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Hormone Therapy: No Sweat for Menopausal Symptoms

Nanette Santoro, MD

Professor and E Stewart Taylor Chair of Obstetrics and Gynecology

University of Colorado School of Medicine

Disclosures

– Stock Options: Menogenix, Inc

– Clinical Advisory Board: Astellas Pharma, Inc

Learning Objectives:

At the end of this lecture the learner is expected to:

– Enumerate the symptoms that are most likely to be 

relieved by hormone therapy

– Engage in shared decision making with patients 

regarding personal preferences and route of 

administration

– Manage patient expectations of therapy

– Initiate appropriate treatment 

Precision Medicine: NIH Definition

"an emerging approach for disease 

treatment and prevention that takes into 

account individual variability in genes, 

environment, and lifestyle for each person”

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Isn’t This What We’ve Been Doing All Along?

Balancing Benefits and Risks

The WHI is the best medical evidence we have to date concerning the risks of hormone therapy

The WHI was not designed to address the benefits of hormones for symptomatic women

We Need to Apply the Appropriate Tools for the Outcomes of Interest

FDA Approved HT

Estrogens

– Transdermal estradiol*

– Oral estradiol*

– Oral conjugated equine estrogens

– Oral estrone

– Vaginal estradiol*

– Estradiol sprays and gels*

Progestins

– Oral micronized progesterone*

– Vaginal progesterone*

– Oral medroxyprogesterone acetate

– Oral norethindrone

– Intrauterine levonorgestrel

*refers to compounds that are ‘bioidentical’

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FDA Approved HT

SERMS

– Ospemifene

– Raloxifene

– CEE/bazedoxifene

Other

– DHEA

The Seven Dwarves of Menopause:Which Are Caused by Menopause?

Which Can Be Relieved by Hormones?

SweatySleeplessBone‐dryGrumpyAnxiousDopeySexless

Benefits of Hormone Therapy

Unequivocal

– Hot flashes and night sweats

– Vaginal dryness

Probably Beneficial

– Poor sleep

– Adverse mood

Conflicting/Inadequate Data

– Sexual function

– Urinary incontinence

– Joint pains

– ‘Brain fog’

– Changes in body composition

– Skin dryness/wrinkling

The Road to Menopause

Normal ovarian reserveRegular 

•Reduced reserve

•At least 1 period/3mos

Skipped cycles

Menses 3‐11                   months apartProlonged 

Amenorrhea

Pre-MT Early MT Late MT

Median Age 47 Median Age 49

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Hot Flashes/Night Sweats

– Affect up to 85% of all women transitioning into 

menopause

– Worse/prolonged symptoms

– If menopause is surgical

– If transition is early/premature

– Interaction with sleep: night sweats 

Natural History of Hot FlashesTransition Stage % affected* Author

Premenopause 20‐45% Gold, 2006

Pre‐ to‐Early Perimenopause 25‐55% Gold, 2006

Early‐to‐Late Perimenopause 50‐80% Gold/Politi, 2008

Late Peri‐to‐Postmenopause 35‐75% Gold/Politi

Late Postmenopause (>5yr) 16‐44% Barnabei, Politi

References:  Barnabei V et al. Obstet Gynecol 2002; 100:1209‐18; Gold EB, et al, Am J Pub Health 2006; 96:1226‐35 ; Politi MC, et al. J Gen Intern Med 2008;23:1507–13.

Date of download: 2/28/2015Copyright © 2015 American Medical Association. All rights

reserved.

JAMA Intern Med. Published online February 16, 2015. doi:10.1001/jamainternmed.2014.8063

Duration of Menopausal Vasomotor Symptoms Over the Menopause Transition

Date of download: 2/28/2015Copyright © 2015 American Medical

Association. All rights reserved.

Persistence of Menopausal Vasomotor Symptoms Over the Menopause Transition

JAMA Intern Med. Published online February 16, 2015. doi:10.1001/jamainternmed.2014.8063

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Hot Flashes (and Vaginal Symptoms) in Hispanic Women By Country of Origin

Symptom PR(56)

Cuban(44)

DR(42)

CA(29)

SA(106)

White(142)

White vsHispanic

Within Hispanic

Vaginal dryness 17.9 25.0 38.1 58.6 31.4 21.1 0.029 0.003

Hot flushes 35.7 20.5 21.4 48.3 27.4 24.7 NS NS

‐uncomfortable 89.5 77.8 77.8 100 89.7 77.1 NS NS

‐upset 72.2 66.7 88.9 92.9 75 35.3 <0.0001 NS

‐embarrassed 68.4 66.7 66.7 85.7 75 35.3 <0.0001 NS

Trouble sleeping 66.1 36.4 64.3 51.7 45.3 50.7 NS 0.01

Green R Womens Health 2009; 5:127‐133 

All Hot Flash Outcomes Improve with HT

– Hot flash diaries: frequency and severity

– Objectively recorded hot flashes

– Night sweats

– Wakening after sleep onset (WASO)

– Hot Flash Interference

McLennan A, Cochrane Database Syst Rev 2004 Oct 18;(4):CD002978;Sood R, Int J Womens Health. 2014; 6: 47–57; Stuenkel C, JCEM 2015; 100: 3975‐4011

Vaginal Dryness/GSM

– Reported by 25‐57% of menopausal women

– Likely under‐treated

– Moisturizers and lubricants: little to no medical evidence

– FDA approved therapies:

– Estrogen (cream, pill, ring)

– Estradiol softgel [pending FDA approval]

– Ospemifene: ER beta agonist

– DHEA

(Hot Flashes and) Vaginal Symptoms in Hispanic Women By Country of Origin

Symptom PR(56)

Cuban(44)

DR(42)

CA(29)

SA(106)

White(142)

White vsHispanic

Within Hispanic

Vaginal dryness 17.9 25.0 38.1 58.6 31.4 21.1 0.029 0.003

Hot flushes 35.7 20.5 21.4 48.3 27.4 24.7 NS NS

‐uncomfortable 89.5 77.8 77.8 100 89.7 77.1 NS NS

‐upset 72.2 66.7 88.9 92.9 75 35.3 <0.0001 NS

‐embarrassed 68.4 66.7 66.7 85.7 75 35.3 <0.0001 NS

Trouble sleeping 66.1 36.4 64.3 51.7 45.3 50.7 NS 0.01

Green R Womens Health 2009; 5:127‐133 

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Scary FDA Labeling Persists for Vaginal Estrogen Products

WARNING: CARDIOVASCULAR DISORDERS, ENDOMETRIAL CANCER, BREAST CANCER and PROBABLE DEMENTIA 

– increased risk of:

– endometrial cancer (in a woman with a uterus who uses unopposed estrogens) 

– stroke, deep vein thrombosis (DVT), pulmonary embolism, myocardial infarction…invasive breast cancer…and increased risk of probable dementia in postmenopausal women 65 years of age and older 

Ospemifene and DHEA

– ER beta agonist SERM

– FDA approved for vaginal dryness/dyspareunia

– No endometrial stimulation

– May be effective against breast proliferation

– May be effective as bone antiresorptive

– 60mg daily, systemic dosing

– May require treatment for up to 6 months to fully appreciate efficacy

– 6.5mg nightly vaginal insert

– Indication: dyspareunia

– Minimal increase in serum E2 after 7 days (<2 pg/ml higher than PBO)

– Significant primary endpoint in 2 pivotal trials (most bothersome symptom related to dyspareunia) N=640

– No apparent endometrial stimulation

Bachmann 2010; 17: 480; Goldstein, Climacteric 2014; 17:173; Labrie, Climacteric 2011; 14:282; Labrie, Menopause 2015; Dec 28 

Mood, Sleep, Cognition

– May improve with HT

– Specific treatments are appropriate for

– Adverse mood (15‐20%)

– Moderate to severe depression: antidepressants

– Persistent poor sleep (30‐60%): hypnotics, CBT 

– Cognitive issues: may respond to low dose CNS stimulants 

Soares Menopause 2014; 21:198; Kravitz Ob Gyn Clin North Am 2011; 38: 567; Epperson Menopause 2011; 18:542; Psychpharmacology 2015; 232:3091

And the Punch Line…

Women with intolerable menopausal symptoms may wish to weigh the 

benefits of symptom relief against the small absolute risk of harm arising 

from short‐term use of low‐dose HT, provided they do not have specific 

contraindications.

Marjoribanks J Cochrane Database Syst Rev. 2017 Jan 17;1:CD004143

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Absolute Risks and Benefits of MHT WHI Cases /10,000 Women-Years

WHI Publications, various.Statistically significant

EVENT E+P E‐Alone

CHD + 6 ‐ 3

Stroke + 7 +12

VTE +18 + 8

Breast Ca + 8 ‐ 6

Hip Fracture ‐ 5 ‐ 6

Colon Ca ‐ 6 + 1

Ovarian Ca +1.5 ‐‐

Lung Ca +2.5 +2.0

But Doctor, What About My…

– ‘Brain fog’: some evidence for adult ADD meds (atomexitine)

– Sex drive: clinical trials currently favor CBT over CNS active agents

– Joint aches and pains: association clearest with use of Ais

– Migraines: improve after menopause, may respond to E2

– Dry eyes: worse with hormones!

– Dry skin: common complaint, causation not established

– Wrinkles: mixed data for improvement with HT

– Contours: mixed data for HT; the real culprit may be high FSH

Oral vs. Transdermal Estrogen and Thromboembolic Complications

(OR and 95% CI)

Study Publication Oral Estrogen

Transdermal Estrogen

Scarabin, et al (1)

3.5 (1.8-6.8)

0.9(0.5-1.6)

Canonico, et al (2)

4.2(1.5-11.6)

0.9(0.4-2.1)

1.Lancet, 2003,362: 428-32.Circulation, 2007,115: 840-845

Can We Be More Precise?

African‐American women (N=1616):

– less risk for breast cancer on E Alone HT, dependent on 

degree of African ancestry: HR 0.32 [0.12‐0.86]

– Global index favors hormones in 50‐59 age group: HR 

0.65 [0.43, 0.98]

– Null effect of hormone use on CHD, VTE 

Chlebowski R, Menopause 2017; 24:133‐141 

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Clinical Guidelines

– The Endocrine Society (Stuenkel, 2015) and the North American Menopause Society (2012) recommendations favor:

– Use of ‘natural’ E and P

– Use of non‐oral E

– Consideration for extended use in women without a uterus (E alone) who remain symptomatic

– Periodic re‐evaluation of risks, benefits and alternatives

The Bottom Line

– HT is still the most effective first line treatment available 

for the common symptoms of menopause

– HT has the potential to address multiple symptoms at 

the same time at low risk for women when given over 

the short term

– If a symptom is atypical with an unknown likelihood of 

response: give HT a try for 3 months; if no benefit is 

observed, discontinue therapy