Levonorgestrel, Pharmacokinetics, Efficacy and Safety 37hypothalamus, pituitary, mammary gland, and uterus. The activity of the
progestogens also depends on the time-course of the serum concentration of
the progestogen after the use. This depends on several factors such as the
absorption, metabolism, liver physiology (first-pass effect), distribution and
storage in fat and other tissues, binding to serum proteins, inactivation and
conjugation. Depending on the route of administration, oral or parenteral
(vaginal, intramuscular, transdermal), progestins can manifest different effects
due to differences in metabolism. This has been demonstrated experimentally
for progesterone [1].
The pharmacokinetics of the 19-nor progestogens are relatively similar.
The individual properties of progestogens are more related to the specificity of
binding to the receptors for progesterone, androgens, and glucocorticoids. The
progestogen activity may be measured as the affinity for the progesterone
receptor. It may also be measured as the ability to suppress luteinizing
hormone (LH) secretion or to stimulate endometrial development in rabbits.
There appear to be several different forms of progesterone receptors, usually
called PR-A and PR-B, the difference being the particular sequence of amino
acids in the two forms. Biologically, both forms have different specifications
[2]. Biological effects at the cellular level are mediated by intracellular steroid
receptors. The ability of any progestin to bind to the progesterone receptor
differs between the compounds, and this influences the biological effect of the
progestin. This is also true in relation to binding to other intracellular steroid
receptors.
All progestins have in common the progestogenic effect i.e., the induction
of a characteristic change in the estrogen-primed endometrium. The total
progestogenic or progestational activity of any substance also depends on the
route and timing of the administration. It varies widely and is often expressed
by the difference in the dose required for the endometrial transformation in a
woman, called the transformation dosage. It is crucial for the compound to be
able to bind to the progesterone receptor. Suppression of gonadotropin
secretion by progestogen appears to be chiefly limited to the preovulatory
surge at midcycle. Tonic levels of gonadotropins at other times during the
menstrual cycle have not been found to be greatly suppressed [3].
Progestogenic effectivity on the level of the endometrium and
antigonadotropic effects (dose for ovulation inhibition) of the different
progestins varies.
Androgenic activity of progestogens varies among different progestogens
and it is responsible for some of the undesirable side-effects. In addition, the
19 - nor steroids are also capable of exerting some estrogenic activity since they