Sexual steroids in serum and prostatic tissue of human non‐cancerous prostate (STERPROSER trial)

Raynaud, Jean‐Pierre; Radulescu, C.; Fiet, Jean; Giton, Frank; Dreyfus, Jean‐François; Ghoneim, T.; Lebrét, Thierry; Botto, Henry

doi:10.1002/pros.23429

Cited by 16 publications

(5 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite the apparent lack of an appreciable effect of HSD3B1 genotype on circulating steroid levels, clear phenotypes with HSD3B1 genotype have been observed in two asthma cohorts 21 and at least eight prostate cancer cohorts 49 , suggesting that the effects of HSD3B1 genotype are mediated largely independent of circulating sex steroid levels. Steroid levels in tissues can differ profoundly from those in circulation [50][51][52] , so HSD3B1 genotype could potentially affect concentrations at the cell or tissue level without measurably affecting concentrations in circulation, which should be further studied. Other measures such as circulating cortisol levels and inflammatory cytokines are also important to analyze, but these data were not available in the UK Biobank.…”

Section: Discussionmentioning

confidence: 99%

Inheritance of a common androgen synthesis variant allele is associated with female COVID susceptibility in UK Biobank

McManus

Sabharwal

Bazeley

et al. 2020

Preprint

View full text Add to dashboard Cite

A sex discordance in COVID exists, with males disproportionately affected. More broadly, sex differences in infectious and inflammatory processes are well known, with women tending to mount stronger immune responses than men. Although there is evidence that sex hormone signaling is immunomodulatory, including downregulation of immune/inflammatory responses by androgens, the existence of numerous other physiologic differences between the sexes leads to great uncertainty in attributing worse infectious disease outcomes in men to androgen signaling. No definitive genetic data exist to support androgen-mediated immune suppression for viral susceptibility, nor for adrenal androgens. Here we show an association between inheritance of the common adrenal-permissive missense-encoding variant HSD3B1(1245C), that enables androgen synthesis from adrenal precursors10, and susceptibility to COVID. The adrenal-permissive HSD3B1(1245C) has previously been linked to suppression of inflammation in severe asthma. In analysis of COVID test results from the UK Biobank, we show that in older (≥ 70 years of age) subjects, the adrenal-permissive variant is associated with a greater chance of being COVID-positive. The effect increases with the number of HSD3B1(1245C) alleles inherited and is greater in females such that increasing androgen synthesis confers risk approaching males. Our study suggests that a common androgen synthesis variant regulates immune susceptibility to COVID infection as well as potentially other immune and inflammatory processes.

show abstract

Section: Discussionmentioning

confidence: 99%

Inheritance of a common androgen synthesis variant allele is associated with female COVID susceptibility in UK Biobank

McManus

Sabharwal

Bazeley

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Others have reported comparisons of serum and tissue concentrations for certain steroids and tissues with varying results. For example, two different groups [39, 40] reported elevated concentrations of DHEA and DHT in prostate tissue compared to serum, but testosterone concentrations that were greater in serum than in tissue. In vivo steroid concentration ratios are affected by factors other than cells’ tendency to take up steroids, including metabolism that occurs within cells; the depressed testosterone concentrations in prostate tissue could reflect its conversion to DHT by enzyme 5α-reductase [41].…”

Section: Discussionmentioning

confidence: 99%

Rapid and structure-specific cellular uptake of selected steroids

et al. 2019

View full text Add to dashboard Cite

Steroid hormones and their respective nuclear receptors are essential mediators in numerous physiologic and pathophysiologic processes, ranging from regulation of metabolism, immune function, and reproductive processes to the development of hormone-dependent cancers such as those of the breast and prostate. Because steroids must enter cells before activating nuclear receptors, understanding the mechanisms by which cellular uptake occurs is critical, yet a clear understanding of these mechanisms has been elusive. It is generally assumed that diffusion-driven uptake is similar across various steroids whereas an elevated cellular concentration is thought to reflect active uptake, but these assumptions have not been directly tested. Here we show that intact cells rapidly accumulate free steroids to markedly elevated concentrations. This effect varies widely depending on steroid structure; more lipophilic steroids reach more elevated concentrations. Strong preferences exist for 3β-OH, Δ5-steroids vs. 3-keto, Δ4-structural features and for progestogens vs. androgens. Surprisingly, steroid-structure-specific preferences do not require cell viability, implying a passive mechanism, and occur across cells derived from multiple tissue types. Physiologic relevance is suggested by structure-specific preferences in human prostate tissue compared with serum. On the other hand, the presence of serum proteins in vitro blocks much, but not all, of the passive accumulation, while still permitting a substantial amount of active accumulation for certain steroids. Our findings suggest that both passive and active uptake mechanisms make important contributions to the cellular steroid uptake process. The role of passive, lipophilicity-driven accumulation has previously been largely unappreciated, and its existence provides important context to studies on steroid transport and action both in vitro and in vivo.

show abstract

“…Sex steroid levels in serum and prostate tissue were recently accurately characterized in men without PCa (Neuzillet et al 2017). Comparing the differences in serum and tissue sex steroids between smaller prostates (<50 g) and those affected by BPH (>50 g), the authors found intraprostatic DHT levels correlate with prostate size.…”

Section: Changes In Sex Steroids During Prostate Cancer Progression Pmentioning

confidence: 99%

“…The relationship between circulating and prostate tissue levels of androgens has been addressed in several studies (Bartsch et al 1986, Miyoshi et al 2014, Cook et al 2017, Neuzillet et al 2017. Overall, intraprostatic levels of DHT and testosterone, as well as dehydroepiandrosterone (DHEA) and androgen metabolites such as androstane-3β,17βdiol (3β-diol) are 5-to 10-fold higher in prostate tissue than those in the serum.…”

Section: Relationship Between Serum and Prostate Tissue Sex Steroid Lmentioning

confidence: 99%

Sex steroids in the tumor microenvironment and prostate cancer progression

Boibessot¹,

Toren²

2018

Endocrine-Related Cancer

View full text Add to dashboard Cite

Prostate cancer is uniquely dependent on androgens. Despite years of research on the relationship between androgens and prostate cancer, many questions remain as to the biological effects of androgens and other sex steroids during prostate cancer progression. This article reviews the clinical and basic research on the influence of sex steroids such as androgens, estrogens and progesterone within the prostate tumor microenvironment on the progression of prostate cancer. We review clinical studies to date evaluating serum sex steroids as prognostic biomarkers and discuss their respective biological effects within the prostate tumor microenvironment. We also review the link between genomic alterations and sex steroid levels within prostate tumors. Finally, we highlight the links between sex steroid levels and the function of the immune system within the tumor microenvironment. As the context of treatment of lethal prostate cancer evolves over time, an understanding of this underlying biology remains central to developing optimal treatment approaches.

show abstract

Sexual steroids in serum and prostatic tissue of human non‐cancerous prostate (STERPROSER trial)

Abstract: STERPROSER trial provides evidence for higher DHT concentration in highvolume prostates, that could reflect either higher 5-alpha reductase expression or lower expression of downstream metabolizing enzymes such as 3a-hydoxysteroid dehydrogenase.

Cited by 16 publications

References 26 publications

Inheritance of a common androgen synthesis variant allele is associated with female COVID susceptibility in UK Biobank

Inheritance of a common androgen synthesis variant allele is associated with female COVID susceptibility in UK Biobank

Rapid and structure-specific cellular uptake of selected steroids

Sex steroids in the tumor microenvironment and prostate cancer progression

Contact Info

Product

Resources

About