How Much Will 100ml Of Testosterone Increase

Abstract

The primary objective of this study was to correlate simultaneous measures of prostate-specific antigen (PSA) and serum testosterone among large samples of eugonadal, untreated hypogonadal and hypogonadal men treated with testosterone replacement therapy (TRT). From 2001 to 2007, laboratory records were reviewed to identify men who underwent simultaneous measurement of PSA and serum testosterone levels. The data were stratified based on three groups of men: group 1 consisted of eugonadal men (T>300 ng per 100 ml) evaluated for BPH, reproductive failure or sexual dysfunction; group 2 consisted of untreated hypogonadal men (T<300 ng per 100 ml); and group 3 comprised symptomatic hypogonadal men receiving TRT. Correlations were found between PSA (total and free fractions) and total serum testosterone levels among the three groups. Group 1: eugonadal men (n=385 patients), mean PSA and serum testosterone were 1.60 ng ml⁻¹ and 484 ng 100 ml, respectively. There was no significant correlation between PSA and total serum testosterone levels (r=−0.01, P=0.8). Group 2: untreated hypogonadal men (n=229 patients), mean PSA and serum testosterone were 1.49 ng ml⁻¹ and 269 ng per 100 ml, respectively. There was no significant correlation between PSA and total serum testosterone levels (r=0.03, P=0.6). Group 3: hypogonadal men on TRT (n=229 patients and 994 individual samples analyzed) mean PSA and serum testosterone were 1.50 ng ml⁻¹ and 555 ng per 100 ml, respectively. There was no significant correlation between PSA and serum testosterone levels (r=−0.005, P=0.9). Mean total serum testosterone levels were increased significantly (P<0.001) following treatment. Mean PSA levels did not increase in a statistically or clinically significant manner following TRT (mean PSA increase from baseline 0.05 ng ml⁻¹, P=0.6). In conclusion, TRT does not appear to significantly influence serum PSA expression and no significant correlation was identified between PSA and serum testosterone among eugonadal, untreated hypogonadal and hypogonadal men receiving TRT.

Introduction

Historically, the principal concern surrounding testosterone replacement therapy (TRT) has centered on prostate health, specifically the potential initiation, progression or recurrence of prostate cancer.^{1, 2, 3} More contemporary clinical trials have shown little, if consistent evidence of a carcinogenic influence or the tendency to 'unmask' subclinical prostate cancer when TRT is prescribed to otherwise healthy hypogonadal men.^{4, 5, 6} On the basis of lingering concerns and uncertainly, coupled with the fact that the prostate is known to be a androgen-sensitive organ, most evidence-based clinical guidelines recommend close surveillance of the prostate with prostate-specific antigen (PSA) and digital rectal examination among men treated with TRT.^{7, 8}

Recognizing that PSA remains the most sensitive screening test available for the early detection of prostate cancer,^{9, 10} a better understanding of the relationship between serum testosterone and PSA levels among men receiving TRT is essential. With this goal in mind, the primary objective of this study was to correlate and compare simultaneous measures of PSA and serum testosterone among large samples of eugonadal, untreated hypogonadal and hypogonadal men treated with TRT.

Materials and methods

Participants

From 2001 to 2007, the records of our electronic laboratory database were reviewed to identify men who underwent simultaneously measurement of PSA and serum testosterone levels. Institutional review board approval for database analysis was obtained. The data were stratified based on three groups of men: group 1 consisted of eugonadal men (total testosterone >300 ng per 100 ml) evaluated for benign prostatic hyperplasia (BPH), reproductive failure or sexual dysfunction; group 2 consisted of untreated hypogonadal men with a low (<300 ng per 100 ml)⁷ or borderline baseline total serum testosterone; and group 3 comprised symptomatic hypogonadal men receiving TRT.

Eugonadal participants were identified based on screening evaluations that included simultaneous measurement of total serum testosterone and PSA. Repeat biochemical testing among these men was performed only if clinically indicted. Before initiation of TRT (group 3), a complete medical and sexual history, physical examination including digital rectal examination and hormonal evaluation was performed in all men. Follow-up evaluations were arranged 4–8 weeks after the initiation of TRT and every 6 months thereafter, once hypogonadal symptoms improved and hormone levels stabilized. At each follow-up visit, hypogondal symptoms were reviewed, digital rectal examination was performed, and PSA and androgen profiles were updated. Forms of TRT included transdermal testosterone gels or intramuscular injections.

Laboratory analysis

Hormonal evaluations included measurement of total serum testosterone and serum PSA including free and total PSA fractions. All PSA and hormone samples were processed and analyzed by a single, experienced laboratory (Laboratory for Male Reproductive Research and Testing, Baylor College of Medicine). Total testosterone measurements were performed using the Beckman's Access II platform assay. Validated normal ranges for men using this assay are 200–1000 ng per 100 ml⁻¹. Total and free PSA determinations were carried out using the Hybritech Tandem-MP assays (Beckman Coulter, San Diego, CA, USA).

Statistical analysis

SPSS statistical software (version 14, 2007) was used to perform the statistical analysis. Pearson's coefficients were used to correlate PSA (free and total fractions) with serum testosterone levels among the three groups of men. Paired T-tests were used to evaluate within-group changes in mean PSA and serum testosterone levels over time (group 3). Analysis of variance was used to compare mean PSA and serum hormone levels among the groups.

Results

Group 1: eugonadal men

Between 2001 and 2007, we identified 385 eugonadal men with a mean age of 53 years who underwent simultaneous measurement of PSA and serum testosterone levels. Mean total PSA, free PSA and serum testosterone were 1.60 ng ml⁻¹ (range: 0.1–22.8 ng ml⁻¹), 0.50 ng ml⁻¹ (range: 0.01–13.9 ng ml⁻¹) and 485 ng per 100 ml (range: 301–3905 ng per 100 ml), respectively. There was no significant correlation between PSA (free: r=0.03, P=0.6, total: r=−0.01, P=0.8) and total serum testosterone levels (Table 1, Figure 1).

Table 1 Correlation between PSA and testosterone among eugonadal, untreated and treated hypogonadal men

Full size table

Group 2: untreated hypogonadal men

During the same time period, we identified 229 hypogonadal men (baseline assessments) with a mean age of 58 years. Among these men, mean total PSA, free PSA and serum testosterone were 1.49 ng ml⁻¹ (range: 0.1–8.8 ng ml⁻¹), 0.46 ng ml⁻¹ (range: 0.02–2.7 ng ml⁻¹) and 269 ng per 100 ml (range: 49–299 ng per 100 ml), respectively. There was no significant correlation between PSA (free: r=0.05, P=0.5, total: r=0.03, P=0.6) and total serum testosterone levels (Table 1, Figure 2).

Group 3: hypogonadal men on TRT

Among the hypogonadal men initiated on TRT (n=229), a total of 994 simultaneous measures of PSA and serum testosterone were available for evaluation. Mean duration of follow-up was 19 months. Following the initiation of TRT, mean total PSA, free PSA and serum testosterone for all measures during the course of therapy were, 1.50 ng ml⁻¹ (range: 0.1–13.8 ng ml⁻¹), 0.42 ng ml⁻¹ (range: 0.02–3.66 ng ml⁻¹) and 555 ng per 100 ml (range: 22–6957 ng per 100 ml), respectively. There was no significant correlation between PSA (free PSA: r=0.02, P=0.5, total PSA: r=−0.005, P=0.9) and serum testosterone levels (Table 1, Figure 3). Moreover, no significant change in PSA (baseline PSA: 1.49 ng ml⁻¹ vs last recorded PSA: 1.54 ng ml⁻¹) following the initiation of TRT was identified (delta PSA=0.05 ng ml⁻¹, P=0.6).

Hypogonadal patients were, on average, 5 years older than the eugonadal patients (P<0.001). Mean total serum testosterone levels were significantly greater among the hypogonadal men treated with TRT compared with both the untreated hypogonadal and eugonadal men (P=<0.001). Mean PSA levels did not significantly differ among the three groups.

Discussion

On the basis of historical concerns regarding the influence of exogenous testosterone administration on prostate health, the primary objective of this study was to establish the relationship between PSA and serum testosterone among large cohorts of eugonadal, untreated hypogonadal and hypogonadal men with TRT. Among all groups studied, we identified no significant correlation between serum testosterone levels and PSA (total and free factions), and no significant (statistical or clinical) increase in PSA following the initiation of TRT.

The present findings support the expanding body of literature detailing the relationship between serum androgen concentrations and serum PSA expression. In 1995, Jarow et al. ¹¹ found no correlation between PSA and serum testosterone variations within the normal physiologic range and concluded that serum testosterone levels do not significantly alter the accuracy of PSA for the detection, staging and monitoring of prostate cancer. Moreover, data collected from more than 1500 men in the Massachusetts Male Aging Study showed no significant relationship between prostate cancer risk and serum androgen concentrations.¹² In a recent (2008) collaborative analysis of 18 prospective studies (including 3886 men with prostate caner and 6438 control participants), the investigators found no association between the risk of prostate cancer and 'endogenous' serum concentrations of testosterone (total and free), dihydrotestosterone and other serum androgens.¹³ In the same year, Mearini et al. (2008)¹⁴ reported that endogenous levels of testosterone were significantly lower in patients with prostate cancer (vs BPH) and that low testosterone levels were an independent predictor of advanced (vs organ-confined) disease. Most recently, Rhoden et al. (2008)¹⁵ discovered that a low (<1.8) testosterone-to-PSA ratio predicted prostate cancer on biopsy in symptomatic hypogonadal men with a PSA ⩽4 ng ml⁻¹ before testosterone therapy.

The relationship between PSA expression and serum testosterone levels among hypogonadal men receiving 'exogenous' testosterone is less established and consistent. In 1995, Douglas et al. ¹⁶ reported no significant correlation between PSA and serum testosterone levels obtained on six successive occasions every 2–4 weeks in a small group of participants (n=10) receiving TRT. Despite lack of statistical significance, PSA levels increased by an average of 0.7 ng ml⁻¹ over the course of the study. Gerstenbluth et al. (2002)¹⁷ reported average PSA increases of 0.96 ng ml⁻¹ in 54 hypogonadal men with sexual dysfunction receiving TRT for a mean of 30 months. Furthermore, in a retrospective review of 48 hypogonadal men on TRT for 1 year, Rhoden et al. (2006)¹⁸ documented a mean PSA increase of 0.3 ng ml⁻¹, which was not influenced by the mode of testosterone replacement, patient age, or baseline levels of PSA or testosterone. Most recently, Saad et al. (2007)¹⁹ reported a slight decrease in PSA (mean 0.2 ng ml⁻¹) following parenteral administration of a long-acting testosterone undeconate for 1 year.

Although smaller studies on this issue have been published (described above), this study is novel in that it (i) reports on a significantly larger group of men on TRT than previously reported; (ii) includes only simultaneous measures of PSA and testosterone; (iii) evaluates the relationship between testosterone and free PSA (vs only total PSA); and (iv) includes large 'eugonadal' and 'untreated hypogonadal' control groups as a basis of comparison in an attempt to isolate the impact of TRT on serum PSA. Analyzing more than 220 men receiving TRT, we report an average PSA increase of 0.05 ng ml⁻¹ following the initiation of androgen replacement therapy and no significant correlation with serum testosterone levels.

The apparent paradox in which castration significantly decreases serum PSA and causes prostate cancer to regress, yet exogenous testosterone administration to physiologic levels fails to stimulate serum PSA expression may be resolved by the 'saturation model' proposed by Morgentaler et al. (2006).²⁰ According to the androgen saturation model, near-maximal androgen receptor saturation within the prostate is reached at relatively low testosterone levels.²⁰ Consequently, restoring serum testosterone levels to within the 'normal' physiologic range should have minimal impact on testosterone-dependent prostate functions including PSA expression. The main findings of this study are (1) a non-significant increase in PSA with TRT; and (2) no significant correlation between PSA and serum testosterone concentrations within physiologic levels among men on TRT are consistent with this hypothesis.

There is the well-established direct relationship between PSA and testosterone in support of the androgen saturation theory in which serum testosterone concentrations are reduced to castrate (or near castrate) levels.^{21, 22, 23} Moreover, among men on androgen depravation therapy for prostate cancer, studies have demonstrated that as men progress from castrate levels (likely unsaturated androgen receptors) toward more physiologic testosterone concentrations, a positive correlation between PSA and serum testosterone is identified.^{22, 23, 24} Additional evidence supporting the androgen receptor saturation hypothesis was recently been provided by Marks et al. (2006)⁶ who, in landmark randomized, double-blind, placebo-controlled trial analyzed prostate tissue concentrations of the principal androgens of the prostate (testosterone and dihydrotestosterone) following 6 months of parenteral TRT in hypogonadal patients. Despite significant increases in serum testosterone concentrations to normal physiologic levels, researchers identified no significant changes in serum PSA, prostate tissue testosterone and dihydrotestosterone concentrations, or prostate cancer biomarkers and gene expression within the prostate tissue itself.

The authors acknowledge that although the relationship between serum testosterone and PSA among men on TRT has practical implications on patient counseling and prostate cancer screening, PSA is not an absolute marker for prostate cancer growth and this study does not provide data on actual prostate cancer risk.

In conclusion, based on the results of this study, TRT does not appear to significantly influence serum PSA expression and no meaningful correlation was identified between PSA and serum testosterone concentrations among large cohorts of eugonadal, untreated hypogonadal and hypogonadal men receiving TRT.

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Acknowledgements

The authors acknowledge the following potential conflicts of interest: Dr Ethan D Grober: Auxilium—speaker; Solvay—speaker, advisory board. Dr Mohit Khera: Auxilium—speaker, investigator; Solvay—investigator. Dr Larry I Lipshultz: Auxilium—advisory board, investigator, speaker; Solvay—speaker.

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Affiliations

Division of Urology, Mount Sinai Hospital and Women's College Hospital, University of Toronto, Toronto, Ontario, Canada

E D Grober
The Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA

D J Lamb, M Khera, L Murthy & L I Lipshultz

Corresponding author

Correspondence to E D Grober.

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Grober, E., Lamb, D., Khera, M. et al. Correlation between simultaneous PSA and serum testosterone concentrations among eugonadal, untreated hypogonadal and hypogonadal men receiving testosterone replacement therapy. Int J Impot Res 20, 561–565 (2008). https://doi.org/10.1038/ijir.2008.40

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Received: 09 June 2008
Revised: 03 September 2008
Accepted: 13 September 2008
Published: 09 October 2008
Issue Date: November 2008
DOI : https://doi.org/10.1038/ijir.2008.40

Keywords

prostate-specific antigen
testosterone replacement
hypogonadism
androgens
testosterone
prostate cancer

How Much Will 100ml Of Testosterone Increase