Fertility preservation and GnRHa for chemotherapy: debate

Dear editor

I have read with interest the review by Rodriguez-Wallberg and Oktay.¹ Although I agree with most of the written opinions for fertility preservation, an important point needs to be raised for the sake of complete and thorough information regarding such a crucial matter.

The authors claim that “Experimental data from prepubertal and adult mouse models treated with cyclophosphamide do not support the notion that a prepubertal stage would be protective for the primordial follicles”, citing their own abstract² which is not indexed in PubMed and cannot be evaluated. More importantly, they failed to mention several other peer review references^3–6 concluding just the opposite, that gonadotropin-releasing hormone (GnRH) agonists are effective in minimizing chemotherapy induced gonadotoxicity in rodents and in humans: “This study has showed a dose-dependent protective effect of GnRH analog (GnRHa) on ovarian reserve against ovarian toxic chemotherapy, thus demonstrating an important role of GnRH analogs in fertility preservation.”³ Furthermore, several recent meta-analyses of randomized controlled trials^7–10 also concluded that the pooled analysis of randomized studies shows that the temporary ovarian suppression induced by GnRHa significantly reduces the risk of chemotherapy-induced POF (premature ovarian failure) in young cancer patients.⁷ Nine prospective randomized studies were included in the most recent meta-analysis⁷ with 225 events of POF occurring in 765 analyzed patients. The pooled odds ratio (OR) estimate indicates a highly significant reduction in the risk of POF (OR =0.43; 95% confidence interval [CI]: 0.22–0.84; P=0.013) in patients receiving GnRHa, without any evidence of publication bias. The Cochrane database analyses also concluded that:

The use of GnRH agonists should be considered in women of reproductive age receiving chemotherapy. Intramuscular or subcutaneous GnRH analogs seem to be effective in protecting ovaries during chemotherapy and should be given before or during treatment […]¹⁰

Furthermore, opposite to the authors’ opinion and declaration regarding fertility,¹ several publications have found that the GnRH agonist co-treatment was also effective in increasing pregnancy rate in addition to decreasing premature ovarian failure.^5,6,11,12 As we have recently summarized the case for and against GnRH agonist for fertility preservation, “An ounce of prevention is worth a pound of cure”.⁶ Since not all the methods are 100% successful, these young women deserve to be informed of all the possible modalities to minimize gonadal damage and preserve ovarian function and future fertility.⁶ It is recommended that GnRHa co-treatment is offered in addition to, and not instead of in vitro fertilization and cryopreservation of embryos, ova, and ovarian tissue, for fertility preservation. 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 GnRHa administration and follicular aspiration, as recently published.⁶ 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 ova, embryos, or primordial follicles to fall back upon. However, in cases where conventional chemotherapy regimens such as those commonly used for young lymphoma patients are applied, GnRHa co-treatment may preserve ovarian function and prevent POF without necessitating the use of cryopreserved ova, embryos or ovarian tissue. Patients should be informed on uncertainties regarding the potential role of GnRHa and the association with adverse events like hot flushes, bone and muscle pains, mood changes, vaginal dryness, etc. Nevertheless, only a few of our 281 GnRHa co-treated patients wanted the estrogen/progestin add back therapy for minimizing side effects.⁶ Similarly, in a recent study¹³ there were no significant differences in the side effects between the GnRHa and control groups, except for the vaginal bleeding which was significantly lower in the GnRHa group.

Disclosure

The author has no conflicts of interest in this communication.

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References

1.	Rodriguez-Wallberg KA, Oktay K. Fertility preservation during cancer treatment: clinical guidelines. Cancer Manag Res. 2014;6:105–117.
2.	Rodriguez-Wallberg KA, Alonso de Mena S, Malm E, Larsson A, Kuiper R, Hassan M. Pre-pubertal status does not protect against follicle depletion induced by cyclophosphamide in mice. A randomized study. Hum Reprod. 2013;28 Suppl 1:321.
3.	Kishk EA, Mohammed Ali MH. Effect of a gonadotropin-releasing hormone analogue on cyclophosphamide-induced ovarian toxicity in adult mice. Arch Gynecol Obstet. 2013;287(5):1023–1029.
4.	Henes JC, Henes M, von Wolff M, Schmalzing M, Kötter I, Lawrenz B. Fertility preservation in women with vasculitis: experiences from the FertiPROTEKT network. Clin Exp Rheumatol. 2012;30(1 Suppl 70):S53–S56.
5.	Behringer K, Thielen I, Mueller H, et al. Fertility and gonadal function in female survivors after treatment of early unfavorable Hodgkin lymphoma (HL) within the German Hodgkin Study Group HD14 trial. Ann Oncol. 2012;23(7):1818–1825.
6.	Blumenfeld Z, Katz G, Evron A. ‘An ounce of prevention is worth a pound of cure’: the case for and against GnRH-agonist for fertility preservation. Ann Oncol. March 20, 2014. [Epub ahead of print.]
7.	Del Mastro L, Ceppi M, Poggio F, et al. Gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in cancer women: systematic review and meta-analysis of randomized trials. Cancer Treat Rev. 2014;40(5):675–683.
8.	Sun X, Dongol S, Jiang J, Kong B. Protection of ovarian function by GnRH agonists during chemotherapy: a meta-analysis. Int J Oncol. 2014;44(4):1335–1340.
9.	Yang B1, Shi W, Yang J, et al. Concurrent treatment with gonadotropin-releasing hormone agonists for chemotherapy-induced ovarian damage in premenopausal women with breast cancer: a meta-analysis of randomized controlled trials. Breast. 2013;22(2):150–157.
10.	Chen H1, Li J, Cui T, Hu L. Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy induced premature ovarian failure in premenopausal women. Cochrane Database Syst Rev. 2011;(11):CD008018.
11.	Clowse ME, Behera MA, Anders CK, et al. Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis. J Womens Health (Larchmt). 2009;18(3):311–319.
12.	Wong M, O’Neill S, Walsh G, Smith IE. Goserelin with chemotherapy to preserve ovarian function in pre-menopausal women with early breast cancer: menstruation and pregnancy outcomes. Ann Oncol. 2013;24(1):133–138.
13.	Demeestere I, Brice P, Peccatori FA, et al. Gonadotropin-releasing hormone agonist for the prevention of chemotherapy-induced ovarian failure in patients with lymphoma: 1-year follow-up of a prospective randomized trial. J Clin Oncol. 2013;31(7):903–909.

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Authors’ reply

Kenny Rodriguez-Wallberg¹, Kutluk Oktay^2,3

¹Department of Clinical Science, Intervention and Technology, Division of Obstetrics and Gynecology and Reproductive Medicine Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden; ²Innovation Institute for Fertility Preservation, New York, NY, USA; ³Department of Obstetrics and Gynecology, NY Medical College, Valhalla, NY, USA

Correspondence: Kenny Rodriguez-Wallberg, Reproductive Medicine, Karolinska University Hospital Huddinge, Novumhuset Plan 4, SE-141 86 Stockholm, Sweden, Email [email protected]

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Dear editor

We appreciate the recent comments on our article “Fertility preservation during cancer treatment: clinical guidelines”¹ by Dr Blumenfeld. As we point out in our article, in females the vast majority of clinical studies investigating gonadal protection by gonadotropin-releasing hormone analogs (GnRHa) during chemotherapy have been small, retrospective, and uncontrolled, and they have almost exclusively used resumption of menstruation as a surrogate marker for fertility. Recent clinical data indicate that fertility is reduced after a chemotherapeutic treatment, even if menstrual cycles are resumed,² and studies investigating fertility are lacking and require long-term follow-up.

The development of sensitive biochemical ovarian markers of ovarian reserve has permitted, in recent years, the investigation of the subsequent benefit of GnRHa during chemotherapy, and some randomized clinical trials have been published. Those studies have not demonstrated any benefits after GnRHa co-treatment with regard to serum concentrations of inhibin B and/or anti-Mullerian hormone, which are considered as gold standard markers of ovarian reserve today.^3–5 A higher pregnancy rate after GnRHa use in those studies has not been demonstrated either.^3–5

The results of our recent experiments in mice, published in the summer supplement of Human Reproduction last year,⁶ do not support the fact that the mouse ovaries might be less susceptible to chemotherapeutic-induced follicle damage just because of the fact of being at a pre-pubertal stage, but that was the only variable investigated in that experiment, and the doses of cyclophosphamide administered in the pre-pubertal group were equivalent to those administered in the adult mice group.

As data from clinical and experimental studies are still conflictive, and given the fact that our guidelines are intended as clinical recommendations, they should be in line with international guidance for fertility preservation, such as that provided by the American Society of Clinical Oncology (ASCO).^7,8 At the time of publication of our manuscript, neither the ASCO nor other large scientific groups had recommended the use of GnRHa for fertility protection during cancer treatment. The provision of information on recognized effective methods for fertility preservation to patients should be encouraged.

Disclosure

The authors have no conflicts of interest in this communication.

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References

1.	Rodriguez-Wallberg KA, Oktay K. Fertility preservation during cancer treatment: clinical guidelines. Cancer Manag Res. 2014;6:105–117.
2.	Letourneau JM, Katz PM, Smith JF, Oktay K, Cedars MI, Rosen MP. The prevalence of self-reported reproductive impairment in young female cancer survivors throughout California. Fertil Steril. 2010;94(4):510.
3.	Gerber B, et al. Effect of luteinizing hormone-releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO study. J Clin Oncol. 2011;29(17):2334–2341.
4.	Elgindy EA, El-Haieg DO, Khorshid OM, Ismail E, Abou-Setta AM, Sallam HN. Gonadotropin-releasing hormone analogue cotreatment does not preserve ovarian function in young women receiving cyclophosphamide-based chemotherapy: a prospective, multicenter, randomized trial. Fertil Steril. 2011;96(Suppl 3):S47–S48.
5.	Munster PN, et al. Randomized trial using gonadotropin-releasing hormone agonist triptorelin for the preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer. J Clin Oncol. 2012;30(5):533–538.
6.	Rodriguez-Wallberg KA, Alonso de Mena S, Malm E, Larsson A, Kuiper R, Hassan M. Pre-pubertal status does not protect against follicle depletion induced by cyclophosphamide in mice. A randomized study. Hum Reprod. 2013;28 Suppl 1:321.
7.	Lee SJ, et al. American Society of Clinical Oncology Recommendations on Fertility Preservation in Cancer Patients. J Clin Oncol. 2006;24(18):2917–2931.
8.	Loren AW, et al. Fertility Preservation for Patients with Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2013;31(19):2500–2510.