Effects of maternal taxane chemotherapy exposure on daughters' ovarian reserve and fertility potential.

OBJECTIVE: To investigate the long-term effects of in utero taxane exposure on exposed daughters' ovarian reserve and reproductive potential. DESIGN: Pregnant dams were treated with a single, human-relevant animal-equivalent dose of saline, docetaxel, or paclitaxel at embryonic day 16.5. In utero-exposed daughters were aged to multiple postnatal time points for ovarian and endocrine analysis or were bred to assess fertility and fecundity. Granddaughters of treated dams were assessed also for ovarian follicle composition and atresia. SETTING: Laboratory study. ANIMALS: C57BL/6 mice. INTERVENTION(S): In utero exposure to saline, docetaxel, or paclitaxel. MAIN OUTCOME MEASURE(S): Ovarian follicle composition, rates of follicle atresia, and rates of multioocyte follicles were analyzed in all exposure groups. Serum hormone levels and oocyte retrieval outcomes following ovarian hyperstimulation were also assessed. Finally, animals from all exposure groups were bred with the number of litters, pups per litter, live births, interlitter time interval, and age at the last litter analyzed. RESULT(S): We found that docetaxel and paclitaxel exposure in utero results in ovarian toxicity later in life, significantly affecting folliculogenesis as well as increasing the rate of follicular abnormalities, including follicle atresia and multioocyte follicles. Furthermore, viability staining indicates that the ovaries of daughters exposed to taxanes in utero demonstrate a significantly higher number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive follicles. Hormone measurements also revealed that serum follicle-stimulating hormone concentration was significantly altered in taxane-exposed daughters, with the ratio of luteinizing hormone to follicle-stimulating hormone significantly elevated, specifically after paclitaxel exposure, coincident with the inability of these animals to properly respond to ovarian stimulation. Breeding studies over the course of a year also suggest that these taxane-exposed mice are fertile, although the duration of their fertility is shortened and they produce significantly fewer litters. Finally, ovarian effects are apparent in granddaughters of mice treated with docetaxel, suggesting persistent and multigenerational effects of taxane exposure. CONCLUSION(S): Our studies demonstrate that in utero exposure to taxane-based therapy during late gestation has a significant effect on the long-term reproductive health of exposed daughters (as well as their daughters) and will be instrumental in helping clinicians better understand which chemotherapies for maternal malignancy are least detrimental to a developing fetus.

Immune checkpoint inhibitor treatment does not impair ovarian or endocrine function in a mouse model of triple negative breast cancer.

Background: Representing 15-20% of all breast cancer cases, triple negative breast cancer (TNBC) is diagnosed more frequently in reproductive-age women and exhibits higher rates of disease metastasis and recurrence when compared with other subtypes. Few targeted treatments exist for TNBC, and many patients experience infertility and endocrine disruption as a result of frontline chemotherapy treatment. While they are a promising option for less toxic therapeutic approaches, little is known about the effects of immune checkpoint inhibitors on reproductive and endocrine function. Results: Our findings in a syngeneic TNBC mouse model revealed that therapeutically relevant immunotherapies targeting PD-1, LAG-3, and TIM-3 had no effect on the quality and abundance of ovarian follicles, estrus cyclicity, or hormonal homeostasis. Similarly, in a tumor-free mouse model, we found that ovarian architecture, follicle abundance, estrus cyclicity, and ovulatory efficiency remain unchanged by PD-1 blockade. Conclusions: Taken together, our results suggest that immunotherapy may be a promising component of fertility-sparing therapeutic regimens for patients that wish to retain ovarian and endocrine function after cancer treatment.