Progestins

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Topics of Special Interest

Lecture Slides
Handout
Introduction
Metabolism
Structure-Activity Relationship
Synthetic Progestins
Progesterone Antagonist

 

Introduction

    In addition to estrogen, progesterone is an important female sex hormone. Progesterone is produced in the ovaries, testes and the adrenal glands. Progesterone is essential for maintaining pregnancy, suppression of ovulation and for the survival of embryo. The structure of progesterone is 

 

Metabolism

    Progesterone is very rapidly metabolished. It has a plasma half life of only 5 mins. Thus progesterone cannot be taken orally. Primarily the A and the D ring are metabolized. Numerous efforts have been put to devise progesterones that have higher affinity for its receptor and also that extend the life of the drug.

 

 

Structure-Activity Relationship

    In contrast to estrogens, progesterone molecule is almost completely recognized by its receptor. The most important group that is critical for progestational activity is the 3-keto-4-ene moiety.

    We saw that this moiety is present in testosterones and will see that it is present in glucocorticoids too. However, the conformation of this group is just so different that the receptor recognizes progestins only.

 

Synthetic progestins

    The D ring seems to be more amenable to modification. Thus one can have 17a-OH esters.

 

    However the metabolism of A ring cannot be slowed down and hence these 17a-esters are not active orally. One can slow down the metabolism of A ring by introducing substituents. The substituents that have been found useful are 6a-methyl, 6-Me, 6-ene and 6-chloro.

    Chemists have synthesized some testosterone derivatives that have progestational activity. These include ethisterone and dimethisterone.

    These are testosterone derivatives but the incorporation of 17a-ethinyl group completely alters the structural profile of the molecule. The testosterone derivative looses its anabolic activity. The alkynyl group also reduces the metabolism of the D ring and hence these derivatives are oral active.

    Introduction of a 19-nor group increases the affinity of the molecule to progesterone receptor and hence the 19-nor testosterone derivatives are more active. These include norethindrone and norgestrel.

The activities of some selected compounds are :

 

Relative oral activity

   

Progesterone

0

17a-hydroxy progesterone caproate

2 - 10

Medroxyprogesterone acetate

12 25

Ethisterone

1

Norethindrone

5 10

Dimethisterone

12

    Progestins are primarily needed for birth control. The rationale is that ovulation is prevented when the body concentration of progesterone is increased as it occurs during pregnancy. Thus if we artificially increase the concentration of progesterone ovulation will be prevented. Thus there will be no possibility of fertilization of the ovum.

Progestins are typically used in combination with estrogens for maximal efficiency.

Brand

Progestin

Estrogen

     

Leven

Norgestrel

Ethinyl estradiol

Genora 0.5/0.35

Norethindrone

Ethinyl estradiol

Nelova 1/50M

Norethindrone

Mestranol

 

Progestational antagonist

    What would happen if during pregnancy we introduce a progesterone antagonist? The antagonist will bind the receptor with high affinity. It will exclude progesterone from the binding site and hence eliminate its agonist activity. Thus pregnancy which is dependent on the progesterone activity will no longer be able to sustain. The fetus will hence be aborted. This is the function of RU38486 the well known drug that reached a high level of controversy. RU486 is a progesterone antagonist.

It is orally active and has additional molecular framework that provides higher affinity.

 

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2000 VCU School of Pharmacy
Revised: October 10, 2000
Questions or Comments : Dr. Umesh R. Desai