Back to the Future: Applying New Evidence in Menopause Management Michael Policar, MD, MPH www. Policar. Lectures. com
Topics To Be Discussed § New information from the WHI § The expanding range of treatments for managing menopausal symptoms – Which treatments are available to your patient? § Practice Recommendations – How can your patient use these treatments safely, effectively, and conveniently?
NAMS Definitions § Progestogen § ET § EPT § HT § CC-EPT § CS-EPT Progesterone or progestin (P) Estrogen (E) therapy Combined E+P therapy Hormone therapy (ET and EPT) Continuous-combined E+P therapy - E+P given every day Continuous-sequential E+P therapy - E daily with P added on set sequence NAMS position statement. Menopause 2007.
Act 1 Let’s Get This Out of the Way…. The WHI Re-analyzed
Background: HRT 1960 -1980 s § Menopause seen as endocrine deficiency requiring hormone replacement therapy § 1960 s: successful oral contraceptive introduction – “The Pill” freed women from fear of pregnancy – HRT offered women freedom from fear of aging § 1972: Forever Feminine by Robert A. Wilson, MD § 1980 s: Expanding uses of HRT – Initially used to treat hot flashes, vaginal sxs – Later uses…protection of bone and heart
Background: Late 1980 s § In 40 retrospective observational studies, both EPT and ET reduced the risk of heart attack by 50% – Most studies included women in their 50 s – Women were self-selected for hormone use (or not); studies were subject to selection bias § Conventional wisdom – All women should use HT for heart protection, unless there was a reason not to do so – Women with CVD risk factors, especially previous MI, stroke, HTN or diabetes, should use HT
Background: 1990 s § 1990: Wyeth requested that FDA add labeling to HT products that included cardioprotection § FDA insisted that RCTs be performed to prove that HT improved CVD outcomes vs. placebo § Two RCTs initiated to evaluate cardioprotection – HERS: secondary prevention trial – WHI: primary prevention trial
HERS Study: 1998 § Does EPT reduce MIs in women with CHD? § 2, 763 women randomized to CC-EPT or placebo – Entry: MI, CABG, balloon angioplasty, + angiogram – Menopausal, intact uterus, 44 -80 years of age – Average follow up: 4. 1 years § Study findings – EPT had no value in reduction of MIs or CHD deaths » More deaths in year 1; neutral thru year 8 » Not seen in prior observational studies – 3 -fold increased risk of VTE events Hulley, JAMA 1998: 280: 605
Women’s Health Initiative (WHI): 2002 § 1993 -2005: RCT with 17, 000 women § Postmenopausal women 50 -79 years old – 33%: 50 -59 yrs old; 45%: 60 -69 yo; 22% 70 -79 yo – Average age: 64 years old § End points – Primary prevention of MI and stroke – Hip fracture, various cancers § Treatment arms – If uterus: CC-EPT (CEE+MPA) vs. placebo – If no uterus: ET (CEE) vs. placebo
WHI: EPT Arm Study Results Released July 2002: Findings after 5. 2 years Event RR Risk/10 K/yr Benefit/10 K/yr Heart attack 1. 29 7 Stroke 1. 41 8 Breast cancer 1. 26 8 TE event 2. 11 18 Colorectal CA 0. 63 6 Hip fractures 0. 66 5 § Discontinued early, as “risks greater than benefits”
WHI : ET-Only Study Arm Released 2004: Findings after 7 years Outcome Coronary heart disease Breast cancer Stroke Hip fractures Dementia, cognitive Change (> 65 years old) Change vs. Placebo No difference in risk Increased risk Decreased risk Trend toward increased risk
WHI and HERS: The 2004 Take Home Message § HT does not protect women from heart attacks over the long term …and actually may increase the risk of MI in the first year of HT use § The rest is “specialty-specific” perception of benefit and risk
Was the WHI designed to evaluate the safety and efficacy of EPT in treating menopausal changes? The Women’s Health Initiative § Was not a menopause study § Was a drug study of the effect of hormones on CVD, cancer, fractures, and memory in older women (average 64 year old)
How Different Were WHI Findings Compared to Earlier Studies? Manson JE, Menopause 2006; 13: 139
WHI: HT and Risk of CV Disease by Age and Years Since Menopause Roussow JE. JAMA. 2007: Combined secondary analysis Age at HT initiation Heart attack Stroke Death from any cause 50– 59 years ↓ 7% ↑ 13% ↓ 30% 60– 69 years ↓ 2% ↑ 50% ↑ 5% 70– 79 years ↑ 26% ↑ 21% ↑ 14% “Women who initiated HT closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause, but this trend test did not meet our criterion* for statistical significance. ” *Statistically significant defined as p<0. 01.
WHI (EPT arm) Re-analyses Age vs. Years Since Menopause Age (years) 1. 27 50– 59 1. 05 60– 69 1. 44 70– 79 Years Since Menopause <10 0. 89 1. 22 10– 19 20 1. 71 Hazard Ratio for CHD Manson JE, et al. N Engl J Med. 2003; 349: 523 -34
WHI: Estrogen and Major Health Outcomes in Women Under 60 Years of Age Total mortality Coronary heart disease Stroke New onset DM Fracture Breast cancer VTE % difference in relative risk -29 (0. 46 -1. 11 -37 (0. 36 -1. 09) Events/ 10, 000 WY of CEE therapy -11 -11 (0. 47 -1. 69 -12 (0. 77 -1. 01) -30 (0. 59 -0. 83) -18 (0. 65 -1. 04) +37 (0. 70 -2. 68) -2 -14 -56 -8 +4 Hodis HN, Mack WJ. Menopause Management 2008
The Unified Hypothesis 2005 WHI Phillips LS, Langer RD, Postmenopausal hormone therapy: critical reappraisal and a unified hypothesis. Fertility and Sterility 2005; 83: 558 -66
Clinical Implications: Unified Hypothesis § Mild cardioprotection – Women in their early-mid 50 s, who – Initiate HT soon after menopause, with – Few or no heart disease or stroke risk factors – And who use estrogen-only regimens § Increased heart disease risk – Women in their mid-60 s or later, who – Initiate HT long after menopause, who have – Heart disease or stroke risk factors – And who use estrogen and progestin regimens
Benchmark HT Cardioprotection Studies Primary Prevention Secondary Prevention “Healthy women” Observational Studies • Nurses Health Study Randomized • WHI Clinical Trials • KEEPS Women with known heart disease Various small studies • HERS
Key Points: NAMS March 2007 Position Statement on Hormone Therapy The North American Menopause Society. Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of The North American Menopause Society. Menopause 2007 Copyright 2007
HT and Coronary Heart Disease § ET/EPT not recommended as single or primary indication for coronary protection in women of any age § Data do not currently support EPT in secondary prevention of CHD NAMS position statement. Menopause 2007.
HT and Stroke § Both ET and EPT appear to increase the risk of ischemic stroke in postmenopausal women § No HT regimen should be used for the primary or secondary prevention of stroke § HT should be avoided for women who have elevated baseline risk of stroke NAMS position statement. Menopause 2007.
HT and Venous Thromboembolism § Significant increase in VTE risk in postmenopausal women using systemic HT § Risk increased with both EPT and ET § VTE risk appears during first 1 -2 years after therapy initiation and decreases over time § Transdermal 17ß-estradiol and oral therapies may have different risk § Lower doses of oral estrogens may be safer than higher doses NAMS position statement. Menopause 2007.
EPT and Breast Cancer Risk § Breast cancer risk increases with EPT use beyond 5 years § Increased absolute risk in WHI is viewed as rare (4 -6 additional invasive cancers/10, 000 women/year when use EPT used for ≥ 5 yrs) § Not clear whether risk differs between CC-EPT and CS-EPT NAMS position statement. Menopause 2007.
ET and Breast Cancer Risk (cont’d) § Women in WHI’s ET arm had 8 fewer cases of invasive breast cancer/10, 000 women/yr of ET use § Available evidence suggests ET for < 5 years has little breast cancer risk impact § Limited observational data suggest ET given longer than 15 years may increase risk NAMS position statement. Menopause 2007.
Act 2 Therapeutic Interventions Non-Hormonal
General Health Recommendations § Exercise: aerobic + strength training – Reduction in hot flashes in some women – Healthier heart; stronger bones § National Osteoporosis Foundation (NOF) Feb 2008 – Adults under age 50 need, per day » 1, 000 mg of calcium* » 400 -800 IU of vitamin D 3 – Adults 50 and over need, per day » 1, 200 mg of calcium* » 800 -1, 000 IU of vitamin D 3 * In divided doses, preferably with meals
Hot Flashes: Lifestyle Changes § § § § Exercise routinely, at least 3 -4 days/week Cool room temperature, especially at night Dress in layers (remove outer layers if warm) Avoid hot and spicy foods Relaxing activities Avoid cigarettes Minimize alcohol North American Menopause Society. Menopause. 2004; 11: 11 -33; Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002; 137: 805 -13; Huntley AL, Ernst E. Menopause. 2003; 10: 465 -76.
Botanicals and Phyto. SERMs Probably better than placebo § Black cohosh No evidence of efficacy § Soy isoflavones § Red clover isoflavones § Evening primrose oil § Dong quai § Ginseng § Vitamin E § Chasteberry (Vitex) Not better than pbo Not better (as monotx) Not better than pbo No studies
Botanicals: Black Cohosh § Total of 14 trials reported, including 4 randomized trials using placebo and/or estrogen treatment arm – 3 of 4 RCTs found black cohosh to be beneficial – 12 of 14 trials reported some benefit – Currently, longest trial is 6 months § NIH-funded, large, randomized, prospective, 2 -year trial ongoing – Preliminary data fail to show binding to E receptors – Binding to serotonin receptor noted
Botanicals: Black Cohosh § Available as Remifemin, Estroven, or other single or combination products § Dosage: 40 -80 mg daily § Adverse effects: headaches, stomach discomfort, heaviness in legs Hot Fla she s
Non-hormonal Hot Flash Therapies Drug Hot Flash Reduction Antidepressants • Paroxetine 62 -65% • Venlafaxine 38 -60% • Fluoxetine 20% Anticonvulsants • Gabapentin 45% Antihypertensives • Methyldopa • Clonidine 65% 38% Menopause 2004; 11(1): 11 -33 ACOG Task Force on HT Obstet Gynecol 2004; 104: 106 s-17 s.
Act 2 Therapeutic Interventions: Hormonal Medications
Prescription HT Options: ET and EPT Oral • Micronized estradiol • Conjugated equine ET estrogens (CEE) • Synthetic conjugated estrogens • Esterified estrogens • Estropipate • Estradiol acetate EPT • CC-EPT • CS-EPT Med Lett Drugs Ther 2004; 46: 98. Transdermal • • Patches Gels Emulsion Spray • E+P (combination) patches Intravaginal • Creams • Intravaginal tablet • Rings
HT Regimens Month 1 Month 2 Estrogen Therapy (ET) Estrogen Continuous combined (CC) EPT Estrogen Progestin Continuous-sequential (CS) EPT Estrogen Off for 14 d Progestin 14 d Continuous-pulsed (CP) EPT 3 d Off for 14 d
Choice of HT Regimen § If no uterus: estrogen only § If uterus present – Goal is to avoid vaginal bleeding entirely, or, at least, to make it predictable § Endometrial activity predicts bleeding pattern – Recent spontaneous or induced bleeding » Continuous sequential – No bleeding for >2 -3 cycles » Continuous combined
ET Oral Tablets Product Estropipate Micronized E 2 Brand Ogen Ortho-est Generic Estrace Generic Estradiol acetate Femtrace Standard dose Low dose 0. 625 m none 1. 0 mg 0. 5 mg 0. 9 mg 0. 45 mg
ET Transdermal: Patch* Brand name Mg/24 hr Use/ wk Alora 0. 025, 0. 075, 0. 1 2 Esclim 0. 025, 0. 0375, 0. 075, 0. 1 2 Estraderm 0. 05, 0. 1 2 Vivelle-Dot 0. 025, 0. 0375, 0. 075, 0. 1 2 Climara 0. 025, 0. 0375, 0. 06, 0. 075, 0. 1 1 Menostar 0. 014 ☼ 1 * All contain 17 B- estradiol only ☼ Indicated only for prevention of osteoporosis
ET Transdermal: Gels, Emulsions, Sprays* Brand name Type mg/24 hr Use Divigel Gel Elestrin Gel 0. 25, 0. 5, 1 mg/ packet 0. 87 gm pump Estro. Gel 1. 25 gm pump Estrasorb Emulsion 1. 74 gm/ pouch 2 pouches daily Evamist Spray 1 spray daily 1. 53 mg/ spray * All contain 17 B- estradiol only 1 packet daily 1 pump daily
Choice of Estrogens § Start low dose transdermal or oral estrogen § If suboptimal response, modify by: – Change the estrogen dose (upward) – Change the estrogen preparation – Change delivery systems (oral transdermal) – Consider an estrogen-androgen combination § Injectable estrogen not recommended – Dosage equivalencies are not known – Estrogen cannot be discontinued easily
Route of Administration § Non-oral routes of ET/EPT administration may offer advantages and disadvantages vs oral routes, but the long-term risk-benefit ratio has not been demonstrated § Possible lower risk of deep venous thrombosis (DVT) with non-oral route § Similar increased breast cancer risks with oral and transdermal estrogens, per large observational study NAMS position statement. Menopause 2007.
Adjusted Odds Ratio (95% CI) Oral vs. TD-E: The Risk of VTE The ESTHER Study Scarabin P-Y, et al. Lancet. 2003; 362: 428 -432 OR = 4. 0 (1. 9 -8. 3)
“First Line” Use of Transdermal Estrogen § Underlying medical conditions – History of DVT or PTE – High triglyceride levels – Gall bladder disease § Need for “steady state” drug release – Daily mood swings (especially while on oral HT) – Migraine headaches § Inability to use oral tablets – Stomach upset due to oral estrogen intake – Problems with taking a daily pill
Lower HT Doses § Provide nearly equivalent vasomotor and genital skin symptom relief and preservation of BMD compared to standard doses § Additional local ET may be required for persistent vaginal symptoms § Lower HT doses better tolerated and may have a better risk-benefit ratio than standard doses (cont’d) NAMS position statement. Menopause 2007.
Lower HT Doses (cont’d) § Lower-than-standard ET/EPT doses should be considered, such as daily doses of – 0. 3 mg oral conjugated estrogens – 0. 25 -0. 5 mg oral micronized 17β-estradiol – 0. 025 mg transdermal 17β-estradiol patch – or the equivalent NAMS position statement. Menopause 2007.
Progestogen Indication § Primary menopause-related indication is endometrial protection from unopposed ET § Adequate progestogen (as CC-EPT or CS-EPT) recommended with intact uterus § Progestogen not generally indicated with ET post-hysterectomy NAMS position statement. Menopause 2007.
Progesterone/ Progestin Products Oral Progestin MPA Micronized progesterone Drospirenone Norethindrone acetate Norethindrone Norgestimate Norgestrel Equiv dose 5 -10 mg 200 -300 mg Available doses 1. 2, 2. 5, 5, 10 mg 100, 200 mg 0. 5 mg/d 1. 0 mg/d 0. 5, 1. 0 mg/d 0. 7 -1. 0 mg/d 0. 09 mg 150 mcg/d 0. 35 mg 0. 09 mg 150 mcg/d
EPT Oral Tablets Activella Estrogen 17 -E 2 1 mg Progestin NETA 0. 5 mg Angeliq 17 -E 2 1 mg CEE 0. 625 mg Drosperinone 0. 5 mg NETA 1 mg NETA 0. 5 mg Micronized NGM 0. 09 mg MPA 5 mg CEE 0. 625 mg 0. 45 mg 0. 3 mg MPA 5. 0 mg; 2. 5 mg 1. 5 mg Fem. HRT Prefest Premphase 14 active 14 placebo Prempro 28 active EE 5 g EE 2. 5 g 17 - E 2 1 mg Dosing Once daily oral E (alone) 3 days E+P 3 days Once daily oral (CS-EPT) Once daily oral (CC-EPT)
EPT Transdermal Patches Estrogen 17 -E 2 Combi. Patch 0. 05 mg Progestin NETA 0. 14 0. 25 mg Dosing Twice weekly 17 -E 2 Climara Pro 0. 045 mg LNG 0. 015 mg Once weekly
Off-Label EPT Uses § Insufficient endometrial safety evidence to recommend off-label use of – Long-cycle progestogen (ie, P every 3 -6 months for 12 -14 days) – Vaginal administration of progesterone – Levonorgestrel intrauterine system (Mirena) – Low-dose estrogen without progestogen § Close endometrial surveillance recommended with these approaches NAMS position statement. Menopause 2007.
Compounded Bioidentical Hormones “Then, suddenly, the Seven Dwarfs of Menopause arrived at my door without warning: Bitchy, Sweaty, Sleepy, Bloated, Forgetful, and All-Dried. Up…. What was it that sent those wretched dwarfs packing? Natural bioidentical hormones. ” Somers S. The Sexy Years: Discover the Hormone Connection: The Secret to Fabulous Sex, Great Health, and Vitality for Women and Men. Front Matter. 2004 Random House, Crown Publishing, NY.
Compounded Hormone Therapy § The marketing of compounded hormonal therapy – Only bioidentical hormones are used – Combination of 2 or 3 estrogens is more “natural” – Dosage is tailored to the individual – More “pure” than commercial products – Safer delivery systems (no dyes, etc) § The reality – The same hormones are used in commercial and compounded 17 b-E 2 and progesterone
Sources of Exogenous Hormones
Compounded Hormone Therapy Compounded hormones will probably work, but… § Salivary hormone levels are not useful § The value of adding E 1 + E 3 has not been evaluated § Progesterone skin cream is not absorbed § Compounded hormone doses are not standardized § FDA-approved HT products will offer – Bioidentical hormones – Choice of delivery systems – Formulary coverage/ lower out-of-pocket costs
http: //www. fda. gov/consumer/updates/bioidenticals 010908. pdf
Act 3 Practice Guidelines How can your patient use these treatments safely, effectively, and conveniently?
Treatment of Hot Flashes § If mild sxs, try exercise, black cohosh + phyto. SERM § Initiate low dose HT if – Moderate or severe symptoms – Non-hormonal treatments have failed – No interest in non-hormonal therapy § Titrate estrogen dosage upward if needed § When estrogen can’t be used, offer – SSRI or SNRI – Gabapentin, clonidine, a-methyldopa, – MPA or Megesterol (Megace) § Attempt discontinuation after 1 -2 years
Treatment of Sleep/ Irritability Sxs § If mild symptoms – Lifestyle change, black cohosh, phyto. SERMs § If severe symptoms or no response to above – Low dose HT, then titrate upward – If mood swings, transdermal E preferred § Depression component, or no response to HT – SNRI or SSRI
HT and Vaginal Atrophy § When HT is considered solely for this indication, local (not systemic) vaginal ET is generally recommended § Progestogen generally not indicated with lowdose, local vaginal ET § Vaginal lubricants often improve vaginal dryness and painful intercourse NAMS position statement. Menopause 2007.
Vaginal Estrogen Therapies Product Conjugated estrogen cream Brand Dosage Premarin 0. 625 mg/ gram cream 0. 01% Estradiol cream Estrace (0. 1 mg/ gm) Estradiol vaginal Vagifem 25 micrograms tablet Estradiol ring* Dose Daily, then 1 -3 time/wk Daily for 2 wks, BIW Estring 7. 5 mcg/ 24 hrs Every 90 days Femring 0. 05 mg/d 0. 1 mg/d *Intended to be used as systemic HT Every 3 months
Vaginal ET: Endometrial Surveillance? § There are insufficient data to recommend annual endometrial surveillance in asymptomatic women using low-dose, local vaginal ET § Closer surveillance may be required if a woman is – At high risk for endometrial cancer – Using a greater dose of vaginal ET – Having symptoms such as spotting, breakthrough bleeding NAMS position statement. Menopause 2007.
HT and Cognition § Initiating EPT after age 65 not recommended for primary prevention of dementia or cognitive decline § Insufficient evidence to support ET/EPT for primary prevention of dementia when therapy is initiated during perimenopause or early postmenopause § ET does not appear to convey direct benefit or harm for treatment of Alzheimer’s disease NAMS position statement. Menopause 2007.
HT and Cognition § Many women experience worsening of short term memory with onset of menopause § 9 RCTs and 8 cohort studies – HT does not improve cognitive performance in women without symptoms – If symptoms, HT improved verbal memory, reasoning, and motor speed tests § Reasonable to provide HT to lessen cognitive changes in symptomatic menopausal women
Hormone Therapy and Fracture Prevention Pros § Good data on fracture prevention (mainly 2 o prevention) § Relatively lower cost than boisphonates § Less concern of adverse effects with ET alone (vs EPT) Cons § Requires long term use and surveillance § Post-menopausal bleeding can be troublesome § Increased risk of breast cancer after 5 years of use Utility § Fracture prophylaxis if using HT for another indication § Otherwise, consider bisphonates as first line
HT and “Quality of Life” § RCTs and retrospective studies show that HT has no effect on “quality of life” measures § Many woman who wean from HT state that they “feel worse”…even after 20 years after menopause! § Conventional wisdom – In women who “feel better on/ worse off” of HT, continue low dose HT if few or no risk factors – When (& how often) to re-attempt wean uncertain – Don’t start HT for solely for improving QOL
Act 4 The Finale
Discontinuation of HT § After 2 years, recommend a trial of HT discontinuation § Is tapering from hormone therapy necessary? – Grady D, Obstet Gynecol 2003; 102: 1233 – n= 377 who attempted discontinuation of HT – 74% successfully stopped; 26% resumed – 71% stopped abruptly; 29% tapered: equal success § “Rebound” hot flashes occur in some women and can last up to 3 months…many experts recommend a taper § Taper hormone therapy over 8 -12 weeks – Reduce dose or extend intervals (every 2, then 3 days) – Cut patches in half
If what I just said sounded unusually clear, then you must have misunderstood me Alan Greenspan
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