Indian Jouma1 of Experimental Biology Vol. 43, November 2005, pp. 1042-1047

Review Article

Perspectives of contraceptive choices for men

N K Lohiya*, B Manivannan, S S Bhande, S Panneerdoss & Shipra Garg Reproductive Pbysiology Section, Department of Zoology, University of Rajasthan, Jaipur 302 004, India

Apart from condoms and vasectomy, which have several limitations of their own, no other methods of contraception are available to men. Various chemical, honnonal, vas based and herbal contraceptives have been examined and few of them have reached the stage of clinica1 testing. Promising leads have been obtained from bucic1atelundecanoate, alone or in combination with butanoate or acetate, RlSUG, an injectable intra vasal contraceptive and a few herba1 products, particularly the seed products of Carica papaya. It is feasible that an ideal . that meets out all the essential criteria will be made available to the community in the near future.

Keywords: Carica papaya, Herbal methods, Honnonal methods. Male contraception, RISUG. Vas based methods

In the new millennium, India has crossed the one lead from sperm production in the testis to sperm egg billion mark. sharing 16% of the world population on interactions and fertilization in the female genital tract 2.4% of the global land area. More than 18 million need to be considered. Accordingly, the biomedical people are added every year, which is almost the options available in control of male fertility are entire population of Australia With the current trend, limited to (1) inhibition of spermatogenesis at the it is projected that India may overtake China in the level of testis, (2) inhibition of sperm maturation at year 2045 to become the most populous country in the the level of epididymis, (3) inhibition of sperm world, the distinction which no Indian would be proud transport at the level of vas deferens, (4) inhibition of of. Although India was the first to launch National sperm deposition in the female genitalia, and (5) Family Planning Programme as early as 1952 in order inhibition of sperm egg interaction at the level of to curtain the population menace, 16% of currently female reproductive traer. The options available to married women in the country have an unmet need for men are limited to condoms, periodic abstinence, family planning; 8% women want child spacing withdrawal and male sterilization. Survey among without contraceptive use, while the other 8% do not married men in developing countries indicate that want any more child but without the use of only 4% of men use condoms, 4% undergo l contraceptive . As per the National Family Planning vasectomy, 3% use periodic abstinence and 4% use Survey (1998-1999), 25% of total family planning withdrawal in which periodic abstinence and programme had an uomet need, and the contraceptive withdrawal have higher failure rates and are often 3 prevalence rate in the country is only a moderate practiced with other contraceptive measures . 48.2%, with female sterilization accounting for 34.2% Current Trials and the currently available male methods accounting It is speculated that men's participation in family negligible. planning would increase, if there are wider choices of Currently men's involvement in regulating family contraception available to them, which should be safe, size is negligible, as there is an argument that they do effective, and economical and that it should provide not have sufficient contraceptive choices to adopt, long term and completely reversible contraception, compared to their female counterparts. For regulation preferably free of surgery with greater acceptability of male fertility, the various steps in reproduction that rate. One of the main problems encountered in development of a male contraceptive is the fact that it *Corresponding Author" is necessary to achieve azoospermia or make all the Phone 0141-2701809; 2703552 (0) sperm nonfunctional, since it is believed that even a 0141-2710071 (R) Fax: 0141-2710880; 2701809 single functional spermatozoon is adequate for e-mail: lohiyank~boImaiI,(;()m fertilization. Azoospermia could be easily achieved by LOHIY A et al.: CONTRACEPTIVE CHOICE FOR MEN 1043 interfering with production of testosterone which is surgical vas occlusion. The latter is considered more indispensable for spermatogenesis, but the same could advantageous because it causes minimal honnonal interfere with libido which is unacceptable4. and systemic side-effects and offers a better scope for A number of approaches including the use of reversal. Currently, alone or or non-hormones involving , in combination with depotmedroxy anti androgens or GnRH analogs with sites of action in acetate or enanthate are also under the testis and epididymis, and non occlusive devices clinical trial to identify more priority leads for male that have either a chemical or mechanical effect on contraception 12,13. spermatozoa as they pass along the vas deferens, are being investigated; these approaches may interfere Vas based methods with sperm function either in the testis, epididymis or Vasectomy is a simple, safe, effective and an in other parts of the male reproductive tract, and are inexpensive method of male contraception; the intended mainly to affect sperm production directly or operation can be easily performed in 10-15 min on an out-patient basis with minimal training for most render the spermatozoa infertile without affecting the 28 30 circulating testosterone level. Most of these appro­ surgeons - • It is perceived in some cultures that aches have reached the stage of clinical testing, but vasectomy reduces physical strength and has been none of them has so far reached the stage of accepta­ claimed by some men who had undergone the bility or commercialization for public utility5. operation and also by their partners that it reduces sexual potency31. In addition, vasectomy is considered Hormonal methods as a permanent method and even if reanastomosis of The hormonal approach to male contraception is the vas is successful, the resulting fertility is poor. based on the suppression of gonadotrophin secretion An ideal intravasal device for male contraception with secondary suppression of spermatogenesis to should be easy to inse~ and be flexible; it should achieve azoospermia, the ultimate goal in male contr­ prevent sperm passage and be capable of being easily aceptive studies. alone in the form of removed for restoration of vas patency and return of 9 testosterone esters6-8, , testo­ fertility32. Initial attempts have been made to solve the lO ll 15 sterone buciclate , testosterone undecanoate - , 7 problems associated with the reversal of vasectomy. alpha methyl 19 nor testosterone [MENT] 16-18, Several mini biomedical devices, viz., intravasal androgen in combination with i.e., depot­ thread, copper wire, biogalvanic cells, and tantalum medroxy progesterone acetate and testosterone clips have been tried. but they failed to meet out the 19 enanthate , medroxy progesterone and testosterone ideal requirements]3. Injectable plugs, employing emmthate, levonorgestrel and testosterone unde­ percutaneous of polyurethane elastomer to 20 canoate , levonorgestrel and testosterone enanthatel form plugs34-J6 and non injectable silicon plugs, called 21 22 . , and testo­ the 'shug,37 have also been tried up to the level of sterone23,24 , and androgen in combination with clinical trial in over lO,OOO men. However, the progestogenic anti androgens viz., surgical intervention for implantation of devices into 25 and testosterone enanthate .26, cyproterone acetate the vas deferens and their reversal limits further and testosterone buciclate27, consideration in use of intravasal devices for mass I2 13 and testosterone undecanoate . and norethisterone family planning programme. Hence, from the delivery enanthate and testosterone enanthatell have been point of view, injection of a polymer into the vas investigated up to clinical trial for many years but lumen, by a minimal invasive procedure that provides without identifying a suitable regimen which would a safe and effective contraception and offers reversal, result in suppression of spermatogenesis to achieve would appear to be more advantageous, convenient contraception, without adverse metabolic effects. and globally acceptable. The WHO consultative meeting on "Setting the Styrene maleic anhydride (SMA), currently Agenda for Fertility Regulation Technology Research renamed as RISUG®, is a co-polymer of styrene and in Reproductive Health for the Next Decade" (held at maleic anhydride and offers fertility control through Geneva, Switzerland, 1996) identified two leads in the multiple modes viz., it blo.;;~ the vas deferens and field of male contraception viz., (i) a tri-monthly prevents forward flow of sperm, induces pH lowering injectable plus testosterone effect and causes charge disturbances to the buciclate or testosterone buciclate alone and (ii) non- membrane of the spermatozoa, resulting into the 1044 INDIAN J EXP BIOL, NOVEMBER 2005

acrosome damageJ8 . Further, SMA has no teratogemc• particular are those which are orally effective, non­ 39 40 effect and is toxicologically safe in animal models • • steroidal, non-estrogenic, safe and effective in Clinical trials at Phase tl and Phase If'2 levels have inhibition of spermatogenesis or interfere with sperm shown contraceptive efficacy and safety of SMA in maturation in men. humans. It has also been demonstrated in Phase II To date, several hundred plants have been reported clinical trials that SMA could be delivered into the to possess significant antifertility properties. In all vas lumen by "No Scalpel injection" method with these plants, studies were restricted only to the level minimal invasion. However, in order to make this of spermatogenesis through histology and fertility procedure widely acceptable as a better alternative to tests in rats and mice. The roots of Aristolochia indica vasectomy, its contraceptive efficacy should last and Plumbago zeylanica, the leaves of Azadirachta longer, with the possibility of reversal at desire. indica, Catheranthus roseus, Vinca rocea and Preliminary investigations have been carried out in Ocimum sanctum, the flowers of Hibiscus rosa­ langur monkeys to ensure reversal by a non-invasive sinensis and Malvaviscus conzatti, the seeds of Carica method, following a short teno vas occlusion with papaya and Vitex neg undo, and the fruits of SMA @ 60 mg in 120 ,d of DMSO in each vas Momordica charantia, have been identified as lead deferens for 150 days. The procedure leads to uniform plants for male fertility regulation. azoospermia in 90 days. Non-invasive reversal The gossypol isolated from the seeds of cotton procedure, following three consecutive azoospermia plant and the glycosides of Tripterygium wilfordii extended for 150 days, by palpation, per-cutaneous have been studied extensively up to the stage of electrical stimulation, supra-pubic percussion, and 47 48 clinical trials • . Although, gossypol was found to be per-rectal digital massage in successive steps resulted more effective with 99% efficacy assessed by semen into reversal of azoospermia with severe oligospermia examination in human trials, further studies were on the same day of reversal manipulations, which abandoned due to its major side effects such as gradually improved and nonoospermia, comparable to hypokalemia. low therapeutic index .and uncertain that of the pretreatment levels, could be achieved 49 recovery upon withdrawal of the drug • The within 30 days of reversal manipulations. Ultra­ glycosides of Tripterygium wilfordii have shown structure of spermatozoa and vas morphology, which reversible impairment of motility in human. However, showed deleterious changes after vas occlusion, also preliminary toxic evaluation indicated that these returned to normalcy after 90 days of reversal. Sperm compounds are immunosuppressive at high dose function tests, i.e., hypo-osmotic swelling test to 50 regimens • Further success of this plant as a male demonstrate membrane integrity, acrosomal intactness contraceptive warrants special attention to prove test to demonstrate the status of acrosome and the deeply to their precise dose/immuno effect sperm mitochondrial activity index test to relationship. demonstrate flageller mitochondria and motility Extensive animal studies carried out with the seed disorders, also indicated regain of fertility following 43 44 extracts of Carica papaya indicated that this product 30 days of reversal • • Repeat vas occlusion and could be identified as a potent testicular/post testicular reversal have also been successfully demonstrated in orally effective contraceptive in the near future. langue monkeys, with a possibility of using the 45 Chloroform extract, benzene chromatographic technique as spacing method • Currently, this fraction of the chloroform extract and its methanol procedure appears to be one of the most promising and ethyl acetate sub-fractions of the benzene among the vas based contraceptive approaches with chromatographic fraction and the isolated compounds the feasibility of reversal at desire. from the sub-fractions have shown promising results Herbal methods in rats, rabbits and langur monkeys. Chloroform The ayurvedic and unani texts mention the use of a extract showed total motility inhibitory action after 60 number of plant preparations for fertility regulation. days in rat, and severe oligospermia by 90 days and 51 52 The Asian countries, particularly India and China, uniform azoospermia by 120 days in rabbit • . With have contributed the most and have identified the benzene chromatographic fraction total sperm motility novel drug prototypes found in plants, which have inhibitory action was achieved within 60 days after been reported to possess fertility regulating pro­ treatment in rats and uniform azoospermia was 46 53 54 perties • The compounds that are being sought in achieved after 15 days in rabbits . • Similar results LOHIY A et al.: CONTRACEPTIVE CHOICE FOR MEN 1045 were achieved with methanol and ethyl acetate sub­ meet out the essential criteria of an ideal male fractions of the benzene chromatographic fraction in contraceptive. 47 rat and rabbit • The effects were free of toxicity up to 180 days study period and completely reversible Acknowledgement following withdrawal of treatment. Fertility test Investigations on Carica papaya are being indicated 100% antifertility effect. Pre-clinical supported by the Indian Council of Medical Research, investigations carried out in langur monkeys revealed New Delhi and the Special Assistance Programme uniform azoospermia after 90 days of treatment with (Phase III), Department of Zoology, University of chloroform extract which continued until one year Rajasthan, Jaipur. Financial support received from 55 study period , while benzene chromatographic Ministry of Health and Family Welfare, Government fraction and its sub-fractions showed total sperm of India, New Delhi for the investigations on SMA motility inhibitory action after 60-90 days of and Carica papaya is also gratefully acknowledged. treatment. The effects were free of toxicity and reversible. 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