Does size matter in prostate cancer? A cross-sectional study on genital dimensions in Caucasian men
¿Importa el tamaño en el cáncer de próstata? Un estudio transversal sobre las dimensiones genitales en hombres caucásicos

2.1 Study design and ethical details

We designed an observational, cross-sectional pilot study involving consecutive Caucasian men undergoing prostate biopsy for suspected PCa at our Institution (University of Campania Luigi Vanvitelli, Naples, Italy) between January 2023 and June 2025. The study was purely observational and non-interventional, and was therefore deemed exempt from formal review by the institutional ethics committee. It was conducted in accordance with the principles of the Declaration of Helsinki and relevant national regulations [14]. Written informed consent was obtained from all participants for inclusion of their data in a dedicated research database and for publication of anonymized results. All patients received appropriate counseling and informed consent about the biopsy procedure. All data were de-identified and stored in a secure institutional database compliant with General Data Protection and Regulation (GDPR). Written informed consent explicitly covered sensitive genital measurements and the use of anonymized data for research and publication.

2.2 Patient enrollment

Consecutive Caucasian men aged ≥50 years who underwent prostate biopsy for suspected PCa were considered for inclusion. Exclusion criteria included congenital penile curvature, congenital genital malformations, Peyronie’s disease, history of priapism, history of penile tumor, prior penile surgery for curvature, tumor, or augmentation, history of cryptorchidism, history of testicular torsion, prior orchidopexy, history of testicular tumor, prior unilateral or bilateral orchiectomy, clinically significant varicocele or prior varicocelectomy, known chromosomal disorders, diagnosed hypogonadism, current or recent (≤12 months) treatment with testosterone therapy, Gonadotropin-Releasing Hormone (GnRH) analogs or antagonists, anti-androgens, estrogens, or use of anabolic-androgenic steroids for doping purposes, and inability or unwillingness to undergo pre-biopsy multiparametric magnetic resonance imaging (MRI). Patients with missing data for primary outcomes or key covariates were also excluded.

2.3 Patient evaluation

Baseline variables collected included age, body mass index (BMI), smoking status, family history of PCa or breast cancer (BCa), serum prostate-specific antigen (PSA), findings on digital rectal examination (DRE), Prostate Imaging Reporting and Data System (PI-RADS) version 2.1 [15] score on pre-biopsy multiparametric magnetic resonance imaging (mpMRI), prostate volume, total testosterone, use of 5α-reductase inhibitors (5-ARI), history of prior benign prostatic hyperplasia (BPH) surgery, and biopsy-naive status. SPL was measured in the supine position using the standard stretched penile length technique, with the penis gently extended to the point of resistance from the pubic bone to the tip of the glans along the dorsal surface. Bilateral testicular volume was assessed by high-resolution scrotal ultrasonography using the ellipsoid formula (length × width × height × 0.52). Scrotal ultrasound was performed using a (1202 Flex Focus 400 Ultrasound digital and multipurpose Scanner (BK Medical, Milan, Italy)), equipped with a (2–8 MHz) linear-array transducer. All genital measurements were performed by a single trained urologist following a standardized protocol to minimize inter-observer variability. The primary outcome was the presence of csPCa defined as Gleason score (GS) ≥7, tumor volume ≥0.5 cc, and/or evidence of extraprostatic extension [15]. PCa lacking these characteristics or negative biopsy findings including cases with prostatic intraepithelial neoplasia (PIN) or atypical small acinar proliferation (ASAP) were classified as non-csPCa.

All biopsies were performed in an outpatient setting by a single experienced urologist using a combined systematic and cognitive-targeted transrectal approach. All histopathological specimens were reviewed by a single dedicated genitourinary pathologist with extensive expertise in PCa diagnosis to ensure uniformity in tumor detection and grading.

2.4 Statistical analysis

Sample size was calculated to detect a clinically meaningful difference in SPL between patients with and without csPCa. Based on published literature, the standard deviation (σ) of SPL in adult men was estimated at 2.0 cm, and a difference of 1.0 cm was considered clinically relevant [16]. Assuming a two-sided α of 0.05, a power of 80%, and an expected 40:60 ratio of csPCa to non-csPCa patients based on previous biopsy cohorts [17], the required sample size was determined using a two-sample t-test formula adapted for unequal group sizes. This calculation yielded a minimum of 53 patients with csPCa and 80 patients without csPCa, for a total of 133 participants. Normality of continuous variables was assessed using the Shapiro-Wilk test [18]. Continuous variables were reported as medians and interquartile ranges (IQRs), whereas categorical variables were expressed as absolute frequencies and percentages. Comparisons between groups were performed using the Chi-square test for categorical variables and the Mann-Whitney U test for non-normally distributed continuous variables. For the comparison between patients with and without csPCa, and between patients with GS 7 and GS >7, results were visually summarized using box-and-whisker plots with overlaid individual values, displaying medians, IQR, and whiskers extending to 1.5× IQR. A p-value < 0.05 was arbitrarily set to indicate statistical significance. RStudio v. 2024.09.0+375 was used for statistical analyses (now Posit, Boston, MA, USA). We prespecified unadjusted analyses, as the sample size did not allow for reliable multivariable modelling; this is recognized as a limitation.

4.1 Main findings and previous literature

In this cross-sectional study of Caucasian men, genital dimensions—SPL and testicular volume—were not significantly associated with the overall presence of csPCa. However, within the csPCa subgroup, men with high-grade tumors (GS >7) had significantly longer SPL, pointing toward a potential role of developmental androgenic influences on tumor severity. Although ours is the first study to directly examine SPL and testicular volume in relation to both the presence and aggressiveness of csPCa, several lines of evidence support the biological plausibility of our findings. Our findings should be interpreted in light of normative genital dimensions and their known hormonal correlates, as reported in recent systematic reviews. Anogenital distance (AGD) a well-established proxy for prenatal androgen exposure has been inversely related to PCa risk. In a Spanish case-control study, each 5-mm increase in AGD was associated with an approximately 17% reduction in the odds of PCa (odds ratio (OR) = 0.83; 95% confidence interval (CI): 0.70–0.99) [19]. Additionally, AGD correlates with genital dimensions in healthy young men, reinforcing its value as a marker of early androgenic programming. Moreover, racial disparities in prostate cancer may reflect differences in pubertal androgen exposure. Seminal studies have shown that African American men have higher circulating testosterone levels in early adulthood approximately 15% greater than white counterparts which may explain their roughly twofold elevated PCa risk [20]. Prospective research also indicates that African American males attain higher peak testosterone earlier and may experience more rapid declines with age compared to white males [21], potentially underpinning the heightened vulnerability to the aggressive disease. In parallel, traditional anthropometric factors have long been linked to PCa prognosis. Data from Swedish cohorts (n ≈ 431,000) indicate that taller stature modestly increases risk for localized disease, while obesity significantly raises the risk of PCa-specific mortality (Hazard Ratio (HR) per 5 kg/m² = 1.11–1.22) [22]. Likewise, findings from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort uphold associations between height, BMI, and aggressive PCa forms [23]. Together, these findings on prenatal androgen exposure (AGD), pubertal testosterone patterns, and systemic growth metrics suggest that genital anthropometry such as SPL may serve as a surrogate for androgen-related developmental imprinting relevant to PCa biology. Our observation that longer SPL is linked solely with higher-grade tumors aligns with this framework. However, these results are exploratory in nature and warrant validation in larger, ethnically diverse, longitudinal studies incorporating endocrine and definitive histological data.

4.2 Strengths and limitations

To our knowledge, while several anthropometric parameters have been investigated in relation to PCa [24], this is the first study to specifically examine SPL and testicular volume in connection with both the presence and pathological aggressiveness of clinically significant prostate cancer within a Caucasian population. The study employed a cross-sectional design, with data collected in real time according to a pre-defined protocol, thereby reducing the risk of bias associated with retrospective analyses. Consecutive patient enrollment, use of standardized and validated measurement tools (including stretched penile length assessment and ultrasound-derived testicular volume), pre-biopsy mpMRI evaluation with PI-RADS v2.1 scoring, and histopathological review by a single experienced genitourinary pathologist strengthen the internal validity and reproducibility of our findings.

However, several limitations should be acknowledged. First, the single-center setting and ethnically homogeneous sample limit external validity and generalizability to other ethnic groups. Second, although the total sample size (n = 156) met the a priori power calculation for the primary analysis, the subgroup of patients with high-grade tumors (GS >7) was relatively small, potentially reducing the power of secondary analyses. Third, the absence of direct longitudinal data on androgen exposure during critical developmental windows precludes causal inference regarding early-life hormonal imprinting. Fourth, the absence of genetic profiling such as germline mutation testing or androgen receptor polymorphism analysis prevents evaluation of the potential contribution of hereditary factors to both genital development and prostate cancer aggressiveness. This limits the ability to disentangle the relative influence of genetic versus hormonal determinants on the observed findings. Fifth, the cross-sectional design precludes assessment of temporal relationships. The absence of adjusted analyses represents a limitation; larger studies should incorporate multivariable models to account for confounders. Finally, the lack of follow-up precludes both confirmation of biopsy findings with surgical specimens and evaluation of long-term oncologic outcomes such as progression, recurrence, treatment response, and survival. The restrictive eligibility criteria increased internal validity by limiting confounders but may reduced representativeness and external validity.

4.3 Clinical relevance and future perspectives

Current evidence, including the present study, does not support the incorporation of genital dimensions such as stretched penile length and testicular volume into routine PCa risk assessment or diagnostic algorithms. Nonetheless, the observed association between larger penile size and greater tumor grade may reflect androgen-driven developmental imprinting, with potential implications for understanding disease biology. These findings highlight a biologically plausible, albeit indirect, link between early-life hormonal exposure and prostate cancer phenotype. Future research should prioritize large-scale, ethnically diverse, and prospectively designed cohorts, ideally with longitudinal endocrine profiling from adolescence to adulthood and pathological confirmation through surgical specimens confirmation to validate and expand upon these findings. Such approaches could clarify the temporal relationship, validate these preliminary associations, and contribute to the development of biologically informed risk stratification models.