Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor alpha signaling.

It was recently demonstrated that antiestrogens prevented prostate cancer (PRCA) in men. The source of estradiol (E2) that contributes to carcinogenesis, as well as the selected estrogen receptor (ER) signaling pathway, is unknown. To evaluate estrogen's effects in carcinogenesis, we developed a new model of PRCA utilizing testosterone and E2 to stimulate PRCA. To determine whether local in situ production of E2 affected incidence of PRCA, aromatase-knockout (ArKO) mice were evaluated. In contrast to the wild-type mice, ArKO mice had reduced incidences of PRCA, which implicates in situ production of E2 as an important determinant of PRCA. To determine whether E2-mediated responses were due to ER alpha or ER beta signaling, ER alpha-knockout (alphaERKO) or ERbeta-knockout (betaERKO) mice were used. Prostates from betaERKO mice underwent biochemical and histological carcinogenesis similar to wild-type mice, whereas prostates from alphaERKO mice remained free of pathology. These data suggest that effective prevention of carcinogenesis will require antagonism of ER alpha but not ER beta. This mouse model provides a means to examine genetic gain and loss of function and determine the efficacy of therapeutics on prostatic carcinogenesis.

Prostate phenotypes in estrogen-modulated transgenic mice.

Estrogen-modulated transgenic mice, such as estrogen receptor-knockouts (alphaERKO and betaERKO), aromatase-knockout (ArKO) and aromatase-overexpressing (AROM+) mice, have contributed to our understanding of the roles of estrogens in male reproductive biology, including prostate growth and development. Varying pathological changes of the prostate have been described as being the result of aberrant actions of estrogen, both directly through the estrogen receptors or indirectly by altering the endocrine status of these mice. This article identifies the consequences of aberrant estrogen signaling on prostate growth and development. Further characterization and manipulation of these estrogen-modulated transgenic mice will lead to a more complete understanding of the hormonal regulation of the mammalian prostate gland.

Pharmacokinetic bioequivalence studies of a fixed-dose combination of tamsulosin and dutasteride in healthy volunteers.

BACKGROUND AND OBJECTIVES: The combination of dutasteride and tamsulosin may be more effective for the treatment of symptomatic benign prostatic hyperplasia than either treatment alone. We report the results of three pharmacokinetics and tolerability studies, which used a dutasteride/tamsulosin HCl (0.5 mg/0.2 mg) fixed-dose combination (FDC) capsules containing a small dutasteride soft gelatin capsule (smaller than commercial Avodart™) and modified-release tamsulosin pellets that have different amounts of enteric coating. These studies compared the test products to commercial Avodart™ (dutasteride 0.5 mg) and two different commercial tamsulosin HCl 0.2 mg products, Harnal™ Capsules or Harnal-D™ Tablets, which are reportedly bioequivalent to each other. METHODS: All three studies were randomized single-dose studies in healthy male adults. Study 1 [N = 86 (NCT01254071)] was a two-period crossover study of a dutasteride/tamsulosin HCl FDC versus coadministered Avodart™ and Harnal-D™ Tablets. The pharmacokinetics of both dutasteride and tamsulosin were studied. Study 2 [N = 27 (NCT01471678)] was a four-period crossover study of dutasteride/tamsulosin HCl FDC formulations versus Avodart™ and Harnal™ Capsules or Harnal-D™ Tablets. Only the pharmacokinetics of tamsulosin were studied. Study 3 [N = 40 (NCT01495026)] was a two-period study of dutasteride/tamsulosin HCl FDC formulations versus coadministered Avodart™ and Harnal-D™ Tablets. In this study, only the pharmacokinetics of tamsulosin were studied. Study 2 assessed fed-state pharmacokinetics. Studies 1 and 3 assessed fed- and fasted-state pharmacokinetics. RESULTS: All dutasteride/tamsulosin HCl FDC formulations and coadministered treatments were well-tolerated. In Study 1, the FDC dutasteride was bioequivalent to Avodart™ coadministered with tamsulosin under fed and fasted conditions. In Study 1, the FDC tamsulosin had a slower release than commercial Harnal-D™ Tablets coadministered with dutasteride (fed and fasted state). In Study 2, the FDC tamsulosin containing 15 % by weight enteric-coated tamsulosin pellets was bioequivalent to Harnal™ Capsules coadministered with dutasteride in the fed state. In Study 3, the FDC containing 15 % by weight enteric-coated tamsulosin pellets combined with uncoated tamsulosin pellets (coated:uncoated = 10:90) were bioequivalent to Harnal-D™ Tablets coadministered with dutasteride in the fasted state but not the fed state. CONCLUSIONS: The FDC formulations were well-tolerated and some FDC formulations were comparable with concomitant administration of commercially available dutasteride and tamsulosin.