Historically, African warriors used a substance called ouabain to coat spear tips to poison their enemies. But new research has suggested that ouabain may have more of an effect on birth than death. This chemical may now be the key to a new form of contraception for men.
Unplanned pregnancies and elective abortions are still a major issue in reproductive medicine. Until now, methods of contraception have affected women significantly more than men. Women have a wide range of options including pills, coils, and diaphragms. However, the only options for men are condoms or a vasectomy.
This is set to change in light of a new study by Gunda Georg and her colleagues at the University of Minnesota, recently published in the Journal of Medicinal Chemistry 1Syeda SS, Sanchez G, Hong KH, Hawkinson JE, Georg GI, Blanco G. Design, synthesis and in vitro and in vivo evaluation of ouabain analogues as potent and selective Na,K-ATPase α4 isoform inhibitors for male contraception. Journal of Medicinal Chemistry. 2018. Available from: https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.7b00925.
What is ouabain and why is it important?
Ouabain is a chemical derived the plants Strophanthus gratus and Acokanthera schimperi 2Medical News Today. Toxic substance may yield male birth control pill. Internet. 2018. Available from: https://www.medicalnewstoday.com/articles/320685.php. It is part of a group of drugs called cardiac glycosides.
This means that it controls the concentrations of sodium (Na) and potassium (K) on each side of the cell membrane in animal cells. Ouabain does this by inhibiting a protein called Na,K-ATPase. In low doses it has been used to treat certain heart conditions, but this is uncommon due to its toxicity and side effects.
The protein Na,K-ATPase is made up of subunits. Previous research has honed in on a subunit called Na,K-ATPase α4 3McDermott J, Sanchez G, Nangia AK, Blanco G. Role of human Na,K-ATPase alpha 4 in sperm function, derived from studies in transgenic mice. Molecular Reproduction and Development. 2015. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25640246, 4Jimenez T, McDermott J, Sanchez G, Blanco G. Na,K-ATPase α4 isoform is essential for sperm fertility. Proceedings of the National Academy of Sciences of the United States of America. 2010. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021039/#. This is crucial in making sperm fertile and it is only present in adult sperm cells. Its concentration is high in the flagellum (or tail) of the sperm.
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Scientists have previously investigated the use of ouabain itself as a male contraceptive, but this was unsuccessful. Ouabain is not a good candidate because it is not specific enough to the sperm cells. This is because it affects other sites in the body where Na,K-ATPase is present including the heart, where it can cause damage.
Scientists modified ouabain to control which cells it would affect
Georg and her colleagues looked into adapting ouabain so that it would only affect sperm cells. They experimented with a number of different adjustments and they successfully created ouabagenin analogue 25. The team achieved this by removing a sugar and a lactone group from ouabain. They replaced the lactone group with a triazole group and they found that this compound was highly specific to Na,K-ATPase α4.
An ouabain-derived compound might be the answer to controlling sperm fertility
Click to find out more about sperm cells
Georg and her team tested the action of the ouabain derived analogue in male rats. Their results were promising. They found that the new compound successfully affected the sperm cells and reduced sperm motility.
Motility, or the ability to swim, is a crucial function for sperm cells. Sperm cells need to be able to travel towards an egg cell in order to successfully fertilise it. The ouabain analogue affected sperm motility both overall and in specific tests of motility patterns. These tests include average path velocities, straight line and curvilinear motility.
Additionally there was a clear winner among the compounds which Georg and the team created. Ouabagenin analogue 25 was the most promising because it had a particular effect on hyperactivation. Hyperactivation describes the activity of a sperm cell when it approaches an egg cell.
Its movement becomes more forceful to propel the sperm towards the egg cell. Ouabagenin analogue 25 significantly reduced the hyperactivation motility of sperm cells, as well as the overall motility.
A further benefit of the ouabain analogue is that it only affects mature sperm cells. Therefore the effects should be reversible in theory. This potentially makes ouabagenin analogue 25 an excellent starting point for creating temporary contraception. These findings are even more important because the new compound caused no major toxic effects in male rats.
Scientists will need to conduct more research before any firm conclusions can be made. There is some way to go before these findings are translated into a safe and reliable form of male contraception, but this is certainly a promising start.
Dr. Jones is an experienced consultant in assisted reproduction.
He has worked as a Fertility specialist at Kingston Hospital Assisted Conception and nearly 10 years experience of working in Obstetrics and Gynaecology across hospitals in the UK.
He completed his Masters in Assisted Reproduction Technology and then his PhD, from Imperial College London. Dr. Jones main areas of interest are Single Embryo Transfer, Endometriosis, PCOS and Implantation failure in IVF patients. He is a member of the British Fertility Society and an associate member of the Royal College of Obstetrics and Gynaecology.
- 1Syeda SS, Sanchez G, Hong KH, Hawkinson JE, Georg GI, Blanco G. Design, synthesis and in vitro and in vivo evaluation of ouabain analogues as potent and selective Na,K-ATPase α4 isoform inhibitors for male contraception. Journal of Medicinal Chemistry. 2018. Available from: https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.7b00925
- 2Medical News Today. Toxic substance may yield male birth control pill. Internet. 2018. Available from: https://www.medicalnewstoday.com/articles/320685.php
- 3McDermott J, Sanchez G, Nangia AK, Blanco G. Role of human Na,K-ATPase alpha 4 in sperm function, derived from studies in transgenic mice. Molecular Reproduction and Development. 2015. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25640246
- 4Jimenez T, McDermott J, Sanchez G, Blanco G. Na,K-ATPase α4 isoform is essential for sperm fertility. Proceedings of the National Academy of Sciences of the United States of America. 2010. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021039/#