1. men.ht
Helping Our Menopausal Patients Make Sound Decisions Regarding Hormone Therapy
Andrew M. Kaunitz MD, FACOG, NCMP University of Florida Term 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

2. Andrew M. Kaunitz, M.D. Menopause-related Disclosures
10/11/2019
Andrew M. Kaunitz, M.D. Menopause-related Disclosures
Clinical Trials
(Funding to University of Florida Research Foundation):
Allergan
Bayer
Endoceutics
TherapeuticsMD
Advisory Boards
AMAG
Consultant
Shionogi
Royalties
UpToDate
Off-label
I refer to off-label use of LNG-IUD for endometrial protection
North American Menopause Society
Menopause Editorial Board
2017 HT Position Statement writing group member 2

3. 10/11/2019
Helping our Menopausal Patients Make Sound Decisions re Hormone Therapy
Learning Objectives I.
Our patients will likely spend more than one third of their lifespan as menopausal women… 3

4. Learning Objectives II:
10/11/2019
Learning Objectives II:
Identify vasomotor symptoms
Recognize risks of HT, with emphasis on breast cancer, coronary heart disease, venous thromboembolism
Review practical issues with use of HT for treatment of symptoms and prevention of osteoporosis
Describe a case: extended use of HT
Up to date OBGYNs can change the conversation, thereby helping our patients make good choices regarding HT 4

5. Abbreviations HT = hormone therapy ET = estrogen therapy
CE = conjugated equine estrogen,E2=estradiol
EPT = combination estrogen-progestin therapy
VMS= vasomotor symptoms
CHD= coronary heart disease
VTE= venous thromboembolism
= Women’s Health Initiative (WHI)
==North American Menopause Society (NAMS)

6. Vasomotor Symptoms (VMS)
Spontaneous sensations of warmth, usually felt on chest, neck and face
‘hot flashes’ , ‘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

7. 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 years
Sobering observation for symptomatic women
Important for decision making re treatment
EW Freeman, et al. Obstet Gynecol 2011
HD Nelson. Lancet 2008

8. Treatment of VMS Appropriate when VMS
Disrupt daytime activities and/or sleep
Impair quality of life
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

9. Hormone Therapy Clear Controversial VMS: most common indication for HT
10/11/2019
Hormone Therapy
Clear
VMS: most common indication for HT
HT’s efficacy in treating VMS well-established
Controversial
Our understanding of HT’s safety….

10. WHI: Women’s Health Initiative
10/11/2019
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
CE/MPA v. placebo: N ~ 17,000 , stopped Summer ’02, mean follow-up 5.2 years
CE v. placebo: N ~ 11,000 , stopped Spring ’04, mean follow-up 6.8 years
Writing Group WHI. JAMA 2002
WHI Steering Committee. JAMA 2004

11. EPT: Breast Cancer 26%* Invasive Breast Cancer Follow-Up Year
10/11/2019
EPT: Breast Cancer
Invasive Breast Cancer
0.03
26%*
E+P
Estrogen + Progestin
0.02
Placebo
Kaplan-Meier
Cumulative Hazard
Placebo
0.01 1 2 3 4 5 6 7
Follow-Up Year
*95% nominal CI Hazard Ratio = 1.26 ( )
Adapted from: Writing Group WHI. JAMA 2002

12. EPT: Coronary Heart Disease (CHD)
10/11/2019
EPT: Coronary Heart Disease (CHD)
Coronary Heart Disease
Initially, no analysis by age/years
post-menopause presented…
0.03
29%*
E+P
0.02
Placebo
Kaplan-Meier
Cumulative Hazard
0.01
Estrogen + Progestin
Placebo
Follow-Up Year
Hazard Ratio = 1.29
*Statistically significant based on 95% nominal CI on Hazard Ratios
Adapted from: Writing Group WHI. JAMA 2002

13. EPT: Pulmonary Embolism
10/11/2019
EPT: Pulmonary Embolism
Pulmonary Embolism
0.03
Estrogen + Progestin
113%*
Placebo
0.02
Kaplan-Meier
Cumulative Hazard
Only oral HT assessed
0.01
E+P
Placebo 1 2 3 4 5 6 7
Follow-Up Year
*95% nominal CI Hazard Ratio = 2.13 ( )
Adapted from: Writing Group WHI. JAMA 2002

14. EPT & Colorectal Cancer, Hip Fracture
10/11/2019
EPT & Colorectal Cancer, Hip Fracture
Colorectal Cancer
Hip Fracture
0.03
0.03
37%*
34%*
0.02
0.02
Kaplan-Meier
Cumulative Hazard
Placebo
Cumulative Hazard
Kaplan-Meier
Placebo
0.01
0.01
E+P
E+P 1 2 3 4 5 6 7 1 2 3 4 5 6 7
Follow-up Year
Placebo
Estrogen + Progestin
*Statistically significant based on 95% nominal CI on Hazard Ratios
Adapted from: Writing Group WHI. JAMA 2002

15. WHI EPT Study: Findings at Early Interruption Summer 2002
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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

16. WHI ET Initial Findings: Summary as of 2004
10/11/2019
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:

17. WHI’s Impact on Use of HT in US Women
10/11/2019
WHI’s Impact on Use of HT in US Women
Since 2002, use of HT has decreased substantially
Many clinicians, including OB/GYNs, remain reluctant to treat women with bothersome menopausal symptoms
Many symptomatic women not treated…
PI Jewett, et al. Obstet Gynecol 2014
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: 18

19. WHI: 13- and 18-Year Follow-up: EPT and ET…
10/11/2019
WHI: 13- and 18-Year Follow-up: EPT and ET…
JE Manson, et al. October, 2013 & September 2017

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

21. EPT and Elevated Risk of Breast Cancer
What does an 1.28 HR for breast cancer
mean?
<1 additional case per 1,000 EPT users annually
can be attributed to HT (WHI). Per WHO: ‘rare’
Elevated risk with EPT slightly higher than that seen with one daily glass of wine; less than with 2 daily glasses (Nurses Health Study)
Breast cancer common with or without use of HT
Only 1 in 5 breast cancers occurring in women using EPT can be attributed to HT (WHI)
JE Manson, et al WY Chen, et al. 2011

22. EPT Hazard Ratios (HRs): All-cause mortality: 1.02 (NS)
Risk of All-cause Years Cumulative f/u in Participants OVERALL (all ages at randomization)
EPT Hazard Ratios (HRs):
All-cause mortality: 1.02 (NS)
ET Hazard Ratios:
All-cause mortality: 0.94 (NS)
WHI recruited women age years--
Age stratified results…
JE Manson, et al. JAMA September 2017

23. All-cause Pooled (EPT+ET) Mortality Hazard Ratios at 18 Years Cumulative f/u by Age at Randomization
1.03
60-69 years
0.98
50-59 years
0.89
Risks with age at randomization
JE Manson, et al. JAMA September 2017

24. HT, CHD and the ‘Timing Hypothesis’
If initiated early in the menopausal transition, HT does not increase coronary heart disease risk
May reduce morbidity/mortality if initiated early
‘Early’: Age years, or < 10 years after menopause onset
HT increases CHD risk if initiated later
Timing hypothesis may also apply to type II diabetes and dementia
J Hsia. Arch Int Med JE Rossouw. JAMA RI Pereira, et al. JCEM 2015
JE Manson. N Eng J Med 2007 S Toh. Annals Int Med 2010 B Imtiaz. Neurology 2017
Stram DO. Menopause 2011 HN Hodis,. N Engl J Med 2016
MA Allison, JE Manson. Editorial. Menopause P Tuomikoski. Obstet Gynecol 2014

25. Treatment of Menopausal Symptoms: Practical Issues
Compounded bioidentical HT
HT/SERM combination therapy
Transdermal vs. oral ET, and risk of VTE
One clinician’s approach to HT initiation, continuation, discontinuation
A case: extended use of HT…

26. Compounded Bioidentical Hormone Therapy
Estimated 2.5 million current users
Use propelled by post-WHI confusion/fear, and 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

27. 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
ACOG and NAMS Recommend against using
Compounded HT unless compelling
reason present
JV Pinkerton, N Santoro. Menopause 2015 ; AM Kaunitz, JD Kaunitz. Menopause 2015; M Gass, et al. Menopause 2015

28. Alternatives to Systemic Progestin when a Uterus is Present
10/11/2019
Alternatives to Systemic Progestin when a Uterus is Present
CE 0.45mg + bazedoxifene 20mg tablets indicated to treat vasomotor symptoms and to prevent osteoporosis in menopausal women with an intact uterus
Contraindications/warnings similar to those for conventional EPT
Less bleeding than with EPT
In contrast with EPT, does not ↑ mammographic breast density
LNG IUD (smaller or larger) can be used off-label for endometrial protection in women taking ET
JV Pinkerton. JCEM JA Harvey, JV Pinkerton. Menopause 2013
H Depypere, P Inki. Climacteric 2015 29

29. EPT: Pulmonary Embolism
10/11/2019
EPT: Pulmonary Embolism
Pulmonary Embolism
0.03
Estrogen + Progestin
113%*
Placebo
0.02
Kaplan-Meier
Cumulative Hazard
Oral estrogen used in WHI
- ↑ hepatic production of clotting factors
- transdermal estradiol does not ↑ clotting factors
0.01
E+P
Placebo 1 2 3 4 5 6 7
Follow-Up Year
*95% nominal CI Hazard Ratio = 2.13 ( )
Writing Group WHI. JAMA 2002 30

30. Risk of VTE: Is Transdermal Estrogen Safer than Oral?
No randomized trial data comparing benefits and risks
7 observational studies: VTE risk increased with oral, but not with transdermal ET
Given consistency and biologic plausibility of observational data, reasonable to counsel patients that transdermal estrogen safer re risk of VTE
Transdermal route particularly appropriate when obesity or other risk factors for VTE present
Appropriate also for women with hypertriglyceridemia
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

31. Start HT using standard dose of estrogen
Initiating HT in Symptomatic Young/Recently Menopausal women: One Clinician’s Approach (I)
Start HT using standard dose of estrogen
Oral estradiol (E2) 1 mg; Oral conjugated equine estrogen (CE) mg
Transdermal (TD) E mg patch
For overweight/obese women, smokers and other women with ↑ risk VTE/CVD, consider TDE2
After VMS have resolved for several years on initial dose of estrogen, encourage trial of lower dose
If VMS or loss of sense of wellbeing occur on the lower dose, patients can resume prior higher dose without an office visit
AM Kaunitz. Menopause June 2014.

32. One Clinician’s Approach (II)
When patient has been using HT with a low dose of estrogen (0.5 mg oral E2, mg CEE, , mg TDE2) for several years, and reports no recent VMS:
If patient not at elevated risk for osteoporosis, encourage discontinuing systemic HT
Patient can restart HT if bothersome VMS or loss of sense of wellbeing recur
Lowering the dose of or stopping systemic HT can result in symptomatic VVA/GSM; start vaginal ET if appropriate
AM Kaunitz. Menopause June 2014.

33. One Clinician’s Approach (III)
If patient at ↑ risk for osteoporosis (e.g. low BMI), discuss pros/cons of long-term/indefinite use of low dose ET with continuous or intermittent P endometrial suppression
If progestin used intermittently, proactive endometrial surveillance appropriate
Regular vaginal ultrasound assessment of endometrial thickness
Prompt assessment of any spotting/bleeding appropriate in all menopausal women
AM Kaunitz. Menopause June 2014.

34. Case: When is Extended Use of HT Appropriate?
62 yo woman, BMI 21, returns for well woman visit
Prior hysterectomy, age 42 for uterine fibroids
Due to bothersome VMS, began oral estrogen therapy in her early 50s
Maternal history of hip fracture (age 76 years)
Recently took 3-week cruise, leaving estrogen tablets at home
Noted no hot flashes off estrogen

35. She asks: Should she continue ET?
VMS no longer a concern for this 62 yo woman. However…

36. Her Risk For Osteoporosis is Elevated
Low BMI; Maternal hip fx
Estrogen effective in preventing osteoporosis and fractures
Most estrogen formulations/doses FDA- approved for prevention of osteoporosis
Standard and low doses effective
NAMS. HT Position Statement. Menopause 2017.
Kaunitz AM. Clinical Obstet Gynecol 2018

37. Osteoporosis Often Not Viewed as Preventable…
Many women would prefer to avoid
a diagnosis of osteoporosis, entailing long term treatment with bisphosphonates or other bone agents
Once VMS resolved, main indication for systemic HT is prevention of osteoporosis
Kaunitz AM. Clinical Obstet Gynecol 2018

38. Use of HT to Prevent Osteoporosis: Clinical Considerations
Use of HT for this indication more appropriate in higher-risk women (e.g. low BMI, +FH)
If osteoporosis prevention the only indication for use, lower than standard dose HT appropriate
Faster loss of BMD after stopping HT than with bisphosphonates
Given EPT’s less favorable safety profile, long-term use of ET to prevent osteoporosis more appropriate than EPT; likewise, transdermal preferred when HT used in older menopausal women
NAMS. HT Position Statement. Menopause Kaunitz AM. Clinical Obstet Gynecol 2018

39. She chooses to continue low dose transdermal ET…
Follow-up of Case
After her cruise (age 62), she chose to continue ET for skeletal health reasons, switching to mg estradiol patch
DXA at age 65:
Lumbar Spine: T= -0.8
Femoral neck: T= -0.2
She is now age 71
BMI now 22; BMD remains normal
She chooses to continue low dose transdermal ET…

40. Notice Received From Insurance Company (72 yo patient on 0
Notice Received From Insurance Company (72 yo patient on mg estradiol patch)
“Your patient is at least 65 years old and has evidence for either an estrogen containing preparation. Estrogen containing preparations should be avoided in older women …“
Insurance companies interpret American Geriatric Society ‘Beers List’ as indicating they should not reimburse for any systemic HT in women age 65+ years
American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults: The American Geriatrics Society 2012 Beers Criteria Update Expert Panel J Am Geriatr Soc 2012; 60 (4):

41. Use of HT in Older Menopausal Women: ACOG and NAMS Guidance
“…ACOG recommends against routine discontinuation of systemic estrogen at age 65 years. As with younger women, use of HT and estrogen therapy should be individualized based on each woman’s risk–benefit ratio and clinical presentation.”
NAMS 2017 HT Position Statement: “The recommendation to use the Beers criteria to routinely discontinue systemic hormone therapy after age 65 is not supported by data”
ACOG. Practice Bulletin 141. Obstet Gynecol January, 2014.
The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24(7): Available at no charge: menopause.org

42. Systemic HT: appropriate to initiate for
In summary, regarding evidence on HT, the pendulum is swinging…
Well informed OB/GYNs can change the conversation, removing fear from discussions re HT, and help women 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

43. Clinical Expert Series
Additional Information
Clinical Expert Series
Management of Menopausal Symptoms
Andrew M. Kaunitz, MD, and JoAnn E. Manson, MD, DrPH
Obstet Gynecol October 2015; 126: 859–-876
The 2017 Hormone Therapy Position Statement of the North American Menopause Society. Available at no charge: Menopause.org
Menopause 2017: Jul;24:
Thank you!