Effects of gonadotropin and testosterone treatments on prostate volume and serum prostate specific antigen levels in male hypogonadism

Various monosialo- and disialo-gangliosides and their derivatives were examined by delayed ion extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry (DE MALDI-TOF MS) in the reflector mode with alpha-cyano-4-hydroxycinnamic acid or 2,5-dihydroxybenzoic acid used as the matrix. Native gangliosides were generally found to give good spectra in the negative ion mode. 2,5-Dihydroxybenzoic acid was a better matrix for gangliosides than alpha-cyano-4-hydroxycinnamic acid, because this matrix seemed to minimize loss of sialic acid and carbon dioxide of gangliosides. About 1 pmol of ganglioside was able to be detected with this matrix. When "A-series" gangliosides such as GD1a and GalNAc-GD1a gave undesirable extra peaks probably due to loss of sialic acid besides molecule-related ion peaks, the methyl-esterification of the gangliosides at the carboxyl groups of sialic acids was found to be necessary to obtain good DE MALDI-TOF mass spectra in the positive ion mode. In contrast, "B-series" gangliosides such as GD1b, GD2, and GD3 gave rise to major dehydrated molecule-related ion [M-H2O-H]- peaks in the negative ion mode without the pretreatment of methyl-esterification. The DE MALDI-TOF mass spectrometric analysis enabled us to distinguish between GD1a and GD1b, which have the same molecular weight. It was also found that not only a purified sample, but also a mixed sample of various gangliosides was amenable to the identification of them by DE MALDI-TOF MS.     

The effect of prostate volume, age, total prostate specific antigen level and acute inflammation on the percentage of free serum prostate specific antigen levels in men without clinically detectable prostate cancer

PURPOSE: We determine the influence of age, prostate volume, total serum prostate specific antigen (PSA) level and histological evidence of acute inflammation in biopsy specimens on the percent free serum PSA level in men without clinically detectable prostate cancer. MATERIALS AND METHODS: We studied 70 men with total PSA levels of 2.6 to 9.9 ng./ml. who had undergone at least 3 sets of prostate biopsies that were negative for cancer as part of our PSA based prostate cancer screening program. Total and free PSA levels were measured using Hybritech immunoassays. Prostate volume and the presence of acute inflammation were determined from the most recent transrectal ultrasonography and prostate needle biopsy. RESULTS: Percent free PSA levels correlated significantly with age (r = 0.48, p = 0.0001) and prostate volume (r = 0.44, p = 0.0002) but not with total PSA (r = 0.04, p = 0.7). The mean percent free PSA did not differ for those with or without acute inflammation. Multivariate regression models demonstrated that age and prostate volume were significant predictors of percent free PSA. CONCLUSIONS: Among men without detectable prostate cancer and a total PSA level between 2.6 and 9.9 ng./ml. percent free serum PSA was higher in older men and in men with a larger prostate gland but was not influenced by total PSA level or the presence of acute inflammation in the prostatic biopsy specimen.     

The effect of parenteral testosterone replacement on prostate specific antigen in hypogonadal men with erectile dysfunction

PURPOSE: Parenteral testosterone supplementation is a common treatment for erectile dysfunction in hypogonadal men. Despite its frequent use, the effect of testosterone on prostate specific antigen (PSA) in these patients has not been documented previously. In this study we determined the effect of parenteral testosterone replacement on PSA and PSA velocity in a group of men being treated for erectile dysfunction. MATERIALS AND METHODS: A retrospective analysis of 48 patients (mean age 65.9) was performed and 2 study groups were identified. Group 1 consisted of 27 patients with a serum PSA level before and after initiating testosterone replacement therapy, and group 2 consisted of 27 men with a minimum of 3 PSA measurements (intervals of 6 months or greater) while on testosterone replacement. Each man had erectile dysfunction, a normal digital rectal examination and a low or low-normal total serum testosterone level before initiating therapy. Testosterone replacement was discontinued if no subjective improvement in erectile function was obtained, or if prostate adenocarcinoma was suggested by digital rectal examination or PSA. RESULTS: The mean increase in PSA after initiating testosterone replacement was 0.29 ng./ml. representing a mean change of 37% from baseline (mean interval 12.8 months). The mean PSA velocity was 0.05 ng./ml. per year. Pretreatment testosterone level, age and testosterone dose did not independently alter the PSA during testosterone replacement. Eleven men required prostate biopsies during treatment. Biopsies were indicated for abnormal digital rectal examination in 10 men and an elevated PSA in 1. All biopsies were benign. CONCLUSIONS: Parenteral testosterone replacement in hypogonadal men with normal pretreatment digital rectal examination and serum PSA levels does not alter PSA or PSA velocity beyond established nontreatment norms. Thus, any significant increase in PSA or PSA velocity should not be attributed to testosterone replacement therapy and should be evaluated.     

Influence of age on serum prostate specific antigen concentration

322 men who had not prostatic diseases were selected at random for defining the characteristics of serum prostate specific antigen (PSA) in order to use PSA more appropriately in detecting clinically significant prostate cancer. The serum PSA concentration is correlated with patient age (r = 0.301; P < 0.0001), PSA is increased with age. The recommended upper limits (mean +2 standard deviations) for serum PSA for men aged 20-49 years was 2.71 ng/ml; for 50-59 years, 5.01ng/ml; for 60-69 years, 6.05 ng/ml; and for greater than or equal to 70 years, 7.92 ng/ml. Our findings led to proposals for using age-specific PSA reference range instead of a single reference range for men of all age groups. These age-specific reference ranges have the potential to increase the specificity of using PSA for detecting prostate cancer.     

The influence of prostate volume on the ratio of free to total prostate specific antigen in serum of patients with prostate carcinoma and benign prostate hyperplasia

BACKGROUND: Determining the ratio of free to total prostate specific antigen (f-PSA to t-PSA, calculated as the percentage of f-PSA [f-PSA%]) in serum allow for a clearer distinction between patients with prostate carcinoma (PCa) and patients with benign prostate hyperplasia (BPH) than determining the level of t-PSA alone. To find influencing factors on f-PSA%, the authors investigated prostate volume, TNM classification, and tumor stage. METHODS: The authors measured f-PSA and t-PSA in 36 men with untreated PCa (tumor classification: T1, 2, 3pNO, MO), 44 patients with BPH, and 54 healthy controls. Prostate volume was determined by transrectal ultrasound. RESULTS: The median values of t-PSA and f-PSA% were 7.8 micrograms/L and 10.5% in PCa patients, 4.3 micrograms/L and 20.8% in patients with BPH, and 1.4 micrograms/L and 23.6% in the control group. Patients with PCa had a significantly lower proportion of f-PSA than BPH patients and healthy men. There was no correlation of f-PSA% to TNM stage or tumor grade. In PCa patients a significant positive correlation (correlation coefficient [r] = 0.51, P < 0.001) was found between f-PSA% and prostate volume, whereas there was no significant correlation in BPH patients (r = -0.27, P > 0.05). There was a significant difference in f-PSA% between PCa and BPH patients with prostate volumes smaller than 40 cm3 (9.0% vs. 21.6%, P < 0.01) but not between patients in these 2 groups with prostate volumes exceeding 40 cm3 (15.1% vs. 18.2%, P = 0.11). CONCLUSIONS: Determining the ratio of f-PSA to t-PSA to discriminate between PCa and BPH patients yields significant results only in men with a prostate volume of less than 40 cm3.     

Comparison of percent free prostate specific antigen and prostate specific antigen density as methods to enhance prostate specific antigen specificity in early prostate cancer detection in men with normal rectal examination and prostate specific antigen between 4.1 and 10 ng./ml

PURPOSE: We analyzed the behavior of prostate specific antigen (PSA) density and percent free PSA to enhance the specificity of PSA in the early diagnosis of prostate cancer in men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml. MATERIALS AND METHODS: PSA serum level, PSA density and percent free PSA were analyzed in 74 men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml. All men underwent systematic prostate biopsy, and the diagnosis was benign prostate hyperplasia in 52 and prostate cancer in 22. Furthermore, we determined the decrease in unnecessary biopsies and the cancer detection rate using 0.10 versus 0.15 as cut points for PSA density, and 20 versus 25 as cut points for percent free PSA. RESULTS: In patients with benign prostatic hyperplasia and prostate cancer, respectively, the median PSA level was 6.7 and 7.0 ng./ml. (p > 0.05), median prostate volume was 50 and 37 cc (p < 0.04), median PSA density was 0.14 and 0.19 (p < 0.007) and median percent free PSA was 18.9 and 10.1 (p < 0.005). Using PSA density cut points of 0.15 and 0.10, the decrease in negative biopsies was 53.8 and 36.5% with a sensitivity of 86.4 and 90.9%, respectively. However, using percent free PSA cut points of 20 and 25, the decrease in negative biopsies was 36.5 and 26.9% with a sensitivity of 77.3 and 95.5%, respectively. CONCLUSIONS: Although both methods could minimize unnecessary biopsies in men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml., the percent free PSA was more cost-effective since transrectal ultrasound was not required. In this small series of symptomatic patients a percent free PSA cut point of 25 could detect at least 95% of prostate cancers and decrease 26.9% of negative biopsies.     

Effect of growth hormone administration on circulating levels of luteinizing hormone, follicle stimulating hormone and testosterone in normal healthy men

A new area of growth hormone (GH) therapy in adults is the treatment of infertility. The aim of this study was to evaluate the effects of pharmacological GH administration on the secretion of pituitary and gonadal hormones in normal men. Eight healthy men, 23-32 years of age (mean 28.1 years), with a normal body mass index were studied in a double-blind, placebo-controlled crossover design. All participants had a normal semen analysis before entering the study. Each participant was treated with placebo and GH (12/IU/day, Norditropin; Novo Nordisk, Denmark) during two different 14-day periods, separated by a 6 week washout period. Administration of GH for 14 days resulted in a significant increase in serum insulin-like growth factor I (IGF-I; P < 0.01) but no changes occurred in IGF-I values during placebo treatment. The concentrations of follicle stimulating hormone and luteinizing hormone displayed no change during the two periods and did not differ between the GH treatment period and the placebo period. The concentration of testosterone was unchanged during the placebo/GH periods and there was no difference between the GH treatment period and the placebo period. We conclude that GH treatment for 14 days in normal healthy men does not affect gonadotrophin or testosterone patterns.     

Prevalence and pathological extent of prostate cancer in men with prostate specific antigen levels of 2.9 to 4.0 ng./ml

Various authors have recommended different values for the upper limit of normal for the monoclonal prostate specific antigen (PSA) assay (for example 4.0 ng./ml. or less by the manufacturer Hybritech or 2.8 ng./ml. or less by others). To our knowledge, no studies have examined the prevalence and pathological extent of prostate cancer detectable by needle biopsy in ambulatory volunteers with PSA levels in the range of 2.9 to 4.0 ng./ml. We evaluated 121 volunteers by rectal examination and transrectal ultrasonography with PSA levels in that range. We performed ultrasound-directed needle biopsy of the prostate if abnormal findings were present on either examination. The prevalence of detectable prostate cancer in this group was 7.2% (8 of 111). All 8 patients had pathologically organ confined cancer, and only 2 had suspicious findings on rectal examination but all had abnormal or suspicious ultrasound findings. We believe that the 7.2% yield from ultrasonography and biopsy in patients with a PSA level of 2.9 to 4.0 ng./ml. is too low to justify further invasive evaluation. Rather, we recommend careful followup and monitoring of these patients with serial PSA measurements and rectal examination, and advise performance of ultrasonography and biopsy if the rectal examination becomes suspicious for cancer or the PSA level increases above 4.0 ng./ml.     

The lack of predictive value of prostate specific antigen density in the detection of prostate cancer in patients with normal rectal examinations and intermediate prostate specific antigen levels

PURPOSE: The management of patients with a normal digital rectal examination and a prostate specific antigen (PSA) level of 4.0 to 10.0 ng./ml. remains controversial. To improve the specificity of cancer detection in this group, PSA density has been recommended with biopsies based on a PSA density of 0.15 or more. To evaluate PSA density as a discriminator of prostate cancer we enrolled patients in a prospective study. MATERIALS AND METHODS: A prospective evaluation was done of 44 consecutive patients with a palpably normal digital rectal examination and a serum PSA level of 4.0 to 10.0 ng./ml. enrolled during a 13-month period. All patients underwent transrectal ultrasound with sextant biopsies regardless of calculated PSA density. RESULTS: Overall, 8 of 44 men (18%) had prostate cancer. There was no significant difference in the mean PSA density between the patients with positive and negative biopsies (mean 0.12 and 0.15, respectively, p = 0.258). Also, there was no significant association between PSA or PSA density and a positive biopsy in multivariate analysis (p = 0.863). Receiver operating characteristic curves for PSA and PSA density failed to demonstrate any superior benefit for PSA density in this patient population. A PSA density of 0.15 was an unreliable indicator of cancer (sensitivity 12.5%, specificity 61.1% and positive predictive value 6.7%). CONCLUSIONS: In our study, PSA density did not discriminate between patients with positive and negative biopsies, and in fact most cancers would not have been detected if a PSA density of 0.15 or more had been used as the sole indication for biopsy. Therefore, we recommend systematic biopsies in these patients independent of calculated PSA density.     

Effect of sulpiride-induced hyperprolactinemia on serum testosterone response to HCG in normal men

In six normal volunteers hyperprolactinemia was induced by sulpiride (150 mg/day) for 10 days. Both before and during sulpiride hCG was injected; the higher testosterone response to hCG, when PRL levels were enhanced, suggests a possible stimulatory role of PRL on Leydig cells.     

Testosterone treatment in men with erectile disorder and low levels of total testosterone in serum

Since decreased serum levels of testosterone (T) do not necessarily predict good outcome of testosterone treatment for erectile disorder, the purpose, of this study was to determine which men with erectile disorder and decreased serum levels might benefit from treatment. From a sample of 31 men (mean age = 39 years), 15 (48%) with erectile disorder and decreased serum levels of T responded well after 8 weeks of testosterone treatment (100 mg of testosterone propionate in the sustained-release form given im once a week). Good treatment outcome was associated with several variables, but only high levels of luteinizing hormone (LH) and low values of the T/LH (testosterone/LH) ratio consistently emerged as significant correlates and/or predictors of effective treatment. Levels of LH above 7.5 IU/L or the values of the T/LH ratio equal to or below 0.87 nmol/IU in patients with erectile disorder and decreased serum levels of T suggest that testosterone treatment may be effective.     

Relationship of prostate-specific antigen levels to prostate volume and age in mass screening subjects

The current TNM staging system is helpful but still not enough to accurately determine prognosis of the patients with squamous cell carcinomas of the oral tongue. Histopathologic variables, however, may be more helpful for predicting nodal metastasis and locoregional recurrences. In this respect, histopathologic examinations were done retrospectively of tumor specimens from 60 patients with squamous cell carcinomas of the oral tongue. Besides T-stage and nodal involvement, histopathologic parameters of tumor thickness, perineural invasion, lymphovascular space invasion, the extent of lymphocyte infiltration and the invasion pattern statistically correlated with locoregional recurrences. For nodal metastasis, tumor thickness of 10 mm or more and the type of invasion pattern were statistically significant. These results revealed that the variables described should be used for managing oral tongue cancers.     

Isolation and characterization of free form prostate specific antigen (f-PSA) in sera of men with prostate cancer

PURPOSE: The free uncomplexed form of prostate specific antigen (f-PSA) from prostate cancer sera was partially isolated and characterized because the molecular form of f-PSA in the serum is unknown. MATERIALS AND METHODS: 230 ml. of sera from 59 men with bone metastasis and individual PSA values of >2000 ng./mL were combined and centrifuged for 60 minutes at 30,000 RPM (4C). The sera were fractionated by gel filtration column chromatography (Sephacryl S-200, 2.5 cm. x 92 cm.). Free and complexed PSA in the eluted fractions were isolated by measuring immunoreactivity of PSA (Tosoh AIA-600 assay); f-PSA from 23 separate runs were combined, concentrated and re-chromatographed. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was used to immobilize the isolated proteins onto a nitrocellulose membrane and a polyvinylidene difluoride (PVDF) membrane. Monoclonal antibody (F5) was used to probe PSA on nitrocellulose membrane and the PSA band was detected by Emission Chemoluminescence (ECL) kit. Amino terminal sequence analysis of the isolated f-PSA was performed with a gas-phase sequentor (Applied Biosyntens 4760 A) using the program designed by the manufacturer. RESULTS: 0.5 cc of f-PSA (27,000 ng./mL) was obtained from serums after rechromatography. SDS-PAGE showed one double band around 30 kDa; with ECL technique, one major band at 30-kDa was identified as PSA. The amino terminal sequence analysis of this band showed residue 1 through 9 and 146 through 152. CONCLUSIONS: In our preliminary experiment, the free form of serum PSA is partially isolated directly from human sera. Amino terminal sequence analysis has shown that serum f-PSA is not a pre-mature or zymogen form of PSA because serum f-PSA has a N-terminus identical to that of seminal fluid PSA. A nicked form of f-PSA is also found in these patient sera.     

The value of prostatic acid phosphatase and prostate specific antigen as serum markers in carcinoma of the prostate

The value of prostatic acid phosphatase (PAP) and prostate specific antigen (PSA) as serum markers in carcinoma of the prostate (CaP) was investigated in this study. A group of 75 patients entered this trial, 25 with CaP, 25 with benign prostatic hyperplasia (BPH) and 25 with urologic disorders other than prostatic diseases. In the CaP group, PAP was above normal levels in 48% of the patients and PSA in 92%. In the BPH group these rates were 20% and 72%, respectively. No elevation was detected in the third group. In CaP patients with capsular invasion, PAP and PSA levels were above normal in 25 and 87.5%. In metastatic carcinoma, PAP was high in 75% and PSA in 100%. Our study reveals that neither of these markers is useful in the initial diagnosis of CaP. Though PSA seems to be more sensitive, it is not more specific than PAP.     

A long follow-up on prostate specific antigen density and prostate biopsy

OBJECTIVE: To determine prostate specific antigen density (PSAD) in a risk population without evidence of prostatic cancer, and to assess the long-term usefulness of PSAD as a parameter for determining the need for a prostatic biopsy in patients with a normal digital rectal examination (DRE) and transrectal ultrasound (TRUS). METHODS: The records of 582 patients referred to the clinic between February, 1992 and February, 1994 were studied retrospectively. All these patients with lower urinary tract symptoms (LUTS) were evaluated based on the following parameters: digital rectal examination, serum PSA levels, prostate volume measured using transrectal ultrasound and PSAD. Prostatic biopsy was performed on 431 patients who had a serum PSA level greater than 4.0 ng/mL. A total of 299 patients (69.3%) had PSA levels between 4.0 and 10.0 ng/mL and represented the target population. The study had two parts, in the first one cancer was diagnosed just by one biopsy and in part II, the patients with negative biopsy in part I were followed for a two-year period and required 2 or 3 biopsies for diagnosis. Of the total of patients who had a negative prostate biopsy in part I of the study, 269 were followed for a period of two years with repeated prostate biopsies. RESULTS: Overall prostate cancer was detected in 22/299 (13.9%) patients, 6/105 (5.7%) with PSAD up to 0.15 and 16/194 (8.2%) with PSAD over 0.15 (p = 0.569). CONCLUSION: PSAD is a useful indicator in decreasing the number of negative biopsies in patients with benign prostatic hyperplasia. However, in a long-term follow-up the PSAD (cutoff level 0.15) was unable to predict which patients had a positive biopsy. According to our results, 5.6% of patients with prostate cancer will be missed using the PSAD criteria.     

Inverse correlation between serum testosterone and leptin in men

Besides its role in the regulation of energy balance, leptin seems to be involved in linking energy stores to the reproductive system. A gender-dependent difference exists in plasma leptin concentration and leptin messenger ribonucleic acid expression in rodents and humans. This difference does not seem to be explained simply by differences in the amount of body fat between genders. To elucidate the relationship of endogenous testosterone and leptin, we studied the serum leptin concentrations in 269 elderly nondiabetic men. In addition, to assess whether exogenously administered testosterone could influence leptin production, we followed the serum levels of leptin in 10 healthy men during a 12-month treatment with 200 mg testosterone enanthate, i.m., weekly for contraceptive purposes. We found that the serum leptin concentration correlated inversely (r = -0.39; P < 0.001) with that of testosterone in elderly men. This inverse correlation was still present when body mass index and plasma insulin were included in the analysis. The administration of testosterone to young men suppressed serum leptin from the pretreatment level of 3.4 +/- 1.4 to 1.9 +/- 0.6 micrograms/L during the therapy. After cessation of testosterone injections, serum leptin concentration returned back to the pretreatment level. It is concluded that testosterone has a suppressive effect on leptin production, as reflected by circulating levels of this hormone.     

Elevated prostate-specific antigen levels in black men and white men

The usual ranges for prostate-specific antigen (PSA) are derived from a community-based population of White men but are used for screening on all men on the assumption that the differences between the PSA levels of different racial groups are small or have no clinical significance. Recently published reports, however, suggest that PSA levels in a specific racial population may vary directly with the relative risk of prostatic cancer within that population. PSA ranges were determined in Black and White men registered with the Veterans Affairs Maryland Health Care System, Baltimore, Maryland. The total patient census of 122,602 has near-equal numbers of Black and White men and maintains records of race designation for inpatients. Among the male patients with no known prostatic cancer, there were 10,808 men 40 years of age or older and 19,482 PSA test results. In this group, there were 3274 men identified as Black; 2993 identified as White, Not of Hispanic Origin, and 4541 identified as Other Race or Race Unknown. The 95th percentile PSA values in Black men and White men 40 through 49 years of age were 2.80 ng/mL and 2.01 ng/mL, respectively; 50 through 59 years old, 5.40 ng/mL and 4.19 ng/mL, respectively; 60 through 69 years old, 9.59 ng/mL and 7.00 ng/mL, respectively; 70 through 79 years old, 15.45 ng/mL and 9.40 ng/mL, respectively; and for men older than 80 years of age, the 95th PSA values were 21.05 ng/mL in Black men and 18.25 ng/mL in White men. In every age group, Black men had a higher range (for the 95th percentile) than did White men. The largest difference was found in men 70 through 79 years old; in this age group, the ratio of the upper limit of PSA for Black men compared with White men was 1.6 ng/mL.     

Prostate specific antigen in the expressed prostatic fluid of men with benign prostatic hyperplasia and prostate carcinoma

PURPOSE: We tested the hypothesis that the histochemically demonstrated prostate specific antigen (PSA) content of prostate carcinoma cells does not necessarily reflect PSA production and secretion by evaluating expressed prostatic fluid. MATERIALS AND METHODS: Expressed prostatic fluid and serum from 152 men with clinical benign prostatic hypertrophy (BPH), 132 with histologically proved BPH and 46 with prostate carcinoma were analyzed with the Hybritech PSA assay. RESULTS: Expressed prostatic fluid PSA levels from carcinoma patients (median 1.70 mg./ml., mean 2.25) were significantly higher than in the histologically proved BPH group (median 1.28 mg./ml., mean 1.42, p < 0.05). CONCLUSIONS: PSA concentration is increased in the expressed prostatic fluid of prostates of men with carcinoma compared to those with histological BPH. This finding may be a functional manifestation of a field change or paracrine effects within the prostate.     

Relationship between prostate specific antigen density, microvessel density and prostatic volume in benign prostatic hyperplasia and advanced prostatic carcinoma

BACKGROUND: Paravertebral block has successfully been used in the treatment of acute and chronic pain. The duration of paravertebral block could theoretically be prolonged by using neurolytic agents. METHODS: We retrospectively analyzed the results of neurolytic paravertebral blocks performed in 7 patients suffering from intense cancer-related thoracic pain. Thirty-seven spinal nerve roots were blocked during 20 visits. Nerve roots were identified by eliciting paresthesia radiating to the painful area. Each root was blocked separately. After test block using 0.5% bupivacaine, the paravertebral blocks were performed with 1-4 ml of 7% phenol in aqua. RESULTS: No technical failures or complications were recorded in the patient files. Pain relief lasted over 2 months after 4 visits (20%), from 1 week to 1 month after 5 visits (25%), and less than 1 week after a single visit (5%). After 9 visits (45%), the results were poor with no significant pain relief. CONCLUSION: Neurolytic paravertebral block with phenol doses used in our patients appears to have only limited use. Some patients with pain restricted to a small number of thoracic segments may benefit from its use. Because of complication risks, this technique should be limited to intractable pain in cancer patients with poor prognosis.