Darrell Hulisz, RPh, PharmD; Melissa Lagzdins, RPh, PharmD


US Pharmacist. 2008;33(9):HS11-HS20. 

In This Article

Estrogens and Progestins

Chronic use of oral contraceptives may slightly raise blood pressure in certain women and may have other adverse effects on cardiovascular risk. Early epidemiologic studies using high-dose estrogen found mean elevations in blood pressure of 3 to 6 mmHg systolic and 2 to 5 mmHg diastolic, with approximately 5% of women developing new hypertension.[24] This was more likely to occur in patients who had previously developed hypertension during a pregnancy or in those with a family history of hypertension. Although the rise in blood pressure is usually mild, malignant hypertension can occur.[25] The main concern with an oral contraceptive-induced rise in blood pressure is the development of persistent hypertension and subsequent premature cardiovascular disease, especially in women who smoke. Cessation of therapy typically leads to a return to baseline blood pressure within two to 12 months, but proteinuria may persist.[25,26]

The mechanisms responsible for the hypertensive effect of oral contraceptives are poorly understood. The renin-angiotensin system may be involved, since estrogen stimulates the hepatic production of the renin substrate angiotensinogen.[27] Both estrogen and progesterone appear to contribute in a dose-dependent fashion. The often-quoted 5% incidence of hypertension associated with estrogen is derived from studies of highdose therapy in which the estrogen dose was at least 50 mcg and the progestin dose was 1 to 4 mg.[24] However, current preparations contain as little as 20% of the amount of estrogen and progestin used in previous preparations. A report from the Nurses' Health Study prospectively evaluated almost 70,000 female nurses, aged 25 to 42 years.[28] After adjustment for age, weight, smoking, family history, and other risk factors, the relative risk of hypertension in the nurses compared to women who never used oral contraceptives was 1.8 for current users and 1.2 for previous users. Overall, only 41.5 cases of hypertension per 10,000 person-years could be attributed to oral contraceptive use, and this number rapidly declined with cessation of therapy. In a meta-analysis of 14 studies published between 1980 and 2003, the relative risk of stroke and heart attack increased twofold in current users of oral contraceptives (<50 mcg of ethinyl estradiol daily).[29]

Postmenopausal estrogen replacement therapy (ERT), or hormone replacement therapy (HRT) when combined with progestin, consists of much lower estrogen doses than those in oral contraceptives. ERT and HRT appear to have a neutral effect on blood pressure as illustrated by the following observations from two large randomized trials. The Women's Health Initiative (WHI) is the largest (N = 16,000) randomized, placebo-controlled trial that has evaluated the effect of estrogen-progestin replacement on outcomes in postmenopausal women.[30] At 5.2 years, HRT produced only a small increase (1.5 mmHg) in systolic pressure compared to placebo. Similar findings were noted in the PEPI trial in which ERT, with or without progestins, did not affect blood pressure at three years.[31]

Additional studies involving fewer women have found a reduction of ambulatory blood pressure and a greater decline of nocturnal pressure in ERT users.[32,33] It is possible that HRT may slow the rise in systolic pressure over a longer period of treatment.[34] However, because of the significant increases in coronary, stroke, and venous thromboembolic risk demonstrated in the WHI, HRT is no longer recommended for cardiovascular protection.[35]


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