Hodgkin's Lymphoma and Male Fertility

Abstract & Commentary

By William Ershler, MD

Synopsis: For young males cured of Hodgkin's Lymphoma, infertility is a significant issue. In a comprehensive review of patients treated on the German Hodgkin Study Group, investigators found that there were both qualitative and quantitative changes in sperm production prior to therapy, and that most drug combinations, particularly those that contained alkylating agents, caused a high rate of azoospermia. Serum FSH levels correlated with fertility status, and may be a useful surrogate for more extensive semen analysis.

Source: Sieniawski M, et al. Assessment of male fertility in patients with Hodgkin's lymphoma treated in the German Hodgkin Study Group (GHSG) clinical trials. Ann Oncol. 2008;19:1795-1801.

Hodgkin's Lymphoma (HL) has a bimodal incidence peak, but the majority of patients are young. When it occurs at younger ages, overall prognosis is good and, for many, the disease will be completely eradicated. However, the treatment required to achieve cure is associated with long-term consequences, including second malignancies, compromised cardiac and pulmonary function, and endocrine deficiencies. Although not life-threatening, infertility engenders a high psychosocial burden and diminished quality of life. A recent report revealed that 51% of men with cancer expressed their wish to preserve their capacity for procreation in the future, including 77% of men who were still childless when their cancer was diagnosed.1

Several factors influence fertility in men after HL treatment. Primary among these is chemotherapy, especially alkylating agents.2 Also to be factored in, however, is the recent observation that a large portion of men with HL have low sperm counts even prior to receiving treatment.3

The current study was undertaken to provide a more comprehensive evaluation of male fertility among patients treated for HL. For this, male patients treated within the German Hodgkin Study Group (GHSG) from 1988 through 2003 were examined before and, for many, at later intervals after HL treatment. Fertility status was correlated with clinical and biological features at the time of diagnosis, as well as the treatment regimen received.

Prior to HL treatment, of 202 patients (median age 26 years), only 20% had normal sperm counts, 11% had complete absence of sperm in the ejaculate (azoospermia), and 69% had either low sperm counts, altered motility, or both (dyspermia). In post-treatment analysis (n = 112), 64% of patients had complete absence of sperm in the ejaculate, 30% other dyspermia, and 6% normal sperm counts (p < 0.001). Azoospermia was observed in 90% of patients treated with chemotherapy alone, 67% of those treated with combined modality, and 11% of those treated with radiotherapy alone (p < 0.001). Azoospermia was more frequent after four cycles of cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP/ABVD) (91%), eight cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) baseline (93%), and eight cycles of BEACOPP escalated (87%), compared with two cycles of COPP/ABVD (56%; p = 0.003). There was a statistically significant difference in post-treatment-follicle-stimulating hormone (FSH) levels between patients with azoospermia and those with preserved spermatogenesis (p = 0.001).

Commentary

Although male infertility is an acknowledged adverse consequence of chemotherapy, the prevalence, as defined in this analysis, was quite remarkable. The current research provides a comprehensive assessment in terms of treatments received and overall effect on male fertility in a fairly large series of patients treated on specific protocols. The data confirm the association with alkylating agents and demonstrate, to some degree, a dose effect. That is, patients who received less cyclophosphamide or procarbazine were less likely to become azoospermic compared to those who received more. Similar rates of azoospermia were observed in those treated with MOPP (mechlorethamine, vincristine, procarbazine and prednisone).4 Although there were few patients included in this series who received ABVD alone, in other series, the incidence of treatment-induced azoospermia is reportedly significantly less, to the order of 5%.5 It is also notable that prior to therapy, only 20% of men had normal semen analyses and 11% had azoospermia. The mechanisms accounting for these findings are incompletely understood, although factors such as disease-related damage to germinal epithelium and disturbances in the hypothalamic-hypophysial axis, as well as the impact of cytokines on spermatogenesis have been proposed.3,6,7

It is also notable that FSH levels were elevated in the majority of patients. In contrast, LH and testosterone levels remained normal in most; findings that had been previously observed in this setting.5,8 The pattern suggests that spermatogonia are sensitive, whereas Sertoli and Leyding cells are more resistant to the toxic effects of alkylating agents. Additionally, FSH levels appear to correlate with fertility status after treatment, and this may be of clinical value in guiding judgment, particularly for those who are disinclined to providing samples for semen analysis.

References

1. Schover LR, et al. Knowledge and experience regarding cancer, infertility, and sperm banking in younger male survivors. J Clin Oncol. 2002;20:1880-1889.

2. Kreuser ED, et al. Reproductive and endocrine gonadal capacity in patients treated with COPP chemotherapy for Hodgkin's disease. J Cancer Res Clin Oncol. 1987;113:260-266.

3. Rueffer U, et al. Male gonadal dysfunction in patients with Hodgkin's disease prior to treatment. Ann Oncol. 2001;12:1307-1311.

4. da Cunha MF, et al. Recovery of spermatogenesis after treatment for Hodgkin's disease: limiting dose of MOPP chemotherapy. J Clin Oncol. 1984;2:571-577.

5. Kulkarni SS, et al. Gonadal function following ABVD therapy for Hodgkin's disease. Am J Clin Oncol. 1997;20:354-357.

6. Dousset B, et al. Seminal cytokine concentrations (IL-1beta, IL-2, IL-6, sR IL-2, sR IL-6), semen parameters and blood hormonal status in male infertility. Hum Reprod. 1997;12:1476-1479.

7. Huleihel M, et al. Distinct expression levels of cytokines and soluble cytokine receptors in seminal plasma of fertile and infertile men. Fertil Steril. 1996;66:135-139.

8. Clark ST, et al. Gonadal function following chemotherapy for Hodgkin's disease: a comparative study of MVPP and a seven-drug hybrid regimen. J Clin Oncol. 1995;13:134-139.