Menopause%20-and-%20hormone%20therapy Treatment

Principles of Menopausal Hormone Therapy (MHT)

• MHT should always be individualized and should be considered only with clear indications and when contraindications have been ruled out and potential individual benefits outweigh the risks
  • Risk factors for MHT include age >60 years, personal or family history of VTE, obesity, insulin resistance and increased CV risk (eg smoking, DM, hypertension, dyslipidemia)
• Indicated for moderate to severe vasomotor symptoms, GSM, hypoestrogenism and osteoporosis prevention and treatment
• Consider age, time since menopause, signs and symptoms and its effect on patient’s quality of life, personal preferences, and risk factors for CVD when planning usage of MHT in young symptomatic postmenopausal women 
• MHT is given to relieve menopausal signs and symptoms and is initiated as soon as these appear, primarily those caused by vasomotor processes (eg hot flushes)
  • For women with early or premature menopause, MHT is recommended and should be initiated regardless of whether menopausal symptoms are present
• Treatment should be given at the lowest effective dose conforming with treatment goals, particularly if to be given long-term (>10 years) 
• Timing of MHT initiation in relation to menopause is important
  • Treatment is beneficial when given during menopausal transition (perimenopause) or within 10 years of menopause or patient <60 years old
  • It is not recommended to begin systemic hormone therapy in women >60 years old, but they may continue treatment started before age 60 provided they undergo regular assessment and monitoring of MHT 
  • If to be given in women >60 years old, start therapy with lower doses, preferably with a transdermal estradiol
  • Absolute risk of CHD, VTE, stroke and dementia is higher in women who start MHT 10 years after menopause; absolute risk of breast cancer, DM, fracture and all-cause mortality is lower in women <60 years old 
• Treatment should be administered for as long as the benefits outweigh the risks (benefits and risks should be periodically assessed), though gradual MHT cessation with dose tapering over a period of 3-6 months should be attempted to avoid symptom rebound  
  
  • 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 with no contraindications, low-dose combined oral contraceptives (COCs) or MHT is continued until at least the median or average age of natural menopause (50 years); MHT may be given thereafter if hormones are still required 
  • Menopausal symptoms may recur when MHT is stopped; if severe rebound vasomotor symptoms occur, low-dose MHT may be restarted
• 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 1st-pass hepatic effect (non-oral routes preferred), hormone blood levels, and biologic activity of ingredients
  • Preferred route of administration depends on the patient’s preference and prior experience and presence of risk factors, though all types and routes of ET are equally effective in the treatment of hot flushes
• Low-dose COCs may be considered in healthy, non-smoking, perimenopausal women (with no contraindications) desiring contraception as these are effective in alleviating hot flushes and controlling irregular bleeding
  • MHT may also be considered in women with perimenopausal symptoms though non-hormonal contraception (if needed) is advised 
• MHT side effects are usually transient and may spontaneously resolve with continued use (at least 3 months)

Contraindications to MHT

• Breast cancer  
• Endometrial cancer  
• Untreated endometrial hyperplasia  
• Ovarian cancer
• Venous thrombosis, pulmonary embolism  
• Active or recent arterial thromboembolic disease (eg angina, myocardial infarction)  
• Acute liver disease  
• Unexplained genital bleeding or pregnancy  
• Hypertriglyceridemia (if estrogen is to be used, select transdermal route)
• Untreated hypertension
• Known hypersensitivity to the active substance of MHT or to any of the excipients  
• Porphyria cutanea tarda
• Stroke or transient ischemic attack

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
• Estrogen-only therapy may be given up to age 50 years to young women who underwent surgical menopause to prevent immediate and long-term menopausal problems 
• Perimenopausal women using the Levonorgestrel-releasing intrauterine system (LNG-IUS) may be given ET either orally or transdermally

Oral

• Avoid in women with thrombophilias, active gallbladder disease or hypertriglyceridemia 
  • Increased risk for VTE because oral estrogen has greater impact on coagulation factors than transdermal or vaginal routes
  • Associated with rapid increase in 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, migraines without aura, hypertension, DM, hypertriglyceridemia with risk of fatty liver or pancreatitis, gallbladder disease, thrombophilia, increased risk for cholelithiasis or VTE, obese women with metabolic syndrome, or women who smoke
  • 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 while an ultra-low-dose patch can deliver 0.014 mg of estrogen per day for reduction of hot flushes and prevention of osteoporosis 

Vaginal

• It is recommended to give low-dose vaginal therapies to women with vulvovaginal and urinary symptoms who did not respond to 1st-line treatment with vaginal lubricants and moisturizers 
• May consider giving vaginal estrogen to women with urogenital atrophy if systemic MHT is contraindicated
• Vaginal application of estrogen helps relieve urogenital atrophy and may decrease recurrent UTI
• Low-dose topical vaginal estrogen therapies (eg creams, tablets, rings) are efficacious and side effects are minimal

Progestogens

• Addition of progestogen reduces the risk of endometrial hyperplasia or cancer from systemic use of estrogen or from elevated estrone production from adipose tissue in obese patients
  • Maximum protection is obtained with 10-14 days progestin exposure/month
• When progesterone use cannot be avoided, consider using micronized progesterone or Dydrogesterone 
• LNG-IUS may be given to perimenopausal women with heavy menstrual bleeding and for contraception and endometrial protection
• Not indicated in postmenopausal women without a uterus and when used with low doses of estrogen administered locally for vaginal atrophy or low-dose transdermal estrogen for osteoporosis prevention

Hormone Regimens

• The type and dose of estrogen administered will determine the dose and duration of progestogen per cycle 

Combined Cyclic or Sequential Regimens 

• Progestogen is given on a cyclical basis along with an estrogen
• Estrogen is usually given for 21-28 days while the progestogen is added for 10-14 days of the month (patient bleeds monthly) or for 10-14 days every 13 weeks (patient bleeds every 3 months)
• Administered to women who are ≤2 years from established menopause (perimenopausal) and up to 1 year from their last menstrual period
• 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
  • Some women will be amenorrheic due to an atrophic endometrium and biopsy is not required, though pregnancy should be ruled out

Continuous Combined MHT

• A no bleed therapy, it is an alternative to cyclic regimen
• Daily administration of both progestogen and estrogen
• Administered to women who are 1-2 years from established menopause
• Risk of irregular bleeding is increased when given to perimenopausal women
• Bleeding pattern: Irregular breakthrough bleeding can occur for up to 4-6 months of therapy thus may be used in women who are at least 2 years past their last menstrual period
  • If irregular bleeding occurs in women after 6 months of use or in those 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

Selective Estrogen Receptor Modulators (SERMs)

• Eg Bazedoxifene, Ospemifene
• Bazedoxifene/conjugated equine estrogen has been approved for the management of vasomotor symptoms and prevention of osteoporosis; may be given to women intolerant of the progestogen effects
  • Combination with conjugated equine estrogen may help decrease hot flushes and improve genitourinary atrophy and dyspareunia
  • Safe for the endometrium; associated with increased breast density and decreased incidence of breast pain and vaginal bleeding
• Ospemifene is used to treat moderate to severe dyspareunia and vaginal dryness and symptoms of vulvovaginal atrophy due to menopause
  • Not approved for use in breast cancer or prevention of osteoporosis

Tibolone

• Synthetic steroid which has estrogenic, progestogenic and androgenic properties
• Suppresses vasomotor problems, improves mood, concentration, sleep, libido, and vaginal atrophy, decreases proliferation of breast epithelial cells, increases muscle mass, and has a protective effect on bone mass 
• Has been used as an alternative to or after transferring from continuous combined MHT
  • May also be used in women with intact uterus amenorrheic for 1 year, after hysterectomy, those intolerant of MHT and are concerned with sexual health issues, and those with fibroids or endometriosis needing menopausal treatment
• Incidence of abnormal vaginal bleeding is lower compared with estrogen-progestogen therapy  
• Initiation of Tibolone in women >60 years old has been associated with increased stroke risk; 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 
• Prasterone is a synthetic equivalent to endogenous dehydroepiandrosterone (DHEA) and is used to treat moderate to severe dyspareunia and also improves vaginal dryness and itching/irritation
• Various combinations of Estrogen and Androgens are available. Please see the latest MIMS for specific formulations and prescribing information

Bioidentical Hormone Therapy

• Safe to use due to its similar structure and behavior to the body’s own hormones 
• Compounded bioidentical hormones have 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

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 the prevention and treatment of osteoporosis
    • Non-hormonal therapy is necessary for osteoporosis and prevention of fragility fractures in women >60 years old or >10 years from menopause
  • Estrogen has significant antiresorptive and antifracture effects
  • Combination MHT results in increased total hip bone mineral density with reduction in hip and vertebral fractures and total number of osteoporotic fractures
• Femoral, vertebral and non-vertebral fractures are reduced with standard-dose MHT in women without osteoporosis 
  • Treatment with low- and ultra-low-dose estrogen has not been proven efficacious in reducing fracture risk 
• 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 1st 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 MHT use in diabetic patients

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 cardioprotective effects on atherosclerosis
• ET in women 50-59 years age group with no evidence of CV disease (CVD) was linked to significantly less coronary calcification and reduced 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 is lower with ET than with estrogen-progestogen therapy 
  • Risk may be less with transdermal or vaginal route
  • Oral MHT should not be given to women with a personal history of or at high risk for VTE, but absolute risk is rare in women <60 years old
• MHT shows increase in the risk of stroke when initiated in women >60 years old and/or >10 years after menopause
  • Risk of stroke is rare in younger postmenopausal women; risk could be reduced with lower-dose oral or transdermal hormonal therapy  
  • Caution should be taken when managing hypertension and other risk factors for stroke in postmenopausal women
• MHT can be used for menopausal symptom treatment in women with blood pressure (BP) that is well controlled

Breast Cancer

• MHT may be recommended for symptomatic menopausal women with a positive BRCA mutation or have a family history of 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 have a higher risk of recurrence
• Women with previous or current estrogen receptor-positive breast cancer can be given vaginal ET for genitourinary symptoms without increased risk of recurrence
• As it is not advisable to use MHT in patients with breast cancer, alternative non-hormonal agents should be used for the 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, ie increased risk with higher dose or longer treatment duration 
  • After hysterectomy, single systemic estrogen is suitable
• Adequate progestogen dose and duration of therapy protects the endometrium 
• MHT is not advisable for menopausal symptom treatment after endometrial cancer surgery due to potential stimulation of any remaining cancer cells 
• For patients with early endometrial cancer who underwent excision of the uterus and bilateral appendages, MHT may be considered if treatment with non-hormonal agents have been ineffective 
  • Menopausal symptoms of patients with high-risk or advanced endometrial cancer should be controlled with non-hormonal therapy 

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
• Either estrogen-only or combined estrogen-progestogen therapy may be used for menopausal symptom treatment in women who have completed ovarian cancer treatment with no increased risk of recurrence 

Cervical Cancer

• MHT does not increase the risk of cervical cancer 
• Estrogen-only therapy for menopausal symptom treatment can be given to women who underwent hysterectomy for cervical cancer and does not increase the risk of recurrence

Colorectal Cancer

• Combination MHT reduces colorectal cancer risk 
  • ET does not have any effect in patients with colorectal cancer 
• Meta-analyses have shown persistence of benefit for 4 years after stopping therapy

Gallbladder Disease

• Risk of gallbladder disease is increased in women taking oral estrogen or estrogen-progestogen therapy 
  • Gallbladder disease should be carefully monitored in women taking oral MHT

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)
  • Oral estrogen significantly improves mood as compared to transdermal preparations
• 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, estrogen has no beneficial effect on cognition
• MHT should not be used with the expectation of beneficial effect on cognitive functioning and 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
    • May be given to women with or at high risk of breast cancer who did not respond to non-hormonal therapy after discussing risks and benefits of treatment with oncologist
• Improves quality of life and results in a fewer all-cause mortality in women between 50-59 years old 
• MHT is not to be used as 1st-line treatment for the aging skin and for menopausal changes to hair, dentition, eyesight, hearing, smell, taste and voice

• Have been used alone or in combination with MHT

Vasomotor Symptoms

Fezolinetant

• An oral neurokinin 3 (NK3) receptor antagonist indicated to treat moderate to severe vasomotor symptoms (eg hot flushes) due to menopause   
• Blocks binding of neurokinin B on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron to modulate the thermoregulatory center’s neuronal activity

Non-hormonal Agents

• Certain selective serotonin reuptake inhibitor (SSRI, eg Citalopram, Paroxetine, Escitalopram, Fluoxetine) and serotonin-norepinephrine reuptake inhibitor (SNRI) (eg Venlafaxine, Desvenlafaxine) antidepressants, Pregabalin, Gabapentin and Clonidine are alternatives to hormonal therapy for the treatment of menopausal vasomotor symptoms
  • May be considered when hormonal therapy is not desired or contraindicated
  • Paroxetine and Fluoxetine reduce Tamoxifen’s efficacy and should be avoided in patients with breast cancer

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
• Appears to have some protective effect against breast and endometrial cancer as well as improve BMD and CV risk, though additional clinical trials need to be performed
• 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

Other Treatments

• Cognitive behavioral therapy, hypnosis and mindfulness-based stress reduction help reduce hot flushes; exercise, acupuncture and yoga have demonstrated inconsistent or negative results in trials for relieving vasomotor symptoms 

Genitourinary Symptoms

• Vaginal dryness: Lubricants and moisturizers, regular sexual activity  
  • Lubricants are preferred to be water-based and have an osmolality of ≤380 mOsm/kg and a pH of 4.5 
  • Moisturizers have more long-term effects than lubricants 
• Dyspareunia: Ospemifene and intravaginal DHEA may be given to postmenopausal women with moderate to severe dyspareunia   
  • Pelvic floor muscle therapy may also be of benefit in women with persistent dyspareunia 
• Energy-based devices (eg radiofrequency or laser [fractional CO₂ laser or erbium:YAG laser]) have been proposed as non-hormonal therapy for symptoms related to menopause, urinary incontinence or sexual function
  • Performed as non-surgical vaginal procedures and may be associated with adverse events; risks and benefits of treatment should be discussed with the patient

Depression

• Antidepressants, psychotherapy

Sleep Disturbances

• Prescription hypnotics, cognitive behavioral therapy