• Sara

What if men could do it too?

Unlike women, who today carry most of the burden of contraception, men have limited birth control options. Indeed, only 14% of contraception methods used worldwide are for males and no pharmaceutical birth control method exists so far[1]. Today only two effective contraceptive options are available: condoms and vasectomy. A recent study presented at the American Chemical Society (ACS) has described an effective alternative to these methods: a non-hormonal contraceptive molecule called YCT529.


Condoms

Condoms are considered the oldest method of contraception, but it was not until 2004 that the specifications for condom manufacturing were established by the WHO[2]. The biggest advantage of condoms is the protection against sexually transmitted diseases, but unfortunately, they have a failure rate ranking between 2 and 18%, making them less effective than many women’s options[3].


Vasectomy

Vasectomy is considered a definitive male sterilization procedure. It consists in disrupting the sperm’s flow of the vas deferens from the proximal to the distal end[4]. It is a minimally invasive technique of high efficiency with failure rates lower than 1% and low complication rates[5], usually performed in the office setting by urologists with an assistant. As this technique is poorly reversible, it is not suitable to a large portion of the population.


Hormonal contraceptive

To address male contraception, it is first important to define the spermatogenesis process.

Spermatogenesis

It is the process of sperm production, which takes place inside coiled hoses in the testes (Figure 1).




Figure 1: The spermatogenesis process.


It all starts with the Spermatogonia, who undergoes 2 rounds of special cellular division (meiosis) giving birth to cells called spermatids. These can now develop a head and a tail to mature into sperm[6].











This process is highly regulated by a hormonal complex. Some clinical studies have evaluated the efficacy of targeting these hormones as a way to disrupt spermatogenesis[7]. However, some of them had to be stopped because of undesirable side effects, such as irritability, mood changes and even depression[8].


Non-hormonal contraceptive

An interesting way to address these side effects is to target non-hormonal pathways important to spermatogenesis. It has been known since 1925 that vitamin A is important for spermatogenesis[9]. Indeed, once inside the tissues, vitamin A is converted into its active derivative, retinoic acid, which binds to its receptor RAR-α[10], thus activating a pathway with an important role in the initiation of spermatogenesis at puberty, and its maintenance in adults[11]. Following this logic, several drugs with nonhormonal targets have been shown to cause complete and reversible infertility in animal models, with low toxicity. Several molecules have been shown to disrupt vitamin A’s regulation of spermatogenesis.


  • Compound WIN 18,446

This compound acts upstream of RAR-α: it targets an enzyme called aldehyde dehydrogenase 1a2 (ALDH1a2), responsible for the conversion of vitamin A into retinoic acid. Scientists show that WIN 18,446 inhibits spermatogenesis by inhibiting retinoic acid production by ALDH1a2[12].

  • Compound JQ1

This molecule targets the BRDT protein, responsible for gene expression regulation through two special protein regions, called bromodomains, that bind histones, the proteins that chromosomal DNA wraps itself around. JQ1 blocks BRDT from binding histone proteins causing reversible infertility in male mice[13].

  • Compound H2- gamendazole

Scientists identified first a compound called lonidamine, an anticancer molecule developed in the 1970s. They showed that this molecule can inhibit spermatogenesis but had elevated toxicity to the liver and kidneys. Scientists identified gamendazole, an analog to Ionidamine, and showed that a single oral dose of the compound makes male rats infertile after three weeks. They also showed that gamendazole disrupts the relationship between developing sperm cells and another type of cell, called a Sertoli cell (responsible for sperm transportation and nourishment as they mature). Without this, spermatids release prematurely from the tubules before they can become mature sperm cells[14]. A chemical modification to gamendazole, transforming it into H2- gamendazole have been tested in several types of animals, including rabbits and monkeys. Results show that the molecule doesn’t have any of the toxicity issues that lonidamine has[15].

  • Compound BMS-189453

This compound is an antagonist of RAR-α which means it can inhibit its action, thus disrupting a late event in spermatogenesis, which leads to an inhibition of sperm production[16]. Indeed, maturing spermatids must line up along the edge of tubes in the testis for release. However, due to this compound they are not aligned properly and thus they cannot exit the testes.


A recent study presented at the American Chemical Society (ACS) has described an effective alternative to these methods. Indeed, scientists have developed a non-hormonal contraceptive: molecule YCT529[17] (Figure 2).




Figure 2: Compound YCT529 chemical structure






  • Compound YCT529

YCT529 is another oral RAR-α antagonist, that has been shown great efficacy to disrupt spermatogenesis. YCT529 is formulated as a sodium salt. The study shows that inhibiting RAR-α gene in male mice makes them sterile, without any obvious side effects. The specificity of this compound and its lack of side effects is that instead of inhibiting all three members of the RAR family (RAR-α, -β and -γ) to cause reversible sterility in male mice[18] (Figure 3), YCT529 selectively inhibit RAR-α in cells.


YCT529 mechanism of action

Figure 3: YCT529 mechanism of action


Male mice are treated orally for 4 weeks with YCT529. Scientists report that this leads to a huge reduction in sperm counts showing a 99% effectiveness in preventing pregnancy, without any observable side effects. The mice could father pups again 4-6 weeks after they stopped receiving the compound (Figure 4).

Given its effectiveness in mice, YCT529 will begin testing in human clinical trials in the third or fourth quarter of 2022. YCT529 may provide an attractive alternative to other male contraceptive methods if proven safe and effective in humans.




Figure 4: Treatment with YCT529 prevents pregnancy.



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References [1] Kanakis GA, et al., Hormones (Athens);14(4):598-614, 2015 [2] Page ST, et al., Endocr Rev 29: 465-493, 2008 [3] Torrice M et al, C&EN west coast news bureau, Science & technology, 2012 [4] Stormont G, et al., Vasectomy, StatPearls, 2022 [5] Barone et al., Urol. 19;4:10, 2004 [6] Torrice M et al, C&EN west coast news bureau, Science & technology, 2012 [7] Mommers E, et al, J Clin Endocrinol Metab 93: 2572-2580, 2008 [8] Nieschlag E J. Reproduktionsmed. Endokrinol; 8 (Special issue 1), 227-238, 2011 [9] Wolbach SB, Iet al., J Exp Med.;42(6):753-77, 1925 Nov 30 [10] Aileen Helsel, et al., Current Opinion in Endocrine and Metabolic Research, V 6 (p 1-6), 2019 [11] Vernet N, et al., Endocrinology. 147:96–110, 2006 [12] Amory, J. K.; et al., Journal of Andrology, 32(1), 111–119, 2011 [13] Martin M. et al., Cell, Volume 150, Issue 4, Pages 673-684, 2012 [14] Tash, J. S.; et al., . Biology of Reproduction, 78(6), 1127–1138, 2008 [15] Raymond K. Hau, et al., Journal of Pharmacology and Experimental Therapeutics July 2, 2022 [16] Chung SS, al., Endocrinology;152(6):2492-502, 2011 [17] https://www.acs.org, non-hormonal-pill-could-soon-expand-mens-birth-control-options, 2022 [18] BioRender.com

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