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Breast Cancer |
aDepartment of Obstetrics and Gynecology, Joan and Sanford I. Weill Medical College of Cornell University, New York, New York, USA; bDepartment of Obstetrics and Gynecology, Ankara University School of Medicine, Ankara, Turkey; cRena Rowan Breast Center, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA; dDepartment of Obstetrics & Gynecology, University of Göttingen, Göttingen, Germany; eDivision of Biostatistics and Epidemiology, Department of Public Health, Weill Medical College of Cornell University, New York, New York, USA
Key Words. Chemotherapy • GnRH analogues • Ovarian damage
Correspondence: Kutluk Oktay, M.D., Department of Obstetrics and Gynecology, Joan and Sanford I. Weill Medical College of Cornell University, 505 East 70th Street, HT-340, New York, New York 10021, USA. Telephone: 212-746-4292; Fax: 212-746-5929; e-mail: Koktay{at}fertilitypreservation.org
Received January 16, 2007; 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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ABSTRACT |
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INTRODUCTION |
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TopAbstractIntroductionBiological Plausibility for...Lack of Randomized Controlled...GnRH Analogues Do Not...The Safety of Administering...Ethical Responsibilities Toward...References |
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For the reasons that are discussed below, we do not believe that these conditions have been met for GnRH analogue treatment to be recommended for preservation of fertility in women undergoing chemotherapy or radiotherapy.
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BIOLOGICAL PLAUSIBILITY FOR GONADAL PROTECTION BY GNRH ANALOGUES IS LACKING |
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It has previously been misquoted that gonadotropin receptor mRNA is expressed in various stages of oocytes [3, 12]. In the study of Patsoula et al. [12], only mature oocytes that failed to fertilize with intracytoplasmic sperm injection were used in addition to embryos of various stages. If GnRH analogues were protective, oocytes of primordial follicles should express FSH receptors (FSHRs), but FSHRs have repeatedly been shown to be absent from these follicles [7, 13]. Moreover, gene expression does not necessarily imply that transcripts are translated in the protein or that these receptors are functionally involved in signal transduction. In the Patsoula et al. [12] study, reverse transcription-polymerase chain reaction (RT-PCR) products for the FSHR and LH receptor (LHR) in humans arose from the extracellular portion of the receptors, which has been shown to appear earlier than the transcripts for the full-length receptor protein [14, 15]. The presence of mRNA does not mean that functional receptors are expressed on cells, and does not prove a "physiological" role. In the study of Zheng et al. [16], which focused on FSH mRNA expression in tubal epithelium, only a weak focal mRNA signal was seen by in situ hybridization in primordial follicles, and the data were not shown. When using in situ hybridization, because of the minute size and flattened shape of primordial pregranulosa cells, it is technically challenging to distinguish background signals from signals in primordial follicles. By RT-PCR, we did not detect FSHR mRNA in isolated human primordial follicles [7]. Moreover, human ovarian follicles continue to initiate growth when xenografted in hypogonadal-immunodeficient mice [13], or in patients with FSHR mutation [9]. There has been no evidence for the presence of FSHR protein in primordial follicles. Primordial follicles continue to initiate growth through hypogonadal states such as prepuberty, pregnancy, and the use of oral contraception, and ovarian suppression by oral contraceptives does not prevent chemotherapy-induced gonadal damage [17]. As the authors of the study pointed out, increased depletion of primordial follicles in LH-overexpressing mutant mice does not indicate a direct effect of LH [18]. In fact, in that study, the authors showed a reduction and not an increase in the fraction of follicles entering the growth pool (primary), and concluded that the effect of LH was indirect, and that their data did not prove that primordial follicles were gonadotropin responsive. As was discussed in that report, LHRs have never been detected in primordial or early preantral follicles, and the authors explained the loss of primordial follicles by the toxic effects of the local endocrine milieu stimulated by supraphysiologically high LH stimulation on stromal cells.
Moreover, as discussed below, because GnRH creates a hormonal milieu similar to the prepubertal state and because prepubertal children are not protected against the gonadal-damaging effects of chemotherapy, hypogonadism cannot be a means to preserve fertility.
Furthermore, GnRH analogue treatment is clearly ineffective in the setting of preconditioning chemotherapy for hematopoietic stem cell transplantation (HSCT). If GnRH analogues were truly protective by means other than hypogonadism, such as inhibition of apoptotic death, one would expect them to be protective against high-dose chemotherapy and radiation as well. For example, the antiapoptotic agent sphingosine-1-phosphate (S1P) blocks oocyte death against chemotherapy and radiation in mice [19, 20]. From the same logic, and considering that similar types of agents are toxic to the testis and ovary, that the testis is mitotically much more active than the ovary, and that germ cell production is more acutely dependent on FSH in the testis, the ineffectiveness of GnRH analogues in the testis can hardly be consistent with the claims that the same agents would protect the ovary against chemotherapy [11, 20].
Likewise, the claims that GnRH analogues may protect ovarian reserve by reducing blood flow are not supported by scientific evidence. Furthermore if GnRH analogues were to cause reduced blood flow to the ovary, one would expect this to happen with other organ systems, and even with the tumor, resulting in an overall lower effectiveness and organ toxicity of the drug.
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LACK OF RANDOMIZED CONTROLLED TRIALS |
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). In two recent studies, Recchia et al. [21] and Del Mastro et al. [22] made valuable contributions on this topic. In the first study, Recchia and colleagues demonstrated that gonadal function was protected in all breast cancer patients receiving cyclophosphamide-based chemotherapy under the age of 40 years, and in 56% of those aged >40 years. All of the 100 patients, almost 50% of whom were negative for estrogen receptors, were cotreated with a GnRH analogue for 2 years. The cumulative dose of cyclophosphamide ranged between 3,600 and 7,200 mg/m2 and the mean follow-up was 75 months. The authors hypothesized that the GnRH analogue could preserve ovarian function against chemotherapy-induced gonadal damage by putting cells of the ovarian epithelium in G0. Moreover, they surmised that the administration of a GnRH analogue did not affect prognosis, because the projected recurrence-free survival rates were 84% and 76% at 5 and 10 years, and the projected overall survival rates were 96% and 91% at 5 years and 10 years, respectively.
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Schmidt et al. [26] evaluated ovarian function postchemotherapy in 22 cancer patients using ovarian reserve tests, including day-3 FSH, estradiol, and inhibin B levels, in addition to the assessment of menstrual pattern. GnRH analogues were not used during the courses of chemotherapy. When only menstrual cycle was considered, none of the eight breast cancer patients receiving cyclophosphamide, epirubicin, and fluorouracil (CEF) for six to eight cycles (n = 6; total cumulative cyclophosphamide dose, 3,600–4,800 mg/m2), cyclophosphamide, methotrexate, and fluorouracil (CMF) for three cycles plus 330 mg doxorubicin (n = 1; total cumulative cyclophosphamide dose, 1,800 mg/m2), or CEF for three cycles plus CMF and doxorubicin (n = 1; total cumulative cyclophosphamide dose, 1,800 mg/m2 + 4.4 g) experienced ovarian failure during a follow-up that ranged between 21 and 45 months. However, despite resumption of menstruation, three breast cancer patients had irregular menstrual cycles and five had undetectable inhibin-B levels or FSH values >50 IU/ml, suggesting impairment in ovarian reserve. The age of breast cancer patients ranged between 27 and 36, while the cumulative dose of cyclophosphamide ranged between 3,000 and 8,000 mg. The authors claimed that the cumulative dose of cyclophosphamide that was used in that study was not adequate to cause complete ovarian failure in that group of young breast cancer patients. However, in the same study, all of the five patients with leukemia and two with Hodgkin's disease undergoing HSCT, and one receiving high-dose chemotherapy with alkylating agents for Hodgkin's disease, had premature ovarian failure (POF) after completion of chemotherapy. Their ages ranged between 21 and 26.
It is known that anti-Müllerian hormone (AMH) is expressed by granulosa cells [27, 28]; its expression is initiated in the smallest growing follicles and declines in the early antral stages as one follicle is selected for dominance and the rest of them become atretic. An important finding from a very recent study was that, compared with estradiol and FSH, AMH showed a more rapid and sustained change after chemotherapy [29]. Moreover, the decrease in AMH occurred without a significant decrease in inhibin-B or increase in FSH concentrations. The authors concluded that the severity and rapidity of the fall in AMH concentrations compared with the partial decline in inhibin-B concentrations might reflect primordial and preantral follicles as the primary site of toxicity. This supports the observation that, even though there may be no clinical signs of ovarian failure, there is always damage to follicular reserve in proportion to the cumulative dose of exposed chemotherapeutic agents that might not be detectable with routinely used laboratory tests. Our recent findings are also in agreement with those of Anderson et al. [30].
Del Mastro and colleagues investigated the role of GnRH analogues to preserve fertility in 29 breast cancer patients receiving CEF for six cycles [22]. All except one patient received CEF for six cycles; the cumulative dose of cyclophosphamide was 3,600 mg/m2. The treatment was defined as successful if menstrual activity returned within 12 months after the last cycle of chemotherapy, or if an FSH level was <40 IU/l between 3 and 12 months postchemotherapy. Based on that definition, the overall success rate was 97%, but there was no control group. Of the 17 patients under 40 years of age, 16 regained menstrual activity (94%), whereas only five patients aged >40 years resumed menstruation postchemotherapy (42%), but it was not specified whether their periods were regular. Up to 97% of the patients suffered from GnRH analogue–related side effects, including hot flushes, headaches, mood changes, and sweating. Unfortunately, the follow-up was too short to assess the impact on fertility. Moreover, fertility is impaired when FSH levels exceed 12 IU/ml, a much lower value than used by the authors [24]. Furthermore, the estradiol levels were also elevated in the patients reported by Del Mastro et al. [22]; baseline estradiol >75 pg/ml is also associated with poor reproductive outcome regardless of FSH level [25]. The latter is a result of the accelerated follicle development induced by the rising baseline FSH levels [31]. Of the 25 patients in whom FSH was measured, 21 had a value <40 IU/l; it would be interesting to know whether they were <12 IU/l. Moreover, as an ovarian stimulant, tamoxifen raises estrogen levels that in turn would spuriously lower FSH levels because of negative feedback. Of the patients with menstrual resumption, one had an FSH value >40 IU/l, and three had an estradiol level <20 pg/ml; both are consistent with ovarian failure. Unreliability of menstruation as a marker of fertility is apparent from the authors' data, where FSH levels well above the menopausal range (up to 59.9 mIU/ml) were found in some patients who continued to menstruate. The authors did not specify whether the pattern of menstruation was similar to the prechemotherapy period; many perimenopausal women continue to menstruate at regular intervals. In their discussion, the authors stated that they could not rule out that age itself, rather than GnRH analogue treatment, is the main determinant of ovarian function preservation.
Somers et al. [32] evaluated the protective role of GnRH analogues in 20 systemic lupus erythematosus patients receiving monthly i.v. bolus cyclophosphamide, and compared them with a historical group of patients matched for age and cumulative cyclophosphamide dose. At a minimum follow-up of 3 years, ovarian failure developed in 1 of 20 GnRH analogue–treated patients (5%), compared with 6 of 20 controls (30%). There were several limitations to the study. The treatments were not randomized, and the study was not designed to assess preservation of ovarian function, as the authors pointed out. In any observational study, including this one, the comparability or homogeneity of comparison groups (via control group selection) in terms of various population characteristics should be preserved as much as possible in the absence of randomization. However, we noted that the control group and study group were not matched for menstrual status and hormonal profile prior to chemotherapy at study entry, among other conditions that could be potentially important. Furthermore, control patients were retrospectively selected from a group of patients who accrued significantly longer follow-up (evidenced by total person-years of 186.9 versus 100.2 or other summary measures such as median or maximum) that may contribute to considerable imbalance and consequently unfair comparison. Even though the authors attempted to mitigate this by using time-to-event analysis and by only including patients with at least 3 years of follow-up, we do not feel that these strategies are of much help or a correct remedy. For example, it was not clear how many patients had irregular menstrual periods or elevated FSH levels (>12 IU/l) at follow-up, and the definition of "normal ovarian function," that is, "lack of amenorrhea of at least 12 months and an FSH level <40 mIU/ml," could not be used to assess fertility. Despite age matching, disease duration was longer in the control group than in the study patients (mean ± standard deviation, 5.1 ± 1.5 years versus 3.6 ± 1.2 years), and as the authors acknowledged, the control patients tended to be more severely ill, all of which might have contributed to the higher ovarian failure rates in the control group. Furthermore, the patients received add-back estrogen treatment with i.m. progesterone, making the menstrual assessment unreliable. There were statistical weaknesses as well; the survival analysis tools beyond the Kaplan–Meier method should have considered or been accompanied by an attempt to adjust some prognostic factors that were differentially distributed between the two cohorts. Moreover, it was not known how many patients attempted pregnancy in either group, making it impossible to compare pregnancy rates. As such, much more information should have been ascertained and properly reported from study patients. In addition to the selection bias problem, another major methodological weakness of the study is the statistical power. Our own calculation shows that the given study provides approximately 40% power to detect the difference in the event rates observed. Let alone this post hoc assessment, it is hard to make a clinical or statistical argument from a study with only one event in one group. It is important to note that the number of events, not necessarily the number of the total sample, governs the power (equivalent, type II error) in the analysis of time-to-event data. This is indeed a fact that is quite intuitive, but that many practitioners and researchers often overlook in designing and operating their studies, although we fully understand that small samples in similar circumstances are difficult to overcome. Any covariate adjustment suggested above may not be feasible solely because of the extremely low number of events. These statistical pitfalls (especially, power and selection by indication in any nonrandomized studies) are relevant to virtually all of the biomedical studies generated by quantitative hypotheses, including our own.
In a case series including 12 patients aged 14.7–20 years (group B), Pereyra Pacheco et al. [33] addressed the effectiveness of GnRH analogues in fertility preservation. Control groups included five premenarchal children aged 3–7.5 years (group A) and four postmenarchal patients aged 15.9–20 years (group C). While the treatment group was followed up prospectively, control patients were chosen retrospectively. Moreover, the length of follow-up was clearly different among the groups: 18 years in group A, 5 years in group B, and 6 years in group C. Although three patients conceived during follow-up in group A, two to five patients had oligomenorrhea, which should have been considered as a clinical sign of diminished ovarian reserve. With group A, the authors argued that prepubertal children were protected from the gonadal effects of cancer treatments, in support of the benefit of GnRH analogue–induced hypogonadism in postpubertal individuals. Not only were the size and design of the study insufficient to reach such a conclusion, but a recent, large, prospective study showed that, when exposed to chemotherapy during childhood, the risk for POF is over 13-fold higher than in controls [34]. The preliminary report by Pereyra Pacheco et al. [33] was exploratory in nature, and no formal statistical analysis was attempted.
In the only prospective, randomized study, reported by Waxman et al. [11], albeit with small numbers, including 31 men and 18 women receiving chemotherapy for Hodgkin's disease, GnRH analogues did not preserve fertility, as judged by sperm count and menstrual function. This was a well-designed study in which all patients underwent complete endocrine evaluation and GnRH stimulation tests before, during, and after chemotherapy. By performing GnRH stimulation tests, the authors determined the amount of ovarian suppression in each patient. They found that estradiol levels were consistently low in both men and women, but gonadotropin levels were more significantly suppressed in men than in women. Based on these observations, the authors pointed out that it is not realistic to expect GnRH analogues to result in complete suppression in women undergoing chemotherapy with the current doses used. Nevertheless, after 3 years of follow-up, all men in both the study (who used 0.6 or 1 mg buserelin/day) and control groups became oligo/azospermic, while four of the eight women treated with a GnRH analogue at a dose of 0.6 mg/day (50%) and six of nine female controls (66.6%) became amenorrheic. The authors concluded that GnRH analogues cannot offer gonadal protection in men or women at the clinically acceptable doses.
Some have cited a monkey study in support of the effectiveness of GnRH analogues, in which only three primates were investigated in each of the cyclophosphamide and cyclophosphamide plus GnRH analogue groups [35]. However, one animal in the cyclophosphamide group died prematurely, reducing the size of the treatment group to two. In contrast, a larger, rodent study did not show a benefit of ovarian suppression [36]. Furthermore, that study did not look at the fecundity rates in these animals, and as shown previously, histological analysis is not sufficient to detect ultrastructural defects induced by chemotherapy in primordial follicles [37].
In another study by Dann et al. [38], the fertility impact of an alternative cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) protocol (mega-CHOP) in 13 patients with non-Hodgkin's lymphoma on the risk for ovarian damage was studied. In that protocol, extremely high doses of cyclophosphamide consistent with the doses used in HSCT (range, 8,000–12,000 mg) were used with a modified time schedule and dose intensity. A similar proportion of patients developed ovarian failure in the GnRH analogue and non–GnRH analogue groups (zero of seven versus one of six) during a median follow-up of 70 months, but no statistical analysis was performed. All patients were 
31 years of age, with the exception of a 40 year-old woman who developed POF. The authors' conclusion was that this mega-dose CHOP regimen resulted in a low incidence of POF regardless of GnRH analogue administration. Interestingly, in a more recent study by the same group, no differences were found between those who received hormonal suppression (the birth control pill or a GnRH analogue) and those who did not during chemotherapy with standard doses for non-Hodgkin's lymphoma [39]. This time, the authors' conclusion was that fertility preservation techniques were not needed for patients <40 years old. It thus appears that there is hardly a group of patients who might benefit from ovarian suppression.
In summary, most of the previous studies used control groups that were retrospectively selected from historical patients treated with similar regimens [40–42]. In some studies, the mean follow-up was longer in the control group than in the study group [43], and it was not clear from the study design whether cumulative doses of cyclophosphamide were similar between the treated and untreated patients [40–42, 44]. Similar concerns have also been raised by other authors previously [4].
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GNRH ANALOGUES DO NOT PRESERVE GONADAL FUNCTION IN PATIENTS UNDERGOING HSCT |
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Finally, a recent study by Sklar et al. [34] clearly showed that children who receive chemotherapy are at an extremely high risk for POF. In that study, the authors followed a cohort of children who were diagnosed with a malignancy before the age of 21 and were menstruating for at least 5 years afterward. They compared 2,819 girls with these characteristics with their 1,065 siblings. The median age at diagnosis was 7 (range, 0–20) and the median age at study was 29 (range, 18–50). They found that those who received chemotherapy by age 21 had a 13.2 (range, 3.26–53.51) times higher likelihood of POF than their siblings.
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THE SAFETY OF ADMINISTERING GNRH ANALOGUES DURING CHEMOTHERAPY IS NOT ESTABLISHED |
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There is a biologically plausible explanation for Dr. Fox's findings. Because the developing follicles, but not the resting ones, are FSH sensitive [7], GnRH analogue treatment would halt the growth of those developing follicles. In the short term, protection of these growing follicles with a resultant resumption of menstrual function postchemotherapy, especially in young patients with a large ovarian reserve, might erroneously give the impression that ovarian function is preserved. Because those follicles have many mitotic granulosa cells and premeitoic oocytes, which would be amenable to residual DNA damage from chemotherapy, they are likely to result in abnormal conceptions [54, 55]. Because ovarian follicle development can take up to 6 months from the resting stage, it is expected that these women will begin menstruation upon discontinuation of GnRH analogues, as the damaged follicles resume their growth and are eventually cleared from the ovary. In support of our hypothesis, Familiari et al. [37] showed that, even though hormonal suppression with medroxyprogesterone acetate appeared to have protected against the acute follicle loss, these follicles were abnormal in ultrastructural analyses and were eventually lost, resulting in early ovarian failure. Thus, it is possible that GnRH analogues may be delaying the inevitable fate, the death of already damaged follicles, by slowing their growth. Moreover, we have histologically shown that, in two age-matched cancer patients, one of whom received gonadotoxic chemotherapy in parallel with a GnRH analogue and the other who did not, primordial follicle density was significantly diminished despite GnRH analogue administration (Fig. 3A and B).
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It was previously claimed that there is potentially no harm in giving GnRH analogues to cancer patients [3]. Not only are GnRH analogues expensive and they cause severe menopausal symptoms, but, in addition, the direct effects of GnRH agonists on human cancer cells are not sufficiently understood. A variety of human cancers, including those of the breast, ovary, and endometrium, express GnRH receptors. These receptors mediate several effects, such as inhibition of proliferation, induction of cell-cycle arrest, and inhibition of apoptosis, induced, for example, by cytotoxic drugs [60]. Thus, it cannot be excluded that GnRH agonist therapy concomitant with cytotoxic chemotherapy might reduce the efficacy of chemotherapy for breast cancer. In addition, for the adjuvant treatment of hormone-responsive breast cancer, a sequence of chemotherapy followed by endocrine manipulation is generally recommended, because concomitant chemoendocrine therapy might lead to inferior results [61]. Therefore, at least for breast cancer patients, it is advisable to investigate the protective effect of GnRH analogues on the ovary in the context of a well-designed, prospective, clinical trial and to limit the concomitant use of GnRH agonists with adjuvant chemotherapy for those patients in whom no negative interaction between the two treatment modalities has to be considered, that is, patients with estrogen receptor– and progesterone receptor–negative tumors.
Direct effects of GnRH analogues on human ovaries are also not clearly understood. It is generally accepted that human granulosa cells, normal ovarian surface epithelial cells, and human ovarian cancer cells express GnRH receptors, which mediate antigonadotropic, antiproliferative, and antiapoptotic effects [60, 62]. In addition, however, proapoptotic effects of GnRH analogues on human granulosa lutein cells and cancer cells have been demonstrated [62]. Nevertheless, there is no evidence that GnRH receptors are expressed in primordial follicles.
A recent study postulated acute depletion of the murine primordial follicle reserve by GnRH antagonists [63], while in human granulosa lutein cells, a GnRH antagonist increased DNA synthesis and blocked the proapoptotic effect of a GnRH agonist [64]. These and a number of additional controversial findings of GnRH analogue effects on human ovaries make it advisable to test these compounds for use in ovarian protection in carefully designed clinical trials.
Another theoretical concern is increased gonadotoxicity. Gonadotropins induce a series of antioxidant enzymes called glutathione S-transferases [65]. These enzymes are present in granulosa cells of follicles of various stages in the ovary [66] and play a role in detoxifying chemotherapeutics [67]. Ovarian suppression can reduce the expression of these enzymes, in theory rendering follicles more vulnerable to the effects of chemotherapy. Moreover, if GnRH analogues protect the ovaries via the S1P route, as has been hypothesized by some authors, this would then raise the possibility that they can also prevent cancer cell death by host immune defense as well as chemotherapy [3, 68, 69].
On a more practical level, up to 97% of patients suffer from hypoestrogenic symptoms when using a GnRH analogue along with chemotherapy [22]. Furthermore, when used for >4 months, patients may experience bone loss, which may not be reversible with longer durations of use [70].
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ETHICAL RESPONSIBILITIES TOWARD PATIENTS WHEN OFFERING UNPROVEN METHODS |
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REFERENCES |
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