Australian Doctor 13th Sept Issue | Page 23

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Table 1 . Normal limits of reference for semen analysis

Normal forms (%) 4 ( 3.9-4 ) Source : Boitrell F et al 10

The deletion of the AZFa candidate genes , ubiquitin specific protease 9 , Y chromosome ( USP9Y ); and dead box on the Y ( DBY ) are responsible for male infertility . While deletions or small mutations in USP9Y seem to be associated with severe hypospermatogenesis only , patients with deletions of DBY may present with either Sertoli cell-only syndrome ( SCOS , where only Sertoli cells line the seminiferous tubules in the testes , and there is very low or absent spermatogenesis ) or severe hypospermatogenesis . 19 The AZFb locus contains two important genes , eukaryotic translation initiation factor 1A , Y isoform ; and RNA-binding motif on Y , and deletion of AZFb often leads to the arrest of spermatogenesis . The AZFc region contains the deleted in azoospermia ( DAZ ) gene family responsible for normal spermatogenesis .

Deletion of AZFc encompasses 60 % of microdeletions and invariably results in limited spermatogenesis . 15 , 16 Deletions of the AZFc locus occur more frequently ( 65-70 %) than the AZFa or AZFb locus , with DAZ accounting for 10 % of cases of males with spermatogenic defects . 20 Partial AZFb and AZFc deletions may be compatible with normal or reduced sperm counts being amenable to successful sperm retrieval , while AZFc deletions produce retrievable sperm in 70-80 % of patients . 4 , 19

While some AZFc-deleted men can father a child , it is clinically observed that these individuals often have a progressive decline in sperm counts and can progress to azoospermia over time . 21 Therefore , patients with mild or moderate oligozoospermia and Y chromosome microdeletions may require appropriate follow-up . This is to evaluate their possible progression to azoospermia and the need for patient counselling regarding the option of sperm cryopreservation for biological parenthood in the future , especially given that most men with Y chromosome microdeletions would require ART for biological parenthood . 21 It is controversial whether these patients with AZF deletions have a slower fertilisation rate , poor embryo quality , impaired blastocyst rate , and lower overall success

15 , 19 of ART .

The Y chromosome has long been a suspected candidate for gonadal and testicular cancer , so long-term follow-up is needed for infertile men harbouring Y chromosome microdeletions . While Y chromosome microdeletions are strongly associated with infertility , a subset of men with Y chromosome defects may have a higher prevalence of mental health disorders such as bipolar disorder , depression , anxiety ,

Experimental / research

Figure 3 . Genetic workup for male infertility with azoospermia .

ADHD , as well as language delay and behavioural problems . 21

CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR GENE Cystic fibrosis , an autosomal recessive condition affecting 1:1600 male babies , is caused by mutations in the CFTR gene that is located on chromosome 7 . 1 The CFTR gene is a chloride channel protein that regulates the body ’ s water and ion balance . The presentations in cystic fibrosis are caused by an imbalance in water and ion homeostasis in the secretory epithelia of the affected organs because of a loss of function in the apical chloride and bicarbonate channel CFTR .

Specific CFTR gene mutations have been identified that lead to obstructive azoospermia , so this genetic test should be conducted in males with congenital bilateral absence ( see figures 8 and 9 ) or atresia of the vas deferens and / or epididymal malformations . 22 These patients often have seminal vesicle abnormalities ranging from hypoplasia to cystic dilatation , resulting in low semen volume or low pH azoospermia on semen analysis . 23 Despite the reproductive tract abnormality associated with cystic fibrosis ,

Hormonal receptor gene deletion Sperm epigenetics Proteomic and metabolomics biomarkers

normal spermatogenesis is often present , and a simple sperm retrieval process is required for ICSI / IVF purposes . In the past , cystic fibrosis was often diagnosed as a paediatric condition presenting primarily as a digestive disorder and severe pancreatic insufficiency . Over time , the morbidity caused by progressive obstructive lung disease with frequent infections leads to a decline in lung function . In addition to pulmonary complications , other organs such as the exocrine pancreas , gastrointestinal tract and sweat glands are affected . Patients with cystic fibrosis are now living longer and additional complications not originally appreciated can emerge , including gastroesophageal reflux disease , cystic fibrosis-related diabetes , liver dysfunction , depression and anxiety . 24

Early treatment strategies for cystic fibrosis are focused on improving mucus clearance , managing chronic infections and pancreatic insufficiency , and improving nutrition . 24 The discovery of CFTR as the genetic determinant for the disease has resulted in the development of novel therapeutic agents to modulate the bioactivity of otherwise defective

CFTR = cystic fibrosis transmembrane conductance regulator ; AZF = azoospermia factor

CFTR variants . Various CFTR modulators to potentiate CFTR or restore diminished protein levels at the cell surface are available to treat diseases of acquired dysfunction . 24

KALLMANN SYNDROME Kallmann syndrome is an X-linked genetic disorder characterised by anosmia and hypogonadotropic hypogonadism . It is thought to occur in approximately one in 10,000-60,000 live births . 1 Males with Kallman syndrome have fertility issues with testicular dysfunction ranging from SCOS to focal areas of complete spermatogenesis . 18 Kallmann syndrome can be present in autosomal dominant , autosomal recessive , and X-linked recessive inheritance patterns . 1 , 25

This rare paediatric genetic condition is thought to be associated with changes in more than 20 genes , although some affected individuals have mutations in more than one of these genes . The genes associated with Kallmann syndrome are also involved in the migration of neurons that produce gonadotropin-releasing hormone ( GnRH ), responsible for sexual development both before birth and during puberty . 26 In

Figure 4 . Cystic fibrosis transmembrane conductance regulator and location of the most frequent mutations ( indicated by the arrows ).

addition , these gene mutations disrupt the migration of both olfactory and GnRH-producing neurons in the developing brain , resulting in diminished or absent smell and delayed or absent puberty . 25 Males born with hypogonadotropic hypogonadism often have a micropenis and bilateral undescended testes . Other features of Kallmann syndrome include a unilateral renal agenesis , bony malformations , cleft palate and lip , vision problems , hearing loss and motor disturbances . 26

At puberty , most affected individuals do not develop secondary sex characteristics ( see figures 10 and 11 ).

Treatment involves lifelong hormone replacement therapy and in male infants , surgery to correct undescended testes . Without treatment , most men are infertile . In middle age , these patients will need vitamin D supplementation and bisphosphonates to minimise the risk of osteoporosis .

HORMONE RECEPTOR GENES Various steroidal and androgen pathways play a critical role in the development and maintenance of spermatogenesis . Perturbations in