Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

initial presentation with mild vasomotor symptoms

1st line – lifestyle changes

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ACUTE
|
initial presentation with mild vasomotor symptoms
1st line – 

lifestyle changes

Despite limited evidence, certain lifestyle changes can improve symptom tolerance. Women may be encouraged to lose weight (where appropriate) and to exercise more.[11] Both have cardiovascular and bone health benefits and can improve overall wellbeing, but may not have a specifically identifiable impact on hot flashes and cannot improve bone density.[8]

Other self-care measures include avoidance of spicy foods, alcohol, caffeine, warm environments, and stress. Alcohol and caffeine intake are associated with worsening vasomotor symptoms.

Wearing layered clothing and use of hand-held fans, drinking cold water, and mist bottles may be helpful.

One qualitative review of randomized controlled trials and meta-analyses found that yoga is moderately effective in the short term for psychological symptoms, but has no impact on somatic, vasomotor, or urogenital symptoms.[37]

ONGOING

women with a uterus, moderate to severe hot flashes, with/without reduced libido

1st line – continuous combined regimen

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ONGOING
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women with a uterus, moderate to severe hot flashes, with/without reduced libido
|
amenorrhea >12 months
1st line – 

continuous combined regimen

Hormonal therapy for a woman with a uterus comprises an estrogen, and a progestin to protect against endometrial hyperplasia and cancer.[17]​ Estrogens are the most effective treatment for vasomotor symptoms, reducing hot flashes by 80% to 90%.[38]

The continuous combined regimen is indicated in women who have had amenorrhea for more than 12 months. It is easy to follow and continues the amenorrhea of menopause.

If the woman has breakthrough bleeding after the first 6 months on the continuous combined regimen, endometrial assessment (pelvic ultrasound ± endometrial biopsy) is required and consideration should be given to switching to a sequential regimen so that she can have a predictable bleeding pattern.

A transdermal estrogen formulation (usually estradiol) is preferable to an oral estrogen for women who have a higher thrombotic risk (including body mass index >30), are taking other medications, have borderline triglyceride levels, are at risk for gallstones, or have difficulty adhering to a daily pill-taking regimen. Because there is no first-pass effect, a transdermal estrogen formulation may reduce the risk of thromboembolism compared with an oral estrogen, but this has not been studied in a randomized controlled trial (RCT). It might also have a lower incidence of nausea.[22][23]

Long-term complications of transdermal estrogen formulations are probably the same as those of oral estrogens, although these were not specifically studied in the Women's Health Initiative. According to UK National Institute for Health and Care Excellence recommendations, a transdermal estrogen formulation at standard therapeutic doses does not increase the risk of venous thromboembolism compared with baseline population risk.[1]

Transdermal estradiol is available in patch, metered-dose spray, or gel formulations, all of which are applied to the skin. One 12-week, multicenter RCT found that, compared with placebo, transdermal estradiol gel significantly reduced the frequency and severity of hot flashes at weeks 4 and 12 in healthy menopausal women who had moderate to severe hot flashes.[40] Headache, infection, breast pain, nausea, and insomnia were the most frequently reported side effects. A network meta-analysis found no difference in efficacy between an estradiol transdermal patch and an estradiol transdermal spray for vasomotor symptoms.[41]

A combination of an estrogen and a progestin is available in a single transdermal patch in most countries.

Hormone replacement preparations are available in different combinations. A few examples of regimens are outlined above.

Primary options

estrogens, conjugated/medroxyprogesterone: 0.3/1.5 mg to 0.625/5 mg orally once daily (dose depends on brand used)

OR

estradiol/norethindrone acetate transdermal: 0.05/0.14 mg patch twice weekly

Secondary options

medroxyprogesterone: 2.5 mg orally once daily

-- AND --

estrogens, conjugated: 0.3 to 1.25 mg orally once daily

or

estrogens, esterified: 0.3 to 1.25 mg orally once daily

or

estradiol transdermal: dose depends on brand of patch, spray, or gel; consult product literature for guidance on dose

1st line – sequential regimen

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ONGOING
|
women with a uterus, moderate to severe hot flashes, with/without reduced libido
|
menstrual irregularity and periods of amenorrhea (perimenopause)
1st line – 

sequential regimen

Hormonal therapy for a woman with a uterus comprises an estrogen, and a progestin to protect against endometrial hyperplasia and cancer.[17]​ Estrogens are the most effective treatment for vasomotor symptoms, reducing hot flashes by 80% to 90%.[38]

In a sequential regimen, a progestin is added to an estrogen for the last 10 to 14 days of the cycle. Sequential hormone therapy (HT) is primarily used by perimenopausal women, but may also be indicated in postmenopausal women.

A transdermal estrogen formulation (usually estradiol) is preferable to an oral estrogen for women who have a higher thrombotic risk (including body mass index >30), are taking other medications, have borderline triglyceride levels, are at risk for gallstones, or have difficulty adhering to a daily pill-taking regimen. Because there is no first-pass effect, a transdermal estrogen formulation may reduce the risk of thromboembolism compared with an oral estrogen, but this has not been studied in a randomized controlled trial (RCT). It might also have a lower incidence of nausea.[22][23]

Long-term complications of transdermal estrogen formulations are probably the same as those of oral estrogens, although these were not specifically studied in the Women's Health Initiative. According to UK National Institute for Health and Care Excellence recommendations, a transdermal estrogen formulation at standard therapeutic doses does not increase the risk of venous thromboembolism compared with baseline population risk.[1]

Transdermal estradiol is available in patch, metered-dose spray, or gel formulations, all of which are applied to the skin. One 12-week, multicenter RCT found that, compared with placebo, transdermal estradiol gel significantly reduced the frequency and severity of hot flashes at weeks 4 and 12 in healthy menopausal women who had moderate to severe hot flashes.[40] Headache, infection, breast pain, nausea, and insomnia were the most frequently reported side effects. A network meta-analysis found no difference in efficacy between an estradiol transdermal patch and an estradiol transdermal spray for vasomotor symptoms.[41]

Hormone replacement preparations are available in different combinations. Transdermal combined sequential HT preparations are available.

2nd line – conjugated estrogens/bazedoxifene

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ONGOING
|
women with a uterus, moderate to severe hot flashes, with/without reduced libido
|
menstrual irregularity and periods of amenorrhea (perimenopause)
2nd line – 

conjugated estrogens/bazedoxifene

Conjugated estrogens/bazedoxifene (a selective estrogen receptor modulator) has been approved by the Food and Drug Administration for the treatment of vasomotor symptoms and osteoporosis prevention in women with an intact uterus.[8][42]​​

Compared with conjugated estrogens/medroxyprogesterone, women treated with conjugated estrogens/bazedoxifene experienced significantly fewer adverse events. Women taking conjugated estrogens/bazedoxifene should not take a progestin.

Bazedoxifene has a favorable (anti-estrogenic) effect on breast tissue.[43] Further research is required.

Primary options

estrogens, conjugated/bazedoxifene: 0.45/20 mg orally once daily

3rd line – selective serotonin-reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI)

Back
ONGOING
|
women with a uterus, moderate to severe hot flashes, with/without reduced libido
|
menstrual irregularity and periods of amenorrhea (perimenopause)
3rd line – 

selective serotonin-reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI)

SSRIs and SNRIs are effective for treating vasomotor symptoms (VMS) in women unable to take hormone therapy.[59][60][61]

Some evidence suggests that escitalopram may be more effective than other SSRIs at reducing hot flashes.[61] Only paroxetine is approved for the treatment of moderate to severe VMS associated with menopause.[38][62]

In an 8-week randomized controlled trial (RCT) of 339 perimenopausal and postmenopausal women with bothersome VMS, venlafaxine (an SNRI) reduced the frequency of symptoms by 1.8 more per day than placebo (P=0.005).[63] Low-dose estradiol appeared to be more effective (2.3 fewer VMS per day than placebo), but it was not compared directly with venlafaxine in this study.[63] Venlafaxine may be a reasonable alternative for women unable to take an estrogen.

Compared with placebo, desvenlafaxine (an SNRI) reduced the frequency and severity of moderate to severe hot flashes over a 12-month period in an RCT of 365 postmenopausal women with bothersome VMS.[64] Subsequent to concerns regarding the safety of desvenlafaxine in this patient population, a discrete safety analysis found no evidence for an increased risk of cardiovascular, cerebrovascular, or hepatic events associated with desvenlafaxine (compared with placebo) for the treatment of menopausal VMS.[65]

Primary options

paroxetine: 7.5 mg orally once daily

OR

escitalopram: 10-20 mg orally once daily

OR

desvenlafaxine: 100 mg orally once daily

OR

venlafaxine: 37.5 to 75 mg orally (extended-release) once daily

Secondary options

fluoxetine: 10-20 mg orally once daily

OR

citalopram: 10-30 mg orally once daily

4th line – gabapentin

Back
ONGOING
|
women with a uterus, moderate to severe hot flashes, with/without reduced libido
|
menstrual irregularity and periods of amenorrhea (perimenopause)
4th line – 

gabapentin

Studies indicate that gabapentin is moderately effective for the treatment of hot flashes.[36][66] However, drowsiness, dizziness, and unsteadiness are commonly reported adverse effects.[66]

Gabapentin may result in intolerable lethargy when used during the day.[36] If night sweats are the primary bothersome symptom of menopause, gabapentin may be taken only at night. For daytime hot flashes, a dose escalation regimen may be used if other pharmacologic options are not available.

Primary options

gabapentin: 300 mg orally once daily initially, increase to 300 mg three times daily if required, increase gradually according to response if required, maximum 2400 mg/day

5th line – clonidine

Back
ONGOING
|
women with a uterus, moderate to severe hot flashes, with/without reduced libido
|
menstrual irregularity and periods of amenorrhea (perimenopause)
5th line – 

clonidine

Clonidine, an antihypertensive agent, reduces hot flashes but may be less effective than selective serotonin-reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors and gabapentin.[36]

Hypotension may be a treatment-limiting adverse effect.[78] Blood pressure should be monitored during therapy and for rebound after discontinuation.

Transdermal patches result in stable blood levels and are preferred to oral clonidine preparations.[36]

Primary options

clonidine transdermal: 0.1 mg/24 hour patch once weekly

Secondary options

clonidine: 0.05 to 0.2 mg orally (immediate-release) once or twice daily

women without a uterus or with levonorgestrel-releasing intrauterine device fitted in the last 5 years, moderate to severe hot flashes, with/without reduced libido

1st line – estrogen alone

Back
ONGOING
|
women without a uterus or with levonorgestrel-releasing intrauterine device fitted in the last 5 years, moderate to severe hot flashes, with/without reduced libido
1st line – 

estrogen alone

Women without a uterus can take an estrogen alone if they do not have contraindications for systemic estrogen therapy.[17]​ Estrogens are the most effective treatment for vasomotor symptoms, reducing hot flashes by 80% to 90%.[38]

A transdermal estrogen formulation (usually estradiol) is preferable to an oral estrogen for women who have a higher thrombotic risk (including body mass index >30), are taking other medications, have borderline triglyceride levels, are at risk for gallstones, or have difficulty adhering to a daily pill-taking regimen. Because there is no first-pass effect, a transdermal estrogen formulation may reduce the risk of thromboembolism compared with an oral estrogen, but this has not been studied in a randomized controlled trial (RCT). It might also have a lower incidence of nausea.[22][23]

Long-term complications of transdermal estrogen formulations are probably the same as those of oral estrogens, although these were not specifically studied in the Women's Health Initiative. According to UK National Institute for Health and Care Excellence recommendations, a transdermal estrogen formulation at standard therapeutic doses does not increase the risk of venous thromboembolism compared with baseline population risk.[1]

Transdermal estradiol is available in patch, metered-dose spray, or gel formulations, all of which are applied to the skin. One 12-week, multicenter RCT found that, compared with placebo, transdermal estradiol gel significantly reduced the frequency and severity of hot flashes at weeks 4 and 12 in healthy menopausal women who had moderate to severe hot flashes.[40] Headache, infection, breast pain, nausea, and insomnia were the most frequently reported side effects. A network meta-analysis found no difference in efficacy between an estradiol transdermal patch and an estradiol transdermal spray for vasomotor symptoms.[41]

Primary options

estradiol transdermal: dose depends on brand of patch, spray, or gel; consult product literature for guidance on dose

Secondary options

estrogens, conjugated: 0.3 to 1.25 mg orally once daily

OR

estrogens, esterified: 0.3 to 1.25 mg orally once daily

2nd line – selective serotonin-reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI)

Back
ONGOING
|
women without a uterus or with levonorgestrel-releasing intrauterine device fitted in the last 5 years, moderate to severe hot flashes, with/without reduced libido
2nd line – 

selective serotonin-reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI)

SSRIs and SNRIs are effective for treating vasomotor symptoms (VMS) in women unable to take hormone therapy.[59][60][61]

Some evidence suggests that escitalopram may be more effective than other SSRIs at reducing hot flashes.[61] Only paroxetine is approved for the treatment of moderate to severe VMS associated with menopause.[38][62]

In an 8-week randomized controlled trial (RCT) of 339 perimenopausal and postmenopausal women with bothersome VMS, venlafaxine (an SNRI) reduced the frequency of symptoms by 1.8 more per day than placebo (P=0.005).[63] Low-dose estradiol appeared to be more effective (2.3 fewer VMS per day than placebo), but it was not compared directly with venlafaxine in this study.[63] Venlafaxine may be a reasonable alternative for women unable to take an estrogen.

Compared with placebo, desvenlafaxine (an SNRI) reduced the frequency and severity of moderate to severe hot flashes over a 12-month period in an RCT of 365 postmenopausal women with bothersome VMS.[64] Subsequent to concerns regarding the safety of desvenlafaxine in this patient population, a discrete safety analysis found no evidence for an increased risk of cardiovascular, cerebrovascular, or hepatic events associated with desvenlafaxine (compared with placebo) for the treatment of menopausal VMS.[65]

Primary options

paroxetine: 7.5 mg orally once daily

OR

escitalopram: 10-20 mg orally once daily

OR

desvenlafaxine: 100 mg orally once daily

OR

venlafaxine: 37.5 to 75 mg orally (extended-release) once daily

Secondary options

fluoxetine: 10-20 mg orally once daily

OR

citalopram: 10-30 mg orally once daily

3rd line – gabapentin

Back
ONGOING
|
women without a uterus or with levonorgestrel-releasing intrauterine device fitted in the last 5 years, moderate to severe hot flashes, with/without reduced libido
3rd line – 

gabapentin

Studies indicate that gabapentin is moderately effective for the treatment of hot flashes.[36][66] However, drowsiness, dizziness, and unsteadiness are commonly reported adverse effects.[66]

Gabapentin may result in intolerable lethargy when used during the day.[36] If night sweats are the primary bothersome symptom of menopause, gabapentin may be taken only at night. For daytime hot flashes, a dose escalation regimen may be used if other pharmacologic options are not available.

Primary options

gabapentin: 300 mg orally once daily initially, increase to 300 mg three times daily if required, increase gradually according to response if required, maximum 2400 mg/day

4th line – clonidine

Back
ONGOING
|
women without a uterus or with levonorgestrel-releasing intrauterine device fitted in the last 5 years, moderate to severe hot flashes, with/without reduced libido
4th line – 

clonidine

Clonidine, an antihypertensive agent, reduces hot flashes but may be less effective than selective serotonin-reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors and gabapentin.[36]

Hypotension may be a treatment-limiting adverse effect.[67] Blood pressure should be monitored during therapy and for rebound after discontinuation.

Transdermal patches result in stable blood levels and are preferred to oral clonidine preparations.[36]

Primary options

clonidine transdermal: 0.1 mg/24 hour patch once weekly

Secondary options

clonidine: 0.05 to 0.2 mg orally (immediate-release) once or twice daily

urogenital atrophy only

1st line – vaginal estrogen ± vaginal moisturizer

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ONGOING
|
urogenital atrophy only
1st line – 

vaginal estrogen ± vaginal moisturizer

Low-dose vaginal estrogen preparations can be considered in women with symptoms of urogenital atrophy.[17]​​

A review of Medline and Cochrane databases showed that vaginal estrogens are more effective than placebo for improving dryness and decreasing dyspareunia, urinary urgency, and urinary frequency.[68] Rates of urinary tract infections also declined with vaginal estrogen use. Serum estradiol levels remained within postmenopausal norms, except for those who used high-dose vaginal estrogen cream.[68]

In women without a history of hormone-dependent cancer, vaginal estrogens can be continued for symptom relief, and there is no evidence to recommend endometrial surveillance.[31] In the Women's Health Initiative observational study, the risk of cardiovascular disease, invasive breast cancer, and endometrial cancer did not differ between women who were vaginal estrogen users and those who were not.[69]

Vaginal estrogens do not require progestin replacement.

Vaginal estradiol tablets do not result in significant systemic absorption and can be used long-term as required. However, in October 2019, the European Medicines Agency recommended limiting the use of high-strength estradiol vaginal creams (containing estradiol 100 micrograms/g or 0.01%) to a single treatment period of up to 4 weeks due to the risk of adverse effects usually associated with systemic (oral or transdermal) hormone therapy (HT). This formulation should not be used in patients already on HT.[70] Therefore, other vaginal estrogen formulations (e.g., conjugated estrogen cream, estradiol intravaginal tablets and rings) may be preferred. There is no evidence to suggest that any one vaginal estrogen preparation is more efficacious than another.[71]

Polycarbophil gel, a vaginal moisturizer, can also be offered for symptoms of vaginal atrophy, including dryness and dyspareunia.[78][79]

Primary options

estrogens, conjugated vaginal: (0.625 mg/g cream) insert 0.5 to 2 g into the vagina once daily for 21 days, followed by no treatment for 7 days, then repeat; or insert 0.5 g into the vagina twice weekly

OR

estradiol vaginal: (intravaginal tablets) 10 micrograms (1 tablet) into the vagina once daily for 2 weeks, followed by 10 micrograms (1 tablet) twice weekly thereafter; (intravaginal ring) 1 ring (7.5 micrograms/24 hours or 50-100 micrograms/24 hours) inserted into the vagina and replaced every 3 months, dose depends on brand used; (0.01% or 100 micrograms/g cream) insert 2-4 g (200-400 micrograms) into the vagina once daily for 1-2 weeks, then taper dose gradually over 1-2 weeks to maintenance dose of 1 g (100 micrograms) once to three times weekly

More

2nd line – ospemifene ± vaginal moisturizer

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ONGOING
|
urogenital atrophy only
2nd line – 

ospemifene ± vaginal moisturizer

Ospemifene is a selective estrogen receptor modulator indicated for the treatment of dyspareunia in postmenopausal women. In a phase 3 trial, ospemifene increased the percentage of superficial cells and reduced dyspareunia compared with placebo.[72] Hot flashes were the most frequently reported adverse event (ospemifene 7% versus placebo 4%).[72][73]

Polycarbophil gel, a vaginal moisturizer, can also be offered for symptoms of vaginal atrophy, including dryness and dyspareunia.[78][79]

Primary options

ospemifene: 60 mg orally once daily

urinary stress incontinence only

1st line – pelvic floor rehabilitation

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ONGOING
|
urinary stress incontinence only
1st line – 

pelvic floor rehabilitation

Pelvic floor rehabilitation may be useful for urinary stress incontinence.[81] In one study, 73.4% of postmenopausal women randomized to a combination of intravaginal estriol and pelvic floor rehabilitation for 6 months experienced subjective improvement in stress urinary incontinence compared with only 9.71% of women in the control (estriol-only) group.[82] Both groups reported improvement in signs and symptoms of urogenital atrophy.

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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