Combination oral contraceptives alter lipid synthesis and in general raise serum levels of triglycerides and of total cholesterol, HDL, and very-low density lipoprotein (VLDL) cholesterol. Estrogen lowers LDL cholesterol concentrations. Oral contraceptives are not atherogenic, and their efect on lipids is clinically inconsequential for most women (Wallach, 2000). In women with dyslipidemias, limited data suggest that COCs increase the risk for myocardial infarction and minimally so for venous thromboembolism or stroke (Dragoman, 2016). For those with multiple additional risk factors for vascular disease, alternative contraceptive methods are recommended.
With COCs, protein metabolism is afected, and estrogens boost hepatic production of various globulins. First, fibrinogen and many of the clotting factor levels rise in direct proportion to the estrogen dose and may lead to thrombosis. Angiotensinogen production is also augmented by COCs, and its conversion by renin to angiotensin I may be associated with "pill-induced hypertension," discussed subsequently. Last, COCs elevate sex hormone-binding globulin (SHBG) levels, which in turn lower concentrations of bioavailable testosterone and lessen androgenic side efects.
Regarding carbohydrate metabolism, current low-dose formulations have minimal efects in women who do not have diabetes (Lopez, 2014). And, the risk of developing diabetes is not increased (Kim, 2002). For diabetic women, COCs may be used in nonsmokers with disease duration <20 years and without associated vascular disease, nephropathy, retinopathy, or neuropathy (Curtis, 2016b).
Of other metabolic changes, thyroid-binding globulin and thyroid-stimulating hormone (TSH) levels are elevated, but free plasma thyroxine (FT4) levels are unchanged (Raps, 2014). Studies have not supported a connection between COCs and weight gain (Gallo, 2014).
Despite increased plasma angiotensinogen (renin substrate) levels, women using low-dose COC formulations rarely develop clinically significant hypertension (Chasan-Taber, 1996). However, it is common practice for patients to return 8 to 12 weeks ater COC initiation for evaluation of blood pressure and other symptoms.
During initial contraception selection, a history of gesta tional hypertension does not preclude subsequent COC use.
Among women with well-controlled hypertension, COC use is linked to greater risks than nonusers for stroke, acute myo cardial infarction, and peripheral arterial disease, and in these women, COCs are considered US MEC category 3 (Curtis, 2016b). Severe forms of hypertension, especially those with end-organ involvement, preclude COC use.
For nonsmoking women younger than 35, the risk of stroke is extremely low (World Health Organization, 1996). COCs are associated with a small increased risk for ischemic stroke (Chan, 2004; Lidegaard, 2012). Rates increase signiicantly for women who have hypertension, who smoke, or who have migraine headaches with visual aura or other focal neurological changes and use COCs (MacClellan, 2007; Tepper, 2016c).
The evidence for stroke risk in migraineurs without aura is less clear (Etminan, 2005; Schurks, 2009). COC initiation may be considered for women with preexisting migraines without aura if they are otherwise healthy, younger, normotensive nonsmok ers. For women with prior stroke, COCs should not be consid ered due to risks for repeat events.