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Your First Choice Journal in Men's Health
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pISSN 2287-4208  eISSN 2287-4690
    World J Mens Health. 2024 Jul;42(3):487-501. English.
    Published online Jan 02, 2024.
    https://doi.org/10.5534/wjmh.230118
    Copyright © 2024 Korean Society for Sexual Medicine and Andrology
    Review

    Advances in Male Contraception: When Will the Novel Male Contraception be Available?

    Jongwon Kim,1 Byeongchan So,1 Yongki Heo,1 Hongyun So,1,2,3 and Jung Ki Jo1,4
      • 1Department of Medical and Digital Engineering, Hanyang University, Seoul, Korea.
      • 2Institute of Nano Science and Technology, Hanyang University, Seoul, Korea.
      • 3Department of Mechanical Engineering, Hanyang University, Seoul, Korea.
      • 4Department of Urology, College of Medicine, Hanyang University, Seoul, Korea.
    • Correspondence to: Jung Ki Jo. Department of Urology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea. Tel: +82-2-2290-8599, Fax: +82-2-2290-4057, Email: victorjo38@hanyang.ac.kr
      Correspondence to: Hongyun So. Department of Mechanical Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea. Tel: +82-2-2220-2901, Fax: +82-2-2220-3129, Email: hyso@hanyang.ac.kr
    Received April 28, 2023; Revised July 18, 2023; Accepted July 26, 2023.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Many contraceptive methods have been developed over the years due to high demand. However, female contraceptive pills and devices do not work for all females due to health conditions and side effects. Also, the number of males who want to actively participate in family planning is gradually increasing. However, the only contraceptive options currently available to males are condoms and vasectomy. Therefore, many male contraceptive methods, including medication (hormonal and non-hormonal therapy) and mechanical methods, are under development. Reversibility, safety, persistence, degree of invasion, promptness, and the suppression of anti-sperm antibody formation are essential factors in the development of male contraceptive methods. In this paper, male contraceptive methods under development are reviewed according to those essential factors. Furthermore, the timeline for the availability of a new male contraception is discussed.

    Keywords
    Azoospermia; Contraception; Contraceptive agents; Drug development; Spermatogenesis; Sterilization

    INTRODUCTION

    Various contraceptive methods have been devised over a long period of time. A United Nations (UN) report published in 2019 provides estimates for the use of a variety of contraceptive methods [1]. Statistics show that 1.1 billion of the 1.9 billion females (or partners) of reproductive age (15 to 49 years) living in the world could physically use contraception, and 84% of them are currently using one or more methods [1].

    Many contraceptive methods targeting females have been developed during the past few decades. However, some of those methods can adversely affect the user’s sexual function, and some couples cannot use them due to health conditions [2]. Also, many males want to be actively involved in family planning. In a survey about new male contraceptive methods, many males responded that the responsibility for contraception should be shared between sexes [3].

    Fig. 1 shows trends in the use of various contraceptives reported in the aforementioned UN document [1]. Although 27.3% of all couples, or 252 million couples, choose male contraception, the only two reliable contraceptive options for males are condoms and vasectomy [4, 5]. Among couples using male contraception, 92.2% depend on male condoms. In other words, males have significantly fewer contraceptive options than females. Therefore, research and development are needed for male contraception methods.

    Fig. 1
    Percentage distribution of contraception used globally by females of reproductive age (15–49 years) in 2019. Caption: Percentage distribution of contraceptive methods (Left), percentage distribution of male contraceptive methods (Right). The withdrawal method is unreliable for contraception due to its high failure rate. Therefore, it is difficult to consider it as an actual contraceptive option for males.

    In this paper, we discuss the male contraception methods currently available and those in development and describe the characteristics and limitations of each method. We also explain the necessary conditions for male contraception and discuss when new male contraception options will become available.

    FACTORS TO BE CONSIDERED WHEN DEVELOPING NEW MALE CONTRACEPTION METHODS

    All methods of contraception must consider both medical and commercial factors. One important factor is reversibility because family planning needs change over time, and divorce rates are high. An additional factor to be considered in male contraception is the fate of sperm that cannot be excreted. Because mature sperm are not present in the body prior to puberty, after the individual's central immune system is established, sperm can be recognized as an antigen by the adult male immune system [6]. For this reason, males who have undergone vasectomy often produce anti-sperm antibodies (ASAs). It is also important to consider the immediacy of the effects of a contraceptive. As the duration between beginning contraceptive use and contraceptive effect becomes longer, the need to use multiple contraceptive options increases. Safety is another important factor that has prevented many male contraceptive methods from being released. Unresolved problems that cause side effects such as pain, sperm granuloma, or congestion in the epididymis often lead to product discontinuance in the clinical trial stage. Finally, the invasiveness of the method is also important. In Table 1, the various methods of contraception described in this paper are organized according to those essential factors.

    Table 1
    Essential factors in the development of male contraceptive methods

    AVAILABLE MALE CONTRACEPTION METHODS

    1. Condoms

    Condoms are the oldest form of male contraception (Fig. 2E). They physically prevent sperm from reaching the egg when worn correctly on an erect penis during sexual intercourse. Their high success rate, 99.8% when used appropriately for one act of intercourse, is the major advantage of condoms. In addition, studies have shown that condoms are highly effective in preventing sexually transmitted infections such as HIV because they block direct body fluid contact during intercourse [7].

    Fig. 2
    Male contraception options that are currently available or in development. (A) Hypothalamic-pituitary-testicular axis feedback control process through exogenous administration of androgens and progestins in hormonal contraception, (B) various contraceptive methods targeting the vas deferens, (C) extra-body control of fertility using heat or ultrasound, (D) various non-hormonal contraceptive drugs that affect fertilization after spermatogenesis and maturation, (E) male condom. FSH: follicle stimulating hormone, LH: luteinizing hormone, GnRH: gonadotropin-releasing hormone.

    However, when the success rate is considered in terms of cumulative risk (the likelihood that pregnancy or disease transmission will occur at least once given the likely number of risk exposures), the contraceptive effect of condoms can fall to as low as 18% over only 100 exposures [8]. This large difference in effect is caused by incorrect use or condom failure (slips, breakage, etc.) [9]. In addition, improperly fit condoms can cause delayed ejaculation [10]. Therefore, condoms are not a reliable contraceptive option for all males.

    2. Vasectomy

    Vasectomy is an outpatient surgery performed under local anesthesia that blocks the movement of sperm by cutting or blocking the vas deference, the passage for sperm out of the penis. Males who have undergone vasectomy typically develop azoospermia within about 4 months of surgery [11]. Therefore, the general recommendation is to perform a semen analysis 3 months after vasectomy or after 20 or more ejaculations and to use another method of contraception until azoospermia is verified.

    One disadvantage of vasectomy is that it is not easily reversible. The procedure to recanalize the vas deferens after vasectomy is not as simple or successful as vasectomy. The patency rate of vasectomy recanalization is greater than 99%, but the rate of successful pregnancy following the procedure is much lower [12]. In addition, the duration between the vasectomy and its reversal affects the success rates of restoration and pregnancy. If the interval from vasectomy to restoration was less than 3 years, the restoration success rate and pregnancy success rate were 97% and 76%, respectively. However, durations of 3 to 8 years showed respective rates of 88% and 53%, those of 9 to 14 years had rates of 79% and 44%, and durations of 15 years or more had rates of 71% and 30% [13]. Despite vas deferens recanalization, the low pregnancy rate is due to the presence of ASAs [14], which are found in 50% of males who have undergone vasectomy [6]. In addition, complications such as bleeding, hematoma, infection, and acute epididymitis can occur during or early after the procedure [15].

    Vasectomy is a suitable contraceptive method for males certain that they do not want to cause a pregnancy for the rest of their lives. However, the percentage of males seeking to reopen their vas deferens after vasectomy was approximately 3.5% in 2015 [16], and that number is likely to increase due to lifestyle changes. Therefore, additional studies are needed to provide more contraceptive options for males.

    MALE CONTRACEPTION IN RESEARCH AND DEVELOPMENT

    This section reports various contraceptive methods for males that are not yet available and describes the characteristics and limitations of each method.

    1. Male hormonal contraception

    As shown in Fig. 2A, the basic mechanism of male hormone contraception is to regulate the hypothalamic-pituitary-testicular axis feedback loop through an exogenous administration of androgens and progestins. Exogenously administered androgens bind to the androgen receptor in the brain and inhibit the production of gonadotropin-releasing hormone (GnRH), follicle stimulating hormone (FSH), and luteinizing hormone (LH), hindering testosterone (T) synthesis and spermatogenesis within the testes. Progestins have an androgen-like negative feedback effect via the brain's progesterone receptor, so including progestins as part of a male contraceptive regimen speeds the suppression of FSH and LH [17]. Many studies have been conducted to use this mechanism to inhibit sperm production, with clinical trials of hormonal male contraception first occurring in the 1970s [18, 19, 20, 21].

    Many male hormonal contraceptives that use androgens (mainly T) and progestins alone or in combination to suppress sperm or GnRH production are in the clinical trial stage. Table 2 lists the androgens and progestins used in previous and current hormonal male contraceptive clinical trials according to the method of administration.

    Table 2
    Androgens and progestins used in prior or currenta hormonal male contraceptive clinical trials

    Hormonal male contraceptives are being studied to reduce their risk of side effects and increase the bio-transmission rate or contraceptive efficacy through pharmaceutical combinations of the various androgens and progestins listed in Table 2. Such drugs have proved to be very effective against conception while taken. However, uncertainties about whether high-dose androgen exposure will increase the risk of developing cancer or cardiovascular disease remain unresolved. In addition, various side effects, such as pain, acne, weight gain, mood change, libido change, behavioral change, and fatigue, have been reported in efficacy studies. Given that unwanted pregnancies pose no direct physical risk to males, it is unclear whether males will use a product with those side effects. It is also important to note that the contraceptive effect of these medications does not appear immediately. Because the contraceptive mechanism affects the spermatogenesis process, which takes 72 days to complete, the onset of a complete contraceptive effect is theoretically delayed by more than 2 months. In fact, in the various efficacy studies conducted to date, the average time to achieve the sperm inhibition threshold ranged from 75 to 170 days [17]. Couples would have to deal with the inconvenience of using other contraceptive options during that time. As shown in Table 2, the administration methods for hormonal contraception (oral, injection, transdermal, and implant) are less invasive than surgery. However, the frequency of administration (daily or weekly) must be maintained consistently throughout the desired period of time. In addition, setting a consistent and appropriate dose, which is vital for commercialization, is very difficult because the contraceptive effect differs by individual and even by race [22]. For male hormonal contraception to be an ideal method, those issues need to be addressed in follow-up studies.

    2. Non-hormonal contraception

    Non-hormonal contraception targets proteins that affect sperm production or sperm function. The effectiveness of non-hormonal contraceptive methods depends primarily on the potency and specificity of the inhibitors for their target proteins. Non-hormonal male contraceptive drugs can act during the process of sperm formation, maturation, migration within the female reproductive system, or fertilization of oocytes. Contraceptive drugs targeting each of those steps are listed in Fig. 2D. Almost all non-hormonal male contraceptives described in this section are in the preclinical stage.

    1) Retinoic acid pathway YCT-529

    It has long been established that retinoic acid (RA), a metabolite of vitamin A, is responsible for spermatogenesis [23, 24, 25]. Because RA is not transported through blood serum, it is normally synthesized from vitamin A within the target tissues. Metabolic conversion of RA synthesized in the testes is mediated by alcohol dehydrogenase and aldehyde dehydrogenase, and the metabolites produced are RA receptors (RARs) and retinoid X receptors, which are intracellular receptors that regulate gene expression [26]. Blocking the biosynthesis of RA or its binding to RAR has been demonstrated to provide male contraception in RAR-knockout animal models [27]. A team led by Professor Gunda Georg at the University of Minnesota, USA, developed YCT-529, an oral contraceptive for males that restricts RA synthesis by blocking α-RAR, and a human clinical trial was planned for the fourth quarter of 2022 [28]. YCT-529 significantly decreased sperm counts and was 99% efficient in preventing conception when given orally to male mice for 4 weeks. It had no observable side effects, and 4 to 6 weeks after administration was stopped, the mice were again able to induce pregnancy [28].

    2) Bromodomain testis-specific protein inhibition

    Bromodomain testis-specific proteins (BRDTs), a subfamily of BET proteins consisting of BRD2, BRD3, BRD4, and BRDT, regulate testis-specific gene expression levels and play an important role in sperm survival [29]. Loss of BD1 and BD2 in mice results in infertility, indicating that BRDT could be a target for male contraception [29, 30]. BET inhibitors such as JQ1 inhibit BRDT function in sperm and spermatozoa and induce complete and reversible contraceptive effects [31]. However, the short half-life and rapid metabolism of JQ1 in the body, along with the fact that JQ1 binds with a higher affinity to BRD4 than BRDT, have impeded its development as a contraceptive [31]. Therefore, efforts are underway to find new inhibitors of BRDT [30, 32]. A study reported in 2022 that CDD-787 and CDD-956 show better selective binding than JQ1 and can be used as excellent BET BD1 inhibitors [32].

    3) EPPIN/EP055

    Epididymal protease inhibitor (Eppin) is a male-specific protein found on the surface of sperm. In 2004, a reversible contraceptive effect was reported in monkeys immunized with Eppin [33]. Eppin binds to seminal plasma protein semenogellin-1 (SEMG1) causing inhibition of sperm motility [34]. Therefore, research to develop male contraceptive methods that mimic EPPIN-SEMG1 binding through small-molecule inhibitors is ongoing. EP055 is an organic compound that inhibits sperm motility by binding to EPPIN on the surface of sperm. In a recent experiment with monkeys, EP055 reduced sperm motility to about 20%, and the contraceptive effect was reversibly restored within 18 days after cessation of use [35]. Thus, EP055 could become a reversible and short-lived male contraceptive. However, to be an effective contraceptive method, a compound with higher affinity for EPPIN than EP055 and a half-life longer than 12 minutes is needed.

    4) Sperm ion-channel targets

    In the late 1980s, studies first reported that calcium signaling regulates the sperm acrosomal response and motility [36, 37, 38, 39]. Research based on that finding confirmed the existence of various sperm ion channels. One of the most widely studied sperm-specific ion channels is Catsper, which is expressed only in mature sperm [40]. After ejaculation, mature mammalian sperm go through several physiological steps that enable fertilization within the female reproductive tract, and all those steps require the regulation of calcium ion concentrations inside sperm cells [41, 42]. Therefore, studies to induce contraceptive effects by regulating Catsper, which is activated through intracellular alkaline pH, or by selectively removing four Catsper ion-channel members (Catsper 1–4) through gene deletion are being conducted [43, 44].

    For Catsper to have full activity, conditions such as intracellular alkalinization, the presence of progesterone, and membrane depolarization are needed [45, 46, 47, 48]. Therefore, Kspers (Slo3, Slo1), which are involved in regulating membrane potential by releasing potassium ions from within sperm cells, are potential contraceptive targets that play an important role in activating Catsper channels [49]. The Slo3 channel directly contributes to an increase in the intracellular calcium concentration by expelling potassium ions from the cell, activating the Catsper channel [50]. The Slo3 protein is encoded by the KCNU1 gene, and mice lacking KCNU1 are infertile, indicating that Slo3 could have an important effect on male fertility [51, 52]. The Slo1 channel, encoded by the KCNMA1 gene, is another potential contraceptive target [49]. However, cases of male infertility in which KCNU1 and KCNMA1 are intact but Ksper-deficient have also been reported [53]. Further studies on the Ksper expression mechanism are required.

    Whereas Ksper (Slo3, Slo1) is a channel that releases potassium ions from sperm cells, Na,K-ATPase α4 moves potassium ions into the cell, making it another important target for male fertility [36]. Na,K-ATPase α4 is encoded by ATP1A4 in both mice and humans [54]. Because complete infertility occurs in male mice from whom Na,K-ATPase α4 has been removed, it is currently being evaluated as a potent male contraceptive target.

    5) Adenylate cyclase inhibitors TDI-10229, TDI-11861

    Adenylate cyclase is a membrane-bound enzyme found in most cells that produces cyclic adenosine monophosphate (cAMP) [55]. Calcium ions introduced into sperm cells through Catsper as described above trigger the activation of soluble adenylate cyclase (sAC) to convert ATP to cAMP. The generated cAMP activates PKA and tyrosine kinase, which results in extensive tyrosine phosphorylation that affects sperm capacitance and hyperactivation [56]. Therefore, targeted disruption of the sAC gene causes severe sperm motility defects, resulting in male infertility [57]. In 2021, TDI-10229, a chemical inhibitor of ADCY10-encoded sAC, was developed and shown to inhibit human sperm motility and prevent capacitation and acrosomal reactions in mammalian sperm [58, 59]. However, TDI-10229 has a short residence time for sAC protein, making it difficult to confirm sAC function in vivo. A follow-up study in 2023 reported TDI-11861, a sAC inhibitor with a longer residence time and better drug-like properties [60]. It has the advantage of being ~50 times more potent, ~15 times more potent in cellular assays, and having a ~200 times longer residence time on sAC proteins than TDI-10229 in vitro. Completely reversible contraception was induced in a mating study of 52 pairs of mice treated with a single injection of TDI-11861 (50 mg/kg). However, the effect of TDI-11861 (50 mg/kg) gradually decreased after 2.5 hours. A longer effective duration is needed for it to be used as a contraceptive in human males because human sperm can survive for several days after passing through the cervix [61]. This conceptual research indicates the potential for developing male contraceptives by temporarily suppressing sperm motility.

    6) Substance targeting the Sertoli cell-germ cell interaction

    Adjudin, a contraceptive candidate that forms non-functional sperm by interfering with attachment to Sertoli cells, was first described in 2001 [62]. When Adjudin was administered to rats, 100% infertility was induced for up to 5 weeks after treatment without hormonal changes, and fertility was restored at 11 weeks, confirming the possibility of reversible contraception [62, 63]. Adjudin also showed completely reversible infertility in rabbits and dogs [64, 65]. However, in a 29-day study of 10 male mice, 3 showed side effects of liver inflammation or signs of skeletal muscle atrophy [66]. Accordingly, researchers conjugated FSH-β mutants with Adjudin to solve the toxicity problem by reducing the dose required for contraception and delivering Adjudin directly to Sertoli cells. This method currently has the limitation of high cost [67].

    Other potential drug candidates include gamendazole and H2-gamendazole, which are indazole carboxylic acid derivatives similar to Adjudin [68, 69]. However, experiments with rats have shown problems such as poor reversibility and toxicity [68]. Further studies are needed to improve the reversibility of those drugs and find an appropriate range of therapeutic dosage.

    CDB-4022, an indenopyridine that inhibits fertility by inducing the production of immature sperm, is also a potential contraceptive. In experiments conducted on animals such as monkeys, horses, and cats, sperm production was reversibly controlled without obvious side effects [70, 71, 72].

    7) Testis-specific serine/threonine kinase

    In 2007, the possibility that testis-specific serine/threonine kinase (TSSK), which is involved in spermatogenesis, could be an important contraceptive target was suggested [73]. TSSK1, TSSK2, TSSK4, and TSSK6, which are members of the TSSK family, are being studied in gene deletion studies [74]. Mice from which those genes were removed developed malformed sperm, resulting in infertility [74, 75, 76]. The possibility of reversible contraception has been reported for TSSK3 knockout mice [77]. Studies of the TSSK family suggest that they are regulated developmentally during spermatogenesis and expressed post-meiosis only in germ cells. They also indicate that inhibiting TSSK kinase activity with certain drugs could reversibly inhibit spermatogenesis and fertilization.

    8) Plant-extract contraceptive ingredients

    In 2021, the contraceptive effect of triptonide, a natural compound extracted from Tripterygium wilfordii, was reported [78]. Because triptonide binds junctional plakoglobin with a higher affinity than spermatid maturation 1 (Spem1), it interferes with the normal interaction between junctional plakoglobin and Spem1, resulting in sperm deformity and male infertility. Experiments with rats and monkeys showed completely reversible contraceptive effects, and triptonide is thus being evaluated as a compound with potential for male contraception.

    Justicia gendarussa is used as an anti-inflammatory, antibacterial, and antifungal agent in Jamu, a traditional Indonesian medicinal treatment, as well as to treat arthritis and cancer [79, 80, 81]. Studies have been conducted on the contraceptive properties of this plant based on its use by Papuan tribes to reduce male fertility [82, 83]. The main components that show contraceptive effects are gendarusin A and gendarusin B [84]. They have been reported to reversibly inhibit the activity of sperm hyaluronidase, an enzyme that promotes sperm penetration during in vitro fertilization. There are reports that fertility is restored within 30 days, but additional research on the mechanism of action and clinical trials are required [85].

    In 2011, an attempt was made to determine the contraceptive effect of curcumin, which is known to have antibacterial, antiviral, anti-inflammatory, and anticancer properties [86]. Curcumin is a component of turmeric, which has a yellow color due to a polyphenol pigment known as curcuminoid, and it showed a reversible contraceptive effect in an in vitro experiment involving male rats [86]. Both human and murine sperm showed significantly inhibited, concentration-dependent acrosome reactions upon incubation with curcumin. Clinical trials on human males have not been conducted, and the exact contraceptive mechanism of curcumin has not been identified.

    3. Contraceptive methods targeting the vas deferens

    This section addresses contraceptive methods targeting the vas deferens (Fig. 2B).

    1) Spermatic duct valve

    In 2017, the German-based company Bimek developed a male contraceptive device that can be turned on and off using a switch attached to the vas deferens [87]. Unlike vasectomy, which is nearly irreversible once performed, this technology allows contraception only when necessary. The procedure is performed under local anesthesia by a urologist in about 30 minutes. After the switch is installed, it takes 3 to 6 months for the sperm to be completely removed from the semen [87]. However, because researchers are still seeking volunteers for clinical trials of the technique, its actual contraceptive effect has not been demonstrated in humans. In addition, because the operating mechanism is the same as that of vasectomy, long periods of obstructing the vas deferens might increase the risk of serious side effects [15].

    2) Vas-occlusion gel

    In the 1970s, Professor Sujoy K. Guha of the Indian Institute of Technology devised a method for destroying sperm traveling through the vas deferens using styrene maleic anhydride (SMA), experimentally demonstrating its contraceptive effect in 1979 [88]. Reversible inhibition of sperm under guidance (RISUG), devised by Professor Guha, is based on SMA anhydride dissolved in 99.9% pure dimethyl sulfoxide (DMSO) [89]. The mechanism of contraception is as follows. First, DMSO and SMA are mixed and injected into the vas deferens in a minimally invasive procedure. The injected solution partially blocks sperm migration by partially blocking the inside of the vas deferens. It also lowers the pH level inside the vas deferens and creates a positive charge that causes sperm inactivation [89, 90]. As a result, the acrosome of the sperm head, which is negatively charged, is destroyed, and the ovum's transparent zone is not dissolved, making it difficult for sperm to penetrate [91]. The injected RISUG is then dissolved at high pH by a second injection of 200 to 500 µL of DMSO or NaHCO3DMSO and excreted through the urethra [16, 92]. Both DMSO and NaHCO3DMSO can dissolve SMA under alkaline conditions [93]. Phase 1 and 2 trials of RISUG were published in 1993 and 1997, respectively [94, 95]. In 2002, the test was stopped due to toxicity, but it was resumed in 2003 as an extended phase 3 trial [96]. The results have shown considerable potential, with administration through a single injection, complete reversibility, and 96.7% efficacy after 6 months [92, 97].

    VASALGEL™ has been under development since 2010 by the Parsemus Foundation of the United States, which purchased the international rights to RISUG technology, and is a modified form of RISUG. Its mechanism is similar to RISUG, but it has important differences in composition and functionality. Because RISUG is composed of SMA anhydride, it can be hydrolyzed in aqueous conditions. However, VASALGEL™ is made of SMA acid, so it has a less complicated production process and long-term stability without the risk of hydrolysis [90]. Like RISUG, VASALGEL™ is injected into the vas deferens to block sperm migration. A single injection provides contraception for 12 months [90, 98]. Clinical trials of VASALGEL™ on rabbits and rhesus monkeys have yielded significant effects, but results from clinical trials in humans are lacking.

    Contraline, a competitor to Parsemus founded in 2015, is developing ADAM™, which is similar to VASALGEL™. This hydrogel is injected into the vas deferens and can be liquefied and removed at the end of its lifespan. Clinical trials in human males began in 2022 [99].

    3) Intra-vas device

    Complete obstruction of the vas deferens can lead to various side effects, including congestion of the epididymis, painful nodules and sperm granulomas, and ASA production inside the body [15]. Thus, early research into an intra-vas device (IVD) that completely occluded the vas deferens using medical silicone and polyurethane was discontinued due to difficulties in restoring fertility [100, 101]. To improve such a device, research is being conducted to develop an implantable IVD that partially closes the vas deferens in various ways to prevent clogging and the need for spermicidal treatment [102, 103, 104, 105, 106]. Among such devices, a copper-IVD showed a significantly increased ratio of dead sperm to motile sperm after the procedure, compared with the control group, and maintained its contraceptive effect for at least 3 months after surgery; fertility recovery was observed 13 months after surgery [105]. However, explosive release of copper ions and the formation of CuO have been observed on the IVD surface, which greatly increases the risk of biological toxicity and limits the long-term use of the Cu-IVD. An IVD using a polyvinyl alcohol-based cross-linked composite containing nanoparticles of silica and copper ions has been developed to solve the problems of the Cu-IVD [103]. Although copper ion release did not occur before or after IVD insertion in dogs and rabbits, long-term contraceptive efficacy, safety, and reversibility could not be evaluated because the study period was limited to 12 months. Clinical trials in humans lasting 24 to 60 months are needed [103].

    4. Extra-body control of fertility

    This section discusses studies on contraceptive methods that control fertility in vitro by targeting the testicles (Fig. 2C).

    1) Testicular heat transfer contraception

    The spermatogenesis process is temperature dependent and occurs optimally at temperatures slightly below body temperature [107]. Because epididymal sperm and testicular germ cells are sensitive to damage by heat, contraceptive methods are being developed to suppress sperm production through the photothermal effects of biomaterials. When gold nanorods modified with α-lipoyl-ω-hydroxyl poly(ethylene glycol) are directly injected into the testis and irradiated with an 808 nm infrared laser, the temperature inside the testis increases [108]. The possibility of using such nanorods for reversible contraception was confirmed in experiments on rat testes. However, the severe pain caused by near-infrared rays, secondary damage to the skin, and the non-degradability of nanoparticles that can potentially cause toxicity has limited photothermal male contraception in clinical trials. To solve those problems, a method of contraception that incorporates magnetic hyperthermia has been proposed to convert electromagnetic energy into heat [109, 110]. Iron oxide nanoparticles, which are being studied as a platform for targeted drug delivery and tumor therapy, can inhibit spermatogenesis by precisely heating the testes. In experiments with male mice, the 37 ℃, 40 ℃, and 43 ℃ groups gradually recovered reproductive function and repaired tissue damage within 60 days, confirming reversibility. Permanent damage occurred in the 45 ℃ group [110]. The effect on humans has not been verified, but follow-up studies are of interest because the method prevents skin damage and effectively forms the thermal environment necessary for topical targeting.

    2) Ultrasound

    In 1975, a study first reported the contraceptive effect of ultrasound applied to the testicles of rats [111]. Subsequent studies have reported that exposing the testicles to ultrasound for 5 to 10 minutes can cause the loss of spermatogenic cells, so ultrasound has potential as a contraceptive method in monkeys, dogs, cats, and humans [102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115]. Based on those findings, various male contraceptive methods using ultrasound have been tested. A study conducted in 2012 replicated the experimental methods of early research on ultrasound contraception in the 1970s [116, 117]. The results of exposing the testes of rhesus macaques to ultrasound in two ways (through a saline-filled cup or directly to the scrotum) are noteworthy [116]. With both methods, exposure to 2.5 W/cm2 ultrasound for 30 minutes, 3 times a week or every other day was followed by a significant decrease in sperm count for at least 7 weeks. Between weeks 7 and 9, sperm counts recovered rapidly to previous levels in all experimental groups. An important finding in this experiment was that more significant results were obtained in monkeys using the cup method. This is probably because the mechanism by which ultrasound shows a contraceptive effect causes an increase in testicle temperature. The results of experiments showing that ultrasound contraception is more effective for subjects with small testicles are likely to be due to insufficient increase of temperature in the testicles of monkeys with a larger testicular mass [116]. No side effects have been noted.

    WHEN WILL NEW MALE CONTRACEPTION BE AVAILABLE?

    Fig. 3 summarizes the development of all male contraceptive drugs and devices described in this paper. Despite more than half a century of research, no new male contraceptive methods have appeared on the market since condoms. Currently, the contraceptive methods closest to commercialization are hormonal drug therapy and vas deferens occlusion gel. To be commercialized, preclinical stages, including animal experiments, and phase 1, 2, and 3 clinical trials for humans are required. The U.S. Food and Drug Administration usually requires a larger number of large-scale clinical trials for drugs than for devices. It takes an average of 10 years to bring a new drug to market, compared with the 3 to 7 years required to commercialize a new medical device [118, 119]. Thus, if current contraceptive development proceeds smoothly, new forms of male contraception, hormonal contraception and vas deferens occlusion gels, can be expected to reach the market before 2030.

    Fig. 3
    Research duration and stage of male contraceptive methods currently under development. Bars represent the period since the concept was first presented for each method in development. “Hormonal methods” refers to male-targeted hormonal methods only. RISUG and hormonal methods, which are in phase 3 clinical trials, are the male contraceptive methods closest to commercialization. RISUG: reversible inhibition of sperm under guidance, TSSK: testis-specific serine/threonine kinase.

    CONCLUSIONS

    Currently, most contraceptive methods are commercialized for females, with the only commercialized methods for males being condoms and vasectomy. Nonetheless, male contraceptive methods continue to be developed using hormone therapy, non-hormonal therapy, vas deferens targeting, and extra-body control. Factors that must be considered in male contraception include reversibility, safety, persistence, degree of invasion, and the suppression of ASA formation. Although hormonal contraception and vas deferens occlusion gels are the contraceptive methods closest to commercialization, a novel male contraceptive method that includes all the factors mentioned above is needed.

    Notes

    Conflict of Interest:The authors have nothing to disclose.

    Funding:This work was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT of the Republic of Korea (No. NRF-2021R1C1C1010836).

    Ministry of Trade, Industry and Energy (MOTIE) funded by the Korea Planning & Evaluation of Industrial Technology (KEIT) (No. RS-2023-00256247).

    Author Contribution:

    • Conceptualization: JKJ.

    • Investigation: JK, BS, YH.

    • Visualization: JK.

    • Supervision: HS, JKJ.

    • Writing - original draft: JK.

    • Writing - review & editing: JK, HS, JKJ.

    • Final approval: All authors.

    Acknowledgements

    None.

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    MeSH Terms
    Antibody Formation
    Azoospermia
    Condoms
    Contraception*
    Contraceptive Agents
    Drug Development
    Family Planning Services
    Female
    Humans
    Male*
    Review
    Spermatogenesis
    Sterilization
    TimeLine
    Vasectomy
    Metrics
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