Observations On the Contrary

Monkey business: reflections on testosterone

BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e4967 (Published 23 July 2012) Cite this as: BMJ 2012;345:e4967
  1. Tony Delamothe, deputy editor, BMJ
  1. tdelamothe{at}bmj.com

Why is it easier to believe in the effects of testosterone than it is to show them?

If ever there was a hormone whose discovery was a foregone conclusion it was testosterone. Almost a century before the steroid was isolated Arnold Berthold showed that transplanting testes into castrated roosters restored their characteristically rooster-like behaviour.1 After this, trapping the essence of masculinity in a bottle was only a matter of time.

Time and, for Adolf Butenandt, 25 000 L of urine donated by a Berlin police barracks.2 From this he extracted 50 mg of the weak androgen androsterone and went on to synthesise testosterone and win the Nobel prize for chemistry in 1939. “Dynamite, gentlemen, it is pure dynamite,” he told the Nobel committee (a joke at the expense of the explosive’s inventor).

Between Berthold and Butenandt, however, came the neurologist Charles-Édouard Brown-Séquard. At the age of 72 he delighted the world by announcing that he had rejuvenated himself by injecting aqueous extracts of testes from freshly killed guinea pigs and dogs. A placebo effect, say modern killjoys—little hormone would have dissolved in water. Nevertheless, soon many doctors were treating their male patients with organ extracts.1

In the 1920s the surgeon Serge Voronoff became famous for transplanting monkey glands into his patients, even influencing the manager of Wolverhampton Wanderers (an English football team) to foist the procedure on to his players.3 Wolves had a few great seasons (almost their last), but it transpired that transplanted glands were rapidly rejected, leaving only scar or inflammatory tissue.4

Soon after Butenandt’s isolation of testosterone came implants and short acting injections that really did work. The question then, as now, was who should get them? There’s no doubt that hypogonadal men should and that men who are merely feeling a bit out of sorts should not. But lots of grey areas—such as men who are a bit hypogonadal and who are feeling a bit out of sorts—remain. To catch up with current thinking I booked my free place on a recent Bayer HealthCare seminar entitled “Restore the Man.”

Brown-Séquard and Voronoff would have recognised the focus of this event: the older man. Testosterone concentrations fall progressively with age, so a proportion of older men will predictably have testosterone concentrations below the normal range of healthy young men. It seems a bit harsh to turn an age related phenomenon into a disease, but that’s what’s happened. These older men risk being labelled as having “late onset hypogonadism” or “age associated testosterone deficiency syndrome,” so it’s important to know where to set the threshold. The best attempt has emerged from the European Male Ageing Study (EMAS), which has defined the syndrome of late onset hypogonadism as a combination of sexual symptoms and testosterone level.5 But it’s still a bit of a mess. As the authors point out, “The prevalence of even the most specific sexual symptoms of androgen deficiency was relatively high among men with unequivocally normal testosterone levels.” Their criteria give a prevalence of late onset hypogonadism of 0.1% in men aged 40-49 years, 0.6% in those aged 50-59, 3.2% in those aged 60-69, and 5.1% in those aged 70-79.

This gives a rough estimate of the size of the market for testosterone replacement therapy, but no one can quite forget what happened with hormone replacement therapy in women. If treatments for prostate cancer seek to drive testosterone levels to zero, what would the effect of testosterone supplements be in men whose age puts them at the highest risk of developing prostate cancer? The position of speakers at the meeting varied from “it might be all right” to the more bullish. Abraham Morgentaler, responsible for the “saturation model and the limits of androgen-dependent growth,” was quoted approvingly. What’s needed now is a large randomised controlled trial of testosterone in men who fit the EMAS criteria for late onset hypogonadism. But it will require steady nerves.

Meanwhile, another purported effect of testosterone, immediately recognisable to Berthold and his roosters, is back in the spotlight: aggression. Here the evidence for a connection is far from clear cut. Summarising what was known in 1993, Gail Vines wrote: “In humans, just as in monkeys and mice, most attempts to link testosterone levels to aggression have failed.”1 Twenty years later David Benatar can find plenty of assertions of a connection in the literature but no convincing proof.6

What’s drawn recent attention to testosterone’s aggressive potential is a study published in 2008,7 which is now the centrepiece of a book.2 It reports endogenous steroids in 17 male traders working over eight consecutive business days in the City of London. (Trades ranged from £100 000 to £500m, “depending on the trader’ s level of experience.”) One key finding was that a trader’s morning testosterone level predicted his day’s profitability. Much about masculinity, aggression, competitiveness, and risk taking has been read into this single finding.

To someone used to reading research in regular medical journals, its presentation comes as a shock. The only testosterone value to appear anywhere in the paper was the mean testosterone of all the estimations performed on all the participants during the study. The outcome of interest was trading returns on days when traders’ morning testosterones were above and below their median levels. I can tell you that the P value for this comparison was 0.008, but nothing else.

The findings were featured in every financial newspaper and magazine and may explain why testosterone “has become Wall Street’s drug of choice as traders seek a competitive edge in the face of job cuts,” according to the Financial Times.8 “I now have a bit more of an alpha male personality and I’m able to get by on less sleep. It’s the positive side of aggression,” says John (not his real name).

For a while testosterone was being blamed for the “irrational exuberance” of City traders, but like almost everything else you read about the hormone you don’t have to believe it.

Notes

Cite this as: BMJ 2012;345:e4967

References