Metabolic effects of contraceptive steroids

Abstract

Estrogen and progestins have been used by millions of women as effective combined contraceptives. The safety of hormonal contraceptives has been documented by years of follow-up and serious adverse events that may be related to their use are rare in the young population exposed to these agents. The balance between the benefits and the risks of contraceptive steroids is generally positive in particular when comparing to the risks of pregnancy and especially in women with risk factors. The metabolic changes induced by the synthetic steroids used in contraception, such as lipoprotein changes, insulin response to glucose, and coagulation factors have been considered as potential markers of cardiovascular and venous risk. Observations of these effects have led to modifications of the composition of hormonal contraceptive in order to minimize these changes and hence potentially decrease the risks. The synthetic estrogen Ethinyl-Estradiol (EE) exerts a stronger effect that natural estradiol (E2) on hepatic metabolism including estrogen-dependent markers such as liver proteins. This stronger hepatic impact of EE has been related to its 17α-ethinyl group which prevents the inactivation of the molecule and results in a more pronounced hepatic effect of EE as compared to estradiol. Due to its strong activity, administering EE via a non-oral route does not prevent its impact on liver proteins. In order to circumvent the metabolic changes induced by EE, newer products using more natural compounds such as estradiol (E2) and estradiol valerate (E2V) have been introduced. The synthetic progestins used for contraception are structurally related either to testosterone (T) (estranes and gonanes) or to progesterone (pregnanes and 19-norpregnanes). Several new progestins have been designed to bind more specifically to the progesterone receptor and to minimize side-effects related to androgenic, estrogenic or glucocorticoid receptor interactions. Dienogest (DNG), and drospirenone (DRSP) and the 19-norpregnanes including Nestorone® (NES), nomegestrol acetate (NOMAc) and trimegestone (TMG) have been combined with estrogen either EE or E2 or estradiol valerate (E2V). Risks and benefits of the newer progestins used in contraception depend upon the type of molecular structure, the type and dose of estrogen associated in a combination and the route of administration. The lower metabolic impact of estradiol-based combinations may result in an improved safety profile, but large surveillance studies are warranted to confirm this plausible hypothesis. So far, the contraindications and warnings for use of current COCs also apply to the estradiol-based COCs.

Early Programming of Obesity Throughout the Life Course: A Metabolomics Perspective

“…Finally, hormonal contraceptives seem to play a crucial role concerning the sex differences in the metabolome, since they affect the lipid and AA metabolism [74,75] . Wiklund et al [76] even excluded participants taking oral contraceptives.…”

The Polycystic Ovary Syndrome Status - A Risk Factor for Future Cardiovascular Disease

“…The progestin component is of variable potency and androgenicity. Hence, while in combined COCs the EE component seems to be responsible for the slight changes in the procoagulation and fibrinolytic balance, most progestins appear not to affect the coagulation factors and liver proteins when given alone (Sitruk-Ware & Nath, 2011). However, the metabolic effects of pills are extremely variable; for example estrogens impair insulin action dose-dependently and the associated progestins may modify these effects (Nader & Diamanti-Kandarakis, 2007).…”

Currently available combined oral contraception

“…The 'natural' estrogens are sometimes thought of as being superior because they are metabolized faster than synthetic EE, have a lower bioavailability and have less of an impact on hepatic function [42,43]. Although data suggest that the impact of natural estrogens may be less, physiologic markers are still altered; therefore, the contraindications do not change [44].…”