Intracrine androgen biosynthesis, metabolism and action revisited

In the paper

“Adrenal vein sampling of healthy women has shown that the adrenal secretes DHEAS (low micromolar range) » DHEA, 11OHA4, A4 (medium nanomolar ranges) > 5-diol, 11-ketoandrostenedione (11KA4), T, 11OHT, 11-ketotestosterone (11KT) and DHT (low nanomolar ranges) (Rege et al., 2013).”

What the sources say

• Not checked yetcites Rege et al., 2013 source

In the paper

“Concentrations of androgen in testicular venous blood of healthy individuals are T (high nanomolar-low micromolar) » A4, DHEA (medium nanomolar) (Hammond et al., 1977, Ishida et al., 1990, Weinstein et al., 1974).”

What the sources say

• Not checked yetcites Hammond et al., 1977 source
• Not checked yetcites Ishida et al., 1990 source
• Not checked yetcites Weinstein et al., 1974 source

In the paper

“This results in a decline of circulating T concentrations of approximately 0.1 nmol/L per year (Camacho et al., 2013).”

What the sources say

• Not checked yetcites Camacho et al., 2013 source

In the paper

“Significantly, our study in healthy and PCOS women showed for the first time that the circulating levels of the active androgen 11KT were 3–4fold higher than that of T in healthy premenopausal women (O'Reilly et al., 2016), highlighting the important contribution of the 11-oxygenated androgens to the circulating androgen pool in women.”

What the sources say

• Not checked yetcites O'Reilly et al., 2016 source

In the paper

“For example, we recently profiled classical and 11-oxygenated androgens in serum of healthy premenopausal women and premenopausal women with PCOS. We found that the 11-oxygenated androgens were the predominant C19 steroids in women with PCOS (O'Reilly et al., 2016).”

What the sources say

• Not checked yetcites O'Reilly et al., 2016 source

In the paper

“Importantly, men and women show comparable concentrations of circulating androgen metabolites (Table 2).”

In the paper

“This mechanism has recently been shown to be of relevance also for colon cancer (Gilligan et al., 2017).”

What the sources say

• Not checked yetcites Gilligan et al., 2017 source

In the paper

“Knock down of OATPs have also been shown to reduce the DHEAS-stimulated proliferation of prostate cancer cell lines (Arakawa et al., 2012).”

What the sources say

• Not checked yetcites Arakawa et al., 2012 source

In the paper

“Conversely, our group has shown that the activation of 11KA4 (Δ4, 17-keto) proceeds by the 17β-reduction to 11KT, followed by 5α-reduction to 11KDHT (5α,17β) (Pretorius et al., 2017) (Fig. 6).”

What the sources say

• Not checked yetcites Pretorius et al., 2017 source

In the paper

“Interestingly, we also showed that in the same cohort 11KT did not correlate with BMI”

In the paper

“We have recently shown that serum T levels correlated with BMI in both healthy women and women with PCOS.”

In the paper

“Ovarian steroid biosynthesis can be described by the “two-cell, two-gonadotrophin” model: Two different cell types - granulosa cells of the follicle and the surrounding theca cells - perform distinct reactions due to specific enzyme expression (Fig. 3).”

In the paper

“While the adrenal glands only produce low levels of the active androgen T, they produce significant levels of the inactive C19 androgen precursors dehydroepiandrosterone (DHEA, androst-5-ene-3βol-17-one) and its sulfate ester DHEAS, androstenedione (A4, androst-4-ene-3,17-dione) and 11β-hydroxyandrostenedione (11OHA4), which in the majority are released into circulation (Rege et al., 2013).”

What the sources say

• Not checked yetcites Rege et al., 2013 source

In the paper

“DHEA is converted to DHEAS by DHEA sulfotransferase (sulfotransferase 2A1, SULT2A1) and as such DHEAS is the major C19 steroid secreted by the adrenal, circulating in low micromolar concentrations.”

In the paper

“Importantly, the expression of CYP17A1 in adrenal of adult mice and rat, which are frequently used as pre-clinical models for endocrine and pharmacology studies, is minimal (Le Goascogne et al., 1991, Mostaghel et al., 2017, Rodriguez et al., 1997).”

What the sources say

• Not checked yetcites Le Goascogne et al., 1991 source
• Not checked yetcites Mostaghel et al., 2017 source
• Not checked yetcites Rodriguez et al., 1997

In the paper

“Adrenal androgen biosynthesis takes place in the zona reticularis and proceeds via the classical Δ5 pathway (Miller and Auchus, 2011, Turcu and Auchus, 2015) as depicted in Fig. 2.”

What the sources say

• Not checked yetcites Miller and Auchus, 2011 source
• Not checked yetcites Turcu and Auchus, 2015 source

In the paper

“The specific co-localisation of the cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) and cytochrome b5 in the zona reticularis favours the 17,20-lyase activity of CYP17A1 and thus C19 steroid production.”

In the paper

“After uptake into a peripheral tissue with the required enzyme machinery, these androgen precursors are converted into active androgens which elicit a physiological response.”

In the paper

“Adrenal androgen biosynthesis takes place in the zona reticularis and proceeds via the classical Δ5 pathway (Miller and Auchus, 2011, Turcu and Auchus, 2015) as depicted in Fig. 2.”

What the sources say

• Not checked yetcites Miller and Auchus, 2011 source
• Not checked yetcites Turcu and Auchus, 2015 source

In the paper

“A peak of adrenal C19 steroid production is reached in the third and fourth decade of human life in both men and women after which levels decline significantly (Labrie et al., 1997b).”

What the sources say

• Not checked yetcites Labrie et al., 1997b

In the paper

“However, the intracellular or intracrine activation of C19 androgen precursors to active androgens in peripheral target tissues of androgen action is of equal importance.”

In the paper

“Intracrine androgen synthesis is often not reflected by circulating androgens but rather by androgen metabolites and conjugates.”

In the paper

“Nonetheless, 80% of the circulating DHEA in postmenopausal women is of adrenal origin with the remainder produced by the ovary (Labrie et al., 2011).”

What the sources say

• Not checked yetcites Labrie et al., 2011 source

In the paper

“The C19 steroid fatty acid ester can then be transferred to other lipoproteins.”

In the paper

“Due to high abundance of HSD3B2 and 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) and the absence of SULTs, the final products are the 3-keto-Δ4 androgens A4 and T (Fig. 4).”

In the paper

“In men, the decline can be explained by simultaneous age-related reductions of both adrenal and testicular androgen biosynthesis (Beattie et al., 2015, Camacho et al., 2013, Golan et al., 2015, Labrie et al., 1997b).”

What the sources say

• Not checked yetcites Beattie et al., 2015 source
• Not checked yetcites Camacho et al., 2013 source
• Not checked yetcites Golan et al., 2015 source

In the paper

“In addition to the classical C19 steroids (DHEAS, DHEA, T and A4), recent advances in mass spectrometry-based analytical methodology have allowed for the identification and quantification of non-classical androgen metabolites (Bloem et al., 2015).”

What the sources say

• Not checked yetcites Bloem et al., 2015 source

In the paper

“The major fractions of androgen metabolites are conjugated to facilitate their excretion.”

In the paper

“Significantly, our study in healthy and PCOS women showed for the first time that the circulating levels of the active androgen 11KT were 3–4fold higher than that of T in healthy premenopausal women (O'Reilly et al., 2016), highlighting the important contribution of the 11-oxygenated androgens to the circulating androgen pool in women.”

What the sources say

• Not checked yetcites O'Reilly et al., 2016 source

In the paper

“In contrast, SHBG binds sex steroids (including active androgens, oestrogens, precursors and metabolites (Avvakumov et al., 2010, Cherkasov et al., 2008, Dunn et al., 1981, Grishkovskaya et al., 2002)) with high specificity and affinity (nanomolar ranges) (reviewed in (Hammond, 2016)).”

What the sources say

• Not checked yetcites Avvakumov et al., 2010 source
• Not checked yetcites Cherkasov et al., 2008 source
• Not checked yetcites Hammond, 2016 source

In the paper

“These sex steroid-binding plasma proteins therefore play a crucial role in the regulation of androgen action (Laurent et al., 2016).”

What the sources say

• Not checked yetcites Laurent et al., 2016 source

In the paper

“DHEA-fatty acid esters can be taken up by peripheral cells via lipoprotein receptors (Lavallee et al., 1996, Roy and Belanger, 1989).”

What the sources say

• Not checked yetcites Lavallee et al., 1996
• Not checked yetcites Roy and Belanger, 1989

In the paper

“Unlike the fetal ovaries, the fetal testes have steroidogenic activity which peaks between 11 and 17 weeks of gestation.”

In the paper

“The majority of unconjugated C19 steroids circulate bound to the plasma proteins albumin or SHBG and only a small fraction (1–2%) circulates in the free form which is accessible to the target tissue.”

In the paper

“HSD17B3 deficiency results in disordered sex development in genetically male children (Boehmer et al., 1999, Mendonca et al., 1999).”

What the sources say

• Not checked yetcites Boehmer et al., 1999
• Not checked yetcites Mendonca et al., 1999

In the paper

“Interestingly, DHEA and 5-diol can be acylated with fatty acids by plasma lecithin:cholesterol acyltransferase located on high density lipoproteins (Jones and James, 1985, Lavallee et al., 1996).”

What the sources say

• Not checked yetcites Jones and James, 1985
• Not checked yetcites Lavallee et al., 1996

In the paper

“In both men and women, ageing leads to decreases in C19 steroid production (Damgaard-Olesen et al., 2016, Haring et al., 2012, Trabert et al., 2016).”

What the sources say

• Not checked yetcites Damgaard-Olesen et al., 2016 source
• Not checked yetcites Haring et al., 2012 source
• Not checked yetcites Trabert et al., 2016 source

In the paper

“and OATP polymorphisms are associated with time to progression during androgen deprivation therapy (Yang et al., 2011).”

What the sources say

• Not checked yetcites Yang et al., 2011 source

In the paper

“Indeed, the conversion of A4 (Δ4, 17-keto) to DHT (5α, 17β) proceeds via the 5α-reduction of A4 to 5α-androstanedione (5α-dione, 5α-androstane-3,17-dione), followed by the conversion of 5α-dione to DHT (Chang et al., 2011' Luu-The and Labrie, 2010, Samson et al., 2010) (Fig. 6).”

What the sources say

• Not checked yetcites Chang et al., 2011 source
• Not checked yetcites Luu-The and Labrie, 2010
• Not checked yetcites Samson et al., 2010 source

In the paper

“The access of a conjugated steroid to a specific cell is determined by (1) the expression level of transporters in combination with (2) the substrate specificity and (3) the transport kinetics of the respective transporters.”

In the paper

“The potential of STS inhibition has been evaluated in promising clinical trials (Geisler et al., 2011, Purohit and Foster, 2012, Thomas and Potter, 2015).”

What the sources say

• Not checked yetcites Geisler et al., 2011 source
• Not checked yetcites Purohit and Foster, 2012 source
• Not checked yetcites Thomas and Potter, 2015

In the paper

“5α-reduction is necessary to achieve maximum AR activation (DHT, 11KDHT).”

In the paper

“Dysregulation of intracrine pathways can result from (1) alterations of expression leading to effects specific for the respective tissue”

In the paper

“By contrast, patients with STS deficiency due to mutation show only a rather mild clinical phenotype with ichthyosis due to the accumulation of sulfated steroids in the skin.”

In the paper

“SRD5A2 encoding steroid 5α-reductase type 2 (SRD5A2) is expressed in male reproductive tissues (Thigpen et al., 1993) and its disruption leads to the impairment of local DHT formation and in consequence disordered sex development in 46, XY individuals (Okeigwe and Kuohung, 2014, Wilson et al., 1993).”

What the sources say

• Not checked yetcites Okeigwe and Kuohung, 2014
• Not checked yetcites Wilson et al., 1993

In the paper

“which is associated with metabolic dysfunction (Conway et al., 2014, O'Reilly et al., 2014b).”

What the sources say

• Not checked yetcites Conway et al., 2014 source
• Not checked yetcites O'Reilly et al., 2014b

In the paper

“Additionally, de-conjugation is required after influx before the steroid can be metabolised and or interact with its receptor.”

In the paper

“and can be associated with metabolic dysfunction or sex steroid-dependent cancer as discussed below.”

In the paper

“or (2) mutations/polymorphisms of involved enzymes leading to systemic effects”

In the paper

“Significantly, the metabolism of DHEA to active androgens reaches saturation with increasing circulating concentrations of DHEA, thereby protecting peripheral tissues from increased intracellular levels of androgens which may result from pathologically increased biosynthesis of androgen precursors in the adrenal (Labrie et al., 2007).”

What the sources say

• Not checked yetcites Labrie et al., 2007 source

In the paper

“Certain polymorphisms of AKR1C3 are associated with PCOS and increased T levels in women (Ju et al., 2015).”

What the sources say

• Not checked yetcites Ju et al., 2015

In the paper

“Circulating, bioavailable androgens and their precursors must cross the plasma membrane of target cells to be (1) metabolised by enzymes that are located intracellularly in the cytosol or membrane of the endoplasmic reticulum and/or (2) to activate the AR, which is localised in the cytosol prior to activation by a suitable ligand.”

In the paper

“STS may therefore rather function as a fine-tuning mechanism for intracellular free steroids.”

In the paper

“The 11-oxygenated androgens also require the conversion of the 11β-hydroxyl to the 11-ketone in order to obtain maximal activity (11KT and 11KDHT; dotted inset).”

In the paper

“It should also be noted that the expression of HSD11B2, which encodes the oxidative HSD11B isoform, is required for the activation of 11OHA4, which is the primary 11-oxygenated C19 androgen precursor in circulation (Rege et al., 2013, Storbeck et al., 2013, Swart et al., 2013) (Table 2).”

What the sources say

• Not checked yetcites Rege et al., 2013 source
• Not checked yetcites Storbeck et al., 2013 source
• Not checked yetcites Swart et al., 2013 source

In the paper

“In humans, the backdoor pathway is relevant in pathological conditions when 17OHPROG accumulates, such as in congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency (PORD) or 21-hydroxylase deficiency (Arlt et al., 2004, Homma et al., 2006, Kamrath et al., 2012, Krone et al., 2012, Miller and Auchus, 2011).”

What the sources say

• Not checked yetcites Arlt et al., 2004 source
• Not checked yetcites Homma et al., 2006 source
• Not checked yetcites Kamrath et al., 2012 source

In the paper

“and their expression and activity correlates with obesity in women and men (Blouin et al., 2005, Blouin et al., 2006).”

What the sources say

• Not checked yetcites Blouin et al., 2005 source
• Not checked yetcites Blouin et al., 2006 source

In the paper

“and the degree of androgen excess correlates with the severity of insulin resistance in PCOS (O'Reilly et al., 2014b).”

What the sources say

• Not checked yetcites O'Reilly et al., 2014b

In the paper

“Muscle cells exhibit 3βHSD, reductive 17βHSD and 5α-reductase activity resulting in the activation of DHEA to T and DHT.”

In the paper

“AKR1C1 (predominant 20αHSD with low reductive 3αHSD activity), AKR1C2 (reductive 3αHSD activity) and AKR1C3 (reductive 17βHSD activity) show the highest expression levels of all steroid converting enzymes expressed in adipocytes of women and men (Blouin et al., 2009b)”

What the sources say

• Not checked yetcites Blouin et al., 2009b

In the paper

“The relative activities of HSD11B2 and HSD11B1 are therefore critical in determining the activity of 11-oxygenated androgens in peripheral tissue.”

In the paper

“It has especially been shown to be an essential pathway for intratumoral DHT production from adrenal androgen precursors in CRPC when circulating levels of T are significantly reduced by physical or chemical castration (Chang et al., 2011, Sharifi and Auchus, 2012).”

What the sources say

• Not checked yetcites Chang et al., 2011 source
• Not checked yetcites Sharifi and Auchus, 2012

In the paper

“Interestingly, phase 2 reactions can precede phase 1 reactions during androgen inactivation.”

In the paper

“The intracrine production of oestrogens from androgen precursors is an essential source of oestrogens in postmenopausal women (Simpson, 2003).”

What the sources say

• Not checked yetcites Simpson, 2003 source

In the paper

“Adipose tissue expresses isoforms of all enzymes required for the activation of androgens from circulating precursors (STS, HSD3B1, reductive 17βHSDs, namely HSD17B1, HSR17B3 and AKR1C3 with involvement in androgen activation, and SRD5A1) as well as their subsequent inactivation (reductive 3αHSDs (mainly AKR1C2), UGT2B15 and UGT2B17) (Blouin et al., 2009b, O'Reilly et al., 2014a, Tchernof et al.,”

What the sources say

• Not checked yetcites Blouin et al., 2009b
• Not checked yetcites O'Reilly et al., 2014a
• Not checked yetcites Tchernof et al., 2015 source

In the paper

“This prevents the conversion of 11OHA4 to 11KA4, which is a prerequisite for the subsequent conversion of 11KA4 to 11KT by AKR1C3 (O'Reilly et al., 2016).”

What the sources say

• Not checked yetcites O'Reilly et al., 2016 source

In the paper

“Unlike 5α-reduction, 5β-reduction inactivates classical AR signalling capability of an androgen.”

In the paper

“As SULT2A1 expression is mainly limited to the liver, adrenal, colon and kidney (Riches et al., 2009), glucuronidation is the more important conjugation reaction in androgen target tissue.”

What the sources say

• Not checked yetcites Riches et al., 2009 source

In the paper

“Androgen excess is recognised as the major determinant driving metabolic dysfunction observed in women with PCOS (Conway et al., 2014)”

What the sources say

• Not checked yetcites Conway et al., 2014 source

In the paper

“Genetic variations of UGTs can change the glucuronidation efficiency for an androgen and alter its excretion (Piper et al., 2016).”

What the sources say

• Not checked yetcites Piper et al., 2016 source

In the paper

“androgens and the expression of the AR have demonstrated both positive and negative outcomes in breast cancer as reviewed in (Hickey et al., 2012, McNamara and Sasano, 2015a, McNamara and Sasano, 2016).”

What the sources say

• Not checked yetcites Hickey et al., 2012 source
• Not checked yetcites McNamara and Sasano, 2015a
• Not checked yetcites McNamara and Sasano, 2016

In the paper

“Both androgens and oestrogens are synthesised from circulating androgen precursors in breast tissue and the homeostasis of these pathways determines health status (McNamara and Sasano, 2015b).”

What the sources say

• Not checked yetcites McNamara and Sasano, 2015b

In the paper

“16α-hydroxy-DHEAS, 5-diol-sulfate, AST-sulfate, EpiAST-sulfate can be measured in nM concentrations in serum of both men and women (Labrie et al., 1997b, Sanchez-Guijo et al., 2015, Zang et al., 2017).”

What the sources say

• Not checked yetcites Labrie et al., 1997b
• Not checked yetcites Sanchez-Guijo et al., 2015 source
• Not checked yetcites Zang et al., 2017 source

In the paper

“Numerous studies have shown that androgen levels are higher within breast tissue than in circulation and are generally higher in benign tissue than cancerous tissue, demonstrating the relevance of intracrinology in breast and its dysregulation in cancer (Stanczyk et al., 2015).”

What the sources say

• Not checked yetcites Stanczyk et al., 2015 source

In the paper

“androgens have been shown to play a crucial role in the development of hepatocellular carcinoma (Kalra et al., 2008, Kanda et al., 2014).”

What the sources say

• Not checked yetcites Kalra et al., 2008 source
• Not checked yetcites Kanda et al., 2014

In the paper

“While T production increases and stays elevated during decidualisation due to constantly increased AKR1C3 levels”

What the sources say

• Not checked yetcites Gibson et al., 2016 source

In the paper

“The liver also shows high SULT expression and activity compared to other tissues, including SULT2A1 and SULT2B1 involved in androgen metabolism (Meloche and Falany, 2001, Riches et al., 2009).”

What the sources say

• Not checked yetcites Meloche and Falany, 2001
• Not checked yetcites Riches et al., 2009 source

In the paper

“Both T and DHT have recently been shown to increase lipogenesis in human hepatocytes of female (but not male) donors (Nasiri et al., 2015)”

What the sources say

• Not checked yetcites Nasiri et al., 2015 source

In the paper

“Importantly, women produce androgen metabolites in concentrations comparable to that of men (Labrie et al., 1997b, Trabert et al., 2016, Zang et al., 2017).”

What the sources say

• Not checked yetcites Labrie et al., 1997b
• Not checked yetcites Trabert et al., 2016 source
• Not checked yetcites Zang et al., 2017 source

In the paper

“It catalyses the interconversion of 7α- and 7β-OH-DHEA via the 7-keto intermediate (Muller et al., 2006).”

What the sources say

• Not checked yetcites Muller et al., 2006 source

In the paper

“Androgens and in particular the intraprostatic conversion of circulating T to DHT by SRD5A2 (Russell and Wilson, 1994) are required for normal prostate development and function (Andersson et al., 1991, Imperato-McGinley et al., 1974).”

What the sources say

• Not checked yetcites Russell and Wilson, 1994 source
• Not checked yetcites Andersson et al., 1991 source
• Not checked yetcites Imperato-McGinley et al., 1974 source

In the paper

“time-dependent changes in SDR5A1 and AKR1C3 expression alter T and DHT secretion.”

What the sources say

• Not checked yetcites Gibson et al., 2016 source

In the paper

“While the contribution of de-novo intratumoral biosynthesis to local androgens has mostly been excluded (Hofland et al., 2010)”

What the sources say

• Not checked yetcites Hofland et al., 2010 source

In the paper

“Selective inhibition of HSD3B1 has been shown to slow down proliferation of breast cancer cell line and might just represent an interesting drug target simultaneously tackling androgen and oestrogen synthesis (Thomas et al., 2011).”

What the sources say

• Not checked yetcites Thomas et al., 2011 source

In the paper

“The main androgen metabolites in circulation derived from hepatic and other peripheral metabolism are 3α-adiol-3-glucuronide, 3α-adiol-17-glucuronide, AST-glucuronide and ETIO-glucuronide with levels higher than for T.”

In the paper

“It should also be noted that menopausal status significantly influences the intracrinology of breast tissue (McNamara and Sasano, 2015b).”

What the sources say

• Not checked yetcites McNamara and Sasano, 2015b

In the paper

“Numerous studies have shown that androgen levels are higher within breast tissue than in circulation and are generally higher in benign tissue than cancerous tissue, demonstrating the relevance of intracrinology in breast and its dysregulation in cancer (Stanczyk et al., 2015).”

What the sources say

• Not checked yetcites Stanczyk et al., 2015 source

In the paper

“DHT secretion initially increases, but then decreases with the progression of the decidualisation process following reductions in SRD5A1 levels (Gibson et al., 2016).”

What the sources say

• Not checked yetcites Gibson et al., 2016 source

In the paper

“Indeed, a recent study showed that the levels of these 11-oxygenated androgens were higher than those of the classical androgens in tissue from two patients with prostate cancer (du Toit et al., 2017).”

What the sources say

• Not checked yetcites du Toit et al., 2017 source

In the paper

“Genetic variations of UGTs significantly contribute to prostate cancer risk and progression and there is evidence for a down-regulation of UGTs in prostate cancer promoting intratumoral androgen accumulation (Barbier and Belanger, 2008, Gauthier-Landry et al., 2015).”

What the sources say

• Not checked yetcites Barbier and Belanger, 2008
• Not checked yetcites Gauthier-Landry et al., 2015 source

In the paper

“Recent studies have also shown that prostate cancer cell lines are able to metabolise the adrenal androgen precursor 11OHA4 (Storbeck et al., 2013, Swart et al., 2013, Swart and Storbeck, 2015).”

What the sources say

• Not checked yetcites Storbeck et al., 2013 source
• Not checked yetcites Swart et al., 2013 source
• Not checked yetcites Swart and Storbeck, 2015

In the paper

“Circulating DHEA can also be used as a precursor to produce active androgens by 3βHSD, 5α-reductase and reductive 17βHSD activity (Nikolakis et al., 2016, Slominski et al., 2013).”

What the sources say

• Not checked yetcites Nikolakis et al., 2016 source
• Not checked yetcites Slominski et al., 2013 source

In the paper

“Functional comparison of different epidermal cell types hint at differential functions for androgen biosynthesis and inactivation (Fritsch et al., 2001).”

What the sources say

• Not checked yetcites Fritsch et al., 2001 source

In the paper

“Prostate cells also express CYP3A4 that can inactivate T by conversion to mainly 6βOH-T (with 2β-, 15α/β- and 11β-hydroxyl side product formation (Niwa et al., 2015))”

What the sources say

• Not checked yetcites Niwa et al., 2015 source

In the paper

“Significantly, both 11KT and 11KDHT have been shown to be able to induce androgen-regulated gene and protein expression as well as cell growth in androgen dependent prostate cancer cell lines”

What the sources say

• Not checked yetcites Pretorius et al., 2016 source

In the paper

“Genetic variations of UGTs significantly contribute to prostate cancer risk and progression and there is evidence for a down-regulation of UGTs in prostate cancer promoting intratumoral androgen accumulation (Barbier and Belanger, 2008, Gauthier-Landry et al., 2015).”

What the sources say

• Not checked yetcites Barbier and Belanger, 2008
• Not checked yetcites Gauthier-Landry et al., 2015 source

In the paper

“In fact, studies with cultured sebocytes suggest that circulating DHEA may be the more important source of androgen precursors (Chen et al., 2010).”

What the sources say

• Not checked yetcites Chen et al., 2010 source

In the paper

“numerous studies have shown that CRPC is dependent on the intracrine conversion of circulating androgen precursors of adrenal origin to active androgens reviewed in (Capper et al., 2016, Luu-The et al., 2008, Pretorius et al., 2017, Sharifi and Auchus, 2012).”

What the sources say

• Not checked yetcites Capper et al., 2016 source
• Not checked yetcites Luu-The et al., 2008 source
• Not checked yetcites Pretorius et al., 2017 source

In the paper

“Acne-prone skin expresses higher levels of androgen generating enzymes than non-acne-prone skin (HSD17B3 and AKR1C3 converting A4 to T, STS and SRD5A1; summarized in (Nikolakis et al., 2016)).”

What the sources say

• Not checked yetcites Nikolakis et al., 2016 source

In the paper

“Several cellular components of the interfollicular epidermis and pilosebaceous unit have the capability of de-novo steroid biosynthesis supported by StAR activity (Anuka et al., 2013).”

What the sources say

• Not checked yetcites Anuka et al., 2013 source

In the paper

“The generation of DHT is essential for beard growth (Diamond et al., 1996, Messenger, 1993).”

What the sources say

• Not checked yetcites Diamond et al., 1996
• Not checked yetcites Messenger, 1993 source

In the paper

“Interestingly, the rate at which 11KT and 11KDHT are inactivated by prostate cancer cell lines has been shown to be significantly lower than for T and DHT, suggesting that these metabolites may remain active for longer than the classical androgens (Pretorius et al., 2016).”

What the sources say

• Not checked yetcites Pretorius et al., 2016 source

In the paper

“and a decrease of CYP3A4 expression is observed in prostate cancer (Fujimura et al., 2009).”

What the sources say

• Not checked yetcites Fujimura et al., 2009 source

In the paper

“In addition, the placenta possesses the enzymatic machinery capable of converting C19 steroids derived from the foetal adrenal and liver (DHEAS and 16αOH-DHEA, respectively) to oestrogens during their transplacental passage (Miller and Auchus, 2011).”

What the sources say

• Not checked yetcites Miller and Auchus, 2011 source

In the paper

“The resulting steroids include glucocorticoids and androgens and these pathways were reviewed in (Labrie et al., 2000, Nikolakis et al., 2016, Slominski et al., 2013).”

What the sources say

• Not checked yetcites Labrie et al., 2000
• Not checked yetcites Nikolakis et al., 2016 source
• Not checked yetcites Slominski et al., 2013 source

In the paper

“This mechanism protects the mother (and female foetus) from virilisation by the high concentrations of C19 steroid released into circulation by the foetal adrenal (Conte et al., 1994).”

What the sources say

• Not checked yetcites Conte et al., 1994

In the paper

“suggesting that these androgens may play a previously overlooked, but important role in the development and progression of CRPC (Pretorius et al., 2016).”

What the sources say

• Not checked yetcites Pretorius et al., 2016 source

In the paper

“C19 steroid conversion in the placenta thus has a protective systemic function rather than an intracrine function.”