Source: Unsplash by Reproductive Health Supplies Coalition
The current contraceptive landscape has always burdened women, and their respective health, with 27.4% of contraceptive use concerning male involvement (condoms, vasectomies, and withdrawal). Sterilisation, male condoms, and IUDs are the most popular methods of contraception worldwide, according to a UN study in 2019. An interesting commonality, of these birth control methods, is the lack of hormonal intervention, which can often cause a cascade of side effects. The IUD itself has its own difficulties that lead to discontinuation; such as increased menstrual bleeding, pain, uterine perforation, and increased risk of infection immediately post-insertion.
Although the typical copper implant shows common side effects, like the IUD falling out of the womb (1/20), the combined pill shows more common, uncommon, rare, and severe side effects; including but not limited to Crohn’s disease, ulcerative colitis, and both cervical and breast cancer. When comparing medical leaflets, the copper IUD showed 3 side effects compared to 36 in the combined pill; ranging from mood swings, and skin rashes, to blood clots and liver dysfunction. There are further risks and possible contraindications of hormonal contraceptives, with multiple potential psychological and physiological implications, that significantly connect these methods; with an increased risk of violent death by either suicide, accident, or homicide.
When perusing the contraceptive options, they are mostly hormonal; with only 4/13 non-hormonal choices, 3 of these using the barrier method (male condoms, female condoms, and the diaphragm/cap). The IUD is the only non-hormonal method that can be used without much forethought; as depending on the type they can last from 5-10 years. The remaining options are either surgical (2/13) or hormonal (7/13).
From the 1970s to the 1990s, testosterone enanthate (TE) underwent various trials; but was terminated when 42 of the men discontinued treatment for personal reasons, dislike of the injection, pregnancy, or medical reasons. Testosterone, taken alongside gonadotropin-releasing hormone (GnRH) antagonists, was studied short-term in 1991 and 1993; with mixed efficacy but practically no side effects. Unfortunately, GnRH antagonists are expensive and mostly only available as an injection; leading current research to be limited, but not gone. Testosterone undecanoate (TU) was also explored in 2003 and 2009 respectively. Phase 2 and 3 trials, showed excellent contraceptive protection and promising fertility restoration. TU was also trialed in combination with etonogestrel, in separate 2001 and 2008 studies; presenting good tolerability and reversibility. However, TU is currently only used in androgen deficiency and hypogonadism, with primary research having halted in 2016. This was due to a large Phase 2 study of the possible contraceptive; resulting in moderate to severe mood changes, acne, libido increase, and tenderness at the injection site. However, 6% of men discontinued using it, due to the side effects. An external safety review committee suggested ending the study early.
However, recent progress has been made in male-led contraceptives, with Phase 2 trials of Nestorone (segesterone acetate) and testosterone; both predicting completion in December 2024. Nestorone is a hormonal transdermal gel, that is administered to the arms and shoulders of the subject; lowering the levels of natural testosterone, and blocking sperm production in the testicles. This reduces the sperm count of the patient, preventing pregnancy. Oral contraceptives such as dimethandrolone undecanoate (DMAU) and 11-beta-methyl-19-nortes-tosterone 17-beta-dodecyl carbonate (11-ßMNTDC), have and continue to be tested; presenting a high possibility of proceeding to Phase 2, due to their high tolerability and lack of side effects.
Although all the male-led birth control, discussed so far, has been hormonal; there are non-hormonal candidates currently being researched. An exciting release in 2022, presented positive implications associated with the RAR-α inhibitor YCT529, administered orally; suggesting imminent clinical trials, although nothing new yet has been reported. Tests have also been conducted on the EPPIN inhibitor EP055, administered intravenously; which has not yet moved to clinical trials but shows contraceptive potential in these early stages. Another option currently under investigation is the ADAMTM system, which consists of a hydrogel-based contraceptive implant; that blocks the vas deferens, predicting a completion date of June 2025.
There seems to be less clinical activity in non-hormonal contraceptives for women, although it is not a deserted field of interest. Currently, soluble adenylyl cyclase (sAC) inhibitors, are in the early stages of research and are being proposed as an intravaginal device that delivers the drug topically. These drugs work by halting the movement of sperm, as well as preventing reactions that allow the sperm to enter the egg. Monoclonal antibodies have also been investigated, in the form of MB66 film that is inserted by a clinician into the vagina. The Phase 1 clinical trial reported good tolerability; but also several side effects including vaginal spotting, asymptomatic microscopic haematuria, proteinuria, vaginal odour, vaginal discharge, vaginal cramping, and UTI. Although the incidences of these were similar in patients with the placebo film. Currently, there is no ongoing Phase 2 trial, for soluble adenylyl cyclase (sAC) inhibitors.
Previous studies have also shown possible therapeutic benefits, in targeting ion channels for contraception; such as the CatSper calcium channel on the flagellum of sperm. The CatSper channel plays important roles in different stages of fertilisation, and therefore has various exploitable avenues for contraception. Recently, a serine hydrolase, ABHD2, inhibitor, has been explored theoretically and performed well in animal testing; but no clinical trials have taken place yet. Due to the presence of sperm in both female and male reproductive tracts, CatSper is a potential target for both male and female contraceptives. Other proteins present in sperm are considered important, as being targets for future research. As our drug research continues to flourish, we must ask, who is benefitting? and, at what cost? It is imperative to develop tolerable efficacious contraceptives, that do not burden the mental or physical health of the population. Moving forward we must continue to create birth control for all that are willing to receive it, regardless of gender, and greatly consider whether the symptomatic burden on women is justified or ever has been.