Effect of fexofenadine, a mast cell blocker, in infertile men with significantly increased testicular mast cells

Selahittin Çayan¹, Duygu Dusmez Apa², Erdem Akbay¹

¹Department of Urology, ²Department of Pathology, University of Mersin School of Medicine, Mersin 33079, Turkey

Asian J Androl 2002 Dec; 4: 291-294           

Keywords: male infertility; testicular biopsy; mast cells; mast cell blocker; fexofenadine; semen quality

Abstract

Aim: To investigate the role of fexofenadine, a mast cell blocker, on semen quality in the treatment of infertile men. Methods: The study included 16 Turkish idiopathic infertile men with azoospermia or oligozoospermia who underwent testicular biopsy to examine mast cells containing tryptase. In all patients, a complete medical history, clinical examination, semen analysis and serum hormone assay were carried out. The biopsy specimens were immunohistochemically stained with antihuman tryptase for mast cells. The number of total mast cells per seminiferous tubule was calculated and recorded as mast cell index. The patients were divided into two groups according to their mast cell index: the higher (1, n=9) and the lower (<1, n=7) index groups. Fexofenadine was administered orally at a dose of 180 mg/day for 4 to 9 months. Pre- and post-treatment semen parameters, including total motile sperm counts (TMC) were recorded and compared. Spontaneous pregnancies after the treatment were registered. Results: There was no statistically significant difference in TMC between the pre-treatment and post-treatment values in patients with higher and lower mast cell index (P0.05). In both groups, nobody had a significant response to the treatment and there was no spontaneous pregnancy after the treatment. Conclusion: Although testicular dysfunction is closely associated with increased number of testicular mast cells, fexofenadine, a mast cell blocker, appears not having any benefit in the treatment of Turkish infertile men with a significant increase in testicular mast cells.

Mast cells are present in many peripheral tissues and human testis [1] and have been shown to play an important role in inflammatory, hypersensitivity and fibrotic disorders [2, 3]. Mast cell products, including histamine and serotonin, could be involved in testicular steroido-genesis [4]. Mast cells activate fibroblasts and promote collagen synthesis [2, 3, 5-7]. Fibrotic changes in the tubular walls have been reported in testes of infertile men [1, 3, 8].

Our previous study [8] and other studies [1,3] showed a marked increase in the number of testicular mast cells in infertile men. Mast cell blockers have been empirically used in the treatment of male infertility with favourable results [9,10]. The aim of the study was to investigate the effect of fexofenadine, a mast cell blocker, in the treatment of infertile men.

The study was approved by the Institutional Ethical Committee at the University of Mersin School of Medicine. Sixteen Turkish infertile men visited or referred to us for infertility evaluation and treatment were included in the study. The mean age of patients was 34.57.2 (range 24 to 49) years and the mean infertility duration was 4.56 3.94 (range 1 to 14) years. All patients had a primary idiopathic infertility for more than one year without an urologically correctable or treatable pathology (varicocele, ejaculatory duct or epididymal obstruction, etc.). A complete history was taken and a general physical examination was performed by the same specialist (SÇ). Semen was collected by masturbation after 2~4 days of abstinence and processed within one hour of ejaculation. Serum follicle stimulating hormone (FSH) and testosterone and semen routine parameters were assessed. Semen analyses were performed at the same andrology laboratory according to the World Health Organization (WHO) criteria [11].

2.2 Testicular biopsy

Testicular biopsy was performed using a window technique by the SÇ after obtaining informed consent. An open biopsy specimen was touched onto or gently moved across a microscope slide with fine tissue forceps for cytologic evaluation [12]. Biopsy specimens were fixed in Bouin's fixative, embedded in paraffin and processed for histologic and immuno-histochemical studies by the same pathologist (DDA). The specimens were stained with haematoxylin-eosin for the evaluation of spermatogenesis and immunohisto-chemically stained with antihuman mast cell tryptase (dilution 1:60; DAKO, Glostrup, Denmark) for mast cells. The number of tryptase-positive mast cells was counted at 400 magnification. In each section, all fields were evaluated for the total number of mast cells as well as the total number of seminiferous tubules. The number of mast cells per seminiferous tubule was calculated and was designated as the mast cell index. The patients were divided into two groups: the higher (1) mast cell index group (n=9) and the lower (<1) mast cell index group (n=7).

2.3 Treatment and observation

Fexofenadine (Telfast, Hoechst, Turkey) was administered orally at a dose of 180 mg/day for 4.7 2.3 (range 4 to 9) months. Pre- and post-treatment semen parameters, including sperm concentration, sperm motility, sperm morphology, were assessed. The total motile sperm count (TMC = ejaculate volumesperm concentration motile fraction) was calculated. A more than 50 % increase in TMC after the treatment was considered a significant response to treatment. The side effects and the spontaneous pregnancies were also recorded.

2.4 Statistical analysis

Data were expressed as mean SD. Statistical analyses were performed using the paired t-test to compare the differences in TMC and the independent t-test, the differences in semen parameters. Probability values of <0.05 were considered significant. Confidential intervals (CI) were also calculated.

3 Results

3.1 Baseline data

The left testicular volume was 15.4 5.8 (range 8 to 25) mL and right, 16.4 ?4.8 (range 10 to 25) mL. The serum FSH and testosterone values were 15.413.7 (range 2.8 to 49.0) mIU/mL and 5.52.6 (range 1.7 to 12.6) ng/mL, respectively. Eight men were azoospermic and 8, oligozoospermic at various degrees. Testicular biopsy indicated hypospermatogenesis at various degrees in 6 patients, normal spermatogenesis in 4, maturation arrest at the spermatocyte or spermatid level in 3, and germ cell aplasia with focal spermatogenesis in 3.

The mean mast cell index of all patients was 1.1 ? 0.4 (range 0.4 to 2.0). The mast cell index was 1 in 9 patients (mean: 1.40.3) and <1 in 7 patients (mean: 0.70.19).

3.2 Post-treatment data

No side effect was observed in all the patients. The mean TMC decreased from 2.41.0 million to 2.2 1.0 million after the treatment, but the change was statistically insignificant (P>0.5, 95 %, CI:-0.918-1.181).

Table 1 lists the clinical and laboratory observation of patients with higher and lower mast cell indices. It can be seen that after the treatment the TMC decreased from 2.91.8 to 2.4 1.4 million in the lower mast cell index group and increased from 1.91.3 to 2.1 1.4 million in the higher mast cell index group, however, there was no statistically significant difference (P>0.05, 95 % CI: -2.86-1.46). Improvement in TMC after the treatment was observed in 4 (44.4 %) out of 9 patients with higher mast cell index and in 3 (42.9 %) out of 7 patients with lower mast cell index, revealing no statistical significance (P>0.05). In both groups, nobody had a significant response to the treatment and no spontaneous pregnancy was observed.

Table 1. Serum hormone and semen characteristics of patients with higher and lower mast cell index. ^cP<0.01, compared with higher mast cell index group.

4 Discussion

Several studies including our previous work have shown that an increase in the number of testicular mast cells is related to spermatogenic disorders and testicular fibrosis [1, 2, 8, 13, 14]. This has also been related to dysfunction of the blood-testis barrier [13]. Mast cells are seen within the intertubular and peritubular areas of human testis [8]. In contrast to intertubular mast cells, peritubular mast cells have been reported to be found in close proximity to seminiferous tubules or in the lamina propria itself [14]. Fibrosis, that occurs in the interstitium and lamina propria of the seminiferous tubules, is one of the main histological changes in infertile men [5-7]. A significant relationship has been observed between the number of mast cells and the ratio of tubules with sclerosis as well as the fibrosis index [3, 8].

Mast cell blockers have been empirically used in the treatment of male infertility with a significant improvement in semen quality and spontaneous pregnancies have been reported [9, 10]. In a placebo-controlled single-blind clinical study done by Yamamoto et al [9], fifty men with severe idiopathic oligozoospermia were prescribed randomly tranilast, a mast cell blocker, or a placebo for 3 months. They reported significantly higher levels of semen parameters and 28.6 % of pregnancy rate in the mast cell blocker group, while no pregnancy occurred in the plasebo group. Matsuki et al investigated the effect of ebastine, a mast cell blocker, on semen quality in 15 idipathic oligospermic men [10]. They reported that 66.7 % of the patients had definite improvement in semen quality and 20 % achieved pregnancy with their partners within 6 months of treatment. In contrast to previous studies, we found that the semen parameters and TMC of the patients in our group did not change significantly after mast cell blocker treatment and no one achieved spontaneous pregnancy. The reason of discrepancy between the previous and this studies may be due to the difference in patient selection, the use of different mast cell blockers and their doses and the possibility of an ethnic difference.

In conclusion, we believe that the use of fexofenadine does not benefit the treatment of Turkish infertile men with a significantly increased number of testicular mast cells.

References

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Correspondence to: Selahittin Çayan, M.D., Assistant Professor, Department of Urology, University of Mersin School of Medicine, 33079- Mersin, Turkey.

Tel: +90-532-346 0509,   Fax: +90-324-337 4332

E-mail: selcayan@mersin.edu.tr

Received 2002-06-07     Accepted 2002-10-29