Review
Inhibiting vitamin A metabolism as an approach to male contraception

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Although oral contraceptives have been available to women since the 1960s, contraceptive options for men have remained limited. Spermatogenesis relies on the active metabolite of vitamin A, retinoic acid, to drive spermatogonial differentiation and to allow the production of normal numbers of sperm. Recent evidence describes how the enzymes which control vitamin A metabolism in the testis could be targeted to generate effective male contraceptives; however, the detailed mechanism(s) regarding how vitamin A regulates normal spermatogenesis are still unknown. The essential nature of vitamin A to male germ cell development and the prospects of developing the proteins responsible for the generation, transport, and storage of retinoic acid as targets for male contraceptive development are discussed in this review.

Section snippets

Spermatogenesis and the search for a male contraceptive

Providing men and women with the ability to choose when they want to bring a child into the world is essential in today's society. To suit the extensive range of people's needs and wants, ongoing development and refinement of contraceptive technologies for both men and women is required. The use and distribution of an oral contraceptive for women was first approved in 1960 [1]. However, the production of a similar product for men has yet to be successful. An effective male contraceptive should

The metabolism and signaling of vitamin A in the testis

In mammals, vitamin A is usually transported via serum as retinol (ROL) bound to retinoid-binding proteins, and conversion of this retinoid for either storage (retinyl esters) or use (RA) takes place in target tissues [11]. Retinol is taken up by cells via the membrane-bound receptor STRA6 and, once inside, the conversion of ROL to RA is controlled by a two-step enzymatic process [12] (Figure 2a). An understanding of which retinoid-metabolizing enzymes are expressed in the mammalian testis is

The regulation of spermatogonial differentiation by vitamin A

The changes in gene expression that drive the A to A1 transition are still being elucidated; however, it is known that RA plays an essential role in rodents [10]. When adult male mice are made VAD by maintaining them on a vitamin A-deficient diet for 2–3 months, all differentiated germ cells are lost from the seminiferous epithelium, and only type A spermatogonia and Sertoli cells remain 10, 40 (Figure 1). This indicates that removing RA blocks the ability of undifferentiated spermatogonia to

Inhibiting vitamin A function - an effective male contraceptive?

The optimal target for testicular contraception should be organ-specific or enriched, essential for germ cell production, and accessible to inhibition by small molecules. Vitamin A is essential for the development and health of many different organ systems, and it appears that there are numerous vitamin A metabolizing enzymes, some of which are enriched in specific tissue types [13]. Expression of Aldh1a2 and Aldh9a1 appears to be selectively enriched in adult testis, and a recent study

Conclusions

Women currently have numerous choices for methods of contraception whereas men only have two, condoms or vasectomy, and the latter is not an appropriate option for men who wish to conceive children in the future. There has been a great deal of work attempting to develop a hormone-based male contraceptive [9]; however, issues regarding drug delivery, efficacy and side effects of hormone administration to men have made this approach problematic. Indeed, despite over 30 years of research into male

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