Charles H. Muller

Semen quality of men employed at a lead smelter.

OBJECTIVE: To evaluate the effects of recent and long term occupational lead exposure on indicators of male reproductive health. METHODS: In a cross sectional study of male employees of a lead smelter (n = 2469), blood samples were obtained from 152 workers including 119 who also provided semen samples. Semen analysis and serum concentrations of testosterone, follicle stimulating hormone, and luteinising hormone were used as indicators of reproductive health. Semen and hormone variables were examined in relation to measures of current and long term body lead burden estimated from current blood lead concentrations and historical blood lead monitoring data. RESULTS: For current blood lead concentration groups of < 15, 15-24, 25-39, > 40 micrograms/dl, the geometric mean sperm concentrations were, respectively, 79.1, 56.5, 62.7, and 44.4 million cells/ml and geometric mean total sperm counts were 186, 153, 137, and 89 million cells (P for trend 0.04). Compared with workers with blood lead concentrations less than 15 micrograms/dl, workers with current blood lead concentrations of 40 micrograms/dl or more had an increased risk of below normal sperm concentration (odds ratio (OR) 8.2, 95% confidence interval (95% CI) 1.2-57.9) and total sperm count (OR 2.6, 95% CI 0.4-15.7), based on World Health Organisation standards. Independent of current lead exposure, sperm concentration, total sperm count, and total motile sperm count were inversely related to measures of long term lead exposure. No association was found between lead exposure and measures of sperm motility, sperm morphology, or serum concentrations of reproductive hormones. CONCLUSIONS: Blood lead concentrations below the currently accepted worker protection criteria seem to adversely affect spermatogenesis.

Deletion of Type IIα Regulatory Subunit Delocalizes Protein Kinase A in Mouse Sperm without Affecting Motility or Fertilization

Cyclic AMP stimulates sperm motility in a variety of mammalian species, but the molecular details of the intracellular signaling pathway responsible for this effect are unclear. The type IIα isoform of protein kinase A (PKA) is induced late in spermatogenesis and is thought to localize PKA to the flagellar apparatus where it binds cAMP and stimulates motility. A targeted disruption of the type IIα regulatory subunit (RIIα) gene allowed us to examine the role of PKA localization in sperm motility and fertility. In wild type sperm, PKA is found primarily in the detergent-resistant particulate fraction and localizes to the mitochondrial-containing midpiece and the principal piece. In mutant sperm, there is a compensatory increase in RIα protein and a dramatic relocalization of PKA such that the majority of the holoenzyme now appears in the soluble fraction and colocalizes with the cytoplasmic droplet. Unexpectedly the RIIα mutant mice are fertile and have no significant changes in sperm motility. Our results demonstrate that the highly localized pattern of PKA seen in mature sperm is not essential for motility or fertilization.

Bacteria in the prostate tissue of men with idiopathic prostatic inflammation

PURPOSE Although antibiotics represent the first line of treatment for prostatitis syndromes, physicians can document infection in remarkably few cases. We examined the relationship of genitourinary infection to inflammatory prostatitis in 85 subjects without bacteriuria. MATERIALS AND METHODS Evaluation consisted of cultures of urethra, urine and transperineal prostate biopsies, specifically for commensal and fastidious organisms, and leukocyte counts of expressed prostatic secretions. RESULTS Men with inflamed expressed prostatic secretions (25) were more likely to have any bacterial isolation (p = 0.01), positive cultures for anaerobic bacteria (p = 0.03), higher total bacterial counts (p = 0.02) and more bacteria, species isolated (p = 0.02) in prostate biopsy cultures than men without expressed prostatic secretion inflammation (60). CONCLUSIONS Bacterial colonization/invasion of the prostate may be associated with inflammatory prostatitis in some cases.

Effects of clinical stage and immunological status on semen analysis results in human immunodeficiency virus type 1‐seropositive men

Summary. Complete semen analyses including computer‐assisted sperm motility and morphology assessments were performed to determine if semen and sperm differed between HIV‐seropositive men and fertile controls, or differed with symptoms, or CD4+ peripheral cell count categories. Previous studies included small numbers of men and presented conflicting conclusions. Two hundred and fifty non‐vasectomized HIV‐seropositive men and 38 fertile controls each provided one semen sample. Non‐parametric statistics were used to analyse both continuous and nominal data. Fertile men had significantly greater semen volume, sperm concentration, percent motility, percent rapid and linear motility and total strictly normal spermatozoa than HIV seropositive men. Neither total number nor subtypes of leukocytes in semen differed between the two groups. Among the HIV seropositive men, significant differences in semen analyses were found between CD4+ cell count, clinical, and AIDS categories. Lower CD4+ cell counts (<200 mm−3) were associated with significantly lower percent motility, percent normal sperm morphology by strict criteria, significantly more spermatids in semen, and higher percentages of teratozoospermia, oligoasthenoteratozoospermia and leukocytospermia. Healthier men, based on clinical categories, had significantly more normal shaped spermatozoa and fewer had azoospermia, oligoasthenoteratozoospermia or leukocytospermia. Many HIV‐seropositive men have normal semen analyses, but as the disease progresses more defects are found, particularly in strict criteria sperm morphology.

Bladder petechiae after cystoscopy and hydrodistension in men diagnosed with prostate pain

PURPOSE We determined if men with prostate pain syndromes have petechiae in the bladder after hydrodistension. MATERIALS AND METHODS A total of 60 men with the diagnosis of prostate pain and without bacteriuria underwent cystoscopy and hydrodistension under a general or regional anesthetic. RESULTS Of the 60 men 35 (58%) had moderate to severe petechiae similar in appearance to women with interstitial cystitis after hydrodistension. Men with moderate to severe bladder petechiae had fewer leukocytes in expressed prostatic secretions, smaller bladder capacities and less often testicular pain than men with more normal appearing bladders after hydrodistension. Symptomatic improvement 2 to 6 weeks after hydrodistension was more common in men with moderate to severe petechiae than in those with fewer petechiae. Absence of rectal pain predicted symptomatic improvement after hydrodistension. CONCLUSIONS We suggest that bladder petechiae, and possibly interstitial cystitis or a related condition, may be more frequently associated with prostate pain syndromes in men than previously appreciated.

Efficacy of treatment and recurrence rate of leukocytospermia in infertile men with prostatitis

OBJECTIVE To identify men with leukocytospermia and prostatitis in an infertility practice and evaluate the effect of various treatments and recurrence rates after treatment. DESIGN A prospective randomized trial of men with leukocytospermia. SETTING Academic tertiary infertility clinic. PATIENTS One hundred two men with leukocytosperimia identified on smear of semen using Bryan-Leishman stain and in expressed prostatic secretion. INTERVENTIONS Treatment groups were no treatment group; antibiotic treatment alone group; frequent ejaculation alone group; and antibiotic treatment with frequent ejaculation group. MAIN OUTCOME MEASURE Resolution of leukocytospermia on semen smear. RESULTS Significant resolution of leukocytospermia occurred in all treatment groups at 1 month compared with no treatment. The resolution was sustained at 2 and 3 months only in those who took antibiotics and frequently ejaculated. CONCLUSIONS Antibiotic treatment, frequent ejaculation, and antibiotic treatment with frequent ejaculation effectively treat leukocytospermia immediately after the treatment phase. However, only antibiotic treatment coupled with frequent ejaculation is effective 3 months after treatment.

PROSTATE BIOPSY CULTURE FINDINGS OF MEN WITH CHRONIC PELVIC PAIN SYNDROME DO NOT DIFFER FROM THOSE OF HEALTHY CONTROLS

PURPOSE Previous reports have identified bacteria in the prostate of men with chronic pelvic pain syndrome. To examine whether prostatic bacteria are more prevalent among patients with chronic pelvic pain syndrome than among those without pelvic pain, we compared 4-glass urine test and prostate biopsy results. MATERIALS AND METHODS A total of 120 patients with types IIIa and IIIb chronic pelvic pain syndrome and 60 asymptomatic controls underwent a standard 4-glass urine test, examination of expressed prostatic secretion leukocytes by hemocytometer and transperineal, digitally guided prostate biopsies. Tissue was cultured for aerobes, anaerobes, Trichomonas vaginalis, Chlamydia trachomatis and herpes simplex virus. Skin cultures were performed on a subset of patients and controls. RESULTS Positive prostate biopsy cultures were obtained from patients and controls. Bacteria were found in 45 of 118 pain patients (38%) and in 21 of 59 controls (36%) (p = 0.74). Older men were more likely to have positive cultures. Men with type IIIa chronic pelvic pain syndrome were more likely than those with type IIIb to have positive prostate biopsy cultures. CONCLUSIONS Bacteria cultured from transperineal prostatic biopsies do not differ between men with and without chronic pelvic pain syndrome. Prostatic bacteria obtained by biopsy are probably not etiologically related to the symptoms in the majority of men with chronic pelvic pain syndrome.

Suppression of Spermatogenesis by Bisdichloroacetyldiamines Is Mediated by Inhibition of Testicular Retinoic Acid Biosynthesis

The bisdichloroacetyldiamine WIN 18,446 reversibly inhibits spermatogenesis in many species, including humans; however, the mechanism by which WIN 18,446 functions is unknown. As retinoic acid is essential for spermatogenesis, we hypothesized that WIN 18,446 might inhibit retinoic acid biosynthesis from retinol (vitamin A) within the testes by inhibiting the enzyme aldehyde dehydrogenase 1a2 (ALDH1a2). We studied the effect of WIN 18,446 on ALDH1a2 enzyme activity in vitro, and on spermatogenesis and fertility in vivo, in mature male rabbits for 16 weeks. WIN 18,446 markedly inhibited ALDH1a2 enzyme activity in vitro with an IC(50) of 0.3 μM. In vivo, the oral administration of 200 mg/kg WIN 18,446 to male rabbits for 16 weeks significantly reduced intratesticular concentrations of retinoic acid, severely impaired spermatogenesis, and caused infertility. Reduced concentrations of intratesticular retinoic acid were apparent after only 4 weeks of treatment and preceded the decrease in sperm counts and the loss of mature germ cells in tissue samples. Sperm counts and fertility recovered after treatment was discontinued. These findings demonstrate that bisdichloroacetyldiamines such as WIN 18,446 reversibly suppress spermatogenesis via inhibition of testicular retinoic acid biosynthesis by ALDH1a2. These findings suggest that ALDH1a2 is a promising target for the development of a reversible, nonhormonal male contraceptive.

Advanced semen analysis: a simple screening test to predict intrauterine insemination success

OBJECTIVE To determine if a simple screening test of sperm recovery through a density gradient preparation and sperm survival after a 24-hour incubation is predictive of IUI success. DESIGN Prospective nonrandomized descriptive study. SETTING Tertiary assisted reproductive technology center. PATIENT(S) Four hundred fourteen couples undergoing IUI for male factor and unexplained infertility. INTERVENTION(S) An advanced semen analysis, which consisted of a basic semen analysis, sperm processing through a density gradient preparation, and a 24-hour sperm incubation, was performed on all couples before beginning IUIs. MAIN OUTCOME MEASURE(S) Cumulative and per cycle pregnancy rates (PRs) were calculated for routine semen parameters, number of sperm processed through density gradient, and percent motile sperm after a 24-hour incubation. RESULT(S) None of the basic semen analysis parameters accurately predicted IUI success. When the processed total motile sperm available for insemination was > or = 10 x 10(6) and their 24-hour survival was > or = 70%, 89% (162 of 182) of couples achieved a pregnancy with a 21.4% (162 of 757) per cycle PR compared to a 2.8% (11 of 403) per cycle PR and 4.7% total PR when survival was <70%. With use of these cutoff values for the advanced semen analysis, the test had a sensitivity of 94% and specificity of 86%. CONCLUSION(S) The number of motile sperm available for insemination and especially their 24-hour survival are highly predictive of IUI success. This advanced semen analysis is an excellent screening test to evaluate couples considering IUI.

Identification of Antigen-Specific IgG in Sera from Patients with Chronic Prostatitis

Antigen-specific vaccines are one of several molecularly targeted approaches under investigation as possible treatments for prostate cancer. Important to the development of vaccines is the identification of appropriate target antigens. We hypothesized that antigens of the prostate might be identified in patients with the chronic prostatitis/pelvic pain syndrome, a syndrome for which an autoimmune pathology has been proposed. Such antigens might represent naturally recognized target antigens of the prostate that could be investigated in the future as prostate tumor antigens. In this report, we used SEREX to identify proteins expressed in a prostate cDNA expression library recognized by IgG from the sera of patients with chronic prostatitis. Candidate proteins were evaluated using a panel of sera from 62 subjects with symptomatic prostatitis and 71 control male blood donors. We identified one protein that was recognized primarily in sera from subjects with prostatitis compared with controls. MAD-PRO-34, a nucleolar autoantigen, was recognized in 6/62 subjects and 0/71 controls (p = 0.00897). This protein had previously been identified as an autoantigen in patients with prostate cancer. In addition, the NY-CO-7 protein was recognized in 9/62 subjects and 3/71 controls (p = 0.0654). Two subjects had IgG specific for both the MAD-PRO-34 and NY-CO-7 gene products. Our results demonstrate that some patients with the chronic prostatitis/pelvic pain syndrome have autoantibodies to specific proteins. Proteins identified, and MAD-PRO-34 in particular, could be further investigated as potential prostate tumor antigens.