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

Learn More – Primary Sources:

EMAS position statement: Vitamin D and menopausal health

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.

Contraindications for HT
Potential risks of HT
FDA approved indications for HT
NAMS recommendations for type / regimen / duration of use
NAMS recommendations for special populations and cancer risk
Hormonal therapy dosage / regimens
Key points
Learn more

CONTRAINDICATIONS FOR HT (oral or transdermal)

• Unexplained vaginal bleeding
• Severe active liver disease
• 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

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Learn More – Primary Sources:

The 2022 hormone therapy position statement of The North American Menopause Society

NAMS Patient Educational Information: Deciding About Hormone Therapy Use

USPSTF Recommendation: Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Persons

ACOG Practice Bulletin 141: Management of Menopausal Symptoms

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”.

Learn More – Primary Sources:

Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women’s Health Initiative Randomized Trials

Menopausal Hormone Therapy: Understanding Long-term Risks and Benefits (JAMA Editorial)

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

Learn More – Primary Sources:

FDA approves Intrarosa for postmenopausal women experiencing pain during sex

FDA: Prescribing information for Intrarosa (prasterone)

ACOG Committee Opinion No. 659: The Use of Vaginal Estrogen in Women With a History of Estrogen Dependent Breast Cancer

Genitourinary syndrome of menopause: an overview of clinical manifestations, pathophysiology, etiology, evaluation, and management