European Journal of Cardiovascular Medicine

Prostate cancer is one of the most prevalent malignancies among men worldwide and represents a major cause of cancer-related morbidity and mortality. Its biological behaviour varies widely, ranging from indolent disease to aggressive cancer with poor prognosis. Serum testosterone levels have long been implicated in the development and progression of prostate cancer, as androgen signaling plays a pivotal role in the growth and maintenance of prostatic tissue [1]. However, the relationship between serum testosterone, particularly free testosterone levels, and prostate cancer aggressiveness remains complex and controversial.

Emerging evidence suggests that low serum free testosterone at diagnosis may be associated with more advanced and biologically aggressive prostate tumors [2]. Hypogonadal states might reflect the tumor’s suppressive effect on hypothalamic-pituitary-gonadal axis activity or represent a host response to cancer-related metabolic alterations [3]. Several studies have demonstrated that patients with low circulating testosterone levels tend to present with higher Gleason scores, increased tumor volume, extraprostatic extension, and higher prostate-specific antigen (PSA) levels at diagnosis [4-6].

Low serum testosterone has also been identified as an independent adverse prognostic factor, correlating with biochemical recurrence, resistance to androgen deprivation therapy, and reduced overall survival [7,8]. Furthermore, it may indicate a more dedifferentiated tumor phenotype with androgen receptor downregulation and loss of hormonal sensitivity [9]. Assessing serum free testosterone in patients

newly diagnosed with prostate carcinoma may therefore provide valuable prognostic information and assist in stratifying patients for tailored therapeutic interventions [10].

The present study aims to evaluate the association between low serum free testosterone levels and adverse prognostic factors in patients newly diagnosed with carcinoma prostate, thereby contributing to the understanding of hormonal influences in prostate cancer progression.

This prospective observational study was conducted in the Department of Urology over a period of two years on patients newly diagnosed with carcinoma of the prostate. Ethical approval was obtained from the Institutional Ethics Committee prior to the commencement of the study, and informed written consent was obtained from all participants. Study population: All men aged ≥50 years who were newly diagnosed with adenocarcinoma of the prostate by transrectal ultrasound-guided (TRUS) biopsy were included in the study. Diagnosis was based on elevated prostate-specific antigen (PSA) levels and/or abnormal digital rectal examination (DRE) findings. Inclusion criteria: Histologically confirmed adenocarcinoma of the prostate. No prior hormonal therapy, chemotherapy, or radiotherapy before enrollment. Serum testosterone and PSA levels measured prior to any intervention. Exclusion criteria: Patients with known endocrine disorders affecting testosterone metabolism. Those on medications influencing serum testosterone (e.g., corticosteroids, antiandrogens, or testosterone supplements). Patients with systemic illness or chronic liver disease affecting hormone levels. Clinical and laboratory evaluation: A detailed clinical history was obtained, and physical examination including DRE was performed. Blood samples were collected in the morning between 8:00 and 10:00 a.m. to minimize diurnal variation. Serum free testosterone levels were measured using enzyme-linked immunosorbent assay (ELISA) kits. Total serum PSA was estimated by chemiluminescent immunoassay. Other relevant investigations included complete blood count, liver and renal function tests. Radiological and pathological evaluation: All patients underwent transrectal ultrasonography (TRUS) for prostate volume estimation, and staging was further assessed with pelvic magnetic resonance imaging (MRI) or bone scan when indicated. The biopsy specimens were graded using the Gleason scoring system according to the 2014 International Society of Urological Pathology (ISUP) guidelines[^11^]. Definition of groups: Based on serum free testosterone levels, patients were divided into two groups: Group A (Low testosterone): Serum free testosterone below 8.9 pg/mL (reference lower limit). Group B (Normal testosterone): Serum free testosterone ≥8.9 pg/mL. Outcome measures: Adverse prognostic factors analyzed included: High Gleason score (≥8) Advanced clinical stage (T3–T4) Presence of lymph node or bone metastasis High baseline PSA (>20 ng/mL) Statistical analysis: Data were analyzed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation (SD) and categorical variables as percentages. Student’s t-test and chi-square test were applied to compare quantitative and qualitative variables respectively. Correlation between serum free testosterone levels and adverse prognostic factors was evaluated using Pearson’s correlation coefficient. A p-value <0.05 was considered statistically significant

A total of 60 patients newly diagnosed with carcinoma prostate were included in the study. The mean age of the study population was 68.4 ± 6.2 years (range: 55–82 years). Based on serum free testosterone levels, 28 patients (46.7%) were classified as having low testosterone (<8.9 pg/mL; Group A), and 32 patients (53.3%) had normal testosterone levels (≥8.9 pg/mL; Group B).

Clinical characteristics:

The mean serum PSA level at diagnosis was significantly higher in the low-testosterone group (48.6 ± 22.4 ng/mL) compared to the normal-testosterone group (31.2 ± 17.8 ng/mL) (p = 0.01). The mean prostate volume was 52.8 ± 10.6 mL in Group A and 46.7 ± 9.2 mL in Group B (p = 0.04).

Histopathological and staging parameters:

Patients with low free testosterone levels had a significantly higher incidence of adverse prognostic features including high Gleason score (≥8), locally advanced disease (T3–T4), and metastatic involvement.

Table 1. Comparison of prognostic factors between low and normal serum free testosterone groups

Correlation analysis: - A significant inverse correlation was observed between serum free testosterone levels and serum PSA (r = –0.42, p = 0.002), as well as between testosterone and Gleason score (r = –0.36, p = 0.007). Low testosterone levels were strongly associated with higher tumor stage and poorer differentiation.

The present study demonstrates that low serum free testosterone levels at the time of diagnosis are significantly associated with adverse prognostic features in patients with carcinoma prostate. Patients with lower testosterone levels exhibited higher PSA values, greater Gleason scores, and more advanced clinical stages, consistent with findings from several previous studies [12–16].

The relationship between serum testosterone and prostate cancer aggressiveness has long been debated. While early theories proposed that higher testosterone levels stimulate tumor growth, emerging evidence suggests that low testosterone may instead reflect more aggressive tumor biology [12]. Lane et al. found that men with low preoperative testosterone were more likely to have high-grade and locally advanced disease following radical prostatectomy [13]. Similarly, Yamamoto et al. reported that reduced preoperative testosterone independently predicted biochemical recurrence after surgery [14].

Several mechanisms may explain this association. Low testosterone levels could indicate tumor-induced suppression of the hypothalamic-pituitary-gonadal axis or reflect metabolic dysfunction secondary to cancer progression [15]. It has been postulated that aggressive prostate cancer cells may lose androgen dependence, allowing proliferation despite reduced hormonal stimulation [16]. Furthermore, decreased androgen receptor expression and the emergence of androgen-independent clones may contribute to disease aggressiveness in hypogonadal states [17].

The present study also found a significant inverse correlation between serum free testosterone and both PSA and Gleason score. This supports earlier reports that low testosterone may serve as a surrogate biomarker for high-grade disease [18]. Salonia et al. observed that preoperative hypogonadism predicted the presence of poorly differentiated tumors at prostatectomy [19]. Additionally, low testosterone has been associated with adverse pathological findings, including extracapsular extension and seminal vesicle invasion, as reported by Imamoto et al. [20].

Clinically, these findings have important implications. Assessment of serum testosterone in newly diagnosed prostate cancer patients can aid in prognostic stratification and treatment planning. Patients presenting with low testosterone may require more aggressive therapeutic approaches and closer follow-up to monitor disease progression [21].

However, this study has certain limitations, including a relatively small sample size and single-center design. Larger multicenter trials are needed to validate the prognostic value of free testosterone and to explore potential therapeutic implications, such as the effect of testosterone replacement in carefully selected low-risk patients.

The study reinforces the association between low serum free testosterone and adverse prognostic indicators in prostate cancer. Measurement of free testosterone levels at diagnosis may thus provide a valuable adjunct for risk assessment and individualized patient management.

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