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Vas deferens,  a  site of male contraception: an overview

Nirmal K. Lohiya, B. Manivannan, Pradyumna K. Mishra, Neelam Pathak

Reproductive Physiology Section, Department of Zoology, University of Rajasthan, Jaipur -302 004, India

Asian J Androl  2001 Jun; 3:  87-95

Keywords:  male contraception; vas deferens; vasectomy;  vas occlusives;   injectable plugs; RISUGR
Abstract
The vas deferens is  a site which can be exploited for male contraception without undue side effects. The only effective technique available for male contraception is vasectomy, being practiced world wide, despite that it is a permanent surgical procedure and its successful reversal is not assured. Although no-scalpel vasectomy minimizes surgical procedures, the fate of its reversal is akin to that of vasectomy. Several occlusive and non-occlusive vasal procedures  which claim to be reversible without surgical intervention, possess  more disadvantages  than  advantages. Vas occlusion with plug, Shug or medical grade silicone rubber, although claimed to produce reversible azoospermia without affecting spermatogenesis,  requires skilled microsurgery for their implantation and later removal. RISUGR, a non-sclerotic polymer styrene maleic anhydride (SMA), could be more advantageous than vasectomy and other vas occlusive procedures in that it could be a totally non-invasive procedure by no-scalpel injection  and non-invasive reversal.  It is claimed to  offer long-term contraception   without adverse side effects and  also to be  possible as a male spacing method by repeated vas occlusion and non-invasive reversal. The drug is currently under multicentre Phase III clinical trial.
1 Introduction
Continued efforts  over the past three decades to develop additional methods of male contraception have made some significant contributions in the field. However, there is still  no method  available in the field of male contraception that satisfies the essential criteria of  safety, efficacy, economy and complete reversibility. As pointed out by Handelsman[1],  the currently available reversible methods are unreliable and the reliable methods are not reversible. However, a number of clinical trials substantiate a view that it is indeed possible to have a male contraceptive that meets all the essential criteria in the near future[2-7].
2 Approaches to male contraception
The options available to men for fertility control  are much more limited compared to those  for women. The male reproductive system, particularly the process of spermatogenesis, sperm maturation and transport and also the sperm-egg interaction  are so complex that it has not so far been possible to find  an effective intervention that can be converted into a product. Currently,  modern approaches  for the development of a male contraceptive target the following five areas: 1) inhibition of sperm production  in the testis; 2) interference with sperm function in the epididymis; 3) interruption of sperm transport  in the vas deferens; 4) prevention of sperm deposition  during ejaculation; and 5) prevention of sperm-egg interaction  in the female reproductive tract. The WHO consultative meeting on Setting the Agenda for Fertility Regulation Technology Research in Reproductive Health for the Next Decade (Geneva, Switzerland, 1996) has identified two male contraceptives, i.e., 1) A three monthly injectable levonorgestrel butanoate plus testosterone buciclate or testosterone buciclate alone, and 2) Non-surgical vas occlusion, as high priority leads in the field of male contraception[8].

3 Vas deferens as a target organ

Although the transport of spermatozoa from the testis towards the ejaculatory duct could be altered or arrested at the level of the testis, epididymis or vas deferens, the vas deferens is the site where intervention would be possible with minimal hormonal and systemic interference and may give better scope for reversal. The present review summarizes the advantages and disadvantages of the issues related to various vas-based methods of contraception.

3.1 Vasectomy

Vasectomy is the first vas-based surgical male contraceptive method and the only effective technique known  as the most simple, popular and readily available form of voluntary family planning for  men. It provides some major advantages that no other birth control measure can offer. It is safe, with minimal morbidity and almost no mortality, effective and simple as a one step procedure. It requires minimal training for most surgeons, taking only 10-15 minutes on an out-patient basis and is inexpensive  compared with female sterilization which requires more extensive surgery and equipment. In the past three decades, it has been practiced in over 40 million couples world wide[9].

However, in India, only 2% of reproductive age males rely on vasectomy for birth control, mainly  because it is a surgical intervention and of the false apprehensions that the procedure reduces sexual potency[6]. Contraindications to vasectomy include scrotal pathology, haematoma, allergy to local anaesthesia, genito-urinary or groin infections and sperm granulomas[10,11]. Fear of cardiovascular sequelae and an increased risk of prostate and testicular cancer have also been indicated[6]. A WHO consultation reviewed the available evidences and reported that any casual relationship between vasectomy and the risk of cancer of the prostate or testis is unlikely and that in the existing family planning polices of WHO towards vasectomy, no changes are warranted[12]. In India, studies carried out by the Indian Council of Medical Research and others have shown that vasectomy has no adverse effects on the cardio-vascular system and does not cause prostate cancer[13-16]. In Denmark, over 73,917 vasectomized men were identified and registered between 1977 and 1989 without indication of increased risk of testicular cancer due to vasectomy[17]. While these conclusions are  encouraging, it will be important to continue monitoring the safety of vasectomy.

Vasectomy is the only available method of male contraception adopted world wide in  family welfare programmes. However, some of the  concerns, particularly the  need for surgical intervention and the enhanced anti-sperm antibodies that may cause failure of reversibility, even after skilled vasovasostomy[18], require serious consideration. Hence further investigations are warranted and being pursued.

3.1.1  No-scalpel vasectomy

A refined technique for vasectomy that eliminates the use of a scalpel, has been developed and widely practiced since its inception. It  is less invasive, being performed under local anaesthesia  using specially designed vas fixing forceps that encircle and firmly fix the vas without penetrating the skin. A curved sharp pointed haemostat  is used to puncture the skin and vas sheath, and  to expose the vas which is then occluded as in conventional vasectomy[19,20].

The procedure offers  many advantages  compared to conventional vasectomy, e.g. no incision, no stitches, faster procedure, faster recovery, less chance of bleeding and other complications, less discomfort and high efficiency, which have helped the technique to increase the acceptability of male sterilization in many parts of the world[21]. In India, the technique was acceptable to more educated and higher income men and the number of vasectomy acceptances increased three times as compared to the conventional counterpart during the corresponding period[22,23]. However, similar to conventional vasectomy, this method also does not assure a successful reversal.

Despite this major limitation, the no-scalpel technique can be used to expose  the vas deferens in order to limit fertility by other means such as chemical injection, the insertion of plugs or the injection of temporary fertility limiting drugs.

3.2 Biomedical devices

An ideal intravasal device used for male contraception should be easy to insert, flexible, prevent sperm passage and be capable of easy removal to restore vas patency and so permit  the return of fertility[24]. Initial attempts have been made to solve the problems associated with the reversal of vasectomy. Several biomedical devices have been  developed with the aim  of having  safe and reversible vas occlusion in animal models and in man.

3.2.1 Intravasal thread (IVT)

It has been shown that the passage of spermatozoa could be blocked by placing surgical nylon or silk thread intravasally. Sperm passage was inhibited temporarily and the luminal patency of the vas could be restored by removing the intravasal thread (IVT)[25]. However, in the course of time, a small portion of the vas lumen  underwent dilation due to the increased intravasal pressure caused by the accumulation of  spermatozoa which allows spermatozoa to pass through the dilated lumen[26]. To avoid such problems, an intravasal thread, made of non-reactive and non-absorbable surgical thread with two strings of black filiform nylon was placed in the vas lumen. As long as the IVT remained in place in the vas, sperm passage was successfully inhibited. When the IVT was removed , the patency of the vas lumen was restored. The filiform nylon attached to the proximal end of the IVT was tied around the vas and held  the IVT in place, preventing  sperm from escaping through the dilated vas lumen and permitting easy and satisfactory restoration of patency by removal of the IVT. Histological studies showed no tissue reaction in the vas. The prevention of sperm passage is believed to be due to mechanical obstruction by the IVT[27,28]. This study laid a foundation for a variety of other occlusive techniques that followed.

In human subjects, it has been described that a thick nylon wire injected into the lumen of the vas deferens significantly reduced the sperm count in the ejaculate. However, there was no guarantee of absolute sterility[29]. PROPLAST, an intravasal plastic device, in the vas of pigs showed appearance of motile spermatozoa throughout the period of observation in serial sperm analysis[30]. However, consistent azoospermia was obtained in dogs 4 weeks after the insertion of a plastic device made  of polyethylene tubing. Removal of the device restored sperm passage in 2 weeks[31]. Kim[32] described that a plastic device, made  of 3 cm long polyethylene tubing and placed in the vas lumen produced consistent azoospermia in men. Histological study of the occluded areas of the vas showed some  destruction of the epithelial layer  although the damage was minimal. No inflammation and other abnormalities were reported. However, as there is species variation and no guarantee for absolute sterility, this method has not been further developed.

3.2.2 Intravasal copper wire

In vas occlusion methods, spermatozoa are accumulated in the epididymis and initiate some immunological reactions, leading to a rise in serum antisperm antibody titres. Although, not fully confirmed, the available data suggest that the high antisperm antibody titre  contributes  to the low pregnancy success rate despite effective vasovasostomy procedures.

Hence, in order to avoid the occlusive intravasal thread procedure, a slightly modified, non-occlusive copper wire has been used[33]. When the spermatozoa come in contact with copper there are toxic alterations in the acrosomal enzymes (particularly in those containing sulphydryl groups) leading to a loss in functional capacity. Copper may also displace zinc from the  acrosome[34,35]. In animals  intravasal  copper wire leads to decapitation of the spermatozoa and infertility. If one end of the copper wire was left protruding outside the vas wall, reversal was possible by removal of the  wire and the return of fertility rate was significant. The major shortcomings of this procedure are that sperm granuloma often occurs  at the site where the wire emerged from the vas wall and that the effectiveness of the procedure declines  with time due to erosion of the copper wire[33].

3.2.3  Intravasal electric device

Another approach  uses the principal that electrical current induces morphological changes in the sperm acrosomal membrane. To deliver an electric current, an external battery or a miniature battery inside the body has been tried [36]. In the external battery system, the  leads entering the body posed risk of recurrent infection. The miniature battery, on the other hand, was impractical as the energy storage was very small. The battery becomes drained in a short time necessitating frequent surgical manipulations.

As an alternative approach, a biogalvanic cell has been used. When the electrolytes in the fluid in the vas comes in contact with two dissimilar metals/materials well apart in the electrochemical series, an electric current is generated which will kill the spermatozoa. The biogalvanic cell may be the choice for affecting the viability and fertilizing ability of spermatozoa inside the vas lumen[33]. Based on this principle, Misro et al[37] developed non-occlusive male contraceptive devices using different combinations of materials, such as, copper, silver, copper-aluminium, silver-aluminium, silver-graphite and graphite-aluminium. The graphite-aluminium combination was found to be the most effective. The electrodes were placed in a teflon housing with short inlet and outlet tubes which were connected to the proximal and distal ends of the vas deferens. This device in rats produced infertility, when the shorting link was closed, leading to current flow. Fertility was restored upon disconnecting the shorting link. The device can be designed in such a way that the closing and opening of the shorting link can be done through the intact scrotal skin by palpation[33]. However, hitherto no further research  on this  procedure has been reported.

3.2.4 Bionyx control valve (phaser)

This is another implantable, reversible intravasal device, developed by Bionyx corporation. It is a T shaped device implanted in the vas, made of 99.99% gold and surgical grade stainless steel. The device is inert and mechanically sound. The cross-bar of the T is approximately 1.5 cm long and of small enough diameter to fit within a gently dilated vas lumen. A perforated ball in the T can be rotated by turning the upright arm of T. Alignment of the perforation in the ball with the lumina of the cross bar allows sperm to flow through the device. Turning the valve stem to  the non-aligned position obstructs the passage of sperm. The device is covered with a fine lattice of gold to allow tissue ingrowth from the de-epithelialized end of vas lumen on to the surface of the device. The method was successful in the human. However,  it also required skilled microsurgery for implantation[38].

Guha et al[39] described an intravasal device in rhesus monkeys comprised of two stainless steel tubes of outer diameter 0.6 mm linked by means of a biocompatible teflon body and a plunger with a cylindrical channel. When the plunger is pushed down, the communication between the tubes is blocked and azoospermia is obtained. When the plunger is pulled up, spermatozoa will pass through. The device is implanted bilaterally between the cut ends of the vas deferens through a high scrotal incision. Manipulations of the plunger is possible either by palpation on the scrotal skin or through a small scrotal incision. Contraceptive efficacy over a period of six months  was demonstrated[33].

3.2.5 Tantalum clips

An extravasal procedure, that involves placement of compression clips over the scrotal skin and pressing over the vas deferens, has also been investigated. Tantalum clips on the vas deferens of dogs produced azoospermia for a short period but leakage of spermatozoa ensued thereafter[40]. In rabbits azoospermia was reported for a 15 month study period[41]. However, the hope of easy removal of the clips for restoration of fertility was not supported by actual experience. Fibrous epithelium which formed surrounding the clip made removal  difficult[33]. 

3.3 Percutaneous injection

With the Biomedical devices approaches, implantation of the devices required highly specialized microsurgery which cannot be carried out on an out-patient basis and over an extended period of time. Besides, an unacceptably high incidence of displacement of the devices out of the vas deferens was noted.

A radically different concept based on inhibiting sperm transport by injecting chemical agents into the lumen of the vas deferens has been developed which minimised the surgical intervention in the scrotal region. It is a further improvement on the no-scalpel technique and is claimed to be completely non-surgical[42,43]. In this method the vas deferens is secured firmly by a specially designed vas clamp, a puncture needle is accurately inserted into the vas and then replaced by an injection needle; then the fertility limiting substance, such as sclerotic or non-sclerotic chemical agents, is injected[44]. One major disadvantage, however, with this method is that it is a delicate procedure and requires training and precision. However, once the technique is mastered, this method  generally takes only ten minutes[42,43].

3.3.1 Chemosterilization

After the advent of the percutaneous injection method,  at least 26 different combinations of chemicals have been tried to achieve permanent sterilization[43,45,46]. The major requirements of the intravasal chemicals are that, they must be non-toxic and sufficiently sclerotic to produce enough scarring on the vas wall to block it.

Initially a combination of carbolic and n-butyl alpha cyanoacrylate has been tried in over 600,000 men. The compound is a sclerotic agent which  solidifies within 20 seconds after injection into the vas lumen and produces a complete blockage of the vas deferens by adhering permanently onto the luminal surface of the vas[47]. Over 96 per cent of cases have been reported to be azoospermic[46,48] and 90 per cent effectiveness over 900 men for 9-12 months has been reported in a WHO based study[49]. Li and Zhu[50] reported  an azoospermic rate of 96% with 99% pregnancy prevention in their eight year follow up study after injection. Studies on pharmacological, toxicological and clinical effects have shown that this compound has no toxic or carcinogenic effects in experimental animals. Ten-year follow up of 822 cases found no long-term complications. In a further study of 3073 cases, 62 children were born  to 60 couples with normal development and intelligence, thus ruling out the possibility of teratogenicity[47]. The method has cleared WHO toxicological tests[49]. However, this method  gives permanent sterilization and does not offer chances of reversibility[46,48].

Freeman and Coffey[51]  tested a series of sclerotic agents viz., 95% ethanol, 10% silver nitrate, 36% acetic acid, 3.6% formaldehyde, 3% sodium tetradecyl sulphate, 5% sodium morrhuate , 5% potassium permanganate and 3.6% formaldehyde in 90% ethanol in the vas deferens of rats and dogs. Five per cent sodium morrhuate and potassium permanganate were shown to be ineffective in producing complete sterility while the other agents resulted in complete sterility eight months following a single injection. The lumen of the vas deferens was damaged and replaced by scar tissue and was free of spermatozoa. The technique is simple and requires no surgery and it has been claimed that once it has been learnt, it can be done quickly and with less expense. Following the success of the technique in rats and dogs, Coffey and Freeman[52] produced sterility in a small number of human volunteers with a percutaneous injection of 90% ethanol containing 3.6% formaldehyde into the vas deferens. Although this procedure appears promising, the sterilization is permanent and there is no evidence of vas recanalization and return of fertility. Dixit et al[53] described that this procedure leads to testicular atrophy and impairment of Leydig cell function. Gallegos et al[54] however, reported that a potent phlogogenic agent, carrageenan, did not produce any effect in the treated animals. They also reported that asingle injection of a mixture of sclerotic agents, containing quinacrine hydrochloride, chloroform, magnesium stearate and carbopol, resulted in azoospermia after  4 weeks of treatment in rabbits. A spontaneous reversal of quinacrine vas occlusion following 6 months has also been reported in rhesus monkeys[55]. The common tissue adhesive, methyl cyanoacrylate has also been shown to produce complete vas occlusion in 60 days in rhesus monkeys[56]. In another approach, a single intravasal administration of 50 L neem oil, injected bilaterally, induced sterility in rats. The treatment resulted in a block of spermatogenesis without affecting testosterone production; the seminiferous tubules, although reduced in diameter,  appeared to be normal and contained early spermatogenic cells. The histology of the epididymis and vas deferens was normal without any inflammatory reaction or obstruction. No anti-sperm antibodies could be detected in the serum. Unilateral administration of neem oil in the vas resulted in a significant reduction of testicular size and spermatogenic block which only occurred on the side of application. The draining lymph node cells of the treated side showed an enhanced proliferative response to in vitro mutagen challenge. It was suggested that the testicular effects following intra vasal injection  of neem oil may possibly be mediated by a local immune mechanism[57]. With a similar approach to block spermatogenesis an intravasal injection of Bacillus Calmette Guerin (BCG), which is shown to provide immune competent cell access to seminiferous tubules, thereby elicited  an autoimmune reaction against haploid-spermatogenic cells[58,59], but it failed to produce infertility in rats[60]. Male fertility regulation by intravasal injection of controlled-releasing gossypol has also been reported[61].  

3.3.2 Injectable plugs

Zhao[62] employed  percutaneous  injection  of polyurethane elastomer to  form plugs.  These plugs are designed for easy removal and are ideal for men who  would like the possibility of reversal in the case of  unforeseen circumstances. In China before 1990, over 12,000 men have been using the elastomer. Over 98% cases showed pregnancy protection for at least 5 years after insertion[63]. Azoospermia was found in 38%, 85% and 96% of men, 6, 12 and 24 months after injection of the elastomer, respectively[63,64]. Studies on over 130 men indicated that these plugs could be easily removed up to 5 years after insertion and were associated with  pregnancy in the spouses of all men studied[44,62,63]. However, as it is a total vas occlusion, the body system is likely to develop anti-sperm antibodies, leading to irreversibility even after plug removal. Such a critical analysis has not been made available[65]. Another shortcoming is that the plug may lead to rupture of the vas[64]. Toxicological uncertainties about the presence of aromatic amines in polyurethane plugs have also been raised, but follow up of acceptors of the method has not so far revealed any justification for this concern[63].

As an alternative, intravasal injection of formed-in-place silicone rubber for vas occlusion has been tried in a small number of human volunteers[66,67]. Azoospermia was obtained after 5 months in 3 men and by 9 months in all men[66]. A comparative study revealed that  the azoospermia rate achieved in 36 months was comparable to that of no-scalpel vasectomy[24,67]. It is claimed that silicone rubber does not interfere significantly in vas physiology and once the plug is removed, the mucosa cells of the vas will soon regenerate to allow free flow of spermatozoa[24,67]. However, details regarding the reversibility trial of silicone rubber vas occlusion are thus far not available.

3.4 Non-injectable plugs

Silicone plugs, called the Shug is a non-injectable plug alternative[68]. The main advantage of this method over injectable plugs is its double design. It is composed of two silicone plugs with nylon tails to help anchor the plugs to the vas, thus giving it the potential to be more leak free, i.e., any spermatozoa which leak past the first plug are likely to be trapped in the space between the plugs. Double plugs could be more reliable than the single one[20].

The Shug can be inserted into the vas by the no-scalpel method. Removal of the plug requires minor surgery. Full return of fertility after seven months of Shug use has been reported in monkeys[69]. However, this  is not a sufficient time for the development of anti-sperm antibodies, which may affect the complete return of fertility. Thus studies on safe reversal with complete return of fertility have not yet been done. Clinical trials revealed 97% decrease in motile sperm counts in the men studied[70]. The Shug has several advantages:  the size of the preformed plug in relation to the size of the vas deferens could be controlled, thus avoiding the possible rupture of the vas; the anchoring mechanism  can prevent the migration of the plug along the length of the vas. The preformed plug also avoided the possibility of entry of toxic substances during the hardening processes as in the case of injectable silicone rubber[68]. In primates, removal of the Shug resulted in the normal passage of the spermatozoa[69]. Studies involving  modifications of Shug devices and insertion techniques are ongoing. 

3.5 Styrene maleic anhydride (SMA)

Styrene maleic anhydride is a co-polymer of maleic anhydride and styrene. In  preliminary studies on rats, rabbits and monkeys[71-75], it was shown that when the compound styrene maleic anhydride (SMA) comes in contact with body fluids, the acid maleic anhydride is hydrolysed and the carboxyl group exerts a pH lowering effect, which is limited to  the immediate vicinity of the polymer. The body fluid is a buffer solution and an equilibrium state between the hydrated and swollen polyelectrolyte SMA and its environment is established like a Donnan membrane equilibrium[76].

The efficacy of SMA as an intravas contraceptive has been tested in albino rats[71,72,77] and in rabbits and monkeys[73,74,78,79]. The procedure offers long term fertility control through several  factors: 1) it blocks the passive transport of sperm; 2) it has a pH lowering action that is deleterious to spermatozoa; and 3) the polymer generates a positive charge that disturbs the negative charge of the sperm head membrane, ultimately resulting in rupture of the acrosomal membrane leading to loss of fertilizing ability[76,80].

In  experiments in langur monkeys, an animal model close to humans in reproductive anatomy and physiology[81-83], SMA, 60 mg in 120 L DMSO injected  as an intravasal occlusive agent,  led  to severe oligo/astheno/necro/teratozoospermia in the initial three ejaculates and to uniform azoospermia subsequently.  Studies of the ejaculated  spermatozoa by scanning and transmission electron microscopy revealed severe damage  predominantly to  the acrosome envelope and mid-piece configuration, indicating the possibility of instant sterility after vas occlusion with SMA[84]. The seminal plasma biochemistry and toxicological parameters were unaltered in the vas occluded langur monkeys[85]  indicating  safety of the drug in the animal.

The feasibility of intravasal administration of SMA and its  safety  were tested in a  Phase I clinical trial. Thirty eight male volunteers were injected  varying doses of SMA in the range  5-140 mg into each vas deferens; azoospermia was achieved with the higher doses of SMA. The volunteers   did not experience any problem with their urinogenital system and libido[80,86].

A phase II clinical trial  has been conducted to ascertain if a single injection of SMA  into each vas impaired fertility  for at least one year and to examine if  libido was affected. A standardized dose regimen of 60 mg SMA per vas was administered to 12  volunteers  by the conventional procedure, and in another  4 volunteers, no-scalpel injection of SMA was  performed. In all subjects, the treatment led to azoospermia and gave pregnancy protection for the one year study period. The volunteers and their spouses retained good health throughout the  study[87].   A two year exploratory  trial in 20 volunteers with SMA ranging 40-70 mg injected into each vas suggested pregnancy protection both in the azoospermic and non-azoospermic status with transient minimal side effects and no effect on libido[88].

Reversal by injection of the solvent DMSO[72] or sodium bicarbonate[89] has been successfully demonstrated in the rat. A non-invasive reversal procedure which involves palpation, percutaneous electrical stimulation, forced vibratory movements in the vas segments and supra-pubic percussion, has also been proposed[90] . Reversal of azoospermia after 5 months vas occlusion with SMA was  demonstrated in langur monkeys with particular attention to the vas morphology. Reversal of azoospermia occurred  in all the monkeys on the same day after the reversal manipulation and normozoospermia with normal motility and viability was obtained after the third ejaculations 30 days later. Vas deferens morphology, which showed exfoliation of epithelial cells following vas occlusion, regained  its normal pattern 90 days after the reversal manipulation[91]. The ultrastructural features of the vas which revealed inhibition of secretory and absorptive function of the vas following vas occlusion,  returned to normal appearance 90 days after the reversal manipulation[92]. The feasibility of a male spacing method by repeated vas occlusion by SMA and its non-invasive reversal has also  been  demonstrated in langur monkeys[93]. It has also been  established that there are no adverse effects nor teratogenicity after intravasal SMA even at 10 times the therapeutic doses[73-75].

4 Conclusion

Among the  options available for the regulation of male fertility, disruption of sperm transport  in the vas deferens is an attractive one. Vasectomy, either by conventional or no-scalpel method is in use world wide as a simple and effective approach despite its several limitations. Intravasal occlusion with plug, Shug or medical grade silicone rubber (MSR), although claimed to induce reversible azoospermia without interrupting spermatogenesis, requires skilled microsurgery for the implantation and removal of these compounds.  The non-sclerotic occlusive polymer SMA is proposed  to be more advantageous than vasectomy and other occlusive agents in that it could be a totally non-invasive procedure with no-scalpel injection and a non-invasive reversal method. These procedures offer several modes of fertility control mechanisms, providing instant infertility  as well as long-term contraceptive efficacy without significant adverse effects. There is also the  possibility of using this method for male spacing by repeated vas occlusion followed by  non-invasive reversal. The drug has been named RISUGR and is currently undergoing multicentre Phase III clinical trial. It is concluded that this option is likely to meet the need for  long-term reversible male contraception with minimal invasive intervention in the near future.

Acknowledgements

Investigations on Styrene Maleic Anhydride (SMA) are supported by the Ministry of Health and Family Welfare, Government of India, New Delhi.

References

[1] Handelsman DJ. Hormonal male contraception. Int J Androl 2000; 23 (suppl 2): 8-12.
[2] Huhtaniemi I. Current challenges of andrology. Asian J Androl 1999; 1: 3-5.
[3] Waites GMH. The contribution of asian scientists to global research in andrology. Asian J Androl 1999; 1: 7-12.
[4] Sriraman V, Rao AJ. Current status in development of male contraceptives. In: Chowdhury SR, Gupta CM, Kamboj VP, editors. Current status in fertility regulation: indigenous and modern approaches. Lucknow: CDRI; 2001. p 163-78.
[5] Rajalakshmi M, Sharma RS. Methods for the  regulation of male fertility. In: Chowdhury SR, Gupta CM, Kamboj VP, editors. Current status in fertility regulation: indigenous and modern approaches. Lucknow: CDRI; 2001. p 179-209.
[6] Puri CP, Gopalkrishnan K, Iyer KS. Constraints in the development of contraceptives for men. Asian J Androl 2000; 3: 179-90.
[7] Hair WM, Wu FCW. Male contraception: prospects for the new millennium. Asian J Androl 2000; 2: 3-12.
[8] Wang CCL. Clinical studies using androgens alone for male contraceptive development. In: Rajalakshmi M, Griffin PD, editors. Male contraception: present and future. New Delhi: New Age Int (P) Ltd; 1999.  p 189-200.
[9] Liskin L, Benoit E, Blackburn R. Vasectomy: new opportunities.  Baltimore, Population Information Programme, John Hopkins University; 1992.
[10] Lipshultz LI, Banson GS. Vasectomy: an  anatomical, physiological and surgical review. In: Cunningham GR, Schill GR, Hafez ESE, editors. Regulation of male fertility. Hague:  Martinus Nijhoff ; 1980.  p 159-86.
[11] Silber SJ. Vasectomy. In: Knobil E, Neill JD, editors. Encyclopedia of reproduction. California: Academic Press; 1998. p  977-85.
[12] Waites GMH. Male contraception: recent developments. WHO Report Series;1998. p 1-8.
[13] Indian Council of Medical Research, Task Force on Male Fertility Regulation. Long-term effects of vasectomy. Part I: Biochemical parameters. Contraception 1983; 28: 423-8.
[14] Tripathy SP, Ramachandran CR, Ramachandaran P. Health consequences of vasectomy in India. Bulletin WHO 1994; 72: 779-81.
[15] Platz EA, Yeole BB, Cho E, Jussawalla DJ, Giovannucci E, Ascherio A. Vasectomy  and prostate cancer: a case control study in India. Int J Epidemiol 1997; 26: 933-7.
[16] Soonawalla FP. Vasectomy-safety and reversibility. In: Rajalakshmi M, Griffin PD, editors. Male contraception: present and future. New Delhi: New age Int(P) Ltd; 1999.  p 251-63.
[17] Moller H, Knudsen LB, Lynge E. Risk of testicular cancer after vasectomy: cohort study of over 73000 men. Br Med J 1994; 309: 295-8.
[18] Handelsman DJ. Hormonal male contraception. In: Puri CP, Van Look PFA, editors. Current concepts in fertility regulation and reproduction. New Delhi: Wiley Eastern Ltd; 1994. p 133-56.
[19] Li SQ, Goldstein M, Zhu J. The no-scalpel vasectomy. J Urol 1991; 145: 341-4.
[20] Hargreave TB. Towards reversible vasectomy. Int J Androl 1992; 15: 455-9.
[21] Xu B, Huang WD. No-scalpel vasectomy outside China. Asian J Androl 2000; 2: 21-4.
[22] Das HC, Bhattacharjee J. No-scalpel vasectomy: hope for the future. J Fam Welfare 1993; 39: 14-6.
[23] Nigam SK, Malik SK, Das HC. A profile of acceptors of non-scalpel vasectomy. J Fam Welfare 1994; 40: 19-21.
[24] Soebadi DM. Medical grade silicone rubber vas occlusion: an alternative method of male contraception. In: Rajalakshmi M, Griffin PD, editors. Male contraception: present and future. New Delhi: New Age Int (P) Ltd; 1999.  p 273-91.
[25] Kar AB, Kamboj VP. Spermatozoa disintigration in rats with an intra-vas deferens   device. Indian J Exp Biol 1964; 2: 240-4.
[26] Lee HY. Studies on vasectomy: I. Experimental studies on nonoperative  blockages of vas deferens and permanent introduction of nonreactive foreign body in a vas. Korean New Med J 1964; 7:  599-608.
[27] Lee HY. Experimental studies on reversible vas occlusion by intravasal thread. Fertil Steril 1969; 20: 735-44.
[28] Lee HY. Studies on vasectomy . IX. Current status of reversible vas occlusion method. Korean J Urol 1972; 13: 17-25.
[29] Kothari MM, Pardanani DS. Temporary sterilization of the male by intravasal contraceptive device. A preliminary communication. Indian J Surg 1967; 29: 357-63.
[30] Hulka JF, Davis JE. Vasectomy and reversible vas occlusion. Fertil Steril  1972; 23: 683-96.
[31] Moon KH, Bunge RG. Temporary occlusion of the vas deferens. Invest Urol 1970; 8: 292-8.
[32] Kim SK. Preliminary report on reversible vas occlusion. Proceedings of 1st National Seminar on Voluntary Sterilization: Korean Association of Voluntary Sterilization,  Voluntary Sterilization, 1975.
[33] Guha SK. Bioengineering in reproductive medicine. Boston: CRC Press; 1990. p 145-50.  
[34] Steven FS, Criffin MM, Chantler EN. Inhibition of human and  bovine sperm acrosin by divalent metal ions. Possible role of zinc as a regulator of acrosin activity. Int J Androl 1982; 5: 401.
[35] Patel KL, Pillai KBD, Shahni  SM. Effect of intravasal copper wire on the fertility and reproductive organs in rats. Indian J Med Res 1983; 77: 465.
[36] Mahajan S, Guha SK, Misro MM. A theoretical  and scanning electron microscope study on the electrically mediated inactivation of spermatozoa. J Biol Phys 1982; 10: 113-24.
[37] Misro MM, Kaur H, Mahajan S, Guha SK. An intravasal non-occlusive contraceptive device in rats. J Reprod Fertil 1982; 65: 9-13.
[38] Lynn CM, Politano V. Early experience with the bionyx control valve (Phaser). In: Sciarra J, Zatuchni GI, Spiedel J, editors. Reversal of sterilization. Hargerstown: Harper & Row; 1977.  p  91-6.
[39] Guha SK, Ahmed AM, Kaur H. Feasibility study of the reversible occlusion device for the vas deferens. Med Biol Eng 1976; 14: 15-8.
[40] Jhaver PS, Davis JE, Lee HY, Hulka JF, Leight G. Reversibility of sterilization using occlusion clip. Fertil Steril 1971; 22: 263-9.
[41] Lohiya NK, Tiwari SN. Vasectomy and vas occlusion by tantalum clip: a comparative study. Iugoslav Physiol Pharmacol Acta 1987; 23: 1-13.
[42] Goldsmith A, Edelman DA, Zatuchni GI. Transcutaneous male sterilization. In: Zatuchni GI, editor. Research frontiers in fertility regulation. Hagerstown: Harper & Row; 1985.p 1-8.
[43] Goldsmith A, Edelman DA, Zatuchni  GI. Transcutaneous procedures for male sterilization. Adv Contracep 1985; 1: 355-61.
[44] Li SQ, Zhu J. Non-incisional sterilization  with intravasal drug injection (10-year follow-up on control of blocking the length of the vas deferens). Adv Contracep 1986; 2: 241.
[45] Davis JE. Vasectomy. In: Lipshultz LI, Corriere JN, Hafez ESE, editors. Surgery of the male reproductive tract. Hague: Martinus Hijhoff; 1980. p 143-56.
[46] Xiao BL. Chemical vas occlusion in the People's Republic of China. In: Diczfalusy E, Bygdeman M, editors. Fertility regulation today and tomorrow. New York, Serono Symposia Publication: Raven Press; 1987. p 265-74.
[47] Nirapathpongporn A. Vas occlusion and reversal. In: Boutaleb Y, Gzouli A, editors. Progress in contraception. New Jersey: The Parthenon Publishing Group; 1991.p 3-12.
[48] Li SQ. Clinical applications of the vas deferens puncture. Chinese Med J 1980; 3: 69-70.
[49] Lissner EA. Frontiers in nonhormonal male contraception: a call for research. Male contraception information project report series; 1994.
[50] Li SQ, Zhu J. Non-operative sterility research with an intravasal injecting drug, clinical report. Presented at The Expert Committee Meeting on Training for Voluntary Surgical Contraception (VSC). Rio de Janeiro; 1984. 
[51] Freeman C, Coffey DS. Sterility in male animals induced by injection of chemical agents into the vas deferens. Fertil Steril 1973; 24: 884-90.
[52] Coffey DS, Freeman C. Vas injection: a new non-surgical procedure to induce sterility in human males. In: Sciarra JJ, Markland C, Speidel JJ, editors. Control of male fertility. Hagerstown: Harper & Row; 1975. p 147-60.
[53] Dixit VP, Lohiya NK, Arya M, Agarwal M. The effects of chemical occlusion of vas deferens on the testicular function of dog: a preliminary study. Acta Europ Fertilitat 1975; 6:349-53.
[54] Gallegos AJ, Potts F, Pedron N. Occlusion of vas deferens after a single intraluminal injection of carrageenan and other chemical agents in rabbits. Arch Androl 1994; 32: 59-62.
[55] Malaviya B, Chandra H. Chemical occlusion of rhesus vas with quinacrine and its spontaneous reversal. Indian J Exp Biol 1980; 18: 1296-7.
[56] Chandra H. Chemical  occlusion of vas with MCA in rhesus monkey. Contraception 1986; 33: 47-50.
[57] Upadhyay SN, Dhawan S, Talwar, GP. Antifertility effects of neem (Azadirachta indica) oil in male rats by single intra-vas administration: an alternate approach to vasectomy. J Androl 1993; 14: 275-81.
[58] Talwar GP, Naz RK, Das C, Das RP. A practicable immunological approach to block spermatogenesis without loss of androgens. Proc Natl Acad  Sci USA 1979; 76: 5882-5.
[59] Talwar GP, Mallick A, Ramakrishnan S, Das C, Gupta SK, Tandon A, Naz RK, Shastri N, Manhar SK, Singh OM. Immunointerception of fertility. In: Wegmann TG, Gill TJ, editors. Immunology of reproduction. New York: Oxford University Press; 1983. p 447-67.
[60] Singh SK, Rovan E, Frick J. Intravasal application of BCG (Bacille Calmette Guerin) is not an effective method for control of fertility in the male: a preliminary report. Contraception 1993; 47: 303-6.
[61] Ye W, Lu G, Den Y. Effect on intra-vas deferens injection of gossypol-polylactic acid on fertility and spermatogenesis in rats. Chinese Med Sci J  1993; 8:20-4.
[62] Zhao SC. Vas deferens occlusion by percutaneous injection of polyurethane elastomer plugs: clinical experience and reversibility. Contraception 1990; 41: 453-9.
[63] Zhao SC, Lian YM, Yu RC, Zhang SP. Recovery of fertility after removal of polyurethane plugs from the human vas deferens occluded for up to 5 years. Int J Androl 1992; 15: 465-7.
[64] Chen ZW, Gu YQ, Liang XW, Wu ZG, Yin EJ, Li-Hong. Safety and efficacy of percutaneous injection of polyurethane elastomer (MPU) plugs for vas occlusion in man. Int J Androl 1992; 15: 468-72.
[65] Wang C, Swerdloff RS, Waites GMH. Male contraception: 1993 and beyond. In: Van Look PFA, Perez-Palacios G, editors. Contraceptive research and development 1984-1994, The road from Mexico city to Cairo & beyond. Oxford: WHO & Oxford University Press; 1994. p 121-34.
[66] Zhao SC, Zhang SP, Yu RC. Intravasal injection  of formed-in-place silicone rubber as method of vas occlusion. Int J Androl 1992; 15: 460-4.
[67] Soebadi DM, Gardjito W, Mensink HJA. Intravasal  injection of formed-in-place medical grade silicone rubber for vas occlusion. Int J Androl 1995; 18,Suppl 1: 45-52.  
[68] Zaneveld LJD, De Castro MP, Faria G, Derrick F, Ferraro R. The soft, hollow plug (Shug): a potentially reversible vas deferens occlusive device. In: Rajalakshmi M, Griffin PD, editors. Male contraception: present and future. New Delhi: New Age Int (P) Ltd; 1999.  p 293-307.
[69] Zaneveld LJD, Depel W, Burns JW, Shapiro S, Beyler S. Development of a potentially reversible vas deferens  occlusion device and evaluation in primates. Fertil Steril 1988; 49:527-33.
[70] Zaneveld LJD, De Castro MP, Derrick F. Clinical evaluation of a reversible vas deferens blocking device- the shug. In: Proceedings IIIrd International Symposium on Contraception, Heidelberg, Germany; 1990.
[71] Misro MM, Guha SK, Singh HP, Mahajan S, Ray AR, Vasudeven P. Injectable  non-occlusive chemical contraception in the male-I. Contraception 1979; 20: 467-73.
[72] Verma K, Misro MM, Singh H, Mahajan S, Ray AR, Guha SK. Histology of the rat vas deferens after injection of a non-occlusive chemical contraceptive. J Androl 1981; 63: 539-42.
[73] Sethi N, Srivastava, RK, Singh RK. Histological changes in the vas deferens of rats after injection of a new antifertility agent SMA and its reversibility. Contraception 1990; 41: 333-9.
[74] Sethi N, Srivastava, RK, Singh RK. Male mediated teratogenic potential evaluation of new antifertility compound SMA in rabbit (Oryctolagus cuniculus). Contraception 1990; 42: 215-23.
[75] Sethi N, Srivastava, RK, Singh RK, Bhatia GS, Sinha N. Chronic toxicity of styrene maleic anhydride, a male contraceptive, in rhesus monkeys (Macaca mulatta). Contraception 1990; 42: 337-47.
[76] Guha SK. Contraceptive for use by a male. USA Patent, 5488075; 1996.
[77] Sethi N, Srivastava, RK, Singh RK. Safety evaluation of a male injectable antifertility agent, styrene maleic anhydride, in rats. Contraception 1989; 39: 217-26.
[78] Guha SK, Ansari S, Anand S, Farooq A, Misro MM, Sharma DN. Contraception in male monkeys by intra-vas deferens injection of a pH lowering polymer. Contraception 1985; 32: 109-18.
[79] Lohiya NK, Manivannan B, Mishra PK, Pathak N. Noninvasive reversible vas occlusion with styrene maleic anhydride: a possible alternative to vasectomy. In: Puri CP, Van Look PFA, editors. Sexual and reproductive health: recent advances, future directions. New Delhi: New Age Int (P) Ltd; 2001. p 249-68.
[80] Guha SK, Singh G, Anand S, Ansari S, Kumar S, Koul V. Phase I clinical trial of an injectable contraceptive for the male. Contraception 1993; 48: 367-75.
[81] David GFX, Ramaswami LS. Reproductive system of North Indian langur (Presbytis entellus entellus Dufresne). J Morphol 1971; 135: 89-130.
[82] Lohiya NK, Sharma RS, Puri CP, David GFX, Anand Kumar TC. Reproductive exocrine and endocrine profile of female langur monkeys Presbytis entellus entellus. J Reprod Fertil 1988; 82: 485-92.
[83] Lohiya NK, Sharma RS, Manivannan B, Anand Kumar TC. Reproductive exocrine and endocrine profiles and their seasonality in male langur monkeys (Presbytis entellus entellus). J Med Primatol 1998; 27: 15-20.
[84] Lohiya NK, Manivannan B, Mishra PK. Ultrastructural changes in the spermatozoa of langur monkeys Presbytis entellus entellus after vas occlusion with styrene maleic anhydride. Contraception 1998; 57: 125-32.
[85] Mishra PK. Contraceptive efficacy of styrene maleic anhydride (SMA) in the lumen of the vas deferens and its reversal in langur monkeys, Presbytis entellus entellus Dufresne. Ph.D. Thesis. Jaipur (India), University of Rajasthan; 1999.
[86] Guha SK. Injectable contraceptives for the male. Exp Opin Invest Drugs 1995; 4: 537-43.
[87] Guha SK, Singh G, Ansari S, Kumar S, Srivastava A, Koul V, et al. Phase II clinical trial of a vas deferens injectable contraceptive for the male. Contraception 1997; 56: 245-50.
[88] Guha SK, Singh S, Srivastava A, Das HC, Bhardwaj JC, Mathur V, et al . Two-year clinical efficacy trial with dose variations of a vas deferens injectable contraceptive for the male. Contraception 1998; 58: 165-74.
[89] Koul  V, Srivastava A, Guha SK. Reversibility with sodium bicarbonate of styrene maleic anhydride, an intravasal injectable contraceptive, in male rats. Contraception 1994; 58: 227-31.
[90] Guha SK. Non-invasive reversal of intraluminal vas deferens polymer injection-induced azoospermia-technology. Asian J Androl 1999; 1: 131-4.
[91] Lohiya NK, Manivannan B, Mishra PK, Pathak N, Balasubramanian SPA. Intravasal contraception with styrene maleic anhydride and its noninvasive reversal in langur monkeys (Presbytis entellus entellus). Contraception 1998; 58: 119-28.
[92] Manivannan B, Mishra PK, Lohiya NK. Ultrastructural changes in the vas deferens of langur monkeys Presbytis entellus entellus after vas occlusion with styrene maleic anhydride and after its reversal. Contraception 1999; 59: 137-44.
[93] Lohiya NK, Manivannan B, Mishra PK. Repeated vas occlusion and non-invasive reversal with styrene maleic anhydride for male contraception in langur monkeys. Int J Androl 2000; 23: 36-42.

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Correspondence to: Prof. N. K. Lohiya, FNASc, Reproductive Physiology Section, Department of Zoology, University of Rajasthan,  Jaipur-302 004, India.
Tel: +91-141-701 809    Fax: +91-141-701 809
E-mail: lohiyank@hotmail.com & lohiyank@rediffmail.com
Received 2001-05-15     Accepted 2001-05-24