Menopause

Intro

• menopause is part of the NORMAL female aging process

• average age is 51 (range b/w 45-55 years)

• women will spend 1/3 of their lives post-menopause

Stages of Reproductive Aging (STRAW)

• Menopausal transition:

  • early: menstrual cycles still regular but can be experiencing sx and also notice some shifts in cycle (freq etc)

  • late: starts missing more periods; cycles become farther apart; a lot of times perimenopause is missed bc they still have regular periods

  • perimenopause: time leading up to last menstrual period

• postmenopause after diagnosis is made

Definitions

• natural menopause:

  • 12 mo of amenorrhea w/ no know pathologic cause

• induced menopause:

  • menopause following surgical removal or iatrogenic ablation of ovaries (e.g. chemo, radiation)

• early menopause:

  • before age of 45

• premature menopause (sometimes called premature ovarian insufficiency/POI:

  • before age of 40

Menopausal transition

• ovarian fxn:

  • decreased number and fxn of follicles - most follicles lost through atresia (dying off of follicles)

  • reduced response to FSH and LH

• menstrual cycles:

  • anovulatory cycles (no ovulation during these cycles) - result in menstrual irregularity

• hormones:

  • altered feedback regulation - increase in FSH/LH levels

  • fluctuating and decline of ovarian hormone production - estrogen and progesterone (since not ovulating)

Estrogen

• Estrone (E1) - 1/3 potency of estradiol; conversion in liver, androstenedione in peripheral tissue (from fat tissue)

• Estradiol (E2): most potent; produced in ovaries; highest amount BEFORE menopause

• Estriol (E3): least potent; metabolite from E1 and 2; highest levels in pregnancy as also produced by placenta

• estrogen production before menopause - 4:1 ratio of estradiol:estrone

• estrogen production AFTER menopause - 4:1 ratio of estrone:estradiol

Estrogen Receptor Signals

• most actions on reproductive fxn mediated via nuclear estrogen receptors alpha (repro areas) and beta (vessels, heart, lungs)

  • transcription factors that regulate gene expression

What happens to estrogen and progesterone during the menopause transition?

Perimenopause

• higher and fluctuating estrogen levels, lower progesterone levels

Postmenopause

• low estrogen and progesterone levels

• elevated FSH and LH (sustained) - no neg inhibition by estrogen

Testosterone

• 25% ovaries, 25% adrenals, 50% peripheral conversion from androstenedione

• helps maintain libido and general well-being

• levels decline gradually as women age; not as drastic as estrogen (ovaries keep making testosterone even after menopause)

  • decline due to aging rather than menopause

• surgical menopause will result in drop of testosterone by 50% (still will see some production in body bc released by adrenal glands)

Diagnosis

Menopause

• cessation of period x 12mo

• elevated follicle stimulating hormone FSH levels (>30 mIU/ml) - not diagnostic, mainly based on not having a period

Perimenopause

• sx

• ± menstrual cycle changes

• NOT diagnosed w/ FSH (can fluctuate)

Symptoms

Duration of sx longer than previously thought:

• duration of 7-8yrs for VMS

  • median duration after last menstrual period ~4.5 yrs

• for third of pts can be longer than 10 yrs

• 20-25% severe enough to negatively effect QofL

• may sx during perimenopause - esp VMS, mood (irritability, PMS), insomnia

• note: pregnancy is STILL POSSIBLE during perimenopause → contraception still important***

Hot flashes independently linked w/ chronic diseases

• earlier and more severe hot flashes have been linked w/ negative CV outcomes later in life; also been shown w/ brain health (cognition, dementia)

Menopausal sx

other sx: muscle or joint aches/pain/back aches, breast tenderness and headaches/migraines (may be more common in peri), heart palpitations, low libido, dry skin/eyes, hair changes

Changes in Menstrual cycle w/ perimenopause

Changes in length:

• early peri: more freq

• late peri: farther apart/missed periods

Changes in flow:

• heavier or lighter

• shorter or longer periods

VMS

• estrogen levels alone not predictive of severity (hormone fluctuations cause the sx)

• occurs in ~75% women

• hot flash: heat in upper body - face, chest, neck; may see perspiration, clamminess, anxiety and increased heart rate/palpitations

• night sweats

• sx peak in early evening

• Mechanism:

  • KNDY neurons in hypothalamus - control thermoregulatory centres

  • stimulated by neurokinin B, inhibited by estrogen

  • low estrogen levels lead to hypertrophy of KNDy neuons

  • target of new tx approaches for VMS (neurokinin receptor antagonists)

Genitourinary Syndrome of Menopause (GSM)

• degeneration of connective tissue:

  • collagen, elastin, SM

  • vaginal shortening and narrowing

• reduced vaginal blood flow and secretions (thinning mucosa)

• glycogen production decreases → change in vaginal pH from acidic to alkaline (increased pH); increased UTIs bc loss of glycogen production

Symptoms of GSM

Vaginal atrophy

• vaginal dryness, irritation/itching, dyspareunia, post-coital spotting

Lower urinary tract

• recurrent UTI

• LUTS (urgency, freq, dysuria)

Sexual fxn

• low libido/desire

Midlife Health Changes

• CV: estrogens and CV - protective effect on artery intimal layer prevents atherosclerosis, thickening of layer before menopause

• bone health:

  • bone loss occurs at faster rate w/ loss of estrogens (greatest decline in first 10 yrs after last period)

  • assess for osteoporosis risk factors

Cognition

• estrogens modulate aspects of brain fxn

  • hippocampus

• estrogens → NTs (5HT, NE, DA, ACh)

• loss of estrogens - may affect concentration, memory (verbal memory - not being able to think of a word, someone’s name etc)

• effect on cognition long term - loss of estrogen or is it aging??

Effects of Early or Premature Menopause (before age 45, esp <40**)

• associated w/ increased risk of:

  • osteoporosis

  • CV disease

  • cognitive impairment/memory

  • early mortality

  • need hormone therapy to prevent effects of estrogen loss**

Assessment of Menopause

Lifestyle Based measures

• cooling techniques

  • dress in layers

  • breathable fabrics

  • use fan

• avoid triggers

  • excessive alcohol

  • spicy foods

• maintain healthy body weight (higher BMI assoc w/ more VMS)

• smoking cessation

• exercise

• yoga

Complementary thereapy

• evidence to support

  • cognitive behavioral therapy

  • mindfulnesss based stress reduction

• Inconsistent evidence

  • acupuncture

  • phytoestrogen or soy based products

NHPs: Phytoestrogens

• plant compounds w/ estrogen-like activity (500-1000x weaker than estradiol)

• isoflavones: soy, red clover, chickpeas etc

• lignans: flaxseed, whole grains etc

• coumestans: red clover, split peas, pinto beans etc

• “marginal effect” w/ hot flashes, inconsistent results in studies

• ~8-12wks to work

• caution w/ hormone-sensitive cancers

Fermented soy bean extract (NHP)

• Femarelle

• RCT showed decrease in VMS

• no adverse changes in breast or endometrium

• no safety data in breast cancer risk

Black Cohosh

• extact MOA unknown (may act as a SERM)

• takes up to 8-12wks for effect

• mixed data; generally well tolerated

• case reports of liver damage

What do guidelines say?

• systemic MHT is a safe, effective option to initiate in healthy individuals <60 years of age or less than 10 years after their last menstrual period

• for early or premature menopause (before age 40) consider MHT until average age of menopause (50-51)

Benefits of MHT: Summary

• systemic MHT is MOST effective option for mod-sev VMS

• other benefits:

  • sleep - reduces latency

  • improves mood

  • contributes to well-being

• preventing bone loss and fractures

• GSM - vaginal estrogen therapy

Initiating MHT Considerations

• individualize MHT to:

  • sx

  • medical conditions

  • risk factors

  • pt preferences

CIs to MHT

MHT and VTE

• estrogen dose-dependent procoagulant effect

• increased risk of VTE w/ both EPT and ET

• greatest risk in first year, w/ familial thrombophilia or other risk factors

• transdermal estrogen may have lower VTE risk however, these are based on observational studies only (PO estrogen has higher first pass effect; can increase clotting factors)

• transdermal MHT does NOT have same VTE risks as transdermal CHC bc doses used in MHT are much lower and less potent (4-5x less)

MHT and CV risk

• age and time since menopause matter!

• individuals at high risk for CVD should avoid MHT, this includes transdermal estrogens or lower dose estrogens

• address all modifiable CVD risk factors! (HTN, smokers, obesity, diabetes)

MHT and breast cancer

• EPT in WHI showed increase risk after 5 yrs of use

  • however - less than1 per 1000 women per year (less than 0.1% so rare)

• ET alone didn’t show increased risk of breast cancer in WHI

• may be differences in risk w/ type of progestogen

  • progesterone may have lower risk compared to synthetic progestins

• breast cancer hx:

  • avoid MHT if personal hx, although could be considered in severe VMS unresponsive to non-hormone options

  • be cautious of fam hx:

    • breast cancer in 2 or more first degree relatives prior to menopause

  • try to reduce breast cancer risk by healthy lifestyle, weight reduction etc

Systemic MHT regimens

EPT continuous - most commonly prescribed

• estrogen and progestogen everyday

• will see spotting/BTB for 6-9mo but will get better

EPT cyclic

• estrogen continuous

• progestogen x 12-14d (often first 14d of the month)

• will lead to small withdrawal bleed when progestogen is stopped at the end of 12-14d cycle

What about for perimenopause?

• sx can start before changes in menstrual periods or opposite may occur

• consider contraceptive needs (up to 1yr from the FMP) - can still get pregnant at 50-51

• options depend on sx, bleeding patterns and contraceptive needs

• options:

  • EPT cyclic, also progesterone alone

  • if irregular bleeding and/or contraceptive needs:

    • low dose CHC

    • estrogen plus LNG-IUS

MHT products: Estrogen

• estrogen types:

  • conjugated estrogen (premarin)

  • 17B-estradiol

  • estrone

• formulations:

  • oral, transdermal: patch, gel; vaginal (for GSM only): cream, tabs, ovules

MHT products: Progestogens

• types:

  • micronized progesterone (Prometrium brand in sunflower oil; generics may contain peanut oil so caution w/ allergy**)

  • synthetic progestins:

    • medroxyprogesterone (MPA)

    • norethidrone acetate (NETA)

  • also LNG, drospirenone

• formulations:

  • oral, transdermal patch in combination w/ estrogen

  • LNG-IUS (NOT INDICATED by Health Canada for endometrial protection w/ estrogen)

Synthetic Estrogen Routes of Admin

Choosing Transdermal Estrogen over oral products

Situations:

• avoid first pass effect:

  • smokers - smoking increases metabolism of oral estrogen

  • high TG’s - no increase in TGs

  • HTN - doesn’t increase BP

  • low libido - less effect on SHBG

  • gall bladder disease - doesn’t exacerbate disease (PO can)

  • risk factors for VTE/CVD - possible less effect on coagulation factors

• for consistent levels:

  • migraines - provides less fluctuating estrogen levels

  • shift workers - allows for consistent dosing

  • malabsorption issues - avoid issues w/ po absorption

Systemic estrogen: Transdermal Products

• patches

  • twice a week patches: Estradot, Oesclim

  • once a week patches: Climara

• gel:

  • Estrogel; apply daily to same area; takes 2-3 days to work

  • Divigel: apply daily (doesn’t have to be same area)

Doses for systemic HT

• start w/ low to standard dose of estrogen

• estrogen:

  • equivalent to 0.5-1mg of oral 17B-estradiol

    • 0.625mg CEE = 1mg 17B-estradiol oral = 50ug patch = 1-2 pumps estrogen = 5ug EE

• progestogens in EPT regimens

  • continuous - MPA 2.5mg or micronized progesterone (take in PM) 100mg daily

  • cyclic - MPA 5mg or micronized progesterone 200mg for 12-14 days/month

AEs w/ MHT

vaginal bleeding/BTB is one of the most commone AEs

• AEs improve over 2-4 wks

• BTB can occur up to 6-9mo after starting continuous EPT, any ongoing bleeding in a postmenopausal individual after 12mo should be investigated

• patches may leave dirt rings on skin

Tibolone (Tibella)

• considered a selective tissue estrogenic activity regulator (STEAR)

• synthetic steroid analogue of progestin, norethynodrel

• converted to 3 active metabolites w/ estrogenic, progestogenic and androgenic activity

• androgenic effects may help w/ libido though not Health Canada approved

• AEs: fatigue, breast tenderness, fluid retention, stomach upset/nausea, increased appetite

• same risk profile as other MHT

• Advantage: less BTB compared to EPT

Tissue-selective estrogen complexes (TSECs)

• combines estrogen w/ a SERM

• Bazedoxifene - SERM that has antagonist ER effects on uterus (inhibits endometrial hypertrophy) and breast, agonists effects on bones

• since lower dose estrogen (0.45 CE) takes ~6-8wks or longer to work

• may have reduced rates of BTB and less breast tenderness compared to EPT

• shows NO increase in breast density (predictor of breast cancer risk)

Progestogens for VMS

• alone may also provide benefit for VMS

• may be an option for women who have CI to estrogen therapy

• higher doses of micronized progesterone 300mg qhs have been used in studies

Bioidentical hormones (BHT)

• chemically identical in molecular structure to human hormones

  • estradiol, estrone, estriol, progesterone, testosterone, DHEA

• sometimes term is used to describe “compounded MHT”

• can be found in both commercial and compounded products

• often promoted as being “natural” but this is a misnomer

• compounded BHT often promoted to be “safer” than commercial MHT products but not enough evidence to say compounded BHT is safer than commercial MHT products

• certain bioidentical hormones might have some benefits but this is not specific to compounded BHT

Compounded BHT:

• both estriol and natural progesterone creams may help w/ VMS however:

  • estriol: ~1/80 potency of estradiol

  • systemic products require endometrial protection w/ progestogen

  • should NOT be promoted as safer

  • natural progesterone creams:

    • should NOT be used w/ estrogen therapy for endometrial protection

Hormone customization

• adjustments in dosing of MHT is based on sx

• hormone customization using blood levels or saliva testing to adjust doses is difficult - esp in perimenopause when hormones are fluctuating (also don’t know what their baseline should be)

  • also women will have different responses to different levels of hormones

Duration of MHT use

• decision to d/c therapy is individual decision (when they turn 60 they do NOT have to stop)

• decision to continue should be reassessed at regular intervals (e.g. annually)

• there is NO age limit to continue MHT - duration can be continued as long as pt is getting benefit, even into their 60’s

• consider baseline risk changes over time

Non-hormonal Rx Options for VMS (all off label)

• SNRI/SSRI

  • increases 5HT levels in thermoregulatory zone

  • trial lower dose for 1-2 wks before increases to recommended dose

  • drug interaction w/ parox/fluox and tamoxifen - inhibits CYP2D6 → inhibits conversionto endoxifen reducing levels of the active metabolite

• gabapentinoids (gaba, pregab)

  • MOA for VMS unknown, may have direct effect on hypothalamic thermoregulatory center

  • gaba - some use qhs doses of 600-900mg to help w/ sleep

• clonidine

  • central acting alpha adrenergic agonist

  • moa unknow, may decrease vascular reactivity in some fashion

  • tolerability at higher doses problematic (dry mouth, dizziness, drowsiness, hypotension)

  • 4 wks for response

  • not as effect as other non-hormonal rx options

• oxybutinin

  • moa: anticholinergic agent

  • newer option for VMS

  • AEs: dry mouth, constipation, blurred vision, cognitive issues

• general principles:

  • less effective than MHT for VMS

  • response w/i 2-4 wks for most agents

  • target options based on sx:

    • mood effects - antidepressants

    • sleep issues - gabapentin

    • urinary sx - oxybutynin

NK receptor antagonists (first non-hormonal that will have indication for VMS)

• NK-3 receptor antagonist: fezolinetant

  • works on KNDy neurons

  • improvement after 1wk seen - freq and severity of VMS

  • well tolerated (headache main SE)

  • check LFTs at baseline and q3months for at least 9mo (the only limitation)

Non-hormonal products for GSM

• lubricants help reduce friction - used w/ intercourse (not for preventative measures)

• vaginall moisturizers replace vaginal moisture - used regularly every 3 days (or 2-3x/wk)

• lubricants may be water, silicone or oil based

  • oil based: may erode condoms so don’t use together

    • natural oil based include olive and coconut oil

• be careful w/ additives/irritants*** - parabens, glycerin, propylene glycol

• polycarbophil - shown to be as effective as vaginal estrogens for dryness (Replens)

• Hyaluronic acid - draws in moisturizer to places applied, may be anti-inflamm, also shown to be as effective as vaginal estrogens in small RCTs

  • available as ovules/suppositories, gel, cream

• both moisturizers and lubricants can be used w/ other therapies

Estrogen: Vaginal Products

• very little systemic absorption - only used for GSM*** NOT VMS or any other sx

• progesterone is NOT NEEDED for endometrial protection

• systemic absorption can occur w/ vaginal creams however at higher than recommended doses (maybe pt is using it too much daily)

• can prevent recurrent UTIs

• 40% of women on systemic MHT will continue to have urogenital sx - CAN be used together w/ vaginal products

• intravaginal cream: CE Cream or estrone cream (Estragyn)

  • daily for 2 wks then twice weekly

• ring: Estring; change every 3 months

• tablets: Vagifem, Imvexxy

  • one tab daily for 2 wks then twice weekly

Ospemifene - first oral agent for GSM

• oral SERM for vaginal dryness and dyspareunia

• AEs: hot flashes

Intravaginal DHEA (prasterone, Intrarosa) for GSM

• inactive sex steroid precursor converted to estrogen and androgen in cell (works directly on cell)

• one ovule inserted qhs

• AEs: vaginal discharge from melting hard-fat excipient in ovules