http://repub.eur.nl/res/aut/895/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/27613/ 2010-10-01T00:00:00Z Objective: To establish the diagnostic value of sperm chromatin structure assessment for the evaluation of male factor infertility, in addition to conventional andrological workup. Design: Cross-sectional controlled study. Setting: A tertiary referral andrology clinic. Patient(s): Two hundred seventy-nine male partners of infertile couples. Intervention(s): None. Main Outcome Measure(s): The DNA fragmentation index (DFI) determined by the sperm chromatin structure assay (SCSA), semen parameters, serum levels of reproductive hormones, and World Health Organization (WHO) classification of male factor subfertility. Result(s): In all patient categories, except those including patients with hypogonadotrophic hypogonadism, sperm antibodies, or normospermia, DFI was significantly higher compared with in proven fertile controls. After classification of the quality of spermatogenesis based on mean testicular volume (<10 ml vs. >15 ml), follicle stimulating hormone (FSH; > 10 U/L vs. <5 U/L), and inhibin-B (<100 nmol/L vs. >150 nmol/L), the DFI was significantly higher in patients with poor spermatogenesis (35.9%) than in patients with normal spermatogenesis (25.9%). In a multiple regression analysis, the teratozoospermia index, sperm vitality, and FSH were significant determinants of the DFI level. Male age was associated with DFI, but leukocytospermia, body mass index, and smoking were not confounders of DFI. Conclusion(s): Impaired spermatogenesis, irrespective of the WHO classification of male factor subfertility, is generally associated with an increase of sperm DNA damage. Copyright http://repub.eur.nl/res/pub/27294/ 2010-01-01T00:00:00Z Purpose: We prospectively evaluated changes in sperm chromatin structure in infertile patients before and after surgical repair of varicocele, and the impact on the pregnancy rate. Materials and Methods: Included in the study were 49 men with at least a 1-year history of infertility, a palpable varicocele and oligospermia. World Health Organization semen analysis and sperm DNA damage expressed as the DNA fragmentation index using the sperm chromatin structure assay were assessed preoperatively and postoperatively. Pregnancy (spontaneous and after assisted reproductive technique) was recorded 2 years after surgery. Results: Mean sperm count, sperm concentration and sperm progressive motility improved significantly after varicocelectomy from 18.3 × 106to 44.4 × 106, 4.8 × 106/ml to 14.3 × 106/ml and 16.7% to 26.6%, respectively (p <0.001). The DNA fragmentation index decreased significantly after surgery from 35.2% to 30.2% (p = 0.019). When the definition of greater than 50% improvement in sperm concentration after varicocelectomy was applied, 31 of 49 patients (63%) responded to varicocelectomy. After varicocelectomy 37% of the couples conceived spontaneously and 24% achieved pregnancy with assisted reproductive technique. The mean postoperative DNA fragmentation index was significantly higher in couples who did not conceive spontaneously or with assisted reproductive technique (p = 0.033). Conclusions: After varicocelectomy sperm parameters significantly improved and sperm DNA fragmentation was significantly decreased. Low DNA fragmentation index values are associated with a higher pregnancy rate (spontaneous and with assisted reproductive technique). We suggest that varicocelectomy should be considered in infertile men with palpable varicocele, abnormal semen analysis and no major female factors. http://repub.eur.nl/res/pub/16543/ 2009-08-20T00:00:00Z http://repub.eur.nl/res/pub/17990/ 2009-05-01T00:00:00Z The aim of this study was to investigate the relation between free testosterone (FT) level and basic cognitive functions in older men. Three cognitive computer tasks were aimed to measure visual-processing speed, ability to suppress inappropriate responses, and visuospatial cognition, respectively. The tasks employed were a visual backward masking task, the Eriksen flanker task, and a mental rotation task. Participants were 72 older men (mean age = 67.2 years, range 57-79). The influence of FT, age, alcohol consumption, and education on task performances was examined by means of multiple linear regression analysis. FT level was positively associated with accuracy on the short intervals (33 and 50 ms) of the backward masking task and negatively with response latency on congruent flanker-task trials. These results indicate faster visual-processing speed in older men with higher FT levels. FT level was positively associated with interference elicited by irrelevant incongruent flankers, which implies that older men with higher levels of free testosterone exert less inhibitory control. Consistent with previous research, higher FT levels were associated with faster 'same-different' responses for unrotated mental rotation stimuli, but not with the slopes of the response time rotation functions. Older age was associated with lower backward masking accuracy at 33 ms and with lower overall mental rotation accuracy. Higher education level was associated with faster processing speed for congruent flankers and with higher overall mental rotation accuracy. Alcohol consumption did not affect the task performances. Our results suggest that higher FT levels in older men may promote sustained visual-processing speed and visuospatial ability, probably at the expense of some inhibitory functioning. http://repub.eur.nl/res/pub/14510/ 2008-12-01T00:00:00Z Background/Aims: Some studies reported an impaired gonadal function in males born small for gestational age (SGA). We investigated Sertoli cell function by measuring serum inhibin B and antimullerian hormone (AMH) levels in prepubertal boys and young men born SGA in comparison with age-matched controls born appropriate for gestational age (AGA). Methods: Inhibin B and AMH levels were determined in 73 prepubertal short SGA boys and in 72 age-matched AGA boys. In addition, 25 SGA boys were re-examined after 2 years of growth hormone (GH) treatment. Furthermore, inhibin B, AMH, testosterone, LH and FSH were studied in three groups of young men: 21 SGA men treated with GH, 15 SGA men with spontaneous catch-up growth and 25 young men born AGA. Results: Prepubertal short SGA boys and AGA boys had similar inhibin B (87.3 and 78.2 ng/ml) and AMH levels (75.6 and 63.6 μg/l, respectively). GH treatment did not result in different inhibin B and AMH levels. In young SGA men, inhibin B, testosterone, LH and FSH levels were similar compared to young AGA men. AMH levels were higher in the young SGA men (p = 0.03). Conclusions: Being born SGA does not impair Sertoli cell function. Young men born SGA have a normal hypothalamic-pituitary- testis axis. http://repub.eur.nl/res/pub/14713/ 2008-10-01T00:00:00Z Objective: To evaluate the feasibility of semen cryopreservation in pubertal boys before they receive gonadotoxic therapy and to identify which pretreatment parameters might predict successful cryopreservation. Design: Retrospective data analysis. Setting: Tertiary fertility center, academic children's hospital. Patient(s): Between 1995 and 2005, 80 boys (median age 16.6 years, range 13.7-18.9 years) consulted the outpatient clinic of andrology for semen cryopreservation before a potentially gonadotoxic treatment. Intervention(s): We assessed the pretreatment semen parameters, hormone levels, and patients' characteristics. Main Outcome Measure(s): Measurement of the number of adolescents able to cryopreserve semen. Result(s): Thirteen boys were unable to produce semen by masturbation. In 53 boys semen quality was adequate for cryopreservation. In 14 patients semen analysis did not show motile spermatozoa, and therefore semen cryopreservation could not be performed. Although inhibin B showed a strong correlation with sperm count, no significant difference was found in serum T, inhibin B, LH, and FSH levels in the patients with or without successful sperm yield. Moreover, median age was not different between patients with and without a successful sperm yield. Conclusion(s): Semen cryopreservation in boys is a feasible method to preserve spermatozoa before gonadotoxic therapy is started and should be offered to all pubertal boys despite their young age. Serum hormone levels do not predict sperm yield. http://repub.eur.nl/res/pub/30057/ 2008-01-01T00:00:00Z 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. http://repub.eur.nl/res/pub/35773/ 2007-07-01T00:00:00Z Mild hyperhomocysteinemia is caused by B vitamin deficiencies. We hypothesize that these biochemical derangements detrimentally affect spermatogenesis. Therefore, the aim of this study was to investigate the folate, cobalamin, pyridoxine, and homocysteine concentrations in blood and seminal plasma and the associations between these biomarkers and semen parameters in men participating in an in vitro fertilization or intracytoplasmic sperm injection program. From 73 men (median age [range]: 37 years [28-53]), blood and semen samples were obtained for the determination of serum and red blood cell (RBC) folate, serum total cobalamin, whole-blood pyridoxal-5′-phosphate, plasma total homocysteine (tHcy), and serum total testosterone. Semen analysis included sperm concentration, motility, and morphology according to World Health Organization criteria. The B vitamins and tHcy concentrations were significantly correlated in blood but not in seminal plasma. The serum and RBC folate concentrations were significantly correlated also with the total folate concentration in seminal plasma (r = .44; P < .001 and r = .39; P < .001, respectively). Likewise, the total cobalamin concentration in serum and seminal plasma was significantly correlated (r = .55; P = .001). Of interest is that the total cobalamin concentration in seminal plasma was significantly correlated with the sperm concentration (r= .42; P< .001). This is in contrast to the absence of significant associations between the other vitamins and tHcy in blood and seminal plasma and any of the semen parameters. These findings suggest that folate and cobalamin are transferred from the blood to the male reproductive organs and emphasize the role of cobalamin in spermatogenesis in human. Copyright http://repub.eur.nl/res/pub/35844/ 2007-02-01T00:00:00Z Determination of sperm DNA fragmentation, as assessed by the sperm chromatin structure assay (SCSA), has become an important tool for the evaluation of semen quality. The aim of the present study was to describe the biological variation of sperm DNA fragmentation in men attending an andrology clinic and to identify clinical correlates of the biological variation of sperm DNA fragmentation. For this study, two consecutive semen samples from 100 patients attending our andrology outpatient clinic were subjected to semen analysis, performed in parallel according to WHO guidelines and by SCSA. A good agreement between pairs of samples was found for SCSA-derived variables, as indicated by a significantly lower median coefficient of variation (CV) of the DNA Fragmentation Index (DFI) and the high DNA stainability (HDS) compared with WHO semen parameters. In half of the men attending our andrology clinic, however, the individual biological variation of DFI and HDS, expressed as CV of two samples, exceeded 10%. Dysregulation of spermatogenesis, as seen as testicular insufficiency or varicocele, was not associated with increased variability of DFI or HDS. A backward multiple linear regression analysis, however, indicated that the biological variation of DFI may be more profound in men with characteristics of normal spermatogenesis. In conclusion, we confirm previous reports that sperm DNA fragmentation has a lower biological variability than classical semen parameters. We hypothesize that the sperm chromatin structure may be more influenced in patients with normal spermatogenesis, whereas in men with disturbed spermatogenesis, the chromatin structure may be already so impaired that the effect of unidentified factors leading to variability of sperm DNA fragmentation in time may not be as profound. http://repub.eur.nl/res/pub/10368/ 2004-01-01T00:00:00Z Little is known on environmental risk factors for cryptorchidism and hypospadias, which are among the most frequent congenital abnormalities. The aim of our study was to identify risk factors for cryptorchidism and hypospadias, with a focus on potential endocrine disruptors in parental diet and occupation. In a case-control study nested within a cohort of 8,698 male births, we compared 78 cryptorchidism cases and 56 hypospadias cases with 313 controls. The participation rate was 85% for cases and 68% for controls. Through interviews, information was collected on pregnancy aspects and personal characteristics, lifestyle, occupation, and dietary phytoestrogen intake of both parents. Occupational exposure to potential endocrine disruptors was classified based on self-reported exposure and ratings of occupational hygienists based on job descriptions. Our findings indicate that paternal pesticide exposure was associated with cryptorchidism [odds ratio (OR) = 3.8; 95% confidence interval (95% CI), 1.1-13.4]. Smoking of the father was associated with hypospadias (OR = 3.8; 95% CI, 1.8-8.2). Maternal occupational, dietary, and lifestyle exposures were not associated with either abnormality. Both abnormalities were associated with suboptimal maternal health, a lower maternal education, and a Turkish origin of the parents. Being small for gestational age was a risk factor for hypospadias, and preterm birth was a risk factor for cryptorchidism. Because paternal pesticide exposure was significantly associated with cryptorchidism and paternal smoking was associated with hypospadias in male offspring, paternal exposure should be included in further studies on cryptorchidism and hypospadias risk factors. http://repub.eur.nl/res/pub/10129/ 2003-01-01T00:00:00Z Human germ cell tumors (GCTs) may have variable histology and clinical behavior, depending on factors such as sex of the patient, age at clinical diagnosis, and anatomical site of the tumor. Some types of GCT, i.e., the seminomas/germinomas/dysgerminomas and embryonal carcinomas (the stem cell component of nonseminomas), have pluripotent potential, which is demonstrated by their capacity to differentiate into somatic and/or extraembryonic elements. Although embryonal carcinoma cells are intrinsically pluripotent, seminoma/germinoma/dysgerminoma cells, as well as their precursor carcinoma in situ/gonadoblastoma cells, have the phenotype of early germ cells that can be activated to pluripotency. The other types of GCT (teratomas and yolk sac tumors of infants and newborn, dermoid cyst of the ovary, and spermatocytic seminoma of elderly) are composed of (fully) differentiated tissues and lack the appearance of undifferentiated and pluripotent stem cells. OCT3/4, a transcription factor also known as OTF3 and POU5F1, is involved in regulation of pluripotency during normal development and is detectable in embryonic stem and germ cells. We analyzed the presence of POU5F1 in GCT and other tumor types using immunohistochemistry. The protein was consistently detected in carcinoma in situ/gonadoblastoma, seminomas/germinoma/dysgerminoma, and embryonal carcinoma but not in the various types of differentiated nonseminomas. Multitumor tissue microarray analysis covering >100 different tumor categories and 3600 individual cancers verified that POU5F1 expression is specific for particular subtypes of GCT of adults. No protein was observed in GCT of newborn and infants, spermatocytic seminomas, and the various tumors of nongerm cell origin. In addition, no difference in staining pattern was found in chemosensitive and chemoresistant GCT of adults. These results indicate preservation of the link between POU5F1 and pluripotency, as reported during normal development, after malignant transformation. Therefore, POU5F1 immunohistochemistry is an informative diagnostic tool for pluripotent GCT and offers new insights into the histological heterogeneity of this cancer. http://repub.eur.nl/res/pub/10242/ 2003-01-01T00:00:00Z Testicular germ-cell tumors (TGCTs) of adolescents and adults originate from intratubular germ cell neoplasia (ITGCN), which is composed of the malignant counterparts of embryonal germ cells. ITGCN cells are characterized, among others, by the presence of stem cell factor receptor c-KIT. Once established, ITGCN will always progress to invasiveness. Approximately 2.5-5% of patients with a TGCT will develop bilateral disease and require complete castration, resulting in infertility, a need for lifelong androgen replacement, and psychological stress. To date, the only way to predict a contralateral tumor is surgical biopsy of the contralateral testis to demonstrate ITGCN. We did a retrospective study of 224 unilateral and 61 proven bilateral TGCTs (from 46 patients, in three independently collected series in Europe) for the presence of activating c-KIT codon 816 mutations. A c-KIT codon 816 mutation was found in three unilateral TGCT (1.3%), and in 57 bilateral TGCTs (93%; P < 0.0001). In the two wild-type bilateral tumors for which ITGCN was available, the preinvasive cells contained the mutation. The mutations were somatic in origin and identical in both tumors. We conclude that somatic activating codon 816 c-KIT mutations are associated with development of bilateral TGCT. Detection of c-KIT codon 816 mutations in unilateral TGCT identifies patients at risk for bilateral disease. These patients may undergo tailored treatment to prevent the development of bilateral disease, with retention of testicular hormonal function. http://repub.eur.nl/res/pub/9814/ 2002-01-01T00:00:00Z BACKGROUND: Male infertility due to severe oligozoospermia and azoospermia has been associated with a number of genetic risk factors. METHODS: In this study 150 men from couples requesting ICSI were investigated for genetic abnormalities, such as constitutive chromosome abnormalities, microdeletions of the Y chromosome (AZF region) and mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. RESULTS: Genetic analysis identified 16/150 (10.6%) abnormal karyotypes, 8/150 (5.3%) AZFc deletions and 14/150 (9.3%) CFTR gene mutations. An abnormal karyotype was found both in men with oligozoospermia and azoospermia: 9 men had a sex-chromosomal aneuploidy, 6 translocations were identified and one marker chromosome was found. Y chromosomal microdeletions were mainly associated with male infertility, due to testicular insufficiency. All deletions identified comprised the AZFc region, containing the Deleted in Azoospermia (DAZ) gene. CFTR gene mutations were commonly seen in men with congenital absence of the vas deferens, but also in 16% of men with azoospermia without any apparent abnormality of the vas deferens. CONCLUSIONS: A genetic abnormality was identified in 36/150 (24%) men with extreme oligozoospermia and azoospermia. Application of ICSI in these couples can result in offspring with an enhanced risk of unbalanced chromosome complement, male infertility due to the transmission of a Y-chromosomal microdeletion, and cystic fibrosis if both partners are CFTR gene mutation carriers. Genetic testing and counselling is clearly indicated for these couples before ICSI is considered. http://repub.eur.nl/res/pub/9880/ 2002-01-01T00:00:00Z BACKGROUND: Reports on increasing hypospadias trends are based on birth defect registries, which are prone to inaccuracy. We assessed the prevalence of hypospadias precisely, by prospective examination of all newborns in Rotterdam over a 2-year period. METHODS: A total of 7292 consecutive male births were examined for the presence of hypospadias, classified by severity. RESULTS: The frequency of hypospadias in newborn boys was 0.73% (53/7292). The rate among live births was 38 per 10 000, which is 6 times the previously reported rate for the Southwestern Netherlands (6.2) (P < 0.0001). This registry excludes glandular hypospadias. Without glandular cases, our rate is 26 per 10 000, which is still 4-fold higher (P < 0.0001). The ratio of minor to major hypospadias was 0.3. In 79% of cases, surgery was indicated. CONCLUSIONS: We found a 4-fold higher than expected hypospadias rate, which may be explained by case ascertainment differences. The proportion of major cases was higher than generally assumed. This study provides evidence for substantial geographical differences. Explanations for temporal and geographical differences need to be explored. To monitor hypospadias rates and trends accurately, complete case ascertainment, including standardized classification of severity, is warranted. http://repub.eur.nl/res/pub/9065/ 1999-01-01T00:00:00Z Congenital bilateral absence of the vas deferens (CBAVD) is found in 1-2% of infertile males and in most male cystic fibrosis (CF) patients. CF and some of the CBAVD cases were found to share the same genetic background. In this study, 21 males with CBAVD had extensive physical and laboratory testing for symptoms of CF. Possible defective cellular chloride transport was measured by interstitial current measurement of rectal suction biopsies. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation analysis was performed for 10 common CFTR mutations. CF-related symptoms were found in six men. On laboratory testing slightly abnormal liver and pancreatic function was found in seven patients. The sweat test was found to be abnormal in four patients; interstitial current measurement showed defective chloride excretion in 11 patients. CFTR gene mutations were found in 66% of the patients: eight were compound heterozygotes; in six, only one common mutation could be detected. The 5T allele in one copy of intron 8 was found in four men. CBAVD appears to be a heterogeneous clinical and genetic condition. A CFTR gene mutation was found in both copies of the allele or interstitial current measurement showed defective chloride excretion in 14/21 cases. Genetic counselling is clearly indicated for couples seeking pregnancy through epididymal or testicular sperm aspiration and intracytoplasmic sperm injection. http://repub.eur.nl/res/pub/8815/ 1998-01-01T00:00:00Z Male genital tract obstructions may result from infections, previous inguinal and scrotal surgery (vasectomy) and congenital bilateral absence of the vas deferens (CBAVD). Microsurgery can sometimes be successful in treating the obstruction. In other cases and in cases of failed surgical intervention, the patient can be treated by microsurgical or percutaneous epididymal sperm aspiration (MESA, PESA) or testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI). We present the results of 39 ICSI procedures for obstructive azoospermia in 24 couples. The aetiology of the obstruction was failed microsurgery in 11 patients, CBAVD in nine and genital infections in four. Sperm retrieval was accomplished via MESA in four cases, PESA in 18 cases and via TESE in 11 cases. TESE was only applied when PESA failed to produce enough spermatozoa for simultaneous ICSI. In six patients, the ICSI procedure was performed with cryopreserved spermatozoa after an initial PESA procedure. Fertilization occurred in 47% of the metaphase II oocytes; embryo transfer was performed in 92% of procedures and resulted in a clinical pregnancy in 13/39 procedures. Ongoing pregnancy was achieved in 10/39 procedures. One pregnancy was terminated early after prenatal investigation showed a cytogenetic abnormality (47,XX+18, Edwards syndrome). The other nine pregnancies resulted in the live birth of 10 children, without any congenital abnormalities. Epididymal and testicular retrieved spermatozoa were successfully used for ICSI to treat obstructive azoospermia, and resulted in an ongoing pregnancy in 10 of 24 couples (41.6%) after 39 ICSI procedures, a success rate of 25.6% per treatment cycle and of 27.7% per embryo transfer. http://repub.eur.nl/res/pub/8871/ 1998-01-01T00:00:00Z During mammalian spermatogenesis, the chromatin of the spermatogenic cells is profoundly reorganized. Somatic histones are partly replaced by testis-specific histones. These histones are then replaced by transition proteins and finally by protamines. This series of nucleoprotein rearrangements results in a highly condensed sperm cell nucleus. In contrast to spermatozoa from other species, human spermatozoa still contain a significant amount of histones, including testis-specific histone 2B (TH2B). In the present study it is shown that an antibody targeting tyrosine hydroxylase, which has been found previously to cross-react with rat TH2B, also specifically immunoreacts with human TH2B on Western blots, in immunohistochemistry of human testis tissue, and in immunocytochemistry of decondensed human spermatozoa. In human testis tissue, TH2B immunostaining first apparent in spermatogonia, shows marked variation, especially at the pachytene spermatocyte stage, and then reaches an intense signal in round spermatids. Shortly before spermatid elongation, a portion of the spermatid nucleus, corresponding to the acrosomal region, loses its immunoreactivity. During condensation of the spermatid nucleus, the immunodetectability of TH2B disappears gradually, from the anterior region of the nucleus onwards. At the final stages of spermiogenesis, the immunostaining is completely absent. Immunocytochemical staining of spermatozoa revealed no TH2B immunosignal, but immunostaining was observed when spermatozoa obtained from semen were decondensed to make nuclear proteins accessible to the antibody. There was, however, a striking intercellular variability in the intensity of staining of spermatozoa within an ejaculate. In a population of 35 men attending our Andrology Clinic, we observed interindividual differences in total sperm TH2B content, which showed a significant, although not very pronounced, negative correlation with normal morphology (P = 0.05). http://repub.eur.nl/res/pub/8902/ 1998-01-01T00:00:00Z Inhibin B is produced by Sertoli cells, provides negative feedback on FSH secretion, and may prove to be an important marker for the functioning of seminiferous tubules. The purpose of the present study was to examine the relationship between the spermatogenic function of the testis of subfertile men and the plasma concentrations of inhibin B and FSH. These parameters were estimated in a group of 218 subfertile men. Serum inhibin B levels were closely correlated with the serum FSH levels (r = -0.78, P < 0.001), confirming the role of inhibin B as feedback signal for FSH production. The spermatogenic function of the testis was evaluated by determining testicular volume and total sperm count. Inhibin B levels were significantly correlated with the total sperm count and testicular volume (r = 0.54 and r = 0.63, respectively; P < 0.001). Testicular biopsies were obtained in 22 of these men. Inhibin B was significantly correlated with the biopsy score (r = 0.76, P < 0.001). Receiver operating characteristic analysis revealed a diagnostic accuracy of 95% for differentiating competent from impaired spermatogenesis for inhibin B, whereas for FSH, a value of 80% was found. We conclude that inhibin B is the best available endocrine marker of spermatogenesis in subfertile men. http://repub.eur.nl/res/pub/8715/ 1997-01-01T00:00:00Z The existing literature on serum insulin-like growth factor I (IGF-I) levels in insulin-dependent diabetes mellitus (IDDM) is conflicting. Free IGF-I may have greater physiological and clinical relevance than total IGF-I. Recently, a validated method has been developed to measure free IGF-I levels in the circulation. Serum free and total IGF-I, IGF-binding protein-1 (IGFBP-1), and IGFBP-3 levels were measured in 56 insulin-treated IDDM patients and 52 healthy sex- and age-matched controls. Diabetic retinopathy was established by direct fundoscopy. In 54 IDDM patients, the glomerular filtration rate (GFR) and effective renal plasma flow were calculated from the clearance rate of [125I]iothalamate and [131I]iodohippurate sodium. Fasting free IGF-I, total IGF-I, and IGFBP-3 levels were significantly lower in IDDM patients than in age- and sex-matched healthy controls (free IGF-I, P < 0.005; total IGF-I, P < 0.001; IGFBP-3, P = 0.001), whereas IGFBP-1 levels were higher (P < 0.001). In IDDM subjects, decreases in free IGF-I, total IGF-I, and IGFBP-3 levels with age were observed (free IGF-I, r = -0.27 and P = 0.05; total IGF-I, r = -0.52 and P < 0.001; IGFBP-3, r = -0.37 and P = 0.005). Free IGF-I was inversely related to fasting glucose in IDDM subjects (r = -0.35; P = 0.01), whereas the relationship between total IGF-I and fasting glucose did not reach significance (r = -0.27; P = 0.06). Age-adjusted free IGF-I levels were significantly higher (P < 0.05) in IDDM subjects with retinopathy than in subjects without retinopathy after adjustment for age. Total IGF-I and IGFBP-3 levels were positively related to GFR (total IGF-I, r = 0.35 and P < 0.05; IGFBP-3, r = 0.28 and P < 0.05). Both of these differences lost significance after adjustment for age. Free IGF-I, total IGF-I, and IGFBP-3 levels were lower and IGFBP-1 levels were higher in insulin-treated IDDM subjects compared to those in age- and sex-matched controls. Free IGF-I, total IGF-I, and IGFBP-3 levels decreased significantly with age in IDDM subjects. Age-adjusted free IGF-I levels in subjects with diabetic retinopathy were higher than those in subjects without diabetic retinopathy. Total IGF-I and IGFBP-3 levels were positively related to GFR in IDDM subjects, but these relations were lost after adjustment for age. Measurement of serum free IGF-I levels in IDDM subjects did not have clear advantages compared to that of total IGF-I, IGFBP-1, and IGFBP-3 levels. Serum IGF-I and IGFBPs reflect their tissue concentrations to a various degree. Consequently, extrapolations concerning the pathogenetic role of the IGF/IGFBP system in the development of diabetic complications at the tissue level remain speculative. http://repub.eur.nl/res/pub/8719/ 1997-01-01T00:00:00Z Two case histories are presented documenting structural chromosome abnormalities in infertile males. The abnormalities were detected only after application of intracytoplasmic sperm injection (ICSI) was repeatedly unsuccessful or resulted in an abnormal pregnancy. A mosaic Robertsonian translocation 45,XY,der(13;13)(q10; q10)/46,XY,t(13;13)(p10;p10), der(13p;13p) incompatible with normal offspring was found in a male with extreme oligozoospermia after three subsequent ICSI treatments were unsuccessful and one had resulted in a spontaneous abortion. A second case involved a Robertsonian translocation 45,XY,der(13;14)(q10;q10) which was detected in a male with extreme oligozoospermia after ultrasound abnormalities were found in an ICSI-induced twin pregnancy. Amniocentesis showed an unbalanced 46,XY,+13,der(13;14)(q10;q10) karyotype in one twin and a Robertsonian 45,XX,der(13;14)(q10;q10) karyotype in the other twin. Chromosome analysis of males with abnormal sperm characteristics is advised prior to ICSI.