Efficacy of Various Natural and Synthetic Androgens to Induce Ductal Branching Morphogenesis in the Developing Anterior Rat Prostate

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Abstract
The studies presented herein quantitated ductal branching mor- phogenesis in the anterior prostate (AP) of the newborn rat. Four parameters were measured: epithelial area, epithelial perimeter, node number, and form factor. Nine natural and synthetic androgens were tested for their effectiveness in inducing postnatal prostatic development using 808 newborn rat APs in 68 dose-response exper- iments. Based on these studies it was shown that testosterone (T) was slightly more effective than dihydrotestosterone (DHT) in supporting ductal branching morphogenesis in the developing rat AP. Further- more, the activity of T could not be accounted for simply by conversion of T to DHT. Synthetic androgens, 7a-methyl-19-nortestosterone and methyltrienolone (R1881), which cannot be 5a-reduced to DHT, also induced extensive ductal branching and elicited responses less than those to T and not statistically different from those to DHT. This suggests that although DHT is sufficient for prostatic development, it is not necessary for postnatal ductal branching morphogenesis and growth of the prostate. 5a-Androstan-3a,17b-diol was particularly potent in inducing ductal branching, eliciting a response greater than or comparable to those of T and DHT. Androsterone, androstanedi- one, 5a-androstan-3b,17b-diol and 5b-androstan-3a,17b-diol induced ductal branching, but to a lesser extent than either T or DHT. These studies challenge the assumption that DHT is essential for prostatic development, specifically during ductal branching morphogenesis of the neonatal rat prostate. (Endocrinology 140: 318 -328, 1999) P ROSTATIC development is androgen dependent. How- ever, the roles of specific androgens in various aspects of prostatic development have not been well defined. The purpose of the studies presented here was to identify an- drogens capable of inducing prostatic ductal branching mor- phogenesis. The experimental model used was the 0 day rat anterior prostate (AP) grown for 6 days in serum-free organ culture. Ductal branching morphogenesis in this model mim- ics in vivo development of this gland. The novel aspect of this study is that developmental effects of androgens were as- sessed quantitatively by computer-interfaced morphomet- rics in a serum-free organ culture system. This method allows for the first time a meaningful quantitative comparison of the effects of various androgens on prostatic development, spe- cifically during the stage in which the prostate undergoes its initial ductal branching, without the systematic complica- tions associated with whole animal studies. Prostatic development involves a coordinated sequence of events beginning with the undifferentiated embryonic urogen- ital sinus (UGS) and culminating in the attainment of full adult function. The embryonic UGS under the influence of androgens becomes committed to form prostate. The first morphological change indicative of prostatic development is the formation of

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