Hormonal Strategies For Fertility Preservation In Patients Receiving Cyclophosphamide To Treat Glomerulonephritis

Main Category: Urology / Nephrology
Also Included In: Fertility
Article Date: 24 Dec 2008 - 0:00 PST

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UroToday.com - Cyclophosphamide is the immunosuppressant drug of choice for the treatment of severe systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody-associated vasculitides, glomerulonephritis and is widely used for the treatment of various immune-mediated rheumatic, renal, neurologic, and hematologic diseases or their complications. However, the impact of this therapy on fertility is an important consideration for many patients. Gonadal failure after immunosuppressive therapy with cyclophosphamide is a common finding in medical practice, often leading to infertility in young patients.

Alterations in gonadal function are, probably the most common long-term side-effects of chemotherapy. Gonadal dysfunction following treatment may be temporary, but recovery is often unpredictable, and damage is permanent in a large proportion of patients. The concern about fertility can play a critical role in the decision to decline treatment with cyclophosphamide and other alkylating agents such as chlorambucil.

Several attempts have been made both in animals and humans to preserve gonads from cyclophosphamide-induced damage, with conflicting results. Prepubertal patients who receive large doses of cyclophosphamide seem to recover gonadal function better than adults do, suggesting that active germinal cells are more sensitive to cyclophosphamide because of their elevated mitotic activity. These observations have led to many trials of suppression of gonadal function, with the aim toward inducing a prepubertal state.

In our previous pilot randomized controlled trial we showed a protective effect of testosterone on cyclophosphamide-induced testicular damage. Of 15 men treated with cyclophosphamide for glomerulonephritis, five received testosterone. All men were azoospermic or severely oligozoospermic within 6 months of commencing cyclophosphamide. Nine of the 10 men who received CPM alone remained azoospermic 6 months after the end of immunosuppressive therapy, whereas sperm concentrations returned to normal in all five of the men who received testosterone therapy. FSH levels were elevated in men who received cyclophosphamide alone, suggesting significant effect on testicular function, whereas it remained within the normal range in men who received testosterone therapy. LH levels were normal in all 15 patients, suggesting that Leydig's cell function was not affected. To our knowledge that was the only trial with a testosterone alone-protocol protection in human setting to date.

The results of the present study confirm in a wider series that testosterone administration is a feasible and safe strategy for preservation of testicular function against cyclophosphamide-induced damage. In these men, hormonal levels after therapy are similar to baseline values and are in keeping with a normal hypothalamic-pituitary-gonadal axis. Following discontinuation of immunosuppressive therapy and testosterone, sperm concentrations increased to levels well above those observed during therapy, and stabilized within the normal range. Mean percentages of sperm motility and sperm that showed no structural abnormalities were in the normal range and did not differ from baseline.

In view of some preliminary encouraging findings in women with malignant diseases and of our previous experience in men with glomerulonephritis, in 1998 we extended our hormonal strategy for fertility preservation to women with various forms of nephritis.

The results of our study demonstrate that GnRH-a triptorelin co-administration may preserve fertility in women treated with cyclophosphamide: all the 13 patients who received this gonadal-protection protocol recovered their normal menses and regular hormonal status, whereas the four patients who received cyclophosphamide alone developed hypergonadotropic amenorrhea, with low E2 levels, consistent with ovarian failure.

Our study adds some interesting findings for the clinicians in a difficult area to study, given evidence of generally poor quality, the relatively overall small number of patients affected, and the difficulty to truly randomize in a meaningful way.

Data from the present study indicates a protective effect of testosterone and triptorelin administration against cyclophosphamide-induced gonadal damage in male and female patients, respectively, with various forms of nephritis. To date, there are no established guidelines for hormonal therapy to preserve fertility during chemotherapy; it is our advice that the clinicians who look after patients undergoing cyclophosphamide therapy should take into consideration this gonadal-protection protocol, which if proved to be feasible, effective and safe, and could prevent some patients from declining treatment with cyclophosphamide out of concern about fertility.

Written by Alessandro Cigni, MD as part of Beyond the Abstract on UroToday.com

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