Menopause

Robert F Casper

Menopause• Occurs on average around age 51• Etiology is genetically programmed loss of

growing ovarian follicles• Result is absence of menstrual periods and

symptoms of low estrogen– Hot flashes– Insomnia– Vaginal dryness

• Confirmation is elevated FSH (>40 IU/L)

Premature Menopause

• Now called premature ovarian insufficiency (POI)

• Menopausal diagnosis under the age of 40

• Etiologies include: – Turner’s syndrome or mosaic– Fragile X (FMR1) gene pre-mutation– Iatrogenic (surgery, chemotherapy, radiation)– Most are unexplained

Menopause Management

• Treatment of symptoms by lifestyle modification

• Discussion of pros and cons of hormonal therapy

After WHI Study (2002)

• HT causes heart attacks and strokes!

• HT causes breast cancer!

• HT shouldn’t be prescribed for menopausal women!

Women’s Health Initiative (WHI)

• Large (16,000) prospective study funded by NIH• Stopped early after interim analysis

demonstrated increased cardiovascular morbidity, slight increase in breast cancer, and an increase in DVT in HT users vs placebo

• A third arm of estrogen only in women with previous hysterectomies was continued because adverse events did not offset beneficial effects

JAMA 2002;288:321-32

WHI Study Population

• Absence of symptoms (hot flushes)• Mean age 63.5 years• Not typical of women who generally start

HT• Mean BMI 28.5 (overweight)• One third of women had BMI > 30 (obese)• 50% past or current cigarette smokers• Received CEE and MPA

WHI Study

• Venous Thromboembolic Disease– HR 2.11 (95% CI, 1.58 – 2.82)

• Stroke – HR 1.41 (95% CI, 1.07 – 1.85)

• Coronary Heart Disease– HR 1.29 (95% CI, 1.02 – 1.63)

HRT and Coagulation• CEE known to increase the risk of coagulation• An increased risk of DVT (2 to 4-fold) also in

menopausal women women taking CEE in the HERS study

• Natural E2 transdermally has a favorable impact on blood clotting

• Recent study of oral HT (2 mg E2 and 1 mg NETA /day) no increased coagulation and improved fibrinolytic activity

Vascular Effects of Estrogen

• Estrogen inhibits oxidation of LDL

• Estrogen prevents oxLDL deposition in vascular wall

• Estrogen promotes vasodilatation

• In primate studies, prevented atherosclerosis (Clarkson and Adams)

Vascular Pathophysiology

Nature 420: 868–874, 2002

Estrogen and Atherosclerosis

• Atherosclerotic plaque has a core of lipid covered by a fibrous cap

• Prevents contact of the lipid core with blood

Nature 420: 868–874, 2002

Estrogen and Atherosclerosis

• E MMP-9• Dissolves shoulder

regions of the fibrous cap• Exposes lipid core to the

circulation• Release of vasoactive

cytokines, tissue factor • Platelet aggregation and

thrombosis

Nature 420: 868–874, 2002

Estrogen and Atherosclerosis

• Result is acute MI, or healed ruptured plaque in which smooth muscle and collagen accumulation allows evolution of a fatty lesion to a more fibrous one

Nature 420: 868–874, 2002

Progestin Component of HT• Adverse CVD effects of MPA in primate studies

(Adams et al 1997)• Blocked direct beneficial effects of estrogen

(decreased LDL deposition in the blood vessel wall)

• Antagonized the vasodilatory effects of estrogens • MPA binds to glucocorticoid receptors with high

affinity • May promote smooth muscle contraction and

vasoconstriction (Minshall et al, 1998)

Progestin Component of HT

• Natural progesterone did not antagonize the beneficial effects of estrogen on blood vessels

• New third generation progestins with little if any androgen receptor activity

• Like natural progesterone, they have no negative impact on HDL cholesterol

Women’s Health Initiative (WHI)

• Increased risk of breast cancer (HR 1.26, CI 1.0 – 1.59)

• Consistent with previous observational studies

• Continuous combined CEE and MPA

• No increased risk in the CEE only arm

Breast Changes in the Menstrual Cycle

• In normal breast tissue, ER are not downregulated by progesterone or progestins

• Supported by continuing proliferation of breast tissue in the luteal phase

Main “Media Message” about HT and Breast Cancer Risk

from the WHI“Hormone therapy resulted in a 26% increase in breast cancer risk”

What did the WHI study actually find:• No increased risk in women using estrogen alone• No increased risk for E&P in the 74% of women

using MHT for first time (HR 1.0 CI0.81-1.38)

• No risk evident for total population with Kaplan Meier analysis until year 5

How Should we Express the Risk of Breast Cancer for Women Considering HT ?

• In the WHI the overall breast cancer incidence was: 30/10,000 placebo users and 38/10,000 HT users

• This is 8 more breast cancers per 10,000 women using combined E&P per year

• Can be described as the “Attributable” risk– 8 cancers per 10,000 women = 0.08% per year

• This is considered a “rare” risk by the World health organization

Perspectives on HT and Breast Cancer Risk

• Hormone Therapy• increased risk <1% per year

• Delayed menopause– increased risk 2.3% per year (JA Collins, 1999)

• Alcohol consumption (2 drinks per day)– increased risk 1-2% per year

• Light exposure at night (shift work)– Increased risk 1-3% per year

• Dense breasts on mammogram– Increased risk 3.5-8% per year

Scary Headlines from 2002

Risks Exceeded Benefits So Study Stopped Prematurely

Many Doctors, Fearful of HormoneEffects, Advised Women to Stop HT

Complementary and Alternative Medicine

Where’s the Evidence?• Six systematic reviews…..

“Although individual trials suggest benefits from certain therapies, data are insufficient to support the effectiveness of any complementary and alternative therapy in the management of menopausal symptoms.”

Nedrow et al . Arch Intern Med 2006; 166(14): 1453-1465

McIntyre RS, Konarski JZ, Grigoriadis S, Fan NC, Mancini DA, Fulton KA, Stewart DE, Kennedy SE. Hormone replacement therapy and

antidepressant prescription patterns: a reciprocal relationship. CMAJ 2005; 172 (1):57-59

 

HT and SSRI Reciprocalsince 2002

HT and SSRI Reciprocal

“The simultaneous increase in prescriptions of serotonergic antidepressants (after the WHI publications) suggests that antidepressants are being prescribed for symptoms (psychological, physical) previously controlled with the use of HRT”

R S McIntyre et al, CMAJ 2005;172:57-59

Rossouw JE et al.

Postmenopausal hormone therapy and risk of cardiovascular disease by age

and years since menopause.

JAMA. 2007;297:1465-77

Benefits of HRT

• Significant reductions in risks of fracture and colon cancer (WHI study)

• Improved quality of life– Hot Flushes

– Sleep Disturbances

– Urogenital Atrophy

– Increased Skin Thickness

Consensus Development

NAMS Recommendations (2012)

• Based on reanalysis of WHI

• HT an acceptable option for symptomatic menopausal women up to age 59 or within 10 years of menopause

• HT most effective treatment for hot flushes and vaginal atrophy

NAMS Recommendations (2012)

• No difference in clotting risk between low dose oral estrogen or transdermal estrogen

• Evidence lacking that custom compounded bioidentical HT is safe or effective

NAMS Recommendations (2012)

• E2 increases risk of VTE but risk is rare in 50 to 59 year olds

• Increased risk of breast cancer with 5 or more years of continuous use of HT

• Less than 5 years recommended for HT but needs to be individualized

• Lack of safety data regarding use of ERT or HT in breast cancer survivors

NAMS Recommendations (2012)

Endorsed by:

• American Academy of Family Physicians

•Society of Obstetricians & Gynaecologists of Canada

•American Association of Clinical Endocrinologists

•SIGMA Canadian Menopause Society

•National Osteoporosis Society

Media Impact

• “Unfortunately the media has pervasive impact on public perceptions of risk

• Research has shown that strong beliefs about risk, once formed, change very slowly and are extraordinarily persistent in the face of contrary evidence”

Vincent Convello,Centre for Risk Communication, Columbia University

WHI Positive Findings Largely Ignored by the Media

The contrasting results of the estrogen-alone trial - no increase in breast cancer, a lower rate of coronary events including revascularizationin women aged 50 – 59 years

were largely ignored because of the negativeperspective surrounding HRT by that time.

RD Langer JA Manson, MA Allison. Climacteric 2012; 15: 206-212

Likelihood of Death from Different Causes in Next Decade

Woloshin S et al J Natl Cancer Inst 2008;100: 845 – 853

Islam S, Liu Q, Chines A, Helzner E. Trend in incidence of osteoporosis-related fractures among 40- to 69-year-old women: analysis of a large insurance claims database, 2000-2005. Menopause

2009; 16(1): 77-83

SSRIs instead of HT at What Cost? Increased Fracture Rates since 2002

Osteoporosis Prevention in Symptomatic Women

• “ Hormone therapy should be considered as first-line therapy for preventing bone loss and fractures in early postmenopausal women who are symptomatic”

Gallagher JC, Levine JP. Preventing osteoporosis in symptomatic postmenopausal women. Menopause 2011;18(1):109-118

Breast Cancer Risk• HT use > 5 yrs 1.3• Early menarche 1.3• Delayed menopause 1.4• Alcohol use 1.2• Shift work 1.5• Late 1st pregnancy 1.8• Menopausal obesity 1.2• Increased breast density 2.4• Age >65 5.8• BRCA gene mutation 200

Modified from Singletary S.E. Ann Surg 2003;237:474

Incidence Of Breast Cancer

Breast Tissue Estradiol Levels

0

10

20

30

HT No HT Premenopausal

ns

Est

rad

iol f

mo

l/mg

Local Blood

Pre-menopausal Post-Menopausal

BREAST ESTROGEN EXPOSURE

Local Blood

Hypothesis

• A combination of an aromatase inhibitor and HT may decrease breast cancer risk

• The AI reduces local estrogen exposure in the breast

• The HT prevents hypoestrogenic symptoms related to AI

• Long-term use of the combination should be safe and free of adverse effects

New Hormone Replacement

• Natural estrogen and low dose progestin

• an aromatase inhibitor to prevent local breast estrogen production

PLUS

Local Blood

Local Blood

Pre-menopausal

Post-Menopausal

HRT plus Aromatase Inhibitor

BREAST ESTROGEN EXPOSURE

Pilot Study

• 23 PMP women on HT for several years

• At least 2 annual mammograms prior to study

• Started on letrozole 2.5 mg on Monday, Wednesday and Friday

• Control group of 22 age matched women on HT only Mousa et al, Menopause 2008

Analysis

• Study group had at least two mammograms one year apart for comparison

• Addition of letrozole for at least one year

• Control group breast density compared on two mammograms, the same interval of time apart, to rule out an age effect on density

Mousa et al, Menopause 2008

Analysis

• Mammograms for each subject digitized• Breast density pre- and post-AI • Image analysis software (Image Quant and

Image J)

Lost density

Mousa et al, Menopause 2008

Conclusion

• Addition of AI to HT significantly reduced mammographic breast density without hypoestrogenic side effects

• May reduce risk of breast cancer in post-menopausal women

Mousa et al, Menopause 2008

AIs vs SERMs• Unlike SERMs, AIs directly prevent estrogen

synthesis in the breast

• Carcinogenic impact of estrogen not only through ER

• May also be associated with genotoxic metabolites of estrogen (catecholestrogens)

• Preventive advantage of AIs over tamoxifen

Conclusions HT

• HT use for menopausal symptom relief accepted as safe for up to 5 years

• Slight increase risk in breast ca associated with HT but not with E only

• Dosing should be lowest that will relieve symptoms (usually 1 mg E2 orally or 50 mcg/day transdermally)

• HT use past 5 years should be considered on an individual basis