Estrogens

 

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Topics of Special Interest

Lecture Slides
Handout
Biosynthesis of Steroid Hormones
Overall Mechanism of Action of Steroid Hormones
Natural Estrogens
Synthetic Estrogens
Schuler's Hypothesis
Diethylstilbesterols
Estrogen Antagonists

 

Biosynthesis of Steroid Hormones

    Numerous steroids are secreted by endocrine glands (ovaries, testes, adrenal glands) and are deposited directly into the blood stream. These steroids are called steroidal hormones. Steroid hormones possess numerous activities. In fact they are so important that absence of these hormones may be lethal. The major classes of steroid hormones are

Let us look at a simplified picture of how these steroids are biosynthesized in our body.

    As might be apparent from this figure, the interconversion occurs between male and female sex hormones. Thus the process occurs in both males as well as females ensuring that each one of us has all these steroids. It turns out that females have more estrogens and progesterones than males while androgens are present to considerably greater extent in males than in females. A typical example, during menstruation females secrete ~20 mg progesterone per day. Males usually have ~ 2 5 mg progesterones.

 

Overall Mechanism of Action of Steroid Hormones

   The overall mechanism of steroid hormone action is the regulation of gene expression. The lipophilic steroid hormones are carried into the blood stream with the majority of hormone reversibly bound to carrier proteins and a small amount of free steroids. The free steroid diffuses throught the cell membrane and enters cells. The sensitive cells contain a high affinity steroid hormone receptor either in the cytosol or in the nucleus. The steroid receptor complex enters the nucleus and initiates a conformational change that involves dimerization to activate the complex to interact with specific regions on cellular DNA referred to as hormone responsive elements (HRE). This initiates the process of transcription to produce mRNA and translations to produce proteins. These proteins regulate cell function, growth differentiation, etc. So it the process of expression of proteins that these hormones regulate. The proteins perform their regular tasks.

 

Natural Estrogens

    Now let us start our discussion of the first class of hormones : estrogens, female sex hormones.

    Besides being natural body products, estrogens may be administered to i) treat or prevent osteoporosis and ii) in birth control in combination with progesterones We will have more chance to study the birth control aspect when we move to progestins. In humans three steroids are the primary constituents of estrogenic steroids.

    Although estradiol is the most active estrogen with 100% activity the advantage with estriol is that it can be taken orally. Estradiol and estrone are relatively quickly oxidized in plasma thereby their life is greatly reduced. Estriol is further converted to either sulfated or glucuronated derivative before being excreted. (To view the structures of these molecules in 3D click on the appropriate hyperlinks. Compare the structures to previous molecules that you have studied, e.g. cholesterol and a,b-unsaturated steroids. See how aromatization of A ring alters the overall shape of the molecule.)

 

Synthetic Estrogens

    Several synthetic estrogens are reported. These include the ethinyl estradiols, DES, dienestrol and chlorotrianisene. Ethinyl group reduces the metabolism through stomach and hence it is can be taken orally.

 

Schuler's Hypothesis

    Schuler proposed a hypothesis that has now been supported by numerous molecules. He proposed that the critical thing is the distance the between the two oxygens. It should be 12.1 .

    This is an overview of how the two molecules look top view and side view. When a water molecule is added to estradiol the overlay shows superposition of the two oxygens. Schuler's hypothesis is now considered to be most probably true.

 

Diethylstilbesterols (DES)

    These are structurally so different from the natural estrogens and yet they possess estrogenic activity. The activity of diethylstilbesterols (DES) led to the above Schuler's hypothesis.

 

Estrogen Antagonists

    Let us now look at estrogen antagonists. Why might one want to have these? It turns out that several cases occurs in which estrogen is blamed for breast cancer especially after pregnancy. Thus if we can block the action of estrogen, then perhaps breast cancer can be controlled. Two drugs are found to be useful- clomiphene and tamoxifen.

    The structures of clomiphene and tamoxifen are very similar to chlorotrianisene. One is an estrogen agonist and the other is an antagonist. Antagonists as you might remember may bind the same site on the protein as the agonist does but is incapable of doing the task that agonist can do. It turns out that both clomiphene and tamoxifen are very weak agonists. However a combination of their affinity and the concentration of these drugs ensure that these are strong competitors of agonists resulting in much reduced estrogenic activity.

 

 

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2000 VCU School of Pharmacy
Revised: October 16, 2000
Questions or Comments : Dr. Umesh R. Desai