Male infertility

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Infertility is a widespread condition that affects approximately 70 million people worldwide. The World Health Organisation estimates that 9% of couples worldwide struggle with fertility problems. Clinical infertility is the inability of a couple to conceive after 12 months of regular, unprotected attempts. Male factors are estimated to contribute to 30-50% of infertility cases. Infertility or reduced male fertility can result from testicular dysfunction, endocrinopathies, lifestyle factors such as tobacco and obesity, congenital anatomical factors, gonadotoxic exposures, ageing and genetic abnormalities. Chromosomal abnormalities affect both sex and autosomal chromosomes and can cause numerical or structural aberrations. Autosome-related genetic mutations are mainly involved in central hypogonadism, teratozoospermia or monomorphic asthenozoospermia, congenital obstructive azoospermia and familial cases of quantitative spermatogenic disorders. On the other hand, sex chromosome abnormalities that may play an important role in severe spermatogenic impairment include syndromes such as Klinefelter syndrome, the most common genetic aneuploidy of testicular failure in oligozoospermic and azoospermic men (10-15%). It affects 1/1,000 to 1/500 males. There are 2 main forms: 47XXY non-mosaic (80-90%) or 47XXY/46XY mosaic (5-10%). The classic phenotype is that of a tall male with small testes and gynaecomastia, however the phenotype can vary from a fully virilised male to one with androgen deficiency. Consequently, the 70% of men with KS remains undiagnosed until late adulthood. The endocrine profile reveals hypergonadotropic hypogonadism (low-normal testosterone, elevated FSH and LH levels and undetectable inhibin B compatible with testicular failure). Sperm analysis normally reveals azoospermia and may be the only phenotypic abnormality in men with KS. Other genetic abnormalities of the sex chromosomes include Robertsonian translocations or Y-chromosome microdeletions. In addition to these, idiopathic sperm abnormalities still account for approximately 30% of male infertility. However, a variety of comorbid medical conditions have also been found to influence sperm parameters. To name a few, kidney disease, liver failure, haemochromatosis, chronic obstructive pulmonary disease, cystic fibrosis and multiple sclerosis. The mechanism by which medical conditions can impact fertility includes effects on hormone levels, impairment of sexual function (including ejaculatory function) or impairment of testicular function/spermatogenesis. Medically optimising a man's health, improvements in medical disease status can improve sperm parameters, sexual function and fertility potential. For instance, obesity is associated with male infertility, probably due to hormonal changes secondary to excess fatty tissue. In the literature, an inverse relationship has been demonstrated between body mass index (BMI) and testosterone, testosterone/estradiol ratio, ejaculate volume, sperm concentration and morphology, with higher rates of azoospermia and oligospermia among obese men. Couples undergoing assisted reproduction (ART), in which the male partner is obese, also experienced a decrease in pregnancy rates and an increase in terminations, probably due to higher rates of DNA fragmentation in obese men.

The assessment of male infertility includes a detailed medical history, a targeted physical examination and selective laboratory tests, including sperm analysis, called a spermiogram. Treatments are aimed at solving or responding to the underlying problem, so they can range from a lifestyle optimisation proposal to the use of an empirical or targeted pharmacological medical therapeutic approach to surgical therapies. The role of conventional male reproductive surgeries aimed at improving or addressing male infertility has recently been studied in an attempt to expand their narrow indications. These surgeries include varicocelectomy and testicular sperm extraction (TESE). Varicoceles, the abnormally dilated and tortuous veins of the pampiniform plexus, are a common cause of male infertility. It is estimated that varicoceles are present in 15-20% of the general male population and in 35-40% of infertile men. It is believed that the mechanism of action by which a varicocele affects fertility is mainly related to blood stasis in the scrotum, creating excess heat, which in turn reduces spermatogenesis. However, there are additional theories on how a varicocele can negatively affect fertility, including reflux of metabolites into the testis and an increase in reactive oxygen species that create damage to sperm DNA and hormonal dysregulation. Varicocelectomy has been shown to improve sperm parameters and also increase pregnancy rates with a significant decrease in abortion rates. Whereas, with regard to testicular sperm extraction, TESE has historically only been used for men with azoospermia. Recently, it has been shown that men with severe oligospermia (sperm concentration below 5 million sperm per millilitre), cryptozoospermia (viable sperm found only on conventional microscopy of centrifuged sperm samples) or sperm with high DNA fragmentation rates may benefit from this technique.

Recent studies examining DNA fragmentation, capacitation and advanced paternal age have shed light on previously unknown issues. Despite recent advances, approximately one third of cases remain idiopathic. With current and future efforts examining the molecular and genetic factors responsible for spermatogenesis and fertilisation, we may be able to better understand the aetiologies of male factor infertility and thus improve outcomes for our patients and couples. Male infertility is recognised as a condition that impacts on the quality of life not only of the male partner but of both members of the infertile couple, we always speak of couple infertility.

 

 

References

Aditi Sharma, et al. Male infertility due to testicular disorders. J Clin Endocrinol Metab. 2021 Jan 23;106(2):e442-e459. doi: 10.1210/clinem/dgaa781.

Jeremy T Choy, et al. Male infertility as a window to health. Fertil Steril. 2018 Oct;110(5):810-814. doi: 10.1016/j.fertnstert.2018.08.015.

Jonathan Fainberg, et al. Recent advances in understanding and managing male infertility. F1000Res. 2019 May 16:8:F1000 Faculty Rev-670. doi: 10.12688/f1000research.17076.1. eCollection 2019.

Michael L Eisenberg, et al. Male infertility. Nat Rev Dis Primers. 2023 Sep 14;9(1):49. doi: 10.1038/s41572-023-00459-w.