Spermatogenesis In Infertile Men Research Articles

Defective Spermatogenesis in Cryptorchid Testes: Cause or Effect?

Martin et al. (2008) recently published their quantitative meta-analysis focusing on the estrogen hypothesis of testicular dysgenesis syndrome. I congratulate the authors on their thorough review and excellent summary of the existing literature. The study findings are in line with other articles; however, there are several concerns that need further attention. Martin et al. (2008) pointed out that a common etiology underlies impaired spermatogenesis, male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer. I am especially interested in exploring the relationship between defective spermatogenesis and cryptorchidism. Maldescended testes is commonly cited as an important cause for defective spermatogenesis (Tomomasa et al. 2002). In contrast, testicular ascent (acquired cryptorchidism) could also be a risk factor for spermatogenesis in infertile men without any history of maldescended testes (Mieusset et al. 1997). However, it remains controversial whether impaired testicular function and spermatogenesis imparts an increased risk—and therefore represents a common pathogenetic mechanism of both congenital and acquired cryptorchidism—or is merely associated with disease. Recently, a potential link was proposed relating spermatogenesis and testicular descent (Skandhan and Rajahariprasad 2007). Observational studies of many lower animals (rodents, bats, and insectivores) have revealed that testicular position is dependent on its functional status: It is scrotal during breeding seasons and inguinal or abdominal at other times (Bannister and Dayson 1995). Therefore, it is possible that maldescended testes or acquired testicular ascent simply report a state of defective testicular function and spermatogenesis. In animal studies, estrogen has been shown to increase the number of type A spermatogonia, together with inhibition of their differentiation into further steps (Kula et al. 1997). Furthermore, supportive evidence suggests that undifferentiated type A spermatogonia are the only germ cells present in cryptorchid testes (Nishimune et al. 1978). I believe that the results of Martin et al. (2008) would have been more convincing if the authors could have shown that high levels of estrogens suppress spermatogenesis. The data of Martin et al. (2008) do not allow us to extrapolate whether exposure to environmental chemicals and pollutants with estrogenic or antiandrogenic effects can cause testicular “ascent” (Barthold and Gonzalez 2003). There is strong experimental evidence that prenatal exposure to environmental chemicals, including phthalate esters, is associated with an increased risk of postnatal cryptorchidism (Imajima et al. 1997). The similarity in the histopathology of the ascending testis and the testis undescended since birth suggests that ascending testes are not retractile testes trapped in scar tissue (Rusnack et al. 2002). Furthermore, this finding also suggests that, as in primary undescended testes, estrogen/antiandrogen hypotheses could explain the cause of ascending testes, because a thermal effect cannot be blamed for the decreased germ cell count in the descended testis. Overall, the systematic review and meta-analysis by Martin et al. (2008) is the most extensive attempt to date to investigate the link between estrogenic agents and testicular dysgenesis syndrome. Although some of the data from the cited studies are of limited quality, the fact that nearly all of the included studies identified an increase in the risk of hypospadias, cryptorchidism, and testicular cancer in the groups prenatally exposed to diethylstilbestrol provides strong support for that association being genuine. However, from the data of Martin et al. (2008), we cannot conclude whether exposure to environmental chemicals with estrogenic effects significantly increases the risk of developing acquired cryptorchidism. Further research to evaluate the effects of endocrine-disrupting chemicals (EDCs)—particularly those with estrogen-like effects on reproductive health—is justified and should continue.

Sperm aneuploidy and meiotic sex chromosome configurations in an infertile XYY male

There is little information regarding the behaviour of the extra Y chromosome during meiosis I in men with 47,XYY karyotypes and the segregation of the sex chromosomes in sperm. We applied immunofluorescent and FISH techniques to study the relationship between the sex chromosome configuration in meiotic germ cells and the segregation pattern in sperm, both isolated from semen samples of a 47,XYY infertile man. The sex chromosome configuration of pachytene germ cells was determined by immunostaining pachytene nuclei for synaptonemal complex protein 3 (SCP3) and SCP1. FISH was subsequently performed to identify the sex chromosomes and chromosome 18 in pachytene cells. Dual- and triple-color FISH was performed on sperm to analyse aneuploidy for chromosomes 13, 18, 21, X, and Y. 46,XY/47,XYY mosaic pachytene cells were observed (22.2% vs. 77.8%, respectively). The XYY trivalent, and X+YY configurations were most common. While the majority of sperm were of normal chromosomal constitution, an increase in sex and autosome disomy was observed. The level of germ cell moscaicism and their meiotic sex chromosome configurations may determine sperm aneuploidy rate and fertility status in 47,XYY men. Our approach of immunostaining meiotic cells in the ejaculate is a novel method for investigating spermatogenesis in infertile men.

Increased testicular 8‐hydroxy‐2′‐deoxyguanosine in patients with varicocele

To assess immunohistochemically 8-hydroxy-2'-deoxyguanosine (8-OHdG, a sensitive biological marker of oxidative damage and stress) in testicular tissue from patients with varicocele, to determine whether 8-OHdG is related to spermatogenesis, as oxidative stress in testicular DNA is associated with poor semen quality and reduced fertility. Testicular tissue samples were collected from the testes of 36 patients with varicocele and five normal volunteers. The mean (sd) age of the patients was 35.3 (5.4) years. The prevalence of immunostained germ cells among all the germ cells in >20 seminiferous tubules was calculated. The mean (sd) sperm concentration and Johnsen's score in the varicocele group was lower than in the normal group, at 27.6 (11.8) vs 80.4 (21.7) million/mL (P < 0.001) and 7.6 (1.1) vs 9.0 (0.7), respectively (P < 0.05). In all patients, 8-OHdG was mainly expressed in the spermatogonia and spermatocytes in the seminiferous tubule. Immunostained germ cells correlated negatively with sperm concentration (r = -0.48, P = 0.01) and Johnsen's score (r = -0.46, P = 0.02), but not with follicle-stimulating hormone, luteinizing hormone or testosterone level. Immunostained germ cells were significantly more prevalent in the varicocele group, at 53.6 (5.7)%, than that in the normal group, at 14.3 (2.3)% (P < 0.001). The prevalence of immunostained germ cells and clinical grades were positively related; the ratio recorded for varicocele grades I, II and III was 38.0 (10.0)%, 41.0 (9.1)%, and 57.0 (9.3)%, respectively (grade I vs grade III, P < 0.05). Increased 8-OHdG expression in the testis was associated with deficient spermatogenesis in infertile men with varicocele.

Nitric oxide produced in the testis is involved in dilatation of the internal spermatic vein that compromises spermatogenesis in infertile men with varicocele

To determine the concentration of nitric oxide (NO) and the location and change in the expression of NO synthase (NOS) isoforms in the testes of subfertile men with varicocele, and to compare the NO concentration or NOS expression with clinical variables, to determine the role of NO on the pathophysiology of varicocele. In all, 27 men who had a left varicocelectomy and five with 'normal' spermatogenesis (controls) who had scrotal surgery for other reasons were enrolled. Intratesticular fluid was taken from the men and the NO concentration determined colorimetrically. The expression and location of NOS isoforms were examined by Western blotting and immunohistochemistry, using testicular biopsy specimens, and NADPH-diaphorase (NADPH-d) staining used to identify NO-producing cells. The relationship between the NO concentration and the expression of NOS isoforms or clinicopathological variables was investigated. In testes with grade 2 and 3 varicoceles there were significant increases in the concentration of NO or the expression of inducible NOS. There was no change in the expressions of endothelial NOS, which is located in vascular endothelial cells, while NADPH-d activity was mainly located in these cells. The concentration of NO was significantly correlated with the maximum and total vein diameter (both P<0.01). In patients aged>35 years, the concentration of NO significantly correlated with a deterioration in total motile sperm count (P<0.05). Increased production of NO in the testis is involved in the enlargement of varicocele and indirectly deteriorates spermatogenesis.

The safety of ultrasonically guided testis aspiration biopsies and efficacy of use to predict varicocelectomy outcome

We hypothesized that infertile men with varicoceles have molecular/genetic defects that interact with varicoceles to induce infertility. Studies directly on testis tissue appeared to be a way to link histology, markers for molecular/genetic defects and spermatogenesis, but testis biopsies may induce morbidity. In this report, we present safety and efficacy data on ultrasonically guided, single stick, percutaneous aspiration. Biopsies were performed on 115 infertile men with varicoceles and five men with obstructive azoospermia. Morbidity was examined by pre- and post-biopsy ultrasound, efficacy by ability of two markers to predict >50% increase in sperm density post-operatively. All patients had three pre- and three post-operative semen analyses. 78.3% of patients had no ultrasonic testicular defects immediately post-biopsy. By 2 months, 100% had no defects. Biopsy markers [testicular cadmium (<0.453 ng/mg tissue) and an intact calcium channel mRNA sequence] predicted >50% increase in sperm density with 82.9 and 90.5% accuracy, respectively. Ultrasonically controlled, percutaneous aspiration testis biopsies are safe. Specimens so acquired can assist study of molecular/genetic markers associated with spermatogenesis in infertile men with varicoceles. Tissue cadmium level, calcium channel sequence and other markers may predict outcome of varicocele surgery.

Serum inhibin pro alphaC in infertile men.

Specific assays have been developed for bioactive inhibin dimers, inhibin A and B, and inhibin alpha-subunit precursor pro alphaC. To better understand the role of serum inhibin pro alphaC in infertile men, the authors measured these forms of inhibin in sera from 39 infertile men and analyzed inhibin relationships with serum gonadotropins, testosterone, and estradiol. All subjects had oligozoospermia. Inhibin A levels were undetectable in all subjects. Inhibin B concentrations were 117 +/- 59 pg/mL. Inhibit B concentrations correlated negatively with serum FSH (r = .584, p < .0001) and positively with sperm count (p < .01) and bilateral testicular volume (r = .607, p < .0001). The concentration of pro alphaC was 556 +/- 236 pg/mL (normal range, 446 +/- 28). Inhibin pro alphaC showed no correlation with serum FSH, LH, testosterone, sperm concentration, and bilateral testicular volume. In addition, inhibin pro alphaC was not correlated with inhibin B. Pro alphaC is unlikely to be a useful marker for spermatogenesis in infertile men compared with inhibin B.

Deoxyribonucleic Acid Flow Cytometry in the Assessment of Spermatogenesis

Purpose We compared deoxyribonucleic acid (DNA) flow cytometric analysis of testicular tissue to quantitative assessment of spermatogenesis. Materials and Methods We studied 35 infertile men with azoospermia or oligospermia. All patients underwent incisional testicular biopsies. DNA flow cytometric analysis was performed on each specimen to evaluate the ability of the method to quantify alterations in spermatogenesis. The results were compared to quantitative histological examination. At least 100 spermatic tubules were examined on each specimen and the number of spermatids per tubule was counted. All histological specimens were examined by the same pathologist. Results Of the 35 specimens analyzed with DNA flow cytometry 5 were normal, while the percentage of haploid cells (spermatids and spermatozoa) was decreased (hypospermatogenesis) in 14, complete maturation arrest was noted in 2 and almost complete absence of haploid cells was found in 14. Comparing the findings on histological examination with histograms, excellent correlation was noted in cases of the Sertoli-cell-only syndrome and complete maturation arrest, while 3 of 14 histograms with hypospermatogenesis demonstrated normal spermatogenesis on histological examination. Additionally 1 of 5 histograms with normal spermatogenesis demonstrated hypospermatogenesis on histological examination. Conclusions DNA flow cytometry of the testicular tissue seems to be an objective and quantified method that can be used to investigate spermatogenesis in infertile men. It is also less time-consuming than any histological examination, permits management decisions within 1.5 hours after biopsy and may replace testicular histopathological study. Flow cytometric diagnoses correlated well with histopathological findings.

Increased oestradiol level in seminal plasma in infertile men.

Seminal hormonal patterns in fertile and infertile men were investigated. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, testosterone and oestradiol were assessed by radioimmunoassay, and dehydroepiandrosterone sulphate (DHAS) by bioluminescence assay, on blood and seminal plasma of 23 fertile men and 83 infertile men. For fertile men, mean FSH, LH, testosterone and DHAS concentrations were lower and mean oestradiol was higher in seminal than in blood plasma; prolactin did not differ. For infertile men, mean seminal FSH and LH showed a moderate but significant increase compared with fertile men; testosterone, DHAS and prolactin did not differ but mean seminal oestradiol was significantly increased. Of the infertile men, 53% had seminal oestradiol concentration above the 90th percentile value for fertile men. The meaning of this seminal oestradiol increase is unclear since it is not known whether it is the cause or the consequence of the alteration of spermatogenesis in infertile men. Further studies are required to explore the possible therapeutic implications.

Association of scrotal hyperthermia with impaired spermatogenesis in infertile men

Scrotal temperatures, testicular volumes, and sperm characteristics were studied in 150 infertile, nonazoospermic men and in 37 fertile men, used as a control group. The mean scrotal temperature values of the infertile men were significantly greater than those observed in the fertile men (+0.4 degrees C for the right; +0.5 degrees C for the left). In the infertile men, it was found that the higher the scrotal temperature, the more alterated the sperm characteristics. The only clinical element that seemed to be linked to the existence of scrotal hyperthermia in the infertile men was testicular hypotrophy. Although the scrotal temperatures of the infertile men with varicocele were significantly higher than those of the fertile men, they did not significantly differ from those of the infertile men without varicocele. No other specific pathologic factor, infectious or surgical urogenital history was found to be responsible for the scrotal hyperthermia observed in the infertile men.

Testicular Testosterone Concentration, Interstitial Cell Density and Spermatogenesis in Infertile Men

No AccessJournal of Urology1 Apr 1982Testicular Testosterone Concentration, Interstitial Cell Density and Spermatogenesis in Infertile Men A.V. Hirsh, J.P.P. Tyler, G. Landon, R.C.B. Pugh, K.M. Cameron, J.P. Pryor, and W.P. Collins A.V. HirshA.V. Hirsh More articles by this author , J.P.P. TylerJ.P.P. Tyler More articles by this author , G. LandonG. Landon More articles by this author , R.C.B. PughR.C.B. Pugh More articles by this author , K.M. CameronK.M. Cameron More articles by this author , J.P. PryorJ.P. Pryor More articles by this author , and W.P. CollinsW.P. Collins More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(17)54089-6AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Testicular Testosterone Concentration, Interstitial Cell Density and Spermatogenesis in Infertile Men." The Journal of Urology, 127(4), p. 839 © 1982 by The American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 127Issue 4April 1982Page: 839 Advertisement Copyright & Permissions© 1982 by The American Urological Association Education and Research, Inc.MetricsAuthor Information A.V. Hirsh More articles by this author J.P.P. Tyler More articles by this author G. Landon More articles by this author R.C.B. Pugh More articles by this author K.M. Cameron More articles by this author J.P. Pryor More articles by this author W.P. Collins More articles by this author Expand All Advertisement PDF downloadLoading ...

Testicular testosterone concentration, interstitial cell density and spermatogenesis in infertile men.

The concentration of testosterone was estimated in testicular biopsies taken from infertile men under general anaesthesia and was found to vary between 0.77 and 9.87 nmol/g wet tissue (median 3.41 nmol/g). Spermatogenesis was assessed by the Johnsen scoring technique but there was no evidence of a deficiency of intratesticular testosterone being associated with dysfunction of the seminiferous tubules. Similarly, there was no direct relationship with testicular size, clinical diagnosis, or the concentration of testosterone found in peripheral plasma taken at the same time as the testicular biopsy. These negative findings were not explained by variation in the volume densities of the Leydig cells assessed in 10 biopsies selected to the representative of the range of testosterone concentrations found in entire series. A retrospective comparison between the concentration of testosterone in peripheral plasma at the time of surgery and the available preoperative levels found in 10 patients provided further evidence for the previously reported lowering of testosterone levels by general anaesthesia. It is suggested that future studies of testicular androgens should be conducted on tissue obtained under local anaesthesia in order to eliminate this effect.