Study Raises Further Questions on the Effectiveness of GnRH Analogs as a Method of Gonadal Protection in Cancer Patients

1 06 2009

To the Editor:

While we read the recent manuscript from Badawy et al. (1) with great interest, we have concerns about their interpretation that GnRH analogs (GnRHa) preserve fertility.

Randomization does not guarantee similarity among groups. Authors did not specify the cycle day on which the hormone levels were drawn and both E2 and P4 were different between groups at baseline (authors stated in the results that E2 was higher in the GnRHa + chemo group, but the table shows the opposite).  Interestingly, both baseline E2 and P4 levels were elevated, indicating that all patients were in luteal phase, which is improbable if the patients were randomly selected.  Thus lower FSH levels in the GnRHa treated group does not indicate better ovarian reserve because higher E2 levels in that group would have spuriously suppressed FSH levels. If these levels were drawn on cycle day 2 or 3, then E2 levels > 75 pg/mL would have indicated diminished reserve in both groups (2). Further, even though the authors stated that ultrasounds were done on “married” patients, antral follicle counts were not reported.

The percentage of patients who were estrogen receptor-positive and used tamoxifen in each group was not mentioned. Tamoxifen is an ovarian stimulant and raises both estrogen and progesterone levels significantly. It can also cause ovarian cysts and even amenorrhea in women with normal function, when in long-term use (3).

We are also concerned with extremely high incidence of amenorrhea in the control group. Despite the authors’ claim, the incidence of amnorrhea after cyclophosphamide-based treatments for women under age 40 has been consistently <30% (4). It is also unclear whether the follow up was up to 8 months from the beginning or completion of chemotherapy. In either case, considering the fact that resumption of menses can take 6-12 months due to the speed of follicle growth from primordial follicles, the follow-up was too short. In fact authors did not provide a mean follow length or controlled for differences in follow-up. What is most concerning to us is that the authors’ claim that GnRHa is an effective method of fertility preservation when fertility was not even investigated.

It is no surprise that a recent prospective randomized study in women with breast cancer proved this strategy to be ineffective (5). In that study, the data were controlled for  age, receptor status, and treatment type. There was no difference in the percentage of patients menstruating 6, 12, and 18 months after chemotherapy in GnRHa vs. controls (44% vs. 60%; 83% vs. 79%; and 88% vs. 84%, respectively). The trial was terminated at 18 months due to the ineffectiveness of GnRHa.  Furthermore, FSH levels in patients in whom menstruation has returned was not significantly different in the GnRHa versus the control arm, and two spontaneous pregnancies occurred in the control group.

In conclusion, the study by Badawy et al. appears to have significant methodological weaknesses and cannot be used as an evidence for the effectiveness of ovarian suppression for fertility preservation.

Kutluk Oktay, M.D.a,b
Murat Sönmezer, M.D.c,d
aDivision of Reproductive Medicine & Infertility Department of Obstetrics & Gynecology
New York Medical College
Valhalla, NY
bInstitute for Fertility Preservation
New York, NY
cAnkara University School of Medicine
Ankara, Turkey
dDepartment of Obstetics and Gynecology
University Center for Research on Human Reproduction
Ankara, Turkey

1. Badawy A, Elnashar A, El-Ashry M et al. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril 2009;91:694-7.

2. Scott RT, Toner JP, Muasher SJ et al. Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil Steril 1989;51:651–4.

3. Shushan A, Peretz T and Mor-Yosef S. Therapeutic approach to ovarian cysts in tamoxifen-treated women with breast cancer. Int J Gynaecol Obstet 1996; 52:249–53.

4. Sonmezer M, Oktay K. Fertility preservation in young women undergoing breast cancer therapy.  Oncologist 2006;11:422-34.

5. Ismail-Khan R, Minton S, Cox C et al. Preservation of ovarian function in young women treated with neoadjuvant chemotherapy for breast cancer: A randomized trial using the GnRH agonist (triptorelin) during chemotherapy. J Clin Oncol 2008;26:15S

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.06.004

To the Editor:

We read with interest the paper by Badawy et al (1), reporting the beneficial effect of Goserelin for the prevention of chemotherapy induced amenorrhea and ovarian failure and in young breast cancer patients undergoing cytotoxic treatment.

Even if we acknowledge the study design and the stringent criteria used for the evaluation of ovarian function recovery after chemotherapy, we have some concerns that we would like to share  with the authors and the readers.

The average age of the study group and the control group is quite low (30 + 3.51 and 29.2 + 2.93 years, respectively) compared to the usual breast cancer population seeking advice for fertility preservation in Europe and United States. This may well be due to the different epidemiology of breast cancer in Egypt, but it is striking that in such a young population, the incidence of amenorrhea, anovulatory cycles and premature ovarian failure (POF) after fluorouracil, doxorubicin and cyclophosfamide chemotherapy (FAC) is so high in the control group (77%, 75% and 66%, respectively). Definition of POF was not mentioned in this article but data from other groups report a much lower incidence of amenorrhea (less than 30%) even for the more gonadotoxic classic cyclophosphamide, methotrexate, fluorouracil chemotherapy (CMF), in an older patient population (2). The results reported in this article may be related to the acute temporary effect of the chemotherapy. The study reports outcome at 8 months from chemotherapy initiation, i.e. 2 months after chemotherapy end  (Figure 1 and Table 2), but in the text it is stated that FSH and LH concentrations were significantly different 6 months after completion of GnRHa/chemotherapy cotreatment (1). This is a crucial detail that should be clarified, as the effect of GnRHa might well be temporary and irrelevant for a subsequent pregnancy if it is limited to the first few months after chemotherapy. GnRHa cotreatment during chemotherapy should increase the probability of achieving a pregnancy after cancer treatment and most guidelines suggest to wait at least 2 years from diagnosis or treatment end before seeking a pregnancy, to reduce the potential chemotherapy toxicity on the conceptus and to allow a sustained disease free period before conception (3).

The authors report in the discussion that the hypogonadotropic milieu decreases the number of primordial follicle entering the differentiation phase, more vulnerable to chemotherapy. The effect of gonadotoxic chemotherapy on the different cellular components of the ovary has been studied in animal and human models (4). Even if data are not completely conclusive, it is quite accepted that GnRH receptors are not present on the primordial follicles, and that GnRH has limited role in primordial follicle recruitment (5). So different explanation should be postulated.

The paper by Badawy et al should be commended for being the first randomized study on GnRHa administration in young breast cancer patients. Nonetheless we believe that it is still too early to say GnRHa cotreatment should be considered in every woman in the reproductive age receiving chemotherapy. Results from the other ongoing randomized studies in breast or lymphoma patients are still eagerly awaited. 

Fedro Peccatori, M.D., Ph.D.a
Isabelle Demeestere, M.D., Ph.D.b
aDepartment of Medicine
European Institute of Oncology
Milan, Italy
bResearch Laboratory on Human Reproduction
Université Libre de Bruxelles (ULB)
Brussels, Belgium

1. Badawy A, Elnashar A, El-Ashry M, Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril 2009; 91:694-7.

2. International Breast Cancer Study Group (IBCSG), Castiglione-Gertsch M, O’Neill A, Price KN, Goldhirsch A, Coates AS, Colleoni M, Nasi ML, Bonetti M, Gelber RD. Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: a randomized trial.J Natl Cancer Inst 2003; 95(24):1833-46.

3. Peccatori F, Cinieri S, Orlando L, Bellettini G. Subsequent pregnancy after breast cancer.Recent Results Cancer Res. 2008;178:57-67.

4. Meirow D, Dor J, Kaufman B, Shrim A, Rabinovici J, Schiff E, Raanani H, Levron J, Fridman E Cortical fibrosis and blood-vessels damage in human ovaries exposed to chemotherapy. Potential mechanisms of ovarian injury. Hum Reprod. 2007;22(6):1626-33

5. Oktay K, Sönmezer M.Gonadotropin-releasing hormone analogs in fertility preservation-lack of biological basis? Nat Clin Pract Endocrinol Metab. 2008;4(9):488-9.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.06.002

The Authors Respond:

I would like to thank Drs. Oktay and Sonmezer for their comments.

By fertility preservation in this trial we meant preservation of the ovarian function, as the gonadotoxicity is the investigated side effect of chemotherapy. They should be aware of the difficulty in recruiting this number of young patients with breast cancer. However, the pretreatment absolute difference in E2 is not expected to affect the subsequent outcome of therapy. Serum FSH and LH were done on day 3 of the cycle, while serum P was estimated on day 21-23 of cycle. Serum E2 was done at different times of the cycle to be sure that it exceeded 50 pg/ml. As we mentioned in the manuscript, follow-up of the patients continued for 8 months after the last dose of chemotherapy (as shown in Table 2). Figure 1 showed the hormonal profile only in the first 3 months after GnRH-a injections were stopped, rather than the 8 months of follow-up. There was no need to show the steady hormonal level after it was normalized. The study proved beyond any doubt the beneficial effect of GnRH-a for preserving ovarian function in breast cancer patients undergoing chemotherapy.

I would also like to thank Drs. Pecatorri and Demeestere for their interest in our study.

The age incidence of breast cancer in young patients in Egypt, which they mentioned, is definitely lower in comparison with European or American populations. We defined POF in this study as absence of previously regular menstruation with serum FSH > 40 mIU/ml. Again, follow-up of the patients continued for 8 months after the last dose of chemotherapy. We did not promote the idea of direct action of GnRH-a on the follicles, but we believe in their indirect effect through lowering the serum FSH and LH.

We still believe that Goserline 3.6 mg injections (or similar analogues) are a simple and effective method for fertility preservation in young cancer patients. All other available techniques are sophisticated and difficult to apply to all patients, either due to their costs, timeframe before cancer therapy, social status of the patients. or their low efficacy.

Ahmed Badawy, M.Sc., M.D., M.R.C.O.G., Ph.D.
Department of Obstetrics and Gynecology
Mansoura University
Mansoura, Egypt

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2009.06.003




One response

18 06 2009
Zeev Blumenfeld

Dr Badawy and his colleagues should be congratulated for their fine results. The readers and especially the opponents to this fine study should be aware that there is an additional recent propective randomized study, from Karolinska Institute, with similar findings, supporting the beneficial effect of GnRH-a for fertility preservation (1). Moreover, a recent meta-analysis (2) has found that: “The use of a GnRHa during chemotherapy was associated with a 68% increase in the rate of preserved ovarian function compared with women not receiving a GnRHa (summary RR=1.68; 95% CI 1.34-2.1). Among the GnRHa-treated women, 22% achieved pregnancy following treatment compared with 14% of women without GnRHa therapy (summary RR=1.65; CI 1.03–2.6).” These investigators have concluded that: “…premenopausal women facing chemotherapy should be counseled about ovarian preservation options, including the use of GnRHa therapy.”

The cited study by Ismail et al (3) cannot be evaluated since it has not been published yet as a peer-reviewed manuscript, although it has been presented as an abstract a year ago…

Finally, Pecatorri and Demeestere claim, in their letter, that the POF in the range of 66% in young patients in the 30s is exceptional and not in keeping with other published studies. With all due respect, we disagree; the manuscript by Mattle et al (4), and several others, cite over 60% POF after 6 cycles of CMF in 30-34-year-old breast cancer patients, and 70-80% POF in 35-39-year-old similarly treated patients.

Therefore, we support the conclusion by Bedawy et al, in keeping with the recent metaanalysis (2), and our reviews (5,6), that GnRH-a should be offered to young women facing gonadotoxic chemotherapy, in addition, and in parallel to IVF, embryo, ova, and ovarian tissue cryopreservation. The added value of the GnRH-a is the prevention of thrombocytopenia associated menorrhagia and anemia (5,6).

1. Sverrisdottir A, Nystedt M, Johansson H, Fornander T.
Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial. Breast Cancer Res Treat. 2009 Jan 20. [Epub ahead of print]

2.Clowse ME, Behera MA, Anders CK, et al. (2009)Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis. J Womens Health (Larchmt) 18:311-9.

3.Ismail-Khan R, Minton S, Cox C et al. Preservation of ovarian function in young women treated with neoadjuvant chemotherapy for breast cancer: A randomized trial using the GnRH agonist (triptorelin) during chemotherapy. J Clin Oncol 2008;26:15S [abstarct]

4. Mattle V, Behringer K, Engert A, Wildt L. Female fertility after cytotoxic therapy–protection of ovarian function during chemotherapy of malignant and non-malignant diseases. Eur J Haematol Suppl. 2005;66:77-82. Review.

5. Blumenfeld Z, von Wolff M. GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy. Hum Reprod Update. 2008;14:543-52. Epub 2008 Sep 29. Review.

6. Blumenfeld Z. GnRH-agonists in fertility preservation. Curr Opin Endocrinol Diabetes Obes. 2008;15:523-8. Review.

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