Hormone Replacement Therapy
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Estrogens and progestins are steroid hormones produced primarily by the ovaries in women. They bind to their corresponding receptors on the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. In postmenopausal women, estrogens are administered at dosages to elicit all the actions of endogenous estrogens and relieve menopause-related symptoms, including hot flashes. Estrogens increase cervical secretions, cause proliferation of the endometrium, increase uterine tone, and prevent postmenopausal osteoporosis; they help preserve bone density but do not reverse existing osteoporosis.
A progestin is a recommended addition to estrogen-based HRT in women with a uterus to reduce endometrial overgrowth/hyperplasia and the incidence of endometrial cancer. Progestins reduce endometrial growth and risk of endometrial cancer by converting the endometrium from proliferative to secretory. Differences in structure, potencies, and receptor (androgen, glucocorticoid, and mineralocorticoid) affinities may have any impact on the safety and efficacy of the available progestins. Newer progestins are expected to be more receptor selective, and over time the issue of relative potency may be less relevant than it was with older progestins.
Bazedoxifene is a selective estrogen receptor modifier (SERM). The drug is an estrogen agonist/antagonist. It acts as an agonist in some estrogen-sensitive tissues and an antagonist in others (e.g., uterus). In postmenopausal women taking estrogens, bazedoxifene helps reduce endometrial overgrowth/hyperplasia.
Progestin Comparisons         
Progesterone Derivatives (Pregnanes)
19 - Nortestosterone Derivatives (Estranes)
19 - Norgestrel (Gonanes)
Starting Dosages and Dosage Ranges for FDA-approved HRT*
0.3 mg - 0.45 mg/day PO
0.3 mg - 1.25 mg/day PO
0.5 mg - 2 mg/day PO
0.75 mg - 6 mg/day PO
0.25 to 0.5 mg/day PO
5 mg to 10 mg/day PO 10 to 14 days/month
2.5 mg to 5 mg/day PO
0.09 mg/day for 3 days, given at 3 day intervals
0.1 mg or 0.5 mg/day PO
200 mg/day PO in the evening 12 days/month
100 mg/day PO in the evening
20 mg/day PO
* Testosterone dosages are not included, as HRT combinations containing methyltestosterone or other androgens have not been found by FDA to be safe and effective, and the labeling of those products has not been FDA-approved.
Guidelines consider all estrogen and estrogen-progestin therapies equally efficacious for accepted indications in postmenopausal women. Some studies may be able to delineate advantages of certain HRT formulations (e.g., transdermal versus oral) over one another in clinical use with respect to side effects. However, in the absence of comparable data the known risks of estrogen should be assumed to be similar. There is no evidence that the use of natural estrogens or "bioidentical HRT" results in a different clinical risk profile than synthetic estrogens of equivalent estrogen dose. For women aged younger than 60 years or who are within 10 years of the onset of menopause and have no contraindications, estrogen-based HRT may be considered for treatment of bothersome vasomotor symptoms and for those patients at elevated risk for osteoporosis for the prevention of osteoporosis. Periodic reevaluation for benefit-risk is needed. Patients must be included in decisions and informed of potential risks, including risks for cancer. For women who initiate HRT more than 10 or 20 years from menopause onset or are 60 years or older, the benefit-risk ratio is not as favorable because of the increased absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia. For women with bothersome genitourinary symptoms alone, low-dose vaginal estrogen therapy or other therapies are recommended. All guidelines emphasize individualization of therapy. Use the lowest effective dose consistent with treatment goals that provides benefits and minimizes risks for the individual woman.
Hormone Replacement Therapy Comparative Trials of Interest
Writing Group for the PEPI Trial. JAMA 1995;273:199-208.15:1145-1150.
Three-year, multicenter, randomized, double-blind, placebo-controlled study conducted to compare placebo, unopposed estrogen, 3 estrogen/progestin combination therapies on risk factors for cardiovascular disease in postmenopausal women aged 45 to 64 years with or without a uterus. Postmenopausal Estrogen/Progestin Intervention (PEPI) Study.
Placebo: n= 174
CEE 0.625 mg/day: n= 175
CEE 0.625 mg/day plus cyclic MPA 10 mg/day for 12 days/month: n = 174
CEE 0.625 mg/day plus continuous MPA 2.5 mg/day: n = 174
CEE 0.625 mg/day plus cyclic MP 200 mg/day for 12 days/month: n = 178
Change in HDL-Cholesterol Levels
Placebo: - 1.2 mg/dL
CEE: 5.6 mg/dL
CEE + Cyclic MPA: 1.6 mg/dL
CEE + Cont MPA: 1.4 mg/dL
CEE + Cyclic MP: 4.1 mg/dL
Change in LDL-Cholesterol Levels
Placebo: - 4.1 mg/dL
CEE: -14.5 mg/dL
CEE + Cyclic MPA: -17.7 mg/dL
CEE + Cont MPA: -16.5 mg/dL
CEE + Cyclic MP: -14.8 mg/dL
Change in Total Cholesterol Levels
Placebo: - 4.2 mg/dL
CEE: -7.6 mg/dL
CEE + Cyclic MPA: -14.1 mg/dL
CEE + Cont MPA: -14 mg/dL
CEE + Cyclic MP: -7.8 mg/dL
Change in Triglyceride Levels
Placebo: - 3.2 mg/dL
CEE: 13.7 mg/dL
CEE + Cyclic MPA: 12.7 mg/dL
CEE + Cont MPA: 11.4 mg/dL
CEE + Cyclic MP: 13.4 mg/dL
No significant differences in blood pressure changes of fasting and 2 hour insulin among treatments.
Significant decrease in fasting glucose seen with all active treatments compared to placebo.
Significant increases in 2 hour glucose seen in all active treatments compared to placebo. CEE with either cyclic or continuous MPA had greatest differences compared to placebo.
Placebo significantly increased fibrinogen levels compared to active treatments; greatest difference seen between placebo and CEE alone. No significant differences between active treatment groups.
CEE + cyclic MP had least effect on HDL-cholesterol levels compared to CEE +cyclic MPA and CEE + continuous MPA.
Canonico M, et al. Arterioscler Thromb Vasc Biol 2010;30:340-345.
E3N Cohort Study
Prospective cohort study conducted to evaluate the risk of venous thromboembolism with oral or transdermal estrogen and different progestin types among postmenopausal women.
Pregnane progestins include medroxyprogesterone, dydrogesterone, medrogestone, chlormadinone acetate and cyproterone.
Norpregnane progestins include nomegesterol acetate and promegesterone.
Nortestostererone progestin derivatives includes norethinedrone acetate.
Total number of cases = 549
Total number of person years = 811,643
Age-Adjusted Hazard Ratios (95% CI) for Idiopathic Venous Thromboembolism
Oral Estrogen: 1.5 (0.9 to 2.3)
Transdermal Estrogen: 1.1 (0.7 to 1.6)
MP: 0.9 (0.6 to 1.4)
Pregnanes: 1.3 (0.8 to 1.9)
Norpregnanes: 1.7 (1.1 to 2.6)
Nortestosterones: 1.4 (0.8 to 2.5)
Multiple Variable Adjusteda Hazard Ratios (95% CI) for Idiopathic Venous Thromboembolism
Oral Estrogen: 1.7 (1.1 to 2.8)
Transdermal Estrogen: 1.1 (0.8 to 1.8)
MP: 0.9 (0.6 to 1.5)
Pregnanes: 1.3 (0.9 to 2.0)
Norpregnanes: 1.8 (1.2 to 2.7)
Nortestosterones: 1.4 (0.7 to 2.4)
Transdermal estrogen had a lower rate of venous thromboembolism compared to oral estrogen therapy.
Nonpregnane progestin derivatives had a higher rate of venous thromboembolism compared to MP and pregnane and nortestosterone progestin derivatives.
Total Cases = 23,505
Total Controls = 231,562
More cases were overweight, had varicose veins or experienced immobilization, surgery or trauma in month prior to index date and diagnosed with cancer within previous year.
Adjusted Rate Ratio (95% CI) for Venous Thromboembolism
Oral: 1.49 (1.37 to 1.63)
Transdermal: 1.01 (0.89 to 1.16)
Oral: 1.54 (1.44 to 1.65)
Patch: 0.96 (0.77 to 1.2)
Progestin: 1.9 (1.14 to 3.17)
Adjusted Rate Ratio (95% CI) for Venous Thromboembolism By Estrogen Dose
Low Dose: 1.19 (1.04 to 1.35)
High Dose: 1.55 (1.45 to 1.65)
Very High Dose: 1.84 (1.63 to 2.09)
Low Dose: 0.99 (0.87 to 1.12)
High Dose: 1.05 (0.81 to 1.36)
Slightly higher risk of thromboembolism seen with use of pregnane versus nortestosterone derivatives.
Adjusted Rate Ratio (95% CI) for Venous Thromboembolism Based on Time Since Discontinuation or Therapy
< 1 month: 1.43 (1.23 to 1.66)
1 – 4 months: 1.27 (1.11 to 1.45)
> 4 months: 0.98 (0.87 to 1.11)
Risk of thromboembolism not increased after discontinuation with transdermal therapy.
Risk of thromboembolism was approximately 2-fold during first year of use with oral estrogen with or without progestin; risk decreased after 1 year.
Transdermal estrogen therapy associated with a lower rate of venous thromboembolism compared to oral estrogen therapy.
Risk of thromboembolism increased with increased oral estrogen doses; this increased risk was not found with transdermal estrogen.
Thromboembolic risk remained elevated within 4 months after discontinuation of oral estrogen therapy; this was not found with transdermal therapy.
Abbreviations: CEE = conjugated equine estrogen, MP = micronized progesterone, MPA = medroxyprogesterone acetate, HRT = hormone replacement therapy, Cont = continuous
athe variables were age, body mass index, parity, education level and time period; bresults for tibolone not provided as not FDA-approved in the U.S.
To minimize the incidence of adverse effects, hormone replacement therapy should be initiated at the lowest dose and titrated to relief of menopausal symptoms. Breakthrough vaginal bleeding, spotting, withdrawal bleeding (with cyclic progestin administration), menorrhagia, dysmenorrhea, vaginitis, vaginal discharge and vaginal candidiasis are commonly reported with hormone replacement therapy. Symptoms should taper and stabilize over 3 to 6 months; symptoms that persist beyond 6 months should be evaluated.
Estrogen-only hormone replacement therapy is associated with an increased risk of endometrial hyperplasia and endometrial cancer at all doses when taken in women with an intact uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15-to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. With concurrent progestin use (cyclically or continuously) or concurrent bazedoxifene use, the incidence of endometrial hyperplasia due to estrogen therapy is estimated to be 1% or less.
The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the Womens Health Initiative (WHI) study. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily estrogen monotherapy was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80]. The most important randomized clinical trial providing information about breast cancer in patients taking combined estrogen-progestin HRT regimens is the WHI study. After a mean follow-up of 5.6 years, the WHI estrogen-progestin substudy reported an increased risk of invasive breast cancer in women who took daily estrogen-progestin vs. placebo. In this substudy, prior use of estrogen-alone or estrogen-progestin therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 vs. 33 cases per 10,000 women-years, for estrogen-progestin compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years for estrogen-progestin vs. placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for estrogen-progestin compared with placebo. In the same WHI substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the combined HRT group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the 2 groups. Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen-progestin HRT, and a smaller increased risk for unopposed estrogen therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with combined HRT as compared to estrogen-alone therapy. These studies have not found significant variation in the risk of breast cancer among different estrogen-progestin HRT combinations, doses, or routes of administration. Micronized progesterone may be associated with a lower risk of breast cancer compared to synthetic progestins, at least with short-term treatment; however, further research is needed.
The Women's Health Initiative (WHI) estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer in women taking combined hormone replacement therapy (HRT). After an average follow-up of 5.6 years, the relative risk for ovarian cancer for estrogen (conjugated estrogens, CE) plus a progestin (medroxyprogesterone, MPA) versus placebo was 1.58 (95% CI, 0.77 to 3.24). The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years. A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used HRT for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risk associated with current use of hormonal therapy was 1.41 (95% CI, 1.32 to 1.5); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI, 1.27 to 1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.
An increased risk of cerebrovascular disease (stroke) and deep venous thrombosis (DVT) has been reported with unopposed estrogen therapy. An increased risk of thromboembolism, including pulmonary embolism (PE), DVT, stroke and myocardial infarction (MI) has been reported with estrogen-progestin hormone replacement therapy (HRT). A positive relationship between estrogen use and an increased risk for thromboembolism has long been demonstrated. In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily unopposed estrogen compared to placebo (30 vs. 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 vs. 15 per 10,000 women years). The increase in VTE risk was demonstrated during the first 2 years. In the WHI estrogen-progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving estrogen-progestin HRT vs. placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. Estrogens with or without progestins should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease). In the Women's Health Initiative (WHI) estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or CHD death ) was reported in women receiving conjugated estrogen-alone vs. placebo. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (estrogen-alone vs. placebo) in women with less than 10 years since menopause (8 vs. 16 per 10,000 women-years). In the WHI estrogen-progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. Studies have also shown no cardiovascular benefit to the use of estrogens or estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD. Estrogens also increase the risk for stroke. In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen-alone vs. placebo (45 vs. 33 per 10,000 women-years). The increase in risk was demonstrated in the first year and persisted. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving estrogen-alone vs. placebo (18 vs. 21 per 10,000 women-years). In the WHI estrogen-progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen-progestin HRT vs. placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women over the age of 65 years were at increased risk for non-fatal stroke. Data from randomized controlled trials show that estrogen-based HRT increases the risk of ischemic stroke, but has no effect on the rate of stroke recurrence or hemorrhagic stroke in healthy postmenopausal women. Transdermal estrogen may be associated with a lower incidence of thromboembolism, stroke, and myocardial infarction compared to oral administration; however, additional research is needed to determine the actual risk with transdermal therapy versus no estrogen/hormone replacement therapy. In a large, multinational study of women taking HRT, drospirenone-estradiol combinations in postmenopausal women were associated with general health risks similar to other estrogen-progestin HRT regimens with a trend toward a lower arterial thromboembolism risk and thus a lower risk for serious cardiovascular-related events.
Estrogen-based HRT regimens may cause idiosyncratic increases in blood pressure in some patients. Drospirenone-estradiol combinations may lower the risk for fluid retention and blood pressure increases in postmenopausal women with hypertension. Of the available progestins, micronized progesterone and drospirenone therapy may increase HDL cholesterol. In contrast, medroxyprogesterone, norethindrone, norethindrone acetate and levonorgestrel may decrease HDL cholesterol and triglycerides. Additionally, non-oral routes of administration of estrogens, such as transdermal, avoid first-pass hepatic metabolism resulting in more consistent blood concentration and may avoid the increases in triglycerides seen with oral estrogen therapy. For this reason, transdermal estrogen may be preferred in patients with hypertriglyceridemia.
Headaches/migraines may be hormonally mediated; thus, hormone replacement may result in the development of headaches/migraines, alter the frequency, duration or severity of existing migraines or decrease the occurrence of migraines.
Diarrhea, dyspepsia, flatulence, nausea, vomiting and abdominal cramps or bloating have been reported. Gallbladder disease, biliary obstruction, cholestatic jaundice, cholelithiasis and cholecycstitis have been reported. Hepatitis, elevated hepatic enzymes, enlargement of hepatic hemangiomas, bowel ischemia due to mesenteric thrombosis, peliosis hepatis, and pancreatitis are rare adverse reactions to estrogen-based hormone replacement. Discontinue hormone replacement therapy and evaluate the individual if jaundice, cholestasis or severe abdominal pain occur.
Hormone replacement therapy, both estrogen plus progestin and estrogen only therapy, fails to prevent mild cognitive impairment (memory loss) and is positively associated with the risk of developing dementia in women 65 years or older.
Mental depression, dizziness, fatigue or asthenia, nervousness or anxiety, insomnia and paresthesias have all been reported with hormone replacement therapy.
In-vitro and in-vivo studies have shown that estrogens and progestins are metabolized partially by CYP3A4. Therefore, inducers or inhibitors of CYP3A4 may affect estrogen and progestin drug metabolism. Inducers of CYP3A4 such as St. John's wort (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens and progestins, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice, may increase plasma concentrations of the estrogen and/or the progestin and may result in side effects.
Estrogen therapy is not recommended during aromatase inhibitor treatment (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) or selective estrogen receptor modulator (SERM) treatment (e.g., tamoxifen, raloxifene) for hormonally-responsive cancers due to opposing pharmacologic actions and potential reduction in efficacy of the cancer treatment. Bazedoxifene is a SERM and should not be used with other SERMs or with progestins.
A subtherapeutic response to metyrapone can be seen in patients on estrogen therapy. When metapyrone is used as a diagnostic drug for testing hypothalamic-pituitary ACTH function, the effect of estrogen may need to be considered, or, another diagnostic test chosen. If possible, consider discontinuing estrogen use before and during testing. During use for Cushing's syndrome, estrogen therapy may increase cortisol levels, which may attenuate the response to metyrapone treatment.
Estrogen-based hormone replacement therapy (HRT) products are contraindicated in patients with an active thromboembolic condition or a history of stroke, cerebrovascular disease, coronary artery disease, coronary thrombosis, thrombophlebitis, thromboembolic disease (including pulmonary embolism and DVT), or valvular heart disease with complications. Concurrent use of HRT in female patients receiving anticoagulation with warfarin is generally avoided. The Women's Health Initiative Trials demonstrated a positive relationship between estrogen-based HRT and the risk of thromboembolic disease. Estrogens increase the hepatic synthesis of prothrombin and factors VII, VIII, IX, and X and decrease antithrombin III; estrogens also increase norepinephrine-induced platelet aggregability. Carefully monitor the INR and for signs and symptoms of thromboembolic complications if the use of estrogen HRT and warfarin is not avoidable. If thromboembolic events occur, discontinue the HRT regimen. Estrogen-based HRT regimens are generally not expected to alter the INR significantly or to affect the hepatic metabolism of warfarin. Base dosage adjustment of warfarin on the measured INR value and clinical response.   
Drospirenone is a spironolactone derivative with antimineralocorticoid effects and may increase serum potassium levels. Thus concurrent administration of drospirenone and potassium containing products (e.g., potassium iodide, potassium salts, dietary salt substitutes), other potassium containing medications (e.g., antibiotics), potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor antagonists or eplerenone may increase the risk of hyperkalemia, especially in the prescence of renal impairment. Monitor serum potassium levels if these drugs are use concurrently with drospirenone; estradiol, particularly during the first month of therapy.
Hormone replacement therapy (HRT) is contraindicated in patients with an active or past history of stroke, thrombophlebitis, thromboembolic disease, or myocardial infarction (MI). Estrogens are also contraindicated in patients with known thrombophilic disorders, such as protein C deficiency, protein S deficiency and antithrombin deficiency, associated with increased risk of venous thromboembolism (VTE). Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, MI, and stroke have been reported with estrogens and/or progestin therapy. Other risk factors for thromboembolism include history of thromboembolism, being overweight or obese, having factor V Leiden, smoking, and older age. Data suggest there is a lower risk of VTE with transdermal than with oral estrogen. Risk of thromboembolism appears to increase with increased estrogen doses. Because certain major surgical procedures and immobilization are associated with increased risk of thromboembolism, estrogens should be discontinued several weeks prior to major surgery or if prolonged immobilization will occur. The decision regarding when to resume estrogens after such procedures or conditions would be based on the perceived additional thromboembolic risk from estrogen use and the need for estrogen therapy; resume only after the patient is fully ambulatory. In addition, women taking estrogens should be advised to move about periodically during travel that involves prolonged immobilization.
The data regarding the impact of hormone replacement therapy (HRT) on cardiovascular (CV)-related events appear to differ with the timing of therapy initiation, duration of treatment, patient age, choice of therapy (combination estrogen/progestin therapy vs. estrogen monotherapy), and the progestin chosen for use. However, the data clearly suggest that HRT should not be used for either primary or secondary prevention of cardiovascular disease. In the Women's Health Initiative (WHI) estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or CHD death) was reported in women receiving conjugated estrogen-alone vs. placebo. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (estrogen-alone vs. placebo) in women with less than 10 years since menopause (8 vs. 16 per 10,000 women-years). In the WHI estrogen-progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. Initiation of HRT within 10 years of menopause or aged 50 to 59 years may result in a lack of effect on or slight reduction in CHD in contrast to starting therapy 20 or more years after menopause or in patients 70 years of age and older, which may result in an increased risk. 
Estrogens are contraindicated in patients with known, suspected or history of breast cancer, endometrial cancer, endometrial hyperplasia, ovarian cancer, uterine cancer, vaginal cancer, other estrogen-responsive tumors and undiagnosed, abnormal vaginal bleeding. Numerous epidemiologic studies have examined the effects of estrogen and estrogen-progestin hormone replacement therapy (HRT) on the development of new primary malignancy (e.g., breast cancer, endometrial cancer, ovarian cancer) in postmenopausal women. The risk for endometrial cancer is increased in women who take unopposed estrogen. Adding a progestin to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. The Women's Health Initiative (WHI) estrogen plus progestin study reported increased risks of invasive breast cancer in patients taking combined estrogen-progestin HRT vs. placebo. The potential risk of breast cancer may increase with longer duration of use. Women who used hormonal therapy for menopausal symptoms also had an increased risk for ovarian cancer, but data are still uncertain if risk is associated with a specific duration of use. Caution should be utilized with estrogen use in patients with uterine leiomyomata (fibroids) or endometriosis since they may exacerbate fibroid or endometrial growth. All women receiving hormone replacement therapy should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography should be scheduled based on patient age, risk factors, and prior mammogram results. Pelvic examinations and associated diagnostic procedures should be used for clinical surveillance as clinically indicated per standards of care.
Changes in blood pressure (increase with estrogen and estrogen/progestin therapies and possible decrease with drospirenone) may occur with the initiation of hormone replacement therapy (HRT); patients with hypertension should be closely monitored for changes. Data indicate in most patients the change is not clinically significant. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. In the PEPI trial, postmenopausal women 45 to 65 years of age randomized to any HRT regimen experienced increases in both systolic and diastolic blood pressure of 3% to 5% after the first year of treatment, but the increases were not statistically different from placebo. Non-oral estrogen, such as transdermal estrogen, avoids first-pass hepatic metabolism resulting in more consistent blood concentration and may avoid the increases in angiotensinogen seen with oral estrogen therapy. For this reason, transdermal estrogen may be preferred in patients with hypertension.
Hormone replacement therapy (HRT) is contraindicated in the presence of hepatocellular cancer, hepatic adenoma, jaundice, hepatic insufficiency or hepatic disease. Estrogens may be poorly metabolized in women with impaired liver function. Estrogens may induce cholestatic jaundice. Rare adverse reactions include hepatitis (and elevated hepatic enzymes), enlargement of hepatic hemangiomas, ischemic colitis, or pancreatitis. Patients with familial hyperlipoproteinemia may be at greater risk of pancreatitis while on estrogen therapy, which may greatly increase their serum triglycerides. Estrogens may induce peliosis hepatis, a very rare consequence of taking estrogens and combined oral contraceptives that is characterized by the presence of blood-filled spaces. Persistent or severe abdominal symptoms should be evaluated by a medical professional. Estrogens should be discontinued in any patient developing jaundice, cholestasis, or severe abdominal pain, and the patient should be evaluated.
Estrogens may increase the risk of gallbladder disease; a 2- to 4-fold increase in the risk of gallbladder disease requiring surgery (e.g., cholecystitis) in postmenopausal women receiving estrogens has been reported. The attributable risk for gallbladder disease as self-reported in the Women's Health Initiative (WHI) was an additional 47 cases per 10,000 women per year for estrogen plus progestin and 58 cases per 10,000 women per year for estrogen alone, both statistically significant (p is less than 0.001). Similar increases in gallbladder disease have not been reported with transdermally administered estradiol, perhaps due to the fact that estradiol does not appear to increase saturation of cholesterol in the bile when administered by this route.
Drospirenone is a progestin with antimineralocorticoid activity that may increase serum potassium levels or impair adrenal function; thus, HRT products containing drospirenone are contraindicated in patients with renal impairment, renal failure, renal disease or adrenal insufficiency. Caution should be utilized if drospirenone is coadministered with other medications that may increase potassium levels. Monitor serum potassium levels in patients at risk for elevations, particularly during the first month of therapy. Drospirenone may cause hyponatremia in high-risk patients.
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