Download PDF
Arzneimittelforschung 2011; 61(9): 515-520
DOI: 10.1055/s-0031-1296237
Sex Hormones and Inhibitors
Editio Cantor Verlag Aulendorf (Germany)

Suppressive effects of the antiandrogen agent, chlormadinone acetate and the 5α-reductase inhibitor, dutasteride on prostate weight and intraprostatic androgen levels in rats

Hideo Kobayashi
1   Pharmacological Research Department, ASKA Pharmaceutical Co., Ltd., Kawasaki, Japan
,
Kotaro Gotanda
1   Pharmacological Research Department, ASKA Pharmaceutical Co., Ltd., Kawasaki, Japan
,
Yasuhiro Shibata
2   Department of Urology, Gunma University School of Medicine, Maebashi, Japan
,
Jun-ichi Watanabe
1   Pharmacological Research Department, ASKA Pharmaceutical Co., Ltd., Kawasaki, Japan
,
Youichi Nakano
1   Pharmacological Research Department, ASKA Pharmaceutical Co., Ltd., Kawasaki, Japan
,
Atsushi Shinbo
1   Pharmacological Research Department, ASKA Pharmaceutical Co., Ltd., Kawasaki, Japan
,
Kazuhiro Suzuki
2   Department of Urology, Gunma University School of Medicine, Maebashi, Japan
› Author Affiliations
Further Information

Publication History

Publication Date:
03 December 2011 (online)

    Permissions and Reprints

Abstract

The objectives of this study were to investigate whether Chlormadinone acetate (CMA, Prostal®, CAS 302-22-7) more markedly decreased ventral prostate and seminal vesicle weights and exerted more beneficial effects on intraprostatic androgen levels than dutasteride (DUT, CAS 164656-23-9) in rats. Dose-dependent inhibiting effects on prostate and seminal vesicle enlargement were observed after the 14-day administration of CMA (30, 100 mg/kg/day) and DUT (0.3, 1 mg/kg/day). The prostate atrophy rates calculated as the percentages relative to the vehicle-treated group were 50.5 and 67.9% with 30 and 100 mg/kg CMA and 34.9 and 37.0% with 0.3 and 1 mg/kg DUT, respectively, and the atrophying effect of CMA was significantly greater than that of DUT (ρ < 0.05). The results of 7-day administration were similar to those of 14-day administration. While CMA dose-dependently and significantly (p < 0.05) reduced the testosterone (T) and di-hydrotestosterone (DHT) concentrations in prostate, DUT reduced the DHT concentration but markedly increased the Τ concentration (20-40 times). Even though it was carried out in rats, this study revealed for the first time that the antiandrogen CMA showed a stronger atrophying effect than the 5α-reductase inhibitor DUT on direct comparison. The difference between the atrophying effects of CMA and DUT is considered to be attributed to the present results that CMA reduced the concentrations of both androgens (T and DHT) in prostate but DUT did not, and the fact that CMA has a potent androgen receptor-blocking action but DUT does not.

Key words

Benign prostatic hyperplasia - Chlormadinone acetate - Dihydrotestosterone - Dutasteride - Rat prostate - Testosterone
 

  • References

  • 1 Tsukamoto T, Masumori N.. Epidemiology and natural history of benign prostatic hyperplasia. Int J Urol. 1997; 4: 233-46
    CrossrefPubMedGoogle Scholar
  • 2 Roehrborn CG.. Benign prostatic hyperplasia: an overview. Rev Urol. 2005; 7: S3-14
    PubMedGoogle Scholar
  • 3 Kaplan SA.. Current role of alpha-blockers in the treatment of benign prostatic hyperplasia. BJU Int. 2008; 102 (S2) 3-7
    CrossrefPubMedGoogle Scholar
  • 4 Lowe F.. Alpha-1-adrenoceptor blockade in the treatment of benign prostatic hyperplasia. Prostate Cancer Prostatic Dis. 1999; 2: 110-9
    CrossrefPubMedGoogle Scholar
  • 5 Kanimoto Y, Okada K.. Antiandrogen therapy of benign prostatic hyperplasia-review of the agents evaluation of the clinical results. Hinyokika Kiyo. 1991; 37: 1423-8
    PubMedGoogle Scholar
  • 6 Okada H, Kawaida N, Ogawa T, Arakawa S, Matsumoto O, Kamidono S et al. Tamsulosin and Chlormadinone for the treatment of benign prostatic hyperplasia. Scand J Urol Nephrol. 1996; 30: 379-85
    CrossrefPubMedGoogle Scholar
  • 7 Gotanda K, Shinbo A, Nakano Y, Sasaki T, Honma S, Miya-saka K.. The effect of Chlormadinone acetate on the prostate of rats treated with adrenal androgens. Medical Consultation New Remedies. 1999; 36: 277-83
    PubMedGoogle Scholar
  • 8 Gotanda K, Shinbo A, Okada M, Nakano Y, Kobayashi H, Sasaki T et al. Effects of combination therapy with a luteinizing hormone-releasing hormone agonist and Chlormadinone acetate on rat prostate weight and plasma testosterone levels. Prostate Cancer Prostatic Dis. 2003; 6: 66-72
    CrossrefPubMedGoogle Scholar
  • 9 Kondo Y, Homma Y, Aso Y, Kawabe K, Mieda M, Takahashi H.. Relative potency of antiandrogens with reference to intracellular testosterone in the rat prostate. Prostate. 1996; 29: 146-52
    CrossrefPubMedGoogle Scholar
  • 10 Shibata Y, Fukabori Y, Ito K, Suzuki K, Yamanaka H.. Comparison of histological compositions and apoptosis in canine spontaneous benign prostatic hyperplasia treated with androgen suppressive agents Chlormadinone acetate and finasteride. J Urol. 2001; 165: 289-93
    CrossrefPubMedGoogle Scholar
  • 11 Bramson HN, Hermann D, Batchelor KW, Lee FW, James MK, Frye SV.. Unique preclinical characteristics of GG745, a potent dual inhibitor of 5AR. J Pharmacol Exp Ther. 1997; 282: 1496-502
    PubMedGoogle Scholar
  • 12 O’Leary MP, Roehrborn CG, Black L.. Dutasteride significantly improves quality of life measures in patients with enlarged prostate. Prostate Cancer Prostatic Dis. 2008; 11: 129-33
    CrossrefPubMedGoogle Scholar
  • 13 Debruyne F, Barkin J, vanErps P, Reis M, Tammela TL, Roehrborn C ARIA3001, ARIA3002 and ARIB3003 Study. Investigators. Efficacy and safety of long-term treatment with the dual 5 alpha-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol. 2004; 46: 488-95
    CrossrefPubMedGoogle Scholar
  • 14 Roehrborn CG, Marks LS, Fenter T, Freedman S, Turtle J, Gittleman M et al. Efficacy and safety of dutasteride in the four-year treatment of men with benign prostatic hyperplasia. Urology. 2004; 63: 709-15
    CrossrefPubMedGoogle Scholar
  • 15 Rittmaster R, Hahn RG, Ray P, Shannon JB, Wurzel R.. Effect of dutasteride on intraprostatic androgen levels in men with benign prostatic hyperplasia or prostate cancer. Urology. 2008; 72: 808-12
    CrossrefPubMedGoogle Scholar
  • 16 Wurzel R, Ray P, Major-Walker K, Shannon J, Rittmaster R.. The effect of dutasteride on intraprostatic dihydrotestos-terone concentrations in men with benign prostatic hyperplasia. Prostate Cancer Prostatic Dis. 2007; 10: 149-54
    CrossrefPubMedGoogle Scholar
  • 17 Paris F, Servant N, Térouanne Β, Sultan C.. Evaluation of androgenic bioactivity in human serum by recombinant cell line: preliminary results. Mol Cell Endocrinol. 2002; 198: 123-9
    CrossrefPubMedGoogle Scholar
  • 18 Kemppainen JA, Langley E, Wong CI, Bobseine K, Kelce WR, Wilson EM.. Distinguishing androgen receptor agonists and antagonists: distinct mechanisms of activation by medroxyprogesterone acetate and dihydrotestosterone. Mol Endocrinol. 1999; 13: 440-54
    CrossrefPubMedGoogle Scholar
  • 19 Ozers MS, Marks BD, Gowda K, Kupcho KR, Ervin KM, DeRosier T et al. The androgen receptor T877A mutant recruits LXXLL and FXXLF peptides differently than wild-type androgen receptor in a time-resolved fluorescence resonance energy transfer assay. Biochemistry. 2007; 46: 683-95
    CrossrefPubMedGoogle Scholar
  • 20 Lazier CB, Thomas LN, Douglas RC, Vessey JP, Rittmaster RS.. Dutasteride, the dual 5alpha-reductase inhibitor, inhibits androgen action and promotes cell death in the LNCaP prostate cancer cell line. Prostate. 2004; 58: 130-44
    CrossrefPubMedGoogle Scholar
  • 21 Shibata Y, Ito K, Suzuki K, Nakano K, Fukabori Y, Suzuki R et al. Changes in the endocrine environment of the human prostate transition zone with aging: Simultaneous quantitative analysis of prostatic sex steroids and comparison with human prostatic histological composition. Prostate. 2000; 42: 45-55
    CrossrefPubMedGoogle Scholar
  • 22 Mieda M, Tarutani M, Takahashi H, Iizuka K, Nakanowa-tari K, Shimazawa H et al. [The effect of Chlormadinone acetate on rat prostatic atrophy]. Kiso To Rinsho. 1977; 11: 158-63 Japanese
    PubMedGoogle Scholar
  • 23 Aso Y, Homma Y, Kumamoto Y, Tsukamoto T, Orikasa S, Yamanaka H et al. [Phase III study of 5 alpha-reductase inhibitor, MK-906 in patients with benign prostatic hyperplasia – A comparable double blind study with Chlormadinone acetate long acting tablets]. Hinyoki Ge Ka. 1995; 8: 237-56 Japanese
    PubMedGoogle Scholar
  • 24 Kogawa T, Yanagiya H, Takashima T, Higashino I, Kudo T, Suzuki T et al. Clinical evaluation of the long-term treatment with Chlormadinone acetate in patients with benign prostatic hypertrophy. Hinyokika Kiyo. 1993; 39: 281-7
    PubMedGoogle Scholar
  • 25 Tsukamoto T, Endo Y, Narita M.. Assessment of recommended dose of dutasteride on Japanese men with benign prostatic hyperplasia: a randomized, double-blind, placebo-controlled, parallel-group, dose response study. Hinyokika Kiyo. 2009; 55: 209-14
    PubMedGoogle Scholar
  • 26 Tsukamoto T, Endo Y, Narita M.. Efficacy and safety of du-tasteride in Japanese men with benign prostatic hyperplasia. Int J Urol. 2009; 16: 745-50
    CrossrefPubMedGoogle Scholar
  • 27 Cunha GR, Alarid ET, Turner T, Donjacour AA, Boutin EL, Foster BA.. Normal and abnormal development of the male urogenital tract. Role of androgens, mesenchymal-epithelial interactions, and growth factors. J Androl. 1992; 13: 465-75
    PubMedGoogle Scholar
  • 28 Ito K, Fukabori Y, Shibata Y, Suzuki K, Mieda M, Gotanda K et al. Effects of a new steroidal aromatase inhibitor, TZA-2237, and/or Chlormadinone acetate on hormone-induced and spontaneous canine benign prostatic hyperplasia. Eur J Endocrinol. 2000; 143: 543-54
    CrossrefPubMedGoogle Scholar
  • 29 Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003; 349: 215-24
    CrossrefPubMedGoogle Scholar
  • 30 Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Mar-berger M, Montorsi F et al. REDUCE Study Group. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010; 362: 1192-202
    CrossrefPubMedGoogle Scholar
  • 31 Nishiyama T, Ikarashi T, Hashimoto Y, Suzuki K, Takahashi K.. Association between the dihydrotestosterone level in the prostate and prostate cancer aggressiveness using the Gleason score. J Urol. 2006; 176: 1387-91
    CrossrefPubMedGoogle Scholar
  • 32 Moguilewsky M, Fiet J, Tournemine C, Raynaud JP.. Pharmacology of an antiandrogen, anandron, used as an adjuvant therapy in the treatment of prostate cancer. J Steroid Biochem. 1986; 24: 139-46
    CrossrefPubMedGoogle Scholar
  • 33 Mo Q, Lu SF, Simon NG.. Dehydroepiandrosterone and its metabolites: differential effects on androgen receptor trafficking and transcriptional activity. J Steroid Biochem Mol Biol. 2006; 99: 50-8
    CrossrefPubMedGoogle Scholar