The trend toward delayed childbearing has meant that many women who plan to have children may be childless at the time they are diagnosed with cancer. The number of these women is likely to further increase concurrently with the increase in cancer survivors, making “the focus on fertility preservation even more important,” Kara N. Goldman, MD, stated at the 13th Annual Oncofertility Conference in Chicago.1 Dr. Goldman is Assistant Professor, Reproductive Endocrinology and Infertility, and Medical Director, Fertility Preservation, Northwestern University, Chicago.
Kara N. Goldman, MD
“Ovaries have a fixed complement of primordial follicles at birth, the ovarian reserve,” Dr. Goldman reminded symposium participants. This reserve is subject to a “progressive nonlinear decline,” with age, but cancer treatment can accelerate this decline.
Currently established options for female fertility preservation include oocyte cryopreservation and embryo cryopreservation. However, both options “provide only a limited supply of gametes or embryos without the benefit of long-term ovarian protection,” according to Dr. Goldman.
Investigational/experimental options include ovarian tissue cryopreservation and pharmacologic fertoprotection. Describing mechanisms of ovarian damage and pharmacologic fertoprotective therapeutic options to address them, Dr. Goldman said, “We need to focus not just on fertility, but on preserving ovarian endocrine function.”
GnRH Agonists: ‘No Clear Benefit’
Gonadotropin-releasing hormone (GnRH) agonists can affect the ovaries directly or indirectly through the hypothalamus and pituitary. “There have been a vast array of studies evaluating the role of GnRH agonists,” noted Dr. Goldman. Some studies in mice and rats have shown activity by GnRH agonists in protecting follicles and the ovarian reserve, whereas other studies have shown no such protection.
Primate and in vitro studies have also yielded mixed results. One older in vitro study using human granulosa cells found that using a GnRH analog with doxorubicin offered protection of ovarian reserve.2 “More recently,” Dr. Goldman reported, an in vitro study using human granulosa cells and ovarian tissue fragments found that GnRH agonists administered with chemotherapy (eg, cyclophosphamide, paclitaxel, fluorouracil, or a TAC [docetaxel, doxorubicin, cyclophosphamide] regimen) offered no protection of ovarian reserve.3
Dr. Goldman offered a perspective on more than 30 years of clinical data with GnRH agonists in this role. “There have been a number of randomized controlled studies in breast cancer, showing potential prolongation of ovarian function and possible decreased primary ovarian insufficiency but really no clear benefit in fertility preservation,” Dr. Goldman noted. Randomized controlled trials in lymphoma that have shown no benefit and “meta-analyses may show a potential benefit in preventing primary ovarian insufficiency but not necessarily preserving fertility. What we know is that there is a clear benefit in menstrual suppression among women with thrombocytopenia at risk of heavy menstrual bleeding,” she added.
Dr. Goldman stated that she counsels patients about these mixed data. “Although GnRH agonists may have a limited role in preventing primary ovarian insufficiency, which is important, we cannot rely on them to preserve fertility,” she commented. According to an ASCO statement issued in 2013,4 providers are encouraged “to inform patients that there is insufficient evidence regarding the effectiveness of ovarian suppression (GnRH analogs) as a fertility preservation method, and these agents should not be relied on to preserve fertility.”
mTOR and mTORC1/2 Inhibitors
The “mTOR pathway is critical to primordial follicle activation,” which has potential clinical implications for fertility preservation and ovarian aging, Dr. Goldman explained. Currently, mTOR inhibitors are widely used for benign and malignant conditions. Everolimus is approved by the U.S. Food and Drug Administration in the treatment of estrogen receptor–positive, HER2-negative breast cancer; advanced renal cell carcinomas; subependymal giant cell astrocytoma; tuberous sclerosis; metastatic pancreatic neuroendocrine tumors, and there is a growing list of indications,” Dr. Goldman said.
The mTORC1/2 (dual) inhibitors (eg, INK128, MLN0128) have also shown promise in preclinical trials of breast cancer, neuroblastoma, pancreatic cancer, renal cell carcinoma, thyroid cancer, acute lymphoblastic leukemia, and non-Hodgkin lymphoma. She reported her studies with mice, showing that “cyclophosphamide causes follicular burnout, but co-treatment with everolimus and INK128 attenuate this effect and preserve fertility.” 5
Growing Landscape of Fertoprotection
There is a growing landscape of pharmacologic fertoprotection, according to Dr. Goldman. A range of different studies have found that the caspase 1 inhibitor AS101 may prevent follicle loss and preserve fertility, that melatonin may prevent cisplatin-induced primordial follicle loss, that anti-Müllerian hormone/Müllerian-inhibiting substance as a contraceptive may protect ovarian reserve during chemotherapy, and that sphingosine-1-phosphate may prevent chemotherapy-induced human primordial follicle death.
“There has been a broad range of work done in this area,” Dr. Goldman noted. “Unfortunately, we are not much farther along than where we started in terms of clinically available agents, but I’m optimistic that we are moving forward.”
Limitations of existing data include that the research is essentially preclinical and that the studies are “highly heterogeneous” in terms of the timing of the administration of the agents and the animal models and chemotherapy regimens used. “Patients are not receiving single agents; polypharmacy in human regimens means that the impact on the ovary is more complex,” stated Dr. Goldman.
In the continuing search for fertoprotective agents, several important qualities should be kept in mind, Dr. Goldman explained: cost, route of administration, availability, efficacy, tolerability. “We should think about how we can repurpose drugs that are already available to address the urgent need for fertoprotective therapeutics.”
DISCLOSURE: Dr. Goldman reported no conflicts of interest.
1. Goldman K: Fertoprotective therapeutics: What is on the horizon for patients? 2019 Oncofertility Conference. Presented November 13, 2019.
2. Imai A, Furui T: Chemotherapy-induced female infertility and protective action of gonadotropin-releasing hormone analogues. J Obstet Gynaecol 27:20-24, 2007.
3. Bildik G, Akin N, Senbabaoglu F, et al: GnRH agonist leuprolide acetate does not confer any protection against ovarian damage induced by chemotherapy and radiation in vitro. Hum Reprod 30:2912-2925, 2015.
4. Loren A, Mangu P, Beck L, et al: Fertility preservation for patients with cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 31:2500-2510, 2013.
5. Goldman KN, Chenette D, Arju R, et al: mTORC1/2 inhibition preserves ovarian function and fertility during genotoxic chemotherapy. Proc Natl Acad Sci USA 114(12): 3186-3191, 2017.