MENOPAUSE To describe risks of HT by age and menopause onset WHATS - - PDF document

7/2/18 1

MENOPAUSE

WHAT’S NEW? WHAT’S SAFE?

Sara W hetstone, MD

OBJECTIVES

• To describe risks of HT by age and

menopause onset

• To recommend specific HT regimen for women

who undergo early menopause and who undergo menopause at the expected time

GLOSSARY

HT–Hormone therapy ET–Estrogen only therapy EPT–Estrogen-progestin therapy CEE–Conjugated equine estrogen MPA–Medroxyprogesterone acetate MP–Micronized progesterone

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PB is 66yo G0 woman who underwent bilateral

• ophorectomy at age 40 after

her sister was diagnosed with

• varian cancer. She was

started on HRT for very bothersome hot flashes. She presents to discuss continuation

• f HRT. She is currently taking

PO conjugated equine estrogen (CEE) and continuous medroxyprogesterone acetate (MPA). PB is 66yo G0 woman who underwent bilateral

• ophorectomy at age 40 after

her sister was diagnosed with

• varian cancer. She was

started on HRT for very bothersome hot flashes. She presents to discuss continuation

• f HRT. She is currently taking

PO conjugated equine estrogen (CEE) and continuous medroxyprogesterone acetate (MPA).

CONSEQUENCES OF EARLY MENOPAUSE AND PRIMARY OVARIAN INSUFFICIENCY

V asom

• tor

sym ptom s G SM Bone loss and

• steoporosis

Increased heart disease Dem entia and cognitive decline Depression and anxiety related disorders Higher overall m

• rtality

MANAGEMENT OF EARLY MENOPAUSE

qHormone replacement qExercise qHealthy diet qAdequate calcium and vitamin D intake qAvoidance of smoking Estrogen therapy

• Dosage higher than usual

post-menopausal ET

• Monitoring estradiol levels

NOT recommended Progestin necessary if patient has intact uterus

INDICATIONS FOR HT

(FDA-APPROVED) Vasomotor symptoms Prevention of bone loss Hypoestrogenism

(caused by hypogonadism, oophorectomy, or POI)

Genitourinary syndrome of menopause (GSM)

(or vulvo-vaginal atrophy)

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PB is 66yo G0 woman who underwent bilateral

• ophorectomy at age 40 after

her sister was diagnosed with

• varian cancer. She was

started on HRT for very bothersome hot flashes. She presents to discuss continuation

• f HRT. She is currently taking

PO conjugated equine estrogen (CEE) and continuous medroxyprogesterone acetate (MPA). PB is 66yo G0 woman who underwent bilateral

• ophorectomy at age 40 after

her sister was diagnosed with

• varian cancer. She was

started on HRT for very bothersome hot flashes. She presents to discuss continuation

• f HRT. She is currently taking

PO conjugated equine estrogen (CEE) and continuous medroxyprogesterone acetate (MPA).

RECOMMENDED TREATMENTS

ACOG Committee Opinion, 2017.

COMMON HT REGIMENS

CHOOSING WHICH REGIMEN TO PRESCRIBE Estrogen replacement

• Transdermal recommended (over oral)
• Can also use vaginal ET
• Lower risk of VTE
• Rovinski D (2018): Oral HT was

associated with increased risk of VTE, while non-oral HT was not

• Lower risk of stroke
• Lower risk of hypertriglyceridemia

Bottom Line: Start with transdermal estrogen patch (17-beta estradiol)

7/2/18 4 BREAST & CV EFFECTS OF PROGESTINS

Llaneza P, Gynecol Endocrinol, 2018.

CHOOSING WHICH REGIMEN TO PRESCRIBE

Progestin therapy § Recommendation for oral micronized progesterone (MP) § Sequential: 200mg/day x 12 days per month § Continuous: 100mg daily

WHAT ABOUT LEVONORGESTEREL IUD?

Using LNG

• IUS for endometrial

protection would be considered an off- label use Reasonable to consider in women who do not tolerate oral progestins Can be utilized by women who desire ET at non-contraceptive levels and who are still at risk of pregnancy Effective for endometrial protection for peri-menopausal and post-menopausal women using ET

WHAT ABOUT OCPS?

D is a d v a n ta g e s (1 ) H ig h e r d o se o f E + P th e ra p y (2 ) ? in fe rio r to h ig h e r d o se H T in re g a rd s to B M D A d v a n ta g e s (1 ) E a sie r to u se , le ss stig m a (2 ) O ffe rs c o n tra c e p tio n

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PB is 66yo G0 woman who underwent bilateral

• ophorectomy at age 40 after

her sister was diagnosed with

• varian cancer. She was

started on HRT for very bothersome hot flashes. She presents to discuss continuation

• f HRT. She is currently taking

PO conjugated equine estrogen (CEE) and continuous medroxyprogesterone acetate (MPA). PB is 66yo G0 woman who underwent bilateral

• ophorectomy at age 40 after

her sister was diagnosed with

• varian cancer. She was

started on HRT for very bothersome hot flashes. She presents to discuss continuation

• f HRT. She is currently taking

PO conjugated equine estrogen (CEE) and continuous medroxyprogesterone acetate (MPA). Should PB stop HT? 1) Yes 2) No 3) It depends…

WHEN TO STOP HORMONE REPLACEMENT?

§Treatment for women with primary ovarian insufficiency/early menopause should continue until the average age of natural menopause (50–51 years) §Treatment may continue past age 50–51 years if a woman has clinical symptoms or indications. §Regardless of age, the decision to continue HT should be individualized and based on a woman’s symptoms and the risk– benefit ratio.

“LOWEST DOSE FOR THE SHORTEST PERIOD OF TIME” PRIOR GUIDING PRINCIPLE “APPROPRIATE DOSE, DURATION, REGIMEN, AND ROUTE OF ADMINISTRATION CURRENT GUIDING PRINCIPLE

DURATION OF TREATMENT WHEN TO STOP?

Extended use m ay benefit w

• m

en for relief of VM S, prevention of bone loss and fracture, and treatment/prevention of G SM V asom

• tor sym

ptom s recur in 50%

• f w
• m

en M any of the benefits/risks of HT do not persist beyond 5 to 7 years

­ Ele va te d (b ut ra re a b so lute risk) o f b re a st ca nce r w ith C EE + M PA in m e d ia n 1 3 y r fo llow -up ­ C V D risk b e ca m e ne ura l ­ B o ne p ro te ctio n ra p id ly d issip a te s a fte r H T d isco ntinua tio n ­ S ig nifica nt re d uctio n in b re a st ca nce r w ith C EE d uring 1 3 ye a r fo llow -up ­ A ll-ca use m o rta lity w a s ne utra l in C EE + M PA g ro up in 1 3 ye a r fo llow -up

Data lacking on benefits/risks of longer duration and w ith discontinuation

• f HT

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OUR ADVICE FOR PB: §Recommend discontinuation of HT §If PB is hesitant to stop HT or has recurrent bothersome menopausal symptoms, would recommend §Trying non-hormonal treatments §Switching to transdermal estrogen §Switching to micronized progesterone §Lowering dose as tolerated §Reassessing HT on an annual basis TG is a 64yo woman who underwent menopause at age 49. She has noticed increased joint stiffness and prolonged fatigue after exercising in the last 18

• months. She was encouraged by

her PCP to present to GYN to discuss initiating hormone replacement therapy for her

• symptoms. Her medical history is

notable for hypertension and hyperlipidemia.

JOINT PAIN AND HT

§ E v id e n c e o f e stro g e n b in d in g to e stro g e n re c e p to rs o n jo in t tissu e s § In c o n siste n t e v id e n c e a b o u t e ffe c ts o f E T o n

• ste o a r th ritis a n d a r th ra lg ia

§ M a y b e b e n e fits o f e stro g e n a n d S E R M s o n jo in t p a in § In W H I: § W o m e n o n C E E + M PA (v s p la c e b o , 4 7 .1 % v s 3 8 .4 % ) h a d le ss jo in t p a in / stiffn e ss, m o re d isc o m fo r t w h e n sto p p in g H T § W o m e n o n C E E h a d sta tistic a lly sig n ific a n t le ss jo in t p a in (v s p la c e b o , 7 6 .3 % v s 7 9 .2 % )

TG is a 64yo woman who underwent menopause at age 49. She has noticed increased joint stiffness and prolonged fatigue after exercising in the last 18

• months. She was encouraged by

her PCP to present to GYN to discuss initiating hormone replacement therapy for her

• symptoms. Her medical history is

notable for hypertension and hyperlipidemia. Would you start TG on HT? 1) Yes 2) No 3) Maybe

7/2/18 7 RISKS OF HT BY AGE

Manson JE, JAMA 2013.

SUMMARY OF HEALTH RISKS OF HT BY AGE AND/OR TIME FROM MENOPAUSE ONSET

Potential risk Age and/or time from menopause onset <60 years or <10 years from menopause >10 years from menopause Coronary heart disease Reduced risk of CHD Potential for increased risk

• f CHD

All-cause mortality Significant reduction in all-cause mortality No protective effect of HT Stroke Meta-analysis of RCTs: No increased risk of stroke Observational studies: mixed Meta-analysis of RCTs: Increased risk of stroke VTE Rare risk but significantly increased with HT Higher absolute risk

NAMS ALGORITHM

Manson JE, Menopause, 2015.

CVD RISK AND TIME SINCE MENOPAUSE ONSET

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“For women who initiate HT more than 10 to 20 years from menopause onset or when aged 60 years or older, the benefit-risk ratio appears less favorable than for younger women because of greater absolute risks of CHD, stroke, VTE, and dementia.”

2017 HT Position Statement of NAMS

BP is a 52yo woman who cannot sleep due to her hot

• flashes. Her last period was

approximately 8 months

• ago. She is miserable. She

is interested in exploring HT but worried specifically about risks of HT. In the past, she has had really bad experiences with progestin therapy.

TREATMENT OF VASOMOTOR SYMPTOMS

Most effective treatment: systemic hormone therapy (HT) with estrogen therapy

If u te r u s p re se n t... If u te r u s a b se n t… E s tro g e n + P ro g e s tin (E P T ) E s tro g e n a lo n e (E T )

INDICATIONS FOR HT

(FDA-APPROVED) Vasomotor symptoms Prevention of bone loss Hypoestrogenism

(caused by hypogonadism, oophorectomy, or POI)

Genitourinary syndrome of menopause (GSM)

(or vulvo-vaginal atrophy)

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RISKS AND BENEFITS OF HT IN WOMEN AGES 50-59 OR <10 YEARS OF MENOPAUSE

Manson JE et al. NEJM, 2016

BENEFITS/RISKS OF HT AMONG WOMEN 50-59

Santen et al. J Clin Endocrinol Metab. 2010

CONTRAINDICATIONS TO SYSTEMIC HT

§Unexplained vaginal bleeding §Severe active liver disease §Estrogen-sensitive breast or endometrial cancer §Coronary heart disease §Stroke §Personal history or inherited high risk of venous thromboembolism BP is a 52yo woman who cannot sleep due to her hot

• flashes. Her last period was

approximately 8 months

• ago. She is miserable. She

is interested in exploring HT but worried specifically about risks of HT. In the past, she has had really bad experiences with progestin therapy. What type of estrogen therapy do you usually start with? 1) Oral CEE 2) Micronized oral 17-beta estradiol 3) Transdermal 17-beta estradiol 4) Oral CEE + bazedoxifene

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SYSTEMIC HORMONE THERAPY (HT) REGIMENS

ACOG Bulletin 141: Management of menopausal symptoms, 2016.

TISSUE SELECTIVE ESTROGEN COMPLEX (TSEC) CEE/BZA

(0 .4 5 m g / 2 0 m g ) Estro g en p resen t to trea t v a so m o to r sy m p to m s FDA a p p rov ed fo r trea tm en t o f v a so m o to r sy m p to m s a n d o steo p o ro sis p rev en tio n SER M to b lo ck estro g en a ctio n in en d o m etriu m /u teru s P ro g estin is N O T n eed ed

BZA - Bazedoxifene

TISSUE EFFECTS OF TSEC VS. TRADITIONAL HT

Ta rg e t T is s u e T S E C O ra l H T (E T a n d E P T ) V M S Im p ro ve d fre q u e n c y a n d se ve rity Im p ro ve d fre q u e n c y a n d se ve rity B o n e Im p ro ve d B M D Im p ro ve d B M D, d e cre a se d fra ctu re risk E n d o m e tria l n e o p la sia N e u tra l a t 2 y N e u tra l w ith E P T, in cre a se d w ith E T a lo n e if u te ru s p re se n t B re a st ca n ce r N e u tra l a t 2 y In cre a se d in W H I tria l < 1 / 1 0 0 0 V T E risk 2 fo ld risk w ith B Z A , n o a d d itive risk w ith C E E / B Z A 2 fo ld risk w ith o ra l E T & E P T, p o te n tia lly le ss w ith tra n sd e rm a l th e ra p ie s Pinkerton JV et al. Clin Obstet Gynecol, 2018.

TABLE 1 BP was excited about CEE/BZA option but appreciated the lower risk

• f VTE with transdermal
• estrogen. In addition, she

chose micronized progesterone for endometrial protection.

A fter th is co u n selin g, I d o n’t d esire h o rm o n a l trea tm en t. A re th ere n o n -h o rm o n a l trea tm en t

• p tio n s?

7/2/18 11 NON-HORMONAL TREATMENTS FOR VASOMOTOR SYMPTOMS

FDA-approved Evidence of benefit ACOG Bulletin 141: Management of menopausal symptoms, 2016. Yes

KG is 64yo P2 woman with no significant PMH who presents for her routine gynecologic

• visit. She reports dyspareunia

despite lubrication. She declines vaginal estrogen, stating “she doesn’t want to try any hormonal medications as she doesn’t perceive them as safe.” GENITOURINARY SYNDROME OF MENOPAUSE … a collection of signs and symptoms associated with a decrease in estrogen and other sex steroid hormones involving changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra, and bladder. Vulvovaginal atrophy Atrophic vaginitis

SYMPTOMS AND SIGNS OF GSM

Gandhi J, Am J Obstet Gynecol, 2016.

7/2/18 12 HORMONAL TREATMENT FOR GSM

Low dose vaginal estrogen preparations are generally safe

Available in creams, tablets, rings Cochrane Review (2016): no difference in efficacy between the various intravaginal estrogen preparations

Estrogen therapy (ET) is the most effective treatment for GSM

SAFETY OF VAGINAL ET

Primary concern: Risk

• f endometrial cancer

associated with unopposed estrogen

Low d o se va g ina l ET p ro d uce s ve ry low se rum le ve ls o f e stro ge n N o e vid e nce o f incre a se d e nd o m e tria l p ro life ra tio n o r hy p e rp la sia w ith low d o se va g ina l ET

SERUM LEVELS OF ESTROGEN

(WITH LOW DOSE VAGINAL ET)

Levels of E2 after administration of 10 mcg estradiol tablet on days 1, 14, and 83 Basal and chronic estradiol levels in women administered vaginal estradiol Santen RJ, 2015

WHAT ABOUT THE UTERUS WITH VAGINAL ET?

U lrich LS et a l (C lim a teric, 2 0 1 0 ) ­ P ro sp e c tiv e c o h o r t stu d y o f p o st-m e n o p a u sa l w o m e n u sin g 1 0 m c g v a g in a l e stra d io l ta b le t ­ P rim a ry e n d p o in t w a s e n d o m e tria l h y p e rp la s ia / c a n c e r a t w e e k 5 2 ­ O u tc o m e s ­ N o c a s e s o f e n d o m e tria l h y p e rp la sia / c a n c e r b y w e e k 5 2 ­ M e a n e n d o m e tria l th ic k n e ss w a s 1 .9 4 m m a t e n d

• f th e stu d y, c o m p a re d to 2 .0 4 m m a t stu d y sta r t

C O N C L U S IO N L o w d o se s o f v a g in a l e stro g e n g e n e ra lly sa fe fo r e n d o m e triu m

7/2/18 13 NON-ESTROGEN THERAPIES FOR GSM

Ospemifene and more

OSPEMIFENE

• O n ly S E R M a p p ro v e d in U S fo r

tre a tm e n t o f m o d e ra te to se v e re d y sp a re u n ia

• M u ltip le R C Ts c o m p a rin g o sp e m ife n e

to p la c e b o d e m o n stra te d

• Im p ro v e m e n t in v a g in a l m a tu rity

in d e x

• V a g in a l p H
• V a g in a l d ry n e ss
• D y sp a re u n ia
• F e m a le se x u a l d y sfu n c tio n

OSPEMIFENE - THE DETAILS

Dosage:

6 0 m g d a ily

1

Advantages:

a v o id u se o f v a g in a l p ro d u c t

2

Disadvantages:

• Requires daily use
• Systemic side effects

(most common: hot flashes; theoretical risk of VTE)

3 INTRAVAGINAL DHEA (DEHYDROEPIANDROSTERONE)

§Also know n as vaginal prasterone §Requires daily adm inistration §M echanism of action is likely aromatization of androstenedione and testosterone locally to estrone and estradiol §Slight increase in serum levels of DHEA, testosterone, and estrone but levels remained w ithin range of postm enopausal w

• m

en §N

• direct com

parison to vaginal estrogen

7/2/18 14 OTHER TREATMENTS (NOT YET APPROVED)

Testosterone

• D a ta su p p o r t th e e ffe ct o f

te sto ste ro n e o n va g in a l m u co sa a n d sy m p to m im p ro ve m e n t o f G S M

• S m a ll stu d ie s sh ow e d im p ro ve m e n t

in va g in a l m a tu ra tio n in d ex , va g in a l d ry n e ss, a n d d y sp a re u n ia

• E le va tio n s in se r u m te sto ste ro n e
• Va g in a l te sto ste ro n e is N O T

re co m m e n d e d a t th is tim e

Vaginal laser

• La c k o f w e ll-d e sig n e d stu d ie s
• O ve ra ll a p p e a rs to b e sa fe a n d

p o te n tia l n o n -p h a rm a co lo g ic in te r ve n tio n fo r G S M

• N O T a p p ro ve d by F D A fo r

tre a tm e n t o f G S M

• A C O G a d v ise s th a t w e n e e d m o re

R C Ts to e va lu a te sa fe ty a n d e ffica c y

CONCLUSIONS

§HT is most effective treatment for vasomotor symptoms and genitourinary syndrome of menopause §Benefits of systemic HT most likely outweigh the risks for symptomatic women who initiate HT < age 60 or who are < 10 years of menopause §“Appropriate dose, duration, regimen, and route of administration” §Be mindful of HT regimen to minimize risk to patient

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