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DIHYROTESTOSTERONE AND ANDROGEN REPLACEMENT THERAPY

Aksam Yassin

Clinic of Urology & andrology, Segeberger Kliniken, Rathausallee 94 A 22846 Noderstedt-Hamburger, Germany Department of Urology, Gulf Medical University School of Medicine, Ajman , UAE yassin@t-online.de

Testosterone is the major androgen in men. Testosterone enters target tissues (the prostate, muscle, skin etcetera). Inside the cell testosterone can be 5a-reduced to 5a-dihydrotestosterone (DHT) or aromatized to estradiol. DHT and testosterone bind to the same receptor, .but they, in part, serve different physiological roles. DHT is responsible for external virilization during prenatal development, and for most androgen-events of male sexual maturation at puberty. But all functions exerted by testosterone are also performed by DHT. The mechanism by which DHT and testosterone, perform in part different functions, is only partially understood. It is known that testosterone binds less strongly to the receptor than does DHT, so DHT appears to be a more potent androgen than T. The net consequence is that DHT amplifies androgen action of testosterone more efficiently than testosterone itself does. The amplification pathway involves conversion of a small fraction (~4%) of circulating testosterone to a more potent androgen, DHT.
The diversification of androgen action also involves testosterone being converted to estradiol by the enzyme aromatase. This is only a small proportion (~0.2%) of testosterone but the much higher potency (~100 fold versus testosterone) of estradiol makes aromatization to estradiol a potentially important mechanism. In eugonadal men, most (~80%) circulating estradiol is derived from extra-testicular aromatisation. The biological importance of aromatisation in male physiology is highlighted by the developmental defects in bone and other tissues of men with genetic mutations inactivating the estrogen receptor a, or with lack of aromatase
DHT transdermal gel (5 g 2.5 %) is available since 1982. Originally, the indications focused on applications of androgens for which aromatization of testosterone was undesired, such as gynecomastia and micropenis, but over time the indications broadened to hypogonadism and catabolic states. Between 1981 and 2002 more than 203.000 patients in France and Belgium have received treatment with this DHT-gel 2.5%. A number of studies have explored potential of DHT gel for androgen replacement treatment.
This contribution focuses on the potential side effects of treatment of testosterone deficiency with a DHT gel. In view of the fact that DHT has a 3-6 fold molar biopotency in comparison to testosterone itself, such side effects might be intuitively anticipated. Nevertheless, new insights into (molecular) biology of androgens, particularly in its main target organ, the prostate, show that DHT administration to hypogonadal men is safe, and might be more prostate sparing than testosterone itself.
Unlike testosterone, DHT cannot be aromatized to estradiol. So, the effects of DHT administration on circulating estradiol levels are important. The minimal plasma estradiol levels in men protecting them from signs and symptoms of estradiol deficiency appeared to range from 40-55 pmol/liter. In the studies of DHT which have measured plasma estradiol, plasma estradiol levels fall but remain above the threshold values for normal skeletal remodeling.
The prostate abounds with androgen receptors and secondly, it has a large potential to convert testosterone to DHT. Thus the prostate possesses an impressive androgen amplification mechanism. The net result is that concentrations of DHT are higher in the prostate than of testosterone, and it is widely believed that intra-prostatic DHT may be the relevant androgen for prostate development and function. An important pathophysiological role of DHT is further suggested by the use of 5a reductase inhibitors (finasteride and dutasteride) in the treatment of benign prostate hyperplasia( and prostate cancer, which could lead one to believe that administration of DHT might provide a more potent stimulus for prostate function than testosterone itself, with potentially harmful effects on benign prostate hyperplasia and prostate cancer. It is paradoxical, therefore, to suggest that DHT might exert androgenic effects with relatively less prostate stimulation than testosterone itself. Reports of elderly hypogonadal men receiving DHT for androgen treatment indicate a reduction in prostate volume or no significant change in total volume. These effects of DHT on the prostate are almost counter-intuitive. But, unlike testosterone, exogenous DHT cannot be further amplified in androgenic potency by 5a reduction. Hence, exogenous DHT will have consistent androgenic effects on all androgen target organs. Further, as indicated above, DHT administration might also lead to a net reduction in estrogen production. There is evidence that estrogen accumulation increasing with advancing age, may be implicated in the etiology of both benign prostate hyperplasia and prostate cancer. In summary: DHT administration, somewhat unexpectedly, but understandably from androgen physiology, appears to be a relatively prostate sparing mode of androgen treatment.
We have recently made a remarkable observation. Circulating DHT levels are approximately 4-6% of the blood testosterone levels. We monitored development of plasma DHT in hypogonadal men receiving testosterone.
Before testosterone administration plasma DHT ranged from 39- 540 ng/L (N 35-580 ng/L). When means of plasma DHT before and after administration of T were calculated, values declined upon testosterone administration from 275± 169 to162± 89 ng/L (p<0.05). When an arbitrary cut-off point was made at 200 ng/L, all 21 values > 200 ng/L had fallen from 376±156 to 226 ng/L (p<0.01). If the ratio T/DHT can be regarded as an indicator of 5 -reductase activity, there was a profound reduction. Below this cut-off point 13 values rose and 21 fell upon T administration. On average values declined from 108±45 to 104 ± 67 ng/L. So, if values below the cut-off point of 200 ng/L fell, they showed a significantly smaller decline than values >200 ng/L.
Apparently, some men with moderate degrees of testosterone deficiency develop high DHT which fall upon testosterone administration. There is somewhere an arbitrary cut-off level of 200 ng/L. In men with DHT below this cut-off, testosterone administration leads sometimes to a rise, sometime to a fall of DHT which is quantitatively smaller than in men with DHT values above >200 ng/L. Since DHT and testosterone serve essentially the same functions, the high levels of DHT in some hypogonadal men might hypothetically protect these men from androgen deficiency through their greater biopotency. This protection may no longer be needed when testosterone levels normalize.