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E Nieschlag

Publications and source records attributed to E Nieschlag.

At least 55 records · Page 3Linked to original sources
PubMed2002

Sperm aneuploidy rates in younger and older men.

BACKGROUND: In order to assess the possible risk of chromosomal abnormalities in offspring from older fathers, we investigated the effects of age on the frequency of chromosomal aneuploidy rates of human sperm. METHODS AND RESULTS: Semen samples were collected from 15 men aged <30 years (24.8 +/- 2.4 years) and from eight men aged >60 years (65.3 +/- 3.9 years) from the general population. No significant differences in ejaculate volume, sperm concentration and sperm morphology were found, whereas sperm motility was significantly lower in older men (P = 0.002). For the hormone values, only FSH was significantly elevated in the older men (P = 0.004). Multicolour fluorescence in-situ hybridization was used to determine the aneuploidy frequencies of two autosomes (9 and 18); and of both sex chromosomes using directly labelled satellite DNA probes on decondensed sperm nuclei. A minimum of 8000 sperm per donor and >330 000 sperm in total were evaluated. The disomy rates per analysed chromosomes were 0.1-2.3% in younger men and 0.1-1.8% in older men. The aneuploidy rate determined for both sex chromosomes and for the autosomes 9 and 18 were not significantly different between the age groups. CONCLUSIONS: The results suggest that men of advanced age still wanting to become fathers do not have a significantly higher risk of procreating offspring with chromosomal abnormalities compared with younger men.

Adult↗
PubMed2002

Manifestation of Y-chromosomal deletions in the human testis: a morphometrical and immunohistochemical evaluation.

BACKGROUND: Deletions of the AZF (azoospermia factor) subregions on the Y chromosome are accompanied by a diverse spectrum of spermatogenic disturbances ranging from hypospermatogenesis to total depletion of germ cells causing infertility. The AZF region encodes gene products which are candidates for the genetic control of spermatogenesis. Although it is known which genes are involved, a general principle of cause and effect cannot yet be deciphered and the deletion type has non-uniform histological phenotypes. METHODS AND RESULTS: We analysed morphological parameters of testicular biopsies from 17 patients diagnosed for Y chromosome microdeletions. As control groups we analysed testes from patients with idiopathic Sertoli cell-only (SCO) syndrome (n = 11), mixed atrophy (n = 10) and complete spermatogenesis (n = 11). A detailed genetic analysis on the extension of the observed microdeletions revealed similar breakpoints in the distal and proximal region of the AZFc region, indicating a common mechanism of homologous recombination for such deletions, as has been suggested before. Morphometric parameters such as the diameter of the tubules, lumen, thickness of the lamina propria and height of the tubule epithelia were investigated. The diameter of the tubules from patients with microdeletions was found to be significantly smaller compared with patients with mixed atrophy. Considering also the size of the tubules, lumen and epithelia, a Y-chromosomal microdeletion represents an intermediate state between an idiopathic SCO and normal spermatogenesis. The immunohistochemical analysis of six different Sertoli cell markers, cytokeratin 18, vimentin, inhibin alpha subunit, 14-3-3 theta, FSH receptor and androgen receptor, revealed no impact of AZF deletion on the specific expression pattern of these genes. CONCLUSIONS: Our results suggest that, notwithstanding the deletion of a common region in the AZFc region, microdeletions of the Y chromosome lead to an intermediate status between idiopathic SCO and complete spermatogenesis, resulting in a heterogeneous histological profile regardless of the seminiferous activity. The Sertoli cell function seems not to be altered.

Adult↗
PubMed2002

Natural transmission of a partial AZFb deletion of the Y chromosome over three generations: case report.

The natural transmission of microdeletions of the Y chromosome is occasionally reported in the literature. Here we describe the natural transmission of a partial AZFb deletion over three generations. PCR amplification of several sequence tagged site markers in the three AZF regions of the Y chromosome was carried out in a patient with oligoasthenoteratozoospermia, his father and his naturally conceived son. The deletion was confirmed by Southern blotting. The propositum, his father and his son showed a probably identical, partial deletion of the distal part of the AZFb region, involving sY130 and sY143. The deletion was confirmed by Southern blotting using the sY130 probe. Partial AZFb microdeletions can be associated with moderate oligozoospermia allowing natural conception and therefore natural transmission of this genetic anomaly. Further studies are needed to define the pathogenetic significance of microdeletions involving sY130 and sY143.

Adult↗
PubMed2002

Testosterone substitution of hypogonadal men prevents the age-dependent increases in body mass index, body fat and leptin seen in healthy ageing men: results of a cross-sectional study.

INTRODUCTION: In healthy men, body weight and total fat content increase with advancing age, while serum testosterone levels decrease. In order to elucidate whether a causal relationship between these phenomena exists, we investigated the influence of testosterone or human chorionic gonadotrophin substitution on body mass index (BMI), total fat mass and serum leptin in testosterone-treated and untreated hypogonadal patients in comparison with ageing eugonadal men. METHODS: In a cross-sectional study, the inter-relationships of body weight, total fat mass, serum sex hormones and leptin were analysed in untreated hypogonadal men (n=24; age 19-65 years), treated hypogonadal men (n=61; age 20-67 years) and healthy eugonadal men (n=60; age 24-78 years). Total fat mass was assessed by bioimpedance measurement. Univariate and multiple linear regression analysis was used to detect possible differences. RESULTS: In eugonadal men, serum testosterone levels decreased with advancing age (correlation coefficients: r=-0.71; P<0.0001), while BMI (r=0.39; P=0.002), total fat content (r=0.51; P<0.0001) and leptin (r=0.48; P<0.0001) increased significantly. In untreated hypogonadal patients, an increase in BMI (r=0.50; P=0.013) and total fat mass (r=0.41; P=0.044) was also observed with advancing age. However, in substituted hypogonadal patients, no age-dependent change in BMI (r=0.067; P=0.606), body fat content (r=-0.083; P=0.522), serum testosterone (r=-0,071; P=0.59) or serum leptin (r=-0.23; P=0.176) was found. CONCLUSION: Since testosterone-substituted older hypogonadal men show BMI and fat mass similar to those of younger eugonadal men and since non-treated hypogonadal men are similar to normal ageing men, testosterone appears to be an important factor contributing to these changes. Thus ageing men should benefit from testosterone substitution as far as body composition is concerned.

Adipose Tissue↗
PubMed2002

Pharmacokinetics of a new transdermal testosterone gel in gonadotrophin-suppressed normal men.

OBJECTIVE: In a phase I single-centre, open, randomized study, the pharmacokinetics of two doses of a transdermal testosterone gel containing 2.5% testosterone were evaluated in 26 healthy male volunteers. DESIGN: To eliminate the influence of endogenous serum testosterone, gonadotrophins and endogenous testosterone secretion were suppressed by a single intramuscular injection of 400 mg norethisterone enanthate. Fourteen men applied 5.0 g and 12 men applied 2.5 g testosterone gel daily for 10 days. Half the men in each group washed the gel off 10 min after it had been applied. RESULTS: In all the men, a marked suppression of LH, FSH, testosterone, dihydrotestosterone (DHT) and oestradiol was observed after norethisterone treatment. Physiological serum concentrations of testosterone were restored during the 10-day treatment period in the group of men applying 5.0 g testosterone gel. Increasing serum concentrations of testosterone from day 1 to day 10 were observed. Oestradiol and DHT concentrations did not exceed normal values. Washing 10 min after gel application did not influence the resorption of testosterone. A dose of 2.5 g testosterone gel was insufficient to achieve physiological serum concentrations of testosterone. CONCLUSION: Testosterone replacement treatment with 5.0 g of this 2.5% testosterone gel is able to achieve constant physiological testosterone concentrations in gonadotrophin-suppressed men. Washing the skin after 10 min does not influence the pharmacokinetic profile and thus significantly reduces the risk of contamination of female partners or infants.

Adult↗
PubMed2001

The CAG repeat polymorphism in the androgen receptor gene affects bone density and bone metabolism in healthy males.

OBJECTIVE: Bone metabolism and bone density (BD) are influenced by sex hormones. Testosterone (T) action is exerted through the androgen receptor (AR). We investigated the potential impact of the CAG repeat (CAGR) polymorphism within the AR gene on BD and bone metabolism in healthy younger males. PATIENTS AND MEASUREMENTS: The number of CAGRs in 110 healthy men aged 20-50 years was determined by sequence analysis. We assessed BD by the radiation-free method of quantitative ultrasound (QUS) of the phalanges. Serum levels of bone-specific alkaline phosphatase (BAP) and urine secretion of free deoxypyridinoline (DPD, corrected for creatinine), serum levels of sex hormones, body fat content and lifestyle factors were determined. RESULTS: In stepwise multiple regression models controlling for age, body fat content and lifestyle factors, the number of CAGRs was an independent negative predictor of BD (partial r = - 0.286, P = 0.001), whereas it was positively associated with markers of bone turnover (for BAP: partial r = 0.32, P= 0.001; for DPD: partial r = 0-241, P = 0.013). Levels of free T and oestradiol showed an independent and positive association with BD; age contributed significantly to lower BD. Age and free T were negatively associated with markers of bone turnover, whereas oestradiol showed a positive correlation with BAP and DPD. ANOVA in groups according to age and the CAGR length suggested an increased age-dependent bone loss in subjects with a CAGR length of 22-31 compared with 14-21 CAGRs (overall P < 0.01). CONCLUSIONS: A high number of CAG repeats within the androgen receptor gene attenuates testosterone effects on bone density and bone metabolism. This seems to be associated with accelerated age-dependent bone loss.

Adult↗
PubMed2001

Occupational risks for male fertility: an analysis of patients attending a tertiary referral centre.

The impact of environment and occupation on male fertility is still under debate. We investigated whether certain occupations may be over- or under-represented among men attending our infertility clinic in relation to the entire population of the area. Diagnoses and semen parameters of 2054 infertile men from the district of Münster were analysed retrospectively. The patients were categorized into 29 occupational groups. The relative size of each group was compared with that of the entire population in the district of Münster. Farmers were over-represented compared with the general population. Farmers and painters/varnishers showed a significantly higher proportion of reduced sperm counts [odds ratios (OR): 2.13 and 2.17, 95% confidence intervals: 1.18-3.88 and 1.02-4.65] and severely reduced sperm concentrations compared with the entire group of infertile men; in addition, significantly more farmers presented with a history of maldescended testes than other occupational groups (OR: 2.76 and 2.84; CI: 1.12-6.75 and 1.27-6.34). Metal workers/welders formed significantly higher proportions of patients with reduced sperm motility (OR: 5.99; CI: 1.38-26.00). The relatively poor semen parameters of the painters/varnishers could be caused by exposure to toxins. This may also apply to the farmers (fertilizers, herbicides); however, the elevated rate of maldescended testes suggests an effect of exposure during prenatal development or a genetic cause. The findings for metal workers/welders may be because of heat or toxins at the workplace. The study demonstrates that certain occupations are preferentially associated with male infertility.

Adult↗
PubMed2001

Prevalence of Y chromosome microdeletions in infertile men who consulted a tertiary care medical centre: the Münster experience.

The long arm of the human Y chromosome is required for male fertility. Microdeletions in three different regions of the human Y chromosome, designated AZFa, AZFb and AZFc, respectively, are frequently associated with male infertility. The varying frequency of Y microdeletions found in cohorts of infertile men (0.4-55.5%) is probably related to the criteria by which the patients are selected. We report the diagnosis of Y chromosomal microdeletion in a total of 1,470 men who attended our infertility clinic, the largest sample of infertile patients to have been analysed to date. This cohort consists of three populations. The first subgroup comprises 228 selected patients with severely impaired spermatogenesis. Since microdeletions had also been reported in patients with less severe defects in spermatogenesis, we then intended to define the deletion frequency in unselected patients (population II: 378 patients). Population III comprises 864 prospectively selected patients and intracytoplasmic sperm injection candidates. Altogether, 19 patients with microdeletions were found (1.3%). The microdeletion frequencies in populations I, II and III were 3.5%, 0.3% and 1.2%, respectively. Our study helps to define a subgroup of infertile men at risk of Y chromosomal microdeletions, and strongly supports the recommendation that Y microdeletion analysis should be limited to azoospermic and severely oligozoospermic men and candidates for intracytoplasmic sperm injection.

Adult↗
PubMed2001

Atherosclerosis in apolipoprotein E-deficient mice is decreased by the suppression of endogenous sex hormones.

To elucidate the influence of gonadotropins, endogenous sex hormones and testosterone on atherosclerosis, 4-week-old male and female apoE-deficient mice received either 100 microg subcutaneous injections of the gonadotropin-releasing hormone (GnRH) antagonist Cetrorelix every 48 hours or a subcutaneous implantation of a permeable silastic tube with 35 mg of testosterone. Control mice received either subcutaneous injections of saline, a silastic implant with saline, or no treatment. The animals were sacrificed after eight weeks of treatment; blood was obtained by cardiac puncture and the aorta was taken out and prepared. The suppression of testosterone led to an increase in atherosclerosis in both the sinus aortae and the ascending aorta despite increases of cholesterol in male and decreases of HDL cholesterol in female mice. Treatment with testosterone led to small but significant increases of cholesterol levels and atherosclerotic lesions in male mice. Female mice showed no change in lipids and fewer atherosclerotic lesions. In conclusion, the suppression of gonadotropins appears to have a moderate anti-atherogenic effect. The effect of testosterone appears to be either neutral or opposed by gonadotropins.

Animals↗
PubMed2001

Reproductive functions, fertility and genetic risks of ageing men.

The changes of reproductive functions, fertility and genetic risks of ageing females have been investigated relatively intensively. The state of knowledge about endocrine and reproductive changes in ageing men as well as possible age-related paternal genetic risks lags far behind. In general serum testosterone levels decrease with increasing age. In ageing men testis morphology and semen production can be absolutely normal. However, in some testes degenerative forms of germ cells can be observed. Fertility may be maintained up to a very high age. The genetic quality of sperm produced by older men may be reduced for several reasons, among which age-related increases in germ cell mutations, impairment of DNA-repair mechanisms and apoptotic processes are the most likely. The incidence of several autosomal dominant diseases, such as achondroplasia, polyposis coli, Marfan syndrome, Apert syndrome or basal cell naevi is associated with advanced paternal age, whereas there is no clear evidence for a paternal effect on structural or numeric chromosome anomalies. Hence even if offspring of older men have a slightly increased incidence of certain genetic diseases, the individual risk of such a new disease must be considered as extremely small, as the incidence of these diseases is very low.

Aging↗
PubMed2001

Changes in cerebral glucose metabolism and visuospatial capability in hypogonadal males under testosterone substitution therapy.

Genders differ concerning abilities of spatial cognition; positive associations of testosterone levels with corresponding scores have been reported, as well. We addressed the question whether there is a testosterone-susceptible area within cerebral structures previously described to be involved in mental rotation. Using F-18-deoxyglucose (FDG)-positron emission tomography (PET), we studied cerebral glucose metabolism during a standardized 3-dimensional mental rotation task in 6 right-handed men with hypogonadotropic hypogonadism before and under testosterone substitution therapy. Under elevated testosterone levels, enhanced cerebral glucose metabolism during mental rotation was observed in the 4 subjects with improved visuospatial capability. Areas involved were previously demonstrated to be activated by such tasks in eugonadal men.

Adult↗
PubMed2001

Suppression of spermatogenesis to azoospermia by combined administration of GnRH antagonist and 19-nortestosterone cannot be maintained by this non-aromatizable androgen alone.

BACKGROUND: For male hormonal contraception, combined administration of gonadotrophin-releasing hormone (GnRH) antagonists and androgens effectively suppresses spermatogenesis to azoospermia. In non-human primates this suppression can be maintained more easily by androgens alone. METHODS: A clinical trial with six healthy volunteers was performed to test this approach in man. Loading doses of 10 mg/day of the GnRH antagonist cetrorelix were given subcutaneously for 5 days, followed by maintenance doses of 2 mg/day up to week 12. At 2 weeks after the first GnRH antagonist injection, androgen substitution was initiated with a loading dose of 400 mg 19-nortestosterone hexyloxyphenylpropionate (19NT-HPP) intramuscularly, followed by injections of 200 mg 19NT-HPP every 3 weeks up to week 26. RESULTS: Serum concentrations of LH, FSH and testosterone were effectively suppressed by cetrorelix administration. Within 12 weeks, azoospermia was achieved in all six volunteers. After cessation of cetrorelix injections in week 12, gonadotrophins and testosterone increased significantly despite continued 19NT-HPP injections. In parallel, spermatogenesis was restimulated in five of six volunteers. CONCLUSIONS: Combined administration of cetrorelix and 19NT-HPP leads to azoospermia within 3 months. However, complete azoospermia cannot be maintained by continued injections of the non-aromatizable 19NT-HPP alone.

Adolescent↗
PubMed2001

First human exposure to FSH-CTP in hypogonadotrophic hypogonadal males.

BACKGROUND: This is the first report of human exposure to the novel compound follicle stimulating hormone (FSH)-C-terminal peptide (CTP) 'FSH-CTP' (Org 36286), a long-acting recombinant FSH like substance, consisting of the alpha-subunit of human FSH and a hybrid beta-subunit. The latter is composed of the beta-subunit of human FSH and the C-terminus part (CTP) of the beta-subunit of human chorionic gonadotrophin (HCG). METHODS: In this phase I, non-blind, multi-centre study, 13 hypogonadotrophic hypogonadal male subjects were enrolled to test the safety of FSH-CTP in terms of antibody formation in humans. Furthermore, the pharmacokinetic profile of this new compound was determined. Subjects were injected four times with 15 microg FSH-CTP with an interval of approximately 4 weeks between each injection. RESULTS: No drug related (serious) adverse events occurred. No antibodies against FSH-CTP or chinese hamster ovary (CHO)-cell derived proteins were detected and measurement of local tolerance demonstrated that s.c. administration of FSH-CTP is well tolerated and no increase in intensity of injection-site responses was observed after repeated exposure to FSH-CTP. After the first and third injection, FSH-CTP serum concentrations were determined. Overall mean (+/- SD) C(max) was 0.426 (+/- 0.116) ng/ml, mean t(1/2) and AUC(0-infinity) were 94.7 (+/- 26.2) h and 81.5 (+/- 18.8) ng.h/ml respectively. Compared with recFSH (Puregon), the half life of FSH-CTP was increased 2-3 times. Following the first and third injection a clear rise in serum inhibin-B concentrations were observed. CONCLUSIONS: The use of FSH-CTP is safe and does not lead to detectable formation of antibodies. Furthermore, the pharmacokinetic and dynamic profile of FSH-CTP may lead to the development of new, more convenient regimens for the treatment of male and female infertility.

Adult↗
PubMed2001

Low-level sex chromosome mosaicism in female partners of couples undergoing ICSI therapy does not significantly affect treatment outcome.

BACKGROUND: There is an increased rate of chromosomal anomalies, in particular low-level sex chromosome mosaicism, in the female partners of couples undergoing intracytoplasmic sperm injection (ICSI). METHODS: Among 811 consecutive couples presenting for pre-ICSI chromosome analysis, chromosomal abnormalities were detected in 54 individuals, of which 26 were low-level sex chromosome mosaicism in the females. Attention was focused on the treatment course and outcome of ICSI in 20 couples with low-level sex chromosome mosaicism in the females actually embarking on ICSI treatment (group I, n = 38 ICSI treatment cycles). Applying a case-control design, each of the 20 couples was matched according to female age and source of spermatozoa to couples without a chromosomal abnormality in either of the partners (group II, n = 38 ICSI treatment cycles). RESULTS: No significant differences were found between the groups in ovarian response, fertilization rate and number of embryos transferred. Pregnancy rates, as well as implantation and abortion rates did not differ significantly between the groups. CONCLUSIONS: The data suggest that low-level sex chromosome mosaicism in females has no major effect on the course and outcome of ICSI.

Abortion, Spontaneous↗
PubMed2001

Intramuscular testosterone undecanoate and norethisterone enanthate in a clinical trial for male contraception.

Recent trials for hormonal male contraception are based on gestagens or GnRH antagonists combined with oral or injectable testosterone substitution. However, the efficacy of most trials remained disappointing. Norethisterone enanthate (NETE) has been used as a long-acting injectable female contraceptive and has shown sustained suppression of spermatogenesis in male monkeys and prolonged suppression of gonadotropins in men. This study was designed to prove the efficacy of the long-acting testosterone undecanoate ester (TU) alone or in combination with NETE in a phase II clinical trial. Fourteen healthy men received injections of 1000 mg TU in combination with injections of 200 mg NETE every 6 weeks over a period of 24 weeks, followed by a control period of 28 weeks. Another 14 volunteers received TU alone. During the study semen variables, reproductive hormones, clinical chemistry and lipid parameters, well-being, and sexual function were monitored. Scrotal content and prostates were checked sonographically. During the entire treatment period mean testosterone serum concentrations remained within the normal limits. Marked suppression of gonadotropins in both treatment groups resulted in azoospermia in 7 of 14 and 13 of 14 volunteers and in oligozoospermia in 7 of 14 and 1 of 14 in the groups given TU only or TU/NETE, respectively. However, the highest azoospermia rate in the TU/NETE group was achieved 8 weeks after the end of the treatment period, and 1 volunteer with very high initial sperm counts (mean, 190 million/mL at baseline) remained oligozoospermic (10.2 million/mL). From week 20 to week 24 there was a significant, fully reversible maximum weight gain of 3.7 kg, on the average, in the NETE group. In the NETE and TU alone groups there were significant 26.6% and 11.5% maximum decreases in high density lipoprotein cholesterol compared with baseline values during the treatment period. A significant elevation of low density lipoprotein and a decrease in lipoprotein(a) were detected in the TU/NETE group. In conclusion, combination treatment with NETE showed suppression of spermatogenesis comparable with results using testosterone esters in combination with GnRH antagonists or cyproterone acetate, but had more favorable injection intervals and better efficacy. Because of its long-lasting, profound suppression of spermatogenesis and the absence of serious side-effects, the combination of TU and NETE can be considered a first choice for further studies of hormonal male contraception.

Adult↗
PubMed2001

The CAG repeat polymorphism in the AR gene affects high density lipoprotein cholesterol and arterial vasoreactivity.

Genomic effects of T are exerted via the AR. The length of the polymorphic CAG repeat sequence in the AR gene is inversely correlated with the transcriptional regulation of target genes by T. In 110 healthy men (20-50 yr), we investigated the interactions among this polymorphism, serum levels of sex hormones, cardiovascular risk factors, and flow-mediated and nitrate-induced vasodilatation of the brachial artery. The number of CAG repeat had no significant correlations with serum concentrations of total or free T. Stepwise multiple regression analysis revealed positive correlations of the number of CAG repeat with serum levels of high density lipoprotein cholesterol (partial r = 0.44; P < 0.001) and flow-mediated vasodilatation (partial r = 0.37; P < 0.001). The association of CAG repeat with high density lipoprotein (HDL) cholesterol was independent of body fat content and serum levels of free T, which both had significant negative correlations with HDL cholesterol. The association of CAG repeat with flow-mediated vasodilatation was independent of cigarette smoking and serum levels of free T and low density lipoprotein cholesterol, which also were correlated with flow-mediated vasodilatation. We conclude that a low number of CAG repeat in the AR gene implies a greater chance for low levels of HDL cholesterol and reduced endothelial response to ischemia, which are both important risk factors for coronary heart disease.

Adult↗
PubMed2001

Inverse correlation between sperm concentration and number of androgen receptor CAG repeats in normal men.

Androgens are essential for the maintenance of normal spermatogenesis. Androgen action is mediated by the androgen receptor (AR), which in the testis is expressed by Leydig, peritubular, and Sertoli cells. The fact that sperm numbers range from 20 up to 300 million/mL in normal men without any indication of changed endocrine parameters led us to assume that genetic variability of transduction of androgen signaling could be important. We therefore compared the variable number of CAG repeats in the AR with sperm concentrations in men with normal ejaculate parameters (62 fathers and 69 volunteers participating in clinical trials). In multivariate analysis CAG repeat length did not differ between the volunteers (19.4 +/- 3.1) and the fathers (20.6 +/- 3.0), but was significantly correlated to sperm concentrations with a coefficient of -0.25. When compared with a group of infertile men with (n = 14) or without (n = 30) a family history of infertility, no such correlation was found. These results indicate that men with short CAG repeats have the highest sperm output within the normal fertile population. Polymorphisms of the AR contribute to the efficiency of spermatogenesis in normal men, but do not play a predominant role in male infertility.

Humans↗