Intracrine Androgen Biosynthesis, Metabolism and Action Revisited

Overview

Journal Mol Cell Endocrinol

Specialties Cell Biology
Endocrinology
Molecular Biology

Date 2017 Sep 4

PMID 28865807

Citations 89

Authors

Lina Schiffer

Wiebke Arlt

Karl-Heinz Storbeck

Affiliations

Soon will be listed here.

Abstract

Androgens play an important role in metabolic homeostasis and reproductive health in both men and women. Androgen signalling is dependent on androgen receptor activation, mostly by testosterone and 5α-dihydrotestosterone. However, the intracellular or intracrine activation of C androgen precursors to active androgens in peripheral target tissues of androgen action is of equal importance. Intracrine androgen synthesis is often not reflected by circulating androgens but rather by androgen metabolites and conjugates. In this review we provide an overview of human C steroid biosynthesis including the production of 11-oxygenated androgens, their transport in circulation and uptake into peripheral tissues. We conceptualise the mechanisms of intracrinology and review the intracrine pathways of activation and inactivation in selected human tissues. The contribution of liver and kidney as organs driving androgen inactivation and renal excretion are also highlighted. Finally, the importance of quantifying androgen metabolites and conjugates to assess intracrine androgen production is discussed.

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References

Rainey W, Nakamura Y . Regulation of the adrenal androgen biosynthesis. J Steroid Biochem Mol Biol. 2007; 108(3-5):281-6. PMC: 2699571. DOI: 10.1016/j.jsbmb.2007.09.015. View

Werner R, Kulle A, Sommerfeld I, Riepe F, Wudy S, Hartmann M . Testosterone synthesis in patients with 17β-hydroxysteroid dehydrogenase 3 deficiency. Sex Dev. 2012; 6(4):161-8. DOI: 10.1159/000336605. View

Simpson E . Sources of estrogen and their importance. J Steroid Biochem Mol Biol. 2003; 86(3-5):225-30. DOI: 10.1016/s0960-0760(03)00360-1. View

OReilly M, House P, Tomlinson J . Understanding androgen action in adipose tissue. J Steroid Biochem Mol Biol. 2014; 143:277-84. DOI: 10.1016/j.jsbmb.2014.04.008. View

Sherbet D, Tiosano D, Kwist K, Hochberg Z, Auchus R . CYP17 mutation E305G causes isolated 17,20-lyase deficiency by selectively altering substrate binding. J Biol Chem. 2003; 278(49):48563-9. DOI: 10.1074/jbc.M307586200. View

Storbeck K, Bloem L, Africander D, Schloms L, Swart P, Swart A . 11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: a putative role in castration resistant prostate cancer?. Mol Cell Endocrinol. 2013; 377(1-2):135-46. DOI: 10.1016/j.mce.2013.07.006. View

Uemura M, Tamura K, Chung S, Honma S, Okuyama A, Nakamura Y . Novel 5 alpha-steroid reductase (SRD5A3, type-3) is overexpressed in hormone-refractory prostate cancer. Cancer Sci. 2007; 99(1):81-6. PMC: 11158902. DOI: 10.1111/j.1349-7006.2007.00656.x. View

Suzuki T, Miki Y, Nakamura Y, Moriya T, Ito K, Ohuchi N . Sex steroid-producing enzymes in human breast cancer. Endocr Relat Cancer. 2005; 12(4):701-20. DOI: 10.1677/erc.1.00834. View

Labrie F, Luu-The V, Labrie C, Pelletier G, El-Alfy M . Intracrinology and the skin. Horm Res. 2001; 54(5-6):218-29. DOI: 10.1159/000053264. View

10.

Niwa T, Murayama N, Imagawa Y, Yamazaki H . Regioselective hydroxylation of steroid hormones by human cytochromes P450. Drug Metab Rev. 2015; 47(2):89-110. DOI: 10.3109/03602532.2015.1011658. View

11.

Chen M, Drury J, Penning T . Substrate specificity and inhibitor analyses of human steroid 5β-reductase (AKR1D1). Steroids. 2011; 76(5):484-90. PMC: 3056882. DOI: 10.1016/j.steroids.2011.01.003. View

12.

Idkowiak J, Lavery G, Dhir V, Barrett T, Stewart P, Krone N . Premature adrenarche: novel lessons from early onset androgen excess. Eur J Endocrinol. 2011; 165(2):189-207. DOI: 10.1530/EJE-11-0223. View

13.

Yang M, Xie W, Mostaghel E, Nakabayashi M, Werner L, Sun T . SLCO2B1 and SLCO1B3 may determine time to progression for patients receiving androgen deprivation therapy for prostate cancer. J Clin Oncol. 2011; 29(18):2565-73. PMC: 3138634. DOI: 10.1200/JCO.2010.31.2405. View

14.

Capper C, Rae J, Auchus R . The Metabolism, Analysis, and Targeting of Steroid Hormones in Breast and Prostate Cancer. Horm Cancer. 2016; 7(3):149-64. PMC: 4860032. DOI: 10.1007/s12672-016-0259-0. View

15.

Turcu A, Nanba A, Chomic R, Upadhyay S, Giordano T, Shields J . Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency. Eur J Endocrinol. 2016; 174(5):601-9. PMC: 4874183. DOI: 10.1530/EJE-15-1181. View

16.

Penning T, Lee S, Jin Y, Gutierrez A, Blair I . Liquid chromatography-mass spectrometry (LC-MS) of steroid hormone metabolites and its applications. J Steroid Biochem Mol Biol. 2010; 121(3-5):546-55. PMC: 2894289. DOI: 10.1016/j.jsbmb.2010.01.005. View

17.

Hogeveen K, Cousin P, Pugeat M, Dewailly D, Soudan B, Hammond G . Human sex hormone-binding globulin variants associated with hyperandrogenism and ovarian dysfunction. J Clin Invest. 2002; 109(7):973-81. PMC: 150924. DOI: 10.1172/JCI14060. View

18.

Ke Y, Gonthier R, Simard J, Labrie F . A validated LC-MS/MS method for the sensitive quantitation of serum 7alpha hydroxy-, 7beta hydroxy- and 7keto-dehydroepiandrosterone using a novel derivatization reagent. Steroids. 2016; 108:112-7. DOI: 10.1016/j.steroids.2016.02.005. View

19.

Hofland J, van Weerden W, Dits N, Steenbergen J, van Leenders G, Jenster G . Evidence of limited contributions for intratumoral steroidogenesis in prostate cancer. Cancer Res. 2010; 70(3):1256-64. DOI: 10.1158/0008-5472.CAN-09-2092. View

20.

Tchernof A, Labrie F, Belanger A, Prudhomme D, Bouchard C, Tremblay A . Androstane-3alpha,17beta-diol glucuronide as a steroid correlate of visceral obesity in men. J Clin Endocrinol Metab. 1997; 82(5):1528-34. DOI: 10.1210/jcem.82.5.3924. View