Karen Carlson, MD Current Clinical Issues in Primary Care
1 Update on Mepause: What s New? Karen Carlson, M.D. Massachusetts General Hospital Harvard Medical School Our agenda: Update on new data from WHI, SWAN, and other studies, and application to practice ce Approach to individualized management for mepausal symptoms The Women s Health Initiative: Translating Results to Practice The Study of Women s Health Across the Nation (SWAN) Multicenter, multiethnic longitudinal study of mepause transition 3300 women followed for 5 years Natural history of mepause: What can your patient expect? Perimepause Transitional stage lasts 4 years on average Mepause Average age is 51; 48 in smokers Early postmepause First 5 years after final period Estradiol Levels During Mepause Transition
2 Are symptoms due to mepause or to aging? 2005 Clear relationship to mepause: Vasomotor symptoms (hot flashes, night sweats) Vaginal dryness Sleep disturbance Unclear relationship to mepause: Mood disturbance Cognitive changes Somatic complaints (fatigue, joint pain) Urinary incontinence Decreased libido NIH Consensus Conference March 2005 Are symptoms due to mepause or to aging? 2009 Clear relationship to mepause: Vasomotor symptoms (hot flashes, night sweats) Vaginal dryness Sleep disturbance Mood disturbance 1 Joint pain 2 Unclear relationship to mepause: Cognitive changes Somatic complaints (fatigue) Urinary incontinence 1 Freeman EW. Arch Gen Psych 2006;63:375 2 Szoeke CE. Climacteric 2008;11:55. Which women have hot flashes? Hot flashes more common: Anxiety symptoms at baseline Smoking African-American or Hispanic women Higher body mass index Lower educational level Gold EB et al. Am J Public Health 2006;96:1226 Percent reporting symptoms What is the natural history of hot flashes? 60 50 40 30 20 10 0-2 years + 1 year + 5 years + 8 years - 30% have hot flashes 5 years after final menstrual period - Median duration of symptoms 4 years Politi MC. J Gen Intern Med 2008;23:1507. Time from mepause Mepause and Mood Disorders Recent prospective studies suggest that depressive and other mood symptoms may increase in mepause transition 2- to 4-fold increase in depressive symptoms 1,2,3,4 Incidence depression 21-26% 1 Schmidt PJ. Am J Psych 2004;161:2238 2 Freeman EW. Arch Gen Psych 2006;63:375 3 Cohen LS. Arch Gen Psych 2006;63:385 4 Bromberger JT J Affect Disord 2007 Mepause and Sexual Function SWAN: in early perimepause, multiple factors have impact on libido 1 Relationship factors, attitudes, vaginal dryness, cultural factors Penn Ovarian Aging Study: Two-fold increase in sexual dysfunction across transition; associations are multifactorial 2 Low DHEAs, absence of partner, anxiety, children under 18 at home 1 Avis NE. Mepause 2005 2 Gracia CR. Obstet Gynecol 2007
3 Changes in Body Composition at Mepause Changes in Body Composition at Mepause Both chrological aging and ovarian aging contribute to changes in body composition at midlife Increase in fat mass (av. 3.4 kg in 6 yrs) Increase in waist circumference (5.7 cm) Decrease in skeletal muscle mass (.2 kg) Sowers M. J Clin Endocril Metab 2007. Metabolic syndrome and mepause transition testosterone, SHBG) associated with increased likelihood for developing metabolic syndrome Relative androgen excess (t estrogen deficiency) present t clear if cause or association Changes in Bone Density during Mepause Transition Finkelstein JS. J Clin Endocril Metab 2008;93:861 Torrens J. Mepause 2009;16:257. Finkelstein JS. J Clin Endocril Metab 2008;93:861 53 year old nurse Mepause at 52 Recent BMD: femoral neck T score = - 2.0 Otherwise healthy Cholesterol 220, HDL 65, LDL 130 Severe hot flashes, insomnia, and vaginal dryness Treatment of mepausal symptoms: integrating evidence from WHI What are benefits and risks of estrogen in early postmepause? What preparation and dosage? How long should treatment be continued? How should treatment be stopped? What are the outcomes after treatment is stopped?
4 % Reduction Effectiveness of treatment options for hot flashes 0-10 -20-30 -40-50 -60-70 -80-90 -100 Estrogen SSRI Clonidine CAM 12 10 8 6 4 2 0-2 -4-6 -8 WHI: Attributable Risks with E, E+P Events per 10,000 women per year CHD Stroke PE BrCa Colon Ca Hip Fx E+P E Markers for increased CHD risk with hormone therapy: WHI results How do WHI results apply to early postmepause? The Timing Hypothesis Baseline LDL cholesterol interacts with hormone therapy to increase CHD risk 1 Women with LDL/HDL ratio <2.5 had increase in CHD risk with estrogen (with or without progestin) 2 1 Rossouw JE. Arch Intern Med 2008;168:2245 2 Bray PF. Am J Cardiol 2008;101:1599 Effects of estrogen on coronary arteries appear to vary with: - reproductive life stage - time since mepause - stage of progression of subclinical atherosclerosis? Mikkola T et al. J Women s Health 2006;15:51 Proximity to mepause determines CHD risk: WHI results Years since mepause Relative risk < 10 years 0.76 (.5-1.2) increased risk > 20 years 1.28 (1.0-1.8) increased risk Roussow JE. JAMA 2007 Estrogen Therapy and Coronary-Artery Calcification: WHI Results In women aged 50-59, calcified plaque burden in coronary arteries lower in women on estrogen (vs. placebo) Provides support for hypothesis that estrogen may have cardioprotective effects in younger women Manson JE. New Engl J Med 2007;356:25
5 Stroke in Early Postmepause: WHI Results Age 50-59: increase in stroke risk (E or E+P) < 10 years after mepause RR 1.77 (1.05 2.98) If women >60 years or with prior CHD excluded, increase in stroke risk (E or E+P) Roussow JE. JAMA 2007 Diabetes and Hormone Therapy: WHI Results Reduced incidence of diabetes in women treated with HT (15 fewer cases per 10,000)? mediated by decrease in insulin resistance unrelated to body size Consistent in both E and E+P arms Margolis KL. Diabetalogia 2004;47:1175 SUMMARY: Hormone Therapy and Cardiovascular Disease Initiation of HT by women ages 50-54 or within 10 years of mepause to treat symptoms does t seem to increase CHD risk Initiation in early postmepause may decrease CHD risk Estrogen plus progestin and breast cancer risk over time Hazard ratio 1 = No increase in risk Hazard Ratio Estrogen and Progestogen Use in Postmepausal Women. North American Mepause Society July 2008 Intervention Phase (yr) Chlebowski RT. N Engl J Med 2009;360:573-587 Treatment of mepausal symptoms: integrating evidence from WHI What are benefits and risks of estrogen in early postmepause? What preparation and dosage? How long should treatment be continued? How should treatment be stopped? What are the outcomes after treatment is stopped? Transdermal Estrogen Available in patch, gel, emulsion, spray Less adverse effects on: Triglycerides Cardiac biomarkers (e.g. CRP) Clotting Liver function Sex hormone binding globulin
6 Transdermal vs. Oral Estrogen: Effect on cardiovascular risk Transdermal estradiol: minimal effects on c-reactive protein and other inflammatory markers 1 In women with metabolic syndrome, coagulation and inflammatory markers unchanged with transdermal estradiol 2 Minimal effect on risk of veus thromboembolism 3 1 Shifren JL. J Clin Endocril Metabol 2008;93:1702 2 Chu MC Am J Obstet Gynecol 2008;199:526. 3 Canico M. BMJ 2008;336:1227 Bioidentical Hormones : FDA Advisory Risks of compounded bioidenticals unkwn No evidence of greater safety, efficacy Estriol is t FDA approved FDA Press Release, January 9, 2008 Treatment of Vulvovaginal Symptoms: Topical Therapy Conjugated estrogen or estradiol vaginal cream 1 gm pv 2x/w Estring delivers estradiol 7.5 ug/day undetectable effect on serum estradiol levels after 2 days Estradiol vaginal tablets (Vagifem) estradiol 25 ug 2x/w Some systemic absorption occurs 1 1 Labrie F. Mepause 2009;16:30. Systemic estrogen for treatment of vulvovaginal atrophy RCT of microdose estradiol 14 mcg/day patch (Mestar) vs 25 mcg estradiol /levorgestrel 60% response rate with both micro and low dose estradiol (vs 30% placebo) Mean E 2 level 8 pcg/ml with micro-dose patch Bachmann G. Mepause 2009;16:877. Effects of estrogen on specific GU symptoms Effective for dryness, dyspareunia Incontinence: WHI In women without incontinence, increased risk of developing it on E, E+P In women with incontinence, symptoms worsened on E and E+P 1 Incontinence: Nurses Health study Increased incidence incontinence with E, E+P 2 1 Hendrix SL et al. JAMA 2005 2 Townsend MC. Am J Obstet Gynecol 2009 SUMMARY: Hormone Therapy and Urinary Symptoms Urge incontinence: local ET may benefit some women Overactive bladder: clear evidence for role of ET Stress incontinence: systemic HT may worsen; effect of local ET controversial Recurrent UTI: local ET reduces risk Estrogen and Progestogen Use in Postmepausal Women. North American Mepause Society July 2008
7 Progestogens Established regimens cyclic or continuous Medroxyprogesterone (Provera) Micronized progesterone (Prometrium) more favorable effects on HDL cholesterol and clotting factors Not FDA approved Progestin IUS (Mirena) Progesterone 4% or 8% vaginal gel Progestogens Long-cycle progestogens Micronized progesterone (Prometrium) 100 mg qd or medroxyprogesterone acetates (Provera) 5-10 mg qd for 14 days every 3 months Limited data on endometrial protection When is a progestogen required? Use with systemic doses of estradiol 25 mcg/day or higher Need for cyclic P with long-term vaginal estrogens and systemic doses < 25 mcg/day E 2 uncertain Current consensus is progestin cycling with vaginal estrogens 2x/week or Estring Treatment of Mepausal Symptoms with HT Use lowest starting dose, for example: transdermal estradiol 25 mcg/d oral esterified estrogens.3 mg Increase dose if symptoms t controlled within 4 weeks For vulvovaginal symptoms only, topical or low-dose transdermal estrogen Treatment of mepausal symptoms: integrating evidence from WHI What are benefits and risks of estrogen in early postmepause? What preparation and dosage? How long should treatment be continued? How should treatment be stopped? What are the outcomes after treatment is stopped? Stopping HRT Options for tapering Slowly decrease daily dose Slowly decrease days/week of HT Back up to previous dose if hot flashes recur; then taper more slowly Continue progestins at least every 3 months Evidence to date suggests tapering t clearly better than stopping abruptly Grady D. New Engl J Med 2006;355:22.
8 Risks and Benefits After Stopping Estrogen and Progestin 3 year follow up of WHI E+P trial Results: CV disease risks disappeared Hip fracture benefits dissipated Breast cancer risk did t seem to persist Heiss G. JAMA 2008;299:1036 55 yr old secretary Mepause age 54, symptoms Hispanic Mother has osteoporosis ( fracture) Active lifestyle Good calcium and vitamin D intake BMD: femoral neck T score = - 1.8 Bone Density Testing at Mepause Consider BMD if major risk factor for osteoporosis or fracture: Personal history of fracture History of fragility fracture in 1 st degree relative Low body weight (weight <127 lbs) Current smoking Use of oral steroids for >3 months Khosla S. New Engl J Med 2007 Osteopenia: When to Treat? Osteopenia defined by BMD T score between 1.0 and 2.5 Fracture risk depends on other factors in addition to T score Falls are a stronger predictor of fracture than bone density Use clinical judgment, considering Estimated risk of fracture Cost-effectiveness and risks of treatment Patient preferences Osteopenia: When to Treat Treat according to absolute fracture risk, t simply T- score, considering: Previous fracture history Age Fall risk FRAX can be used to estimate future fracture risk FRAX www.shef.ac.uk/frax
9 Using FRAX to Estimate Fracture Risk Age 55 Sex F Weight 59 kg Height 162 cm Previous fracture Parent fractured hip Current smoking Glucocorticoids Rheumatoid arthritis Secondary osteoporosis Alcohol > 3 units/day Femoral neck BMD.64 gm/cm 2 T score - 1.8 BMI 22.3 10 year probability of fracture (%) Major osteoporotic 12 Hip fracture 1.2 Source: WHO FRAX Limitations of FRAX Applies only to patients who have t previously been treated Leaves out other important fracture risk factors (history of falls, muscle strength, balance) Does t consider spine BMD Has t been validated as a criterion for treatment Thresholds for Treatment to Prevent Osteoporosis Consider clinical significance for individual patient Consider cost-effectiveness Treatment is cost-effective when 10 year risk of hip fracture is 3% 1 Consider patient preference Tosteson ANA. Osteoporos Intl 2008;19:437 Osteopenia: When to treat? Unless prior fracture or major risk factor present, most osteopenic mepausal women will t benefit significantly ifi from treatment Need better tools for identifying osteopenic women at higher risk of fracture who would benefit from treatment SUMMARY: Hormone Therapy and Osteoporosis BMD is one of many factors that affects fracture risk Estrogen therapy has FDA approval for osteoporosis prevention Extended use is an option for women with low BMD when alternative rx t appropriate or tolerated Estrogen and Progestogen Use in Postmepausal Women. North American Mepause Society July 2008
10 58 year old professor Mepause age 53 Topical estrogen effective for vaginal dryness Bothered by decreased libido Healthy marriage No other medical issues Prevalence of low sexual desire at mepause SWAN study 42% of midlife women report infrequent or sexual desire 90% report being content t with sexual experiences Community-based sample (2207 women): reports of low sexual desire 27% of premepausal women 52% of naturally mepausal women 1 Basson R. NEJM 2006 2 West SL Arch Intern Med 2008;168:1441. Androgen Deficiency: What is the Evidence? Evidence lacking to support androgen deficiency syndrome in postmepausal women 1 No well-defined clinical syndrome Inadequate rmative data on testosterone or free testosterone levels in women across lifespan to define a disorder Wierman ME et al. J Clin Endocril Metab 2006;91: 3697 Androgen Therapy in surgically mepausal women Several RCTs show improved sexual desire and response with 300 ug testosterone patch biw No adverse lipid id or other androgenic effects Testosterone transdermal t FDA approved for women; Estratest (.2.5 mg) and Estratest HS (1.25 mg methyltestosterone) available Androgen therapy in naturally mepausal women: randomized trials INTIMATE NM1 study 1 RCT of 483 women for 24 weeks Testosterone 300 ug patch biw Results: Increased sexual desire and satisfaction No sig. increase in androgenic side effects (18% vs 12% placebo) 1 Shifren JL. Mepause 2006;13:770. Androgen therapy in naturally mepausal women: randomized trials RCT of 814 women for 52 weeks Testosterone 150, 300 mcg/d patch vs placebo Results: - Both doses associated with modest improvement in sexual function - 300 ug dose: number of satisfying sexual episodes increased by 2 per month Davis SR. New Engl J Med 2008;359:2005.
11 Androgen therapy in naturally mepausal women: randomized trials Free testosterone levels with 300 ug dose equivalent to those of women 18-24 years of age Androgenic side effects (mostly hair growth) in 30% (vs 23% placebo) 4 women diagsed with breast cancer Davis SR. New Engl J Med 2008;359:2005. 49 year old accountant Missed two periods in past 6 months c/o hot flashes, insomnia, mood fluctuations Does t want to use estrogen Alternatives to hormone therapy for vasomotor symptoms Relaxation techniques Multiple studies of soy, black cohosh, other botanicals fail to show effectiveness 1 HALT study: RCT of black cohosh, soy, multibotanical, vs placebo for 12 months. No benefit from any compared with placebo 2 1 Nedrow A. Arch Int Med 2006;166:1453. 2 Newton KM. Ann Int Med 2006 Nonhormonal Therapy for Vasomotor Symptoms SSRIs and SNRIs Fluoxetine 20 mg qd Venlafaxine SR 37.5 75 mg qd Desvenlafaxine 100 mg qd 1 Paroxetine CR 12.5 25 mg qd 1 Speroff L. Obstet Gynecol 2008;111:67 2 Archer DL. Am J Obstet Gynecol 2009;200:238 Nonhormonal Therapy for Vasomotor Symptoms Gabapentin 1,2 300 mg tid 800 mg tid Clonidine 0.1-0.2 mg bid po or 0.1 mg qd patch 1 Reddy SY. Obstet Gynecol 2006;108:41 2 Butt DA. Mepause 2008;15:310. Current Studies in Early Mepausal Women KEEPS (Kros Early Estrogen Prevention Study) Premarin.45 mg or Estradiol 50 ug patch (with cyclic micronized progesterone) Outcomes: carotid intimal thickness and coronary artery calcium ELITE (Early vs Late Intervention Trial with Estrogen) Oral estradiol; carotid IMT in perimepause vs 6 years post-mepause