Reproduction, retinoid effects

Vitamin A (retinol) and its naturally occurring and synthetic derivatives, collectively referred to as retinoids (chemical structure), exert a wide variety of profound effects in apoptosis, embryogenesis, reproduction, vision, and regulation of inflammation, growth, and differentiation of normal and neoplastic cells in vertebrates. 

For early clinical trials, where it is unlikely there will be full reproductive toxicology data, any application should include a discussion of whether any effects on reproduction can be anticipated from the primary pharmacodynamics. The nature of the target receptor binding and any potential for binding to receptors involved in reproduction should be considered. For compounds in classes already known to be teratogenic such as cytotoxic anticancer products, retinoids, or histone deacetylase inhibitors, it can be reasonably expected that... 

Retinoids are known for their importance in general growth, the growth and differentiation of epithelial tissues, visual function, and reproduction. The mechanism by which retinoids manifest all their biological effects is largely unknown. To facilitate additional basic research on the biochemistry and pharmacology of... 

Importantly, retinoids are devoid of myelosuppressive effects and, in certain instances, actually stimulate myelopoesis. This finding is of special relevance in cancer therapy. Since many drugs used for cancer treatment are myelosuppressive, retinoids may eventually be introduced into combination cancer therapy regimens. Animal reproduction studies indicate that both etretinate and isotretinoin are teratogenic. Therefore, caution must be exercised in the treatment of female patients of reproductive age. With respect to semen, no abnormalities of ejaculate volume, sperm count, motility, or morphology have been demonstrated (Schill et a/., 1981). 

The current leading hypothesis is that nuclear RAR and RXR play a direct role in this process. The retinoid receptors can be activated by physicochemical binding of free retinoic acid to RAR and RXR. Alternatively, covalent forms, such as retinoyl derivatives of RAR and RXR, might also exist. Interestingly, retinyl and retinoyl p-glucuronide stimulate the differentiations of HL-60 cells well without evident conversion to retinol and retinoic acid, respectively. Retinoic acid has also been implicated as a morphogen in embryonic development (18). The adverse effects of vitamin A deficiency on reproduction, growth, and the immune response, in all likelihood, are an expression of perturbations in the process of cellular differentiation. 

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