The biology of infertility: research advances and clinical challenges

Abstract

Reproduction is required for the survival of all mammalian species, and thousands of essential ‘sex’ genes are conserved through evolution. Basic research helps to define these genes and the mechanisms responsible for the development, function and regulation of the male and female reproductive systems. However, many infertile couples continue to be labeled with the diagnosis of idiopathic infertility or given descriptive diagnoses that do not provide a cause for their defect. For other individuals with a known etiology, effective cures are lacking, although their infertility is often bypassed with assisted reproductive technologies (ART), some accompanied by safety or ethical concerns. Certainly, progress in the field of reproduction has been realized in the twenty-first century with advances in the understanding of the regulation of fertility, with the production of over 400 mutant mouse models with a reproductive phenotype and with the promise of regenerative gonadal stem cells. Indeed, the past six years have witnessed a virtual explosion in the identification of gene mutations or polymorphisms that cause or are linked to human infertility. Translation of these findings to the clinic remains slow, however, as do new methods to diagnose and treat infertile couples. Additionally, new approaches to contraception remain elusive. Nevertheless, the basic and clinical advances in the understanding of the molecular controls of reproduction are impressive and will ultimately improve patient care.

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

“…Correlations of genes previously identified to be associated with ovarian disease [34–41] (Supplemental Table S13) with the transgenerational granulosa cell genes of this study identified a number of genes associated with ovarian disease, Figure 11 and Supplemental Table S14. A gene that was present in the DDT and vinclozolin DMR associated genes and ovarian disease associated genes was Pkp4, plakophilins 4 [34,55].…”

“…Extensive reviews previously published have summarized the genes that have been associated with ovarian disease [34–41]. These published ovarian disease-associated genes were compiled into a list of 416 genes that are listed in Supplemental Table S13.…”

“…The specific overlapped genes are presented in Figure 11(C) and Table S14. Therefore, a number of ovarian disease-associated genes previously identified [34–41] were in common with the transgenerational granulosa cell DMRs and mRNA identified.

10.1080/15592294.2018.1521223-F0011Figure 11.Ovarian disease gene associations. (a) DMR associated gene overlap with published ovarian disease genes.

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Human male infertility and its genetic causes

“…Genetic causes of azoospermia include chromosomal abnormalities, Y chromosome microdeletions, and specific mutations or deletions of several Y chromosomal genes 2, 3. Thus, in 1995, it was demonstrated that DAZ mutations (Yq11.23) cause various forms of human male infertility that range from oligospermia to azoospermia 4, 5. In 1997, it was reported that RBMY (Yq11.223) mutations cause azoospermia via meiotic arrest5, 6 and, in 1999, it was shown that USP9Y (Yq11.2) mutations lead to azoospermia that is secondary to hypospermatogenesis 5, 7.…”

“…Thus, in 1995, it was demonstrated that DAZ mutations (Yq11.23) cause various forms of human male infertility that range from oligospermia to azoospermia 4, 5. In 1997, it was reported that RBMY (Yq11.223) mutations cause azoospermia via meiotic arrest5, 6 and, in 1999, it was shown that USP9Y (Yq11.2) mutations lead to azoospermia that is secondary to hypospermatogenesis 5, 7. The azoospermia factor (AZF) region on the Y chromosome is one of the most intensively studied regions in male infertility 8, 9.…”