Demand for male contraception

Review

Demand for male contraception Expert Rev. Pharmacoecon. Outcomes Res. 12(5), 00–00 (2012)

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Department of Population, Family and Reproductive Health, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Suite E4622, Baltimore, MD 21205, USA *Author for correspondence: [email protected]

The biological basis for male contraception was established decades ago, but despite promising breakthroughs and the financial burden men increasingly bear due to better enforcement of child support policies, no viable alternative to the condom has been brought to market. Men who wish to control their fertility must rely on female compliance with contraceptives, barrier methods, vasectomy or abstinence. Over the last 10 years, the pharmaceutical industry has abandoned most of its investment in the field, leaving only nonprofit organisations and public entities pursuing male contraception. Leading explanations are uncertain forecasts of market demand pitted against the need for critical investments to demonstrate the safety of existing candidate products. This paper explores the developments and challenges in male contraception research. We produce preliminary estimates of potential market size for a safe and effective male contraceptive based on available data to estimate the potential market for a novel male method.

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Emily Dorman and David Bishai*

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Keywords: contraceptive development • contraceptive responsibility • male fertility • male hormonal contraception • male non-hormonal contraception • male reproductive rights • market analysis

Background: history & current pipeline of male methods

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Evidence that spermatogenesis could be controlled via manipulation of the pituitary in rats was published in the 1920s [1] and successful suppression of spermatogenesis in humans was achieved via the administration of exogenous testosterone soon after [2,3] . Proof-of-concept for the effectiveness and reversibility of hormoneinduced suppression of sperm production was demonstrated many years later through two landmark studies sponsored by the WHO [4,5] . These trials, in which 670 men in 10 countries participated, not only provided evidence that hormonal regulation of male fertility could be highly effective, reversible and well tolerated but established a safety monitoring strategy based on the analysis of monthly semen samples [6] . The current landscape of potential male contraceptive products include a number of hormonal formulations that build on these early developments, as well as numerous nonhormonal methods. Both types of method aim to disrupt male fertility through the means of one or more of three basic mechanisms: suppression of sperm production, disruption of sperm maturation and/or function or disruption of sperm transport or motility [7] . Hormonal methods were the first type of novel male method to be investigated and are therefore

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10.1586/ERP.12.52

further along in development than nonhormonal methods. The primary approach for hormonal methods has been the suppression of spermatogenesis through disruption of the hypothalamic– pituitary–testicular axis through a progestogen or gonadotropin-releasing hormone analogue with androgen replacement. Current formulations (Table 1) include androgen-only therapies, androgen and progestin combinations, gonadotropin-releasing hormone antagonist, androgen combinations and selective androgen-and progestin-receptor modulators [8] . It is necessary to maintain physiological levels of testosterone in order to avoid androgen deprivation (which presents through symptoms such as fatigue, muscle loss, mood changes, low libido), or excess androgenic effects (which presents through symptoms such as acne, fluid retention and weight gain). As oral administration of testosterone is subject to high first-pass hepatic metabolism, maintenance of steady physiological androgen levels requires parenteral or transdermal drug delivery [9] . Current nonhormonal approaches (Table 1) use various means to disrupt the production, function or motility of sperm by targeting cellular and physiological processes unique to the male reproductive system [8] . Two nonhormonal methods currently in development function as a temporary and reversible vasectomy. The intravas device, a set of tiny implants that block

© 2012 Expert Reviews Ltd

ISSN 1473-7167

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Dorman & Bishai

Table 1. Male contraceptive product pipeline. Product

Description

Developer

Status

Hormonal

Testosterone and NET-EN

Injectable testosterone undecanoate and injectable norethindrone enanthate

CONRAD and WHO

Phase II trial canceled in 2011 owing to safety concerns

7 {alpha} -Methyl-19Nortestosterone

A synthetic steroid that resembles testosterone and does not enlarge the prostate. Formulated as an implant, transdermal gel and patch

Population Council

Phase II

DMPA-TU injections

Injections of depot medroxyprogesterone acetate and testosterone undecanoate 2 or 3 months apart

Chinese National Research Institute for Family Planning

Phase I

Oral desogestrel with depot testosterone

Oral formulation found to be effective in Caucasian males

University of Edinburgh

Phase I

RISUG

Injection into the testes, chemically inactivates sperm, likened to chemical vasectomy

Indian Medical Research Council

Phase III trials in India

Intra Vas Device

Physical, reversible occlusion of the vas deferens via surgery

Chinese National Research Institute for Family Planning

Phase II

Shepherd Medical Company

Phase I Preclinical

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Indazole carbozylic acid derived from lonidamine, active orally

University of Kansas

Adjudin

Derived from the anticancer drug lonidamine, has been identified as having potent antispermatogenic effects in vivo

Population Council

Internal heat

Concept proven in small-scale human studies, researchers investigating safety of long-term use

Centre d’Etudes et de Conservation des Oeufs et du Sperme humain Midi-Pyrenees in Toulouse

Drug candidates identified that may block the contractions of the vas deferens, not yet tested in vivo in any animal model

King’s College London

Genes for sperm-specific calcium ion exchange channels identified, drugs that block their action being sought

Harvard University

Newly identified sperm tail energy carrier protein (SFEC1) involved in glycolysis. May be target for a small-molecule drug

University of Virginia

Novel sperm tail protein (Cα-s) identified, drugs sought to block its action

University of Massachusetts Medical Center and Spermatech

Sperm surface enzyme blockers

Enzymes involved in sperm–egg binding are still being identified and drugs that will bind to each of them are being sought

Norfolk State University

Immunocontraceptives

An eppin immunocontraceptive has been tested in monkeys

University of North Carolina at Chapel Hill

An LDH-C4 immunocontraceptive has been tested in mice

Northwestern University, various research institutes in China

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Gamendazole

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Nonhormonal

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Product class

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Dry orgasm pill

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Sperm motility blockers

Basic research

RISUG: Reversible inhibition of sperm under guidance. Data taken from [104].

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Expert Rev. Pharmacoecon. Outcomes Res. 12(5), (2012)

Demand for male contraception

Current challenges in male contraceptive research

namely efficacy, safety and acceptability. We then synthesized data from a number of sources to estimate the current potential market for male contraception in view of recent trends in the costs men bear for unwanted pregnancies. Efficacy

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Developing an universally effective male contraceptive has indeed proven challenging. While female oral contraception is designed to suppress ovulation, mimicking the natural process accompanying pregnancy or lactation, no comparable natural period of infertility exists in male physiology that researchers can seek to replicate [18] . Using the efficacy of female methods as a benchmark for male contraception is legitimate, especially when considering which method would appeal to couples choosing from the whole spectrum of available options. However, another legitimate efficacy end point would be to compare hormonal methods to condoms, the only other reversible male method. In trials where male hormonal contraception was used as a sole means of pregnancy prevention, all subjects in four trials were suppressed to below a threshold of 1–5 million sperm/ml resulting in pregnancy prevention of over 95%, even in those who were incompletely suppressed [5,19,20] . This efficacy is a great improvement over the 12% failure rate of condoms [21] and is close to the first-year failure rate of oral contraceptive pills (3%) [17] . Racial differences in efficacy are often characterized as a major obstacle in developing a male hormonal method. Consistent product responses would lead to simpler dosing algorithms and fewer physician visits to get patients established on regimens. However, the variations in response could be exploited through the development of regional formulations. In Asia, where population density and growth rates are high, men are extremely responsive to low, physiologic doses of testosterone, suggesting a potential market for a regionally formulated product [7] .

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the flow of sperm, completed a randomized, Phase II trial in China [10] . Reversible inhibition of sperm under guidance, which involves injecting gel into the vas deferens to chemically inactivate sperm, has been shown to be effective in clinical tests and has been patented in the USA [11] . Genetic approaches target genes or gene products specific to the reproductive tract in order to selectively disrupt reproductive functions. The discovery that sperm tails contain calcium ion channels has led to work to develop a drug to disable these channels [12] , including further investigation into a Chinese herbal medicine that seems to incapacitate sperm using this mechanism [101] . Two drugs – an antihypertensive and an antipsychotic – have been found to keep men from ejaculating during orgasm [13] . However, these drugs would need modification to ameliorate their effects on blood pressure and mood. Finally, immunocontraception is a method that involves the use of antigens and antibodies to target different aspects of sperm production as a means of inducing infertility. This line of research has existed for several decades but results in this area are still preliminary [14] .

Review

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Despite the diversity of approaches and advances in research, no novel male contraceptive has come to market. Many challenges continue to impede progress toward a viable male method, especially in the hormonal field. One of the biggest issues, first identified in the initial WHO trials, is the large ethnic difference in efficacy of hormonal contraception, with Asian men consistently showing higher rates of therapeutic azoospermia (~95%) than Caucasian men (60–70%) [15] . These variations raise doubt as to whether a hormonal male method would ever be as universally effective as current female methods. Furthermore, because most methods deliver testosterone subdermally or parenterally, there are concerns over the potential acceptability of the delivery system. As with any new pharmaceutical product, it is also necessary to address issues of side effects and long-term safety. As contraceptives are administered to a relatively young and healthy population for potentially long periods of time, understanding these longterm effects is particularly important. Finally, female methods of birth control have been improved over time and are now safer and less expensive than when they first emerged, giving novel male products steeper competition. Perhaps a greater challenge in male contraceptive development is uncertainty over whether the revenue from the market would justify the investments necessary to resolve the remaining obstacles in product development. Although Bayer, Wyeth and Organon were once active in research and development of a male method, all three discontinued their programs between 2005 and 2008 [16] , although the industry continues to actively pursue programs for hormonal contraception and hormonal-replacement therapy for women [17] . In withdrawing support, company representatives cited corporate changes in direction and the perception that safety standards demanded by regulatory bodies would require such extensive evidence as to make further research financially infeasible [16] . This paper reviews the challenges that have impeded the progress of male contraceptive development, www.expert-reviews.com

Safety & side effects

Side effects of hormonal male contraception have been well documented in clinical trials. Early trials of progestins found evidence of weight gain, transient loss of libido in some men and some regimens tested caused gynecomastia and liver function impairment [22] . Certain nonhormonal methods, such as adjudin, show a narrow-dosing margin between efficacy and safety, raising concerns about long-term use [23] . Participants in clinical trials of current formulations have reported frequent side effects, including night sweats, frequent changes in mood and libido [24] and changes in body composition (weight or fat gain) [25] . A 2011 Phase II trial of injectable testosterone undecanoate and injectable norethindrone enanthate was terminated owing to reports of depression in participants [102] . Longer-term safety concerns related to cardiovascular, hematological and prostate effects persist, although there is evidence that the effects on the prostate are not significant [25] . Long-term systemic effects on vital organs may be significant and have not yet been well documented [14] . However, there is no evidence of long-term risks and similar safety concerns apply to all hormonal female methods. 3

Dorman & Bishai

Market size for male contraception

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Doubt over the existence of sufficient demand for male contraception has been expressed in a number of ways. First, given the variety of products already on the market, there is skepticism regarding whether additional methods are needed. Another argument is that men would not be willing to use novel male methods, nor that women would trust men to use contraception. Current usage patterns of contraceptives, however, indicate that dissatisfaction with current methods is high and that men all over the world are involved in family planning practices. Furthermore, a great deal of research has been carried out on male and female attitudes towards male contraception. The results of these studies indicate a healthy interest in male methods from both men and women even given regional variations in attitudes [17,29,33–35] . Finally, the financial responsibility of child support required for men in certain countries provides an incentive for men in casual sexual relationships to take control of their own fertility. The worldwide, unmet need for contraception has been estimated to be between 137 and 200 million women [36] and need is as high as 40% in certain African countries [37] . Data from the 2002 National Survey of Family Growth indicated that 25% of American women discontinue using their method of birth control within the first year. Importantly, the highest discontinuation rates were those for male methods: 57% discontinued using condoms and 54% discontinued using withdrawal within the first year [38] . These data indicate that there is plenty of room for improvement and innovation in current contraceptive methods, especially for couples that choose male methods. The belief that women have always been the ones responsible for contraception is flawed. Until the advent of the oral contraceptive pill in the late 1950s, the only contraceptive options available were vasectomy, condoms, periodic abstinence and withdrawal, all of which are male-oriented methods [7] . Male participation in contraception played a large role in the demographic transition from high to low fertility in many countries [17] . Even now, in an era where women have many more options for fertility control than men, male-reliant contraception is used by 150 million couples, over a quarter of the couples using contraception [39] . The sexual revolution that started after improvements in female contraception has also shifted the economic prospects for male contraception. Currently, 40% of births in the USA are nonmarital births [40] . These births have always had and continue to have economic consequences for single women. In bygone days, single men could easily dodge these costs. However, owing to rising rates of paternity establishment, nonmarital births can also impose high costs on men, often without the accompanying rewards of involved fatherhood. In 2000, the Offices of Child Support Enforcement established 1,555,581 paternities [41] . In 2010, after a steady annual increase, the number of established paternities reached 1.7 million [42] . While established couples are able to make cooperative contraceptive choices and plan families, single men who want to have casual sexual relationships, where there is less trust and cooperation, have few options to reliably avoid the serious financial

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Assurance that infertility is reversible will be vital for any method to be successful. There is variability in both patterns of spermatogenesis suppression, from 6–12 weeks and recovery, from 6 weeks to 6 months [25] . However, return to fertility has been found to be complete. In 30 trials including 1549 men, no participant failed to recover concentrations of 20 million sperm/ ml and the median recovery time was 3.4 months [26] . While these lag times are perhaps not ideal, similar lag times apply to vasectomy and a lag of 1 month generally applies to female oral contraceptives [27] . As nonhormonal approaches do not usually interfere with androgen-dependent functions or organs, such as the prostate and because of the specificity of many of their targets, it is likely that their side effects would be minimal. Depending on the nature of the target (e.g., sperm maturation or motility), there is evidence that nonhormonal male contraceptives could evoke both faster onset and recovery time than hormonal approaches [23] . As with any new pharmaceutical agent, a complete understanding of the long-term effects will not be possible until Phase IV postmarketing data can be collected. Despite the questions that remain regarding side effects and safety, there is currently much more information relating to the efficacy and safety of male methods compared with what was known about female methods when they were launched in the 1960s [17] .

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Acceptability of male methods: clinical trial data

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Male and female acceptance of novel formulations have been measured through interviews and surveys of participants in clinical trials. In the WHO trials, where weekly injections were administered, 85% of participants said they would prefer the trial method to the method they had been using before the trial if the injection were offered at 3-month intervals. Three quarters of the women in the study said they would have continued the trial method if allowed [28] . In a study of Italian men receiving regular injections (at 6, 8 or 12 weeks), 61% of men said the method in the study was ‘excellent’ or ‘good’ [29] . Slightly less positive results were found in a study of American men treated with a 3-monthly injection of depomedroxyprogesterone and daily testosterone transdermal gel. Half of those who completed the trial reported being satisfied; 45% said they would use it in future and 40% found it preferable to the method they had been using before the study [30] . Aggregate analysis of acceptability from clinical trials indicates that discomfort at the injection site and injection schedules account for 35–40% of dissatisfaction with injection methods [31,32] . Similarly, one-third of users of topical gels indicated daily application of the gel negatively interrupted their daily routine [30] . Acceptability of data from clinical trials improve upon hypothetical surveys in that they are based on real experience with male contraception. However, men who participate in clinical trials of contraceptives are not representative of the general population. Even with these caveats, these data provide strong evidence of acceptability and even some preference for male injectable methods. 4



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[35] . However, even in Indonesia where willingness was lowest, a quarter of the population surveyed (28.5%) responded positively. Survey data of women’s attitudes also show support for male contraceptive methods. In a survey of women in Edinburgh, Cape Town, Shanghai and Hong Kong, more than 70% of all women and over 90% of women in South Africa and Scotland, thought that a ‘male pill’ was a good idea and 65% of women overall felt that the responsibility of contraception fell too heavily upon women [34] . In Hong Kong and Shanghai, of the women who were negative or unsure about male contraception, the primary concern was health risks. In Scotland and South Africa, women were more likely to attribute their negative attitudes to a reluctance to rely on their partner [34] . However, only 2% of women overall indicated that they would not trust their partner to use contraception. These data indicate that while women may not trust men in general to take the pill, they were more trusting when it came to their own partner [29] . In a UK survey of 134 female and 54 male users of contraceptives, acceptability of a ‘male pill’ was 49.5%. Forty-two percent of respondents expressed concerns that men would forget to take a male pill, women being much more likely to express this concern than men [45] , contrasting with the 2% of women in the Glasier et al. (2000) study. Those who were unwilling or undecided about the pill were likely to express concerns about the effect of a pill on future fertility [45] . Since the majority of current hormonal formulations do not require daily adherence and the return to fertility from current formulations is estimated to be 100%, there is potential to adequately address these concerns. Finally, the attitudes of minority youth were assessed in a survey of 30 young, African American men and women. Overall, 67% of males and females had positive impressions of male hormonal contraception. A large majority (85%) of females indicated they would trust their partners to use the method and a majority of males (60%) indicated intentions to use the product were it available [46] . Survey data is very likely to overestimate the population of potential users of male contraception. However, even the lowest expressions of interest in male contraception from these surveys are many times the usage rates for most current, ‘successful’ female birth control methods (Table 2) . Even assuming that only 25% of men who indicated they would ‘definitely’ or ‘probably’ use male contraception in the Heinemann et al. survey, the estimated number of potential users aged 15–64 years in those nine countries alone is close to 44 million (Table 3) .

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consequences of single fatherhood and a child support order. US trends show that single men are facing an increasing financial risk from child support orders. Condoms, which are the best reversible male option besides abstinence, are only 93% reliable [43] . An American worker earning US$36,000 per year would face a child support order worth US$400 per month. Therefore, an unmarried man who believes that his partner would not get an abortion is facing an undiscounted stream of payments until the child’s 18th birthday amounting to US$86,400. This number is the product of US$400 per month for 18 years. If future installments of child support payments were discounted by 5%, the total drops to US$56,100. One year of unprotected sexual activity with his partner would expose him to an 85% chance of conceiving – a risk worth US$48,000 (= 0.85 × US$56,100). His best option to personally control this risk would be to comply perfectly with condom use but this could only reduce this risk by 90%, reducing expected risk from 1 year of sex with condoms and an unreliable partner to US$4800 (= 0.1 × US$48,000). A yet to be marketed male contraceptive that was safe and 99% effective could reduce his risk by US$4320 (= S$4800 − US$480). This brief informal exercise suggests that the financial value of the prevention of a child support order from a 9-point gain in contraceptive efficacy would be worth US$4320 per year to a man of modest means who does not fully trust his sex partner to use contraception adequately or to abort an unwanted pregnancy. In theory, a pharmaceutical company could price their product at US$4319 per year (US$11.80 per day) and consumers would be better off purchasing it. How much revenue would be generated depends on how many single men are having sex with partners they do not trust. We shed light on this question below.

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Male willingness to use novel contraception: survey data

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Male willingness to use a novel male method has been studied through a number of survey studies, as have female attitudes toward male contraception. While surveys measure only hypothetical behaviors, they offer an important perspective and can gauge differences across groups. A cross-cultural study to assess attitudes toward hormonal male contraception interviewed a total of 1843 men in Edinburgh, Cape Town, Shanghai and Hong Kong. The majority of participants (44–83%) stated they would use a male contraceptive pill [33] . In a survey of over 9000 men aged 18–50 years from nine countries, 28.5–71.4% of various nationalities expressed willingness to use a hormonal male contraceptive, with an overall willingness rate of 55% [44] ; 55–81.5% of these participants indicated that both they and their partner participate in the selection of a contraceptive method [44] . Even more positive figures were reported in a study of Australian men’s attitudes toward male contraception in which 75.4% of new fathers interviewed indicated they would be willing to try a male method if it were available [35] . These surveys shed light on cultural differences in acceptability. The predominantly Muslim communities in Indonesia were less willing to use male contraceptives, citing religious beliefs [44] and Australian migrants were less receptive than those born in Australia www.expert-reviews.com

Estimating demand based on secondary data analysis

Data on the use of male contraceptives among key demographics offers an alternative perspective to quantifying the demand for novel male methods (Table 4) . The National Survey for Family Growth indicates that 6% of American men have had a vasectomy (2006–2010 cycle) and 7.5% of married couples rely exclusively on condoms [47] . While not all men who choose vasectomy would substitute another male method were it available and not all married couples use condoms only for contraceptive purposes, these percentages suggest a potential consumer pool as large or larger 5

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Dorman & Bishai

Table 2. Percentage of women aged 15–49 years in a marriage or union using modern contraceptive methods, by region. Region

Method Pill

Injectable

Intrauterine device

Male condom

Female sterilization

Male sterilization

Implant

World

8.8

3.5

14.3

7.6

18.9

2.4

0.3

Africa

7.8

6.4

4.4

1.6

1.6

0.0

0.4

Asia

6.0

3.2

17.9

6.9

23.4

2.2

0.4

Europe

21.4

0.3

12.4

17.1

3.1

2.5

0.1

Latin American and the Caribbean

16.4

5.4

7.0

9.6

25.9

2.3

0.1

North America

16.8

1.4

4.6

12.0

22.3

13.7

0.6

Expert commentary

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Despite over 80 years of research into male contraception, condoms, vasectomy, withdrawal and abstinence remain the only options for male fertility control. Challenges in physiology, acceptability and safety have been obstacles in male method development, but there is great potential for the current pipeline of products to produce a safe and acceptable novel option that will improve on the efficacy of temporary male methods. Doubts over the market for male contraception persist and may have contributed to the pharmaceutical industry’s exit from the field. However, a growing body of evidence indicates that both men and women are strongly interested in using a novel male method. Furthermore, owing to

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than several current female methods. For instance, only 0.3% of all women between 15 and 49 years of age who are married or in a union currently use a hormonal implant for contraception, amounting to approximately 3.5 million users; approximately 41.3 million such women use injectables globally (Table 2) [48] . Furthermore, 9% of never married American men have fathered a child [103] , which helps to approximate the number of men who may desire more control over their own fertility. The population of US men likely to be in sexual unions with fertile women (age 15–45 years) could be conservatively estimated from census 2010 at 75 million men (age 15–49 years) or more liberally at 110 million (age 15–69 years).

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Data taken from [48].

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Table 3. Estimates of potential users of male contraception: survey data. Participants (n)

Willing to use male contraception (%)

Number of men aged 15–64 years

Potential market size §

German

1021

69

28,039,000

4,836,728

[44]

French

725

47

19,708,000

2,315,690

[44]

Spanish

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Group

Ref.

1049

71.4

15,008,000

2,678,928

[44]

1023

58.1

2,999,000

435,605

[44]

1500

49.3

99,499,000

12,263,252

[44]

1000

44.5

12,156,000

1,352,355

[44]

1000

62.7

60,416,000

9,470,208

[44]

1024

65.4

32,892,000

5,377,842

[44]

Indonesian

1000

28.5

Edinburgh Cape Town, black

Swedish American Brazilian Mexican

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Argentinian

73,700,000

5,251,125

[44]

303

‡

66 , 32

NA

NA

[32]

79

55†, 48‡

NA

NA

[32]

Cape Town, colored

119

66 , 55

NA

NA

[32]

Cape Town, white

121

83 , 62

NA

NA

[32]

Hong Kong

300

‡

44 , 32

NA

NA

[32]

Shanghai

298

50†, 35‡

NA

NA

[32]

Total

†

†

†

†

‡ ‡

43,981,732

Would ‘probably or definitely’ use a male pill. ‡ Would ‘probably or definitely’ use an injection. § Calculation: Percentage willing to use × 25% (‘lower bound’ or low estimate to keep calculation conservative) × country population of 15–64 year old males using population estimates from UN (2004) [49]. NA: Not available. †

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they did not unwillingly or unknowingly impregnate a partner [28] . Overtime, men may come to view having control over their Group Users (% of 15–44 Lower Number of potential users own fertility to be a right just as women year olds) bound† of a novel method (15–64 have done. year olds) ‡ A male contraceptive should appeal not Never married fathers 9% (2006–2010) 50% 4,477,455 only to single males but also to couples in Married condom users 7.5% (2002) 50% 3,731,213 stable relationships. A small survey of 47 couples showed modest support for the Vasectomy customers 6% (2006–2010) 50% 2,984,970 † Calculations were reduced by 50% to keep calculations conservative. idea that egalitarian sex-role preferences ‡ Using population estimates from UN (2004) [49]. are related to a belief that contraception is Data taken from [103]. a shared responsibility [50] . Analysis of the modern paternity testing methods, child support payments are 1991 National Survey of Men indicates that 78% of men surveyed a real and significant financial burden fathers face today. This believe that men and women should share equal responsibility potential burden is estimated to be US$4800 per year for a man for decisions about contraception [51] . In a stable relationship in the USA relying on condoms. Were a novel method with 99% where trust is established, a male method would enable couples efficacy available, it would reduce this burden to US$4320, mak- greater freedom and flexibility in their reproductive choices. ing financial sense for a man to spend up to US$4319 per year on Furthermore, if side effects are considered as something to be a method with 99% efficacy. shared between partners, male methods would offer couples a ‘gallantry option’ by shifting a portfolio of tolerable side effects Five-year view from contraception from females to males [28] , thus halving the Without financial investments from the pharmaceutical industry, overall burden to each partner. many experts believe it is unlikely that a novel, male contraceptive If a new male contraceptive could be marketed for dual purwill be brought to market [49] . If one has an economists’ faith that poses, for beneficial side effects, it could enjoy better user adherthe market will never leave big bills on the sidewalk, the absence ence and acceptability. Though not engineered or necessarily of significant private pharmaceutical investment in male contra- taken for its side effects, female oral contraception reduces the ceptives is ipso-facto evidence that this market has been judged risk of endometrial and ovarian cancer [18] . While no such forto be unprofitable. However, there are new social developments mulation has yet emerged for the male, a male contraceptive that that might contribute to a rosier future for male contraceptives. conferred an added benefit to the user might have much more Unwanted fertility is in transitioning from being primarily a success in attracting investment from pharmaceutical companies couples’ concern to a singles’ concern, which bodes well for male because of its higher potential revenue. contraceptives. Our examination of national data on patterns of sexual behavior suggests that over 9% of men in the USA are ‍Acknowledgements never married but have fathered children, an unknown fraction The authors are grateful for helpful comments by Barry Zirkin. of which started as unintended pregnancies [103] . A drug company that used a more effective contraceptive to compete against Financial & competing interests disclosure the condom could charge US$480 per year for every 1% reduc- The authors have no relevant affiliations or financial involvement with any tion in pregnancy risk. With today’s genotyping methods for organization or entity with a financial interest in or financial conflict with establishing paternity and the legal requirement that fathers pay the subject matter or materials discussed in the manuscript. This includes child support, it is possible that men will demand more choices employment, consultancies, honoraria, stock ownership or options, expert in contraception [8] . Indeed, men in the WHO 12-year follow- testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. up study indicated interest in relying on themselves to ensure

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Table 4. Estimates of potential users of male contraception: National Survey for Family Growth populations.

Key issues • Despite over 80 years of research into male contraception, no new male method has come to market in 300 years. • The current product pipeline of male methods include many promising strategies, both hormonal and nonhormonal, with great potential to be safe and acceptable while improving on the efficacy of current temporary male methods. • In the early 2000s, several major pharmaceutical companies terminated their research into male contraception, leaving only nonprofit organisations, governments and universities with much more limited budgets in the field. • Survey data indicates strong interest from both women and men in having more male options for fertility control. • If only 25% of men who indicated a willingness to use male contraception actually adopted the method, the potential market in just nine countries would approach 44 million consumers. • Owing to advances in paternity testing and the financial burden of child support payments, men have a sizeable incentive to take responsibility for their own contraception. • Increase in male contraceptive choice is a key part of reproductive freedom for both couples and individuals.


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Darszon A, López-Martínez P, Acevedo JJ, Hernández-Cruz A, Treviño CL. T-type Ca2+ channels in sperm function. Cell Calcium 40(2), 241–252 (2006).

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Amobi NI, Chung IP, Smith IC. Attenuation of contractility in rat epididymal vas deferens by Rho kinase inhibitors. Auton. Autacoid Pharmacol. 26(2), 169–181 (2006).

Papers of special note have been highlighted as: • Of interest •• Of considerable interest

Smith PE. The disabilities caused by hypophysectomy and their repair: the tuberal (hypothalamic) syndrome in the rat. JAMA. 88, 158–161 (1927).

2

McCullagh EP, McGurl FJ. Further observation on the clinical use of testosterone propionate. J. Urol. 42, 1256–1267 (1939).

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5

6

7

WHO Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia in normal men. Lancet 336, 955–959 (1990). WHO Task Force on Methods for the Regulation of Male Fertility. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil. Steril. 65, 821–829 (1996). Diczfalusy E. World Health Organization special programme of research, development, and research training in human reproduction. The first fifteen years: a review. 34(1), 113–119 (1986).

15

Zhang GY, Gu YQ, Wang XH, Cui YG, Bremner WJ. A clinical trial of injectable testosterone undecanoate as a potential male contraceptive in normal Chinese men. J. Clin. Endocrinol. Metab. 84(10), 3642–3647 (1999).

16

Page ST, Amory JK, Bremner WJ. Advances in male contraception. Endocr. Rev. 29(4), 465–493 (2008).

17

Handelsman DJ. Editorial: Hormonal male contraception – lessons from the east when the western market fails. J. Clin. Endocrinol. Metab. 88(2), 559–561 (2003).

•• Provides evidence to challenge the most common arguments against the potential for male contraceptive adoption. 18

Wu FCW. Male contraception. Baillieres Clin. Obstet. and Gynaecol. 10(1), 1–23. (1996).

Lyttle CR, Kopf GS. Status and future direction of male contraceptive development. Curr. Opin. Pharmacol. 3(6), 667–671 (2003).

19

A

•• Provides a concise summary of milestones in male contraceptive development and addresses the financial and societal challenges in the adoption of male methods. 9

Walton M, Anderson RA. Hormonal contraception in men. Curr. Drug Targets Immune Endocr. Metabol. Disord. 5(3), 249–257 (2005).

10

Song L, Gu Y, Lu W, Liang X, Chen Z. A phase II randomized controlled trial of a novel male contraception, an intra-vas device. Int. J. Androl. 29(4), 489–495 (2006).

11

8

Chaudhury K, Bhattacharyya AK, Guha SK. Studies on the membrane integrity of human sperm treated with a new injectable male contraceptive. Hum. Reprod. 19(8), 1826–1830 (2004).

Matthiesson KL, McLachlan RI. Male hormonal contraception: concept proven, product in sight? Hum. Reprod. Update 12(4), 463–482 (2006).

26

Waites GMH. Development of methods of male contraception: impact of the World Health Organization Task Force. Fertil. Steril. 80(1) (2003).

27

Wu FC. Hormonal approaches to male contraception: approaching reality. Mol. Cell. Endocrinol. 250(1-2), 2–7 (2006).

28

Ringheim K. Whither methods for men? Emerging gender issues in contraception. Reprod. Health Matters. 7, 79–89 (1996).

•• Offers analysis of the reproductive rights and responsibilities germane to increasing contraceptive options for men.

29

Glasier A. Acceptability of contraception for men: a review. Contraception 82(5), 453–456 (2010).

•

In-depth review of the evidence of women’s attitudes toward male contraception.

30

Amory JK, Page ST, Anawalt BD, Matsumoto AM, Bremner WJ. Acceptability of a combination of testosterone gel and depomedroxyprogesteroneacetate male contraceptive regimen. Contraception 75, 218–223 (2007).

31

Meriggiola MC, Cerpolini S, Bremner WJ et al. Acceptability of an injectable male contraceptive regimen of norethisterone enanthate and testosterone undecanoate for men. Hum. Reprod. 21(8), 2033–2040 (2006).

32

Zhang L, Shah IH, Liu Y, Vogelsong KM, Zhang L. The acceptability of an injectable, once-a-month male contraceptive in China. Contraception 73(5), 548–553 (2006).

33

Martin CW, Anderson RA, Cheng L et al. Potential impact of hormonal male contraception: cross-cultural implications for development of novel preparations. Hum. Reprod. 15(3), 637–645 (2000).

34

Glasier AF, Anakwe R, Everington D et al. Would women trust their partners to use a male pill? Hum. Reprod. 15(3), 646–649 (2000).

35

Weston GC, Schlipalius ML, Bhuinneain MN, Vollenhoven BJ. Will Australian men use male hormonal contraception? A survey of a postpartum population. Med. J. Aust. 176(5), 208–210 (2002).

Potts M. The myth of a male pill. Nat. Med. 2(4), 398–399 (1996).

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. 88(2), 562–568 (2003).

20

Turner L, Conway AJ, Jimenez M et al. Contraception efficacy of a depot progestin and androgen combination in men. J. Clin. Endocrinol. Metab. 88, 4659–4667 (2003).

21

Amory JK, Page ST, Bremner WJ. Drug insight: Recent advances in male hormonal contraception. Nat. Clin. Pract. Endocrinol. Metab. 2(1), 32–41 (2006).

22

Schearer BS, Alvarez-Sanchez F, Anseimo J et al. Hormonal contraception for men. Int. J. Androl. 1(2b), 680–712 (1978).

23

Mruk DD, Cheng CY. Delivering non-hormonal contraceptives to men: advances and obstacles. Trends Biotechnol. 26(2), 90–99 (2008).

ut

8

Heckel NJ. Production of oligospermia in a man by the use of testosterone propionate. Proc. Soc. Exp. Biol. Med. 40, 658–659 (1939).

Cheng CY, Mruk DD. New frontiers in nonhormonal male contraception. Contraception 82(5), 476–482 (2010).

ho

3

14

25

of

1

recovery after hormonal male contraception: an integrated analysis. Lancet 367(9520), 1412–1420 (2006).

ro

References

rP

Review

•

Cogently presents the progress and challenges in developing nonhormonal methods for men.

24

Liu PY, Swerdloff RS, Christenson PD, Handelsman DJ, Wang C; Hormonal Male Contraception Summit Group. Rate, extent, and modifiers of spermatogenic



United Nations, Population Division. World contraceptive use 2011, wall chart. Department of Economic and Social Affairs, Population Division (2011).

38

Vaughan B, Trussell J, Kost K, Singh S, Jones R. Discontinuation and resumption of contraceptive use: results from the National Survey of Family Growth. Contraception 78, 271–283 (2008).

39

United Nations. Levels and trends of contraceptive use as assessed in 1998. New York Department of International Economic and Social Affairs (2000). National Vital Statistics Reports. Births: preliminary data for 2009. Natl. Vital. Stat. Rep. 59(3) (2010).

41

United States Department of Health and Human Services. Child support enforcement FY 2010 preliminary report. Administration for Children and Families, Office of Child Support Enforcement (2001).

42

United States Department of Health and Human Services. Child support enforcement FY 2010 preliminary report. Administration for Children and Families (2011).

44

Heinemann K, Saad F, Wiesemes M, White S, Heinemann L. Attitudes toward male fertility control: results of a multinational survey on four continents. Hum. Reprod. 20(2), 549–556 (2005).

51

Grady WR, Tanfer K, Billy JO, LincolnHanson J. Men’s perceptions of their roles and responsibilities regarding sex, contraception and childrearing. Fam. Plann. Perspect. 28(5), 221–226 (1996).

•

In-depth analysis of survey data on male attitudes toward using contraception.

45

Walker SZ. Attitudes to a male contraceptive pill in a group of contraceptive users in the UK. J. Men’s Health 8(4), 267–273 (2011).

46

47

Marcell AV, Plowden K, Bowman SM. Exploring older adolescents’ and young adults’ attitudes regarding male hormonal contraception: application for clinical practice. Hum. Reprod. 20(11), 3078–3084 (2005).

48

49

Walsh TL, Frezieres RG, Peacock K et al. Effectiveness of the male latex condom:

Websites 101

Lissner EA. (2006). Frontiers in nonhormonal male contraception: the next step. Male Contraception Information Project. www.newmalecontraception.com

102

Chandra A, Martinez GM, Mosher WD et al. Fertility, contraception, and fatherhood: data on men and women from Cycle 6 (2002) of the national survey of family growth. National Center for Health Statistics. Vital Health Stats. 23(26) (2005). United Nations. World contraceptive use 2011. Department of Economic and Social Affairs, Population Division (2011).

United Nations. World population prospects, the 2004 revision, volume II: sex and age. UN Econ. and Soc. Affairs (2004).

CONRAD. Press Release: male contraceptive trial ending early. (2011, April 22). www.conrad.org/news-pressreleases-63. html

103

National Survey of Family Growth, 2006-2010. Male respondent data 2006-2010. Centers for Disease Control and Prevention (2011). www.cdc.gov/nchs/nsfg/nsfg_2006_2010_ puf.htm (Accessed 22 February 2012)

104

International Male Contraception Coalition. Male contraceptive development pipeline. www.imccoalition.org/pipeline.php

A

ut

43

Marsiglio W, Menaghan EG. Couples and the male birth control pill: a future alternative in contraceptive solutions. J. Sex Research 23(1), 34–49 (1987).

ho

40

50

of

37

combined results for three popular condom brands used as controls in randomized clinical trials. Contraception 70(5), 407–413 (2004).

ro

Singh S, Darroch JE, Ashford LS, Vlassoff M. Adding it up: the costs and benefits of investing in family planning and maternal and newborn health. Guttmacher Institute and United Nations Population Fund (2003).

rP

36

Review


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