:: Asian Journal of Andrology ::

Non-invasive reversal of intraluminal vas deferens polymer injection-induced azoospermiatechnology

Sujoy K. Guha

Centre for Biomedical Engineering, Indian Institute of Technology and All India Institute of Medical Sciences, New Delhi-110016, India

Asian J Androl 1999 Sep; 1: 131-134

Keywords: vas deferens; male contraceptive agents; maleic anhydrides; sterilization reversal; palpation; electric stimulation

Abstract

Aim: The rationale and technique underlying a novel concept of non-invasive removal of an intravasal vas deferens polymeric contraceptive drug to reverse drug injection-induced azoospermia are explained. Thus the conventional methods of surgical exploration to remove vas deferens plugs and intravasal injection of solvents to flush out contraceptive drugs are to be replaced by steps which will be readily accepted by subjects. Methods: The approach is based upon the non-invasive application of specific forces to various segments of the vas deferens so that non-sclerosing and non-tissue-adherent compounds, in particular styrene maleic anhydride (SMA) can be expelled. Forces are generated by palpation; percutaneous electrical stimulation; vibration application; and percussion. The forces help to propel the intravasal polymer towards the ejaculatory duct for expulsion during ejaculation. All aspects of the total technique are clinically acceptable, simple, atraumatic, unlikely to cause pain and discomfort even without tranquilizers, local or general anaesthetics. The procedure may be repeated several times in different sittings spaced apart by about one week to achieve adequate plug expulsion. Results: Model experiments demonstrated the feasibility of the concept. The polymer was nonadherent and could be moved within the vas deferens by the application of specific forces. Sufficient removal was possible to enable spermatic fluid to be transported along a region previously occupied by the polymer. A corroborating subhuman primate study by an independent investigator has shown that the semen profile becomes normal following the reversal. Conclusion: Adoption of the new technique may provide a means of non surgical restoration of normal semen profile after a period of fertility control obtained by intravasal drug injection.

1 Introduction

Contraception following injection of a biologically active drug into the lumen of the vas deferens was reported earlier^[1]. The drug is a specific preparation of styrene maleic anhydride (SMA) polymer mixed in dimethyl sulphoxide^[2] and is named RISUG. One administration of RISUG in a therapeutic dose gives prolonged azoospermia and contraception. The azoospermia being taken as the absence of intact functional sperms. Electrical charge effect destroys spermatozoa^[3]. Above threshold doses of 60 mg or more of SMA in the monkey can give over five years of azoospermia in all cases. Administration of SMA over the threshold level of 60 mg in the monkey produces azoospermia for more than 5 years. Followup of the Phase-I Clinical Trial^[4] subjects until now indicates that in higher doses azoospermia continues beyond seven years. Phase-II Clinical Trial with 60 mg of SMA^[5] and related two years clinical trials with dose variations^[6] showed that in all subjects administered 60 mg or higher dose of SMA in a single injection have azoospermia and contraception. Even all subjects who were treated three years ago are having fertility control. In all the animal and clinical studies the drug was injected by a direct observation of the vas deferens. The vas deferens was accessed either by an approach as in conventional vasectomy or by a technique similar to the Chinese method of No Scalpel Vasectomy (NSV) which has been given the male `No Scalpel Injection' (NSI). NSI differs from NSV in respect of the vas deferens pickup forcep, the former being done with a forcep which does not injure the vas deferens. Toxicological studies have shown the safety of the drug and that within the vas deferens the drug does not sclerose and also does not induce fibrosis^[7].

Earlier, the reversal was being affected by flushing out the drug by injecting the solvent dimethyl sulphoxide^[8,9] and alternatively with sodium bicarbonate^[10]. Experience with the injection method of reversal shows that there are some difficulties. At the injection site there is a nodule which regresses over several years. For reversal injection, the vas deferens has to be approached at a point further proximal to the testes than the injection point. The vas deferens narrows proximally. In the animal studies this problem was not encountered because the injections were given high up, that is, very close to the external (superficial) inguinal ring, thus leaving considerable length of wide calibre vas deferens avialable more proximal to the testes for reversal injection. In the human the contraceptive injection must be given lower down, that is more proximal to the testes. There is rapid narrowing of vas deferens further proximally. Therefore in reversal injection, a fairly large scrotal opening to get a clear view of the vas deferens is required and considerable skill in injection is necessary. Consequently the procedure, although quite feasible, does not meet the criteria of simplicity. In the above background it is appropriate to devise a convenient non-invasive reversal method. For the intraluminal vas deferens polymer injection approach where styrene maleic anhydride is used, the properties that SMA is not a sclerosing agent and also does not have adhesive character become advantageous. Retention of the plug is a result of the intrinsic bulk shear resistance and some anchorage provided by the invaginations in the vas deferens mucosal wall. Therefore, if these retention effects are overcome by suitable forces, the compound may be propelled towards the distal end of the vas deferens, ultimately to be evacuated via the ejaculatory duct. Azoospermia thereby will be terminated. From earlier studies, both in rhesus monkey and the human it is known that total removal of SMA from the vas deferens by external forces is not essential to reverse azoospermia. If the net amount of SMA in the lumen is brought to a low level, the bulk shear forces are so much reduced that with normal muscular contraction of the vas deferens the remaining SMA is spontaneously evacuated during ejaculations. Consequently the objective of the present method is to reduce the amount of SMA in the vas deferens lumen instead of total expulsion.

2 Materials and methods

For the purpose of present discussion, the vas deferens may be considered to be comprised of the following segments: scrotal segment extending from the cauda epididymis to the external inguinal ring; inguinal segment from the external inguinal ring to the internal inguinal ring; upper pelvic segment from the internal inguinal ring up to the beginning of the dilated ampulla of the vas deferens; and finally the terminal segment including the ampulla and the ejaculatory duct. The scrotal vas deferens is almost entirely palpable through the intact scrotal skin. The thin tortuous part close to the epididymis can not be very well felt but the spermatic cord is palpable and any pressure on the cord may be expected to be transmitted to the vas deferens. Stabilizing the spermatic cord in a proximal site by means of two fingers of one hand, a squeezing action progressing towards the external inguinal ring can readily be applied percutaneously. This `milking' action loosens the SMA depot and propels the contents towards the external inguinal ring.

Under normal circumstances the inguinal vas deferens can not be palpated. Its course in the inguinal canal is well defined. Taking the pubic tubercle and the anterior superior iliac spines as landmarks, the location of the internal inguinal ring can reasonably be marked one centimeter above the mid inguinal point. The reflected part of the inguinal ligament, conjoint tendon of the internal oblique muscle and fascia transversalis provide a firm base against which the spermatic cord can be pressed when force is applied from the skin. In this procedure, the tips of all four palpating fingers of both hands are placed over the surface marking of the spermatic cord in the inguinal region. A peristaltic propulsive effect within the vas deferens is generated by pressing down with the fingers sequentially beginning from the finger over the external inguinal ring and moving toward the finger tip over the internal ring. This sequence is repeated about 15 times in one treatment course for each vas deferens.

Additional clearance effect is derived from contraction of the vas deferens musculature. Low frequency electric stimulation produces contraction^[11]. In the present exercise the stimulation is delivered by means of surface electrodes. To obtain a peristaltic effect a pair of stimulation electrodes are moved along the surface from the location of the external inguinal ring to the internal inguinal ring. Concurrently pressure is applied. To realize these two effects concurrently an insulating rubber roller 20 mm diameter and 15 mm wide was prepared. On the outer cylindrical face of this roller, pairs of small tags of electrically conducting rubber were affixed. An electrical connection arrangement was made such that the electrode pair in contact with the skin received the current from the electrical stimulator set to deliver constant voltage pulses of 30 V amplitude and pulse repetition rate of 15 Hz. By means of a handle, the roller was pressed over the inguinal body surface and rolled upward and laterally from the external inguinal ring to the internal inguinal ring with 20 repetitions of the procedure.

The upper pelvic segment of the vas deferens is the least accessible to manipulations. A combination of forces have been generated to loosen the SMA deposits and to some extent propel the material. One of the steps involves the placement of a mechanical vibrator delivering vibrations with amplitude of 2 mm and frequency of 10 Hz at the surface marking of the internal inguinal ring. The rationale underlying the step is that the vibration is transmitted to the vas deferens through the skin and subcutaneous tissue. Mechanical tissue properties of the vas deferens differ from that of the surrounding tissues and this difference accounts for the whipchord like feel of the vas deferens. In effect the vas deferens becomes a distinct tube-like structure. Vibrations are preferentially transmitted along such a structure. A light pressure on the skin just proximal to the vibrator, that is toward the external ring, will enhance the transmission toward the pelvic portion of the vas deferens. Vibration of the wall loosens the deposits in the lumen. Furthermore, vibration produces stretch effects and can itself induce segmental contractions of the vas deferens. Concurrent forceful percussion is applied to the abdominal wall in the suprapubic region with the pleximeter finger well pressed down. Additionally the subject is asked to cough. These last two manoeuvres raise pelvic pressures transiently and are analogous to the removal of bronchial secretions by percussion and coughing.

Finally the terminal segment of the vas deferens is manipulated. Basically the approach is similar to rectal prostatic massage. The difference being that instead of massaging the prostate per se, the finger is moved in a sweeping action from a superior lateral location to an inferior medial location to follow the path of the ampulla of the vas deferens. Subjects are placed in the left lateral or the knee-elbow position. Nominal suprapubic abdominal compression is maintained to enhance easy accessibility of the region of the ampulla of the vas deferens by the palpating finger.

Because of the small size of the monkey, the palpating finger in the rectum reaches well beyond the region of the ampulla of the vas deferens and no assistant devices are necessary. In the human the palpating finger falls short of the full extent of the ampulla. To overcome the above difficulty construction of a rubber extension of the finger was attempted but the feeling of contact pressure was lost. An experimental device in the form of an extension of the finger by a length of 15 mm has now been made. Five parallel rubber balloons are embedded so that one end of the balloons press against the rectal wall and the other end is in contact with the distal phalange pulp of the palpating finger. Such a device gives extension along with a feel of pressure and to some extent contours. Nevertheless the device is still experimental and would be required only if restoration of normal semen profile is quickly required. Otherwise the finger without special provision will suffice.

3 Results

Some aspects of the action of the physical forces were verified in experiments on a rhesus monkey which had been previously injected with 100 mg of SMA in each vas deferens. The vas deferens was exposed and sectioned above the external inguinal ring. Percutaneous palpation of the scrotal segment of the vas deferens produced oozing out of the SMA from the cut end of the vas deferens. On the other side, the vas deferens was exposed and sectioned at the internal inguinal ring. On applying pressure and electrical stimulation percutaneously over the surface marking of the vas deferens between the external and internal ring, SMA was seen to ooze out of the cut end of the vas deferens at the internal inguinal ring. Allowing for some dilution effect on account of residual polymer emerging with the spermatic fluid, the sperm concentration in the fluid oozing out seems to be similar to that observed when spermatic fluid which later on was squeezed out from a vas segment proximal to the injection site. The volumes being extremely small, the assessment of sperm concentration was only qualitative. Further verifications of the action were left to an overall efficacy assessment carried out by an independent investigator on studies on a different species of monkey and reported separately^[12]. The finding of that study showed that azoospermia reversal is feasible by the non-invasive approach presented here.

4 Discussion

For the SMA injection contraception, a comparison of the present non-invasive method of reversal with the solvent injection approach of reversal has already been given. It is of value to compare the new technique with the reversal procedures for other vas deferens based contraceptive techniques.

Plugs which serve purely as blocking agents can be removed by surgical manipulation^[13]. In order to achieve azoospermia the plugs are either made long or of large diameter of as much as 2.5 mm. With a fibrous nodule usually present at the site of the insertion of the plug, the approach to the vas deferens lumen and removal of the plug is not a simple exercise. Moreover, the presence of any plug in the lumen of the vas deferens leads to hypolastic changes in the vas deferens musculature with the wall becoming thin and fragile. Surgical manipulations are therefore fraught with the danger of rupture of the vas deferens necessitating reanastamosis. Valves^[14] placed in the vas deferens are also not free from problems. Very often the valve is surrounded by a tissue pseudocapsule and operation of the valve calls for careful dissection to remove the encapsulating tissue. While carrying out this process, the tubular ends of the valves are liable to slip out of the lumen and replacement and anchorage is a difficult task.

Copper wire inserted into the lumen of the vas deferens achieves fertility control^[15] but studies are still limited to animal models. Reversal is possible by pulling out the wire, but a number of problems arise. The wire may fragment inside the lumen and more commonly the protruding end of the wire, kept outside of the vas deferens wall by choice to facilitate removal, gets covered by tissue requiring careful dissection.

Since the other modes of vas deferens contraception do not have any convenient reversal approach available, the somewhat elaborate steps in the present technique become justifiable. Of the steps required to expel the plug only the rectal palpation, although not painful, may generate some concern amongst human acceptors. Prior counselling can overcome inhibitions inherent in any rectal manipulations.

It therefore can be concluded that an acceptable multi-modal procedure has been devised to apply forces to all segments of the vas deferens to propel non-adherent intraluminal vas deferens polymers towards the ejaculatory duct. Use of this procedure can reduce the intraluminal vas deferens contents to a low level so that azoospermia is reversed.

Carrying out the procedure requires skill and there can be variabilities. To have standardization, equipment has been designed which can deliver the electric stimulation and pressure on the inguinal region as well as to perform the rectal palpation forces in a reproducible form[16]. Nevertheless, experience shows that such equipment is not essential and some variations in the force of application only brings to a change in the number of treatment sessions required without affecting the ultimate outcome.

References

[1] 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.
[2] Guha SK, inventor. Contraceptive for use by a male. US patent 5488075. 1996.
[3] Guha SK. Electrical effects on mammalian sperms. Proc Ann Conf IEEE Eng Med Biol 1988; 10: 1881-82.
[4] 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.
[5] 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.
[6] Guha SK, Singh G, 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.
[7] 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.
[8] Misro M, Guha SK, Singh H, Mahajan S, Ray AR, Vasudevan P. Injectable non-occlusive chemical contraception in the male-I. Contraception 1979; 20: 467-73.
[9] Sethi N, Srivastava RK, Singh RK. Histological changes in the vas deferens of rats after injection of a new male antifertility agent SMA and its reversibility. Contraception 1990;41: 333-9.
[10] Koul V, Srivastav A, Guha SK. Reversibility with sodium bicarbonate of styrene maleic anhydride, an intravasal injectable contraceptive, in male rats. Contraception 1998; 58: 227-31.
[11] Kihara K, Sato K, Ando M, Ushiyama T, Azuma H, Oshima H. A new method to generate canine seminal emission and its application to men: direct electrical stimulation of the vas deferens. J Androl 1994; 15: 479-83.
[12] Lohiya NK, Manivanan B, Mishra PK, Pathak N, Balasubramanian SP. Intravasal contraception with styrene maleic anhydride and its noninvasive reversal in langur monkeys (Presbytis entellus entellus). Contraception 1998; 58: 119-28.
[13] Zhao SC, Zhang SP, Yu RC. Intravasal injection of formed-in-place silicone rubber as a method of vas occlusion. Int J Androl 1992; 15: 460-64.
[14] Free MJ. Reversible intravasal devices: state of the art. In: Sciarra JJ, Zatuchni GI, Speidel JJ, editors. Reversal of Sterilization. Maryland: Harper Row Publishers; 1977. p 64-9.
[15] Kapur MM, Mokkapati S, Farooq A, Ahsan RK, Laumas KR. Copper intravas device (IVD) and male contraception. Contraception 1984; 29: 45-54.
[16] Guha SK, inventor. A device for restoration of male fertility. Indian patent 928/Del/97. 1997.

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Correspondence to Dr. S.K. Guha.
Tel: +91-11-658 1823 Fax: +91-11-686 2037
E-mail: guhask@cbme.iitd.ernet.in
Received 1999-06-29 Accepted 1999-08-25