Menopausal hormone therapy: Benefits and risks

By Dr Shabani

Women's Health Initiative (WHI)In the past, MHT was also often prescribed for prevention of coronary heart disease (CHD) and osteoporosis, based upon epidemiologic data demonstrating a protective effect of estrogen on the heart and bone.

Data from WHI, a set of two hormone therapy (HT) trials (unopposed estrogen and continuous, combined estrogen-progestin therapy versus placebo) in approximately 27,000 postmenopausal women (mean age 63 years)

showed a number of adverse outcomes:

excess risk of CHD, stroke, venous thromboembolism (VTE), and breast cancer

• updated 2017 United States Preventive Services Task Force (USPSTF) meta-analysis of 18 trials included the WHI, and the mean age of subjects was >60 years

• the USPSTF continues to recommend against the use of both combined estrogen-progestin and unopposed estrogen (for women posthysterectomy) for the prevention of chronic conditions

• However, they do not address the use of MHT for menopausal symptoms, nor do they present the WHI data showing the low absolute risks of MHT in younger menopausal women

• While the WHI clearly demonstrated the adverse effects of MHT in older postmenopausal women (over age 60 years), this is not the age group that presents with new onset of menopausal symptoms

• Almost all women who seek medical therapy for menopausal symptoms do so in their late 40s or 50s

Importance of patient age

• Women in this age group reassured that the absolute risk of complications for healthy, young postmenopausal women taking MHT for five years is very low

• Initiation of menopausal hormone therapy (MHT) to be a safe option for healthy, symptomatic women who are within 10 years of menopause or younger than age 60 years and who do not have contraindications to MHT (history of breast cancer, coronary heart disease [CHD], a previous venous thromboembolic event or stroke, or active liver disease)

• Estrogen-progestin therapy should be used for women with a uterus and unopposed estrogen for those posthysterectomy

• For women with vaginal atrophy symptoms only, we suggest vaginal estrogen

Goals of therapy

• The goal of MHT is to relieve menopausal symptoms

most importantly hot flashes (vasomotor symptoms)

• Other symptoms associated with perimenopause and menopause that respond to ET include:

• mood lability/depression

• vaginal atrophy, dyspareunia

• sleep disturbances (when related to hot flashes)

• in some cases, joint aches and pains

Indications

• The most common indication for MHT is vasomotor symptoms (or hot flashes)

• Vasomotor symptoms occur most often in the late menopausal transition and early postmenopause

• Although there are alternative therapies for vasomotor symptoms, none are as effective as estrogen.

Mood lability/depression

• MHT, alone or in combination with an antidepressant such as a selective serotonin reuptake inhibitor (SSRI), is effective for women who experience mood lability or depression during the menopausal transition

Joint aches and pains

• It is unclear if the pain is related to estrogen deficiency or a rheumatologic disorder

• But in WHI, women with joint pain or stiffness at baseline were more likely to get relief with either combined EPT or unopposed ET than with placebo

CHD

• We suggest not using MHT for the prevention of CHD, even in young postmenopausal women

Osteoporosis

• previously recommended estrogen as a first-line choice for prevention and treatment of osteoporosis

• we now recommend bisphosphonates

• In the occasional patient with persistent menopausal symptoms who cannot tolerate first- and second-line therapies for osteoporosis, estrogen may be a reasonable option

Cognitive function and dementia• Do not suggest the routine use of MHT for peri- and postmenopausal

women with cognitive symptoms (memory loss and difficulty concentrating)

• Although substantial biologic evidence supports the importance of estrogen to cognitive function

• clinical trial evidence has generally ruled out any global cognitive benefits

• not using MHT to prevent dementia

Contraindications• Hx of breast cancer

• CHD, a previous venous thromboembolic event or stroke or TIA

• active liver disease

• unexplained vaginal bleeding

• high-risk endometrial cancer

• Oral estrogens should be avoided in women with hypertriglyceridemia, active gallbladder disease, or known thrombophilias such as factor V Leiden

• Transdermal estrogen is also preferred for women with migraine headaches with auras.

Choosing candidates

• MHT is a safe option for healthy, symptomatic women

• who are within 10 years of menopause or younger than age 60 years

• do not have contraindications to MHT (such as a history of breast cancer, coronary heart disease [CHD], a previous venous thromboembolic event or stroke, or active liver disease

• MHT is indicated for the management of menopausal symptoms

• But not for the prevention of cardiovascular disease (CVD), osteoporosis, or dementia

Estrogen therapy

• Route :transdermal 17-beta estradiol because it is associated with a lower risk of VTE, stroke, and hypertriglyceridemia than oral estrogens

• The transdermal route is particularly important in women with hypertriglyceridemia or risk factors for thromboembolism

• or 0.025 mg of transdermal estradiol) unless the patient has severe symptoms

• If hot flashes are still present after one month, we increase transdermal estradiol to 0.0375 mg and reassess one month later

• If symptoms are still not relieved, we increase further to 0.05 mg

• "Standard" doses of estrogen given daily (conjugated estrogen 0.625 mg or its equivalent) are adequate for symptom relief in the majority of women

• An exception is younger women after BSO :

• They often require higher doses for the first two to three years after surgery

• the dose can subsequently be tapered down.

• Estrogen should be continuously

• past regimens where estrogen was administered days 1 to 25 of the calendar month are considered to be obsolete

• Women will often get hot flashes during the days off, and there is no known advantage to stopping for several days each month

• MPA(2.5 mg daily) While MPA is endometrial protective, it was associated with an excess risk of CHD and breast cancer when administered with conjugated estrogen in the WHI

• For women who are perimenopausal or newly menopausal, we start with cyclic administration of oral micronized progesterone (200 mg/day for 12 days of each calendar month)

• For women who are ≥2 to 3 years postmenopause, we use a continuous regimen (micronized progesterone 100 mg/day); irregular and breakthrough bleeding is less of a problem once ovarian function has ceased

Monitoring with mammography

• Routine mammograms and breast exams are recommended in women taking MHT, even when used short-term

• In the WHI, the risk of breast cancer with combined EPT did not increase until the fourth year. However, abnormal mammograms were more common with both ET and EPT (although more common with EPT)

Tapering

• Although tapering MHT has not been proven to be more effective than stopping treatment abruptly

• we suggest a gradual taper:

particularly in women with severe vasomotor symptoms

• decrease the estrogen by one pill per week every few weeks (ie, six pills per week for two to four weeks, then five pills per week for two to four weeks, etc)

• The progestin is tapered on the same schedule

• some women with severe, recurrent symptoms :

try a much slower taper, sometimes over one year (six pills per week for two months, five pills per week for one month, etc).

Primary ovarian insufficiency• (WHI), a set of MHT trials in older postmenopausal women, should

not be extrapolated to women with POI (menopause before age 40 years)

• Hormone therapy is started at a younger age in these women, and current guidelines suggest that therapy should be continued until the average age of menopause (age 50 to 51 years) to prevent premature bone loss, coronary heart disease (CHD), and stroke

• At that point, if hormone therapy is stopped and menopausal symptoms are moderate to severe, the same discussion of potential risks and benefits of MHT should take place

Menopausal hot flashes

practical classification of hot flashes and nights sweats:

●(1) Not present

●(2) Mild :Do not interfere with usual activities

●(3) Moderate : Interfere somewhat with usual activities

●(4) Severe : So bothersome that usual activities cannot be performed

General principles●Symptom intensity and frequency

●Medical history : Is the patient a candidate for menopausal hormone therapy (MHT)

●Personal choice : Is the patient interested in MHT?

●Coexistence of other menopausal symptoms: such as depression, as these women often require treatment with both MHT and antidepressants (usually selective serotonin reuptake inhibitors [SSRIs]

Women with mild hot flashes• Women with mild flashes (hot flashes that do not interfere with

usual activities) usually do not need pharmacotherapy

• simple behavioral measures, such as lowering room temperature, using fans, avoiding triggers (such as spicy foods and stressful situations)

• Importance of placebo effect : Interpretation of the efficacy of various agents studied in clinical trials is confounded by the placebo effect, which can reduce hot flashes by approximately 20 to 50 percent

• Women with higher anxiety scores may be more likely to respond to placebo

Role of complementary and alternative therapies• Promising therapies: Need further study:

• Neurokinin 3 receptor antagonist

• Cognitive behavioral therapy (CBT): modestly effective intervention for menopause-associated insomnia but less so for hot flashes

• Hypnosis

• Mind-body-based therapies

Inconsistent evidence of efficacy

• Plant-based therapies

• Herbal therapies:• Black cohosh• Chinese herbs

• Weight loss may help reduce hot flashes

• have not found a significant beneficial effect of exercise on hot flashes:exercise raises core body temperature, thereby triggering hot flashes

Ineffective therapies

• Acupuncture

• Evening primrose oil

Moderate to severe hot flashes

• Menopausal hormone therapy : For most women with moderate to very severe hot flashes and no contraindications, we suggest MHT

SSRIs/SNRIs

• The most effective pharmacologic alternatives to estrogen include some of the antidepressants in the SSRI and SNRI classes

• venlafaxine, desvenlafaxine, paroxetine, citalopram, escitalopram

• first choice of SSRIs/SNRIs, only agent approval by the FDA for the treatment of hot flashes: Paroxetine (7.5 mg/day)

• paroxetine should be avoided in women taking tamoxifen

• citalopram as the first choice of SSRI/SNRIs

• dose 20 mg, and side effects are minimal and similar to those of the other SSRI/SNRIs

• suggest against the use of sertraline and fluoxetine, because neither has a clinically important effect on hot flashes

• neither of these agents should be used in women on tamoxifen

• venlafaxine :nausea and vomiting and have significant withdrawal symptoms in occasional patients

• sustained-release preparation starting with 37.5 mg/day for one week, increasing to 75 mg/day after the first week, to reduce the incidence of initial nausea

• gabapentin may be as effective as estrogen but it is limited by its side effects

• side effects : headache, dizziness, and disorientation

General principles●Symptom intensity and frequency

●Medical history : Is the patient a candidate for menopausal hormone therapy (MHT)

●Personal choice : Is the patient interested in MHT?

●Coexistence of other menopausal symptoms: such as depression, as these women often require treatment with both MHT and antidepressants (usually selective serotonin reuptake inhibitors [SSRIs]

Thank you