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Breast Cancer |
Department of Obstetrics and Gynecology, Rambam Medical Center, Technion-Faculty of Medicine, Haifa, Israel
Key Words. Fertility preservation • Chemotherapy • Gonadotoxicity • GnRH-agonist • Premature ovarian failure
Correspondence: Zeev Blumenfeld, M.D., Department of Obstetrics and Gynecology, Rambam Medical Center, Technion-Faculty of Medicine, Haifa 31096, Israel. Telephone: 972-4-8542577; Fax: 972-4-8543746; e-mail: bzeev{at}techunix.technion.ac.il, z_blumenfeld{at}rambam.health.gov.il
Received December 13, 2006; accepted for publication July 20, 2007.
Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.
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GnRH Agonist Treatment in...
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ABSTRACT |
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BACKGROUND |
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GNRH AGONIST TREATMENT IN CANCER PATIENTS |
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Similarly, Sklar et al., [21] recently found that survivors of childhood cancer have an 8% risk of suffering POF before the age of 40, compared with <1% in the general population. This is in keeping with our and others' results whereby women of reproductive age receiving a GnRH agonist in addition to chemotherapy suffer POF in about 7%–10% of cases (simulating prepubertal exposure), whereas those treated without the agonist have about a 40% risk for POF [1–7, 10,11,14,16–19, 22, 23].
As opposed to young girls, most prepubertal boys receiving chemotherapy and radiotherapy suffer azoospermia; therefore, there is little rationale to expect a significant benefit from a similar GnRH agonist cotreatment in men [1, 4, 7, 10, 11, 14, 16–19]. In contrast to the encouraging protective effect of GnRH agonist cotreatment with chemotherapy, no protection from ovarian damage caused by irradiation to rats could be provided by the GnRH agonist [1, 7, 14, 16].
Similar experience and results regarding the protective effect of a GnRH agonist against chemotherapy-associated gonadotoxicity were recently reported in adolescent female patients [22]. Whereas all the GnRH agonist–treated patients resumed cyclic ovarian function, all patients in the chemotherapy-alone (without a GnRH agonist) group experienced hypergonadotropic amenorrhea in spite of their young, adolescent age [22]. Similarly, Castelo-Branco et al. [23] reported a 10% rate of POF in their GnRH agonist–treated hemato-oncologic female patients, compared with a 77% POF rate in their control group.
Similarly, a GnRH agonist prevented chemotherapy-associated POF in premenopausal breast cancer patients [24–29]. All 13 patients in one study [24], aged 26–39 years, resumed normal ovarian function after a mean of 4.9 months postchemotherapy, and in another study [25], 86% of the 64 premenopausal patients (27–50 years of age) resumed cyclic menstruation, despite a relatively advanced median age of 42 years. In a recent update of their previous study [25], Recchia et al. [26] found that all their breast cancer patients younger than 40 who received GnRH agonist cotreatment in addition to chemotherapy resumed cyclic ovarian function, with excellent 5- and 10-year survival rates. In breast cancer, at least four phase II studies evaluated the activity of ovarian suppression with GnRH agonists in preserving fertility and ovarian function [24–29]. Those studies [24–29] have clearly demonstrated that GnRH agonist cotreatment enables the resumption of ovarian function in a high percentage of treated patients, in the range of 83%–96% [28]. A few ongoing, phase III, randomized controlled trials (such as the Southwest Oncology Group led U.S. Intergroup Trial S0230, which also has the participation of the International Breast Cancer Study Group) will probably be able to unequivocally answer the debated question regarding the role of GnRH agonists in preserving ovarian function and fertility in young premenopausal patients exposed to gonadotoxic chemotherapy [29–31].
Although pregnancies occurred in both groups in our series, it should be emphasized that, whereas all the 22 pregnancies in the "control" group occurred in patients aged 16–26 years when exposed to chemotherapy, the ages of the 33 patients who conceived 46 times in the GnRH agonist/chemotherapy cotreatment were 18–33 years at exposure to chemotherapy [1, 4, 7, 10, 11, 14, 16–19]. This difference may suggest a possible prolongation of the "fertility window" by 7 years (or more) using GnRH agonist adjuvant cotreatment in parallel with chemotherapy. This is in keeping with the experience reported by others [32, 33] who also found the median age of pregnant survivors of lymphomas to be 18 years (range, 13–28), with only few reported pregnancies for female patients >30 years old.
If this protective effect observed in our and others' recent preliminary studies of GnRH agonists and chemotherapy on future ovarian function is confirmed in larger and prospective randomized studies, which are currently ongoing in Italy [29], the U.S. [30], and Germany [34], for breast cancer [29, 30], HD (German Hodgkin's Lymphoma Study Group), and lupus erythematosus patients [34] receiving cyclophosphamide pulsatile therapy, it may become mandatory to use this cotreatment protocol in every young woman undergoing chemotherapy. Thus, ovarian protection may enable the preservation of future fertility in survivors and, in addition, prevent the bone demineralization and osteoporosis associated with hypoestrogenism and ovarian failure, and the menorrhagia with resultant anemia associated with chemotherapy-induced thrombocytopenia [1, 4, 7, 10, 11, 14, 16–19, 34–37].
Notwithstanding all the above, two studies published in the New England Journal of Medicine [38, 39] reported that good observational studies give results similar to those of randomized controlled trials. The first [38] "found little evidence that estimates of treatment effects in observational studies reported after 1984 are either consistently larger than or quantitatively different from those obtained in randomized, controlled trials." Moreover, the second [39] concluded that "the results of well-designed observational studies, do not systematically overestimate the magnitude of the effects of treatment as compared with those in randomized, controlled trials on the same topics."
It has been suggested that future studies should examine GnRH antagonists instead of agonists for the achievement of a faster pituitary–ovarian desensitization, eliminating the waiting period of 7–14 days needed by the GnRH agonist to achieve downregulation [4, 7, 10, 11, 14, 16–18]. However, a recent study [40] has concluded that, in contrast to the "well known effects of GnRH agonists to reduce chemotherapeutic destruction of primordial follicles, GnRH antagonists do not protect the ovary from the damaging effects of cyclophosphamide." In that study [40], administration of cyclophosphamide to adult mice caused a nearly 50% reduction in the number of primordial follicles. The GnRH agonist leuprolide (Lupron®; TAP Pharmaceuticals, Lake Forest, IL) alone had no effect on the number of primordial follicles, but significantly minimized the follicular depletion caused by cyclophosphamide when coadministered [40]. In contrast, the GnRH antagonist antide did not prevent the depletion of primordial follicles caused by cyclophosphamide. Surprisingly, both tested antagonists, antide and cetrorelix, caused a significant reduction in the number of primordial follicles (even without cyclophosphamide) (p < .05) [40]. This observation, although preliminary, casts significant doubt on the assumption that GnRH antagonists may possibly be substituted for agonists in the future for minimizing chemotherapy-associated gonadotoxicity. Furthermore, this preliminary study may possibly explain the tendency toward lower pregnancy rates in assisted-reproduction technique/IVF cycles using antagonists versus agonists [41].
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GNRH AGONIST TREATMENT IN OTHER DISEASES |
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POTENTIAL MECHANISMS OF GONADOTOXIC PROTECTION |
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I: Interruption of Follicle-Stimulating Hormone Secretion
One can conceivably hypothesize that alkylating agents may bring about an increased rate of destruction/apoptosis of nonresting follicles, and subsequently a decrease in the secretion of sex steroids and inhibins produced by these follicles at different stages of maturation and differentiation. The resultant decrease in sex steroid and inhibin secretion will decrease their plasma concentrations and subsequently the negative feedback on the hypothalamus and pituitary, resulting in an increase in follicle-stimulating hormone (FSH) secretion. The increased FSH secretion may bring about an increased recruitment of preantral follicles to enter the one-way differentiational path of maturation, being further exposed to the gonadotoxic effects of the alkylating agents, ending in an increased, exponential rate of follicular apoptosis and degeneration. This unfortunate vicious cycle may be interrupted by the GnRH agonist administration through its ability to prevent the increase in FSH concentrations [6] (Fig. 1).
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Moreover, others [45–47] have shown that primordial and primary follicles may express mRNA for FSH and LH receptors, in keeping with our suggested vicious cycle pathophysiologic mechanism and with the notion that even primordial and primary follicles may be gonadotropin dependent, although indirectly [48], in contrast to the previous theory claiming that they are totally gonadotropin independent. Even if we assume that the primordial follicles are gonadotropin independent, because no gonadotropin receptors have been demonstrated on their primordial granulosa cells (GCs), they are dependent on growth factors (GFs) such as bone morphogenic protein (BMP)-4, BMP-7, and BMP-9 and activin [48], which are secreted by the more advanced, preantral follicles, beyond the secondary stage, and these secreted GFs induce the maturation of primordial follicles [48]. The more mature, preantral follicles, beyond the secondary stage, secrete these GFs in response to FSH stimulation [48]. Pituitary desensitization, induced by GnRH agonist administration, prevents the secretion of GFs by the FSH-dependent follicles; thus, secondarily preserving more primordial follicles in the "dormant" stage, and minimizing their unidirectional maturation and ultimate destruction by alkylating agents [1, 12, 14, 36, 48, 49]. Supporting this hypothesis is the recent demonstration [50] that gonadotropins may have an apoptotic effect on the theca-interstitial cells of isolated rat follicles in vitro. This group [50] has shown that gonadotropins enhance caspase-3 and caspase-7 and apoptosis in the theca-interstitial cells of rat preovulatory follicles in culture. The elevations in caspase-3 and caspase-7 activities in theca-interstitial cells were accompanied by an increase in apoptosis [50]. Furthermore, Adriaens et al. [51] have shown that differential FSH exposure in preantral follicle culture has marked effects on folliculogenesis and oocyte developmental competence. Although early preantral follicles are independent of FSH for their initial growth, FSH receptors are present on the GCs of these follicles [51]. The best known FSH receptor is FSHR-1 [51]. However, several events occur well before the expression of the stimulatory G-protein–coupled FSHR-1 [51], suggesting that other FSHR motifs might function to play a role during development. It was proven that a new splice variant, FSHR-3, is present in immature ovaries and that there is a positive correlation between follicle differentiation and the expression of this receptor [51, 52]. In the human, one third of the primary and two-layered follicles produce FSHR mRNA and all multilaminar follicles are positive for FSHR mRNA [46, 47]. Human ovarian xenografts in nude and hypogonadal mice contain follicles progressed beyond the secondary stage only when animals are treated with FSH [53]. These observations are in contrast to the older assumption that early follicles are completely gonadotropin independent [51]. Furthermore, two recent publications found that the proliferation of primordial germ cells is gonadotropin dependent and is mediated by Akt/phosphatase and tensin homologue deleted on chromosome ten (PTEN) signaling [54, 55]. High concentrations of estrogens stimulate mouse primordial germ cell growth in vitro through the somatic cells of the gonad [54, 55]. Moreover, estrogens stimulate the transcription of the Steel gene and the production of c-Kit ligand in gonadal somatic cells, and this GF is likely to be responsible for the observed stimulation of primordial germ cell growth via an Akt/PTEN pathway [54, 55]. Although the initiation of primordial follicle growth and the early stages of folliculogenesis can occur without gonadotropins, FSH may affect the rate of preantral follicle growth [56]. Therefore, the older assumption that early follicles are Gn independent may need re-evaluation and reassessment [47–52, 54–56].
II: Decrease in Utero-Ovarian Perfusion
Another possible explanatory mechanism for the beneficial effect of GnRH agonists on decreasing chemotherapy-associated gonadotoxicity is the decrease in utero-ovarian perfusion resulting from the hypoestrogenic state generated by pituitary–gonadal desensitization [57, 58]. High estrogen concentrations significantly increased ovarian perfusion and vessel endothelial area in a rat model of ovarian hyperstimulation, and this effect was significantly and dose-dependently inhibited by administration of a GnRH agonist [58]. The decreased utero-ovarian perfusion induced by the GnRH agonist may result in a lower total cumulative exposure of the ovaries to the chemotherapeutic agents as compared with a "control" patient, in a normoestrogenic milieu, thus resulting in less gonadotoxicity.
III: Activation of GnRH Receptors
It has been shown that not only rodent but also primate and human gonads contain GnRH receptors [1, 59–61]. In an ovarian carcinoma cell line, Grundker and Emons [60] have shown that GnRH-I and GnRH-II receptor activation may result in decreased apoptosis. Whether the GnRH agonist effect is direct on the oocyte–cumulus complex or on the GC, or possibly on another ovarian compartment in addition to its possible hypogonadotropic effect, is an open question of significant interest. Additional studies are obviously necessary to answer this important question. Most recently, proof of a direct effect of GnRH agonists, independent of the hypogonadotropic milieu, was provided by Imai et al. [62]. Those investigators [62] have shown direct in vitro protection from doxorubicin-induced GC damage by a GnRH agonist.
IV: Upregulation of Sphingosine-1-Phosphate
Another possibility is that GnRH agonists may upregulate an intragonadal antiapoptotic molecule such as sphingosine-1-phosphate (S1P). Tilly et al. [63–65] have identified several molecules that are required for chemotherapy-induced oocyte apoptosis. While much of their work has relied on gene knockout mice, they have identified a small lipid antagonist of the proapoptotic second messenger ceramide, S1P, as a potent protective molecule [63–65].
Mouse oocytes that were exposed to doxorubicin did not degenerate in a pathological fashion, but initiated programmed cell death [65]. Targeted disruption of the Bax gene in mice or, more recently, targeted expression of the Bax antagonist Bcl-2 to the female mouse germ line may protect the oocytes from the gonadotoxic effect of doxorubicin [66, 67]. Unfortunately, comparable genetic technologies for protection against chemotherapy-induced gonadotoxicity are not yet feasible in humans [4].
Experiments in mice tested the possibility that S1P could be administered in vivo to protect the ovaries from radiotherapy-induced damage [64]. Suppression of caspase activity in models of Bax-driven apoptosis eventually activated a default pathway of cell death, which is more akin to primary necrosis, probably because the mitochondria are still "damaged" by Bax in a caspase-independent manner [68]. Whereas oocyte death induced by chemotherapy is Bax dependent [65], caspase inhibition was excluded as a possibility. Therefore, a preceding step in the oocyte death program was elected—the proapoptopic molecule ceramide.
Many somatic cell types generate ceramide, by either synthetic or hydrolytic mechanisms, in response to radio- or chemotherapy [69]. Ceramide may function in several stages of the programmed cell-death pathway, such as "capping" of death receptors [70] and helping Bax to insert into mitochondrial membranes [71]. In hematopoietic cells, S1P counteracts ceramide proapoptotic effects [72, 73]. The S1P molecule can also prevent doxorubicin-induced oocyte death in vitro [64, 65]. Furthermore, oocytes that lack acid sphingomyelinase—a hydrolytic enzyme that generates ceramide [69]—are resistant to doxorubicin-induced apoptosis in vitro [64]. Young adult female mice were given a single injection of S1P into the bursal cavity, which surrounds each ovary [64, 74]. Two hours later, they were irradiated with an amount sufficient to destroy the majority of the primordial oocyte reserve. Two weeks after irradiation, the ovaries were analyzed. No differences were observed between mice that had not been irradiated and those that had been protected by S1P in vivo before irradiation. In contrast, irradiated mice that did not receive S1P suffered a pronounced loss of oocytes and reduced embryonic developmental potential of the remaining oocytes [64, 74]. With preliminary data from in vivo mating trials supporting the conclusions that S1P preserves a normal level of fertility in female mice that are exposed to anticancer therapy [74, 75], minimizing the gonadal toxicity of such treatments in female cancer patients might one day prove feasible [1, 11, 63, 73–76].
More recently, it was demonstrated, for the first time, that S1P-based protection of the female germ line from radiation is not associated with discernible propagation of genomic damage at the anatomical, histological, biochemical, or cytogenetic level [75]. Moreover, this investigation [75] provides the first credible prospective evidence that preservation of ovarian function and fertility postirradiation can be safely and effectively achieved in vivo, using S1P-based strategies.
Whether the GnRH agonist adjuvant cotreatment positive effect is direct or possibly associated with an intraovarian increase in S1P is a question of tremendous interest and clinical impact. It obviously awaits further investigation [76].
V: Protection of Undifferentiated Germ Line Stem Cells
Most recently, Johnson et al. [77] presented revolutionary data whereby mouse ovaries may possess mitotically active germ cells that continuously replenish the pool of immature follicles. These germ line stem cells (GSCs) may exist in the mouse ovary and regenerate the primordial follicle pool. Their observations contradict the basic doctrine of reproductive biology, whereby most mammalian females lose the capacity for germ-cell renewal during fetal life, such that a fixed reserve of germ cells (oocytes) enclosed within follicles is endowed at birth.
Exposure of prepubertal female mice to the mitotic germ-cell toxicant busulphan eliminated the primordial follicle reserve by early adulthood without inducing atresia [77]. These data may establish the existence of undifferentiated proliferative germ cells in the female gonad, similar to the situation in the male, that sustain oocyte and follicle production in the postnatal mammalian ovary [77]. One may speculate that the GnRH agonist protective effect may possibly be through protection of the undifferentiated GSCs, which ultimately generate de novo primordial follicles. Indeed, the observation of temporary, high, reversible FSH concentrations in one third of our patients several months after the chemotherapy and GnRH agonist cotreatment, even in those who spontaneously conceived later on, may point toward reversible gonadotoxicity. The possible de novo formation of follicles by the surviving GSCs brings about a decrease in FSH concentration and return of regular cycles, ovulation, and even gestation.
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GNRH AGONISTS AS AN ADJUNCT TO CURRENT FERTILITY-PRESERVING STRATEGIES |
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It is agreed by all that a large, prospective, randomized study is needed to unequivocally substantiate the role of GnRH agonists as a possible effective adjunct to minimize chemotherapy-associated gonadotoxicity. Indeed, several such prospective, randomized studies are presently ongoing: the Zoladex Rescue of Ovarian Function (ZORO) study in Germany, an Italian multicenter study for breast cancer patients, the Southwest Oncology Group led U.S. Intergroup trial S0230 (which also has participation of the International Breast Cancer Study Group) [30], the German Hodgkin's Lymphoma Study Group multicenter study, a U.K. lymphoma multicenter study, and a Spanish Lymphoma multicenter study. If these studies come up with unequivocal results demonstrating the beneficial effect of GnRH agonists in minimizing chemotherapy-associated gonadotoxicity, the categorical statement of Sonmezer and Oktay [81] against GnRH agonist cotreatment may do harm to many patients who could benefit from such a clinical combination, in addition to IVF and ovarian tissue cryopreservation, while waiting for the results of these prospective studies in humans.
If GnRH agonist cotreatment proves to be of no value, its use will not have done any harm, because it is presently recommended in addition to IVF and embryo cryopreservation and/or ova or ovarian tissue cryopreservation. Furthermore, it may decrease thrombocytopenia-associated menorrhagia, as recently described [37]. Moreover, the recent studies of Recchia et al. [25, 26] and Del Mastro et al. [27] supporting this cotreatment in breast cancer have shown that, in premenopausal women with early breast carcinoma, the addition of a GnRH agonist to adjuvant therapy and temporary total estrogen suppression in patients with estrogen receptor–positive disease was well tolerated, protected long-term ovarian function, and appeared to improve the expected clinical outcome [25, 26]. After a median follow-up of 75 months, normal menses resumed in all patients <40 years of age and in 56% of patients >40 years old [25, 26]. The projected recurrence-free survival rates at 5 years and 10 years were 84% and 76%, respectively, and the projected overall survival rates at 5 years and 10 years were 96% and 91%, respectively [25, 26], contradicting the speculations that GnRH agonists may decrease the effect of chemotherapy on malignant cells [81]. In the study by Del Mastro et al. [27], menses resumption was observed in 16 of 17 patients (94%) <40 years of age and in five of 12 patients (42%) >40 years old. Those authors concluded that goserelin given before and during chemotherapy may prevent premature menopause in the majority of patients. These results [25–27] corroborate the findings of other studies in breast cancer patients, showing that the activity of GnRH agonists in preventing early menopause is in the range of 86%–100% [25–29]. Using cyclophosphamide, epirubicin, and fluorouracil regimens like that used in the study of Del Mastro et al. [27], the expected rate of menstrual activity resumption is nearly 40% in the overall group of premenopausal patients, 64% in patients <40 years old, and 30% in those aged 
40. These studies [25–29] suggest a significant improvement in the preservation of ovarian function by the use of GnRH agonists in keeping with our studies in hematologic malignancies [1,4, 7, 10,11,14,16–19, 49]. Sonmezer and Oktay [81] claim that they do not accept the published studies on GnRH agonist cotreatment because they do not include a prospective, randomized, control group. Their studies on IVF and those on ovarian cryopreservation did not either. Sonmezer and Oktay [81] erroneously cite a study by Waxman et al. [82] from 1987 as proof of negative results, although it was conducted mainly in men, whereas we clearly pointed out that GnRH agonists are effective only in women and ineffective in men [1,4, 7, 10,11,14,16–19, 49]. Waxman et al. [82] treated only eight women (and 20 men) with buserelin. There was not enough power to show a difference between the GnRH agonist–treated group of women (4 of 8 patients with POF) and the controls (6 of 9 with POF) [82]. Furthermore, in a later publication [83], Waxman himself refers to his previous study, suggesting that the used analogue might have been inappropriate: "Unfortunately, a randomized trial has shown no protection, but the wrong analogue regimen may have been used."
Most recently, Burns et al. [84] have found that parents and female adolescents are interested in options to help preserve fertility during cancer treatment, but they are not willing to postpone treatment for this purpose. For those patients who refuse postponement for IVF [84], a GnRH agonist may be an alternative option. Failure to offer this option may be considered as a possible conflict of interest for those commercial centers that are interested in the income from IVF.
Because most of the methods involving ovarian or egg cryopreservation are not yet clinically established and successful, one should be very careful to provide these young patients with all the information concerning the various modalities to minimize gonadal damage and preserve ovarian activity and future fertility [49]. Furthermore, combining the various modalities for a specific patient may increase the odds of preservation of future fertility. There is no contraindication to ovarian biopsy for cryopreservation combined with GnRH agonist administration and follicular aspiration for IVF and embryo freezing where the patient has a spouse/partner. In cases where the chemotherapy has caused POF, as is frequently the case in total body irradiation and bone marrow transplantation, the patient has cryopreserved primordial follicles and/or frozen embryos to fall back upon. However, in cases where conventional chemotherapy regimens such as those commonly used for young lymphoma patients are applied, GnRH agonist cotreatment may preserve ovarian function without necessitating the use of cryopreserved ova or embryos.
Future investigation is needed to address the safety and efficacy of oocytes, follicles, or ovary cryopreservation, and the most efficient way of using the cryopreserved, thawed tissue. The results of multicenter, prospective, randomized studies are awaited to substantiate the in vivo ef-fect of GnRH agonists as an unequivocal means for minimizing follicular apoptosis.
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ADDENDUM |
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