The most common side effects of<unk>  in general include breast tenderness, breast enlargement, headache, nausea, fluid retention, and edema. In women,<unk>  can additionally cause vaginal bleeding, vaginal discharge, and anovulation, whereas in men,<unk>  can additionally cause gynecomastia (male breast development), feminization, demasculinization, sexual dysfunction (reduced libido and erectile dysfunction), hypogonadism, testicular atrophy, and infertility.<unk>  can or may increase the risk of uncommon or rare but potentially serious issues including endometrial hyperplasia, endometrial cancer, cardiovascular complications (e.g., blood clots, stroke, heart attack), cholestatic hepatotoxicity, gallbladder disease (e.g., gallstones), hyperprolactinemia, prolactinoma, and dementia. These adverse effects are moderated by the concomitant use of a progestogen, the type of progestogen used, and the dosage and route of<unk> used. Around half of women with epilepsy who menstruate have a lowered seizure threshold around ovulation, most likely from the heightened<unk> levels at that time. This results in an increased risk of seizures in these women. Long-term effects Endometrial hyperplasia and cancer Unopposed<unk> therapy stimulates the growth of the endometrium and is associated with a dramatically increased risk of endometrial hyperplasia and endometrial cancer in postmenopausal women. The risk of endometrial hyperplasia is greatly increased by 6 months of treatment ( = 5.4) and further increased after 36 months of treatment ( = 16.0). This can eventually progress to endometrial cancer, and the risk of endometrial cancer similarly increases with duration of treatment (less than one year, = 1.4; many years (e.g., more than 10 years), = 15.0). The risk of endometrial cancer also stays significantly elevated many years after stopping unopposed<unk> therapy, even after 15 years or more ( = 5.8). Progestogens prevent the effects of<unk>  on the endometrium. As a result, they are able to completely block the increase in risk of endometrial hyperplasia caused by<unk> therapy in postmenopausal women, and are even able to decrease it below baseline ( = 0.3 with continuous<unk> progestogen therapy). Continuous<unk> progestogen therapy is more protective than sequential therapy, and a longer duration of treatment with continuous therapy is also more protective. The increase in risk of endometrial cancer is similarly decreased with continuous<unk> progestogen therapy ( = 0.2–0.7). For these reasons, progestogens are always used alongside<unk>  in women who have intact uteruses. Cardiovascular events<unk>  affect liver protein synthesis and thereby influence the cardiovascular system. They have been found to affect the production of a variety of coagulation and fibrinolytic factors, including increased factor IX, von Willebrand factor, thrombin–antithrombin complex (TAT), fragment 1+2, and D-dimer and decreased fibrinogen, factor VII, antithrombin, protein S, protein C, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1). Although this is true for oral<unk>  transdermal estradiol has been found only to reduce PAI-1 and protein S, and to a lesser extent than oral<unk>  Due to its effects on liver protein synthesis, oral<unk> is procoagulant, and has been found to increase the risk of venous thromboembolism (VTE), including of both deep vein thrombosis (DVT) and pulmonary embolism (PE). Conversely, modern oral contraceptives are not associated with an increase in the risk of stroke and myocardial infarction (heart attack) in healthy, non-smoking premenopausal women of any age, except in those with hypertension (high blood pressure). However, a small but significant increase in the risk of stroke, though not of myocardial infarction, has been found in menopausal women taking hormone replacement therapy. An increase in the risk of stroke has also been associated with older high-dose oral contraceptives that are no longer used. Menopausal hormone therapy with replacement dosages of<unk>  and progestogens has been associated with a significantly increased risk of cardiovascular events such as VTE. However, such risks have been found to vary depending on the type of<unk> and the route of administration. The risk of VTE is increased by approximately 2-fold in women taking oral<unk> for menopausal hormone therapy. However, clinical research to date has generally not distinguished between conjugated<unk>  and estradiol. This is of importance because conjugated<unk>  have been found to be more resistant to hepatic metabolism than estradiol and to increase clotting factors to a greater extent. Only a few clinical studies have compared oral conjugated<unk>  and oral estradiol. Oral conjugated<unk>  have been found to possess a significantly greater risk of thromboembolic and cardiovascular complications than oral estradiol ( = 2.08) and oral esterified<unk>  ( = 1.78). However, in another study, the increase in VTE risk with 0.625 mg/day oral conjugated<unk>  plus medroxyprogesterone acetate and 1 or 2 mg/day oral estradiol plus norethisterone acetate was found to be equivalent ( = 4.0 and 3.9, respectively). Other studies have found oral estradiol to be associated with an increase in risk of VTE similarly ( = 3.5 in one, = 3.54 in first year of use in another). As of present, there are no randomized controlled trials comparing oral conjugated<unk>  and oral estradiol in terms of thromboembolic and cardiovascular risks that would allow for unambiguous conclusions, and additional research is needed to clarify this issue. In contrast to oral<unk>  as a group, transdermal estradiol at typical menopausal replacement dosages has not been found to increase the risk of VTE or other cardiovascular events. Both combined birth control pills (which contain ethinylestradiol and a progestin) and pregnancy are associated with about a 4-fold increase in risk of VTE, with the risk increase being slightly greater with the latter ( = 4.03 and 4.24, respectively). The risk of VTE during the postpartum period is 5-fold higher than during pregnancy. Other research has found that the rate of VTE is 1 to 5 in 10,000 woman-years in women who are not pregnant or taking a birth control pill, 3 to 9 in 10,000 woman-years in women who are on a birth control pill, 5 to 20 in 10,000 women-years in pregnant women, and 40 to 65 in 10,000 women-years in postpartum women. For birth control pills, VTE risk with high doses of ethinylestradiol (>50 μg, e.g., 100 to 150 μg) has been reported to be approximately twice that of low doses of ethinylestradiol (e.g., 20 to 50 μg). As such, high doses of ethinylestradiol are no longer used in combined oral contraceptives, and all modern combined oral contraceptives contain 50 μg ethinylestradiol or less. The absolute risk of VTE in pregnancy is about 0.5 to 2 in 1,000 (0.125%). Aside from type of<unk> and the route of administration, the risk of VTE with oral<unk> is also moderated by other factors, including the concomitant use of a progestogen, dosage, age, and smoking. The combination of oral<unk> and a progestogen has been found to double the risk of VTE relative to oral<unk> alone ( = 2.05 for<unk> monotherapy, and = 2.02 for combined<unk> progestogen therapy in comparison). However, while this is true for most progestogens, there appears to be no increase in VTE risk relative to oral<unk> alone with the addition of oral progesterone or the atypical progestin dydrogesterone. The dosage of oral<unk> appears to be important for VTE risk, as 1 mg/day oral estradiol increased VTE incidence by 2.2-fold while 2 mg/day oral estradiol increased VTE incidence by 4.5-fold (both in combination with norethisterone acetate). The risk of VTE and other cardiovascular complications with oral<unk> progestogen therapy increases dramatically with age. In the oral conjugated<unk>  and medroxyprogesterone acetate arm of the WHI, the risks of VTE stratified by age were as follows: age 50 to 59, = 2.27; age 60 to 69, = 4.28; and age 70 to 79, = 7.46. Conversely, in the oral conjugated<unk>  monotherapy arm of the WHI, the risk of VTE increased with age similarly but was much lower: age 50 to 59, = 1.22; age 60 to 69, = 1.3; and age 70 to 79, = 1.44. In addition to menopausal hormone therapy, cardiovascular mortality has been found to increase considerably with age in women taking ethinylestradiol-containing combined oral contraceptives and in pregnant women. In addition, smoking has been found to exponentially increase cardiovascular mortality in conjunction with combined oral contraceptive use and older age. Whereas the risk of cardiovascular death is 0.06 per 100,000 in women who are age 15 to 34 years, are taking a combined oral contraceptive, and do not smoke, this increases by 50-fold to 3.0 per 100,000 in women who are age 35 to 44 years, are taking a combined oral contraceptive, and do not smoke. Moreover, in women who do smoke, the risk of cardiovascular death in these two groups increases to 1.73 per 100,000 (29-fold higher relative to non-smokers) and 19.4 per 100,000 (6.5-fold higher relative to non-smokers), respectively. Although<unk>  influence the hepatic production of coagulant and fibrinolytic factors and increase the risk of VTE and sometimes stroke, they also influence the liver synthesis of blood lipids and can have beneficial effects on the cardiovascular system. With oral estradiol, there are increases in circulating triglycerides, HDL cholesterol, apolipoprotein A1, and apolipoprotein A2, and decreases in total cholesterol, LDL cholesterol,
Estrogen 
Estradiol 
Estradiol
Androgen
Sex hormone
Progesterone
Progesterone 
Estriol