Review Article Current Status of Male Contraception Dey D. *1, Chatterjee A. 2, D. Banji 2 and Bhowmik B.B.3

1Pukhraj Health Care Pvt. Ltd, Jalandhar, Punjab-144022, India. 2Department of Industrial Pharmacy,Nalanda College of Pharmacy, Charlapally, Hyderabad Road, Nalgonda-508001,Andhra Pradesh, India 3Himalayan Pharmacy Institute, Majhitar, East Sikkim, 737132

ABSTRACT

Rapid Population growth has caused a serious problem in economic growth and human development in the developing countries like India. The control of human fertility, in the sense of its limitation is the most important and urgent one, amongst all bio-social and Address for actuarial problems, confronting mankind today. Methods and Correspondence intentions, typically termed for are generally considered a pivotal ingredient to family planning. Male Contraception is one of Pukhraj Health Care the promising answers to the above problems perhaps. The Pvt. Ltd, Jalandhar, development of male contraceptive is relatively newer concept, Punjab-144022, India. researched or reviewed so far. Mechanism of male contraception, different methods and different intelligent drug delivery systems and E-mail: possible novel drug delivery system (NDDS) are reviewed in this dip_mpharm@ article. yahoo.co.in Keywords : Male contraception, Mechanisms, Advanced drug delivery systems, Herbal microcapsules.

INTRODUCTION The developments of male oral contraceptives for women. Likewise, contraceptives represent relatively novel are very effective but few men method of contraception. Male involvement are willing to undergo the surgery. 1 in the field of contraception has been low. Human is optimally produced The limited work on male contraception at a temperature that is a few degrees below may be due to cultural background, social body temperature. Infertility is induced if and economic condition, indifference and the temperature of the testes is elevated. For poor understanding of factors controlling this reason, men trying to conceive are often male fertility. The only method available to encouraged to avoid wearing snugly-fitting men is still those that were available during undergarments. The thermal suspensory the first half of the century, namely method of male contraception utilizes , , Withdrawal etc. specially designed suspensory briefs to use While prophylactic provide good natural body heat or externally applied heat barrier protection from unwanted to suppress . Such briefs but they are not as effective as hold the testes close to the body during the

American Journal of Phytomedicine and Clinical Therapeutics www.ajpct.org Dey et al______ISSN 2321 – 2748 day, ideally near the inguinal canal where (iv) prevention of sperm deposition. local body heat is optimum. Sometimes this method is also called artificial , as it is simulates the (i) Agents for Suppression of infertility in men with undescended Spermatogenesis testicles. 2 The ability of an -alone Drug therapy is also being evaluated modality to induce and maintain as a potential form of male contraception. was evaluated in a multicentre contraceptive Many drugs have been investigated in male efficacy study carried out by WHO, using contraception. One such drug, , is weekly injections of 200 mg of testosterone thought to induce sterility by blocking enanthate (TE), as a prototype androgen. The calcium channels of sperm cell membranes results showed that the cumulative lifetable to which results in cholesterol deposition and achieve azoospermia was only 64.5%. 5 The membrane instability of the sperm, inability of an androgen-alone regimen to rendering them incapable of fertilization. induce and maintain uniform azoospermia Herbal preparations have also been was evident even when used as male contraceptives. Gossypol, a (TB) was used. 6 TB, when administered to constituent of cottonseed oil, was found to short-term castrated rhesus monkeys be an effective and reliable male exhibited a pharmacokinetic profile, which contraceptive in very large-scale was superior to that induced by TE. These experiments conducted in China. Most studies clearly indicated the need for caution recently, a form of sugar that sperm interact in using relatively short-acting like with in the fertilization process has been TE for male contraception. 7 isolated from the outer coating of human eggs. (ii) Combination Regimens Perhaps one of the most researched In – androgen methods of male contraception using drugs combination regimes, smaller doses of involves the use of hormones. Like female androgens are needed, compared to androgen- contraceptive pills, Male Hormone only modality, since androgen potentiates the Contraceptives (MHCs) seek to stop the antispermatogenic activity of the progestogen, production of sperm by stopping the which acts as the primary antispermatogenic production of hormones that direct the agent in the regimen. Effective suppression of development of sperm. 3 spermatogenesis could be achieved only by use of a potent and long-acting progestogen MECHANISM OF ACTIONS OF MALE like depot medroxyprogesterone acetate. It CONTRACEPTIVES 4 would be worthwhile to initiate studies in Indian men, since this would make available a Current researches in India to develop viable contraceptive option for use in family a male contraceptive are directed mainly planning programmes in India. 8 towards: (I) development of antispermatogenic agents (iii) Follicle-Stimulating Hormone to suppress sperm production, Suppression (ii) prevention of sperm maturation, While a role for follicle-stimulating (iii) prevention of sperm transport through vas hormone (FSH) in the maintenance of deferens (or rendering these sperm infertile) spermatogenesis was well known, details of and its site of action were shown. These studies

AJPCT1[3][2013]282-290 Dey et al______ISSN 2321 – 2748 carried out at the Indian Institute of Science, by Guha and colleagues at the Indian Institute Bangalore showed that FSH deprivation by of Technology. 11 immunoneutralization significantly reduced the proliferation of spermatogonial cells and a marked inhibition in the transformation of (v) Prevention of Sperm Deposition 12 spermatogonia to primary spermatocytes. 9 Barrier methods like use of condoms have Another study showed that immunizing dual effectiveness, viz. prevention of sperm bonnet monkeys with recombinant FSH deposition in the female tract and prevention receptor protein affected testicular function of transmission of STDs and HIV. The and fertility. contraceptive prevalence of condom in India is an insignificant 31% (NFHS 1998–99). (iv) Inhibition of Sperm Maturation Recently, scientists and experts agreed that to With the development of new increase use of condoms four major issues andrology techniques like subzonal needed to be addressed: insemination of sperm and intracytoplasmic • changing norms about sexual behavior sperm injection, the relevance of the and condom use, in sperm maturation has come • assuring effective use, under increasing doubt. A role for epididymis • providing greater access to condoms, in sperm maturation was established in • changing restrictive policies concerning nonhuman primates and in humans at the All condoms. India Institute of Medical Sciences. These studies evaluated changes in sperm motility DIFFERENT METHODS OF MALE and its hormonal dependence, changes in CONTRACEPTION sperm ultrastructure and reorganization of Emerging approaches to male lipid bilayer and changes in lectin binding to contraception can be broadly classified into 10 sperm. As an extension of the above two groups. One direction does not directly studies, sperm surface proteins undergoing affect spermatozoa production and early maturational changes were identified. These stages of development, but subsequently, studies clearly showed the occurrence of during passage in the epididymis and the vas modification in sperm surface epididymal difference, the functional character is altered glycoproteins during maturation. and the number passing on the ejaculatory duct reduced. There is thus the possibility of (iv) Prevention of Sperm Transport localized intervention with virtually no This is essentially a systemic effect. The second class of method based approach. Vasectomy has been in use aims to suppress spermatozoa production since many decades as a terminal method to generally by manipulating the hormonal prevent sperm transport; intra- and extra-vasal status. Moreover, there is a requirement of non-occlusive methods have been developed regular intake of drugs orally or by injection. in India. Two major approaches have been Different methods of male contraception are attempted in India to prevent sperm transport shown in Fig.1. through the vas deferens. These are use of intravasal copper by Kapur and colleagues at (i) Natural Method the All India Institute of Medical Sciences, Withdrawal method (coitus and injection of a non-sclerosing agent, interruptus) and periodical abstinence styrene maleic anhydride (SMA) into the vas particularly in mid-cycle are the only two natural methods of contraception for males.

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Although discouraged and rightly so, by In the first large scale efficacy trial westerners because of high failure rates, these of male contraception, it was demonstrated methods have a good place in India and other that 200mg injections of testosterone given developing countries as they need no special i.m. weekly rendered 65% of the 399 training. volunteers azoospermia. Complete azoospermia or oligospermia was seen (ii) Physical Methods 13 within six months. Recovery was seen within 4-8 weeks of cessation. A single a) Barrier Methods injection of 1200mg testosterone buciclate Barrier methodes place a physical when given i.m. produced azoospermia in 3 impediment to the movement of sperm into of 8 volunteeres in week 10 after the female reproductive tract.The most administration and persisted upto 18 weeks popular barrier method is the male condom , a by average.A dose of 25mg testosterone latex or polyurethane sheath placed over the propionate given daily i.m. was studied for a penis. There are about 50 million condoms period of 6 weeks on rats and was found to usere world wide. Effectiveness can be produce sperm suppression. improved with proper and consistence use and the use of . The condom has traveled a long way from what it was to the b) Androgen / Progestin Combination colored and flavored forms, which exist as of Regimen date. Condoms are now available at an The addition of progestin to an optimal thickness and in a variety of sizes, “androgen only regimen,” has induced long shapes, widths, and lengths. The ever- term azoospermia with fewer side effect, increasing rate of sexually transmitted due to synergistic actions of androgen and diseases, more specifically AIDS, and the progestin.The dose combination of rising figures of teenage have testosterone enanthate (TE) and oral restored the condom its previous importance. supreesed sperm production significantly by week 8 and all subjects became azoospermic after 20 weeks of b) Vas occulation 15 Newer "vas occlusive" methods offer treatment. Preliminary results from a alternatives to vasectomy with completely study using 6-month depot medroxy reversible effects. Vas occlusive devices acetate and implanted T pellets block the flow of or render dysfunctional the indicated effective sperm suppression. Although there were no majore side effects. sperm in the vas deferens. The most recent 16 form of vas occlusive male contraception, called Reversible Inhibition of Sperm Under Guidance (RISUG), involves the use of a 17 c) Synthetic Androgen styrene that is combined with the chemical In a clinical trial to study the effect DMSO (dimethyl sulfoxide). The complex is of MENT (7 α-methyl-19-nor testosterone) injected into the vas deferens. The complex implants, two subdermal implants each then partially occludes passage of sperm and containing 112mg MENT acetate in also causes disruption of sperm cell polyethylene vinyl acetate polymer were membranes. administered for 4 weeks. MENT acetate

rapidly hydrolyzed rapidly hydrolyzed to (iii) Hormonal Methods MENT in vivo . The implants produced a a) Androgen Only Regimen 14 reversible, nontoxic decrease in fertility, and

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MENT is also being studied as a long acting It was found that plasma serum contraceptive. derived Protein C Inhibitor (PCI) and a synthetic peptide derived from its sequence inhibited both binding and penetration of d) Gonadotropin Releasing Hormone (GRH) 18 zona- free hamster oocytes by human sperm. agonist analogs PCI retards sperm activity by inhibiting The paradoxical antigonadotropic enzymes that are involved in sperm motility effects of highly potent GRH agonist or by inhibiting sperm-zona penetration or analogs have provided a new tool for by inhibiting, binding and penetration to the contraception. Treatment with high doses of plasma membrane of the egg. PCI therefore, these analogs inhibits human testicular has the potential to be developed as a androgen production. The unavoidable side contraceptive. effects accompanying decrease in testosterone are eliminated by simultaneous (v) Plant Product exogenous testosterone treatment, but The Chinese plant Tripterygium antispermatogenic effects remains due to wilfordii and its botanical cousins contain persistent decrease in FSH secretion. several orally active compounds that provide male contraception. Pills made from Tripterygium have been used in traditional (iv) Non Hormonal Methods Chinese medicine for over 1000 years. Researchers are isolating the compounds a) Immunocontraceptive Mechanism with contraceptive effects for further Targeting Sperm Protein research. 20 Novel surface constituents called When extracts from the seeds of differentiation get inserted on the papaya fruits ( Carica papaya ) were fed to surface of the sperm during various stages monkeys, the monkeys had no sperm in their of development and maturation, which play ejaculate. Researchers are trying to a role in the process of fertilization. Lactate determine whether papaya seed extracts are dehydrogenase C4 (LDH – C4) has been safe for use in additional studies. 21 identified as a sperm specific antigen. The neem tree ( Azadirachta indica ),

common in India, has many medicinal uses. b) Epididymal Enzyme Targeted Approach 19 Very small quantities of neem oil have been N- acetyl–β–D–hexosaminosidase successfully tested as an alternative to enzyme ( NAH) is secreted in the surgical vasectomy. Fresh neem leaves epididymis and enters the sperm cells after caused reversible contraception in male rats, they leave the testis. The enzyme has two and there are anecdotal claims of the use of variant forms A & B. Sperm cells contain neem leaf extracts as effective male 22 only the B type. The B form gives the sperm contraception. cells the ability to recognize , bind with and Pills made from Gossypol, a penetrate the egg resulting in fertilization. compound found in cotton seeds, have been By inhibiting the B variant , the sperm can abandoned as a potential male contraceptive no longer recognize the egg, but the A because of unreliable reversibility in clinical variant is available for performing the trials. Researchers have suggested that necessary physiological function of NAH in gossypol might make a good non-invasive 23 the rest of the body. The analogue was alternative to surgical vasectomy. tested on male mice, inhibiting 90% of The leaf extract of Beal (Aegle enzyme activity in vivo and in vitro. marmelos) result a significant diminution in

AJPCT1[3][2013]282-290 Dey et al______ISSN 2321 – 2748 the activities of key testicular steroidogenic For the convenience of consumer, enzyme along with low levels of plasma controlled release contraceptive preparations testosterone and relative wet weights of sex are very useful. The prolonged release organs in respect to control without any character of a controlled release drug significant alteration in general body delivery system is to minimize the need for growth. Germ cells numbers in different frequent drug intake and assure better generation at stage VII of seminiferous compliance. Very few male contraceptives epithelial cell cycle were diminished are available today, hence the area of male significantly after the treatment of the above contraceptive NDDS can be maneuvered extract without any toxicity in liver and intelligently, as suggested in fig. 2. kidney. 24

Biodegradable Pellets 26 (vi) Miscellaneous 25 In this system, crystalline Lonidamine is an anticancer drug testosterone is fused into a pellet formation that showed antispermatogenic activity and six 200-mg pellets are implanted in the however it caused renal damage. Oral abdominal wall. The pellets are Ornidazole, 400 micrograms / kg daily for 2 biodegradable and the release of drug to 3 weeks induced rapid infertility after 6 suppresses sperm output for about 6 months. days. After withdrawal of the drug, fertility The release kinetics have been shown to returned within 7 days. Nifedipine, an approach zero order. hypertensive drug produced antispermatogenic activity by slowing the 27 movement of the calcium through cell Long Acting Contraceptive Preparations membrane, which was essential for sperm to The injectable LH-RH-containing function. The effect was reversible and the poly (DL-Lactide-co-glycolide) PLGA drug was found to be safe in the regimen spheres is act as a contraceptive agent in that was followed. males. Developments are being made for an A new male contraception method is injectable system much like Depo-Provera, undergoing clinical trials in India. The goal in which testosterone enanthate would be of this research is to achieve a method administered along with depot which restricts its effects to the region of the medroxyprogesterone acetate(DMPA). vas deferens. First, the belief that there was Synthetic testosterone, 7 α-methyl-19- a strong peristaltic movement in the vas nortestosterone(MENT) for use in during ejaculation had to be examined. It subdermal contraceptive implants in men. In was found that only the ampula part of the conjunction with an LH-RH analogue, this vas is given a tight squeeze to release the potent steroid could be used in a system stored sperm into the semen. Therefore, a designed for 1 year of contraceptive use. device to manipulate sperm could safely be inserted into the vas. Using the fact that the 28 Transdermal Devices acrosomal membrane of the sperm is A further development is the novel disturbed when sperm are subjected to administration of testosterone via a electrical currents. transdermal device. The device is designed

to administer testosterone for 1 month or NOVEL CONTROLLED RELEASE longer, and initial testing shows a zero order MALE CONTRACEPTIVES release both in vitro and in vivo testing on

AJPCT1[3][2013]282-290 Dey et al______ISSN 2321 – 2748 rhesus monkeys. The system is a disk of public opinion surveys throughout the shaped bandage-type device that containes world have reported that 60-80% of men microspheres of hormone suspended in would use new contraceptive techniques, if liquid and immobilized in a crossed linked made available. 30 In view of efficacy and polymer. safety of different male contraceptives demonstrated in animal trials the Drug Controller of India gave permission for phase- Implantable Controlled Release 29 I Clinical Trial. Development of novel Preparations contraceptive devices will be very useful for Cylindrical capsules of PLGA have population. Further there is a potential need also been investigated for their use in for research and development of male delivering buserelin acetate. Buserelin is a contraceptive NDDS and ofcource colloidal Gonadotrpin-releasing hormone (GnRH) particulate carriers are promising in this agonist. A GnRH agonist inhibits FSH and perspective. LH secretion from the pituitary, thus decreasing testosterone secretion and REFERENCES suppressing spermatogenesis. Preliminary testing of the device as a contraceptive has 1. Ecochard R, Pinguet F, Ecochard I, been inconclusive as the delivery of GnRH DeGouvello R, Guy M. and Huy F. Analysis agonists must be carefully combined with of natural family planning failures, Fertilite the administration of androgens so as to Contraception Sexualite;1998, 26: 291-296 inhibit only spermatogenesis and avoid 2. Kathieen J.W, Wilson and Waugh A. The adversely affecting other androgen reproductive system, in: Green E.(ed.). Anatomy and physiology in health and supported functions in the body. th illness, 8 edition, Churchill Livingstone, London,1998, pp.431-435. Herbal Microencapsulation 3. Rajalakshmi M, Pal P.C, Antony Jeyaraj D. Research can be possible for and Sharma R.S. Current status of fertility encapsulation of active and potent control methods in India. J. Biosci; 2001, 26:391-405 compound, isolated from herbal resource 4. Sharma R.S, Rajalakshmi M. and Jeyaraj utilizing different synthetic and natural D.A. Current status of fertility control polymer by different techniques. In the point methods in India. J. Biosci; 2001, 26:391- of view the herbal microencapsulation 405 which have anti fertility effect can be claim 5. Guha S.K. Non-invasive reversal of some what novel work, for avoiding the intraluminal vas deferens polymer injection complication of the conventional herbal induced azoospermia technology; Asian J. dosage form and drug to be released at Androl; 1999, 1: 131–134 controlled fashion. 6. Kinger S, Pal P.C, Rajalakshmi M, Suresh Kumar P.K, Sharma D.N. and Bajaj J.S. Effects of testosterone buciclate on testicular CONCLUSION and epididymal sperm functions in bonnet monkeys, Contraception; 1995, 52: 121– The review is aimed at a new male 127. 7. Rajalakshmi M. and Ramakrishnan P.R. contraceptive technique likely to be reversible Pharmacokinetics and pharmacodynamics of and also useful for spacing birth. A high rate a new long-acting androgen ester: of acceptability of male contraception was maintenance of physiological androgen seen among the urban population. A number

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Figure.1. Different existing methods of male contraception

Figure.2. Different advanced drug delivery systems of male contraceptions.

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