Comparison of the effectiveness of placebo and a-blocker therapy for the treatment of idiopathic oligozoospermia *

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1 FERTILITY AND STERILITY Copyright c 1995 American Society for Reproductive Medicine Printed on acid-free paper in U. S. A. Comparison of the effectiveness of placebo and a-blocker therapy for the treatment of idiopathic oligozoospermia * Masanori Yamamoto, M.D.t Hatsuki Hibi, M.D. Koji Miyake, M.D. Department of Urology, Nagoya University School of Medicine, Nagoya, Japan Objective: To determine whether a-blocker (bunazosin) improves fertility and/or semen parameters in oligozoospermic men. Design: Placebo-controlled, double-blind clinical study. Setting: Nagoya University Hospital Andrology Clinic, Nagoya, Japan. Patients: Thirty-four men with sperm density between 5 and 20 X 10 6 sperm/ml, normal serum gonadotropins and T, and a fertile partner were enrolled in this study. Interventions: After a 3-month control period, patients randomly were prescribed bunazosin 2 mg/d or a placebo, two tablets per day, for 6 months. Semen and blood samples were collected before and after therapy. Semen parameters, serum gonadotropins, T, PRL, and E2 were evaluated before and after therapy. Results: The pregnancy rate (PR) in the a-blocker group was 25%, compared with 6.7% in the placebo group. There was no statistical difference in the PR between groups. The a-blocker group had significantly higher levels of sperm density and total motile sperm count. There were no differences between the placebo and a-blocker groups in seminal volume, the percentage of motile sperm, and normal morphology or hormone levels. Conclusions: The authors conclude that a-blocker is a useful drug in the treatment of idiopathic moderate oligozoospermic men. Fertil Steril 1995;63: Key Words: a-blocker, idiopathic male infertility, pregnancy rate Many therapies for male infertility have been tested using drugs that theoretically could improve semen parameters by acting directly on spermatogenesis or epididymal maturation. However, there is no standard established method for the treatment of idiopathic male infertility. Gonadotropins (1), GnRH (2), clomiphene citrate (3), tamoxifen (4), and high-dose T (5) are rarely, if ever, more successful than no treatment. Recent research has demonstrated that the oral administration of a-blocker and ~-stimulator in- Received April 4, 1994; revised and accepted August 19, * Supported by a grant-in-aid for Scientific Research (no ) from the Ministry of Education, Science, and Culture of Japan, Tokyo, Japan. t Reprint requests: Masanori Yamamoto, M.D., Department of Urology, Nagoya University School of Medicine 65, Tsurumai-cho, Showa-ku Nagoya 466, Japan (FAX: ). creases the ejaculated spermatozoa output (6). More recently, several subsequent papers have suggested that a-blocker and ~-stimulator combined therapy for idiopathic male infertility revealed only a slight effectiveness and substantial adverse effects because of ~-stimulator (7, 8). Yamashita et al. (7) and Yamashita (8) have attempted to treat the patients with oligozoospermia or azoospermia with a-blocker therapy alone. They suggest that a blocker therapy for idiopathic male infertility is clinically useful and that the mechanism of the therapy is due to the dilatation of epididymal tubules. On the basis of effectiverwss ofa~blocker therapy for male infertility, we attempted to carry out a placebo-controlled, double-blind trial of a-blocker therapy in patients with idiopathic male infertility. Here we have demonstrated for the first time convincing evidence of improvement in fertility after oral administration of a-blocker. 396 Yamamoto et al. a-blocker therapy in male infertility

2 MATERIALS AND METHODS Research Subjects Thirty-one adult males, ranging in age from 25 to 42 years, participated in this study. These men had no evidence of major systemic illness. They had a diagnosis of infertility, which was defined as an inability to have children after 1 year of unprotected sexual intercourse. The sterility of the couples lasted from 1 to 8 years (mean, 3.4 years). These male partners fulfilled the following criteria: [1] three semen analyses in which highest sperm density ranged between 5 and 20 X 10 6 /ml, normal sperm morphology was >60%, and sperm motility was> 10%; [2] normal serum values for LH, FSH, T, PRL, and E 2 ; and [3] a female partner who was determined to be fertile on the basis of history, physical examination, BBT, menstrual history, sexual hormone levels, and, when performed, a normal hysterosalpingogram. Examinations of hysterosalpingography were distributed evenly between the a-blocker group and placebo group. All couples included in this study were informed fully about the nature and aims ofthe study, an essential prerequisite for obtaining accurate information. They were provided with a written description of the protocol, including any potential adverse effects of the drug and the information that one of the drugs to be administered was a placebo. Experimental Design All patients were followed up for a 3-month control period. After this period, the patients received either a-blocker (group 1) or a placebo (group 2) for 6 months. The patients were assigned randomly and blindly treatment with oral administration of a-blocker (2 mg/d, Bunazosin; Eisai Co., Ltd., Tokyo, Japan) or a placebo tablet two times per day. Sixteen patients received a-blocker, and 15 received placebo. The drug and placebo were dispensed in identical appearing tablets. During the control period and after treatment, three semen samples and one blood sample were collected. Semen was evaluated for a standard semen analysis. All semen analyses were carried out by the same examiner in a blind protocol. Blood was evaluated for LH, FSH, T, PRL, and E 2, and the routine laboratory test. The highest sperm density and percentage of motile sperm and normal form sperm before treatment were defined as the baseline value of each subject. The lowest sperm density and percentage of motile sperm and normal form sperm after treatment were defined as the value over the treatment period of each subject. Semen Analysis Each subject was asked to abstain from ejaculation for 5 days before submission of the specimen. Semen sample collections were scheduled to coincide with the partner's menses, but semen samples after the period of treatment were obtained within 1 month of stopping treatment. The specimens were obtained by masturbation into a clean, dry, widemouth glass container and delivered to the examiner within 30 minutes of collection. Samples were evaluated in the fashion described by the World Health Organization manual for semen analysis (9). Electrolytes, liver, and kidney function tests, and a complete blood count were performed before and after treatment. Physical examinations including measurement of blood pressure were performed on each subject during the control period and after treatment to document any side effects and possible changes in physical examination. Statistical Analysis Means ± SEs were calculated on all the variables measured in the two groups. To assess the efficacy of treatment on seminal parameters, we compared for each patient, the after treatment value with the before treatment value. This comparison was performed by subtracting the before treatment value from the after treatment value. The difference in these values between placebo group and treatment group was analyzed statistically by using Wilcoxon's rank sum test (for nonparametric statistics). The x 2 test was used to compare the pregnancy rate (PR) in the a-blocker and placebo groups. A P value < 0.05 was considered to indicate a statistically significant difference. Statistical calculations were performed by a personal computer (IBM Corp., Boca Raton, FL) using Systat software (SYSTAT, Inc., Evanston, IL). Physical Examination RESULTS Side effects reported by patients in the a blocker-treated group consisted of nasal obstruction in one patient that was well tolerated, and treatment continued. Three patients suffered from orthostatic dizziness that disappeared spontaneously and did not necessitate discontinuation of the Yamamoto et al. a-blocker therapy in male infertility 397

3 Table 1 Changes in Semen Parameters After Administration of Placebo or a-blocker Sperm concentration (X10 6 /ml) Total motile sperm count (X10 6 ) Seminal volume (ml) Motility (%) Normal morphology (%) Values are means ± SE. After treatment valuebefore treatment value a-blocker Placebo (n = 16) (n = 15) Probability 23.1 ± ± ± ± ± ± ± ± ± ± treatment. No significant changes in physical examination were observed in any of the patients in the placebo group. There was no significant change in blood pressure between before and after treatment in placebo or a-blocker group. Toxicologic Studies No adverse effects were noted in either group throughout the study. There was no significant alteration in the parameters measured. Treatment Versus Placebo Group During the control period, there were no significant differences in the semen analyses or hormonal values between the two groups. After treatment, there were no significant differences in hormonal values between the two groups. These statistical comparisons were made by Student's t-test. The changes in semen parameters after treatment in both groups are shown in Table 1. The mean baseline for sperm concentration was 9.93 X lob jml (median, 9.0) and 9.47 X lo B jml (median, 7.0) for patients receiving placebo and for those treated with a-blocker, respectively. There was a statistically significant higher increase in sperm concentration in patients treated with a-blocker than in those receiving placebo (P < ). The mean baseline for total motile sperm count was 12.1 X lob (median, 12.0) and 7.0 X lob (median, 5.2) for patients receiving placebo and for those treated with a-blocker, respectively. There was a significant increase in the total motile sperm count in the a blocker treatment group compared with the control group (P < ). These statistical analyses were performed by Wilcoxon's rank sum test. There were no significant differences in seminal volume or sperm motility between the two groups. No significant difference was noted in the percentage of normal morphology between the two groups. There were no significant differences in semen quality or hormone factors between the patients who achieved pregnancy and those who did not achieve pregnancy. However, those who achieved a pregnancy had improved post-treatment semen quality. Pregnancy Rates The cumulative PR was determined for the cumulative period of treatment. This rate in the partners of men taking a-blocker was 25% (4 pregnancies) compared with 6.7% in the partners of men taking placebo (1 pregnancy). The difference between the PRs was not significant (P = 0.16), possibly because of the small number of patients (Table 2). DISCUSSION We have conducted the first placebo-controlled, double blind trial to evaluate the promise of a blocker as a potential therapeutic modality for idiopathic oligozoospermic men. In this study, we used bunazosin as the a-blocker. Bunazosin is claimed to be a highly selective a-adrenoceptor antagonist that has presynaptic and postsynaptic a-adrenoceptor blocking effects on the isolated vas deferens of the rat (10) and therapeutic efficacy in the treatment of mild-to-moderate hypertension in humans (11). The oral administration of a-blocker to the patients with idiopathic oligozoospermia demonstrated a significant increase in the sperm concentration and total motile sperm count. These results are apparently paradoxical because contractions of the seminiferous tubules and epididymal tubules for propelling sperm toward the vas deferens are mediated by stimulation of the adrenergic sympathetic nerve (12, 13). Nevertheless, recently a number of papers have suggested that an a-adrenoceptor antagonist could have some effect on male Table 2 Pregnancy Rate After Administration of a-blocker or Placebo a-blocker Placebo Pregnancy (+) 4 (25)* 1 (6.7) * Values in parentheses are percentages. Pregnancy (-) Total Yamamoto et al. a-blocker therapy in male infertility

4 fertility (8, 14, 15). Yamashita (7) treated 22 infertile men with oral administration of a-blocker (bunazosin, 3 mg/d), and effective sperm density and sperm motility rates were observed in 36% of patients after 12 weeks of bunazosin therapy and in 60% after 24 weeks (7). Bunazosin therapy was ineffective in azoospermic men and only slightly effective in men with elevated plasma levels of gonad- 0tropin. Only 2 men (9.1 %) experienced side effects to bunazosin therapy (8). In our present study, a significant increase in sperm density and total motile sperm count was recognized in the a-blocker therapy group compared with the placebo group. Ratnasooriya et al. (14) reported that terazosin, which is one of the a-blockers, induced an increase in the vaginal sperm count index substantially on day 7 after se injection ofterazosin into the rat. On the other hand, Gulmez et al. (15) treated 33 infertile men with a combination of a-blocker and ij-stimulator for 7 days, and the sperm density and motility changed insignificantly, whereas the seminal volume decreased insignificantly. Their unfavorable results may be due to the short term of the therapy. The exact mechanism responsible for the increase in sperm output after administration of a blocker and the importance of the autonomic nervous system in the reproductive tract and sperm fertility remains to be elucidated. Billups et al. (16) investigated the involvement of the sympathetic nervous system in the transport and storage of spermatozoa in the rat reproductive tract by surgically ablating the inferior mesenteric plexus that provides adrenergic innervation to the epididymis. Ablation of the inferior mesenteric plexus resulted in a sustained increase in the number of epididymal spermatozoa without apparent effects on testicular weight, sperm production, or T (16). They interpret the increase in epididymal sperm numbers after ablation of the inferior mesenteric plexus as the loss of tubular sympathetic tone that may, in part, increase the rate of sperm transport from caput to cauda epididymis and subsequently elicit the increased accumulation of the cauda epididymal sperm numbers (16). Blockage of the a-adrenoceptor, which means chemical sympathectomy, seems to have an effect similar to ablating the inferior mesenteric plexus. Therefore, the same mechanism as seen in the ablation of the inferior mesenteric plexus could be involved in the increase in sperm density after a-blocker therapy. These previous investigations, combined with the results of our present studies, suggest strongly that the autonomic nervous system has a very important role in the sperm output in the ejaculates. We did not find differences in the percentage of motile spermatozoa between the a-blocker therapy and placebo groups. Thus, it would be effective to treat idiopathically infertile men with a combination of a-blocker and other drugs that can increase sperm motility. Experimental animal studies on the effect of a-blocker on epididymal semen quality, intratubular pressure, tubular diameter, and velocity of fluid movement in the epididymis using the in vivo micropuncture technique are currently underway in our laboratory. In conclusion, we have shown a significant improvement in the sperm concentration and total motile sperm count 6 months after oral administration of a-blocker to patients with moderate oligozoospermia. Although the number of patients was not large, the results of this study strongly suggest that a-blocker possesses considerable promise as a future regimen of medical treatment for idiopathic male infertility. Further studies to confirm our results should be encouraged. REFERENCES 1. Knuth UA, Honigl W, Bals-Prratsch M. 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