The first injectable male contraceptive has passed clinical trials. Is the era of male contraception just around the corner?

Indian researchers claim to have completed the world's first clinical trial of a male contraceptive. Historically, the responsibility of contraception has mainly been placed on women. Will the new breakthrough change the pattern of human contraception?

Written by reporter Li Li, Photo and text editor: Ding Lin

New Media Editor/Chen Xuanzhi

Interview experts:

Li Haisong (Director of Andrology Department, Dongzhimen Hospital, Beijing University of Chinese Medicine)

In addition to condoms, scientists have found a new male contraceptive method. In mid-August, the Indian Council of Medical Research announced that it had successfully completed the clinical trial of RISUG, the world's first injectable male contraceptive. The drug has a contraceptive success rate of 97.3% and is effective for 13 years. If the drug is eventually approved by the Drug Controller General of India (DCGI), it will become the world's first injectable male contraceptive.

▲The mechanism of action of the injectable male contraceptive RISUG (Source: bloomberg.com)

In fact, modern scientific contraception has only become what it is today after thousands of years of long and tortuous exploration. Throughout history, people have continuously invented simpler and more effective contraceptive tools and methods. Understanding how these hard-won achievements of human civilization came about may allow today's men and women to share the responsibility of contraception more rationally.

Early contraceptive methods

When human civilization was just beginning, they mainly lived by hunting, fishing and gathering. The harsh natural environment and low productivity could not support the existence of a large population. At that time, humans may not have understood the inevitable connection between sex and pregnancy. Some civilizations even believed that pregnancy and childbirth were "magic" unique to women.

After entering the agricultural society, humans were inspired by the production practice of "sowing and harvesting" and began to realize that male semen is the direct cause of pregnancy and childbirth. The contraceptive methods developed subsequently also turned to men. These methods are mainly divided into three categories: one is to limit the frequency of sexual life. As early as the Spring and Autumn Period, China had the moral code of "the way of a gentleman is to have sex once every five days"; the second is to stop sexual intercourse before ejaculation or ejaculate outside the body. This contraceptive method was widely used by all nations in the world before modern times; the third is to change the sexual lifestyle to prevent semen from entering the uterus. Obviously, due to the lack of understanding of the actual process and accurate physiological mechanism of pregnancy, the success rate of the above primitive methods is not high.

According to ancient papyrus documents, the ancient Egyptians also made contraceptive suppositories using local "local products": honey and gum arabic were mixed and soaked in a linen ball and inserted into the female vagina. This is indeed useful - gum arabic can plug the vagina after absorbing water and swelling, and honey will produce a large amount of lactic acid after microbial fermentation, which will quickly inactivate sperm.

In the medieval Arab region and India, where the culture was relatively developed and the society was relatively tolerant of contraception, contraceptive methods were at the forefront of the world. Nearly a thousand years ago, they had already adopted methods such as douching the vagina, plugging the cervix with sponges, and wrapping the penis to prevent pregnancy. This was also one of the earliest male contraceptive methods to be widely adopted.

In addition, there were attempts at vasectomy in India, and there were many local medical works on the principles and methods of contraception, which became enlightenment readings and textbooks for Europeans in the early modern period.

The invention and popularization of condoms

Condoms are one of the most popular and widely used contraceptive measures today. In 1564, the Italian Frobius published a book proposing the initial idea of ​​condoms. However, there was no matching manufacturing technology at the time (so he also suggested stretching the male foreskin and tying it up to prevent semen from flowing out).

Early condoms appeared in Britain in the late 17th century and were often made from sheep intestines or fish skin.

▲Condoms made from animal intestines (Source: esquire.com)

In the British society at that time, traditional Christian concepts and laws still dominated, and contraception was a felony. Therefore, people invented and used condoms not for contraception, but to prevent the spread of sexually transmitted diseases such as syphilis. At that time, condoms could only be sold in brothels, and pharmacists and drug dealers could only sell condoms to people who had syphilis or were likely to be infected with syphilis in the future, such as ambassadors or businessmen stationed abroad, sailors at sea, visiting foreigners, etc.

From the 17th century to the mid-18th century, scientists discovered the physiological process of eggs and pregnancy, and contraceptive methods began to make their first major progress in modern times. Condoms began to be widely used for contraception.

In 1839, after the invention of rubber vulcanization technology, rubber condoms were introduced in 1855. They are thin, strong, uniform in specifications, stable in nature, good in quality and cheap in price, and quickly became popular around the world. In 1919, natural latex condoms and supporting automatic production lines appeared, which greatly reduced the price of condoms and made them more and more popular. Condoms have become an important means to prevent the spread of AIDS, played a pivotal role in the field of public health, and gradually became an indispensable part of people's daily necessities.

In recent years, due to technological improvements, the thickness of condoms has been greatly reduced. In addition, condom manufacturers have begun to realize that condoms of the same size cannot meet the needs of different customers, so today there are condoms of different shapes, widths, lengths, and colors.

60 years after the female contraceptive pill was introduced, there is no news about the male contraceptive pill

In 1951, Carl Djerassi, professor emeritus of chemistry at Stanford University, synthesized the key ingredient of the earliest contraceptive pill, norethindrone, in Mexico City. He was called the "Father of the Contraceptive Pill" for this contribution.

The original intention of the developers of the contraceptive pill was to launch a birth control drug. However, due to the moral constraints at the time, when the US Food and Drug Administration (FDA) approved the drug (trade name Enovid) in 1957, it only listed it as a drug for treating "severe menstrual problems" and warned people that the drug may have the side effect of preventing pregnancy.

In June 1960, the FDA officially approved Enovid as a contraceptive. In addition to contraception, the drug can also be used to assist in the treatment or relief of a variety of other diseases, such as polycystic ovary syndrome, endometriosis, anemia, acne, etc. In the late 1980s, Enovid, as a representative of the first generation of contraceptives, withdrew from the market.

▲Enovid medicine bottle in the early 1960s (Source: time.com)

The birth of the female oral contraceptive pill has a significant and far-reaching impact on mankind - it frees men and women from the burden of childbearing. In order to distinguish the contraceptive pill from other medicines, the first letter of the "pill" is capitalized and becomes the proper name of the contraceptive pill.

It has been 60 years since the female oral contraceptive was officially launched on the market. During this period, male contraceptives have been "silent", mainly because it is too difficult to manufacture male contraceptives. The principle of male contraception is simple, that is, to control sperm production, but it is too difficult to operate in practice - it is necessary to reduce the sperm production of the testicles in a short period of time from the source, and to restore sperm production after stopping the medication, without harming the body. The strict requirements have slowed the development of suitable male contraceptives. Some experimental drugs will more or less cause liver damage and even male sexual dysfunction. These difficulties have made pharmaceutical companies lose the motivation to continue to develop related drugs.

To this day, male contraceptives remain a long-awaited innovation. Finding the most effective compound with the least side effects is the goal of many researchers.

Men have a new contraceptive option

For a long time, the problems of menstrual disorders caused by female contraceptive pills have been a headache. However, due to the low success rate, many complications and irreversibility of traditional male contraceptive methods (condoms, vasectomy, etc.), the topic of male contraception has always been in an embarrassing situation of "often mentioned, but forgotten". Therefore, exploring reversible, safe and easy-to-use male contraceptive methods has always been a hot research topic in the medical community.

Since the first male contraceptive conference organized by the International Coalition for Male Contraception (ICMC) in 2016, the demand for male contraceptive methods has increased. During this period, some promising non-hormonal targets have been transferred from preclinical to in vivo trials to determine whether these new chemical structures can selectively block specific targets in the male reproductive system. The National Institutes of Health has issued a new competitive application to provide funding for the research and development of male contraceptives. In the future, the support of governments, health institutions and global decision-makers will accelerate the progress of male contraceptive research around the world and help build a healthy "male contraceptive era".

Zhang Xiaowei, Yang Dan and others from Liaoning Provincial Family Planning Science Research Institute mentioned in the article "Research Overview and Feasibility Analysis of Male Contraceptive Methods": The ideal contraceptive method for men should be highly effective, safe, reversible, and not affect sexual desire and male sexual characteristics. At present, male contraception interferes with reproduction in the following ways: inhibiting sperm production, hindering sperm maturation, interfering with sperm capacitation and fertilization, blocking sperm transport, etc. The methods include follicle-stimulating hormone immunization, exogenous testosterone contraception, interfering with estrogen receptors or epididymis-specific proteins to affect sperm maturation, etc.

▲Various male contraceptive methods tried throughout history (Source: cosmopolitan.com)

Li Haisong, chief physician and director of the Department of Andrology at the Dongzhimen Hospital of Beijing University of Chinese Medicine, commented that the main mechanism of many male contraceptive drugs is to reduce male androgen levels to a low level, thereby achieving the contraceptive effect. If the dosage is too small, it will not achieve the contraceptive effect, because even if only a small amount of sperm is produced, it may lead to pregnancy. However, if the dosage is too large, it will turn men into "eunuchs", and such a contraceptive mechanism may not be feasible. This is also the real reason why male oral contraceptives have not been widely used for decades.

Scientists have never stopped researching male contraception. At the end of March 2019, the research team of the Los Angeles Biomedical Research Institute and the University of Washington announced that the second male oral contraceptive had passed Phase I clinical trials and is expected to be available on the market within 10 years. This male oral contraceptive is called 11-β-MNTDC. The principle is to reduce sperm production while retaining sexual desire through the combined effects of androgens and progesterone; at the same time, the contraceptive effect of this oral medication is reversible: once men stop taking the medication, they can slowly restore their fertility. During the 28-day treatment period, the 30 male volunteers who took the medication produced a significantly reduced number of sperm without any serious side effects.

RISUG, the first male contraceptive injectable that recently passed clinical trials, is actually a polymer called "styrene maleic anhydride" (SMA). The polymer has been studied for nearly 40 years since it was created by the Indian Institute of Technology in the 1970s. Researchers inject the polymer into the vas deferens of male subjects, where the polymer can directly contact sperm and inhibit sperm production.

In Western countries, it takes an average of 10 to 15 years for a drug to go from idea to clinical trial and then to the shelf. The development of RISUG is much longer than this period, and it is still one step away from completion. This year, the developers and potential users of male contraceptives seem to have finally reached the end of the stage - is the male contraceptive really coming?

References:

1. Pan Suiming. The social and historical footprints of scientific contraception[J]. Population and Economy, 1987(03):23-25.

2. Jia Mengchun, Gu Yiqun. "Second Paris Declaration" - May 7, 2018 Male contraception: moving forward[J]. Journal of Reproductive Medicine, 2018, 27(08): 815-816.

3. Zhang Xiaowei, Yang Dan. Research overview and feasibility analysis of male contraceptive methods[J]. Chinese Journal of New Drugs and Clinical Practice, 2014, 33(02):97-104.

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