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

Abstract

The increase in cancer incidence in younger people and the significant improvement in long and permanent remission have brought concern about their reproductive future and quality of life. Up to two-thirds of adult female patients undergoing chemotherapy for malignancies eventually develop premature ovarian failure. This condition is related to many complaints including vasomotor symptoms, osteoporosis, increased risk of cardiovascular diseases, sexual dysfunction, and infertility. Therefore, protection against iatrogenic infertility and loss of endocrine ovarian function caused by chemotherapy is currently of high priority. Several options have been used for preserving ovarian function. Established methods include cryopreservation of embryos and/or ova, and ovarian transposition, while others such as ovarian tissue preservation are new, yet promising treatments for fertility preservation. The administration of gonadotropin releasing hormone (GnRH) agonistic analogs (GnRH-a) is still considered experimental. However, the recent evidence is strong to recommend the use of GnRH-a co-treatment during chemotherapy in young women with cancer to protect ovarian function, with promising results regarding fertility preservation. As the use of GnRH-a is non-invasive, highly available and without impact on cancer treatment outcomes, it should be offered to all young female cancer patients to preserve their ovarian function.

Keywords:

• Premature ovarian insufficiency
• ovarian preservation
• chemotherapy
• GnRH agonists

The risk of women developing cancer before 40 years of age is approximately 1 in 49. Although some of these cases occur during infancy and childhood, more than 99% will occur during the reproductive years¹. With the development of combination chemotherapy and combined modality treatment, the prognosis has dramatically improved, especially in hematologic malignancies². The 5-year survival of young patients treated with cytotoxic chemotherapy for Hodgkin’s disease, the most frequent malignancy in the 15–29-year-old population, is nearly 90%³. The increase in cancer incidence in the young and the significant improvement in long and permanent remission have brought concern about their reproductive future and quality of life.

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 factors⁴. As a consequence, POF can cause serious side-effects, including vasomotor symptoms, osteoporosis, increased risk of cardiovascular diseases, sexual dysfunction, and infertility⁵. Protection against iatrogenic infertility and loss of endocrine ovarian function caused by chemotherapy is currently of high priority³.

Few chemotherapeutic agents are cell cycle-specific; they therefore inflict damage on a wide range of rapidly dividing cell types¹. Although the cytotoxic effect of these treatments is reversible in tissues with rapidly dividing cells such as bone marrow, the gastrointestinal tract, and thymus, it appears to be progressive and irreversible in the ovary, in which germ cells are limited in number and cannot be regenerated³. Permanent ovarian failure can either develop during treatment or occur years after treatment, reflecting the early depletion of oocytes caused by gonadotoxic treatment². Therefore, chemotherapy is responsible for DNA damage that directly affects the ovary. These lesions induce apoptosis that not only affects the follicle but also the growing population of primordial follicles⁶.

The risk of developing POF is correlated with age, the status of the ovarian reserve before treatment initiation, the type of chemotherapy and the cumulative dosage⁶. Among the chemotherapeutic regimens, alkylating agents are the most gonadotoxic agents. Cyclophosphamide has a four-fold increased risk of inducing amenorrhea when compared with other chemotherapeutic agents, mostly by causing apoptotic oocyte death in primordial follicles⁷.

Because most cancer patients receive combination chemotherapy, it is difficult to estimate an individual’s risk of subsequent infertility or POF¹. Nevertheless, it is important to integrate POF as an early measure during planning for cancer treatment⁸. Several options have been used for preserving female fertility with different success rates. Established methods include cryopreservation of embryos and/or ova, and ovarian transposition. Others such as ovarian tissue preservation are new, yet promising, fertility preservation treatments, with the first live birth after autotransplantation of human ovarian tissue reported in 2004. To date, there have been at least 60 live births after ovarian tissue reimplantation, with an estimated pregnancy rate of 25.0% in the largest series⁹. 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 fertility⁴, 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.

Publications regarding co-treatment with GnRH-a for POF prevention have increased rapidly during the last decade. The administration of GnRH-a creates a pseudoprepubertal state with an overall decrease in ovarian function. The theoretical basis behind this approach is the observation that ovarian function is less likely to be destroyed when chemotherapy is given before puberty but is likely to be destroyed when chemotherapy is given after puberty¹.

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 cell⁴.

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. But the primordial and primary follicles are accepted as gonadotropin-independent and they lack FSH receptors; also the development from the primordial follicle up to the small preantral follicle is a gonadotropin-independent process, subtracting support for this mechanism. However, the more advanced antral follicles, which are unequivocally gonadotropin-responsive and -dependent, secrete growth factors, from the transforming growth factors (TGF-β) superfamily, such as TGF-β itself, bone morphogenic proteins 2, 4, 5, 6, 7 and 15, growth differentiation factor-9, activin and others, which, in a paracrine manner, cause the primordial and primary follicles to grow. 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. Hence, as soon as the cancer is diagnosed and chemotherapy is planned, GnRH-a could be offered as the only method of fertility preservation if the chemotherapy has to start immediately and there is no time for other procedures, or preferably established methods of fertility preservation.

Similar protocols have been used in randomized, controlled trials. In summary, GnRH-a is administered every 4 weeks beginning 1 or 2 weeks before the initial chemotherapy dose and continued until the end of the chemotherapy regimen in most cases or even until 2 years. To prevent the flare-up produced by GnRH-a, some protocols add a GnRH antagonist at the initial phase, followed by agonist protocol treatment, especially if an early start of chemotherapy is needed, and some studies add oral contraceptives for the management of climacteric-like symptoms.

A total of 13 randomized, controlled trials with different aims, results and methods have been conducted to assess the efficacy of this strategy, and their results have been analyzed in several meta-analyses. To date, the largest meta-analysis by Lambertini and colleagues, published in 2015, showed that the temporary ovarian suppression with GnRH-a during chemotherapy significantly reduced the occurrence of treatment-related POF in breast cancer patients (odds ratio (OR) 0.36; p < 0.001), resulting in a significantly larger number of menstruating woman 1 year after the end of chemotherapy (OR 0.55; p < 0.001). Also, its use almost doubled the chance of achieving subsequent pregnancies (OR 1.83; p = 0.041; 33 vs. 19 patients)¹¹.

These data are in accordance with those from previous meta-analyses that showed similar results, supporting GnRH co-treatment during chemotherapy^5,12. In the meta-analysis by Del Mastro and colleagues, including nine randomized, controlled trials, and considering three different cancers, 225 events of POF were reported among 765 patients (29.4%). This meta-analysis provided convincing evidence in support of the efficacy of GnRH-a-based strategy in reducing the risk of chemotherapy-induced POF. The pooled estimate of the effect of this strategy has an OR of 0.43 (95% confidence interval (CI) 0.22–0.84, p = 0.013), which means that, in a group of women with a 30–35% risk of POF, approximately half of the expected cases of ovarian failure are prevented⁵. Likewise, the Cochrane meta-analysis concluded that intramuscular or subcutaneous GnRH-a seemed to be effective in protecting ovaries during chemotherapy (resumed menses: relative risk (RR) 1.90, 95% CI 1.30–2.79; amenorrhea: RR 0.08, 95% CI 0.01–0.58; ovulation: RR 2.70, 95% CI 1.52–4.79) and should be given before or during treatment, although no significant difference in pregnancy rates was seen¹².

To date, there is a paucity of data available on recovery of ovarian function at longer time-points, of more than 1 year, but the limited information is promising. One study showed a significant increase in the proportion of menstruating woman 36 months after chemotherapy in the GnRH-a arm (36% vs. 10%; p = 0.006); in another study, the 5-year cumulative incidence estimate of menstrual resumption was statistically significantly higher in the chemotherapy + GnRH-a arm (72.6% vs. 64%: age-adjusted hazard ratio 1.48; p = 0.006)^5,11.

Also, there is limited information regarding fertility prognosis in these woman. First, none of the trials were primarily designed to study fertility outcomes, and limited information on the number of patients who attempted to become pregnant are available. Second, the median follow-up of most studies was short, and patients were recommended to delay attempts to become pregnant until complete remission was achieved, especially in those with hormone-dependent malignancies¹¹.

The NIH-sponsored prospective, randomized, controlled trial, the POEMS-SWOG S0230 study, studied 257 premenopausal patients with estrogen receptor-negative breast cancer who received chemotherapy with or without GnRH-a. Two years after chemotherapy, only 8% of the GnRH-a arm experienced POF versus 22% of the control group. In the GnRH-a group, 21% conceived and 15% delivered, versus only 11% and 7%, respectively, in the controls¹³.

GnRH-a therapy in these patients could have other potential benefits. Menstrual suppression and reversal of menorrhagia-associated anemia are particularly important in patients with hematologic cancers¹.

In an unexpected finding, the POEMS-SWOG S0230 study showed that the 4-year mortality rate in the GnRH-a group was significantly lower. Preclinical studies have shown that the use of GnRH analogs is associated with growth inhibition, reduction in metastasis, and apoptotic cell death in xenograft models of triple-negative breast cancer, and this may explain these results¹³. Also, the groups of Del Mastro and Recchia demonstrated an improvement in 5- and 10-year survival rates with GnRH-a compared with the studies without the agonist⁵. Similar evidence has been published, based on 11 906 young breast cancer patients randomized in 16 trials, which concluded that the addition of GnRH-a to tamoxifen, chemotherapy, or both, reduced recurrence by 12.7% (p < 0.02) and death after recurrence by 15% (p < 0.03)¹⁴.

Finally, the actual evidence is strong to recommend the use of GnRH-a co-treatment during chemotherapy in young women with breast cancer to protect ovarian function, with promising results regarding fertility preservation. Although favorable results have been shown in hematologic malignancies such as lymphoma¹⁵, better-quality evidence is still needed. Probably, a longer follow-up of the last patients in randomized, controlled trials will clarify the usefulness for fertility preservation. It is clear that the different chemotherapy schedules, the mean age of the subjects and concomitant treatments may explain the different outcomes for leukemia and lymphoma cancer, with fertility preservation rates ranging from 10%¹⁵ to 87%³, respectively.

The use of GnRH-a is non-invasive, highly available and without impact on cancer treatment outcomes; therefore, it should be offered to all young female cancer patients to reduce gonadotoxicity and to reduce the chance of POF to over 50%⁵. Even when patients have been given a recommended and established method of fertility preservation, the use of GnRH-a can decrease the need for hormonal replacement therapy, when is it is not contraindicated, and so reduce the bothersome climacteric symptoms and loss of bone density that affect the quality of life of so many young women treated for cancer. Finally, whether or not GnRH-a has no fertility-sparing action, this method causes menstrual suppression and protection from thrombocytopenia that could be beneficial in some malignancies, and therefore can be recommended.

Conflict of interest

The authors report no conflict of interest. The authors alone are responsible for the content and writing of this paper.

Source of funding

Nil.