Estrogens General Statement (Monograph)

Drug class: Estrogens
ATC class: G03CC
VA class: HS300

Introduction

Estrogens are naturally occurring hormones or synthetic steroidal and nonsteroidal compounds with estrogenic activity.

Uses for Estrogens General Statement

Estrogen Replacement Therapy

Estrogens are used for the treatment of moderate to severe vasomotor symptoms and other symptoms, including vulvar and vaginal atrophy, associated with menopause and for the prevention and treatment of osteoporosis.^{101 129} When estrogens are used alone, such therapy is referred to as estrogen replacement therapy (ERT); when estrogens are used in combination with progestins, such therapy usually is referred to as hormone replacement therapy (HRT) or postmenopausal hormone therapy. Another therapeutic option for postmenopausal women involves use of estrogens in combination with an estrogen agonist-antagonist (e.g., bazedoxifene); this combination is referred to as a tissue-selective estrogen complex (TSEC).²⁶³ Long-term therapy with estrogens is associated with an increased risk of endometrial hyperplasia and/or carcinoma in postmenopausal women; however, use of progestins in conjunction with estrogen therapy (HRT) substantially reduces the risk.^{129 134 231 261} Women with an intact uterus must receive progestin in addition to estrogen to avoid the increased risk of endometrial carcinoma; long-term use of estrogen alone in women with an intact uterus is not recommended.^{231 236} As an alternative to progestin therapy, the use of bazedoxifene (an estrogen agonist-antagonist) in fixed combination with conjugated estrogens reduces the risk of endometrial hyperplasia.^{261 262 263} HRT is associated with increased risks of myocardial infarction (MI), stroke, invasive breast cancer, pulmonary emboli, and deep-vein thrombosis.^{101 129 231 232 238 239 247 248} ERT is associated with increased risks of stroke and deep-vein thrombosis.²⁵⁰ Because of the potential risks associated with HRT and ERT, the benefit to risk should be assessed for each patient, considering alternative therapies as part of this assessment.^{101 129 238} If ERT or HRT is used, it should be prescribed at the lowest effective dosage and for the shortest duration consistent with treatment goals and risks for the individual woman.^{101 129 238 239 261}

In the past, estrogens were used for prevention of cardiovascular disease in postmenopausal women; however, recent data indicate that use of ERT or HRT does not decrease the incidence of cardiovascular disease, and estrogen replacement therapy alone (ERT) or combined with progestins (HRT) should no longer be used for the prevention of cardiovascular disease.^{101 129 177 231 232 233 238 239 250 254 255}

While estrogen or estrogen/progestin therapy is effective for the management of certain menopausal symptoms and for the prevention and treatment of osteoporosis, results of a recent controlled study (Women’s Health Initiative [WHI] study of estrogen plus progestin) indicate that HRT, specifically conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily, is associated with a small increase in the risk of breast cancer, cardiovascular disease, stroke, and venous thromboembolism.^{230 231 232 246} Results of the WHI study of estrogen alone indicate that ERT (specifically conjugated estrogens 0.625 mg daily) is associated with a small increase in the risk of stroke and deep-vein thrombosis.²⁵⁰ Results of the WHI also showed that HRT had no clinically important effect on measures of depression, insomnia, sexual function, or cognition (i.e., health-related quality-of-life measures) in women without menopausal symptoms.^{242 243} Based on the WHI findings, recommendations on the appropriate use of hormone therapy have been revised.^{230 231 234 251 255} Because the risks of hormone therapy exceed the benefits for the prevention of chronic diseases in postmenopausal women, experts state that ERT or HRT should not be used for the prevention of chronic conditions in postmenopausal women.^{230 250 251 254} The American Heart Association (AHA), the American College of Obstetricians and Gynecologists (ACOG), FDA, and manufacturers recommend that hormone therapy not be used to prevent heart disease in healthy women (primary prevention) or to protect women with preexisting heart disease (secondary prevention).^{101 129 230 231 234 238 239 250 251 254 255} ACOG, FDA, and the manufacturers also recommend that women receiving hormone therapy solely for the prevention of postmenopausal osteoporosis consider alternative therapy (e.g., alendronate, raloxifene, risedronate).^{101 129 231 238 239 250 251 254} Although these recommendations are based on results of the WHI study that evaluated one specific estrogen (conjugated estrogens 0.625 mg) and one estrogen/progestin preparation (conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg), the risks should be assumed to be similar with other hormonal regimens, including different dosages of these drugs as well as other estrogen/progestin combinations not studied in WHI, in the absence of comparable data to the contrary.^{101 129 231 239 250 251 254}

While the risks of HRT are likely to exceed the benefits in most women receiving these agents for prevention of chronic diseases (e.g., cardiovascular disease, osteoporosis), the long-term safety of short-term use of HRT for the management of menopausal symptoms remains to be precisely established.^{231 235} Estrogen or estrogen/progestin therapy is the most effective therapy for the relief of vasomotor symptoms such as hot flushes (flashes) and sleep disturbances.^{231 261} The fixed combination of conjugated estrogens with bazedoxifene acetate also is used for the management of moderate to severe vasomotor symptoms associated with menopause.²⁶² Estrogen or estrogen/progestin therapy also is effective in the treatment of genitourinary symptoms such as vaginal dryness; however, the use of topical vaginal preparations should be considered when only vulvar and vaginal symptoms are being treated.^{101 129 231 261} The decision to use estrogen or estrogen/progestin therapy for management of menopausal symptoms should be individualized taking into account the woman’s preference, her risk for specific chronic diseases, and the presence and severity of menopausal symptoms.^{230 231 261} ACOG, FDA, and the manufacturers recommend that women who choose hormone therapy for the relief of menopausal symptoms receive such therapy for the shortest possible time and in the lowest effective dosage; women also should regularly consult their clinician and undergo regular breast cancer screenings.^{101 129 231 238 239 261} ACOG recommends against routine discontinuance of systemic estrogen therapy when a women reaches 65 years of age, since some women 65 years of age or older may continue to need systemic hormone therapy for management of vasomotor symptoms.²⁶¹ Continuation of hormone therapy for management of vasomotor symptoms should be individualized taking into account the woman's symptoms and the risks and benefits of hormone therapy, regardless of age.²⁶¹

Regardless of a woman's age or duration of hormone therapy, discontinuance may be associated with recurrent vasomotor symptoms in approximately 50% of women.²⁶¹ There is insufficient evidence to recommend one method of stopping hormone therapy (e.g., abrupt discontinuance, dosage tapering) over another to prevent recurrent symptoms.²⁶¹

Lifestyle modifications that may help reduce menopausal symptoms such as hot flushes include smoking cessation, dietary manipulation (avoid/limit spicy foods, caffeine, and alcohol), stress reduction, and loose or layered clothing.^{231 261} There is increasing evidence that drugs other than hormone preparations may alleviate certain menopausal symptoms.²⁶¹ For women experiencing vasomotor symptoms, selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), gabapentin, or clonidine has been used for treatment.^{231 257 261} SSRIs, SNRIs, and gabapentin have been shown to be effective for treatment of vasomotor symptoms in randomized, controlled trials, while evidence supporting the efficacy of clonidine is limited.²⁶¹ For symptoms such as vaginal dryness, topical administration of estrogen alone usually is effective.^{231 261} Although only limited amounts of estrogen are systemically absorbed from vaginal tablets and rings, limited data are available regarding long-term safety of vaginally administered estrogen.²³¹

Estrogens also are used in the treatment of a variety of other conditions associated with a deficiency of estrogenic hormones, including female hypogonadism and castration and primary ovarian failure. In addition, estrogens also may be used in the treatment of abnormal uterine bleeding caused by hormonal imbalance not associated with organic pathology; however, progestins are usually preferred.

Osteoporosis

Prevention in Postmenopausal Women

Estrogen replacement therapy (ERT) is effective for the prevention of osteoporosis in women and has been shown to reduce bone resorption and retard or halt bone loss associated with estrogen deficiency in postmenopausal women.^{100 101 129 136 137 165 166 167 206} Oral estrogens (e.g., estradiol, estropipate, conjugated estrogens) and transdermal estrogens (e.g., estradiol) are used adjunctively with other therapeutic measures (e.g., diet, calcium, vitamin D, weight-bearing exercise, physical therapy) to retard further bone loss and the progression of osteoporosis in postmenopausal women.^{100 101 129 134 135 136 137 138 165 166 167 171 206} The fixed combination of conjugated estrogens with bazedoxifene acetate also is used for the prevention of osteoporosis.²⁶²

In a placebo-controlled study in postmenopausal women, administration of estrogen replacement therapy (conjugated estrogens) with (HRT) or without (ERT) a progestin for 36 months was associated with a 1.7% increase in hip bone mineral density (BMD) and 3.5–5% increase in lumbar spine BMD compared with baseline, while placebo recipients lost an average of 1.7% in hip BMD and 1.8% in spinal BMD.¹⁷¹ Increases in BMD observed in women receiving estrogen replacement therapy without a progestin (ERT) generally have been essentially the same as those observed in women receiving combined estrogen/progestin therapy (HRT).^{137 165 166 171}

In case-controlled studies in Caucasian women, estrogen replacement therapy has been associated with a substantial (about 60%) reduction in the incidence of hip and wrist fractures in those in whom estrogen therapy was initiated within a few years of menopause; some studies suggest that estrogens may also reduce the incidence of vertebral fracture.^{100 136 137} In the WHI study, there was a 24% reduction in total fractures in postmenopausal women receiving HRT compared with those receiving placebo^{231 232} and a 30–39% reduction in total fractures in women receiving ERT compared with women receiving placebo.²⁵⁰ The number of cases of hip fracture per 10,000 patient-years of exposure was 10 or 15 in women receiving HRT or placebo, respectively.^{231 232} The number of cases of hip fracture per 10,000 patient-years of exposure was 11 or 17 in women receiving ERT or placebo, respectively.²⁵⁰ Estrogen replacement therapy reportedly prevents further estrogen deficiency-induced bone loss in postmenopausal women when started up to 6 years after menopause, but such therapy does not appear to restore bone mass to premenopausal levels. In addition, when estrogen therapy is discontinued, bone mass declines at a rate similar to that occurring in the immediate postmenopausal period. It has been suggested that optimum estrogen replacement therapy for the prevention of osteoporosis should be initiated within 5 years of menopause and be continued for long-term (exceeding 10 years);¹³⁷ however, risks associated with such long-term use should be considered. (See Carcinogenicity.)

Caucasian or Asian women are at a higher risk for osteoporosis than black women. Other risk factors include premature ovarian failure; a family history of osteoporosis; a small, slim body frame; endocrine disorders such as thyrotoxicosis, hyperparathyroidism, Cushing’s syndrome, hyperprolactinemia, insulin-dependent diabetes mellitus (type 1, IDDM); cigarette smoking; drinking excessive amounts of alcohol; a sedentary lifestyle and/or lack of physical exercise; low body weight; and low dietary calcium intake. Premature ovarian failure (surgical or nonsurgical) hastens the onset of osteoporosis, and estrogen deficiency in premenopausal women (e.g., secondary to anorexia nervosa- or exercise-induced amenorrhea or to hyperprolactinemia) induces bone loss and may reduce peak bone mass.^{165 170}

While estrogen or estrogen/progestin therapy is effective for the prevention of osteoporosis in postmenopausal women,^{100 101 129 136 137 165 166 167} results of a recent controlled study (WHI study) indicate that HRT, specifically conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily, is associated with a small increase in the risk of breast cancer, cardiovascular disease, stroke, and venous thromboembolism.^{230 231 232} Results of the WHI estrogen-alone study indicate that ERT (specifically conjugated estrogens 0.625 mg daily) is associated with a small increase in the risk of stroke and deep-vein thrombosis.²⁵⁰ Because the risks of hormone therapy exceed the benefits for the prevention of chronic diseases in postmenopausal women, experts state that ERT or HRT should not be used for the prevention of chronic conditions (e.g., osteoporosis) in postmenopausal women.^{230 250 251 254} ACOG, FDA, and the manufacturers recommend that women receiving hormone therapy solely for the prevention of postmenopausal osteoporosis consider alternative therapy.^{101 129 231 250 251 254} Alternative agents that can be used for the prevention of osteoporosis include alendronate, raloxifene, or risedronate.^{231 236} However, experience with these agents is not as extensive as with HRT.^{165 173 174} In addition, alendronate and risedronate are associated with substantial adverse GI effects (e.g., esophagitis).^{165 166 231 236}

Women being considered for estrogen replacement therapy should have no contraindications to estrogen therapy and should fully understand the risks associated with estrogen use and agree to regular medical examinations.^{100 101 129 134 136 165 166 167} The choice of estrogen replacement therapy, alendronate, raloxifene, or risedronate for the prevention of postmenopausal osteoporosis should be individualized, taking into account differences in tolerability and safety and individual preference.^{172 174 175 231 236} For all women, lifestyle modifications for healthy bones include a diet high in calcium (postmenopausal women should receive 1.2–1.5 g of calcium daily), adequate intake of vitamin D (as supplied by a multivitamin), and regular weight-bearing exercise such as walking or jogging.^{165 166 167 168 169 172 174 231 236} Whether additional preventive therapy generally should be offered to all women or just recommended for selected women at highest risk of developing osteoporosis remains to be established.^{172 176}

Although there is no biologic reason to suspect that the effects of estrogens would differ in nonwhite women, the efficacy of estrogen replacement therapy in preventing osteoporosis in nonwhite women has not been established to date.¹³⁶

Treatment in Postmenopausal Women

Estrogen replacement therapy has been effective in the treatment of osteoporosis in postmenopausal women and has been recommended as first-line therapy for women with osteoporosis.^{165 166 172 173 174} However, results of a recent controlled study (WHI study) indicate that HRT, specifically conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily, is associated with a small increase in the risk of breast cancer, cardiovascular disease, stroke, and venous thromboembolism.^{230 231 232} Results of the WHI estrogen-alone study indicate that ERT (specifically conjugated estrogens 0.625 mg daily) is associated with a small increase in the risk of stroke and deep-vein thrombosis.²⁵⁰ Based on these findings, recommendations on the appropriate use of hormone therapy are being revised.^{230 231 234} The risks and benefits of long-term use of hormone therapy in the management of osteoporosis should be evaluated taking into account the increased risk of breast cancer and cardiovascular disease, availability of other pharmacologic modalities (e.g., alendronate, calcitonin, calcium, raloxifene, risedronate, vitamin D), and life-style factors that can be modified.^{101 129 165 166 167 168 169 170 198 231 236 238 239}

Estrogen replacement therapy produces the most marked benefits when begun soon (e.g., within 5 years) following menopause; such therapy also appears to be effective even when initiated many years after menopause in older women.^{166 167 190} Some clinicians suggest that prolonged therapy (e.g., at least 5 years) with estrogens is necessary since the beneficial effects of estrogen replacement therapy do not appear to persist after discontinuance of treatment.^{165 190}

Various estrogen-containing therapies (e.g., conjugated estrogens, estrogen/progestin combinations) have been used concomitantly with bisphosphonates (e.g., alendronate, etidronate) and calcium in the treatment of osteoporosis in postmenopausal women. ^{207 208 209} In several clinical trials in postmenopausal women with osteoporosis, the combination of estrogen-containing therapy and alendronate resulted in a greater degree of suppression of bone turnover than either therapy given alone. ^{207 208 209} In a placebo-controlled, 2-year clinical trial comparing monotherapy with alendronate (10 mg daily) or conjugated estrogens (0.625 mg daily) with the combination of these drugs at the same monotherapy dosages in postmenopausal women with osteoporosis not currently receiving antiresorptive therapy, combination therapy increased bone mineral density (BMD) (as determined by dual-energy radiographic absorption measurements) in the lumbar spine and femoral neck compared with either agent given alone or placebo (calcium 500 mg daily).^{208 209} A bone histology study in these patients indicated that the bone formed during therapy was of normal quality.^{208 209} Compared with calcium supplementation alone, bone turnover after 18 months was suppressed by 98% with combined alendronate-estrogen replacement therapy, 94% with alendronate therapy alone, and 78% with estrogen replacement therapy alone.^{208 209} In another comparative study in postmenopausal women who had osteoporosis despite hormone replacement therapy with estrogen (conjugated estrogens) or estrogen plus progestin (medroxyprogesterone) for at least 1 year (mean duration about 10 years), the addition of alendronate (10 mg daily) increased BMD (as determined by dual-energy radiographic absorption measurements) in the lumbar spine and hip trochanter compared with hormone replacement therapy alone at 12 months; all patients also received calcium and vitamin D supplementation.^{207 208} In both trials, the incidence of new fractures was similar across treatment groups.^{207 209} In these trials, sample size and study duration may have been inadequate to detect differences in fracture incidence with combination therapy, monotherapy with alendronate or estrogen, or placebo, and further studies are needed.^{207 209} The safety of combination therapy was similar to that with each antiresorptive agent alone.²⁰⁸

Prevention in Women with Anorexia Nervosa

Estrogens have been used in a limited number of anorexic women with chronic amenorrhea to reduce calcium loss^{† [off-label]} and, thereby, reduce the risks of osteoporosis. ²¹⁰ However, results of various controlled and uncontrolled studies indicate that estrogens appear to benefit only a subset of low-weight (initial body weight less than 70% of ideal body weight) women with anorexia nervosa.²¹⁰ Because data supporting use of estrogen therapy for the treatment or prevention of osteoporosis in female children, adolescents, or adults with anorexia nervosa are limited or lacking, the American Psychiatric Association (APA) concludes that therapy with estrogens alone does not appear to reverse osteoporosis or osteopenia, and unless there is weight gain, such therapy does not prevent further bone loss.²¹⁰ Furthermore, many clinicians state that the decision to initiate estrogen therapy in these patients should be deferred until weight gain and normal menses have been restored, since artificially inducing menses carries the risk of supporting or reinforcing a patient’s denial that she does not need to gain weight.²¹⁰

Cardiovascular Risk Reduction

While results from earlier observational studies indicated that estrogen replacement therapy or combined estrogen/progestin therapy was associated with cardiovascular benefit in postmenopausal women, results of the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women’s Health Initiative (WHI) study indicate that use of estrogen replacement therapy (ERT) or combined estrogen/progestin replacement therapy (hormone replacement therapy, HRT) does not decrease the incidence of cardiovascular disease.^{101 129 177 231 232 238 239 250}

Substantial epidemiologic evidence has indicated that postmenopausal women receiving ERT may have a reduction of up to 50% in the risk of ischemic heart disease^{107 108 109 110 112 113 115 117 118 119 120 121 131 134 162 178} and a similar reduction in total mortality^{111 112 117 131 134 181 182 195} compared with women who have never received such therapy.^{102 107 108 109 110 111 112 113 114 115 116 131 132 133 134 162 178 181 182} In observational studies, the increase in life expectancy based on a reduced risk of coronary heart disease (CHD) in postmenopausal women receiving ERT has been estimated to be 2–3 years.^{178 180 182} While these studies generally enrolled healthy women, observational studies in women with preexisting coronary disease also suggest that ERT reduces the risk of reinfarction and CHD-related death.^{178 183 184 185 186 187} However, the conclusions of these studies have been criticized for methodological reasons.²⁶⁸

Although some observational studies have shown a cardioprotective effect with estrogen alone or in combination with progestin,^{205 268} conflicting data have been reported in large prospective, randomized studies.^{129 268} In one of these studies (HERS), no overall cardiovascular benefit was reported with HRT in postmenopausal women with established coronary disease.^{177 178 179 193 194 233} In addition, results of the WHI study indicate that HRT, specifically conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily, is associated with a small increase in the risk of cardiovascular disease and stroke in predominantly healthy postmenopausal women.^{230 231 232} Results from the WHI estrogen-alone study indicate that ERT (specifically conjugated estrogens 0.625 mg daily) does not affect the risk of CHD but is associated with a small increase in the risk of stroke in healthy postmenopausal women who have undergone a hysterectomy.²⁵⁰ In another randomized study, ERT (conjugated estrogens 0.625 mg daily) or HRT (conjugated estrogens 0.625 mg daily and medroxyprogesterone acetate 2.5 mg daily) was associated with reductions in LDL-cholesterol and increases in HDL-cholesterol concentrations but had no effect on progression of coronary atherosclerosis in women with established CHD.²⁰⁵

In HERS, 2763 postmenopausal women with established CHD were randomized to receive HRT (conjugated estrogens 0.625 mg daily in conjunction with medroxyprogesterone acetate 2.5 mg daily) or placebo.^{177 178 179} After a follow-up averaging 6.8 years, HRT was not associated with an overall reduction in the rate of CHD events (e.g., nonfatal MI, CHD-related death).^{177 178 179 193 194 233} Based on year of randomization, women who received HRT experienced an increased incidence of CHD events during the first year and a lower incidence in the fourth year compared with women who received placebo.^{177 233} However, based on the entire 6.8 years of follow-up, a trend toward a lower or higher incidence of CHD over time was not evident.²³³ Analysis of data from 2 observational studies in postmenopausal women with cardiovascular disease (i.e., the Nurses’ Health Study and a Group Health Cooperative study) indicate that the risk for a recurrent major coronary event in women with established coronary heart disease is increased early (up to 1 year) after initiation of HRT and decreases with long-term use.^{215 216} Women with CHD often have risk factors such as diabetes mellitus and obesity that influence the tendency to develop thrombosis, and any procoagulant effects of hormone therapy would be greatest in such women.¹⁷⁸ Whether estrogen/progestin therapy (HRT) is associated in susceptible subgroups with immediate prothrombotic, proarrhythmic, or proischemic effects that are gradually outweighed by a beneficial effect on the underlying progression of atherosclerosis (perhaps as a result of favorable effects on lipoproteins) requires further study.^{177 178 194}

The WHI was a long-term study sponsored by the National Institutes of Health (NIH) that focused on strategies that can potentially reduce the incidence of heart disease, breast and colorectal cancer, and fractures in postmenopausal women.^{231 232} One part of this initiative followed 16,608 predominantly healthy women (with an intact uterus) who were 50–79 years of age who received HRT (i.e., conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily) or placebo.^{231 232} The goal of this 8.5-year study was to evaluate the relationship between HRT and CHD, stroke, pulmonary embolism, breast cancer, endometrial carcinoma, colorectal cancer, hip fracture, and death from other causes.²³² The study was stopped early because health risks exceeded benefits over an average follow-up of 5.2 years.²³² At the time the study was stopped, the increased number of cases of invasive breast cancer, CHD, stroke, and pulmonary embolism in the estrogen/progestin group relative to the placebo group was not counterbalanced by reductions in the number of cases of hip fracture and colorectal cancer.²³² Estrogen/progestin therapy did not affect all-cause mortality.²³²

In the WHI estrogen plus progestin study, there was a 29% increase in the incidence of heart disease in postmenopausal women receiving HRT compared with those receiving placebo.^{231 232} The number of CHD events (e.g., MI) per 10,000 patient-years of exposure was 37 or 30 in women receiving HRT or placebo, respectively.^{231 232} In addition, there was a 41% increase in the incidence of stroke in postmenopausal women receiving HRT compared with those receiving placebo.^{231 232} The number of cases of stroke per 10,000 patient-years of exposure was 29 or 20 in women receiving HRT or placebo, respectively.^{231 232}

Another part of the WHI initiative followed 10,739 predominately healthy women who were 50–79 years of age and had undergone a prior hysterectomy, and received ERT (conjugated estrogens 0.625 mg daily) or placebo.²⁵⁰ The goal of this study was to evaluate the relationship between ERT and CHD, stroke, pulmonary embolism, breast cancer, colorectal cancer, hip fracture, and death from other causes.²⁵⁰ At the time the study was stopped (after nearly 7 years), results indicated that ERT did not affect the incidence of CHD or overall mortality but did increase the risk of stroke.²⁵⁰ There was a 39% increase in the incidence of stroke in women receiving ERT compared with those receiving placebo.²⁵⁰ Approximately 80% of all strokes were ischemic.²⁵⁶ The number of cases of stroke per 10,000 patient-years of exposure was 44 or 32 in women receiving ERT or placebo, respectively.²⁵⁰

An ancillary substudy of the WHI examined the effect of ERT (conjugated estrogens 0.625 mg daily) or placebo on coronary-artery calcification in women 50–59 years of age at the time of randomization.^{259 260} Imaging of the coronary arteries 8.7 years after study start (7.4 years of treatment and 1.3 years after study completion) indicated that women who received estrogen had a lower prevalence and quantity of coronary-artery calcium than placebo-treated women.^{259 260} Intent-to-treat analysis showed that administration of estrogen reduced coronary calcification by 42%; in women with at least 80% adherence to study medication for 5 years, administration of estrogen reduced coronary calcification by 61%.^{259 260}

Based on the finding of no overall cardiovascular benefit observed in HERS and the WHI study and the lack of effect of ERT or HRT on angiographic progression of coronary artery disease, the AHA, ACOG, FDA, and manufacturers recommend that hormone therapy not be used to prevent heart disease in healthy women (primary prevention) or to protect women with preexisting heart disease (secondary prevention).^{101 129 230 231 234 238 239 255 268}

If a woman with cardiovascular disease receiving long-term HRT experiences an acute cardiovascular event (e.g., MI) or is immobilized, discontinuance of HRT or administration of venous thrombosis prophylaxis during hospitalization should be considered to reduce the risk of thromboembolism.^{214 217} Decisions to resume HRT should be based on established noncoronary risks and benefits and patient preference.^{214 217}

Corticosteroid-induced Hypogonadism and Osteoporosis

Patients receiving long-term corticosteroid therapy may develop hypogonadism secondary to inhibition of secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary as well as secondary to direct effects on the ovaries and testes, and such hypogonadism may be associated with bone loss.^{221 229} Therefore, all patients receiving prolonged corticosteroid therapy should be assessed for possible hypogonadism, which should be corrected if present.²²¹

Hormone replacement therapy (HRT, combined estrogen and progestin therapy) has been effective in increasing lumbar spine but not femoral neck bone mass density (BMD) in postmenopausal women with asthma or rheumatoid arthritis who were receiving chronic corticosteroid therapy.^{221 222 223 229} HRT in a control group of women receiving long-term low-dose corticosteroid therapy in one study appeared to prevent BMD loss at the lumbar spine, hip, and distal radius over the course of 1 year.²²⁴ While there currently are no well-designed studies establishing the preventive efficacy of HRT on corticosteroid-induced bone loss and radiographic vertebral fractures, data from existing studies suggest that HRT is adequate to prevent bone loss in postmenopausal women receiving low-to-moderate-dose corticosteroid therapy^{† [off-label]}, and postmenopausal women receiving long-term corticosteroid therapy should be offered HRT if no contraindications exist.^{221 222 223 224} The protective efficacy of HRT in such women who are receiving moderate-to-high doses of corticosteroids remains to be established.²²¹ Corticosteroid-treated women who develop fractures while receiving HRT or in whom HRT is not well tolerated should receive calcium and vitamin D supplementation along with bisphosphonate therapy (e.g., alendronate, risedronate) in an attempt to prevent bone loss and/or increase BMD as well as to prevent apoptosis of osteocytes and osteoblasts and reduce the risk of radiographic vertebral fractures.^{221 227 228}

There also currently are no controlled studies of HRT in premenopausal women receiving chronic corticosteroid therapy.²²¹ However, observational studies in premenopausal female athletes with menstrual irregularities suggest that estrogen-progestin combination (e.g., oral contraceptive) use is associated with a higher adjusted bone mineral content and BMD relative to women who do not take estrogen-progestin combinations.^{221 225 226} Therefore, premenopausal women who develop menstrual irregularities (e.g., oligomenorrhea, amenorrhea) while receiving long-term corticosteroid therapy should be offered combined cyclic estrogen and progestin therapy (e.g., estrogen-progestin combination oral contraceptives) in an attempt to treat hypogonadism and possibly reduce the risk ofcorticosteroid-induced osteoporosis^{† [off-label]} when contraindications to estrogen-progestin therapy are not present.²²¹

Alzheimer’s Disease

Some data from observational studies indicate that prior use of hormone replacement therapy (HRT), but not current HRT unless such use exceeds 10 years, is associated with reduced risk of Alzheimer’s disease^{† [off-label]}.²³⁷ Estrogens have not been shown to prevent progression of Alzheimer’s disease, and the American Academy of Neurology (AAN) recommends that estrogens not be used for the treatment of Alzheimer’s disease.²²⁰

Findings from the Women’ Health Initiative Memory study (WHIMS; an ancillary study of the Women’s Health Initiative [WHI] study in women 65 years of age or older without dementia at study entry) indicate that use of ERT (conjugated estrogens 0.625 mg daily) or HRT (conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily) does not improve cognitive function relative to placebo in these women and may adversely affect cognition.^{244 252 253} In the WHIMS study, more women receiving ERT or HRT had substantial and clinically important declines in the Modified Mini-Mental State Examination total score compared with women receiving placebo, suggesting that some women receiving these hormonal therapies experience detrimental effects.^{244 245 252 253} In addition, the rate of probable dementia in women receiving ERT or HRT was higher than that in women receiving placebo.^{245 252} Women with relatively low baseline cognitive function were at particularly high risk for adverse cognitive effects.²⁵³ Use of hormone therapy to prevent dementia or cognitive decline in women 65 years of age or older is not recommended.^{252 253}

Metastatic Breast Carcinoma

Estrogens are used in the palliative treatment of advanced, inoperable, metastatic carcinoma of the breast in postmenopausal women and in men. Estrogens are one of several second-line agents that can be used in certain postmenopausal women with metastatic breast cancer.

Prostate Carcinoma

In males, estrogens are used for the palliative treatment of advanced carcinoma of the prostate; however, the risk of adverse cardiovascular effects of the drugs must be considered.

Other Uses

Estrogens also are used in combination with progestins for ovulation control in the prevention of conception and for the treatment of moderate acne vulgaris; estrogen-progestin combinations also are used in short-course, high-dose regimens in women for the prevention of contraception after unprotected intercourse (postcoital contraception, “morning-after pills”) as emergency contraceptives.

Although in the past estrogens have been used for the prevention of postpartum breast engorgement^{† [off-label]}, FDA has withdrawn approval of estrogen-containing drugs for this indication since estrogens have not been shown to be safe for use in women with postpartum breast engorgement.¹⁹¹ Data from controlled studies indicate that the incidence of substantial painful engorgement is low in untreated women, and the condition usually responds to appropriate analgesic or other supportive therapy.

Estrogens have not been shown to be effective for any purpose during pregnancy.

For information on the uses of specific estrogens, see the individual monographs in 68:16.04.

Estrogens General Statement Dosage and Administration

Administration

Estrogens may be administered orally, parenterally, intravaginally, or topically.

Dosage

Dosage equivalencies for estrogens have not been clearly established, and reported comparative values vary greatly. The dosage range of estrogens is generally wide, and dosage should be individualized according to the condition being treated and the response and tolerance of the patient. To minimize the risk of adverse effects, the lowest possible effective dosage and the shortest duration of therapy consistent with treatment goals and risks for the individual woman should be used.²⁶² When estrogen therapy is used in the management of vasomotor symptoms or vulvar and vaginal atrophy associated with menopause, the lowest dosage that will control such symptoms 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.

Estrogen therapy is administered in a continuous daily regimen or, alternatively, estrogens are administered cyclically. When estrogens are administered cyclically, the drugs are usually given once daily for 3 weeks, followed by 1 week without the drugs, and then this regimen is repeated as necessary. While estrogen therapy alone may be appropriate in women who have undergone a hysterectomy, a progestin generally is added to estrogen therapy in women with an intact uterus.^{129 130} Addition of a progestin 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.^{129 130} 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. When a progestin is used in conjunction with estrogen therapy, 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 potential adverse effects.

As an alternative to progestins, the use of bazedoxifene (an estrogen agonist-antagonist) in fixed combination with conjugated estrogens reduces the risk of endometrial hyperplasia.^{261 262 263} When bazedoxifene is used in fixed combination with estrogen therapy, the usual precautions associated with bazedoxifene therapy should be observed.²⁶²

Cautions for Estrogens General Statement

Numerous adverse effects have been reported in patients receiving estrogens and these may be similar to the adverse effects associated with estrogen-progestin oral contraceptives. Most of the serious adverse effects of estrogen-progestin oral contraceptives (e.g., thromboembolic disorders, hepatocellular adenoma) generally have not been associated with postmenopausal estrogen therapy, which may reflect the comparatively low dosages of estrogens used in postmenopausal women. When larger dosages of estrogen are used (e.g., for the palliative treatment of carcinoma of the breast or prostate), an increased risk of the serious adverse effects may occur.

GI Effects

Nausea has been frequently associated with estrogen therapy. Other adverse GI effects include vomiting, abdominal cramps, bloating, and diarrhea. Changes in appetite and changes in weight may also occur.

In patients with hypertriglyceridemia, estrogen therapy may be associated with further increases in plasma triglycerides resulting in pancreatitis and other complications.^{129 262} If acute pancreatitis occurs, estrogens should be discontinued.^{161 262} The risk of gallbladder disease appears to be increased 2- to 4-fold in postmenopausal women receiving estrogen replacement therapy.^{129 177 262} In one study, an increased risk of gallbladder disease occurred after 2 years of use of the drugs and doubled after 4 or 5 years of use. In another study, an increased risk of gallbladder disease was apparent between 6–12 months of use.

Dermatologic Effects

The most frequent adverse dermatologic reaction associated with estrogen therapy is chloasma or melasma. Women who have had melasma during pregnancy appear to be most susceptible. Irregular brown macules may develop slowly on the face within 1 month to 2 years following initiation of estrogen therapy. The macules fade more slowly than in melasma gravidarum and may be permanent.

Other dermatologic reactions include erythema multiforme, erythema nodosum, and hemorrhagic eruption. Hirsutism and alopecia have also occurred. Porphyria cutanea has reportedly been adversely affected in some women receiving estrogen therapy.

Cardiovascular Effects

In the absence of comparable data, the cardiovascular risks identified in the Women’s Health Initiative (WHI) study with conjugated estrogens 0.625 mg daily alone or in conjunction with medroxyprogesterone acetate 2.5 mg daily should be assumed to be similar for other dosages of these drugs as well as for other combinations of estrogens and progestins.^{101 129 238 239 250 255}

Elevated Blood Pressure

There is no evidence that estrogen replacement therapy in postmenopausal women is associated with elevated blood pressure;^{131 132} in fact, unopposed estrogen therapy in postmenopausal women has been associated with blood pressure reductions in some studies.^{108 127} However, increases in blood pressure may occur in some women receiving estrogens,²⁶² particularly if high dosages are used. Blood pressure elevations are usually minor, but clinically important hypertension may occur in some women. Elevated blood pressure may gradually decrease or persist after discontinuance of estrogen therapy. The precise cause of increased blood pressure is not known, but it may result from a stimulatory effect of estrogen on the renin-angiotensin system.

Women receiving high dosages of estrogens or those with a history of hypertension, preexisting renal disease, a history of toxemia or elevated blood pressure during pregnancy, a familial tendency toward hypertension or its consequences, or a history of excessive weight gain or fluid retention during the menstrual cycle may be at increased risk of developing elevated blood pressure during estrogen therapy and, therefore, should be monitored closely. Even though elevated blood pressure may remain within the normal range, the clinical implications of elevations should be considered in all patients. All women, but particularly those with other risk factors for cardiovascular disease or stroke and those receiving high dosages of estrogens, should have blood pressure measurements before an estrogen is prescribed and at regular intervals during therapy. Estrogens should be discontinued if the patient becomes hypertensive during therapy.

Results of a recent controlled study (WHI study) indicate that hormone replacement therapy, specifically conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily, is associated with a small increase in the risk of cardiovascular disease.^{230 231 232} In the WHI estrogen plus progestin study, there was a 29% increase in the incidence of heart disease in postmenopausal women receiving hormone replacement therapy compared with those receiving placebo.^{231 232} The number of coronary heart disease (CHD) events (e.g., myocardial infarction [MI]) per 10,000 patient-years of exposure was 37 or 30 in women receiving hormone replacement therapy or placebo, respectively.^{231 232} In the WHI estrogen-alone study, ERT did not affect the incidence of CHD.²⁵⁰

Thromboembolic Disorders

Oral contraceptive use is associated with an increased risk of thromboembolic and thrombotic disorders including thrombophlebitis, pulmonary embolism, stroke, subarachnoid hemorrhage, and MI. Retinal thrombosis and mesenteric thrombosis also have been reported in women receiving oral contraceptives. An increased risk of postsurgery thromboembolic complications has also been reported in patients receiving oral contraceptives.

Estrogen replacement therapy and hormone (estrogen/progestin) replacement therapy are associated with an increased risk of venous thromboembolic events.^{129 177 189 196 232 262} Results of some studies indicate that the risk of venous thromboembolic events with estrogen or hormone replacement therapy is about 2–3 times greater than that in women not receiving such therapy.^{129 189} In the WHI estrogen plus progestin study, the rate of venous thromboembolism, deep-vein thrombosis, or pulmonary embolism in women receiving hormone replacement therapy was twice the rate of these events in women receiving placebo.^{231 232} The number of cases of venous thromboembolism per 10,000 patient-years of exposure was 34 or 16 in women receiving hormone replacement therapy or placebo, respectively.^{231 232} In the WHI estrogen-alone study, the incidence of deep-vein thrombosis was increased in women receiving estrogen compared with women receiving placebo.^{250 262} Venous thrombosis is more likely to occur during the first year of therapy; patients with risk factors for thrombosis are at increased risk of venous thrombosis.²⁵¹

Data are conflicting on whether estrogen therapy alone or in combination with progestins is associated with an increased risk of stroke.^{111 162 164} While some studies suggest that estrogen replacement therapy may be associated with both an increased¹⁶⁴ and a decreased risk of stroke in postmenopausal women,^{111 162 164} results from a large prospective study (the Nurses’ Health Study) indicate no association between risk of stroke and use of estrogen replacement therapy either alone or in combination with progestins.¹⁶² In the WHI estrogen plus progestin study, there was a 41% increase in the incidence of stroke in postmenopausal women receiving hormone replacement therapy compared with those receiving placebo.^{231 232} The number of cases of stroke per 10,000 patient-years of exposure was 29 or 21 in women receiving hormone replacement therapy or placebo, respectively.^{231 232} In the WHI estrogen-alone study, there was a 39% increase in the incidence of stroke in women receiving estrogen compared with those receiving placebo.^{250 262} Approximately 80% of all strokes in the WHI estrogen-alone study were ischemic strokes.²⁵⁶ The number of cases of stroke per 10,000 patient-years of exposure was 44 or 32 in women receiving ERT or placebo, respectively; this represents an absolute excess risk of 12 additional strokes per 10,000 patient-years.²⁵⁰ The American Heart Association (AHA) states that hormone therapy should not be used to prevent stroke in postmenopausal women.²³⁴

In a study in men, large dosages (i.e., 5 mg daily) of conjugated estrogens have been shown to increase the risk of nonfatal MI, pulmonary embolism, and thrombophlebitis.¹²⁹

The clinician and the patient using estrogens should be alert to the earliest signs and symptoms of thromboembolic and thrombotic disorders (e.g., thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, coronary occlusion, retinal thrombosis, mesenteric thrombosis). Estrogen therapy should be discontinued immediately when any of these disorders occurs or is suspected. (See Cautions: Precautions and Contraindications.)

Other Cardiovascular Effects

Estrogens may cause some degree of fluid retention.^{262 264 265} Estrogen therapy should therefore be used with caution in patients with conditions that might be aggravated by fluid retention.^{262 264 265} (See Cautions: Precautions and Contraindications.)

Endocrine and Metabolic Effects

Endocrine function test results (e.g., glucose tolerance, thyroid function) may be altered in patients receiving large dosages of estrogens. (See Laboratory Test Interferences.)

Decreased glucose tolerance has occurred in women receiving estrogen-containing oral contraceptives and may occur in patients receiving large dosages of estrogens. Prediabetic and diabetic patients should be carefully monitored during estrogen therapy.

Increased serum triglyceride concentrations have occurred in some women receiving estrogen-containing oral contraceptives and may occur during therapy with estrogens.²⁶² The clinical importance of these alterations in lipid and lipoprotein concentrations has not been established; however, women with elevated serum lipid concentrations who have decided to use estrogens in combination with progestins should be monitored closely.

Estrogens have reportedly caused severe hypercalcemia in patients with breast cancer and bone metastases. If severe hypercalcemia occurs, estrogen therapy should be discontinued and appropriate therapy to decrease serum calcium concentration should be instituted.

Estrogen therapy should be used with caution in women with hypoparathyroidism because estrogen-induced hypocalcemia may occur.²⁶²

Hepatic Effects

Liver function test results may be altered in patients receiving estrogen therapy; if results of these tests are abnormal, they should be repeated 2 months after discontinuance of the drug. Increased sulfobromophthalein retention has reportedly occurred in women receiving estrogen-containing oral contraceptives, as a result of interference with the transfer of dye conjugates from liver cells into bile; uptake, conjugation, and storage do not appear to be affected. Less frequently, increased serum aminotransferase and alkaline phosphatase concentrations have occurred. Liver function test results usually return to normal within several weeks after estrogen-containing oral contraceptives are discontinued; occasionally, however, abnormal test results may persist for longer periods. The possibility that these alterations in liver function test results may occur in patients receiving estrogens should be considered.

Cholestatic jaundice has been reported in women receiving estrogen-containing oral contraceptives, and the possibility that this effect may occur during estrogen therapy should be considered. Cholestasis is manifested by the development of malaise, anorexia, and pruritus about 2 weeks to 2 months after the start of therapy. Occasionally, arthralgia, fever, and rash may occur. Serum bilirubin may range from 3–10 mg/dL and is mostly conjugated. Women with a history of jaundice during pregnancy have an increased risk of jaundice recurrence while receiving estrogen-containing oral contraceptives. If jaundice occurs during estrogen therapy, the drug should be discontinued. Estrogens may precipitate hepatic forms of porphyria, and the drugs probably should not be used by women who have a familial history of hepatic porphyrias, since the occurrence of these conditions appears to be genetically determined. Steroid hormones (including estrogens) may be poorly metabolized in patients with hepatic dysfunction; therefore, estrogens should be administered with caution to these individuals.

Liver tumors have been associated with use of estrogen-containing oral contraceptives. Liver tumors have been benign or malignant and have occurred during short-term and long-term use of oral contraceptives. Most commonly, liver tumors are benign hepatocellular adenomas and occur only rarely in oral contraceptive users; however, they may result in death because their vascularity predisposes them to rupture and cause massive hemorrhage. Although benign hepatocellular adenomas have not been reported to date with estrogens, the possibility of a liver tumor should be considered in any patient receiving an estrogen who develops sudden severe abdominal pain or shock.

Genitourinary Effects

Breakthrough bleeding, spotting, changes in menstrual flow, missed menses (during use), or amenorrhea (after use) may occur in women receiving estrogen therapy. Dysmenorrhea and a premenstrual-like syndrome also have been reported. In patients with breakthrough bleeding or irregular vaginal bleeding, nonfunctional causes should be considered. Appropriate diagnostic procedures should be performed in patients with undiagnosed persistent or recurrent vaginal bleeding.²⁶²

Changes in cervical erosion and secretions may occur during estrogen therapy. In addition, preexisting uterine leiomyoma may increase in size in women receiving estrogens. A cystitis-like syndrome has been reported but has not been definitely attributed to estrogens. An increased incidence of Candida vaginitis has been associated with estrogen therapy.

The possibility that estrogen replacement therapy in postmenopausal women, particularly prolonged use, may be associated with an increased risk of endometrial^{129 262} or ovarian^{212 213 262} cancer should be considered. (See Cautions: Mutagenicity and Carcinogenicity.)

Nervous System Effects

Mental depression may occur in patients receiving estrogens. In a few women receiving estrogen-containing oral contraceptives, mental depression was severe and led to suicidal behavior. Patients with a history of mental depression should be observed carefully and estrogens discontinued if severe depression recurs during use.

Dizziness, changes in libido, and chorea have been reported in patients receiving estrogens.

Headache, especially migraine headache, may occur during estrogen therapy. Estrogens should be discontinued and the cause evaluated when migraine occurs or is exacerbated, or when a new headache pattern develops that is recurrent, persistent, and/or severe.

Ocular Effects

Estrogens have been reported to produce keratoconus (steepening or corneal curvature) and intolerance to contact lenses. Contact lens wearers who develop visual disturbances or changes in lens tolerance during estrogen therapy should be assessed by an ophthalmologist; temporary or permanent cessation of contact lens wear should be considered.

Retinal vascular thrombosis has been reported in patients receiving estrogens.²⁶² If unexplained, sudden or gradual, partial or complete loss of vision; proptosis or diplopia; papilledema; or retinal vascular lesions occur during therapy with an estrogen, the drug should be discontinued and appropriate diagnostic and therapeutic measures instituted.²⁶²

Hematologic Effects

Changes in various blood factors and blood components have been observed in women receiving estrogen-containing oral contraceptives and may occur in patients receiving estrogens; however, further studies are required before the clinical importance of these changes can be established. Estrogen (ERT) and hormone replacement therapy (estrogen/progestin, HRT) are associated with an increased risk of venous thromboembolic events in postmenopausal women.^{129 177 189 196} Increases in prothrombin and blood coagulation factors VII, VIII, IX, and X levels may occur in patients receiving estrogens; decreases in antithrombin III activity and decreased fibrinolysis also have been reported. In a clinical study in patients receiving conjugated estrogens in conjunction with medroxyprogesterone acetate, factors VII and X concentrations and plasminogen activity were increased and antithrombin III activity usually was decreased following 1 year of therapy.¹³⁰ Estrogens may also enhance norepinephrine-induced platelet aggregation.

Other Adverse Effects

Breast changes, including tenderness, enlargement, and secretion, may occur during estrogen therapy. The incidence of breast pain may be increased in patients receiving estrogens in conjunction with progestins compared with those receiving estrogens alone; breast pain was reported in about 33% of women receiving conjugated estrogens concomitantly with medroxyprogesterone acetate compared to 12% of women receiving unopposed conjugated estrogen therapy.¹²⁹

Precautions and Contraindications

Use of estrogens may be associated with an increased risk of several serious conditions including deep-vein thrombosis, stroke, MI, pulmonary embolism, liver tumor, gallbladder disease, visual disturbances, and malignancy.²⁶² Clinicians prescribing estrogens should be aware of the risks associated with the use of estrogens; the manufacturers’ labeling also should be consulted for further discussion of these risks and associated precautions. When estrogens are used in combination with other drugs (e.g., androgens, progestins, bazedoxifene), the usual precautions associated with the other drugs should also be observed. If a progestin is administered concomitantly with estrogen therapy, potential risks may include adverse effects on lipid metabolism, glucose tolerance, or possible enhancement of mitotic activity in breast epithelial tissue.¹⁰¹

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.^{101 129 238 239 262} Therapy with estrogen, estrogen/progestin, or conjugated estrogens in fixed combination with bazedoxifene should be periodically reevaluated.^{101 129 262}

Patients receiving estrogens should be under the supervision of a physician who should inform them of the possible risks involved. Patients receiving estrogens should also be given a copy of the patient labeling for the drugs.

A complete medical and family history should be taken prior to initiation of estrogen therapy and periodically thereafter. Estrogens should generally not be prescribed for longer than 1 year without a repeat physical examination being performed. Physical examination should include special attention to blood pressure, breasts, abdomen, and pelvic organs and should include a Papanicolaou test (Pap smear) and relevant laboratory tests.

Patients receiving estrogens should be informed to notify their physician if signs or symptoms of thromboembolic or thrombotic disorders (e.g., thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, coronary occlusion, retinal thrombosis, mesenteric thrombosis) occur, including sudden severe headache or vomiting, disturbance of vision or speech, sudden partial or complete loss of vision, dizziness or faintness, weakness or numbness in an extremity, sharp or crushing chest pain, unexplained cough, hemoptysis, sudden shortness of breath, calf pain, or heaviness in the chest. If signs or symptoms consistent with a thromboembolic or thrombotic disorder occur, hormone replacement therapy (HRT) should be discontinued immediately.¹²⁹ Use of ERT or HRT is not advised in women with a history of stroke or transient ischemic attacks. ²⁵¹ If hormone therapy is initiated or discontinued in a woman receiving oral anticoagulant therapy, effectiveness of the anticoagulant may be altered and dosage adjustment needed.²⁵¹ Patients receiving estrogens should also be advised to inform their physician if abdominal pain, swelling, or tenderness (indicating possible gallbladder disease), or an abdominal mass (indicating a possible liver tumor), jaundice, severe mental depression, or unusual bleeding occurs. Since endometrial hyperplasia and endometrial carcinoma have been reported in women receiving estrogen therapy, adequate diagnostic tests should be performed in women with undiagnosed, persistent, or recurring abnormal vaginal bleeding.¹²⁹ (See Carcinogenicity.) Women receiving estrogens should be instructed in self-examination of their breasts and should report lumps in the breast to their physician.

Estrogens should be used with caution, and only with careful monitoring, in patients with conditions that might be aggravated by fluid retention (e.g., cardiac or renal insufficiency);²⁶² in patients with cerebrovascular or coronary artery disease (including MI); and in women with a strong family history of breast cancer or who have breast nodules, fibrocystic disease, or abnormal mammographic findings (see Cautions: Carcinogenicity).

Women undergoing surgery and those with fracture or who are immobilized have a relatively high risk of venous thromboembolic events.¹⁹⁶ Therefore, estrogens should be discontinued, whenever feasible, at least 4–6 weeks prior to surgery that is associated with an increased risk of thromboembolism or prolonged immobilization.²⁶² The decision as to when to resume estrogen therapy following major surgery or immobilization should be based on the risks of postsurgery thromboembolic complications and the need for such therapy. In addition, some clinicians recommend that women discontinue estrogen replacement therapy during immobilization due to fracture, stroke, or other severe illness; estrogen replacement therapy can be restarted when normal activity is resumed.¹⁹⁶ Since acute pancreatitis, associated with increased triglyceride concentrations, has been reported in a few women receiving estrogens alone or in conjunction with a progestin,^{129 138 161} it is recommended that serum lipid concentrations be monitored prior to and during estrogen therapy.^{138 161} (See Cautions: GI Effects.)

Because estrogens influence the metabolism of calcium and phosphorus, the drugs should be used with caution in patients with renal insufficiency and in patients with metabolic bone diseases that are associated with hypercalcemia.

Metabolism of estrogens may be decreased in patients with impaired hepatic function.^{101 262} Caution is advised in patients with a history of cholestatic jaundice associated with estrogen use or pregnancy; if cholestatic jaundice recurs, estrogen therapy should be discontinued.^{129 262}

Estrogens may exacerbate asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.^{129 262} Estrogens also may exacerbate symptoms of angioedema in women with hereditary angioedema.^{262 264 265 266 267}

Estrogens are contraindicated in patients with known or suspected pregnancy, undiagnosed abnormal genital bleeding, known or suspected breast cancer or a history of breast cancer (except when used for the palliative treatment of metastatic disease in appropriately selected individuals), or known or suspected estrogen-dependent neoplasia.^{101 129 262} Estrogens also are contraindicated in patients with active deep-vein thrombosis or pulmonary embolism; a history of deep-vein thrombosis or pulmonary embolism; active or recent (within the past year) arterial thromboembolic disease (e.g., stroke, MI); liver disease or impairment; known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders; or known hypersensitivity to estrogen or any ingredient in the formulation.^{101 129 262 264 265}

Pediatric Precautions

Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay.¹⁰¹ Safety and efficacy of estrogens in children have not otherwise been established.¹⁰¹ Estrogen therapy should be used with caution in young individuals in whom bone growth is not yet complete, since estrogens may cause premature closure of the epiphyses.

Geriatric Precautions

When the total number of patients studied in the Women’s Health Initiative (WHI) study is considered, 44–46% were 65 years of age or older, while 6.6–7.1% were 75 years of age or older.^{101 129} In the estrogen plus progestin WHI study, there was a higher relative risk of nonfatal stoke or breast cancer in women 75 years of age or older compared with women younger than 75 years of age.^{101 129}

Carcinogenicity

Prolonged continuous administration of natural or synthetic estrogen in certain animal species increases the frequency of certain benign or malignant tumors including those of the breast, cervix, uterus, vagina, ovary, pituitary, and liver.

Endometrial Cancer

Several studies have shown an increased relative risk of endometrial carcinoma in postmenopausal women who received prolonged estrogen replacement therapy for relief of menopausal symptoms. This risk was independent of other known risk factors for endometrial carcinoma and appeared to depend on duration and dosage of estrogen therapy. While there appears to be no increased risk of endometrial carcinoma in postmenopausal women receiving estrogen therapy for less than 1 year, prolonged estrogen therapy may be associated with an increased risk of such carcinoma.¹²⁹ The risk of endometrial carcinoma reportedly is increased 2- to 12-fold in postmenopausal women receiving unopposed estrogen therapy compared with those not receiving estrogens; such increased risk may depend on dosage and duration of therapy and may be 15- to 24-fold higher in women receiving long-term (5 years or more) estrogen therapy.¹²⁹ Limited data indicate that a substantial increased risk of endometrial carcinoma may persist for up to 15 years following discontinuance of estrogen therapy.¹²⁹ Because of the increased risk of endometrial carcinoma associated with prolonged estrogen therapy, patients receiving prolonged treatment with the drugs should be evaluated at least twice yearly to reassess the need for continued therapy. Results of several studies indicate that when progestins are used concomitantly with estrogen replacement therapy, the incidence of endometrial hyperplasia and endometrial carcinoma is reduced substantially.^{129 140 158 159 160 163} In a randomized, controlled, multicenter study in postmenopausal women, endometrial hyperplasia occurred in 20 or 1% or less of women receiving estrogen therapy alone or in conjunction with progestins, respectively.^{129 140} In the WHI study, the incidence of endometrial carcinoma in women receiving hormone replacement therapy (conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily) was similar to the incidence in women receiving placebo.²³² As an alternative to progestins, the use of bazedoxifene (an estrogen agonist-antagonist) in fixed combination with conjugated estrogens reduces the risk of endometrial hyperplasia, which may be a precursor to endometrial carcinoma.^{261 262 263}

Although estrogen-associated risk of endometrial carcinoma is substantially reduced when estrogens are administered concomitantly with progestins or bazedoxifene, a risk still exists.²⁶² Therefore, clinical surveillance and evaluation of all menopausal women receiving estrogen therapy is essential.^{129 262} Diagnostic tests, including endometrial sampling when indicated, should be performed to rule out malignancy in all women who have undiagnosed, persistent, or abnormal vaginal bleeding.^{129 130 262}

Currently, there is no evidence that estrogens derived from natural sources are more or less hazardous than synthetic estrogens at equiestrogenic dosages.

Breast Cancer

All women receiving estrogens should perform monthly self-examinations of their breasts and be monitored at least annually by a health-care provider for breast abnormalities and more frequently if there are any signs and symptoms.^{211 262} Periodic mammography should be scheduled based on patient age, risk factors, and prior mammogram results.^{238 262} Women with a strong family history of breast cancer or who have breast nodules, fibrocystic disease, or abnormal mammographic findings should be monitored particularly closely if they elect to use estrogens. Although the clinical importance remains to be established, therapy with estrogen/progestin increases mammographic breast density relative to therapy with estrogen alone or placebo.^{247 249}

Because breast tissue is sensitive to reproductive hormones, there has been long-standing concern about the risk of breast cancer in women receiving hormone replacement therapy (HRT).²³⁰ The estrogen/progestin arm of the WHI study recently was terminated prematurely because of an increased incidence of breast cancer in women receiving HRT.^{230 232} In the WHI study, the risk of invasive breast cancer was 26% higher in women receiving HRT (conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily) compared with those receiving placebo; the estimated hazard ratio for breast cancer was 1.26.^{230 232} While there have been several observational studies evaluating the risk of breast cancer in women receiving HRT, conclusions are limited by healthy-user bias; variations in specific preparations, dosage, and duration of therapy; and differences in the methods used to determine breast cancer end points.²³⁰ In aggregate, breast cancer incidence is slightly increased among current (relative risk: 1.21–1.4) or long-term (longer than 5 years) recipients (relative risk: 1.23–1.35) compared with nonusers.²³⁰ Based on these findings, recommendations on the appropriate use of hormone therapy have been revised.^{230 231 234} Because the risks of hormone therapy exceed the benefits for the prevention of chronic diseases in postmenopausal women, experts state that ERT or HRT should not be used for the prevention of chronic conditions in postmenopausal women.^{230 250 251 254} The American Heart Association (AHA), the American College of Obstetricians and Gynecologists (ACOG), FDA, and manufacturers recommend that hormone therapy not be used to prevent heart disease in healthy women (primary prevention) or to protect women with preexisting heart disease (secondary prevention).^{101 129 230 231 234 238 239 250 251 254 255} ACOG, FDA, and the manufacturers also recommend that women receiving hormone therapy solely for the prevention of postmenopausal osteoporosis consider alternative therapy (e.g., alendronate, raloxifene, risedronate).^{101 129 231 238 239 250 251 254}

The decision to use estrogen or estrogen/progestin for management of menopausal symptoms should be individualized taking into account the women’s preference, her risk for specific chronic diseases, and the presence and severity of menopausal symptoms.^{230 231 251}

Results of a large (involving more than 100,000 women) prospective cohort study (the Nurses’ Health Study) in postmenopausal women who received conjugated estrogens indicated an increased risk of breast cancer in such women; in addition, an increased risk of breast cancer also was observed in individuals who received estrogen therapy in conjunction with progestins.^{141 142} The relative risk of breast cancer increased with age and duration of therapy, with the greatest risk being observed in women 60–64 years of age and in women who received estrogen replacement therapy for more than 10 years.¹⁴¹ In women receiving estrogens alone or in conjunction with progestins, the relative risk of developing breast cancer was 1.32 or 1.41, respectively.^{141 142} The relative risk of breast cancer was similar in women who had never received estrogen replacement therapy, women who received prior estrogen therapy, and women who received estrogen therapy for less than 5 years; however, the relative risk of developing breast cancer increased to 1.63 in women 60–64 years who received estrogens for at least 5 years.^{141 142 146} Results of this study also indicated that the relative risk of developing breast cancer was similar in women with and without a family history of the disease; consumption of alcohol did not affect results.¹⁴⁶

Data from the Nurses’ Health Study, the Breast Cancer Detection Demonstration Project, and other studies indicate that estrogen/progestin regimens are associated with an increased risk of breast cancer beyond that associated with estrogen alone.^{141 142 197 198 204} In the Breast Cancer Detection Demonstration Project (a study that included 46,000 women), the relative risk of breast cancer in women who received estrogen or estrogen/progestin within the previous 4 years was 1.2 or 1.4, respectively.^{197 198} Similar to results from other studies, the increased risk was generally limited to current or recent recipients and was related to duration of use.^{197 198 202} The relative risk (adjusted for mammographic screening, age at menopause, body mass index [BMI], education, age) increased by 0.01 with each year of estrogen use and by 0.08 with each year of estrogen/progestin use in recent recipients.¹⁹⁷ Among recent recipients of progestin for fewer than 15 days per month, the relative risk of breast cancer associated with therapy for less than 4 years was 1.1 while the relative risk associated with therapy for longer than 4 years was 1.5; estimates for risk were not available for recipients of progestins for 15 or more days per month due to insufficient data.¹⁹⁷ The relative risk of breast cancer in recent recipients of estrogen or estrogen/progestin increased 0.03 or 0.12, respectively, each year in women with a BMI of 24.4 kg/m² or less; an increase in risk associated with duration of use was not observed in heavier women.¹⁹⁷

The WHI, a long-term study sponsored by the National Institutes of Health (NIH), followed 16,608 predominantly healthy women with an intact uterus who were 50–79 years of age and who received HRT (i.e., conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily) or placebo with the goal of evaluating the relationship between HRT and coronary heart disease (CHD), stroke, pulmonary embolism, breast cancer, endometrial carcinoma, colorectal cancer, hip fracture, and death from other causes.²³² The study was stopped early because health risks exceeded benefits over an average follow-up of 5.2 years.²³² At the time the study was stopped, the increased number of cases of invasive breast cancer, CHD, stroke, and pulmonary embolism in the estrogen/ progestin group relative to the placebo group was not counterbalanced by reductions in the number of cases of hip fracture and colorectal cancer.²³² The WHI study is the first randomized, controlled study to confirm that estrogen/progestin therapy increases the risk of breast cancer in postmenopausal women and to quantify the risk.²³² In the WHI estrogen plus progestin study, the risk of invasive breast cancer was 26% higher in women receiving HRT (conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily) compared with those receiving placebo; the estimated hazard ratio for breast cancer was 1.26.^{230 232} The number of cases of breast cancer per 10,000 patient-years of exposure was 38 or 30 in women receiving HRT or placebo, respectively.^{230 232} The increase in breast cancer risk was apparent after 4 years of estrogen/progestin therapy, and the risk appeared to be cumulative.^{231 232} In addition, the risk associated with HRT appeared to increase at a higher rate than would be expected based on advancing age.^{231 232} The hazard ratio for HRT was not higher in women with a family history or other risk factors for breast cancer, except for prior postmenopausal hormone therapy.²³² In the WHI estrogen-alone study, use of estrogen was not associated with an increased risk of breast cancer.^{230 250 258}

Whether the effect of hormone replacement therapy on breast cancer incidence varies among histologic types of invasive carcinomas remains to be established.^{197 203} Findings from the Breast Cancer Detection Demonstration Project and the WHI estrogen plus progestin study indicate that such therapy is associated with an increase in risk for the majority of invasive tumors classified as lobular and/or ductal carcinomas.^{197 247} Findings from other studies indicate that estrogen/progestin therapy is associated with an increased risk of invasive lobular carcinoma.²⁴⁸ While data from some studies (e.g., the Iowa Women’s Health Study) suggest that estrogen/progestin therapy is associated with an increased risk of invasive breast cancer with a favorable prognosis, findings from the WHI indicate that such therapy is associated with cancers that are at least as invasive as those in women not receiving estrogen/progestin therapy.^{203 247 249} Analysis of breast cancer characteristics in women enrolled in the WHI indicate that the invasive breast cancers diagnosed in women receiving estrogen/progestin were similar in histology and grade but were larger (1.7 versus 1.5 cm, respectively) and were at a more advanced grade (regional/metastatic disease in 25.4 versus 16%, respectively) than those diagnosed in women receiving placebo.^{247 249}

The US Department of Health and Human Services 1985 DES Task Force concluded that the weight of evidence to date indicates that women who used diethylstilbestrol (DES) during pregnancy may subsequently experience an increased risk of breast cancer; however, because of limitations of current data and study methodologies, a causal relationship to the drug has not been established. Data from studies to date suggest an overall relative risk of breast cancer for DES-treated women ranging from 1.2–1.5 times that for untreated women, an excess risk that is similar to that associated with a number of other breast cancer risk factors; however, in epidemiologic analyses, these levels of excess risk are difficult to evaluate since various sources of bias that could be responsible for such excesses cannot be easily ruled out. It should be noted that conclusions regarding the likelihood of causality for this association between DES use and breast cancer could be substantially influenced by further follow-up of exposed women who have already been identified and studied and by initiation of studies of other exposed women which pay particular attention to matching DES-exposed and unexposed groups based on indications for DES use, to evaluating dose-latency relationships, and to the possibility of bias toward early diagnosis of breast cancer among exposed women. Initiation of studies that investigate interactions with other risk factors, considering possible additive and cumulative risks, and endocrinologic and immunologic considerations may also influence conclusions about the likelihood of causality.

Ovarian Cancer

While findings from epidemiologic (e.g., case-control) studies on the association between postmenopausal hormone replacement therapy and the risk of ovarian cancer have been inconsistent,²⁶² results from 2 large, prospective cohort studies with average follow-up of 13–14 years indicate that postmenopausal estrogen use is associated with an increased risk of ovarian cancer.^{212 213}

In the American Cancer Society’s Cancer Prevention Study II, which included over 200,000 postmenopausal women, women receiving oral estrogen replacement therapy at study entry (baseline) had higher death rates from ovarian cancer (adjusted rate ratio: 1.51) than women who had never received estrogen replacement therapy.²¹² Duration of estrogen use also was associated with increased risk; women who received estrogen replacement therapy for 10 or more years and who were receiving such therapy at baseline were more than twice as likely to have died from ovarian cancer as never users (adjusted rate ratio: 2.2).²¹² Estrogen use for less than 10 years was not associated with an increased risk of ovarian cancer mortality.²¹² Among women who discontinued estrogen after 10 or more years of use, the risk decreased with time; the adjusted rate ratio was 2.05 in those who received estrogen within the previous 15 years and 1.31 in those who had not received estrogen within the previous 15 years.²¹² Whether women receiving oral estrogen also received progestin was not evaluated in this study; however, most hormone replacement regimens for postmenopausal women contained only estrogenic compounds until the late 1970’s and most women receiving hormone replacement therapy in 1982 (baseline) presumably were receiving unopposed estrogen therapy.²¹²

Data from the Breast Cancer Detection Demonstration Project also indicate that estrogen replacement therapy is associated with an increased risk of developing ovarian cancer and that the risk associated with estrogen-only hormone replacement therapy is greater than that associated with estrogen-progestin replacement therapy.²¹³ In a study in over 40,000 postmenopausal women, those who received estrogen-only hormone replacement therapy were twice as likely to develop ovarian cancer as never users (adjusted relative risk: 2) with a lower risk (adjusted relative risk: 1.3) in women who received estrogen-progestin replacement therapy.²¹³ Although the lifetime risk of ovarian cancer is low (1.7%), any increase in risk of ovarian cancer related to long-term estrogen therapy should be considered in the risk/benefit assessment of such therapy.²¹²

GI Cancers

Data from observational studies, the Heart and Estrogen/progestin Replacement Study (HERS), and the WHI estrogen plus progestin study indicate that hormone replacement therapy reduces the incidence of colorectal cancer.^{230 232} In the WHI estrogen plus progestin study, the risk of colorectal cancer was reduced by 37% in women receiving hormone replacement therapy (conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily) compared with those receiving placebo.^{231 232} The number of cases of colorectal cancer per 10,000 patient-years of exposure was 10 or 16 in women receiving hormone replacement therapy or placebo, respectively.^{231 232} Results from the WHI estrogen-alone study indicate that ERT (conjugated estrogens 0.625 mg daily) does not affect the incidence of colorectal cancer.²⁵⁰

Pregnancy and Lactation

Pregnancy

Estrogens can cause fetal harm when administered to pregnant women.²⁶² In utero exposure of females to diethylstilbestrol (DES [no longer commercially available in the US]), a nonsteroidal estrogen, is associated with an increased risk of developing a rare form of vaginal or cervical cancer (clear-cell adenocarcinoma) in later life. In addition, such exposure to DES causes epithelial changes in the vagina and cervix in 30–90% of these exposed female offspring.

In utero exposure of females to DES is also associated with an increased risk of developing a rare form of vaginal or cervical cancer (clear-cell adenocarcinoma) in later life. In addition, such exposure to DES causes epithelial changes (adenosis) in the vagina and cervix in 30–90% of these exposed female offspring. Experience from the National Collaborative Diethylstilbestrol Adenosis (DESAD) Project indicates that women exposed to DES in utero appear to have an increased risk of dysplasia and carcinoma in situ of the cervix and vagina; the rate of these changes was 15.7 versus 7.9 cases per 1000 person-years of follow-up for exposed and unexposed women, respectively, and was even higher in exposed women with squamous metaplasia extending to the outer half of the cervix or onto the vagina. The 1985 DES Task Force concluded that, based on the results of the DESAD Project, women exposed to DES in utero may be at increased risk of cervical and vaginal dysplasia, particularly if they have extensive metaplasia; however, further documentation and evaluation of this association are necessary, and the relationship between DES exposure in utero and subsequent risk of squamous cell carcinoma of the cervix remains unclear.

In utero exposure to DES in females has not been associated with an increased risk of developing cancer other than an increased risk of developing vaginal or cervical clear-cell adenocarcinoma.¹⁰⁹ In utero exposure of males to DES has been associated with an increased incidence of genital tract abnormalities including epididymal cysts, maldescended testes, hypoplastic testes, varicoceles, low sperm counts, and spermatozoal defects (e.g., decreased motility, possibly abnormal forms). Similar data are not available for other estrogens, but it cannot be presumed that they would not induce similar changes.

Although estrogens were previously used to treat threatened or habitual abortion, there is no evidence that estrogens are effective for these uses; in addition, the potential for adverse effects of the drugs on the fetus exists. Estrogens should not be used during pregnancy.^{101 129}

Lactation

Administration of estrogens to nursing women has been associated with decreased amounts and lower quality of milk.^{129 262} In addition, detectable amounts of estrogens and progestins have been identified in milk of women receiving these drugs.^{101 129 262} Although estrogens were previously used for the prevention of postpartum breast engorgement, such use is no longer recommended. Caution is advised when estrogens are administered to nursing women.^{101 129} Conjugated estrogens in fixed combination with bazedoxifene should not be used in nursing women.²⁶²

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Metabolism of estrogen is mediated in part by cytochrome P-450 (CYP) isoenzyme 3A4, and the possibility exists that drugs that induce or inhibit this isoenzyme may affect plasma estrogen concentrations.^{101 129 262} Concomitant use of estrogens with drugs that induce CYP3A4 (e.g., carbamazepine, phenobarbital, rifampin, St. John’s wort [Hypericum perforatum]) may result in decreased plasma concentrations of estrogen, resulting in decreased therapeutic effects and/or changes in uterine bleeding profile.^{101 129 262} Concomitant use of estrogen with drugs or foods that inhibit CYP3A4 (e.g., clarithromycin, erythromycin, grapefruit juice, itraconazole, ketoconazole) may result in increased plasma concentrations of estrogens and an increase in the incidence of adverse effects.^{101 129 262}

Rifampin reportedly decreases estrogenic activity during concomitant use with estrogens. This effect has been attributed to enhanced metabolism of estrogen, presumably by induction of hepatic microsomal enzymes.

Corticosteroids

Estrogens have been reported to enhance the anti-inflammatory effect of hydrocortisone in patients with chronic inflammatory skin diseases. It has been suggested that estrogens may decrease the hepatic metabolism of corticosteroids and/or alter serum corticosteroid protein binding. Patients receiving concomitant estrogen and corticosteroid therapy should be observed for signs of excessive corticosteroid effects, and alterations in corticosteroid dosage may be necessary when estrogens are started or discontinued.

Oral Anticoagulants

Estrogens may decrease the action of oral anticoagulants. When estrogen therapy is initiated in patients receiving anticoagulants, an increase in anticoagulant dosage may be required.

Laboratory Test Interferences

Estrogen-containing oral contraceptives have caused abnormal thyroid function test results. Estrogen-containing oral contraceptives have altered response to the metyrapone test and liver function test results. Estrogen-containing oral contraceptives have also caused decreased pregnanediol excretion.

The manufacturers state that the pathologist should be advised of estrogen use when relevant specimens from a patient exposed to estrogens are submitted.

Acute Toxicity

Acute overdosage of large doses of oral contraceptives in children reportedly produces almost no toxicity except nausea and vomiting. Acute overdosage of estrogens may cause nausea, and withdrawal bleeding may occur in females.

Pharmacology

Estrogens are hormones secreted principally by the ovarian follicles and also by the adrenals, corpus luteum, placenta, and testes, or are synthetic steroidal and nonsteroidal compounds. Estrogenic hormones are secreted at varying rates during the menstrual cycle throughout the period of activity of the ovaries. During pregnancy, the placenta becomes the main source of estrogens. At the menopause, ovarian secretion of estrogens declines at varying rates. The gonadotropins of the anterior pituitary regulate secretion of the ovarian hormones, estradiol and progesterone; hypothalamic control of pituitary gonadotropin production is in turn regulated by plasma concentrations of the estrogens and progesterone. This complex feedback system results in the cyclic phenomenon of ovulation and menstruation.

Estrogen Receptors

Estrogens have an important role in the reproductive, skeletal, cardiovascular, and central nervous systems in women, and act principally by regulating gene expression. Biologic response is initiated when estrogen binds to a ligand-binding domain of the estrogen receptor resulting in a conformational change that leads to gene transcription through specific estrogen response elements (ERE) of target gene promoters; subsequent activation or repression of the target gene is mediated through 2 distinct transactivation domains (i.e., AF-1 and AF-2) of the receptor. The estrogen receptor also mediates gene transcription using different response elements (i.e., AP-1) and other signal pathways. Recent advances in the molecular pharmacology of estrogen and estrogen receptors have resulted in the development of selective estrogen receptor modulators (e.g., clomiphene, raloxifene, tamoxifen, toremifene), agents that bind and activate the estrogen receptor but that exhibit tissue-specific effects distinct from estrogen. Tissue-specific estrogen-agonist or -antagonist activity of these drugs appears to be related to structural differences in their estrogen receptor complex (e.g., specifically the surface topography of AF-2 for raloxifene) compared with the estrogen (estradiol)-estrogen receptor complex. A second estrogen receptor also has been identified, and existence of at least 2 estrogen receptors (ER_α, ER_β) may contribute to the tissue-specific activity of selective modulators. While the role of the estrogen receptor in bone, cardiovascular tissue, and the CNS continues to be studied, emerging evidence indicates that the mechanism of action of estrogen receptors in these tissues differs from the manner in which estrogen receptors function in reproductive tissue.

Intracellular cytosol-binding proteins for estrogens have been identified in estrogen-responsive tissues including the female genital organs, breasts, pituitary, and hypothalamus. The estrogen-binding protein complex (i.e., cytosol-binding protein and estrogen) distributes into the cell nucleus where it stimulates DNA, RNA, and protein synthesis. The presence of these receptor proteins is responsible for the palliative response to estrogen therapy in women with metastatic carcinoma of the breast.

Estrogenic Effects

Exogenous estrogens elicit, to varying degrees, all the pharmacologic responses usually produced by endogenous estrogens. Endogenous estrogens are essential hormones that are responsible for the normal growth and development of the female sex organs and for maintenance of secondary sex characteristics, including the growth and maturation of the vagina, uterus, and fallopian tubes; enlargement of the breasts; maintenance of tone and elasticity of urogenital structures; growth of axillary and pubic hair; and pigmentation of the nipples and genitals.

Although the mechanism(s) has not been elucidated, estrogens contribute to the shaping of body contours and the skeleton, to the growth spurt that occurs during adolescence, and to the eventual termination of linear growth that results from fusion of the epiphyseal centers. Estrogens cause an increase in cell height and secretions of the cervical mucosa, thickening and cornification of the vaginal mucosa, proliferation of the endometrium, and an increase in uterine tone. The estrogen-stimulated endometrium may bleed within 48–72 hours after discontinuance of estrogen therapy. Paradoxically, prolonged estrogen therapy may cause shrinkage of the endometrium and an increase in size of the myometrium.

Menstrual Effects

During the preovulatory or nonovulatory phase of the menstrual cycle, estrogen is the principal determinant in the onset of menstruation. A decline of estrogenic activity at the end of the menstrual cycle also may induce menstruation; however, the cessation of progesterone secretion is the most important factor during the mature ovulatory phase of the menstrual cycle.

Gonadotropic Effects

Although the precise actions of estrogens on secretory activity of the pituitary have not been fully characterized, estrogens affect the release of gonadotropins (e.g., follicle-stimulating hormone [FSH]) from the pituitary, apparently as a result of feedback inhibition; the effect of estrogens on luteinizing hormone (LH) is complex and biphasic. The effects of estrogens on pituitary secretion of gonadotropins result in inhibition of lactation, inhibition of ovulation, development of a proliferative endometrium and, by inhibiting androgen secretion, a reduction of sebaceous secretions.

Anabolic and Metabolic Effects

Estrogens have a weak anabolic effect and may cause sodium retention with associated fluid retention and edema. Estrogens also affect bone by increasing calcium deposition and accelerating epiphyseal closure, following initial growth stimulation.

Cardiovascular Effects

Estrogens have generally favorable effects on blood cholesterol and phospholipid concentrations.^{102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 129 130 131 132 133} Estrogens reduce LDL-cholesterol and increase HDL-cholesterol concentrations in a dose-related manner.^{102 103 104 105 106 129 130 131 132 133} The decrease in LDL-cholesterol concentrations associated with estrogen therapy appears to result from increased LDL catabolism, while the increase in triglyceride concentrations is caused by increased production of large, triglyceride-rich, very-low-density lipoproteins (VLDLs);¹⁰² changes in serum HDL-cholesterol concentrations appear to result principally from an increase in the cholesterol and apolipoprotein A-1 content of HDL₂- and a slight increase in HDL₃-cholesterol.¹⁰²

Results of several clinical studies in postmenopausal women indicate that replacement therapy with unopposed conjugated estrogens (estrogen replacement therapy, ERT) may reduce LDL-cholesterol and increase HDL-cholesterol by about 8–15%; however, use of progestins in conjunction with estrogen (hormone replacement therapy, HRT) may blunt these favorable effects on the lipid profile.^{131 132 133} In a 1-year prospective, randomized, double-blind study in healthy, postmenopausal, predominately white women at low risk for cardiovascular disease, HDL-cholesterol concentrations increased 14.1 or 4.4% in women receiving conjugated estrogens (0.625 mg daily) alone (ERT) or conjugated estrogens (0.625 mg daily) in conjunction with cyclic medroxyprogesterone acetate (5 mg daily on days 15–28 of the cycle) (HRT), respectively;¹³³ decreases in LDL-cholesterol concentrations were similar in women receiving estrogens alone (ERT) or in conjunction with the progestin (HRT).¹³³ In this study, serum triglyceride concentrations increased by 39.4 or 27.5% in women receiving estrogens alone (ERT) or in conjunction with the progestin (HRT), respectively.¹³³ In addition, in a 3-year, placebo-controlled, multicenter study in postmenopausal women, HDL-cholesterol concentrations were higher in patients receiving conjugated estrogens alone (ERT) than in those receiving conjugated estrogens in conjunction with progestins (HRT); HDL-cholesterol concentrations were lower in patients receiving placebo than in those receiving estrogen replacement therapy.^{131 132} Concomitant progestin therapy blunts some of the favorable effects of estrogens on the lipid profile of postmenopausal women.^{130 133}

Although most experience to date on the lipid-lowering effect of estrogens included administration of conjugated estrogens, limited evidence indicates that postmenopausal women who received oral micronized estradiol (2 mg daily for 6 weeks) had changes in LDL- and HDL-cholesterol and triglyceride concentrations that were similar to those produced by low-dose conjugated estrogen therapy, but transdermal estradiol (0.1 mg twice weekly) did not substantially affect serum lipoprotein concentrations.¹⁰²

Other effects of estrogens that may contribute to effects on cardiovascular risk indicators include reduction of insulin and blood glucose concentrations and direct effects on blood vessels.^{108 124 125 131 132 133} Estrogen receptors have been identified in the heart and coronary arteries, suggesting that estrogens may have specific effects on these tissues.^{108 126}

The Women’s Health Initiative (WHI) study provided evidence of increased cardiovascular risk associated with combined estrogen and progestin therapy (HRT).^{231 232 238 239} (See Cautions: Cardiovascular Effects.)

Estrogens General Statement Pharmacokinetics

Absorption

Following oral administration, the natural, unconjugated estrogens are inactivated in the GI tract and liver. Conjugated estrogens and some synthetic derivatives of the natural estrogens may be administered orally. Absorption and metabolism following oral administration of these drugs is rapid and daily doses are usually required. Chlorotrianisene (no longer commercially available in the US), however, has a prolonged duration of action which may result from the storage in and slow release of estrogenically active substance from adipose tissue. Similarly, quinestrol (no longer commercially available in the US) has a prolonged duration of action as a result of its extensive storage in and slow release from adipose tissue.

Following IM administration of estrogen oil solutions, absorption begins promptly and continues for several days. When estrogen is conjugated with aryl and alkyl groups, the rate of absorption of estrogen is slowed.

Estrogens are readily absorbed through the skin and mucous membranes. Depending on the amount of estrogen applied, systemic as well as local effects may occur following topical application.

Distribution

Estrogens are distributed throughout most body tissues. Studies utilizing radioisotopes have indicated that the greatest concentrations of estrogens may occur in the fat deposits of the body; obese patients have demonstrated slower and more prolonged estrogen excretion. Estrogens are 50–80% bound to plasma proteins. Estriol is bound less to plasma proteins than is estrone or estradiol but all 3 estrogens are bound to approximately the same extent by erythrocytes. Studies using radioisotopes have demonstrated a rapid transfer of free estrone and estradiol between mother and fetus. Fetal estrogens appear to originate principally from the placenta and mother.

Elimination

The steroidal estrogens are metabolized principally in the liver, although the kidneys, gonads, and muscle tissues may be involved to some extent. The steroids and their metabolites are conjugated at the hydroxyl group of the C 3 position with sulfuric or glucuronic acid; these conjugates may undergo further metabolic change. Conjugation increases water solubility and facilitates excretion in urine. Large amounts of free estrogens are also distributed into the bile, reabsorbed from the GI tract, and recirculated through the liver where further degradation occurs. Estrogens and their metabolites are excreted mainly in urine; however, small amounts are also present in feces.

The metabolic fate of the synthetic estrogens has not been fully elucidated. Diethylstilbestrol (no longer commercially available in the US) metabolism, however, appears to be similar to that of the natural estrogens with the drug being excreted mainly as the glucuronide in urine.

Chemistry

Estrogens are naturally occurring hormones or synthetic steroidal and nonsteroidal compounds with estrogenic activity. The estrogens can be divided into 2 groups based on their chemical structures: steroidal and nonsteroidal compounds. All naturally occurring estrogens are steroids that contain a cyclopentanoperhydrophenanthrene ring structure with an unsaturated A ring, a methyl group at the C 13 position, a phenolic hydroxyl group at the C 3 position, and a ketone or hydroxyl group at the C 17 position. Only a limited number of changes can be made in this basic steroid structure without losing estrogenic activity. These changes are limited to an interconversion of the hydroxyl and ketone groups or the addition of various side chains at the C 3 and C 17 positions.

The natural steroidal estrogens (estradiol, estrone, estriol, equilin, and equilenin) and their conjugates are usually obtained from pregnant mares’ urine or prepared synthetically. The natural steroidal estrogens, both those obtained exclusively from natural sources and those prepared synthetically, are insoluble in water but when conjugated as the sulfates or glucuronides, these hormones become water soluble. Synthetic derivatives of the natural steroidal estrogens were previously available. The nonsteroidal estrogens include diethylstilbestrol (DES) (no longer commercially available in the US) and dienestrol (no longer commercially available in the US).

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