Synthetic progestins are used by millions of women as contraceptives and in hormone
replacement therapy (HRT), although their molecular mechanisms of action are not well
understood. The importance of investigating these mechanisms, as compared to those
of progesterone, has been highlighted by clinical evidence showing that medroxyprogesterone
acetate (MPA), a first generation progestin, increases the risk of breast cancer and
coronary heart disease in HRT users. A diverse range of later generation progestins
with varying structures and pharmacological properties is available for therapeutic
use and it is becoming clear that different progestins elicit beneficial and adverse
effects to different extents. These differences in biological activity are likely
to be due to many factors including variations in dose, metabolism, pharmacokinetics,
bioavailability, and regulation of, and/or binding, to serum-binding proteins and
steroidogenic enzymes. Since the intracellular effects on gene expression and cell
signaling of steroids are mediated via intracellular steroid receptors, differential
actions via the progesterone and other steroid receptors and their isoforms, are likely
to be the major cause of differential intracellular actions of progestins. Since many
progestins bind not only to the progesterone receptor, but also to the glucocorticoid,
androgen, mineralocorticoid, and possibly the estrogen receptors, it is plausible
that synthetic progestins exert therapeutic actions as well as side-effects via some
of these receptors. Here we review the molecular mechanisms of intracellular actions
of old (MPA, norethisterone, levonorgestrel, gestodene) vs. new (drospirenone, dienogest,
trimegestone) generation progestins, via steroid receptors.
Copyright © 2011 Elsevier Inc. All rights reserved.