The Infertility Workup
Steven R. Bayer, Michael M. Alper, Alan S. Penzias in The Boston IVF Handbook of Infertility, 2017
Hypergonadotropic hypogonadism results from overt testicular failure. This is often associated with either acquired or congenital anatomic defects of the testicles or from chromosomal abnormalities and rearrangements found during karyotype testing. Genetic deletions within specific regions of the Y-chromosome is another common cause of failed spermatogenesis in the presence of normal testosterone levels. As a result, all men with sperm counts of under 5 million should undergo both karyotype and Y-chromosome microdeletion testing. Conversely, hypogonadotropic hypogonadism is common among men with eating and body dysmorphic disorders. Men who routinely overexert themselves with strenuous exercise or those who have central nervous system tumors affecting hypothalamic and pituitary function may have a reversible cause of their azoospermia. Abuse and use of specific medications known to impact spermatogenesis include anabolic steroids, chronic opioids exposure, and past or present use of certain chemotherapeutic agents. Eighty percent of all men treated for testicular cancer will resume spermatogenesis within 5 years after completion of chemotherapy, and only 20% will have permanent azoospermia.
Genetic Testing of Y-Chromosome Microdeletion
Nicolás Garrido, Rocio Rivera in A Practical Guide to Sperm Analysis, 2017
Diagnostic testing for Y-chromosome microdeletion is performed by PCR assays. STS primers identify various sections related to microdeletions within the AZF locus (Figure 5.6). It is important that STS primers come from regions of the Y chromosome that are conserved within azoospermic/oligozoospermic men with YCMD. STS primers are used to amplify anonymous regions within each AZF region. Microdeletion detection occurs from a lack of amplification, when the STS primers are unable to bind to their deleted complementary DNA. Gene-specific amplification within these regions does not increase the detection rate of clinically relevant microdeletions, emphasizing that the location of the primer is more important than the amplification content.59
Sex Chromosome Anomalies
Merlin G. Butler, F. John Meaney in Genetics of Developmental Disabilities, 2019
Foresta et al. (165) reported that of 4868 infertile men studied between 1991 and 2000, 1 in 12 carried a Y chromosome microdeletion, compared to only 1 in 221 of 2663 fertile males. Among the studies cited, the prevalence varied from 1% to 35% reflecting different patient selection criteria. The highest frequencies of deletions were found in idiopathic oligospermia (<5 x 106 per mL) (14%), idiopathic azoospermia (18%), idiopathic severe hypospermatogenesis (24.7%), and idiopathic Sertoli cell only syndrome (35%). Thus, careful selection of patients to include only idiopathic cases will increase the likelihood of finding Yq deletions. No correlation was observed between the location of the deletion (AZFa,b,c,) and the clinical phenotype. The variability of the phenotype may be explained by the size of the deletions, the deletion of specific genes or gene clusters affecting different testicular or spermatogenic functions, the role of homologous genes located elsewhere in the genome, and the genetic background. The recent discovery of eight massive palindromic sequences in the MSY which are recombinogenic and appear to be maintained by frequent gene conversion—“the nonreciprocal transfer of information between one DNA duplex to another” (166)—has already allowed investigators to identify four distinct classes of recurrent MSY deletions, identify the absent genes as a result of these deletions, typically members of testis-specific gene families, and demonstrate that most such deletions are due to homologous recombination between nearidentical segments of DNA (15,167–171). Evidently, microdeletions and other rearrangements of Yq (Fig. 1) are relatively frequent and play a significant role in male infertility. Furthermore, these deletions have little effect on general health, and would normally behave as classical genetic lethal dominant mutations arising de novo in each generation, only rarely being transmitted to male offspring.
Sperm DNA damage and its impact on male reproductive health: a critical review for clinicians, reproductive professionals and researchers
Published in Expert Review of Molecular Diagnostics, 2019
Ashok Agarwal, Manesh Kumar Panner Selvam, Saradha Baskaran, Chak-Lam Cho
Epigenetics plays a major role in male infertility and alteration in the epigenetic makeup affects the gametogenesis and gamete maturation [24,25]. Epigenetic abnormalities in methylation and acetylation process mediated by ROS have deleterious effects on sperm function. Hypomethylation of sperm DNA is associated with hypospermatogenesis [26,27]. In addition, hypermethylation also has adverse effect on the spematogenesis [28]. Global hypermethylation was reported in infertile males [29] and 143 hypermethylated sites were noticed in nonobstructive azoospermia [30]. Apart from epigenetic changes, Y chromosome microdeletions are also the cause of male infertility [31,32]. Increased levels of ROS result in SDF-associated promutagenic changes that could lead to AZF microdeletion of Y chromosome [33]. Other factors that induce Y chromosome microdeletion are abortive apoptosis and defective chromatin packaging.
Successful extraction of sperm cells after autologous bone marrow transplant: a case report
Published in Scandinavian Journal of Urology, 2019
Frederik M. Jacobsen, Mikkel Fode, Jens Sønksen, Dana A. Ohl, Christian Fuglesang S. Jensen
By the end of the follow-up period the patient and his partner had been trying to get pregnant for 2 years without success, so they contacted a fertility clinic. Two semen samples both demonstrated azoospermia. From his further diagnostic evaluation, the man was diagnosed with non-obstructive azoospermia. This evaluation included hormonal evaluation, Y chromosome microdeletion testing and karyotype analysis. Follicle-stimulating hormone was elevated (21 mIU/ml) and Inhibin B was low (12 pg/ml). No microdeletions were found. Karyotype analysis demonstrated an inversion of the Y chromosome, more specifically inv(Y) p11.2q11.22. The patient underwent genetic counselling and, according to current knowledge, the specific type of inversion should not affect the fertility or in other ways change his phenotype [2].
High frequency of de novo DAZ microdeletion in sperm nuclei of subfertile men: possible involvement of genome instability in idiopathic male infertility
Published in Human Fertility, 2018
Hossein Mozdarani, Pegah Ghoraeian, Sohail Mozdarani, Parvin Fallahi, Anahita Mohseni-Meybodi
Screening of the Y chromosome microdeletion in the diagnostic work-up of infertile men is mainly done using polymerase chain reaction (PCR) on blood leukocytes (Simoni, Kamischke, & Nieschlag, 1998). However, there is evidence showing that presence of DAZ in somatic cells might not be indicative of its presence in germ cell lineage (Yasin et al., 2014). It is known that sperm DNA damage is clearly associated with male infertility and abnormal spermatogenesis (Nili, Mozdarani, & Aleyasin, 2009; Nili et al., 2011; Simoni et al., 1997). Therefore, DAZ genes might be deleted during spermatogenesis. These changes are certainly not detectable with somatic cell analysis. Higher frequencies of Yq microdeletions in sperm DNA were previously reported as compared to DNA isolated from blood (Dada et al., 2007; Sakthivel & Swaminathan, 2008; Yasin et al., 2014) using PCR and real-time PCR techniques. Although these are sensitive techniques, there is a dilution effect which prevents assessment of genetic mosaicism occurring in a cell population and also they are not capable of showing situation of DAZ on individual cells.
Related Knowledge Centers
- Azoospermia
- Fertility
- Genetic Marker
- Mutation
- Oligospermia
- White Blood Cell
- Y Chromosome
- Genetic Disorder
- Natural Selection
- Sequence-Tagged Site