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Keywords:

  • Prostate-specific antigen;
  • prostatic neoplasm;
  • benign prostatic hyperplasia;
  • testosterone

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Authors

Objective To investigate any differences in changes in serum prostate specific antigen (PSA) levels in patients with benign and malignant prostatic disease in response to the testosterone surge after administering a luteinizing hormone-releasing hormone (LHRH) analogue.

Patients and methods The study included 54 patients referred to the urology clinic with intermediate PSA levels (4–10 ng/mL) or an abnormal digital rectal examination. Forty-five patients received a single injection of LHRH analogue depot each at one week before prostate biopsy and nine served as a control group. Changes in PSA levels in response to the testosterone surge from the LHRH analogue were recorded after 5 and 7 days, and were correlated with the biopsy results. The PSA changes were compared with basal PSA levels and the free/total PSA ratio(f/tPSA).

Results Of the 45 patients who underwent prostate biopsy, histopathology showed prostate cancer in 11, benign prostatic hyperplasia in 33 and prostatic intraepithelial neoplasia in one. Patients with cancer had a significantly greater increase in serum PSA levels during the first week after LHRH injection than those in the benign and control groups. Receiver operating characteristic curves showed that the percentage change in PSA level on day 5 was more diagnostic than total PSA and f/tPSA.

Conclusions There was a marked difference in the PSA response of patients with benign or malignant disease to the testosterone surge produced by the LHRH analogue. Although a larger study would be needed before LHRH-induced provocation could be proposed as a clinical test, in this small series the response was better than that for total PSA or f/tPSA in differentiating benign and malignant disease.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Authors

Prostate cancer has become the most common male cancer in Australia and one of the leading causes of male cancer deaths [1,2]. The mortality rate from prostate cancer in Australia has slowly increased since the beginning of the 20th century from 2.5 per 100 000 in 1910–14, to 17.8 per 100 000 in 1990–91 [2]. The incidence of prostate cancer appears to be increasing throughout the western world [3]. In the USA there were ≈ 244 000 new cases of prostate cancer diagnosed in 1995; this represents an 18% increase from 1994 [4]. Prostate cancer, if diagnosed in the early stages, can potentially be cured by radical prostatectomy or radiation therapy.

PSA is the most commonly used tool for the early detection of prostate cancer. The American Cancer Society [5] and AUA [6] support the annual measurement of serum PSA levels in addition to a DRE in men over the age of 50 years who are seeking evaluation of prostatic disease. The limitation of PSA testing is its lack of sensitivity and specificity. This lack of diagnostic accuracy is most striking in patients with small increases in PSA level, when the possibility that prostatic carcinoma is localized and therefore potentially curable is greatest. The test specificity is particularly clinically significant, as the low specificity of PSA testing means that biopsies are taken unnecessarily in men who have elevated PSA levels but with benign pathology. Alternative methods for increasing the sensitivity and specificity of PSA testing have been proposed, e.g. PSA density [7], PSA velocity [8], age-specific reference ranges [9] and the ratio of free to total PSA (f/tPSA) [10]. All these methods have been extensively investigated but their clinical application has been limited.

This present study compared the response of PSA level in patients with benign and malignant prostatic disease to the testosterone surge after administering an LHRH analogue, with the possibility that this might be the basis of a new discriminatory test. Patients were given one injection with a slow-release LHRH analogue to provoke a testosterone increase; the analogue increases the serum testosterone level in the first week after injection and the level then declines. We hypothesized that the testosterone surge after LHRH analogue injection would cause a greater rise in PSA levels in patients with prostate cancer than in those with benign pathology. As a potential test, we also compared the prognostic performance of the PSA response with total PSA and f/tPSA.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Authors

This study commenced in January 1996 with approval from the Human Research Ethics Committee. In all, 54 patients were enrolled in the study after obtaining their informed consent. Patients were included if they had intermediate PSA levels (4.0–10.0 ng/mL) requiring further evaluation, or with a PSA of < 4.0 ng/mL and a suspicious DRE. Patients with a clinical suspicion of advanced prostate cancer and with chronic debilitating medical illness were excluded. Patients were recruited from the urology outpatient clinics. A slow-release preparation of LHRH analogue (leuprolide acetate) was used for the transient testosterone provocation; this was available as a depot injection, incorporated into lactic and glycolic acids (Lucrin, Abbott Australasia Pty Ltd, Cronulla, NSW, Australia) supplied as a microsphere in a single-dose vial, reconstituted with supplied diluent solution, and given as an intramuscular injection with a 22 G needle. Of the 54 patients enrolled, 45 received an injection with Lucrin and underwent TRUS-guided prostate biopsy (study group, mean age 61 years, range 45–76). The remaining nine patients received no Lucrin and served as a control group (mean age 65.5 years, range 55–86).

The study protocol comprised collecting the first blood sample for estimating total PSA, f/tPSA and testosterone levels, followed by an injection with Lucrin 7.5 mg intramuscularly on day 0. Subsequently, two more blood samples were collected on day 5 and day 7. A TRUS-guided prostate biopsy was taken on day 7 after collecting a third blood sample. The DRE was avoided for 2 weeks before administering Lucrin and in the period between collecting blood samples. The transrectal prostate biopsy was taken conventionally under TRUS guidance, collecting six cores of prostatic tissue (three from each peripheral lobe) targeted between the base and apex of the prostate in each patient. Additional cores were obtained from any hypoechoic or suspicious focus. Norfloxacin 400 mg orally twice a day was given for 5 days starting one day before the biopsy. Two laxative tablets were given on the night before prostatic biopsy as a bowel preparation. Three blood samples were also collected from each patient in the control group on day 0, 5 and 7.

Serum was separated within 4 h after blood sampling; all sera were immediately stored at −20 °C. All serum samples were analysed together at the completion of patient enrolment, after thawing the samples slowly to room temperature. All samples were analysed for testosterone, total PSA and f/tPSA. Serum testosterone was assayed using a radioimmunoassay (Diagnostics Products Corp., Los Angeles, CA) with a method coefficient of variation (CV) of 7.7%. PSA was measured using the AxSym (Abbot Australasia) monoclonal/polyclonal total PSA assay while the f/tPSA was calculated using corresponding monoclonal/monoclonal assays. All PSA assays were calibrated against the Tandem E standard (Hybritech Corp., San Diego, CA). The CV of the PSA assay in the range of the study group was ≈ 7.7%. The Wilcoxon paired signed-rank test was used to determine any significant percentage change in testosterone/PSA levels on day 5 and 7 relative to day 0. The Kruskal-Wallis test was used to determine whether the percentage PSA change differed significantly among the three groups (cancer, benign and control). The areas under ROC curves were used to compare the performance of four diagnostic indices; the PSA on day 0, the percentage change in PSA at day 5 and 7, and f/tPSA. The ROC curves were compared using the method of Hanley and McNeil [11].

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Authors

Of the 45 patients in the study group, the prostate biopsy showed benign pathology in 33, prostate cancer in 11 and high-grade prostatic intra-epithelial neoplasia (PIN) in one. The last patient was not included in the study group for the data analysis. Of the 11 patients with prostate cancer, one showed benign pathology on TRUS biopsy but at subsequent TURP was found to have prostate cancer. The mean (range) age in the benign group was 59 (45–76) years and in the cancer group 67 (52–74) years. Serum testosterone levels increased significantly after Lucrin injection in both the benign and cancer groups, with peak levels occurring on day 5 ( Table 1). There was no statistically significant change in serum testosterone level either on day 5 or 7 in the control group.

Table 1.  Serum testosterone and PSA levels on days 0, 5 and 7, and the corresponding percentage changes from day 0
  Testosterone level (nmol/L)% changePSA (ng/mL)% change,
GroupDaymean (median, sd, range)median (95% CI)mean (median, sd, range)median (95% CI)
  1. P<0.01; ‡P<0.001.

Benign015.2 (14.9, 4.6, 5.6–27.2) 5.9 (6.0, 2.7, 0.6–11.3) 
(n=33) 523.5 (21.9, 6.3, 13.4–38.7)56.4 (39.1–78.8)‡5.8 (5.8, 2.8, 0.5–13.1)−4.6 (−9.3–0.5)
 720.5 (20.3, 6.2, 8.6–38.4)39.9 (25.7–54.4)‡6.3 (6.2, 3.2, 0.6–14.2)1.7 (−6.7–12.1)
Cancer015.6 (16.6, 4.7, 8.7–24.6) 7.4 (6.4, 3.1, 3.9–12.5) 
(n=11) 523.6 (25.0, 8.4, 11.2–38.2)52.1 (22.4–88.4)†8.3 (6.2, 3.4, 4.6–13.8)13.3 (7.4–18.4)†
 717.2 (17.6, 5.6, 9.5–25.4)11.7 (−10.9–40.7)8.7 (6.6, 3.4, 4.6–14.5)19.2 (11.9–27.1)†
Control016.6 (16.1, 4.6, 11.2–24.4) 6.4 (6.9, 2.5, 3.3–11.1) 
(n=9) 514.9 (15.2, 5.0, 8.5–22.0)−8.9 (−30.9–17.7)5.8 (6.5, 1.8, 3.1–8.3)−5.2 (−14.7–0.0)
 715.8 (16.2, 5.1, 5.4–22.6)−3.0 (−23.2–18.2)6.2 (5.7, 2.6, 3.7–11.8)−2.7 (−15.5–8.8)

Descriptive statistics for PSA levels in all three groups on day 0, 5 and 7 are also shown in Table 1. The patients with cancer showed significant increases in PSA level at 5 and 7 days but the benign and control groups did not ( Table 1). The Kruskal–Wallis test showed significant differences among the three groups in the percentage change in PSA levels on day 5 and 7 ( Table 1). Pair-wise comparisons showed that the percentage change in PSA level was significantly higher in the cancer group than in the two other groups on day 5 and 7. The median ( sd) f/tPSA was lower in the cancer group, at 12.9 (10.6)%, than in the benign group, at 23.0 (7.9)%.

The respective area under the ROC curves ( Fig. 1) showed that the percentage change in PSA on day 5 was the better of the four diagnostic variables, even though the areas under the ROC curves were not statistically significantly different. The sensitivity and specificity values are shown in Table 2.

image

Figure 1. ROC curves comparing PSA levels on day 0 (green) with the percentage change in PSA on day 5 (light green) and 7 (light red), and f/tPSA (red). The area under the ROC curves (95% CI) are: PSA day 0, 0.62 (0.40–0.83); % PSA at day 5, 0.83 (0.70–0.90); % PSA at day 7, 0.76 (0.62–0.90); and f/tPSA, 0.70 (0.47–0.93).

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Table 2.  Comparison of the specificity of the PSA level on day 0 with the percentage change in PSA on day 5 and 7, and with the f/tPSA
IndexThresholdSensitivity (%)Specificity (%)
PSA on day 0 (ng/mL) 4.68234
% PSA change at day 5 8.28288
% PSA change at day 711.38266
f/tPSA28.78219

There was no major morbidity related to TRUS-guided biopsy or Lucrin injection. Of 45 patients who received Lucrin, 18 had varying degrees of hot flushes, lasting for 2–4 weeks. Temporary impotence developed in 20 patients, lasting for 2–5 weeks; 16 patients reported no change in their sexual activity after Lucrin and nine were not concerned, as they were not sexually active before treatment.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Authors

The enthusiasm for PSA testing to detect prostate cancer in its early stages has increased rapidly in recent years. A threshold value of 4.0 ng/mL is normally used to define an abnormal PSA level, but an increase in PSA level is not specific for prostate cancer. This is particularly true when the PSA level is in the diagnostic ‘grey’ zone of 4.0–10.0 ng/mL. In this subset of patients there is a significant overlap in PSA levels between patients with BPH or prostate cancer. The incidence of prostate cancer in patients with a PSA level of 4.0–10.0 ng/mL has been reported to be 22.4–26.5% when PSA was used as the sole criterion to initiate further evaluation of the screened population [12,13]. Thus, most patients with PSA levels of 4.0–10.0 ng/mL are subjected to an unnecessary prostatic biopsy, as the sample shows no evidence of prostate cancer. Because of the cost, patient discomfort and potential complications involved in prostatic biopsy, there is a need to restrict it to those with the greatest likelihood of disease. However, the other variables suggested (e.g. PSA density, f/tPSA) have not been universally helpful in improving the sensitivity and specificity of PSA testing. Thus we evaluated the possibility that changes in PSA level after testosterone provocation could be used to separate benign disease from prostate cancer, and thus increase the performance of PSA testing.

It was assumed that Lucrin would cause a greater increase in PSA levels in patients with prostate cancer than in those with BPH. This hypothesis is based on several premises. First, the growth of prostate cancer is dependent upon circulating androgens. Huggins et al.[14] found that castration resulted in an improvement in clinical symptoms and a decrease in elevated serum PAP levels in patients with advanced prostatic carcinoma. Second, it has been shown in vivo[15] and in vitro[16] that PSA production by a human prostate cancer cell line (LNCaP) is partly regulated by androgens. Gleave et al.[15] found serum PSA levels decreased rapidly, up to eight-fold, after castration and increased up to 20-fold after androgen supplementation in mice bearing the prostate LNCaP tumour.

The effect of androgen provocation in the group of patients who are at increased risk of having BPH or localized prostate cancer remains undefined. We are unaware of any published report examining the effect of an LHRH analogue-induced testosterone surge on serum PSA levels in a group of patients such as those in the present study; the present report is the first of its kind in the English literature. Mean serum PSA levels increased significantly with the testosterone surge induced by the LHRH analogue in patients who had prostate cancer. There are a few reports of changes in serum PSA levels associated with the testosterone surge associated with LHRH analogue administration in patients with metastatic prostatic carcinoma. Sasagawa et al.[17] reported a transient rise in PSA and PAP in all 18 patients with metastatic prostate carcinoma when treated with LHRH analogues. Kuhn et al.[18] reported an early transient increase of > 25% in serum PSA levels after LHRH analogue administration in eight of 19 patients with metastatic prostatic carcinoma. A further study showed that three of eight patients had a transient rise in PSA levels when treated with LHRH analogues [19]. However, patients in these studies had advanced prostatic carcinoma, in contrast to the present patients with localized disease.

There were no significant changes in PSA levels as a result of the testosterone surge after Lucrin injection in those with benign disease. This finding is supported by earlier observations that serum PSA levels do not change significantly in response to the exogenous administration of testosterone in normal men. Wallace et al.[20] found no change in serum PSA levels in 30 young men (mean age 28 years) receiving weekly parenteral testosterone for male contraception, despite supraphysiological serum testosterone levels. Cooper et al.[21] also found no change in serum PSA level in nine healthy young men (mean age 26 years) after a weekly injection of testosterone for 15 weeks. However, patients in these reports were younger than the present study group and unlikely to have prostatic disease.

PSA in sera exists in bound and unbound forms. It has been shown that men with prostate cancer have a greater fraction of PSA complexed to α-1-antichymotrypsin (a lower f/tPSA) than men with BPH [10]. Catalona et al.[22] suggested that f/tPSA can be used clinically to improve the specificity of PSA in detecting prostate cancer. In the present study, the percentage change in PSA level on day 5 had the maximum area under the ROC curve, compared with the other three variables, with a sensitivity of 82% and a specificity of 88% (threshold value > 8.2%). At the reference threshold of > 4.0 ng/mL, PSA had a sensitivity of 90% and a low specificity of 21%. This high sensitivity was a result of most patients having a serum PSA level of > 4.0 ng/mL. In a screened population, the sensitivity of PSA at a threshold of > 4.0 ng/mL is 43–81%[23]. One of the present patients with prostate cancer had a PSA level of < 4.0 ng/mL. The cancer was detected by the PSA response but could have been missed using the accepted PSA threshold of > 4.0 ng/mL. Of men with prostate cancer, 20–33% have PSA levels of < 4.0 ng/mL [24]. The PSA response to LHRH-induced testosterone surge may also be helpful in this group of patients, although there was only one such patient in the present study.

One patient in the present study had a significant increase in PSA level on days 5 and 7 but showed benign pathology on biopsy. Subsequently, he was found to have prostatic carcinoma on TURP. It may be possible that in some patients with benign disease who had significant increases in PSA level with the LHRH analogue, the biopsy may have missed cancerous foci. One patient with high-grade PIN showed a 24% and 49% rise in PSA level on days 5 and 7, respectively, after the LHRH analogue. It has been suggested that high-grade PIN may be a precursor lesion to intermediate to high-grade adenocarcinoma of the prostate. In patients with high-grade PIN, there is a 30–50% risk of finding carcinoma in subsequent biopsies [25]. This patient will be followed closely to assess any developing prostate carcinoma, but as yet has not been re-biopsied.

The testosterone-provocation test using exogenous androgens in patients suspected of having prostate cancer may be of concern, as it could exacerbate the growth of cancer cells. An LHRH analogue was used in the present study because a single injection increases the testosterone level during first week after administration, after which the levels decline rapidly, reaching castration levels by the end of first month [26]. The effect of this brief testosterone surge in patients with localized prostatic carcinoma is not well defined. ‘Disease flare’, caused by a testosterone surge with LHRH analogues has been reported in 10% of patients with metastatic prostate cancer [19] but should not be a concern in localized cancer. Perren et al.[27] found that no patient without skeletal metastasis had ‘disease flare’ in a group of patients treated with LHRH analogues. Also, LHRH analogues have been used as neoadjuvant therapy in patients with localized prostatic carcinoma, with no ‘disease flare’[28].

LHRH analogues increased the present serum testosterone levels by ≈ 1.5 times, peaking on day 5, which is in accord with a previous report [26]. The optimum safe testosterone level for maximal PSA expression is unknown. Lee et al.[16] found that PSA production by LNCaP cells was dose-dependent; the level of PSA production increased as the concentration of DHT in the culture medium rose. Mazzei et al.[26] found that leuprolide depot at a dose of 3.75 mg provided paradoxically higher levels of DHT during the first week after injection than did a 7.5-mg preparation. Investigation is needed to determine if leuprolide in a 3.75-mg dose may provide a better PSA response than a 7.5-mg preparation. PSA levels in response to a testosterone surge increased progressively from day 5 to 7 in the present study. It is not known when or whether PSA would reach a peak level, as blood samples were not obtained beyond 7 days.

The use of LHRH analogues can be associated with hot flushes and impotence [28]; in the present study these side-effects were transient. Hot flushes were mild to moderate in most patients, except in two in whom they were severe. Impotence was temporary and reversible in all 20 patients. The patients were informed beforehand about the possibility of these side-effects. Linde et al.[29] found that LHRH analogues when given as a daily subcutaneous injection produced impotence in five of eight normal men, but it resolved in all within 2 weeks of stopping treatment. The acceptability of causing these side-effects, albeit temporarily, during a diagnostic procedure in men who may not have cancer, needs careful consideration. This procedure could not be advocated at present unless as part of a larger study to assess its value and acceptability as a diagnostic test.

In conclusion, this pilot study showed that androgenic provocation leads to a greater rise in PSA level in patients with localized prostatic carcinoma than in those with BPH. The PSA changes at 5 days after androgenic provocation provided better differentiation of disease than did total PSA level or f/tPSA. The optimum dose of LHRH analogue for the maximum PSA response and the time of the peak in PSA level need to be identified to further improve the sensitivity and specificity of this test. However, there can be no definite conclusions about the clinical application of the procedure because there were too few patients; a larger study is required to confirm the findings.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Authors

We acknowledge the help of Florence Choo (Statistical Consulting Centre, University of Melbourne) for the statistical analysis and Abbott Australia for partly supporting this study.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Authors
  • 1
    Jelfs P, Coates M, Giles G et al. Cancer in Australia 1989–90 (with projection to 1995). Cancer Series no. 5. Canberra: Australian Institute of Health and Welfare, 1996
  • 2
    Giles G, Thursfield V, Staples M. The bottom line: trends in cancer mortality, Australia 1950–91. Cancer Forum 1994; 18: 12 23
  • 3
    Buck CA. Prostate cancer question and answers. 1st edn, Chapt 1. Merit Publishing International, 1995: 10 9
  • 4
    Wingo PA, Tong T, Bolden S. Cancer statistics, 1995. CA Cancer J Clin 1995; 45: 8 30
  • 5
    Mettlin C, Jones G, Averett H et al. Defining and updating the American Cancer Society guidelines for the cancer-related checkup. Prostate and endometrial cancers. CA Cancer J Clin 1993; 43: 42 6
  • 6
    American Urological Association Policy Statement. Early detection of prostate cancer and use of transrectal ultrasound. 1992 Policy Statement Book. Baltimore: American Urological Association, 1992: 4.20
  • 7
    Benson MC, Whang IS, Pantuck A et al. Prostate specific antigen density: a means of distinguishing benign prostatic hypertrophy and prostate cancer. J Urol 1992; 147: 815 6
  • 8
    Carter HB, Pearson JD, Metter EJ et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA 1992; 267: 2215 20
  • 9
    Oesterling JE, Jacobsen SJ, Chute CG et al. Serum prostate-specific antigen in a community-based population of healthy men: establishment of age-specific reference ranges. JAMA 1993; 270: 860 4
  • 10
    Christensson A, Bjork T, Nilsson O et al. Serum prostate specific antigen complexed to α1-antichymotrypsin as an indicator of prostate cancer. J Urol 1993; 150: 100
  • 11
    Hanley JA & McNeil BJ. A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology 1983; 148: 839 43
  • 12
    Catalona WJ, Smith DS, Ratliff TL et al. Measurement of prostate specific antigen in serum as a screening test for prostate cancer. New Engl J Med 1991; 324: 1156 61
  • 13
    Brawer MK, Chetner MP, Beatie J et al. Screening for prostatic carcinoma with prostate specific antigen. J Urol 1992; 147: 841 5
  • 14
    Huggins C, Stevens RE, Hodges CV. Studies on prostatic cancer: II. The effects of castration on advanced carcinoma of prostate gland. Arch Surg 1941; 43: 209
  • 15
    Gleave ME, Hsieh JT, Wu HC, Eschenbach AC, Chung LWK. Serum prostatic specific antigen levels in mice bearing human prostate LNCaP tumors are determined by tumor, and endocrine and growth factors. Cancer Res 1992; 52: 1598 605
  • 16
    Lee C, Sutkowski DM, Sensibar JA et al. Regulation of proliferation and production of prostate-specific antigen in androgen sensitive prostatic cancer cells, LNCaP, by dihydrotestosterone. Endocrinology 1995; 136: 796 802
  • 17
    Sasagawa I, Nakada T, Kubota Y, Sawamura T, Izumiya K. Changes in serum levels of prostatic acid phosphatase and prostate specific antigen after luteinizing hormone-releasing hormone analogue administration in patients with metastatic prostatic cancer in relation to glandular differentiation. Int Urol Nephrol 1995; 27: 769 74
  • 18
    Kuhn JM, Billbaud T, Navratil H et al. Prevention of the transient adverse effects of a gonadotropin releasing hormone analogue (Buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (Nilutamide). NJ Med 1989; 321: 413
  • 19
    Takeuchi S, Yoshida K, Tosaka A, Kobayashi N, Uchijima Y, Saitoh H. Dynamic study of the hormonal levels and tumor markers after the first administration of long-acting LH-RH analogue in patients with prostate cancer. Acta Urol Jap 1994; 40: 393 400
  • 20
    Wallace EM, Pye SD, Wild SR, Wu FC. Prostate-specific antigen and prostate gland size in men receiving exogenous testosterone for male contraception. Int J Androl 1993; 16: 35 40
  • 21
    Cooper CS, MacIndoe JH, Perry PJ, Yates WR, Williams RD et al. The effect of exogenous testosterone on total and free prostate specific antigen levels in healthy young men. J Urol 1996; 156: 438 42
  • 22
    Catalona WJ, Smith DS, Wolfert RL et al. Evaluation of percentage of free serum prostatic specific antigen to improve specificity of prostate cancer screening. JAMA 1995; 274: 1214 20
  • 23
    Dorr VJ, Williamson SK, Stephens RL. An evaluation of prostatic-specific antigen as a screening test for prostate cancer. Arch Intern Medicine 1993; 53: 2529 37
  • 24
    Ruckle HC, Klee GG, Oesterling JE. Prostate-specific antigen: critical issues for the practicing physician. Mayo Clin Proc 1994; 69: 59 68
  • 25
    Brawer MK, Bigler SA, Sohlberg OE et al. Significance of prostatic intraepithelial neoplasia on prostate needle biopsy. Urology 1991; 38: 103 7
  • 26
    Mazzei T, Mini E, Eandi M et al. Pharmacokinetics, endocrine and antitumor effects of leuprolide depot (TAP-144-SR) in advanced prostatic cancer: a dose response evaluation. Drugs Exptl Clin Res 1989; 15: 373 87
  • 27
    Perren TJ, Clayton RN, Blackledge G et al. Pharmacokinetic and endocrinological parameters of a slow-release depot preparation of the GnRH analogue ICI 118630 (Zoladex) compared with a subcutaneous bolus and continuous subcutaneous infusion of the same drug in patients with prostatic cancer. Cancer Chemother Pharmacol 1986; 18: 39 43
  • 28
    Aus G, Abrahamsson PA, Ahlgren G et al. Hormonal treatment before radical prostatectomy: a 3-year followup. J Urol 1998; 159: 2013 6
  • 29
    Linde R, Doelle GC, Alexander N et al. Reversible inhibition of testicular steroidogenesis and spermatogenesis by a potent gonadotrophin-releasing hormone agonist in normal men. N Engl J Med 1981; 305: 663 7

Authors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Authors

D.K. Agarwal, MBBS, MS, DNB(Urol), FRACS, Fellow in Urology.

A.J. Costello, MBBS, FRACS, MD, Director of Urology.

J. Peters, MBBS, FRACS, Senior Urologist.

K. Sikaris, MBBS, FRCPA, FAACB, Medical Director.

H. Crowe, RN, BApp Sci, G Dip Epi Biostats, Urology Research Nurse.