Fertility maintenance and 5-fluorouracil timing within the mammalian fertility cycle

The mammalian fertility cycle is responsible for tight coordination of mole cular, biochemical and cellular events. We have investigated whether timing of 5-fluorouracil (5-FU) chemotherapy within this cycle affects its reprod uctive toxicology. When this very short half-life, largely S-phase active c ytotoxic antimetabolite is administered during the estrous phase (immediate postovulatory) of the fertility cycle, female mice suffer,greater subseque nt loss of fertility (decreased successful pregnancy rate) than those mice receiving 5-FU during the metestrous, diestrous, or proestrous stages. Pups subsequently horn to mothers given 5-FU during the estrous and metestrous stages are of lower weight compared with those born to mothers treated with 5-FU during diestrus or proestrus. Acute lethality is similarly affected b y the fertility cycle timing of 5-FU administration. Treatment during estru s is associated with the greatest overall lethal toxicity. This finding ind icates that the 5-FU susceptibility of nonreproductive tissues, the integri ty of which is essential for survival, may also be coordinated by the mamma lian fertility cycle. It is concluded that optimizing the fertility cycle t iming of 5-FU (e.g., during the periovulatory, proestrous stage) diminishes the frequency and severity of long-term reproductive damage.