menopause%20-and-%20hormone%20therapy
MENOPAUSE & HORMONE THERAPY
Spontaneous/Natural menopause is the final menstrual period confirmed after 12 consecutive months of amenorrhea with no pathological cause.
Induced menopause is the permanent cessation of menstruation after bilateral oophorectomy (ie surgical menopause) or iatrogenic ablation of ovarian function (eg pelvic radiation therapy, chemotherapy).
Perimenopause/Menopause transition/Climacteric is the duration when menstrual cycle & endocrine changes occur a few years before and 12 months after the final menstrual period resulting from natural menopause.
Premature menopause is menopause before 40 years of age whether natural or induced while early menopause is spontaneous or induced menopause that occurs before the average age of natural menopause at 51 years or under 45 years of age.

Principles of Therapy

Principles of Menopausal Hormone Therapy (MHT)

  • MHT should be considered only with clear indications and contraindications have been ruled out and potential individual benefits outweigh the risks
  • MHT is given to relieve menopausal symptoms, primarily those caused by vasomotor processes (eg hot flushes)
  • Treatment should be given at the lowest effective dose conforming with treatment goals
  • Consider age, time since menopause and risk factors for CVD when planning usage of MHT in young symptomatic postmenopausal women 
  • Timing of MHT initiation in relation to menopause is important
    • Treatment is beneficial when given during menopausal transition (perimenopause) or early menopause (eg within 10 years of menopause or patient <60 years old)
  • Treatment should be administered for as long as the benefits outweigh the risks; benefits and risks should be periodically assessed
    • Absolute risk of complications is very low in healthy postmenopausal women on MHT for 5 years  
    • MHT should be individualized and not routinely discontinued in women ≥60 or 65 years old
    • For women with early or premature menopause, MHT is continued until at least 52 years old (median age of menopause)
  • No clear benefit of one route of administration versus another for systemic estrogen therapy (ET)
    • Local ET has its advantages and disadvantages compared with oral route but long-term benefit-risk ratio has not been shown
      • Consider low-dose vaginal products when treating vulvovaginal symptoms
    • Differences are associated with first-pass hepatic effect, hormone blood levels, and biologic activity of ingredients
    • Preferred route of administration depends on the patient’s preference and prior experience, though all types and routes of ET are equally effective in the treatment of hot flushes 
  • Low-dose oral contraceptives may be considered in healthy, non-smoking, perimenopausal women desiring contraception 

Pharmacotherapy

Estrogens

  • Effectively relieves menopause-related symptoms of hot flushes and vulvovaginal atrophy as well as other urogenital symptoms  
  • ET decreases overall fat mass, improves insulin sensitivity and reduces rate of developing type 2 diabetes
  • Unopposed ET (without a progestogen) should only be used in women who have had a hysterectomy
  • Combine with progestogen in women who still have a uterus to prevent endometrial hyperplasia and carcinoma
  • WHI studies show a more favorable safety profile for ET than with estrogen-progestogen therapy
  • Perimenopausal women with Levonorgestrel-releasing intrauterine system (LNG-IUS) may be given ET

Oral

  • Avoid in women with thrombophilias, active gallbladder disease or hypertriglyceridemia 
    • Increased risk for venous thromboembolism (VTE) because oral estrogen has greater impact on coagulation factors than transdermal or vaginal routes
    • Associated with rapid increase in high-density lipoprotein C and triglycerides (HDL-C and TG)
  • Produce more biologically active substrates in the liver than transdermal estrogen

Transdermal

  • Preferred in women with intolerance to oral therapy, malabsorption, hypertension, DM, hypertriglyceridemia with risk of fatty liver or pancreatitis, increased risk for cholelithiasis or VTE, or obese women with metabolic syndrome
    • Preferred also over oral estrogens in women with decreased libido as transdermal estrogens do not decrease testosterone’s bioavailability and do not increase the level of sex hormone-binding globulin
  • Better side effect profile and lower thrombotic risk (eg VTE, stroke, CAD) than oral estrogens
  • Less effect on lipid profile
  • High levels in the portal circulation are not produced
  • The new estradiol metered-dose transdermal spray (EMDTS) has the advantage of possibly being given with precise dosing

Vaginal

  • Vaginal application of estrogen helps relieve urogenital atrophy and may decrease recurrent urinary tract infection (UTI)
  • May consider giving vaginal estrogen to women with urogenital atrophy if systemic HRT is contraindicated

Progestogens

  • Addition of progestogen reduces the risk of endometrial hyperplasia or cancer from systemic use of estrogen
    • Max protection is obtained with 10-14 days progestin exposure/month
  • When progesterone use cannot be avoided, consider using the micronized form 
  • Not indicated in postmenopausal women without a uterus and when used with low doses of estrogen administered locally for vaginal atrophy

Hormone Regimens

Combined Cyclic Regimens

  • Progestogen is given on a cyclical basis along with an estrogen
  • Estrogen is usually given for 21-28 days while the progestogen is given for 10-14 days of the months
  • Hong Kong College of Obstetricians and Gynaecologists (HKCOG) recommends that cyclic regimen be administered to women who are ≤2 years from established menopause
  • May be given to perimenopausal women who wish to menstruate 
  • Bleeding pattern: This regimen is likely to cause regular bleeding at or near end of progestogen phase
    • If bleeding occurs at other times and is persistently irregular, endometrial biopsy is required
    • Eventually, women may reach amenorrhea and biopsy is not required

Continuous Combined MHT

  • Alternative to cyclic regimen
  • Daily administration of both progestogen and estrogen
  • HKCOG recommends that continuous regimen be administered to women who are ≥2 years from established menopause
  • May be given to perimenopausal women who do not wish to menstruate
  • Bleeding pattern: Irregular breakthrough bleeding can occur for up to 4-6 months of therapy
    • If irregular bleeding occurs in women who are previously amenorrheic when using this regimen, endometrial biopsy is required
    • Most women reach amenorrhea at the end of 1st year of use

Alternative Regimen

  • Estrogen-progestin MHT alternative in women with intact uterus is conjugated equine estrogen with Bazedoxifene

Tibolone

  • Has been used as an alternative to or after transferring from MHT
  • Synthetic agent which has weak estrogenic, progestogenic and androgenic properties
  • Suppresses vasomotor problems, improves mood, libido, and vaginal atrophy, decreases proliferation of breast epithelial cells, and has a protective effect on bone mass 
  • Prolonged use has been associated with increased stroke risk in older women; evidence also shows a slightly increased risk of breast cancer recurrence 

Androgens

  • Used to treat decreased libido in women following bilateral oophorectomy if adequate estrogen does not correct the problem
  • May also be used in women after ovarian function has ceased, on MHT and have no other cause for loss of libido and/or other symptoms of androgen deficiency
    • Symptoms of androgen deficiency: Loss of sexual desire, loss of clitoral and nipple sensation, difficulty reaching orgasm, thinning of pubic hair, muscle-tone reduction, loss of sense of well-being
  • Should not be used in premenopausal women
  • Testosterone therapy should be deemed as a clinical trial and should not be continued if without significant benefit by 6 months of therapy 
  • Various combinations of Estrogen and Androgens are available. Please see the latest MIMS for specific formulations

Selective Estrogen Receptor Modulators

  • Eg Bazedoxifene, Raloxifene
  • Minimal or no therapeutic effect on acute menopausal symptoms and can induce or worsen hot flushes
    • Combination with conjugated equine estrogen may help decrease hot flushes and improve vaginal dryness
    • Bazedoxifene/conjugated equine estrogen has been approved for the management of vasomotor symptoms and may be given to women intolerant of the progestogen effects
  • Can be used in asymptomatic postmenopausal women with a high risk of breast cancer for prevention and treatment of osteoporosis
  • Prevent breast cancer and endometrial cancer
  • Decrease the risk of vertebral fractures
  • Ospemifene may be used to treat dyspareunia in postmenopausal women

Compounded Bioidentical Hormone Therapy

  • Has safety concerns regarding its monitoring and regulation, variable dosing, and lack of sterility and label indicating potential risks with use; no available current evidence on safety and efficacy
  • May consider giving in patients with allergies or a need for a formulation or dose not currently available in approved therapies

Risks Versus Benefits of Estrogen Therapy/Menopausal Hormone Therapy (ET/MHT)

Osteoporosis

  • Prevention of osteoporosis is well documented
    • MHT is effective and suitable in women younger than 60 years old or within 10 years after menopause in preventing fractures associated with osteoporosis
    • Estrogen has significant antiresorptive and antifracture effects
    • Low-dose estrogen can prevent osteoporosis in postmenopausal women and ultra-low dosage estrogen has beneficial skeletal effects
    • Combination MHT results in increased total hip bone mineral density, with reduction in hip and vertebral fractures and total number of osteoporotic fractures
  • Decision to use hormonal therapy to prevent/treat osteoporosis should involve both patient and physician
    • When hormonal therapy is considered solely for osteoporosis prevention, non-estrogen treatments should first be considered
    • Bone loss resumes once treatment is stopped
  • MHT has a positive effect on osteoarthritis and integrity of intervertebral disks
  • Various agents for the prevention and treatment of postmenopausal osteoporosis are available. Please see Osteoporosis in Women disease management chart for dosage guidelines

Diabetes Mellitus (DM)

  • MHT use reduces the incidence of new-onset type 2 DM
    • Associated with an improvement in insulin resistance in postmenopausal women
    • May require lower doses of medications for glycemic control
  • MHT is not recommended for the prevention of DM in perimenopausal or postmenopausal women
  • Consider age and cardiovascular (CV) and metabolic risk factors when individualizing HRT use in diabetic patients

Colorectal Cancer

  • MHT seems to have protective benefit
  • Meta-analyses  have shown persistence of benefit for 4 years after stopping therapy

Coronary Heart Disease (CHD), Venous Thromboembolism (VTE) and Ischemic Stroke

  • MHT causes very minimal CV risk in the 1st decade after menopause
    • Early initiation of ET may have protective effects on atherosclerosis
  • ET in women 50-59 years age group was linked to significantly less coronary calcification and redued all-cause mortality when therapy was initiated shortly after menopause
    • Initiation of MHT in women >60 years old for the primary prevention of CHD is not recommended
  • Risk for VTE appears to be increased in MHT users
    • Risk may be less with transdermal route
    • Oral MHT should not be given to women with a personal history of or at high risk for VTE, but absolute risk is infrequent below 60 years old
  • MHT shows increase in the risk of stroke when initiated in women >60 years old and/or >10 years after menopause
    • Caution should be taken when managing hypertension and other risk factors for stroke in postmenopausal women

Breast Cancer

  • Short-term hormonal use is unlikely to alter the personal risk of breast cancer
  • Risk of breast cancer returns to baseline after cessation of therapy in women who have used it for <5 years
  • Combination MHT may cause an increase in breast cancer risk after 5 years of use
    • Greater risk of breast cancer with combination MHT than with unopposed ET
    • Risk may be reduced with Dydrogesterone or micronized progesterone than with a synthetic progesterone in combination with ET
  • ET use of up to 7 years does not cause an increase in breast cancer risk
    • Effect of estrogen alone on breast cancer is small and is usually undetectable with short-term exposure
    • There appears to be an increase in the risk with long-term use
  • Women who use MHT after being diagnosed with breast cancer had a higher risk of recurrence
    • Alternative non-hormonal agents should be used for treatment of menopausal symptoms

Endometrial Cancer

  • Risk is increased only in women with intact uterus taking unopposed estrogen
    • Also associated with estrogen dose and duration of use
    • After hysterectomy, single systemic estrogen is suitable
  • Adequate progestogen dose and duration of therapy protects the endometrium 

Ovarian Cancer

  • Increased risk of ovarian cancer in women who use ET
    • More significant risk in women who take estrogen for >10 years
    • Risk is decreased when estrogen is given with progestin

Gallbladder Disease

  • Risk of gallbladder disease seems to be increased in women taking oral estrogen

Cognitive Functioning/Dementia/Mood

  • MHT improves mood and estrogen may be an effective treatment for depressive disorders in perimenopausal women and may augment the clinical response to antidepressant therapy particularly with selective serotonin reuptake inhibitors (SSRIs)
  • MHT should not be used with the expectation of beneficial effect on cognitive functioning
  • Cognitive benefits from ET may depend on the age of initiation
    • Early use of hormonal therapy in menopause may be associated with diminished risk of late dementia; some studies showed neuroprotective effect against Parkinson’s disease
    • ET started at the time of oophorectomy may have short-term cognitive benefit  
  • Based on the Women's Health Initiative (WHI) Memory Study, it shows that the combination of estrogen and progestogen increases older women’s (>65 years old) risk for probable dementia
  • MHT is not recommended for the prevention of dementia or Alzheimer’s disease

Others

  • Vasomotor symptoms
    • MHT is the most effective treatment and is beneficial for women younger than 60 years or within 10 years after menopause
  • Vaginal dryness, dyspareunia and other genitourinary menopausal symptoms
    • Low-dose estrogen applied locally is preferred
  • Treatment with MHT should always be individualized

Other Therapeutic Options

  • Have been used alone or in combination with MHT

Vasomotor Symptoms

  • Propranolol, Clonidine, Gabapentin, antidepressants eg selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs)
    • Non-hormonal agents, eg certain SSRI (Citalopram, Paroxetine) and SNRI (Venlafaxine, Desvenlafaxine) antidepressants, Gabapentin and Clonidine, are alternatives to hormonal therapy (HT) for the treatment of menopausal vasomotor symptoms
      • May be considered when HT is not desired or contraindicated
      • Paroxetine and Fluoxetine reduce Tamoxifen’s efficacy and should be avoided in patients with breast cancer
    • Regular aerobic exercise, deep breathing, cognitive behavioral therapy, acupuncture

Phytoestrogens

  • Sterol molecules with weak estrogenic activity that are produced by plants
  • Similar to the structure of human estrogens
  • Shown to interact and have estrogen-like activity with the estrogen receptor especially at the beta-receptor
  • Eg Isoflavone
    • Obtained from soybeans, soy products, or red clover; broken down to form daidzein which can be metabolized by intestinal bacteria to equol, which is a stable compound with estrogenic activity
    • Has been shown to reduce hot flushes in menopausal women
      • Multiple, randomized, controlled trials showed inconsistent results regarding its effect on reduction of hot flushes; hence, long-term studies on efficacy and safety in postmenopausal women with vasomotor symptoms are needed

Black Cohosh

  • Has also been used to control menopausal symptoms like hot flushes
  • Studies show safety concerns and conflicting data on efficacy

Eucommia ulmoides Bark and Vigna radiata Bean Combination

  • In a randomized, placebo-controlled study, the number and severity of night sweats and hot flushes were significantly decreased with combination of E ulmoides bark and V radiata bean compared with placebo with no significant difference in adverse effects between the two groups
  • However, studies are needed on the long-term risks and benefits of complementary therapies on patient’s health if chosen over hormone therapy for vasomotor symptom relief

Vaginal Dryness

  • Vaginal lubricants and moisturizers, regular sexual activity

Depression

  • Antidepressants, psychotherapy

Sleep Disturbances

  • Prescription hypnotics, behavioral therapy

Dyspareunia

  • Ospemifene and intravaginal DHEA may be given to postmenopausal women with moderate to severe dyspareunia
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