Androgens

"THE MATERIAL PRESENTED HERE ONLY ENHANCES CLASSROOM TEACHING AND IN NO WAY SHOULD BE CONSTRUED AS REPLACING IT.  THE INSTRUCTOR is not responsible for any problems and SHOULD BE CONSULTED AT THE EARLIEST IN CASES OF DIFFICULTY, CONFUSION, or PLAIN DISILLUSIONMENT.  VISIT THE HOMEPAGE FOR INFORMATION PERTAINING TO REACHING HIM/HER"

Topics of Special Interest
Lecture Slides
Handout
Introduction
Metabolism
Physiologic Activities of Androgens
Structure-Activity Studies
Androgen Antagonists

 

Introduction

    One of the most important member in this class of steroidal hormones is testosterone which is heard of a lot. The structure of testosterone is :

    Testosterone has 19-carbons and in general such a steroidal skeleton is called androgenic skeleton. Another member that keeps making the news is androstenedione affectionately called andro. The structure of androstenedione is :

 

    Andro raised a lot of concern when Richmond Times-Dispatch printed a new article on McGwire's reported use of andro to enhance his performance. 

    Androgens are typically used as performance enhancing agents. The National Institute of Drug Abuse has to say the following to athletes who use these drugs regularly for performance enhancement.

    Andro and testosterone are interconvertible in our body. Another steroid that is a dominant player is 5a-dihydrotestosterone. The structure of 5a-DHT is

Metabolism

   

    Testosterone is significantly metabolized by the GI tract. Approximately 44% is lost in first pass metabolism. Esterification of the 17b-OH group reduces both the metabolism in the GI tract and by liver.e.g., testosterone cypionate and enanthate are significantly more active.

Physiologic Activities of Androgens

There are primarily two activities associated with androgens :

True androgenic activity : which relates to the role in sexual characteristics of human body, e.g.,

And anabolic activity : which relates to the role in development of muscle mass.

Now one can immediately predict the application of anabolic activity. One could be  in sports for possible performance enhancement. However a more critical role might be for severely traumatized individuals who has lost a high proportion of their body mass. For example, for burn victims or accident victims. One can also imagine the use of androgenic activity, e.g., in the use against the loss of sexual function or in hypogonadism in which the testes stop working efficiently. So we really need to devise molecules that either possess only anabolic activity or have androgenic activity.

Structure-Activity Studies

    Testosterone and 5a-DHT have both anabolic and androgenic activities. Nature has however devised our body in a fashion that it has become difficult to completely separate these two activities.

General guidelines for anabolic/androgenic activity of androgens

  1. We need a steroid skeleton for both activities.
  2. An electronegative atom is necessary for both activities.
  3. A/B ring juncture should be trans or a,b-unsaturated for both activities. Cis ring fusion is not active.
  4. Alkyl group at 17a-position is necessary for anabolic activity while alkynyl group (CCH; C-triple bond-CH) at that position provides progestational activity (see section on progestins).

    Some natural androgens have greater androgenic activity than anabolic activity.

 

Androgen Antagonists

Prostate cancer is highly androgen sensitive and it has been found that by blocking testosterone receptors the cancer can be inhibited or slowed. Two anti-androgens have been approved by FDA.

Bicalutamide and Flutamide. However both have a very high failure rate of ~50%. It is interesting to see that none of these have structures closely resembling the testosterone.

    Another anti-androgen is Danazol. This drug is used in the treatment of endometriosis which is the growth of endometrial tissue growing outside the uterus, especially in the pelvis. Danazol is a weak androgen and it binds to numerous steroid hormone receptors and blocks the synthesis of estradiol, progesterone, testosterone, and glucocorticoids. Although containing a 17a-ethinyl group it has not estrogenic or progestin activity.

    Finasteride is an anti-androgen that inhibits the metabolism of testosterone to 5a-dihydrotestosterone. It is an inhibitor of 5a-reductase. It turns out the among several other places that this enzyme is present it is present in hair follicles. In addition, bald men display greater proportion of 5a-DHT than normal men indicating that if we reduce the metabolism than perhaps baldies may decrease. Indeed the drug has now been approved for re-growth.

[home] [school of pharmacy] [department of medicinal chemistry]
[links to sites of interest and download center] [instructions for downloading and installing software]

 

2000 VCU School of Pharmacy
Revised: October 20, 2000
Questions or Comments : Dr. Umesh R. Desai