Do cancer therapies damage the uterus and compromise fertility?

Abstract

BACKGROUND As cancer survival rates improve, understanding and preventing the adverse off-target and long-term impacts of cancer treatments, including impacts on fertility, have become increasingly important. Cancer therapy-mediated damage to the ovary and depletion of the primordial follicle reserve are well characterised. However, our knowledge of the full extent of damage to the rest of the female reproductive tract, in particular the uterus, is limited. OBJECTIVE AND RATIONALE Improving our understanding of the off-target effects of cancer therapies on the entire female reproductive tract is a critical step towards developing truly effective strategies to protect the fertility of cancer survivors. The objective of this narrative review was to critically evaluate the available literature regarding the capacity for the uterus to sustain a healthy pregnancy following exposure to radiotherapy or chemotherapy. SEARCH METHODS The authors performed PubMed (Medline) searches using the following key words: uterus, cancer survivors, radiotherapy, chemotherapy, pregnancy outcome, fertility preservation, infertility. There were no limits placed on time of publication. OUTCOMES Overall, there were major limitations to the current available literature, meaning that interpretations should be taken with caution. Despite these drawbacks, data suggest that the uterus may sustain off-target damage, with the extent of damage dependent on the type of cancer treatment and patient age. Specifically, uterine growth is stunted and resistant to hormone replacement therapy in prepubertal girls receiving abdominal, pelvic or whole-body radiotherapy. In contrast, females treated with radiotherapy post-puberty can benefit from hormone replacement therapy, as demonstrated by increased uterine volume and function. No live births have been reported in women previously exposed to radiotherapy after transplantation of cryopreserved ovarian tissue, even when menstruation returns. However, this technique has proven to be a successful fertility preservation method for women previously treated with chemotherapy. Obstetricians commonly report that women who maintain sufficient ovarian function can achieve pregnancy naturally following radiotherapy, but they have thin and/or fibrotic myometrium at delivery, compromising safe delivery and subsequent pregnancy. Furthermore, women exposed to either radiotherapy or chemotherapy have a higher prevalence of preterm birth and low birth weight infants, even in those with normal ovarian function or when oocyte donation is utilised. The mechanisms of potential uterine damage are poorly understood. While the myometrium, vasculature and endometrial progenitor cells are possibly targets, further studies are clearly required and well-controlled animal models could provide the best avenue for these types of future investigations. WIDER IMPLICATIONS Female cancer survivors experience greater rates of early pregnancy loss and complications, suggesting that cancer therapy-induced damage to the uterus contributes to infertility. Despite clinical reports dating back to 1989, we highlight a surprising lack of detail in the literature regarding the precise nature and extent of off-target damage inflicted to the uterus in response to cancer therapies. Young women requiring cancer treatment, and the clinicians treating them, must be equipped with accurate information to aid informed decision-making regarding cancer treatment regimens as well as the development and use of effective fertility preservation measures. As the current literature on the impacts of cancer treatments is limited, we hope that our narrative review on this subject will stimulate more research in this important field.

Clinical summary guide: reproduction in women with previous abdominopelvic radiotherapy or total body irradiation

“…AP RT in particular increased the risk of preterm delivery (OR 3.81; CI 2.02–7.19) with 13 out of 72 survivors in this subgroup delivering before 37 weeks ( Madanat-Harjuoja et al , 2010 ). However, it is important to note that while the risk of LBW and prematurity may be partly due to decreased uterine volume as a result of pelvic radiation, other studies have observed these finding for cancers not typically treated with pelvic radiation and among those treated with chemotherapy only, suggesting that other factors may also contribute ( Griffiths et al , 2019 ).…”

“…In addition, there is some evidence that chemotherapy (which often accompanies radiation) directly damages the uterus, as summarized in Fig. 1 ( Griffiths et al , 2019 ; van de Loo et al , 2019 ).…”

Cyclophosphamide Exposure Causes Long-Term Detrimental Effect of Oocytes Developmental Competence Through Affecting the Epigenetic Modification and Maternal Factors’ Transcription During Oocyte Growth

“…Meanwhile, an earlier study found that exposure to CTX in vivo had adverse effects on oocyte function, and it can be partially reversible. However, pregnancy failure may also be related to uterus- and pregnancy-supporting dysfunction ( Garg et al, 2020 ; Griffiths et al, 2020 ).…”

Stereological and histopathological evaluation of doxorubicin-induced toxicity in female rats’ ovary and uterus and palliative effects of quercetin and vitamin E

“…49 Moreover, damage to the uterine muscles and decreased myometrium volume can be involved in further problems with uterine contractions during labor. 49 Consistently, the study findings indicated a decrease in the size of uterine glands after DOX administration. The uterine glands play a pivotal role in uterine receptivity.…”