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Estrogen production declines in women when ovarian function changes with aging or after surgical removal of the ovaries. This drop in estrogen levels can trigger a vasomotor response resulting in a sensation of flushing and sweating that interferes with function and sleep (hot flashes or flushes). Other symptoms, such as mood changes and urogenital atrophy, contribute to reduced quality of life for many women. Several other effects on health also occur because estrogen receptors are located in many areas of the body and estrogen has interactions with processes such as blood clotting. Studies conducted in recent years have identified additional health benefits of postmenopausal estrogen besides symptom management (osteoporosis) as well as potential harms (cardiovascular disease, breast cancer, and cholecystitis). Estrogen was approved as a hormone supplement in the 1940’s to treat estrogen withdrawal symptoms in menopausal women. A national survey conducted in 1995 indicated that 37% of women age 50 and older were using estrogen for multiple purposes [1]. More recent US national data indicate that hormone use in postmenopausal women has declined following publicity about the potential harms of postmenopausal estrogen use [2].
Several oral estrogen preparations are available, although conjugated equine estrogen (CEE) is the most commonly used in the U.S. Other routes of delivery, such as transdermal, intramuscular, and topical, are less common. Treatment with transdermal 17-beta estradiol (E2) provides higher estradiol levels than corresponding doses of CEE that provide higher levels of estrone and estrone sulfate [3]. This difference reflects the hormonal compositions of the different drugs as well as the consequences of hepatic first-pass metabolism effect with oral use. It is not known if these differences result in important clinical effects.
Recent research and current practices dictate that systemically administered estrogen is combined with a progestin or progesterone for a woman with a uterus to avoid endometrial hypertrophy and endometrial cancer associated with estrogen-only therapy. Both agents can be combined into one daily pill, or taken separately, concurrently, or sequentially over a monthly cycle.
The current FDA approved indications for postmenopausal estrogen include treatment of menopausal symptoms and prevention of low bone density and fractures. When prescribing solely for the prevention of postmenopausal osteoporosis, FDA recommends that therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate.
The FDA added health warnings to its label including new data on health harms from the Women’s Health Initiative (WHI) trial published in July 2002 [4] and the WHI Memory Study (WHIMS) published in 2003 [5]. The U.S. Preventive Services Task Force, as well as several professional organizations, are currently recommending against use of estrogen and progestin/progesterone for prevention of chronic conditions [6]. It is possible that the clinical uses of postmenopausal estrogen could change in the near future.
The purpose of this review was to compare the efficacy and adverse effects of different estrogens. The Oregon Evidence-based Practice Center wrote preliminary key questions, identifying the populations, interventions, and outcomes of interest. These questions were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review (DERP) Project. The participating organizations of DERP were responsible for ensuring that the scope of the review reflected the populations, drugs, and outcome measures of interest to clinicians and patients. The participating organizations approved the following key questions to guide this updated review:
What is the comparative effectiveness of different hormone therapy preparations when used by postmenopausal women or women in the menopausal transition stage for reducing symptoms of menopause: hot flashes/flushes, sleep disturbances/night sweats, mood changes (depression), urogenital atrophy, sexual function, and quality-of-life measures?
What is the comparative effectiveness of different hormone therapy preparations when used by postmenopausal women or women in the menopausal transition stage for preventing low bone density and fractures?
What is the comparative safety of different hormone therapy preparations for short-term use (<5 years)?
What is the comparative safety of different hormone therapy preparations for long-term use (5 or more years)?
Are there subgroups of patients based on demographics, other medications, co-morbidities, length of use, or initiation of use relative to onset of menopause, for which one medication or preparation is more effective or associated with fewer adverse effects?
Study participants include women recruited from any health care setting or a population-based sample experiencing menopause. When possible, data are considered separately for women with natural versus surgical menopause (oophorectomy) and for postmenopausal women versus women in the menopausal transition stage.
Women in the menopausal transition stage are those transitioning through natural menopause who have had irregular menstrual periods within the last 12 months.
Postmenopausal women are those with surgical or natural menopause and amenorrhea for more than 12 months.
| Included Estrogen Products | |||
|---|---|---|---|
| Drug | Trade names | Available strengths | FDA-approved indications |
| Oral estrogens | |||
| 17b Estradiol | Estradiol (generic) Estrace | 0.5, 1, 2 mg 0.5, 1, 2 mg | 1. Treatment of moderate to severe vasomotor symptoms associated with menopause. 2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar or vaginal atrophy, topical vaginal products should be considered. 3. Treatment of Hypoestrogenism due to hypogonadism, castration, or primary ovarian failure. 4. Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease. 5. Treatment of advanced androgen dependant carcinoma of the prostrate (for palliation only). 6. Prevention of osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. |
| Estradiol acetate | Femtrace | 0.45, 0.9, 1.8 mg | Treatment of moderate to severe vasomotor symptoms associated with the menopause. |
| Esterified estrogens | Menest Neo-Estrone | 0.3, 0.625, 1.25, 2.5 mg 0.3, 0.625, 1.25 mg | 1. Treatment of moderate to severe vasomotor symptoms associated with menopause. 2. Atrophic vaginitis. 3. Kraurosis Vulvae. 4. Female hypogonadism. 5. Female castration. 6. Primary ovarian failure. 7. Breast cancer (for palliation only) in appropriately selected women and men with metastatic disease. 8. Prostatic carcinoma-palliative therapy of advanced disease. |
| Estropipate | Estropipate (generic) Ogen Ortho-est | 0.75, 1.5, 3 mg 0.75, 1.5, 3 mg 0.75, 1.5 mg | 1. Signs and symptoms of naturally occurring or surgically induced estrogen deficiency states associated with menopausal and post- menopausal symptoms, e.g., hot flashes, sleep disturbances and urogenital atrophy. 2. Osteoporosis induced by estrogen deficiency states in conjunction with other pertinent measures. |
| Conjugated equine estrogens (CEE) | Premarin | 0.3, 0.45, 0.625, 0.9, 1.25 mg | 1. Treatment of moderate to severe vasomotor symptoms associated with the menopause. 2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. 3. Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure. 4. Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease. 5. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only). 6. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. |
| Synthetic conjugated estrogens | Cenestin Enjuvia C.E.S Congest PMS-Conjugated | 0.3, 0.45, 0.625, 0.9, 1.25 mg 0.625, 1.25 mg 0.3, 0.625, 0.9, 1.25 0.3, 0.625, 0.9, 1.25, 2.5 mg 0.3, 0.625, 0.9, 1.25 mg | 1. Treatment of moderate to severe vasomotor symptoms associated with the menopause: 0.45mg, 0.625mg, 0.9mg, 1.25mg 2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. 0.3 mg |
| Estrogen-progestin combinations | |||
| CEE, medroxyprogesterone | Prempro Premplus Premphase | 0.3 mg CEE/1.5 mg medroxyprogesterone, 0.45/1.5 mg, 0.625/2.5 mg, 0.625/5 mg 2.5/0.625 mg, 5/0.625 mg 0.625 mg CEE, 5.0 mg progesterone | 1. Treatment of moderate to severe symptoms associated with menopause. 2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. 3. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. |
| 17b-estradiol, norgestimate | Ortho-Prefest | 1 mg estradiol/0.9 mg norgestimate | 1. Treatment of moderate to severe vasomotor symptoms associated with the menopause. 2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribed solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. 3. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered. |
| 17-b estradiol, norethindrone acetate | Activella | 1 mg estradiol/0.5 mg norethindrone acetate | 1.0 mg/0.5mg and 0.5mg/0.1mg 1. Treatment of moderate to severe vasomotor symptoms associated with menopause. 2. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered. 1.0mg/0.5mg 3. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause. When used solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. |
| 17b-estradiol, drospirenone | Angeliq | 1.0 mg estradiol, 0.5 mg drospirenone | 1. Treatment of moderate to severe vasomotor symptoms associated with the menopause. 2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. |
| Ethinyl estradiol, norethindrone acetate | FemHRT | 5 mcg ethinyl estradiol/1 mg norethindrone acetate | 1. Treatment of moderate to severe vasomotor symptoms associated with the menopause. 2. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis. Non-estrogen medications should be carefully considered. |
| Transdermal estrogens | |||
| 17b-estradiol matrix patch | Alora Climara Esclim Vivelle Vivelle-Dot Menostar Estradot Oesclim 17-b estradiol (generic) | 0.025, 0.05, 0.075, 0.1 mg/d 0.025, 0.05, 0.06, 0.075, 0.1 mg/d 0.025, 0.0375, 0.05, 0.075, 0.1 mg/d 0.05, 0.1 mg/d 0.025, 0.0375, 0.05, 0.075, 0.1 mg/d 14 mcg/d 25, 37.5, 50, 75, 100 μg/d 25, 50 μg/day 25, 50, 100 μg/d 0.1, 0.05 mg/d | 1. Treatment of moderate to severe vasomotor symptoms associated with the menopause. 2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. 3. Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure. 4. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered. |
| 17b-estradiol reservoir patch | Estraderm | 0.025, 0.0375, 0.05, 0.075, 0.1 mg/d | 1. Treatment of moderate to severe vasomotor symptoms associated with the menopause. 2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. 3. Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure. 4. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risks of osteoporosis and non-estrogen medications should be carefully considered. |
| 17b-estradiol, norethindrone acetate patch | Combi-Patch Estalis Estalis Sequi Estracomb | 0.05 mg estradiol/0.14 mg norethindrone, 0.05/0.25 mg 140 μg norethindrone acetate/50 μg estradiol-17β per day, 250/50 μg/day 0.05 mg estrogen twice/week (Vivelle 50 patch) for 2 weeks, then 9 or 16 cm2 Estalis patch twice/week for 2 weeks 0.05 mg estrogen twice/week for 2 weeks, then 0.05 mg estrogen + 0.25 mg progesterone for 2 weeks | 1. Treatment of moderate to severe vasomotor symptoms associated with the menopause. 2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. 3. Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure. |
| 17b-estradiol, levonorgestrel patch | Climara Pro | 0.045 mg estradiol/0.015 mg levonorgestrel | Treatment of moderate to severe vasomotor symptoms associated with menopause |
| 17b-estradiol transdermal gel | EstroGel Elestrin Divigel | 1.25 g (0.75 mg estradiol) 0.87 g (0.52 mg estradiol) 0.25, 0.5, 1.0 g (0.25, 0.5, 1.0 mg estradiol) | 1. Treatment of moderate to severe vasomotor symptoms associated with menopause. 2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. |
| Estradiol hemihydrate topical emulsion | Estrasorb | 1.74 g (0.5 mg estradiol) | Estrasorb is indicated for the treatment of moderate to severe vasomotor symptoms associated with menopause. |
| Topical products | |||
| 17b-estradiol vaginal cream | Estrace vaginal cream | 0.1 mg estrogen/g | Treatment of vulvar and vaginal atrophy. |
| CEE cream | Premarin vaginal cream | 0.625 mg estrogen/g | Treatment of atrophic vaginitis and kraurosis vulvae. |
| Esterified estrogen cream | Neo-Estrone vaginal cream | 1 mg estrogen/g | 1. Treatment of menopausal and post menopausal symptoms. 2. Should be prescribed with an appropriate dosage of a progestin for women with intact uteri to prevent endometrial hyperplasia/carcinoma. |
| 17-b estradiol intravaginal ring | Femring Estring | 0.05 mg estradiol, 0.1 mg/d 2 mg (7.5 μg estradiol/day) | 1. Treatment of moderate to severe vasomotor symptoms associated with the menopause. 2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. |
| Estradiol hemihydrate vaginal tablet | Vagifem | 25 μg | Treatment of atrophic vaginitis. |
Hot flashes or flushes defined as any otherwise unexplained sensation of flushing/sweating experienced by the woman being studied. Studies will be included if they measured frequency, severity, presence versus absence, or a combination measure of frequency and severity as either primary or secondary outcomes at baseline, 3 months, and/or the end of the study.
Symptoms such as sleep disturbances/night sweats, mood changes (depression), sexual function, urogenital atrophy, and quality-of-life measures.
Prevention of osteoporosis measured by improvement in bone density and fracture outcomes after at least 1 year of use.
Withdrawals
Withdrawals due to adverse effects
Withdrawals due to specific adverse effects
Atypical bleeding; endometrial hypertrophy
Nausea and vomiting
Breast tenderness
Headaches
Weight changes
Dizziness
Thrombosis (including relationship to estradiol levels)
Cardiovascular events
Rash and pruritus
Cholecystitis
Effects on the liver
Cardiovascular events
Breast cancer
Thrombosis
Cholecystitis
Ovarian cancer
Endometrial cancer
Symptoms: Double-blind, randomized controlled trials of at least 3 months duration of one hormone therapy preparation versus another hormone therapy preparation or versus placebo.
Prevention of osteoporosis: Double-blind or open, randomized controlled trials of postmenopausal women who are treated for at least 1 year versus another hormone therapy preparation or versus placebo.
Good quality systematic reviews and meta-analyses.
