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 methods. Among all male contraceptive methods that are being investigated, the hormonal approach is the closest to clinical application. provides pregnancy protection by means of spermatogenic suppression. -progestin regimens currently represent the best available hormonal combination for induction of a profound suppression of spermatogenesis. Further development of new is mandatory for increasing the choices of available contraceptive formulations and to optimize long-term safety of these regimens.

DESCRIPTORS: . 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 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- 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 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 the fertility of ceptive strategies involving the inhi- maintenance dose, gonadotropin and men displaying severe oligozoosper- bition of FSH action or the manipula- testicular testosterone production are mia may be affected6. Using a similar tion of inhibin levels. blocked, but peripheral testosterone study protocol, men with oligo- The elimination of testicular testo- levels are preserved to maintain the zoospermia below 3 X 106/mL were al- sterone production by gonadotropin physiological extragonadal action of lowed to begin a 12-month use of tes- suppression also suppresses the extra- the . The other practically tosterone. Altogether, of the 349 men gonadal levels of androgens, thereby feasible antigonadotropin agents in- entering study, 77% remained consist- abolishing their anabolic effects on clude progestins and gonadotropin re- ently azoospermic, 10% were consist- potency and libido. To avoid this, leasing hormone (GnRH) analogs. ently oligozoospermic but never physiologically low levels of pe- Since these hormones only provide the azoospermic, and 13% fluctuated be- ripheral testosterone have to be main- gonadotropin suppression, androgen tween oligozoospermia and azoosper- tained by androgen supplementation. supplementation must be included in mia. Only 2.2% failed to achieve the The physiological testosterone levels the regimen to maintain the extrago- required azoospermia or oligozoosper- needed are so low that they do not nadal activity of the androgens. mia (< 3.0 X 106/mL). No pregnancies reinitiate spermatogenesis – as stated occurred amongst the azoospermic before, the normal intratesticular tes- Feasibility of hormonal male men, but in those with oligozoosper- tosterone concentration is 100-fold contraception: the WHO mia, pregnancies occurred at a rate of higher than that found in the periph- multicenter trials 8.1 per 100 persons/year. The likeli- eral circulation. hood of contraceptive failure was di- Gonadotropin suppression can be Clinical trials testing the suppres- rectly related to the remaining sperm achieved by a variety of hormonal regi- sion spermatogenesis by androgen count. mens (Table 2). An ideal alternative is treatment have been conducted since The combined efficacy rate of the testosterone itself, since it has the ad- the late 1970s. A common feature of 200 mg/week these trials is that about two-thirds of (TE) method is similar to those of hor- Table 2 - The various strategies for the men involved, usually of Cauca- monal female methods but superior to hormonal male contraception. sian origin, display reversible suppres- the reversible male methods (con- sion of spermatogenesis to the point of doms, withdrawal, periodic absti- 1. Testosterone alone azoospermia, while variable suppres- nence). The risk of pregnancy is al- testosterone enanthate in oil sion is observed in the rest, usually to most exclusively in the oligozoos- testosterone pellets the point of severe oligozoospermia. permic group. Whether this rate of testosterone microspheres The first World Health Organization contraceptive efficacy is enough or 2. New parenteral testosterone preparations (WHO) multicenter study showed that whether only 100% azoospermic can testosterone buciclate the azoospermia achieved in this fash- be accepted is a matter of debate. It ion, using a standard regimen of 200 may be feasible to state that, on the 3. Testosterone or progestins mg testosterone enanthate (TE) per basis of these findings, azoospermia

4. Testosterone and antiandrogens week intramuscularly, resulted in effec- should be set as a goal for future de- tive contraception5. The men partici- velopmental work on this method. 5. Testosterone and estrogens pating developed azoospermia, used It is evident that weekly testoster-

6. Testosterone and GnRH analogs no other form of contraception for 12 one injections, as used in the WHO tri- months, and among the 137 couples als, are not practical means of male 7. Other androgens involved, only 1 pregnancy occurred. contraception and have served prima- 19-nortestosterone 7α-methyl-19-nortestosterone (MENT) The compliance of the men was good, rily to prove that the principle works. 5α- the side effects were tolerable, and in Once a method with satisfactory con- all cases the antispermatogenic effect traceptive efficacy has been devel- 8. Immunizations against FSH or FSH receptor was reversible. An interesting feature oped, the challenge of developing a against GnRH or GnRH receptor was that the rate of azoospermia was more practical means of administration

277 Trends in male contraception REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(5):275-283, 2003 Pasqualotto FF et al. of the hormone treatment can be trans- equal to the daily production rate of gen/progestin combination. This pos- ferred to pharmaceutical companies. testosterone, i.e. 3-10 mg, the limited sibility is likely in the light of the lat- solubility of testosterone esters in the est studies using a combination of tes- The strategies of hormonal male oil vehicles used for intramuscular in- tosterone and a variety of progestins contraception jection calls for large injection vol- (dimedroxyprogesterone 75 acetate, umes. Therefore, more potent andro- , and )29. Testosterone alone genic molecules would be desirable. It also remains to be seen whether In most of the earlier male hormo- Since the severity of the side effects of the potential advantage of reducing nal contraceptive trials, including those a drug is often related to its molar the androgen load and its side effects of the WHO5,6, the androgen prepara- dose, more potent androgens might will in fact materialize. Although tion used has been TE by intramuscu- also mean reduced side effects. Even progestins effectively suppress gona- lar administration. In many respects, more potent androgens exist, and in dotropin secretion, we do not know this regimen is suboptimal in terms of the future they might be able to re- whether the hormone combination for contraceptive place the compounds currently under- works in an additive or synergistic purposes. The plasma androgen levels going testing. fashion. The latter mechanism could achieved immediately after the injec- be the key to achieving uniform tion are too high and display consider- Testosterone in combination with azoospermia in all men treated, as well able variation at different times in rela- some other gonadotropin- as to reducing the load. tion to the injection. This may be the suppressing agent Progestins also have direct inhibitory reason for the side effects reported. A effects on Leydig cell steroidogenesis30 weekly 200 mg TE dose has been found Testosterone plus progestin and 5a-reductase activity31, which may optimal for contraception, but for the The advantage of testosterone is further increase the antispermatogenic above reasons it is considered unsatis- that the same molecules provide both effect. On the negative side, progestins factory for wider use. suppression of gonadotropins and sup- may have untoward effects on high- A more prolonged and steady effect plementation of peripheral androgen density lipoprotein (HDL) choles- can be achieved with testosterone im- levels. However, several potential ad- terol27, and the worst possible scenario plants that last for 4 to 6 months21,22 and vantages, including faster suppression would be that gains in increased effi- biodegradable spheres lasting for 2-3 of spermatogenesis, increased efficacy, cacy were achieved at the expense of months23. An optimal preparation is con- reduction of the androgen load, and increased side effects. To minimize the sidered to be an injectable depot that potential by fewer side effects, can be side effects, the androgen compo- would provide constant release of the seen if the testosterone is used in com- nent of the treatment should mimic the steroid for several months. A very prom- bination with some other agent inhib- endogenous plasma androgen levels as ising compound in this respect is testo- iting gonadotropin secretion. These closely as possible, while the addi- sterone buciclate (TB), synthesized un- potential advantages still await prac- tional antigonadotropic substance der the auspices of the WHO. It has a tical demonstration. should block gonadotropin secretion long effective phase of 3-4 months after Recent studies have shown that a as effectively as possible. a single injection. A dose of 1200 mg of combination of a suboptimal dose of the compound in a contraceptive trial on testosterone, either 100 mg TE/week Testosterone plus antiandrogen spermatogenic suppression was shown intramuscularly plus levonorgestrel Another alternative is the use of to be comparable to a weekly injection 500 mg/day orally27, or 4 testosterone acetate (CPA), which is of TE24. Another promising preparation pellets (800 mg, 6 mg/day) plus 300 both an antiandrogen and antigona- is injectable testosterone undecanoate, mg depot medroxyprogesterone ac- dotropic factor, due to its progesta- which has been given every 6 weeks in etate28, were more effective than testo- tional effect. recent successful contraceptive trials25,26, sterone alone in suppressing sperma- clearly enhances the antispermato- and it is possible that even a less fre- togenesis. However, the overall effect genic effect of a submaximal dose of quent interval of treatment would be at- was comparable to that of the WHO TE (100 mg/week)32, but it remains un- tainable with this compound. studies with the TE dose (200 mg/ known whether the combinations of One problem with testosterone is week) that was optimal for contracep- CPA + TE offer any advantage over a the relatively weak androgenic po- tive efficacy, and it remains open as to maximally effective dose of TE alone. tency of this molecule. Since the whether improved contraceptive effi- In theory, its main systemic effect amount administered has to be at least cacy can be achieved with the andro- could be antigonadotropic in synergy

278 REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(5):275-283, 2003 Trends in male contraception Pasqualotto FF et al. with testosterone, and in the testes it sidual gonadotropic activity, appears specificity of the synthetic, secretory, could additionally be antiandrogenic, critical in such failures. and transport process in the epidi- thereby eliminating the action of the The GnRH antagonists have prac- dymis, although immunological se- residual androgen levels. tically no side effects other than skin questration of epididymal proteins is reactions with some compounds due being seriously considered for humans. Testosterone plus GnRH analogs to the release of histamine. At present, Specific epididymal transporters need The gonadotropin releasing hor- they do not constitute a viable alter- to be better identified before drugs mone (GnRH) agonists and antagonists native for male contraception because that make changes in the fluid compo- are a very promising group of com- of their high cost, difficulty of admin- sition can be tested. Selective inhibi- pounds for combination with testoster- istration, low potency, and local irri- tion of sperm glycolysis is the most one, especially due to their specific tation caused. successful approach in animals and suppressive effects on gonadotropins could be effective in man. and their very few side effects. The Epididymal approaches to male GnRH agonists have paradoxical contraception Remaining problems in the antigonadotropic effects through the development of a hormonal male down-regulation of the GnRH signal The advantage of post-testicular contraceptive transduction system. The antagonists contraception lies in the rapid onset of function as competitive inhibitors of infertility, its reversible nature, and the As stated above, the maximal sup- endogenous GnRH action. rapid return to fertility once the pression of the intratesticular androgen The GnRH agonists used alone ef- therapy is discontinued. Therefore, level is the key to hormonal suppres- fectively suppress serum testosterone post-testicular contraception has much sion of spermatogenesis and is simple to the castration range in prostatic can- more to offer than the hormonal ap- in principle. A high enough dose of cer patients, which brings about effec- proaches that block testicular sperm testosterone, alone or in combination tive suppression of spermatogenesis33. production and take months to reduce with another antigonadotropic agent, Paradoxically, additional testosterone spermatozoa concentration sufficiently should suppress gonadotropin secre- supplementation in contraceptive tri- for effective contraception. Although tion to such a low level that the Ley- als attenuates the suppressive effect of epididymal malfunction has been sug- dig cell function is blocked. However, GnRH agonists on spermatogenesis. In gested to account for 20% of all the as experience shows, there seems to be 12 clinical trials with various GnRH cases of human necrozoospermia, there a fine balance between success and agonists, azoospermia was achieved in are a undoubtedly few cases of male failure. If the antigonadotropic dose is only 24 out of 106 subjects (23%). The infertility caused by epididymal dys- too low, the desired suppression of reason for this failure remains un- function35. Since there is increasing intratesticular testosterone is not known, but it is conceivable that the evidence that human spermatozoa achieved. If the androgen component recovery of FSH secretion during the within the epididymal canal undergo of the treatment is too high, it may treatment34, together with the low re- a similar maturational process to that have stimulatory effects on sperma- maining intratesticular testosterone, of the sperm of other species, post-tes- togenesis. Moreover, the doses of sin- could reinitiate spermatogenesis. ticular contraceptives for animals gle or multiple compounds used must Therefore, the GnRH agonists have based on physiological principle of guarantee maximal efficiency with been abandoned for further develop- sperm transport, maturation, and stor- minimal side effects. The studies so far ment as male contraceptives. age are applicable to man. performed have shown convincingly The combination of testosterone Those approaches involving arrest that hormonal male contraception is with GnRH antagonists for male con- of contraction at ejaculation could be possible. However, 3 main problems traception has proven much more close to clinical testing, since auto- remain: lack of uniform suppression to promising. The azoospermic effect nomic drugs are known, have been the point of azoospermia, the mode of seems to be especially profound if the tested, and should shortly be available, hormone administration, and potential testosterone supplementation is de- with only small developments in tim- short-term and long-term side effects. layed and the dose is low. Since higher ing and modes of delivery being re- doses of testosterone supplementation quired36-39. Altering the composition of The lack of uniform suppression to reduce the contraceptive efficacy, the epididymal fluid for contraceptive the point of azoospermia marginally increased intratesticular purpose does not currently seem prom- testosterone level, perhaps with re- ising because of the lack of organ There is still no clear-cut answer as

279 Trends in male contraception REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(5):275-283, 2003 Pasqualotto FF et al. to why all men, especially those of key gene(s) regulating spermatogen- ment of a suitable pharmaceutical an- Caucasian origin, should not respond esis. It is even possible that the LH or drogen preparation for wide use is a to the treatment and attain azoosper- FSH receptors of these men have less demanding technical challenge. mia. WHO scientists have assessed the polymorphisms allowing higher than Very promising results have very re- anthropometric, seminal, hormonal, normal constitutive, non-ligand-de- cently been obtained with a combina- and biochemical data before, during, pendent signal transduction. tion of progestin with slow-release in- and after TE treatment as potential A genetic cause for the variable jectable testosterone esters. The opti- predictors of inconsistent azoosper- spermatogenetic response is strongly mal preparation that may be within our mia40,41. The only significant findings suggested by the ethnic differences reach on the basis of today’s knowl- were that the azoospermic men had observed44. When Caucasian and edge could thus be a subcutaneous faster rates of the decline and recov- Asian (mostly Chinese) men were com- progestin/androgen implant. ery of spermatogenesis, higher pre- pared, the rates of spermatogenic sup- treatment FSH levels, and longer-term pression to the point of azoospermia Potential short-term and long-term rebound of gonadotropins after treat- were 66.7% and 89.2%, respectively. side effects ment. No differences were found in the However, when the rates of suppression of TE as between to the point of azoospermia and/or be- Testosterone plays a major role in the 2 groups42. One study showed that low 3 million/mL were compared, the male sexual development. Exposure of the responder had significantly lower respective figures were 95.6% and females to testosterone in utero can in- levels of sex-hormone-binding globu- 98.4% (thus, the ethnic difference al- duce masculine characteristics such as lin (SHBG) throughout the whole treat- most disappeared). Hence, the differ- anovulation, increased anogenital dis- ment and lower LH and testosterone ence is seen only at the lower end of tance, absence of nipples, retention of levels at the baseline. In addition, an- the response, from severe oligo- male-like tissues, and agenesis of the other study reports higher 5a-reductase zoospermia to complete azoospermia. lower vagina. In addition, high levels activity of the non-responders during of androgens during fetal development the TE therapy, which could indicate The mode of hormone can lead to toxic effects such as re- that the suppression of bioactive an- administration duced litter size and viability. How- drogen levels may be less profound in ever, there is no data regarding these these men than in those achieving An optimal means for hormone ad- possible side effects in case of a preg- azoospermia43. ministration has not yet been identi- nancy involving men taking oral con- No clear-cut reasons for nonuni- fied. It is clear that a long-acting de- traceptives45. form azoospermia can be identified pot preparation would be the most de- Because healthy men will be re- from the existing observations. They sirable method. Whether the active an- ceiving the hormonal contraceptive, give the impression that there is a sub- drogen should be testosterone or a strict safety margins are required, and tle difference in hormonal equilibrium synthetic androgen needs also to be the potential short-term and long-term and set point of the feedback mecha- determined. The testosterone molecule side effects of the therapy must be fully nisms for gonadotropins and androgen has characteristically a relatively low recognized. Concerning acute side ef- dependence of spermatogenesis be- rate of side effects. However, its low fects, the most common medical rea- tween the 2 groups of men. It may also intrinsic androgen activity makes it sons for discontinuation in the recent be that spermatogenesis in the poor re- technically difficult to use in the de- treatment trials have been acne (3%) sponders is less closely dependent on velopment of a depot preparation, and changes of mood, behavior, and li- androgens, or that their intratesticular since rather high doses of steroids are bido (4%), while other idiosyncratic or androgen production has a higher go- needed. Likewise, it is still an open incidental conditions were uncommon nadotropin-independent component, question as to whether combining an- (<1%)46. With respect to metabolic ef- either autonomously or through drogen with another antigonadotropic fects, a small but significant decrease paracrine stimulation. It may also be compound is really advantageous, be- in HDL cholesterol (15-20%), but not possible that some other blood-borne cause no convincing data on increased in other lipoproteins, is a consistent factors may be able to maintain their efficiency or less intense side effects finding47-49. The significance of these testicular steroidogenesis. The variable have been presented. Nevertheless, findings remains uncertain. No sus- testicular physiology may be caused probably, once the problem of lack of tained, marked prothrombotic effects by genetic polymorphism, reflecting uniform suppression to the point of of the treatment were found50. borderline functional alterations in the azoospermia is solved, the develop- From the above studies, it was con-

280 REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(5):275-283, 2003 Trends in male contraception Pasqualotto FF et al. cluded that the acute effects reflect the prostatic diseases. One study reported production profile. relatively high peak levels and fluctua- a slight, though significant, increase tion of plasma testosterone levels with in prostatic size but no effect on pros- the weekly TE injections, rather than tate-specific antigen (PSA)51. FUTURE PERSPECTIVES an inherent feature of hormonal male One concern has been the effect of contraception, highlighting the need androgens on behavior. In normal men, In the short term, as outlined above, for long-acting preparations of testo- supraphysiological doses of testoster- 3 main questions remain to be an- sterone with more stable delivery ki- one may result in some degree of swered in the development of a male netics. This is suggested by the lower sexual arousal without stimulating hormonal contraceptive. Once these frequency of the above side effects in sexual activity, but no increase in ag- questions have been solved, the first men treated with testosterone implants gression has been scientifically docu- generation of hormonal male contra- that result in closer-to-normal physi- mented52,53. Serious physiological side ceptives could be ready for use. It is ological levels of plasma testosterone effects of androgens are extremely rare, still difficult to predict how long it will without compromising contraceptive despite reports of such cases amongst take to find answers to these questions. efficacy21. abusers. In these This depends very much on the avail- While the role of androgens in the cases, anabolic steroid abuse is more ability of research facilities, which de- progression of benign hyperplasia and likely to be the consequence than the pend on the interest of the lay public, carcinoma of the prostate is well docu- cause of the mental instability re- health professionals, sociopolitical mented, it is not known whether the ported54. Due to the inevitable uncer- opinion leaders, and the pharmaceuti- lifetime exposure to androgens affects tainty of long-term adverse effects of cal industry. If adequate resources for the morbidity of these diseases. At this treatment, a good approach is to this work were to be made available least theoretically, androgen therapy use treatments that mimic as closely as soon, the task might be completed increases the risk of developing possible the physiological androgen within the next 5 years.

RESUMO

PASQUALOTTO FF e col. - Tendênci- masculinos desde então. É de extrema de a melhor combinação hormonal dis- as na contracepção masculina. Rev. urgência o desenvolvimento de um ponível para induzir uma profunda su- Hosp. Clín. Fac. Med. S. Paulo novo método contraceptivo seguro, efe- pressão na espermatogênese. O desen- 58(5):275-283, 2003. tivo e reversível. Entre todos os méto- volvimento futuro de uma nova formu- dos contraceptivos que estão sendo in- lação esteróide é mandatório para me- Métodos disponíveis para contra- vestigados, a abordagem hormonal é a lhorar as chances de formulações cepção como coito interrompido, pre- que está mais perto para aplicação clí- contraceptivas disponíveis e otimizar o servativo e vasectomia são usados des- nica. A contracepção hormonal forne- efeito a longo-prazo de tais regimes. de o século 19. Com exceção a alguma ce proteção contra a gravidez por meio melhora nestes métodos, nenhum pro- da supressão na espermatogênese. Tra- DESCRITORES: Testosterona. gresso maior tem sido feito com relação tamentos que incluem andrógeno e Andrógeno. Hormônios. Contra- à introdução de novos contraceptivos progestágenos representam na atualida- cepção. Estéril.

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