There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be taken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal genital bleeding.
Estrogen-alone therapy should not be used for the prevention of cardiovascular disease. The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (0.625 mg) alone, relative to placebo.
Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease. The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (0.625 mg) combined with medroxyprogesterone (2.5 mg), relative to placebo.
The Women's Health Initiative (WHI) estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.
Estrogen-alone therapy should not be used for the prevention of dementia. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years or older during 5.2 years of treatment with daily conjugated estrogens (0.625 mg) alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.
Estrogen plus progestin therapy should not be used for the prevention of dementia. The WHIMS estrogen plus progestin ancillary study of WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.
Risk vs benefits:
In the absence of comparable data, these risks should be assumed to be similar for other doses of conjugated estrogens (with or without medroxyprogesterone acetate) and other dosage forms of estrogens (with or without progestins). Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Estrace: 0.1 mg/g (42.5 g) [contains edetate disodium, methylparaben, propylene glycol]
Generic: 0.1 mg/g (42.5 g)
Imvexxy Maintenance Pack: 4 mcg (8 ea); 10 mcg (8 ea) [contains alcohol, usp, fd&c red #40]
Imvexxy Starter Pack: 4 mcg (18 ea); 10 mcg (18 ea) [contains alcohol, usp, fd&c red #40]
Ring, Vaginal, as base:
Estring: 2 mg (1 ea)
Tablet, Vaginal, as base:
Vagifem: 10 mcg [contains corn starch]
Yuvafem: 10 mcg [contains corn starch]
Generic: 10 mcg
Mechanism of Action
In studies for vulvar and vaginal atrophy in postmenopausal women, local estrogens have been shown to reduce vaginal pH levels and mature the vaginal and urethral mucosa after 12 weeks of therapy, thereby improving vaginal dryness and mucosal atrophy.
Average serum estradiol concentrations (Cavg) vary by product
Vaginal: Vaginal absorption is typically low; any contribution to circulating estradiol concentrations via systemic absorption does not exceed normal postmenopausal ranges (Ulrich 2010; Weisberg 2005).
Estring: Average steady state serum concentrations decrease from 11.2 pg/mL at 48 hours to 8 pg/mL at 12 weeks
Imvexxy: Cavg: 3.6 pg/mL (4 mcg dose); 4.6 pg/mL (10 mcg dose) following once daily dose for 14 days
Vagifem: Cavg: 10.9 pg/mL on day 1, 5.5 pg/mL on day 83
Widely distributed; high concentrations in the sex hormone target organs
Hepatic; partial metabolism via CYP3A4 enzymes; estradiol is reversibly converted to estrone and estriol. Sulfate conjugates are the primary form found in postmenopausal women.
Primarily urine (as estradiol, estrone, estriol and their glucuronide and sulfate conjugates)
Time to Peak
Estring: 0.5 to 1 hour
Bound to sex hormone-binding globulin and albumin
Use: Labeled Indications
Vulvar and vaginal atrophy associated with menopause: Treatment of moderate-to-severe vulvar and vaginal atrophy associated with menopause
Note: The International Society for the Study of Women’s Sexual Health and The North American Menopause Society have endorsed the term genitourinary syndrome of menopause (GSM) as new terminology for vulvovaginal atrophy. The term GSM encompasses all genital and urinary signs and symptoms associated with a loss of estrogen due to menopause Portman 2014.
Angioedema, anaphylactic reaction, or hypersensitivity to estradiol or any component of the formulation; undiagnosed abnormal genital bleeding; DVT or PE (current or history of); active or history of arterial thromboembolic disease (eg, stroke, MI); breast cancer (known, suspected, or history of); estrogen-dependent tumor (known or suspected); hepatic impairment or disease; known protein C, protein S, antithrombin deficiency, or other known thrombophilic disorders; pregnancy.
Canadian labeling: Additional contraindications (not in US labeling): Endometrial hyperplasia; partial or complete loss of vision due to ophthalmic vascular disease; breastfeeding; porphyria.
Documentation of allergenic cross-reactivity for estrogens is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Dosage and Administration
General dosing guidelines: When treating symptoms of menopause, hormone therapy should be evaluated routinely for appropriate dose, duration, and route of administration for each individual patient based on treatment goals, risk factors, and overall health (NAMS 2017). Combined estrogen/progestin therapy is indicated for postmenopausal persons with a uterus to decrease the risk of endometrial cancer. Individuals who have had a hysterectomy generally do not need a progestin; however, one may be needed if there is a history of endometriosis. Adjust dose based on patient response.
Vulvar and vaginal atrophy associated with menopause: Intravaginal:
Vaginal cream (Estrace): Insert 2 to 4 g daily intravaginally for 1 to 2 weeks, then gradually reduce to 1/2 the initial dose for 1 to 2 weeks, followed by a maintenance dose of 1 g 1 to 3 times per week.
Vaginal insert (Imvexxy): Initial: Insert 4 mcg once daily intravaginally for 2 weeks, then gradually reduce to 1 insert twice weekly, every 3 to 4 days (eg, Monday and Thursday).
Vaginal ring (Estring): 2 mg intravaginally; following insertion, ring should remain in place for 90 days
Vaginal tablet (Vagifem): Initial: Insert 1 tablet (10 mcg) once daily for 2 weeks; Maintenance: Insert 1 tablet twice weekly
Refer to adult dosing.
Vaginal cream: Gently insert applicator filled with vaginal cream deeply into vagina. Cleanse applicator after use with warm water and mild soap (do not boil or use hot water).
Vaginal insert: Insert with smaller end up approximately 2 inches into the vaginal canal at the same time each day.
Vaginal ring: Insert as deeply as possible into the upper one-third of the vagina; exact positioning is not critical for efficacy; however, patient should not feel anything once inserted. In case of discomfort, ring should be gently pushed further into vagina. Straining at defecation may make the ring move down in the lower part of the vagina; if this occurs, push up ring with finger. If ring is expelled prior to 90 days, it may be rinsed in lukewarm water and reinserted. If vaginal infection, ulceration, erosion, or adherence to vaginal wall develops, remove ring and reinsert only after healing is complete.
Vaginal tablet: Insert tablet with supplied applicator at the same time each day. Once inserted, press plunger until fully depressed, then remove applicator and discard. If tablet comes out of applicator prior to insertion, do not replace; use a new tablet filled applicator instead (if the tablet has fallen out of applicator but still remains in the package, it can be reinserted in the applicator for use). Local abrasion caused by the vaginal applicator has been reported in women with severely atrophic vaginal mucosa.
Vaginal cream: Store at room temperature; protect from temperatures in excess of 40°C (104°F).
Vaginal insert: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF).
Vaginal ring: Store at 15°C to 25°C (59°F to 77°F).
Vaginal tablet: Store at 25°C (77°F); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF). Do not refrigerate.
Ajmaline: Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy
Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Avoid combination
Anthrax Immune Globulin (Human): Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human). Monitor therapy
Anticoagulants: Estrogen Derivatives may diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Ascorbic Acid: May increase the serum concentration of Estrogen Derivatives. Monitor therapy
Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
C1 inhibitors: Estrogen Derivatives may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy
Chenodiol: Estrogen Derivatives may diminish the therapeutic effect of Chenodiol. Management: Monitor clinical response to chenodiol closely when used together with any estrogen derivative. Monitor therapy
CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy
Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). Monitor therapy
Cosyntropin: Estrogen Derivatives may diminish the diagnostic effect of Cosyntropin. Management: Discontinue estrogen containing drugs 4 to 6 weeks prior to cosyntropin (ACTH) testing. Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Estrogen Derivatives. Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Estrogen Derivatives. Monitor therapy
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Dantrolene: Estrogen Derivatives may enhance the hepatotoxic effect of Dantrolene. Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Dehydroepiandrosterone: May enhance the adverse/toxic effect of Estrogen Derivatives. Avoid combination
Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy
Exemestane: Estrogen Derivatives may diminish the therapeutic effect of Exemestane. Avoid combination
Hemin: Estrogen Derivatives may diminish the therapeutic effect of Hemin. Avoid combination
Herbs (Estrogenic Properties): May enhance the adverse/toxic effect of Estrogen Derivatives. Monitor therapy
Hyaluronidase: Estrogen Derivatives may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving estrogens (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification
Immune Globulin: Estrogen Derivatives may enhance the thrombogenic effect of Immune Globulin. Monitor therapy
Indium 111 Capromab Pendetide: Estrogen Derivatives may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Avoid combination
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
LamoTRIgine: Estrogen Derivatives may decrease the serum concentration of LamoTRIgine. Monitor therapy
Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination
Lenalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Lenalidomide. Monitor therapy
Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification
Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification
Mivacurium: Estrogen Derivatives may increase the serum concentration of Mivacurium. Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the thrombogenic effect of Estrogen Derivatives. Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase the serum concentration of Estrogen Derivatives. Monitor therapy
Ospemifene: Estrogen Derivatives may enhance the adverse/toxic effect of Ospemifene. Estrogen Derivatives may diminish the therapeutic effect of Ospemifene. Avoid combination
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy
Pomalidomide: May enhance the thrombogenic effect of Estrogen Derivatives. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations. Consider therapy modification
Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy
ROPINIRole: Estrogen Derivatives may increase the serum concentration of ROPINIRole. Monitor therapy
Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Somatropin: Estrogen Derivatives may diminish the therapeutic effect of Somatropin. Shown to be a concern with oral hormone replacement therapy in postmenopausal women. Management: Monitor for reduced growth hormone efficacy. A larger somatropin dose may be required to reach treatment goal. This interaction does not appear to apply to non-orally administered estrogens (e.g., transdermal, vaginal ring). Consider therapy modification
Succinylcholine: Estrogen Derivatives may increase the serum concentration of Succinylcholine. Monitor therapy
Thalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Thalidomide. Monitor therapy
Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy
Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Monitor therapy
Tipranavir: Estrogen Derivatives may enhance the dermatologic adverse effect of Tipranavir. The combination of tipranavir/ritonavir and ethinyl estradiol/norethindrone was associated with a high incidence of skin rash. Tipranavir may decrease the serum concentration of Estrogen Derivatives. Management: Women using hormonal contraceptives should consider alternative, non-hormonal forms of contraception. Consider therapy modification
TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Ursodiol: Estrogen Derivatives may diminish the therapeutic effect of Ursodiol. Monitor therapy
Reduced response to metyrapone test.
>10%: Central nervous system: Headache (4% to 13%)
1% to 10%:
Central nervous system: Insomnia (4%), stress (2%), migraine
Endocrine & metabolic: Hot flash (2%)
Gastrointestinal: Diarrhea (5%), abdominal pain (4%), nausea (3%)
Genitourinary: Vulvovaginal pruritus (8%), genital candidiasis (6% to 8%), leukorrhea (7%), vaginitis (5%), vaginal discomfort (≤5%), vaginal pain (≤5%), bacterial vaginosis (4%; asymptomatic), vaginal hemorrhage (4%), urinary tract infection (2%), mastalgia (1%)
Hypersensitivity: Hypersensitivity (1%)
Neuromuscular & skeletal: Back pain (6% to 7%), arthritis (4%), arthralgia (3%), skeletal pain (2%)
Respiratory: Upper respiratory tract infection (5%), sinusitis (4%), flu-like symptoms (3%), pharyngitis (1%)
Frequency not defined: Dermatologic: Allergic skin rash
<1%, postmarketing and/or case reports: Abdominal distention, arthropathy, breast engorgement, breast hypertrophy, decreased libido, deep vein thrombosis, depression, dizziness, endometrial carcinoma, endometrial hyperplasia, erythematous rash, exacerbation of migraine headache, excoriation of skin (vaginal), fluid retention, genital edema, genital pruritus, increased plasma estrogen concentration, intermenstrual bleeding, intestinal obstruction (ring), malignant neoplasm of breast, mechanical complication of genitourinary device (ring adherence to vaginal wall), nervousness, pruritic rash, pruritus, pruritus ani, skin rash, thrombophlebitis, urethral disease, urinary frequency, vaginal discharge, vaginal disease (erosion), vaginal ulcer, vaginismus, visual disturbance, vomiting, vulvar disease, vulvar swelling, vulvovaginal burning, weight changes, weight gain
Concerns related to adverse effects:
- Anaphylaxis: Anaphylaxis requiring emergency medical management has been reported following oral estrogen administration and may develop at any time during therapy. Angioedema involving the face, feet, hands, larynx, and tongue has also been reported.
- Breast cancer: [US Boxed Warning]: Based on data from the Women’s Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in postmenopausal women using conjugated estrogens (CE) in combination with medroxyprogesterone acetate (MPA). Observational studies noted this risk declines once therapy is discontinued. The WHI study did not observe an increased risk of invasive breast cancer in women with a hysterectomy using CE alone. The risk of breast cancer in postmenopausal patients on hormone therapy may depend upon type of estrogen and/or progestin, dose, timing of therapy initiation, duration of therapy, route of administration, and individual patient characteristics (AACE/ACE [Cobin 2017]; NAMS 2017). Hormone therapy may be associated with increased breast density (NAMS 2017); an increase in abnormal mammogram findings requiring further evaluation has been reported with estrogen alone or in combination with progestin therapy. Estrogen use may lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs. Due to increased risks, estrogens are contraindicated in patients with known or suspected breast cancer; however, in appropriately selected patients, low-dose vaginal estrogen that has limited systemic absorption may be considered for the treatment of GSM when non-hormonal treatments are ineffective (ACOG 659 2016; ES [Stuenkel 2015]; NAMS 2017).
- Dementia: [US Boxed Warning]: Estrogens with or without progestin should not be used to prevent dementia. In the Women’s Health Initiative Memory Study (WHIMS), an increased incidence of probable dementia was observed in women ≥65 years of age taking CE alone or in combination with MPA. Because the WHI memory studies were conducted in women ≥65 years of age, it is unknown if these findings apply to younger postmenopausal women. However, hormone therapy is not recommended at any age to prevent or treat cognitive decline or dementia (AACE [Goodman 2011]; NAMS 2017).
- Endometrial cancer: [US Boxed Warning]: The use of unopposed estrogen in women with a uterus is associated with an increased risk of endometrial cancer. The addition of a progestin to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer. Adequate diagnostic measures, including endometrial sampling if indicated, should be performed to rule out malignancy in postmenopausal women with undiagnosed abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. The risk of endometrial cancer appears to be dose and duration dependent, greatest with use ≥5 years, and may persist following discontinuation of therapy. The use of a progestin is not generally required when low doses of estrogen are used locally for vaginal atrophy, although long-term data (>1 year) supporting this recommendation are lacking (NAMS 2013; NAMS 2017). The increased risks of cancer outcomes associated with systemic estrogen or estrogen/progestin therapy may not be the same with low dose vaginal estrogen (Crandall 2018). When non-hormonal treatments are not effective for GSM, low-dose vaginal therapy that has limited systemic absorption may be considered in appropriately selected patients with endometrial cancer (ES [Stuenkel 2015]; NAMS 2017).
- Endometriosis: Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestin in women with residual endometriosis posthysterectomy.
- Lipid effects: Estrogen compounds are generally associated with lipid effects such as increased HDL-cholesterol and decreased LDL-cholesterol. Triglycerides may also be increased in women with preexisting hypertriglyceridemia; discontinue use if pancreatitis occurs.
- Ovarian cancer: Available information related to the use of menopausal estrogen or estrogen/progestin therapy and risk of ovarian cancer is inconsistent. If an association is present, the absolute risk is likely rare and may be influenced by duration of therapy (AACE [Goodman 2011]; ES [Stuenkel 2015]; NAMS 2017).
- Retinal vascular thrombosis: Estrogens may cause retinal vascular thrombosis; discontinue if migraine, loss of vision, proptosis, diplopia, or other visual disturbances occur; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.
- Asthma: Use caution in patients with asthma; may exacerbate disease.
- Carbohydrate intolerance: May impair glucose tolerance; use caution in patients with diabetes. Prior to therapy, consider age, cardiovascular and metabolic risk factors in patients previously diagnosed with diabetes (AACE/ACE [Cobin 2017]).
- Cardiovascular disease: [US Boxed Warning]: Estrogens with or without progestin should not be used to prevent cardiovascular disease. Using data from the Women’s Health Initiative (WHI) studies, an increased risk of deep vein thrombosis (DVT) and stroke has been reported with CE and an increased risk of DVT, stroke, pulmonary emboli (PE) and myocardial infarction (MI) has been reported with CE with MPA in postmenopausal women 50 to 79 years of age. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of venous thromboembolism (VTE). Risk factors should be managed appropriately; discontinue use immediately if adverse cardiovascular events occur or are suspected. Due to possible lower risk of thrombotic events, transdermal administration may be preferred for treating vasomotor symptoms of menopause in patients with risk factors for cardiovascular disease (AACE/ACE [Cobin 2017]; ACOG 556 2013; ES [Stuenkel 2015]). Use is contraindicated in women with active DVT, PE, arterial thromboembolic disease (stroke and MI), or a history of these conditions. The increased risks of cardiovascular outcomes associated with systemic estrogen or estrogen/progestin therapy may not be the same with low dose vaginal estrogen (Crandall 2018).
- Diseases exacerbated by fluid retention: Use with caution in patients with diseases which may be exacerbated by fluid retention, including cardiac or renal dysfunction.
- Epilepsy: Use caution with epilepsy; may exacerbate disease.
- Gallbladder disease: Use of postmenopausal estrogen may be associated with an increased risk of gallbladder disease requiring surgery.
- Hepatic impairment: Estrogens are poorly metabolized in patients with hepatic dysfunction. Use caution with a history of cholestatic jaundice associated with prior estrogen use or pregnancy. Discontinue if jaundice develops or if acute or chronic hepatic disturbances occur. Use is contraindicated with hepatic impairment or disease.
- Hepatic hemangiomas: Use with caution in patients with hepatic hemangiomas; may exacerbate disease.
- Hereditary angioedema: Exogenous estrogens may exacerbate angioedema symptoms in women with hereditary angioedema.
- Hypoparathyroidism: Use caution in patients with hypoparathyroidism; estrogen-induced hypocalcemia may occur.
- Migraine: Use caution with migraine; may exacerbate disease.
- Porphyria: Use with caution in patients with porphyria; may exacerbate disease.
- SLE: Use with caution in patients with SLE; may exacerbate disease.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
- Thyroid replacement therapy: Estrogens may increase thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels. Women on thyroid replacement therapy may require higher doses of thyroid hormone while receiving estrogens.
- Pediatric: These products are only approved for use in postmenopausal women.
- Surgical patients: Whenever possible, estrogens should be discontinued at least 4 to 6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
Dosage form specific issues:
- Vaginal ring: Use may not be appropriate in women with narrow or short vagina, vaginal stenosis, vaginal infections, prolapse, or other conditions that may increase the risk of vaginal irritation, or ulceration. Ring should be removed in case of infection, ulceration, erosion, or adherence to vaginal wall; do not reinsert until healing is complete.
- Vaginal tablet: Local applicator-induced abrasion may occur in women with severely atrophic vaginal mucosa.
- Duration of use: Extended use of menopausal hormone therapy may be considered for persistent vasomotor symptoms or issues related to quality of life. Menopausal hormonal therapy does not need to be routinely discontinued in women >60 years of age and may continue in women >65 years of age after clinical evaluation and discussion of benefits and risks of treatment. Annual exams should be performed with a review of comorbidities; possible adjustments to safer lower-dose and/or route of administration should be discussed (ACOG 565 2013; NAMS 2017).
- Genitourinary syndrome of menopause (GSM): Low-dose vaginal estrogen is preferred over systemic therapy for GSM in the absence of vasomotor symptoms due to increased efficacy and decreased systemic effects (eg, cardiovascular effects, cancer risk) (Crandall 2018; NAMS 2013; NAMS 2017).
- Laboratory changes: The use of estrogens and/or progestins may change the results of some laboratory tests (eg, coagulation factors, lipids, glucose tolerance, binding proteins). The dose, route, and the specific estrogen/progestin influence these changes.
- Risks vs benefits: When used for the relief of menopausal symptoms, the benefit-risk of hormone therapy is most favorable if started in patients who have no contraindications to therapy, are <60 years of age, within 10 years of menopause onset, have a favorable lipid profile, and do not have the factor V Leiden genotype or metabolic syndrome. Risk factors for cardiovascular disease should also be considered when evaluating therapy and route of administration (AACE/ACE [Cobin 2017]; NAMS 2017). [US Boxed Warning]: Estrogens with or without progestin should be used for the shortest duration possible at the lowest effective dose consistent with treatment goals and risks for the individual woman. Patients should be reevaluated as clinically appropriate to determine if treatment is still necessary. Available data related to treatment risks are from Women’s Health Initiative (WHI) studies, which evaluated oral CE 0.625 mg with or without MPA 2.5 mg relative to placebo in postmenopausal women. Other combinations and dosage forms of estrogens and progestins were not studied. Outcomes reported from clinical trials using CE with or without MPA should be assumed to be similar for other doses and other dosage forms of estrogens and progestins until comparable data becomes available. Systemic absorption occurs following vaginal use; warnings, precautions, and adverse events observed with oral therapy should be considered.
Prior to therapy, baseline risk for breast cancer and CVD. During therapy, age appropriate breast and pelvic exams; blood pressure; unscheduled bleeding lasting >6 months for endometrial pathology (sooner in patients who are obese, diabetic, or have a history of endometrial cancer); serum triglycerides (2 weeks after starting therapy in patients with baseline level >200 mg/dL); TSH. Efficacy beginning 1 to 3 months after starting therapy, then every 6 to 12 months as appropriate. Duration of treatment should be evaluated at least annually (ES [Stuenkel 2015]).
Note: Monitoring of FSH and serum estradiol is not useful when managing symptoms associated with GSM.
Use is contraindicated during pregnancy.
In general, the use of estrogen and progestin as in combination hormonal contraceptives has not been associated with teratogenic effects when inadvertently taken early in pregnancy.
What is this drug used for?
- It is used to treat vaginal irritation and dryness caused by menopause, urinary signs caused by change of life, and vaginal pain during sex caused by changes that happen with menopause. It may be given to you for other reasons. Talk with the doctor.
Frequently reported side effects of this drug
- Hair loss
- Tender breasts
- Abdominal pain
- Abdominal cramps
- Back pain
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- High calcium like weakness, confusion, fatigue, headache, nausea and vomiting, constipation, or bone pain
- Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
- Gallstones like pain in the upper right abdominal area, right shoulder area, or between the shoulder blades; yellow skin; or fever with chills
- Severe cerebrovascular disease like change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes
- Low thyroid level like constipation; difficulty handling heat or cold; memory problems; mood changes; or burning, numbness, or tingling feeling
- Severe headache
- Severe dizziness
- Passing out
- Pelvic pain
- Vaginal irritation
- Abnormal vaginal bleeding
- Vaginal pain, itching, and discharge
- Lump in breast
- Breast soreness or pain
- Nipple discharge
- Mood changes
- Trouble with memory
- Bulging eyes
- Contact lens discomfort
- Vision changes
- Weight gain
- Difficulty breathing
- Vaginal pain
- Vaginal edema
- Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood
- Toxic shock syndrome like diarrhea, dizziness, passing out, severe muscle pain, nausea, vomiting, or sunburn like rash
- Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.