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Menopause Therapies

Prescribing MHT

Many clinicians are familiar with the term “hormone replacement therapy” or “HRT”. While this term is used in various countries and contexts, in Canada we use the term menopausal hormone therapy (“MHT”) to refer to the use of hormones to treat menopause and menopausal symptoms.

Guidelines agree that systemic menopausal hormone therapy (MHT) is the most effective treatment for vasomotor symptoms (hot flashes, night sweats). Additional benefits are conferred for symptoms of the genitourinary syndrome of menopause (GSM) (previously referred to as ‘vaginalvulvaratrophy’ or ‘VVA’) and for bone protection. There is also evidence for benefit for other menopause-related symptoms such as joint pains, reported sleep and mood disturbances, and quality of life.

The key to successful prescribing for menopausal patients is an individualized treatment plan based on shared decision making. Following the MQ6 algorithm will give the health care professional some general guidance around prescribing, however no algorithmic approach can be exhaustive to account for all individual factors.  The information on this website is intended to educate and support clinicians in managing menopausal concerns. It should be noted that one must always treat within the limits of one’s training and knowledge and seek guidance or consultation if uncertain.

Here are some prescribing pearls based on current guidelines:

Menopausal hormone therapy (MHT) is safest when initiated in patients without contraindications who are under the age of 60 or within 10 years of their final menstrual period (FMP). This patient group exhibits a more favourable risk/benefit ratio.

For older women, those more than 10 years past their FMP or those with high baseline cardiovascular risk, non-hormonal options for treatment are preferred.

For those patients for whom MHT is indicated and appropriate, there are a number of products for the healthcare professional to choose from.  A list of products available in Canada effective Jan 1, 2023  can be found below.  You may also find a list of available products on page 43 of the Canadian Menopause Society Pocket Guide for Menopause Management.

Choice of product will depend on patient demographics, some of which are considered through the use of the MQ6 algorithm/decision tool.

As unopposed estrogens put patients at risk of endometrial hyperplasia or cancer, most systemic MHT regimens will include  a progestogen to protect the endometrium. These products are called “EPT” (estrogen + progestogen) and are available either as individual estrogens and progestogens to be prescribed together or as manufactured combined products which come in both oral and transdermal forms.  There are also two newer products (1. Tibolone and 2. the TSEC combination of conjugated equine estrogen and bazedoxifene) that do not require the addition of a progestogen which will also provide for endometrial protection.

When just treating symptoms of the genitourinary syndrome of menopause (GSM) alone, the use of therapies with local effects are preferred. Historically this has included a variety of vaginal estrogens (cream, insert or ring) which when prescribed at recommended dosing (see table) do not require the addition of a progestogen for endometrial protection. Newer products include vaginal DHEA and oral Ospemifene which is an oral SERM (Selective Estrogen Receptor Modulator).  These products are designed to have effects on the urogenital tissues.

Duration of MHT treatment also requires individualization as there is no fixed or recommended duration of use and no “5-year” rule.   When counselling patients about the expected length of treatment consider the following: the median duration of vasomotor symptoms is 7.4+ years however the duration of vasomotor symptoms (VMS) will depend on when they begin in relation to the onset of menopause.  Patients who develop vasomotor symptoms before their final menstrual period (FMP) are reported to experience VMS for over 11 years on average, whereas those who start VMS after their FMP will average VMS of 3-4 years duration. Sharing this information with patients will help them understand their expected treatment trajectory.

Stopping MHT is not required based on age or duration of use. Timing of discontinuation should be a result of shared decision-making with the patient.  Tapering slowly or simply stopping the medication “cold turkey” are equally acceptable options. Be prepared that up to 50% of patients may experience a recurrence in symptoms.

Understanding Risks of MHT

An excellent summary of the benefits and risks related to menopausal hormone therapy (MHT) can be found in this handout prepared by the North American Menopause Society.

Many healthcare providers have been hesitant to prescribe MHT since the findings of the large Women’s Health Initiative study (WHI) were published in 2002, reporting increased risks of breast cancer, heart attacks, stroke and thrombotic events.  These results created alarm for both healthcare professionals and women around menopausal hormone therapy, resulting in decades of non-prescribing. This publication left patients to suffer and clinicians without adequate tools and knowledge to address menopausal concerns.

In the two decades that have followed, the science has been revisited and a number of expert guidelines have concluded that there are both benefits and risks associated with MHT use, however treatment with MHT can be safely initiated in appropriately screened women under the age of 60 or within 10 years of the final menstrual period.

This conclusion is, in part, informed by the re-evaluated WHI data. Clinicians should note that the WHI study population included women ages 50-80 who initiated MHT on average at age 63, much older than our typical menopausal patients.   The study showed that while there was a marginal increase (less than 1 case per 1000 women) in breast cancer risk for women in the EPT (estrogen + progestin) arm of the study, this is considered a “rare” medical risk and compares to the risk women assume by drinking 1-2 alcoholic drinks a day or being overweight-obese.  Of note, although more cases of breast cancer were reported in the EPT group (who took conjugated equine estrogen + medroxyprogesterone acetate) follow-up data reported that there was no increase in rates of deaths from breast cancer as a result of taking MHT.  In addition, for women in the WHI who took Estrogen alone (ET – conjugated equine estrogen), a reduction in the risk of breast cancer was observed. Breast effects persisted in both groups, even after hormone therapy was stopped. As a result of the WHI findings the International Menopause Society guidelines concluded that the risk of breast cancer with MHT relates to duration of use of estrogen and the use of a progestogen.

With respect to heart health, recent metanalyses report there is some evidence for cardiac protection in younger MHT users: while this is not an indication for treatment it reassures us that MHT is safe for the heart in appropriately chosen women. Similarly, while stroke risk was increased in older patients there was no significant increase in risk for those initiating MHT before age 60. 

The WHI study did report that MHT was associated with an increase risk of venous thromboembolic events (VTE): risk reported was 1.1/1000 women years for EPT and 0.4/1000 women years for ET for women initiating in their 50s. Incidence was highest the first 1-2 years after starting MHT.

Risks for VTE events are also increased with smoking, obesity and advancing age.

Data from observational studies suggest that transdermal estrogens, lower doses of estrogen and/or the use of a less thrombogenic progestogen (progesterone vs synthetic progestins) may reduce VTE risk.

While MHT is safe when initiated in younger women the WHI also reported an increase in dementia for women initiating therapy over the age of 65.

MHT is still considered the most effective treatment for vasomotor symptoms, with benefits for GSM, and bone health.  Women may also experience benefits to sleep, mood and quality of life. Evidence from the WHI study also reported a significant reduction in the incidence of type 2 diabetes mellitus for women on EPT and ET, and a persistent reduction in breast cancer incidence in women on ET (specifically for the conjugated equine estrogen used in the WHI).

Menopausal Hormone Therapies

In this section you will find tables of MHT products available in Canada as of Jan 1, 2023. (see below)

Systemic Hormone Therapies
  1. Estrogen alone (ET): used for women without a uterus who require MHT.
  1. Combined hormone therapies: used for women who require MHT and who require endometrial protection (as unopposed estrogen can cause endometrial hyperplasia or cancer). These include:
    1. Estrogen + Progestogen therapies
    2. Products that do not require an additional Progestogen
      1. TSEC: Tissue Selective Estrogen Complex – contains Estrogen + SERM
      2. STEAR: Selective Tissue Estrogenic Activity Regular – sex steroid with hormonal activity*

*while the STEAR (Tibolone) only contains a single compound (ie. Tibolone), it acts like a combined hormone therapy

  1. Progestogen: a progestogen without estrogen is sometimes used for perimenopausal women for cycle control. Progestogens may have a small direct benefit for vasomotor symptoms but are much less effective than estrogen-based therapies.
1A. EstrogenS

Type of Estrogen

Starting dose*

Oral

Conjugated estrogen (PremarinⓇ)

0.3 – 0.625 mg daily

17β-estradiol (EstraceⓇ)

0.5 – 1 mg daily

Transdermal Patch

17β-estradiol (EstradotⓇ, OesclimⓇ, generic)

25 – 50 mcg twice weekly

17β-estradiol (ClimaraⓇ)

25 – 50 mcg once weekly

Transdermal Gel

17β-estradiol (EstrogelⓇ)

1 pump = 0.75 mg 17β-estradiol 

1 – 2 pumps daily

17β-estradiol (DivigelⓇ)

0.5 – 1 mg sachet daily

*Starting doses may be higher when treating premature ovarian insufficiency (POI).

1B. ProgestogenS

Type of Progestogen

Doses

Oral

Medroxyprogesterone (ProveraⓇ, generic)

2.5 mg daily (continuous)
5 mg daily x 12 – 14 days (cyclic)

Micronized progesterone (PrometriumⓇ, generic)

100 mg daily (continuous)
200 mg daily x 12 – 14 days (cyclic)

Norethindrone (NorlutateⓇ)

5 mg daily

Intrauterine System

Levonorgestrel IUS* (MirenaⓇ)

LNG 52 mg releases 20 mcg/day

x 5 years (off-label for MHT)

2A. Combined Continuous Products

Estrogen (1A) and progestogen (1B) products may be combined to create a cyclic OR continuous EPT regimen or you may choose existing daily products which provide for continuous therapy.

Type of Continuous Combined Product

Starting doses*

Oral

17β-estradiol + NETA oral (ActivelleⓇ, Activelle LDⓇ)

1 mg E2/0.5 mg NETA daily

0.5 mg E2/0.1 mg NETA daily (LD)

One tablet daily

17β-estradiol + Drospirenone oral (AngeliqⓇ)

1 mg E2/1 mg DRSP

One tablet daily

17β-estradiol + Progesterone (BijuvaⓇ)

1 mg E2/100 mg Progesterone

One tablet daily

Transdermal Patch

17β-estradiol + NETA patches (EstalisⓇ 140/50; 250/50)

140 mg NETA /50 mg E2

250 mg  NETA/50 mg E2

One patch twice weekly

Custom Combined Regimen

Combine an estrogen (oral or transdermal) from Table 1A with a progestogen from Table 1B to create EPT

Estrogen + Progestogen daily, or

Estrogen daily + LNG-IUS (off-label)

Continuous MHT Options: no additional Progestogen

Doses

Selective Tissue Estrogenic Activity Regulator (STEAR)

Tibolone (TibellaⓇ)

2.5 mg tablet

One tablet daily

Tissue Selective Estrogen Complex (TSEC)

Conjugated estrogen (0.45 mg) + bazedoxifene (DuaviveⓇ)

0.45 mg CEE + 20 mg BZA

One tablet daily

2B. Cyclic MHT Products

There are no manufactured cyclic MHT options available in Canada. To create a cyclic regimen, consider prescribing the following:

Cyclic MHT Regimens

Type of Hormone

Dosing Options

An Estrogen (from Table 1A)

Oral = daily

Patch = 1-2 x a week (depends on product)

Gel = daily

+

A Progestogen (from Table 1B)

Daily: One tablet daily days 1 to 12-14 of the calendar month

Progestogen containing IUS

3. GSM Treatments

Therapies with local Vaginal (GSM) Benefit

Therapies with local Vaginal Benefit

Doses

Vaginal Estrogens

Vaginal Cream: Conjugated Equine Estrogen (PremarinⓇ)

0.5 – 1.0 gm nightly pv x 2 weeks then 2/week*

differs from product monograph

Vaginal Cream: Estrone (Estragyn®)

0.5 – 1.0 gm nightly pv x 2 weeks then 2/week*

differs from product monograph

Vaginal Tablet: 17B Estradiol (VagifemⓇ)

One tablet nightly pv x 2 weeks then 2/week

Vaginal Softgel Insert: 17B Estradiol (ImvexxyⓇ)

4 mcg or 10 mcg nightly pv x 2 weeks then 2/week

Vaginal Ring: 17B Estradiol (EstringⓇ)

Change ring q3 months

Vaginal DHEA

Vaginal Insert: Prasterone (IntrarosaⓇ)

6.5 mg pv daily

Oral agent for GSM

SERM: Ospemifene (OsphenaⓇ)

60 mg po daily

*Product monograph dosing is higher than as posted and could require endometrial protection.  Start with 0.5-1.0 gm nightly pv x 2 weeks then twice weekly.  At those doses endometrial protection should not be required however any unexplained vaginal bleeding should be investigated.

There are no studies at this time supporting the use of vaginal prasterone with systemic MHT.
Oral ospemifene cannot be combined with systemic MHT.

Nonhormonal therapies for vasomotor symptoms

Non-Hormonal Medications

Non-hormonal therapies for menopausal vasomotor symptoms (VMS) include a number of medications which are used “off-label” and are indicated for patients who cannot or do not wish to take menopausal hormone therapy (MHT). Each option will provide some relief from vasomotor symptoms but also provides benefits to other menopause related symptoms such as mood, sleep or urinary symptoms. 

The answers to the MQ6 assessment tool can inform as to which of these options may be preferred given the patient’s individual symptom profile. The chart below indicates options available in Canada as of January 2023. 

The “+” indicates relative impact for the symptom listed based on consensus/low-level evidence.

Non-Hormonal Treatment Options**

Gabapentin*

Antidepressants*

ie. SSRI, SNRI

Clonidine

Oxybutinin*

Vasomotor Symptoms

++(1)

++

+

++

GSM

+(2)

Sleep

+++(1)

+/-

Mood

+/-(3)

++/+++

  1. Gabapentin can be sedating at higher doses and has shown particular benefit for night sweats
  2. Oxybutynin is indicated (on-label) for symptoms of overactive bladder (OAB)
  3. There is some evidence for benefits of gabapentinoids on mood/anxiety

*indicates off-label use for vasomotor symptoms
**based on low-level evidence/consensus opinion

Type

Doses

Antidepressants: SNRI*

Venlafaxine XR

37.5-75 mg once daily

Desvenlafaxine

100 mg once daily

Antidepressants: SSRI*

Paroxetine

10-20 mg once daily

Citalopram

10-20 mg once daily

Escitalopram

10-20 mg once daily

Gabapentinoids*

Gabapentin

up to 900 mg per day in divided doses

Other

Clonidine (on-label)

0.05 mg twice daily

Oxybutinin*

2.5-5 mg twice daily

*NB all the above are off-label uses of these medications

Lifestyle and non-medication management for milder vasomotor symptoms

There is some evidence for the use of cognitive behavioral therapy or hypnotherapy in treating vasomotor symptoms, however these studies used regimens designed specifically for the treatment of menopausal symptoms. Nonetheless these interventions may also be helpful in treating accompanying mood and sleep disturbances.

Research findings are inconclusive for the use of acupuncture, yoga, exercise or phytoestrogens in treating VMS. Similarly, there is insufficient evidence for benefit with most natural health products such as herbal or vitamin supplements.

Avoiding triggers such as smoking and alcohol may provide some relief from mild VMS. Weight loss, layering of clothing, fans and other cooling techniques may be of some benefit as well but efficacy is limited in moderate to severe vasomotor symptoms. 

Guidelines do recommend that lifestyle and other non-medication treatment options for vasomotor symptoms should not delay treatment with more effective options.

Counselling Patients about MHT

Clinicians may struggle with counselling patients when prescribing systemic menopausal hormone therapy. A helpful handout is available from the North American Menopause Society.

Here is a counselling tool you may use when initiating MHT in appropriately selected women:

FAQ's

Cyclic MHT includes a daily estrogen with a progestogen 12-14 days of the month. A typical Rx may look like this:

Rx:    Transdermal estradiol 50ug patch, change twice weekly  +

Rx:    Micronized progesterone 200 mg po OD day 1-14 of the calendar month

OR

Rx Conjugated equine estrogen  0.625 mg po od +

Medroxyprogesterone acetate 5 mg po od day 1-12 of the calendar month

Although there is only one year of scientific data, experts have concluded that additional progestogen is NOT required when only providing local estrogen therapy at low doses.

Ie. Estradiol 10ug vaginal inserts, Estrone vaginal cream 0.5 gm or CEE vaginal cream 0.5 gm nightly x 2 weeks then 2/week pv

However, if a patient develops abnormal uterine bleeding, this should be promptly investigated.

These patients, as are those with Premature Ovarian Insufficiency (POI) whose FMP is before age 40, are at higher risk for osteoporosis, dementia and earlier cardiovascular disease. These patients should be treated with menopausal hormone therapy (MHT) until the age of natural menopause and then discuss options for future treatment once they reach the typical menopausal age (learn more). Patients with menopause at younger ages usually require higher hormone doses.  Consider consultation with a gynecologist for appropriate diagnosis and treatment.

Patients asking for bioidentical hormones often are actually requesting custom-compounded bioidentical hormone therapy (BHT).  Pharmaceutical products containing estradiol, estrone or micronized progesterone are identical in chemical structure to the hormones produced by the body and are considered “body-identical”. Most guidelines recommend these government approved therapies in lieu of custom-compounded products as they provide consistency and purity in dosage.

Transdermal products are preferred as the patient is at higher risk for VTE and cardiovascular disease due to their BMI. As obesity confers additional breast cancer risk, there may be a benefit to the use of a natural progesterone (micronized progesterone) over a synthetic progestin, based on observational data. These patients are also at higher risk for endometrial hyperplasia. To address this, you may need to prescribe higher doses of the progestogen. In addition, there is data suggesting that continuous EPT regimens may provide greater endometrial protection when compared with cyclic regimens with respect to uterine cancer risk.

Your patient may have a family history of breast cancer, a personal history of dense breasts, painful breasts, or other breast concerns.   In this group micronized progesterone may be preferable if using EPT or consider the use of MHT that does not require additional progestogen i.e. the TSEC (CEE/BZA) or the STEAR (Tibolone) which are more breast neutral.

Estrogen or progestogen therapies do not generally improve libido. However, in users of oral estrogen, the first-pass effect in the liver stimulates the production of sex hormone-binding globulin (SHBG) which binds testosterone.  This increases the levels of SHBG and reduces free testosterone levels. Transdermal hormone therapy avoids this effect and may be preferred when libido is an issue.

Some studies have reported better sexual function outcomes with a STEAR (Tibolone), although this is not a Health Canada approved indication for use.

Some women will experience vasomotor symptoms during their pill-free week and this may be an indicator of perimenopause/menopause.

FSH blood levels are not helpful when a patient is on a COC. However, to confirm menopausal hormone levels you may consider switching to a norethindrone-based progestogen only pill (POP); then check the FSH levels at 6 and 12 weeks. If the FSH is in the menopausal range x 2, you may consider the patient to be menopausal. 

Another option would be to stop the COC, use condoms and see if the patient starts to menstruate or develops symptoms.

A third option would be to continue the COC up to age 50-55, if appropriate, based on a patient’s individual risk profile.

MHT is not a contraceptive. Menopause is confirmed after one year of amenorrhea. It is notable that fertility persists for one year after the final menstrual period in women achieving menopause in their 50’s.  By the time menopause is confirmed, contraception is not required. For women in their 40s, fertility persists for 2 years after the final menstrual period, which is one additional year once menopause is confirmed. Remember to address contraceptive needs in your perimenopausal and early menopausal patients.

Start at 100-200 mg nightly and titrate to symptom relief. You may increase by 100 mg every 3 days up to 600-800 mg nightly.  Increase more slowly if the patient has excessive morning somnolence.  Some patients will not tolerate more than 600 mg at night, in which case additional daytime dosing (up to a total of 900 mg daily) can be initiated, but may cause excessive daytime fatigue.  Gabapentinoids may cause weight gain at higher doses.

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