Faculty Bibliography

Although controversial, increasing paternal age has been shown to negatively affect assisted reproductive technology (ART) outcomes and success rates. Most studies investigating the effect of paternal age on ART outcomes use a donor oocyte model to minimize maternal aneuploidy contribution. This study sought to determine whether increasing paternal age is associated with adverse in vitro fertilization (IVF) outcomes when aneuploidy is minimized using preimplantation genetic screening. There were 573 single thawed euploid embryo transfers from 473 patients undergoing oocyte donor and autologous IVF cycles. Cycles were categorized according to paternal age at oocyte retrieval, and an age adjustment was performed for maternal age in order to evaluate for an isolated paternal age effect. Fertilization rate was found to decrease significantly with increasing paternal age ( P = .04). After controlling for oocyte age, there was no significant difference in pregnancy outcomes across all paternal age categories after euploid embryo transfer, including implantation rate ( P = .23), clinical pregnancy rate ( P = .51), and spontaneous abortion rate ( P = .55). Therefore, if a couple is able to produce and transfer a single thawed euploid embryo, no difference in IVF pregnancy outcomes is identified with increasing paternal age.

The ovaries have a fixed pool of immature (primordial) follicles at birth known as the ovarian reserve. Activation or loss of follicles in this reserve causes an irreversible decline in reproductive function that culminates in menopause. Premenopausal women with cancer who are treated with conventional genotoxic chemotherapy have accelerated loss of the ovarian reserve, leading to subfertility and infertility. Cyclophosphamide (CY), a highly gonadotoxic drug, is widely used as part of combination cancer chemotherapy. This drug induces ovarian damage in large part by activating the mammalian/mechanistic target of rapamycin (mTOR) pathway, leading to activation of primordial follicles, follicular burnout, and premature menopause. As a result, the probability of pregnancy in premenopausal female cancer survivors is significantly diminished. There has been little progress in preserving ovarian function during cancer chemotherapy. As part of multiagent chemotherapeutic regimens, inhibitors of themTORC1 pathway have a growing role in cancer treatment and are being studied as treatment for a growing number of malignant and nonmalignant conditions. Mammalian/mechanistic target of rapamycin inhibitors block the primordial-to-primary follicle transition. The investigators used a clinically relevant mouse model of chemotherapy-induced gonadotoxicity to investigate whether inhibitors of mTOR could block CY-induced premature activation of primordial follicles and also preserve fertility during chemotherapy. Two inhibitors of the mTOR pathway were used: everolimus (RAD001), a drug clinically approved for treatment of tamoxifen-resistant or relapsing estrogen receptor-positive breast cancer), and INK128, an experimental drug. Female mice were treated with CY weekly and then randomized to also receive either everolimus, INK128, or nothing.