Abstract
Dacarbazine is commonly administered for the treatment of cancers prevalent in reproductive age females. However, investigations of off-target effects of dacarbazine on the ovary are limited. We assessed the impact of dacarbazine on the ovarian reserve of primordial follicles, essential for fertility. Eight week and 6 month old C57BL/6 J mice were administered with dacarbazine or saline on day (d)0 and d7, then sacrificed after 12 hours (h), or 14d (n = 4–5/group). Follicle numbers, follicle density, serum AMH and corpora lutea were quantified and estrous cyclicity monitored. In reproductively young mice, dacarbazine did not affect primordial follicle numbers at 12 h, but resulted in a 36% reduction at 14d (p < 0.05). Dacarbazine-mediated primordial follicle depletion was accelerated with age, with a 24% (p < 0.05) and 36% (p < 0.01) reduction at 12 h and 14d. Follicle density remained unchanged between treatment groups at either age. Dacarbazine depleted antral follicles at 14d (p < 0.05), at both ages. Despite partial reduction of antral follicles, serum AMH, estrous cyclicity and corpora lutea (indicative of ovulation) remained unchanged between treatment groups, at both ages. Importantly, diminished ovarian reserve can result in premature ovarian insufficiency and infertility, thus, fertility preservation options should be considered for young female patients prior to dacarbazine treatment.
Highlights
The ovary contains a finite number of germ cells within primordial follicles
Follicle numbers were quantified in 8 week old mouse ovaries either 12 h, or 14d following the final administration of dacarbazine, or saline control
Healthy antral follicles were significantly reduced by dacarbazine (p < 0.05) (Fig. 1D), while there were no effects on other follicle classes
Summary
The ovary contains a finite number of germ cells (oocytes) within primordial follicles. McLaughlin et al investigated follicle density in ovarian tissue biopsies from women treated with ABVD and found a higher density of primordial follicles compared to an untreated, or combined vincristine, etoposide, prednisone, doxorubicin (OEPA) and cyclophosphamide, vincristine, prednisone, dacarbazine (COPDAC) treated cohort of women[19] This unexpected finding was contradicted by a study from Sonigo et al, in which the number of cumulus-oocyte complexes recovered, as well as the total number of matured oocytes vitrified was significantly lower in 22 patients that previously received AVBD treatment at least 2 years prior, versus 44 age-matched women that received no chemotherapy[20]. Despite these inconsistent findings and paucity of experimental studies, it is the current clinical recommendation that the dacarbazine-containing ABVD protocol has a low-risk of causing ovarian toxicity and that fertility preservation should not be considered[21]
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