2411 G Snaterse et al. Circulating steroids in prostate 24:11 R403–R420 Review cancer Circulating steroid hormone variations throughout different stages of prostate cancer Gido Snaterse1, Jenny A Visser1, Wiebke Arlt2 and Johannes Hofland1,2 Correspondence should be addressed 1 Section of Endocrinology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands to J Hofland 2 Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK Email [email protected] Abstract Steroid hormones play a central role in the maintenance and progression of prostate Key Words cancer. The androgen receptor is the primary driver of tumor cell proliferation and f androgens is activated by the androgens testosterone and 5α-dihydrotestosterone. Inhibition of f prostate cancer this pathway through medical or surgical castration improves survival in the majority f circulating markers of advanced prostate cancer patients. However, conversion of adrenal androgen precursors and alternative steroidogenic pathways have been found to contribute to tumor progression and resistance to treatment. The emergence of highly accurate detection methods allows us to study steroidogenic mechanisms in more detail, even after treatment with potent steroidogenic inhibitors such as the CYP17A1 inhibitor abiraterone. A clear overview of steroid hormone levels in patients throughout the local, Endocrine-Related Cancer Endocrine-Related metastatic and castration-resistant stages of prostate cancer and treatment modalities is key toward a better understanding of their role in tumor progression and treatment resistance. In this review, we summarize the currently available data on steroid hormones that have been implicated in the various stages of prostate cancer. Additionally, this review addresses the implications of these findings, highlights important studies in this Endocrine-Related Cancer field and identifies current gaps in literature. (2017) 24, R403–R420 Introduction Prostate cancer (PC) is the most prevalent form of treated with curative intent by prostatectomy or localized cancer, with the exception of non-melanoma skin radiotherapy (Attard et al. 2016). Active surveillance may cancers, in men in Western countries with an estimated be employed in some cases if immediate treatment is not 677.473 new cases in Europe and North America in deemed necessary or beneficial, for example in patients 2014 (Forman & Ferlay 2014). In addition, it is a major with low risk (Klotz & Emberton 2014, Hamdy et al. 2016). contributor to cancer-related mortality in these regions Metastatic prostate cancer is very difficult to treat due to with an estimated 126.430 prostate cancer-related deaths, its tendency to metastasize to the bone (Ye et al. 2007). ranking third in men after lung and colorectal cancers As such, only palliative treatment options exist. (Forman & Ferlay 2014). PC presents relatively late in The androgen receptor (AR) is the main driver of life, after a median of 68 years and is often discovered prostate cancer proliferation and is primarily activated during routine examinations or upon examination of by the androgenic steroid hormones testosterone and urogenital discomfort. Early stage, localized PC can be 5α-dihydrotestosterone (DHT). Androgens are derived http://erc.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-17-0155 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 11:25:27PM via free access 10.1530/ERC-17-0155 Review G Snaterse et al. Circulating steroids in prostate 24:11 R404 cancer from cholesterol in a multi-step process (Fig. 1) that is converted by 5α-reductase (SRD5A1 and 2) into DHT, primarily involves the testes, although androgens which has higher affinity and improved retention at the precursors are also secreted from the zona reticularis of the AR compared to testosterone (Askew et al. 2007). Upon adrenal cortex. In the prostate, circulating testosterone activation, the AR dissociates from its chaperone heat Endocrine-Related Cancer Endocrine-Related Figure 1 Overview of steroidogenesis leading to the production of androgens, estrogens, mineralocorticoids and glucocorticoids. The classical pathway produces DHT through conversion of DHEA, androstenedione and testosterone. The backdoor pathway of DHT synthesis completely bypasses canonical androgen synthesis and instead involves 5α-reduced conversion products ultimately leading to the production of androsterone or androstanediol as precursors for DHT. An alternative pathway produces DHT with androstanedione as intermediary rather than testosterone. Black arrows depict conversions steps with the responsible enzymes listed in red. The 11-oxygenated androgen synthesis pathway is listed, starting with the conversion of androstenedione to 11-hydroxy-androstenedione. DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone-sulfate; DHT, 5α-dihydrotestosterone; DOC, deoxycorticosterone. http://erc.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-17-0155 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 11:25:27PM via free access Review G Snaterse et al. Circulating steroids in prostate 24:11 R405 cancer shock protein 90 (HSP90) and translocates to the nucleus flutamide and biculatamide, it shows less agonistic where it acts as a transcription factor (Trepel et al. 2010). properties in AR-mutated or AR-overexpressing settings The AR subsequently drives the expression of oncogenes (Tran et al. 2009, Korpal et al. 2013), which is critical as causing proliferation of PC cells. one of the mechanisms sustaining PC growth is through Androgen deprivation therapy (ADT) through medical continuously evolving AR mutations in the cancer cells. castration with or without anti-androgens is the mainstay The clinical benefits shown in phase III randomized clinical therapy for advanced prostate cancer (Perlmutter & Lepor trials with enzalutamide and abiraterone suggest that AR 2007). First-line ADT typically consists of treatment with activation is still an essential component of CRPC growth gonadotropin-releasing hormone (GnRH) agonists or and progression, both before as well as after docetaxel antagonists reducing the secretion of luteinizing hormone chemotherapy (de Bono et al. 2011, Scher et al. 2012, Ryan (LH) and consequently preventing the production of et al. 2013b, Beer et al. 2014). Continued expression of testosterone in testicular Leydig cells. GnRH agonists AR-regulated genes such as prostate-specific antigen (PSA) initially cause an LH surge followed by downregulation during second-line anti-androgen axis treatment supports of the GnRH receptor and sustained suppression of LH this hypothesis (Conteduca et al. 2016). levels, while GnRH antagonists cause an immediate Several mechanisms for continued AR activation in the reduction of LH secretion. This treatment improves presence of low circulating levels of androgenic steroids survival in most men, but resistance to treatment typically have been proposed. Key observations have come from occurs within 2–3 years. This next stage of the disease is studies looking at continued relevance of the AR (Chen termed castration-resistant prostate cancer (CRPC) and is et al. 2004a) and residual androgen presence in PC tissues accompanied by a poor overall survival of 16–18 months (Mohler et al. 2004). Conversion of circulating adrenal on average (Harris et al. 2009). androgens androstenedione, DHEA and its sulfated form CRPC can be treated with docetaxel chemotherapy (DHEAS) into testosterone and DHT through elevation of (Tannock et al. 2004), the second-line anti-androgen axis 17β-hydroxysteroid dehydrogenase (HSD) has been shown drugs abiraterone and enzalutamide, but resistance to to occur in CRPC (Stanbrough et al. 2006, Hofland et al. these drugs typically occurs within 6–18 months (Ryan 2010, Kumagai et al. 2013). It has been suggested that, in et al. 2013b, Beer et al. 2014). Compared to first-line the absence of testis-derived testosterone, expression of ADT, abiraterone causes a more complete suppression of steroidogenic enzymes may allow tumor cells to generate androgen synthesis by inhibiting cytochrome P450 (CYP) androgens themselves (Locke et al. 2008, Montgomery Endocrine-Related Cancer Endocrine-Related 17-hydroxylase/17,20-lyase (CYP17A1), a protein that et al. 2008, Ishizaki et al. 2013). However, in what way catalyzes key steps in the production of androgens (Fig. 1). de novo synthesis of androgens contributes to the CRPC As a result, the production of the androgen precursors resistance phenotype in the clinical setting has not yet dehydroepiandrosterone (DHEA) and androstenedione been determined. and subsequently that of potent androgens is inhibited. Alternatively, additional DHT synthesis pathways Hence, abiraterone also suppresses adrenal androgen have been proposed that completely bypass the classic precursor synthesis, while first-line ADT only suppresses androgen synthesis pathway via testosterone (Fig. 1). gonadal androgen synthesis. Abiraterone has to be Other mechanisms involved in resistance to castration co-administered with glucocorticoids as CYP17A1 include AR ligand promiscuity due to mutations, inhibition results in enhanced ACTH-stimulation of allowing the AR to become activated by a variety of the adrenal, which, in combination with the CYP17A1 steroid hormones (Duff & McEwan 2005). As such, block, causes significant