https://orcid.org/0000-0002-1157-9930
Chemotherapy-induced gonadotoxicity is of particular concern for premenopausal women being associated with menopause-related symptoms and the possible risk of infertility [Citation1]. Cancer and anticancer treatments may have several effects on ovarian function due to a reduction in ovarian reserve; a disturbed hormonal balance; or by anatomical or functional damages to the ovaries, uterus, cervix or vagina. Ovarian reserve can be evaluated by measuring serum anti-Müllerian hormone (AMH) levels and/or antral follicle count [Citation2]. Embryo and oocyte cryopreservation are considered to be the standard practice and are widely available strategies for fertility preservation in cancer patients but they cannot prevent the risk of chemotherapy-induced premature ovarian insufficiency (POI) related to several other negative consequences on the quality of life and wellbeing (several menopausal symptoms, such as osteoporosis, cognitive dysfunction, and cardiovascular disease).
There has been extraordinary interest in medical agents that can potentially preserve fertility from the ovarian toxicity of chemotherapy. In this sense, temporary ovarian suppression obtained by administering a gonadotropin-releasing hormone agonist (GnRHa) has been studied as a strategy to reduce the gonadotoxic effect of chemotherapy. When ovarian suppression with GnRHa is offered, GnRHa should be started at least one week before the initiation of systemic gonadotoxic treatment and prolonged until after the administration of the last chemotherapy cycle [Citation3]. The debate on the efficacy of GnRHa for fertility preservation is still heated, but the 2018 ASCO guidelines recommended that GnRHa may be offered to premenopausal patients for reducing the likelihood of chemotherapy-induced ovarian insufficiency [Citation4]. Nowadays, studies regarding the role of GnRHa as a fertility preservation treatment are evolving. In fact, the difference in the efficacy of GnRHa could not be assigned to the type of cancer, but rather to the regimen of chemotherapy. It is well known that gonadotoxic impact depends on the type of chemotherapeutic agent and the duration of administration [Citation5]. The most common chemotherapy regimen used for the treatment of gynecological cancers (epithelial ovarian cancer) includes a combination of a platinum agent (carboplatin) and a taxane (paclitaxel). Currently, there is a lack of robust evidence to advise and recommend women on the risk of gonadotoxicity associated with this combination. Bleomycin, etoposide, and cisplatin (BEP)- or etoposide and cisplatin (EP)-chemotherapy regimens are often used for the treatment of non-epithelial ovarian cancers. Overall, chemotherapy regimens used for young women with gynecological cancers are considered to be associated with a low risk of gonadotoxicity, but this risk seems to be different according to the type of chemotherapy agent, the dose and length of exposure, and the age of the patient [Citation2]. To investigate the impact of newer gonadotoxic treatments (including targeted agents and immunotherapy) on ovarian function, ovarian reserve and fertility potential of cancer patients should be considered a research priority. Instead, the gonadotoxic effect of chemotherapy in premenopausal women with early breast cancer is well known; the highest risk of gonadotoxicity is associated with the administration of the alkylating agent cyclophosphamide, commonly given as part of (neo)adjuvant chemotherapy regimens [Citation6].
After more than 30 years of research and controversy in the gonadotoxicity battles, five theoretical mechanisms could explain how the GnRHa could minimizing the gonadotoxic effect of chemotherapy:
Simulating the prepubertal hormonal milieu: GnRHa treatment has been identified to induce an initial release of gonadotropins, which desensitize the GnRH receptors on the pituitary gonadotropes, preventing pulsatile GnRH secretion, thus resulting in a hypogonadotropic, prepubertal hormonal milieu. In this prepubertal hypogonadotropic milieu, the follicles remain in the quiescent phase and are less vulnerable to chemotherapy-induced gonadotoxicity. Therefore, the administration of GnRHa, after the initial flare-up effect, decreases FSH concentration through pituitary desensitization, preventing the secretion of growth factors by the more advanced FSH-dependent follicles, and secondarily preserving more primordial follicles (PMFs), which are metabolically inactive, in the dormant stage.
Interrupting the burnout effect: the administration of GnRHa may interfere with the accelerated follicle recruitment induced by chemotherapy by desensitizing the GnRH receptors in the pituitary gland, preventing an increase of FSH level despite low estrogen and inhibin concentrations.
Decreased utero-ovarian perfusion: a result of the hypoestrogenic milieu generated by pituitary-gonadal desensitization. The decreased utero-ovarian perfusion could result in a reduction of exposure of the ovaries to chemotherapeutic agents’ injuries.
A possible direct effect mediated by ovarian GnRH receptors: human gonads also contain GnRH receptors and the activation of the ovarian GnRH receptor may decrease apoptosis.
Possible protection of ovarian germinative stem cells (GSCs): in patients undergoing chemotherapy, high menopausal FSH levels, and undetectable AMH levels have been observed. Approximately a year after the chemotherapeutic ovarian insult, FSH concentrations have been shown to decrease to normal levels and AMH has been found to increase in a large number of patients co-treated with GnRHa. Based on these clinical findings, it has been speculated that the administration of GnRHa may interact with these protected GSCs through some pathways essential for the initiation of folliculogenesis, maturation, and secretion of AMH, inhibin, and estrogens; and the latter two lead to a decrease in FSH levels to normal [Citation7].
For premenopausal women interested in fertility preservation, with the hope of reducing chemotherapy-induced ovarian insufficiency and minimizing the gonadotoxic effect of treatments, temporary ovarian suppression with GnRHa during chemotherapy should not be considered an equivalent or alternative option for fertility preservation, but it should be proposed after embryo and oocyte cryopreservation. Temporary ovarian suppression during chemotherapy achieved by administering a GnRHa is the only strategy that has entered clinical use [Citation8].
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References
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