Willem P. A. Boellaard

Body mass index and central adiposity are associated with sperm quality in men of subfertile couples

BACKGROUND The incidence of overweight and obesity in men of reproductive ages is rising, which may affect fertility. Therefore, this study aims to assess the associations between BMI, central adiposity and sperm parameters in men of subfertile couples. METHODS Ejaculate volume (ml), sperm concentration (millions per ml), percentage of progressive motile and immotile spermatozoa and total motile sperm count (millions) were measured in 450 men of subfertile couples visiting a tertiary outpatient clinic for reproductive treatment and preconception counseling. RESULTS Overweight was negatively associated with the percentage of progressive motility type A [β -0.32 (SE 0.2), P=0.036] and positively associated with the percentage of immotility type C [β 0.21 (SE 0.07), P=0.002]. Obesity was negatively associated with ejaculate volume [β-0.23 (SE 0.1), P=0.02], sperm concentration [β -0.77 (SE 0.3), P=0.006] and total motile sperm count [β -0.91 (SE 0.3), P=0.007]. Waist circumference≥102 cm, a measure for central adiposity, was inversely associated with sperm concentration [β -0.69 (SE 0.2), P=0.001] and total motile sperm count [β-0.62 (SE 0.3), P=0.02]. All associations remained significant after adjustment for age, ethnicity, active and passive smoking, alcohol and medication use and folate status. CONCLUSIONS This study shows that in particular, sperm concentration and total motile sperm count in men of subfertile couples are detrimentally affected by a high BMI and central adiposity. The effect of weight loss on sperm quality and fertility needs further investigation.

Gonadal dysfunction in male cancer patients before cytotoxic treatment

Male patients diagnosed with cancer are often referred for semen cryopreservation before gonadotoxic treatment but often have low semen quality. The aim of this study was to evaluate which type of cancer affects gonadal function and proposes a risk factor for low pre-treatment semen quality. Between January 1983 and August 2006, 764 male cancer patients were referred for semen cryopreservation prior to chemotherapy and radiotherapy. We compared semen characteristics and reproductive hormones between different groups of cancer patients. In addition, we evaluated the role of tumour markers in patients with testicular germ-cell tumours (TGCT) on fertility. Abnormal semen parameters were found in 489 men (64%) before cancer treatment. Patients with TGCT and extragonadal germ-cell tumours had significantly lower sperm concentrations and inhibin B levels than all other patient groups. No semen could be banked in 93 patients (12.2%). Eight hundred and thirty-nine of 927 (90%) produced semen samples were adequate for cryopreservation. Inhibin B in all groups showed to be the best predictor of semen quality. Although pre-treatment raised tumour markers were associated with a decrease in inhibin B and increased follicle stimulating hormone, both predictive for low semen quality; no direct linear association could be found between raised beta-HCG, alfa-fetoprotein and semen quality. Only 1/3 of cancer patients had normal semen parameters prior to cancer treatment. Patients with TGCT and extragonadal GCT have the highest risk for impaired semen quality and gonadal dysfunction at the time of semen cryopreservation.

Heterogeneous Distribution of ITGCNU in an Adult Testis: Consequences for Biopsy-Based Diagnosis

Carcinoma in situ (CIS) of the testis, also referred to as intratubular germ cell neoplasia unclassified (ITGCNU), is currently accepted as the common precursor for all malignant germ cell tumors of adolescents and adults— that is, the seminomatous and nonseminoma cancers. These preinvasive cells have specific cellular characteristics, which can be used for the early diagnosis—routinely done by morphological analysis, sometimes supported by immunohistochemistry—of tissue obtained by an open surgical biopsy. False-negative biopsy results can occur mostly because of the nonrandom distribution of ITGCNU within the testis, misdiagnosis, or suboptimal tissue treatment and analysis. In this article, we demonstrate the potential pitfalls in the diagnosis of ITGCNU. The results support the use of the highly specific and sensitive immunohistochemical marker OCT3/4 for the diagnosis of ITGCNU and provide evidence for the nonrandom distribution of ITGCNU, which is a significant limitation in the diagnosis of this preinvasive lesion.

Management of Single Large Nonstaghorn Renal Stones in the CROES PCNL Global Study

PURPOSE We compared stone characteristics and outcomes in patients with a single large nonstaghorn renal calculus treated with percutaneous nephrolithotomy in the Clinical Research Office of Endourological Society global study. MATERIALS AND METHODS Two statistical analyses were done, including one comparing renal stone size (20 to 30, 31 to 40 and 41 to 60 mm) and the other comparing renal stone site (pelvis, or upper, mid or lower calyx). Surgical outcomes, including operative time, hospital stay, stone-free rate and postoperative fever, were compared between groups. Fitness for surgery was assessed using the American Society of Anesthesiologists scoring system. Severity of postoperative complications was graded with the modified Clavien classification. RESULTS Of 1,448 stones 1,202 (83%) were 20 to 30 mm, 202 (14%) were 31 to 40 mm and 44 (3%) were 41 to 60 mm. Of the large stones 73% were located in the renal pelvis. A statistically significantly lower stone-free rate, and higher postoperative fever and blood transfusion rates were seen with increased calculous size. With increased American Society of Anesthesiologists score the proportion of large stones in the calyces increased. At a score of III the proportion of large stones in the calyces was more than twice that of stones in the renal pelvis (13.5% vs 5.7%). Generally more patients with large calyceal than large pelvic stones had postoperative complications across the range of Clavien scores from I to IIIB. CONCLUSIONS Calyceal site was associated with decreased fitness for surgery and an increased risk of postoperative complications compared to renal site. An increase in stone size results in a lower stone-free rate, and higher rates of postoperative fever and blood transfusion.

A pathologist's view on the testis biopsy

Aspects of the biopsy of the testis from the pathologists point of view are discussed. Direct enzyme-histochemical staining for alkaline phosphatase (dAP) on frozen sections of biopsies taken during operation is a useful diagnostic tool to aid surgeons in testis-sparing surgery. Biopsy of the contralateral testis for the diagnosis of carcinoma in situ (CIS) in patients with a testicular germ cell tumour is not standard of care in most countries because of the high rate of negative biopsies. Based on risk factors for germ cell tumours, i.p. microlithiasis, a patient population is defined in which the rate of CIS in the contralateral biopsy is about 25%. It is reiterated that the diagnosis of CIS in testicular biopsies requires expertise, and should not be carried out without immunohistochemistry for markers for CIS. As OCT3/4 is increasingly used as marker, it is important to be aware that it may be false-negative in biopsies fixed in Bouins or Stieves fixative. Preliminary results are presented on a series of biopsies from cryptorchid testes in infants and children allowing the definition of morphological and immunohistochemical criteria for delayed maturation of gonocytes and pre-CIS.

Fatherhood in Tall Men Treated with High-Dose Sex Steroids during Adolescence

BACKGROUND/OBJECTIVE Sex steroid treatment to reduce final height of tall boys has been available since the 1950s. In women, it has been shown to interfere with fertility. In men, no such data are available. We therefore evaluated fertility and gonadal function in tall men who did or did not receive high-dose androgen treatment in adolescence. METHODS We conducted a retrospective cohort study of 116 tall men, of whom 60 had been treated. Reproductive and gonadal function was assessed by standardized interview, semen analysis, endocrine parameters, ultrasound imaging, and fatherhood. Mean age at treatment commencement was 14.2 yr, and mean follow-up was 21.2 yr. RESULTS Sixty-six men (36 treated and 30 untreated) had attempted to achieve fatherhood. The probability of conceiving their first pregnancy within 1 yr was similar in treated and untreated men (26 vs. 24; Breslow P=0.8). Eleven treated and 13 untreated men presented with a left-sided varicocele (P=0.5). Testicular volume, sperm quality, and serum LH, FSH, and inhibin B levels were comparable between treated and untreated men. However, treated men had significantly reduced serum T levels, adjusted for known confounders [mean (sd) 13.3 (1.8) vs. 15.2 (1.9) nmol/liter; P=0.005). In addition, testicular volume and serum inhibin B and FSH levels in treated men were significantly correlated with age at treatment commencement. CONCLUSION At a mean follow-up of 21 yr after high-dose androgen treatment, we conclude that fatherhood and semen quality in tall treated men are not affected. Serum testosterone levels, however, are reduced in androgen-treated men. Future research is required to determine whether declining testosterone levels may become clinically relevant for these men as they age.

Timelines of the “free-particle” and “fixed-particle” models of stone-formation: theoretical and experimental investigations

Two major theories on renal stone formation will be reviewed, the “free-particle” and “fixed-particle” mechanisms. These theories combine data on intrinsic factors (inborn metabolic errors), extrinsic factors (diet), renal cell responses and the physico-chemistry and biochemistry of urine into mechanisms of stone formation. This paper describes the specific role of time in both mechanisms. The timeline of crystal- and stone formation was deducted from literature data and was measured for two stones using radioisotope decay analysis. The stones of similar size and composition showed, respectively, a timeline of a few years and a development that took decades. In combination with data on stone architecture and patient characteristics these timelines are explained using the free-particle and fixed-particle mechanisms. Consideration of the timeline of stone formation has clinical implications. We conclude that the fixed-particle mechanism can be a slow process where decades pass between the first formation of a precipitate in the renal interstitium and the clinical presentation of the stone. Added to the fact that the mechanism of this initial precipitation is still ill defined, the conditions that started fixed-particle stone formation in an individual patient can be obscure. Blood and urine analysis in such patients does not necessarily reveal the individual’s risk for recurrence as lifestyle may have changed over time. This is in fact what defines the so-called idiopathic stoneformers. For these patients, prevention of outgrowth of previously formed precipitates, papillary plaques, may be more relevant than prevention of new plaque formation. In contrast, a patient who has formed a stone in a relatively short time through the free-particle mechanism is more likely to show abnormal values in blood and urine that explain the starting event of stone formation. In these patients, measurement of such values provides useful information to guide preventive measures.

Kans op testiculair carcinoma in situ in cohort van 204 patiënten met niet-obstructieve azoöspermie

SamenvattingIntroductie:Mannen met infertiliteit hebben mogelijk een hogere kans op testiculaire kiemceltumoren (TKCT). Het nietinvasieve stadium van TKCT, carcinoma in situ (CIS), kan alleen met een testisbiopsie worden vastgesteld. Testiculair CIS wordt gezien bij 2,2% van de mannen met vruchtbaarheidsproblemen. Bij mannen met TKCT in de voorgeschiedenis wordt in 5% van de gevallen na verloop van tijd een contralaterale tumor gezien. Bij routinebiopsie ten tijde van een unilaterale TKCT wordt bij 5% van de patiënten ook CIS in de contralaterale testis gezien. We hebben geen literatuurstudies gevonden over de prevalentie van CIS bij mannen die een TEsticulaire Sperma Extractie (TESE) ondergaan in verband met een niet-obstructieve azoöspermie (NOA).Patiënten en methoden:Van 2007 tot 2014 werd de testishistologie bekeken van alle mannen die een TESE ondergingen vanwege NOA. Bovendien werden reproductieve hormonen, scrotale echografie, genetisch onderzoek en risicofactoren op TKCT bepaald.Resultaten:Bij 204 patiënten met NOA hadden acht patiënten CIS (4,0%). Vier van deze patiënten hadden een TKCT in de voorgeschiedenis. Van de overige vier patiënten met CIS (2,0%) had één patiënt bilaterale CIS. Twee van de vier patienten met alleen CIS en geen TKCT in de voorgeschiedenis hadden cryptorchisme in de voorgeschiedenis.Conclusie:Testiculair CIS komt vaker voor bij mannen met NOA dan in de algehele populatie. Een patiënt zonder unilaterale TKCT in de voorgeschiedenis heeft, net als de algehele mannelijke infertiele populatie, een verhoogde kans om CIS te hebben. Bij mannen met NOA en een TKCT in de voorgeschiedenis is de kans om CIS te hebben in de contralaterale testis hoog (57%).Trefwoorden:testiculair carcinoma in situ, niet-obstructieve azoöspermie, TESESummaryRisk of testicular carcinoma in situ in a cohort of 204 patients with non-obstructive azoospermiaIntroduction:Infertile men have a higher chance of testicular germ cell tumors (TGCT). The non-invasive stage of TGCT, also known as carcinoma in situ (CIS), can only be diagnosed by a testicular biopsy. Testicular CIS is found in 2,2% of the general infertile male population. Five percent of men with a history of TGCT will develop a contralateral TGCT. At routine biopsy during orchiectomie for TGCT 5% of men will have CIS in the contralateral testis. We found no reports on the prevalence of CIS in men undergoing TEsticular Sperm Extraction (TESE) for non-obstructive azoospermia (NOA).Patients and methods:From 2007 to 2014 testicular histology was performed in all men that had TESE for NOA. In addition, reproductive hormones, scrotal ultrasound, genetic analyses and risk factors for TGCT were determinedResults:In 204 patients with NOA, eight patients had CIS (4,0%). Four of these patients had a history of a TGCT. Of the remaining four patients with CIS (2,0%), one had bilateral CIS. Two of the four patients had a history of cryptorchidism.Conclusion:Testicular CIS is more prevalent in men with NOA than in the general male population. If a patient has no history of unilateral TGCT the chance of having CIS is equal to that of the male infertile population. In men with NOA and a history of TGCT the chance of having CIS in the contralateral testis is high (57%).Keywords:testicular carcinoma in situ, non-obstructive azoospermia, TESE