Review CPD

A pragmatic approach to the management

of menopause
Iliana C. Lega MD MSc, Alexa Fine BSc, Margarita Lam Antoniades MD, Michelle Jacobson MD MHSc

n Cite as: CMAJ 2023 May 15;195:E677-82. doi: 10.1503/cmaj.221438

Menopause is defined as 1 year of amenorrhea caused by

declining ovarian reserve or as the onset of vasomotor Key points
symptoms in people with iatrogenic amenorrhea. It is preceded • Menopausal symptoms can occur for as long as 10 years before
by perimenopause or the menopause transition, which can last the last menstrual period and are associated with substantial
for as long as 10 years. Although many treatments exist for morbidity and negative impacts on quality of life.
menopausal symptoms, fears around the risks of menopausal • Menopausal hormone therapy is indicated as first-line
hormone therapy and lack of knowledge regarding treatment treatment of vasomotor symptoms, and is a safe treatment
option for patients with no contraindications.
options often impede patients from receiving treatment. In this
review, we summarize the evidence for treating menopausal
• Though less effective, nonhormonal treatments also exist to
treat vasomotor symptoms and sleep disturbances.
symptoms and discuss their risks and benefits to help guide
• It is critical that clinicians inquire about symptoms during the
clinicians to evaluate and treat patients during the menopausal menopause transition and discuss treatment options with
transition (Box 1). their patients.

What is the prevalence and impact of

menopausal symptoms? these symptoms for more than 10 years.6 In addition, vasomotor
symptoms have been shown to independently predict increased
The median age of menopause is 51 years, which has remained cardiovascular risk, bone loss and high bone turnover.7,8
consistent over the last century, despite a trend toward an A higher burden of menopausal symptoms is associated with
earli­er age of menarche.1,2 “Symptoms of menopause often start decreased mental and physical quality of life.9 The transition into
during the perimenopausal period, even as early as 10 years menopause, irrespective of symptoms, has also been associated
before the last menstrual period. 1,3 Globally, 1.0%–3.7% of with decreased health-related quality of life.10 Symptoms can
women experience premature ovarian insufficiency, which leads substantially affect work productivity, as well as health care use
to menopause before age 40 years and has a variety of causes, and costs.9,11,12
including chromosomal abnormalities, autoimmune processes,
cancer treatment, surgery or idiopathic etiologies.4 How is menopause diagnosed?
Menopausal symptoms are variable and reflect a complex
interaction between biological, psychological and social factors. For people older than 45 years who have symptoms of meno-
Vasomotor symptoms (e.g., hot flashes, night sweats) are the pause or amenorrhea, a work-up with laboratory tests and
most commonly reported and may affect as many as 80% of im­aging is not indicated unless symptoms are suggestive of an
women. 5 Most vasomotor symptoms persist for fewer than alternative diagnosis. Pregnancy should be ruled out among sex-
7 years after the final menstrual period; however, 25% of women ually active patients who are not using contraception.
may experience flushing for as long as 10 years, and 10% have For patients younger than 45 years who present with irregu-
lar or absent menstrual cycles, clinicians should order follicle-
stimulating hormone (FSH) levels, although FSH levels vary con-
Box 1: Evidence used in this review
siderably during perimenopause.13 Endocrine disorders should
We searched PubMed from inception until April 2022 using the be ruled out as causes of secondary amenorrhea (e.g., hyperpro-
term “menopause” with keywords “symptoms,” “diagnosis” and
lactinemia, hypothyroidism), as well as pregnancy (Table 1). For
“treatment.” We also reviewed relevant articles from the reference
lists of selected articles. Selected articles included a combination patients younger than 40 years who present with irregular cycles
of systematic reviews, practice guidelines, randomized controlled and menopausal symptoms, clinicians should conduct a com-
trials and cohort studies. plete work-up for secondary amenorrhea, including a FSH and
serum estradiol.

© 2023 CMA Impact Inc. or its licensors CMAJ | May 15, 2023 | Volume 195 | Issue 19 E677
 regard to stroke and clot risk.14 Progestins are available as both syn-
Table 1: Investigations for secondary amenorrhea when thetic progestins and micronized progesterone, and come in the
indicated for patients younger than 45 years
form of oral pills, transdermal systems (in combination with estro-
Differential diagnosis Diagnostic test gen) and an intrauterine device (Table 3).
Review

Newer, single-dose combination treatments like tissue select­

Premature ovarian insufficiency FSH, estradiol ive estrogen complexes (TSECs; e.g., conjugated estrogen and
or early menopause
bazodoxifene) and selective tissue estrogen activity regulators
Hyperprolactinemia Serum prolactin (e.g., tibolone) can also be used as first-line treatments in place
Pregnancy β-hCG of traditional combination estrogen–progestin products. Tibo-
Hypo- or hyperthyroidism TSH lone carries similar risks to standard menopausal hormone ther-
Polycystic ovary syndrome Clinical diagnosis (i.e., Rotterdam apy.17 Although TSECs have similar adverse effects as meno-
criteria), with or without total pausal hormone therapy, they are associated with less
serum testosterone break-through bleeding and mastalgia; however, they have been
Note: FSH = follicle-stimulating hormone, hCG = human chorionic gonadotropin,
unavailable in Canada since 2020 because of a packaging prob-
TSH = thyroid-stimulating hormone. lem that has recently been resolved.
In the absence of contraindications, menopausal hormone
therapy is the treatment of choice for patients within 10 years of
For patients with vasomotor symptoms that are atypical, their final menstrual period or, if this is unknown, younger than
more frequent than would be expected or associated with other 60 years (Table 4).14,16 Standard doses of menopausal hormone
symptoms not usual in menopause, alternative diagnoses should therapy for patients of average menopausal age are included in
be considered — such as carcinoid syndrome, pheochromo­ Table 3; doses for patients with premature ovarian insufficiency
cytoma, and hematologic or solid organ malignant diseases — should be higher.18 Duration of treatment after starting meno-
and investigated accordingly (Table 2). pausal hormone therapy is no longer limited to 5 years, but
rather is individualized, where the safest regimen is used at the
How should troubling symptoms be treated? appropriate doses to control symptoms.15 For patients with pre-
mature ovarian insufficiency, hormone replacement should con-
Menopausal hormonal therapy tinue until the average age of menopause, irrespective of symp-
Several international societies, including the Society of Obstetricians tom burden and in absence of contraindications.
and Gynaecologists of Canada and the North American Menopause In Canada, no product for testosterone treatment has been
Society, recommend menopausal hormone therapy as the first-line approved or recommended for menopausal symptoms, but the
treatment for vasomotor symptoms for both menopausal and peri- International Menopause Society has a position statement regarding
menopausal patients.14,15 The estrogen component of menopausal the off-label treatment of menopausal hypoactive sexual desire.19
hormone therapy reduces bothersome menopausal symptoms,
while the progestin protects the endometrium from hyperplasia and Nonhormonal therapies
reduces the risk of endometrial cancer. Treatment with combined Although less effective than menopausal hormone therapy,17
estrogen and progestin regimens (or estrogen alone, in patients who nonhormonal options should be considered if menopausal
have had a hysterectomy) reduces the frequency and severity of hot hormone therapy is not appropriate because of contraindications
flashes and night sweats by around 75%.16 In Canada, systemic or patient preference.14 Options include certain selective serotonin
estrogens are available in oral form, or as a transdermal patch or gel; reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake
vaginal formulations exist in the form of creams, vaginal tablets or an inhibitors (SNRIs), gabapentinoids, clonidine and oxybutynin
insertable ring. Transdermal estrogen formulations bypass the first- (Table 5). Gabapentionoids are particularly useful when taken at
pass effect of the liver and may be safer than other formulations with night to help alleviate nocturnal symptoms. A newer class, still

Table 2: Red flags and secondary work-up to consider for menopausal patients with vasomotor symptoms

Symptom Differential diagnosis Secondary work-up

B symptoms — night sweats accompanied by Malignancy (solid or hematological) Appropriate work-up for malignant disease
weight loss and fever
Worsening VMS, remote from menopause Coronary artery disease Cardiac testing, as indicated (e.g., stress test,
transition stress echo)
VMS with skin flushing, diarrhea or shortness Carcinoid syndrome 24-hour urine collection for 5-HIAA
of breath
Episodic headache, hypertension and Pheochromocytoma 24-hour urine collection for total
palpitations metanephrines
Note: 5-HIAA = 5-hydroxyindoleacetic acid, VMS = vasomotor symptoms.

E678 CMAJ | May 15, 2023 | Volume 195 | Issue 19

awaiting approval, is the neurokinin-3 receptor antagonist, which being treated primarily for this issue can be treated with lubri-
acts to stabilize the temperature control centre in the hypo­ cants, moisturizers, vaginal estrogens or oral selective estrogen
thalamus. 20 Although some herbal supplements have been receptor modulators alone.
associated with improvement in menopausal symptoms, a review Despite early concerns of an increased risk of cardiovascular

Review
of nonpharmacologic treatments is beyond the scope of this article; events with menopausal hormone therapy after the Women’s
the topic was recently reviewed in a menopause practice guideline Health Initiative (WHI) trial,25 increasing evidence shows a pos­
by the Society of Obstetricians and Gynecologists of Canada.14 sible reduction in coronary artery disease (CAD) with meno-
pausal hormone therapy among younger menopausal patients,
What are the benefits and risks of menopausal speci­fically those who start menopausal hormone therapy before
hormone therapy? age 60 years or within 10 years of menopause.26–30 Data from both
randomized controlled trials (RCTs) and observational studies
Benefits consistently show that menopausal hormone therapy is associ-
Menopausal hormone therapy can improve vasomotor symp- ated with a reduction in CAD events among these patients;
toms by as much as 90% in patients with moderate-to-severe hot menopausal hormone therapy should therefore be preferentially
flushes.21 It also improves sleep quality22 and mood disturb­ started during these time windows.29 A reduction in overall mor-
ances.23,24 Although systemic menopausal hormone therapy may tality among patients who begin menopausal hormone therapy
also alleviate genitourinary syndrome of menopause, patients before age 60 years has also been reported.27,31

Table 3: Systemic menopausal hormone therapy products available in Canada

Relative cost per year, before

Generic name Dosage pharmacy dispensing fees*†

Conjugated estrogens 0.3–0.625 mg once daily +

17-β-estradiol (micronized) 0.5–1 mg once daily +
Transdermal patch
Twice weekly 17-β-estradiol patches 25–50 μg twice weekly ++
Transdermal gel
17-β-estradiol gel For 0.06% gel, 0.75 mg estradiol per 1.25 g metered dose (1 actuation). ++
1–2 metered doses/actuation daily
Progestins
Oral
Medroxyprogesterone 2.5 mg daily for continuous regimen or 5 mg daily for 12–14 d/mo +
Progesterone (micronized) 100 mg daily for continuous regimen or 200 mg daily for 12–14 d/mo +
for cyclic regimen
Intrauterine
Levonorgestrel intrauterine system‡ 52 mg per intrauterine system for 5 years +
Combination hormone therapy
preparations
Oral
17-β-estradiol and NETA 1 mg 17-β-estradiol and 0.5 mg NETA once daily +++
0.5 mg 17-β-estradiol and 0.1 mg NETA once daily +++
17-β-estradiol and DRSP 1 mg 17-β-estradiol and 1 mg DRSP once daily ++
Transdermal patch
17-β-estradiol and NETA 50 μg 17-β-estradiol and 140 mg NETA patch twice weekly ++
50 μg 17-β-estradiol and 250 mg NETA patch twice weekly ++
TSEC
Conjugated estrogen and bazedoxifene 0.45 mg conjugated estrogen and 20 mg bazedoxifene once daily +++
Synthetic steroid
Tibolone 2.5 mg once daily +++

Note: DRSP = drospirenone, NETA = norethindrone acetate, TSEC = tissue selective estrogen complex.
*Available from www.rxfiles.ca.
†Range of costs: + = < $300, ++ = $301–1000, +++ = > $1001.
‡Not approved for menopausal hormone therapy by Health Canada.

CMAJ | May 15, 2023 | Volume 195 | Issue 19 E679

 Table 4: Contraindications to systemic menopausal Table 5: Nonhormonal menopausal treatments and
hormone therapy14 suggested doses14

Hormone therapy Contraindication Type Starting dose

Review

Estrogen Undiagnosed abnormal vaginal bleeding SNRIs

Known, suspected or history of breast cancer Venlafaxine 37.5–75 mg oral daily
Known, suspected or history of estrogen- Desvenlafaxine 100–150 mg oral daily
dependent cancers (i.e., endometrial, ovarian) SSRIs
Active or history of coronary artery disease Paroxetine 10–20 mg oral daily
Active or history of venous thromboembolism Citalopram 10–20 mg oral daily
Active or history of stroke Escitalopram 10–20 mg oral daily
Known thrombophilia Gabapentinoids
Active liver disease (e.g., with abnormal liver Gabapentin 100–300 mg oral at bedtime
function tests, cirrhosis)
Pregabalin 150–300 mg oral twice daily
Progestin Undiagnosed abnormal vaginal bleeding
Clonidine 0.05 mg oral twice daily
Current or history of breast cancer
Oxybutynin
Reproduced with permission (Yuksel et al., 2021).14
Oxybutynin immediate release 2.5–5 mg oral twice daily
Oxybutynin XL 15 mg daily
The metabolic benefits of menopausal hormone therapy Note: SNRI = serotonin–norepinephrine reuptake inhibitor, SSRI = selective serotonin
reuptake inhibitor.
include an improvement in lipid profile (increase in high-density Reproduced with permission (Yuksel et al., 2021).14
lipoprotein, decrease in low-density lipoprotein, decrease in lipo-
protein [a]), although oral estrogen may also increase triglycer-
ide levels.32 Some studies suggest an improvement in insulin placebo. Other studies also showed a lower risk of breast cancer
sensi­tivity and, perhaps, a reduction in risk of diabetes.33–35 For among those on estrogen alone, compared with those on com-
both lipid and insulin sensitivity, the benefits are seen primarily bined menopausal hormone therapy,41,42 with synthetic proges-
with oral estrogen therapy rather than transdermal formulations, tins conferring a higher risk of breast cancer than micronized
given their hepatic first-pass effects. progesterone.43 In patients with additional risk factors for breast
Menopausal hormone therapy has been consistently associ- cancer (e.g., family history, obesity, alcohol intake), the lowest
ated with a reduction in the incidence of osteoporosis-related effective dose of micronized progesterone or no progestin should
fractures.25,36,37 The WHI study provided the best evidence on be considered, if appropriate (i.e., TSEC or estrogen alone).
fracture risk reduction with menopausal hormone therapy, Although early RCT data suggested an increased risk of
reporting a 34% reduction in hip fractures, a 34% reduction in is­chemic stroke among patients on menopausal hormone therapy
vertebral fractures and a 23% reduction in other osteoporotic (odds ratio 1.29), more recent data suggest that this risk is primar-
fractures among women who took hormone therapy compared ily among older patients (aged > 60 yr) who start menopausal hor-
with those who did not.25 Although menopausal hormone ther- mone therapy after the 10 years following the onset of meno-
apy is not recommended by most osteoporosis guidelines as a pause.44 For those younger than 60 years, the absolute risk of
primary treatment, it should be considered as a second-line stroke from standard dose hormone therapy is about 2 additional
treatment in symptomatic menopausal patients.38 strokes per 10 000 person-years of use. With regard to venous
thromboembolic events, the WHI reported a twofold increased risk
Risks with hormone therapy, with the risk highest in the first year of use
Although many RCTs and observational studies have shown an and with higher doses.25 The reported absolute risk was 2–10 cases
increased risk of breast cancer with menopausal hormone ther- per 1000 users with short-term use (< 2 yr) and up to 28 cases per
apy, these findings need to be interpreted carefully in the context 1000 users with long-term use (> 7 yr).45 Most recent studies show a
of the individual patient. The WHI first reported that patients lower risk of venous thromboembolic events with transdermal
treated with combined menopausal hormone therapy had an estrogen formulations compared with oral treatments.46–48
increased risk of invasive breast cancer (hazard ratio 1.2).39 How-
ever, the attributable risk is much lower among people aged What are the considerations for starting
50–59 years or among those who start treatment within the first menopausal hormone therapy?
10 years of menopause, for whom the additional risk of breast
cancer is estimated at 3 additional cases for every 1000 women For average-aged menopausal or perimenopausal patients with
who use combined menopausal hormone therapy for 5 years.40 In no contraindications for menopausal hormone therapy and no
the WHI 20-year follow-up study, patients on conjugated estro- specific individual risk factors, no specific hormone regimen is
gen alone showed a lower risk of breast cancer than those on preferred for menopause management. When starting a patient

E680 CMAJ | May 15, 2023 | Volume 195 | Issue 19

on menopausal hormone therapy, clinicians should consider the Conclusion
patient’s individual risk of disease (e.g., breast cancer, venous
thrombolic events, stroke), preferred mode of delivery (oral v. Menopause and perimenopause can be associated with distress-
transdermal, combination v. separate dosing), need for uterine ing symptoms and reduced quality of life. Menopausal hormone

Review
protection and cost. Patients with risk factors for specific dis- therapy is the first-line treatment for vasomotor symptoms in the
eases like breast cancer should be offered an individualized regi- absence of contraindications. Patients with contraindications to
men (e.g., the TSEC, conjugated estrogen alone, combination estrogen and progestin therapy can be offered nonhormonal
therapy with cyclic progesterone). Similarly, a patient at risk for alternatives. Choice of menopause treatments depends on
venous thromboembolic events should be offered low-dose symptoms, patient preference, risk factors, absolute contraindi-
transdermal therapy. cations, availability and costs. Complex patients should be
Common adverse effects of menopausal hormone therapy referred to specialists. Important clinical questions remain unan-
include vaginal bleeding, mastalgia and headache. Unexpected swered and should be tackled by future research (Box 2).
vaginal bleeding is the most common adverse event with meno-
pausal hormone therapy. Investigations for endometrial hyper- References
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Competing interests: Iliana Lega holds research funding from the Can­ Contributors: Iliana Lega, Alexa Fine and Michelle Jacobson were
adian Institutes of Health Research (CIHR) and Canadian Menopause involved in the conception and design of this manuscript. All of the
Society, and has received travel support from Diabetes Canada. Michelle authors drafted the manuscript, revised it critically for important
Jacobson reports funding from CIHR, travel support from Women’s College intellectual content, gave final approval of the version to be pub-
Hospital and consulting fees from Abbvie, Astellas, Biosyent, Duchesnay, lished and agreed to be accountable for all aspects of the work.
Lupin and Pfizer. She has received honoraria from Abbvie, Bayer, Biosyent,
Funding: There is no funding associated with this manuscript.
Duchesnay, Lupin, Organon, Pfizer and Searchlight. She consults on Dua-
vive, Tibolone, Mirena and Estrogel. She is a vice chair with the Ontario Content licence: This is an Open Access article distributed in accord­
Medical Association, and sits on the advisory boards of Pfizer, Duchesnay, ance with the terms of the Creative Commons Attribution (CC BY-NC-
Astellas, Lupin and Eisai. No other competing interests were declared. ND 4.0) licence, which permits use, distribution and reproduction in
any medium, provided that the original publication is properly cited,
This article was solicited and has been peer reviewed.
the use is noncommercial (i.e., research or educational use), and no
Affiliations: Women’s College Hospital (Lega, Jacobson); Departments modifications or adaptations are made. See: https://creativecommons.
of Medicine (Lega), Family and Community Medicine (Lam Antoniades), org/licenses/by-nc-nd/4.0/
and Obstetrics and Gynecology (Jacobson), University of Toronto,
Correspondence to: Iliana Lega; [email protected]
Toronto, Ont.; Queen’s School of Medicine (Fine), Queen’s University,
Kingston, Ont.; Unity Health Toronto (Lam Antoniades), Toronto, Ont.

E682 CMAJ | May 15, 2023 | Volume 195 | Issue 19