The Effect of Radiation on Semen Quality and Fertility in Men Treated With Brachytherapy for Early Stage Prostate Cancer

The Effect of Radiation on Semen Quality and Fertility in Men Treated With Brachytherapy for Early Stage Prostate Cancer Dilpreet K. Singh, Karen Hersey, Nathan Perlis, Juanita Crook, Keith Jarvi and Neil Fleshner*,† From the Division of Urology, Princess Margaret Hospital and Mount Sinai Hospital (DKS, KH, NP, KJ, NF), Samuel Lunelfeld Research Institute, Mount Sinai Hospital (KJ) and The Institute of Medical Sciences, University of Toronto, Toronto, Ontario (KJ), British Columbia Cancer Agency, Kelowna, British Columbia (JC), Canada

Purpose: We determined the effects of prostatic brachytherapy on semen parameters and sperm DNA integrity, and the potential impact on fertility. Materials and Methods: Five screened patients treated with brachytherapy participated in a pilot study visit to undergo early morning blood collection for serum hormone evaluation and semen collection for semen analysis and DNA integrity assay by sperm chromatin structure assay. Data on 7,617 infertile men, each with at least 1 semen analysis and sperm DNA integrity assay, were obtained from an institutional database for comparison. Published data on fertile men were compared to data on those with brachytherapy for DNA fragmentation analysis. Results: All brachytherapy cases had normal serum luteinizing hormone, folliclestimulating hormone and testosterone. Specific semen parameters, such as semen volume (p ⬍0.0005), total sperm concentration (p ⬍0.0004) and percent sperm motility (p ⬍0.004), were significantly lower than normal reference values. As measured by the DNA fragmentation index, the mean sperm DNA fragmentation of 46.4% in brachytherapy cases was significantly higher than in the fertile group (13.3%, p ⬍0.0003), the total infertile group (20.4%, p ⬍0.0002) and the age matched infertile group 45 to 53 years old (27.9%, p ⬍0.03). All men with brachytherapy had an abnormal sperm DNA fragmentation index, indicating likely infertility in all. Conclusions: Infertility may well be a long-term adverse effect of brachytherapy for localized, low grade prostate cancer. All men who undergo brachytherapy should be counseled about its potential impact on fertility.

Abbreviations and Acronyms BT ⫽ brachytherapy DFI ⫽ DNA fragmentation index Submitted for publication July 18, 2011. Study received institutional review ethics board approval. * Correspondence: Division of Urology, Department of Surgical Oncology, Princess Margaret Hospital, 610 University Ave., 3-130, Toronto, Ontario, M5G 2M9, Canada (telephone: 416-9464501, extension 2899; e-mail: Neil.Fleshner@uhn. on.ca). † Financial interest and/or other relationship with AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, BioAdvantex and Merck.

Key Words: prostate; prostatic neoplasms; infertility, male; brachytherapy; DNA damage THE post-cancer treatment effects of radiation on fertility have been described for patients who survive testicular cancer and leukemia, which are diseases that afflict young men.1 In contrast, the post-radiation effects of prostate cancer treatment on fertility are not well understood. As prostate cancer screening becomes more prevalent and cancer detection increases among asymptomatic men, younger men are being diagnosed and radically

treated.2 At the same time as younger men have a cancer diagnosis, men in the fourth or fifth decade of life are increasingly attempting paternity.3 Many men with low volume, low grade prostate cancer elect BT. This therapy is particularly suited for those interested in maintaining sexual function since some data suggest that it has the least adverse effects on erectile function compared to radical prostatectomy or external beam radi-

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EFFECT OF RADIATION ON SEMEN QUALITY AND FERTILITY

ation therapy.4 Particularly in men 55 years or younger Gomez-Iturriaga de Piña et al reported erectile function preservation, and low genitourinary and gastrointestinal toxicity rates when treated with BT as monotherapy, showing its effectiveness in this patient group.5 The impact of BT on semen parameters has not been well studied. Theoretical reasons, such as radiation induced anatomical changes and radiation scatter, may affect fertility. There are several recent case reports of men who purposefully or accidentally fathered children after radiation therapy for prostate cancer but most cannot father children after being treated.6 To better understand the relationship between prostate BT and fertility we examined routine semen parameters and sperm DNA integrity in 5 men after BT in a pilot study. Our goal was to better understand the pathophysiology of posttreatment infertility so that we can better counsel our patients with prostate cancer on the likelihood of fathering a child and options for posttreatment infertility.

MATERIALS AND METHODS Study Inclusion and Exclusion Criteria Cases of post-radiation prostate cancer treated with BT at least 1 year before analysis were identified from the BT program database.7 All patients were younger than 55 years, had Gleason score 6 or 7 disease and could provide a semen specimen. All men signed a consent form. This protocol was approved by the institutional review ethics board. Patients with a history of infertility or vasectomy, or androgen deprivation therapy within the last 6 months, 5␣-reductase inhibitor within the last 4 months or ␣-blockers within 7 days of semen specimen provision were ineligible for study.

Assessment Eligible patients determined by a prior screening visit underwent early morning blood collection for serum hormonal evaluation of testosterone, luteinizing hormone and follicle-stimulating hormone measurements. They also provided a semen sample to evaluate sperm volume, total and motile sperm concentration, viability, viscosity, morphology, motility, count and DNA integrity (by sperm chromatin structure assay). Semen samples were obtained by masturbation after 2 to 5 days of sexual abstinence. Seminal parameters were compared to those from an institutional database on 7,617 infertile men, which served as the positive control, and WHO 1998 normal reference ranges. Published data on the mean sperm DNA fragmentation of fertile men (control group), as measured by DFI,8 were compared to the DFI of BT cases. DFI is the index of the percent of damaged sperm measured by DNA fragmentation, as determined by sperm chromatin structure assay using a flow cytometer. These fertile control data also came from our laboratory. Mean values were compared to those of irradiated cases by the Student t test. Mean serum blood measurements of BT cases were compared to institutional laboratory nor-

mal values by the Student t test. Statistical analysis was done with SPSS®, version 18.0.

RESULTS The mean age of men in this study was 49.4 years (range 45 to 53). Data were collected on 5 eligible patients. DNA integrity assay was performed for 4 of the 5 BT cases. One man with BT could not provide sufficient motile sperm and was excluded from semen and DNA fragmentation analysis. Serum hormonal levels were determined for all 5 BT cases. No patient received prior androgen deprivation therapy or 5␣reductase inhibitors. All 5 BT cases had been treated with BT a mean of 4.3 years (range 3.4 to 5.8) from the semen collection date. Mean serum testosterone, luteinizing hormone and follicle-stimulating hormone in BT cases were within normal reference ranges (2.92 IU/l, 4.80 IU/l and 16.96 nmol/l, respectively). Semen analysis revealed that the mean percent of sperm viability was normal in all BT cases. There was no significant difference in mean normal morphology of BT cases compared to the reference value (22.5% vs greater than 30% normal, p ⫽ 0.0577). However, other mean ⫾ SD values of study BT cases were significantly lower than those of controls, including semen volume 0.38 ⫾ 0.24 vs 1.5 to 7.0 ml (p ⫽ 0.0005), total sperm concentration 248.90 ⫾ 232.01 vs less than 20 million ml⫺1 (p ⫽ 0.0004) and sperm motility 24.18% ⫾ 3.96% vs greater than 40% (p ⫽ 0.0041). The mean DFI of 46.38% in BT cases was significantly higher than in the fertile group (13.3%, p ⬍0.0003), the total infertile group of 7,617 men (20.41%, p ⬍0.00016) and the age matched group of 662 men 45 to 53 years old (27.87%, p ⬍0.03095). The proportion of infertile men with DFI greater than 30%, greater than 40% and greater than 50% was examined. Overall 18.4% of infertile men had DFI greater than 30%, 8.7% greater than 40% and 4.5% DFI greater than 50%.

DISCUSSION To our knowledge this pilot study is the first to show the long-term negative impact of radical prostatic radiation on sperm parameters and sperm DNA integrity. Sperm DNA fragmentation in patients with prostate cancer after BT was significantly greater than in fertile and infertile men, as evidenced by a mean DFI of 46.4%. DNA damage is common in infertile men. Nicopoullos et al determined that a DFI of greater than 30% to 40% is incompatible with fertility in vivo,9 indicating that men with prostate cancer may become infertile after BT. We also report that seminal parameters of patients with prostate cancer after BT were lower than

EFFECT OF RADIATION ON SEMEN QUALITY AND FERTILITY

WHO reference limits. A decrease in the seminal fluid volume reported for our BT cases may have been due to radiation induced alterations in the prostate.10,11 Low ejaculatory volume after BT is an intermediate term and long-term effect of treatment. Although one may hypothesize that ejaculatory duct obstruction is a mechanism of this, other hypotheses may also have a role, such as microacinar ductal obstruction and generalized ductal atrophy. Transrectal ultrasound, which was not done in this study, could help determine the mechanism of this observation. The radiation effect on the prostate may be substantial since radiation induced exocrine dysfunction, prostate and seminal vesicle obstruction may develop. Prostate architecture may undergo degeneration and be altered after irradiation, decreasing semen volume with time and altering the seminal fluid composition.10,11 We also noted decreased sperm motility in patients treated with BT. Erenpreiss et al reported that this negatively correlates with sperm DNA damage.12 Along with our DFI results this finding strongly suggests that infertility can occur among patients treated for prostate cancer after BT. Small numbers make interpreting the hormonal data somewhat problematic. Nevertheless, all of our BT cases had serum hormone levels within normal reference ranges. A limitation of this study is its cross-sectional design. Ideally pretreatment and posttreatment semen and hormonal analyses would be determined to analyze the serial change. Another limitation is its small sample size. A prior group calculated that the dose received by the testes in patients implanted with 125I was 0.18 Gy.13 Others argued that the dose varies between

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0.03 and 2.5 Gy based on the differing anatomical relationship between prostate and testes.6 Based on these findings patients treated with BT are likely exposed to a low testicular dose. As a result, they are not expected to become azoospermic and should have normal follicle-stimulating hormone since the dose exposure is below the 0.65 Gy threshold. Despite these theoretical considerations the degree to which post-BT semen analysis and fertility are affected remains poorly studied. Nevertheless, our semen analysis results are dramatic and give insight into the potential adverse effects of BT on fertility in patients with prostate cancer. Since few reports describe post-BT effects, further investigation in this area is necessary. Fertility has been documented after BT. Mydlo and Lebed noted no significant difference in pre-BT vs post-BT semen analyses in 4 patients interested in fathering children after therapy.11 Three of the 4 men successfully impregnated the partner after the 4-month posttreatment waiting period. Unlike in our study, Mydlo et al reported results a short time after BT. There are other reports of unintentional paternity up to 40 months after treatment.5 However, the DFIs in our study reveal the significant negative impact that radiation may have on fertility. Although fertility recovery is possible in these patients, the uncertainty of predicting which men will recover indicates the need for clinicians to counsel all men about the potential adverse effects of BT on fertility. Young men often favor BT because of preservation of erectile function14 but they should be counseled about the possible ramifications on fertility and be encouraged to consider pretreatment sperm cryopreservation.15

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