MENOPAUSE PART 3: Therapeutic Options

Question 1

Management of Menopausal Symptoms:
Postmenopause

flowchahrt
see sllide 4

Answer 1

> 1 yr since FMP

Age >60,, or >10 yr since menopause?
contra to MHT? high risk of CVD?

Yes –> consider non-hormal prescription options

No –? hyserectomy? –> Yes –> estrogen alone tx

No –> estrogen and progestogen tx
other MHT tibolone, TSEC

Question 2

Systemic MHT regimens

Answer 2

§ EPT continuous - most commonly prescribed.
§ EPT cyclic:
§ ET - Use of estrogen alone if hysterectomy.
Estrogen Continuous
Progestogen Continuous
Estrogen Continuous
Progestogen x 12 - 14d

Estrogen always
When pt stop progestin, there is light withdrawal bleed
Breakthru bleeding 6- monhts
Any breakthru bleeding past 12 months should be investigated

Question 3

What about for perimenopause?

Answer 3

§ Symptoms can start before changes in menstrual periods
§ Consider contraceptive needs (up to 1 year from the FMP)
§ Options depend on symptoms, bleeding patterns and
contraceptive needs

Options for perimenopause:
* EPT cyclic, also progesterone alone
* If irregular bleeding and/or
contraceptive needs:
* low dose CHC
* estrogen plus LNG-IUS*

Question 4

MHT Products: Estrogen

Answer 4

Estrogen types:
* conjugated estrogen
* 17b-estradiol
* estrone

Formulations:
* oral
* transdermal: patch, gel
* vaginal (for GSM only):
cream, tablets, ovules
See table of MHT products in Canada

Question 5

MHT Products: Progestogens

Answer 5

Progestogen types:
* micronized progesterone* most common
* synthetic progestins:
medroxyprogesterone (MPA), also common
norethindrone acetate (NETA) (not first line)
* also: levonorgestrel,
drospirenone (oral pdt with estradiol)

Formulations:
* oral
* transdermal patch in
combination with estrogen
* levonorgestrel IUS**
*note: Prometrium® brand now in sunflower oil, there may be generics in peanut oil, cautioun with peanut allergy
** LNG-IUS not indicated by health Canada for endometrial protection with estrogen

Question 6

Systemic Estrogen Routes of Administration
Oral ET

Answer 6

Ø High first pass effect
* á TG’s
* á SHBG
* á TBG
* á C-reactive protein
Ø Some fluctuations in hormones
Ø Improve lipids á HDL, â LDL

affect thyroid binding globulin
increase sex hormone binding globulin

Transdermal ET
Ø No first pass effect
Ø Less fluctuations
Ø Less effect on lipids

Question 7

Choosing Transdermal Estrogen Over Oral Products

Answer 7

Rationale with transdermal
Avoid first pass effect
Smokers Smoking increases metabolism of oral estrogen
High triglycerides No increase in triglycerides
Hypertension Does not increase BP
Low libido Less effect on SHBG
Gall bladder disease Does not exacerbate gall bladder disease
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 with oral absorption

Question 8

Systemic Estrogen: Transdermal Products

Answer 8

Patches:
Twice a week patches: Estradot,`
Oesclim
Once a week patches: Climara

Gel: Estrogel
Apply daily (to same area).
Can accumulate in skin after a few days of use, enough levels to get to systemic
if doing arms, always stick with arms
if legs, always stick with legs

Gel: Divigel
Apply daily (does not have to be to
same area)

Question 9

Doses for Systemic HT

Answer 9

Start with low to standard dose of estrogen
estrogen:
equivalent* to 0.5 – 1 mg of oral 17b-estradiol

progestogens in EPT regimens
continuous - MPA 2.5mg or micronized progesterone 100mg daily
cyclic - MPA 5mg or micronized progesterone 200mg for 12 – 14 days per month
Estrogen “equivalence” approximately*:
0.625mg CEE = 1mg 17ß-estradiol
(oral) = = 50µg patch = 1- 2 pumps

Estrogel = 5µg ethinyl estradiol
*Note: there is no true “equivalence”, as difficult to determine, you can consider these as starting doses

Question 10

Adverse Effects with MHT

Answer 10

Vaginal bleeding/breakthrough bleeding is one of the most common adverse effects
Estrogen related:
§ breast tenderness
§ fluid retention
§ headaches
§ nausea
Vaginal estrogen:
vaginal discharge, irritation

Progestogen related:
* breast tenderness
* fluid retention
* bloating
* headaches
* mood: depression, PMS, fatigue
* micronized progesterone –
sleepiness, nightmares

take at night to help with sleep

Question 11

Dealing With MHT Adverse Effects

Answer 11

§ Adverse effects will improve with time over 2 - 4 weeks.
§ Breakthrough bleeding can occur up to 6 - 9 months after starting
continuous EPT, any ongoing bleeding in a postmenopausal
individual after 12 months should be investigated.
§ Cyclic EPT will lead to a small withdrawal bleed when progestogen
is stopped at the end of the 12 - 14 day cycle

Answer 12

§ Considered a selective tissue estrogenic activity regulator (STEAR)
§ Synthetic steroid analogue of the progestin, norethynodrel
§ Converted to three active metabolites with estrogenic,
progestogenic, and androgenic activity
§ Androgenic effects may help with libido though not Health Canada
approved for this
Dose: 2.5 mg oral tablet daily

§ Adverse effects: fatigue, breast tenderness, fluid retention,
stomach upset/nausea and increased appetite
§ Same risk profile as other MHT
§ Adv: less breakthrough bleeding compared to EPT

Question 13

Tissue-Selective Estrogen Complexes (TSEC’s)

Answer 13

§ Combines estrogen with a SERM
§ Bazedoxifene – SERM that has antagonist ER effects on uterus
and breast, agonists effects on bones
§ 0.45 CE + 20 mg bazedoxifene – Duavive® Dose: one tablet daily

CE + bazedoxifene con’t
§ May have reduced rates of breakthrough bleeding and less breast
tenderness compared to EPT.
§ Shows no increase in breast density (which is a predictor of breast
cancer risk).
§ Currently temporarily withdrawn by the company due to issues
with packaging; company anticipates return of the product

Question 14

What are Bioidentical Hormones?

Answer 14

§
“Bioidentical” → chemically identical in
molecular structure to human hormones
* estradiol, estrone, estriol, progesterone,
testosterone, DHEA
§ Sometimes the term is used to describe
“compounded MHT”
§ Bioidentical hormones can be found in
BOTH co

Question 15

MHT Sources

Answer 15

§ Most products available in Canada come from plant sources →
extracted from wild yam or soy and then synthesized
* This includes commercially manufactured products AND
compounded products

soy and yam prescurs

Question 16

A Few Words on Compounded Bioidentical
Hormone Therapy (BHT)

Answer 16

§ Many compounded estrogen products use estriol in combination
(topical creams/capsules/etc):
pBiest – estriol (80%), estradiol (20%) OR estriol (50%),
estradiol (50%)
pTriest – estriol (80%), estradiol (10%), estrone (10%)
§ Compounded progesterone: progesterone creams, capsules
§ Dosage adjusted according to salivary or blood levels
§ Sometimes you may see the addition of testosterone or DHEA to
the BHT regimen.

Question 17

Both estriol and natural progesterone creams may help with VMS, however need to
keep these points in mind:

Answer 17

Estriol: ~1/80 potency of estradiol
§ Systemic products will require
endometrial protection with a
progestogen.
§ At this time, data is inconclusive if
lower risk of breast cancer with estriol –
it should not be promoted to be safer.1,2
Natural progesterone creams:
p Compounded prescription creams:
Should NOT be used with estrogen
therapy for endometrial protection –
lack of studies to show that it will
prevent endometrial hyperplasia

Natural creams should not be used in combinaton with estrogen for endometrial protection

Question 18

Hormone Customization

Answer 18

§ Adjustments in dosing of MHT is made based on symptoms.
§ Hormone customization using blood levels or saliva testing to
adjust doses is difficult to achieve – especially in perimenopause
when hormones are fluctuating.
* Also women will have different responses to different levels of
hormones

Question 19

Duration of MHT Use

Answer 19

§ Decision to discontinue therapy is an individual decision
§ The decision to continue therapy should be reassessed at regular
intervals (ie annually)
§ There is NO age limit to continue MHT – duration can be
continued as long as the individual is getting benefit, even into
their 60’s
§ Consider that baseline risk changes over time

Question 20

Non-hormonal Prescription Options

Answer 20

Non-hormonal prescription
options for VMS
§ SNRI/SSRI antidepressants
§ Gabapentinoids – gabapentin,
pregabalin
§ Clonidine
§ Oxybutinin

have evidence for VMS improvmenet

Question 21

SSRI/SNRI Antidepressants

Answer 21

§ Mechanism: increase in serotonin levels in thermoregulatory zone
§ Trial lower dose for 1 – 2 weeks, before increasing to recommended
dose
Watch drug interaction with paroxetine (also fluoxetine) and tamoxifen –
inhibition of CYP2D6 by paroxetine/fluoxetine - inhibits the conversion of
tamoxifen to endoxifen (reducing the levels of endoxifen, the active metabolite of
tamoxifen)

Question 22

Gabapentinoids

Answer 22

)
* Mechanism: for VMS unknown, may have direct effect on
hypothalamic thermoregulatory center
* Gabapentin more studied than pregabalin
can also help with sleep

Gabapentin
§ Some clinicians use nightly doses of 600 – 900 mg qqhs to help
with sleep (vs daily doses as per studies)\
usuing night doses often

start with 3oomg, increase dose q 2-3 days until target dose

Question 23

Clonidine (generic)

Answer 23

§ Central acting α2 adrenergic agonist
§ Mechanism: though exact mechanism unknown, may decrease
vascular reactivity in some fashion
§ Not as effective as other non-hormonal prescription options.

Question 24

Oxybutinin

Answer 24

§ Mechanism: anticholinergic agent
§ Newer option for treating VMS (note: women who were using
oxybutynin for overactive bladder noticed improvement in VMS
symptoms)

Question 25

Non-hormonal Prescription Options: General
Principles

Answer 25

§ Less effective than MHT for VMS
§ Evidence for both breast cancer survivors or natural menopause -
RCT’s available for most agents
§ Response within 2 – 4 weeks for most agents
§ Target options based on other symptoms:
* Mood effects – antidepressants
* Sleep issues – gabapentin*
* Urinary symptoms - oxybutynin

Question 26

Treatment Approach for GSM

Answer 26

pharm
non-pharm

see slide 32

Question 27

Non-hormonal Products for GSM

Answer 27

§ Lubricants help reduce friction – used with intercourse
§ Vaginal moisturizers replace vaginal moisture – used regularly
every 3 days (or 2 - 3x a week)
§ Lubricant products may be water, silicone or oil based.
* Oil based: may erode condoms do not use together
Ø Natural oil based include olive oil, coconut oil

Be careful of additives/irritants ie parabans, glycerin, propylene glycol

polycarbopil effective for dryness (Replens)

hyaluronic acid - draws in moisturizer to places applied, anti inflamm, effective as vaginal estrogen in small RCTs

Repagyn

both moistur and lubricants can ebe used with other tx

Question 28

Estrogen: Vaginal Products

Answer 28

§ Very little systemic absorption – only used for GSM, NOT for VMS
or other symptoms
§ Progesterone is NOT needed for endometrial protection.
§ Systemic absorption can occur with vaginal creams however at
higher than recommended doses.
§ Vaginal estrogen can prevent recurrent UTI’s.
§ 40% of women on systemic MHT will continue to have urogenital
symptoms – can be used together with vaginal products

Intravaginal Cream: CE Cream
or estrone cream (Estragyn®)
CE 0.5 gm (1/4 of an applicator)
for 2 weeks, then twice weekly

Ring: Estring®
Intravaginal sustained-release
Change every 3 months

blet: Vagifem®
Estradiol vaginal tablets (10ug)
One vaginal tablet everyday for 2
weeks, then twice weekly

Answer 29

New products for GSM…

Ospemifene
* Oral SERM for vaginal dryness and dyspareunia
* Dose: 60 mg oral tablet daily
* Adverse effects: hot flashes

action directly on vaginal wall

§ Intravaginal DHEA (prasterone, Intrarosa®)
§ Inactive sex steroid precursor converted to estrogen and
androgen in cell
§ Dose: one ovule inserted vaginally every night
§ Adverse effects: vaginal discharge from melting of hard-fat
excipient in ovules

Question 30

Menopause and LGBTQ2+

Answer 30

§ The importance of inclusivity when discussing menopause and
symptoms, understand that experiences may differ
§ Added stigma with menopause and ageing
§ Considerations:
* Trans men:
* may go through surgical menopause (depending on age
when surgery is completed)
* may go through natural menopause if still having periods
* Trans women: may have menopause symptoms if stop
estrogen therapy (high doses of estrogen used)
* Non-binary individuals who do not identify as woman