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)

North American Menopause Society: Hormone Therapy Statement

SUMMARY:

NAMS updated its position statement on hormone therapy (2017), 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).

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

• • Unexplained vaginal bleeding

• • Severe active liver disease

• • Prior estrogen-sensitive breast or endometrial cancer

• • Coronary heart disease

• • Stroke

• • Dementia

• • Personal history/inherited high risk of thromboembolism

• Other: porphyria cutanea tarda, hypertriglyceridemia, endometriosis/leiomyoma with concern for worsening symptoms or growth

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

Women across the age spectrum

• MI
• Stroke
• Dementia

FDA APPROVED INDICATIONS FOR HT

(Level I: Based on good and consistent scientific evidence / Level II: Based on limited or inconsistent scientific evidence / Level III: Based primarily on consensus and expert opinion)

• Bothersome vasomotor symptoms (Level I)
• Prevention of bone loss (Level I)
• Hypoestrogenism caused by hypogonadism, surgical castration or premature ovarian insufficiency (Level II)
• Genitourinary symptoms (Level I)

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 ET (Level I)
  • Evaluate endometrium if bleeding does occur
• Lower doses/transdermal HT may be appropriate in women with metabolic syndrome that include hypertriglyceridemia / risk of pancreatitis / fatty liver (Level III)
• Avoid compounded bioidentical HT given concerns about safety (Level I)
• Do not use salivary hormone testing to dictate dosing

Individualize duration

• Premature menopause, either natural or induced < age 45 and especially if < age 40
  • 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 (Level III)

NAMS RECOMMENDATIONS FOR SPECIAL POPULATIONS AND CANCER RISK

Family history of breast cancer

• Use of HT does not appear to increase risk (Level II)

• Family history is a risk factor for breast cancer and should be assessed when counseling about HT

BRCA positive without breast cancer

• For BRCA positive women who have undergone prophylactic oophorectomy, risks due to premature loss of estrogen need to be considered (Level II)
• Limited observational studies suggest HT until age 52, then individualize (Level II)

Ovarian Cancer

• Data does not support estrogen as an initiator or promotor of epithelial ovarian cancer
  • In WHI, no increased risk of ovarian cancer with CEE + medroxyprogesterone acetate (5.6 years’ therapy with 13 years follow-up)
  • If association between HT and ovarian cancer exists, absolute risk likely to be rare (<1/1,000) or very rare (<0.01/1,000) and related to duration of use
• Limited data has not demonstrated increased risk in women with family history of ovarian cancer or BRCA mutation carriers who use estrogen-progestogen therapy
• Observational data inconsistent with some (not all studies) demonstrating increased risk after 5 to 10 years
• Data limited on ER+ tumors such as low-grade serous carcinomas and sex cord stromal malignancies

Breast and endometrial cancer survivors: Systemic HT for VMS

• Encourage nonhormonal therapies (Level III)
• Endometrial cancer survivor
  • If VMS not well controlled, may consider HT in conjunction with oncologist (Level III)
• 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 (Level II)
• Endometrial cancer survivor following hysterectomy and successful treatment
  • Consider low-dose vaginal ET in nonhormonal options are unsuccessful (Level II)
• Breast cancer survivors
  • Decisions regarding low-dose vaginal estrogen should involve the treating oncologist especially if patient is on aromatase inhibitors (Level III)

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

Note:

• 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
• Progestin
  • Not recommended as first line therapy due to safety concerns related to breast cancer risk
  • Depot medroxyprogesterone acetate 400 mg demonstrated to improve VSM symptoms in RCT
    • Not FDA approved for this indication
• Combined estradiol and progesterone capsules
  • 1 capsule (1 mg/100 mg) /d
  • Bioidentical therapy
  • Molecularly identical to circulating hormones (see ‘Related ObG Topics’ below)

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
• Vaginal inserts (4-μg and 10-μg)
  • 1 vaginal insert daily for 2 weeks
  • Maintenance is 1 insert twice weekly

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

The USPSTF Guidance on the Role of Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Women (December 2017)

• The USPSTF assessed the evidence for harms and benefits for chronic disorders such as coronary heart disease, dementia, stroke, fractures, and breast cancer
• The magnitude of both the benefits and the harms of hormone therapy in postmenopausal women is small to moderate
• 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 women. (*D recommendation)
  • The USPSTF recommends against the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal women 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 2017 hormone therapy position statement of The North American Menopause Society

Scientific Background Report for the 2017 Hormone Therapy Position Statement of The North American Menopause Society

ACOG Practice Bulletin 141: Management of Menopausal Symptoms

Practice Bulletin 141: Management of Menopausal Symptoms: Correction

Perspective on prescribing conjugated estrogens/bazedoxifene for estrogen-deficiency symptoms of menopause: a practical guide

Kaunitz and Manson: Management of Menopausal Symptoms

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

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