Estradiol Adverse Reactions

abdominal pain
acne vulgaris
alopecia
amenorrhea
anorexia
anxiety
biliary obstruction
breakthrough bleeding
breast discharge
breast enlargement
candidiasis
cervical dysplasia
cervicitis
cholecystitis
cholelithiasis
cholestasis
depression
diarrhea
diplopia
dysmenorrhea
edema
elevated hepatic enzymes
emotional lability
endometrial hyperplasia
erythema
erythema nodosum
fatigue
fluid retention
galactorrhea
gingivitis
gynecomastia
headache
hepatitis
hepatoma
hyperglycemia
hypertension
hypocalcemia
impaired cognition
injection site reaction
insomnia
jaundice
keratoconus
libido decrease
libido increase
maculopapular rash
mastalgia
melasma
menorrhagia
migraine
myocardial infarction
nausea/vomiting
optic neuritis
pancreatitis
peliosis hepatis
pruritus
pulmonary embolism
retinal thrombosis
secondary malignancy
stroke
teratogenesis
thromboembolism
thrombosis
urinary incontinence
urticaria
vaginal bleeding
vaginitis
weight gain

Estradiol Adverse Reactions

Many of the serious adverse reactions reported with the use of estrogens are similar to those reported with the use of estrogen-containing oral contraceptives. However, the risk of these serious events are typically lower in the postmenopausal use of these drugs, presumably due to the comparatively low estrogen doses used in this population for hormone replacement therapy versus oral contraceptive use in premenopausal women. The use of estrogens for other indications, like cancer, require higher estrogen doses and thus may be associated with a higher incidence of serious estrogen-related side effects.

A variety of endocrine and urogenital effects can occur during therapy with estradiol or ethinyl estradiol. Changes in sexuality include libido increase or libido decrease. Positive changes in libido may occur as a result of improvements in vulvar and vaginal atrophy in postmenopausal women. Vaginal discharge, vaginal irritation, vaginal candidiasis, vaginitis, cervicitis, or changes in cervical erosion may appear. Estrogens may cause enlargement of uterine leiomyomatas (fibroids), if present. Dysmenorrhea is reported in up to 15% of women on combination estrogen-progestin HRT regimens. Alterations in bleeding patterns are common in women with an intact uterus and include breakthrough bleeding or spotting, decreased menses duration, or menorrhagia. In post-menopausal women, changes in uterine bleeding patterns will usually taper and stabilize within 3 - 6 months of beginning cyclic or continuous HRT combinations. Amenorrhea is desirable in many postmenopausal women and not considered to be an adverse effect of estrogen therapy. However, when estrogens are used for the treatment of hypogonadism in premenopausal females, continued amenorrhea may signal a lack of response to estrogen therapy. Unusual vaginal bleeding or spotting that persists beyond 6 months in any woman on estrogen therapy should be evaluated by a health care professional. Women who take estrogens should follow current recommendations for annual pelvic examinations and also receive regular Papanicolaou smears to detect cervical dysplasia.

Breast changes that may occur with estrogen therapy include mastalgia and breast tenderness, which occur in up to 20% of women taking estradiol. Women on estrogen therapy may also complain of breast enlargement or galactorrhea. Gynecomastia may occur in men on estrogen therapy. Patients should report breast changes, lumps, or breast discharge to their health care professionals, and follow current recommendations for routine mammography and clinical breast examinations.

Gastrointestinal effects from estradiol administration are relatively limited. Nausea/vomiting occurs in approximately 3% of patients receiving estradiol at normally prescribed doses. Abdominal bloating or cramping, diarrhea, or anorexia can occur rarely with estrogen therapy. Nevertheless, abdominal pain can indicate biliary obstruction, hepatitis (and elevated hepatic enzymes), peliosis hepatis, hepatoma, hepatic hemangioma enlargement, or pancreatitis. Oral estrogens enhance hepatic lipoprotein uptake and inhibit bile acid synthesis, resulting in increased concentration of cholesterol in the bile which can lead to cholestasis and cholelithiasis. Gallbladder disease and cholecystitis are twice as frequent in women taking oral HRT compared with controls. Similar increases in gallbladder disease have not been reported with transdermally administered estradiol, perhaps due to the fact that estradiol does not appear to increase saturation of cholesterol in the bile when administered by this route. Patients with familial hyperlipoproteinemia may be at greater risk of pancreatitis while on estrogen therapy, which may greatly increase their serum triglycerides. While most case-control studies have shown a relationship between oral contraceptives and the incidence of benign hepatoma and hepatocellular cancer, no such evidence exists at this time for this effect if estrogens are used in postmenopausal replacement regimens. The incidence of hepatoma or liver cancer is expected to be extremely rare. Estrogens should be discontinued in any patient developing jaundice or severe abdominal pain, and the patient should be evaluated.

Thromboembolism and thrombus formation are occasional, serious adverse reactions to estrogen therapy, and may include myocardial infarction, deep venous thrombosis, pulmonary embolism, or stroke. A positive association has been noted between estrogen dosage and thrombotic disorders. Smoking appears to greatly increase the risk of thrombotic events, and women on estrogens should be advised not to smoke. Since 1970, at least 15 studies have evaluated the effect of estrogen use on stroke risk in women. Some of these studies showed a slightly increased risk for stroke in estrogen recipients while other studies showed a decreased risk. One analysis calculated the pooled estimate of the relative risk for stroke in estrogen recipients to be 0.96. In the Women’s Health Initiative (WHI) Trial, an increase in the incidence of strokes were observed in both the estrogen-alone and the estrogen-progestin sub-studies when the active treatment groups were compared to placebo groups. While the details from the estrogen-alone sub-study are preliminary, in the estrogen-progestin sub-study, women in the active treatment group had 8 more strokes per year for every 10,000 women than those taking placebo; this increase in risk was observed after the first year and persisted. In addition, in the estrogen-progestin sub-study of WHI, an increased risk of coronary heart disease (CHD) events (defined as non-fatal MI and CHD death) was observed with estrogen-progestin HRT compared to placebo. The increase in risk was observed in year one and persisted. In postmenopausal women with documented cardiac disease, a controlled clinical trial (i.e., HERS trial) demonstrated no cardiovascular benefit to using estrogen-progestin HRT as secondary prevention. During an average follow-up of 4.1 years, treatment did not reduce the overall rate of CHD events in postmenopausal women with established coronary artery disease. There were more CHD events in the HRT-treated group than in the placebo group in year 1, but not during the subsequent years. Over two thousand women from the original HERS trial agreed to participate in an open label extension of HERS, known as HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the estrogen-progestin HRT group and the placebo group in HERS, HERS II, and overall. In men treated with estrogen for palliation of prostate and breast cancer, estrogens have increased the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. In the WHI trial, an increase in VTE has been observed in women receiving estrogen compared to placebo. In the estrogen-progestin sub-study of WHI, a 2-fold greater rate of VTE, including DVT and PE, was observed with combined HRT compared to placebo. The increase in VTE risk was observed during the first year and persisted.

Estrogens can cause sodium and fluid retention, resulting in peripheral edema or mild weight gain. They should be prescribed cautiously to patients in whom edema formation would be detrimental. In addition, estrogens can slightly increase blood pressure, occasionally causing hypertension. In the PEPI trial, postmenopausal women 45 - 65 years of age randomized to any hormone replacement therapy regimen experienced increases in both systolic and diastolic blood pressure of 3 - 5% after the first year of treatment, but the increases were not statistically different from placebo. Per the manufacturers, estradiol preparations do not appear to cause significant blood pressure elevations at recommended doses.

The relationship of headache, specifically migraine headache, and the administration of estrogens is not clearly defined. A number of changes can occur when a woman initiates HRT and include 1) migraines can appear for the first time, 2) a change in frequency, severity and duration of migraine headaches may be seen, or 3) an improvement or decrease in the occurrence of migraine headaches. Such adverse events are not frequent. When initiating estrogens an individual’s headache pattern should be observed and, if migraines worsen, consider discontinuing therapy.

Emotional lability or nervous system changes occur in some women taking hormonal replacement therapy. These changes can include mental depression, anxiety, fatigue, dizziness, or insomnia. Women with a history of depression may need special monitoring. If significant depression occurs, the hormone replacement therapy should be discontinued.

Estrogens can cause a variety of dermatological reactions. Melasma, in the form of tan or brown patches, may develop on the forehead, cheeks, temples and upper lip. These patches may persist after the drug is discontinued. Estradiol transdermal systems may cause localized erythema, pruritus, rash, or urticaria in up to 5% of patients. Redness and irritation at the application site is more common. Estradiol topical emulsion has been associated with a 5% rate of pruritus in clinical trials. Estradiol cypionate or valerate injections may cause an injection site reaction which may include erythema and mild pain, and rarely may cause sterile abscess. Other dermatologic reactions to estrogens are infrequent and include alopecia, maculopapular rash, erythema nodosum, pruritus, or other erythematous eruptions. In some cases estrogens may induce or aggravate an existing acne vulgaris.

Some women taking estrogens notice tenderness, swelling, or minor bleeding of their gums, which may lead to gingivitis. Proper attention to oral care and regular dental visits are recommended.

Ocular disorders can occur during therapy with HRT. These can include optic neuritis, diplopia, loss of vision, or retinal thrombosis. Estrogens can cause keratoconus. A conical cornea develops from steepening or increased curvature of the cornea, caused by thinning of the stroma. Patients with contact lenses may develop intolerance to their lenses. Any change in vision or visual acuity should be examined by an ophthalmologist. Estrogens should be discontinued in patients developing any unexplained visual disturbance.

Estrogens, when used in combination with a progestin, can cause impaired carbohydrate metabolism and impaired glucose tolerance, leading to hyperglycemia in some women taking HRT. Limited clinical studies of estradiol regimens have not noted significant alterations in glucose metabolism in healthy post-menopausal women. However, altered glucose tolerance secondary to decreased insulin sensitivity may be important for patients with hyperglycemia or diabetes mellitus. They should be observed for changes in glucose tolerance when initiating or discontinuing estrogen therapy.

Estrogens are known to cause teratogenesis during pregnancy and are in FDA category X. Increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the use of estrogens in pregnant women. The use of diethylstilbestrol, DES is well known for creating disturbances in the reproductive systems of both male and female offspring; similar disturbances are reported to occur in female offspring of rats exposed to estradiol during gestation. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing estradiol use.

Unopposed estrogen therapy can promote endometrial hyperplasia in approximately 10% of patients with an intact uterus, and increase the risk of endometrial cancer. In the majority of studies, the risk of endometrial adenocarcinoma is elevated for all doses and increases with increasing dose and duration of estrogen use. The pooled estimate of the relative risk compared to women who never used estrogen is 2.31. At diagnosis, endometrial cancers in estrogen recipients are generally of an earlier stage and a lower grade and show less myometrial invasion than tumors in women who have not used estrogen. Survival is also better in estrogen recipients than in women who have not received estrogen and develop endometrial cancers. Thus, while the risk of endometrial cancer increases with increased duration of estrogen use, the risk of dying does not. The World Health Organization, International Agency for Research on Cancer (WHO IARC) classifies combined menopausal HRT as carcinogenic to humans. When progestin therapy is taken for < 10 days per month, the risk of endometrial cancer is increased; however, if the progestin is taken daily in combination with estrogen, the risk of endometrial cancer is similar to that in women who have never used HRT. Furthermore, histologic and clinical data, as well as limited epidemiologic data suggest that the addition of a progestin to estrogen therapy offsets, but does not eliminate, the risk of endometrial hyperplasia caused by exogenous estrogen. With concurrent medroxyprogesterone (or other progestin) use, the incidence of endometrial hyperplasia due to conjugated estrogens is estimated to be 1% or less.

Numerous epidemiologic studies have examined the effects of estrogen HRT and estrogen-progestin HRT on the development of secondary malignancy (e.g., breast cancer, ovarian cancer) in postmenopausal women. The Women’s Health Initiative (WHI) Trial has reported slight increased risks of breast cancer in women taking estrogen or estrogen-progestin HRT. The WHO IARC, classifies combined menopausal HRT as carcinogenic to humans; in current and recent users, the risk of breast cancer increases with duration of use and is higher in women taking combined HRT verus estrogen-only therapy. Another study has reported an increased risk of ovarian cancer in women taking estrogen-only HRT for 10 or more years; short-term use of estrogen-progestin HRT did not increase ovarian cancer risks, but the authors caution that further investigation is needed.

Estrogen/progestin combination fails to prevent mild impaired cognition (memory loss) and is positively associated with the risk of developing dementia in women 65 years and older. The WHIMS study, an ancillary study of the WHI trial, found that patients receiving either estrogen/progestin combination therapy or placebo had similar rates of developing mild cognitive impairment as expected in a population of this age. However, patients receiving estrogen/progestin combination therapy were more likely than those receiving placebo to be diagnosed with dementia. Preliminary data from the estrogen-alone arm of the WHIMS study indicate that the administration of estrogen, compared to placebo, causes a trend in increased risk of probable dementia and/or mild cognitive impairment. The applicability of this finding to the typical user of HRT (i.e., younger, symptomatic women taking hormone replacement therapy to relieve menopausal symptoms) is unclear.

In women with a history of cardiovascular disease, the use of estrogen and progestin combination therapy increases the risk of developing urinary incontinence. Patients in the HERS study who did not have urinary incontinence prior to the studies initiation were observed to determine if hormone replacement therapy was helpful in preventing urinary incontinence. The study found that women who received estrogen/progestin therapy were almost twice as likely as patients receiving placebo to develop urge incontinence and 3 times as likely to develop stress incontinence after 1 year of treatment. At 4 years, the effect of hormone replacement therapy became even more pronounced, increasing the risk to 3.23 for urge incontinence and to 4.81 for stress incontinence. The applicability of these findings to women who use estrogen alone is unclear.

Other adverse events that have been reported include leg cramps, hypocalcemia, and exacerbations of asthma and systemic lupus erythematosus.

Estradiol Adverse Reactions

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