leighann frattarelli, md, mph february 3,...

LeighAnn Frattarelli, MD, MPH

February 3, 2018

State North American Menopausal Society (NAMS)’s position on hormone therapy

Be familiar with newer treatments for ◦ Vasomotor symptoms of menopause (VMS)

◦ Genitourinary symptoms of menopause (GSM)

.

75 to 80 percent of menopausal women in the US

Study of Women across the Nation (SWAN):

Median total VMS duration was 7.4 years, persisting

median of 4.5 years after the final menstrual period

(FMP.)

Premenopausal or early perimenopausal when first

experienced VMS longest total duration (>11.8 years.)

Probability of VMS: Average observed probability of VMS at each time point within each trajectory subgroup. No factors were included in the model.

From: Tepper PG, Brooks MM, Randolph JF, et al. Characterizing the trajectories of vasomotor symptoms across the menopausal transition. Menopause 2016 23:1067.

Key points from the

2017 Position Statement of

The North American Menopause Society

© 2017

Menopause. 2017 Jul;24(7):728-753.

The 2017 NAMS Hormone Therapy Position

Statement has been endorsed by

Academy of Women’s Health

American Association of Clinical

Endocrinologists

American Association of Nurse Practitioners

American Medical Women’s Association

American Society for Reproductive Medicine

Asociación Mexicana para el Estudio

del Climaterio

Association of Reproductive Health

Professionals

Australasian Menopause Society

Chinese Menopause Society

Colegio Mexicano de Especialistas

en Ginecologia y Obstetricia

Czech Menopause and Andropause Society

Dominican Menopause Society

European Menopause and Andropause Society

German Menopause Society

Groupe d’études de la ménopause

et du vieillissement Hormonal

HealthyWomen

Indian Menopause Society

International Menopause Society

International Osteoporosis Foundation

International Society for the Study of Women’s Sexual

Health

Israeli Menopause Society

Japan Society of Menopause and Women’s Health

Korean Society of Menopause

Menopause Research Society of Singapore

National Association of Nurse Practitioners

in Women’s Health

SIGMA Canadian Menopause Society

SOBRAC and FEBRASGO

Società Italiana della Menopausa

Society of Obstetricians and Gynaecologists of Canada

South African Menopause Society

Taiwanese Menopause Society

Thai Menopause Society

The American College of Obstetricians and Gynecologists supports the value of this clinical document as an

educational tool, June 2017. The British Menopause Society supports this Position Statement.

No evidence to recommend discontinuation after age 65 if

indication remains and no contraindications

Breast cancer risk does not increase appreciably with short-

term use of estrogen-progestogen therapy and may be

decreased with estrogen alone

No increased risk of breast cancer in women who are BRCA-

positive on hormone therapy after risk-reducing bilateral salpingo-oophorectomy

© 2017

Benefits are likely to outweigh risks for

symptomatic women who initiate hormone therapyage <= 60 years

or within10 years of menopause onset

(Level I)

© 2017

The 2017 hormone therapy position statement of The North American Menopause Society.

Menopause. 2017;24(7):728-753.

Low-dose vaginal estrogen therapy (ET)◦ Minimal systemic absorption

Blood levels in postmenopause range

◦ Based on limited data, minimal risk for recurrence of breast cancer (Level II)

For survivors of breast cancer with bothersome genitourinary

syndrome of menopause symptoms, low-dose vaginal ET

may be an option◦ After a failed trial of nonhormone therapies

◦ In consultation with an oncologist

◦ Concern even with low-dose vaginal ET for women on aromatase inhibitors

because of suppressed estradiol levels (Level III)

© 2017

The 2017 hormone therapy position statement of The North American Menopause Society.

Menopause. 2017;24(7):728-753.

Randomized, double-blinded, placebo-controlled, multicenter trial

Test whether estrogen-replacement therapy slows progression of atherosclerosis when begun within 36 months of the last menstrual period

727 KEEPS participants: 42 to 58 years old (mean, 52.7 years) and within 36 months of the last menstrual period at enrollment

Many favorable benefits (results beginning 2012)

The women with symptoms appeared to have quality-of-life benefit and an overall favorable benefit:risk ratio

Transdermal estrogen, but not oral, associated with improvement in sexual function scores

KEEPS Taylor HS, Tal A, Pal L, et al. Effects of oral vs transdermal estrogen therapy on sexual function in early postmenopause: ancillary study of the Kronos Early Estrogen Prevention Study (KEEPS) [published online ahead of print August 28, 2017]. JAMA Intern Med.

Prescription rates for custom-compounded bioidentical hormones approach those of US Food and Drug Administration (FDA)-approved MHT prescriptions

Importance of physician and patient education about the differences

Bazedoxifene: estrogen agonist and antagonist. Agonist on bone and antagonist effects on the endometrium.

Duavee FDA indicated for postmenopausal women for treatment of moderate to severe vasomotor symptoms and prevention of osteoporosis (2013)

Phase III Trials: Selective Estrogen, Menopause and Response to Therapy (SMART) Progams:

Significantly reduced number of hot flashes by 74% (47% placebo) and severity by 39% (13% placebo)

Increased BMD at hip and spine at 1 and 2 years

Common Side Effects (5-9%)

◦ Muscle spasm

◦ Nausea

◦ Diarrhea

◦ Upset stomach

◦ Abdominal pain

◦ Throat pain

◦ Dizziness

◦ Neck Pain

Benefits◦ Similar rates of amenorrhea as placebo (87%)

◦ Lower rates of breast pain compared to EPT (5-8% vs 20-24%)

◦ No increase in breast density

Differential effects of menopausal therapies on the endometrium. MirkinS, et al; Menopause. 2014;21(8):899

50% to 80% of North American women use nonhormonal therapies for VMS at midlife

©2015

North American Menopause Society. Menopause. 2015;22(11).

North American Menopause Society. Menopause. 2015;22(11).

FDA-approved 7.5mg paroxetinesalt (Brisdelle)

Other SSRIs and SNRIs yielding significant VMS reductions in large RCTs

Gabapentin and pregabalin

©2015

FDA approved 2013

Paroxetine 7.5mg a day

Up to 60% decrease in hot flashes

Not for use with Tamoxifen: Strong inhibitor in CDYP2D6

Large RCTs show significant VMS reductionswith—Paroxetine—Escitalopram—Citalopram—Venlafaxine—Desvenlafaxine

North American Menopause Society. Menopause. 2015;22(11). ©2015

North American Menopause Society. Menopause. 2015;22(11).

Start lowest dose first; titrate up to effect, tolerance

When stopping, taper therapy over 1-2 wk

Re-evaluate carefully and regularly (eg, every 6-12 mo)

©2015

Level II evidence suggests these may be beneficial Weight loss Mindfulness-based stress

reduction S-equol derivative of soy Stellate ganglion block

North American Menopause Society. Menopause. 2015;22(11). ©2015

Do not recommend

North American Menopause Society. Menopause. 2015;22(11). ©2015

Level I evidence shows these are unlikely to alleviate VMS, although they may have other health benefits Exercise Yoga Paced respiration Acupuncture

Vaginal lubricants and moisturizers— Should be considered first-line

therapies— Over-the-counter products can

significantly decrease or eliminate symptoms for many women

Herbal products have not demonstrated any beneficial effect in clinical trials

North American Menopause Society. Menopause. 2013;20(9):886-904. ©2013

North American Menopause Society. Menopause. 2013;20(9):886-904.

US FDA-approved vaginal ET products

— Estradiol vaginal cream (Estrace)a:

— Conjugated estrogen vaginal cream (Premarin)a

— Estradiol vaginal ring (Estring)

— Estradiol acetate vaginal ring (Femring)b

— Estradiol hemihydrate vaginal tablet (Vagifem) and generic

Generic Estradiol vaginal cream approved 2017

©2013

aMultiple doses available; use low dose for VVA.bThis product delivers systemic levels of estradiol.

Typically provides greater benefit than nonhormonal interventions

Preferred mode of delivery when vaginal symptoms are the only complaint

Shown in clinical trials to be more effective than systemic oral ET

May also reduce risk of urinary urgency and recurrent urinary tract infections

North American Menopause Society. Menopause. 2013;20(9):886-904. ©2013

Ospemifene: Osphena

North American Menopause Society. Menopause. 2013;20(9):886-904. ©2013

Nonhormonal selective estrogen-receptor modulator (SERM)

Only SERM approved in the United States to treat moderate to severe dyspareunia

Ospemifene: Effectiveness

North American Menopause Society. Menopause. 2013;20(9):886-904. ©2013

Two 12-week studies showed improvements with daily use (60 mg) in— Vaginal maturation index — Vaginal pH— Most bothersome symptom (vaginal

dryness) 52-week extension study showed

sustained improvements with no casesof venous thromboembolism, endometrial hyperplasia, or carcinoma

Ospemifene: Adverse effects

North American Menopause Society. Menopause. 2013;20(9):886-904. ©2013

Vasomotor symptoms most common

Prescribing information contains precautions similar to those for estrogens and other SERMs

Data in women with breast cancer or at high risk of developing breast cancer are lacking

Intracrinology: Aromatization at the cellular level to estrone and estradiol

At 12 weeks, significant increase from baseline in serum DHEA, testosterone, and estrone, but not estradiol levels

DHEA, estradiol, estrone, and testosterone remained within the range of an average postmenopausal women [76].

Approved by FDA Nov 2016

Vaginal discharge most common side effect

12 week trials 665 women

5.7% vaginal discharge Intrarosa vs. 3.7% placebo

Non-comparative study 521 participating: 74 cases of vaginal discharge (14.2 percent)

Comparison of intravaginal 6.5mg (0.50%) prasterone, 0.3mg conjugated estrogens and 10μg estradiol on symptoms of vulvovaginal atrophy

Concluded AT LEAST as effective as 0.3mg vaginal CEE and 10mcg estradiol

◦ J Steroid Biochem Mol Biol. 2017 Nov;174:1-8. doi: 10.1016/j.jsbmb.2017.03.014. Epub 2017 Mar 18.

Effect of Intravaginal Prasterone on Sexual Dysfunction in Postmenopausal Women with Vulvovaginal Atrophy.

Randomized placebo controlled trial: all the six domains of the Female Sexual Function Index (FSFI) improved over placebo (from P = 0.047 to 0.0005)

Labrie F, et al; Journal of Sexual Function 2015

Overall satisfaction with sexual life significantly improved (p < 0.001).

Seventeen (85%) out of 20 (26%) women, not sexually active because of VVA severity at baseline, regained a normal sexual life at the 12-week follow-up.

Significant improvement in each VVA symptom (p < 0.001) and in quality-of-life evaluation, both for the scores in the physical (p = 0.013) and mental (p = 0.002) domains.

Salvatore, S. Climacteric, 2015

Significant improvement in VVA symptoms (vaginal dryness, burning, itching and dyspareunia) (P<0.0001)

VHI scores were significantly higher at T1 (P<0.0001)

Overall, 91.7% of patients were satisfied or very satisfied with the procedure and experienced considerable improvement in quality of life (QoL)

No adverse events due to fractionalCO2 laser treatment occurred.

Perino A. Maturtis, 2015

Proof of Concept Study

Funded by the Medical Research Council and the National Institute for Health Research (NIHR)

Significantly reduced menopausal flushing by 73% during a four-week treatment period