24 HOW TO TREAT : GENETIC EVALUATION OF MALE INFERTILITY
24 HOW TO TREAT : GENETIC EVALUATION OF MALE INFERTILITY
13 SEPTEMBER 2024 ausdoc . com . au their functions can result in spermatogenic failure and male infertility . While these novel genetic tests provide insight into testicular dysfunction and arrest of spermatogenesis , their clinical utility in ART is limited unless hormonal manipulation is effective in restoring the underlying process of spermatogenesis .
Mutations in the androgen receptor ( AR ) gene , an X-linked genetic condition , is thought to affect at least 2 % of infertile males , especially those with signs of androgen insensitivity . 26 The AR gene is located on chromosome Xq11-12 . Recent studies have shown that mutations or polymorphisms in the AR gene and its expressed protein may also result in depressed spermatogenesis and idiopathic male infertility , without any abnormalities in male secondary sexual characteristics . 1 , 27 , 28 The human sex hormone-binding globulin ( SHBG ) that is expressed in testicular germ cells is responsible for the concentration of androgen within the testes by binding to or increasing androgen bioavailability ; an abnormality in the SHBG gene located on chromosome 17 may adversely impact androgen bioavailability , spermatogenesis and male fertility . 1 Similarly , mutations in the FSH and LH receptor genes may interfere with hormonal regulation , male development and spermatogenesis . While the exact role of oestrogen signalling in male reproduction is not well defined , abnormalities in two functional isoforms of oestrogen receptors known as ERα ( alpha ) and ERβ ( beta ) that are encoded by two different genes on the long arm of chromosomes 6 and 14 , can be responsible for issues relating to epididymal sperm concentration and germ cell progression or viability . 28
Other steroidal-related hormone genes such as the insulin-like 3 growth gene on chromosome 19 and Leydig insulin-like protein on chromosome 13 are responsible for testicular descent and maturation during fetal development . 1 , 8 The enzyme 5-methylenetetrahydrofolate reductase ( MTHFR ), encoded by the MTHFR gene , is a key enzyme in folate metabolism ; MTHFR enzyme deficiency and hypo-methylation may inhibit gene expression , causing the absence of germinal cells and spermatogenesis arrest . 1 , 2
Mutations in the AR gene and other steroidal-related hormone gene abnormalities can cause a range of phenotypic abnormalities in male sexual development . Depending on the degree of androgen responsiveness , patients with androgen insensitivity syndrome can present with a broad spectrum of abnormalities in the external genitalia . This is largely classified into three main phenotypes ( see box 2 ).
In the majority of cases , the levels of most of the serum hormones , including FSH , LH , oestradiol and testosterone , are within or elevated above the normal male reference range .
In patients with steroidal-related hormone gene abnormalities , the clinical phenotypes may range from normal to unusual developmental and metabolic conditions . Patients with cortisol hypersecretion will likely have cushingoid features and growth retardation .
In contrast , patients with adrenal insufficiency , such as in
Figure 5 . Y chromosome microdeletions . All chromosomes are divided into a long and a short arm . Most deletions that cause azoospermia or oligozoospermia occur in the azoospermia factor ( AZF ) regions of the long arm . These are AZFa ( proximal ), AZFb ( central ) and AZFc ( distal ).
Figure 6 . Karyotype 47 , XXY .
congenital adrenal hyperplasia , often achieve precocious puberty , have atypical genitalia and fertility issues , while those with more complex genetic mutations may exhibit unusual syndromic features , delayed puberty with testicular failure , and malformations of various organs .
SPERM EPIGENETICS RNA sequencing in sperm may play an important role in regulation of spermatogenesis , influencing fertilisation and early embryogenesis . 29 Awareness of the presence of a myriad of groups of RNAs and their functions in spermatogenesis , fertility and early embryo development has led to an increased focus on small regulatory RNAs and their functions . Small regulatory RNAs are non-coding RNAs that regulate gene expression at the transcriptional or post-transcriptional levels , or through chromatin remodelling . 30 The RNA can serve as a useful biomarker to predict the fertility success rate , thereby allowing
Box 2 . Phenotypes in androgen insensitivity syndrome
• Complete androgen insensitivity syndrome ( AIS ) with typical female external genitalia .
• Partial AIS with predominantly male or ambiguous external genitalia .
• Mild AIS with typical male external genitalia or an isolated micropenis , but often present with gynaecomastia at puberty and infertility in adulthood .
couples to identify the need for early ART and reduce the requirement for future invasive testing as well as time wasted to achieve a live birth . 6 Unfortunately , these tests require high technical expertise and are not widely available .
There is increasing evidence that anomalies in sperm mitochondrial DNA ( mtDNA ) may lead to male infertility because the mitochondria play a critical role in energy production , metabolism and maintenance of spermatozoa motility . 31 Recent studies found that mtDNA point mutations or multiple deletions , mtDNA single nucleotide polymorphisms and mtDNA haplogroups can greatly influence sperm parameters and quality , especially defects in the sperm tail formation or energy production for sperm motility . 32
Another newly identified class of small RNAs deemed to regulate spermatogenesis and male infertility is that of piwi-interacting RNAs ( piR- NAs ), which are small non-coding RNA molecules involved mostly in the epigenetic and post-transcriptional silencing of transposable elements . Thus , it is likely that piRNAs are potentially involved in regulating the processes of meiosis and post-meiosis of male germ cell development . 1
Proteomic and metabolomic profiles of other male infertility biomarkers
Novel breakthroughs in gene and protein interactions have been achieved in the field of male infertility using genome-wide proteomics and transcriptomics technologies . 33 Proteomics is the study of the interactions , function , composition and structures of proteins and their cellular activities . However , there are too many variables within the proteomic and metabolomic profiles of the sperm to accurately map the relevant area of the genetic defect ( s ), since these can be affected by various environmental factors , thereby limiting its clinical use .
Human sperm and seminal plasma contain many proteins involved in spermatogenesis such as heat shock protein , fibronectin , semenogelins and laminin , as well as enzymes such as serine protease and protease inhibitors . 34 These proteins are critical to various sperm functions such as motility , structural organisation , energy production and metabolism , as well as antioxidant activity . 33 The combination of transcriptomic and proteomic approaches can shed important information on spermatozoa function , and seminal plasma proteomic studies have identified various protein biomarkers responsible for gene expression for each of the male genital tract organs , including post-transcriptional and translational gene regulation involved during spermatogenesis . 34-36