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Is gene therapy for the treatment of male infertility feasible?

Nature Clinical Practice Urology volume 5, pages 590–593 (2008)Cite this article

Infertility is a common problem; according to the 2002 National Survey of Family Growth, 7% of married US women of reproductive age did not become pregnant within a year of not using contraception.1 Male factor infertility exists in approximately 50% of infertile couples.2 For men with defects in sperm delivery or sperm function, medical or surgical therapy might be available to improve fertility. If these therapies are not suitable, but the patient has sperm in his semen, assisted reproductive techniques often result in pregnancies. In some men, infertility is due to a lack of sperm in the ejaculate; approximately 15% of men with infertility are azoospermic. Normal sperm production combined with obstruction of the ductal system accounts for 40% of azoospermia cases, while 60% are due to defective spermatogenesis.3 Treatment options for obstructive azoospermia include surgical correction and sperm retrieval from the testis or ductal system, combined with intracytoplasmic sperm injection (ICSI). In approximately 50% of patients with nonobstructive azoospermia, low levels of sperm are produced in the testes,4,5 which might be obtained by testicular sperm extraction with fertilization attempted by ICSI. For men with nonobstructive azoospermia and no sperm in their testes, testicular sperm extraction is unsuccessful. This population of infertile men would benefit most from gene therapy.

Men can have a range of genetic causes of infertility. Certain ultrastructural spermatozoal defects, such as primary ciliary dyskinesia, have a known genetic cause. Developmental defects, such as congenital bilateral absence of the vas deferens, cryptorchidism and Kallmann syndrome, often have a genetic basis but are not amenable to gene therapy: anatomic defects present from embryogenesis can not be corrected in the adult. Karyotypic abnormalities, such as Klinefelter's syndrome (XXY), are present in 5–15% of severely oligospermic or azoospermic men,6,7 and Y-chromosome azoospermia factor microdeletions are noted in another 5–10%.7 These genetic disorders involve additions or deletions of large amounts of DNA. In general, current technology cannot manipulate the amount of DNA that would be required for effective gene therapy for these disorders. Although some genetic causes for male infertility have been identified, many men with severe infertility do not have identifiable genetic defects, making gene therapy impossible. A genetic cause is likely, however, for some patients with “idiopathic” infertility.

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Figure 1: Potential methods for correcting a genetic defect that causes infertility.
Figure 2: Embryonic stem cells and transplantation: a future approach to gene therapy for the treatment of infertility due to spermatogenic failure.

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  1. K Boekelheide is a Professor at the Department of Pathology and Laboratory Medicine, Department of Surgery, and M Sigman is an Associate Professor of Surgery (Urology), Brown University, Providence, RI, USA.,

    Kim Boekelheide & Mark Sigman

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Correspondence to Mark Sigman.

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Boekelheide, K., Sigman, M. Is gene therapy for the treatment of male infertility feasible?. Nat Rev Urol 5, 590–593 (2008). https://doi.org/10.1038/ncpuro1234

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