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Contraception Corner

Research in Male Contraception

Barbara Clark, RN, MSN, MPH; John K. Amory, MD

Male contraception is often portrayed as every womanÍs dream, but the choices have long been limited to condoms and vasectomy. Now, though, several new methods that promise safety and efficacy may soon be on the market.

Increasing the number of male contraceptive options available will help make men equal partners in family planning, provide additional options for couples in which the woman is unable to use birth control, and provide more options for population control in a hazardously growing global population.1

There has been substantial progress toward the development of more male contraceptive options. The drug gossypol, a male ñpill,î and a progestin implant are just a few of the possibilities under investigation. More male contraceptive methods are needed: Based on the 2002 National Survey of Family Growth, 5.7% of all contraceptive users rely on vasectomy and 11% on male condoms—the only two effective methods for men in the United States.2 This article reviews current methods and explores potential male contraceptive alternatives. It also discusses the acceptability of these methods by men and women.

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CURRENT METHODS


Condoms and vasectomy will continue to be valuable contraceptive methods. Condoms are affordable, and easy to obtain and use—and the condom is a reversible method. However, as with other contraceptives, there are disadvantages: Condoms are obtrusive; they require proper, consistent usage to be effective; and they can break or slip. And as the condom also offers the best protection against sexually transmitted infections (STIs)—especially human immunodeficiency virus/acquired immunodeficiency syndrome—researchers are exploring new condom designs and materials.

Unlike condoms, vasectomy is considered a permanent method. More than 500,000 vasectomies are performed in the United States each year; they are nearly 100% effective and have few serious side effects. Depending on the technique used, vasectomy can be difficult to reverse and cause chronic testicular discomfort—and it does not protect against STIs. It can also take up to 3 months to achieve azoospermia postprocedure.

Traditional vasectomy (ie, ñscalpelî vasectomy) is the most common US technique. However, the ñno-scalpelî technique, which uses a small puncture in the scrotum, is gaining popularity. Compared with the traditional vasectomy, the no-scalpel method is quicker, involves less pain and swelling, has a faster recovery, and does not require sutures.3 In addition, plastic clamps that are about the size of a grain of rice were introduced into the United States in 2003; these clamps attach to each vas deferens to permanently block the flow of sperm.

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EXPERIMENTAL NONHORMONAL METHODS

Gossypol

Gossypol (Figure 1), which is derived from cottonseed oil, has been tested in more than 8,000 men in China as a potential contraceptive. Gossypol was 98.5% effective in those who used an initial dose of 20 mg/d for 75 days, followed by 40 to 50 mg/wk. However, 9.90% of patients remained azoospermic after stopping gossypol use, and 0.75% developed hypokalemia.4 Low-dose gossypol (loading dose of 10 or 12.5 mg/d, followed by a maintenance dose of 35 or 43.75 mg/wk) was tested in 55 men with 22 controls. Azoospermia occurred with no side effects, and fertility returned in all patients after the drug was stopped.5

Figure not available online

FIGURE 1. Gossypol is derived from cottonseed oil.

Vas Occlusion Methods

The most promising vas occlusion method is reversible inhibition of sperm under guidance (RISUG). In RISUG, a copolymer styrene maleic anhydride dissolved in dimethyl sulfoxide is injected into the vas deferens to cause partial blockage and rupture of sperm membranes. In a study of 25 men who received RISUG injections, azoospermia occurred after 2 months in 84%, and after 4 months in 100%.6

Three other vas occlusion methods are under study. Two of these methods block sperm with an injected elastomer plug using either medical-grade polyurethane or medical-grade silicone rubber. The third method, the ñshug,î blocks sperm with a preformed, flexible rubber plug. All plugs are injected using a no-scalpel technique.

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EXPERIMENTAL HORMONAL METHODS

Male hormonal contraceptives use testosterone alone, testosterone plus progestins, or testosterone plus gonadotropin-releasing hormone (GnRH) antagonists (Table). They work by blocking the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland, depriving the testicles of the signals required for spermatogenesis (Figure 2).1

Table not available online

TABLE. Male Hormonal Contraception

Figure not available online

FIGURE 2. Male hormonal contraceptives work by blocking pituitary release of luteinizing hormone and follicle-stimulating hormone to inhibit spermatogenesis.

Androgens Only

In the trials using androgen alone, 60% of white men and 90% of Asian men achieved azoospermia. Side effects of testosterone included weight gain, acne, decrease in high-density lipoprotein cholesterol (HDL), decrease in testicular size, and painful injection sites in techniques that used injections. None of these side effects was serious.7

Testosterone Enanthate.—In a World Health Organization (WHO) study in seven countries, 157 of the 271 men who received intramuscular (IM) testosterone enanthate (TE), 200 mg/wk, became azoospermic within 6 months.8 In the efficacy phase, there was only one pregnancy in 1,500 months (Pearl Index of 0.8). A second WHO study found that only eight of 399 men who received TE injections, 200 mg/wk, did not have suppression to < 5 million sperm/mL.9 Four pregnancies occurred during 49.5 person-years in those with oligospermia, and none during 230.4 person-years in those with azoospermia.

Testosterone Undecanoate.—In a phase II study, 308 Chinese men received an initial loading dose of testosterone undecanoate (TU), 1,000 mg, followed by 500-mg monthly injections until azoo-spermia or severe oligospermia occurred. Azoospermia or counts of < 3 million sperm/mL were achieved in 299 men during the 6-month suppression phase. Only one pregnancy occurred among the partners of 296 men who used TU for 1 year.10

7α-Methyl-19-nortestosterone.—This synthetic androgen inhibits gonadotropin secretion about 10 times more than testosterone does, although its efficacy has not been firmly established.11 7α-Methyl-19-nortestosterone is delivered through a subdermal implant in the arm; transdermal gel and patch formulations are being developed. It does not appear to cause testosterone-associated side effects.

Testosterone Plus Progestin

Like androgens, progestins also inhibit GnRH, LH, and FSH secretion. Progestins may also directly inhibit testicular function, affecting testosterone production and other functions. When testosterone is combined with a second agent such as a progestogen, azoospermia improves and allows for the use of a lower dose of testosterone.

Testosterone Plus Levonor-gestrel.—Of 18 men receiving IM TE, 100 mg/wk, plus oral levonorgestrel (LNG), 500 mcg/d, 67% achieved azoospermia within 6 months, and 94% achieved severe oligospermia or azoospermia.12 In those who received TE, 100 mg/wk only, 33% achieved azoospermia, and 61% achieved severe oligospermia or azoospermia. In addition, HDL levels decreased less and average weight gain was lower in those taking the combined medications than in those taking the single medication.

Testosterone Undecanoate Plus Depot Medroxyprogesterone Acetate.—Thirty Chinese men received IM injections every 8 weeks of either TU, 1,000 mg; TU, 1,000 mg, plus depot medroxy-progesterone acetate (DMPA), 150 mg; or TU, 1,000 mg, plus DMPA, 300 mg.13 All except two men achieved azoospermia or severe oligospermia; the two exceptions took TU only and had a rebound in sperm concentrations. No serious adverse effects were reported.

Testosterone Plus Cyproterone Acetate.—All 10 men who received TE, 100 mg/wk, plus cyproterone acetate (CPA), 100 or 50 mg/d, became azoospermic. By contrast, three of the five men receiving TE alone, 100 mg/wk, became azoospermic.14 Hemoglobin, hematocrit, and red blood cell levels decreased in the CPA groups, and testis size decreased in both groups.

Testosterone Decanoate Plus Etonogestrel.—Ninety percent of 120 men who received subdermal etonogestrel implants plus testosterone decanoate injections every 4 to 6 weeks achieved azoospermia.15 Phase III testing is underway.

Testosterone Plus Gonadotropin-releasing Hormone Antagonists.—oth GnRH antagonists and agonists suppress GnRH secretion from the hypothalamus. All 15 men who received IM TE, 100 mg/wk, plus a GnRH antagonist, 10 mg/d subcutaneously, for 12 weeks and those who went on to receive TE alone for 20 more weeks achieved azoospermia or severe oligospermia. There were no adverse effects. One drawback is that GnRH antagonists are expensive to synthesize. Oral versions are being explored.16

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ACCEPTABILITY OF MALE CONTRACEPTION

According to a recent survey, men would be receptive to using male hormonal contraception: 89 (75.4%) of 118 Australian men said that they would consider trying such a contraceptive.17 The most popular method was an oral pill (33.3%), followed by an injection every 3 months (27.4%), an injection every 2 years (21.4%), an injection every month (13.1%), a skin patch (3.6%), and a weekly injection (1.2%). Those who have used a male hormonal contraceptive have expressed satisfaction; the majority of 25 men in a WHO trial who received weekly testosterone injections for 1 year rated the contraceptive to be as expected or better than expected.18 There was no change in the quality of life, and a slight increase in the frequency and quality of sexual activity.

Would women trust their partners to use a male contraceptive reliably? Of 1,894 women attending family planning clinics in Scotland (450), China (900), and South Africa (544), only 13% did not think that a ñmale pillî was a good idea, and only 2% said that they would not trust their partner to use it.19

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CONCLUSION

Experimental male contraception methods appear promising. With new male contraceptives will come more contraceptive choices—especially reversible ones. Also promising are preliminary studies on menÍs and womenÍs attitudes toward male contraceptives. Once the contraceptivesÍ safety and efficacy are established, the next steps are to make the contraceptives available to everyone, and to provide guidance on using the methods. Researchers around the world are committed to finding safe, effective, and convenient male contraceptives.

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Barbara Clark, RN, MSN, MPH, is a freelance writer in Arlington, Va. John K. Amory, MD, is assistant professor of medicine, Division of General Internal Medicine, University of Washington, Seattle.

References

1. Amory JK. Male contraception: update 2003. Presented at: the Association of Reproductive Health Professionals 40th annual meeting, La Jolla, Calif, September 2003.
2. Mosher WD, Martinez GM, Chandra A, Abma JC, Willson SJ. Use of contraception and use of family planning services in the United States: 1982-2002. Adv Data. 2004;350:1-36.
3. Sokal DC. Recent research on vasectomy techniques. Asian J Androl. 2003;5(3):227-230.
4. China. National Collaborative Team on the Clinical Study of Gossypol as Male Antifertility Drug. [The clinical study of gossypol in 8,806 men.] Shengzhi Yu Biyun. 1985;5(4):5-11.
5. Gu ZP, Mao BY, Wang YX, et al. Low dose gossypol for male contraception. Asian J Androl. 2000;2(4):283-287.
6. Chaki SP, Das HC, Misro MM. A short-term evaluation of semen and accessory sex gland function in phase III trial subjects receiving intravasal contraceptive RISUG. Contraception. 2003;67(1):73-78.
7. Wu FC, Farley TM, Peregoudov A, Waites GM. Effects of testosterone enanthate in normal men: experience from a multicenter contraceptive efficacy study. World Health Organization Task Force on Methods for the Regulation of Male Fertility. Fertil Steril. 1996;65(3):626-636.
8. Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on Methods for the Regulation of Male Fertility. Lancet. 1990;336 (8721):955-959.
9. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril. 1996;65(4):821-829.
10. Gu YQ, Wang XH, Xu D, et al. A multicenter contraceptive efficacy study of injectable testosterone undecanoate in healthy Chinese men. J Clin Endocrinol Metab. 2003;88(2):562-568.
11. Suvisaari J, Moo-Young A, Juhakoski A, Elomaa K, Saleh SI, Lahteenmaki P. Pharmacokinetics of 7 alpha-methyl-19-nortestosterone (MENT) delivery using subdermal implants in healthy men. Contraception. 1999;60(5):299-303.
12. ebb RA, Anawalt BD, Christensen RB, Paulsen CA, Bremner WJ, Matsumoto AM. Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. J Clin Endocrinol Metab. 1996;81(2):757-762.
13. Gu YQ, Tong JS, Ma DZ, et al. Male hormonal contraception: effects of injections of testosterone undecanoate and depot medroxyprogesterone acetate at eight-week intervals in Chinese men. J Clin Endocrinol Metab. 2004;89(5):2254-2262.
14. Meriggiola MC, Bremner WJ, Paulsen CA, et al. A combined regimen of cyproterone acetate and testosterone enanthate as a potentially highly effective male contraceptive. J Clin Endocrinol Metab. 1996;81(8):3018-3023.
15. Brady BM, Amory J, Perheentupa A, et al. A multi-centre study investigating subcutaneous etonogestrel implants with injectable testosterone decanoate as a potential long-acting male contraceptive. Hum Reprod. In press.
16. Swerdloff RS, Bagatell CJ, Wang C, et al. Suppression of spermatogenesis in man induced by Nal-Glu gonadotropin releasing hormone antagonist and testosterone enanthate (TE) is maintained by TE alone. J Clin Endocrinol Metab. 1998;83(10): 3527-3533.
17. Weston GC, Schlipalius ML, Bhuinneain MN, Vollenhoven BJ. Will Australian men use male hormonal contraception? A survey of a postpartum population. Med J Aust. 2002; 176(5):208-210.
18. Sjogren B, Gottlieb C. Testosterone for male contraception during one year: attitudes, well-being and quality of sex life. Contraception. 2001;64(1):59-65.
19. lasier AF, Anakwe R, Everington D, et al. Would women trust their partners to use a male pill? Hum Reprod. 2000;15(3):646-649.

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