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Biomedical subjects

E Nieschlag

Publications and source records attributed to E Nieschlag.

At least 19 recordsLinked to original sources
PubMed2006

Association of three isoforms of the meiotic BOULE gene with spermatogenic failure in infertile men.

The complex process of spermatogenesis requires the expression and precise coordination of a multitude of genes. Abnormal function of such genes is frequently associated with male infertility. Among these candidates is the human BOULE gene that is a possible fundamental mediator of meiotic transition. In this study, we describe for the first time the existence of three BOULE transcript variants (B1, B2 and B3). We investigated their tissue specificity and mRNA transcript levels in 23 testis biopsies from infertile men. B1, B2 and B3 differed solely in their N-terminal sequences, which are encoded by three alternatively spliced exons 1. In humans, all three isoforms are exclusively expressed in the testes in a relative proportion of 80:220:1 for B1, B2 and B3, respectively. RT-PCR quantification revealed significantly reduced mRNA expression of all three variants in testicular biopsies with meiotic arrest (MA) compared with those with qualitatively complete spermatogenesis. Alteration of the B1/B2 and B1/B3 transcript ratios was correlated with reduced meiotic capacity of spermatocytes to produce round spermatids as assessed by flow cytometry. Furthermore, BOULE mRNA reduction in biopsies with MA paralleled the absence of BOULE protein as analysed by immunohistochemistry. In conclusion, the relative proportions of B1, B2 and B3 may serve as predictive markers for meiotic efficiency and thus the probability of finding haploid cells in the human testis. Among the three isoforms, B2 might have the major role for meiotic completion.

Amino Acid Sequence↗
PubMed2006

Clinical experience with the new long-acting injectable testosterone undecanoate. Report on the educational symposium on the occasion of the 5th World Congress on the Aging Male, 9-12 February 2006, Salzburg, Austria.

This symposium report summarizes first extensive clinical findings with injectable testosterone undecanoate (Nebido) in hypogonadal patients showing clinical symptoms of androgen deficiency with or without erectile dysfunction (ED). This new testosterone formulation (1000 mg testosterone undecanoate in 4 ml castor oil) possesses nearly ideal long-term kinetics, i.e. sustained close mimicking of eugonadal testosterone serum levels without supra- or sub-physiological serum concentrations. The generally accepted administration scheme recommends the second injection 6 weeks after the first one followed by further injections every 12 weeks. Applying this regimen, administration intervals are drastically reduced in comparison to conventional i.m. testosterone preparations (e.g. about 16 injections of testosterone enanthate vs. 4-5 injections of testosterone undecanoate per year). Depending on the testosterone serum levels, individualized therapy is possible by shortening (every 10 weeks) or prolonging (every 14 weeks) the injection intervals. In hypogonadal patients with ED 58% respond to testosterone undecanoate alone. Best results are seen in diabetic hypogonadal patients. The regimen of injectable testosterone undecanoate administration ideally fits recommendations regarding pharmacokinetics, efficacy and safety monitoring.

Aged↗
PubMed2006

Y-chromosomal microdeletions and partial deletions of the Azoospermia Factor c (AZFc) region in normozoospermic, severe oligozoospermic and azoospermic men in Sri Lanka.

AIM: To assess for the first time the occurrence of Y chromosomal microdeletions and partial deletions of the Azoospermia Factor c (AZFc) region in Sri Lankan men and to correlate them with clinical parameters. METHODS: In a retrospective study, we analyzed 96 infertile men (78 with non-obstructive azoospermia) and 87 controls with normal spermatogenesis. AZFa, AZFb, AZFc and partial deletions within the AZFc region were analyzed by multiplex polymerase chain reaction (PCR) according to established protocols. RESULTS: No AZFa, AZFb or AZFc deletions were found in the control group. Seven patients in the group of infertile men were found to have deletions as following: one AZFa, two AZFc, two AZFbc and two AZFabc. The relative distribution of these patterns was significantly different compared with that found in the German population. Extension analysis confirmed that the deletions occurred according to the current pathogenic model. gr/gr deletions were found to be equally present both in the patients (n=4) and in the control group (n=4). One b2/b3 deletion was found in the patient group. CONCLUSION: These results suggest that the frequency and pattern of microdeletions of the Y chromosome in Sri Lankan men are similar to those found in other populations and confirm that gr/gr deletions are not sufficient to cause spermatogenetic failure.

Chromosome Deletion↗
PubMed2005

A multicentre study investigating subcutaneous etonogestrel implants with injectable testosterone decanoate as a potential long-acting male contraceptive.

BACKGROUND: The combination of etonogestrel implants with injectable testosterone decanoate was investigated as a potential male contraceptive. METHODS: One hundred and thirty subjects were randomly assigned to three treatment groups, all receiving two etonogestrel rods (204 mg etonogestrel) and 400 mg testosterone decanoate either every 4 weeks (group I, n = 42), or every 6 weeks (group II, n = 51) or 600 mg testosterone decanoate every 6 weeks (group III, n = 37) for a treatment period of 48 weeks. RESULTS: One hundred and ten men completed 48 weeks of treatment. Sperm concentrations of <1 x 10(6)/ml were achieved in 90% (group I), 82% (group II) and 89% (group III) of subjects by week 24. Suppression was slower in group II, which also demonstrated more frequent escape from gonadotrophin suppression than groups I and III. Peak testosterone concentrations remained in the normal range throughout in all groups. Mean trough testosterone concentrations were initially subphysiological but increased into the normal range during treatment. Mean haemoglobin levels increased in group I, and a non-significant increase in weight and decline in high-density lipoprotein cholesterol was observed in all groups. Fourteen subjects discontinued treatment due to adverse events. CONCLUSIONS: Subcutaneous etonogestrel implants in combination with injectable testosterone decanoate resulted in profound suppression of spermatogenesis that could be maintained for up to 1 year. Efficacy of suppression was less in group II, probably due to inadequate testosterone dosage. This combination has potential as a long-acting male hormonal contraceptive.

Administration, Cutaneous↗
PubMed2005

A common single nucleotide polymorphism in exon 10 of the human follicle stimulating hormone receptor is a major determinant of length and hormonal dynamics of the menstrual cycle.

CONTEXT: FSH is essential for follicular maturation. Data from ovarian hyperstimulation cycles suggest that FSH action is attenuated by a frequent single nucleotide polymorphism of the FSH receptor gene exchanging Asn for Ser at codon 680. OBJECTIVE: We hypothesized that the FSH receptor genotype influences menstrual cycle dynamics. DESIGN: Menstrual cycle was monitored from the midluteal phase through ovulation until the consecutive menstruation. SETTING: The study was conducted at the University research center. SUBJECTS: Women homozygous for the Asn680 (n = 12) and Ser680 (n = 9) variants with normal menstrual cycles volunteered for the study. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASUREMENTS: Follicular growth, serum LH, FSH, estradiol, progesterone, inhibin A, inhibin B and antimullerian hormone were measured. RESULTS: During the luteo-follicular transition, serum levels of estradiol, progesterone, and inhibin A were significantly lower, and FSH started to rise earlier in the Ser680/Ser680 group. FSH levels were steadily and significantly higher, and the mean area under the FSH curve was 31% greater in this group (P < 0.002). No differences were observed in estradiol, inhibin B, and growth velocities of dominant follicles. The time from luteolysis to ovulation was significantly longer in women with the Ser680/Ser680 (13.6 +/- 1.01 d) compared with Asn680/Asn680 (11.3 +/- 0.61 d, P < 0.05) genotype with a significant difference in total menstrual cycle length (29.3 vs. 27.0 d, respectively; P < 0.05). CONCLUSIONS: The FSH receptor Ser680/Ser680 genotype is associated with higher ovarian threshold to FSH, decreased negative feedback of luteal secretion to the pituitary during the intercycle transition, and longer menstrual cycles.

Adolescent↗
PubMed2005

Mosaic status in lymphocytes of infertile men with or without Klinefelter syndrome.

BACKGROUND: Gonosomal aneuploidies such as Klinefelter syndrome (47,XXY) are the most frequent chromosomal aberration in infertile men. Normally the chromosomal status of patients is detected by karyotyping of up to 20 metaphase spreads of lymphocyte nuclei, whereby low grade mosaicism may be overlooked. To test whether Klinefelter patients with 47,XXY karyotype or infertile men with 46,XY karyotype represent gonosomal mosaicisms, we performed meta- and interphase fluorescence in situ hybridization (FISH) on 45 men. METHODS AND RESULTS: A total of 400 interphase and 40 metaphase lymphocyte nuclei per patient were scored after hybridization with DNA probes specific for chromosomes X and Y, and chromosome 9 as a control. On the basis of conventional karyotype, hormone levels and clinical appearance, patients were subdivided into 18 Klinefelter syndrome patients with 47,XXY (group I), 11 Klinefelter syndrome-like patients with normal karyotype, 46,XY (group II) and six non-Klinefelter-like infertile patients with normal 46,XY karyotype (group III). Ten normal men (group IV) served as controls. Testicular volume in the Klinefelter group I was smaller compared with group II (P = 0.016), group III (P < 0.001) and group IV (P < 0.001). In addition, testicular volumes in group II were lower compared with group III and group IV (P < 0.004). No significant differences between the aneuploidy rate analysed by FISH in interphase nuclei and metaphases were found in either single patients or groups. Patients with Klinefelter syndrome, 47,XXY (group I) or with symptoms similar to those in Klinefelter patients 46,XY (group II) showed a similar aneuploidy rate (group I 7.1 +/- 4.0% and group II 4.6 +/- 3.4%) and two 47,XXY patients with a high prevalence for normal 46,XY lymphocytes had sperm in their ejaculate. However, in general, no correlations between FISH mosaic status and serum hormone parameters, nor with ejaculate parameters were found. CONCLUSIONS: The results suggest that 47,XXY patients with an increased incidence of XY cells (average of 4.2 +/- 2.3) may have a higher probability of germ cells as we found sperm only in the ejaculate of Klinefelter syndrome patients with mosaic 46,XY cells (6.0 and 7.0%). On the other hand, 46,XY patients with mosaic sex chromosome aneuploidies detected by FISH analysis more often show symptoms of hypogonadism phenotypically resembling Klinefelter syndrome.

Adult↗
PubMed2005

Glucagon-like peptide-1 reduces the pulsatile component of testosterone secretion in healthy males.

BACKGROUND: Glucagon-like-peptide-1 (7-36) amide (GLP-1), a potent regulator of glucose homeostasis, has been implicated in the control of hypothalamic-pituitary function. In vivo it is a relevant neuroendocrine modulator of gonadotropin-releasing hormone release, suggesting its possible role as a metabolic signal to the reproductive system. The present study was undertaken to establish its effect on luteinizing hormone (LH) and testosterone secretion in nine healthy male volunteers. MATERIALS AND METHODS: Each subject underwent an oral glucose tolerance test to establish LH, testosterone, and GLP-1 responses to glucose. Euglycaemic clamp experiments (6 h) were performed on two occasions with saline or with a constant infusion of GLP-1 (0.4 pmol kg(-1) min (-1)). Blood samples were drawn at 10-min intervals to measure the pulsatile pattern of LH and testosterone secretion. RESULTS: Ingestion of oral glucose resulted in a reduction in plasma testosterone levels at 30 min compared with baseline (P < 0.004) despite unaltered LH levels (P = 0.5). Constant GLP-1 infusion resulted in no change in LH (P = 0.83), testosterone (P = 0.96), follicle stimulating hormone (FSH) (P = 0.86) and leptin levels (P = 0.3). Pulse analysis revealed no significant difference in the number (P = 0.1) or median absolute amplitude (P = 0.3) of the LH pulses. However, there was a significant decrease in the number (3.0 +/- 0.6 vs. 1.3 +/- 0.4; P < 0.05) and a tendency for increased duration of testosterone pulses (97.4 +/- 16.7 vs. 170 +/- 27.1 min; P = 0.06). CONCLUSION: Oral glucose ingestion and intravenous GLP-1 infusion reduce the pulsatile component of testosterone secretion by a mechanism independent of LH release.

Administration, Oral↗
PubMed2005

Testosterone substitution with a new transdermal, hydroalcoholic gel applied to scrotal or non-scrotal skin: a multicentre trial.

OBJECTIVE: Testosterone-containing gels have improved testosterone substitution therapy, but they are associated with the risk of interpersonal transfer. Therefore, we tested a new hydroalcoholic 2.5% testosterone gel (TGW), which was removed by washing 10 min after administration. DESIGN: The gel was applied to scrotal or non-scrotal skin in comparison to two 2.5 mg Androderm patches in a randomised, three-arm, parallel-group, controlled multicentre trial over a period of 24 weeks. We included symptomatic hypogonadal men whose morning testosterone levels were <10 nmol/l. Either 1 g TGW was applied to scrotal skin (n = 54) or 5 g to non-scrotal skin (n = 56) once daily; the patch group (n = 52) applied two patches/day. Dose titration was allowed. RESULTS: Whereas serum testosterone levels and the pre-post changes of the areas under the curve of testosterone and free testosterone between weeks 0 and 24 indicated equivalent treatment success for the patch and scrotal groups, the dermal gel group was significantly superior to the other two groups. Questionnaires on sexual function, mood and quality of life did not differ significantly between study groups, nor were prostate volume, prostate-specific antigen (PSA) levels and prostate symptoms different. However, tolerability was much better in the gel groups than the patch group. CONCLUSION: Efficacy, safety and tolerability suggest TGW as a favourable treatment for hypogonadal patients.

Administration, Cutaneous↗
PubMed2004

Partial deletions in the AZFc region of the Y chromosome occur in men with impaired as well as normal spermatogenesis.

BACKGROUND: Partial deletions of the AZFc region of the Y chromosome were reported to be a significant risk factor for oligo-/azoospermia. In this study, we assessed the occurrence and frequency of partial AZFc microdeletions in patients with spermatogenic failure and in controls with normal spermatogenesis. METHODS: In a retrospective study design, gr/gr, b1/b3 and b2/b3 deletions were analysed by multiplex PCR in 170 men with normal spermatogenesis and 348 men with non-obstructive oligo-/azoospermia. RESULTS: gr/gr deletions were found in 14 men with oligozoospermia or azoospermia (4.0%) and in three normozoospermic men (1.8%) (NS). b1/b3 deletions were found both in controls (n=1) and in patients (n=1). b2/b3 deletions were significantly more frequent in the normozoospermic (five out of 170) than in the oligo-/azoospermic men (two out of 348). Three novel partial AZFc deletion patterns were found in four oligo-/azoospermic men. No correlation with semen or other clinical parameters was found. CONCLUSIONS: The frequency of gr/gr deletions is not significantly increased in men with oligo-/azoospermia, indicating that they are not sufficient per se to cause spermatogenetic impairment and infertility. b1/b3 and b2/b3 deletions are probably irrelevant for spermatogenesis. Novel deletion patterns found exclusively in infertile men suggest that other, still unexplored partial deletions might contribute to spermatogenic failure.

Case-Control Studies↗
PubMed2004

Testosterone replacement therapy: current trends and future directions.

Male hypogonadism is characterized by abnormally low serum testosterone levels associated with typical symptoms, including mood disturbance, sexual dysfunction, decreased muscle mass and strength, and decreased bone mineral density. By restoring serum testosterone levels to the normal range using testosterone replacement therapy, many of these symptoms can be relieved. For many years, injectable testosterone esters or surgically implanted testosterone pellets have been the preferred treatment for male hypogonadism. Recently, newer treatment modalities have been introduced, including transdermal patches and gels. The development of a mucoadhesive sustained-release buccal tablet is the latest innovation, which will provide patients with an additional option. The availability of new treatment modalities has helped to renew interest in the management of male hypogonadism, highlighting the need to address a number of important but previously neglected questions in testosterone replacement therapy. These include the risks and benefits of treatment in different patient populations (e.g. the elderly) and the need for evidence-based diagnosis and treatment monitoring guidelines. While some recommendations have been developed in individual countries, up-to-date, internationally accepted evidence-based guidelines that take into account national differences in clinical practice and healthcare delivery would optimize patient care universally.

Androgens↗
PubMed2004

Regulation of the initial segment of the murine epididymis by dihydrotestosterone and testicular exocrine secretions studied by expression of specific proteins and gene expression.

The murine caput epididymidis responded to deprivation of luminal fluid from the testis by regression of the initial segment but maintenance of the adjacent proximal and distal caput regions, as judged by immunohistochemical staining of the glutamate transporter EAAC1 and the lipocalin MEP17 and enzymatic activity of beta-galactosidase (beta-Gal). Additional removal of circulating androgens by bilateral castration similarly led to loss of the initial segment and of the proximal caput but the distal caput was transformed into an epithelium containing more apical than principal cells staining for EAAC1; this epithelium resembled the precursor epithelium usually only seen in prepubertal juveniles. Administration of dihydrotestosterone (DHT) to the castrates maintained the proximal and distal caput epithelia and induced a proximal epithelium, which resembled the initial segment in its prominent staining for Golgi, EAAC1 and beta-Gal activity, although it was short and exhibited no MEP17 expression. DHT was present in the c-ros knockout caput epididymidis lacking the initial segment and in the heterozygous organ but the DHT concentration was lower in the knockout corpus. The maintenance of the full complement of epithelia in the murine caput epididymidis in the adult thus requires a combination of luminal fluid from the testis, tissue DHT and the presence of the c-ros oncogene.

Amino Acid Transport System X-AG↗
PubMed2004

Detection of structural and numerical chromosomal abnormalities by ACM-FISH analysis in sperm of oligozoospermic infertility patients.

BACKGROUND: Modern reproductive technologies are enabling the treatment of infertile men with severe disturbances of spermatogenesis. The possibility of elevated frequencies of genetically and chromosomally defective sperm has become an issue of concern with the increased usage of ICSI, which can enable men with severely impaired sperm production to father children. Several papers have been published reporting aneuploidy in oligozoospermic patients, but relatively little is known about chromosome structural aberrations in the sperm of these patients. METHODS: We examined sperm from infertile, oligozoospermic individuals for structural and numerical chromosomal abnormalities using a multicolour ACM fluorescence in situ hybridization (FISH) assay that utilizes DNA probes specific for three regions of chromosome 1 to detect human sperm that carry numerical chromosomal abnormalities plus two categories of structural aberrations: duplications and deletions of 1pter and 1cen, and chromosomal breaks within the 1cen-1q12 region. RESULTS: There was a significant increase in the average frequencies of sperm with duplications and deletions in the infertility patients compared with the healthy concurrent controls. There was also a significantly elevated level of breaks within the 1cen-1q12 region. There was no evidence for an increase in chromosome 1 disomy, or in diploidy. CONCLUSIONS: Our data reveal that oligozoospermia is associated with chromosomal structural abnormalities, suggesting that oligozoospermic men carry a higher burden of transmissible, chromosome damage. The findings raise the possibility of elevated levels of transmissible chromosomal defects following ICSI treatment.

Adult↗
PubMed2004

Case report: natural transmission of an AZFc Y-chromosomal microdeletion from father to his sons.

Y-chromosomal microdeletions, associated with oligozoospermia or azoospermia, are usually de novo deletions in the affected patients. We report here the rare case of an affected father who transmitted a Y-chromosomal microdeletion to at least two of his three sons naturally and who also fathered a daughter. The extent of the deletion, which was determined with new STS-primers and covers 3.5 Mb, was identical in the father and his azoospermic sons. To determine any possibly modifying influence of other genes involved in spermatogenesis, we analysed two polymorphisms of the DAZL gene, the autosomal homologue of the deleted DAZ gene. DAZL and DAZ might be functionally related to each other. However, we found identical polymorphisms in exon 2 and 3 of the DAZL gene, in both father and his sons, corresponding to the most prevalent genotype in fertile men. Thus, other genes or environmental factors must modify spermatogenesis in men with identical Y-chromosomal microdeletions.

Adult↗
PubMed2003

Testosterone replacement therapy in male hypogonadism.

In human males 6-7 mg of testosterone are secreted by the testes in a circadian rhythm with a nocturnal rise in testosterone followed by a decline during the day. Testosterone is necessary to induce and maintain secondary sexual characteristics, lean muscle mass, bone density and for normal sexual behaviour and cognitive function in men. Replacement therapy has been shown to be beneficial in men with overt hypogonadism. Natural testosterone should be used and not modified molecules. Testosterone is currently available in oral, intramuscular, subcutaneous and transdermal preparations. Recent advances in testosterone replacement therapy include testosterone gels which provide flexibility in dosing and minimal skin irritation resulting in good compliance, and the development of longer acting intramuscular preparations which result in more stable testosterone levels with longer injection intervals. All patients receiving testosterone should be carefully monitored for changes in hematocrit, liver function, lipid parameters and prostate specific antigen (PSA).This article reviews the current experience with the use of various forms of testosterone for the treatment of male hypogonadism.

Androgens↗