source of progesterone as well as estrogens. Through its feedback effect on the
hypothalamus, progesterone prevents ovulation and also stops uterine contraction, thus
avoiding dislodgement of the fertilized egg or embryo. In the absence of pregnancy, the
progesterone level, together with the estrogen concentration, declines, resulting in
estrus or menses—the shedding of uterine endometrium along with the unfertilized egg.
At the same time, low steroid levels disinhibit hypothalamo-pituitary endocrine
secretion, the peptide hormone levels rise, and the cycle starts again.
Progesterone itself has been used in the past in the treatment for threatened sponta-
neous abortion. However, the clinical trials that supported this therapeutic application
have been called into question and, presently, progestins do not have any place in the
treatment of threatened or habitual abortion; indeed, in the United States, the Food and
Drug Administration (FDA) has strongly warned against the use of progestins during
pregnancy. Likewise, there have been claims that progestins may reduce the unpleasant
effects of PMS (premenstrual syndrome). As with the use of progestins for threatened
abortion, there are no medical data to support this claim. Progestins have been used
successfully as palliative treatments in inoperable endometrial cancer.
The main use of progestins is based on their antifertility effect. Since progesterone is
poorly absorbed, it cannot be given orally; furthermore, it is not particularly potent
and has an unacceptably short serum half-life of about 5 minutes. In early work, ethis-
terone (5.39), an acetylenic compound prepared from androsterone, was an orally active
progestin, but also had male hormone action. In subsequent work, a large number of
semisynthetic progesterone derivatives (progestogens) were synthesized (levonorgestrel
(5.40), desogestrel (5.41), norethindrone (5.42), norgestrel (5.43), and ethynodiol
(5.44)) and found their principal use in oral contraceptive formulations. In preparing
these synthetic progestogens, maintaining the progesterone 4-en-3-one A ring is
essential for preserving receptor binding. Adding 17 α-alkyl groups slows metabolism;
incorporating either 6-methyl or 6-chloro substituents enhances bioactivity while also
slowing metabolism.
5.9.1 Combinations of Progestins and Estrogens (Oral Contraceptives)The concept of oral contraception was pioneered by Pincus in the early 1950s.
Modifications of the ethisterone molecule—removal of the 19-methyl group or the
introduction of additional methyl groups in position C-6 of 17α-acetoxyprogesterone—
led to a series of highly active progestins. Acetylation increases the lipid solubility and
therefore extends the duration of activity of such derivatives, whereas the introduction
of a methyl group on C-6 (and C-11) interferes with metabolic destruction of the drug
326 MEDICINAL CHEMISTRY