Idiopathic Severe Oligozoospermia Research Articles

Sperm retrieval and intracytoplasmic sperm injection outcomes with testicular sperm aspiration in men with severe oligozoospermia and cryptozoospermia.

Several studies addressed the role of testicular sperm aspiration with intracytoplasmic sperm injection (ICSI) in azoospermic men, but few have included non-azoospermic men. The aim of this study was to evaluate testicular sperm aspiration (TESA) sperm retrieval rates and ICSI outcomes in men with severe oligozoospermia. Data were collected retrospectively from 88 consecutive, non-azoospermic, infertile men with idiopathic severe oligozoospermia who underwent TESA between January 2011 and January 2018. Patients were categorized into four groups according to sperm concentration: <5 and >1 million/ml (group 1), <1 and > 0.1 million/ml (group 2), <0.1 million/ml (group 3), and cryptozoospermia (group 4). Mean male age was 37±7 years and the mean female age was 33±4 years. Sperm was recovered successfully in 90% (79/88) of the men overall and in 100% (30/30) of the men in group 1, 97% (29/30) of the men in group 2, 88% (15/17) of the men in group 3, and 45% (5/11) of the men in group 4. Most (65%, 57/88) of the couples had an embryo transfer (ET). The overall clinical pregnancy rate per ET was 46% (26/57). The clinical pregnancy rates (per ET) were 43% (9/21) in group 1, 65% (13/20) in group 2, 36% (4/11) in group 3, and 0% (0/5) in group 4. Our data indicate TESA allows for high sperm retrieval rates and acceptable ICSI pregnancy rates in men with severe oligozoospermia. However, in our experience, TESA sperm retrieval rates and ICSI outcomes are poor in cryptozoospermic men.

An M1AP homozygous splice-site mutation associated with severe oligozoospermia in a consanguineous family.

Severe oligozoospermia (SO) is an important cause of male infertility. Its etiology and pathogenesis are associated with genetic abnormalities; however, the genetic causes of the majority of idiopathic human SO remain unclear. Here, we report a homozygous splice-site mutation in M1AP (meiosis 1 associated protein; NM_138804, c.1435-1G>A) observed in a patient with SO from a consanguineous Han Chinese family. His parents and fertile brother were heterozygous for the mutation. The splice variant led to a lack of M1AP protein in the patient's spermatozoa. Ultrastructural and immunostaining analyses of patient's spermatozoa showed highly aberrant swollen mitochondrial sheaths with normal axonemal structures. Subsequent mutation screening identified three additional heterozygous M1AP variants in 4/243 subjects with idiopathic SO, but no M1AP variants among 223 fertile subjects. Additionally, a previously study reported that M1ap knock-out mice exhibited SO due to meiotic arrest. Hence, our findings indicate that M1AP mutation might represent novel genetic alteration responsible for human SO.

Do men with normal testosterone–oestradiol ratios benefit from letrozole for the treatment of male infertility?

Previous studies of aromatase inhibitors on male infertility have focused on men with low testosterone-oestradiol ratio of less than 10. Can aromatase inhibitors improve spermatogenesis in men with idiopathic male infertility with normal testosterone-oestradiol ratio? Prospective study of men with idiopathic severe oligozoospermia (sperm concentration <5 million/ml) carried out between February 2015 and March 2017. The objective was to assess if semen-analysis parameters improved after treatment with letrozole. Secondary objectives were to monitor the safety of letrozole in men, and to measure the alterations in serum FSH, LH, oestradiol and testosterone levels. Fifteen men with normal testosterone-oestradiol ratio (>10) were treated with letrozole 2.5 mg daily for 4 months. This produced a 5.5-fold increase in sperm concentration (P = 0.0068). All men had increased total serum testosterone and suppressed oestradiol levels after treatment, thus raising the overall testosterone-oestradiol ratio (P < 0.0001). Adverse effects from letrozole were relatively minor and included loss of libido (54%), headaches (25%), fatigue (21%), weakness (13%), loss of hair (8%) and dry mouth (8%). Letrozole improves sperm concentration and increases testosterone-oestradiol ratio for men with oligozoospermia who have normal testosterone-oestradiol ratio; its role in the treatment of male infertility may be extended to this group of patients. In addition, it is a relatively well-tolerated drug with no serious adverse effects.

High frequency of TTTY2-like gene-related deletions in patients with idiopathic oligozoospermia and azoospermia.

Genes located on Y chromosome and expressed in testis are likely to be involved in spermatogenesis. TTTY2 is a Y-linked multicopy gene family of unknown function that includes TTTY2L2A and TTTY2L12A at Yq11 and Yp11 loci respectively. Using PCR amplification, we screened for TTTY2L2A- and TTTY2L12A-associated deletions, in 94 Greek men with fertility problems. Patients were divided into three groups as following: group A (n=28) included men with idiopathic moderate oligozoospermia, group B (n=34) with idiopathic severe oligozoospermia and azoospermia, and group C (n=32) with oligo- and azoospermia of various known etiologies. No deletions were detected in group C patients and 50 fertile controls. However, two patients from group A had deletions in TTTY2L2A (7.1%) and six in TTTY2L12A (21.4%), whereas from group B, four patients had deletions in TTTY2L2A (11.8%) and 10 in TTTY2L12A (29.4%). In addition, five patients from both groups A and B (8%) appeared to have deletions in both studied TTTY2 genes, although these are located very far apart. These results indicate that the TTTY2 gene family may play a significant role in spermatogenesis and suggest a possible mechanism of nonhomologous recombinational events that may cause genomic instability and ultimately lead to male infertility.

Copy Number Variants in Patients with Severe Oligozoospermia and Sertoli-Cell-Only Syndrome

A genetic origin is estimated in 30% of infertile men with the common phenotypes of oligo- or azoospermia, but the pathogenesis of spermatogenic failure remains frequently obscure. To determine the involvement of Copy Number Variants (CNVs) in the origin of male infertility, patients with idiopathic severe oligozoospermia (N = 89), Sertoli-cell-only syndrome (SCOS, N = 37)) and controls with normozoospermia (N = 100) were analysed by array-CGH using the 244A/400K array sets (Agilent Technologies). The mean number of CNVs and the amount of DNA gain/loss were comparable between all groups. Ten recurring CNVs were only found in patients with severe oligozoospermia, three only in SCOS and one CNV in both groups with spermatogenic failure but not in normozoospermic men. Sex-chromosomal, mostly private CNVs were significantly overrepresented in patients with SCOS. CNVs found several times in all groups were analysed in a case-control design and four additional candidate genes and two regions without known genes were associated with SCOS (P<1×10−3). In conclusion, by applying array-CGH to study male infertility for the first time, we provide a number of candidate genes possibly causing or being risk factors for the men's spermatogenic failure. The recurring, patient-specific and private, sex-chromosomal CNVs as well as those associated with SCOS are candidates for further, larger case-control and re-sequencing studies.

Clinical and laboratory evaluation of idiopathic male infertility in a secondary referral center in India

The genetic basis of infertility has received increasing recognition in recent years, particularly with the advent of assisted reproductive technology. It is now becoming obvious that genetic etiology for infertility is an important cause of disrupted spermatogenesis. Y-chromosome microdeletions and abnormal karyotype are the two major causes of altered spermatogenesis. To achieve biological fatherhood, intracytoplasmic sperm injection (ICSI) is performed in cases of severe infertility with or without genetic abnormalities. There is a concern that these genetic abnormalities can be transmitted to the male progeny, who may subsequently have a more severe phenotype of infertility. A total of 200 men were recruited for clinical examinations, spermiograms, hormonal profiles, and cytogenetic and Yq microdeletion profiles. Testicular biopsy was also performed whenever possible and histologically evaluated. Genetic abnormalities were seen in 7.1% of cases, of which 4.1% had chromosomal aberrations, namely Klinefelter's mosaic (47XXY) and Robertsonian translocation, and 3.0% had Yq microdeletions, which is very low as compared to other populations. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) were significantly increased in men with nonobstructive azoospermia (NOA) as compared to severe oligoasthenozoospermia (P<0.0001), whereas testosterone levels were significantly decreased in men with microdeletions as compared to men with no microdeletions (P<0.0083). Low levels of androgen in men with microdeletions indicate a need to follow-up for early andropause. Patients with microdeletions had more severe testicular histology as compared to subjects without deletions. Our studies showed a significant decrease (P<0.002) in the serum inhibin B values in men with NOA, whereas FSH was seen to be significantly higher as compared to men with severe oligoasthenozoospermia (SOAS), indicating that both the Sertoli cells as well the germ cells were significantly compromised in cases of NOA and partially affected in SOAS. Overall inhibin B in combination with serum FSH would thus be a better marker than serum FSH alone for impaired spermatogenesis. In view of the genetic and hormonal abnormalities in the group of infertile men with idiopathic severe oligozoospermia and NOA cases, who are potential candidates for ICSI, genetic testing for Y-chromosome microdeletions, karyotype, and biochemical parameters is advocated.

Mutation screening of the DAZLA gene-a candidate gene in male subfertility

Mutation screening of the DAZLA gene-a candidate gene in male subfertility

New treatment of idiopathic severe oligozoospermia with mast cell blocker: results of a single-blind study

To determine whether mast cell blocker (tranilast) improves fertility and/or semen parameters in severe oligozoospermia. Placebo-controlled single-blind clinical study. Nagoya University Hospital Andrology Clinic, Nagoya, Japan. Fifty men with sperm density < 5 x 10(6) sperm/mL, normal serum gonadotropins, and T, and a fertile partner were enrolled in this study. Patients were prescribed randomly 300 mg/d tranilast or a placebo, three tablets per day, for 3 months. Semen and blood samples were collected before and after therapy. Semen parameters, serum gonadotropins, T, and PRL were evaluated before and after therapy. The pregnancy rate (PR) in the mast cell blocker group was 28.6% compared with 0% in the placebo group. There was a statistical difference in the PR between groups. The mast cell blocker group had significantly higher levels of sperm density, sperm motility, and total motile sperm count. There were no differences between the mast cell blocker and placebo groups in seminal volume and normal sperm morphology. The authors conclude that mast cell blocker is clinically useful for the treatment of idiopathic severe oligozoospermic men.