Preserving fertility when choosing chemotherapy regimens – the role of gonadotropin-releasing hormone agonists

Abstract

Until now, 20 studies (15 retrospective and 5 randomized controlled trial) have reported on 2038 patients treated with GnRH-a in parallel to chemotherapy, showing a significant decrease in premature ovarian failure (POF) rate in survivors versus 8 studies reporting on 509 patients, with negative results. Patients treated with GnRH-a in parallel to chemotherapy preserved their cyclic ovarian function in 91% of cases as compared to 41% of controls, with a pregnancy rate of 19 - 71% in the treated patients. Furthermore, over 10 recent meta-analyses have concluded that GnRH-a are beneficial and may decrease the risk of POF in survivors. Because most of the methods involving ovarian or egg cryopreservation are not yet clinically established and unequivocally successful, these young patients deserve to be informed with all the various modalities to minimize gonadal damage and preserve ovarian function and future fertility. Combining the various modalities for a specific patient may increase the odds of preservation of future fertility.

Controversies over the use of GnRH agonists for reduction of chemotherapy-induced gonadotoxicity

“…Up to two-thirds of adult female patients undergoing chemotherapy for malignancies eventually develop premature ovarian failure (POF) 1 . This risk ranges from below 10% to over 95% depending on risk factors 4 . As a consequence, POF can cause serious side-effects, including vasomotor symptoms, osteoporosis, increased risk of cardiovascular diseases, sexual dysfunction, and infertility 5 .…”

“…Unfortunately, this method does not preserve ovarian function but is the preferred method in prepubertal girls to preserve fertility. Even though the administration of gonadotropin releasing hormone (GnRH) agonistic analogs (GnRH-a) is still considered experimental as a method to preserve fertility and cannot guarantee future fertility 4 , it has the advantage of the preservation of ovarian function, thus diminishing the adverse outcomes associated with POF, making a difference compared with the other methods mentioned above.…”

“…The mechanisms of action whereby GnRH-a preserves ovarian function are not fully understood. The suggested possible mechanisms include: (1) simulation of the prepubertal, hypogonadotropic milieu with levels of follicle stimulating hormone (FSH) dramatically decreased; (2) decreasing ovarian perfusion secondary to the low estrogen levels; (3) a possible direct effect on ovarian cells; (4) possible up-regulation of an anti-apoptotic molecule such as sphingosine-1-phosphate; and (5) possible protection of the ovarian germinative stem cell 4 . A decrease in FSH secretion occurs with the continuous use of analogs, with subsequent prevention of secondary follicular recruitment, thus stopping the vicious circle of more follicular development and destruction.…”

“…The gonadotoxic effect of chemotherapy brings about follicle death, resulting in decreased estrogen and inhibin levels, causing the FSH concentration to increase and enter the unidirectional path of apoptosis, the so-called 'burn-out theory'. The GnRH-a decreases FSH levels, and therefore the effect of further recruitment of primordial follicles and their burn-out is minimized 4,7,8,10 . Even though the use of GnRH-a is not an established form of fertility preservation, it is a non-invasive and easy available method to decrease the risk of gonadotoxicity and POF after chemotherapy.…”

Closing the gap: Novel therapies in treating acute lymphoblastic leukemia in adolescents and young adults

“…Cryopreservation of oocytes and embryos should be offered to all young female patients, though this strategy is invasive and may require delaying the initiation of chemotherapy [84]. A non-invasive approach of fertility preservation for women involves the use of gonadotropin-releasing hormone agonists throughout therapy, though in multiple studies including randomized controlled trials, the data has not been conclusive that these drugs prevent infertility, and therefore this therapy is not currently recommended by several national gynecological organizations [85]. Further studies are needed to help determine the optimal methods to preserve ovarian function.…”