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Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis
  1. Peter M Villiger1,
  2. Gion Caliezi1,
  3. Véronique Cottin2,
  4. Frauke Förger1,
  5. Alfred Senn3,
  6. Monika Østensen1
  1. 1Department of Rheumatology, Clinical Immunology and Allergology, University Hospital and University of Bern, Switzerland
  2. 2Laboratory Viollier, Bern, Switzerland
  3. 3Centre de Procréation Medicalement Assistée et d'Endocrinologie Gynécologique, Lausanne, Switzerland
  1. Correspondence to Professor Peter M Villiger, Department of Rheumatology, Clinical Immunology and Allergology, University Hospital and University of Bern, CH-3010 Bern, Switzerland; peter.villiger{at}insel.ch

Abstract

Objective To study the influence of tumour necrosis factor (TNF) antagonists on spermatogenesis in a cohort of patients with spondyloarthritis (SpA).

Patients and methods Semen samples of 26 patients with SpA were analysed according to WHO 1999 guidelines with and without TNF blocking agents (infliximab, etanercept or adalimumab). Results were compared with semen samples of 102 healthy volunteers.

Results Sperm abnormalities were found in 10/11 patients without anti-TNF therapy. The sperm of these 11 patients had significantly poorer motility (p=0.001) and vitality (p=0.001) than found in 15 patients tested during longstanding anti-TNF therapy, but sperm concentration and morphology were similar in the two groups. There was no significant difference of sperm quality between healthy controls and anti-TNF treated patients with SpA. Notably, sperm abnormalities were also found in 102 healthy controls.

Conclusion Sperm abnormalities are a common finding in healthy men, they are more pronounced in patients with active SpA. The sperm quality of patients with SpA with inactive disease receiving long-term TNF inhibition is comparable to that in healthy controls. The data support continuation of anti-TNF treatment when fatherhood is planned.

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Introduction

Since the launch of the first tumour necrosis factor (TNF) blocking agent, infliximab, a rapidly increasing number of patients have been treated with biological agents. However, knowledge about potential detrimental, or, conversely, positive effects of these agents on spermiogenesis and fertility is scarce. For spondyloarthritis (SpA), there has been an increasing perception among young male patients that TNF blockers may impair fertility or be mutagenic.

TNF has an important positive role in the male gonadal tract with effects on germ cell apoptosis, regulation of secretion of peritubular cells and sperm survival.1 However, at high tissue concentration, adverse effects on spermatogenesis have also been seen.2 Currently, there are no solid data indicating an impairment of spermatogenesis by TNF antagonists in men.3 A study of three men with SpA treated with infliximab for 8–24 months showed asthenozoospermia (reduced sperm motility) and teratozoospermia (abnormally shaped sperms), but there was no comparison with male patients not treated with TNF inhibitors or with healthy volunteers.4 No reports have been published about the effects of etanercept and adalimumab on male gonadal function.

The aim of the study was to investigate the influence of the currently available TNF antagonists on spermatogenesis in men with SpA.

Patients and methods

Twenty-six patients fulfilling the European criteria for SpA5 were included in the study during the years 2005–9. Sperm analysis was performed in a group of 11 patients without anti-TNF therapy, of whom five patients were retested after at least 3 months (five paired samples). In addition, a group of 15 patients receiving long-term and successful treatment with TNF blocking agents was analysed. Table 1 shows patient's characteristics, treatment and median duration of anti-TNF treatment before semen analysis. The control cohort consisted of 102 healthy volunteers applying for sperm donation whose sperm was analysed by two different Swiss laboratories using the methods described below. The volunteers were analysed during the years 2005–9 and did not differ from the patients in regard to any of the above mentioned health variables. Their median age was 35 years (range 18–51).

Table 1

Characteristics of patients with SpA not treated or treated with TNF inhibitors

To achieve and sustain disease remission, doses of 3–5 mg/kg of infliximab were given at intervals of 4–12 weeks (mean 9 weeks), 40 mg of adalimumab (every 2 weeks) or etanercept 50 mg (weekly). Clinical assessment of the patients included the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and measurement of C-reactive protein. All men answered a questionnaire providing information on events and exposures with a possible influence on spermatogenesis. Topics considered were disease duration, former and actual drug treatment, use of nicotine, alcohol, illicit drugs, presence of non-rheumatic chronic disease, occupational exposure to toxic agents and diseases or trauma of the genital tract.

Concomitant immunosuppressive treatment was methotrexate (MTX; median dose 10 mg/weekly), sulfasalazine (median 2.25 g/day) and azathioprine (50 mg/day in one patient with Crohn's disease). Eight patients used nicotine and 24 reported alcohol intake once or several times weekly. Gonadal pathology was present in four men: two with late surgery for undescended testes, one with trauma of the testes and one with varicocele.

The semen samples were collected by masturbation after 3–7 days of sexual abstinence. Sperm quality was assessed according to the WHO guidelines from 1999.6 Sperm morphology was assessed as described by Menkveld et al.7 Parameters measured were sperm concentration (reference limit >20 G/l), vitality (reference limit >50%), sperm motility (reference limit >50%) and morphology (reference limit >14% of normal oval forms). Asthenozoospermia (reduced sperm motility), teratozoospermia (abnormally shaped sperms) and oligospermia (low sperm count) all contribute to male infertility. When the first sample was abnormal, patients were advised to repeat the semen analysis within 2 weeks. Additional hormonal tests, including determination of follicle-stimulating hormone, luteinising hormone and testosterone, were performed in six patients.

The study was approved by the ethics committee of the University of Bern and informed consent was obtained from all patients.

Statistics

Before/after treatment comparisons were made by the Wilcoxon test for paired samples. Study groups were compared using the Mann–Whitney U test for unpaired samples. A p value <0.05 was accepted as significant.

Results

Eleven patients with SpA not receiving anti-TNF therapy had a sperm analysis. Teratozoospermia was detected in 10, with additional asthenozoospermia in five and oligospermia in three. Fifteen patients were studied during treatment with a TNF inhibitor (duration of treatment 6 months to 4 years). Four of these patients had a normal spermatogram. In 11 patients teratozoospermia (of moderate degree in five cases) was detected, combined with asthenozoospermia in one, and oligospermia in two patients. No difference in sperm quality was detected between patients concomitantly treated with azathioprine or MTX and those without such treatment (not shown). Six patients receiving treatment repeated the semen analysis because of initial sperm abnormality, but the semen of only one man turned from pathological to normal, the other samples were unchanged. Hormonal status in six men with repeated semen analysis was normal. Three patients receiving treatment with a TNF inhibitor fathered healthy children.

When the sperm quality of the 11 anti-TNF naive patients was compared with that of 15 patients tested during anti-TNF therapy, a significant difference was detected in motility and vitality (motility p=0.001, vitality p=0.001). We saw no difference in sperm concentration or morphology (figure 1). Accordingly, sperm quality tended to improve within the five paired samples for sperm vitality (p=0.08) and sperm motility (p=0.08), yet owing to the small number of longitudinal samples the values did not reach statistical significance. The longitudinal data for sperm concentration (p=0.9) and percentage of normal forms (p=0.2) were more heterogeneous.

Figure 1

Sperm concentration, motility, vitality and forms of 102 healthy donors (HC) as compared with 11 patients with spondyloarthritis (SpA) without anti-tumour necrosis factor (TNF) treatment and 20 patients with spondyloarthritis with anti-TNF treatment (SpA/anti-TNF). Among the patients with spondyloarthritis, five paired samples were followed up before and during anti-TNF treatment (shown by interconnected dots). Horizontal bars show the median.

Impaired sperm quality was especially found in the group of anti-TNF naive patients with active disease (table 1). However, no significant correlation between disease activity as measured by BASDAI or C-reactive protein levels and sperm quality was found.

Sperm characteristics of the 11 patients without TNF inhibitors were compared with those of the healthy control group: motility and vitality were significantly reduced in patients compared with controls (motility p=0.007, vitality p=0.004). When the spermiograms of all patients receiving anti-TNF-treatment were compared with those from 102 controls no significant difference in sperm quality emerged.

Discussion

This is the first study comparing sperm quality in patients with SpA receiving TNF inhibitors, anti-TNF naive patients with SpA and healthy controls. In our study long-term successful treatment with anti-TNF therapy appeared to have positive effects on certain sperm characteristics such as motility and vitality, probably by reducing disease activity. This contrasts with the findings of semen quality in 10 men receiving infliximab for inflammatory bowel disease (IBD).8 Seven of the patients with IBD were receiving maintenance treatment with infliximab, three men were infliximab naive. Motility and percentage of normal oval forms were below normal pre- and postinfusions, and the proportion of normal oval forms was lower in the men receiving maintenance treatment. The different results may be due to differences in study design, in disease pathogenesis or disease activity.

Five of our patients were treated with TNF antagonists combined with MTX. MTX given in high doses or combined with other cytotoxic drugs has occasionally induced oligospermia.9 However, no data exist indicating alterations in sperm quality or quantity if MTX is given in low doses at weekly intervals.9 Accordingly, the five patients receiving combination treatment and the men receiving monotherapy with TNF antagonists had similar spermiograms.

The majority of our patients with SpA showed sperm abnormalities before treatment with TNF antagonists. Importantly, however, 80% of the healthy controls also showed one or several sperm abnormalities. This is in line with a recent investigation on semen quality in Swiss conscripts aged 18–20 years.10 Of the 770 men participating, 55% showed one or several sperm parameters below the WHO 1999 reference values. In another Swiss study performed in the same region as the present investigation, some degree of sperm pathology was found in all 34 healthy men.11 Of note, all of these volunteers were fertile, their female partners were pregnant at the time of the spermiogram. Collectively, the data indicate that the WHO 1999 reference values were not adequate for all parameters of sperm quality. Indeed, a revision of the reference limits was published in 2009.12

Gonadal function has been studied in men with ankylosing spondylitis (AS) and psoriatic arthritis by investigating hormonal status. Hypogonadism has been found in some studies, but others found normal levels of testosterone, luteinising hormone and follicle-stimulating hormone in men with AS,13 as we did in our study. Normal reproductive function has been reported in male patients with IBD or AS who have fathered healthy children during treatment with infliximab.3 14

In conclusion, our results show comparable sperm abnormalities in successfully, long-term treated patients with SpA and healthy volunteers. TNF inhibition in this autoimmune inflammatory disease did not impair any of the sperm characteristics. Thus, patients facing TNF blocking therapy should be informed that treatment with these biological agents does not affect reproduction and that treatment need not be interrupted if fatherhood is planned. A larger study should be done to confirm these data.

Acknowledgments

The authors would like to thank all the patients who participated in this study. The authors also would like to thank Yves Bartels from the Institute for Statistics, Department of Mathematics, University of Bern, for performing the statistical analysis.

References

Footnotes

  • Funding This study was supported by an unrestricted grant from Wyeth.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the ethical committee of Bern, Switzerland.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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