Objectives Following this presentation, participants will be able to: 1. Identify common symptoms women experience related to menopause 2. Differentiate the risks and benefits of various therapies for menopause-‐related symptoms as identified in recent research 3. Apply evidence from recent studies in making individualized clinical decisions for managing menopause-‐related symptoms
Physiologic Changes in the Natural Menopausal Transition Variable cycle length1 Endocrinologic milieu shifts Inhibin2-‐4 FSH2-‐4 Variable changes in E15 Testosterone: no significant change3,6 1. Treolar et al. Int J Infertil. 1967;12:77. 4. Lenton et al. J Clin Endocrinol Metab. 1991;73:1180.2. Burger. Hum Reprod. 1993;8(suppl 2):129. 5. Santoro et al. J Clin Endocrinol Metab. 1996;81:1495.3. Burger et al. J Clin Endocrinol Metab. 1995;80:3537. 6. Bancroft et al. Clin Endocrinol. 1996;45:577.
Dilemma in Diagnosing Menopause Clinical symptoms are the best guide to diagnosing menopause Natural menopause can be diagnosed after 12 consecutive months of amenorrhea that has no other obvious pathologic/physiologic cause Biochemical tests alone are not reliable guides to an accurate diagnosis FSH levels are not reliable predictors of menopause because FSH levels are variable in perimenopausal women Creinin MD. Fertil Steril. 1996;66:101; Gebbie AE et al. Contraception. 1995;52:221.
Management for Selected Symptoms Sleep GU Changes & Sex Memory and Cognition Vasomotor Symptoms
Management Strategies for Sleep Disturbances (Frequently related to hot flashes) Reduce hot flashes Keep room cool, fan Wicking sleepwear Avoid all stimulants Good bedtime practices (sleep hygiene) Sleep retraining Many women use CAMs Estrogen
Estrogen Improves Sleep Decreases the frequency of Night sweats1-‐4 Periods of night awakenings3,4 Reduces sleep latency1,2 Improves sleep in menopausal women with insomnia, even in the absence of vasomotor symptoms4 Increases the percentage of REM sleep1,5 May alleviate sleep apnea3,4 1Schiff I, et al. Maturitas. 1980;2:179-83.2Scharf MB, et al. Clin Ther. 1997;19:304-11.3Erlik Y, et al. JAMA. 1981;245:1741-4.4Polo-Kantola P, et al. Am J Obstet Gynecol. 1998;178:1002-9.5Antonijevic IA, et al. Am J Obstet Gynecol. 2000;182:277-82.
Genitourinary Changes After Menopause Genitourinary Atrophy* Vaginal Dysfunction Urinary Dysfunction (pain with penetration/ sexual dysfunction) Most inevitable, least publicized consequence of estrogen loss 100% of women affected not bothersome for all women Up to 45% of older women suffer from urinary incontinence High prevalence of sexual dysfunction in menopause clinics Weinberger. Clin Obstet Gynecol. 1995;38:175; Sarrel. Obstet Gynecol Clin North Am. 1987;14:49;Elia et al. Obstet Gynecol Surv. 1993;48:509.
Sexual Physiologic Changes with Aging Time to achieve vaginal lubrication, Vaginal lubrication Vaginal elasticity, rugation, color Petechiae and bleeding after minor trauma in lactobacilli Vaginal pH Vulnerability to urogenital pathogens Superficial vaginal epithelial cells Collagen and adipose in vulva Labial involution and clitoral exposure Vagina thinner and paler Bachmann et al. In: Lobo, ed. Treatment of the Postmenopausal Woman:Basic and Clinical Aspects. 2nd ed. New York: Lippincott Williams & Wilkins; 1999:195.
Sexual Function Declines with Menopause and Aging Sexual libido Sexual responsivity Sexual activity Vaginal dyspareunia partner Dennerstein et al. Fertil Steril. 2001;76:456.
Sexual Dysfunction in Women Includes desire, arousal, orgasmic, and pain disorders Can be caused by: physiological changes of menopause breakdown in interpersonal relationships family, societal and religious beliefs Medications, partner problems, aging A detailed patient history is required to diagnose sexual dysfunction Basson R, et al. J Urol. 2000;163:888-93.; Laumann EO, et al. JAMA. 1999;281:537-44; Basson R. Menopause. 2004;11(6 pt2):714-25; and Dennerstein L, et al. Fertil Steril. 2005;84:174-80.
Management Strategies for Sexual Dysfunction/Complaints Lubricants/moisturizers Hormone therapy (FDA approved for vaginal dryness, off label use for sexual dysfunction) Local estrogen cream, ring, tablet Systemic estrogen ring, patch, cream, gel, mousse, spray, oral tablet Estrogen + progestin Estrogen + androgen (+/-‐ progestin) Androgen
Vaginal Lubricants and Moisturizers OTC water-‐based vaginal lubricants (short acting) and moisturizers (longer acting) Women may need both Vitamin E oil, olive oil Product selection is based on individual preference
Efficacy of Low-‐dose Vaginal Estriol on Urogenital Symptoms Treatment Group (n = 44) Control Group (n = 44) Before After Before After P-Variables Treatment Treatment Treatment Treatment Value* Clinical Vaginal dryness 100% 20.5% 100% 90.9% <.001 Dyspareunia 86.4% 20.5% 84.1% 86.4% <.001 Urogenital atrophy 100% 27.3% 100% 93.2% <.01Urodynamic MUP (cm H20) 50.82 6.15 62.15 8.64 52.35 6.30 49.40 6.54 <.05 MUCP (cm H20) 45.25 7.20 56.87 9.23 44.77 6.86 43.32 6.32 <.05 PTR (%) 72.52 10.31 88.85 9.66 70.75 9.08 70.77 9.04 <.05*P-value is comparison between treatment and control groups. MUP = maximum urethral pressure; MUCP =mean maximum urethral closure; PTR = abdominal pressure transmission ratio.Adapted from Dessole S, et al. Menopause. 2004;11:49-56.
Vaginal Epithelium & Estrogen 6 weeks of estrogen Without estrogen - atrophic With estrogen1 Vagina/urethra highest concentration of estrogen receptors2 Most efficient response with local application3,4 1. Freedman. Unpublished data. 3. Elia et al. Obstet Gynecol Surv. 1993;48:509.2. Losif et al. Am J Obstet Gynecol. 1981;141:817. 4. Weinberger. Am Clin Obstet Gynecol. 1995;38:175.
Sexual Function Population-‐based cohort of 438 Australian women, 45-‐55 years of age, who were still menstruating at baseline Hormonal levels, age, menopausal status, partner status, and feelings for partner were measured and evaluated The authors concluded that prior function and relationship factors are more important than hormonal determinants of sexual function for women in midlife Dennerstein L, et al. Fertil Steril. 2005;84:174-80.
Comparative Efficacy of Oral Esterified Estrogen With or Without MTestosterone in Postmenopausal Women With Hypoactive Sexual Desire Mean Change in Sexual Desire Scores 1.0 EE/MT Mean Change 0.8 EE 0.6 * 0.4 0.2 0.0 Baseline 4 8 12 16 MT = methyltestosterone. *P < .02. Study Week Lobo RA, et al. Fertil Steril. 2003;79:1341-52.
Testosterone Transdermal Patch vs Placebo: Total Satisfying Sexual Activity 3.0 Testosterone Placebo * * 4-Week Mean Change 2.5 * * from Baseline 2.0 * 1.5 1.0 0.5 0.0 0 4 8 12 16 20 24 Weeks *PSimon J, et al. J Clin Endocrinol Metab. 2005;90:5226-33.
Testosterone Transdermal Patch vs Placebo: Personal Distress 0 Testosterone Placebo 4-Week Mean Change -5 from Baseline -10 -15 * -20 * -25 * * -30 0 4 8 12 24 Weeks *PSimon J, et al. J Clin Endocrinol Metab. 2005;90:5226-33.
Physiology of Memory Changes Frequently due to sleep interruptions Stress is a powerful mediator Forgetfulness among women and men similar at midlife
Cognitive Changes With Age 60 Verbal meaning Spatial orientation 55 Inductive reasoning Mean T score Number 50 Word fluency 45 40 35 25 32 39 46 53 60 67 74 81 88 Age (years)Longitudinal estimates of mean T scores for single markers of the primary mental ability in men and womenSchaie. Am Psychol. 1994;49:304.
Management Strategies for Memory/Cognition Treatment aimed at restoring sleep, reducing stress Diet, exercise, relaxation techniques Use of memory aids Maintain mental acuity games, puzzles, etc Stress management strategies ? HT + / -‐
Effects of Estrogen on Neuronal Function Neurotransmission Neuroprotection Neurite Branching Synaptogenesis Trophic Factor Cerebral Blood Flow Expression Adapted from Birge SJ. Menopause Management. 2000;July/August:13-21.
CEE Promotes Cellular Mechanisms of Memory Neuronal outgrowth Synapse formation No CEE Prior to CEE After CEE CEE treatment treatedBrinton et al. Neurobiol Aging. 2000;21:475.
Cerebral Blood Flow (SPECT): 48-‐Yr-‐Old Healthy Menopausal Woman During a Hot Flush CEESPECT, single photon emission computed tomography.Greene. Neurobiol Aging. 1998;19:757.
ET/HT May Protect Against Cognitive Decline ET/HT users perform better than nonusers on tests of memory and other cognitive functions1-‐4 ET/HT modulates brain activation patterns during cognitive testing3-‐5 As women age, ET/HT increases blood flow to cerebral and hippocampal brain structures involved in memory3 May prevent AD with early intervention ET = estrogen therapy; HT = hormone therapy. 1Jacobs DM, et al. Neurology. 1998;50:368-73. 2Maki PM, et al. AmJ Psychiatry. 2001;158:227-33. 3Resnick SM, et al. Horm Behav. 1998;34:171-82. 4Maki PM, Resnick SM.Neurobiol Aging. 2000;21:373-83. 5Shaywitz SE, et al. JAMA. 1999;281:1197-202.
Improved Memory Gerontology Research Center at NIH National Institute on Aging1 50-‐ to 89-‐year-‐old postmenopausal women; n=103 HRT improved verbal learning and memory tests Cache County Study2 1357 men & 1889 women incidence > after age 80 in women and exceeded risk for men (HR 2.11, 1.22-‐3.86) >10 years HRT 1Maki et al. Am J Psychiatry. 2001;158:227-233;2Zandi et al. JAMA. 2002;288:2123-2129.
WHIMS Outcomes Outcome E+P Placebo RR (95%CI) n = 2,229 n = 2,303Probable dementia 40 21 2.05 (1.21-3.48) Mean (SD) F/U yrs 4.01 (1.21) 4.06 (1.18) Rate per 10,000 woman yrs 45 22Mild Cognitive Impairment 56 55 1.07 (0.74-1.55) Mean (SD) F/U yrs 3.99 (1.23) 4.04 (1.20) Rate per 10,000 woman yrs 63 59Shumaker S et al. JAMA. 2003;289:2651-2662
Critical Window & Dementia? US HMO Study 26% risk reduction for dementia when HT used during midlife only 48% risk increase for dementia when HT used only later in life ??provide a bridge for observation vs WHIMS results Whitmer RA, et al (2010). Timing of hormone therapy and dementia: the critical window theory revisited. AnnNeurol. EPUb
SWAN Study: Reported Prevalence of Vasomotor Symptoms Ages 40 to 55 Years African American 50 HispanicHot Flushes/Night Sweats Caucasian % of Women Reporting Chinese 40 Japanese 30 20 10 0 Race/EthnicityGold EB, et al. Am J Epidemiol. 2000;152:463-73.
Hot Flushes May Continue Years After Menopause 50 Number of years women report having hot flushes as 45 estimated by a survey of 501 self-‐selected women who have experienced hot flushes.1 40Number of subjects 35 30 25 20 15 10 5 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 26 28 29 30 32 36 38 41 44 Years Hot flushes are reported in 58% to 93% of postmenopausal women 2,3 1Kronenberg. Ann NY Acad Sci. 1990;592:52; 2Thompson et al. J Biosoc Sci. 1973;5:71; 3Berg et al. Maturitas. 1988;10:192.
The Vasomotor Cascade Night sweats Interrupted sleep FatigueIrritability, mood changesKronenberg. Ann NY Acad Sci. 1990;592:52-86.Beers et al, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. 1999.Baker et al. J Psychosom Res. 1997;43:359-369.
Physiology of The Hot Flash No inherent health hazard Related to reduced thermoneutral zone Many women have a prodrome Aura followed by measurable increase in heat over entire body surface increase skin temp and conductance followed by decrease in core body temp
Could Hot Flashes be Protective? Hazard Ratio Ductal carcinoma1 Inv Lobular carcinoma1 OR Inv Ductal-Lobular carc1 Stroke2 CVD2 HR Death2 0.5 1.0 1.5Huang, Y et al. (2011). Relationship between menopausal symptoms and risk of postmenopausal breast cancer.Cancer Epidemiol Biomarkers Prev; 20(2); 1 10; Szmuilowicz, E. D., J. E. Manson, et al. (2011). Vasomotorsymptoms and cardiovascular events in postmenopausal women. Menopause. available at:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21358352
Vasomotor Management Strategies Complementary and Alternative Medicine Lifestyle Strategies Behavioral Therapies Paced respirations Mindfulness Program Acupuncture Non-‐hormonal Medications Hormone Therapy: ET EPT
Lifestyle Strategies Diet Exercise Avoidance of Regular Frequency caffeine Aerobic sugar Breathable Fabrics alcohol Cotton Increase Water Linen Low Fat Layers Vegetables, Protein Avoid High Neck Stress Management Air flow / Fans Alexander, et al. Menopause. 2003:10(6), 601; Irvin. Mind, Body & Menopause Study. 1996; Kronenberg & Fugh-‐Berman. Ann Intern Med. 2002;137:805-‐813.
Relaxation Techniques Paced respirations Acupuncture Mindfulness program1 No difference in frequency of HF Sig decrease in stress, improved sleep, and less bother from HFs in tx group 1Carmody, J. F., S. Crawford, et al. (2011). "Mindfulness training for coping with hot flashes: results of a randomized trial."Menopause. published oinline:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21372745
Paced Respirations Reduces frequency and severity of HF Study used elaborate respiration monitoring 4-‐7-‐9 breathing is effective -‐ ??stress mediation Freedman RR, et al. Biochemical and thermoregulatory effects of treatment for menopausal hot flashes. Menopause.1995;2:211 218; Freedman RR, Woodward S. Behavioral treatment of menopausal hot flushes: Evaluation by ambulatorymonitoring. Am J Obstet Gynecol. 1992;167(2):436 439.; Irvin JH, et al. The effects of relaxation response training onmenopausal symptoms. J Psychosom Obstet Gynaecol. 1996;17(4):202 207.; and Carson KM, et al. Yoga programdecreases hot flashes in breast cancer survivors: Results from a randomized trial. Presented at the Second IAYTSymposium on Yoga Therapy and Research, March 6-9, 2008, Los Angeles, Calif.
Acupuncture for HFs Well accepted CAM Known to provide relaxation and pain relief Of 8 studies published 1995-‐20081-‐8: 3 showed significant decrease in HF severity1, 2, 3 1 showed significant decrease in HF frequency for both tx and sham groups4 3 showed beneficial effects on mood1, 3, 5 1 showed no difference4 1Cohen SM, et al. Can acupuncture ease the symptoms of menopause? Holist Nurs Pract. 2003;17(6):295 299. 2Nir Y, et al.Acupuncture for postmenopausal hot flashes. Maturitas. 2007;56(4):383 395. 3Huang MI, et al. A randomized controlled pilotstudy of acupuncture for postmenopausal hot flashes: effect on nocturnal hot flashes and sleep quality. Fertil Steril.2006;86(3):700 710. 4Avis NE, et al. A randomized, controlled pilot study of acupuncture treatment for menopausal hotflashes. Menopause. 2008;15(6):1070 1078. 5Wyon Y, et al. Effects of acupuncture on climacteric vasomotor symptoms,quality of life, and urinary excretion of neuropeptides among postmenopausal women. Menopause. 1995;2:3 12. 6Deng G, etal. Randomized, controlled trial of acupuncture for the treatment of hot flashes in breast cancer patients. J Clin Oncol.2007;25(35):5584 5590. 7Vincent A, et al. Acupuncture for hot flashes: a randomized, sham-controlled clinical study.Menopause. 2007;14(1):45 52. 8Wyon Y, et al. A comparison of acupuncture and oral estradiol treatment of vasomotorsymptoms in postmenopausal women. Climacteric. 2004;7(2):153 164.
Acupuncture for HFs In head to head trial with venlafaxine Women with hormone receptor-‐positive breast cancer No difference in HF improvement between two arms Conclusion: acupuncture as effective as venlafaxine, Possibly safer and with fewer side effects Walker EM, Rodrigues AI, kohn B et al. Acupuncture versus vanlafaxine for the management of vasomotor symptoms inpatietns with hormone receptor-positive breast cancer: a randomized controlled trial. J Clin Oncol 2010;28:634-640.
Phytoestrogens for HFs Efficacy Side-effects & Cautions Isoflavones Not effective or mixed results in six Generally well tolerated trials of red clover1 Long-term use of soy Effective or mixed results in four of 11 extracts (>5 years) can trials of soy extract1 increase risk for Not effective in meta-analysis of five endometrial hyperplasia3 trials of red clover extract and not No increase in effective in additional trial of red clover proliferation seen with 6 extract (not in meta-analysis due to months use4,5 differences in study design)2 Not effective in seven of nine trials of dietary soy2 Not effective in four of nine trials of soy extracts2 Not effective in six trials using other phytoestrogens21Nelson HD, et al. JAMA. 2006;295(17):2057 2071. 2Lethaby AE, et al. Cochrane Database Syst Rev. 2007(4):CD001395.3Unfer V, et al. Fertil Steril. 2004;82(1):145 148, 265. 4Balk JL, et al. J Soc Gynecol Investig. 2002;9(4):238 242. 5Kaari C, etal. Maturitas. 2006;53(1):49 58. (table frm: Alexander. Advance for NPs. 2009;17(7):31-36.)
Botanicals for HF Botanical Efficacy Side-effects & Cautions Black cohosh Effective in 5 of 9 trials1 Headache, short-term dizziness, gastrointestinal symptoms Caution for possible liver toxicity (may relate to contaminants in product as opposed to black cohosh itself)Ginseng Not effective in 2 trials1 Headache, gastrointestinal symptoms, sleep disruptions May interact with warfarinDong quai Effective in 1 trial Can cause photosensitivity (combo w/ chamomile)2 May interact with warfarin Not effective in 1 trial3Oil of evening No significant decrease May potentiate seizure side effects inprimrose in one trial4 some medications (e.g., phenothiazines)1Ihenacho. Drug Ther Bull. 2009;47(1):2 6. 2Hirata JD, et al. Fertil Steril. 1997;68(6):981 986. 3Kupfersztain C, et al. Clin Exp Obstet Gynecol. 2003;30(4):203 206. 4Chenoy R, et al. Effect of oral gamolenic acid from evening primrose oil on menopausalflushing. BMJ. 1994;308(6927):501 503. (table frm: Alexander. Advance for NPs. 2009;17(7):31-36.)
Non-Hormonal Medications for Hot Flashes SSRIs or SNRIs effective, 4 of 6 trials Clonidine effective, 4 of 7 trials Gabapentin effective, 2 of 2 trials Isoflavone extracts -‐ mixed results, no difference 6 trials red clover, improvement in 3 of 7 trials soy extracts Effects are less than for Estrogen Nelson, Vesco, et al. JAMA. 2006;295(17):2057-20716
Non-hormonal Medications for Treating Hot Flushes Drug Starting Dose % Reduction in Cost, $ Flushes* Estrogen 0.625mg/d oral 80-100 23 conjugated estrogen or equivalent Megestrol 20mg/d 80 25 Venlafaxine or 75mg/d 60 78 Paroxetine 10mg/d (12.5 CR) Clonidine 0.1mg/d 40 10 *Based on published randomized trials in which treatment with placebo reduced the severity and frequency oh hot flushes 20 to 40% Cost data based on prices from a national chain pharmacy Other estrogen preparations such as 17B estradiol, 1.0mg orally. And transdermal estradiol, 0.05mg) are equally effectiveGrady. JAMA. 2002;287:2130.
E and E+P Reduce Hot Flashes HOPE Study) Placebo Placebo 10 10 0.625 mg 0.625/2.5 mg 0.45 mg 0.45/2.5 mg 0.3 mg 0.45/1.5 mgAdjusted Mean Number* Adjusted Mean Number* 8 8 0.3/1.5 mg 6 6 4 4 2 2 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 1 2 3 4 5 6 7 8 9 10 11 12 13 Cycle Cycle *Adjusted for baseline Mean hot flushes at baseline = 12.3 (range 11.3 13.8) Utian et al. FETil Steril. 2001;75:1065.
Milestones in Hormone Therapy 1940-‐2000 Breast cancer risk Identified (Berkquist) 1989 Robert Wilson and Endometrial cancer Feminine forever 1962 risk defined HERS WHI CEE arm 1975 1998 halted 2004 1940 1950 1960 1970 1980 1990 2000 DES approved 1941 DES banned for Wyeth files for CVD WHI CEE + Conjugated equine human use 1975 prevention indication for MPA haltedestrogens (CEE) 1942 Premarin 2002* HERS = Heart and Estrogen/Progestin Replacement Study
HT and CVD Meta analysis 1993 (Grady et al) Application to FDA for CEE as cardiopreventive in healthy women FDA requested RCT First trial designed 2nd prevention (HERS) Second designed for primary prevention (WHI) HERS and WHI designed as statin trials
Heart and Estrogen/progestin Replacement Study (HERS) Study design: Randomized, double-‐blind, placebo-‐ controlled, secondary prevention Subjects: 2763 postmenopausal women, <80 years old (mean age, 66.7 years) with CAD Intervention: CEE 0.625 mg + MPA 2.5 mg daily or placebo Follow-‐up: HERS I 4.1 years HERS II open-‐label 2.7 years 1 end point: Nonfatal MI or CHD death CAD = coronary artery disease; MI = myocardial infarction; CHD = coronary heart disease. Hulley S, et al. JAMA. 1998;280:605-13. Grady D, et al. JAMA. 2002;288:49-57.
Effect of HT vs Placebo on Second CHD Events (HERS I and II) HT Placebo 50 40 30 20 10 HERS HERS II 0 1 2 3 4 5 6 to 8 YearsWriting group for the Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II) JAMA.2002;288:49.
Papworth HRT Atherosclerosis Study (PHASE) RCT of 255 postmenopausal women with angiographically confirmed coronary disease Randomized to 17 -‐estradiol with or without NETA (n=134) or placebo (n=121) for 4 years Primary outcome: hospital admission with unstable angina, proven MI, or death 15.6 / 100 patient-‐years (EPT all) 12.6 / 100 patient-‐years (placebo) RR 1.23 (95% CI: 0.82-‐1.86; p=0.3) Event rates were highest in first 2 years Clarke S et al. Abstract. Eur Heart J, 2000; 21:212.
CEE/MPA Arm Study design: Randomized, double-‐blind, placebo-‐ controlled, primary prevention trial Subjects: 16,608 postmenopausal women without vasomotor symptoms 50 to 79 years old (mean age, 63.3 years) Intervention: CEE 0.625 mg + MPA 2.5 mg daily or placebo Follow-‐up: 5.2 years (average) terminated early (8.5 years planned) 1° end point: Nonfatal MI or CHD death Writing Group for the Womens Health Initiative Investigators. JAMA. 2002;288:321-33.
Gap Hypothesis: British Million Women Study ET and EPT use Overall No risk if start 5 yr after menopause ET RR = 1.05, 95% CI = 0.89 to 1.24 EPT RR = 1.53, 95% CI = 1.38 to 1.70 risk if start at or before menopause ET RR = 1.43, 95% CI = 1.35 to 1.51 EPT RR = 2.04, 95% CI = 1.95 to 2.14 Incidence among women aged 50 59 yrs Never users = 0.30 % (95% CI = 0.29% to 0.31%) Current ET* = 0.43% (95% CI = 0.42% to 0.45%) Current EPT* = 0.61% (95% CI = 0.59% to 0.64%) *initiated use <5 years after menopause Beral V et al (2011). Breast Cancer Risk in Relation to the Interval Between Menopause and StartingHormone Therapy. J Natl Cancer Inst 2011;103:296 305.
Breast Cancer Risk is Important Re-‐analysis of the WHI E-‐only arm data Risk analysis is important Women at low risk for breast cancer do not have increased risk with ET Risk factors: family hx (esp 1st or 2nd degree), +BRCA-‐1/2, dense breasts, bx = atypical hyperplasia, radiation, obesity, alcohol use, inactivity Risk mediators: early age of full-‐term pregnancy, long-‐ term breast feeding, +exercise, no hx fibrocystic breast dz. Archer DF. IMS Press Release, Dec 13, 2010; Ragaz J et al. (2010) Dual estrogen effects on breast cancer:endogenous estrogen stimulates, exogenous estrogen protects. Further investigation of estrogenchemoprevention is warranted. San Antonio Breast Cancer Symposium, abstract # 1410.
WHI ET Arm and Breast CA: 10.7 Yr Follow-‐up Data 23% risk of invasive breast CA in ET group versus placebo after 10.7 years (3.5 yrs use) (HR 0.77, CI 0.62 0.95) No significant effects overall for CHD, DVT, CVA, hip fx, colorectal ca, or total mortality LaCroix AZ, Chlebowski RT, Manson JE et al. Health outcomes after stopping conjugated equine estrogen among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011;305:1305-1314.
Breast Cancer in Primary CHD Prevention Trials Hormone Therapy1,2 Lipid Lowering3 CHD 0.68 (0.48-0.96) 0.89 (0.69-1.09) Total Mortality 0.61 (0.39-0.95) 0.95 (0.62-1.46) No. Additional No. of Patients Breast Cancer (Annualized %) Cases per 10,000 Hazard Women per Year Study Placebo Statin Ratio 95% CI of Stain UseStatins meta4 64 (0.23) 81 (0.30) 1.33 (0.79-2.26) 7Statins meta5 124 (0.29) 132 (0.31) 1.04 (0.81-1.33) 2WHI-EP6 150 (0.33) 199 (0.42) 1.24 (adj 0.97-1.59) 9WHI-E7* 161 (0.42) 129 (0.34) 0.82 (0.65-1.04) -8*Adherence adjusted = 0.67 (0.47-0.97) 1Salpeter S, et al. J Gen Intern Med 2004;19:791-804.*Ductal carcinoma = 0.71 (0.52-0.99) 2Salpeter S, et al. J Gen Intern Med 2006;21:363-366. 3Walsh JME, et al. JAMA 2004;21:363-366. 4Dale KM, et al. JAMA 2006;295:74-80. 5Stefanos, et al. J Clin Oncol 2005;23:8606-8612. 6Chlebowski RT, et al. JAMA 2003;289:3243-3253. 7Stefanick ML, et al. JAMA 2006;295:1647-1657.
Latest Epidemiological News on Breast Cancer and EPT: Breast CA incidence -‐ Canada study:1 incidence 2002 after WHI incidence again 2005/6, ??EPT promotes tumor growth but not causative WHI EPT Br CA Mortality, ~ 11 yr follow-‐up (~5 years on therapy):2 of 10,000 women, 1.3 deaths/yr on placebo of 10,000 women, 2.6 deaths/yr on EPT 1Prithwish et al. Breast cancer incidence and hormone replacement therapy in Canada. J Natl Cancer Inst 2010; 102:1489-1495.2Chlewbowski et al. (2010). Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA304(15): 1684-92
Time Effects of HT and CVD: WHI ET Arm 10.7 Yr Follow-‐up Data Women aged 50 59: 40% to 50% risks for HD endpoints in tx grp Of 10,000, tx grp had 12 fewer MIs, 13 fewer deaths, 18 fewer AEs Women aged 70 79: risks for HD endpoints in tx grp Of 10,000, tx grp had 16 more MIs, 19 more deaths, 48 more AEs LaCroix AZ, Chlebowski RT, Manson JE et al. Health outcomes after stopping conjugated equine estrogen among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA 2011;305:1305-1314.
Time Effect with Estrogen ?? Meta analysis of observational studies beneficial effects on heart disease if ET/HT started at time of menopause (Salpeter, et al, 2004) WHI data analysis of women initiating therapy at time of menopause had protective cardiovascular effects (Hsia, et al, 2006) Early versus Late Intervention Trial with Estrogen (ELITE) trial, Kronos Early Estrogen
On the Horizon Estrogen with Bazedoxifene (BZA) Tissue-‐Selective Estrogen Complex (TSEC) Protects bone Reduces menopause-‐related symptoms ( HFs, vaginal dryness, sexual function) No increase in endometrial or breast cancer Lewiecki EM. Bazedoxifene and bazedoxifene combined with conjugated estrogens for the management ofpostmenopausal osteoporosis. Expert Opin Investig Drugs. Oct 2007;16(10):1663-1672.Ronkin et al. Endometrial effects of bazedoxifene acetate, a novel selective estrogen receptor modulator, inpostmenopausal women. Obstet Gynecol. Jun 2005;105(6):1397-1404.
Individualizing Management for Women with Menopause-‐related Symptoms
Weighing the Benefits vs Risks of HT BarriersExamples Tolerability Benefits Fears Examples Misperceptions Vasomotor Risks Sexuality QOL Osteoporosis
Resources NIH -‐ National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/ The Hormone Foundation http://www.hormone.org/ http://nccam.nih.gov/ National Osteoporosis Foundation http://www.nof.org/ Herbal Product Information http://consumerlabs.com North American Menopause Society http://www.menopause.com
Acknowledgements Some slides courtesy of: NAMS (purchased slide set) NOF NPWH Council on Hormone Education Colleagues Used with permission, copyright held by original authors