Menopause

Average age of menopause is

51 years (range is 45-55)

Most people will have symptoms of menopause

5-10 years earlier than menopause

Premenopause

Reproductive years

Estrogen is stable

Cycle stable

Start seeing changes as early as 35 yrs old

Menopause

Dx from last menstrual period

If they haven’t gone a full year without a period we do not say they’ve had it yet

Perimenopause

Changes in cycle, symptoms, change in bleed patterns

Severe symptoms can be found in peri menopause and first few years of menopause

Postmenopause

After diagnosis (full year after not having a period)

Early peri menopause

Regular cycle

Some change maybe

• Closer or farther apart

• Heavier or lighter

Late peri menopause

Missed periods

• 60-90 days without a period

• More symptoms of menopause outside cycle changes

Early Post menopause

First 5 years of menopause

Late post menopause

After 5 years of diagnosis

Natural menopause

1 year of amenorrhea no known cause

induced menopause

From sx removal or iatrogenic ablation of ovaries

early menopause

Before age of 45

premature menopause / premature ovarian insufficiency (POI) / premature ovarian failure (POF)

menopause before age of 40 years

Estrone E1

1/3 potency of estadios

Convert in liver, and rotes Dione in peripheral tissue (why we can have estrogen after menopause, can convert to estadios)

estadiol E2

Most potent produced by ovaries

estriol E3

least potent

Metabolite from estradiol and estrone

Highest levels in preg and produced by placenta

Post menopause has lots of

estrone from body fat

pre menopause has a lot of

estradiol

ovaries have both

alpha and beta estrogen receptors

progesterone is reduced in

peri menopause

Perimenopause has lots of fluctuations in hormones = bad symptoms or experience symptoms

FSH and LH rise in

perimenopausal and post menopausal (sustained FSH and LH)

testosterone in women after menopause

Decrease of testosterone in menopause but not as drastic

More from aging rather

BUT if sx menopause can drop testosterone by 50%

testosterone made in woman’s body

¼ ovaries, ¼ adrenal, ½ peripheral conversion androstenedione

Why shouldn’t you take hormone levels to determine perimenopausal condition?

FSH cannot be used to determine it - especially if they are still menstruating

Menopause dx

No period 1 year

Elevated FSH >30

Symptoms of menopause

vasomotor symptoms (hot flush, night sweats) can last 7-10 years and years before menopause… these improve with time

Mood (hormone flux)

Sleep issues - fragmented sleep or cannot fall askeep ( maybe bc night sweats)

Concentration, memory issue

GSM - vag dry, painful sex, more UTIs gets worse with time

Deficiency of estrogen (bone, joint pain, dryness)

Deficiency of testosterone (low libido)

duration of menopausal symptoms

Usually 7-8

Median is 4.5 years

1/3 can have it longer than 10 years

¼ is severe enough to -ve effect qol

Why do SSRI and Antidepressants work for VMS?

loss of estrogen decreases endorphins in hypothalamus → increased NE and decreased 5HT → narrow thermoreg zone in hypothalamus = easier to feel hot or cold

KNDy meachanism for VMS

KNDy neurons are in hypothalamus and control thermoregulatory centres

Inhibited by estrogen ! = low estrogen leads to hypertrophy of KNDy neurons and if more active means more hot flashes

GSM (genitourinary syndrome of menopause) symptoms

Degeneration of connective tissue in vaginal from loss of estrogen

Reduced blood flow = dryness

Glycogen decreased = more alkaline environment, less lactobaccilli (lives in acidic environment), more likely to have UTI

LUTS

Low libido = tied to Dyspareunia (painful intercourse) = tied to vaginal dryness and irritation

Post coital spotting

UTI tx in menopausal patients

Vaginal estrogen can help alongside Abx

GSM symptoms get

Worse OT

vasomotor symptoms get

Better OT

Estrogen on arteries

Protective effect = on intimal layer

Put at increased risk of CVD if early premature menopause

Also could help control BP, lipids

long term estrogen

decreases plaques

Stabilizes plaque

Decrease endothelial injury

Vasodilation

Decrease smooth muscle cell growth

estrogen on bone health

bone loss is faster if less estrogen

Osteoporosis risk

estrogen on brain

many receptors in brain

Effect neurotransmitters, concentration and memory (side effect of menopause)

Long term memory = don’t know if it’s from loss of estrogen or aging but those that go through premature menopause have more issues with memory and early onset dementia

Effects of Early or Premature Menopause

Associated with increased risk of:

• Osteoporosis

• Cardiovascular disease

• Cognitive impairment/memory

• Early mortality

Lifestyle measures to help with Menopause

Cooling (dress in layer, fan, breathable)

Avoid trigger (alcohol, spicy food)

Smoking cessation (smoking induces estrogen metabolism, can start menopause earlier)

Asian women have less VMS - why?

Have less reports of VMS - why - soy in Asian diet is higher in NA or Caucasian diets

Soy, flaxseed must be ground (Isoflavone is in cell wall)

Supplements CI

With hormone sensitivity cancer etc

Not an issue from diet

phytoestrogens - 3 kinds

weaker than estrogen but work in same way

Isoflavones

Lignans

Coumestans

Isoflavones

soy

Red clover

Chickpeas

Garbanzo

Lentil

Beans

Lignans

flaxseed (ground)

Sunflower seed

Whole grain

Coumestans

red clover

Split peas

Pinto beans

Alfalfa sprout

Isoflavones of soy and why they are interesting

Daidzein

Genistein

Glycerin

Mimic estrogen ins shape

Flaxseed for phytoestrogens

must be ground (estrogen in seed wall)

1- 3 tablespoons?

Soy protein for phytoestrogens

30 -50gm qd in diet

Isoflavone supplements for phytoestrogens

40-80mg qd

How long does it take for phytoestrogens to work?

8-12 weeks - inconsistent results

Food is the best source for phytoestrogens and caution supplements only in hormone-sensitive cancers.

Black Cohosh as estrogen supplement

SERM (selective estrogen receptor modulator)

takes 8-12 weeks to see effect

can cause liver damage

Why did menopausal therapy drop in early 2000s?

fear of CVD risks. - how it was published in media

26% increase in breast cancer risk and 29% increase in heart disease (from hazard ratio)

did not talk about benefit in hip fracture or colorectal cancer

Systemic Menopause Hormonal Therapy (MHT) is safe to initiate in who?

timing hypothesis: in healthy <60 years of age or less than 10 years after their last menstrual period

For premature menopause, use MHT until average age of menopause

Early HT helps prevent plaques, later HT will be more risky (more plaques in body if older)

How does MHT help with VMS?

Thermoregulation from estrogen

Estradiol and mood —> prevents enzymes breakdown of endorphins and increases production of 5HT

Other benefits of MHT

Sleep - reduces latency

bone mineral density

GSM - vaginal estrogen therapy

Progestogen is needed in MHT when estrogen is used because

endometrial protection of estrogen supplementation → prevent unopposed endometrial growth and risk of cancer for those who have a uterus

CI to MHT

undx abnormal vag bleed

hx or current breast cancer

Heart disease

VTE, Stroke

Thrombophilia

Liver disease

Pregnant

WHI (womens health initiative study)

mean age was 63 yrs

extrapolation not studied

If women had symptoms they were excluded from study - benefits on symptoms not addressed…

NOTE THAT ANALYSIS WAS DONE POST MEDIA PUBLICATION ! - ESTROGEN ALONE WAS FINE.

used conjugated equine estrogen and medroxyprogesterone acetate DMPA)

Reanalysis of EPT and ET arms in WHI

Less risk in younger age groups

Starting MHT in older ages associated with

What is the timing hypothesis

primary benefits of Hormone therapy found 45-60 years (perimenopause)

VTE and estrogen

risk greatest in first year and with risk factors

transdermal lower VTE risk? only based on observational studies

T/F Transdermal MHT at low standard doses have the same risk of VTE as transdermal CHC

False -

Why ; the amount of estrogen that is given in menopausal dose is lower than the potency in COC ( CHC is much higher vs standard dose menopausal HT)

If doses are higher in menopause therapy, then it will have a higher risk that is equal to COC

Breast cancer and MHT

ET alone - no increased risk

Nowadays, natural progesterone has lower risk of Cancer than the SYNTHETIC ones

Breast cancer history and MHT

Caution:

(Breast cancer in younger members is likely from estrogen )

Breast cancer in two or more first degree relative prior to menopause

Must do SDM

Reduce breast cancer by

less than 2 alcoholic drinks a day

Not obese

No MHT ?

Management of menopausal symptoms

More than 1 yr since final menstrual period

If severe or moderate consider age → over 60 or over 10 yrs since menopause do non hormonal rx

→ if less than 60, less than 10 rs since menopause consider if they have a uterus or not (estrogen only if none, E+P if uterus)

EPT cyclic

Estrogen continuous but progestogen is given on first of month for 14 days

may get withdrawal bleed after stopping progesterone! counsel on this

EPT continuous

both E+P continuous

more likely to get BTB any time during course

Can you get pregnant even after 1 year from the Final Menstrual Period?

Yes! still need for contraception

If perimenopause and irregular bleeding / contraceptive needs, use:

low dose CHC or E + IUD (MUST BE MIRENA)

micronized progesterone

may be concern for peanut allergies → now it is made in sunflower oil, but generics may use peanut oil

Are IUDs indicated by health canada for endometrial protection with estrogen?

NO

Transdermal > oral E tx because

no 1st past effect

less flux in hormone

less effect on lipids

should one be put on estrogen due to decreasing lipids?

NO! even though it decreases LDL and increases HDL

What does oral ET effect?

increases:

Triglycerides

Sex Hormone Binding Globulin

thyroid binding globulin

CRP

when to use transdermal over oral

Smoker

high TG, HTN, risk for VTE

gall bladder disease

low libido (no effect on SHBG)

migraines, shift workers (easier to dose), malabs

starting dose of MHT is

4-5 times lower than potency of CHC → why there is a lower baseline risk in MHT vs CHC

vaginal estrogen AE

vaginal discharge

irritation → will decrease as tissue becomes stronger and less fragile from more estrogen

micronized progesterone AE

sleepy

nightmare

give at night to help with night flashes and sleep

most common AE of MHT is

BTB

adverse effects with MHT last

2-4 weeks (at least, they improve over this timeframe)

BTB: for at least 12 months after starting continuous EPT, but if it lasts longer than 12 months it should be investigated

cyclic EPT- withdrawal bleed at end of cycle

Tibella / Tibolone

selective tissue estrogenic activity regulator (STEAR)

Converted to three active metabolites with estrogenic, progestogenic, and androgenic activity - do not give with progesterone since it has activity

May help with libido

Tibella AE

fatigue, breast tenderness, fluid retention, stomach upset/nausea and increased appetite

less BTB vs EPT

Tissue-Selective Estrogen Complexes (TSEC’s)

Estrogen + SERM

Bazedoxifene

– SERM that has antagonist ER effects on uterus and breast, agonists effects on bones

CE and Bazedoxifene

less BTB and breast tenderness vs EPT

no increase in breast density

Biocidentical hormones means (3)

1. Chemically identical molecular structure to human hormones ; estradiol, estrone, estriol, progesterone, testosterone, dhea

2. Compounded MHT

3. Can be referring to something natural

Plant sourced estrogen

All estrogen is from plant sources (Soy, yam)

All manufactured or compounded products

Biest

– estriol (80%), estradiol (20%) OR estriol (50%), estradiol (50%)

Triest

– estriol (80%), estradiol (10%), estrone (10%)

Compounded bioidentical hormone therapy - caution

Adjusted according to salivary or blood levels BUT we should not do this due to flux in hormones during Perimenopause

Considerations for Compounded BHT Estriol

Estriol: ~1/80 potency of estradiol

• systemic product need endometrial protection with progestogen

• not safer in regards to breast cancer - no evidence

Compounded BHT natural progesterone cream consideration

Should NOT be used with estrogen therapy for endometrial protection – lack of studies to show that it will prevent endometrial hyperplasi

When should a woman stop MHT?

No direct answer - reassess yearly and do SDM with patient

No age limit to continue MHT, duration can be continued as long as individual is getting benefit even into 60s

Baseline risk changes over time for diseases

Non hormonal prescription options (in cancer patients)

SNRI/ SSRI

GABA or pre gaba

Clonidine

Oxybutinin

SSRI or SNRI MOA

Increase 5HT in thermoreg zone (less flashes and improved mood)

Dosing for SSRI/SNRI

Trial for low dose 1-2weeks then increase to rec dose