Khat (Catha edulis) is a plant that has been cultivated for centuries in East Africa and the Arabian peninsula. Chewing the leaves of the plant releases cathinone, a stimulant that produces feelings of euphoria. Cathinone is not very stable and is broken down into cathine (pseudonorephedrine) and norephedrine; all belong to a group of chemicals called phenylpropanolamines (PPAs), which are structurally similar to amphetamines and adrenaline.
Until now there have been conflicting reports of the effects of PPAs on male fertility. Amongst people who chew khat leaves there is a belief that it improves a man's sex drive and ability to maintain an erection, but there is a question mark over whether prolonged use might adversely affect the male reproductive system, possibly causing abnormalities in sperm.
Now, researchers at the Centre for Reproduction, Endocrinology and Diabetes at King's College London, UK, have studied the effects of PPAs on mouse and human sperm and found the first evidence that they stimulate the final stage of sperm maturation (capacitation) when sperm develop the ability to fertilize an egg. They then maintain the sperm in a potentially fertilizing state for longer, allowing them more time to reach an egg.
Lynn Fraser, Professor of Reproductive Biology at King's College London, believes that these preliminary findings might lead to over-the-counter products that couples could buy to boost their fertility during attempts at natural conception, as well as providing another way to help infertile couples during IVF treatment.
"A number of PPAs related to the compounds we have studied are currently used in prescription and over-the-counter products, such as herbal dietary supplements used for weight loss and treatment of asthma," said Prof Fraser. "We envisage the development of products that could be taken by individuals, either couples who might be having trouble conceiving or even those who have just decided to try to conceive, and who have no obvious problems. PPAs could also be used in IVF clinics as additives to sperm prepared for IVF or artificial insemination."
Dr Susan Adeoya-Osiguwa, a senior post-doctoral research associate at King's College London, and Prof Fraser incubated mouse and human sperm with cathine and then tested the sperm to see what effect there had been on capacitation and on the acrosome reaction, which is the final phase of capacitation when the cap (acrosome) present in the sperm head ruptures and releases enzymes that enable the sperm to enter the egg. Mouse sperm were also tested for their responses to norephedrine.
They found that cathine and norephedrine significantly stimulated capacitation in mouse sperm, while preventing the acrosome reaction. Cathine had a similar effect on human sperm. Cathine also stimulated the production of cAMP (cyclic adenosine monophosphate - a chemical messenger within cells) in uncapacitated sperm whilst inhibiting it in capacitated sperm.
Prof Fraser explained: "We know that cAMP stimulates sperm motility and that it plays an important role in the phosphorylation of many proteins, some of which allow sperm to 'switch on' and acquire fertilizing potential. This research provides the first evidence that cathine can regulate the availability of cAMP, first stimulating and then inhibiting its production; and that inhibition of cAMP in capacitated cells appears to be the molecular basis for preventing the acrosome reaction. If sperm continue to produce cAMP in an unregulated manner, then some will undergo spontaneous acrosome reactions and so 'burn out' before reaching the egg. Even if they are still motile, they will not be able to fertilize an egg because the acrosome-intact sperm has special docking molecules that play a vital role when sperm contact unfertilised eggs. No docking molecules, no fertilization!
"This study has shown for the first time that PPAs have a direct effect on sperm, initially stimulating the final maturing process and then preventing spontaneous acrosome reactions in mature sperm, thus maintaining them in a potentially fertilizing state*. When mouse sperm treated with cathine were mixed with unfertilised eggs, they were able to fertilise much more quickly than untreated control sperm; this indicates that PPAs do not interfere with the acrosome reaction induced in the fertilizing sperm by the egg. These preliminary data suggest that PPAs, at appropriate doses, might provide a new approach for enhancing natural fertility."
More research has to be carried out in live animals, administering PPAs and then evaluating effects on the ovaries, the testes and the sperm, before this work can be translated into treatments for people. For instance, Prof Fraser and Dr Adeoya-Osiguwa would like to confirm the findings of another study that showed that sperm production in rabbits was stimulated when the rabbits were fed a diet containing dried, ground khat leaves. However, she said: "The fact that other PPAs have already been approved for use in preparations taken by humans should make the development of any product easier than if one had to start from scratch; toxicity testing will have been carried out already for the related compounds."
Abstract no: O-024 (Monday 10.45 hrs CET Hall 14.2)
* While the PPAs blocked a spontaneous acrosome reaction by inhibiting one signalling pathway, they did not block the acrosome reaction when it was induced by the egg. When the sperm's docking molecules interact with the layer surrounding the egg, a different signalling pathway is activated that triggers a "real" acrosome reaction.