38 Usha Verma and Neil Verma
have been shown to stimulate proliferation of mammary tumor cells only in
cells that contain the estrogen receptor. In vitro studies with COS7 cells on the
ERα and ERβ have shown some differences between progestins. The most
significant up-regulation of ERα-activity was found with norethisterone,
norethinodrel and desogestrel. In contrast, ERβ was markedly activated only
by norgestrel and to a lesser extent by norethisterone, norethinodrel and LNG.
LNG is used as a steroidal contraceptive in different formulations and
administered in a number of different ways. Most of the information regarding
the pharmacokinetics of LNG is available from studies with oral
contraceptives. As the other delivery methods of this compound were
introduced more knowledge has been attained regarding pharmacokinetics in
other delivery methods.
PHARMACOKINETICS OF LEVONORGESTREL
After oral administration, synthetic progestins are in general rapidly
absorbed and reach a maximum serum concentration within 2–5 hours, they
have a longer half-life than progesterone and display stable plasma levels for
long-term use. Many of them are metabolized in the liver and are excreted via
the urine [4, 5, 6 and 7]. When taken orally, LNG is rapidly absorbed and is
not subject to first-pass effect in the liver. It is approximately 90%
bioavailable after oral intake and the circulating half- life is around 15 hours
[8]. The peak-plasma-level is obtained between 1 and 3 hours after
administration. There is insufficient information regarding the AUC (Area
under the serum concentration -time curve) and the dose. Since LNG is a
synthetic hormone, the pharmacokinetics of LNG is different compared to
natural progesterone. The binding of different progestogens to sex hormone
binding globulin in the plasma also varies. In circulation, 47.5% of LNG is
bound to SHBG, 50% to albumin, while 2.5% is unbound [9]. LNG causes a
50% decrease of SHBG [5, 6, 10]. When LNG binds to progesterone receptors
in the hypothalamus, it results in slowing of gonadotropin-releasing hormone
(GnRH) pulse release, which extinguishes the preovulatory luteinizing
hormone (LH) surge. Eventually, this phenomenon results in inhibition of
ovulation. [11].
LNG not only it binds to progesterone receptors, but like other
progesterone agonists, it also binds to several other steroid receptors. In vitro,
relative binding affinity of LNG to steroid receptors has been demonstrated as
follows: for the progesterone receptor, 323% that of progesterone; for the