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Gonadotropin-releasing Hormone (GnRH) Analogues could be used in conjunction with other fertility preservation options to synergistically maximize their effects. GnRH analogues may be a valuable prophylactic agent against chemotherapeutic infertility by inhibiting rapid cellular turnover on growing follicles that contain types of cells unintentionally targeted during anti-cancer treatments. These could create a prepubertal-like effect in adult women, limiting the gonadotoxicity to the lower levels that young girls have.
- GnRH analogues
- fertility preservation
- cancer
- AMH
- GnRH agonists
- GnRH antagonists
1. Introduction
Treatment protocols for cancer patients often include chemotherapy and radiation therapy, both of which are associated with gonadotoxicity, which may result in premature ovarian failure (POF) or infertility. POF is caused by apoptosis of primordial follicles and a subsequent loss of ovarian reserve [1]. Alkylating agents are the most toxic, though treatment duration and cumulative dose also plays an important role [2]. Radiotherapy, when targeted to the pelvis, abdomen, or head (by adversely affecting the hypothalamic-pituitary-adrenal axis [3]) can also be gonadotoxic [4]. Past studies showed that ovarian function was preserved in over 90% of long-term female survivors who were treated for lymphoma before puberty, but only in a minority of similarly treated adult patients [5]. The mechanisms behind the toxicity are multiple, such as direct ovarian toxicity through apoptosis of the oocytes, as well as oxidative stress and decreased ovarian blood flow [1].
Due to the treatment’s gonadotoxicity, premenopausal patients are advised to seek fertility preservation, as is the official recommendation of all the cancer such as ASCO [6] and NCCN [7]. Patients would have a range of choices when it comes to fertility options once cancer treatment is imminent. Depending on age, treatment choice, and type of cancer, the patient should be informed of their options by a fertility specialist. They may elect to cryopreserve oocytes, embryos, cryopreserve ovarian tissue itself, transpose the ovaries, and use GnRH analogues (agonists and antagonists) [8][9]. These treatments may be used in combination. This applies especially to the use of GnRH analogues, which may be used either as part the ovarian stimulation protocols or as a chemoprotective agent for ovarian function preservation. They could be used alongside other, non-pharmaceutical, fertility preservation procedures.
The primary issue with most fertility treatments is, however, that they require several days to be completed. Cryopreservation of oocytes can be used as fertility preservation method for women after menarche without a partner [6], with embryo cryopreservation also being a choice for those partnered, or for those wishing to use a sperm bank, and where legally allowed. For oocyte collection, patients may seek in vitro maturation, an experimental procedure [10]. It allows for the immediate collection of immature oocytes, valuable to cancer patients that cannot undergo hormone treatment or delay chemotherapy.
Ovarian tissue cryopreservation after removal by laparoscopic surgery is the only option for young prepubertal females and patients who cannot undergo ovarian stimulation [11]. An experimental surgical method for fertility preservation is transposition of the ovaries outside the radiation field.
Presently, GnRH analogues, consisting of agonists and antagonists, are used for fertility preservation. ESHRE recommends ovarian stimulation in women seeking fertility preservation for medical reasons the usage of GnRH antagonist protocol and they further add that there is moderate quality evidence of the necessity of considering a specific GnRH analogue protocol. They state that GnRH antagonist protocols are preferred, since they shorten the duration of ovarian stimulation, offer the possibility of triggering final oocyte maturation with GnRH agonist in the case of high ovarian response, and reduce the risk of ovarian hyperstimulation syndrome. Data on live births are extremely scarce, in particular in cancer patients with vitrified oocytes [12]. ASRM recommends that “GnRH analogues may be used “off label for fertility preservation” [13]. They also state that GnRH agonists may be offered to breast cancer patients to reduce the risk of premature ovarian insufficiency [14] but should not be used in place of other fertility preservation alternatives [6] and that more studies are required to establish the efficacy of this treatment and to determine which patients are the best candidates for its use. According to the National Comprehensive Cancer Network (Guidelines Version 2.2022) GnRH agonists are not considered a form of fertility preservation [15].
2. GnRH Analogues; Agonists and Antagonists
The two types of analogues act through different pathways to produce a similar decrease in GnRH secretion. Agonists, such as Buserelin and Triptorelin [16], take advantage of Gonadotropin-releasing hormone receptor (GnRHR) down-regulation that occurs in chronic GnRH surges, by increasing GnRH secretion. They exert their effect by competitively binding to GnRHR while having a higher affinity and lower enzymatic degradation than GnRH. The GnRHR are desensitized to both the exogenous (analogue) and endogenous GnRH, as the receptor is internalized through receptor-mediated endocytosis [16]. This process is known as homologous desensitization, meaning the attenuation is caused by the agonists on their target receptors. Initially, this creates a flare-up of gonadotrophin production until the receptors down-regulate, which in the long-term inhibits gonadotrophin secretion. GnRH agonistic analogues have two distinct differences from GnRH. In the GnRH agonistic decapeptides, the glycine in position 6 is substituted for hydrophobic groups, as this is the primary site of degradation. Many of them also have a deletion of the glycine in position 10, with an ethyl-amide group substituting the C-terminal [16][17], making them nonapeptides. This increases their affinity to GnRHR. The combined effects of a higher affinity and lower degradation make them two hundred times more potent than endogenous GnRHR [17]. They have a couple of disadvantages; they have a flare-up effect, are contraindicated in estrogen receptor positive breast cancer, reduce bone mass in >6-month treatments, and require an administration of minimum one week pre-chemotherapy [8]. GnRHas are administered every four weeks starting 1 to 2 weeks before the initial chemotherapy dose and are usually continued until the end of the chemotherapy regimen. Some protocols, in order to prevent a flare up produced by GnRHa, add an GnRH antagonist at the initial phase followed by agonist protocol treatment, especially if an early start of chemotherapy is needed [18].
Antagonists, such as Ganirelix and Cetrorelix [16], bind competitively to GnRHR preventing pituitary stimulation and the release of gonadotrophins [19]. GnRH antagonists have a higher number of substitutions than the two found in agonists. They exhibit substitutions in positions 1–3, 6, 8 and 10 [16], remaining decapeptides. Their multiple substitutions increase their affinity and lower their degradation rate compared to endogenous GnRHR, without activating the receptors. Their immediate action, while a benefit when time is limited, also comes with the disadvantage of requiring a constant presence in the blood stream, making long-term preparations necessary. Another disadvantage is their generally poor solubility and subsequent high dosing concentrations [16].
3. Anti-Müllerian Hormone as an Estimator of Ovarian Reserve
Anti-Müllerian Hormone (AMH) is produced by the primary, secondary, pre-antral and small antral follicles up to 8 mm in diameter. Larger antral follicles (more than 8 mm) in diameter do not produce AMH [20]. Thus, it is produced by all pre-antral follicles and early antral follicles, except for the primordial ones. As such, it is a marker of ovarian reserve and a predictor of quantitative response to controlled ovarian stimulation.
There are some reasons for using AMH as an ovarian reserve marker: it is not menstrual cycle dependent, with only small fluctuations occurring throughout it [21]. However, it may be influenced by the usage of oral contraceptives, which may lower AMH levels [22].
4. Rationale of Using GnRH Analogues in Fertility Preservation Post Cancer Treatment
The use of GnRH analogues in order to achieve reduction of ovarian toxicity is based on the observation that chemotherapy mostly affects tissues with rapid cellular turnover, such as gonadal ones [23]. It also based on the fact that gonadotoxicity is lower in prepubertal girls than in adult women [5][24]. The latter could be because of their higher ovarian reserve, in addition to the hypogonadotropic prepubertal milieu. This could be because of a decrease in the proliferation rate of granulosa cells and a suppression of follicular recruitment, as GnRHas seem to stimulate the prepubertal hypogonadotropic milieu. Potential mechanisms for ovarian protection could be: (a) a reduction in ovarian blood flow via a direct effect on GnRH receptors that causes a decrease in the amount of chemotherapeutics that reach the ovary [25][26], (b) via a direct effect on ovaries such as up-regulation of intra-ovarian anti-apoptotic molecules and protection of germ line stem cells [27][28] and (c) indirectly by having an anti-apoptotic event on surrounding cumulus cells [29], as has been recently been stipulated.
5. GnRH Agonists and Fertility Preservation after Cancer Treatment
Up to date, publications have reported on over 3100 patients during chemotherapy, receiving concurrently GnRH agonists for preservation of ovarian function via temporary ovarian suppression. These patients were treated for breast cancer, hematologic cancers, or autoimmune diseases. The above studies reported that the GnRHa adjuvant co-treated patients resumed regular menses and normal ovarian function in about 85% to 90% of cases as compared to the 40% to 50% in the chemotherapy only group. Furthermore, natural pregnancy rates in survivors who were co-treated with GnRHa adjuvant during gonadotoxic chemotherapy ranged from 23% to 88%, as compared to the 11% to 35% (p < 0.05) in control patients who were not co-treated [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. More specifically, a long-term follow-up analysis (up to 15 years) of adolescent and young adults with Hodgkin’s lymphoma co-treated with triptorelin confirmed the gonadoprotective effect of GnRHa [46].
6. GnRH Antagonists and Fertility Preservation Post Cancer Treatment
An animal research assessed whether a GnRH antagonist (GnRHant) was able to protect ovaries from chemotherapy damage in 42 female Wistar rats. The rats were divided into four groups: group I (n = 9) received placebo; group II (n = 12) received placebo+cyclophosphamide (CPA); group III (n = 12) received GnRHant+CPA; and group IV (n = 9) received GnRHant+placebo. The estrous cycle was studied using smears, pregnancies were documented, the number of live pups measured, and the ovarian cross-sectional area was measured, together with follicle count. The ovarian cross-sectional area was not different between groups, neither was the number of individual follicle types. However, rats on GnRH antagonists and placebo (Group IV) had a higher total number of ovarian follicles than those in the control group. Researchers conclude that the use of a GnRH antagonist before CPA chemotherapy provided fertility protection [47] (Table 1).
Table 1. GnRH antagonists only & fertility preservation during cancer treatment.
| Author | Study Design | Results | Discussion |
|---|---|---|---|
| Lemos et al. [47] | 42 female Wistar rats treated in four different groups: placebo or cyclophosphamide, GnRHa antagonist or placebo. Data collected up to 2010. Published in 2010. | Rats in the group that received GnRHant treatment had a higher number of total follicles than the control group (p < 0.05). | GnRHant treatment before chemotherapy resulted in some fertility protection in rats. |
7. Combination of GnRH Agonists and Antagonists and Fertility Preservation Post Cancer Treatment
To date it is already known that both GnRH agonists and antagonists have disadvantages that limit their use; GnRHas causes a flare-up effect during the first week after administration and no long-acting GnRHant agent is available. GnRHas combined with GnRHants may prevent the flare-up effect of GnRHa and rapidly inhibit the female gonadal axis. A small number of experimental animal studies with small sample sizes have reported controversial conclusions.
In a research involving 30 female Sprague Dawley rats of adolescent age, rats were randomized into five treatment groups (n = 6/group): (1) placebo, (2) cyclophosphamide (CPA) alone, (3) GnRH antagonist followed by GnRH agonist with placebo, (4) GnRH antagonist followed by GnRH agonist with CPA, and (5) GnRH agonist with CPA. The main outcome measure was live birth rate (LBR), and secondary measures included rat weight, ovarian volume, and follicles. Group 2 had decreased LBR. Group 4 and 5 had LBR similar to placebo. Ovarian volume did not vary between the groups. The CPA-alone group had fewer antral follicles compared to the control. The combination of GnRH antagonist and GnRH agonist and GnRH agonist alone preserved fertility in female adolescent rats following gonadotoxic chemotherapy treatment [48].
In another controlled animal research, researchers investigated the advantages of combination treatment with GnRHas and GnRHants in rats aged 12 weeks. The combination of a GnRH agonist with an antagonist completely prevented the flare-up effect and protected primordial ovarian follicles in the rats’ ovary from cisplatin-induced gonadotoxicity [49].
8. Summary
Regarding the use of GnRH antagonists, as a co-treatment with chemotherapy in gynecological cancer and hematological malignancies, data are not conclusive as there are only a few, limited, animal data. Any potential beneficial effects of GnRH analogues as a co-treatment in fertility preservation could depend on the type and maybe the stage of cancer treated and possibly the type of alkylating agents used. The latter is based on the observation of the significant differences seen in fertility preservation of breast and hematological cancer compared to other gynecological breast cancers. In addition to that. age and/or ovarian reserve could be an important factor as females in pre-pubertal stage seem to be more protected. Lastly, studies need to be homogeneous regarding the fertility preservation criteria they use as outcomes. Researchers might need to clarify the criteria they use to study the effectiveness of GnRH analogue co-treatment in fertility preservation treatments for premenopausal patients with gynecological cancers. For example, not all studies consider ovarian reserve as a criterion of fertility preservation assessment and use instead pregnancy rates, live birth rates, and look at long-term fertility.
Basic future research could focus on investigating the differential effects of GnRH analogue co-treatment on the physiology of different ovarian cell populations. In particular, the potential antiapoptotic effect of GnRHas on the several types of follicular cells as well as in the mesenchymal stroma cells should be further investigated. Whereas GnRHRs have been identified in several cell lines in the ovary [50] their absence from pre-antral follicles per se [29] creates several questions as to the protective effect of GNRH analogues. Furthermore, the impact of decreased ovarian perfusion and thus decreased delivery of the cytotoxic agents to the ovary as protective mechanism should also be evaluated. Clinical research could focus on the effects of GnRHa co-treatment with chemotherapy: first by evaluating surrogate markers of ovarian reserve such as AMH before during and after gonadotoxic therapy, secondly by evaluating other markers of ovarian reserve that could be more accurate, and thirdly by presenting the actual impact of their use in women that attempt pregnancy after treatment.
This entry is adapted from the peer-reviewed paper 10.3390/ijms23042287
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