| BACKGROUNDThere are two types of potential male contraceptives, hormonal and non-hormonal. Although hormonal male contraceptives appear close to the final stage of development, long-term use of them might cause some side effects. Non-hormonal agents include chemicals targeting the testis (such as gossypol), the epididymis, sperm motility, sperm-egg fusion, and vaccines against gametes or hormones. But until now, there has been no safe and effective non-hormonal agent available, and only gossypol ever reached Phase Ⅱ trials.The al-adrenoceptor antagonists have been widely used in the treatment of lower urinary tract symptoms caused by benign prostatic hyperplasia, and have been innovatively applied to chronic prostatitis/chronic pelvic pain syndrome and urolithiasis recently. As the indications for using α1adrenoceptor antagonists have been extended to younger populations, adverse effects, especially ejaculatory dysfunction (EjD), are drawing more and more attention. It was reported that EjD occurred at1.6%ith tamsulosin and22.3%ith silodosin in a Phase III study. In another clinical study, tamsulosin caused an80%ecrease in ejaculatory volume in all six subjects and five of them showed azoospermia. According to Hellstrom’s study, tamsulosin caused the decrease in sperm concentration and total sperm count in healthy men.Semen transportation is accomplished by contraction of the smooth muscles of the genital tract, which is mediated through α1-adrenoceptors controlled by the sympathetic nervous system. There are three subtypes of al-adrenoceptors:alA-α1B-, and α1D-adrenoceptors. The distribution of al-adrenoceptors in human seminal vesicles is:α1A,75.0±4.0%; alB,11.7±3.1%; and α1D13.3±1.5%. In the human vas deferens, the expression ratio of al-adrenoceptors in the same order is97:0:3. The al A-adrenoceptor is also the dominate subtype in the smooth muscles of the prostate, and mainly mediates the contraction of them. Thus, blocking the a1A-adrenoceptor may inhibit the contractions of the seminal vesicles and the vas deferens, prevent sperm transportation and hence achieve contraception. So far, few studies have focused on interfering with sperm transportation in the genital tract to achieve contraception. EjD caused by tamsulosin was initially thought to be a result of retrograde ejaculation due to relaxation of the bladder neck, but emission failure has been recently considered as the main cause. Thus, either retrograde ejaculation or failure of seminal emission has provided valuable clues for innovative application of the al-adrenoceptor antagonist as a means of male contraception. To date, the use of tamsulosin for contraception has not yet been explored。 Therefore, we carried out the present study and tried to find satisfying answers to all the above problems.OBJECTIVESTo investigated the effectiveness and safety of tamsulosin as a potential male contraceptive.SUBJECTS and METHODSForty healthy male volunteerswere enrolled. Their health status including concomitant diseases, medication history, and sexuality were assessed. Prior to administration of tamsulosin or placebo, conventional semen analysis was performed by masturbation for each subject after3days of abstinence Parameters obtained included total semen volume, functional sperm concentration (FSC, which is the number of sperms moving forward and having normal morphology per mL of semen), and total functional sperm count (TFSC, which is the total number of sperms moving forward and having normal morphology in the semen sample, i.e., the product of FSC and semen volume). Conditions that mimic the adverse effects of al-adrenoceptor antagonists such as headache, dizziness, rhinitis, diarrhea, thirst, hypotension, etc., were examined. This study was in a placebo controlled, randomized and crossover design. We administered placebo and tamsulosin (at a single oral dose of0.4-mg or0.8-mg) sequentially in a crossover manner in order to eliminate bias among drugs and doses. The volunteers were equally divided into two groups (A and B). Group A was treated sequentially with placebo,0.4-mg of tamsulosin, and0.8-mg of tamsulosin, while Group B received the agents in the opposite order. There was a washout period of7days between administrations of agents. Ejaculatory profiles were assessed by masturbation4-6h after each administration, including conventional semen analysis and sperm count in midstream urine after ejaculation (in case of anejaculation). Libido and adverse effects of tamsulosin were noted. Seven days after the last administration, endpoint ejaculatory profiles were evaluated in all volunteers by masturbation. No sex, including masturbation, was allowed for three days prior to each administration or prior to semen collection during interval periods.RESULTSAnejaculation occurred in all subjects after taking0.8-mg of tamsulosin. Total functional sperm count was significantly reduced in subjects after taking0.4-mg of tamsulosin. Six subjects receiving0.8-mg of tamsulosin complained of tolerated discomfort which disappeared10hours after administration.CONCLUSIONSWhen administered at0.8mg, tamsulosin can cause anejaculation with some transient side effects. Our results implie that tamsulosin and related drugs might potentially be used as male contraceptive agents in the future, which needs more studies to verify. BACKGROUND and OBJECTIVEDespite significant advances in contraceptive options for women over the last50yr, world population continues to grow rapidly, and overpopulation continues to be a significant contributor to environmental degradation and human suffering worldwide. Therefore, there is a need for expanded, effective, contraceptive option. Notwithstanding their paucity of options, male methods including vasectomy and condoms account for almost one third of contraceptive use in the United States and other countries. Thus, male contraceptive becomes a new trend and a urgent requirement.The ideal male contraceptiv must have the characteristics:(1) high efficiency,(2) few side effects,(3) easy to use,(4) reversible. So far, there is no ideal male contraceptive has been created. The male ejaculation process consists of three stages, namely secretion fine, ejaculation, and the closure of the bladder neck, which are controlled finely by the sympathetic and parasympathetic nerve, in particular, depend on the functional integrity of the sympathetic and alA receptor. Therefore, Blocking alA-R can inhibit this process and lead to ejaculation disorders, which makes alA blockers as a new male contraceptive.al receptor is one kind of Ca2+-activated G protein-coupled receptor (GPCR), and can activate a variety of signal transduction pathways within cells, which mediated a series of physiological and pathophysiological processes. The al receptor can be divided into α1A, α1B, α1D subtypes, each with different pharmacological properties. The distribution and function ofal receptor subtypes in the male reproductive system is different. Ejaculation disorders include retrograde ejaculation and secretion fine obstacles. Marco Grasso reported oral alA receptor blockers can relax the bladder neck and lead to retrograde ejaculation. Other reports showed that the ejaculation dysfunction caused by oral alA blockers is not retrograde ejaculation, but the secretion fine obstacle caused by relaxation of the smooth muscle in the reproductive tract. The incidence rate of ejaculation disorder is far greater in oral super selective alA-blocker (tamsulosin and Silodoxin) than the α1-blockers (alfuzosin and prazosin).Our previous clinical trials have showed that4to6hours after single oral administration of different doses of tamsulosin, anejaculation occurred in all subjects after taking8-mg of tamsulosin, and the sperm count in midstream urine after ejaculation is zero. The ejaculation and semen volume resumed normal7days after administrations. The clinical trials indicated that the ejaculation dysfunction caused by tamsulosin is not retrograde ejaculation, but secretion fine obstacle. On this basis, we select male rats as subjects to explore the mechanism of inhibiting ejaculation of alA-blocker tamsulosin, which can provide a theoretical basis and valuable clues for the the clinical use of al A blockers as a male contraceptive.METHODS1. The change of the expression levels of α1A, α1B, α1D receptor in rat vas deferens after administration of alA receptor blocker, tamsulosin.24Wistar male rats were randomly divided into four groups (n=6), and once daily given saline or different doses of tamsulosin (30ug/kg,60ug/kg,120ug/kg) for30days. Then, the vas deferens was dissected and separated, and the proteins were extracted from the vas deferens. We detected the changes of expression level of α1A, α1B, α1D receptor in vas deferens with Western blot.2. The effect of tamsulosin on the contractile activity of vas deferens.24Wistar male rats were randomly divided into four groups (n=6), and once daily given saline or different doses of tamsulosin (3ug/kg,6ug/kg,12ug/kg) for one week. Then, the vas deferens was dissected and separated, and connected to the tension transducer. We recorded the contraction curve of the vas deferens and the difference between the systolic peak and baseline after give norepinephrine.3. The effect of tamsulosin on ejaculatory function in rats.24healthy male rats were randomly divided into three groups, namely the experimental (A3, B3) and control (C3) group. The experimental groups were daily given different dose of tamsulosin (6ug/kg,12ug/kg) respectively, while8rats in control group were given normal saline (3ml). After1week, we collected the semen of the rats after mating with female rats and analysis the semen volume, sperm density and the total number of sperm.RESULTSAfter administration of tamsulosin for30days, we detected the expression level of alA receptor was dose-dependently increased with Western blot, while the expression levels of α1B, α1D receptor had no similar changes.After continuous administration of tamsulosin for1week, we recorded that the contractile activity of vas deferens was dose-dependently decreased in vitro. Meanwhile, the semen analysis showed that the semen volume, sperm density and the total number of sperm were significantly dose-dependently reduced in experimental groups (P<0.05).CONCLUSIONSThis study showed that alA receptor blockers can selectively dose-dependently increase the expression of the alA receptor, while it has little effect on expression levels of α1B,α1D receptor. Meanwhile, in vitro cases, αl A receptor blocker could inhibit the reaction of the vas deferens to noradrenaline, reducing its peristaltic frequency. In addition, semen analysis also showed that the α1A receptor blockers can significantly reduce the total number of sperm. Therefore, α1A receptor blockers can achieve contraception by inhibiting the peristalsis of the vas deferens and the transport of semen, which make alA receptor blockers becoming a new and effective male contraceptive in the future. |
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