1. Treatment of Menopausal Symptoms: A 2017 Update for Clinicians
Andrew M. Kaunitz MD, FACOG, NCMP University of Florida Research Foundation Professor and Associate Chairman Department of Obstetrics and Gynecology University of Florida College of Medicine - Jacksonville Medical Director, and Director of Menopause & GYN Ultrasound Services UF Southside Women’s Health Specialists
FOMA.District2.men.ht

2. Learning Objectives: Menopause & Hormone Therapy
5/11/2018
Learning Objectives: Menopause & Hormone Therapy
Our patients will likely spend more than one third of their lifespan as menopausal women…
By remaining up to date, we can help our patients make sound choices regarding HT
Identify vasomotor symptoms (VMS) and recommend hormonal / nonhormonal treatment
Recognize risks of HT, with emphasis on breast cancer, venous thromboembolism (VTE), and coronary heart disease (CHD) 2

3. Abbreviations HT = hormone therapy ET = estrogen therapy
CE = conjugated equine estrogen,E2=estradiol
EPT = combination estrogen-progestin therapy
= Women’s Health Initiative (WHI)

4. Andrew M. Kaunitz, M.D. DISCLOSURES
5/11/2018
Andrew M. Kaunitz, M.D. DISCLOSURES
Clinical Trials
(Funding to University of Florida Research Foundation):
Bayer
TherapeuticsMD
Advisory Boards
Allergan
Mithra
Pfizer
Consultant
Shionogi
Royalties
UpToDate
North American Menopause Society
Menopause Editorial Board
Board of Trustees
HT Position Statement writing group member 4

5. Vasomotor Symptoms (VMS)
Spontaneous sensations of warmth, usually felt on chest, neck and face
may be called ‘hot flushes’ or ‘night sweats’
often associated with perspiration, palpitations and anxiety
may impair quality of life
Variable in frequency, duration and severity
usually < 5 minutes
Can be triggered by warm environments, hot drinks, emotional stress
VMS: Most common reason women seek care at time of menopausal transition
HD Nelson. Lancet 2008

6. Prevalence and Timing of VMS
Experienced by > 50% of menopausal women
Substantial increase in frequency and severity during menopausal transition (perimenopause)
For some women, VMS persist 6 months to several years, with ↓ frequency and intensity over time
Mean duration bothersome VMS 10.2 years
EW Freeman, et al. Obstet Gynecol 2011
HD Nelson. Lancet 2008

7. Treatment of VMS
Treatment appropriate when VMS disrupt daytime activities and/or sleep
Estrogen used for many decades used to treat VMS
most effective treatment 
numerous randomized, placebo-controlled trials
75% reduction in VMS frequency
significant reduction in VMS severity
Oral and transdermal estrogen have similar efficacy
Progestin therapy, including DMPA and megestrol
also effective in treating VMS
HD Nelson. JAMA AH MacLennan, et al. Cochrane Database Syst Rev 2004
HD Nelson. Lancet 2008

8. Hormone Therapy Clear Controversial VMS: most common indication for HT
5/11/2018
Hormone Therapy
Clear
VMS: most common indication for HT
HT’s efficacy in treating VMS well-established
Controversial
Our understanding of HT’s safety….

9. WHI: Women’s Health Initiative
5/11/2018
Multicenter, double-blind, placebo-controlled trial of women age years at baseline, designed to assess HT’s impact on cardiovascular disease
Mean age at screening years
Planned 10-year trial; stopped early
CEE/MPA v. placebo: N= 16,608 , stopped Summer ’02, mean follow-up 5.2 years
CEE v. placebo: N = 10,739 , stopped Spring ’04, mean follow-up 6.8 years
Largest RCT of menopausal hormone therapy
Writing Group WHI. JAMA 2002
WHI Steering Committee. JAMA 2004

10. WHI EPT Study: Findings at Early Interruption Summer 2002
5/11/2018
WHI EPT Study: Findings at Early Interruption Summer 2002
Risks
Benefits
Fracture
VTE/PE
Colon Cancer MI
CVA
Breast Cancer
Adapted from: Writing Group WHI. JAMA 2002

11. WHI ET Initial Findings: Summary as of 2004
5/11/2018
WHI ET Initial Findings: Summary as of 2004
ET component of study stopped early
after 6.8 years of follow-up
ET not found to significantly impact risk of breast cancer, CHD, PE, or colorectal cancer
significant reduction in hip fracture risk
Overall safety of ET appears greater than EPT
2004 findings received less attention than 2002 report
WHI Steering Committee. JAMA 2004
Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:

12. WHI’s Impact on Use of HT in US Women
5/11/2018
WHI’s Impact on Use of HT in US Women
Since 2002, use of all HT has decreased substantially
Main initial conclusion from WHI is that HT not appropriate to prevent coronary heart disease
Nonetheless, following WHI findings in 2002, many clinicians remain reluctant to treat women with bothersome menopausal symptoms
Many symptomatic women not treated…
PI Jewett, et al. Obstet Gynecol 2014 J Shifren and I Schiff. Obstet Gynecol 2010
Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288: 12

14. WHI: 13-Year Follow-up: EPT and ET…
5/11/2018
WHI: 13-Year Follow-up: EPT and ET…
JE Manson, et al. October 2, 2013

15. EPT Hazard Ratios (HRs): Significant ↑ risk breast cancer: 1.28
Risk of Breast Years Cumulative f/u in Participants OVERALL (all ages at randomization)
EPT Hazard Ratios (HRs):
Significant ↑ risk breast cancer: 1.28
ET Hazard Ratios:
Significant ↓ risk breast cancer: 0.79
JE Manson, et al. JAMA October 2, 2013

16. EPT and Elevated Risk of Breast Cancer
What does an HR of breast cancer of 1.28 mean?
Putting HR of 1.28 in context:
<1 additional case per 1,000 EPT users annually (WHI)
can be attributed to HT
HR with EPT slightly higher than that seen with one daily glass of wine; less than HR with 2 daily glasses (Nurses Health Study)
1 in 5 breast cancers occurring in women using EPT can be attributed to HT JE
JE Manson, et al WY Chen, et al. 2011

17. WHI recruited women age 50-79 years…
Risk of All-cause Years Cumulative f/u in Participants OVERALL (all ages at randomization)
EPT Hazard Ratios (HRs):
All-cause mortality: 0.99 (NS)
ET Hazard Ratios:
WHI recruited women age years…
JE Manson, et al. JAMA October 2, 2013

18. 50-59 years ET: 0.78 EPT: 0.88 60-69 years ET: 1.02 EPT: 0.99
All-cause Mortality Hazard Ratios* at 13 Years Cumulative f/u by Age at Randomization
50-59 years ET: 0.78 EPT: 0.88
60-69 years
ET: 1.02
EPT: 0.99
70-79 years
ET: 1.06
EPT:1.04
* All p-values>0.05; but trend by age is meaningful
JE Manson, et al. JAMA October 2, 2013

19. Overall, R:B ratio more favorable for ET than EPT
Conclusions: WHI EPT+ET Trial-- 13 Years of Follow-Up, and Published Literature Overall
HT Risk: Benefit ratio most favorable when initiated in younger menopausal women
HT appropriate for symptomatic patients in their 50s or within 10 years of menopause onset
Overall, R:B ratio more favorable for ET than EPT
AM Kaunitz, JE Manson. Obstet Gynecol 2015

20. Compounded Bioidentical Hormone Therapy
Use growing in the US, with an estimated 2.5 million current users
Use propelled by celebrity endorsements
Most users not aware that Compounded HT not FDA monitored or approved
Salivary testing often employed by MDs prescribing
compounded HT
Such testing does not correlate with
serum steroid levels
Compounded Progesterone cream often Rxed…
JV Pinkerton, N Santoro. Menopause 2015 ; AM Kaunitz, JD Kaunitz. Menopause 2015; M Gass, et al. Menopause 2015

21. Compounded Bioidentical Hormone Therapy
National survey: cases of endometrial cancer in women using compounded HT
FDA-approved bioidentical HT formulations available:
estradiol patches, tablets, vaginal cream/tablets, progesterone
in oil capsules
JV Pinkerton, N Santoro. Menopause 2015 ; AM Kaunitz, JD Kaunitz. Menopause 2015; M Gass, et al. Menopause 2015

22. VTE & CVA Risk and Route of ET: 7 Observational Studies
Oral estrogen therapy: ↑ risk VTE & CVA
Transdermal ET: no ↑ risk
Biologic plausibility (transdermal=no first pass hepatic effect)
PY Scarabin, et al. Lancet M Canonico, Arterioscler Thromb Vasc Biol A Bergendal et al.; JA Simon et al. Menopause 2016
C Renoux, et al. J Thromb Haemost 2010 C Renoux, et al. BMJ 2010
L Laliberté, et al. Menopause 2011 RE Roach, et al. J Thromb Haemost 2012

23. Oral vs. Transdermal Estrogen
No randomized trial data comparing benefits and risks
Given consistency and biologic plausibility of observational data, reasonable to conclude transdermal estrogen safer re risk of VTE
Clinicians and women should discuss this safety issue when making decisions regarding route of HT
Transdermal route particularly appropriate for overweight/obese and other HT users at elevated baseline risk
Reasonable starting dose 0.05 mg estradiol patch (equivalent to 1.0 mg oral estradiol, or mg conjugated equine estrogen)
PY Scarabin, et al. Lancet M Canonico, Arterioscler Thromb Vasc Biol A Bergendal et al.; JA Simon et al. Menopause 2016
C Renoux, et al. J Thromb Haemost 2010 C Renoux, et al. BMJ 2010
L Laliberté, et al. Menopause 2011 RE Roach, et al. J Thromb Haemost 2012

24. Menopausal Hormone Therapy: A Clinician’s Evidence-based 2017 Perspective
The pendulum is swinging…towards an evidence-based perspective on use of hormone therapy
Clinicians who remain up to date can help patients make sound choices regarding treatment of menopausal symptoms
Systemic HT: appropriate to initiate for most healthy women with bothersome VMS who are <age 60, or within 10 years of menopause onset
Thank you!