Am 11.20 alexander


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Am 11.20 alexander

  1. 1. Menopause  Management:     2012  Update     Ivy  M.  Alexander,  PhD,  APRN,  ANP-­‐BC,  FAAN   Professor,  Yale  University  School  of  Nursing        
  2. 2. Disclosures   (within  past  12  months)  for:   PDR  Network   Medscape   NPACE,  CT  APRN  Soc,  NPWH   Engage   Amgen   Datamonitor   Pfizer      
  3. 3. 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  
  4. 4. 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.
  5. 5. 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.
  6. 6. Management  for  Selected   Symptoms   Sleep   GU  Changes  &  Sex   Memory  and  Cognition   Vasomotor  Symptoms      
  7. 7. Approaches    Evaluate  risks  Stepped  approach:   Lifestyle  Strategies   CAM  Therapies   Behavioral  Therapies   Acupuncture   Botanicals     Pharmacotherapeutics   Non-­‐hormone   Hormone  
  8. 8. Sleep  Disruption  
  9. 9. 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  
  10. 10. 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.
  11. 11. GU  Changes  &  Sexual  Health  
  12. 12. 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.
  13. 13. 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.
  14. 14. Sexual  Function  Declines  with   Menopause  and  Aging    Sexual  libido    Sexual  responsivity    Sexual  activity    Vaginal  dyspareunia         partner  Dennerstein et al. Fertil Steril. 2001;76:456.
  15. 15. 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.
  16. 16. Prevalence  of  Male  and  Female     Sexual  Complaints   National  Health  and  Social  Life  Survey  Ages  18  to  59  Years   Experience Pain During Sex Women (n = 1664) Sex Not Pleasurable Men (n = 1330) Unable to Achieve Orgasm Lacked Interest in Sex Anxiety About Performance Climax Too Early Men Unable to Keep an ErectionWomen Have Trouble Lubricating 0 5 10 15 20 25 30 35 PercentageLaumann EO, et al. The Social Organization of Sexuality: Sexual Practices in the United States. Chicago, Ill: University ofChicago Press; 1994. © 1994 by Edward O. Laumann, Robert T. Michael, CSG Enterprises, Inc., and Stuart Michaels. Allrights reserved.
  17. 17. 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  
  18. 18. 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  
  19. 19. 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.
  20. 20. 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.
  21. 21. 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.
  22. 22. 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.
  23. 23. 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.
  24. 24. 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.
  25. 25. Memory  &  Cognition  
  26. 26. Physiology  of  Memory  Changes  Frequently  due  to  sleep  interruptions  Stress  is  a  powerful  mediator  Forgetfulness  among  women  and  men  similar  at  midlife  
  27. 27. 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.
  28. 28. 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  +  /  -­‐                                  
  29. 29. 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.
  30. 30. 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.
  31. 31. 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.
  32. 32. 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.
  33. 33. 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.
  34. 34. 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
  35. 35. 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
  36. 36. Vasomotor  Symptoms  
  37. 37. 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.
  38. 38. 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.
  39. 39. 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.
  40. 40. 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  
  41. 41. 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:
  42. 42. Vasomotor  Management  Strategies  Complementary  and  Alternative  Medicine   Lifestyle  Strategies   Behavioral  Therapies   Paced  respirations   Mindfulness  Program   Acupuncture    Non-­‐hormonal  Medications  Hormone  Therapy:  ET  EPT  
  43. 43. 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.  
  44. 44. 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:
  45. 45. 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.
  46. 46. 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.
  47. 47. 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.
  48. 48. 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.)
  49. 49. 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.)
  50. 50. 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
  51. 51. 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.
  52. 52. 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.
  53. 53. Historical  Swings  in  HT  History  
  54. 54. 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
  55. 55. 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  
  56. 56. HT  Today:  The  Evidence-­‐base  from  Prevention    
  57. 57. 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.
  58. 58. 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.
  59. 59. 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.
  60. 60.   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.
  61. 61. All-­‐Cause  Mortality  Was  Not  Affected     by  HT  in  WHI  or  HERS     WHI (cumulative hazard) HERS (incidence %) 0.15 Estrogen + Progestin 15 Estrogen + Progestin Placebo PlaceboCumulative Hazard Incidence (%) 0.1 HR = 0.98 10 P = NS P = NS 0.05 5 0 0 0 1 2 3 4 5 6 7 0 1 2 3 4 5 Time (years) Follow-up, Years (number at risk) Writing Group for the Womens Health Initiative Investigators. JAMA. 2002;288:321-33. ©2002 American Medical Association. All rights reserved. Hulley S, et al. JAMA. 1998;280:605-13. ©1998 American Medical Association. All rights reserved.
  62. 62. 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.
  63. 63. 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.
  64. 64. 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.
  65. 65. 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.
  66. 66. 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
  67. 67. 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.  
  68. 68. 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    
  69. 69. 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.
  70. 70. Individualizing  Management  for   Women  with     Menopause-­‐related  Symptoms  
  71. 71. Weighing  the  Benefits  vs  Risks   of  HT   BarriersExamples Tolerability Benefits Fears Examples Misperceptions Vasomotor Risks Sexuality QOL Osteoporosis
  72. 72. Resources  NIH  -­‐  National  Heart,  Lung,  and  Blood  Institute  The  Hormone  Foundation  National  Osteoporosis  Foundation  Herbal  Product  Information  North  American  Menopause  Society  
  73. 73. Acknowledgements  Some  slides  courtesy  of:   NAMS  (purchased  slide  set)   NOF     NPWH   Council  on  Hormone  Education   Colleagues  Used  with  permission,  copyright  held  by  original  authors    
  74. 74. Thank  You  Questions?