An advisory panel was selected to review current literature regarding nonhormone therapy based on levels of evidence. In the treatment of vasomotor symptoms in women within ten years of menopause and who are not candidates for or who decline hormone therapy, evidence-based nonhormone options such as behavioral therapies, medications such as SSRIs or gabapentin, and weight loss should be discussed and considered.
Vasomotor Post Menopausal Symptoms
Vasomotor symptoms (VMS)
Defined as hot flashes and night sweats
Incidence
Mean 7 to 10 years
30% >10 years
Standard Management
Hormone therapy
First line recommended treatment
Underutilized therapy
Contraindications
Estrogen sensitive tumors
Coronary artery disease/myocardial infarction history
Stroke
Venous thromboembolism
Recommended Nonhormone Techniques and Therapies
Mind-Body Techniques
Clinical hypnosis
Cognitive behavior therapy
Prescription Medications
SSRIs and SNRIs demonstrate mild to moderate improvement
Ecitalopram 10 to 20 mgs/day
Paroxetine salt 7.5 mg/day
Paroxetine 10 to 25 mg/day
Citalopram 10 to 20 mg/day
Desvenlafaxine 100 to 150 mg/day (start at 25 to 50 mg/day)
Venlafaxine 37.5 to 150 mg/day (start at 37.5 mg/day)
Gabapentin
900 to 2400 mg/day in divided doses (start with 100 to 300 mg at night, add 300 mg at night, then an AM dose of 300 mg)
Fezolinetant
Neurokinin B antagonist
45 mg/day
Oxybutynin
2.5 to 5.0 mg twice daily or 15 mg extended release daily
Long term use may be associated with cognitive decline in older adults
EMAS Position Statement: Use of Vitamin D Among Postmenopausal Women
SUMMARY:
EMAS, an international society that promotes health in women and men at midlife and beyond, has produced a position statement targeting the use of vitamin D in postmenopausal women. The literature suggests “an association between vitamin D deficiency and adverse health outcomes in postmenopausal women, although they cannot establish causality.” The document includes an extensive literature review.
‘Vitamin D’ Overview
What is it?
Group of lipophilic hormones
Regulates calcium homeostasis via kidney, gastrointestinal tract, skeleton and parathyroid
Critical for skeletal health but impacts multiple tissues
Two major forms
Vitamin D2 (ergocalciferol)
Vitamin D3 (cholecalciferol)
Major source through cutaneous synthesis through exposure to sunlight
Small amount from animal diet (fatty fish, eggs and milk)
Measurement
Vitamin D status: Measure serum 25-hydroxyvitamin D levels
<20 ng/ml (<50 nmol/l): Vitamin D deficiency
<10 ng/ml (<25 nmol/l): Severe Vitamin D deficiency
Vitamin D Deficiency and Associated Health Outcomes
Skeletal
Increased fracture risk
Menopausal Symptomatology
Evidence is inconsistent
Some studies have demonstrated increased risk
Hot flashes | Depression | Sexual dysfunction | Sleep disturbances
Cardiac
Increased prevalence for CVD risk factors
Metabolic syndrome | Type 2 diabetes | Atherogenic dyslipidemia
Increased incidence for CVD events
Cancer
Increased risk for cancers: Colorectal | Lung | Breast
Overall and cancer-specific mortality rates are increased in postmenopausal women
No evidence for ovarian or other gyn cancers
Infections and Inflammation
Increased risk for respiratory infection
Increased risk for autoimmune disorders
Vitamin D Supplementation Recommendations for Postmenopausal Women
Skeletal Health
No vitamin D deficiency or low fracture risk
No evidence to support vitamin D supplementation
Vitamin D deficiency with osteoporosis and/or high fracture risk (FRAX model)
Vitamin D: 2000 to 4000 IU (4000 to 6000 IU in obese patients)
Calcium: 1000 to 1200 mg of calcium (dietary or supplements)
Encourage Vitamin D and calcium use for minimum 3 to 5 years
Check vitamin D levels 3 to 6 months with target above 20 ng/ml (<50 nmol/l)
Menopausal Symptomatology
Vitamin D supplementation is not recommended to improve menopausal symptoms
Cardiovascular Disease
No effect of vitamin D supplementation on decreasing CVD risk
Cancer
No effect of vitamin D supplementation on cancer incidence although some studies identified a small reduction in cancer-related mortality
Infections and Inflammation
Vitamin D supplementation may ‘modestly’ decrease the risk for acute respiratory tract infections including COVID-19
Concerns regarding study design such as “heterogeneity in design, duration, population and vitamin D dosage among studies must be underscored”
KEY POINTS:
Typical daily dose of 1000 to 1200 mg of calcium is not associated with increased risk for cardiovascular disease or nephrolithiasis
Studies on vitamin D supplementation have significant limitations due to heterogeneity regarding dose, inclusion of calcium and baseline vitamin D status
More research needed to
Discriminate between vitamin D replacement and supplementation
Determine the need for universal vitamin D screening in postmenopausal women
North American Menopause Society: Hormone Therapy Statement
SUMMARY:
NAMS updated its position statement on hormone therapy, based on an extensive literature review. Hormone therapy (HT) is the most effective treatment for vasomotor symptoms (VMS; hot flashes, night sweats) and genitourinary syndrome of menopause (GSM). The statement has been endorsed by over 20 international organizations.
Prior estrogen sensitive cancer (including breast cancer)
Prior coronary heart disease
Stroke, MI or VTE
Personal history/inherited high risk of thromboembolic disease
POTENTIAL RISKS OF HT
Women <60 Years or Who are Within 10 Years of Menopause
Breast cancer (rare risk) with combined estrogen-progestogen therapy
Endometrial hyperplasia and cancer with unopposed estrogen
VTE
Biliary issues
FDA APPROVED INDICATIONS FOR HT
Bothersome vasomotor symptoms
Prevention of bone loss
Hypoestrogenism caused by hypogonadism, surgical castration or premature ovarian insufficiency
Genitourinary symptoms
NAMS RECOMMENDATIONS FOR TYPE / REGIMEN / DURATION OF USE
Individualize Type, Dose & Regimen
For women with a uterus and using systematic estrogen, ensure endometrial protection (Level I)
Use adequate dose and duration of a progestogen
In WHI, addition of medroxyprogesterone acetate 2.5 mg daily resulted in same risk of endometrial cancer as placebo (hazard ratio 0.81 (95% CI 0.48-1.36)
combine conjugated equine estrogens (CEE) with bazedoxifene
Progestogen therapy not recommended for low-dose vaginal estrogen therapy (ET)
Evaluate endometrium if bleeding does occur
Avoid compounded bioidentical HT given concerns about safety
Do not use salivary hormone testing to dictate dosing
Individualize Duration
Premature menopause, either natural or induced <45 years and especially if <40 years
Continue HT at least until age 52, which is the median age of menopause (Level II)
The recommendation to routinely discontinue HT in women aged 65 and older is not supported by data
Decision to continue >60 years of age includes quality of life, VMS, bone loss/fracture and other medical risks vs benefits
NAMS RECOMMENDATIONS FOR SPECIAL POPULATIONS AND CANCER RISK
Family History of Breast Cancer or BRCA Positive Following Prophylactic Oophorectomy
Use of HT does not appear to increase the relative risk for breast cancer
Family history is a risk factor for breast cancer and should be assessed when counseling about HT
Ovarian Cancer
Recent and current use of hormone therapy is associated with a small increase in serous type of ovarian cancer
One additional ovarian cancer death in 1,700 to 3,300 HT users
Both combined estrogen-progestogen therapy and ET
Risk dissipates within 5 years of discontinuing HT
After diagnosis of epithelial ovarian cancer, HT does not affect recurrence risk or survival
Benefits of use outweigh risks
Not recommended in hormone-dependent ovarian cancers (granulosa-cell tumors and low-grade serous carcinoma)
Breast and Endometrial Cancer Survivors: Systemic HT for VMS
Encourage nonhormonal therapies
Endometrial cancer survivor
If VMS not well controlled, may consider HT in conjunction with oncologist
Breast cancer survivor (especially ER+)
Systemic HT should not be offered but if other nonhormonal alternatives have failed, shared decision making that includes an oncologist can be considered
Breast and Endometrial Cancer Survivors: Low-dose Vaginal ET
Low-dose vaginal ET has minimal systematic absorption and appears to hold minimal to no risk for breast or endometrial cancer
Endometrial cancer survivor following hysterectomy and successful treatment
Consider low-dose vaginal ET in nonhormonal options are unsuccessful
Breast cancer survivors
Decisions regarding low-dose vaginal estrogen should involve the treating oncologist especially if patient is on aromatase inhibitors
Colorectal Cancer
Overall decreased risk of colorectal cancer in current HT users compared to non-users
No benefit associated with prior use
Lung Cancer
No effect on lung cancer incidence and/or survival
HORMONAL THERAPY DOSAGE/REGIMENS
NOTE: For women with a uterus and using systematic estrogen, ensure endometrial protection with an adequate dose of a progestogen
VSM: Systemic
Standard Dose
Conjugated estrogen 0.625 mg/d
Micronized estradiol-17β 1 mg/d
Transdermal estradiol-17β 0.0375–0.05 mg/d
Low Dose
Conjugated estrogen 0.3–0.45 mg/d
Micronized estradiol-17β 0.5 mg/d
Transdermal estradiol-17β 0.025 mg/d
CEE + SERM
Conjugated estrogen 0.45 mg/d and bazedoxifene 20 mg/d
19-nortestosterone derivative synthetic steroid
Tibolone 2.5 mg/d
Note: Progestin-only medications, testosterone, or compounded bioidentical hormones for the treatment of vasomotor symptoms are not recommended
GSM: Systemic
Standard Dose
Conjugated estrogen 0.625 mg/d
Micronized estradiol-17β 1 mg/d
Transdermal estradiol-17β 0.0375–0.05 mg/d
Low Dose
Conjugated estrogen 0.3–0.45 mg/d
Micronized estradiol-17β 0.5 mg/d
Transdermal estradiol-17β 0.025 mg/d
PROGESTOGENS FOR UTERINE PROTECTION – when using standard dose estrogen
Medroxyprogesterone acetate
2.5 mg po daily for continuous therapy
5 mg daily po with sequential therapy for 12 – 14 days sequentially per 28-day cycle (start day 1 or 16)
Micronized progesterone
100 mg po daily for continuous therapy
200 mg po nightly for 12 days sequentially per 28-day cycle
Formulated with peanut oil – do not use in women with peanut allergies
May cause hypnotic effects and should be taken at bedtime
GSM: Local (vaginal, and in the case of creams may also be applied to vestibular area)
Estradiol-17β ring (releases 7.5 micrograms/d): replace every 3 months
Estradiol vaginal tablet (10 micrograms/d): place nightly for 2 weeks
Maintenance is one tablet 2 times/week
Note: this is the corrected dose in ACOG PB 141
Estradiol-17β cream (0.1 mg active ingredient/g): 2-4 g/d for 1 to 2 weeks
Gradually reduce to ½ initial dosage for 1 – 2 weeks
Maintenance is 1 g, 1 to 3 times/week
Conjugated estrogen cream (0.625 mg/g): 0.5–2 g/d for 21 days then off for 7 days
In practice during maintenance therapy, most women apply 1 – 3 times /week
KEY POINTS:
Risks of HT differ depending on type/dose/duration/route/timing of initiation and whether a progestogen is needed
Individualize treatment to maximize benefits/minimize risk
Reassess periodically
Women younger than 60 or within 10 years of menopause without contraindications have a favorable benefit-risk ratio for use of HT in the treatment of VMS and reducing bone loss/fracture for those at increased risk
Longer duration may be more favorable for estrogen therapy alone vs combined estrogen-progestin therapy based on the WHI RCTs
Women who begin HT more than 10 years from menopause onset or aged 60 or older have a less favorable benefit-risk ratio, with greater absolute risks of CHD, stroke, thrombosis and dementia
Low-dose vaginal estrogen therapy is recommended for GSM symptoms not relieved with other therapies
Nonestrogen therapies like ospemifene and intravaginal DHA are approved for use in postmenopausal women
Cognition
HT is not recommended to prevent cognitive decline
Starting HT >65 years has been associated with increased risk for dementia | Normal cognition prior to initiation may attenuate this effect
ET may have cognitive benefits if started immediately following hysterectomy with bilateral oophorectomy
HT in the early natural postmenopause period does not appear to impact cognitive function
The USPSTF Guidance on the Role of Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Persons
The USPSTF assessed the evidence for harms and benefits for chronic disorders such as coronary heart disease, dementia, stroke, fractures, and breast cancer
The USPSTF concludes with moderate certainty that there is no net benefit in the use of hormone therapy
The USPSTF recommends against the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons (*D recommendation)
The USPSTF recommends against the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal persons who have had a hysterectomy (*D recommendation)
*D recommendation Suggestion for Practice: Discourage the Use of This Service
The WHI Randomized Trials: Is Menopausal Hormone Therapy Associated with Long-Term Mortality?
PURPOSE:
The original WHI trials were designed to assess risk vs benefits of menopausal hormone therapy
Double-blinded, placebo-controlled, randomized clinical trials, conducted among US postmenopausal women aged 50 to 79 years at enrollment using the following 2 drug regimens
Conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for women with an intact uterus
CEE alone for women with hysterectomy
The CEE plus MPA trial was stopped early (after 5.6 years) due to an increased risk of breast cancer and overall risks exceeding benefits
CEE-alone trial was stopped after 7.2 years due to an increased risk of stroke
Postintervention follow up has been ongoing
Manson et al. (JAMA, 2017) report the extended follow up on all-cause and cause-specific mortality with attention to age
METHODS:
Postintervention follow up study of the two WHI studies (1993-1998)
Total 27,347 postmenopausal women ages 50 to 79 years were recruited at 40 US clinical centers
16,608 women with a uterus received daily oral CEE (0.625 mg) plus MPA (2.5 mg) or placebo
10,739 women with hysterectomy received daily oral CEE (0.625 mg) alone or placebo
Primary outcome: All-cause mortality
Cause-specific mortality (cardiovascular disease cancer and other major causes)
18 year follow up in 2 trials separately and combined (pooled)
RESULTS:
All-cause mortality
Pooled cohort: 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03])
CEE plus MPA: HR 1.02 (95% CI, 0.96-1.08)
CEE alone: HR 0.94 (95% CI, 0.88-1.01)
Cardiovascular mortality
Pooled cohort: HR 1.00 (95% CI, 0.92-1.08)
Total cancer mortality
Pooled cohort: HR 1.03 (95% CI, 0.95-1.12)
Other causes
Pooled cohort: HR 0.95 (95% CI, 0.88-1.02)
results did not differ significantly between trials
Comparing younger women (50-59 years) to older women (70-79 years) in the pooled cohort for all-cause mortality
During intervention phase: all-cause mortality reduced compared to older women
ratios of HRs 0.61 (95% CI, 0.43-0.87)
During cumulative 18-year follow-up: no difference seen in all-cause mortality compared to older women
ratios of HRs 0.87 (95% CI, 0.76-1.00)
No significant difference between trials
CONCLUSION:
There was no long-term association between hormone replacement and all-cause or cause-specific mortality during a follow up period of 18 years in women who used combination estrogen plus progestin for 5.6 or estrogen-alone group for 7.2 years
Limitations include specific hormone replacement formulations and therefore results may not be generalizable
Cause-specific mortality results should be considered exploratory because multiple smaller subgroups were analyzed
The accompanying editorial states that this present study supports the recently released 2017 NAMS guidance and women should be reassured and hormone therapy appears “safe and efficacious”.
Prasterone for Vulvovaginal Atrophy – What is it and How to Prescribe
CLINICAL ACTIONS:
Vulvovaginal atrophy is a common symptom of atrophic vaginitis (also referred to as the genitourinary syndrome of menopause or GSM) and can occur in both perimenopausal and postmenopausal women. If a patient reports vaginal dryness consider the following:
Confirm diagnosis of postmenopausal atrophy through vaginal exam
Discuss use of vaginal estrogen as an option
If patient is not an appropriate candidate for local estrogen or if patient would prefer not to use a direct estrogen product, prasterone may be an effective alternative
One vaginal insert (6.5 mg of prasterone) each evening at bedtime
SYNOPSIS:
Prasterone is an approved, steroid-based FDA treatment for postmenopausal vaginal atrophy. Use is appropriate for women who complain of dyspareunia, or general discomfort due to dryness and thinning of the vaginal mucosa.
KEY POINTS:
During perimenopause and menopause, estrogen levels decline in vaginal tissues and is referred to as vulvovaginal atrophy (VVA), which may result in discomfort or pain during intercourse
Local estrogen can be considered a first line treatment of VVA but may not be appropriate or desired by all patients
The FDA approved prasterone to treat women experiencing moderate to severe dyspareunia, a symptom of VVA, due to menopause
Prasterone is the first FDA approved product containing the synthetic active ingredient dehydroepiandrosterone (DHEA)
DHEA can convert to androgens and/or estrogens and, while the likelihood is low and the quantities minimal, a physician should disclose the following
Based on the fact that there is minimal data on safety in the setting of hormonally sensitive malignancy, the FDA warns against using prasterone if there is a history of or known or suspected breast cancer
Unexplained uterine bleeding is a contraindication to use
It is indicated for use only in postmenopausal women
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