The Phosphorus Male Infertility Panel: A Newer, More Useful Genetic Assay For Evaluation Of Men With No Sperm In the Ejaculate (Azoospermia)
The finding of no sperm in the ejaculate on semen analysis can be a devastating finding for men trying to conceive a pregnancy with their wives. Urologic evaluation typically includes repeat semen analysis, imaging, serum hormone levels and genetic testing.
Standard Genetic testing has remained constant over the past fifteen years and includes cystic fibrosis (CF) mutation testing, y chromosome microdeletion testing and karyotype.
CF mutation is most relevant in the setting of congenital absence of the vas deferens as there is a causal link between both the gene mutation and the disorder. Findings that most men with cystic fibrosis have absence of the vas led to this discovery.
Karyotype is a look at the whole chromosomes. Men are normally 46 Xy and women, 46 XX. The most common abnormalities seen in the setting of male infertility are 47XXy, (Klinefelters syndrome) and 47 Xyy.
Y chromosome microdeletion focuses on the AZF region in the y chromosome where genes essential to sperm production are located. Deletions of AZF a, b and or c regions can lead to the inability make any or to make more than just very few sperm.
WHAT DOES PHOSPHORUS ADD?
Phosphorous adds in additional genetic considerations, previously not available through a commercial lab. These genes relate to defects and disorders of sperm fertilization, of spermatogenesis (sperm production) itself, and disorders of sexual development.
Genes associated with fertilization included:
AURKC: mutations cause abnormalities in the formation of the head and tails of the sperm including globozoospermia.
CATSPER-1: Mutations impair “capacitation” and the “acrosome reaction”, maturational changes sperm must achieve in order to fertilize and egg
DPY19L2: Mutations cause sperm to be formed without “acrosomes” and therefore cause inability to fertilize and egg.
Genes associated with problems of spermatogenesis include:
USP9Y: mutations are a cofactor in the inability to produce sperm.
FSHB: mutations cause an inability for the pituitary to make FSH (follicle stimulating hormone), a peptide necessary for sperm production.
FSHR: mutations of the FSH receptor can cause very low or no sperm production due to an inability to respond to FSH.
Genes associated with problems of spermatogenesis include:
AR: mutations of the androgen receptor causes varying inability to respond to Male hormone. The most severe form of this is called androgen insensitivity syndrome where genetic males have a female appearance. But less severe forms can have an impact on male fertility.
LHCGR: Luteinizing hormone/chorionic gonadatropin receptor mutation causes an abnormality in the receptor for luteinizing hormone. This can have a variety of effects including precocious puberty at one end of the spectrum and limited ability to make testosterone at the other end.
SRY: 46 Xy Sex reversal: The sry gene is necessary for normal male genital development. Mutations of this gene may confer a variety of genital disorders.
This expanded panel of genetic testing should broaden our ability to diagnose underlying causes of male infertility related to azoospermia and severe oligospermia (severe low count) and is expected to significantly affect the management of such patients.
