men.ht..8.7.18 helping our menopausal patients make sound ... · compounded bioidentical hormone...

Andrew M. Kaunitz MD, FACOG, NCMPUniversity of Florida Term Professor and Associate Chairman

Department of Obstetrics and GynecologyUniversity of Florida College of Medicine ‐ Jacksonville

Medical Director, and Director of Menopause & GYN Ultrasound Services UF Southside Women’s Health Specialists

men.ht..8.7.18

Helping Our Menopausal Patients Make Sound Decisions

Regarding Hormone Therapy

Andrew M. Kaunitz, M.D.Menopause‐related Disclosures

Clinical Trials(Funding to University of Florida Research Foundation):

• Allergan• Bayer• Endoceutics• TherapeuticsMDAdvisory Boards ● AMAGConsultant● 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

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…

● 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

Learning Objectives II:

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)

Vasomotor Symptoms (VMS)

● 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

● 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

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 me– Mean duration bothersome VMS >10 years

o Sobering observation for symptomatic women

o Important for decision making re treatment

EW Freeman, et al. Obstet Gynecol 2011HD Nelson. Lancet 2008

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

o numerous randomized, placebo‐controlled trialso 75% reduction in VMS frequencyo significant reduction in VMS severityo oral and transdermal estrogen have similar efficacy

● Progestin therapy, including DMPA and megestrol– also effective in treating VMS

HD Nelson. JAMA 2004 AH MacLennan, et al. Cochrane Database Syst Rev 2004HD Nelson. Lancet 2008

Hormone Therapy

● Clear– VMS: most common indication for HT

– HT’s efficacy in treating VMS well‐established

● Controversial– Our understanding of HT’s safety….

WHI: Women’s Health Initiative

● Multicenter, double‐blind, placebo‐controlled trial of women age 50‐79 years at baseline, designed to assess HT’s impact on cardiovascular disease

● Mean age at screening 63‐64 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

Follow-Up Year

EPT: Breast Cancer

0

0.01

0.02

0.03

Cum

ulat

ive

Haz

ard

Invasive Breast Cancer

E+P

0 1 2 3 4 5 6 7

26%*

*95% nominal CI Hazard Ratio = 1.26 (1.00-1.59)

Kap

lan-

Mei

er

Placebo

Adapted from: Writing Group WHI. JAMA 2002

PlaceboEstrogen + Progestin

EPT: Coronary Heart Disease (CHD)C

umul

ativ

e H

azar

d

Coronary Heart Disease


Placebo

0

0.01

0.02

0.03

29%* E+P

0 2 4 6

Follow-Up YearHazard Ratio = 1.29*Statistically significant based on 95% nominal CI on Hazard Ratios

Kap

lan-

Mei

er


Initially, no analysis by age/years post-menopause presented…

Follow-Up Year

EPT: Pulmonary Embolism

0

0.01

0.02

0.03

Cum

ulat

ive

Haz

ard

Pulmonary Embolism

0 1 2 3 4 5 6 7

113%*


Kap

lan-

Mei

er

Placebo

E+P



Only oral HT assessed

EPT & Colorectal Cancer, Hip Fracture

0

0.01

0.02

0.03

Cum

ulat

ive

Haz

ard

Hip Fracture

0 1 2 3 4 5 6 7

Placebo

E+P

0

0.01

0.02

0.03

Cum

ulat

ive

Haz

ard

Colorectal Cancer

0 1 2 3 4 5 6 7

Placebo

E+P

37%* 34%*

*Statistically significant based on 95% nominal CI on Hazard Ratios

Follow-up Year

Kapl

an-M

eier

Kapl

an-M

eier



CVA

WHI EPT Study: Findings at Early Interruption Summer 2002

VTE/PEMI

Risks Benefits

Breast Cancer

FractureColon Cancer


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

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

PI Jewett, et al. Obstet Gynecol 2014

Many symptomatic women not treated…

WHI: 13- and 18-Year Follow-up: EPT and

ET…

JE Manson, et al. October, 2013 & September 2017

Risk of Breast Cancer @13 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

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 annuallycan 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. 2013 WY Chen, et al. 2011

Risk of All‐cause Mortality @18 Years Cumulative f/uin 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)

JE Manson, et al. JAMA September 2017

WHI recruited women age 50‐79 years‐‐Age stratified results…

All‐cause Pooled (EPT+ET) Mortality Hazard Ratios at 18 Years Cumulative f/u by Age at Randomization

JE Manson, et al. JAMA September 2017

50‐59 years0.89

60‐69 years0.98

70‐79 years1.03

Risks with age at randomization

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 50‐59 years, or < 10 years after menopause onset

– HT increases CHD risk if initiated later● Timing hypothesis may also apply to type II diabetesand dementia

J Hsia. Arch Int Med 2006 JE Rossouw. JAMA 2007 RI Pereira, et al. JCEM 2015JE Manson. N Eng J Med 2007 S Toh. Annals Int Med 2010 B Imtiaz. Neurology 2017Stram DO. Menopause 2011 HN Hodis,. N Engl J Med 2016MA Allison, JE Manson. Editorial. Menopause 2011 P Tuomikoski. Obstet Gynecol 2014

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…

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 approvedo Salivary testing often employed by MDs prescribing

compounded HT» Such testing does not correlate with

serum steroid levelsCompounded Progesterone cream often Rxed…

JV Pinkerton, N Santoro. Menopause 2015 ; AM Kaunitz, JD Kaunitz. Menopause 2015; M Gass, et al. Menopause 2015

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

ACOG and NAMS Recommend against using Compounded HT unless compelling

reason present

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 2014 JA Harvey, JV Pinkerton. Menopause 2013 H Depypere, P Inki. Climacteric 2015

Follow-Up Year

EPT: Pulmonary Embolism

0

0.01

0.02

0.03

Cum

ulat

ive

Haz

ard

Pulmonary Embolism

0 1 2 3 4 5 6 7

113%*


Kap

lan-

Mei

er

Placebo

E+P

Writing Group WHI. JAMA 2002

Oral estrogen used in WHI- ↑ hepatic production of clotting factors- transdermal estradiol does not ↑ clotting factors


Risk of VTE: Is Transdermal Estrogen Safer than Oral?

PY Scarabin, et al. Lancet 2003 M Canonico, Arterioscler Thromb Vasc Biol 2010 A Bergendal et al.; JA Simon et al. Menopause 2016C Renoux, et al. J Thromb Haemost 2010 C Renoux, et al. BMJ 2010L Laliberté, et al. Menopause 2011 RE Roach, et al. J Thromb Haemost 2012

● 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

Initiating HT in Symptomatic Young/Recently Menopausal women: One Clinician’s Approach (I)

● Start HT using standard dose of estrogeno Oral estradiol (E2) 1 mg; Oral conjugated equine estrogen (CE) 0.625 mg

o Transdermal (TD) E2 0.05 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.

One Clinician’s Approach (II)

●When patient has been using HT with a low dose of estrogen (0.5 mg oral E2, 0.3‐0.45 mg CEE, 0.0375, 0.025 mg TDE2) for several years, and reports no recent VMS: – If patient not at elevated risk for osteoporosis, encourage discontinuing systemic HToPatient can restart HT if bothersome VMS or loss of sense of wellbeing recur

o Lowering the dose of or stopping systemic HT can result in symptomatic VVA/GSM; start vaginal ET if appropriate


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


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 homeoNoted no hot flashes off estrogen

She asks: Should she continue ET?

●VMS no longer a concern for this 62 yowoman. However…

Her Risk For Osteoporosis is Elevated

– Low BMI; Maternal hip fx

– Estrogen effective in preventing osteoporosis and fractures oMost 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

Osteoporosis Often Not Viewed as Preventable…

Kaunitz AM. Clinical Obstet Gynecol 2018

• Many women would prefer to avoida 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

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 2017 Kaunitz AM. Clinical Obstet Gynecol 2018

Follow‐up of Case

●After her cruise (age 62), she chose to continue ET for skeletal health reasons, switching to 0.025 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…

Notice Received From Insurance Company (72 yo patient on 0.025 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 2012 J Am Geriatr Soc 2012; 60 (4): 616‐631.

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):728-753. Available at no charge: menopause.org

• 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 formost healthy women with bothersomeVMS who are <age 60, or within 10 years of menopause onset

In summary, regarding evidence on HT, the pendulum is swinging…

Clinical Expert SeriesManagement of Menopausal SymptomsAndrew M. Kaunitz, MD, and JoAnn E. Manson, MD, DrPHObstet Gynecol October 2015; 126:859–-876

The 2017 Hormone Therapy Position Statement of the North American Menopause Society. Available at no charge: Menopause.orgMenopause 2017: Jul;24:728-753

Additional Information

Thank you!

men.ht..8.7.18 helping our menopausal patients make sound ... · compounded bioidentical hormone...

Documents