Eberhard Nieschlag

Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure

Hypergonadotropic ovarian dysgenesis (ODG) with normal karyotype is a heterogeneous condition that in some cases displays Mendelian recessive inheritance. By systematically searching for linkage in multiplex affected families, we mapped a locus for ODG to chromosome 2p. As the previously cloned follicle-stimulating hormone receptor (FSHR) gene had been assigned to 2p, we searched it for mutations. A C566T transition in exon 7 of FSHR predicting an Ala to Val substitution at residue 189 in the extracellular ligand-binding domain segregated perfectly with the disease phenotype. Expression of the gene in transfected cells demonstrated a dramatic reduction of binding capacity and signal transduction, but apparently normal ligand-binding affinity of the mutated receptor. We conclude that the mutation causes ODG in these families.

Investigation, Treatment, and Monitoring of Late-Onset Hypogonadism in Males: ISA, ISSAM, EAU, EAA, and ASA Recommendations

The new ISA, ISSAM, EAU, EAA and ASA recommendations on the investigation, treatment and monitoring of late-onset hypogonadism in males provide updated evidence-based information for clinicians who diagnose and treat patients with adult onset, age related testosterone deficiency.

Klinefelter's syndrome

Klinefelters syndrome is the most common genetic cause of human male infertility, but many cases remain undiagnosed because of substantial variation in clinical presentation and insufficient professional awareness of the syndrome itself. Early recognition and hormonal treatment of the disorder can substantially improve quality of life and prevent serious consequences. Testosterone replacement corrects symptoms of androgen deficiency but has no positive effect on infertility. However, nowadays patients with Klinefelters syndrome, including the non-mosaic type, need no longer be considered irrevocably infertile, because intracytoplasmic sperm injection offers an opportunity for procreation even when there are no spermatozoa in the ejaculate. In a substantial number of azoospermic patients, spermatozoa can be extracted from testicular biopsy samples, and pregnancies and livebirths have been achieved. The frequency of sex chromosomal hyperploidy and autosomal aneuploidies is higher in spermatozoa from patients with Klinefelters syndrome than in those from normal men. Thus, chromosomal errors might in some cases be transmitted to the offspring of men with this syndrome. The genetic implications of the fertilisation procedures, including pretransfer or prenatal genetic assessment, must be explained to patients and their partners.

Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations

Demographic data clearly demonstrate that the percentage of the population in the older age group is increasing. Androgen deficiency in the aging male has become a topic of increasing interest and debate throughout the world. Cross-sectional and longitudinal data indicate that the testosterone falls progressively with age and that a significant percentage of men over the age of 60 years have serum testosterone levels that are below the lower limits of young adult (age 20–30 years) men (1–4). The principal questions raised by these observations are whether older hypogonadal men will benefit from testosterone treatment and what will be the risks associated with such intervention. The past decade has brought evidence of benefit of androgen treatment of hypogonadal men on multiple target organs and the recent studies show short-term beneficial effects of testosterone in older men that are similar to those in younger men. This has been comprehensively reviewed and summarized by the Institute of Medicine in ‘Testosterone and Aging: Clinical Research Directions’ (5). Long-term data on the effects of testosterone treatment in the older population are limited mainly to effects on body composition and bone mass (6–11). Key questions of the effects of testosterone on patient reported outcomes and functional benefits that may retard physical or mental frailty of the elderly or improve the quality of life are not yet available. Specific risk data on the prostate and cardiovascular systems are needed.

Prostate volume in testosterone‐treated and untreated hypogonadal men in comparison to age‐matched normal controls

OBJECTIVE The potential use of testosterone preparations for substitution therapy for ageing men and for male contraception, In addition to the well established substitution therapy of male hypogonadism, make increased testosterone use likely. However, little clinical information is available on the effect of testosterone therapy on the prostate in hypogonadal men.

Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens

Abstract Congenital absence of the vas deferens (CAVD) is a frequent cause for obstructive azoospermia and accounts for 1%–2% of male infertility. A high incidence of mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has recently been reported in males with CAVD. We have investigated a cohort of 106 German patients with congenital bilateral or unilateral absence of the vas deferens for mutations in the coding region, flanking intron regions and promotor sequences of the CFTR gene. Of the CAVD patients, 75% carried CFTR mutations or disease-associated CFTR variants, such as the “5T” allele, on both chromosomes. The distribution of mutation genotypes clearly differed from that observed in cystic fibrosis. None of the CAVD patients was homozygous for ΔF508 and none was compound heterozygous for ΔF508 and a nonsense or frameshift mutation. Instead, homozygosity was found for a few mild missense or splicing mutations, and the majority of CAVD mutations were missense substitutions. Twenty-one German CAVD patients were compound heterozygous for ΔF508 and R117H, which was the most frequent CAVD genotype in our study group. Haplotype analysis indicated a common origin for R117H in our population, whereas another frequent CAVD mutation, viz. the “5T allele” was a recurrent mutation on different intragenic haplotypes and multiple ethnic backgrounds. We identified a total of 46 different mutations and variants, of which 15 mutations have not previously been reported. Thirteen novel missense mutations and one unique amino-acid insertion may be confined to the CAVD phenotype. A few splice or missense variants, such as F508C or 1716 G→A, are proposed here as possible candidate CAVD mutations with an apparently reduced penetrance. Clinical examination of patients with CFTR mutations on both chromosomes revealed elevated sweat chloride concentrations and discrete symptoms of respiratory disease in a subset of patients. Thus, our collaborative study shows that CAVD without renal malformation is a primary genital form of cystic fibrosis in the vast majority of German patients and links the particular expression of clinical symptoms in CAVD with a distinct subset of CFTR mutation genotypes.

Screening for Deletions of the Y Chromosome Involving the DAZ (Deleted in Azoospermia) Gene in Azoospermia and Severe Oligozoospermia

OBJECTIVE To evaluate the occurrence and prevalence of microdeletions of the Y chromosome involving the DAZ (Deleted in AZoospermia) gene in patients with azoospermia or severe oligozoospermia. DESIGN Controlled clinical study. SETTING University infertility clinic. PATIENT(S) Infertile men (n = 168) with nonobstructive, idiopathic azoospermia or severe oligozoospermia and normal LH. The control group consisted of proven fathers (n = 86). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Semen analysis; polymerase chain reaction amplification of the loci sY84, sY143, sY254, and sY255; serum FSH, LH, and T; testicular volume. RESULT(S) Deletions involving the sY254 and sY255 DAZ loci were found in three azoospermic patients and two men with sperm concentration < 1 x 10(6)/mL. Serum FSH was elevated in four patients and was normal in one. All five patients had decreased testicular volumes compared with controls. No deletions involving the sY84 and sY143 loci were found. The four loci were amplified normally in the control group. CONCLUSION(S) The estimated frequency of deletions involving the DAZ locus is 3% in azoospermic-severely oligozoospermic men consulting an infertility clinic. Polymerase chain reaction amplification of the DAZ locus is useful for the diagnosis of microdeletions of the Y chromosome. Deletions involving more proximal regions of the Y chromosome seem to be rare.

Paternal age and reproduction

BACKGROUND Due to various sociological factors, couples in developed countries are increasingly delaying childbearing. Besides ethical, economical and sociological issues, this trend presents us with several complex problems in reproduction. Although it is well-known that maternal age has a negative effect on fertility and increases the risk of adverse outcome during pregnancy and in offspring, the paternal influence on these outcomes is less well researched and not well-known. METHODS We performed a systematic search of PubMed, and retrieved original articles and review articles to update our previous survey in this journal. RESULTS This review highlights the link between male age and genetic abnormalities in the germ line and summarizes the knowledge about the effects of paternal age on reproductive function and outcome. Increasing paternal age can be associated with decreasing androgen levels, decreased sexual activity, alterations of testicular morphology and a deterioration of semen quality (volume, motility, morphology). Increased paternal age has an influence on DNA integrity of sperm, increases telomere length in spermatozoa and is suggested to have epigenetic effects. These changes may, at least in part, be responsible for the association of paternal age over 40 years with reduced fertility, an increase in pregnancy-associated complications and adverse outcome in the offspring. CONCLUSION Although higher maternal age can be an indication for intensive prenatal diagnosis, including invasive diagnostics, consideration of the available evidence suggests that paternal age itself, however, provides no rationale for invasive procedures.

Testosterone levels in men with chronic obstructive pulmonary disease with or without glucocorticoid therapy

Under the clinical impression that patients with chronic obstructive pulmonary disease (COPD) may demonstrate signs compatible with hypogonadism, we investigated whether oral glucocorticoid therapy is associated with testosterone deficiency. Thirty six men with COPD of whom 16 were receiving oral glucocorticoid medication (mean+/-SEM dose 9.4+/-1.1 mg prednisolone) were investigated in a cross-sectional cohort study. Patients with or without oral glucocorticoid therapy were not different in terms of age, smoking history and additional therapy. Vital capacity, forced expiratory volume in one second, airway resistance, intrathoracic gas volume and blood gases at rest were not different between the groups. However, patients receiving glucocorticoids had a shorter 6 min walking distance (mean+/-SEM 205+/-27 versus 288+/-26 m; p=0.02) compared to patients without oral steroid therapy. Serum levels of testosterone (mean+/-SEM 13.7+/-0.9) were below normal (<12 nM) in 15 of 36 patients. Serum testosterone did not correlate with any other evaluated parameter. Serum levels of free testosterone (free T) (mean+/-SEM 172.3+/-7.8 pM) were decreased in 25 of the 36 patients, including all patients receiving glucocorticoid treatment. In the 16 patients taking glucocorticoids free T was correlated (p=0.016) with the current glucocorticoid dosage (r=-0.504; p=0.007) and the body mass index (r=0.241; p=0.037). All other parameters examined revealed no significant correlations in multiple regression analysis. Glucocorticoid treatment appears to aggravate hypogonadism and a therapeutic study using testosterone in patients with chronic obstructive pulmonary disease receiving glucocorticoid medication appears warranted.

Gene polymorphisms and male infertility – a meta-analysis and literature review

Many genetic polymorphisms have been studied extensively to elucidate their role in the pathophysiology of male infertility. This article presents a review of the literature following a thorough search of PubMed, a compilation of meta-analyses of studies reporting an association with male fertility where the population(s) could be clearly identified as fertile and/or infertile, and a summary of all polymorphisms that have been investigated in single case-control studies to date. The meta-analyses revealed significant associations between polymorphism and male fertility only for AZF gr/gr deletions (OR 1.81, 1.46-2.24 CI, P<0.00001) and MTHFR 677C-->T (OR 1.39, 1.15-2.69 95% CI, P=0.0006) but not for POLG, DAZL, USP26 or FSHR. The influence of CAG repeat length in AR remains open and debated. Genes encoding nuclear proteins (PRM1/2, TNP1/2) and ER1 are possible candidates for further examination, while the role of TAF7L remains unclear. Polymorphisms in 16 other genes have been investigated in single studies, but the results remain doubtful due to often small and heterogeneous cohorts and in the absence of independent replications. The genetic studies performed so far emphasize the complexity of male infertility as a presumably polygenetic trait amended by environmental, lifestyle or occupational factors.