Nuts & Bolts of Menopausal Hormone Therapy

Lubna Pal, MBBS, MRCOG, MS. Division of Reproductive Endocrinology & Infertility Department of Obstetrics and Gynecology & Reproductive Sciences Yale University School of Medicine, CT, USA

[email protected]

Disclosure Consultant, Merck Learning Objectives At the conclusion of this presentation, participants should be able to:

 Identify the spectrum of benefits & risks relating to menopausal hormone therapy (MHT)  Compare & contrast the efficacy, safety & side effects of available therapies (hormonal & non-hormonal)  Individualize risk assessment and management strategies Case Studies

Case 1 Case 2

• 51 year old, LMP 9 months, • 65 year old, menopausal frequent bothersome night since age 53 presents with sweats, difficulty disturbed sleep, concentrating. bothersome VMS • Otherwise healthy, • BMI 32Kg/m2 nonsmoker, BMI 28Kg/m2 • WC 95 cm. • Exercises regularly. • History of HTN • Mom fractured hip at 72 • Mom had stroke at 63. Case 3 Case 4

• 49 year old, irregular • 55 year old, menopausal cycles, hot flashes, poor since age 53 presents sleep with progressively • History of wrist # at 45 worsening dyspareunia & insomnia • Maternal h/o Br. Ca at 50 • BMI 34Kg/m2 • Nonsmoker, BMI • WC 98 cm. 25Kg/m2 • History of type II DM • Dense breasts on mammography • Father died at 52 of MI. Weighing Risks vs Benefits

Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333. WHI

E+P E-Alone WHI- Take Home Message MHT ….. Why Consider?

• VMS • Poor Sleep • Cognition • Mood & Affect • Urogenital Symptoms • Musculoskeletal • Hair & Skin Symptom Burden…..When? Symptom Burden…..Who? • Perimenopause – VMS – Sleep – Mood/affect/cognition – Hair • Obese • Race • Remote from LMP – Urogenital • Unique – PMS – HIV – Surgical menopause MHT – Is the Most Efficacious of Available Rx Options for Common Menopausal Symptoms

Hot Flashes Night Sweats 50 40

45 35

40 30 35 25 30

% 20 % 25 HF ITT-OCEE HF ITT-t-E2 20 HF ITT-PBO 15

15 10 10 5 5

0 0 0 6 12 24 36 48 0 6 12 24 36 48 Months Months

KEEPS Trial: 727 early postmenopausal women within 3 years of final menses OCEE-0.45mg/d; t-E2: 50mcg/d + cyclic micronized P 200mgx12 days/month vs. Placebo Risks VS. Benefits • Vascular (VTE, stroke, MI) • Symptom control – Age – Improved QOL – Obesity • Skeletal benefit – Comorbidities • Breast cancer risk – Family history reduction with E alone? – Lifestyle • Breast Cancer – Age – Obesity – Parity – Comorbidities – Lifestyle MHT & Breast Cancer Risk MHT & VTE Risk

Age Body Mass VTE Risk: Drug & Route

Route of HT & Progestin Oral vs. Transdermal E Age, MHT & Stroke Risk

Age Age & HT… double whammy! Stroke Risk & HT in Nurses Health Study (1980-2004) Risk for current versus never users by dose of CE Decreasing HR Increasing HR CEE Dose 0.3mg/day HR 0.93 (0.62-1.40) (33, 391 women yr, n=25) 0.625mg/day (233,249 women yr, n=268) HR 1.54 (1.31-1.81)* 1.25mg/day HR 1.62 (1.23-2.14) (59,373 women yr, n=60)

-0.5 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Reference: No estrogen (452,957 women-years; n=349) Adjusted: age, BMI, high cholesterol, high BP, DM, smoking, husband’s education, FH MI Grodstein et al. Arch Intern Med. 2008;168:861-866. Progestin only Option ?

• Who for? • What for? – When E is – Symptoms contraindicated • VMS • Prior DVT • Sleep • Underlying CVD – Skeleton? • History of severe endometriosis?

Considerations? • Type-natural vs. synthetic? • Dose

1. Gambacciani M. Progesterone to treat vasomotor symptoms. Climacteric. 2012 Oct;15(5):501-2. 2. Seifert-Klauss V, et al. Progesterone and bone: a closer link than previously realized. Climacteric. 2012; 1:26-31.

Individualize MHT Decision for Each Woman

Her Risks? Her Gain? • Underlying • Symptom control? atherosclerosis? – Stroke/MI – What symptoms? • VTE? • Skeletal benefit • Breast cancer? … does she have a uterus and therefore will need E+P Symptom Specific Management

VMS Sexual • MHT is highly efficacious • Psychological wellbeing? – Right patient • Relationship – Right dose – counseling? – Right formulation • Vaginal estrogen for • Non-hormonal regimens atrophy st – 1 line for at risk women • Lubricants, moisturizers – Combinations MAY be and dilators have a role! individualized • Androgen Rx • Lifestyle interventions – Surgical menopause – Do work! Symptom Specific Management

Skeleton Sleep Disturbances • Prevention vs. Rx • Co morbidities • Calcium 1000-1200mg/d – Apnoea – Restless leg syndrome • Vitamin D – Depression – 800-2000U D3 per day • Sleep Hygiene • Exercise • MHT – Weight bearing • Sedative/hypnotics – Impact sport • Anxiolytics • Antiseizure – – Walking Neurontin/Gabapentin • Physical therapy • Environment MHT Considerations Formulation Route • Estrogen – Oral – TD – Bioavailable-E2 – Vaginal – CEE – Intrauterine – EE – Parenteral • Progesterone Regimens – Natural – Continuous – Synthetic – Cyclic / Sequential • TSEC – Long Regimens • Oral E + oral SERM • Infrequent P dosing Long Cycle MHT

Sequential Regimens Considerations • Infrequent P dosing • Progesterone – Alternate month P – Formulation – Every third month P – Dose – Every 6 months – Duration – Biweekly P – Interval • Rationale? • Estrogen dose – Minimize P related SE’s • Patient’s Risk Profile – Breast Ca risk mitigation? – Risk for Endometrial Ca? • Endometrial surveillance? 1. Hormone therapy in postmenopausal women and risk of endometrial hyperplasia: Cochrane Database Syst Rev. 2012 Aug 15;8:CD000402. 2. Adverse endometrial effects during long cycle hormone replacement therapy. Maturitas 1999;32:161–70. 3. Archer DF. The effect of the duration of progestin use on the occurrence of endometrial cancer in postmenopausal women. Menopause. 2001; 8(4):245-51. 4. Ultra-low-dose micronized 17B-estradiol and bone density & bone metabolism in older women: a randomized controlled trial. JAMA 2003;290(8):1042–8. 5. Fournier A et al. Risks of Endometrial Cancer Associated With Different Hormone Replacement Therapies in the E3N Cohort, 1992-2008. Am J Epidemiol. 2014 ; 1;180(5):508-17. Future of MHT… the Future is NOW!

Target SERMs Estrogens TSECs Breast Uterus

Hot Flush + + Vagina + Bone + + +

Tissue-selective estrogen complexes for postmenopausal women. Maturitas. 2013 Nov;76(3):213-20. Non-Hormonal Rx options Class Commonly used agents Anti depressants SSRI’s:

Paroxitene (Paxil, 12.5-25mg/day)

Fluoxetine (Prozac, 20mg/day)

Escitalopram (Lexapro, 10-20mg/day); Citalopram (Celexa, 10- 30mg/day))

SNRI’s:

Venlafaxine (Effexor, 37.5-75mg/day) Duloxetine (Cymbalta 60-120 mg/day) Hypnotic Eszopiclone (Lunesta, 3mg/day) Antiseizure Gabapentin (100-300mg starting dose, increasing to 900mg/day) Antihypertensive Clonidine (0.05mg twice daily orally or 0.1mg/day patch

Methyldopa (250mg three times /d ay) Natural products Vitamin E/ Herbals/ Phytoestrogens Lifestyle Relaxation/ Exercise/Yoga/Weight reduction Acupuncture +/- Lubricants & moisturizers Water based lubricants; bio-adhesive moisturizers Steallate ganglion blockade Take Home Points

 Management strategies MUST be individualized to:  address nature and severity of symptoms  while maintaining individualized risk/s in perspective  For early menopausal women, MHT is the MOST efficacious of available strategies.  Non-hormonal therapies SHOULD be 1st line Rx for symptomatic women who are deemed “at risk” for MHT related adverse effects.  Estrogen dose reduction, TD administration, choice of progestin & regimen CAN offer risk reduction. Case Study

Case 1 Case 2

• 51 year old, LMP 9 months, • 65 year old, menopausal frequent bothersome night since age 53 presents with sweats, difficulty disturbed sleep, concentrating. bothersome VMS • MHT OFFERS SYMPTOM • AT INCREASED RISK FOR • CONTROLOtherwise & healthy,SKELETAL BENEFIT • BMIVASCULAR 32Kg/m EVENTS2 (AGE, • MHTnonsmoker, 1ST LINE APPROACHBMI 28Kg/m 2 OBESITY, HISTORY) • TRANSDERMAL E ROUTE •• WCNON 95-HORMONAL cm. OPTIONS • PREFERREDExercises regularly. • HistorySHOULD BEof FIRSTHTN LINE CONSIDERATION • Mom fractured hip at 72 • Mom had stroke at 63. Case Study

Case 3 Case 4

• TSEC49 year old, irregular cycles, • 55 year old, menopausal hot• SYMPTOMflashes, poor CONTROL sleep since age 53 presents with • SKELETAL BENEFIT • progressivelyAT INCREASED RISK worsening FOR • History• NO NEED of wrist FOR #P at 45 VASCULAR EVENTS (AGE, dyspareunia & insomnia • Maternal• REDUCED h/o RISKBr. Ca FOR at BR 50 OBESITY, HISTORY) CA? • DOES NOT NEED2 SYSTEMIC 2 • BMI 34Kg/m • TDNonsmoker, E2 + PROGESTERONE BMI 25Kg/m IUD MHT! • Dense• SYMPTOM breasts CONTROL on •• WCVAGINAL 98 cm.ESTROGEN • SKELETAL BENEFIT • NONHORMONAL RX mammography• ENDOMETRIAL • History of type II DM PROTECTION • Father died at 52 of MI. • MINIMAL BREAST TISSUE EFFECT?

Long Cycle MHT

• Take Home Points: Risk for Endometrial Ca • Duration of P use matters • >10 days (12-14) • Dose of P matters • 200-400mg micronized P • 10mg MPA • 1mg NETA • Dose of E matters • higher risk with higher E dose • Length of MHT use matters • Increased risk with >5 year use • Type of P matters • Progestins are superior to natural P in antagonizing endometrial effects of E