Estradiol (estradiol)

Dosage of estradiol, estradiol acetate, estradiol cypionate, estradiol valerate, and ethinyl estradiol must be individualized according to the condition being treated and the tolerance and therapeutic response of the patient. To minimize the risk of adverse effects, the lowest possible effective dosage should be used. When short-term estrogen therapy is indicated (e.g., for the management of vasomotor symptoms associated with menopause; vulvar and vaginal atrophy), therapy should be discontinued as soon as possible; attempts to reduce dosage or discontinue the drug should be made at 3- to 6-month intervals. Because of the potential increased risk of cardiovascular events, breast cancer, and venous thromboembolic events, estrogen and estrogen/progestin therapy should be limited to the lowest effective doses and shortest duration of therapy consistent with treatment goals and risks for the individual woman. Estrogen and estrogen/progestin therapy should be periodically reevaluated.

Estrogen therapy is administered continuously or cyclically. While estrogen therapy alone may be appropriate in women who have undergone a hysterectomy, many clinicians currently recommend that a progestin be added to estrogen therapy in women with an intact uterus. Addition of progestin therapy for 10 or more days of a cycle of estrogen administration or daily with estrogen in a continuous regimen reduces the incidence of endometrial hyperplasia and the attendant risk of endometrial carcinoma in women with an intact uterus. Morphologic and biochemical studies of the endometrium suggest that 10-13 days of progestin are needed to provide maximum maturation of the endometrium and to eliminate any hyperplastic changes. The manufacturer of Menostar(R) recommends that women with an intact uterus receive a progestin for 14 days every 6-12 months. When a progestin is used in conjunction with an estrogen, the usual precautions associated with progestin therapy should be observed. Clinicians prescribing progestins should be aware of the risks associated with these drugs and the manufacturers' labeling should be consulted. The choice and dosage of a progestin may be important factors in minimizing adverse effects.

When long-acting parenteral preparations are used in the management of conditions associated with estrogen deficiency, the drugs are usually administered once every 3-4 weeks.

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There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Selected Vaginal Estrogens/Selected Anti-Aromatase Agents

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aromatase inhibitors(1-6) and inactivators(7-10) treat breast cancer by inhibiting estrogen synthesis therefore lowering serum estrone and estradiol levels. In postmenopausal women, androgens are metabolized to estrogens via the primary pathway of the aromatase enzyme.

CLINICAL EFFECTS: Concurrent administration of estrogen may decrease the effectiveness of aromatase inhibitors.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian,(1) UK,(2) and US(3) manufacturers of anastrozole state that estrogen containing therapies should not be used during anastrozole therapy. The Australian,(7) Canadian,(8) UK,(9) and US(10) manufacturers of exemestane state that exemestane should not be administered with estrogen containing therapies. The Canadian(4) and UK(5) manufacturer of letrozole state that estrogen containing therapies should be avoided during letrozole therapy. A clinical consensus from the American College of Obstetricians and Gynecologists states that low-dose vaginal estrogen may be used in patients on aromatase inhibitors who have failed non-hormonal treatment after shared decision making.(11) The Fifth International Consultation on Sexual Medicine also made recommendations on treatment of genitourinary syndrome of menopause (GSM). They state that local estrogen therapy cannot be a first line treatment for GSM in women on adjuvant hormone therapy but low- and ultra-low dose local estrogens can be used after trying non-hormonal approaches, and after a discussion of risks and benefits with the patient.(12)

DISCUSSION: Many breast cancers have estrogen receptors and their growth can be stimulated by estrogen. Anastrozole is a potent and selective non-steroidal aromatase inhibitor that lowers serum estradiol levels. Concurrent use of estrogen may diminish the effects of anastrozole.(1-3) Exemestane is a steroidal aromatase inactivator that lowers serum estradiol levels. Concurrent use of estrogen may diminish the effects of exemestane.(7-10) Several meta-analyses and systematic reviews have concluded that vaginal estrogens are likely to be safe in women on aromatase inhibitors. Nevertheless, they recommend using vaginal estrogens after a trial with nonhormonal therapies has failed and following shared decision making including a discussion with the patient of the risks and benefits of treatment.(13-16)

There are no moderate interactions for this drug.

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• Endometrial carcinoma

• Carcinoma of breast
• Disease of liver
• Estrogen-dependent neoplasm
• Hereditary angioedema
• Malignant neoplasm of the ovary
• Neoplasm of female genital organ

• Diabetes mellitus
• Endometriosis
• Gallbladder disease
• Hepatic porphyria
• Hypertension
• Hypertriglyceridemia
• Hypothyroidism
• Mammography abnormal
• Migraine
• Seizure disorder
• Systemic lupus erythematosus
• Tobacco smoker
• Uterine leiomyoma

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Rare or Very Rare

• Acute myocardial infarction
• Anaphylaxis
• Angioedema
• Cerebrovascular accident
• Deep venous thrombosis
• Dementia
• Endometrial carcinoma
• Endometrial hyperplasia
• Gallbladder obstruction
• Hypercalcemia
• Hypersensitivity drug reaction
• Hypertension
• Hypertriglyceridemia
• Malignant neoplasm of the ovary
• Neoplasm of breast
• Precocious puberty
• Pulmonary thromboembolism
• Retinal thrombosis
• Thromboembolic disorder
• Uterine leiomyoma

More Frequent

• Abdominal distension
• Back pain
• Headache disorder
• Infection
• Mastalgia
• Vulvovaginal candidiasis
• Weight gain

Less Frequent

• Acne vulgaris
• Candidiasis
• Cramps
• General weakness
• Gynecomastia
• Libido changes
• Migraine
• Pelvic pain
• Pruritus of skin
• Vaginitis

Rare or Very Rare

• Abdominal pain with cramps
• Abnormal vaginal bleeding
• Body fluid retention
• Chloasma
• Depression
• Diarrhea
• Dysmenorrhea
• Genital organ pruritus
• Insomnia
• Nipple discharge
• Urticaria
• Vaginal discharge
• Vaginal irritation

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