Associating serum testosterone levels with African ancestral prostate cancer health disparities

Associating serum testosterone levels with African ancestral prostate cancer health disparities | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Associating serum testosterone levels with African ancestral prostate cancer health disparities Maphuti Tebogo Lebelo, Naledi Mmekwa, Weerachai Jaratlerdsiri, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4366943/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Apr, 2025 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Serum testosterone levels decrease in the aging male, while the risk for prostate cancer (PCa) increases concomitantly. Higher levels in younger men have been linked with racially driven PCa disparities, with African men disproportionately impacted. In turn, higher levels of serum lipids have been associated with aggressive disease, while racial disparity between serum testosterone, cholesterol and cancer mortality has been suggested. Having previously reported a 2.1-fold increased age-adjusted risk for aggressive PCa in Black South African over Black American men, we determined the serum testosterone and associated lipid levels in 250 Black South African men either with or without clinicopathologically diagnosed disease. Observing no associations with serum lipid levels, Black South Africans presented with testosterone levels between 1.24 (< 60 years) and 1.3-fold (≥ 60 years) greater than African Americans. Notably, a rapid drop in total-, bioavailable- and free testosterone levels in men 65 years or older was significantly associated with PCa risk ( P = 0.0057, 0.009 and 0.005, respectively), while irrespective of age, further associated with advanced disease ( P = 0.004, 0.0012 and 0.0036, respectively). These preliminary data provide insights into the potential role of androgens in driving PCa health disparities, with important consequence for tailoring treatment for Black men. Biological sciences/Cancer/Urological cancer/Prostate cancer Health sciences/Urology/Prostate testosterone African ancestry prostate cancer cholesterol health disparity Figures Figure 1 Introduction Prostate cancer (PCa) is characterized by significant ancestral disparity. In the United States, African American men are diagnosed at a younger age, present with more advanced disease, and have the greatest lifetime risk of dying from PCa [ 1 , 2 ]. With Black men at double the risk for lethal disease compared to White American men, this disparity increases to 4.2-fold for men younger than 50 years [ 3 ]. Globally, the regions of sub-Saharan Africa and the Caribbean are the most impacted by PCa mortality, with the highest rates reported for Southern Africa [ 4 ], which is notable when considering the average life expectancy for southern African men is 1.2-fold lower than the worldwide average at birth (World Bank 2020). Previously we showed that, compared to African American men and after adjusting for age, Black South African men are 2.1-fold more likely to present with aggressive disease [ 5 ]. What is clear, African ancestry is a well-established risk factor for PCa adversity. While the reasons for this disparity are likely multifactorial, including socioeconomic and healthcare access as obvious contributing factors, an extensive review of the literature concurred that PCa presentation in African American men is both genomically and biologically unique [ 6 ]. While data is comparably scare for Sub-Saharan Africa, most recently we demonstrated that even within the broad ‘African’ racial identifier men of southern African ancestry present with regionally unique inherited and somatic mutational profiles [ 7 , 8 , 9 ]. However, how these genomic differences translate into biological differences is largely unknown. Testosterone is required for normal prostate growth, which makes androgen deprivation therapy (ADT) an obvious first-line treatment for advanced or metastatic disease [ 10 ]. However, a lack of consensus exists regarding the role of serum testosterone levels in PCa development and progression [ 11 ]. While some studies refute an association between testosterone and PCa predisposition [ 12 , 13 , 14 ], others have linked high testosterone levels to elevated risk [ 15 , 16 , 17 ]. Overall, circulating testosterone levels drop both as men age (rate of 1.6% per year) and as cancer progresses, with low levels (≤ 300 ng/dL) associated with aggressive disease [ 18 ]. For ADT treated patients, achieving chemical castration requires total serum testosterone to drop below 50 ng/dl, while levels of 25 ng/dl have been shown to have prognostic potential and patient stratification for combination therapies [ 19 ], although castration-resistance is inevitable [ 20 ]. Furthermore, age-related racial variations in testosterone levels show that compared to White Americans, Black American men present with overall higher levels, peak earlier and higher, with more dramatic decline [ 21 ]. As testosterone is a cholesterol-derived steroid hormone, it has been postulated that a link exists between testosterone and cholesterol levels and in turn PCa risk. Notably, hypercholesterolemia has been associated with poor PCa prognosis or risk for aggressive disease, with risk reduction concurring with the use of cholesterol-lowering statins [ 22 , 23 , 24 ]. While a single study reported significance between elevated cholesterol and PCa recurrence in Black over White men, triglyceride levels were found to be associated with recurrence in both races [ 25 ]. Introducing further complexity concerning serum testosterone levels and ancestry associated PCa health disparities, decreased testosterone levels has been shown to elevate the risk of cardiovascular disease in Black men, with an inverse association observed for White Americans [ 26 ]. Most recently, irrespective of race and after adjusting for potential cofounding factors, serum cholesterol and testosterone levels were not associated in a study of 1996 American men [ 27 ]. Despite decades of research, there is a dearth of data for the African continent. In this study, we assessed serum testosterone, cholesterol and triglyceride levels in a cohort of 250 self-identified Black South African men, distinguishing between those with treatment naïve localized disease, and without clinicopathologically confirmed PCa. Compared with Black Americans, we found testosterone levels to be higher in Black South African men, with age-related decline pronounced for men with PCa. Acknowledging our small study size, the power lies in highlighting the importance of expanding efforts across Sub-Saharan Africa if we are to understand the clinical significance of biological contributions to PCa health disparities within the continent. Results Clinicopathological presentation and ancestry All recruited men visited a Southern African Prostate Cancer Study (SAPCS) urology clinic due to urological complaints, including erectile dysfunction, lower urinary tract symptoms, swollen scrotal region, dysuria or hematuria, and were recommended for prostate biopsy. Through histopathological analyses of 12 or more biopsy cores per patient, PCa diagnosis was confirmed via Gleason score and International Society of Urologic Pathologists (ISUP) group grading, resulting in 120 men receiving a positive diagnosis (case) and 130 a negative diagnosis (control; Table 1 ). Patients with PCa were further grouped according to their ISUP grading (or Gleason score) as high-risk (HRPCa, ISUP 3 - 5, n = 51) or low-risk (LRPCa, ISUP 1 - 2, n = 69) PCa. The mean age at presentation was 66.5 years for patients with PCa and 66.2 years for controls. As expected, prostate-specific antigen (PSA) levels were significantly elevated in cases versus controls (102.4 vs. 31.4 µg/L, P <0.001) and in HRPCa vs LRPCa and no PCa groups ( Figure S1A ). Concurring with previous data reported for Black South African men [5], PSA levels far exceeded global averages for both groups, while appear greatest for men with PSAs ≥20 µg/L (68.4% cases vs. 21.6% controls, P = 0.009; Figure S1B ). Notably, the largest racial-based study out of the United States recently showed Black men without PCa to have the highest PSA levels than all other racial groups [28]. Here, African ancestry was further defined through two generational self-identification, with the inclusion of one or more of the following southern Bantu or Black South African ethno-linguistic groupings defined via Guthrie Zone-S linguistic groups as S20-Venda (Tshivenda speakers), S30-Sotho-Tswana (Sesotho, Sepedi, Setswana), S40-Nguni (isiNdebele, isiXhosa, isiZulu, siSwazi), and S50-Tsonga (Xitsonga, including in our study ethnically reported Shangaan). Observing no significant clinicopathological, including PSA levels ( Figure S1C ), between the ethno-linguistic groups, with Sotho-Tswana speakers representing the largest study contributors (52.4%, 131/250; Table 1 ) participants were comfortably classified in downstream analyses as a single Southern Bantu or Black South African representative population. Testosterone and lipid levels and PCa status Controlling for time of sampling, defined in this study as prior to 10h00, men presenting at the clinic were tested for total serum testosterone, including albumin and sex hormone binding globulin (SHBG) to determine free and bioavailable testosterone, as well as patient- and time-matched serum cholesterol and triglyceride levels. Overall, 18% of the study population had low (1,000 ng/dL) total testosterone ( Table 1 ). Men with PCa (525.6 ± 308.4 ng/dL) did not have significantly lower testosterone levels than men without PCa (574.6 ± 286.5 ng/dL). The mean cholesterol and triglyceride levels were similar between men with and without PCa (5.1 ± 1.2 vs. 5.2 ± 1.3 mmol/L; triglyceride levels: 1.66 ± 0.81 mmol/L, respectively). The proportion of patients with high cholesterol levels (>6.18 mmol/L) did not differ significantly between PCa patients and healthy controls (15% vs. 14.6%). Table 1 . Clinical and hormone/lipid biochemical characteristics of the study cohort of 250 Black South African men, either with (positive) or without (negative) clinicopathologically confirmed prostate cancer PCa positive (n = 120) PCa negative (n = 130) P -value Age Number Mean years (Range) 119 66.5 (43 – 89) 128 66.2 (45 – 91) 0.79 Ethno-linguistic identifier Venda Sotho-Tswana Nguni Tsonga Other Unknown PSA Mean µg/L ± SD Number < 4 µg/L Number 4 – 19.9 µg/L Number 20 – 99 µg/L Number ≥ 100 µg/L 16 (13.3%) 69 (57.5%) 20 (16.7%) 9 (7.5%) 3 (2.5%) 3 (2.5%) 102.4 ± 208.2 2 (1.67%) 36 (30.0%) 59 (49.2%) 23 (19.2%) 10 (7.7%) 62 (47.7%) 29 (22.3%) 22 (16.9%) 5 (3.8%) 2 (1.5%) 31.4 ± 123.6 18 (13.9%) 84 (64.6%) 24 (18.5%) 4 (3.1%) <0.0001 PCa rating LRPCa (ISUP 1 & 2) HRPCa (ISUP 3, 4 & 5) 69 (57.5%) 51 (42.5%) Total testosterone Mean ng/dL ± SD Number 1000 ng/dL 525.6 ± 308.4 24 (20%) 91 (75.8%) 5 (4.2%) 574.6 ± 286.5 21 (16.2%) 100 (76.9%) 9 (6.9%) 0.19 Cholesterol Mean mmol/L ± SD Number 6.18 mmol/L 5.1 ± 1.2 68 (56.7%) 34 (28.3) 18 (15%) 5.2 ± 1.3 72 (55.4%) 39 (30%) 19 (14.6%) 0.58 Triglycerides Mean mmol/L ± SD Number 1.7 mmol/L 1.66 ± 0.81 75 (62.5%) 45 (37.5%) 1.66 ± 0.81 82 (63.1%) 48 (36.9%) 0.95 Abbreviations: PCa: Prostate Cancer; LRPCa: low-risk PCa; HRPCa: high-risk PCa; PSA: Prostate Specific Antigen; SD: Standard Deviation Age-associated testosterone and lipid levels, PCa status and presentation While total ( Figure 1A ), bioavailable ( Figure 1B ), and free ( Figure 1C ) testosterone decreased with age as expected, this decrease became more pronounced for cases over controls after 70 years of age. Compared with younger men, men aged 65 years with PCa had significantly lower levels of bioavailable (340.42 vs. 188.40 ng/dL, P = 0.045) and free testosterone (12.54 vs. 7.37 ng/dL ng/dL, P = 0.048), while total testosterone levels did not quit reach significance ( Table 2 ). Irrespective of age, patients presenting with high-risk (ISUP 3 – 5) PCa had significantly lower total ( Figure 1D ), bioavailable ( Figure 1E ), and free testosterone levels ( Figure 1F ) than the low-risk (ISUP <3) patients and the control group ( P = 0.004, P = 0.0036, and P = 0.0012, respectively). The latter holding true for men 65 years ( P = 0.0057 ( Figure S2A ), P = 0.009 ( Figure S2B ), and P = 0.005 ( Figure S2C ), respectively), with significance increasing for men 70 years of age ( P = 0.0032 ( Figure 1G ), P = 0.00012 ( Figure 1H ), and P = 0.00039 ( Figure 1I ), respectively). Unlike testosterone, neither cholesterol nor triglyceride levels were linked to age-associated PCa status ( Figure S3A and S3B , respectively) or disease presentation ( Figure S3C and S3D , respectively). Additionally, no correlation was observed between total testosterone and cholesterol levels according to PCa status ( Figure S4A ) or age ( Figure S4B ). Age-associated testosterone levels between Black South African and American men According to the US-based National Health and Nutritional Examination Survey (NHANES), healthy Black men (n=355) have on average 1.2-fold higher serum testosterone levels than White American men (n=631), with testosterone levels appearing to decrease more rapidly for African American men [26]. As such, NHANES provides a foundation for comparative analyses for our Black South African control data (n=130). Here we observe largely an incremental change in testosterone levels between White and Black American and Black South African men, which is greatest for men 60 years of age and over ( Table 3 ). While the fold increase is comparable for total- (1.29) and free testosterone (1.28) for Black South African versus Black American men, the greatest change was observed for bioavailable testosterone at 1.54-fold; or 1.80-fold between Black South African and White American men. Table 2 : Mean testosterone, cholesterol and triglyceride levels in younger (<65 years) and older (≥65 years) Black South African men (n=250) defined by PCa status. PCa Negative PCa Positive Age 40–64 years (n = 58) ≥65 years (n = 72) P-value 40–64 years (n = 52) ≥65 years (n = 68) P-value Total T (ng/dL) 590.45 561.89 0.578 585.70 479.55 0.065 Free T (ng/dL) 9.41 9.50 0.944 12.54 7.37 0.048 Bioavailable T (ng/dL) 245.28 247.26 0.955 340.42 188.40 0.045 Cholesterol (mmol/L) 5.04 5.24 0.356 5.10 5.04 0.759 Triglycerides (mmol/L) 1.73 1.61 0.405 1.76 1.58 0,2060 0.206 Abbreviations: PCa: Prostate Cancer; T: Testosterone Table 3 . Testosterone levels (total, free and bioavailable) between Black South African (this study, n=130) and Black- (n=355) and White (n=631) American (NHANES study) men with diagnosis of prostate cancer Testosterone Ethnicity Age 40 – 59 years Age ≥ 60 years ng/dL Fold ng/dL Fold Fold Total White American 439 (402 – 478) - 359 (326 – 395) - 1.22 Black American 524 (465 – 592) 1.19 1 432 (374 – 499) 1.20 1 1.21 Black South African 648.70 (451.32 – 846.08) 1.24 2 557.46 (506.60 – 608.33) 1.29 2 1.16 Free White American 8.80 (7.95 – 9.73) - 5.50 (4.99 – 6.07) - 1.6 Black American 10.16 (8.97 – 11.52) 1.16 1 6.84 (6.05 – 7.72) 1.24 1 1.49 Black South African 10.08 (8.28 – 11.88) 0.99 2 8.74 (7.99 – 9.49) 1.28 2 1.15 Bioavailable White American 209.38 (189.43 – 231.43) - 127.52 (115.49 – 140.81) - 1.64 Black American 231.36 (203.48 – 263.06) 1.11 1 149.44 (131.13 – 170.31) 1.17 1 1.55 Black South African 263.34 (213.13 – 313.56) 1.14 2 229.73 (205.48 – 253.98) 1.54 2 1.15 1 Fold increased between Black Americans and White Americans. 2 Fold increase between Black South Africans and Black Americans. Discussion It is well established that total testosterone levels decrease progressively in the aging male [29] and that an increase in SHBG leads to a greater decrease in free testosterone [30]. Furthermore, while the rate of decline is independent of ethnicity, overall, American men of African over European over Asian ancestry have the highest to lowest lifetime testosterone levels [21;31]. The latter mirroring ethnically-driven PCa incidence and mortality rate disparities [32,33]. Having previously reported a 2.1-fold increased age-adjusted risk for aggressive PCa at presentation for Black South African versus Black American men [5], it is notable that through the inclusion of clinicopathologically confirmed non PCa Black South African men in this study we observe the highest global testosterone levels for men 40 years and over (451.32 to 846.08 ng/dL). Intriguingly, while only free testosterone levels in the younger age group (40-59 years) mirrored levels reported for Black Americans, irrespective of age, the total, free and bioavailable testosterone levels were all elevated in Black South Africans. Compared with NHANES data, the rate of the age-associated decline is lowest for Black South African men. In contrast, our study demonstrated that this decline is more pronounced in men with PCa, with rates more closely reflecting or slightly surpassing those reported for Black and White Americans. Specifically, for Black South African men over 65 years of age the rate of testosterone decline ranged from 1.05 to 1.22-fold for total, 0.99 to 1.70-fold for free, with the steepest decline noted for bioavailable testosterone 0.99 to 1.81-fold, for men with PCa versus our population matched controls. Irrespective of age at diagnosis, we found lower total, free and bioavailable testosterone levels to be significantly associated with high-risk disease presentation ( P =0.004, P =0.0012 and P =0.0036, respectively), which increased significantly for free and bioavailable testosterone in men ≥70 years ( P =0.00039 and P =0.00012, respectively). No correlations were observed with PSA levels (log transformed, data not shown). Besides hormones, evidence is growing that lipid metabolism not only plays a critical role in PCa risk, outcomes and PSA, but also testosterone levels in the aging male. Intriguingly, the community appears to remain divided on the direction of association between total cholesterol levels and PCa risk and/or high-risk disease [34,35,36]. Here, we found no association between total serum cholesterol levels and either PCa risk or aggressive disease presentation. Additionally, in a study of American men without PCa, total cholesterol and LDL levels were positively correlated with PSA levels in White but not in Black men, suggesting that the effect of cholesterol on prostate cancer biology may differ by race [37]. Similarly, no correlation between PSA and cholesterol in our Black South African men with- and without PCa was observed (log transformed, data not shown). As with cholesterol, the jury is also out regarding the direction of correlation with triglycerides including both positive [38] and negative correlations with PCa risk and/or high-risk disease [39]. While the Arthur et al., 2016 study correlated high serum triglycerides with elevated PSA levels, the NHANES study has negatively correlated serum triglycerides with PSA levels among American males [40]. Again, we found no correlation between triglycerides and PCa risk or presentation, PSA (log transformed, data not shown) or testosterone levels. Limitations of our study include, lack of fasted sampling and information regarding potential cofounding factors, most notably patient body mass index and lifetime cumulative data. Additionally, while there was no clinicopathological evidence for PCa in our control group, the high PSA values observed within our study, as previously reported for Black South African men [4], means we are unable to exclude for the possibility that presence of cancer had been missed at 12-core minimal biopsy. While our study is notably underpowered, data for sub-Saharan Africa is either scarce or lacking. Scanning the literature, we found a single 1981 study including Nigerian men (n=55) which reported lower population-based testosterone levels compared to African American men also recruited at PCa diagnosis, with lower levels linked to PCa status [41]. In line with our findings, a smaller case-only study out of South Africa (n=109), associated low levels of free testosterone with aggressive disease presentation and higher PSA levels [42], while a more comprehensive South African study (n=878) found no correlation between total cholesterol levels and PCa status, although elevated high-density lipoprotein (HDL) was associated with a positive PCa diagnosis [43]. Based on genetic ancestry profiling using 33,410 linkage disequilibrium pruned single nucleotide polymorphisms, we have demonstrated that men contributing to the SAPCS and self-identifying as Southern Bantu or Black South African are genetically distinct from west, east and central African populations and in turn also African Americans, with regional within SSA population substructure separation occurring prior to European-Asian population distinction [9]. Additionally, further interrogation of genetic substructure within the SAPCS we identified Southern Bantu or Guthrie Zone S linguistically-driven ancestral substructure [44]. Accordingly, while the patterns of testosterone expression across diverse populations in SSA remain to be determined and in turn the impact on PCa biology and associated health disparity, studies will need to consider and define the deep genetic and in turn biological diversity across the region. While our study lacks lifetime cumulative data, our findings align with those of a 2010 meta-analysis that demonstrated population differences in testosterone levels in younger people, which were associated with disparities in PCa in later years [45]. In our study, younger black South Africans with PCa had an approximately 1.4-fold overall increase in testosterone levels. Alternatively, considering our treatment-naïve patients at sampling, our results suggest that a rapid decline in testosterone levels in older patients might predispose men to aggressive PCa. However, further studies are needed to determine the biological relevance of the observed rapid decreases in testosterone and advanced disease presentation in aging African men. Our study raises critical questions about the appropriate use of ADT in the African population, underscoring the urgent need for increased inclusion of Africans in addressing what may be perceived as an ‘old story’. Methods Ethics and participant recruitment The study was approved by the University of Pretoria Faculty of Health Sciences Research Ethics Committee in South Africa (with US Federal wide assurance FWA00002567 and IRB00002235 IORG0001762), which included both project specific (HREC#58/2021) and SAPCS Consortia approval (HREC#43/2010), with research performed in accordance with the Declaration of Helsinki. Additional IRB review and approval was granted by the Human Research Protection Office of the US Army Medical Research and Development Command as part of the HEROIC PCaPH Africa1K Consortium (E03333.3a). Providing informed consent, 250 treatment-naïve Black South African men were recruited from participating SAPCS urology clinics, specifically Tshilidzini Hospital in Limpopo Province and Dr. George Mukhari Academic Hospital in Gauteng Province of South Africa. Furthermore, patients were not fasted prior to sampling. Clinicopathology and sampling Blood (serum) was collected prior to 10h00. The samples were stored at −20°C on site and during transportation. At the University of Pretoria Laboratory, Department of Urology, the samples were thawed overnight at 2°C and subsequently left to stand for 1 h to separate the serum. The serum samples were aliquoted into Eppendorf tubes at a volume of 400 μl and stored at 2°C during transportation to the PathCare Laboratory, Pretoria, South Africa. Total testosterone, total albumin, sex hormone binding globulin (SHBG), total cholesterol and triglyceride levels were tested in the laboratory. Quantitative measures An Architect 4100 (Immuno) quantitative chemiluminescent microparticle immunoassay was used to test for total testosterone and SHBG, and an Architect 8200 (Chemistry) quantitative Bromocresol purple was used to measure albumin. Total testosterone, albumin, and SHBG were used to calculate the free and bioavailable testosterone concentrations using the calculator available at http://www.issam.ch/freetesto.html following Vermeulen’s formula. Total cholesterol was measured using the Architech 8200 (Chemistry) quantitative enzymatic reaction, whereas the glycerol phosphate oxidative chemical reaction, on the same equipment, was used to measure the triglyceride levels. American relevant NHANES data The National Health and Nutrition Examination Survey (NHANES) is a survey which collected health and nutritional data of the United States population over several years [46]. We sourced a subset of the NHANES testosterone data of men without PCa from Hu et al. 2015 [21], selecting only the age group of 40 – 59 years (further categorized as younger men) and men ≥60 years (further categorized as older men). Statistical analyses The data were analyzed using R software with the following packages: ggpubr and tidyverse (ggplot2) for boxplots and LOESS curves, respectively. The difference between the means of PCa-positive and -negative patients was analyzed using Student’s t test and the Kruskal‒Wallis test. A p <0.05 value indicated significance. Locally estimated scatterplot smoothing (LOESS) curves were generated to visually examine the relationships between biochemical factors. Declarations Acknowledgements We owe gratitude to the study participants, past and present contributors to the Southern African Prostate Cancer Study (SAPCS), as well as the Department of Research and Innovation of the University of Pretoria, for their support. The authors thank Dr. Cheryl Tosh for editing support. This research was funded by Ampath Laboratories, the National Research Foundation (NRF) and the University of Pretoria in South Africa, the National Health and Medical Research Council (NHMRC) of Australia Ideas Grant (APP2001098), as well as the U.S.A. Congressionally Directed Medical Research Programs (CDMRP) Prostate Cancer Research Program (PCRP) Health Equity Research Outcomes Integrity Consortium (HEROIC) Award (PC210168, HEROIC PCaPH Africa1K). The Southern African Prostate Cancer Study is further supported by a Cancer Association of South Africa (CANSA) Development Grant to M.S. Riana Bornman, while Vanessa M. Hayes is supported by the Petre Foundation in Australia. Author contributions M.S.R.B. and V.M.H. conceived and designed the study. M.T.L., N.M., S.B.A.M. and M.S.R.B. collected and assembled the data. M.T.L. performed data statistical analysis, wrote the main manuscript and generated the figures under the supervision of V.M.H., W.J. and M.S.R.B, with M.L. providing critical study review. All authors have reviewed the final manuscript. Data availability statement The data are available for bona fide researchers upon request to the corresponding authors. References Bigler, S.A., Pound, C.R., Zhou, X. A retrospective study on pathologic features and racial disparities in prostate cancer. Prostate Cancer . 2011, e 239460 (2011). Siegel, R.L., Miller, K.D., Fuchs, H.E., Jemal A. Cancer statistics. CA Cancer J Clin . 72 , 7-33 (2022). Kelly, S.P. et al . Trends in the Incidence of Fatal Prostate Cancer in the United States by Race. Eur Urol . 71 , 195-201 (2017). Bray, F. et al . Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin . 1-35 (2024). Tindall, E.A. et al . Clinical presentation of prostate cancer in black South Africans. Prostate. 74, 880-891 (2014). Nair, S.S., Chakravarty, D., Dovey, Z.S., Zhang, X., Tewari, A.K. Why do African-American men face higher risks for lethal prostate cancer? Curr Opin Urol . 32, 96-101 (2022). Jaratlerdsiri, W. et al . African-specific molecular taxonomy of prostate cancer. Nature . 609, 552-559 (2022). Soh, P.X., Hayes, V.M. Common Genetic Variants Associated with Prostate Cancer Risk: The Need for African Inclusion. Eur Urol . 84, 22-24 (2023). Soh, P.X. et al . Prostate cancer genetic risk and associated aggressive disease in men of African ancestry. Nat Commun . 14, 8037 (2023). Yassin, A., AlRumaihi, K., Alzubaidi, R., Alkadhi, S., Al Ansari, A. Testosterone, testosterone therapy and prostate cancer. The Aging Male . 22, 219-227 (2019). Klap, J., Schmid, M., Loughlin, K.R. The relationship between total testosterone levels and prostate cancer: a review of the continuing controversy. J Urol . 193, 403-414. (2015). Shahait, M. et al . Does perioperative testosterone predict post-prostatectomy genomic risk score? J Urol . 207, 1214-1221 (2022). Isbarn, H. et al . Testosterone and prostate cancer: revisiting old paradigms. Eur Urol . 56, 48-56 (2009). Morgentaler, A., Conners, III W.P. Testosterone therapy in men with prostate cancer: literature review, clinical experience, and recommendations. Asian J Androl . 17,206-211 (2015). Watts, E.L., et al . Circulating free testosterone and risk of aggressive prostate cancer: Prospective and Mendelian randomization analyses in international consortia. Int J Cancer . 151, 1033-1046 (2022). Parsons, J.K. et al . Serum testosterone and the risk of prostate cancer: potential implications for testosterone therapy. Cancer Epidemiol Biomarkers Prev . 14, 2257-2260 (2005). Pierorazio, P.M. et al . Serum testosterone is associated with aggressive prostate cancer in older men: results from the Baltimore Longitudinal Study of Aging. BJU Int . 105, 824-829 (2010). Stanworth, R.D., Jones, T.H. Testosterone for the aging male; current evidence and recommended practice. Clin Interv Aging . 3 , 25-44 (2008). Wang, Y., Dai, B., Ye, D.W. Serum testosterone level predicts the effective time of androgen deprivation therapy in metastatic prostate cancer patients. Asian J Androl . 19 , 178-183 (2017). Harris, W.P., Mostaghel, E.A., Nelson, P.S., Montgomery B. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat Clin Pract Urol . 6, 76-85 (2009). Hu, H., Odedina, F.T., Reams, R.R., Lissaker, C.T., Xu, X. Racial differences in age-related variations of testosterone levels among US males: Potential implications for prostate cancer and personalized medication. J Racial Ethn Health Disparities. 2, 67-76 (2015). Schnoeller, T.J., Jentzmik F., Schrader A.J., Steinestel J. Influence of serum cholesterol level and statin treatment on prostate cancer aggressiveness. Oncotarget . 8, 47110-47120 (2017). Jamnagerwalla, J. et al . Serum cholesterol and risk of high-grade prostate cancer: results from the REDUCE study. Prostate Cancer Prostatic Dis . 21, 252-259 (2018). Hirano H. et al . Impact of pretreatment total cholesterol level is associated with metastasis of prostate cancer. Am J Mens Health . 14, 1557988320918788 (2020). Allott, E.H. et al . Racial Differences in the Association Between Preoperative Serum Cholesterol and Prostate Cancer Recurrence: Results from the SEARCH Database. Cancer Epidemiol Biomarkers Prev . 25, 547-554 (2016). Lopez, D.S. et al . Low testosterone and high cholesterol levels in relation to all-cause, cardiovascular disease, and cancer mortality in White, Black, and Hispanic men: NHANES 1988-2015. Hormones . 21, 399-411 (2022). Gomes G.K. et al . Cholesterol intake and serum total cholesterol levels are not associated with total testosterone levels in men: a cross-sectional study from NHANES 2013–2014. Lipids Health Dis . 22, 168 (2023). Barlow, M. et al . Ethnic differences in prostate-specific antigen levels in men without prostate cancer: A systematic review. Prostate Cancer and Prostatic Diseases. 26, 249-456 (2023). Harman, S.M., Metter, E.J., Tobin, J.D., Pearson, J., Blackman, M.R. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab . 86 , 724-731 (2001). Snyder, P.J. What We Have Learned from The Testosterone Trials. Urol Clin North Am . 49 , 637-644 (2022). Xu, L., Au Yeung, S.L., Kavikondala, S., Leung, G.M., Schooling C.M. Testosterone concentrations in young healthy US versus Chinese men. Am J Hum Biol. 26, 99-102 (2014). Yamoah, K. et al . Racial and ethnic disparities in prostate cancer outcomes in the veterans affairs health care system. JAMA Netw Open . 5, e2144027 (2022). Raymundo, E.M., Rice K.R., Chen Y., Zhao J., Brassell S.A. Prostate cancer in Asian Americans: incidence, management and outcomes in an equal access healthcare system. BJU Int . 107, 1216-1222 (2011). Shafique, K. et al . Cholesterol and the risk of grade-specific prostate cancer incidence: evidence from two large prospective cohort studies with up to 37 years' follow up. BMC Cancer . 12, 25 (2012). Heir, T. et al . Cholesterol and prostate cancer risk: a long-term prospective cohort study. BMC Cancer . 16, 643 (2016). Garrido, M.M., Marta, J.C., Ribeiro, R.M., Pinheiro, L.C., Guimarães, J.T. Serum lipids and prostate cancer. J Clin Lab Anal . 35, e23705 (2021). Zapata, D. et al . Is PSA related to serum cholesterol and does the relationship differ between black and white men? Prostate . 75, 1877-1885 (2015). Arthur, R. et al . Association between baseline serum glucose, triglycerides and total cholesterol, and prostate cancer risk categories. Cancer Med . 5, 1307-1318 (2016). Häggström, C. et al . Prospective study on metabolic factors and risk of prostate cancer. Cancer . 118, 6199-6206 (2012). Wei, C. et al . Association between serum triglycerides and prostate specific antigen (PSA) among U.S. males: National Health and Nutrition Examination Survey (NHANES), 2003–2010. Nutrients . 14, 1325 (2022). Ahluwalia, B. et al . Blood hormone profiles in prostate cancer patients in high‐risk and low‐risk populations. Cancer . 48, 2267-2273 (1981). Alsharef, M., Kahie, A., Conradie, M., Goad, E., Fourie, T. Association between low serum free testosterone and adverse prognostic factors in men diagnosed with prostate cancer in KwaZulu-Natal. S Afr J Surg . 50 , 40-42 (2012). Mapanga, W. et al . Prevalence of multimorbidity in men of African descent with and without prostate cancer in Soweto, South Africa. PLoS One . 17, e0276050 (2022). Gheybi, K. et al . Linking African ancestral substructure to prostate cancer health disparities. Sci Rep . 13, 20909 (2023). Alvarado, L.C. Population differences in the testosterone levels of young men are associated with prostate cancer disparities in older men. Am J Hum Biol . 22, 449-455 (2010). CDC. Questionnaires, datasets and related documentation: CDC; 2013. http://www.cdc.gov/nchs/nhanes.htm. Accessed 02 May 2022. Additional Declarations No competing interests reported. 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Hayes","email":"data:image/png;base64,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","orcid":"","institution":"University of Sydney","correspondingAuthor":true,"prefix":"","firstName":"Vanessa","middleName":"M.","lastName":"Hayes","suffix":""},{"id":301889823,"identity":"32551a4d-2df6-4af0-827d-f04abf4f200c","order_by":6,"name":"M. S. Riana Bornman","email":"","orcid":"","institution":"University of Pretoria","correspondingAuthor":false,"prefix":"","firstName":"M.","middleName":"S. Riana","lastName":"Bornman","suffix":""}],"badges":[],"createdAt":"2024-05-04 06:11:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4366943/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4366943/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-92539-y","type":"published","date":"2025-04-08T16:04:53+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":56526405,"identity":"0a4e2f44-0dff-41fa-8125-15b68b23d3e0","added_by":"auto","created_at":"2024-05-15 10:26:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":294351,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLOESS curves and boxplots of serum testosterone levels according to age and prostate cancer (PCa) status in black South African men with (n=120) or without (n=130) prostate cancer, including high-risk (HRPCa) or low-risk (LRPCa) disease defined by pathology\u003c/strong\u003e. LOESS curve by age for total testosterone \u003cstrong\u003e(A)\u003c/strong\u003e, bioavailable testosterone \u003cstrong\u003e(B)\u003c/strong\u003e and free testosterone \u003cstrong\u003e(C)\u003c/strong\u003e. Boxplot of PCa status and risk for total testosterone \u003cstrong\u003e(D),\u003c/strong\u003e bioavailable testosterone \u003cstrong\u003e(E)\u003c/strong\u003e, and free testosterone \u003cstrong\u003e(F)\u003c/strong\u003e, and restricted for men \u0026gt;70 years for total testosterone \u003cstrong\u003e(G),\u003c/strong\u003e bioavailable testosterone \u003cstrong\u003e(H)\u003c/strong\u003e, and free testosterone \u003cstrong\u003e(I)\u003c/strong\u003e,\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4366943/v1/a64acd3f61492ce7d6ad5009.png"},{"id":80558922,"identity":"d6891486-686a-4615-ba0a-7ee47e1957a6","added_by":"auto","created_at":"2025-04-14 16:17:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1279232,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4366943/v1/10d5cad4-34a2-4c03-861b-92b4dd5f01c4.pdf"},{"id":56526406,"identity":"65554aa9-6fd3-4bab-9257-5a2a5d3be04f","added_by":"auto","created_at":"2024-05-15 10:26:05","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1314039,"visible":true,"origin":"","legend":"","description":"","filename":"HormonesSuppData.docx","url":"https://assets-eu.researchsquare.com/files/rs-4366943/v1/554f47e968cc0f7a5b263834.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Associating serum testosterone levels with African ancestral prostate cancer health disparities","fulltext":[{"header":"Introduction","content":"\u003cp\u003eProstate cancer (PCa) is characterized by significant ancestral disparity. In the United States, African American men are diagnosed at a younger age, present with more advanced disease, and have the greatest lifetime risk of dying from PCa [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. With Black men at double the risk for lethal disease compared to White American men, this disparity increases to 4.2-fold for men younger than 50 years [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Globally, the regions of sub-Saharan Africa and the Caribbean are the most impacted by PCa mortality, with the highest rates reported for Southern Africa [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], which is notable when considering the average life expectancy for southern African men is 1.2-fold lower than the worldwide average at birth (World Bank 2020). Previously we showed that, compared to African American men and after adjusting for age, Black South African men are 2.1-fold more likely to present with aggressive disease [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. What is clear, African ancestry is a well-established risk factor for PCa adversity. While the reasons for this disparity are likely multifactorial, including socioeconomic and healthcare access as obvious contributing factors, an extensive review of the literature concurred that PCa presentation in African American men is both genomically and biologically unique [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. While data is comparably scare for Sub-Saharan Africa, most recently we demonstrated that even within the broad \u0026lsquo;African\u0026rsquo; racial identifier men of southern African ancestry present with regionally unique inherited and somatic mutational profiles [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, how these genomic differences translate into biological differences is largely unknown.\u003c/p\u003e \u003cp\u003eTestosterone is required for normal prostate growth, which makes androgen deprivation therapy (ADT) an obvious first-line treatment for advanced or metastatic disease [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, a lack of consensus exists regarding the role of serum testosterone levels in PCa development and progression [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. While some studies refute an association between testosterone and PCa predisposition [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], others have linked high testosterone levels to elevated risk [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Overall, circulating testosterone levels drop both as men age (rate of 1.6% per year) and as cancer progresses, with low levels (\u0026le;\u0026thinsp;300 ng/dL) associated with aggressive disease [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. For ADT treated patients, achieving chemical castration requires total serum testosterone to drop below 50 ng/dl, while levels of 25 ng/dl have been shown to have prognostic potential and patient stratification for combination therapies [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], although castration-resistance is inevitable [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Furthermore, age-related racial variations in testosterone levels show that compared to White Americans, Black American men present with overall higher levels, peak earlier and higher, with more dramatic decline [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs testosterone is a cholesterol-derived steroid hormone, it has been postulated that a link exists between testosterone and cholesterol levels and in turn PCa risk. Notably, hypercholesterolemia has been associated with poor PCa prognosis or risk for aggressive disease, with risk reduction concurring with the use of cholesterol-lowering statins [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. While a single study reported significance between elevated cholesterol and PCa recurrence in Black over White men, triglyceride levels were found to be associated with recurrence in both races [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Introducing further complexity concerning serum testosterone levels and ancestry associated PCa health disparities, decreased testosterone levels has been shown to elevate the risk of cardiovascular disease in Black men, with an inverse association observed for White Americans [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Most recently, irrespective of race and after adjusting for potential cofounding factors, serum cholesterol and testosterone levels were not associated in a study of 1996 American men [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite decades of research, there is a dearth of data for the African continent. In this study, we assessed serum testosterone, cholesterol and triglyceride levels in a cohort of 250 self-identified Black South African men, distinguishing between those with treatment na\u0026iuml;ve localized disease, and without clinicopathologically confirmed PCa. Compared with Black Americans, we found testosterone levels to be higher in Black South African men, with age-related decline pronounced for men with PCa. Acknowledging our small study size, the power lies in highlighting the importance of expanding efforts across Sub-Saharan Africa if we are to understand the clinical significance of biological contributions to PCa health disparities within the continent.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eClinicopathological presentation and ancestry\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll recruited men visited a Southern African Prostate Cancer Study (SAPCS) urology clinic due to urological complaints, including erectile dysfunction, lower urinary tract symptoms, swollen scrotal region, dysuria or hematuria, and were recommended for prostate biopsy. Through histopathological analyses of 12 or more biopsy cores per patient, PCa diagnosis was confirmed via Gleason score and International Society of Urologic Pathologists (ISUP) group grading, resulting in 120 men receiving a positive diagnosis (case) and 130 a negative diagnosis (control; \u003cstrong\u003eTable 1\u003c/strong\u003e). Patients with PCa were further grouped according to their ISUP grading (or Gleason score) as high-risk (HRPCa, ISUP 3 - 5, n = 51) or low-risk (LRPCa, ISUP 1 - 2, n = 69) PCa. The mean age at presentation was 66.5 years for patients with PCa and 66.2 years for controls. As expected, prostate-specific antigen (PSA) levels were significantly elevated in cases \u003cem\u003eversus\u0026nbsp;\u003c/em\u003econtrols (102.4 \u003cem\u003evs.\u003c/em\u003e 31.4 \u0026micro;g/L, \u003cem\u003eP\u003c/em\u003e \u0026lt;0.001) and in HRPCa vs LRPCa and no PCa groups (\u003cstrong\u003eFigure S1A\u003c/strong\u003e). Concurring with previous data reported for Black South African men [5], PSA levels far exceeded global averages for both groups, while appear greatest for men with PSAs \u0026ge;20 \u0026micro;g/L (68.4% cases \u003cem\u003evs.\u003c/em\u003e 21.6% controls, \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.009; \u003cstrong\u003eFigure S1B\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNotably, the largest racial-based study out of the United States recently showed Black men without PCa to have the highest PSA levels than all other racial groups [28]. Here, African ancestry was further defined through two generational self-identification, with\u0026nbsp;the\u0026nbsp;inclusion of one or more of the following southern Bantu or Black South African ethno-linguistic groupings\u0026nbsp;defined via Guthrie Zone-S linguistic groups as\u0026nbsp;S20-Venda (Tshivenda speakers), S30-Sotho-Tswana (Sesotho, Sepedi, Setswana), S40-Nguni (isiNdebele, isiXhosa, isiZulu, siSwazi), and S50-Tsonga (Xitsonga, including in our study ethnically reported Shangaan). Observing no significant clinicopathological, including PSA levels\u0026nbsp;(\u003cstrong\u003eFigure S1C\u003c/strong\u003e), between the ethno-linguistic groups, with Sotho-Tswana speakers representing the largest study contributors (52.4%, 131/250; \u003cstrong\u003eTable 1\u003c/strong\u003e) participants were comfortably classified in downstream analyses as a single Southern Bantu or Black South African representative population.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTestosterone and lipid levels and PCa status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eControlling for time of sampling, defined in this study as prior to 10h00, men presenting at the clinic were tested for total serum\u0026nbsp;testosterone, including albumin and sex hormone binding globulin (SHBG) to determine free and bioavailable testosterone, as well as patient- and time-matched serum cholesterol and triglyceride levels.\u0026nbsp;Overall, 18% of the study population had low (\u0026lt;300 ng/dL)\u0026nbsp;total testosterone,\u0026nbsp;and 5.6%\u0026nbsp;had\u0026nbsp;high (\u0026gt;1,000 ng/dL) total testosterone (\u003cstrong\u003eTable 1\u003c/strong\u003e). Men with PCa (525.6 \u0026plusmn; 308.4 ng/dL) did not have significantly lower testosterone levels than men without PCa (574.6 \u0026plusmn; 286.5 ng/dL). The mean cholesterol and triglyceride levels were similar between men with and without PCa (5.1 \u0026plusmn; 1.2 vs. 5.2 \u0026plusmn; 1.3 mmol/L; triglyceride levels: 1.66 \u0026plusmn; 0.81 mmol/L, respectively). The proportion of patients with high cholesterol levels (\u0026gt;6.18 mmol/L) did not differ significantly between PCa patients and healthy controls (15% \u003cem\u003evs.\u003c/em\u003e 14.6%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e. Clinical and hormone/lipid biochemical characteristics of the study cohort of 250 Black South African men, either with (positive) or without (negative) clinicopathologically confirmed prostate cancer\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"614\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.30016313213703%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePCa positive \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;(n = 120)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.732463295269167%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePCa negative \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 130)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;P\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.30016313213703%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Number\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Mean years (Range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u0026nbsp;119\u003c/p\u003e\n \u003cp\u003e66.5 (43 \u0026ndash; 89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.732463295269167%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u0026nbsp;128\u003c/p\u003e\n \u003cp\u003e66.2 (45 \u0026ndash; 91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.30016313213703%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEthno-linguistic identifier\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003eVenda\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Sotho-Tswana\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Nguni\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Tsonga\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Other\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Unknown\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePSA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003eMean \u0026micro;g/L \u0026plusmn; SD\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp; Number \u0026lt; 4 \u0026micro;g/L\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Number 4 \u0026ndash; 19.9 \u0026micro;g/L\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Number 20 \u0026ndash; 99 \u0026micro;g/L\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Number \u0026ge; 100 \u0026micro;g/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e16 (13.3%)\u003c/p\u003e\n \u003cp\u003e69 (57.5%)\u003c/p\u003e\n \u003cp\u003e20 (16.7%)\u003c/p\u003e\n \u003cp\u003e9 (7.5%)\u003c/p\u003e\n \u003cp\u003e3 (2.5%)\u003c/p\u003e\n \u003cp\u003e3 (2.5%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e102.4 \u0026plusmn; 208.2\u003cbr\u003e\u0026nbsp;2 (1.67%)\u003c/p\u003e\n \u003cp\u003e36 (30.0%)\u003cbr\u003e\u0026nbsp;59 (49.2%)\u003cbr\u003e\u0026nbsp;23 (19.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.732463295269167%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10 (7.7%)\u003c/p\u003e\n \u003cp\u003e62 (47.7%)\u003c/p\u003e\n \u003cp\u003e29 (22.3%)\u003c/p\u003e\n \u003cp\u003e22 (16.9%)\u003c/p\u003e\n \u003cp\u003e5 (3.8%)\u003c/p\u003e\n \u003cp\u003e2 (1.5%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e31.4 \u0026plusmn; 123.6\u003cbr\u003e\u0026nbsp;18 (13.9%)\u003c/p\u003e\n \u003cp\u003e84 (64.6%)\u003cbr\u003e\u0026nbsp;24 (18.5%)\u003cbr\u003e\u0026nbsp;4 (3.1%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.30016313213703%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePCa rating\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; LRPCa (ISUP 1 \u0026amp; 2)\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; HRPCa (ISUP 3, 4 \u0026amp; 5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u0026nbsp;69 (57.5%)\u003cbr\u003e\u0026nbsp;51 (42.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.732463295269167%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.30016313213703%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal testosterone\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Mean ng/dL \u0026plusmn; SD\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Number \u0026lt;300 ng/dL\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Number 300\u0026ndash;1000 ng/dL \u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Number \u0026gt;1000 ng/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u0026nbsp;525.6 \u0026plusmn; 308.4\u003cbr\u003e\u0026nbsp;24 (20%)\u0026nbsp;\u003cbr\u003e\u0026nbsp;91 (75.8%)\u003cbr\u003e\u0026nbsp;5 (4.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.732463295269167%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cbr\u003e\u0026nbsp;574.6 \u0026plusmn; 286.5\u003cbr\u003e\u0026nbsp;21 (16.2%)\u003cbr\u003e\u0026nbsp;100 (76.9%)\u003cbr\u003e\u0026nbsp;9 (6.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.30016313213703%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCholesterol\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Mean mmol/L \u0026plusmn; SD\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Number \u0026lt;5.17 mmol/L\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Number 5.17-6.18 mmol/L\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Number \u0026gt;6.18 mmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5.1 \u0026plusmn; 1.2\u003cbr\u003e\u0026nbsp;68 (56.7%)\u003cbr\u003e\u0026nbsp;34 (28.3)\u003cbr\u003e\u0026nbsp;18 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.732463295269167%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5.2 \u0026plusmn; 1.3\u003cbr\u003e\u0026nbsp;72 (55.4%)\u003cbr\u003e\u0026nbsp;39 (30%)\u003cbr\u003e\u0026nbsp;19 (14.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.30016313213703%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTriglycerides\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Mean mmol/L \u0026plusmn; SD\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Number \u0026lt;1.7 mmol/L\u003cbr\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Number \u0026gt;1.7 mmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.533442088091356%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.66 \u0026plusmn; 0.81\u003cbr\u003e\u0026nbsp;75 (62.5%)\u003cbr\u003e\u0026nbsp;45 (37.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.732463295269167%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.66 \u0026plusmn; 0.81\u003cbr\u003e\u0026nbsp;82 (63.1%)\u003cbr\u003e\u0026nbsp;48 (36.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.43393148450245%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAbbreviations: PCa: Prostate Cancer; LRPCa: low-risk PCa; HRPCa: high-risk PCa; PSA: Prostate Specific Antigen; SD: Standard Deviation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAge-associated testosterone and lipid levels, PCa status and presentation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWhile total (\u003cstrong\u003eFigure 1A\u003c/strong\u003e), bioavailable (\u003cstrong\u003eFigure 1B\u003c/strong\u003e), and free (\u003cstrong\u003eFigure 1C\u003c/strong\u003e) testosterone decreased with age as expected, this decrease became more pronounced for cases over controls after 70 years of age. Compared with younger men, men aged \u0026nbsp;65 years with PCa had significantly lower levels of bioavailable (340.42 \u003cem\u003evs.\u003c/em\u003e 188.40 ng/dL,\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003eP\u003c/em\u003e = 0.045) and free testosterone (12.54 \u003cem\u003evs.\u0026nbsp;\u003c/em\u003e7.37 ng/dL ng/dL, \u003cem\u003eP\u003c/em\u003e = 0.048), while total testosterone levels did not quit reach significance (\u003cstrong\u003eTable 2\u003c/strong\u003e). Irrespective of age,\u0026nbsp;patients presenting with high-risk (ISUP 3 \u0026ndash; 5) PCa had significantly lower\u0026nbsp;total (\u003cstrong\u003eFigure 1D\u003c/strong\u003e), bioavailable (\u003cstrong\u003eFigure 1E\u003c/strong\u003e), and free testosterone levels (\u003cstrong\u003eFigure 1F\u003c/strong\u003e)\u0026nbsp;than the\u003cem\u003e\u0026nbsp;\u003c/em\u003elow-risk (ISUP \u0026lt;3)\u0026nbsp;patients\u0026nbsp;and\u0026nbsp;the\u0026nbsp;control group (\u003cem\u003eP\u003c/em\u003e = 0.004, \u003cem\u003eP\u003c/em\u003e = 0.0036, and \u003cem\u003eP\u003c/em\u003e = 0.0012, respectively). The latter holding true for men \u0026nbsp;65 years (\u003cem\u003eP\u003c/em\u003e = 0.0057 (\u003cstrong\u003eFigure S2A\u003c/strong\u003e), \u003cem\u003eP\u003c/em\u003e = 0.009 (\u003cstrong\u003eFigure S2B\u003c/strong\u003e), and \u003cem\u003eP\u003c/em\u003e = 0.005 (\u003cstrong\u003eFigure S2C\u003c/strong\u003e), respectively), with significance increasing for men \u0026nbsp;70 years of age (\u003cem\u003eP\u003c/em\u003e = 0.0032 (\u003cstrong\u003eFigure 1G\u003c/strong\u003e), \u003cem\u003eP\u003c/em\u003e = 0.00012 (\u003cstrong\u003eFigure 1H\u003c/strong\u003e), and \u003cem\u003eP\u003c/em\u003e = 0.00039 (\u003cstrong\u003eFigure 1I\u003c/strong\u003e), respectively). Unlike testosterone, neither cholesterol\u0026nbsp;nor\u0026nbsp;triglyceride levels were linked to age-associated PCa status (\u003cstrong\u003eFigure\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;S3A\u0026nbsp;\u003c/strong\u003eand\u003cstrong\u003e\u0026nbsp;S3B\u003c/strong\u003e, respectively) or disease presentation (\u003cstrong\u003eFigure\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;S3C\u0026nbsp;\u003c/strong\u003eand \u003cstrong\u003eS3D\u003c/strong\u003e, respectively). Additionally, no correlation was observed between total testosterone and cholesterol levels\u0026nbsp;according to\u0026nbsp;PCa status (\u003cstrong\u003eFigure S4A\u003c/strong\u003e) or age (\u003cstrong\u003eFigure S4B\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAge-associated testosterone levels between Black South African and American men\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to\u0026nbsp;the US-based National Health and Nutritional Examination Survey (NHANES), healthy Black men (n=355) have on average\u0026nbsp;1.2-fold higher serum testosterone levels than White American men (n=631), with\u0026nbsp;testosterone\u0026nbsp;levels appearing to\u0026nbsp;decrease\u0026nbsp;more rapidly for African\u0026nbsp;American men\u0026nbsp;[26]. As such, NHANES provides a foundation for comparative analyses for our Black South African control data (n=130). Here we observe largely an incremental change in testosterone levels between White and Black American and Black South African men, which is greatest for men 60 years of age and over (\u003cstrong\u003eTable 3\u003c/strong\u003e). While the fold increase is comparable for total- (1.29) and free testosterone (1.28) for Black South African \u003cem\u003eversus\u003c/em\u003e Black American men, the greatest change was observed for bioavailable testosterone at 1.54-fold; or 1.80-fold between Black South African and White American men.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e: Mean testosterone, cholesterol and triglyceride levels in younger (\u0026lt;65 years) and older (\u0026ge;65 years) Black South African men (n=250) defined by PCa status.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"804\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.1706102117061%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.60896637608966%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePCa Negative\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"41.220423412204234%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePCa Positive\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.1706102117061%\" valign=\"top\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.317559153175592%\" valign=\"top\"\u003e\n \u003cp\u003e40\u0026ndash;64 years\u003cbr\u003e\u0026nbsp;(n = 58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.706102117061022%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge;65 years\u003cbr\u003e\u0026nbsp;(n = 72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.58530510585305%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;P-value\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.562889165628892%\" valign=\"top\"\u003e\n \u003cp\u003e40\u0026ndash;64 years \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; (n = 52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.07222914072229%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge;65 years\u003cbr\u003e\u0026nbsp;(n = 68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.58530510585305%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;P-value\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.1706102117061%\" valign=\"top\"\u003e\n \u003cp\u003eTotal T (ng/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.317559153175592%\" valign=\"top\"\u003e\n \u003cp\u003e590.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.706102117061022%\" valign=\"top\"\u003e\n \u003cp\u003e561.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.58530510585305%\" valign=\"top\"\u003e\n \u003cp\u003e0.578\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.562889165628892%\" valign=\"top\"\u003e\n \u003cp\u003e585.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.07222914072229%\" valign=\"top\"\u003e\n \u003cp\u003e479.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.58530510585305%\" valign=\"top\"\u003e\n \u003cp\u003e0.065\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.1706102117061%\" valign=\"top\"\u003e\n \u003cp\u003eFree T (ng/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.317559153175592%\" valign=\"top\"\u003e\n \u003cp\u003e9.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.706102117061022%\" valign=\"top\"\u003e\n \u003cp\u003e9.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.58530510585305%\" valign=\"top\"\u003e\n \u003cp\u003e0.944\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.562889165628892%\" valign=\"top\"\u003e\n \u003cp\u003e12.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.07222914072229%\" valign=\"top\"\u003e\n \u003cp\u003e7.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.58530510585305%\" valign=\"top\"\u003e\n \u003cp\u003e0.048\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.1706102117061%\" valign=\"top\"\u003e\n \u003cp\u003eBioavailable T (ng/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.317559153175592%\" valign=\"top\"\u003e\n \u003cp\u003e245.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.706102117061022%\" valign=\"top\"\u003e\n \u003cp\u003e247.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.58530510585305%\" valign=\"top\"\u003e\n \u003cp\u003e0.955\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.562889165628892%\" valign=\"top\"\u003e\n \u003cp\u003e340.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.07222914072229%\" valign=\"top\"\u003e\n \u003cp\u003e188.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.58530510585305%\" valign=\"top\"\u003e\n \u003cp\u003e0.045\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.1706102117061%\" valign=\"top\"\u003e\n \u003cp\u003eCholesterol (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.317559153175592%\" valign=\"top\"\u003e\n \u003cp\u003e5.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.706102117061022%\" valign=\"top\"\u003e\n \u003cp\u003e5.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.58530510585305%\" valign=\"top\"\u003e\n \u003cp\u003e0.356\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.562889165628892%\" valign=\"top\"\u003e\n \u003cp\u003e5.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.07222914072229%\" valign=\"top\"\u003e\n \u003cp\u003e5.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.58530510585305%\" valign=\"top\"\u003e\n \u003cp\u003e0.759\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.1706102117061%\" valign=\"top\"\u003e\n \u003cp\u003eTriglycerides (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.317559153175592%\" valign=\"top\"\u003e\n \u003cp\u003e1.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.706102117061022%\" valign=\"top\"\u003e\n \u003cp\u003e1.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.58530510585305%\" valign=\"top\"\u003e\n \u003cp\u003e0.405\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.562889165628892%\" valign=\"top\"\u003e\n \u003cp\u003e1.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.07222914072229%\" valign=\"top\"\u003e\n \u003cp\u003e1.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.58530510585305%\" valign=\"top\"\u003e\n \u003cp\u003e0,2060 \u0026nbsp; \u0026nbsp; \u0026nbsp; 0.206 \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: PCa: Prostate Cancer; T: Testosterone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e. Testosterone levels (total, free and bioavailable) between Black South African (this study, n=130) and Black- (n=355) and White (n=631) American (NHANES study) men with diagnosis of prostate cancer\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"935\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.316239316239317%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTestosterone\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918803418803419%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eEthnicity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.22222222222222%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge 40 \u0026ndash; 59 years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1581196581196584%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.32051282051282%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge \u0026ge; 60 years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.982905982905983%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.081196581196581%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"31.852986217457886%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eng/dL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.260336906584993%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFold\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.29402756508423%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eng/dL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.575803981623277%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFold\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.016845329249618%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFold\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.316239316239317%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918803418803419%\" valign=\"top\"\u003e\n \u003cp\u003eWhite American\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.22222222222222%\" valign=\"top\"\u003e\n \u003cp\u003e439 (402 \u0026ndash; 478)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1581196581196584%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.32051282051282%\" valign=\"top\"\u003e\n \u003cp\u003e359 (326 \u0026ndash; 395)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.982905982905983%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.081196581196581%\" valign=\"top\"\u003e\n \u003cp\u003e1.22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.5785536159601%\" valign=\"top\"\u003e\n \u003cp\u003eBlack American\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.935162094763093%\" valign=\"top\"\u003e\n \u003cp\u003e524 (465 \u0026ndash; 592)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.354114713216958%\" valign=\"top\"\u003e\n \u003cp\u003e1.19\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.551122194513717%\" valign=\"top\"\u003e\n \u003cp\u003e432 (374 \u0026ndash; 499)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.982543640897756%\" valign=\"top\"\u003e\n \u003cp\u003e1.20\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.598503740648379%\" valign=\"top\"\u003e\n \u003cp\u003e1.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.5785536159601%\" valign=\"top\"\u003e\n \u003cp\u003eBlack South African\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.935162094763093%\" valign=\"top\"\u003e\n \u003cp\u003e648.70 (451.32 \u0026ndash; 846.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.354114713216958%\" valign=\"top\"\u003e\n \u003cp\u003e1.24\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.551122194513717%\" valign=\"top\"\u003e\n \u003cp\u003e557.46 (506.60 \u0026ndash; 608.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.982543640897756%\" valign=\"top\"\u003e\n \u003cp\u003e1.29\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.598503740648379%\" valign=\"top\"\u003e\n \u003cp\u003e1.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.316239316239317%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eFree\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918803418803419%\" valign=\"top\"\u003e\n \u003cp\u003eWhite American\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.22222222222222%\" valign=\"top\"\u003e\n \u003cp\u003e8.80 (7.95 \u0026ndash; 9.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1581196581196584%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.32051282051282%\" valign=\"top\"\u003e\n \u003cp\u003e5.50 (4.99 \u0026ndash; 6.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.982905982905983%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.081196581196581%\" valign=\"top\"\u003e\n \u003cp\u003e1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.5785536159601%\" valign=\"top\"\u003e\n \u003cp\u003eBlack American\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.935162094763093%\" valign=\"top\"\u003e\n \u003cp\u003e10.16 (8.97 \u0026ndash; 11.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.354114713216958%\" valign=\"top\"\u003e\n \u003cp\u003e1.16\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.551122194513717%\" valign=\"top\"\u003e\n \u003cp\u003e6.84 (6.05 \u0026ndash; 7.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.982543640897756%\" valign=\"top\"\u003e\n \u003cp\u003e1.24\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.598503740648379%\" valign=\"top\"\u003e\n \u003cp\u003e1.49\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.5785536159601%\" valign=\"top\"\u003e\n \u003cp\u003eBlack South African\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.935162094763093%\" valign=\"top\"\u003e\n \u003cp\u003e10.08 (8.28 \u0026ndash; 11.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.354114713216958%\" valign=\"top\"\u003e\n \u003cp\u003e0.99\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.551122194513717%\" valign=\"top\"\u003e\n \u003cp\u003e8.74 (7.99 \u0026ndash; 9.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.982543640897756%\" valign=\"top\"\u003e\n \u003cp\u003e1.28\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.598503740648379%\" valign=\"top\"\u003e\n \u003cp\u003e1.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.316239316239317%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eBioavailable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918803418803419%\" valign=\"top\"\u003e\n \u003cp\u003eWhite American\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.22222222222222%\" valign=\"top\"\u003e\n \u003cp\u003e209.38 (189.43 \u0026ndash; 231.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.1581196581196584%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.32051282051282%\" valign=\"top\"\u003e\n \u003cp\u003e127.52 (115.49 \u0026ndash; 140.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.982905982905983%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.081196581196581%\" valign=\"top\"\u003e\n \u003cp\u003e1.64\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.5785536159601%\" valign=\"top\"\u003e\n \u003cp\u003eBlack American\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.935162094763093%\" valign=\"top\"\u003e\n \u003cp\u003e231.36 (203.48 \u0026ndash; 263.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.354114713216958%\" valign=\"top\"\u003e\n \u003cp\u003e1.11\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.551122194513717%\" valign=\"top\"\u003e\n \u003cp\u003e149.44 (131.13 \u0026ndash; 170.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.982543640897756%\" valign=\"top\"\u003e\n \u003cp\u003e1.17\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.598503740648379%\" valign=\"top\"\u003e\n \u003cp\u003e1.55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"18.5785536159601%\" valign=\"top\"\u003e\n \u003cp\u003eBlack South African\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.935162094763093%\" valign=\"top\"\u003e\n \u003cp\u003e263.34 (213.13 \u0026ndash; 313.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.354114713216958%\" valign=\"top\"\u003e\n \u003cp\u003e1.14\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.551122194513717%\" valign=\"top\"\u003e\n \u003cp\u003e229.73 (205.48 \u0026ndash; 253.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.982543640897756%\" valign=\"top\"\u003e\n \u003cp\u003e1.54\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.598503740648379%\" valign=\"top\"\u003e\n \u003cp\u003e1.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003e1\u0026nbsp;\u003c/sup\u003eFold increased between Black Americans and White Americans.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u003c/sup\u003e Fold increase between Black South Africans and Black Americans.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIt is well established that total testosterone levels decrease progressively in the aging male [29] and that an increase in SHBG leads to a greater decrease in free testosterone [30]. Furthermore, while the rate of decline is independent of ethnicity, overall, American men of African over European over Asian ancestry have the highest to lowest lifetime testosterone levels [21;31]. The latter mirroring ethnically-driven PCa incidence and mortality rate disparities [32,33].\u0026nbsp;Having previously reported a 2.1-fold increased age-adjusted risk for aggressive PCa at presentation for Black South African \u003cem\u003eversus\u0026nbsp;\u003c/em\u003eBlack American\u0026nbsp;men [5], it is notable that through the inclusion of clinicopathologically confirmed non PCa Black South African men in this study we observe the highest global testosterone levels\u0026nbsp;for men 40 years and over\u0026nbsp;(451.32 to 846.08 ng/dL). Intriguingly, while only free testosterone levels in the younger age group (40-59 years) mirrored levels reported for Black Americans, irrespective of age, the total, free and bioavailable testosterone levels were all elevated in Black South Africans. Compared with NHANES data, the rate of the age-associated decline is lowest for Black South African men.\u003c/p\u003e\n\u003cp\u003eIn contrast, our study\u0026nbsp;demonstrated\u0026nbsp;that this decline is more\u0026nbsp;pronounced\u0026nbsp;in men with PCa, with rates more closely reflecting or slightly surpassing those reported for Black and White Americans. Specifically, for Black South African men over 65 years of age the rate of testosterone decline ranged from 1.05 to 1.22-fold for total, 0.99 to 1.70-fold for free, with the steepest decline noted for bioavailable testosterone 0.99 to 1.81-fold, for men with PCa \u003cem\u003eversus\u003c/em\u003e our population matched controls. Irrespective of age at diagnosis, we found lower total, free and bioavailable testosterone levels to be significantly associated with high-risk disease presentation (\u003cem\u003eP\u003c/em\u003e=0.004,\u003cem\u003e\u0026nbsp;P\u003c/em\u003e=0.0012 and \u003cem\u003eP\u003c/em\u003e=0.0036, respectively), which increased significantly for free and bioavailable testosterone in men ≥70 years (\u003cem\u003eP\u003c/em\u003e=0.00039 and \u003cem\u003eP\u003c/em\u003e=0.00012, respectively). \u0026nbsp;No correlations were observed with PSA levels (log transformed, data not shown).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBesides hormones, evidence is growing that lipid metabolism not only plays a critical role in PCa risk, outcomes and PSA, but also testosterone levels in the aging male. Intriguingly,\u0026nbsp;the community appears to remain divided on the direction of association between total cholesterol levels and PCa risk and/or high-risk disease [34,35,36].\u0026nbsp;Here, we found no association between total serum cholesterol levels and either PCa risk or aggressive disease presentation. Additionally, in a study of American men without PCa, total cholesterol and LDL levels were positively correlated with PSA levels in White but not in Black men, suggesting that the effect of cholesterol on prostate cancer biology may differ by race [37].\u0026nbsp;Similarly, no correlation between PSA and cholesterol in our Black South African men with- and without PCa was observed (log transformed, data not shown).\u0026nbsp;As with cholesterol, the jury is also out regarding the direction of correlation with triglycerides including both positive [38] and negative correlations with PCa risk and/or high-risk disease\u0026nbsp;[39]. While the Arthur et al., 2016 study correlated high serum triglycerides with elevated PSA levels, the\u0026nbsp;NHANES study has\u0026nbsp;negatively correlated serum triglycerides with PSA levels among American males [40]. Again, we found no correlation between triglycerides and PCa risk or presentation, PSA (log transformed, data not shown)\u0026nbsp;or\u0026nbsp;testosterone levels.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLimitations of our study include, lack of fasted sampling and information regarding potential cofounding factors, most notably patient\u0026nbsp;body mass index and lifetime cumulative data. Additionally, while there was no clinicopathological evidence for PCa in our control group, the high PSA values observed within our study, as previously reported for Black South African men [4], means we are unable to exclude for the possibility that presence of cancer had been missed at 12-core minimal biopsy. While our study is notably underpowered, data for sub-Saharan Africa is either scarce or lacking. Scanning the literature, we found a single 1981 study including Nigerian men\u0026nbsp;(n=55) which reported\u0026nbsp;lower population-based testosterone levels compared to African American men also recruited at PCa diagnosis, with lower levels linked to PCa status [41]. In line with our findings, a smaller case-only study out of South Africa (n=109), associated low levels of free testosterone with aggressive disease presentation and higher PSA levels [42], while a more comprehensive South African study (n=878) found no correlation between total cholesterol levels and PCa status, although elevated high-density lipoprotein (HDL) was associated with a positive PCa diagnosis [43]. Based on genetic ancestry profiling using 33,410 linkage disequilibrium pruned single nucleotide polymorphisms, we have demonstrated that men contributing to the SAPCS and self-identifying as Southern Bantu or Black South African are genetically distinct from west, east and central African populations and in turn also African Americans, with regional within SSA population substructure separation occurring prior to European-Asian population distinction [9]. Additionally, further interrogation of genetic substructure within the SAPCS we identified Southern Bantu or Guthrie Zone S linguistically-driven ancestral substructure [44].\u0026nbsp;Accordingly, while the patterns of testosterone expression across diverse populations in SSA remain to be determined and in turn the impact on PCa biology and associated health disparity, studies will need to consider and define the deep genetic and in turn biological diversity across the region.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhile our study lacks lifetime cumulative data, our findings align with those of a 2010 meta-analysis that demonstrated population differences in testosterone levels in younger people, which were associated with disparities in PCa in later years [45]. In our study, younger black South Africans with PCa had an approximately 1.4-fold overall increase in testosterone levels. Alternatively, considering our treatment-naïve patients at sampling, our results suggest that a rapid decline in testosterone levels in older patients might predispose men to aggressive PCa. However, further studies are needed to determine the biological relevance of the observed rapid decreases in testosterone and advanced disease presentation in aging African men. Our study raises critical questions about the appropriate use of ADT in the African population, underscoring the urgent need for increased inclusion of Africans in addressing what may be perceived as an ‘old story’.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eEthics and participant recruitment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the University of Pretoria Faculty of Health Sciences Research Ethics Committee in South Africa (with US Federal wide assurance FWA00002567 and IRB00002235 IORG0001762), which included both project specific (HREC#58/2021) and SAPCS Consortia approval (HREC#43/2010), with research performed in accordance with the Declaration of Helsinki. Additional IRB review and approval was granted by the\u0026nbsp;Human Research Protection Office of the US Army Medical Research and Development Command as part of the HEROIC PCaPH Africa1K Consortium (E03333.3a).\u0026nbsp;Providing informed consent, 250 treatment-na\u0026iuml;ve Black South African men were recruited from participating SAPCS urology clinics, specifically Tshilidzini Hospital in Limpopo Province and Dr.\u0026nbsp;George Mukhari Academic Hospital in Gauteng Province of South Africa. Furthermore, \u0026nbsp;patients were not fasted prior to sampling.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinicopathology and sampling\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBlood (serum) was collected prior to 10h00.\u0026nbsp;The samples\u0026nbsp;were stored at \u0026minus;20\u0026deg;C on site and during transportation. At the University of Pretoria\u0026nbsp;Laboratory, Department of Urology, the samples were thawed overnight at\u0026nbsp;2\u0026deg;C\u0026nbsp;and subsequently left to stand for 1 h to separate the serum. The serum samples were\u0026nbsp;aliquoted\u0026nbsp;into Eppendorf tubes at a volume of 400 \u0026mu;l\u0026nbsp;and stored at\u0026nbsp;2\u0026deg;C\u0026nbsp;during transportation to\u0026nbsp;the\u0026nbsp;PathCare\u0026nbsp;Laboratory, Pretoria, South Africa. Total testosterone, total albumin,\u0026nbsp;sex hormone binding globulin (SHBG), total cholesterol and triglyceride levels were tested\u0026nbsp;in\u0026nbsp;the laboratory.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuantitative measures\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn Architect 4100 (Immuno) quantitative chemiluminescent microparticle immunoassay was used to test for total testosterone and SHBG, and an Architect 8200 (Chemistry) quantitative Bromocresol purple was used to measure albumin. Total testosterone, albumin, and SHBG were used to calculate the free and bioavailable testosterone concentrations using the calculator available at http://www.issam.ch/freetesto.html following Vermeulen\u0026rsquo;s formula. Total cholesterol was measured using the Architech 8200 (Chemistry) quantitative enzymatic reaction, whereas the glycerol phosphate oxidative chemical reaction, on the same equipment, was used to measure the triglyceride levels.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAmerican relevant NHANES data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe National Health and Nutrition Examination Survey (NHANES) is a survey which collected health and nutritional data of the United States population over several years [46]. We sourced a subset of the NHANES testosterone data of men without PCa from Hu et al. 2015 [21], selecting only the age group of 40 \u0026ndash; 59 years (further categorized as younger men) and men \u0026ge;60 years (further categorized as older men).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data were analyzed using R software with the following packages: ggpubr and tidyverse (ggplot2) for boxplots and LOESS curves, respectively. The difference between the means of PCa-positive and -negative patients was analyzed using Student\u0026rsquo;s t test and the Kruskal‒Wallis test. A p \u0026lt;0.05 value indicated significance. Locally estimated scatterplot smoothing (LOESS) curves were generated to visually examine the relationships between biochemical factors.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe owe gratitude to the study participants, past and present contributors to the Southern African Prostate Cancer Study (SAPCS), as well as the Department of Research and Innovation of the University of Pretoria, for their support. The authors thank Dr. Cheryl Tosh for editing support. This research was funded by Ampath Laboratories, the National Research Foundation (NRF) and the University of Pretoria in South Africa, the\u0026nbsp;National Health and Medical Research Council (NHMRC) of Australia Ideas Grant (APP2001098), as well as the\u0026nbsp;U.S.A.\u0026nbsp;Congressionally Directed Medical Research Programs (CDMRP) Prostate Cancer Research Program (PCRP)\u0026nbsp;Health Equity Research Outcomes Integrity Consortium (HEROIC) Award (PC210168, HEROIC PCaPH Africa1K). The Southern African Prostate Cancer Study is further supported by a Cancer Association of South Africa (CANSA) Development Grant to M.S. Riana Bornman, while Vanessa M. Hayes is supported by the Petre Foundation in Australia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eM.S.R.B. and V.M.H. conceived and designed the study. M.T.L., N.M., S.B.A.M. and M.S.R.B. collected and assembled the data. M.T.L. performed data statistical\u0026nbsp;analysis, wrote the main manuscript and generated the figures under the supervision of V.M.H., W.J. and M.S.R.B, with M.L. providing critical study review. All authors have reviewed the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data are available for bona fide researchers upon request to the corresponding authors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eBigler, S.A., Pound, C.R., Zhou, X. A retrospective study on pathologic features and racial disparities in prostate cancer. \u003cem\u003eProstate Cancer\u003c/em\u003e.\u0026nbsp;2011,\u0026nbsp;e\u0026nbsp;239460 (2011).\u003c/li\u003e\n \u003cli\u003eSiegel, R.L., Miller, K.D., Fuchs, H.E., Jemal A. Cancer statistics. \u003cem\u003eCA Cancer J Clin\u003c/em\u003e. \u003cstrong\u003e72\u003c/strong\u003e, 7-33 (2022).\u003c/li\u003e\n \u003cli\u003eKelly, S.P. \u003cem\u003eet al\u003c/em\u003e.\u0026nbsp;Trends in the Incidence of Fatal Prostate Cancer in the United States by Race. \u003cem\u003eEur Urol\u003c/em\u003e. \u003cstrong\u003e71\u003c/strong\u003e, 195-201 (2017).\u003c/li\u003e\n \u003cli\u003eBray,\u0026nbsp;F.\u0026nbsp;\u003cem\u003eet al\u003c/em\u003e. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. \u003cem\u003eCA Cancer J Clin\u003c/em\u003e. 1-35 (2024).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTindall, E.A. \u003cem\u003eet al\u003c/em\u003e. Clinical presentation of prostate cancer in black South Africans. \u003cem\u003eProstate.\u003c/em\u003e 74, 880-891 (2014).\u003c/li\u003e\n \u003cli\u003eNair, S.S., Chakravarty, D., Dovey, Z.S., Zhang, X., Tewari, A.K. Why do African-American men face higher risks for lethal prostate cancer? \u003cem\u003eCurr Opin Urol\u003c/em\u003e.\u0026nbsp;32, 96-101 (2022).\u003c/li\u003e\n \u003cli\u003eJaratlerdsiri, W. \u003cem\u003eet al\u003c/em\u003e. African-specific molecular taxonomy of prostate cancer. \u003cem\u003eNature\u003c/em\u003e.\u0026nbsp;609, 552-559 (2022).\u003c/li\u003e\n \u003cli\u003eSoh, P.X., Hayes, V.M. Common Genetic Variants Associated with Prostate Cancer Risk: The Need for African Inclusion. \u003cem\u003eEur Urol\u003c/em\u003e.\u0026nbsp;84, 22-24 (2023).\u003c/li\u003e\n \u003cli\u003eSoh, P.X. \u003cem\u003eet al\u003c/em\u003e. Prostate cancer genetic risk and associated aggressive disease in men of African ancestry. \u003cem\u003eNat Commun\u003c/em\u003e.\u0026nbsp;14, 8037 (2023).\u003c/li\u003e\n \u003cli\u003eYassin, A., AlRumaihi, K., Alzubaidi, R., Alkadhi, S., Al Ansari, A. Testosterone, testosterone therapy and prostate cancer. \u003cem\u003eThe Aging Male\u003c/em\u003e.\u0026nbsp;22, 219-227 (2019).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eKlap, J., Schmid, M., Loughlin, K.R. The relationship between total testosterone levels and prostate cancer: a review of the continuing controversy. \u003cem\u003eJ Urol\u003c/em\u003e.\u0026nbsp;193, 403-414. (2015).\u003c/li\u003e\n \u003cli\u003eShahait, M. \u003cem\u003eet al\u003c/em\u003e. Does perioperative testosterone predict post-prostatectomy genomic risk score? \u003cem\u003eJ Urol\u003c/em\u003e.\u0026nbsp;207, 1214-1221 (2022).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eIsbarn, H. \u003cem\u003eet al\u003c/em\u003e. Testosterone and prostate cancer: revisiting old paradigms. \u003cem\u003eEur Urol\u003c/em\u003e.\u0026nbsp;56, 48-56 (2009).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eMorgentaler, A., Conners, III W.P. Testosterone therapy in men with prostate cancer: literature review, clinical experience, and recommendations. \u003cem\u003eAsian J Androl\u003c/em\u003e.\u0026nbsp;17,206-211 (2015).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eWatts, E.L., \u003cem\u003eet al\u003c/em\u003e. Circulating free testosterone and risk of aggressive prostate cancer: Prospective and Mendelian randomization analyses in international consortia. \u003cem\u003eInt J Cancer\u003c/em\u003e.\u0026nbsp;151, 1033-1046 (2022).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eParsons, J.K. \u003cem\u003eet al\u003c/em\u003e. Serum testosterone and the risk of prostate cancer: potential implications for testosterone therapy. \u003cem\u003eCancer Epidemiol Biomarkers Prev\u003c/em\u003e.\u0026nbsp;14, 2257-2260 (2005).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePierorazio, P.M. \u003cem\u003eet al\u003c/em\u003e. Serum testosterone is associated with aggressive prostate cancer in older men: results from the Baltimore Longitudinal Study of Aging. \u003cem\u003eBJU Int\u003c/em\u003e.\u0026nbsp;105, 824-829 (2010).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eStanworth, R.D., Jones, T.H. Testosterone for the aging male; current evidence and recommended practice.\u003cem\u003e\u0026nbsp;Clin Interv Aging\u003c/em\u003e. \u003cstrong\u003e3\u003c/strong\u003e, 25-44 (2008).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eWang, Y., Dai, B., Ye, D.W. Serum testosterone level predicts the effective time of androgen deprivation therapy in metastatic prostate cancer patients. \u003cem\u003eAsian J Androl\u003c/em\u003e. \u003cstrong\u003e19\u003c/strong\u003e, 178-183 (2017).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eHarris, W.P., Mostaghel, E.A., Nelson, P.S., Montgomery B. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. \u003cem\u003eNat Clin Pract Urol\u003c/em\u003e.\u0026nbsp;6, 76-85 (2009).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eHu, H., Odedina, F.T., Reams, R.R., Lissaker, C.T., Xu, X. Racial differences in age-related variations of testosterone levels among US males: Potential implications for prostate cancer and personalized medication. \u003cem\u003eJ Racial Ethn Health Disparities.\u003c/em\u003e 2, 67-76 (2015).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSchnoeller, T.J., Jentzmik F., Schrader A.J., Steinestel J. Influence of serum cholesterol level and statin treatment on prostate cancer aggressiveness. \u003cem\u003eOncotarget\u003c/em\u003e.\u0026nbsp;8, 47110-47120 (2017).\u003c/li\u003e\n \u003cli\u003eJamnagerwalla, J. \u003cem\u003eet al\u003c/em\u003e. Serum cholesterol and risk of high-grade prostate cancer: results from the REDUCE study. \u003cem\u003eProstate Cancer Prostatic Dis\u003c/em\u003e.\u0026nbsp;21, 252-259 (2018).\u003c/li\u003e\n \u003cli\u003eHirano H. \u003cem\u003eet al\u003c/em\u003e. Impact of pretreatment total cholesterol level is associated with metastasis of prostate cancer. \u003cem\u003eAm J Mens Health\u003c/em\u003e.\u0026nbsp;14, 1557988320918788 (2020).\u003c/li\u003e\n \u003cli\u003eAllott, E.H. \u003cem\u003eet al\u003c/em\u003e. Racial Differences in the Association Between Preoperative Serum Cholesterol and Prostate Cancer Recurrence: Results from the SEARCH Database. \u003cem\u003eCancer\u003c/em\u003e \u003cem\u003eEpidemiol Biomarkers Prev\u003c/em\u003e.\u0026nbsp;25, 547-554 (2016).\u003c/li\u003e\n \u003cli\u003eLopez, D.S. \u003cem\u003eet al\u003c/em\u003e.\u0026nbsp;Low testosterone and high cholesterol levels in relation to all-cause, cardiovascular disease, and cancer mortality in White, Black, and Hispanic men: NHANES 1988-2015. \u003cem\u003eHormones\u003c/em\u003e.\u0026nbsp;21, 399-411 (2022).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eGomes G.K. \u003cem\u003eet al\u003c/em\u003e.\u0026nbsp;Cholesterol intake and serum total cholesterol levels are not associated with total testosterone levels in men: a cross-sectional study from NHANES 2013\u0026ndash;2014. \u003cem\u003eLipids Health Dis\u003c/em\u003e.\u0026nbsp;22, 168 (2023).\u003c/li\u003e\n \u003cli\u003eBarlow, M. \u003cem\u003eet al\u003c/em\u003e. Ethnic differences in prostate-specific antigen levels in men without prostate cancer: A systematic review. Prostate Cancer and Prostatic Diseases.\u0026nbsp;26, 249-456 (2023).\u003c/li\u003e\n \u003cli\u003eHarman, S.M., Metter, E.J., Tobin, J.D., Pearson, J., Blackman, M.R. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. \u003cem\u003eJ Clin Endocrinol \u0026nbsp;Metab\u003c/em\u003e. \u003cstrong\u003e86\u003c/strong\u003e, 724-731 (2001).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSnyder, P.J. What We Have Learned from The Testosterone Trials. \u003cem\u003eUrol Clin North Am\u003c/em\u003e. \u003cstrong\u003e49\u003c/strong\u003e, 637-644 (2022).\u003c/li\u003e\n \u003cli\u003eXu, L., Au Yeung, S.L., Kavikondala, S., Leung, G.M., Schooling C.M. Testosterone concentrations in young healthy US \u003cem\u003eversus\u003c/em\u003e Chinese men. \u003cem\u003eAm J Hum Biol.\u003c/em\u003e 26, 99-102 (2014).\u003c/li\u003e\n \u003cli\u003eYamoah, K. \u003cem\u003eet al\u003c/em\u003e. Racial and ethnic disparities in prostate cancer outcomes in the veterans affairs health care system. \u003cem\u003eJAMA Netw Open\u003c/em\u003e.\u0026nbsp;5, e2144027 (2022).\u003c/li\u003e\n \u003cli\u003eRaymundo, E.M., Rice K.R., Chen Y., Zhao J., Brassell S.A. Prostate cancer in Asian Americans: incidence, management and outcomes in an equal access healthcare system. \u003cem\u003eBJU Int\u003c/em\u003e.\u0026nbsp;107, 1216-1222 (2011).\u003c/li\u003e\n \u003cli\u003eShafique, K. \u003cem\u003eet al\u003c/em\u003e. Cholesterol and the risk of grade-specific prostate cancer incidence: evidence from two large prospective cohort studies with up to 37 years\u0026apos; follow up. \u003cem\u003eBMC Cancer\u003c/em\u003e.\u0026nbsp;12, 25 (2012).\u003c/li\u003e\n \u003cli\u003eHeir, T. \u003cem\u003eet al\u003c/em\u003e. Cholesterol and prostate cancer risk: a long-term prospective cohort study. \u003cem\u003eBMC Cancer\u003c/em\u003e.\u0026nbsp;16, 643 (2016).\u003c/li\u003e\n \u003cli\u003eGarrido, M.M., Marta, J.C., Ribeiro, R.M., Pinheiro, L.C., Guimar\u0026atilde;es, J.T. Serum lipids and prostate cancer.\u0026nbsp;\u003cem\u003eJ Clin Lab Anal\u003c/em\u003e.\u0026nbsp;35, e23705 (2021).\u003c/li\u003e\n \u003cli\u003eZapata, D. \u003cem\u003eet al\u003c/em\u003e. Is PSA related to serum cholesterol and does the relationship differ between black and white men? \u003cem\u003eProstate\u003c/em\u003e.\u0026nbsp;75, 1877-1885 (2015).\u003c/li\u003e\n \u003cli\u003eArthur, R. \u003cem\u003eet al\u003c/em\u003e. Association between baseline serum glucose, triglycerides and total cholesterol, and prostate cancer risk categories. \u003cem\u003eCancer Med\u003c/em\u003e.\u0026nbsp;5, 1307-1318 (2016).\u003c/li\u003e\n \u003cli\u003eH\u0026auml;ggstr\u0026ouml;m, C. \u003cem\u003eet al\u003c/em\u003e. Prospective study on metabolic factors and risk of prostate cancer. \u003cem\u003eCancer\u003c/em\u003e.\u0026nbsp;118, 6199-6206 (2012).\u003c/li\u003e\n \u003cli\u003eWei, C. \u003cem\u003eet al\u003c/em\u003e. Association between serum triglycerides and prostate specific antigen (PSA) among U.S. males: National Health and Nutrition Examination Survey (NHANES), 2003\u0026ndash;2010. \u003cem\u003eNutrients\u003c/em\u003e.\u0026nbsp;14, 1325 (2022).\u003c/li\u003e\n \u003cli\u003eAhluwalia, B. \u003cem\u003eet al\u003c/em\u003e. Blood hormone profiles in prostate cancer patients in high‐risk and low‐risk populations. \u003cem\u003eCancer\u003c/em\u003e.\u0026nbsp;48, 2267-2273 (1981).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAlsharef, M., Kahie, A., Conradie, M., Goad, E., Fourie, T. Association between low serum free testosterone and adverse prognostic factors in men diagnosed with prostate cancer in KwaZulu-Natal. \u003cem\u003eS Afr J Surg\u003c/em\u003e. \u003cstrong\u003e50\u003c/strong\u003e, 40-42 (2012).\u003c/li\u003e\n \u003cli\u003eMapanga, W. \u003cem\u003eet al\u003c/em\u003e. Prevalence of multimorbidity in men of African descent with and without prostate cancer in Soweto, South Africa. \u003cem\u003ePLoS One\u003c/em\u003e.\u0026nbsp;17, e0276050 (2022).\u003c/li\u003e\n \u003cli\u003eGheybi, K. \u003cem\u003eet al\u003c/em\u003e. Linking African ancestral substructure to prostate cancer health disparities. \u003cem\u003eSci Rep\u003c/em\u003e.\u0026nbsp;13, 20909 (2023).\u003c/li\u003e\n \u003cli\u003eAlvarado, L.C. Population differences in the testosterone levels of young men are associated with prostate cancer disparities in older men. \u003cem\u003eAm J Hum Biol\u003c/em\u003e. \u003cstrong\u003e22,\u0026nbsp;\u003c/strong\u003e449-455 (2010).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eCDC. Questionnaires, datasets and related documentation: CDC; 2013. http://www.cdc.gov/nchs/nhanes.htm. Accessed 02 May 2022.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"testosterone, African ancestry, prostate cancer, cholesterol, health disparity","lastPublishedDoi":"10.21203/rs.3.rs-4366943/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4366943/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSerum testosterone levels decrease in the aging male, while the risk for prostate cancer (PCa) increases concomitantly. Higher levels in younger men have been linked with racially driven PCa disparities, with African men disproportionately impacted. In turn, higher levels of serum lipids have been associated with aggressive disease, while racial disparity between serum testosterone, cholesterol and cancer mortality has been suggested. Having previously reported a 2.1-fold increased age-adjusted risk for aggressive PCa in Black South African over Black American men, we determined the serum testosterone and associated lipid levels in 250 Black South African men either with or without clinicopathologically diagnosed disease. Observing no associations with serum lipid levels, Black South Africans presented with testosterone levels between 1.24 (\u0026lt;\u0026thinsp;60 years) and 1.3-fold (\u0026ge;\u0026thinsp;60 years) greater than African Americans. Notably, a rapid drop in total-, bioavailable- and free testosterone levels in men 65 years or older was significantly associated with PCa risk (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0057, 0.009 and 0.005, respectively), while irrespective of age, further associated with advanced disease (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004, 0.0012 and 0.0036, respectively). These preliminary data provide insights into the potential role of androgens in driving PCa health disparities, with important consequence for tailoring treatment for Black men.\u003c/p\u003e","manuscriptTitle":"Associating serum testosterone levels with African ancestral prostate cancer health disparities","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-15 10:26:00","doi":"10.21203/rs.3.rs-4366943/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-09T05:26:18+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-29T17:40:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3735547882115640555906558752578887512","date":"2024-07-19T16:54:23+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-21T23:17:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"327970076241583945827713843627809955837","date":"2024-05-31T11:30:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"119374703314849973374451286121058992206","date":"2024-05-30T19:55:58+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-08T12:23:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-08T12:22:42+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-05-08T10:03:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-08T04:15:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-05-04T06:04:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fe595faa-375f-4b5d-9f42-dbc105fdcc72","owner":[],"postedDate":"May 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":31849696,"name":"Biological sciences/Cancer/Urological cancer/Prostate cancer"},{"id":31849697,"name":"Health sciences/Urology/Prostate"}],"tags":[],"updatedAt":"2025-04-14T16:13:59+00:00","versionOfRecord":{"articleIdentity":"rs-4366943","link":"https://doi.org/10.1038/s41598-025-92539-y","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-04-08 16:04:53","publishedOnDateReadable":"April 8th, 2025"},"versionCreatedAt":"2024-05-15 10:26:00","video":"","vorDoi":"10.1038/s41598-025-92539-y","vorDoiUrl":"https://doi.org/10.1038/s41598-025-92539-y","workflowStages":[]},"version":"v1","identity":"rs-4366943","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4366943","identity":"rs-4366943","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}