Studies on intratubular androgens in idiopathic male infertility

No significant effective therapy has been established for patients with idiopathic male infertility up to now. In order to assess the role of androgens in idiopathic male infertility, testosterone (T) and 5 alpha-dihydrotestosterone (DHT) levels in isolated seminiferous tubules (intratubular levels) were measured by radioimmunoassay (RIA) in 100 patients with idiopathic male infertility. RIA of T and DHT levels in the whole testis (intratesticular levels) were also conducted simultaneously. Seminiferous tubules were separated by a two step incubation system using collagenase and mesh No. 100. 1. Intratubular T levels were higher than intratubular DHT levels with both azoospermia and oligozoospermia. 2. No significant correlations to either intratubular T or DHT levels were present in the plasma LH, FSH, or T levels and the thickness of seminiferous tubular wall. These data suggest that plasma hormones are not the main regulators for intratubular androgens. 3. Moderate correlation between the intratesticular T and intratubular T levels was noted (r = 0.49), but there was no correlation between the intratesticular DHT and intratubular DHT levels (r = 0.33). There was no significant correlation to either intratubular T or DHT as to the testicular volume or the mean germinal epithelium score count method of Johnsen. Therefore, it is considered that the intratubular T level is partially dependent on endogenous T secreted from Leydig cells. However, spermatogenesis may be regulated by various factors including the intratubular T level.     

Effects of steroids on oxytocin secretion by the human prostate in vitro

Oxytocin (OT) concentrations are elevated in prostate tissue of patients with benign prostatic hyperplasia (BPH). Oxytocin specifically increases growth, 5 alpha-reductase activity and contractility in the prostate. In the rat prostatic OT concentrations are regulated by gonadal steroids, with androgens reducing but oestrogens increasing OT concentrations. The regulation of prostatic oxytocin in man is not understood. This study investigates the effects of gonadal steroids on oxytocin production by the human prostate. Primary explants (approx. 1 mm3) of prostate tissue from patients with BPH were incubated in Dulbecco's modified Eagle's media in the absence or presence of 10 nmol/L testosterone (T), 10 nmol/L dihydrotestosterone (DHT), T or DHT plus 100 nmol/L of the anti-androgen cyproterone acetate (CPA), 55 pmol/L diethylstilbestrol (DES), or DES plus DHT. The amount of oxytocin secreted into the media after 3 days was measured by radioimmunoassay. Testosterone and DHT significantly increased oxytocin concentrations secreted into the media from 0.86 +/- 0.11 ng/g of tissue (control) to 1.51 +/- 0.14 ng/g (p < 0.01) and 1.54 +/- 0.13 ng/g (p < 0.05), respectively. Incubation of tissue samples with CPA resulted in oxytocin concentrations similar to control levels. Treatment with DES caused a significant increase from 1.99 +/- 0.71 to 3.98 +/- 1.36 ng/g (p < 0.05). A similar increase was measured in media of tissue incubated in DES plus DHT (p < 0.001). The results demonstrate that, unlike the rat where androgens decrease oxytocin, in hyperplastic human prostate tissue both androgens and oestrogens increase oxytocin. This imbalance in the regulation of oxytocin may result in promoting prostatic overgrowth in the pathogenesis of BPH.     

Testicular endocrine function in patients with prostatic cancer receiving medical castration by long-term administration of LH-RH agonists

Six patients with advanced prostatic cancer who had been treated by long-term administration of LH-RH agonistic preparations (Buserelin or Leupron) were tested for their pituitary-testicular endocrine functions. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), prolactin (PRL), estradiol (E2) and dihydrotestosterone (DHT) were measured consecutively. In all medically castrated patients, serum levels of LH, FSH, T, DHT and E2 were suppressed and particularly serum T levels were below the castration level of 1.0 ng/ml. On the other hand, serum PRL levels were unchanged after the long-term treatment with the agonists. Serum LH and FSH levels failed to respond to LH-RH stimulation after the treatment, whereas serum T responded to stimulation by human chorionic gonadotropin (hCG) to various degrees. It was remarkable that, in 4 out of 6 medically castrated patients treated up to more than 3 years, serum T response levels above 1.0 ng/ml were noted. It is suggested that testicular endocrine function to secrete T and DHT in patients under treatment with long-term LH-RH agonist administration are still preserved in response to hCG stimulation.     

Biological significance of measurable androgen levels in the rat ventral prostate following castration

Within 12 hr after castration, there is a dramatic drop in the serum testosterone (T) levels to approximately 1.3% of the intact value (2.5 +/- 0.8 ng/ml). By 1 day following castration, the serum T levels are approximately 3.3% of the intact control level. In contrast, serum 5 alpha-dihydrotestosterone (DHT) levels decrease to only 50% of the intact value within 12 hr postcastration and remain at a value greater than 50% of the intact control level even following long-term castration for up to 20 weeks. Following castration, tissue T and DHT concentrations in rat ventral prostate (RVP) exhibited a similar sequence of changes. Within 12 hr after castration, there is a substantial decrease in T to 27% and DHT to 20% of their intact values; after a further transient decrease during the subsequent 7 days, these levels remain constant with RVP at approximately 40% for T and 20% for DHT of the intact control levels even following long-term castration. Thus castration induces only a partial withdrawal of the tissue androgens. The low but measurable androgen levels in RVP of castrated host are of adrenal origin, since following surgical adrenalectomy these remaining androgen levels become undetectable. Thus castration plus adrenalectomy produces a complete androgen withdrawal within the RVP. To determine the biological significance of the measurable androgen levels remaining following castration, the RVP cell number and the rate of prostatic DNA synthesis were compared in RVP following castration alone (ie, partial androgen withdrawal) or castration combined with surgical adrenalectomy (ie, complete androgen withdrawal). These results demonstrated that complete elimination of the remaining androgens in the RVP of long-term castrates, by means of surgical adrenalectomy, did not induce any further reduction in either of these prostatic growth parameters. Therefore, in the rat, DHT must be decreased to a critical threshold but does not have to be completely eliminated to decrease maximally androgen effect on the prostate.     

Study on ethane dimethane sulphonate (EDS)-induced spermatogenic damage and protective drugs against this damage in the rat]

The effects of a single administration of ethane dimethane sulphonate (EDS), which has a direct cytotoxic effect on Leydig cells, was assessed for its spermatogenic damage and intratubular androgen level in SD male adult rats. The protective effect of human chorionic gonadotropins (hCG) (s.c.), testosterone propionate (TP) (s.c.) and intratesticular administration of testosterone microcrystal suspension (Tmcs) against the spermatogenic damage in rats EDS given was also evaluated. EDS caused a decrease of the seminiferous tubular diameter and impaired spermatogenesis remarkably; moreover, it also caused significant decreases in intratubular androgen levels. These results suggest that EDS-treated SD male adult rats may be suitable as a model for hormone dependent infertility. The administration of hCG and intratesticular Tmcs prevented tubular damage and increased the intratubular T level. On the other hand, the administration of TP prevented tubular damage while remarkably decreasing intratubular androgen level. In this connection, it was inferred that priming of rats with TP caused an increase in intratubular androgen binding protein, which would stimulate spermatogenesis. The fact that a single injection of Tmcs caused no tubular damage suggests that intratubular T level is one of the factors playing an important role in spermatogenesis and that an intratesticular injection of Tmcs may be useful for the treatment of some cases of idiopathic male infertility.     

Androgen receptor levels and androgen contents in the prostate lobes of intact and testosterone-treated Noble rats

Plasma testosterone (T) levels were correlated with androgen receptors, tissue content of T, and 5 alpha-dihydrotestosterone (DHT) in the three anatomically-discrete prostate lobes of intact and castrated Noble (Nb) rats bearing T-filled silastic capsules. Differences in androgen receptor content and tissue androgen levels were observed among the three prostatic lobes of intact Nb rats. Total (cytosolic and nuclear) androgen receptor levels were highest in the ventral prostate followed by the dorsolateral and anterior prostate lobes. In the ventral and anterior prostate, androgen receptors were found to be equally distributed between cytosols and nuclear extracts, whereas in the dorsolateral prostate, androgen receptors were predominantly nuclear (cytosolic: nuclear = 1.5). The ventral prostate had the highest total androgen content and DHT was the major tissue androgen in all three lobes. The ratio of tissue DHT:T varied among the lobes; the highest value was observed in the dorsolateral prostate. The higher proportions of nuclear androgen receptor, as well as the elevated tissue DHT:T found in the dorsolateral prostate compared to other lobes, suggest that differences in the androgen activation process may exist between the dorsolateral prostate and other prostatic lobes. Despite lower plasma and tissue T levels, the DHT content, weight and cytodifferentiation in all lobes of T-treated castrated rats closely approximated the situation found in intact animals. Total androgen receptor levels were, however, elevated in all prostatic lobes of T-treated, castrated rats as compared to intact controls. These increases were primarily attributed to the augmented levels of androgen receptor in the nuclear extracts of the three prostate lobes. Exposure of the prostate to a constant level of T, produced by silastic implantation, might be responsible for the higher total androgen receptor levels and enhanced nuclear androgen receptor retention found in the prostates of T-treated, castrated rats.     

A study of quantitative and qualitative abnormality of androgen receptor in patients with hypospadias associated with enlarged prostatic utricle]

The prostatic utricle, a rudimentary structure present in the male prostatic urethra, is currently thought to be of mixed origin, with its cranial portion being derived from müllerian duct and caudal segment from wolffian and müllerian ducts and the urogenital sinus. Enlargement of prostatic utricle has often been demonstrated in patients with hypospadias and its incidence increased according to the severity of hypospadias. It has been suggested that insufficient androgenic stimulation of the urogenital sinus and urethral groove during the critical period of sexual differentiation may cause this entity. Since 5 alpha-dihydrotestosterone (DHT) is a major androgen for the normal development of urogenital sinus, androgen receptor levels in the patients with hypospadias associated with enlarged prostatic utricle may concern this ontogenesis. Fibroblasts derived from penile skin in these patients were assayed for androgen receptor levels using dispersed whole cell binding assay after Eil (1970). Thermostability of androgen receptor in the same fibroblasts was also evaluated by the remaining androgen receptor activity after incubation at 42 degrees C, and expressed as a ratio (percentage) to the androgen receptor activity in the incubation at 22 degrees C. Preputial skin of endocrinologically normal boys in the same range of age (3 to 8 years) was served as controls. There was a significant difference in averages of maximum binding capacities of [3H]DHT to the androgen receptor between those of controls (n = 4) and patients with grade II utricle (n = 4) (89 +/- 5.7 (SE) x 10(2) sites/cell vs. 37 +/- 7.1 x 10(2) sites/cell).(ABSTRACT TRUNCATED AT 250 WORDS)     

DES lead-in to use of luteinizing hormone releasing hormone analogs in treatment of metastatic carcinoma of prostate

Luteinizing hormone releasing hormone (LHRH) analogs have been shown to be an effective alternative endocrine treatment of metastatic prostatic carcinoma. After a transient stimulation of testosterone (T) and dihydrotestosterone (DHT) during the first week of therapy, continued administration of LHRH analogs has reliably suppressed serum androgens to castrate levels. About 10 per cent of previously untreated patients begun on LHRH therapy will experience transient worsening of disease symptoms corresponding to the initial rise in androgen levels. In an attempt to eliminate the early rise of T and DHT, 9 patients with metastatic prostatic carcinoma were pretreated with diethylstilbestrol (DES), 3 mg/day, for one week prior to the initiation of LHRH therapy. Following this, both DES and LHRH were given concomitantly for a week, after which DES was discontinued. LHRH was then continued as long as patients experienced clinical benefit. T and DHT levels were performed pre-study and on days 4, 8-11, 13, 15, and 29 of study. Results indicate that pretreatment with DES did not completely prevent the rise in T and DHT seen during the first week of LHRH therapy, although T and DHT levels rose to only slightly above baseline during the first four days. T and DHT levels then markedly decreased, and castrate levels were achieved by day 29 of treatment.     

Testosterone and dihydrotestosterone levels in the epididymis, vas deferens and preputial gland of mice during sexual maturation

The levels of testosterone (T) and dihydrotestosterone (DHT) in the epididymis, vas deferens and preputial gland were assessed in mice from 1 to 90 days. The weight increase of these 3 organs was proportionately greater than that of the whole body until 50 or 60 days, and they attained their adult histological appearance approximately 20 days prior to puberty. Expressed in ng/g, the concentration of androgens (T+DHT) in the epididymis (14.3 to 36.5), vas deferens (6.6 to 24.0) and preputial gland (1.5 to 4.7) were higher than in plasma (0.2 to 3.6 ng/ml). The concentration of either androgen varied little during sexual maturation and was not correlated with circulating levels. The highest concentration of androgen (T+DHT) was observed at birth suggesting that the neonatal period is crucial for development of the accessory sexual organs. In the epididymis and preputial gland T was the predominant androgen during the infantile phase of development, whilst DHT predominated thereafter. In the vas deferens concentrations of T were always equal to or higher than those of DHT. These results suggest that the ability of the accessory sexual organs to accumulate androgens appears to be more important than the circulating concentration of androgens in determining their growth and differentiation.     

Simultaneous quantification of steroids in rat intratesticular fluid by HPLC-isotope dilution tandem mass spectrometry

An isotope dilution mass spectrometry method has been developed for the simultaneous measurement of picolinoyl derivatives of testosterone (T), dihydrotestosterone (DHT), 17β-estradiol (E(2)), and 5α-androstan-3α,17β-diol (3α-diol) in rat intratesticular fluid. The method uses reversed-phase high-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry. Following derivatization of 10-μL samples of testicular fluid with picolinoyl chloride hydrochloride, the samples were purified by solid phase extraction before analysis. The accuracy of the method was satisfactory for the 4 analytes at 3 concentrations, and both inter- and intraday reproducibility were satisfactory for T, DHT, and E(2). Measurements of intratesticular T concentrations in a group of 8 untreated adult rats by this method correlated well with measurements of the same samples by radioimmunoassay. As in men, there was considerable rat-to-rat variability in T concentration, despite the fact that the rats were inbred. Although its levels were more than an order of magnitude lower than those of T, DHT was measured reliably in all 8 intratesticular fluid samples. DHT concentration also varied from rat to rat and was highly correlated with T levels. The levels of E(2) and 3α-diol also were measurable. The availability of a sensitive method by which to measure steroids accurately and rapidly in the small volumes of intratesticular fluid obtainable from individual rats will make it possible to examine the effects, over time, of such perturbations as hormone and drug administration and environmental toxicant exposures on the intratesticular hormonal environment of exposed individual males and thereby to begin to understand differences in response between individuals.     

A study on the intratubular androgen receptor in male infertility

In order to investigate the presence of androgen insensitivity in patients with male infertility, intratubular androgen receptor (AR) was measured in patients with idiopathic oligozoospermia and azoospermia. The specimens were obtained by testicular biopsy or orchiectomy from 56 patients with oligozoospermia and 5 with azoospermia for clinical study, and 17 with varicocele, 22 with vas disorders and prostatic cancer, which had a mean germinal epithelium score count of 8.5 or greater by the method of Johnsen (JSC) for deciding the cut-off levels, as the control group. Intratubular AR was measured by a 5-point micro-receptor assay, an exchange assay with the DCC method, using 40 microliters of each sample extract and 3H-methyltrienolone as the ligand. The genital skin AR assay was also conducted simultaneously in 34 patients. The results were as follows: 1) No significant correlation was noted between intratubular ARs and genital skin ARs. 2) The maximum binding (Bmax) of AR in the total intratubular extract was intermediate between that of the cytosol fraction and the nuclear extract. 3) Significant correlation was noted between the Bmax of ARs by the micro-receptor assay and those by the conventional assay. 4) The Bmax of AR in the control group (n = 22) was 30.38 +/- 9.89 fmol/mg protein (mean +/- S.D.) and was over 11 fmol/mg protein in all cases. Therefore, 11 fmol/mg protein was decided as the cut-off level for androgen insensitivity. 5) Comparative studies were undertaken between two groups, i.e., low AR group and normal AR group, with AR as a parameter for male infertility.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of chronic oral testosterone undecanoate administration on the pituitary-testicular axes of hemodialyzed male patients

Testosterone undecanoate (TU) or placebo was administered orally (for 12 weeks) in a double blind study, to 19 patients with chronic renal insufficiency on hemodialysis in a daily dose of 240 mg. Effect on plasma testosterone (T), dihydrotestosterone (DHT), androstenedione (A), 110H androstenedione (110A), FSH, LH and PRL concentration and the pituitary responsiveness to LH-RH/TRH stimulation was studied. These hormone levels were determined before the study and after 6 and 12 weeks of treatment. There was a rise in plasma androgen concentration in all treated patients. Mean plasma DHT, A and 110A increased at 12 weeks from 0.3, 0.85 and 1.13 ng/ml to 1.13 (p less than 0.05), 1.4 (p less than 0.05) and 1.44 (p less than 0.05) respectively. There was no change in plasma T or free testosterone. However, basal LH, FSH fell progressively from 5.51 and 5.51 ng/ml to 2.13 and 1.84 ng/ml (p less than 0.05). The level of significance of these changes was confirmed when the response to LH-RH was considered. Basal plasma PRL also decreased from 376 microU/nl to 306 (p less than 0.05), but PRL response to TRH remained unchanged. In contrast, none of these modifications were observed in placebo-treated patients. We conclude that oral TU restored to normal the pituitary-testicular axis. This form of treatment should be preferentially chosen instead of intramuscular injections in these frequently heparinized patients on hemodialysis.     

Relationship of seminal plasma testosterone and dihydrotestosterone to sperm count and motility in man.

A radioimmunoassay previously described for serum T and DHT was adapted for use in the measurement of these hormones in seminal plasma. The seminal plasmas of 273 semen specimens were assayed for T and DHT concentration. Mean levels of these hormones for various sperm count and sperm motility categories were determined. We found that: (1) the DHT level of the azoospermic group was significantly lower than all other groups; (2) the T level of the group whose mean sperm count exceeded 40 x 10(6)/ml was higher than that of all other groups; (3) the DHT level of the group with absent sperm motility was lower than the level of all other groups; and (4) changes in sperm motility were not accompanied by changes in T levels. We concluded that idiopathic male subfertility as evidenced by oligospermia, azoospermia, and decreased sperm motility may be related to insufficient androgen production due to a primary intratesticular defect.     

Serum androgen bioactivity during 5alpha-dihydrotestosterone treatment in elderly men

The androgens used in the treatment of age-related androgen decline have different bioactivities that cannot be evaluated with conventional detection methods for serum steroids. We have recently developed a recombinant cell bioassay for the determination of androgen bioactivity in human serum that is based on androgen-specific interaction between the ligand-binding domain (LBD) and the N-terminal region of the androgen receptor (AR). In this work, we examined the effect of topically applied 5alpha-dihydrotestosterone (DHT; 7.5-10 g of 2.5% DHT gel daily for 6 months) on circulating androgen bioactivity in 14 men (age range, 51-63 years) with symptoms of andropause and pretreatment serum testosterone less than 15 nM, or serum sex hormone-binding globulin concentration greater than 30 nM, or both. The mean (+/-SEM) pretreatment androgen bioactivity was 3.3 +/- 0.3 nM testosterone equivalents, and the levels correlated with serum testosterone concentration (r =.55, P <.05). DHT gel treatment induced a sixfold increase (from 1.5 +/- 0.1 nM to 9.0 +/- 0.7 nM) in mean serum DHT level, whereas endogenous testosterone and estradiol levels measured with radioimmunoassays were suppressed by approximately 70% and approximately 50%, respectively (P <.0001). Concomitantly, serum androgen bioactivity increased by sevenfold (from 3.3 +/- 0.3 to 23.6 +/- 2.8 nM testosterone equivalents; P <.0001). We conclude that DHT gel therapy in elderly men significantly increases their circulating androgen bioactivity as measured with a mammalian cell bioassay. An androgen-specific bioassay such as ours may enable investigation of other androgens with different bioactivities, such as selective AR modulators.     

Interaction of prolactin and testosterone in the human prostate

Summary Three experiments were performed to determine whether human prolactin (hPr) affects prostatic uptake and metabolism of testosterone (T). 1) Patients with prostatic cancer were infused twice with radio-labelled androgens, the first time with basal hPr, the second time with oral thyrotrophin-releasing hormone (TRH)-elevated hPr. In 5/7, significant increases in metabolic clearance of dihydrotestosterone (DHT) and in conversion of T to DHT accompanied increased hPr. 2) The incorporation of labelled T into minced benign prostatic hypertrophy (BPH) tissue from subjects with high (40 ng/ml) hPr was measured and was found to be more than twice the uptake into tissue from those with low hPr (6.5±1.9 ng/ml). 3) Uptake and metabolism in vivo of a bolus of ³H-T by BPH and carcinomatous prostates was measured and was far greater in subjects whose hPr was elevated by chlorpromazine than in untreated controls. It is concluded that prolactin increases prostatic uptake and metabolism of T. It is suggested that the best management of prostatic cancer should include depletion of prolactin as well as androgen.Presented at the Annual Meeting of the Endocrine Society, Chicago, Illinois, 1977Supported by Grant CI126 from the American Cancer Society and Veterans Administration Medical Research Funds     

Functional and anatomical effects of hormonally induced experimental prostate growth: a urodynamic model of benign prostatic hyperplasia (BPH) in the beagle

BACKGROUND: Benign prostatic hypertrophy (BPH) produces a variety of changes in the urodynamic pattern of micturition and is usually associated with high detrusor voiding pressure and poor urine flow-rate. In most previous experimental models, designed to simulate this condition, some degree of obstruction is immediately imposed by the technique employed to produce urethral occlusion. Consequently these models cannot reproduce the gradual onset of obstruction. In the present study a canine prostatic enlargement model, using 5alpha-dihydrotestosterone (DHT) + 17beta-estradiol (E) was adapted in order to produce a more gradual onset of partial obstruction and impaired voiding. MATERIALS AND METHODS: Hormonally induced prostatic enlargement was produced using seven beagles, given DHT 75 mg/day together with E 0.75 mg/day for 28 days via an implantable pump. The functional effects of DHT + E treatment on micturition pressure/flow were measured in the conscious animal. Identical measurements were also made using a separate older group of five beagles with symptoms of BPH. In addition seven beagles similarly instrumented were used as controls. RESULTS: Pressure/flow studies show that DHT + E produced obstructive micturition, characterized by a significantly increased micturition detrusor pressure, from 33.3 +/- 10.5 to 50.8 +/- 10.7 cmH(2)O and significantly decreased low urine flow-rate from 8.6 +/- 2.1 to 6.9 +/- 0.9 ml/sec. Associated with the obstructive micturition, this treatment increased wet prostate weight from 11.9 +/- 2.5 to 31.6 +/- 10.0 g. Prostate volume of the BPH beagles was 29.3 +/- 8.9 g. Morphologic studies show that DHT + E produced epithelial hyperplasia extending focally into the lumen. CONCLUSIONS: Hormonally induced prostate growth produced bladder obstruction, in terms of pressure/flow characteristics, that are analogous to BPH. It is suggested that this type of hormonal treatment can be used to create a model for the study of the effects of controlled increased in prostate growth and the development of BPH on micturition.     

Failure to maintain a suppressed level of serum testosterone during long-acting depot luteinizing hormone-releasing hormone agonist therapy in patients with advanced prostate cancer

OBJECTIVES: It was the aim of this study to analyze the failure rates in achieving or maintaining castrate levels of serum testosterone in patients with advanced prostate cancer treated with the 3-month luteinizing hormone-releasing hormone agonist (LH-RH) therapy. METHODS: Total serum testosterone was determined in 234 patients with prostate cancer in a cross-sectional study. A subset of 90 patients submitted to radical prostatectomy was used as the control group (group 1), and 144 patients with advanced prostate cancer under androgen suppression therapy were included in the study group (groups 2 and 3). The study group was divided into 93 patients (group 2) treated with 50 mg daily bicalutamide and LH-RH agonist (maximal androgen blockade, MAB) and 51 patients treated with the LH-RH agonist alone (group 3). Median follow-up after androgen suppression was 42 months. The castrate testosterone level was defined below 50 ng/dl. RESULTS: The mean serum testosterone level was 29.1 ng/dl in patients undergoing MAB (group 2) and 29.5 ng/dl in patients treated with the LH-RH agonist (group 3; p > 0.05). In group 1, the mean serum testosterone was 445.2 ng/dl (p < 0.0001). The rate of patients with a serum testosterone level higher than 50 ng/dl was 10.9% in patients undergoing androgen suppression, 10% in patients with MAB treatment and 12.5% in those with LH-RH agonist therapy (p > 0.05). In group 1, 98.9% of the patients had a serum testosterone level higher than 50 ng/dl. CONCLUSIONS: A small but clinically significant rate of patients under 3-month LH-RH agonist therapy fail to achieve or maintain castrate testosterone serum levels. This finding supports the need of monitoring testicular response during LH-RH agonist therapy.     

A study on usefulness of the crude nuclear DHT measurement in prostatic cancer patients

The nuclear and crude nuclear 5 alpha-dihydrotestosterone (DHT) levels were measured in patients with benign prostatic hypertrophy (BPH) and prostatic cancer (PC). In the fundamental study using BPH tissues, nuclear DHT levels were not influenced by the treatment for nuclear purification such as DTT, Triton X-100 or DNase I. The correlation between DHT levels and androgen receptor contents was found in only the crude nuclear salt extractable fractions (r = 0.748, p less than 0.01). In the relation of DHT levels to prostatic cancer patients, crude nuclear salt extractable and salt resistant DHT in both the low grade and in early stage group were significantly higher than those in the high grade and in advanced stage. Moreover, DHT levels in the both crude nuclear salt extractable and salt resistant fractions were below 5 pg/mg protein in all of clinical non-responders to endocrine therapy, and the total crude nuclear DHT, the sum of the crude extractable and salt resistant DHT, was below 10 pg/mg protein in all of the non-responders to endocrine therapy. When the relation between the total crude nuclear DHT level and the clinical course of 34 prostatic cancer patients followed for over 12 months was studied, the elevated DHT group (over 20 pg/ml protein) responded to endocrine therapy and experienced long-term remissions, but the low DHT group (below 10 pg/ml protein) did not respond to endocrine therapy. Therefore, it is suggested that the total crude nuclear DHT levels were appropriate biochemical indicators for androgen dependency in prostatic cancer patients.     

Prostate-specific antigen adjusted for the transition zone volume versus free-to-total prostate-specific antigen ratio in predicting prostate cancer

BACKGROUND: We performed this study to assess the efficacy of prostate-specific antigen adjusted for the transition zone volume (PSATZ) and free-to-total prostate-specific antigen (PSA) ratio (F/T ratio) in predicting prostate cancer in men with intermediate PSA levels of 4.1-10.0 ng/mL. METHODS: Between March 1997 and September 1998, PSATZ was obtained from 67 patients who underwent ultrasonography guided systemic sextant biopsies and had a PSA of 4.1-10.0 ng/mL. PSATZ was compared with F/T ratio via receiver operating characteristic (ROC) curves. RESULTS: Of 67 patients, 22 (32.8%) had prostate cancer and 45 (67.2%) had benign prostatic hyperplasia (BPH) on pathologic examination. Mean PSA, PSA density, F/T ratio and PSATZ were 7.96+/-2.01ng/mL, 0.28+/-0.14 ng/mL/cc, 0.10+/-0.06 and 0.70+/-0.28 ng/mL/cc in patients with prostate cancer and 6.39+/-1.68 ng/mL, 0.16+/-0.06 ng/mL/cc, 0.15+/-0.05 and 0.29+/-0.10 ng/mL/cc in patients with BPH, respectively. The ROC curve analysis demonstrated that PSATZ predicted the biopsy outcome significantly better than F/T ratio in all 67 patients (P<0.01) and in a subset of 53 men with normal digital rectal examination (P<0.01). With a cut-off value of 0.35 ng/mL/cc, PSATZ had a sensitivity of 86% and a specificity of 89% for predicting prostate cancer. CONCLUSIONS: These results suggest that PSATZ and F/T ratio may be useful in diagnosing prostate cancer with intermediate levels of PSA. Prostate-specific antigen adjusted for the transition zone volume is more accurate than F/T ratio in distinguishing benign prostatic disease from prostate cancer. But large prospective studies are required to assess the precise role of PSATZ and F/T ratio in early prostate cancer detection.