Description of the condition

Chemotherapy has significantly improved the prognosis in patients with malignancies including breast cancer, lymphoma and gynaecological cancer and certain non‐malignancies such as rheumatoid arthritis and systemic lupus erythematosus. This treatment, however, is associated with significant long‐term physical and psychological effects. Of these, ovarian toxicity, has been subjected to wider scrutiny. Animal studies have shown that cyclophosphamide causes follicular destruction (Meirow 1999). Ovarian biopsies have also revealed the complete absence of ova or a small numbers of inactive ova with fibrosis and no evidence of follicular maturation in patients receiving cyclophosphamide‐based chemotherapy (Koyama 1977; Warne 1973). Ovarian damage caused by chemotherapy is not an 'all or none' phenomenon and can present with a variety of symptoms (such as irregular menses, amenorrhoea and infertility) that reflect varying degrees of damage, culminating in premature ovarian failure (POF) (Ataya 1989; Ataya 1995; Blumenfeld 1996; Lutchman Singh 2005; Meirow 2001). POF is a condition in which the ovaries stop functioning, however it is not the same as premature menopause as this is when a women's mentstrual cyce ends before the age of 40. Missed periods are usually the first sign of POF, but some women with POF may still have occasional irregular periods. In a review by Bines et al the authors found that a uniform definition of menopause and chemotherapy‐related amenorrhoea (CRA) was lacking (Bines 1996) and therefore the rates quoted for CRA can vary between 20% to 100% in breast cancer patients for example. Sonographic (ovarian volume, follicle counts etc) and endocrine changes (serum levels of FSH, LH, estradiol etc) might suggest an impairment of ovarian potential in patients with preserved menstrual cycles (Larsen 2003). Clinical information such as regular menses shortly after chemotherapy does not rule out POF as this may subsequently occur. The restoration of menstruation after CRA is also possible (Byrne 1992; Lutchman Singh 2005). Animal studies have shown in mice ovulation and pregnancy rates were not altered after exposure to doses of chemotherapy strong enough to destroy half of the ovarian primordial reserve (Meirow 1999). Long‐time fertility, however, may still be affected due to POF.

Factors which may affect the risk level of chemotherapy‐induced ovarian damage include patient's age and regimen of chemotherapy. The long‐term follow‐up of 240 children (15 years of age or younger) receiving chemotherapy for Hodgkin's disease showed POF in 13% of girls compared with azoospermia, failure of formation of spermatozoa, in 83% of boys (Ortin 1990). Similar results were reported by other researchers (Chiarelli 1999; Larsen 2003; Tangir 2003), indicating that pre‐pubertal female gonads are much less vulnerable to chemotherapy unlike pre‐pubertal male gonads. Ovaries, however, become more sensitive to chemotherapeutic agents in older patients (Chapman 1979; Goodwin 1999; Kreuser 1987; Rivkees 1988). The average rates of CRA for CMF‐based chemotherapy (cyclophosphamide plus methotrexate plus fluorouracil) is 40% for women aged less than 40 years and 76% for those greater than 40 years (Bines 1996) and complete ovarian failure and permanent infertility occur more often in older women (Behringer 2005; Bines 1996; Moore 2000).

The majority of chemotherapeutic agents can be categorized as alkylating agents (cyclophosphamide, mechlorethamine etc), plant alkaloids (vinblastine, taxanes etc), antitumour antibiotics (adriamycin, dactinomycin, bleomycin etc), antimetabolites (fluorouracil, methotrexate, mercaptopurine etc), topoisomerase inhibitors (topotecan, etoposide phosphate etc) and others (cis‐platinum etc). They can be used via intravenous injection, intra‐muscular injection, intraperitoneal infusion. Chemotherapeutic agents are often used in combination and therefore it is difficult to evaluate the risk of POF of each individual agent. There were some reports concluding that alkylating agents, cis‐platinum and adriamycin are among the most toxic agents, while fluorouracil, methotrexate, dactinomycin, bleomycin, vinblastine and mercaptopurine are among the least (Blumenfeld 1999; Falcone 2005). Alkylating agents, which are non‐cell‐cycle‐specific and act on proliferating cells of all stages, can affect oocytes and possibly the pre‐granulosa cells of primordial follicles. This may induce the impairment of follicular maturation and/or the depletion of primordial follicles and result in temporary or permanent amenorrhoea (Bines 1996; Sobrinho 1971). Goldhirsch et al reported that between 10% to 33% of the breast cancer patients treated with one cycle of CMF experienced amenorrhoea (Goldhirsch 1990). This rate increased to between 33% to 81% after six cycles of treatment (cumulative dose of cyclophosphamide, 8400 mg/m²) and to between 61% to 95% after 12 cycles (cumulative dose of cyclophosphamide, 16800 mg/m²) (Goldhirsch 1990). Brincker et al reported that the cumulative dose and dose‐intensity were directly related to POF rate, while the duration of treatment was held constant (Brincker 1987). In the review by Bines et al the effects of duration and the route of administration on POF rates remained to be determined (Bines 1996).

Description of the intervention

Gonadotropin‐releasing hormone (GnRH), also known as luteinizing‐hormone releasing hormone (LHRH), is a peptide hormone responsible for the release of follicle‐stimulating hormone (FSH) and luteinizing‐hormone (LH). GnRH is synthesized and released from the hypothalamus, and then the portal blood carries the GnRH to the pituitary gland, where GnRH activates GnRH receptors and stimulates synthesis and secretion of the gonadotropins LH and FSH. GnRH activity, critical for reproductive function, is very low during childhood and is activated at puberty. The frequency of the pulses varies during the menstrual cycle. Low frequency GnRH pulses lead to FSH release, whereas high frequency GnRH pulses stimulate LH release.

GnRH analogues, designed to interact with the GnRH receptor and modify the release of gonadotropins are synthetic peptide drugs modelled on GnRH. Two types of analogues have been developed: GnRH agonists and GnRH antagonists, with specific amino acid substitutions typically in position 6 and 10 (Goserelin and Leuprorelin) or only a single substitution at position 6 (Triptorelin). GnRH agonists inhibit rapid degradation and do not dissociate from the GnRH receptor quickly and as a result there is an increase in FSH and LH secretion initially, followed by a profound hypogonadal effect through receptor down‐regulation (Couzinet 1991; Matikainen 1992). GnRH antagonists are derivatives of the natural GnRH decapeptide with multiple amino acid substitutions. Competing with GnRH for its receptor, GnRH antagonists decrease or block GnRH action to shut down the output of FSH and LH within hours (Couzinet 1991; Matikainen 1992; Rabinovici 1992). However, their action is short‐live with return of endogenous FSH and LH activity about 40 hours after cessation of GnRH antagonist administration. Thus daily injections are necessary to maintain their effect. Side effects of the GnRH analogues are signs and symptoms of hypoestrogenaemia, including hot flushes, headaches and bone loss.

How the intervention might work

Several proposed mechanisms have been put forward on how the effect of GnRH analogues may work.

1. Suppression of the gonadotrophin levels to simulate the pre‐pubertal hormonal milieu and subsequently prevent the primordial follicles from maturation which probably decrease the follicles destroyed by chemotherapy (Blumenfeld 1999).

2. Decrease in utero‐ovarian perfusion, resulting in a decreased exposure of the ovaries to the chemotherapeutic agents (Blumenfeld 2007; Meirow 2004).

3. Direct activation of GnRH receptors on ovaries (Blumenfeld 2007; Imai 2007).

4. Up‐regulation of intra‐gonadal anti‐apoptotic molecules such as sphingosine‐1‐phosphate (S‐1‐P) (Blumenfeld 2007).

5. Protection of the undifferentiated germline stem cells (Blumenfeld 2007).

Why it is important to do this review

Since more and more adolescents and adults are long‐term survivors of malignancies or certain non‐malignancies, POF causing oestrogen deficiency symptoms and loss of fertility can significantly impact on quality of life (QoL) and self‐esteem. GnRH analogues are easily available drugs, administration is simple and there are few side effects. The possibility of administering an adjuvant GnRH analogues, which may minimize the ovarian damage caused by an otherwise successful chemotherapy, is a good clinical option.

Research has been done to investigate the protective effect of GnRH analogues on the ovaries. Glode et al reported that GnRH agonistic analogues appeared to protect male mice from the gonadal damage produced by cyclophosphamide (Glode 1981). Ataya et al reported that GnRH agonists prevented chemotherapy‐induced ovarian follicular loss in rats (Ataya 1985), and similar results were confirmed by Bokser et al (Bokser 1990). It was also found that GnRH agonists protected against chemotherapy‐induced fertility reduction in female rats by increasing the pregnancy rate, the number of implantations and reduced the need for re‐mating (Ataya 1993). A prospective, randomised controlled trial (RCT) conducted in rhesus monkeys showed that GnRH agonists protected the ovaries against cyclophosphamide‐induced damage by significantly decreasing the number of follicles lost (Ataya 1995). In clinical studies, GnRH agonists have been used to protect ovaries from chemotherapy in premenopausal breast cancer patients (Del Mastro 2006; Recchia 2006; Urruticoechea 2008), hematologic patients (Blumenfeld 2008a; Huser 2008), and autoimmune patients (Blumenfeld 2000; Somers 2005).

GnRH antagonists have been found to decreased ovarian damage caused by cyclophosphamide in mice (Meirow 2004) and to deplete primordial follicles in a murine model in a prospective primary research study (Danforth 2005). It has also been found that in at study on rats GnRH antagonists did not show a protective effect on ovaries from cyclophosphamide (Peng 2007). However, GnRH antagonists may help GnRH agonists to achieve a faster down‐regulation compared with GnRH agonists alone (Blumenfeld 2008b). The combination of GnRH antagonists and agonists has been found to induce a long‐lasting and reliable suppression of gonadotrophin secretion, allowing chemotherapy to be started without delay (Mardesic 2004). We have not found any research for GnRH antagonists alone.

There have been no previous meta‐analysis assessments on the protective effect of GnRH analogues on ovaries given either before or in parallel to chemotherapy. This review sets out to determine the benefits and harms from GnRH analogues given to premenopausal women who will undergo or are undergoing chemotherapy for malignancies or non‐malignancies. It will assess the importance of factors such as patients age at the time treatment, type of disease, types of chemotherapy agents given, chemotherapy regimen and the timing of the GnRH analogues supplementation.