275 Trends in Male Contraception REV

REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(5):275-283, 2003 TRENDS IN MALE CONTRACEPTION Fábio Firmbach Pasqualotto, Antônio Marmo Lucon, Eleonora Bedin Pasqualotto and Sami Arap PASQUALOTTO FF et al. - Trends in male contraception. Rev. Hosp. Clín. Fac. Med. S. Paulo 58(5):275-283, 2003. Methods that are available for male contraception, namely coitus interruptus, condoms, and vasectomy, have been used since the 19th century. With the exceptions of a few improvements of these methods, no major progress has been made with respect to introducing new male contraceptives since then. It is extremely urgent to develop new, safe, effective, and reversible male contraceptive methods. Among all male contraceptive methods that are being investigated, the hormonal approach is the closest to clinical application. Hormonal contraception provides pregnancy protection by means of spermatogenic suppression. Androgen-progestin regimens currently represent the best available hormonal combination for induction of a profound suppression of spermatogenesis. Further development of new steroids is mandatory for increasing the choices of available contraceptive formulations and to optimize long-term safety of these regimens. DESCRIPTORS: Testosterone. Androgen. Hormones. Contraception. Sterile. During recent decades, the most of men would use “the pill” if it were encouraging sign, and the first “male important trends in family planning available2,3. Of all the different contra- pill” might be available in a few years. services have been improvement in the ceptive strategies tested for the male, quality of care, reaching out to new the hormonal methods come closest to Nonhormonal methods population groups such as men and the ideal (Table 1)4 . Considerable adolescents, and integrating family progress recently has been made in this Extracts of the Chinese medicinal planning services into other reproduc- field, in particular with the multicenter plant Tripterygium wilfordii have been tive health services1. contraceptive efficacy trials of the shown to contain compounds that A number of methods aimed at the World Health Organization.5,6 These cause infertility in male rats. One of suppression of sperm production, the studies have established the feasibil- them, triptolide, appears to be effective inhibition of sperm motility, or the ity of hormonal male contraception in reducing epididymal sperm concen- prevention of sperm transport are un- and have clearly identified the prob- tration and in inducing an almost der development2,3. However, new con- lems that still remain before such a complete loss of sperm motility7. traceptive methods are still not avail- method is ready for wider use. The These characteristics make it an attrac- able for the male. The reasons for this awakening of interest of the pharma- tive lead as it is a substance that would are numerous, including insufficient ceutical industry in the development induce infertility without suppressing research funding, lack of interest by of male hormonal contraceptives is an spermatogenesis, would act quickly, both the scientific community and and would be easily reversible8. pharmaceutical companies, fear of side Further, several chemical com- effects, and doubts regarding accept- pounds including a-chlorohydrin, 6- ability, as well as those inherent in the From the Urology Department and chloro-6-deoxy sugars, gossypol, and difficulty of the task. Of these obsta- Andrology Group, Hospital das Clínicas, triptolide have been shown to inhibit Faculty of Medicine, University of São Paulo cles, at least the doubts as to accept- - São Paulo, Brazil. either spermatogenesis or epididymal ability seem to be unfounded, since re- Received for publication on sperm maturation9; however, their se- April 24, 2003. cent surveys show that well over 50% vere side effects, such as hypokalemia, 275 Trends in male contraception REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(5):275-283, 2003 Pasqualotto FF et al. Table 1 - Requirements of an ideal male contraceptive method. over latex condoms are that they are loose-fitting except at the base of the As effective as comparable female methods penis, are stronger in vitro, do not de- Acceptable to both partners teriorate in storage, are not affected by Rapidly effective Free of side effects and especially without influence on masculinity, libido, and potency oil-based lubricants, and can be used Without influence on progeny by individuals who are allergic to la- Reversible with regard to fertility ® Easily available and financially affordable tex. Polyurethane condoms as Avanti and styrene-based plastic condoms such as Tactylon®15 are already on the neurotoxicity, immunosuppression, approach has been the identification of market, and others are under develop- and irreversibility of azoospermia, pre- an appropriate antigen and the avoid- ment. Clinical trials with Avanti16 sug- clude them from use in humans. ance of possible irreversible effects in gest that it may have higher slippage The strategies of nonhormonal the testis. Other approaches based on and breakage rates than the male latex male contraception relate to the phar- anti-FSH (follicle-stimulating hor- condom; however, its acceptability is macological inhibition of testicular mone), anti-FSH receptor or anti-GnRH generally greater. The cost of these de- sperm production, in particular meio- are being investigated as possible in- vices is likely to remain an obstacle to sis, and disruption of sperm maturation hibitors of gametogenesis. their widespread use in national fam- in the epididymis. ily planning programs. Our knowledge of the molecular Improved methods for male and cell biology of spermatogenesis sterilization Principles of hormonal male and sperm maturation has increased contraception greatly. Findings regarding reproduc- Vasectomy is easy to perform and tive failures are often made in has fewer associated complications The purpose of hormonal male transgenic and knockout mice. It is compared to female sterilization, but contraception is to alter the endocrine possible that these studies will iden- the need for a skin incision, and the environment of the body in such a way tify single genes that are critical in the lack of assured reversibility appear to that the hormonal control of sperma- production of fertile sperm. If such a be the main issues limiting its accept- togenesis is blocked. Spermatogenesis gene codes for, for instance, a testis or ability. Two major techniques have requires the stimulatory action of the germ cell-specific enzyme, receptor, or been developed to overcome these prob- two pituitary gonadotropins, luteiniz- ion channel, specific blockage of its lems: the no-scalpel method of vasec- ing hormone (LH) and follicle-stimu- function by pharmacological means tomy, which is gaining in popularity, lating hormone (FSH). The role of LH could be feasible. Such findings would and the percutaneous nonsurgical vas is to stimulate Leydig cell testosterone provide concepts for the development occlusion technique12. Occlusion tech- production and to maintain the very of specific nonhormonal male contra- niques based on polyurethane or me- high intratesticular testosterone con- ceptives. Unfortunately, despite its thylcyanoacrylate have been shown to centration (100-fold compared to pe- clear potential, such a method must have high local toxicity, with local re- ripheral circulation) that is needed for await future development9,10. action and occlusion on either side of spermatogenesis. The role of FSH is the plug. Methods using silicone are less clear, but it seems to be important Immunological methods under evaluation13. A new approach to for the maintenance of qualitatively nonsurgical vas occlusion under study normal spermatogenesis by stimulat- Clinical observations have sug- involves an injection into the vas def- ing the recruitment of spermatogonia gested that the presence of antisperm erens of a preparation of styrene maleic into the spermatogenic maturation antibodies might be a cause of infer- anhydride dissolved in dimethyl sul- process. Hence, the effective suppres- tility and might also explain the low foxide. In monkeys, this approach has sion of gonadotropins, in particular pregnancy rate observed after vasec- been shown to be reversible using a that of the LH/testosterone link, can be tomy reversal11. Since the presence of combination of palpation and percuta- expected to inhibit spermatogenesis. antisperm antibodies is not associated neous electrical stimulation14. Although FSH action is also involved with any side effects other than infer- in spermatogenesis, the selective inhi- tility, the option of developing an Non-latex male condoms bition of FSH is not enough to inhibit antisperm vaccine seems possible. it, as has been demonstrated recently However, to date the difficulty in this Advantages of non-latex condoms in mice with disrupted function 276 REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(5):275-283, 2003 Trends in male contraception Pasqualotto FF et al. (knockout) of the FSH b-subunit and vantage that the same compound pro- much greater in men of Asian origin FSH receptor genes17-19 and in men duces both gonadotropin suppression than among Caucasians (91% vs. 60%). with an inactivating mutation in the and the supplementation of peripheral The second phase of the WHO FSH receptor gene20. This finding casts androgen levels. If the dose given study consisted of an investigation doubts on the efficacy of male contra- slightly exceeds the physiological into the extent to which

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