Comment on: sexual and fertility adverse effects associated with chemotherapy treatment in women

Keywords::

• breast cancer
• chemotherapy
• fertility preservation
• gonadotoxicity
• gonadotropin releasing hormone agonists
• premature ovarian failure

To the Editor: Turan and Oktay [1] declare that the efficacy of gonadotropin releasing hormone agonists (GnRHa) for the prevention of chemotherapy-induced gonadal damage is controversial, and there are no well-designed prospective randomized controlled trials (RCTs) supporting this modality.

However, Del Mastro et al [2] and several other recent meta-analyses of RCTs concluded that the significant reduction (p = 0.013) in premature ovarian failure (POF), associated with GnRHa, provides convincing evidence in support of the efficacy of this preventive strategy. The pooled odds ratio (OR) estimate indicates a highly significant reduction in the risk of POF (OR = 0.43; 95% CI: 0.22 – 0.84; p = 0.013) in patients receiving GnRHa [2].

Several other meta-analyses [3], including a Cochrane database [4], support the use of GnRHa co-treatment for fertility preservation. As we have recently summarized [3], there are 4 prospective RCTs, in addition to 15 non-RCTs, and over 10 meta-analyses supporting GnRHa co-treatment. Even Demeestere et al [5], who initially did not find a difference in POF rate after 1 year, have presented an abstract at the Third World Congress of the International Society for Fertility Preservation in Valencia, November 2013, whereby at 2 years follow-up of [5]: “…the number of patients who totally restored their ovarian function was significantly higher in the GnRHa group (p = 0.049) confirming results of AMH”. This supports our published explanation that short follow-up may be responsible for the discrepancy between studies and lead to incorrect conclusions [3].

Furthermore, a recent publication [6] from one of the previous opponents to GnRHa use for fertility preservation [3] has found that the use of GnRHa during chemotherapy has also significantly increased the probability of becoming pregnant (OR = 12.87; p = 0.001), concluding that “the multivariate analysis reveals that the use of GnRH analogues during therapy is a strong, independent, and a highly significant predictor of pregnancies”.

Recently, we have also shown that the GnRHa co-treatment is beneficial not only against regular chemotherapy but also for lymphoma patients undergoing stem cell transplantation [3].

In the last month’s ASCO annual meeting, Dr. Halle Moore presented the results of an NIH-sponsored prospective RCT trial, whereby 257 premenopausal breast cancer patients received chemotherapy with or without GnRHa. Two years after chemotherapy, only 8% of the GnRHa arm experienced POF versus 22% of control. In the GnRHa group, 21% conceived and 15% delivered, versus only 11 and 7%, respectively, in the controls. In an unexpected finding, the 4-year mortality rate in the GnRHa group was significantly lower.

Declaration of interest

The authors’ work is partially funded by NICHD grants. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Bibliography

• Turan V, Oktay K. Sexual and fertility adverse effects associated with chemotherapy treatment in women. Expert Opin Drug Saf 2014;13:775-83
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Author's response

Kutluk Oktay MD ^†1

Volkan Turan MD

^bAuthor for correspondence New York Medical College, Innovation Institute for Fertility Preservation and IVF and Department of Obstetrics and Gynecology, NY, USA [phone]; [email protected]

To the Editor: We have read Dr Blumenfeld’s letter to the editor with interest and will be brief in our response since we have already provided information in our answers to his prior letters to the editors to other journals [1-3]. While the literature contains some studies with differing opinions, it is best to interpret the information based on the big picture and not in a selective fashion. One must also put the findings into biological perspective. While some studies suggested potential improvement in return of menses, many failed to confirm this. Nevertheless, menstruation is not a reliable marker of ovarian reserve or infertility, and studies utilizing better markers of ovarian reserve such as anti-Mullerian hormone and/or inhibin-B did not find that GnRHa treatment preserved ovarian reserve or fertility [4-6]. A recent update from the ASCO Clinical Guidelines Committee for Fertility Preservation looked at the totality of the evidence and concluded that GnRHa could not be recommended as an effective fertility preservation method [7]. A fertility preservation benefit from GnRHa is also biologically not plausible; neither it is practically possible to completely abolish gonadotropin production with the short period available before chemotherapy nor are primordial follicles gonadotropin-sensitive. We have shown that chemotherapy causes follicle death by inducing double-strand DNA breaks in oocytes and some may survive despite these breaks [8]. It is quite probable that ovarian suppression suspends these damaged follicles in development enabling them to temporarily survive as has been shown with other pharmacological manipulation [9,10]. Upon discontinuation of ovarian suppressing drugs, damaged and would be lost follicles resume growth and induce some form of menstrual bleed that has no functional significance. In fact, a study by Kevin Fox et al. on ovarian suppression in breast cancer patients was terminated because of high incidence of birth anomalies [11]. The recent abstract presentation by Hale et al. [12] at ASCO 2014 annual meeting surmised that menstruation may be more likely to return in women with breast cancer who were suppressed with a GnRHa. The authors should be applauded for such an undertaking. In this preliminary work, only about half of the registered subjects were evaluable at the end of the study. After adjusting for confounders, the difference in amenorrhea rates yielded a p-value of 0.08. The authors then took a more liberal approach of combining high FSH with amenorrhea as an end point, at which time there was significance. Serum FSH levels have to be measured on menstrual cycle day 2 or 3 for standardization. Since the FSH levels were measured on a random day of the menstrual cycle and these values highly vary by cycle day and are affected by estrogen levels (which can also be paradoxically elevated in diminished ovarian reserve patients, thereby spuriously lowering FSH levels via negative feedback), this approach further reduces the reliability of using elevated FSH as a sign of diminished ovarian reserve at this setting. Serum AMH levels, which would have provided less cycle day-dependent ovarian reserve information, were not measured. There were 22 pregnancies in the GnRHa group (of unspecified number in the abstract) and 13 in the controls (of unspecified number). The p-value for this difference was p = 0.05 with a confidence interval including unity (1 – 4.92). Moreover, because it is difficult to determine who actually attempted or were motivated for pregnancy in each group, a raw comparison of the ratios of pregnant in all women who received GnRHa versus those served as controls cannot be reliable. In contrast to what was reported in the lay media, before the study is completed with larger number of patients and published in a peer-reviewed journal, this preliminary work is not sufficient to prove a fertility benefit from ovarian suppression. Until then, treating ovarian suppression as an effective fertility preservation method carries the risk of diverting patients from proven methods such as gamete cryopreservation. Finally, the study was limited to ER-negative patients and thus it is not surprising that there was no adverse impact on the effectiveness of chemotherapy (as ovarian suppression may in theory make hormone-sensitive cells dormant and less sensitive to chemotherapy). We understand and appreciate the commitment of Dr. Blumenfeld in seeking for a simpler approach to fertility preservation. Our laboratory is also committed to the same and showed that a ceramide-induced cell death inhibitor sphingosine-1-phosphate maybe a promising candidate [13] as it may directly block the chemotherapy-induced damage to DNA.