MANAGEMENT OF MENOPAUSAL SYMPTOMS

PATTI BALLER, RN, CNM, MSN APRIL 24, 2015

OBJECTIVESDefine perimenopause, menopause, and

postmenopause.Discuss updated findings of the Women’s

Health Initiative (WHI).Discuss management options for the

treatment of hot flashes and night sweats.Discuss management options for the

treatment of vulvovaginal atrophy and dyspareunia.

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DEFINITIONS BY NAMSPREMENOPAUSE - The span of time from

puberty to perimenopause.PERIMENOPAUSE - A span of time typically

lasting 6 years or more that begins with the onset of menstrual cycle changes and other menopause-related symptoms and extends through menopause to 1 year after menopause. (Also called menopause transition – MT)

MENOPAUSE - The final menstrual period, which can be confirmed after going 12 consecutive months without a period.

POSTMENOPAUSE - The span of time after menopause. 3

HORMONE THERAPYFDA approved RXs for HT fell by half from

17.9 million in 1995 to 8.9 million in 2003, the year following the release of the WHI findings.

Only 3.7 million in 2013 use some form of HT.

In 1990’s, > 90% of women with hysterectomy used ET, currently 30% of women use ET.

Reasons:Confusion among clinicians and women

regarding WHI results.Concerns re: breast Ca risk, CV risk.

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WHI STUDYPrimary prevention RCTDesigned to evaluate effects of estrogen in

promoting CV health and in retarding the progression of cognitive decline.

Not designed to:Evaluate impact of treatment on PM symptoms.

These women were excluded from study.Assess safety or efficacy of established FDA-

approved drugs.

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WHI STUDY16,608 healthy postmenopausal womenEPT arm stopped after 5.2 yearsAverage age 63.4 years2/3 between ages 60-79 with most women

postmenopausal for more than 10 years.3.5% of women in HT group 50-54 y.o.

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WHI – ESTROGEN ARM Stopped after 6.8 yrs in February, 2004.Findings published in JAMA, April 14,

2004.Women aged 50-59, no increase in

number of strokes in CE and placebo groups.

Study suggests younger women who use CEE may be at decreased risk of CVD.

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Incidence of CVD: Relation to Menopause Status

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0.6 0.6

2.0

3.6

2.2

3.64.0

6.5

0

1

2

3

4

5

6

7

<40 40–44 45–49 50–54

Premenopausal

Postmenopausal

Inci

den

ce

(p

er

10

00

wo

men

)

Age (years)

n = 2873.Kannel WB, et al. Ann Intern Med. 1976;85:447-52.

The Framingham Study

Effect of Hormone Therapy on Atherosclerosis Varies With Stage of Reproductive Life

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35-45 yrs 45-55 yrs 55-65 yrs 65 yrs

~5%

15-25 yrs 25-35 yrs

~15%

Premenopause Perimenopause Postmenopause

Mikkola TS, et al. Ann Med. 2004;36:402-13.

Primary Benefits of HT No Benefits of HTBenefits of Endogenous E2

Hypothetical Pathogenetic Sequence

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No HT Adventitia

Media

Fatty Streak/Plaque

InternalElastic

Lamina

Necrotic Core

Plaque

FibrousCap

FibrousCap

Plaque Necrotic Core

Plaque

FibrousCap

MMP-9

Early and Continued HT

Late HT

HT

Age 35–45 years 45–55 years 55–65 years >65 years

HT

Mural Thrombus

RISK OF BREAST CANCERFor every 100 women who do not take

HT or ET, 2.8 will develop breast cancer after 10 years.

WHI results indicate a hazard risk for breast cancer of 1.26 after 5 yrs of HT useFor every 100 women who take HT,

3.5 will develop breast cancer after 10 yrs.

Rate of breast cancer in obesity – 10% wt gain is associated with 2.5 times the breast cancer risk found in WHI.

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NEW CONSENSUS STATEMENTSystemic hormone therapy is the most

effective tx for most menopausal sxs, including vasomotor sxs and vaginal atrophy.

Local estrogen therapy is effective and preferred for women with sxs of vaginal dryness or dyspareunia only.

Systemic HT is acceptable option for relatively young (up to age 59 or within 10 years of menopause) and healthy women who are bothered by moderate-severe menopausal sxs.

Individualization is key. Consider quality of life, age, time since menopause, risks of blood clots, HD, stroke and breast cancer.

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NEW CONSENSUS STATEMENTRate of breast cancer-not statistically

significant. (Risk for an individual woman taking HT is <1%)^ risk seen with ≥ 5 yrs of

continuous EPT (Estrogen + progestin)

Use of estrogen alone for a mean of 7 yrs did not increase breast cancer risk.

Risk decreases after HT is D/C.

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NEW CONSENSUS STATEMENT

Although HT increases risk for stroke, PE, VTE’s, the risk is rare in the 50-59 yo age group.

The lowest dose of HT should be used for the shortest amount of time to manage menopausal symptoms.

Although fewer than 5 yrs is recommended for EPT, duration should be individualized.

For ET, more flexibility in duration of therapy may be possible. 14

NEW CONSENSUS STATEMENT

Data demonstrates HT reduces hip fractures and a 40% reduction in colon cancer.

Conclusion- for younger women undergoing therapy close to the time of menopause, the benefits generally outweigh the risks.

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ORAL PREPARATIONSPrimarily metabolized in liver- 80-90%

of E2 (estradiol) converted to less biologically active estrone and estrone sulfate.

Peak concentrations in 4-6 hrsIncreases C-reactive protein and can

increase the cholesterol saturation of bile.

Smoking decreases estrogen levels by 40-70%.

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ESTROGENSUsed in EPT and ET.1 ug. Ethinyl estradiol = biologic potency to 0.625 mg. conjugated equine estrogens.

Vaginal and transdermal applications, bypass liver and act directly on target tissue.

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ESTROGENSEstrones

CEE (Conjugated equine estrogen) - from pregnant mares’ urine Potent estrogen, stored in fat, long-

lasting.Recommended starting dose 0.3 mg.

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ESTROGENSEstradiols - synthetically produced natural

17B-estradiol. (Bioidentical )Micronized estradiol – oral (Estrace)

Recommended starting dose 0.5 mg.Transdermal systems - Estraderm,

Vivelle, Climara, etc.Vaginal Ring (Estring)

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ESTROGENSEsterified estrogens - estradiol esters

(Oral)Do not ^ plasma triglyceridesNot linked to ^ risk of venous

thrombosisUse in diabetic women or

hypertriglyceridemiaMenest- no animal precursorsEsterified estrogens +

methyltestosterone (Estratest, Estratest HS)

Not indicated for use for osteoporosis.

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SYNTHETIC CONJUGATED ESTROGENS

Cenestin - Mixture of 9 estrogenic substances.

Enjuvia – Mixture of 10 estrogenic substances.

Synthesized from soy and yam plants.Estradiol principal physiologic estrogen.Doses - 0.3 - 1.25 mg./day.Not approved for osteoporosis.

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DUAVEEApproved by FDA in October, 2013.Tissue selective estrogen complex.Conjugated estrogen 0.45 mg with

bazedoxifene 20 mgHas estrogen agonist effect on bones and

blocks estrogen activity at uterus and breast.

Does not cause change in breast density, thickness of endometrium, or increase in breast pain.

Provides an alternative to progestin. 22

DUAVEE (CONT)Indication: For prevention of osteoporosis

and tx of mod-severe vasomotor symptoms.Indicated only for use in women with a

uterus.Side effects: muscle spasms, nausea,

diarrhea, dyspepsia, upper abdominal pain, oropharyngeal pain, dizziness and neck pain.

Drug interactions: concomitant use with CYP3A4 inhibitors such as erythromycin, clarithromycin, ketoconazole, itraconazole, and ritonavir and grapefruit juice. (Increases estrogen exposure)

Contraindications: Women with or H/O blood clots, liver problems, breast cancer or uterine cancer.

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PROGESTINSMedroxyprogesterone acetate

(MPA) - most common.Less androgenic activity, negates estrogen’s benefits to lipid profiles.

Found in Prempro and Premphase.

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PROGESTINSNorethindrone or NETA

Developed from testosterone molecule.

Greater binding affinity for endometrium and myometrium.

Less side effects of depression and mood changes.

Found in FemHRT, Activella and Combipatch.

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PROGESTERONEPrometrium – FDA approved bio-identical

hormone, micronized oral progesterone.Synthesized from yam plant sources.Contains peanut oil.Recommended for women at risk for

CVD and those intolerant to synthetic progestins.

Dose: 200 mg every evening for 12 days every 28 days with food

Side effects: Somnolence, breast tenderness, constipation, H/A, dizziness, abdominal pain, joint pain. 26

OTHER PROGESTINS USED IN HRTDrospirenone – in AngeliqNorgestimate – in PrefestLevonorgestrel – in Climara Pro

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ANDROGENSMethyltestosterone (Estratest,

estratest HS)Primarily used in women who undergo surgical menopause for sxs of decreased libido, fatigue and changes in cognition or memory, moodiness.

Continue use only if sxs. alleviated

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HT REGIMENS

Numerous options available. Indications:

Tx of moderate-severe menopausal sxs. (6-8 hot flashes/day)Symptoms are bothersome, disrupt sleep,

or adversely affect quality of life. (NAMS)Tx of vulvar and vaginal atrophy.Prevent osteoporosis in women at high

risk for fracture.

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HT REGIMENS - CONTINUOUS ESTROGEN ONLY (ET)Continuous estrogen

Indications - Hx. of hysterectomy with or without oophorectomy.

Risks - Increased risk of endometrial hyperplasia and cancer with unopposed estrogen use in women with a uterus.

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HT - CONTINUOUS COMBINED (EPT)

Estrogen and progestin daily, either as 2 separate preparations or combined in 1 preparation.

Advantages:Lower progestin doseDaily progestin causes endometrial atrophy

Minimal spotting first 6 mos, then amenorrhea within 1 year.

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HT - CONTINUOUS COMBINED (CONT)Advantages:

Decrease in PMS symptomsUterine atrophy leads to asymptomatic fibroids.

Convenience, better compliance.

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HT: CYCLIC – COMBINED (EPT)Estrogen daily + Progestin for 14 days

of cycle. (Premphase)Estrogen daily for 28 days each month,

with a progestin for last 10-14 days of estrogen tx.

Disadvantages:80-90% experience withdrawal

bleedingInconvenient

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CHOICE OF HT REGIMENIf no uterus: estrogen onlyIf uterus present:

Goal is to avoid vaginal bleeding entirely or at least to make it predictable.

Current endometrial activity predicts bleeding patternRecent spontaneous or induced bleeding

Cyclic combined or OCP’s if no contraindications.

No bleeding for > 2-3 cyclesContinuous combined

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TRANSDERMAL PREPARATIONS - PATCHESUses 17B-estradiol.Avoids first pass- globulins, lipoproteins,

and clotting factors less likely to change.Peaks in serum concentration less likely.Insulin sensitivity improved.Does not increase C-reactive protein or

triglycerides.HDL increases less than oral HTPeak concentrations in 2-8 hrsSite reactions 20-40%

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FIRST LINE USE OF ESTROGEN PATCHHigh triglyceride levelsGallbladder disease DiabetesMigraine headacheDaily mood swingsSmokersStomach upset due to oral estrogen

intakeProblems with taking a daily pillNight sweats unrelieved with oral

estrogen. 37

GEL FORMULATIONSPopular in Europe since 1975Uses 17B-estradiol.Absorbed into an intradermal reservoir,

from which physiologic plasma concentrations are delivered for steady- state bioavailability.

Onset of action is rapid.Needs to be spread over wide skin

area.Elestrin, Divagel, Estrogel and

Estrasorb. 38

GEL FORMULATIONSSkin irritation is uncommon, may cause

pruritus.Avoid skin contact with others for 1

hour after application.Estrogel- 1 pump full applied to 1 arm

from wrist to shoulder.Estrasorb- topical emulsion. Apply 2

foil packets to each thigh and calf and rub in for 3 minutes.Avoid sunscreens which increase estrogen

absorption.39

ESTROGEN SPRAYEvamist –Each 90mcL spray delivers

0.021 mg estradiol.Applied to inner forearm. Slow

absorption thru epidermis to dermis where it reaches circulation thru capillaries.

Quick drying and no residue on skin.Skin irritation uncommon.Risk of transfer to another person less

than with gel preps. No difference in estradiol levels in males.

May use up to 3 sprays per day. 40

FEMRINGTransvaginal systemic estrogen.Avoids first pass through liver.FDA approved for menopausal symptoms and

VVAInserted in vagina for 90 days.2 doses: 0.05 mg/day and 0.1 mg/dayIf used in a woman with an intact uterus,

must also give a progestin.

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CHOICE OF ESTROGENSStart low dose transdermal (patches, gels,

spray) vaginal (Femring) or oral estrogen.If suboptimal response, modify by:

Change the estrogen dose (upward)Change the estrogen preparationChange delivery systems (oral vs

transdermal vs vaginal)Consider an estrogen-androgen

combinationWait at least 12 wks before changing

dose.42

SSRI’sBRISDELLEParoxetine mesylate 7.5 mg at hs.Non hormonal option.FDA approved in June, 2013 for

vasomotor symptoms.1-2 fewer hot flashes/day compared to

placebo.On average, starts working 4 weeks after

starting.

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BRISDELLE (CONT)Side effects:

H/AFatigueNausea Vomiting

Doesn’t cause wt gain or sexual dysfunction.Inhibits cytochrome P450 and CYP2D6

enzyme.Reduces effectiveness of tamoxifen, other

warnings – increased bleeding risk and serotonin syndrome. 44

SSRI’sEscitalopram (Lexapro) 10 mg qd, increase to

20 mg after 4 wks.54% reduction in hot flashes (Ms-FLASH 3

clinical trial)Bleeding risk if used with ASA, NSAIDS,

warfarin, or other anticoagulants.Use with caution if H/O recent MI or unstable

heart disease, hepatic or renal impairment.Mild effect on CYP2D6 enzyme.Can be given with tamoxifen.Generic available.

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SSRI’sCitalopram 10 mg, may increase to 20 mg if

nec.49-55% reduction in hot flashes.$4 generic available for 20 mg.Few, if any side effects in studies.Safe for elderlyFew CV or anticholinergic adverse events.Mild effect on CYP2D6 enzyme.Can be given with tamoxifen.

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SSRI’sConsidered second line therapy:

Fluoxetine 20 mg qd 58% withdrawal rate due to ineffectiveness

of tx.Sertraline 50 mg qd

Side effects nausea and decreased sexual function.

Poor trial data.Less effective for hot flashes.Both decrease effectiveness of Tamoxifen.

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SNRI’s

Venlafaxine 37.5 mg daily or Venlafaxine XR 75 mg.Serotonin/Norepinephrine reuptake

inhibitor.Side effects: nausea and constipation,

higher dose increases dry mouth.Use with caution in women with HTNMay cause increase in BP 49% reduction in hot flashes (Ms-FLASH

3 clinical trial), improvement in sleep, decrease in insomnia, and increase in sleep quality.

Good choice for tamoxifen users.48

SNRI’sDesvenlafaxine (Pristiq) 100 mg qd- higher

doses increase risk of discontinuation.Desvenlafaxine has same precautions with BP

as venlafaxine. Applied for FDA approval and denied.60-66% reduction in hot flashes.Side effects: nausea, tends to subside after a

few days, dizziness and H/A.Good choice for tamoxifen users.

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OTC BOTANICALS AND ISOFLAVONES

Some studies (slightly) better than placebo, most studies no effect.

Soy isoflavones Minimal to no benefit

Red clover isoflavones Not better than pboBlack cohosh (20-40mg BID) Inconclusive (Remifemin)No evidence of efficacy Evening primrose oil Not better than pbo Chasteberry (Vitex) No studies Dong quai Not better as

monotx Ginseng Not better than pbo Vitamin E Not better than pbo 50

CUSTOM COMPOUNDED HORMONESCustom made HT formulations.Never undergone clinical testing, safety or

efficacy studies.Not FDA approved.Same or possibly additional risks.SALIVARY TESTING –

Large patient to patient variability and no biologically meaningful relationship between saliva and serum hormone concentrations.

Not proven accurate or reliable.51

Bioidentical hormone therapy: clarifying the misconceptions. Cleve Clin J Med. 2011;78:829-836

FDA APPROVED BIO-IDENTICAL HORMONES

Oral esterase (Estrace)17-beta estradiol

Transdermal patches, gels, and sprayVaginal ring (Estring)

Prometrium

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VAGINAL PREPARATIONSMinimize systemic exposure.Limited to urogenital atrophy.*Exception: Femring- serum levels

equivalent to patch, used for tx of menopausal sxs and vaginal atrophy. Caution- if patient has a uterus, must also give a progestin.

Improves urge incontinence symptoms.Reduces risk for recurrent urinary tract

infections.1st line therapy for decreased libido, mod-

severe dyspareunia, and other vulvovaginal symptoms. (NAMS)

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TREATMENT OF ATROPHIC VAGINITISEstrace cream 2-4 g/day for 1-2 weeks,

then 1 g/d 1-3x/week.Premarin vaginal cream 0.5-2 g/day for

2x/week or daily for 3 weeks, then 7 days off

Estring 2 mg ring x 90 daysVagifem 10 mcg/day for 2 weeks, then 10

mcg 2x/week.No progestin required with above meds.Femring x 90 days- use only if also having

menopausal sxs. (Systemically absorbed)All evidence A.

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OSPEMIFENE (OSPHENA)Approved by FDA for atrophic vaginitis in

Feb, 2013.Selective estrogen receptor modulator

(SERM)- estrogen agonist/antagonist.Estrogen agonist on vaginal tissue and

estrogen antagonist in breast tissue.Makes vaginal tissue thicker and less fragile. Can lead to endometrial hyperplasia.Indication: moderate to severe dyspareunia.Dose: 60 mg PO daily with food.Should be closely monitored for abnormal

uterine bleeding. 55

OSPEMIFENE (OSPHENA) CONT.SE: Hot flashes (most common), vaginal D/C,

muscle spasms or leg cramps, and excessive sweating.

Drug Interactions: Metabolized through cytochrome P450; fluconazole, ketoconazole and omeprazole increase levels, and rifampin decreases levels.

Not recommended to use with other SERMs or estrogen therapy.

Contraindications: undiagnosed vaginal bleeding, pregnancy, estrogen dependent neoplasia, active or prior VTE, previous stroke, HD, prior MI or severe hepatic impairment.

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NONHORMONAL THERAPIESMoisturizers

ReplensVagisilSilken SecretMe AgainFemineaseK-Y Silk-ELuvena

LubricantsWater based

K-Y jellyAstroglideSlippery StuffLiquid Silk

Silicone basedAstroglide XK-Y IntriquePinkID Millennium

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RECOMMENDATIONS AND CONSIDERATIONS

Do not use for primary or secondary prevention of heart disease.

Low risk for CHD if HT initiated within 10 yrs of menopause or by age 59.

Extended use of HT is acceptable in certain circumstances, especially with ET therapy.

Evidence suggests HT route of administration has an impact on potential risks.

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Questions????

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Case Study64 yo, Cau female presents with C/O 10 hot flashes/day since menopause at age 52. She took HT for 1 year after menopause then stopped because everyone told her it caused breast cancer and heart disease. PMH: HTN, hyperlipidemia, DM. PSH: None. Meds: Lisinopril 20 mg qd, atorvastatin 80 mg qd. Allergies: NoneBP today: 130/80 No recent labs done.

She would like something for her hot flashes, what will you give her and why? 60

Case Study56 yo AA, female presents with c/o hot flashes all day long, night sweats that continually wake her up and vaginal dryness. Has tried remifemin, lubricants and moisturizers without relief. Menopause: age 52. PMH: HTN. PSH: Hysterectomy for adenomyosis. Meds: HCTZ 25 mg daily. No allergies. Nonsmoker. BP today: 130/84.

What will you give her for her complaints and why?

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Case Study53 yo Cau, female presents with c/o >10 hot flashes daily. She finds it embarrassing at work and everyone can tell when she gets one. Menopause: age 50. Smoker 1 ppd. PMH: Osteopenia, hyperlipidemia. PSH: None.Meds: Caltrate 600 mg bid, atorvastatin 20 mg daily. Last lipid panel normal 3 mos ago. BP 120/70

What will you give her and why?

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ReferencesAmerican College of Obstetricians and

Gynecologists. Website: www.acog.orgNorth American Menopause Society. Website:

www.menopause.orgWriting 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; 288:321-333.

Chlebowski, RT, Hendrix, SL, Langer, RD, et al, for the WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA. 2003; 289: 3243-3253.

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ReferencesWriting Group for the Women’s Health Initiative

Investigators. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA. 2004; 291:1701-1712.

Rossouw, JE, Prentice, Rl, Manson, JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007; 297: 1465-1477.

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ReferencesLaCroix, AZ, Chlebowski, RT, Manson, JE, et al,

for the WHI Investigators. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA. 2011; 305: 1305-1314.

Stuenkel, CA, Gass, MLS, Manson, JE, et al. A decade after the Women’s Health Initiative-the experts do agree. Menopause. 2012; 19(8): 1-2.

North American Menopause Society. Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause 2013; 20(9): 888-899.

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