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4 December 2013

Australia: Male pill ‘a step closer’

New research has been reported that might aid the development of a male contraceptive pill.

Researchers identified two proteins that can be blocked to prevent the launch of sperm cells from the testes during ejaculation. Knocking out the proteins in genetically engineered mice resulted in male animals that were completely infertile, though they continued to mate normally. A similar goal could theoretically be achieved by suppressing the proteins with drugs, the scientists say.

‘This concept is indeed a feasible mechanism of producing male contraception,’ the Australian and British researchers wrote in the journal Proceedings of the National Academy of Sciences.

A male contraceptive pill has been the holy grail of fertility scientists, but one that has proved frustratingly elusive, the Guardian reports. Compared with developing a female pill, designing a male version is a far more difficult process. Most approaches have relied on hormonal targets or rendering sperm dysfunctional. One major problem is ensuring that every one of the millions of sperm cells produced by a man is stopped from carrying out its job of fertilising the female egg, because it takes only one sperm to produce a baby.

Tampering with sperm must also present no risk of altering an offspring’s genetics. In addition, a male oral contraceptive should ideally be readily reversible, and leave sexual function unaffected. The new approach appears to tick all these boxes, raising the prospect of a pill for men that is 100% reliable and can be taken when needed.

The two proteins, alpha1A-adrenoceptor and P2X1-purinoceptor, are both “receptor” molecules on which other agents act to trigger biological processes. Together they enable sperm cells to be transported from the testes to the penis through a muscular tube called the vas deferens, which contracts during ejaculation.

Deleting genes for the proteins produced male mice that were 100% infertile, wrote the researchers led by Dr Sabatino Ventura, from Monash University in Victoria, Australia. Importantly, complete loss of fertility in the “knockout” mice did not affect their sex drive or normal sexual activity. “This bypasses perhaps the greatest stumbling block in the quest for a socially acceptable male contraceptive,” the scientists wrote.

The mice appeared normal and did not suffer any side-effects that would make such a treatment unthinkable for humans. They were also able to father normal offspring, after having sperm extracted from their testes and injected into female eggs.

Adrenoceptor-blocking drugs are already in widespread use as treatments for benign prostate hyperplasia (BPH) – non-cancerous prostate enlargement – and high blood pressure, the researchers pointed out. ‘Development of only a suitable P2X1-purinoceptor antagonist [blocker] is required before this pharmacological strategy for male contraception can be trialled,’ they added.

The journal abstract reads:

Signficance

The search for a viable male contraceptive target has been a medical challenge for many years. Most strategies have focused on hormonal or germ-line strategies to produce dysfunctional sperm that are incapable of fertilization. The problem with such approaches is that they have intolerable side effects such as affecting male sexual activity or causing long-term irreversible effects on fertility. In addition, some strategies may transmit detrimental changes to future offspring. This manuscript describes a male contraceptive target within the autonomic nervous system, which would not affect the long-term viability of sperm nor the sexual or general health of males. In addition, due to the nature of the target, the contraceptive has the potential to be orally administered.

Abstract

Therapeutic targets for male contraception are associated with numerous problems due to their focus on disrupting spermatogenesis or hormonal mechanisms to produce dysfunctional sperm. Here we describe the dual genetic deletion of α1A-adrenergic G protein-coupled receptors (adrenoceptors) and P2X1-purinoceptor ligand gated ion channels in male mice, thereby blocking sympathetically mediated sperm transport through the vas deferens during the emission phase of ejaculation. This modification produced 100% infertility without effects on sexual behavior or function. Sperm taken from the cauda epididymides of double knockout mice were microscopically normal and motile. Furthermore, double knockout sperm were capable of producing normal offspring following intracytoplasmic sperm injection into wild-type ova and implantation of the fertilized eggs into foster mothers. Blood pressure and baroreflex function was reduced in double knockout mice, but no more than single knockout of α1A-adrenoceptors alone. These results suggest that this autonomic method of male contraception appears free of major physiological and behavioral side effects. In addition, they provide conclusive proof of concept that pharmacological antagonism of the P2X1-purinoceptor and α1A-adrenoceptor provides a safe and effective therapeutic target for a nonhormonal, readily reversible male contraceptive.

Male contraceptive pill ‘a step closer’. Press Association. The Guardian, Monday 2 December 2013

Male contraception via simultaneous knockout of α1A-adrenoceptors and P2X1-purinoceptors in mice. White CW, Choong YT, Short JL, Exintaris B, Malone DT, Allen AM, Evans RJ, Ventura S. Proceedings of the National Academy of Sciences of the United States of America, 2013 Dec 2.

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