Menopause  Management:    2012  Update  

 

Ivy  M.  Alexander,  PhD,  APRN,  ANP-­‐BC,  FAAN  Professor,  Yale  University  School  of  Nursing  

   

 

Disclosures  

(within  past  12  months)  for:  PDR  Network  Medscape  NPACE,  CT  APRN  Soc,  NPWH  Engage  Amgen  Datamonitor  Pfizer    

   

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. 2. Burger. Hum Reprod. 1993;8(suppl 2):129. 3. Burger et al. J Clin Endocrinol Metab. 1995;80:3537.

4. Lenton et al. J Clin Endocrinol Metab. 1991;73:1180. 5. Santoro et al. J Clin Endocrinol Metab. 1996;81:1495. 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  

   

Approaches    

Evaluate  risks  Stepped  approach:  

Lifestyle  Strategies  CAM  Therapies  

Behavioral  Therapies  Acupuncture  Botanicals  

 Pharmacotherapeutics  

Non-­‐hormone  Hormone  

Sleep  Disruption  

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  

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.

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  

GU  Changes  &  Sexual  Health  

Genitourinary Atrophy*

Genitourinary  Changes  After  Menopause  

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.

Vaginal Dysfunction (pain with penetration/

sexual dysfunction)

Urinary Dysfunction

 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        

Sexual  Physiologic  Changes  with  Aging  

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 pt 2):714-25; and Dennerstein L, et al. Fertil Steril. 2005;84:174-80.

Prevalence  of  Male  and  Female    Sexual  Complaints  

National  Health  and  Social  Life  Survey  Ages  18  to  59  Years  

0 5 10 15 20 25 30 35

Women Have Trouble Lubricating

Men Unable to Keep an Erection

Climax Too Early

Anxiety About Performance

Lacked Interest in Sex

Unable to Achieve Orgasm

Sex Not Pleasurable

Experience Pain During Sex

Percentage

Women (n = 1664)

Men (n = 1330)

Laumann EO, et al. The Social Organization of Sexuality: Sexual Practices in the United States. Chicago, Ill: University of Chicago Press; 1994. © 1994 by Edward O. Laumann, Robert T. Michael, CSG Enterprises, Inc., and Stuart Michaels. All rights reserved.

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  

Adapted from Dessole S, et al. Menopause. 2004;11:49-56.

Efficacy  of  Low-­‐dose  Vaginal  Estriol  on  Urogenital  Symptoms  

Variables  

Treatment  Group  (n  =  44)   Control  Group  (n  =  44)  P-­

Value*  Before  Treatment  

After  Treatment  

Before  Treatment  

After  Treatment  

Clinical Vaginal dryness Dyspareunia Urogenital atrophy Urodynamic MUP (cm H20) MUCP (cm H20) PTR (%)  

100% 86.4% 100%

50.82 6.15 45.25 7.20 72.52 10.31

20.5% 20.5% 27.3%

62.15 8.64 56.87 9.23 88.85 9.66

100% 84.1% 100%

52.35 6.30 44.77 6.86 70.75 9.08

90.9% 86.4% 93.2%

49.40 6.54 43.32 6.32 70.77 9.04

<.001 <.001 <.01 <.05 <.05 <.05

*P-value is comparison between treatment and control groups. MUP = maximum urethral pressure; MUCP = mean maximum urethral closure; PTR = abdominal pressure transmission ratio.

Vaginal  Epithelium  &  Estrogen  

Vagina/urethra  highest  concentration  of  estrogen  receptors2  Most  efficient  response  with  local  application3,4  

6 weeks of estrogen

Without estrogen - atrophic With estrogen1

1. Freedman. Unpublished data. 2. Losif et al. Am J Obstet Gynecol. 1981;141:817.

3. Elia et al. Obstet Gynecol Surv. 1993;48:509. 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.

0.0

0.2

0.4

0.6

0.8

1.0

Baseline 4 8 12 16

EE/MTEE

Mean  Change  in  Sexual  Desire  Scores  

Mea

n C

hang

e

Study Week MT = methyltestosterone. *P < .02. Lobo RA, et al. Fertil Steril. 2003;79:1341-52.

*

Comparative  Efficacy  of  Oral  Esterified  Estrogen    With  or  Without  MTestosterone    in  Postmenopausal  Women  

With  Hypoactive  Sexual  Desire  

Testosterone  Transdermal  Patch  vs  Placebo:  Total  Satisfying  Sexual  Activity  

0.0

0.5

1.0

1.5

2.0

2.5

3.0

0 4 8 12 16 20 24

Weeks

4-W

eek

Mea

n C

hang

e fr

om B

asel

ine

TestosteronePlacebo

Simon J, et al. J Clin Endocrinol Metab. 2005;90:5226-33.

*

* * *

*

*P

Testosterone  Transdermal  Patch  vs  Placebo:  Personal  Distress  

-30

-25

-20

-15

-10

-5

0

0 4 8 12 24

Weeks

4-W

eek

Mea

n C

hang

e fr

om B

asel

ine

TestosteronePlacebo

*

*

* *

*P

Simon J, et al. J Clin Endocrinol Metab. 2005;90:5226-33.

Memory  &  Cognition  

Physiology  of  Memory  Changes  

Frequently  due  to  sleep  interruptions  

Stress  is  a  powerful  mediator  

Forgetfulness  among  women  and  men  similar  at  midlife  

Schaie. Am Psychol. 1994;49:304.

Cognitive  Changes  With  Age    

35

40

45

50

55

60

25 32 39 46 53 60 67 74 81 88Age (years)

Mea

n T

scor

e

Verbal meaningSpatial orientationInductive reasoningNumberWord fluency

Longitudinal estimates of mean T scores for single markers of the primary mental ability in men and women

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  +  /  -­‐                                  

Neurotransmission  Neuroprotection  

Neurite  Branching  Synaptogenesis  

Cerebral  Blood  Flow  

Trophic    Factor    

Expression  

Effects  of  Estrogen  on    Neuronal  Function  

Adapted from Birge SJ. Menopause Management. 2000;July/August:13-21.

CEE  Promotes  Cellular  Mechanisms  of  Memory    

Brinton et al. Neurobiol Aging. 2000;21:475.

No CEE

CEE treated

Neuronal outgrowth Synapse formation

Prior to CEE

After CEE treatment

Cerebral  Blood  Flow  (SPECT):  48-­‐Yr-­‐Old  Healthy  Menopausal  Woman  

During a Hot Flush CEE

SPECT, 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. Am J 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  

Shumaker S et al. JAMA. 2003;289:2651-2662

RR (95%CI) Placebo n = 2,303

E+P n = 2,229

Outcome

4.06 (1.18) 22

4.01 (1.21) 45

Mean (SD) F/U yrs Rate per 10,000 woman yrs

1.07 (0.74-1.55) 55 56 Mild Cognitive Impairment

4.04 (1.20) 59

3.99 (1.23) 63

Mean (SD) F/U yrs Rate per 10,000 woman yrs

2.05 (1.21-3.48) 21 40 Probable dementia

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. Ann Neurol. EPUb

Vasomotor  Symptoms  

0

10

20

30

40

50African AmericanHispanicCaucasianChineseJapanese

% o

f Wom

en R

epor

ting

H

ot F

lush

es/N

ight

Sw

eats

Gold EB, et al. Am J Epidemiol. 2000;152:463-73.

SWAN  Study:  Reported  Prevalence    of  Vasomotor  Symptoms  

Race/Ethnicity

Ages 40 to 55 Years

Hot  Flushes  May  Continue  Years  After  Menopause  

Number  of  years  women  report  having  hot  flushes  as  estimated  by  a  survey  of  501  self-­‐selected  women  who  have  experienced  hot  flushes.1  

05

101520253035404550

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

Num

ber o

f sub

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s

1Kronenberg. Ann NY Acad Sci. 1990;592:52; 2Thompson et al. J Biosoc Sci. 1973;5:71; 3Berg et al. Maturitas. 1988;10:192.

Hot flushes are reported in 58% to 93% of postmenopausal women 2,3

The  Vasomotor  Cascade  

Night sweats

Interrupted sleep

Fatigue

Irritability, mood changes Kronenberg. 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?    

0.5

Hazard Ratio

Ductal carcinoma1 Inv Lobular carcinoma1 Inv Ductal-Lobular carc1 Stroke2 CVD2 Death2

1.0 1.5 Huang, 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). Vasomotor symptoms 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

OR

HR

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    Avoidance  of  

caffeine  

sugar  

alcohol  

Increase  Water  

Low  Fat  

Vegetables,  Protein  

Stress  Management  

Air  flow  /  Fans  

Exercise Regular Frequency Aerobic

Breathable Fabrics Cotton Linen Layers

Avoid High Neck

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 ambulatory monitoring. Am J Obstet Gynecol. 1992;167(2):436 439.; Irvin JH, et al. The effects of relaxation response training on menopausal symptoms. J Psychosom Obstet Gynaecol. 1996;17(4):202 207.; and Carson KM, et al. Yoga program decreases hot flashes in breast cancer survivors: Results from a randomized trial. Presented at the Second IAYT Symposium 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 pilot study 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 hot flashes. 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, et al. 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 vasomotor symptoms 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 in patietns 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 trials of red clover1

Effective or mixed results in four of 11 trials of soy extract1

Not effective in meta-analysis of five trials of red clover extract and not effective in additional trial of red clover extract (not in meta-analysis due to 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 phytoestrogens2

Generally well tolerated Long-term use of soy

extracts (>5 years) can increase risk for endometrial hyperplasia3

No increase in proliferation seen with 6 months use4,5

1Nelson 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, et al. 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 warfarin

Dong quai Effective in 1 trial (combo w/ chamomile)2

Not effective in 1 trial3

Can cause photosensitivity May interact with warfarin

Oil of evening primrose

No significant decrease in one trial4

May potentiate seizure side effects in 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 menopausal flushing. 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  

10 40 0.1mg/d Clonidine

78 60 75mg/d 10mg/d (12.5 CR)

Venlafaxine or Paroxetine

25 80 20mg/d Megestrol

23 80-100 0.625mg/d oral conjugated estrogen or equivalent

Estrogen

Cost, $ % Reduction in Flushes*

Starting Dose Drug

*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 effective

Grady. JAMA. 2002;287:2130.

E  and  E+P  Reduce  Hot  Flashes  HOPE  Study)  

0

2

4

6

8

10

1 2 3 4 5 6 7 8 9 10 11 12 13Cycle

Adj

uste

d M

ean

Num

ber*

0

2

4

6

8

10

1 2 3 4 5 6 7 8 9 10 11 12 13Cycle

Adj

uste

d M

ean

Num

ber*

*Adjusted for baseline Mean hot flushes at baseline = 12.3 (range 11.3 13.8)

0.625 mg 0.45 mg 0.3 mg

Placebo 0.625/2.5 mg 0.45/2.5 mg 0.45/1.5 mg 0.3/1.5 mg

Placebo

Utian et al. FETil Steril. 2001;75:1065.

Historical  Swings  in  HT  History  

1940 1950 1960 1970 1980 1990 2000

DES approved 1941 Conjugated equine

estrogens (CEE) 1942

Robert Wilson and Feminine forever 1962

DES banned for human use 1975

Wyeth files for CVD prevention indication for Premarin

* HERS = Heart and Estrogen/Progestin Replacement Study

Milestones  in  Hormone  Therapy    1940-­‐2000  

Endometrial cancer risk defined 1975

HERS 1998

WHI CEE + MPA halted 2002

WHI CEE arm halted 2004

Breast cancer risk Identified (Berkquist) 1989

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  

HT  Today:  The  Evidence-­‐base  from  Prevention    

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.

0

10

20

30

40

50

1 2 3 4 5 6 to 8

HT Placebo

Effect  of  HT  vs  Placebo  on  Second  CHD  Events  (HERS  I  and  II)  

Writing group for the Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II) JAMA. 2002;288:49.

Years

HERS HERS II

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.

 

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 Women's Health Initiative Investigators. JAMA. 2002;288:321-33.

CEE/MPA Arm

All-­‐Cause  Mortality  Was  Not  Affected    by  HT  in  WHI  or  HERS    

0

0.05

0.1

0.15

0 1 2 3 4 5 6 7Time (years)

Cum

ulat

ive

Haza

rd

Estrogen + ProgestinPlacebo

HR = 0.98 P = NS

WHI (cumulative hazard)

0

5

10

15

0 1 2 3 4 5

Follow-up, Years (number at risk)

Inci

denc

e (%

)

Estrogen + ProgestinPlacebo

HERS (incidence %)

P = NS

Writing Group for the Women's 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.

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 Starting Hormone 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 estrogen chemoprevention 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)

7 (0.79-2.26) 1.33 81 (0.30) 64 (0.23) Statins meta4

9 (adj 0.97-1.59) 1.24 199 (0.42) 150 (0.33) WHI-EP6 -8 (0.65-1.04) 0.82 129 (0.34) 161 (0.42) WHI-E7*

95% CI

No. of Patients (Annualized %)

No. Additional Breast Cancer

Cases per 10,000 Women per Year

of Stain Use Hazard Ratio

Statin

Placebo

Study

*Adherence adjusted = 0.67 (0.47-0.97) *Ductal carcinoma = 0.71 (0.52-0.99)

1Salpeter S, et al. J Gen Intern Med 2004;19:791-804. 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.

2 (0.81-1.33) 1.04 132 (0.31) 124 (0.29) Statins meta5

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. JAMA 304(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 of postmenopausal 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, in postmenopausal women. Obstet Gynecol. Jun 2005;105(6):1397-1404.

Individualizing  Management  for  Women  with    

Menopause-­‐related  Symptoms  

Weighing  the  Benefits  vs  Risks  of  HT  

Vasomotor Sexuality QOL Osteoporosis

Examples

Benefits Tolerability Fears Misperceptions Risks

Examples

Barriers

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  

 

Thank  You  

Questions?