Use of progestins in male contraception
Introduction
Progesterone is active in the feedback-mechanism between hypothalamus, pituitary and ovary and plays an important biologic role in the female reproductive system, namely to prepare and support pregnancy and to provide nourishment to the conceptus. Progestins are essential components of female hormonal contraceptives. In the male a significant biologic role is not known, although progesterone is part of the steroid biosynthetic pathway(s) and small concentrations circulate in blood. Why then should progestins be used in male hormonal contraception?
Section snippets
Principle of hormonal male contraception
Hormonal male contraception aims at the suppression of sperm production, i.e. spermatogenesis and sperm release from the testis, i.e. spermiation. These processes are strongly dependent on the pituitary gonadotropins LH and FSH and these, in turn, on hypothalamic GnRH. Both gonadotropins act through specific receptors which for FSH are located on the Sertoli cells and for LH on the Leydig cells. The latter produce testosterone which is responsible for spermatogenesis within the testis, but also
Testosterone as sole contraceptive steroid
According to this principle, testosterone is the first choice for hormonal male contraception since it not only suppresses pituitary LH and FSH secretion, and thereby sperm production, but also replaces endogenous testosterone. Indeed since the 1970s various investigations have been undertaken to suppress spermatogenesis with testosterone. The first study ever performed on the efficacy of hormonal male contraception used testosterone as the single compound [3]. Volunteers in 10 centers on four
Testosterone plus GnRH antagonists
GnRH antagonists have been shown to be one of the promising additives to testosterone. GnRH antagonists block the pituitary GnRH receptors so that the pituitary can no longer produce gonadotropins under the influence of hypothalamic GnRH, and thereby gonadotropins are eliminated. GnRH antagonists in combination with testosterone lead to a more rapid onset and complete suppression of sperm [11], but the preparations currently available require daily or weekly injections and are expensive.
Testosterone and progestins
The other option to enhance the effectiveness of testosterone in suppressing spermatogenesis is the addition of progestins. Progestins are synthetic steroids with progestagenic activity and have mainly been developed for female contraception. Many of the progestins available for female contraception have also been tested for male hormonal contraception as they are potent inhibitors of LH and FSH, although in an unsystematic fashion.
Among the early progestins to be tested for male contraception
DMPA
The first longer-acting androgen ester to be tested for male contraception was 19-nortestosterone-hexoxyphenylpropionate. Unlike testosterone enanthate, it only needed to be injected every 3 weeks and thereby azoospermia could be achieved in 70% of the Caucasian volunteers [16]. When this 19-nortestosterone ester was combined with 250 mg DMPA azoospermia or severe oligozoospermia was achieved in all volunteers [17].
These promising results prompted the WHO Task Force on the Regulation of Male
Levonorgestrel
Levonorgestrel has been widely used for contraception in females either orally or as an implant and has proven to be safe and effective. Although early studies combining 0.5 mg levonorgestrel orally with testosterone enanthate were not very encouraging [21], more recent studies comparing testosterone enanthate alone or in combination with levonorgestrel orally showed that the combination resulted in a more pronounced suppression of spermatogenesis than testosterone enanthate alone [22].
19-Noresthisterone
19-Noresthisterone, one of the earliest progestins derived from testosterone [27], has some undesirable androgenicity when given to women which could even be of advantage when administered to men. An early study with only few volunteers using a combination of orally effective 19-noresthisterone acetate with either a transdermal testosterone gel or oral testosterone undecaoate led to azoospermia in all volunteers [28]. Considering its properties and these promising results, it was surprising
Cyproterone acetate
While the addition of an androgenic progestin to testosterone is a rational choice, the use of an antiandrogenic progestin without testosterone appears not quite logical. However, cyproterone acetate is a derivative of 17-hydroxyprogesterone and thereby primarily a progestin with antiandrogenic activity. Cyproterone acetate alone has been used in contraceptive trials under the assumption that it may selectively prevent sperm maturation in the epididymis. However, while suppression of
Desogestrel and etonogestrel
The orally administered desogestrel, a levonorgestrel derivative was evaluated in clinical trials using 300 μg per day together with weekly injections of 50 or 100 mg testosterone enanthate for 24 weeks. A third group received 150 μg per day desogestrel and 100 mg testosterone enanthate per week intramuscularly. The group receiving 50 mg TE showed complete suppression of spermatogenesis, i.e. azoospermia, the other groups incomplete suppression. In the most effective group total serum testosterone
Dienogest
The latest progestin to be tested for male contraceptive purposes is the orally effective dienogest. This is another 19-norprogestin where position 17 is not substituted by the common ethinyl group, but by a cyanomethyl group and a double bond is introduced in ring B. When given in 2, 5 or 10 mg doses, over 21 days, 10 mg showed a suppression of gonadotropins comparable to 10 mg of cyproterone acetate. Semen parameters were not affected, as one would expect with this short application period [41].
Side-effects
The ideal male contraceptive should fulfil the following prerequisites:
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it should be applied independent of the sexual act;
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it should be acceptable for both partners;
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it should not interfere with libido, potency and sexual activity;
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it should have no short or long-term toxic side-effects;
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it should have no impact on the eventual offspring;
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it should be rapidly effective and fully reversible;
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it should be more effective than condoms.
When using progestins in combination with testosterone the possible
Outlook
As this review has shown, some testosterone/progestin combinations have a very good chance to become a licensed hormonal male contraceptive. Although an oral pill is considered the most popular option in opinion polls [43], [44], it is unlikely that a self-administered modality, be it a pill or a pill combined with transdermal testosterone-preparation, may become a viable option. For the time being modalities resulting in constant serum levels of the contraceptive steroids appear to be the most
Acknowledgements
Our own studies reported here were in part supported by the German Federal Health Ministry (A.K.) or by the Deutsche Forschungsgemeinschaft Research Group “The Male Gamete” (E.N.). We would like to thank Susan Nieschlag, MA, for editing this manuscript.
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Dual estrogenic regulation of the nuclear progestin receptor and spermatogonial renewal during gilthead seabream (Sparus aurata) spermatogenesis
2017, Comparative Biochemistry and Physiology -Part A : Molecular and Integrative PhysiologyCitation Excerpt :In different teleosts, elevated expression of pgr mRNA in Sertoli cells that contact rapidly proliferating spermatogonia has also been observed, suggesting that this might be a common phenomenon (Chen et al., 2010, 2011, 2012). In mammals, progestins are known to inhibit spermatogenesis and sperm vitality (Nieschlag et al., 2003; Walton et al., 2006; Wang and Swerdloff, 2010), and accordingly the knockout of the Pgr increases testicular development and sperm production (Lue et al., 2013). In contrast, in teleosts progestins seem to be necessary for spermatogonia recruitment and meiosis (Miura et al., 2006; Chen et al., 2013; Liu et al., 2014), as well as for the stimulation of the spermiation process (Scott et al., 2010; Bryan et al., 2015; Shahi et al., 2015).
Male Contraception
2015, Endocrinology: Adult and PediatricCongenital hypogonadotropic hypogonadism and Kallmann syndrome as models for studying hormonal regulation of human testicular endocrine functions
2014, Annales d'EndocrinologieCitation Excerpt :This dependency was also found in primate models [88], in which gonadotropin inhibition by GnRH antagonists resulted in low circulating IB levels. It is further supported by the decline in IB levels observed during gonadotropin inhibition induced by testosterone esters, used alone or in combination with a progestagen for male contraception [89]. Studies of hypogonadotropic hypogonadism confirm that the decrease in pituitary gonadotropins is accompanied by a corresponding decrease in this testicular peptide (Fig. 2) [40,41,80,90–94].
Male contraception: History and development
2014, Urologic Clinics of North AmericaCitation Excerpt :Numerous formulations of testosterone in various injectable, implantable, transdermal, or oral forms, along with their modulators in different iterations of doses and frequencies have been studied and published. In developing an alternative male contraceptive, an ideal agent should have the following parameters fulfilled, as outlined by Nieschlag and colleagues20 (Fig. 1): Applied independent of the sexual act
Contraception technology: Past, present and future
2013, ContraceptionCitation Excerpt :Most of the studies using androgen and progestins were conducted in small groups of volunteers, and large studies testing a combination of ENG implants and testosterone undecanoate injections [104] and the WHO large efficacy study testing norethisterone enanthate combined with testosterone injections have both shown high efficacy on sperm suppression. However, the former was the result of a collaboration between two pharmaceutical industries that have withdrawn from this field of research, and the WHO study was interrupted due to a high number of side effects, most likely the result of high-dose combinations of both hormones [105]. Therefore, it seems that new types of molecules should be designed and combinations with newer progestins with SARMs may be a better avenue for future development.