36 Usha Verma and Neil Verma
INTRODUCTION
Progestogens
The progestins are derived synthetically from either testosterone or
progesterone. The pharmacological properties of progestins depend on the
original molecule from which they are derived. Very small changes in the
structure of the original molecule may significantly modify the effects of
progestins. Norgestrel was synthesized in the 1950s as a racemic mixture.
Norgestrel was found to be a more potent progestogen with progestational and
ovulation inhibitory activity that was higher than existing progestogens.
Norgestrel has a dextrorotatory isomer and the levorotatory isomer. The
dextrorotary isomer of norgestrel is active while the levorotary form is
biologically inactive. The active dextrorotatory form of norgestrel was later
named Levonorgestrel (LNG). The two isomers differ significantly in their
pharmacokinetics. Due to its potent biological activity and high efficacy in
small doses, LNG became the progestogen of choice for contraception.
Initially, LNG was incorporated in oral contraceptive pills (OCPs) along with
estrogen. Later it was used alone for emergency contraception, in implants and
in intrauterine devices (IUDs).
Synthetic progestogens are metabolized and inactivated much more slowly
than natural progesterone. Two types of compounds have been synthesized,
compounds with or without the angular methyl group in the C-19 position of
the steroid molecule (the 17 - acetoxy compounds, such as
medroxyprogesterone acetate, and the 19-nor compounds, such as
norethindrone). Only the 19-nor compounds are used in OCP or IUDs. The 17-
acetoxy compounds are used mainly in injectable contraceptives.
The level of progestogens in the blood depends on several factors such as
rate of absorption, metabolism, and binding to plasma proteins. Synthetic
progestogens are metabolized and inactivated much more slowly than natural
progesterone. Since LNG is a synthetic hormone, the pharmacokinetics of
LNG is different compared to natural progesterone. The binding of several
progestogens to sex hormone binding globulin (SHBG) also differs
significantly. LNG has approximately half the SHBG binding affinity of
testosterone. The degree of binding to plasma proteins affects the clearance
rate of the drug and the concentration of free steroid in blood. The
concentration of free or unbound drug is that which is available to diffuse from
the bloodstream into the target organs to bind to receptors in the