Molecular Mechanisms Determining Mammalian Oocyte Quality with the Treatment of Cancer Therapy

Abstract

Cancer is a global public health issue and remains one of the leading causes of death in the United States (Siegel et al. CA Cancer J Clin. 72:7-33, 2022). It is estimated in the US in 2022, about 935,000 new cases of cancer will be diagnosed in women, and the probability of developing invasive cancer is 5.8% for females younger than 50 years old (Siegel et al. CA Cancer J Clin. 72:7-33, 2022). However, advances in screening programs, diagnostic methods, and therapeutic options have greatly increased the five-year survival rate in reproductive-age women with a variety of cancers. Given the clinical consequences of gonadotoxic cancer therapies, young, female cancer survivors may face compromised fertility, premature ovarian insufficiency, early-onset menopause, and endocrine dysregulation (Bedoschi et al. Future Oncol. 12:2333-44, 2016). Gonadotoxic side effects may include decreased oocyte quality within surviving follicles, loss of ovarian follicles, and impaired ovarian function. In reproductive-age women, oocyte quality is an important element for successful clinical pregnancies and healthy offspring as poor-quality oocytes may be a cause of infertility (McClam et al. Biol Reprod. 106:328-37, 2022; Marteil et al. Reprod Biol. 9:203-24, 2009; Krisher. J Anim Sci. 82: E14-E23, 2004). Thus, it is critical to determine the quantity and quality of surviving follicles in the ovary after cancer treatment and to assess oocyte quality within those surviving follicles as these are markers for determining the capacity for ovarian function restoration and future fertility, especially for young cancer survivors (Xu et al. Nat Med. 17:1562-3, 2011). The long-term effects of cancer therapeutics on oocyte quality are influenced by factors including, but not limited to, individual patient characteristics (e.g. age, health history, comorbidities, etc.), disease type, or treatment regimen (Marci et al. Reprod Biol Endocrinol. 16:1-112, 2018). These effects may translate clinically into an impaired production of viable oocytes and compromised fertility (Garutti et al. ESMO Open. 6:100276, 2021).

Keywords: Gonadotoxic cancer therapy; Oocyte quality; Primordial follicles; Reproductive health.

Figure 1.. Impact of cancer therapy on oocyte quality.

Ovarian follicles consist of oocytes and granulosa and theca cell layers during folliculogenesis in the ovary. Oocytes (Oo) communicate with granulosa cells (GCs) to develop into healthy follicles and are ready for producing hormones and ovulating oocytes. Thus, the communication between cells is key to developing high-quality oocytes for fertilization. However, cancer therapy can directly cause damage to oocytes and induce oocyte death via the TAp63-apoptotic pathway in primordial follicles (PF). In addition, it can indirectly cause somatic cell damage in GCs and theca cells and hinder the normal development of ovarian follicles because the communication between unhealthy cells (colored gray) is blocked or affects the growth of oocytes, especially growing follicles including antral follicles (AF). In this case, ovarian follicles cannot produce ovarian hormones, healthy oocytes, or high- quality oocytes, resulting in low pregnancy outcomes and infertility. Healthy versus unhealthy communication are indicated with arrows colored with purple and black, respectively. Healthy versus unhealthy granulosa cells are colored green and gray, respectively.