Ovariostasis

The efficacy of GnRH analog treatment to protect gonads from the cytotoxic effects of cancer therapy is controversial. It appears that GnRH analogs are more useful for female than male cancer patients, since previous studies have shown no difference in testicular failure rates after chemotherapy in male patients with or without GnRH agonist protection (1, 2). On the other hand, most animal and human studies have shown that GnRH agonist can protect primordial follicles during chemotherapy, because prepubertal ovaries were found to be more resistant to alkylating agents (3, 4). The precise mechanism by which GnRH analogs protect primordial follicles from alkylating agents is still unknown. However, there are several possible mechanisms that may explain the protective effects of GnRH agonist, which include:

1) preventing follicular growth by suppressing gonadotropin secretion

2) decreasing exposure to chemotherapeutic agents by reducing utero-ovarian perfusion

3) direct effect of GnRHa independent of the suppression of gonadotropin levels

4) upregulation of intragonadal antiapoptotic molecules (5). 

It should be borne in mind, however, that GnRH analogs cannot protect primordial follicles from radiation therapy.

Animal studies

These protective effects of GnRH agonists have already been demonstrated in several rodent studies (6, 7). Furthermore, the ovarian protective effects of GnRH antagonists against cyclophosphamide (Cy) were also reported in a mouse model, which showed that the extent of protection provided by GnRH antagonists is dose-dependent and decreases with increasing doses of Cy (8).

A prospective, randomized study in a primate model demonstrated that GnRHa inhibits Cy-induced ovarian follicle depletion (64.6 ± 2.8% in the Cy group vs 28.9 ± 9.1% in the GnRHa and Cy group) (9). However, GnRHa treatment did not show any protective effect against radiation-induced ovarian injury in the rhesus monkey model (9), which was consistent with the previous rodent study (10).

Clinical studies

1. Female cancer patients

Increasing numbers of studies are demonstrating the beneficial effects of GnRHa treatment in cancer patients undergoing chemotherapy, but most of these studies are small, retrospective or non-randomized. The results of the 2002 study by Blumenfeld’s group, comparing premature ovarian failure (POF) rates between chemotherapy with GnRHa treatment and chemotherapy alone in lymphoma patients (Hodgkin’s lymphoma and non-Hodgkin’s lymphoma), are very convincing (5% vs 55%) (11). However, the sample size was not large enough if all the variables, such as the heterogeneity of the study population and treatment regimens, are taken into account.

The same group published new data in 2008 confirming the protective effects of GnRHa against chemotherapy-induced POF (5). Although it was not a prospective, randomized study (but a prospective, non-randomized study with concurrent and historical controls), its quality was superior to previous studies. The authors investigated one single disease, Hodgkin’s lymphoma, and compared the protective effects of GnRHa in the context of different chemotherapy regimens. The study showed that the POF rate with most chemotherapeutic regimens was 44%, but in GnRHa-treated patients, it was just 5%. However, there was no statistical difference in POF rates in patients receiving ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). It is worth noting that there was no difference in pregnancy rates between patients who received GnRHa treatment with chemotherapy or chemotherapy alone.

The ovarian protective effect of GnRHa can also be seen in premenopausal breast cancer patients undergoing chemotherapy. Recchia et al. retrospectively evaluated 100 premenopausal women (range, 27-50 yrs) with high-risk early breast carcinoma, who received GnRHa to protect the ovaries during adjuvant chemotherapy (12). Chemotherapy regimens included CMF (cyclophosphamide, methotrexate, 5-fluorouracil) and anthracycline-based treatments. After a median follow-up of 75 months, normal menses were recovered by all patients under 40 years of age and by 56% of patients over 40 years of age. Furthermore, a prospective, non-randomized, phase II study, aiming to assess the protective effects of GnRHa in young breast cancer patients undergoing adjuvant chemotherapy, showed that GnRHa (goserelin 3.6 mg) prevented POF in the majority of patients (13). Of 29 women with a median age of 38 years (range 29-47 yrs), menstrual cycles resumed in 16 out of 17 patients (94%) under 40 years of age and in 5 out of 12 patients (42%) over 40 years of age.

Although the results of these studies are encouraging, it will be difficult to confirm the protective effects of GnRHa treatment against the ootoxicity of chemotherapy without prospective, randomized studies. In fact, there are several large prospective, randomized studies currently under way worldwide, such as the Southwest Oncology Group trial in the USA.

Besides GnRH agonists, new GnRH antagonists can also be used to protect the ovaries during chemotherapy. However, it is too early to draw any firm conclusions on the beneficial effects of GnRH antagonists until further studies are completed.

2. Male cancer patients

In contrast to female cancer patients, most studies on male cancer patients have revealed that GnRHa does not protect male gonads and germ cells from the gonadotoxicity of chemotherapeutic agents. Indeed, most prepubertal boys receiving chemotherapy and/or radiotherapy suffered azoospermia, even with GnRHa treatment (Table 1).

 Conclusions

Treatment with GnRH analogs can be a useful strategy to preserve fertility and prevent POF by protecting ovarian follicles from the toxic effects of chemotherapy in women with cancer. However, the beneficial effects of GnRHa in chemotherapy patients should be further investigated by prospective, randomized studies.

GnRH analogs are not indicated for patients who undergo radiation therapy. There is no role for GnRH analogs in the treatment of male cancer patients.

References:

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