STEROIDS - A MAN'S GOTTA DO WHAT A MAN'S GOTTA DO!

My most favorite course in both pharmacy school and medical school was biochemistry. I've been channeling this interest into studying why our performance declines with age, especially in males.

As we men hit our forties, several changes begin to occur. Hormonal changes are blamed for many of the maladies affecting middle-aged women. I don't think we hear nearly as much about the changes occurring in males.

Middle-aged males typically experience a decline in free testosterone, the active form of the hormone. Several things can cause this: a primary failure of testes, a pituitary problem, or a hypothalmic problem. Let's discuss how the system should work: the hypothalamus, sensing a fall in testosterone levels, releases a hormone called LHRH (luteinizing hormone releasing hormone). This LHRH stimulates the pituitary gland to release LH (luteinizing hormone). The LH then stimulates the testes to produce testosterone. A disorder anywhere in this pathway could lead to suboptimal testosterone levels.




Figure 1: notice the "A" ring (lower leftmost ring). A single double bond within the ring and a double-bonded oxygen attached to it.



So, do most middle-aged men have a hypothalmic, pituitary, or testicular problem leading to low testosterone? Probably not. I suspect most men are producing enough testosterone. Then what's happening? Estrogens.



Figure 2: Estradiol has been formed by "aromatizing" the A-ring. Note the hydroxy groups in red. Two -OH groups in the molecule make it a "di-ol", in this case, Estradiol.



Estradiol, a potent estrogen produced by our bodies, is a metabolite of testosterone. An enzyme called "aromatase" is necessary for this conversion and it becomes more active in older males.

Women can have mood changes and other problems with hormonal changes ... why don't men? Well, probably because they do experience these things ... changes in mood, such as depression, changes in sexual performance (ever hear of Viagra?), and changes in our bodies, such as muscle atrophy and fat deposition.

So, the answer is testosterone supplementation, right? Well, my experience has been that things are rarely that simple in biochemistry. Adding more testosterone to the mix may actually worsen the problem. How? Read on!

My high school chemistry teacher, Mr. Brandt, would be so proud of me! I actually paid attention in his class and remember something he taught me about thirty years ago. A French chemist, Henry Louis Le Chatelier, described a principle that bears his name. Le Chatelier's Principle, simply stated, says "If you place a stress on a chemical system at equilibrium, the system will shift to try to minimize the effect of that stress". So, if you add more testosterone to the system, the aromatase enzyme will work to convert even more testosterone to estradiol. Bummer.

Hold on ... it gets worse. It turns out that estradiol stimulates the production of SHBG (sex hormone binding globulin), a protein that binds free testosterone, making it unable to bind to testosterone receptor sites. If testosterone can't bind to its receptors, it's inactive. The net effect of testosterone supplementation may be increased estradiol (bad), increased SHBG (bad), and no significant increase (and possibly a decrease) in free testosterone (bad).

Is there any hope? Are we men destined to become hormonal cripples? The answers are "yes" and "no", respectively. A drug already exists that may be the answer. Breast cancer research has led to the development of a drug called "anastrozole" (brand name: Arimidex). It turns out that anastrozole is a potent inhibitor of the aromatase enzyme. It blocks the production of estrogen. Certain forms of breast cancer are responsive to estrogen and their growth can be inhibited by lower estrogen levels.

Oh, I almost forgot! Good luck finding a doctor who will prescribe a breast cancer drug to middle-aged man that he, incorrectly, views as "normal". I'll throw you a bone, though ... google the word "chrysin" and see what you can find. Anastrozole has a more rapid onset and is more powerful, but chrysin is more readily available. Since chrysin by itself is poorly absorbed, you'll have to wade through the reports that it is ineffective. By itself, it very well may be ineffective. Look into novel formulations that claim to improve absorption and document in vivo efficacy.