The life course of a sperm

Spermatogenesis begins in the brain. The hypothalamus secretes gonadotrophin-releasing hormone (GnRH), which in turn stimulates the anterior pituitary to release luteinising hormone (LH) and follicle stimulating hormone (FSH). These hormones then act on the Leydig and Sertoli cells within the testis.

Leydig cells produce testosterone, which is secreted into the bloodstream. Serum testosterone supports a wide range of male functions and is a key component of the negative feedback loop that controls GnRH and gonadotrophin production. Testicular levels of testosterone are approximately 40 times higher than in blood2 and support Sertoli cells in their role in spermatogenesis.

After release from Sertoli cells (‘spermiation’), sperm progress through the seminiferous tubules and into the epididymis for storage, concentration and maturation to functional sperm. Finally, at the point of ejaculation, sperm are transferred from the epididymis via the vas deferens to the urethra and then out of the body (figure 1).

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Figure 1

The hypothalamic-pituitary-testicular axis and its role in spermatogenesis. CCBY 4.0 Licence – John Reynolds-Wright. Image accessible via https://flic.kr/p/2hgvk5V6A. FSH, follicle stimulating hormone; GnRH, gonadotrophin-releasing hormone; LH, luteinising hormone.

Potential novel male contraceptives can be divided into those based on a hormonal approach, acting via gonadotrophin suppression, and non-hormonal methods. Hormonal strategies for male contraception involve the hypothalamic-pituitary-testicular (HPT) axis, using exogenous testosterone in combination with progestogen to drive the negative feedback response and suppress GnRH, FSH and LH. Exogenous replacement of testosterone prevents hypogonadal side effects from HPT axis suppression but is not delivered at high enough concentrations to support spermatogenesis directly. Non-hormonal methods can act at any point during spermatogenesis or can target sperm maturation, detachment, motility or transport out of the testis. This includes physical methods of infiltration of the vas with a dissolvable compound to block or damage sperm during their movement along the vas.

A brief history of hormonal male contraception

The question asked most frequently about male contraception, other than ‘When will it be ready?’, is ‘what is taking so long?’. The following summary on the history of male contraception will hopefully answer this question.

The quest to develop new forms of male contraception started at more or less the same time as the development of female hormonal contraceptive methods, but has taken a very different course. The culture shift that took place in the wake of the phenomenon of the hormonal contraceptive pill for women3 in 1965 led to the creation of the WHO Special Programme of Research, Development and Research Training in Human Reproduction (WHO-HRP).3 Within the WHO-HRP a task force for developing methods of male fertility regulation was developed. This identified possible modalities for male contraceptives through basic science research projects and multicentre landmark clinical trials of testosterone alone and in combination with progestogens.3 The task force also focused efforts on the development and promotion of no-scalpel vasectomy, which has become the predominant technique globally, and gossypol, which was planned as a reversible contraceptive but unfortunately had to be abandoned due to issues with toxicity and irreversibility.3

Over approximately a decade from the mid-1980s, the task force developed new esters of testosterone with the hope that they would be developed by industry partners for use in treatment of hypogonadal patients and as male contraceptives. However, this did not come to fruition, for reasons including concerns in industry about security of patents, possibility of litigation, perception of a ‘small market’ and competition with their existing female contraceptives. Nevertheless, landmark contraceptive efficacy studies were conducted at this time using weekly injections of testosterone enanthate. The first of these demonstrated that most men (70%) became azoospermic when administered 200 mg/week of testosterone enanthate, and couples then used this as their exclusive method of contraception for 12 months. This proved to be a highly effective contraceptive, with only 0.8 pregnancies per 100 person-years of exposure.4 A second study extended this to ask ‘how low does a sperm count need to go?’, and used 3 million/mL as the cut-off for entry to the efficacy phase. This increased the response rate (92% of men achieved sperm counts below this threshold and entered the efficacy phase), and again excellent efficacy was demonstrated with a Pearl Index of 1.4 (95% CI 0.4 to 3.7).5 Although a Pearl Index of 8.1 (95% CI 2.2 to 20.7) was achieved even in men who were not azoospermic, it was subsequently decided that <1 million/mL was the appropriate sperm count cut-off for future contraceptive efficacy studies.6

While these studies demonstrated that hormonal contraception using testosterone was a real possibility for men, subsequent studies have focused on a combination with progestogens, which are potent gonadotrophin suppressors in men as they are in women. In combination, they allow a much lower dose of testosterone to be used, essentially using the progestogen to do the gonadotrophin suppression, with approximately physiological doses of testosterone providing replacement for the suppressed Leydig cell function. The 1990s saw a lot of activity exploring a range of progestogens, although generally in small studies with spermatogenic suppression as the end point, rather than contraceptive efficacy.7 A key limitation at that time was the absence of a long-acting testosterone preparation, although testosterone pellets were used in studies, predominantly in the UK and Australia. In prototype long-acting reversible contraceptive (LARC) studies, testosterone pellets were combined with etonogestrel implants, showing excellent spermatogenic suppression,8 and in combination with depot medoxyprogesterone acetate (DMPA) were used in an efficacy study, with no pregnancies in 55 couples over 35.5 person-years of exposure.9

The development of long-acting testosterone undecanoate (TU) by Schering led to a collaborative study with Organon, which developed specific etonogestrel implants for men for a trial of that combination, confirming effective spermatogenic suppression.10 Unfortunately, this industry involvement was short-lived due to changing priorities in both companies, and there are no commercially funded active studies at present. In China, large studies were also conducted using TU alone.11 The combination approach was developed into an efficacy study by WHO and CONRAD (Contraception Research and Development network), using TU with norethisterone enanthate, both given at 8-week intervals (with the anticipation of a single combination injection being developed). This study recruited over 300 couples internationally, with 96.8% of men achieving sufficient spermatogenic suppression to enter the 1-year efficacy phase. While the trial was stopped early by a WHO review panel due to concern over side effects (despite very few men discontinuing treatment), there were just four pregnancies, giving a contraceptive efficacy of 1.59% (CI 0.6 to 4.2),12 thus matching hormonal female methods and substantially better than condoms, the only current reversible male method.

The essential role of GnRH in regulating reproductive function makes it an obvious target for study, since the early days of development of GnRH agonists in reproductive medicine. Both agonists and antagonists have the potential to act as contraceptives. GnRH agonists do not result in sufficient gonadotrophin suppression in men, but GnRH antagonists are very effective and there have been several studies that have investigated GnRH antagonists (with testosterone); however, these did not reduce sperm concentrations to a greater degree than testosterone-progestogen combinations.13 GnRH antagonists have only been available in parenteral preparations requiring serial injections or infusions, which have practicality and cost implications. New oral GnRH antagonists are becoming available, developed for the treatment of endometriosis,14 and may have a role to play as part of a patient-controlled contraceptive in the future.

Current and future hormonal approaches

Non-hormonal approaches acting on spermatogenesis

Non-hormonal approaches acting on the epididymis

The epididymis is responsible for concentrating sperm within the seminiferous fluid and conditioning the lipids and proteins on the surface of the sperm. This process takes several weeks and is essential for maturation of the sperm to improve their functionality. There are several areas currently being explored as potential sites of intervention for a male contraceptive. There are proteins, for example Eppin,29 expressed in the epididymis (and nowhere else in the body) that could be targeted with drugs that disrupt their functions. As these proteins are only expressed in the reproductive tract, there should theoretically be few side effects to these methods.29

Non-hormonal approaches acting on the vas

Will novel male methods meet the general principles of contraceptive development?

There are five domains broadly sought after in a novel contraceptive method35:

1. Contraceptives must have high efficacy, both in controlled settings and in real-world use.

2. The contraceptive effect must be reversible: while there may be some utility to alternative methods of permanent contraception, safe effective methods of achieving this already exist and the gap in the market is for true, on-demand reversibility.

3. Speed of action: the time taken from initiating the contraceptive until the method offers protection from pregnancy should be as short as possible to prevent unintended pregnancy.

4. Ease of use: novel contraceptives should be simple to use, whether they are patient-initiated (pills and gels) or clinician-initiated (injections and implants), with clear ‘missed pill’ rules. This also includes issues of accessibility.

5. Safety: side effects should be minimal to reduce discontinuation, particularly with regard to secondary sex characteristics, sexual function and sexual pleasure. Non-contraceptive benefits should be maximised and should not be worse than no contraception.

It is clear that fulfilling all of these domains is closer than ever before for some of the approaches discussed above. Efficacy of currently studied methods looks to be high, with low rates of residual spermatogenesis and low rates of pregnancy. Likewise, reversibility following discontinuation appears complete and treatment modalities are familiar and easy to use (injections, gels and pills). Speed of action is where this approach falls down slightly—hormonal methods currently being investigated require several weeks of use before they can be relied on, although this is similar to vasectomy. Male hormonal methods also appear to be largely safe, being based on steroids that have been used in large numbers of people over many years, without detriment to secondary sex characteristics. Hormonal methods can have a negative effect on cholesterol, particularly decreases in high-density lipoprotein cholesterol, which may play a role in heart disease risk, but this must be interpreted with caution as it may largely reflect historical approaches based on high doses of testosterone, and risk of cardiovascular disease is complex and multifactorial. There may be positive non-contraceptive benefits of these drugs in terms of prostate function, muscle mass and bone density that will not be understood until there are longer-term, population-level data, and the use of novel steroids may increase these benefits.

Social probabilities

Ample evidence exists to show that high proportions of men find the idea of a male contraceptive acceptable and that women would rely on their male partners to use a male contraceptive method.36

It is important to remember that many women rely on their male partner for contraception already—approximately 54% of women in the UK use either male sterilisation, male condom or withdrawal method as their main method of contraception.37

Thus, men want to engage in reproductive health, but their current options are limited compared with the range of contraceptive choices available to women. Male hormonal contraceptive methods do not currently exist on the market anywhere globally and so we cannot base our assumptions on future use of these methods on how current methods are used. Men may be attracted to male hormonal contraceptives for non-contraceptive benefits, similar to the familiar non-contraceptive benefits of female hormonal methods, and this is an aspect that can potentially be ‘engineered’ into methods based on novel steroids.

Challenges for services

In the current research paradigm, male contraception development involves frequent semen analysis to confirm azoospermia/oligospermia prior to relying on the method as a contraceptive. During later phase studies and then as male contraceptives enter clinical practice, the focus will need to shift from intensive monitoring of sperm concentrations and more to general rules of use. However, semen analysis remains in routine clinical practice for confirming vasectomy efficacy, and home testing for spermatogenic suppression may also be a possibility with several companies developing such technology in relation to infertility.38

Summary

More diverse methods of male contraceptives are needed to help meet the unmet contraceptive need of men and women everywhere. Research into these methods has been ongoing since the 1970s, but development has been hindered by a wide range of factors: challenges for funding of male methods and lack of industry involvement, disbelief that there is a real need for novel male methods, slow development of novel testosterone preparations, and the underlying physiology whereby men produce millions of sperm per day rather than releasing one oocyte per month. Fortunately, we are closer than ever to new hormonal methods coming to the market, and while non-hormonal methods seem at present more distant they have the potential to make a major contribution in the future.