Menopause and hormone therapy

Your body has preferred levels of hormones that allow it to function at its best. It is normal for hormone levels to change as you age, but sometimes the change in the female hormone cycle can cause symptoms that affect your quality of life. When you are experiencing symptoms throughout your menopause transition you may be referred to an endocrinologist – if not, you may request to see one by asking your healthcare provider. If you do not already have a healthcare practitioner who is familiar with identifying and treating symptoms of menopause, the North American Menopause Society provides a list of menopause practitioners  here.

Your healthcare provider is the best source to advise you on whether or not this therapy will improve your quality of life. To get HT, you will need a prescription from a medical doctor (GP, OB/GYN, or an endocrinologist), nurse practitioner, or, in some places, a naturopathic doctor (ND).

What are the Main Types of Hormone Therapy?

There are multiple types and delivery methods for hormone therapy. The Society of Obstetricians and Gynaecologists of Canada (SOGC) has published a document outlining hormone therapy products approved and available for use in Canada.[1]  A summary table can be found here

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What are the Issues with Hormone Therapies and Menopause?

The first hormone therapy used specifically to treat symptoms of the menopausal transition happened in 1942. By the 1960s, estrogen was considered a ‘vital substance’ for all women and was prescribed broadly. This all changed in 2002, when the first set of results from the Women’s Health Initiative study were published.  These results, which showed that post-menopausal women taking combination (estrogen and progestin) hormone therapy for menopause symptoms had an increased risk for breast cancer, heart disease, stroke, blood clots, and urinary incontinence, caused a decline of over 80% in the prescription of hormone therapy and created fear and uncertainty that exist into the present day. [7]

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Hormone Therapy and Menopausal Transition Symptoms

HT has been shown to assist with hot flashes, night sweats, bone loss and fracture, vaginal dryness and urinary incontinence. The North American Menopause Society (NAMS) position statement [3] and other research [2] [4] [5] [6] provide the following information specific to different symptoms of the menopausal transition:

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Women’s Health and Hormone Therapy

Hormone therapy is an excellent therapy for the treatment many women’s menopausal transition symptoms. However, hormone therapy has effects in the body beyond just bothersome symptoms.

What is Bioidentical Hormone Therapy?

Bioidentical hormones are synthetic compounds that are manufactured to mimic natural hormones. They are intended to interact with hormone receptors in the body in the same way as natural, or conventional, hormones. [1] [1a]

Menopause and Hormone Therapy

Your body has preferred levels of hormones that allow it to function at its best. It is normal for hormone levels to change as you age, but sometimes the change in the female hormone cycle can cause symptoms that affect your quality of life. When you are experiencing symptoms throughout your menopause transition you may be referred to an endocrinologist – if not, you may request to see one by asking your healthcare provider. If you do not already have a healthcare practitioner who is familiar with identifying and treating symptoms of menopause, the North American Menopause Society provides a list of menopause practitioners here

Your healthcare provider is the best source to advise you on whether or not this therapy will improve your quality of life. To get HT, you will need a prescription from a medical doctor (GP, OB/GYN, or an endocrinologist), nurse practitioner, or, in some places, a naturopathic doctor (ND).

It is highly recommended that women considering HT have an open and comprehensive discussion with their health care provider about their specific symptoms and preferred outcomes. Note the following:

  • The goal of HT is to use an appropriate, often the lowest, effective dose of systemic (“throughout the body”) estrogen therapy consistent with treatment goals and that provides benefits while minimizing risks. This means that the formulation, dose, and route of administration for HT should be determined individually and reassessed periodically. 
  • Regularly track your symptoms (and any new ones that develop) as the result of your HT medication. Did your symptoms go up or down over time? A simple notebook and pencil will help to track the date and record how you felt at that time. Share this with your health care provider at appointments to make them more efficient. 
  • The appropriate formulation, dose, and route of administration of progestogen (a steroid hormone that acts like progesterone) is needed to counter the effects of estrogen on the lining of the uterus, as estrogen can cause an uncontrolled buildup of endometrial cells that form the lining of the uterus. 
  • Potential risks of HT for women aged younger than 60 years or who are within 10 years of menopause onset include the rare risk of breast cancer with combined estrogen-progestogen therapy (EPT), thickening of the uterine lining (endometrial hyperplasia), and cancer when there is too much estrogen with no progestogen, blood clots, and gall bladder issues. [3]
  • Different hormone therapies, even within the same HT drug class, may have different effects on target organs, so there are options available to minimize risk. 
  • Additional risks across ages include heart attack, stroke, and dementia. [3]

Women with early or premature natural menopause (when periods stop before the age of 40) and Primary Ovarian Insufficiency (POI – a condition where the ovaries stop working properly for no obvious medical reason) experience an extended period of time without ovarian hormone activity leading to a potential estrogen deficiency in all tissues compared with women experiencing normal menopause.

Health risks of early natural menopause and primary ovarian insufficiency (POI) may include persistent vasomotor symptoms (VMS – hot flashes and night sweats), bone loss, genitourinary syndrome, mood changes, and increased risk of heart disease, dementia, stroke, Parkinson’s disease, eye disorders, and overall mortality.[3] As well, women with POI have a higher risk of death from ischemic heart disease (heart disease caused by narrowed arteries) as well as from all causes, compared with women who have a normal age of natural menopause, which may be reflective of premature aging. They also have a higher risk of digestive tract cancer but a decreased risk of mortality from breast, uterine, and endometrial cancer. [3]
Effective management may include appropriate doses of HT along with calcium, vitamin D, exercise, and screenings to detect medical issues.
Results of the Women’s Health Initiative (WHI) studies in older women [7] do not apply to women with early menopause, and observational evidence suggests benefits for HT taken to the average age of menopause. [3]
Hormone therapy such as transdermal (through the skin) estradiol in higher doses with adequate endometrial protection may be superior to oral contraceptive therapy to restore or maintain bone mineral density.[3]

When both ovaries are surgically removed (bilateral oophorectomy), the loss of ovarian hormones – estrogen, progesterone, and testosterone – is abrupt. This can trigger vasomotor symptoms as well as a variety of estrogen deficiency-related symptoms and diseases that can have a major effect on quality of life (QOL). You can assess your own Quality of Life here .

Potential adverse events (AEs) can occur in the cardiovascular system, and on bone health, mood, sexual health, and cognition. All of these have been shown (in clinical observational studies ) to be improved by estrogen therapy. [3]

Unless contraindications are present, estrogen therapy (ET) is indicated for women who have had a bilateral oophorectomy and are low in estrogen to reduce the risk for genitourinary symptoms, painful sex and improved bone health.

Observational data suggest a benefit on atherosclerosis (hardening or thickening of the arteries) and other cardiovascular disease, cognitive decline and dementia.

Younger women may require higher doses for symptom relief and/or protection against bone loss.

What are the Main Types of Hormone Therapy?

There are multiple types and delivery methods for hormone therapy. The Society of Obstetricians and Gynecologists’ of Canada (SOGC) has published a document outlining hormone therapy products approved and available for use in Canada.[1] A summary table can be found here.
Hormone therapy is prescribed as either systemic HT (throughout the body) or low-dose vaginal HT. Systemic estrogen comes in many forms (e.g. cream, tablets, skin patches etc.) and typically contains a higher dose of estrogen that is absorbed throughout the body. Low-dose vaginal HT comes in multiple forms (cream, tablet, or insertable vaginal ring) and minimizes the amount of estrogen absorbed by the body. Low-dose vaginal HT is only used to treat the vaginal and urinary symptoms of menopause.

There are a variety of hormones used in HT including estrogen alone (multiple types of estrogens, as shown in the table or a mix of estrogen and progesterone (multiple combinations, as shown in the table. In addition to estrogen or estrogen-progestone combinations, other HT treatments include the use of selective estrogen receptor modulators (SERMs).

SERMs act by blocking some estrogen receptors and activating others. For example, raloxifene (a type of SERM) blocks estrogen receptors on breast tissue to decrease the risk for breast cancer, while activating estrogen receptors in bone to stimulate bone retention. In this way, SERMs can offer targeted, multi-benefit care for specific estrogen-sensitive tissues.

 

Non-Hormonal Therapies for VMS

Selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) can also be prescribed, although they are technically non-hormone therapies. SSRIs and SNRIs are antidepressant medications, but they can be used to treat hot flashes. They work by rebalancing or intercepting epinephrine and serotonin, which are chemicals in the brain that can trigger hot flashes. SSRIs increase serotonin levels in the brain, while SNRIs increase both serotonin and norepinephrine levels. [2][5]

One large study that reviewed and re-analyzed multiple studies’ data found that in half of the trials analyzed clonidine, often used to treat high blood pressure, significantly reduced VMS frequency compared to placebo. However, the remaining trials show no significant difference. Clonidine is associated with a number of adverse effects, including dry mouth, constipation, and drowsiness. Given this, clonidine is not considered the ideal choice for VMS treatment but it can be an option for some women. [5a]

Gabapentin, which is an anticonvulsant used to treat and prevent seizures, can also be used to treat vasomotor symptoms. Multiple randomized controlled trials (RCTs) have shown that gabapentin can successfully reduce the frequency of vasomotor symptoms compared to a placebo. More research data is needed to further study the usefulness and safety of gabapentin to treat VMS.

What are the Issues with Hormone Therapies and Menopause?

The first hormone therapy used specifically to treat symptoms of the menopausal transition happened in 1942. By the 1960s, estrogen was considered a ‘vital substance’ for all women and was prescribed broadly. This all changed in 2002, when the first set of results from the Women’s Health Initiative study were published. These results, which showed that post-menopausal women taking combination (estrogen and progestin) hormone therapy for menopause symptoms had an increased risk for breast cancer, heart disease, stroke, blood clots, and urinary incontinence, caused a decline of over 80% in the prescription of hormone therapy and created fear and uncertainty that exist into the present day. [7]

The reduction in hormone therapy prescriptions was a direct result of the US Food and Drug Administration’s (FDA) warning labels that were issued for ‘all women and pertaining to all estrogens and progestogens, and to all doses and routes of administration’. [2]

It is unfortunate that the results were interpreted by the FDA in this manner, because, while they were accurate for the group under study (women aged 50-79), this is not the age group that is typically considered to start hormone therapy. There were limited study participants with bothersome menopausal transition symptoms (hot flashes and night sweats) where were younger than 60 years old or who were fewer than 10 years from the onset of menopause; this is the group for whom hormone therapy is usually indicated. The study design assessed ‘Does hormone therapy help prevent coronary artery disease?’, and used one group to investigate one type of estrogen/progesterone treatment and another group to investigate an estrogen-only treatment. While the study results themselves were accurate, the results were applied far too broadly, well beyond the scope of the study. [2]

Work to accurately communicate results of hormone therapy studies continues to the present day. Worldwide, there has been a shift to develop updated recommendations. For example, the 2017 hormone therapy position statement of The North American Menopause Society (NAMS) provides a much more accurate recommendation. [3] An advisory panel of clinicians and researchers with expertise in women’s health and menopause assessed the WHI paper as well as all subsequently published research to develop the updated position statement, which reads:

Hormone therapy (HT) remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM) and has been shown to prevent bone loss and fracture. The risks of HT differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. Treatment should be individualized to identify the most appropriate HT type, dose, formulation, route of administration, and duration of use, using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of the benefits and risks of continuing or discontinuing HT.

For women under 60 years old or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is most favorable for treatment of bothersome VMS and for those at elevated risk for bone loss or fracture.

For women who initiate HT more than 10 or 20 years from their menopause onset or are over 60 years old, the benefit-risk ratio appears less favorable because of the greater absolute risks of coronary heart disease, stroke, venous thromboembolism (blood clots), and dementia.

Longer durations of therapy should be for documented indications such as persistent VMS or bone loss, with shared decision making and periodic reevaluation. For bothersome GSM symptoms not relieved with over-the-counter therapies and without indications for use of systemic HT ,low-dose vaginal estrogen therapy or other therapies are recommended.

The full position statement can be found at menopause.org [3]

Despite the warning labels included in all prescriptions, the FDA currently approves hormone therapy for:

  • bothersome vasomotor symptoms (VMS);
  • prevention of bone loss;
  • hypoestrogenism (low estrogen) caused by hypogonadism (low to no production of sex hormones), castration (removal of the ovaries), or Primary Ovary insufficiency (POI – when the ovaries stop working properly); and
  • genitourinary symptoms (vaginal dryness, painful sex, incontinence etc.)

Extended Use of HT and Risks of Discontinuing HT

Decisions about how long to stay on HT are difficult because the long-term follow-up data is complicated to interpret, especially with respect to breast cancer. However, NAMS states with confidence that:

  • The benefits of HT include relief of persistent vasomotor symptoms, prevention of bone loss and fracture, and prevention or treatment of GSM.
  • Concerns include potential risk of breast cancer that may increase with longer duration of use.
  • Coronary heart disease and all-cause mortality may be decreased when HT is initiated closer to menopause onset, with fewer heart attacks occurring with estrogen-only HT.
  • Women who initiate HT when aged older than 60 years or who are more than 10 years from the onset of menopause are at higher absolute risks of coronary heart disease, blood clots, and stroke than women initiating HT in early menopause.
  • More research is needed on benefits and risks of longer durations of use and potential benefits and risks with discontinuation.

Hormone Therapy and Menopausal Transition Symptoms

Hormone Therapy and Menopausal Transition Symptoms HT has been shown to assist with hot flashes, night sweats, bone loss and fracture, vaginal dryness and urinary incontinence. The North American Menopause Society (NAMS) position statement [3] and other research [2] [4] [5] [6] provide the following information specific to different symptoms of the menopausal transition:

According to the International Menopause Society, HT remains the most effective therapy for hot flashes and night sweats and it is well documented that the frequency and intensity of hot flashes and night sweats can be reduced by estrogen HT. [3][4]

  • Vasomotor symptoms may be caused by thermoregulatory dysfunction. HT using estrogen may modulate your body’s “thermostat” in the hypothalamus of the brain. Skin temperature-sensing in the brain is also modulated. HT using estrogen may also reduce the amount of blood sent to the surface of your torso and face, and reduce sweating.
  • Estrogen-alone therapy (ET) can be used for symptomatic women after hysterectomy.
  • For symptomatic women with a uterus, combination therapy (estrogen + progestogen or conjugated estrogens + bazedoxifene) protects against uterine lining tissue growth (neoplasia).
  • Micronized progesterone (300 mg) nightly significantly decreases VMS (hot flashes and night sweats) compared with placebo and improves sleep. 
  • Synthetic progestins have also shown scientific evidence of benefit in clinical studies.

During the menopause transition, women with vasomotor symptoms are more likely to report reduced sleep. Hormone therapy has been shown to improve sleep in women with bothersome night time VMS by reducing night time awakenings.  [2][3][6]

  • A 2015 literature review found that HT in the form of low dose estrogen or progestogen could improve chronic insomnia in menopausal women, with 14 of the 23 studies reviewed showing positive results. 
  • HT with estrogen can reduce the effect of hot flashes on sleep quality. Improved sleep is connected to improved mood, thinking (cognition) and reducing depression  
  • Oral progesterone has mildly sedating effects, reducing wakefulness without affecting daytime cognitive functions, although the actual mechanism causing this effect is poorly understood.

Vaginal symptoms of GSM may include genital dryness, burning, and irritation and sexual symptoms of diminished lubrication and painful intercourse. [3]

  • Low-dose vaginal estrogen preparations are effective and generally safe for the treatment of GSM, with minimal absorption throughout the body. It is preferred over systemic (body-wide) therapies when estrogen therapy is only being used for treatment of GSM symptoms. 
  • For women with breast cancer, low-dose vaginal estrogen should be considered and prescribed in consultation with their oncologists. 
  • Progestogen therapy is not needed with low-dose vaginal estrogen therapy, but randomized trial data are lacking beyond 1 year study durations.  
  • postmenopausal bleeding in women using low-dose vaginal ET must be thoroughly evaluated.

Urinary tract symptoms of GSM include pelvic floor disorders (prolapse), urinary symptoms of urgency, incontinence, and painful urination, and recurrent urinary tract infections (UTIs). 

  • Estrogen therapy is the most effective treatment for GSM. 
  • Vaginal estrogen therapy may improve incontinence by increasing the number of vessels around the urethral area and bladder neck region.
  • Estrogen therapy, along with pelvic floor training (Kegel exercises), pessaries (a device that is inserted into the vagina to support the uterus), or surgery, may improve the state of vaginal tissues, but evidence for effectiveness for pelvic organ prolapse is currently lacking. 
  • Systemic HT does not improve urinary incontinence and may increase the incidence of stress urinary incontinence. 
  • Low-dose vaginal estrogen therapy may provide benefits for urinary symptoms, including prevention of recurrent UTIs, overactive bladder, and urge incontinence. However, HT does not have FDA approval for any urinary health indications.

Systemic HT and low-dose vaginal estrogen therapy (ET) provide effective treatment of sexual problems by increasing lubrication, blood flow, and sensation in vaginal tissues. Studies have not found any significant effect of ET on sexual interest, arousal, and orgasmic response outside of its role in treating menopause symptoms – so if your sexual issues are not a result of menopausal transition symptoms, then HT or ET will not help. [3]

Both systemic HT and low-dose vaginal estrogen increase lubrication, blood flow, and sensation of vaginal tissues.
If sexual function or libido are concerns in women with menopause symptoms, transdermal ET may be preferable over oral ET because of less effect on sex hormone-binding globulin and free testosterone levels.
Non-estrogen alternatives are approved for painful sex (dyspareunia), so speak with your health care provider if you would like to know whether these are an alternative for you.

Hormone Therapy and Women’s Health

Hormone therapy is an excellent therapy for the treatment many women’s menopausal transition symptoms. However, hormone therapy has effects in the body beyond just bothersome symptoms. The impacts of HT on various body systems and health conditions are detailed below.

One review study showed that hormone therapy provides a significant benefit for menopause-specific quality of life in midlife women, mainly through relief of symptoms. Treatment can also cause an increase in the overall quality of life. [6a]

Women who experience severe symptoms tend to experience statistically significant improvement in both health-related and menopause-specific quality of life measures. Similar levels of improvement are not shown to be statistically significant for women who do not experience severe symptoms as measured during clinical trials.[6a]

Another review study also concluded that HT improves quality of life of symptomatic menopausal women. This study also found reliable evidence on quality of life improvements beyond just a reduction in vasomotor symptoms.[6b]

Visit our resources page here to find the tools to assess your Quality of Life.

Standard-dose ET and HT prevent bone loss in postmenopausal women by inhibiting bone resorption, which is the process by which osteoclasts (a type of bone cell) break down the tissues making up bones and release those minerals causing a transfer of calcium from bone tissue to the blood. ET or HT also result in a reduced rate of bone remodeling from a healthy state to a more fragile state. The estrogen in HT is highly effective at preventing menopause-related bone loss. [2][3]

  • Hormone therapy prevents bone loss in healthy postmenopausal women, with dose-related effects (larger doses produce larger effects).
  • Women with premature menopause who require prevention of bone loss are best served with HT or oral contraceptives (which are less effective than HT) rather than other bone-specific treatments until the average age of menopause, when treatment may be reassessed, unless there are contraindications.
  • Randomized, controlled trials and observational studies show that standard-dose HT reduces postmenopause osteoporotic fractures, including hip, spine, and all non-spine fractures, even in women without osteoporosis.
  • HT using estrogen, together with a minimum of 800 IU of vitamin D, 1200 IU Calcium and smoking cessation is effective at preserving bone mineral density and reducing fracture incidence and risk.

Hormone therapy can be used to manage symptoms that affect the skin, hair, sight, hearing and balance. [3]

  • Estrogen therapy appears to have beneficial effects on skin thickness and elasticity and collagen when given at menopause.
  • Changes in hair density and female pattern hair loss worsen after menopause, but no positive role has been identified for HT.
  • Hormone therapy appears to increase the risk of dry eye symptoms but may decrease the risk of cataracts and primary glaucoma. As the research shows conflicting results – in some cases HT helps, in others it doesn’t – this use of HT needs further study.
  • Hormone therapy may play a role in hearing loss and olfactory changes.
  • In small trials, HT appears to decrease dizziness or vertigo and improve postural balance.

Direct binding of estrogen to estrogen receptors in joint tissues provides protection of the biomechanical structure and function and helps maintain overall joint health. [3]

  • Women in the Women’s Health Initiative (WHI) and other studies have shown less joint pain or stiffness compared with those on placebo.

Sarcopenia results in frailty and is associated with adverse events such as falls, hospitalization, disability, and death. While skeletal muscle does contain estrogen receptors, little is known about the interactions between estrogen and muscle.

  • Sarcopenia and osteoporosis are related to aging, estrogen depletion, and the menopause transition.
  • Preclinical studies suggest a possible benefit of ET when combined with exercise to prevent the loss of muscle mass, strength, and performance.

  • Risk of gallstones, inflammation of the gallbladder, and the need to surgically remove the gallbladder is increased with oral estrogen-alone and combination HT.
  • Observational studies report lower risk with transdermal HT than with oral and with oral estradiol compared with CEE, but neither observation is confirmed in RCTs. An association of HT with slower fibrosis progression in hepatitis C and with fatty liver has been observed, but randomized trials are needed to establish any potential benefits and risks of HT in postmenopausal women with liver disease.

  • Hormone therapy significantly reduces the diagnosis of new-onset type 2 diabetes, but it is not currently FDA approved for this purpose.
  • Hormone therapy may help attenuate abdominal fat accumulation and the weight gains that are often associated with the menopause transition.

  • In the absence of more definitive findings, HT cannot be recommended at any age to prevent or treat a decline in cognitive function or dementia.
  • Caution should be taken in initiating some types of HT in women aged older than 65 years, as there is a relatively small or infrequent increase in risk for dementia.
  • Estrogen therapy may have positive cognitive benefits when initiated immediately after early surgical menopause, but HT in the early natural postmenopause period has neutral effects on current cognitive function.
  • Only limited support (observational studies) is available to support the use of HT in Alzheimer disease prevention.
  • The effect of HT may be modified by baseline cognitive function, with more favorable effects in women with normal cognitive function before HT initiation.
  • Evidence is insufficient to support HT use in the treatment of clinical depression. In small randomized control studies, ET was effective in improving clinical depression in perimenopausal but not postmenopausal women.
  • Progestins may contribute to mood disturbance.
  • Women whose depression improves with HT are likely to experience a worsening of mood after estrogen withdrawal.

A research study out of the United Kingdom looked at whether HT increases the risk for dementia, and gives estimates for risks of developing dementia and Alzheimer’s disease in women exposed to different types of menopausal hormone therapy for different durations. The results showed no increased risks of developing dementia overall. There was, however, a slightly increased risk of developing Alzheimer’s disease among long term users of oestrogen-progestogen therapies. [8a]

  • Newer observational data and reanalysis of older studies by age or time since menopause, including the WHI, suggest that for healthy, recently menopausal women, the benefits of HT (estrogen alone or with a progestogen) outweigh its risks, with fewer cardiovascular events in younger versus older women.
  • In women who initiate HT more than 10 years after the onset of their menopause, there is potential for increased risk of coronary heart disease.
  • The analysis of data combined from multiple independent studies of randomized control trials found no increased risk of stroke in women aged younger than 60 years or who were within 10 years of menopause onset. Note that the results of observational study findings are mixed. There is an increased risk of stroke in women who initiate HT when aged older than 60 years and/or who are more than 10 years from menopause onset.
  • If HT is initiated when aged younger than 60 years, the absolute risk of venous thromboembolism (VTE – blood clots) was rare but significantly increased.
  • Personal and familial risk of CVD, stroke, and VTE should be considered when initiating HT.

Different types of estrogen may have different effects on the breast so the results of studies are limited in how generalized they can be. The type and severity of breast cancer risk from HT varies depending on the type of HT, the dosage, the duration of the treatment, the time the treatment is initiated and individual patient characteristics.

  • Estrogen-alone HT:
    • Compared with women who received placebo, women who received conjugated equine estrogens (CEE) alone in the WHI study [7] showed a nonsignificant reduction in breast cancer risk after an average of 7.2 years.
    • The nonsignificant pattern of reduction in breast cancer remained evident for up to a median of 13 years’ cumulative follow-up
    • A statistically significant reduction of breast cancer risk resulting from CEE was observed overall in women who were at least 80% compliant with therapy and in women with no prior HT use versus those women who had prior use of HT.
    • There are no randomized controlled trials designed yet to inform the understanding of long durations of ET and the risk of breast cancer.
  • Estrogen-Progestogen HT:
    • In the WHI study [7], daily continuous-combined CEE with medroxyprogesterone (MPA) (CEE + MPA) resulted in increased risk of breast cancer, with 9 additional breast cancer cases per 10,000 person-years of therapy.
    • In subgroup analysis after the study, the increased incidence of breast cancer was limited to women who had prior exposure to HT, whereas in women without prior exposure to HT, breast cancer incidence was not significantly affected.
    • The attributable risk of breast cancer in women (mean age, 63 years) randomized in the study to the CEE + MPA in the WHI is less than 1 additional case of breast cancer diagnosed per 1,000 users annually. This is a risk slightly greater than that observed with one daily glass of wine, less than with two daily glasses, and similar to the risk reported with obesity, low physical activity, and other medications.
  • Early hormone therapy in women at genetic risk for breast cancer:
    • One study looked at 1,419 sister-matched cases of breast cancer in women aged younger than 50 years compared to 1,665 controls. The results showed no increased risk of young-onset breast cancer with use of Estrogen-Progestogen HT, whereas estrogen-only HT was associated with a reduced diagnosis of young-onset breast cancer. [9]
  • Hormone therapy after breast cancer:
    • The use of systemic (body-wide) HT in survivors of breast cancer is generally not advised.
    • Observational studies and randomized trials report both neutral effects and increased risk of breast cancer recurrence.
    • However, low-dose vaginal ET remains an effective treatment option for genitourinary issues, with minimal systemic absorption. Treatment may be considered in consultation with an oncologist. [3]
  • Different HT regimens may be associated with increased breast density, which may obscure mammographic, leading to more mammograms or more breast biopsies.

  • The use of HT may be considered in symptomatic women with surgically treated, early stage endometrial cancer (low risk) if other options are not effective, particularly in women with early surgical menopause who are at higher risk of health consequences related to estrogen loss.
  • Non-hormone therapies are recommended for women with more advanced cancer or higher-risk endometrial cancer.

  • There are no convincing data that estrogen initiates or promotes the development of epithelial ovarian cancer.
  • In the WHI, the only randomized trial to date to study ovarian cancer, CEE + MPA HT had no significant effect on the incidence of ovarian cancer relative to placebo after 5.6 years’ active therapy and 13 years’ follow-up.

  • Observational studies suggest a reduced incidence of colorectal cancer with HT, particularly if initiated early in menopause.
  • The use of low-dose conjugated equine estrogen (CEE) + medroxyprogesterone acetate (MPA) as HT reduced colorectal cancer incidence across all ages during treatment.

  • There appears to be an overall neutral effect of HT on lung cancer incidence.[3]

Bioidentical Hormone Therapy

Bioidentical hormones are synthetic compounds that are manufactured to mimic natural hormones. They are intended to interact with hormone receptors in the body in the same way as natural, or conventional, hormones. [1] [1a]

In addition to the risks associated with conventional, fully-regulated hormone therapies, there are additional risks with bioidentical  hormones. These risks are due to the absence of regulatory oversight. Consider that government-approved (FDA-approved) bioidentical hormones, including estradiol and estrone, are regulated, are monitored for purity and effectiveness, come with extensive product information, and include warnings for any potential adverse effects. Any FDA-approved products also undergo extensive clinical testing and reporting. 

Compounded bioidentical hormones are made at a compounding pharmacy using a prescription from a health-care provider. Compounding a product can be necessary if there are allergies or sensitivities to ingredients found in medicines made by a pharmaceutical company. Bioidentical hormones may combine multiple hormones such as estradiol, estrone, estriol, dehydroepiandrosterone [DHEA], testosterone, and/or progesterone, and may use untested, unapproved combinations or formulations. As well, they can be offered in untested applications such as subdermal implants. 

Bioidentical hormones are often prescribed based on the use of salivary testing, however this type of testing for HT is considered to be unreliable. The issues are due to how hormones travel throughout the body (call pharmacokinetics) and differences in how they are absorbed, variations in hormone levels throughout the day and individual variations in hormone levels that are seen in saliva (compared to urine or serum levels for example). 

The North American Menopause Society (NAMS) 2017 hormone therapy position statement, which is endorsed by the Society of Obstetricians and Gynaecologists of Canada (SOGC), reads: 

  • Compounded ‘bioidentical’ hormone therapy presents safety concerns, such as minimal government regulation and monitoring, overdosing or underdosing, presence of impurities or lack of sterility, lack of scientific efficacy (effectiveness) and safety data, and lack of a label outlining risks.
  • Salivary hormone testing to determine dosing is unreliable.
  • Prescribers of compounded ‘bioidentical’ HT should document the medical indication for compounded HT over government-approved therapies, such as the presence of allergies to ingredients, the need for specific dosing not currently available, or the need for a formulation not available in FDA-approved products.

The Science

The endocrine system is made up of a series of glands that produce and secrete hormones directly into your bloodstream for use throughout the body. The hormones are used for a wide range of functions (beyond reproduction in women) and act as chemical messengers throughout the body. The endocrine system works by sending signals from your brain to different glands that secrete specific hormones for specific purposes. 

 

This table shows the most important hormones during the menopause transition, what the hormones are, where in the body they are produced and what they do in the body. [10] [11] [12]

Statistics

0%

Women with symptoms currently undiagnosed.

0%

Women who went more than a year before being formally diagnosed.

0%

Women who don’t know the difference between perimenopause and menopause prior to experiencing symptoms.

MYTH

Hormone therapy for treatment of menopausal symptoms was thought to increase the risk of a woman’s chance of breast cancer, stroke and blood clots.  This evidence has been re-evaluated, and HT using estrogen has been shown to be safe and effective. [2] [3] What is now known is:

  • HT remains the most effective treatment for vasomotor symptoms and genitourinary syndromes of menopause and has been shown to prevent bone loss and fracture. 
  • The risks of HT differ depending on the type of hormones, their dose, duration of use, route of administration, timing of initiation, and whether progestogen is used.
  • Treatment should be individualized to identify the most appropriate HT type, dose, formulation, route of administration, and duration of use.
  • HT must use the best available evidence to maximize the benefits and minimize the risks.
  • HT needs periodic reevaluation for the benefits and risks of continuing or discontinuing HT.

MYTH

HT alone does not increase the risk of a heart attack. Heart attacks are the number two killer of women in Canada. Healthy perimenopausal women benefit from a protective effect from HT and in fact have a lowered risk of heart attack.

Post- menopause, as a woman grows older, the risks of heart disease increase. Risks for HT are age and life-style related.

The seven major risk factors for heart disease can all be modified, so a woman can adjust her lifestyle and reduce these risks. These risks are:

  1. Smoking
  2. Abnormal lipid profiles
  3. Hypertension
  4. Abdominal obesity
  5. Poor diet
  6. Excess alcohol
  7. Chronic stress

If you have any of these risk factors in your life, tell your healthcare provider when you are discussing hormone therapy.

MYTH

It is uncertain whether HT will increase your personal risk of breast cancer since breast cancer risk varies based on the type of HT plus a woman’s family history and overall health.

To date, the evidence shows that in North America, the estrogen in HT does not cause, nor increase the risk for breast cancer overall.

In menopausal women, short-term HT using estrogen will not increase a woman’s risk of developing breast cancer. However, HT may slightly increase the risk for breast cancer in late menopause after 4 or more years of continuous use.

Some women are at high risk for breast cancer. Please discuss your personal risks when discussing HT with your healthcare provider.

Risk Factors for Breast Cancer:

  1. Age (your risk increases significantly after age 55)
  2. Family history / genetics (e.g. BRCA 1 or 2; PALB 2 variants)
  3. Previous breast biopsy that showed abnormal cells
  4. Increased breast density on mammography
  5. Not bearing children (or having first child after age 30).
  6. Lifestyle 
  7. Lack of exercise
  8. Excessive alcohol intake
  9. Obesity and weight gain after menopause
  10. Smoking
  11. Lack of breast-feeding after childbirth

Short-term use of HT for symptom control and quality of life will have little effect on personal breast cancer risk.  Longer use of HT does increase breast cancer risk. Currently, the only proven strategy to reduce breast cancer deaths is early detection through mammography in women over 50.

MYTH

Data about the influence of HT on stroke are mixed. HT may increase the incidence of stroke, but this is nullified in women who exercise moderately. A stroke (ischemic stroke) is a clogged blood vessel blocking blood flow to the brain. Without blood flow and oxygen, brain tissue will die. Strokes can lead to serious losses of brain function. Strokes are the third leading cause of death in Canadian women and the risk for stroke increases with age.

The key to reducing the risk of stroke is a healthy lifestyle. The risk factors are:

  1. Hypertension
  2. Obesity
  3. Smoking
  4. Excessive alcohol
  5. Lack of exercise
  6. Diabetes
  7. Migraine headaches [with visual aura]
  8. Too little or too much sleep

Please discuss your personal risks for stroke when discussing HT with your healthcare provider.

MYTH

Risk for colon-rectal cancer increases with age. Menopause transition and HT/HRT themselves do not increase your risk for colorectal cancer. It is unclear right now whether HT protects you against colorectal cancer. If you do not already, please start medical screening for CRC starting at age 50 as part of your overall self-care regimen.

MYTH

HT can benefit women with mild-to-moderate common symptoms such as 

  • Vaginal weakness and dryness (vaginal atrophy)
  • Urine leak
  • Hot Flashes
  • Wound healing
  • Osteopenia or weakened bones, high risk for fracture

Please talk to your healthcare provider about any of your health concerns. Many are manageable and some can be moderated with simple behavioral changes.

MYTH

Osteoporosis is a biological process of bone density loss and increased bone breakage. It is part of the natural aging process for both men and women. Strong bones depend on many factors including your genetics, how you grew during puberty, exercise levels, your diet, smoking, and alcohol consumption. Your bones are at peak strength and density around age 30.

HT including estrogen is very effective at supporting bone density and strength, especially when combined with a healthy lifestyle. As well, strength training such as weight lifting, plus a good diet including calcium and vitamin D3 can help maintain bone strength.

Mid-life sees many hormone changes. Those plus decreased physical activity can contribute to osteoporosis, which can affect you in your early 50’s, causing low-impact bone breaks.

Why enquire about hormone therapy?

Decrease

The frequency and intensity of hot flashes and night sweats.

Preserve

Bone mineral density and fracture incidence and risk.

Reduce

Vaginal dryness.

Improve

Quality of sleep.

Decrease

Body aches that are not related to bone loss.

Improve

Urinary Control.

Compiled References

[1] SOGC 2018. Hormone Therapy Products available in Canada for the Treatment of Menopausal Symptoms, Physician Desk Reference – 3rd edition

[1a] Harvard Health Publications, Harvard Medical School. https://www.health.harvard.edu/press_releases/myths-and-truths-about-bioidentical-hormones

[2] Minkin MJ. Menopause: Hormones, Lifestyle, and Optimizing Aging. Obstet Gynecol Clin North Am. 2019 Sep;46(3):501-514. doi: 10.1016/j.ogc.2019.04.008. Epub 2019 Jun 21. PMID: 31378291.

[3]  The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of the North American Menopause Society

[4] R. J. Baber, N. Pa nay & A. Fenton the IMS Writing Group (2016): 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy, Climacteric, DOI: 10.3109/13697137.2015.1129166 3] 

[5]  Bulun_Physiology and pathology of the female reproductive axis. William’s Textbook of Endocrinology, 14 th edition. Elsevier, 2019. 

[5a] Umland EM, Falconieri L. Treatment options for vasomotor symptoms in menopause: focus on desvenlafaxine. Int J Womens Health. 2012;4:305-319. doi:10.2147/IJWH.S24614

[6] Attarian H, Hachul H, Guttuso T, Phillips B. Treatment of chronic insomnia disorder in menopause: evaluation of literature. Menopause 2015;22:674-684

[6a] Utian, W. H., & Woods, N. F. (2013). Impact of hormone therapy on quality of life after menopause. Menopause (New York, N.Y.), 20(10), 1098–1105. https://doi.org/10.1097/GME.0b013e318298debe

[6b] Pines, A., Sturdee, D. W., & MacLennan, A. H. (2012). Quality of life and the role of menopausal hormone therapy. Climacteric : the journal of the International Menopause Society, 15(3), 213–216. https://doi.org/10.3109/13697137.2012.655923

[7] Writing Group for the Women’s Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women’s Health Initiative Randomized Controlled Trial. JAMA. 2002;288(3):321–333. doi:10.1001/jama.288.3.321

[8] Craig, M. C., Maki, P. M., & Murphy, D. G. (2005). The Women’s Health Initiative Memory Study: findings and implications for treatment. The Lancet. Neurology, 4(3), 190–194. https://doi.org/10.1016/S1474-4422(05)01016-1

[8a] Vinogradova Y, Dening T, Hippisley-Cox J, Taylor L, Moore M, Coupland C et al. Use of menopausal hormone therapy and risk of dementia: nested case-control studies using QResearch and CPRD databases BMJ 2021; 374 :n2182 doi:10.1136/bmj.n2182

[9] O’Brien KM, Fei C, Sandler DP, Nichols HB, DeRoo LA, Weinberg CR. Hormone therapy and young-onset breast cancer. Am J Epidemiol 2015;181:799-807

[10] You and Your Hormones (The Society for Endocrinology) https://www.yourhormones.info/hormones/follicle-stimulating-hormone/

[11] https://www.endocrineweb.com/endocrinology/introduction-endocrinology-endocrine-surgery

[12] Melmed, S., Polonsky, K. S., Larsen, P. R. & Kronenberg, H. M. (2016) Williams Textbook of Endocrinology. Philadelphia, Pa: Elsevier.