抗雄激素

抗雄激素
	Bicalutamide, a nonsteroidal antiandrogen and the most widely used androgen receptor antagonist in the treatment of prostate cancer.
用途	Various
生物目标	Androgen receptor
ATC代码	L02BB
外部链接
MeSH	D000726

抗雄激素（anti-androgens），或称为雄性激素拮抗剂（androgen antagonists）。于1960年代时被发现，借由阻断特定的受体而抑制雄性激素的作用。可以竞争细胞表面的接受器或是影响雄性激素的产生。^[1]抗雄激素可用来治疗一系列的疾病。在男性，抗雄激素经常用来治疗前列腺癌。^[2]对女性使用通常用来减少体内过多的雄性激素。抗雄激素对环境的影响已经受到高度的关注。许多的工业化学物质、杀虫剂都有抗雄激素的作用。一些特定的植物也被发现会产生抗雄激素。环境中的抗雄激素对于生殖系统还在发育的小孩会有深远的影响。

机转

抗雄激素可按原理分为雄性激素受体阻断剂、雄性激素合成抑制剂，和抗促性腺激素三种。

阻断受体

雄激素和抗雄激素对AR的结合^[3]^[4]
物质	RBA (%)
Metribolone	100
双氢睾酮	85
醋酸环丙孕酮	7.8
螺内酯	2.3
比卡鲁胺	1.4
Nilutamide	0.9
Hydroxyflutamide	0.57
氟他胺	<0.0057

阻断受体的可按结果分为类固醇类和非类固醇类两种。类固醇类抗雄激素与睾酮、孕酮等类固醇类似，由于其类固醇的结构经常会激活其他激素受体，造成偏离目标的活性。^[5]因为它有高脂性，所以可以扩散穿过细胞膜的双磷脂层，阻挡睾酮和双氢睾酮（DHT）键结到受体上，进而影响基因表现活性。^[6]比卡鲁胺和氟他胺这类非类固醇类抗雄激素则没有这类副作用，因此有时候也叫“纯”抗雄激素。^[5]

抑制合成

雄性激素合成抑制剂是抑制雄激素生物合成的酶抑制剂。^[7]雄激素的合成主要集中于性腺和肾上腺，但在前列腺、毛囊等位置也有发生。如酮康唑不只跟睾酮还有双氢睾酮竞争雄性激素受体，还会去抑制负责将孕烷类转换为雄激素的CYP17A1的活性，从而抑制了雄性激素的合成，导致肾上腺皮质生产的睾酮量下降。^[8]>由于CYP17A1还负责将盐皮质激素转换为糖皮质激素，使用这类药物时经常需要配合强的松之类的糖皮质激素，用以防止肾上腺功能不足。^[7]^[8]螺内酯也是通过抑制CYP17A1发挥抗雄作用。

5α-还原酶抑制剂会抑制5α-还原酶，从而抑制双氢睾酮的合成。^[9]

抗促性腺激素

促性腺激素，如黄体生成素（LH）、促卵泡激素（FSH），负责促使性腺制造性激素。抗促性腺激素会抑制垂体在GnRH作用下释放促性腺激素的功能。^[10]各种GnRH类似物都可以有效压制促性腺激素的产生，从而将男性的血浆雄激素含量降低95%。^[10]由于下丘脑—垂体—性腺轴的负反馈调节，雌激素、孕激素也能有效降低促性腺激素的作用。^[11]^[12]^[13]大剂量雌激素可以将雄激素降低到阉割水平，^[14]大剂量孕激素也同样可以将男性的雄激素水平降低七到八成。^[15]^[16]

医药应用

抗雄激素药物可以用于一系列跟雄性激素有关的医学问题。通常用于男性的前列腺癌，良性前列腺增生症，性欲亢进，男性不孕症，还有正在进行性别肯定激素治疗（GAHT）的跨性别者。

参见

参考文献

↑ Mowszowicz I.（1989）. "Antiandrogens. Mechanisms and paradoxical effects". Ann Endocrinol (Paris) 50 (3): 50 (3):189–99. ，
↑ Mowszowicz I.（1989）. Gillatt D.（2006）. "Antiandrogen treatments in locally advanced prostate cancer: are they all the same?". J Cancer Res Clin Oncol. 1: S17-26.. [2012-05-28].
↑ Ayub M, Levell MJ. The effect of ketoconazole related imidazole drugs and antiandrogens on [3H] R 1881 binding to the prostatic androgen receptor and [3H]5 alpha-dihydrotestosterone and [3H]cortisol binding to plasma proteins. J. Steroid Biochem. 1989-08, 33 (2): 251–5. PMID 2788775. doi:10.1016/0022-4731(89)90301-4.
↑ Yamasaki K, Sawaki M, Noda S, Muroi T, Takakura S, Mitoma H, Sakamoto S, Nakai M, Yakabe Y. Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals. Toxicology. 2004, 195 (2-3): 177–86. PMID 14751673. doi:10.1016/j.tox.2003.09.012.
↑ ^5.0 ^5.1 Thomas L. Lemke; David A. Williams. Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. 2012-01-24: 228–231, 1371–1372. ISBN 978-1-60913-345-0.
↑ "Steroidal Antiandrogens" ，Health and Prostate. Retrieved 9 December 2011.
↑ ^7.0 ^7.1 William Figg; Cindy H. Chau; Eric J. Small. Drug Management of Prostate Cancer. Springer Science & Business Media. 2010-09-14: 71–72,75,91–96. ISBN 978-1-60327-829-4.
↑ ^8.0 ^8.1 Jerome F. Strauss, III; Robert L. Barbieri. Yen and Jaffe's Reproductive Endocrinology. Elsevier Health Sciences. 2013-09-13: 90–. ISBN 978-1-4557-2758-2.
↑ Flores E, Bratoeff E, Cabeza M, Ramirez E, Quiroz A, Heuze I. Steroid 5alpha-reductase inhibitors. Mini-Reviews in Medicinal Chemistry. 2003-05, 3 (3): 225–37. PMID 12570838. doi:10.2174/1389557033488196.
↑ ^10.0 ^10.1 Peter B. Farmer; John M. Walker. The Molecular Basis of Cancer. Springer Science & Business Media. 2012-12-06: 232–. ISBN 978-1-4684-7313-1.
↑ Brueggemeier, Robert W. Sex Hormones (Male): Analogs and Antagonists. 2006. doi:10.1002/3527600906.mcb.200500066.
↑ de Lignières B, Silberstein S. Pharmacodynamics of oestrogens and progestogens. Cephalalgia : an International Journal of Headache. 2000-04, 20 (3): 200–7. PMID 10997774. doi:10.1046/j.1468-2982.2000.00042.x.
↑ Neumann F. The physiological action of progesterone and the pharmacological effects of progestogens--a short review. Postgraduate Medical Journal. 1978,. 54 Suppl 2: 11–24. PMID 368741.
↑ Jacobi GH, Altwein JE, Kurth KH, Basting R, Hohenfellner R. Treatment of advanced prostatic cancer with parenteral cyproterone acetate: a phase III randomised trial. Br J Urol. 1980, 52 (3): 208–15. PMID 7000222. doi:10.1111/j.1464-410x.1980.tb02961.x.
↑ Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA. Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set. Elsevier Health Sciences. 2011-08-25: 2938–. ISBN 978-1-4160-6911-9.
↑ Kjeld JM, Puah CM, Kaufman B, Loizou S, Vlotides J, Gwee HM, Kahn F, Sood R, Joplin GF. Effects of norgestrel and ethinyloestradiol ingestion on serum levels of sex hormones and gonadotrophins in men. Clinical Endocrinology. 1979, 11 (5): 497–504. PMID 519881. doi:10.1111/j.1365-2265.1979.tb03102.x.

[Mowszowicz-1] Mowszowicz I.（1989）. "Antiandrogens. Mechanisms and paradoxical effects". Ann Endocrinol (Paris) 50 (3): 50 (3):189–99. ，

[2] Mowszowicz I.（1989）. Gillatt D.（2006）. "Antiandrogen treatments in locally advanced prostate cancer: are they all the same?". J Cancer Res Clin Oncol. 1: S17-26.. [2012-05-28].

[pmid2788775-3] Ayub M, Levell MJ. The effect of ketoconazole related imidazole drugs and antiandrogens on [3H] R 1881 binding to the prostatic androgen receptor and [3H]5 alpha-dihydrotestosterone and [3H]cortisol binding to plasma proteins. J. Steroid Biochem. 1989-08, 33 (2): 251–5. PMID 2788775. doi:10.1016/0022-4731(89)90301-4.

[pmid14751673-4] Yamasaki K, Sawaki M, Noda S, Muroi T, Takakura S, Mitoma H, Sakamoto S, Nakai M, Yakabe Y. Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals. Toxicology. 2004, 195 (2-3): 177–86. PMID 14751673. doi:10.1016/j.tox.2003.09.012.

[LemkeWilliams2012-5] 5.0 ^5.1 Thomas L. Lemke; David A. Williams. Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. 2012-01-24: 228–231, 1371–1372. ISBN 978-1-60913-345-0.

[6] "Steroidal Antiandrogens" ，Health and Prostate. Retrieved 9 December 2011.

[FiggChau2010-7] 7.0 ^7.1 William Figg; Cindy H. Chau; Eric J. Small. Drug Management of Prostate Cancer. Springer Science & Business Media. 2010-09-14: 71–72,75,91–96. ISBN 978-1-60327-829-4.

[IIIBarbieri2013-8] 8.0 ^8.1 Jerome F. Strauss, III; Robert L. Barbieri. Yen and Jaffe's Reproductive Endocrinology. Elsevier Health Sciences. 2013-09-13: 90–. ISBN 978-1-4557-2758-2.

[Flores-9] Flores E, Bratoeff E, Cabeza M, Ramirez E, Quiroz A, Heuze I. Steroid 5alpha-reductase inhibitors. Mini-Reviews in Medicinal Chemistry. 2003-05, 3 (3): 225–37. PMID 12570838. doi:10.2174/1389557033488196.

[FarmerWalker2012-10] 10.0 ^10.1 Peter B. Farmer; John M. Walker. The Molecular Basis of Cancer. Springer Science & Business Media. 2012-12-06: 232–. ISBN 978-1-4684-7313-1.

[Brueggemeier2006-11] Brueggemeier, Robert W. Sex Hormones (Male): Analogs and Antagonists. 2006. doi:10.1002/3527600906.mcb.200500066.

[pmid10997774-12] Lignières B, Silberstein S. Pharmacodynamics of oestrogens and progestogens. Cephalalgia : an International Journal of Headache. 2000-04, 20 (3): 200–7. PMID 10997774. doi:10.1046/j.1468-2982.2000.00042.x.

[pmid368741-13] Neumann F. The physiological action of progesterone and the pharmacological effects of progestogens--a short review. Postgraduate Medical Journal. 1978,. 54 Suppl 2: 11–24. PMID 368741.

[pmid7000222-14] Jacobi GH, Altwein JE, Kurth KH, Basting R, Hohenfellner R. Treatment of advanced prostatic cancer with parenteral cyproterone acetate: a phase III randomised trial. Br J Urol. 1980, 52 (3): 208–15. PMID 7000222. doi:10.1111/j.1464-410x.1980.tb02961.x.

[WeinKavoussi2011-15] Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA. Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set. Elsevier Health Sciences. 2011-08-25: 2938–. ISBN 978-1-4160-6911-9.

[pmid519881-16] Kjeld JM, Puah CM, Kaufman B, Loizou S, Vlotides J, Gwee HM, Kahn F, Sood R, Joplin GF. Effects of norgestrel and ethinyloestradiol ingestion on serum levels of sex hormones and gonadotrophins in men. Clinical Endocrinology. 1979, 11 (5): 497–504. PMID 519881. doi:10.1111/j.1365-2265.1979.tb03102.x.

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