Update on Menopausal Therapy: No new bad news

Some new good newsSome new options

Kirtly Parker Jones MD

Dr. Jones Has the Following Disclosures

She is a reproductive endocrinologistShe is a post menopausal femaleShe has an unreasonable regard for

the ovaries of all speciesShe has no financial conflicts to

disclose

Objectives: participants will be able to

counsel patients regarding risks of hormone therapy

counsel patients regarding new FDA approved drugs for libido and dyspareunia

discuss tissue specific estrogenic mixed agonist/antagonist compounds with patients (and that is a mouthful as well as a cognitive challenge)

70 Years of HRT Research

Case series in the 40’s and 50’s Retrospective studies in the 60’s and 70’s Prospective cohort studies in the 70’s and 90’s Prospective Randomized Trials in 90’s and

2000’s New steroids for menopausal symptoms 2010-

We think we know what we thought we knew

HRT is highly effective for menopausal vasomotor flushes ET is the highly effective treatment for

symptomatic vaginal atrophy HRT/ET is very effective in decreasing the

risk of postmenopausal osteoporotic fractures

We think we know what we thought we knew

HRT/ERT attributed thromobembolic events are rare (1/1000/year)

HRT attributed breast cancers are rare (1/1000/year) and no increase with ERT in WHI

HRT/ET attributed coronary artery events are NOT increased in the original target population of postmenopausal women (the symptomatic young women who we treated)

Risk of Death from breast cancer: HT users v Non users.

489,104 Finnish Women taking HT (E or E+P) 1994-2009 1578 women taking HT with breast cancer were followed from

diagnosis to death Risk of death in HT users diagnosed with breast cancer

compared to non HT users. Risk of death from breast cancer non users 1 in 10 Risk of death in HT users 1 in 20

Mikkola et al. Menopause, Vol. 23, No. 11, 2016

What are CLEARLY (mostly) symptoms related to estrogen withdrawal?

Hot flushes/night sweats Vaginal Dryness

Alternatives for Hot Flushes

Progestins decrease hot flushes by about 50% Progesterone (oral micronized progesterone) has the

advantage of being a gaba agonist – promotes normal sleep and decreases sleep apnea)

SSRI/SNRIs work a little bit Soy, black cohosh, chinese herbs don’t really work better

than placebo Placebo works (30% reduction for 30% over 3 months)

NAMS Position Statement 2015: Nonhormonal therapy. Menopause.org

Progesterone and Sleep

Progesterone improves sleep quality in menopausal women directly as a gaba agonist

Progesterone does NOT act as a sedative hypnotic –it promotes “normal” sleep

Progesterone decreases sleep disordered breathing Progesterone decreases hot flushes (not as much as

estradiol…)

Caufriez A et al. JCEM. April 2011Spark MJ. Maturitas 2012

Gabapentin ER and Hot Flushes

p<.0001 p<.0001 p<.0035

Pinkerton et al. Menopause 2012. Abstract presented NAMS Oct 2012

Paroxetine 7.5mg for Hot Flashes…better?

0

2

4

6

8

10

12

Baseline 4 weeks 12 weeks

Placeboparoxetine

P<.01

P<.01

Data From FDA approved advertisement in Obstetrics and Gynecology

New Selective Estrogen Receptor Modulators

Bazedoxifene combined with conjugated estrogens “Tissue Selective Estrogen Complex” an industry

invented name for a combination agonist/antagonist Decreased vasomotor flushes Improved vaginal atrophy Improved bone density NO PROGESTINS: “low rate of endometrial hyperplasia”

(less than 1%)

Pinkerton JV et al. JCEM 2013

Pinkerton JV et al. JCEM 2013

Agonist/Antagonist: TSEC

HRT and Sexual FunctionNew Dosing

HRT/ET is very effective in treating dyspareunia due to vaginal atrophy

For otherwise asymptomatic women, vaginal estrogens given twice a week treats atrophy without significant systemic side effects or risks

10mcg pill, ½ gram cream is new effective dosing

HRT/ET is not recommended or effective for other problems of sexual function

Ospemifene (SERM)

FDA approved daily 60mg for symptomatic vaginal atrophy Improved vaginal thickness, decreased atrophy Slightly increase incidence of hot flushes (6% v 3% in

placebo) Slight increase in endometrial thickness which was the

endometrial safety monitoring Advertised to women as the “First Non-Hormonal Therapy

for vaginal dryness” [big fat endocrine fib]

Portman DJ et al. Menopause, June 2013

Prasterone for vaginal atrophy

DHEA (dehydroepiandrosterone) in vaginal insert once daily

RX “Intrarosa” FDA approved November 2016 for treatment of moderate to

severe pain during intercourse caused by vaginal atrophy Your local compounding pharmacy would like to make it for

you…check $$

ET and WHI – no fuss

No increase in ischemic heart disease (in fact a slight decrease in women 50-60)

30% DECREASE in breast cancer (not statistically significant)

1/1000 attributable risk of stroke (but only in 60-70 year olds, not in “young” women)

HRT for women with hot flushes: QOL

Finnish menopause researchers 72 women with hot flushes, 78 without Randomized to HRT or placebo HRT improved hot flushes in those who had them

Estradiol therapy improves sleep, anxiety and fears, and memory in relation to alleviation of hot flashes. Did not improve these sx in women who didn’t have hot flushes

Savolainen-Peltonen et al: Menopause, Vol. 21, No. 7, 2014

“Hot Flushes Won’t Kill You”

Sort of true, but persist for an average of 7 years Women with hot flushes have different cardiovascular risks

than women who don’t have hot flushes

©2010The North American Menopause Society.  Published by Lippincott Williams & Wilkins, Inc. 2

History of hot flashes and aortic calcification among postmenopausal women.Thurston, Rebecca; Kuller, Lewis;  MD, DrPH; Edmundowicz, Daniel; MD, MS; Matthews, Karen

Menopause. 17(2):256‐261, March 2010.

HRT Risks: Numbers for the PatientNew HRT Starts in women 50-60

One extra blood clot per 2000 women per year One extra breast cancer detected per 2000 women per year (no increase in estrogen only) No differences in deaths over 5 years between

women who take MHT and women who don’t

HRT: Numbers for the PatientLong term users

The data regarding blood clots and myocardial infarction (from WHI and HERS) suggests that the risks are clustered in the first few years. Long term studies do not suggest increased risks increasing over time

One extra breast cancer detected per 100 women per 10 years of use

HRT and Mortality

WHI trials consistent with observational studies indicating that HRT may reduce total mortality when initiated soon after menopause

30% reduction over course of study when data from WHI ET and HRT combined for women initiated before 60

(no significant difference over a lifetime, though)

Mayo Clinic Cohort Study ofOophorectomy and Aging

1091 bilat1274 unilat2383 controls

Only for benignConditions

Only prior to menopause

Rivera et al, Menopause, 2009

2010 Endocrine Society Statement:JCEM Supplement July 2010

2010 Endocrine Society Scientific Statement:JCEM Supplement July 2010

HRT: NAMS 2016 Position Statement

Change from: smallest dose for shortest time To Risk: benefit ratio is very different from patient to patient

and large long term studies do not show clinically significant increase in risks

Decisions should be made individually for each patient (this takes time and an informed patient and physician)

SEE NAMS website for clinical tools for patients and physicians

HRT after 65: NAMS position statement

“Use of HT should be individualized and not discontinued solely based on a woman’s age. The decision to continue or discontinue HT should be made jointly by the woman and her healthcare provider.”

Menopause, Vol. 22, No. 7, 2015

Recommended Reading:

Postmenopausal Hormone TherapyAn Endocrine Society Scientific StatementJCEM Supplement July 2010

North American Menopause Society:menopause.org Click “publications” and go to “position statements”:2016 Hormone Therapy2015 Non Hormonal Therapy2014 Algorithm and mobile app for menopausal symptom management: a clinical decision support tool

Question

A 48 year old woman who had a hysterectomy for fibroids when she was 35 now experiences hot flushes (8 per day with sleep disturbances). The most appropriate approach would be:

A. Supportive therapy with reassurance that hot flushes will probably go away in 6 months

B. Discussion regarding risks and benefits of Estrogen and progestin therapy with option of Rx.

C. Discussion of regarding risks and benefits of Estrogen therapy with option of RX

D. Discussion regarding risks and benefits of Tissue Specific Estrogen Complex with option of RX Answer C