Barrier contraception without a condom
Anna Petrenko, "Biomolecule"
"I avoided those women who by the birth of a child [... you could tie me up.
However, maybe there were children [....], but I pretended as if they did not exist."
Leo Tolstoy. Kreutzer Sonata
In the world of contraceptive methods, the deepest injustice reigns against men. For them, unlike women, there is no long-term reversible and reliable contraceptive. However, as the researchers say, the first such contraceptive may appear on the market in the near future. About what methods were used before and what methods are being developed now – in this material!
The use of female contraceptives has become so widespread that even environmentalists are sounding the alarm: fish will die from synthetic estrogens entering reservoirs together with sewage [1]. But, despite the massive use and availability of contraception, almost half of all pregnancies, even in the richest countries, are unplanned [2].
About 80% of men believe that women and men should be equally responsible for making decisions about contraception [3]. In addition, despite all the advantages of condoms, including those related to the prevention of sexually transmitted diseases, up to 50% of men would like to use other methods of reversible contraception. If they were [4, 5].
Condoms
Since the XIX century, the condom has been the most popular method of contraception in the world.
The first mention of using a condom dates back to the ancient Greeks and Romans. However, condoms similar to modern ones appeared much later – in the XVI century.
The Italian anatomist and physician Gabriele Falloppio, who created the treatise De Morbo Gallico ("French disease", that is, syphilis) in 1564, proposed to wrap a linen cloth soaked in a chemical solution around the penis to protect against syphilis.
In the XVII century in England, condoms were already used from the shell of the intestines of sheep or from the bladder, both of their own manufacture and brought by merchants from other countries. In Japan, at that time, thin leather products were used.
The circumstances of the appearance of the word condom are shrouded in darkness. The most common legend is about a certain Dr. Charles Condom at the court of Charles II, who was given the task to come up with such a specific protection against syphilis for English soldiers. Many people were engaged in collecting information about Dr. Condom, they wrote articles and even monographs (such as "In search of Dr. Condom" by William Krak), but in the end the version was declared untenable. Nevertheless, in 1666, the word condon was mentioned for the first time in the report of the English Fertility Commission. And in its modern form (condom), the word first appeared in the writings of the physician Daniel Turner in 1717 [6, 7]. – Ed
The real breakthrough occurred in 1844, when the American Charles Goodyear created and patented the first rubber condom. Soon after, condoms became a mass-produced product. In 1916, the Polish Jew Julius Fromm patented a method for the production of seamless latex condoms, which were stronger and made of thinner material. Soon they conquered the whole world.
The material of modern condoms is latex, but polyisoprene and polyurethane are also used [8].
A competitor to the condom
Everyday projects for the development of male contraceptives are numerous, but they are still far from entering the market. There are many reasons: sometimes it takes too long to restore fertility, then the drug turns out to be absolutely incompatible with alcohol. And although many projects were closed in the 90s, in just a couple of years a serious competitor to condoms and vasectomy should appear on the market - Vasalgel.
Vasalgel is a non–hormonal drug, and this is one of its main advantages compared not only with existing methods of contraception, but also with those being developed. So, when using hormonal drugs, a reliable level of contraception is achieved after 4 months of use. At the same time, not all patients respond equally to therapy: 20% do not recover fertility after testosterone withdrawal. Also, acne appears against the background of hormonal contraception, body weight changes, mood swings appear and libido may decrease. Therefore, hormonal contraception is not in demand for men.
The mechanism of hormonal contraception
The most obvious way to suppress spermatogenesis is to influence the hypothalamic–pituitary-testicular axis, which regulates the work of the sex glands. Exogenous sex steroids can affect spermatogenesis by disrupting the hypothalamic-pituitary-testicular axis and affecting the testicles – directly or through their metabolites. In men, exogenous administration of progestins reduces the production of GnRH (gonadotropin-releasing hormone), LH (luteinizing hormone) and FSH (follicle-stimulating hormone). Exogenous testosterone additionally suppresses gonadotropins, forming androgens circulating in the blood to maintain secondary sexual characteristics (Fig. 1).
Figure 1. The physiological mechanism of male hormonal contraception. a – Normal positive stimulation from the hypothalamus and pituitary gland, which activate testosterone production and spermatogenesis. Thick black arrows show negative feedback. b – A change in feedback by exogenous androgens (with or without progestin), causing persistent negative feedback and suppression of hormone release from the hypothalamus and pituitary gland. Figure from [15].
Since it takes about 72 days for spermatogony to mature, it will take 2-3 months for the hormonal contraceptive to show full effect. Just as in the case of mechanical methods of contraception, the desired result is reversible azoospermia, that is, when there are no sperm in the ejaculate. Achieving a pronounced form of oligozoospermia is also acceptable, since then the concentration of spermatozoa is < 1 million per 1 ml of ejaculate compared to 14 million per 1 ml of ejaculate for a fertile man. The risk of pregnancy with such a concentration of sperm is approximately 1% per year, and this is the effectiveness of modern female hormonal contraceptives [9].
Intra-Vas Devices, or various "plugs" for the vas deferens, are an alternative to vasectomy, providing reversible sterility. Two types of "plugs" made of different materials have already been tested. Some of the experiments conducted in China turned out to be even very successful: out of 12 thousand participants, almost 98% achieved azoospermia, although it took 18-24 months for this result. Complications during the primary operation are usually few and the removal of the "plug" is carried out under local anesthesia on an outpatient basis. Fertility is restored in approximately 85% of men, but this is a very slow process, taking up to 4 years. There is still a question about the toxicity of aromatic amines contained in the "plug" material [2].
Another contraceptive method, which, unlike those mentioned above, has a bright future, is reversible controlled suppression of sperm (reversible inhibition of sperm under guidance, RISUG). Its development began in India back in the 80s, and now the technology has already been tested in phases I and II of clinical research. It has been shown that a single application of RISUG can provide effective contraception for up to 10 years. Guided by ultrasound guidance, the vas deferens are bilaterally clogged with a sterile styrene and maleic anhydride copolymer. The reversibility of this procedure has already been shown in animal models [10]. No serious side effects have been identified so far, and, unlike vasectomy (ligation or removal of part of the vas deferens leading to complete sterilization), RISUG does not cause the formation of granulomas or an autoimmune response. However, there is concern due to the potential toxicity and teratogenicity of the material used in the application of the technique [2].
"Vasalgel"
Vasalgel is a serious competitor to RISUG and all other methods of contraception. A report on its use on rabbits has just appeared in Basic and Clinical Andrology under the authorship of Donald Waller [11].
"Vasalgel" consists of styrene-alt-maleic acid dissolved in dimethyl sulfoxide. It is injected into the vas deferens in the same way as RISUG, and after implantation forms a hydrogel that tightly fills the lumen of the vas deferens (Fig. 2). This semi-permeable gel barrier mechanically prevents sperm from passing through it. Small molecules and ions present in the sperm in addition to spermatozoa freely cross the "obstacle" [12].
Figure 2. How does Vasalgel work? The drawing is adapted and published with the permission of the Parsemus Foundation.
Scientists have tried two types of gel, differing in the ratio of styrene and maleic acid, and both were effective.
"Vasalgel" quickly caused azoospermia – within 29-36 days after its introduction, the spermatozoa disappeared from the sperm. Of the 12 rabbits, 11 had this effect 12 months after the introduction of the gels, and one animal was found to have oligospermia. The effect on the structure of the ducts is minimal, and after removing the gel, nothing should interfere with the restoration of fertility. The developers are confident that Vasalgel will be able to become the first male contraceptive of its kind, and continue to study it, focusing on the process of removing hydrogel from the ducts. In addition, they believe that the development has advantages over RISUG: the new gel composition is easier to produce and more stable.
The use of the drug "Vasalgel"
About the use of "Vasalgel" in clinical practice, we turned to the developers of an innovative contraceptive.
"In the first quarter of 2017, recruitment for the first clinical trial will begin in the United States, exact data on the date, venue and protocol have not yet been established," said Ben Carlson, head of the press service of the Parsemus Foundation. – Presumably, about 30 candidate patients for vasectomy will participate in the protocol. This choice regarding the profile of participants is due to the fact that we have not yet proved the reversibility of the contraceptive effect of Vasalgel."
According to the official statement of the Parsemus Foundation, the development and research of Vasalgel is a social project not aimed at enriching pharmaceutical companies.
At the end of 2017 or in 2018, a larger clinical trial will be conducted, after which it is planned to bring Vasalgel to the market.
Other perspectives
Non-hormonal drugs include not only mechanical barriers to sperm, but also drugs with active molecules that are not hormones themselves and do not affect hormone secretion.
Despite the fact that no drug has yet entered clinical practice, many approaches may be successful. One of the interesting methods is the effect on the longitudinal muscles of the vas deferens: their contraction can be "turned off", leaving the circular muscles in working condition. Thus, ejaculation does not occur, but there is no negative effect on libido, erection or orgasm. The possibility of using immunological methods is also being considered: some results have been obtained in experiments on immunization against the follicle-stimulating hormone receptor.
Many experts are studying whether it is possible to immobilize spermatozoa or disrupt spermatogenesis without resorting to the introduction of hormones. There are studies on mice where researchers purposefully destroyed the gene that encodes CatSper, a potential–dependent ion channel located in the main part of the sperm flagellum. Without this channel, male germ cells cannot move, which leads to sterility. To illustrate the second approach, we can take studies of the role of vitamin A in spermatogenesis – a whole group of molecules similar in structure, the most famous of which is retinol. It has been shown that antagonists of all types of retinoic acid receptors have a certain contraceptive effect.
It was also found that lonidamine and its analogues block the maturation of spermatozoa in the testicles [13], destroying the connections between Sertoli cells and immature gametes. For example, one of the analogues – adjudin – provides reliable reversible contraception, which was discovered back in the 1980s. However, a fly in the ointment turned out to be a fly in the ointment: the drug had nephrotoxicity when used in high doses. The researchers did not give up and began studying various chemical modifications of this molecule. However, some of them are still too expensive for mass production, and for others there is no information about toxicity [8].
Another potential pharmacological class of non–hormonal drugs for male contraception are inhibitors of bromodomains and testicular-specific reader proteins (bromodomain testis-specific protein, BRDT). In particular, the JQ1 molecule, by inhibiting the bromodomain during spermatogenesis, disrupts the formation of spermatozoa and impairs their mobility. The result of this is a reversible contraceptive effect without the involvement of the endocrine system. Various derivatives of JQ1 with increased specificity to BRDT are also considered [8]. You can read more about this class of drugs on biomolecule: "Finally: a contraceptive pill for men!" [14].
Market question
The male contraception industry sector has been developing extremely slowly over the past decade, as large pharmaceutical and biotech companies have practically stopped working in it. Funding from States and individuals was also extremely low. As a result of limited funding from government and philanthropic supporters, most clinical trials of the effectiveness of male contraceptives have been relatively small [15].
Despite the non–competitive entry into the market, "Vasalgel", according to the manufacturer's assurances, will be an affordable tool - its cost should not exceed the level of daily earnings in developed countries.
The original version of this article was published in the journal "Urology Today".
Literature
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- Kruck W.E. Looking for Dr. Condom. University of Alabama Press, 1981. – 112 p.;
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- Roth M.Y. and Amory J.K. (2016). Beyond the condom: frontiers in male contraception. Semin. Reprod. Med. 34, 183–190;
- Waller D., Bolick D., Lissner E., Premanandan C., Gamerman G. (2016). Azoospermia in rabbits following an intravas injection of Vasalgel ™. Basic Clin. Androl. 26, 6;
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- Biomolecule: "Finally: a contraceptive pill for men!";
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07.09.2016