Research Article: Male Infertility and Its Causes in Human

Date Published: October 20, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Toshinobu Miyamoto, Akira Tsujimura, Yasushi Miyagawa, Eitetsu Koh, Mikio Namiki, Kazuo Sengoku.


Infertility is one of the most serious social problems facing advanced nations. In general, approximate half of all cases of infertility are caused by factors related to the male partner. To date, various treatments have been developed for male infertility and are steadily producing results. However, there is no effective treatment for patients with nonobstructive azoospermia, in which there is an absence of mature sperm in the testes. Although evidence suggests that many patients with male infertility have a genetic predisposition to the condition, the cause has not been elucidated in the vast majority of cases. This paper discusses the environmental factors considered likely to be involved in male infertility and the genes that have been clearly shown to be involved in male infertility in humans, including our recent findings.

Partial Text

One of the most serious social problems facing developed countries today is the declining birth rate, although it is generally not well recognized that the number of infertile couples is on the rise in these countries. While both social (i.e., social progress for women and the resulting increase in the age at which women marry) and environmental (i.e., pollution and global warming) factors are behind part of the increase in the number of patients with infertility, infertility in the male partner contributes to approximately half of all cases.

There has long been debate over whether male reproductive ability is determined by environmental factors, such as those present in the workplace or area of residence. Having a major effect on this debate was the sensational report by Whorton et al. published in 1977, which found that of 25 male workers involved in producing the insecticide dibromo-3-chloropropane (DBCP), 14 were diagnosed as azoospermic or oligospermic [2]. In 1992, Carlsen et al. reported that the previous 50 years saw a marked decrease in sperm count [3]. That same year, Brake and Krause reported that during the period since 1970 in Scotland, sperm counts had decreased by approximately 25% compared with the period prior to 1959, a mean annual rate of 2.1% [4].

In 1976, Tiepolo and Zuffardi first proposed an explanation for the role of the human Y chromosome in spermatogenesis [19]. They microscopically identified the presence of microdeletions on the long arm of the Y chromosome in six patients with azoospermia and proposed an important spermatogenesis gene in this region. They named this the azoospermia factor (AZF) region. Various subsequent studies have been conducted, particularly by Vogt et al. [20], and in 1995, Reijo et al. examined 89 patients with nonobstructive azoospermia and found that 12 (13%) had a deletion in the AZF region. These results brought recognition to the close relationship between human azoospermia and this region [21]. Vogt et al. further showed the microdeletions to be concentrated in three regions according to the testicular tissue type and divided the AZF region into subregions, AZFa, AZFb, and AZFb [22].

Genetic polymorphisms may also increase susceptibility to some forms of male infertility. We have identified polymorphisms of several genes that are associated with the human azoospermic population—MEI1, PRDM9 (MEISETZ), SPATA17, PARP-2, and UBR2 genes are genetic risk factors for the patients with azoospermia by meiotic arrest [48–52], and polymorphisms of the SEPTIN12 gene are associated with patients with Sertoli cell-only syndrome [53]. Genetic polymorphisms and male infertility have been under much investigation recently. Some genes identified to be associated with male infertility in the past three years include: MTHFR, SHBG, Piwi, CYP19A1, NER, GSTM1, BCL2, ESR1, ESR2, eNOS, TNP1, SOHLH1, EPPIN, GSTT1, TSSK6, TSSK2, MDR1, MSH5, MLH3, H2BFWT, PACRG, and FASLG [54–74]. Despite identification of these genes, neither the mechanisms of human spermatogenesis nor the association of these genes with each other is well known. We believe that environment is an important factor associated with genetic polymorphisms in human spermatogenesis. Further analysis is thus strongly needed to determine the association between genetic polymorphisms and environmental factors.

This paper discussed the gene groups that have been reported to date to play a role in human spermatogenesis, as well as our recent research findings. Recent mouse studies and our genetic polymorphism studies suggest that numerous human spermatogenesis gene groups are present in regions other than the AZF region of the Y chromosome, for which analysis has progressed worldwide. As patients with a microdeletion in the AZF region of the Y chromosome account for approximately 13% of those with human azoospermia (recent reports indicate an even lower percent of approximately 7%), new human azoospermia culprit genes are expected to be identified in areas other than the Y chromosome.




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