The potent synthetic androgens, dimethandrolone (7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone, do not require 5α-reduction to exert their maximal androgenic effects

Abstract

Dimethandrolone (DMA: 7α,11β-dimethyl-19-nortestosterone) and 11β-methyl-19-nortestosterone (MNT) are potent androgens in development for hormonal therapy in men. As 5α-reduced androgens, such as 5α-dihydrotestosterone (DHT), may raise the risk of benign prostate hyperplasia, accelerate the development of prostate carcinoma, and increase male pattern baldness and acne, we investigated the role of 5α-reduction in the androgenic activity of DMA and MNT. The authentic 5α-reduced metabolites, 5α-dihydroDMA (5α-DHDMA) and 5α-dihydroMNT (5α-DHMNT), were prepared by chemical synthesis and compared in vitro and in vivo to the parent compounds. Both 5α-reduced androgens bound with high affinity to the rat androgen receptor (AR) and were potent inducers of transactivation of 3XHRE-LUC in CV-1 cells cotransfected with a human AR expression plasmid. To examine in vivo androgenic (stimulation of ventral prostate [VP] and seminal vesicle [SV] weights) and anabolic (stimulation of levator ani [LA] muscle weights) activity, 22-day-old castrate male rats were treated sc for 7 days with various doses of DMA, 5α-DHDMA, or testosterone (T) or MNT, 5α-DHMNT, or T and necropsied on day 8. 5α-DHDMA was at least threefold more potent than T in stimulating growth of the VP but only 30-40% as potent as DMA. 5α-DHMNT was four- to eightfold more potent than T, whereas MNT was approximately equipotent to T. To assess the possible role of 5α-reduction in VP and SV growth, castrate immature rats were treated with maximally effective doses of T, DHT, DMA, MNT, or the related 19-norandrogen, 7α-methyl-19-nortestosterone (MENT), or vehicle, with or without dutasteride (DUT), an inhibitor of 5α-reductases types 1 and 2. In rats treated with T+DUT, serum T was significantly higher (P<0.05) than in rats treated with T alone, and serum DHT was decreased (P<0.001) to levels observed in castrate vehicle-treated rats. DUT significantly reduced both VP and SV weights in T-treated rats, whereas there was no significant effect of DUT on weights of these accessory sex glands in rats treated with DMA, MNT, DHT, or MENT. These results indicate that inhibition of 5α-reductase activity in vivo does not affect the androgenic potency of DMA, MNT, or MENT.

Fig. 1

Effect of 5α-DHDMA compared to DMA and T after 7 days in the sc androgenic assay. 5α-DHDMA was less potent than DMA and more potent than T in increasing ventral prostate weight (A). DMA was more potent than 5α-DHDMA and T in increasing levator ani muscle weight (B). Groups with different letters are significantly different (P<0.05).

Fig. 2

Effect of 5α-DHMNT compared to MNT and T after 7 days in the sc androgenic assay. 5α-DHMNT was more potent than MNT and T in increasing ventral prostate weight (A). MNT, 5α-DHMNT and T increased levator ani muscle weight compared to vehicle, but there was no significant difference among them at the highest doses (B). Groups with different letters are significantly different (P<0.05).

Fig. 3

Effect of dutasteride on accessory sex gland weights after 8 days in the sc androgenic assay. Dutasteride significantly suppressed T-stimulated ventral prostate (*P<0.05) and seminal vesicle (**P<0.001) weights. There was no significant effect of dutasteride on accessory sex gland weights in rats treated with vehicle, DMA, or MNT.

Fig. 4

Effect of dutasteride on serum androgen levels in the rats from Fig. 3. (A) In rats treated with T + dutasteride (DUT), there was a significant decrease in serum DHT levels (**P<0.001) and a significant increase in serum T levels (*P<0.05) compared to rats treated with T + vehicle (Veh). (B) There was a slight, but not significant (P=0.12), increase in serum DMA levels in rats treated with DMA + DUT compared to rats treated with DMA + Veh. In rats treated with MNT + DUT, serum levels of MNT were significantly elevated (*P<0.01) compared to rats treated with MNT + Veh.

Fig. 5

Effect of dutasteride on accessory sex gland weights after 8 days in the sc androgenic assay. As in the experiment shown in Fig. 3, dutasteride significantly suppressed T-stimulated ventral prostate (*P<0.05) (A) and seminal vesicle (**P<0.001) (B) weights. There was no significant effect of dutasteride on accessory sex gland weights in rats treated with MENT or DHT. VP, but not SV, weights were increased in rats treated with vehicle + DUT (*P<0.05).

Fig. 6

Effect of dutasteride on serum androgen levels in the rats from Fig. 5. (A) In rats treated with T + DUT, there was a significant decrease in serum DHT levels (**P<0.001) and a significant increase in serum T levels (*P<0.01) compared to rats treated with T + vehicle, confirming the results in Fig. 4A. (B) There was no significant difference in serum DHT levels (P=0.78) between rats treated with DHT + DUT or DHT + Veh. In rats treated with MENT + DUT, serum levels of MENT were significantly lower (**P<0.05) than in rats treated with MENT + Veh.