Dihydrotestosterone Prostate Paradox

First, the basics.  Testosterone is converted into dihydrotestosterone (DHT) by 5-alpha-reductase (5AR) enzyme.  Testosterone appears to have some effect on prostate growth & size (but I'm not going to comment upon the strength of this evidence, much less any potential neoplastic effect).  What is the basis for this belief?  Men with benign prostate hypertrophy (BPH) who take 5AR inhibitors (5ARI), currently only available as finasteride & dutasteride here in the US, report an improvement in lower urinary tract symptoms (LUTS) in 6 months accompanied by a 50% decrease in PSA (prostate specific antigen).  So perhaps it's really DHT that causes the prostate to enlarge, since lower levels of DHT are followed soon thereafter by smaller prostates.

However, a study published this week has just thrown this theory out the door.  The authors randomized 114 healthy men >50yo w/o BPH in a double blind fashion to daily transdermal DHT or placebo for 2yrs.  My initial reaction was to ask "Why?" especially given what we know as reviewed above.  On the other hand, the authors hypothesized that exogenous DHT might actually shrink the prostate via its metabolite, 3-beta-androstanediol-5-alpha and by negative feedback on a systemic basis.  Bottomline, it didn't work.  As measured by transrectal ultrasound, the prostate didn't shrink (nor did PSA).  On the other hand, it didn't grow either, at least not due to the addition of DHT (the prostate also grew and PSA increased just from placebo alone, which is what we know happens as we age).  To be sure, those given transdermal DHT saw their DHT levels increase by ten-fold while those randomized to placebo saw no measurable change in DHT.

What else did the authors find out?  The increase DHT was accompanied by a decrease in both testosterone and estradiol.  Most likely this was due to a negative inhibitory effect at the hypothalamic-pituitary axis since both luteinizing hormone and follicle-stimulating hormone plummeted.  Bad news?  Bone mineral density at the lumbar spine (but not the femoral neck) decreased significantly in those given DHT compared to those on placebo.  Hematocrit increased significantly, too, dropping to baseline after cessation.  Good news?  More muscle and less fat in those randomized to DHT versus placebo, despite the fact that DHT is really a pure androgen with minimal anabolic effects.  How much?  Just 1-1.5kg each for a net improvement of 2-3kg. 

So perhaps we don't need to worry so much about elevated DHT levels in our patients receiving testosterone supplementation.  In other words, consider offering a 5ARI only because they're suffering from BPH/LUTS, not just because their DHT is elevated.  It's obviously more complicated than that.  For another perspective, check out the editorial.