madman
Super Moderator
Background
Advances in chromatography and mass spectrometry have allowed us to develop a novel technique for measuring intraprostatic hormone concentrations directly on prostate needle biopsies, rather than using traditional punch excision. This has significant clinical implications as intraprostatic dihydrotestosterone and testosterone levels could help monitor prostate growth, neoplasia and castration resistance.
Methods
Patients undergoing radical cystoprostatectomy for bladder cancer were prospectively included. Each prostate specimen received one 90 mg punch excision and six needle biopsies. Intraprostatic hormones were dosed through gas chromatography-mass spectrometry.
Results
We included twenty patients, of which eleven were incidentally diagnosed with prostate cancer; four had ISUP 1 (20%) and seven had ISUP 2 (35%). The prostate biopsy technique was unable to obtain measures for testosterone, Delta-4-androsterone and androstenedione. Tissue concentrations of DHEA, DHT, E1 and E2 can be obtained with no significant difference from the reference established on a punch from a single biopsy core sample.
Conclusions
Our study demonstrates that intraprostatic concentrations of DHEA, DHT, E1 and E2 can be measured without significant difference from the reference established on a single punch excision. This finding opens the way to research on the interactions between endocrinology and prostate oncogenesis and particularly on the mechanisms of resistance to hormone therapies in vivo. Level of evidence: 2
4. Discussion
We showed that DHT concentrations were comparable between the prostate punch technique and one or two biopsies and could be an easily accessible surrogate for intraprostatic DHT concentration. This is an important finding as it shows the feasibility of in vivo prostate biopsies to measure prostatic hormones. Intratumoral synthesis of dihydrotestosterone (DHT) is of utmost importance as it could partly explain the castration resistance of prostate cancer [10]. Intraprostatic DHT is associated with cancer aggressiveness: its concentration is lower in high Gleason stages[11]. Interestingly,serum and intraprostatic hormonal concentrations do not react the same way to medical castration: a study on thirteen healthy men found a decrease in serum T by 94% whereas prostatic T and DHT levels were 70 and 80% lower [12], further advocating the importance of in vivo intraprostatic dosage. However, three biopsies and one or two biopsies for DHT and DHEA respectively differed from the punch concentration, this could be explained by concentration heterogeneity within the prostate. DHEA can be a direct ligand for the AR and induce weak androgenic effects, potentially promoting prostate cancer growth[13].
The prostate biopsy technique was unable to obtain measures for testosterone, Delta-4-androstenedione, and androstenedione. Conversely, these hormones have less value than intraprostatic DHT: while T concentrations in recurrent PCa and androgen-stimulated benign prostate remain stable, DHT prostatic levels decrease by 91% in recurrent PCa[14]. This suggests that recurrent PCa prostate may develop the capacity to biosynthesize testicular androgens from adrenal androgens or cholesterol, thus explaining the efficacy of abiraterone in castration resistant prostate cancers. Dosing intraprostatic hormones could have clinical implications to monitor the efficacy of second-generation antiandrogens. The determination of steroid concentrations is questionable when performed by immuno-histochemical methods [15], thus alternatives using the GC-MS technique should be used to dose these hormones
Steroids level degradation occurs between sampling and freezing, once frozen, they no longer present a risk of degradation [16], all of the samples in this study were frozen within less than an hour while assays were performed within one month after freezing.
The proportion of incidentally diagnosed pCa in patients undergoing radical cystoprostatectomy (CPT) for bladder cancer was higher than the 28% reported in literature [17]: this can partly be explained by the centralized pathological examination.
The present study presents several limitations: first, it lacks information on the localization of the prostate biopsies: it has been shown that T and DHT accumulate in the stroma of enlarged prostates and the degree of accumulation correlated with prostate volume [18,19]:attributed to either higher 5a-reductase expression or the lower expression of downstream metabolizing enzymes [20]. This study suggests the realization of three systematic prostate biopsies. We chose not to correlate intraprostatic and circulating hormonal concentration because circulating concentrations of sex steroid hormones have proven to be poor surrogate measures of the intraprostatic hormonal milieu [21].Conjugated excretion product dosage was not included in our protocol.
The strengths of this study are the use of the GC/MS method,which has proven to be the most reliable [7] in accordance with current guidelines[15] and a relatively large number of patients. This study is the first prospective comparative study of these two techniques: previous comparisons between punch and biopsy were only done in retrospective meta-analyses [6]. Biopsies allow a standardization of the intraprostatic tissue sampling and therefore dosage technique. Differentiation of peripheral and transitional zones is easier on these biopsies.
5. Conclusion
Using the reference technique based on GC-MS, the evaluation of intraprostatic concentrations of DHEA, DHT, E1, and E2 could be obtained without significant differences from the reference established on a single biopsy core. The demonstration of the possibility of a reliable determination of these hormones within prostate tissue opens the way to research on the interactions between endocrinology and prostate oncogenesis and particularly on the mechanisms of resistance to hormone therapies.
Advances in chromatography and mass spectrometry have allowed us to develop a novel technique for measuring intraprostatic hormone concentrations directly on prostate needle biopsies, rather than using traditional punch excision. This has significant clinical implications as intraprostatic dihydrotestosterone and testosterone levels could help monitor prostate growth, neoplasia and castration resistance.
Methods
Patients undergoing radical cystoprostatectomy for bladder cancer were prospectively included. Each prostate specimen received one 90 mg punch excision and six needle biopsies. Intraprostatic hormones were dosed through gas chromatography-mass spectrometry.
Results
We included twenty patients, of which eleven were incidentally diagnosed with prostate cancer; four had ISUP 1 (20%) and seven had ISUP 2 (35%). The prostate biopsy technique was unable to obtain measures for testosterone, Delta-4-androsterone and androstenedione. Tissue concentrations of DHEA, DHT, E1 and E2 can be obtained with no significant difference from the reference established on a punch from a single biopsy core sample.
Conclusions
Our study demonstrates that intraprostatic concentrations of DHEA, DHT, E1 and E2 can be measured without significant difference from the reference established on a single punch excision. This finding opens the way to research on the interactions between endocrinology and prostate oncogenesis and particularly on the mechanisms of resistance to hormone therapies in vivo. Level of evidence: 2
4. Discussion
We showed that DHT concentrations were comparable between the prostate punch technique and one or two biopsies and could be an easily accessible surrogate for intraprostatic DHT concentration. This is an important finding as it shows the feasibility of in vivo prostate biopsies to measure prostatic hormones. Intratumoral synthesis of dihydrotestosterone (DHT) is of utmost importance as it could partly explain the castration resistance of prostate cancer [10]. Intraprostatic DHT is associated with cancer aggressiveness: its concentration is lower in high Gleason stages[11]. Interestingly,serum and intraprostatic hormonal concentrations do not react the same way to medical castration: a study on thirteen healthy men found a decrease in serum T by 94% whereas prostatic T and DHT levels were 70 and 80% lower [12], further advocating the importance of in vivo intraprostatic dosage. However, three biopsies and one or two biopsies for DHT and DHEA respectively differed from the punch concentration, this could be explained by concentration heterogeneity within the prostate. DHEA can be a direct ligand for the AR and induce weak androgenic effects, potentially promoting prostate cancer growth[13].
The prostate biopsy technique was unable to obtain measures for testosterone, Delta-4-androstenedione, and androstenedione. Conversely, these hormones have less value than intraprostatic DHT: while T concentrations in recurrent PCa and androgen-stimulated benign prostate remain stable, DHT prostatic levels decrease by 91% in recurrent PCa[14]. This suggests that recurrent PCa prostate may develop the capacity to biosynthesize testicular androgens from adrenal androgens or cholesterol, thus explaining the efficacy of abiraterone in castration resistant prostate cancers. Dosing intraprostatic hormones could have clinical implications to monitor the efficacy of second-generation antiandrogens. The determination of steroid concentrations is questionable when performed by immuno-histochemical methods [15], thus alternatives using the GC-MS technique should be used to dose these hormones
Steroids level degradation occurs between sampling and freezing, once frozen, they no longer present a risk of degradation [16], all of the samples in this study were frozen within less than an hour while assays were performed within one month after freezing.
The proportion of incidentally diagnosed pCa in patients undergoing radical cystoprostatectomy (CPT) for bladder cancer was higher than the 28% reported in literature [17]: this can partly be explained by the centralized pathological examination.
The present study presents several limitations: first, it lacks information on the localization of the prostate biopsies: it has been shown that T and DHT accumulate in the stroma of enlarged prostates and the degree of accumulation correlated with prostate volume [18,19]:attributed to either higher 5a-reductase expression or the lower expression of downstream metabolizing enzymes [20]. This study suggests the realization of three systematic prostate biopsies. We chose not to correlate intraprostatic and circulating hormonal concentration because circulating concentrations of sex steroid hormones have proven to be poor surrogate measures of the intraprostatic hormonal milieu [21].Conjugated excretion product dosage was not included in our protocol.
The strengths of this study are the use of the GC/MS method,which has proven to be the most reliable [7] in accordance with current guidelines[15] and a relatively large number of patients. This study is the first prospective comparative study of these two techniques: previous comparisons between punch and biopsy were only done in retrospective meta-analyses [6]. Biopsies allow a standardization of the intraprostatic tissue sampling and therefore dosage technique. Differentiation of peripheral and transitional zones is easier on these biopsies.
5. Conclusion
Using the reference technique based on GC-MS, the evaluation of intraprostatic concentrations of DHEA, DHT, E1, and E2 could be obtained without significant differences from the reference established on a single biopsy core. The demonstration of the possibility of a reliable determination of these hormones within prostate tissue opens the way to research on the interactions between endocrinology and prostate oncogenesis and particularly on the mechanisms of resistance to hormone therapies.
