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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.

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Figure 1: Simple molecular pathway for sex determination in the mammalian gonads.
Figure 2: Sex differentiation in humans.
Figure 3: Neuroendocrine control of pituitary and gonadal function.
Figure 4: Genetic dissection of female fertility pathways in mice.
Figure 5: Mouse models of male reproductive defects provide new insights into the causes of male infertility.

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Acknowledgements

Reproductive biology and cancer research in the Matzuk and Lamb laboratories have been supported by US National Institutes of Health grants P01 HD36289, R01 DK078121, R01 HD32067, R01 HD42500, R01 CA60651, R37 HD33438, U54 HD07495, T32 DK00763 and K12 DK083014, by the US Department of Defense, US Army Materiel Command PC061154 and by the Ovarian Cancer Research Fund. We thank our many colleagues, S. Alexander, S. Han, M. Hsieh, R. Khavari, M. Louet, S. Mukhajee, A. Nagaraja, R. Nalam, S. Whirledge, and H. Yao, for their outstanding insights and critiques of this review. We apologize to colleagues whose work is not referenced herein because of space limitations. The supplementary information online contains more detailed references.

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Matzuk, M., Lamb, D. The biology of infertility: research advances and clinical challenges. Nat Med 14, 1197–1213 (2008). https://doi.org/10.1038/nm.f.1895

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