

Route of Administration and Type of Progestin:

• Breast cancer was not elevated within the first 3 years of use, but it 

rose to 1.31 (95% confidence interval 1.20‐1.42) for the use from 3‐5 

years and to 2.07 (1.84‐2.30) with 10 or more years of use. 

• Sequential progestogen for 5 years or more was accompanied with a 

lower risk elevation (1.78, 1.64‐1.90) than exposure to continuous 

use (2.44, 2.17‐2.72). 

• Oral and transdermal use of E2‐progestogen therapy was associated 

with comparable risk elevations for breast cancer. 

Obstet Gynecol. 2009 Jan;113(1):65‐73 

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HT in Clinical Perspective

Comparison of VTE, DVT and PE in RCTsAbsolute Risk-Events per 10,000 Women per Year

No. Additional Cases per 10,000

Women per Year of Therapy

WHI-EP CEE+MPAVTE 2.06 (1.57-2.70) 17 35 18DVT 1.95 (1.43-2.67) 13 26 13PE 2.13 (1.45-3.11) 8 18 10

WHI-E CEE aloneVTE 1.32 (0.99-1.75) 22 30 8DVT 1.47 (1.06-2.06) 15 23 8PE 1.37 (0.90-2.07) 10 14 4

WEST 17B-Estradiol aloneVTE 0.8 (0.2-3.4) 44 32 -12DVT 0.5 (0.0-5.8) 22 11 -11PE 1.0 (0.1-7.1) 22 21 -1

NSABP TamoxifenVTE NR NR NR --DVT 1.60 (0.91-2.86) 8 13 5PE 3.01 (1.15-9.27) 23 69 46

RUTH RaloxifeneVTE 1.44 (1.06-1.95) 25 36 11DVT 1.37 (0.94-1.99) 16 23 7PE 1.49 (0.89-2.49) 8 13 5

FIELD FenofibrateVTE NR NR NR --DVT NR 20 27 7PE NR 13 22 9

TherapyPlaceboTrial and Outcome

Relative Risk (95% CI)

Outcome WHI-E RUTHn= 10,739 n=10,101

mean age 63.6 years 67.5 yearsmean follow-up 6.8 years 5.6 years

No. cases/10,000 women/year of treatment

CHD -5 -7Stroke 12 (8) 9VTE 7 11PE 4 4DVT 6 6Breast cancer -8 -8Bone fracture -56 -15

Hsia, et al. Arch Intern Med 2006;166:357-365.Writing Group for the Women's Health Initiative Investigators. JAMA 2004;291:1701-1712.Curb JD, et al. Arch Intern Med 2006;166:772-780.Stefanick ML, et al. JAMA 2006;295:1647-1657.RUTH. New Engl J Med 2006;355:125-137.

WHI-E in Perspective Primary Prevention of CHD withLipid-Lowering Therapy in Women

Primary6 RCTs11,435 women

Outcome RR (95% CI)

CHD events 0.89 (0.69-1.09)Non-fatal MI 0.61 (0.22-1.68)CHD mortality 1.07 (0.47-2.40)Total mortality 0.95 (0.62-1.46)

Secondary8 RCTs8,272 women

RR (95% CI)

0.80 (0.71-0.91)0.73 (0.59-0.90)0.74 (0.55-1.00)1.00 (0.77-1.29)

Walsh JME, et al. JAMA 2004;21:363-366.

Breast Cancer in Randomized Controlled Trials of Hormone and Statin Therapy

TherapyPlacebo Study

-21.005 (0.53)5 (0.55)

80.97-1.591.24199 (0.42)150 (0.33)

CEE+MPA

WHI-EP

120.77-2.191.3032 (0.57)25 (0.45)HERS

150.78-3.491.6518 (0.38)11 (0.23)

STATIN

PROSPER

95% CI

No. of Patients (Annualized %)

No. Additional Breast Cancer Cases per 10,000 Women per

Year of TherapyRelative Risk

150.62-3.361.4413 (0.50)9 (0.35)AFCAPS

50.46-4.521.447 (0.17)5 (0.11)4S-10 y f/u

772.48-59.8012.1712 (0.82)1 (0.07)CARE

00.42-2.421.0010 (0.22)10 (0.22)LIPID

-20.58-1.480.9334 (0.28)37 (0.30)ALLHAT-LLT

-80.65-1.040.82129 (0.34)161 (0.42)

CEE alone

WHI-E

0.30-3.5017B-E2 alone

WEST

-100.49-1.130.7538 (0.30)51 (0.40)HPS

CONCLUSIONS:

The synthesis of data using Bayesian meta-analysis indicates a reduction in mortality in younger postmenopausal women taking hormone therapy compared with no treatment. This finding should be interpreted taking into account the potential benefits and harms of hormone therapy.

Salpeter S et al. Am J Med 2009; 122: 1016-1022

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Take Home message

The synthesis of pooled data indicates that hormone therapy reduces total mortality by 25% in younger postmenopausal women.

A similar reduction in mortality is seen with randomized trialsand observational studies.

The probability that hormone therapy reduces total mortality in younger women is almost 1.

This finding of reduced mortality should be interpreted taking into account the potential benefits and harms of hormone therapy.

Salpeter S et al. Am J Med 2009; 122: 1016-1022

Conclusions of S.Salpeter…

CONCLUSIONS: Hormone therapy for 5 to 30 years in younger postmenopausal women increases quality adjusted life-years and is cost-effective. Hormone therapy started in later years results in a loss of quality-adjusted life for several years before a net gain can be realized.

Salpeter SR et al. Am Journal of Medicine 2008; 122: 42-52

Does the type of progestogen matter?

E2: estradiol; mic P4: micronized progesterone; DHG: dydrogesterone; synt. Prog,: synthetic progestins (mainly nomegestrol acetate, promegestone, chlormadinone acetate, cyproterone acetate, medrogestone)

Relative risks for invasive breast cancer by type of HRT and type of progestagen, compared with HRT never-use (E3N cohort study, N=80,377)

Fournier A et al. Breast Cancer Res Treat 2008; 107: 103-111.

00.20.40.60.8

11.21.41.61.8

2

E2 alone E2 + mic P4 E2 + DHG E2 + synth. Prog.

1.30

1.001.10

1.60

Is There a Difference Among Progestins?

• Comparative data is insufficient

• Current research is ongoing in light of WHI findings that suggested possible harm from progesterone (EPT compared with ET)

• PEPI, a large RCT, suggested micronized progesterone has less negative impact on lipids.

• Small trials suggest VTE with micronized progesterone

• Caveat: formulated in a peanut oil suspension so ask about peanut allergies!

Canonico, et al. Circulation. 2007;115(7):840-845.;Goletiani, et al. Exp Clin Psychopharmacol. 2007;15(5):427-444.

Progestin Routes of Administration

• Oral − Medroxyprogesterone − Micronized progesterone

• Transdermal progestin (combined with estrogen) • IUD with levonorgestrol

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Levonorgestrel IUD HT for Endometrial ProtectionWildemeersch D . Gynecol Endocrinol. 2013 Jun;29(6):569‐73. Epub 2013 Mar 7

Femilis Slim (LNG‐IUS releasing 20mcg/d  LNG)

102 women (part of original contraception trial, devel VMS, given Estrogen)

Pirimoglu ZM, et al. J Obstet Gynaecol Res. 2011 Oct;37(10):1376‐81.   Epub 2011 May 22.

LNG‐IUS 20mcg/d (+1mg oral Estradiol) vs1 mg 17 beta‐estradiol/2 mg drospirenone)

30 women fitted with LNG‐IUS60 women taking oral HT

Depypere HT, et al. Eur J Obstet Gynecol Reprod Biol. 2010 Dec;153(2):176‐80. [Bayer Phase 3 Study]

LNG‐IUS 20mcg/d (Mirena)(+Climara; or 1‐2mg Estradiol valerate)

168 women eligible for ERT phase (from original study of 348 women, using LNG‐IUS for contraception at least 9 months

Wildemeersch D et al. Maturitas. 2007 Jun 20;57(2):205‐9. Epub 2007 Jan 16.

2 consecutive LNG‐IUS (First 3 years of Fibroplant 14mcg/d; followed by 5 years of Femilis Slim, 20mcg/d)[+ E gel, patch or oral] 

102 women with severe climacteric symptomsHad used the Fibroplant for 3 years (full lifespan), then received Femilis Slim and were followed out to 5 years

Wildemeersch D, et al. Gynecol Endocrinol. 2005 Jun;20(6):336‐42.

Fibroplant (14mcg/d – indicated for 3 years use) + estrogen gel or patch

150 women had LNG‐IUS placed

Wildemeersch D, Janssens D, Weyers S. Maturitas. 2005 Jun 16;51(2):207‐14.

Femilis Slim (20mcg/d) + estrogen gel or patch

170 insertions were performed in postmenopausalwomen with median age of age 56.6 (range 43.5‐80.3).

Hampton NR, et al Hum Reprod. 2005 Sep;20(9):2653‐60. Epub 2005 May 19.

LNG‐IUS 20mcg/d (Mirena)(plus CEE 1.25mg/d)

N= 80 insertionsThe mean age was 47.9 years (SD 3.3)

Sturdee DW, Rantala ML, Colau JC, Zahradnik HP, Riphagen FE; Climacteric. 2004 Dec;7(4):404‐11.

LNG‐IUS 10mcg/d (MLS – menopause levonorgestrel system ‐ 28x28mm)

294 menopausal women. median age 52.6 years (range 41.7‐59.6 years), 90% within 3‐5 years of LMP; 78% had prior HT

Wildemeersch D, Schacht E, Wildemeersch P, et al.Maturitas. 2004 May 28;48(1):65‐70.

FibroPlant (LNG‐IUS 14mcg/d) [+ estrogen‐percutaneous, oral, patch]

N=24 used for 3 years 

Wildemeersch D, Schacht E, Wildemeersch P.Maturitas. 2003 Mar 28;44(3):237‐45.

FibroPlant‐LNG‐IUS 14 mcg/d [+percutaneous Oestrogel, 1.5 mg daily]

Eighty‐three insertions in perimenopausal women and 58 in postmenopausal women (total=141)

Raudaskoski T, Tapanainen J, Tomás E, et al. BJOG. 2002 Feb;109(2):136‐44.

LNG‐IUS 10mcg/d (Bayer Menopause Levo System 28x28mm); LNG‐IUS 20mcg/d (Mirena) MPA [+ 2mg E2V]

N=54 (10mcg/d LNG‐IUS); N=56 Mirena; N=53 MPA

Varila E, Wahlström T, Rauramo I. Fertil Steril. 2001 Nov;76(5):969‐73

LNG‐IUS 20mcg/d (Mirena) 39 completed 12 months (LNG‐IUS + Estrogen). After 5 years, 32 still using the LNG IUS; 31 consented to further study, 29 still on ERT  at 5yr Mean age = 60 years (SD 4.2)

Wildemeersch D, Schacht E. Maturitas. 2000 Jul 31;36(1):63‐8.

Fibroplant LNG‐IUS10mcg/d and a 14mcg/d

N=11 (10mcg/d)N=19 (14mcg/d)

Suvanto‐Luukkonen E, Malinen H, Sundström H, et al. Acta Obstet Gynecol Scand. 1998 Aug;77(7):758‐63.

(20mcg/d LNG‐IUD ‐Mirena) (n=18);  progesterone 100 mg po daily (n= 19) or vaginally (n=15) days 1‐25 calendar/mo.

N=18 recv’d LNG‐IUS (Mirena); 2 discontinued

CONCLUSION: The levonorgestrel-releasing intrauterine system may have a protective effect against endometrial malignant transformation. Using the levonorgestrel-releasing intrauterine system for treatment of menorrhagia during reproductive years was associated with a lower incidence of endometrial, ovarian, pancreatic, and lung cancers than expected. Levonorgestrel-releasing intrauterine system use was associated with a higher than expected incidence of breast cancer.

Soini T1, Hurskainen R, Grénman S, et. al. Cancer risk in women using the levonorgestrel-releasing intrauterine system in Finland.Obstet Gynecol. 2014 Aug;124(2 Pt 1):292-9.

WHI E+P Evolving Conclusions: 2002

“Results from WHI indicate that the combined postmenopausal hormones CEE, 0.625 mg/d, plus MPA, 2.5 mg/d, should not be initiated or continued for the primary prevention of CHD. In addition, the substantial risks for cardiovascular disease and breast cancer must be weighed against the benefit for fracture in selecting from the available agents to prevent osteoporosis.”

Rossouw JE, et al. JAMA. 2002;288:321-333.

WHI E+P Evolving Conclusions: 2003

“These conclusions are consistent with those of recently published guidelines. The trial did not address the role of estrogen plus progestin for the short-term treatment of menopausal symptoms, which remains the only clear indication for the use of this regimen…. Women with indications for treatment, such as menopausal symptoms, need to consider with their clinicians the suggestion of a slight overall increase in the risk of CHD and information on the risks of other outcomes in making decisions about the use of estrogen plus progestin therapy.”

Manson JE, et al. N Engl J Med. 2003;349:523-534.

WHI E+P Evolving Conclusions: 2007

“These analyses, although not definitive, suggest that the health consequences of hormone therapy may vary by distance from menopause, with no apparent increase in CHD risk for women close to menopause, and particularly high risks in women who are distant from menopause….

We did not identify any subgroup with reduced risk of CHD, although total mortality was reduced among women aged 50 to 59 years.”

Rossouw JE, et al. JAMA. 2007;297:1465-1477.

Recent publications make this an opportune moment for action!

1. 2011 WHI report: decreased mortality in hysterectomized women who start ET before age 60. 

2. 2012: WHI “Estrogen decreases risk of breast cancer and breast ca mortality.”

3. 2013: Long‐term WHI results re‐enforce benefits of ET.4. 2013: Mortality Toll of Estrogen Avoidance5. 2013‐2014:  Economics papers: Whiteley/Sarrel et al. substantiate the 

“cost” ($$$ in extra health care and lost work) of not treating   symptomatic women

6. 2014: WHI economics paper documents “savings” from declining use of estrogen‐progestin Rx for women with a uterus; no mention of ET

An AHAH Moment

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And What if You Stop…?

Mikkola TS, Tuomikoski P, Lyytinen H, et al. Increased cardiovascular mortality risk in women discontinuingpostmenopausal hormone therapy [published online ahead of print September 28, 2015]. J Clin Endocrinol Metab.

THE END

Suggested Reading Pollycove R, Naftolin F, and Simon JA. The evolutionary origin and significance of

Menopause. Menopause. 2011 Mar;18(3):336-42.

Lobo RA. Where Are We 10 Years After the Women’s Health Initiative? J Clin Endocrinol Metab. 2013 May;98(5):1771-80.

Hodis HN, Mack WJ. The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. Part 1: comparison of therapeutic efficacy. J Am Geriatr Soc. 2013 Jun;61(6):1005-10.

Hodis HN, Mack WJ. The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. Part 2: comparative risks. J Am Geriatr Soc. 2013 Jun;61(6):1011-1018.

Gurney EP, Nachtigall MJ, Nachtigall LE, Naftolin F. The Women's Health Initiative trial and related studies: 10 years later: A clinician's view. J Steroid Biochem Mol Biol.2014 Jul;142:4-11.

Simon JA. What if the Women's Health Initiative had used transdermal estradiol and oral progesterone instead? 2014 Jul;21(7):769-83.

Sarrel P, Portman D, Lefebvre P, et. al. Incremental direct and indirect costs of untreated vasomotor symptoms. Menopause. 2015 Mar;22(3):260-6.

Questions?