Anti-inflammatories, Heart Attacks, and GI Bleeding

          This blog is based on an article that recently appeared in Lancet, vol. 382, pp779-789, Sept. 6, 2013. The article was a meta-analysis (and see my previous blogs on the problems inherent inj meta-analyses) of over 700 studies that looked at the relationship between anti-inflammatory drugs, heart attacks, and GI bleeding. (Recall that Vioxx was taken off the market because of an increase in heart attacks and strokes.)

     A little biochemistry is in order. There are two enzymes released by platelets that synthesize prostaglandins, called COX-1 and COX-2 for short. COX-2 prostaglandins mediate pain and inflammation, and COX-1 prostaglandins protect against GI bleeding, especially in the stomach. Aspirin blocks the production of both enzymes irreversibly, which is why aspirin is used to prevent strokes and reduce pain and inflammation,  and can cause GI bleeding. The studies looked at NSAIDs such as ibuprofen (Advil, Motrin), naproxen (Naprosen, Aleve), and diclofenac. These NSAIDS block both COX-1 and COX-2. The studies also looked at anti-inflammatory drugs such as Celebrex that only blocked COX-2,(called coxibs), and therefore did not increase the risk of GI bleeding.

     The study showed that all NSAIDs increased the risk for GI bleeding, but in no case were acid-blockers such as Prilosec and Prevacid used, which would have decreased the risk. The surprising result was that not only did coxibs increase the risk of heart attacks by one-third, but that all the NSAIDs except Aleve did as well, so that Aleve is the safest from a vascular point of view. Unfortunately, naproxen also had the highest risk of GI bleeding.

     Thus the safest anti-pain and anti-inflammatory drug would appear to be Aleve, but an acid-blocking drug should be taken with it to reduce the risk of GI bleeding.

Men, Testosterone, and Estrogen

     There was an article published recently in the New England Journal of Medicine ( Vol 369, pp1011-1022, Sept. 12 2012) about the effect on men of testosterone and estrogen suppression. It was only a 12 week study, but the results are interesting. I will summarize the study here.

     Firstly, I should mention that the male production of testosterone decreases slowly with age. This actually means that even an "normal" level of testosterone at age 60 is abnormal in the sense that it is diminished from the level at age 20. All men have an enzyme that converts some testosterone to estradiol, an estrogen, and this conversion provides 80% of the circulating estradiol. (I should also mention here that in addition to estrogen and progesterone, all women secrete testosterone.) There are also studies showing that one of the causes of diminished sexual drive in menopausal women is a reduction in their testosterone level, so that estrogen replacement alone may not be enough to restore their sex drive. This was shown initially by a female OB-GYN in Canada.

     The experiment reported in the NEJM showed the effects of chemical castration which eliminated testosterone production. Some of the men also received a drug to inhibit the production of estrogen when the testosterone level was allowed to rise. The results of this climical study can be summarized as follows:

     Testosterone directly regulates lean mass,  muscular strength and sexual function. Testosterone deficiency decreases lean mass, muscle strength, muscle size and sexual function. Low estradiol also contributes to loss of libido and sexual function. Interestingly enough, low estradiol also contributes to increased abdominal fat, and possibly to osteoporosis as well.

     The increase in abdominal fat is medically worrisome, because this increase is associated with resistance to insulin (i.e. to pre-diabetes) as well as the metabolic syndrome. But the solution to low estradiol should not be estrogen replacement, because that was tried with men with prostate cancer and they developed severe cardiovascular problems. 

     The message I take from this study is that after replacing testosterone when necessary, then the estradiol level should be measured. If that level is still low, then the testosterone dose should be increased to normalize the estradiol level and thereby decrease the risk of the patient's developing the metabolic syndrome. It is also trivial to add that menopausal women should have their testosterone level measured.