POCKET GUIDE

MENOPAUSE
MANAGEMENT
A practical tool for
healthcare professionals
TABLE OF CONTENTS
Introduction --------------------------------------------------------------1

Impact of Menopause -------------------------------------------------5

Essentials of Management -----------------------------------------13

Choosing Therapy -----------------------------------------------------17

Hormone Therapy and Cancer -------------------------------------20

When to Refer ---------------------------------------------------------25

Troubleshooting -------------------------------------------------------28

Special Considerations ---------------------------------------------- 33

Complementary and Alternative Medicine ---------------------40

Abbreviations ----------------------------------------------------------42

Tables 1-5 for HT Products in Canada -----------------------------43

Tables 6-7 for Non-hormonal Medications ----------------------48

Acknowledgements ---------------------------------------------------50
INTRODUCTION
The menopausal transition can be a time of significant disrup-
tion and stress for women. Symptoms associated with meno-
pause may have a major effect on a woman’s quality of life.
Providing safe and effective management of these symptoms,
and mitigating potential health risks in the postmenopausal
years, are critical roles for health care providers.

In this pocket guide we summarize the recommendations

made in the guidelines for management published by four
professional associations: the Society of Obstetricians and
Gynaecologists of Canada (SOGC 2014), the International
Menopause Society (IMS 2016), the North American Meno-
pause Society (NAMS 2017), and the Endocrine Society (ES
2015).

• The publication of the report on the combined estrogen-

progestin arm of the Women’s Health Initiative in 2002
led to great uncertainty about the management of meno-
pausal women. The report caused a media firestorm
because it concluded that use of conjugated estrogens
and medroxyprogesterone acetate in postmenopausal
women was associated with increased risks of breast can-
cer, coronary heart disease, and stroke. Use of hormone
therapy in postmenopausal women was largely aban-
doned in the years that followed.

1
INTRODUCTION (CONT.)
• Reanalysis of the results of this study, and subsequent
publication of the results of the WHI estrogen-only study,
suggested that the initial negative response to the WHI
findings was ex-cessive. It is critical to note that the WHI
hormone therapy studies were not designed to assess
the risks of hormone therapy in symptomatic women.
Instead, they were designed to find out whether the ben-
efits of hormone therapy seen in observational studies
of younger menopausal women (chiefly cardiac benefits)
applied to older women as well. As it turned out, they did
not.

• In general, hormone therapy in postmenopausal women

should only be initiated in women < 60 years of age or <
10 years past menopause.

Indications for hormone therapy

• All four guidelines advise that hormone therapy (estro-
gen plus progestogen in women with a uterus, estrogen
alone in women without a uterus) is the most effective
treatment for bothersome vasomotor symptoms, with or
without additional climacteric symptoms, in menopausal
women.

• The NAMS statement also notes that hormone therapy is

approved by the United States FDA for four indications:
2
INTRODUCTION (CONT.)
bothersome VMS; prevention of bone loss; hypoestrogen-
ism caused by hypogonadism, castration, or premature
ovarian insufficiency; and genitourinary symptoms.

Choice of treatment
• The guidelines agree that MHT must be individualized and
tailored according to each woman’s symptoms, her need
for disease prevention, her personal and family history,
the results of relevant investigations, and her own prefer-
ences and expectations. The choice of treatment should
be reassessed periodically.

Dosing
• The guidelines acknowledge that in choosing a dose for
MHT, the “appropriate” dose is one which minimizes
risk while still providing benefit. For older women, lower
doses reduce cardiovascular risk.

• For women at higher risk of venous thromboembolism a

non-oral form of estrogen at the lowest effective dose is
recommended.

• In women with a uterus, the proliferative effects of sys-

temic estrogen on the endometrium must be countered
by an appropriate dose of progestogen (or a SERM, in the
case of the TSEC).
3
INTRODUCTION (CONT.)
Duration of treatment
• The guidelines agree that the duration of MHT for women
should be individualized, because long-term follow-up
data regarding use of MHT and risk are complicated.
This individualization should take into account the level
of symptom control and effect on quality of life, and a
woman’s individual risk of cancer, coronary heart disease,
and venous thromboembolism.

• Each guideline recommended that the decision to contin-

ue MHT be revisited at least annually. There appear to be
no reasons to place mandatory limitations on the duration
of MHT.

• Longer duration courses of estrogen-alone therapy (ET)

may be more appropriate because of the more favourable
risk profile.

• The guidelines also universally recommended that women

who undergo early menopause (before age 45) be advised
to use hormone therapy, at least until the average age of
menopause. This is because of proven health benefits for
menopause symptoms, prevention of bone loss, cogni-
tion and mood issues, and (in observational studies) heart
disease.

4
IMPACT OF MENOPAUSE
Vasomotor symptoms (VMS)
• Vasomotor symptoms (hot flashes and night sweats)
are a common reason for women to seek medical atten-
tion. 60-80% of women will experience VMS during the
menopausal transition. Although the exact physiology of
VMS is not well understood, they are thought to repre-
sent altered thermoregulatory functioning, possibly due
to alterations in reproductive hormones. Hypothalamic
activity of norepinephrine, serotonin, and neurokinin 3
may be involved.

• VMS are associated with physiologic circulatory changes,

with initial vasodilatation followed by vasoconstriction.

• Although 50% of women experience VMS for 7 years or

less, 15% may experience VMS for 15 years or longer.

• VMS are associated with diminished sleep quality, irrita-

bility, difficulty concentrating, and reduced quality of life,
as well as poorer health status. Women with VMS have
less favourable markers of CV health than those without
VMS, and may have an increased risk of developing coro-
nary heart disease.

• Menopausal hormone therapy (systemic estrogen alone,

or with appropriate endometrial protection in women
5
IMPACT OF MENOPAUSE (CONT.)
with a uterus) is the current standard therapy for reduc-
tion of VMS. Use of a progestogen alone may be effective
in treating VMS,but the safety of long term use has not
been established. For those with contraindications to
hormone therapy or a desire to avoid it, SSRI/SNRIs,
gabapentinoids, or clonidine may reduce VMS in some
women.

• When MHT is discontinued, vasomotor symptoms return

in approximately 50% of women, irrespective of years
since menopause or duration of MHT use. There is no
consensus about whether stopping MHT “cold turkey” or
tapering is preferable.

Mood and Cognition

• Depressive symptoms increase during the menopause
transition (as opposed to older age and younger age
groups), as does the risk for clinical depression.

• The following may influence or mediate the risk for de-

pression during the transitional years: the presence and
severity of VMS (hot flashes, night sweats), the occur-
rence of stressful life events, sleep problems, a history of
depression, and, most importantly, a history of reproduc-
tive-related mood sensitivity (premenstrual dysphoric

6
IMPACT OF MENOPAUSE (CONT.)
disorder, postpartum depression, or mood alterations
during pregnancy). There is currently insufficient evi-
dence to support the use of MHT as an adjunct in
the treatment of depression.

• Forgetfulness, trouble concentrating, and other mild cog-

nitive symptoms are common during midlife. Three large
RCTs showed neutral effects of MHT on cognitive function
when initiated early in the postmenopausal period.

• Observational studies have found associations between

early initiation of MHT and a reduced risk of developing
Alzheimer’s disease. Studies involving women experi-
encing early surgical menopause suggest that estrogen
therapy improves cognitive function.

• Women who initiated MHT after the age of 65 years

showed impairment in memory and increased risk of
dementia. Women in the pre-clinical stages of dementia
may be the most vulnerable cognitively to an adverse
effect of MHT.

Osteoporosis and Somatic Symptoms

• Postmenopausal osteoporosis results from a failure to
attain peak bone density, accelerated bone loss after
menopause, age-related bone loss, or a combination of
factors. 7
IMPACT OF MENOPAUSE (CONT.)
• Accelerated postmenopausal bone loss is induced by es-
trogen deprivation. The 10-year probability of a fracture
in an individual can be estimated using a model such as
FRAX or CAROC, which integrates various risk factors. In-
tervention thresholds for therapy can be based on 10-year
fracture probability. Lifestyle changes should be part of
treatment strategy. The choice of pharmacologic therapy
should be based on a balance of effectiveness, risk and
cost.

• Therapeutic options include MHT (in appropriately se-

lected patients), bisphosphonates, SERMs (raloxifene),
RANK-ligand inhibitors (denosumab), or parathyroid hor-
mone (teriparatide).

• Standard dose ET and MHT (estrogen plus appropri-

ate endometrial protection) prevent bone loss in most
healthy postmenopausal women through inhibition of
bone resorption and a reduced rate of bone remodelling
mediated through the RANK/RANK-ligand interaction.

• RCTs and observational studies show that standard-dose

ET and MHT reduce the incidence of osteoporotic frac-
tures, including spine, hip and all non-spine fractures, in
postmenopausal women, even those without osteoporo-

8
IMPACT OF MENOPAUSE (CONT.)
sis. MHT is the most appropriate therapy for fracture
prevention in the early menopause.

• Unless there is a contraindication, administration of ET,

MHT, or oral contraceptives is optimal for reducing the
risk of osteoporosis in women with premature or early
menopause, rather than other bone-specific agents.

• Osteoarthritis increases in prevalence after menopause.

There is evidence for a beneficial effect of endogenous
and exoge-nous estrogens on joint health. Women in the
CEE-alone arm of the WHI had significantly fewer hip and
knee joint replacements than those in the placebo arm.

Cardiovascular Disease

• Cardiovascular disease is the leading cause of morbidity

and mortality in postmenopausal women.

• Primary prevention strategies include smoking cessation,

weight loss, blood pressure control, regular aerobic exer-
cise, and diabetes and lipid control. Use of low-dose ASA
and/or statins does not reduce the risk of coronary heart
disease, cardiovascular mortality, or all-cause mortality in
women.

9
IMPACT OF MENOPAUSE (CONT.)
• Estrogen therapy initiated at the time of menopause is
likely cardioprotective. In the WHI, the hazard ratio for
coronary heart disease in women who initiated MHT ≤10
years after menopause was 0.50.

• Initiation of MHT > 10 years after menopause or after age

60 is associated with increased risk.

• Use of MHT for primary prevention of cardiovascular

disease is not supported in any guideline. Women at high
risk of cardiovascular events should be offered non-hor-
monal management of menopausal symptoms. Women
at moderate risk of cardiovascular events, if offered MHT,
should preferentially use transdermal estrogen rather
than oral. Use of micronized progesterone is preferable in
higher risk women who require endometrial protection.

• In a Cochrane review, women who initiated oral MHT at <

60 years of age or within 10 years of menopause did not
have an increased risk of stroke but women who initiated
MHT at ≥60 years of age or > 10 years after menopause
did have an increased risk.

Genitourinary Syndrome of Menopause

• Genitourinary syndrome of menopause (GSM) encom-

10
IMPACT OF MENOPAUSE (CONT.)
passes the genital and lower urinary tract symptoms as-
sociated with postmenopausal estrogen deficiency. Symp-
toms may include genital dryness, burning and irritation;
sexual symptoms of diminished lubrication and pain dur-
ing sexual activity; and urinary symptoms of urgency,
dysuria, and recurrent urinary tract infections.

• Low-dose vaginal estrogen preparations are safe and

effective treatments for vulvovaginal symptoms due to
estrogen deficiency.

• Because GSM symptoms often worsen with age and time

since menopause, long-term low-dose vaginal estrogen
therapy may be necessary. Concomitant use of an endo-
metrial protective agent with low-dose vaginal estrogen
therapy is not required, but any woman who has vaginal
bleeding should be thoroughly investigated. Endometrial
safety data with use of vaginal estrogens beyond one
year are not available.

• Women in whom vaginal estrogens are contraindicated,

or who do not wish to use vaginal estrogen, may have
relief of pain during intercourse with the use of vaginal
lubricants prior to intercourse. Vaginal moisturizers or
vaginal hyaluronic acid therapies may help with vaginal
dryness and pain with intercourse, but do not restore
11
IMPACT OF MENOPAUSE (CONT.)
normal anatomy and function.

• Low- dose vaginal estrogen therapy may provide benefit

for urinary symptoms, including over-active bladder and
urge incontinence, and may aid in prevention of recurrent
urinary tract infections.

• Symptoms of vulvovaginal atrophy are strongly associated

with sexual dysfunction in postmenopausal women. Low-
dose vaginal estrogen improves sexual function in these
women.

• As there is minimal systemic absorption, the standard

contraindications for systemic hormone therapy do not
apply to vaginal estrogen therapy.

• Use of vaginal estrogens is not contraindicated in women

with a past history of breast cancer, but consultation with
their oncologist is recommended. In women with current
breast cancer who are being treated with an aromatase
inhibitor, the decision to use low-dose vaginal estrogen
should be made, in consultation with their oncologist,
only after non-hormonal methods have been unsuccessful
in relieving symptoms.

12
ESSENTIALS OF MANAGEMENT
Vasomotor symptoms

Mild hot flashes: lifestyle strategies only

- keeping core body temperature cool: (light clothes, air
conditioning, ventilation)
- participating in regular exercise
- avoiding alcohol intake and cigarette smoking
- following a healthy diet
- behavioural modification (avoid stressful situations)

Moderate to severe hot flashes: MHT is the gold standard

and best therapy for reduction of VMS (Tables 1-5), followed
by non-hormonal prescription medications (Tables 6, 7) as a
second choice. Cognitive behavioural therapy may be helpful.
If these strategies are ineffective or unacceptable, comple-
mentary and alternative medicine may be used, although
efficacy is unproven.

Hormone therapy
• Women without a uterus can use systemic estrogen-
alone therapy (ET).

• Women with a uterus can use either systemic estrogen

combined with a progestogen (EPT) or the tissue-selec-
tive estrogen complex (conjugated equine estrogens and
bazedoxifene).
13
ESSENTIALS OF MANAGEMENT (CONT.)
• Combined low-dose oral contraceptives can be used in
perimenopausal women.

• Progestogens alone may be used in women with contrain-

dications to estrogen therapy.

Contraindications to HT
Estrogens
- unexplained vaginal bleeding
- acute liver dysfunction
- estrogen-dependent cancer
- coronary heart disease
- previous history of stroke
- history of thromboembolic disease
- starting treatment after 60 years of age or after 10
years post-menopause (relative)

Progestogens
- unexplained vaginal bleeding
- breast cancer
- hypersensitivity to peanuts /peanut oil (used in
some preparations of micronized progesterone)

14
ESSENTIALS OF MANAGEMENT (CONT.)
Complementary and alternative medicine options

• Non-prescription remedies: natural health products

- phytoestrogens: soy foods, red clover, isoflavone
supplements, flaxseed
- black cohosh
- dong quai
- evening primrose oil
- ginseng
- ginko

• Acupuncture

Urogenital Health

• Systemic MHT for treatment of VMS is usually sufficient

to relieve symptoms; other options can be added to
systemic MHT or used alone
- Maintain sexual activity
- Lubricants
- water-based
- silicone-based

15
ESSENTIALS OF MANAGEMENT (CONT.)
- Moisturisers
- hyaluronic acid
- adhesive polycarbophil polymer
- Low-dose vaginal estrogens (no progestogen required)
- tablets
- creams
- ring
- DHEA vaginal insert (available in USA and Europe;
awaiting Health Canada approval in Canada)

Osteoporosis

• Weight-bearing and high impact exercise (brisk walking,

climbing stairs, dancing, etc)
• Nutrition and supplements
- calcium: 1200 mg of daily intake combination of diet
and supplements, preferably mostly from diet (i.e., 3
servings of milk/dairy)
- vitamin D: over 50 years of age: 800-2000 IU daily
• Hormone therapy (ET or EPT)
• Bisphosphonates
- oral alendronate (daily, weekly), risedronate (daily,
weekly, monthly)
- zoledronic acid (yearly IV)

16
ESSENTIALS OF MANAGEMENT (CONT.)
• RANKL inhibitor
- denosumab (subcutaneous injection every 6 months)

• Parathyroid hormone therapy (PTH)

- teriparatide (daily subcutaneous injection)

• Selective estrogen receptor modulator (SERM)

- raloxifene (oral)

CHOOSING THERAPY
Clinical indications for initiation of systemic MHT
• Vasomotor symptoms and night sweats

• Prevention of bone loss

• Reduction in fracture risk in women at increased risk of

osteoporosis or fracture

• Early menopause (< age 45) or premature ovarian insuf-

ficiency

• Sleep disturbance

• Depressive symptoms: ET may be beneficial during or

shortly after the menopause transition 17
CHOOSING THERAPY (CONT.)
Therapeutic goal: in each woman, to choose the optimal
therapy that will alleviate symptoms with minimal side
effects

• The appropriate initial choice of therapy is the first step in

preventing problems.

• Choice of therapy will depend on any contraindications,

the woman’s symptoms, age, time since menopause,
medical risks, family history, personal preferences, and
insurance coverage for medications.

Therapeutic options for systemic MHT (Tables 1-5)

• Estrogen alone in women without a uterus

• Estrogen and progestogen for women with a uterus

• Systemic estrogen options: oral tablets, transdermal

patches and transdermal gels

• Progestogens: oral tablets, transdermal patch (combined

with estrogen) or intrauterine system

• Schedules: continuous estrogen and progestogen, con-

tinuous estrogen and cyclical progestogen (10-14 days/
month)
18
CHOOSING THERAPY (CONT.)
• TSEC (tissue selective estrogen complex) containing con-
jugated equine estrogen and bazedoxifene, a selective
estrogen receptor modulator

General principles

• Higher doses of estrogen require higher doses of pro-

gestogens for endometrial protection, and higher doses
result in more side effects.

• Younger women (premature ovarian insufficiency) re-

quire higher estrogen doses for bone protection.

• Lower doses of estrogen and progestogen reduce breast

discomfort and vaginal bleeding.

Regimen Decisions

• Symptomatic perimenopausal women (i.e., with con-

tinuing menstrual cycles) will have less unscheduled
bleeding with use of oral contraceptives, estrogen with a
progestin-releasing IUS, or estrogen with cyclical proges-
togen.

• Cyclical progestogen therapy usually produces regular

withdrawal bleeding.
19
CHOOSING THERAPY (CONT.)
• Continuous progestogen therapy in a postmenopausal
woman usually results in amenorrhea after several
months.

Route of Administration
• Transdermal estrogen therapy may be preferable for
women who are smokers or have migraine headaches,
hypertriglyceridemia, malabsorption syndromes, hetero-
zygous carriers of Leiden Factor V mutation, a history of
thrombosis (on anti-coagulation), metabolic syndrome,
and hypertension.

HORMONE THERAPY AND CANCER

MHT and Breast Cancer
In women, mortality from breast cancer is far less than from
cardiovascular disease.

• ET (for women without a uterus) has minimal effect on

the risk of breast cancer. Observational studies suggest a
small increase in risk on long term ET. In the WHI, CEE-on-
ly therapy resulted in a significantly reduced risk of breast
cancer.

• EPT (CEE+MPA) in both observational studies and the WHI

resulted in a small increase in breast cancer risk after 5
20
years of use (the absolute risk is very small). Women using
HORMONE THERAPY AND CANCER (CONT.)
EPT for the first time showed no increase in breast
cancer incidence. In the WHI, EPT accounted for less
than 1 additional breast cancer diagnosis per 1,000
women per year of use.

• Different progestogens may exert different effects on the

breast, but there is no conclusive evidence to suggest a
differential effect on breast cancer risk.

• The recently introduced TSEC combines estrogen (CEE)

with a second agent (bazedoxifene) that blocks any
stimulatory effect on the breast. Longer term data on
whether this will reduce or eliminate breast cancer risk
are not yet available.

Family History of Breast Cancer

• There is a marginal increase in personal risk with a single
relative who develops breast cancer after menopause.

• A woman with two first-degree relatives who develop

breast cancer after age 50 or one first-degree relative
who develops breast cancer before age 50 has approxi-
mately double the lifetime risk.

• Lifetime risk quadruples in women with two first-degree

relatives affected before age 50 (these women should be
assessed for genetic mutation). 21
HORMONE THERAPY AND CANCER (CONT.)
• Observational studies have shown no further increase in
risk with the use of MHT in women with a family history
of breast cancer.

• BRCA mutation increases the risk of breast and ovarian

cancer, and surgery to remove the tubes and ovaries is
common in these women. Subsequently, MHT may be
required to alleviate vasomotor symptoms; no increased
risk of MHT has been identified in several observational
studies.

MHT after Treatment of Breast Cancer

• Most observational studies found no increase in breast
cancer recurrence with MHT use (possibly due to selec-
tion bias).

• Two RCTs came to opposite conclusions about the effect

of systemic MHT after treatment of breast cancer. Both
trials were terminated prematurely because of worrisome
findings in one of them.

• If quality of life is significantly affected and the breast

cancer has a favourable prognosis, women may elect to
use MHT after careful counselling about the uncertainty in
the available data. For women with more advanced breast
cancers, avoiding use of MHT is prudent.
22
HORMONE THERAPY AND CANCER (CONT.)
• Observational data suggest that low-dose vaginal estro-
gen therapy has no effect on breast cancer recurrence.

• Women on aromatase inhibitors should use vaginal estro-

gen therapy with caution.

MHT and Endometrial Cancer

• ET in women with a uterus has a stimulatory effect in

the endometrium and increases the risk of endometrial
cancer. Addition of a progestogen (EPT) will counteract
this effect.

• Treatment with the currently available TSEC does not

increase the risk of endometrial cancer.

• Use of MHT in women after treatment of early stage en-

dometrial cancers (grade 1 and 2 with negative estrogen
and progesterone receptors) does not increase the risk of
recurrence or mortality.

HT and Ovarian Cancer

• The WHI showed no significant effect of MHT on the risk

of ovarian cancer.

23
HORMONE THERAPY AND CANCER (CONT.)
• A few observational studies suggest an increased risk of
epithelial and endometrioid ovarian cancers with long
term MHT; the absolute risk is rare (<1/1,000).

• MHT use after treatment of ovarian cancer has not been

shown to affect rates of recurrence or survival.

MHT and Colorectal Cancer

• A protective effect of MHT has been shown on the inci-

dence of colorectal cancer in some preclinical observation
and observational studies; this was also observed in the
WHI EPT arm.

• However, follow-up of the WHI found no evidence to

support the use of MHT to reduce the risk of colorectal
cancer.

MHT and Lung Cancer

• In non-smokers, MHT may reduce or have no effect on

lung cancer risk.

• In the EPT arm of WHI, current and former smokers over

age 60 were shown to have a small increase in the risk of
death from non-small cell lung cancer (4/10,000 per year).
24
WHEN TO REFER
A number of symptomatic challenges may arise as women
approach menopause. While many presentations are eas-
ily addressed by the primary care provider, there are times
when a referral to a specialist is indicated:

Perimenopausal vaginal bleeding

Although common and expected, further assessment is re-

quired for:
• Prolonged heavy bleeding – initial investigations such as a
CBC, vulvovaginal inspection, Pap smear, bimanual exami-
nation, pelvic ultrasound and endometrial biopsy should
be done. If the history is suggestive, von Willebrand’s
disease should be ruled out.

Postmenopausal bleeding
• Bleeding more than one year after the final menstrual
period requires investigation consisting of vulvovaginal
inspection, Pap smear, bimanual examination, pelvic
ultrasound, and endometrial biopsy if endometrial thick-
ness > 4 mm.

• If there is no abnormality but bleeding recurs, refer for

hysteroscopy. Unscheduled bleeding more than 6 months
after initiating EPT should be investigated.

25
WHEN TO REFER (CONT.)
Concerns about MHT
• A referral may be helpful when there are concerns or un-
certainty about comorbidities, risk factors due to personal
or family history, or if the MHT regimens prescribed are
poorly tolerated.

• A referral can also be useful if there is uncertainty about

prolonged MHT, use of MHT at advanced age, or difficulty
having patients discontinue MHT.

Premenstrual syndrome/Premenstrual dysphoric disorder

• When lifestyle recommendations for PMS/PMDD (regard-
ing diet, exercise, use of caffeine or alcohol, and sleep) fail
and/or herbal or pharmaceutical treatments are ineffec-
tive, careful evaluation of the cyclic nature of these com-
plaints should be documented and referral initiated.

Breast changes
• Complaints of breasts becoming fibrous and/or having
recurrent cystic changes can be further evaluated by
mammography ± ultrasound.

• Unexplained breast pain, a rash, or a persistent palpable

lump should be referred for evaluation because mam-
mography may (rarely ) not detect a malignancy.

26
WHEN TO REFER (CONT.)
Dyspareunia
• GSM that results in dyspareunia can be diagnosed during
careful vulvovaginal inspection. It may be treated with
lubricants/moisturizers, vaginal estrogen, ospemifene
(not currently available in Canada) and intravaginal DHEA
(not currently available in Canada).

• Pain that is unresponsive to this treatment requires fur-

ther evaluation to rule out vaginismus, deep pain related
to pelvic pathology or past surgical treatment, infections,
and skin conditions such as lichen sclerosus, eczema, and
Behcet’s disease. Referral for evaluation of skin lesions is
appropriate. Referral to a pelvic floor physiotherapist can
be helpful for myofascial pain and incontinence.

Insomnia
• Sleep disturbance is common in perimenopausal and
postmenopausal women. Sleep patterns often improve
with treatment of vasomotor symptoms and micronized
progesterone improves the efficiency of sleep.

• If persistent, disorders such as obstructive sleep apnea,

fibromyalgia and restless legs syndrome need to be
excluded or managed by means of a sleep study and/or
specialist referral.

27
WHEN TO REFER (CONT.)
Relevant family history
• Referral may be appropriate for women with a family his-
tory of breast cancer, or of thrombophilias such as Protein
C and Protein S deficiency or Factor V Leiden mutation.

Osteoporosis
• Fracture risk assessment is critical in postmenopausal
women. Referral to an osteoporosis clinic for women with
increased risk is often helpful.

TROUBLESHOOTING
Vaginal bleeding
• Unscheduled bleeding is the most common problem for
women on MHT. Some bleeding for up to 6 months after
beginning MHT is acceptable. If bleeding is heavy or fre-
quent, investigations should be carried out sooner.

• The incidence of endometrial cancer in women on EPT

using continuous progestogen is not increased above the
incidence in the general population. Women on EPT with
cyclical progestogen have a slight increase in endometrial
cancer risk.

• Investigations should include history, physical examina-

28
TROUBLESHOOTING (CONT.)
tion, vulvar and vaginal inspection, Pap smear, directed
cultures, and bimanual examination. Ensure that the
bleeding is vaginal and not urethral or rectal.

• Pelvic ultrasound to check for endometrial thickness can

be carried out before performing an endometrial biopsy.
An endometrial thickness ≤ 4 mm is reassuring.

• If bleeding recurs, endometrial biopsy, diagnostic hyster-

oscopy, or sonohysterogram should be performed.

• Therapeutic options are to switch from continuous pro-

gestogen use to cyclical progestogen, to reduce the dose
of estrogen or the route of administration, or to switch to
use of a TSEC.

Breast Pain
• Breast symptoms are least likely to occur with the lowest
doses of MHT.

• Women who used a TSEC for 2 years had no increase in

breast density or discomfort.

Mood Change
• Women who experience depression or irritability with
use of progestogens may benefit from changing the type
29
TROUBLESHOOTING (CONT.)
of progestogen or the regimen used (cyclical or continu-
ous).

• If this is unsuccessful, discontinuing use of the proges-

togen may be necessary. If continuing with unopposed
ET, endometrial monitoring with ultrasound or biopsy is
required.

• Use of a TSEC avoids use of a progestogen and any associ-

ated mood change.

Headaches
• Headache in women on MHT may be tension headache,
migraine headache with or without aura, or cluster head-
ache.

• Tension headache will frequently respond to lifestyle

modifications, stress management, and use of non-narcot-
ic analgesics.

• Migraine headache is usually managed with use of trip-

tans, beta-blockers, anti-depressants or anticonvulsants.
However, because the frequency and severity of migraine
may be affected by fluctuations in hormone levels, hor-
mone therapy may be helpful. Migraine frequency may
increase in the perimenopause and decrease after meno-
30 pause.
TROUBLESHOOTING (CONT.)
• Menstrual migraine may improve with use of transder-
mal estradiol beginning in the week before menses and
continuing to the end of menses.

• Women who have migraine headaches without aura may

have improvement with MHT. Transdermal estradiol and
micronized progesterone may be preferred because oral
estrogen provides less stable serum estradiol levels and
synthetic progestins may aggravate headache.

• Women who have migraine headaches with aura may be

adversely affected by MHT. If auras worsen, MHT doses
should be reduced and possibly discontinued.

• Migraine headache with aura is associated with double

the risk of stroke.

• When in doubt, a headache expert should be consulted.

Progestogen Intolerance
• Some women may have specific intolerance to a proges-
togen, with symptoms including bloating, breast tender-
ness, and mood changes. Micronized progesterone can
also cause excess drowsiness in some patients.

• These symptoms may improve with switching from cycli-

31
TROUBLESHOOTING (CONT.)
cal to continuous progestogen use, switching to another
progestogen, administering micronized progesterone vagi-
nally, insertion of a progestogen-releasing IUS, a reduction
in the doses of both estrogen and progestogen, or switch-
ing to use of a TSEC.

• If these options are not effective and estrogen therapy is

required, the effects of unopposed estrogen therapy on
the endometrium must be monitored with transvaginal
ultrasound and endometrial biopsy.

Vaginal Symptoms
• Systemic low-dose estrogen therapy may not relieve
symptoms of vaginal mucosal atrophy and may require
vaginal administration of estrogen (creams, tablets, or
estradiol-releasing silastic ring).

• If symptoms persist with vaginal therapy, consider apply-

ing vaginal cream to the introitus and non-hair bearing
vulvar tissues.

• Attempting intercourse in the presence of mucosal atro-

phy may lead to secondary vaginismus.

• In women with persistent vulvovaginal burning and itch-

ing, vulvar dermatoses including lichen sclerosus, chronic
32 dermatitis, psoriasis, and cancer must be ruled out.
TROUBLESHOOTING (CONT.)
• Women with persistent vulvar pain may have sexual dys-
function. Sexual counselling may be appropriate.

SPECIAL CONSIDERATIONS
Hypertension
• Hypertension is not a contraindication to use of MHT.

• Hypertension in menopausal women (including a history

of pregnancy-induced hypertension) indicates an in-
crease in the future risk of cardiovascular complications.
The INTERHEART study found that women with hyper-
tension had a 97% increase in risk of CV disease over
normotensive women.

• Reversible risks for hypertension (obesity, poor dietary

habits, high sodium intake, sedentary lifestyle, and high
alcohol consumption) should be carefully assessed and
reduced where possible during assessment of the newly
menopausal woman.

• The WHI combined hormone therapy trials found that

oral CEE, with or without added MPA, was associated
with an increased risk of hypertension in older post-
menopausal women, but a 2014 review found that oral
MHT had a largely neutral effect on blood pressure in 33
SPECIAL CONSIDERATIONS (CONT.)
normotensive women and a neutral effect in hypertensive
women.

• Chronic (but not acute) administration of transdermal

estradiol has been shown to reduce ambulatory blood
pressure in normotensive postmenopausal women. Use
of transdermal estradiol may therefore be preferable to
oral estrogen in hypertensive postmenopausal women.

Endometriosis
• A history of endometriosis is not a contraindication to use
of MHT in symptomatic menopausal women, but the low-
est effective estrogen dose should be used.

• There is no convincing evidence that women with a his-

tory of endometriosis who have undergone hysterectomy
should be routinely treated with EPT rather than estrogen
alone.

• Similarly, in women who have undergone surgery for

endometriosis, there is no evidence that subsequent
progestogen-only therapy, or delaying use of estrogen for
6 months, reduces the risk of recurrence of endometriosis
or the development of malignancy in residual or recurrent
endometriotic deposits.

34
SPECIAL CONSIDERATIONS (CONT.)
• Use of progestogens in postmenopausal women without
a uterus and with a history of endometriosis remains a
matter for clinical judgement and informed choice.

Premature ovarian insufficiency

• Women without contraindications should receive HT until
the average age of menopause (51 years).

• Women with surgical POI have more severe symptoms.

• Typical daily doses for MHT in women with POI are 100
μg transdermal estradiol, 2 mg oral micronized estradiol,
or 1.25 mg CEE, with 10mg MPA or 300 mg progester-
one for 12 days per month. Younger women need higher
doses of hormones.

• Meta-analyses have shown that women with POI at

age <40 and even <45 have a greater incidence of early
death, cardiac disease, Parkinson’s disease, lowered cog-
nitive function, increased affective disorders, GSM and
sexual dysfunction in the absence of hormone therapy.
Rates of osteoporosis may also be increased.

• Healthy ovaries should not be removed electively in

women aged < 50 unless they are at high risk for ovarian
cancer.
35
SPECIAL CONSIDERATIONS (CONT.)
Previous endometrial ablation
• There is no common recommendation for use of MHT in
symptomatic postmenopausal women with a history of
endometrial ablation.

• Because endometrial ablation procedures are unable to

reliably remove all of the endometrium, EPT should be
used in these women.

Thrombophilia
• The incidence of venous thromboembolism (deep vein
thrombosis and pulmonary embolism) in women on MHT
is generally estimated at 1-2 cases per 1000 woman-years.
This incidence is significantly increased in women with
thrombophilia.

• Women with high-risk thrombophilia (deficiency of anti-

thrombin, Protein C, Protein S, Factor V Leiden mutation)
should generally avoid use of MHT.

• The risk of VTE is increased with use of oral estrogen, but

observational studies have not found any increased risk
with use of transdermal estradiol.

• Observational studies have suggested that the risk of

VTE is higher with use of synthetic progestins than with
36 micronized progesterone.
SPECIAL CONSIDERATIONS (CONT.)
• Postmenopausal women with an increased risk of VTE
who require MHT will have least risk with use of trans-
dermal estradiol and micronized progesterone.

• Population screening for thrombophilia prior to MHT use

is not justified.

Diabetes
• Diabetes is not a contraindication to use of MHT.

• RCTs and observational studies suggest MHT reduces the

prevalence of diabetes by 14-19% while taking the
medication.

• A few short-term RCTs have shown either no effect or

improved control for women with diabetes on MHT.

• The approach to therapy therefore should be individual-

ized - preferably transdermal estradiol with micronized
progesterone should be used.

• If diabetes occurs with concurrent CV disease, non-

hormonal therapies for menopausal symptoms are
preferred.

37
SPECIAL CONSIDERATIONS (CONT.)
Uterine fibroids
• MHT is not contraindicated in women with fibroids.

• Fibroids may enlarge or remain stable on MHT.

• The location of fibroids (submucous, intramural, serosal)

may affect the incidence of breakthrough bleeding on
MHT.

Long-term MHT
• HT should not usually be initiated more than 10 years
after menopause or after 60 years of age as there are
greater risks of coronary heart disease, VTE and stroke.

• Long-term use should be individualized for persistent

vasomotor symptoms, prevention of bone loss or fracture,
and quality of life.

• It is advisable for women to use the lowest dose possible

to control symptoms as they age.

• It is not necessary to stop MHT at age 65.

• 50% of women will experience symptoms when they stop

MHT. Of these, 50% will subsequently restart MHT. When
stopping, there is no evidence to suggest greater success
38
SPECIAL CONSIDERATIONS (CONT.)
with sudden stoppage or tapering of therapy.

• Low-dose vaginal estrogen therapy can be used life-long.

• Bone loss and GSM will continue with aging.

• The incidence of breast cancer may increase with longer

use of MHT, especially with continuous combined estro-
gen-progestogen.

• The incidence of DVT and PE increases with age.

• There is currently insufficient evidence on benefits and

risks for long term users. One large Finnish database
has found increased risk of CV mortality, coronary heart
disease and stroke death in the year after discontinuation
of MHT.

Professional associations currently recommend greater flex-

ibility for longer MHT use if there are no contraindications
and the balance of risk and benefit is evaluated annually.

39
COMPLEMENTARY AND ALTERNATIVE MEDI-
CINE
• More than 50% of perimenopausal and postmenopausal
women use some form of complementary and alterna-
tive medicine, including natural health products, dietary
changes, massage, acupuncture, and stress therapies for
management of midlife and menopausal symptoms.

• Natural health products are regulated by the Natural

Health Products Directorate (NHPD), a division of the
Health Products and Food Branch of Health Canada, and,
following approval, are assigned an NPN number. Choos-
ing products with an NPN number is therefore advisable.

• Of “natural” and “alternative” products, phytoestrogens

(especially phytoestrogen supplements) have been the
most extensively studied. Phytoestrogens comprise two
major categories: (1) isoflavones (particularly genistein),
which have shown benefit in treating mild vasomotor
symptoms, and (2) flaxseed, which has not.

• Soy diets rich in isoflavones have been claimed to show

some benefit in managing mild vasomotor symptoms and
GSM, as well as providing bone and breast protection, but
results are not definitive.

40
COMPLEMENTARY AND ALTERNATIVE MEDI-
CINE (CONT.)
• St John’s Wort has been shown to improve sleep and
quality of life in menopausal women.

• Acupuncture and mind-body techniques (yoga, relax-

ation, tai chi, meditation) have not been shown to be
effective in reducing vasomotor symptoms and other
menopausal symptoms.

• Cognitive behavioural therapy and, to a lesser extent,

clinical hypnosis have been shown to be effective in
reducing vasomotor symptoms.

41
ABBREVIATIONS
ASA acetylsalicylic acid
CEE conjugated equine estrogens
CV cardiovascular
DHEA dehydroepiandrosterone sulphate
DVT deep vein thrombosis
ET estrogen (alone) therapy
EPT estrogen-progestogen therapy
FDA Food and Drug Administration
GSM genitourinary syndrome of menopause
IUS intrauterine system
MHT menopausal hormone therapy
MPA medroxyprogesterone acetate
PE pulmonary embolism
PMS premenstrual syndrome
PMDD premenstrual dysphoric disorder
POI premature ovarian insufficiency
RCT randomized controlled trial
SERM selective estrogen receptor modulator
SNRI selective norepinephrine reuptake inhibitor
SSRI selective serotonin reuptake inhibitor
TSEC tissue selective estrogen complex
VMS vasomotor symptoms
VTE venous thromboembolism
WHI Women’s Health Initiative

42
HORMONE THERAPY PRODUCTS IN CANADA
Table 1: Estrogen Products in Canada
Type of Estrogen Trade Names Strengths Available Comments
Oral Estrogen
conjugated estro- Premarin® 0.3, 0.625, 1.25 mg tablets One tablet daily
gen (CE)
17β estradiol Estrace® 0.5, 1, 2 mg tablets One tablet daily
Transdermal Estrogen Patches
17β estradiol Estradot® 25, 37.5, 50, 75, 100 µg patches Twice weekly application
patch Sandoz Estradiol 50, 75, 100 µg patches Twice weekly application
Derm® (generic)
Oesclim® 25, 50 µg patches Twice weekly application
Climara® 25, 50, 75, 100 µg patches Once weekly application
Transdermal Estrogen Gel
17β estradiol gel Estrogel® 0.75 mg estradiol per 1.25 g Daily application, use in same
metered dose(=one actuation) area (do not rotate sites)
Divigel® 0.25, 0.5, 1 mg individual packets Daily application
43
HORMONE THERAPY PRODUCTS IN CANADA (CONT.)
Table 2: Vaginal Estrogen Products in Canada
Type of Estrogen Trade Names Strengths Available Comments
conjugated estrogen Premarin® Vaginal 0.625 mg/gram vaginal 0.5 gm (0.3 mg) vaginally daily for
(CE) Cream cream 14 days, then 0.5 gm (0.3 mg) 2 – 3
Refillable applicator times weekly

17β estradiol Vagifem® vaginal 10 µg vaginal tablet with one tablet vaginally daily for 14
inserts applicator days, then one tablet twice weekly

17β estradiol Estring® vaginal 2 mg/vaginal ring Inserted every 3 months

ring
estrone Estragyn® 0.1% 1 mg/gm vaginal cream 0.5 – 4 gm (0.5 – 4 mg) daily cyclic
vaginal cream Refillable applicator (3 weeks on, one week off) or 2 – 3
times weekly*

*note: the product monograph for Estragyn® recommends cyclic (three weeks on, one week off) and
concomitant progestogen therapy

44
HORMONE THERAPY PRODUCTS IN CANADA (CONT.)
Table 3: Progestogen Products in Canada
Type of Progestogen Trade Names Strengths Available Comments
Oral progestogen
progesterone, micronized Prometrium®, generics 100 mg capsule Take at bedtime because
of sedating effect. Note:
generics may contain
peanut oil
medroxyprogesterone Provera®, generics 2.5, 5, 10 mg tablets
acetate
norethindrone acetate Norlutate® 5 mg tablets
Levonorgestrel intrauterine system (IUS)
levonorgestrel IUS Mirena®* 52 mg/IUS, for 5 years Off-label use

*Mirena is the only LNG-IUS marketed in Canada that has evidence for endometrial protection

45
HORMONE THERAPY PRODUCTS IN CANADA (CONT.)
Table 4: Combination Hormone Therapy Products in Canada

Type Trade Names Strengths Available Comments

Oral Combination Estrogen and Progestogen Products
17B estradiol/ noreth- Activelle® 1 mg estradiol/0.5 mg norethindrone tablet One tablet daily
indrone acetate
Activelle® LD LD - 0.5 mg/0.1 mg tablet

17B estradiol/ drospi- Angeliq® 1 mg estradiol/1 mg drospirenone tablet One tablet daily
renone
Transdermal Combination Estrogen and Progestogen Products
17B estradiol/ noreth- Estalis® patch 140/50 (50 µg estradiol/140 µg norethindrone) Twice weekly
indrone acetate 140/50 250/50 (50 µg estradiol/250 µg norethindrone) application

Tissue Selective Estrogen Complex (TSEC) – Estrogen and selective estrogen receptor modulator (SERM)

conjugated estrogen Duavive® 0.45 mg CE/20 mg bazedoxifene tablet One tablet daily
(CE)/ bazedoxifene

46
Table 5: Suggested Doses in Hormone Therapy Regimens
Type of Product Starting Doses
Estrogen*
Oral estrogen:
conjugated estrogen (CE) 0.3 - 0.625 mg tablet daily
17ß-estradiol oral 0.5 – 1 mg tablet daily
Transdermal estrogen:
17ß-estradiol (patch) 25 – 50 µg patches once or twice weekly (see transdermal estrogen products)
17ß-estradiol (gel) 1 - 2 metered doses/actuation daily (Estrogel®)
0.5 – 1 mg packets daily (Divigel®)
Progestogen
Oral progestogens:
progesterone micronized 100 mg daily for continuous regimen**
200 mg daily for 12 – 14 days/month for cyclic regimen*
medroxyprogesterone 2.5 mg daily continuous regimen*
acetate 5 mg cyclic regimen (12 -14 days/month)*
Combined Patches: 50/140 µg continuous regimen twice weekly patch
17ß-estradiol/norethin- 50/140 µg or 50/250 µg cyclic regimen (i.e., 12 - 14 days/month) twice weekly
drone acetate patch
*higher doses of progestogens will be required when higher estrogen doses are used **off-label use
47
 NON-HORMONAL MEDICATIONS FOR MENOPAUSE IN CANADA
Table 6: Non-hormonal Medications for Menopausal Vasomotor Symptoms (VMS)
Drug Trade Names/Strengths Doses Comments
Available
Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)
venlafaxine* Effexor XR®, generics 37.5 mg – 150 mg Start 37.5 mg daily x 1 week,
37.5, 75, 150 mg caps then increase to 75 mg daily.
Taper to discontinue.
desvenlafaxine* Pristiq®, generic 100 - 150 mg daily Start with 50 mg, then increase
50, 100 mg tabs to 100 mg over a few days. Taper
to discontinue.
Selective Serotonin Reuptake Inhibitors (SSRI)
paroxetine* Paxil CR®, generics 12.5 – 25 mg daily Taper to discontinue
12.5, 25 mg tabs
fluoxetine* Prozac®, generics 20 mg daily
10, 20 mg caps
citalopram* Celexa®, generics 20 mg daily Taper to discontinue.
20, 40 mg tabs
escitalopram* Cipralex®, generics 10 – 20 mg daily Taper to discontinue
48 10, 20 mg tabs
NON-HORMONAL MEDICATIONS FOR MENOPAUSE IN CANADA (CONT.)
Table 7: Non-hormonal Medications for Menopausal Vasomotor Symptoms (VMS) (CONT.)
Drug Trade Names/Strengths Doses Comments
Available
Alpha-adrenergic agonists
clonidine generic** 0.05 mg bid Some women may require
0.025 mg tabs higher doses (ie 0.05 mg tid), but
side effects may limit use. Taper
slowly to discontinue
Gabapentinoids
gabapentin* Neurontin®, generics Start 300 mg daily, May take 1 – 2 weeks to see ef-
100, 300, 400 mg caps then increase to 300 fective dose for VMS
600, 800 mg tabs mg tid at 3 – 4 day
intervals***
pregabalin* Lyrica®, generics 150 – 300 mg daily Less well studied in menopause
25, 50, 75, 100, 150, 200, 225,
300 mg caps
*off-lable use (not approved by Health Canada for this indication)
**Dixarit® tablets have been discontinued
***doses of 2,400 mg of gabapentin have been used in one study but were associated with more side effects
49
ACKNOWLEDGEMENTS
Canadian Menopause Society/Société Canadienne de Méno-
pause (CMS/SCM) wishes to thank the following health care
experts for the development of this pocket guide:

Denise Black, MD, FRCSC

Celine Bouchard, MD, FRCSC
Christine Derzko, MD, FRCSC
Michel Fortier, MD, FRCSC
Susan Goldstein, MD, CCFP, FCFP, NCMP
Vicki Holmes, MD, NCMP
Elaine Jolly, MD, FRCSC
Robert Reid, MD, FRCSC
Timothy Rowe, MB BS, FRCSC, FRCOG
Wendy Wolfman, MD, FRCSC, FACOG, NCMP
Chui Kin Yuen, MD, FRCSC, FACOG, MBA
Nese Yuksel, BSc. Pharm, Pharm.D, FCSHP, NCMP

CMS/SCM also wishes to thank our readers who have been

very supportive and help distribute to others.

Layout and Design: Lini Qiao

Publisher: CMS/SCM

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