Australian Doctor 13th Sept Issue | Page 22

22 HOW TO TREAT : GENETIC EVALUATION OF MALE INFERTILITY

22 HOW TO TREAT : GENETIC EVALUATION OF MALE INFERTILITY

13 SEPTEMBER 2024 ausdoc . com . au
Box 1 . Genetic testing in clinical practice
• Genetic karyotyping with chromosomal analysis and screening for cystic fibrosis transmembrane conductance regulator gene mutations ( see figure 4 ).
• Sperm epigenetics .
• Biomarkers for proteomic and metabolomic profiles in determining underlying causes for male infertility .
OpenStax College / CC BY 3.0 / bit . ly / 3ybDpdF microdeletion , and cystic fibrosis transmembrane conductance regulator ( CFTR ) gene testing are well-established and validated diagnostic tests commonly used in the evaluation of male infertility . It is estimated that chromosomal anomalies can be detected in 5.5 % of males with primary infertility , and up to 2.5 % in males with secondary infertility . 1 , 6 , 9 Secondary infertility denotes male patients who have previously fathered a child / children but now have infertility issues , which may be caused by a variety of factors such as age or metabolic disease . For males with normal semen analyses ( see table 1 ), chromosomal abnormalities are found in 0.02 % of patients with primary infertility and 0.3 % of patients with secondary infertility . 1 , 9
The chromosomal aberrations are thought to involve sex chromosomes in 3.8 % of cases and autosomes in 1.3 % of cases . 1 , 6 The severity of the phenotypic manifestations depends on which chromosomes are affected . 1 Furthermore , chromosomal abnormalities such as deletions ( see figure 5 ), duplications , or translocations are 8-10 times more common in infertile males than in the general population . 9
Specific syndromes and / or diseases associated with sex chromosomes have been closely connected with male infertility . Common abnormalities include Klinefelter syndrome , 46 , XX , mutations in X-linked ubiquitin specific peptidase 26 , and 45 , X / 46 , XY mosaicism , as well as Y chromosome microdeletions . These chromosomal alterations or abnormalities may be associated with abnormal development of specific sexual characteristics or urogenital organs . In most cases , a microscopic sperm retrieval technique with testicular microdissection is considered the standard of care and is often required for intracytoplasmic sperm injection ( ICSI )/ IVF purposes .
Figure 2 . Microphotography showing azoospermia and white cells ( left ) and normozoospermia ( right ).
Figure 1 . Spermatogenesis .
KLINEFELTER SYNDROME
and will invariably need ART , there
testes are small ( usually below 5mL ).
such as breast cancer , extragonadal
infertility in future generations . If
Klinefelter syndrome ( 47 , XXY , see figures 6 and 7 ) is the most common sex chromosomal abnormality found
have been few patients , typically in mosaic cases ( 46 , XY / 47 , XXY ), who can conceive naturally .
The presence of the extra X chromosome material is thought to be responsible for testicular hyalinisation and
germ cell tumours , and non-Hodgkin ’ s lymphoma . 14 Thus , vigilance and proper counselling are impor-
there is full deletion such as in AZF a and b , then it is likely full azoospermia will occur , but if it is AZFc ,
among infertile males ; it has an esti-
Most patients with Klinefelter syn-
fibrosis , leading to primary gonadal
tant with investigations warranted if
then partial or abnormal spermato-
mated prevalence of about 5 % in
drome can exhibit unique pheno-
failure over time . 13
there are suspicious symptoms .
genesis may be encountered . Given
severe oligospermia and 10 % in azoospermia . 11 A 47 , XYY male birth occurs in approximately 1:1000 live births , and while these males are often phenotypically normal , they often have small testes and underlying testicular failure . 1 The mosaic karyotype 45 , X / 46 , XY can be found in 4 % of infertile males . 12
types , although in many cases these men are largely asymptomatic until they are discovered to be infertile or have hypogonadism . 13 , 14 It is estimated that approximately a quarter of individuals with the condition have no discernible diagnostic features on history or examination . 1 In some affected newborns , features such as a small
Most patients with Klinefelter syndrome will present with tall stature and long limbs , reflected in a low upper / lower segment ratio . Behavioural difficulties or psychological problems such as immaturity , insecurity and relationship difficulty may be present . 13 , 14 In the long term , men with the condition are more
Y CHROMOSOME MICRODELETION Microdeletions in the long arm of the Y chromosome containing the azoospermia factor ( AZF ) gene often result in abnormal spermatogenesis . 15 , 16 The prevalence of Y chromosome deletions is estimated to be 1:2000-1:3000 in males and represents the second
these children are at an increased risk of having phenotypic anomalies associated with sex chromosome mosaicism such as Turner syndrome , genetic counselling is advised for couples during the fertility evaluation . 16
Specific subsections of AZF are critical for spermatogenesis , with AZF deletions found in 8-12 % of
Males with karyotypes 47 , XYY , mosaic 45 , X / 46 , XY , 45 , X , and 46 , XX can have variable degrees of fertility . Within the testes of azoospermic
penis ( micropenis ), hypospadias , cryptorchidism and tiny testes may be present . During puberty , some teens may achieve incomplete puberty and
likely to develop disorders related to insulin resistance such as dyslipidaemia , fatty liver disease , type 2 diabetes , peripheral vascular disease ,
most common genetic cause of spermatogenetic failure in infertile males after Klinefelter syndrome . 17 These deletions are passed on to 100 % of
azoospermic males and 3-7 % of oligospermic males . 4 , 15 The Y chromosome locus is divided into three regions , the proximal , middle
males with Klinefelter syndrome , successful sperm retrieval is possible in up to 50 % of cases . 1 , 3 , 8 While most males with this condition are infertile
develop gynaecomastia . There is discordant pubertal development with fairly normal development of the penis and pubic hair , although the
thromboembolic disease and osteopenia / osteoporosis . 14 Some studies also report higher rates of autoimmune disorders and malignancies
male children born through ART ; therefore testing for Yq deletions allows couples to make an informed choice about the perpetuation of male
and distal Yq11 , and is designated as AZFa , AZFb , and AZFc , with a fourth AZFd region that overlaps with the AZFb and AZFc regions . 18