Progestins exert their progestational activity by binding to the
progesterone receptor (form A, the most active and form B, the less active) and may also interact with other
steroid receptors (
androgen,
glucocorticoid,
mineralocorticoid,
estrogen). They can have important effects in other tissues besides the endometrium, including the breast, liver, bone and brain. The
biological responses of
progestins cover a very large domain:
lipids,
carbohydrates,
proteins, water and
electrolyte regulation, hemostasis, fibrinolysis, and cardiovascular and immunological systems. At present, more than 200
progestin compounds have been synthesized, but the
biological response could be different from one to another depending on their structure, metabolism, receptor affinity, experimental conditions, target tissue or cell line, as well as the
biological response considered. There is substantial evidence that
mammary cancer tissue contains all the
enzymes responsible for the local biosynthesis of
estradiol (E(2)) from circulating precursors. Two principal pathways are implicated in the final steps of E(2) formation in
breast cancer tissue: the '
aromatase pathway', which transforms
androgens into
estrogens, and the '
sulfatase pathway', which converts
estrone sulfate (E(1)S) into
estrone (E(1)) via
estrone sulfatase. The final step is the conversion of weak E(1) to the potent biologically active E(2) via reductive
17beta-hydroxysteroid dehydrogenase type 1 activity. It is also well established that
steroid sulfotransferases, which convert
estrogens into their
sulfates, are present in
breast cancer tissues. It has been demonstrated that various
progestins (e.g.
nomegestrol acetate,
medrogestone,
promegestone) as well as
tibolone and their metabolites can block the
enzymes involved in E(2) bioformation (
sulfatase, 17beta-
hydroxysteroid dehydrogenase) in
breast cancer cells. These substances can also stimulate the
sulfotransferase activity which converts
estrogens into the biologically inactive
sulfates. The action of
progestins in
breast cancer is very controversial; some studies indicate an increase in
breast cancer incidence, others show no difference and still others a significant decrease.
Progestin action can also be a function of combination with other molecules (e.g.
estrogens). In order to clarify and better understand the response of
progestins in
breast cancer (incidence, mortality), as well as in
hormone replacement therapy or endocrine dysfunction, new clinical trials are needed studying other
progestins as a function of the dose and period of treatment.