Why It Could Be Time for Sex-Specific Drugs

(Inside Science) -- Basic biochemical differences between males and females are so substantial that modern society would be better served through his and her medicine cabinets, say a group of experts.

A new piece of research published in The Journal of Clinical Investigation last month bolsters their arguments by showing that the therapeutic power of some anti-inflammatory drugs differs significantly depending on sex. But the movement towards male or female-specific medication is not without its challenges. There are questions about how the transgender community would be best treated, the economics is unclear and more women still need to be included in clinical trials.

“If a biochemical process is different between men and women then we should investigate if the drugs acting on that process behave differently and therefore ask if it’s worth developing gender-specific drugs,” said Oliver Werz, one of the study’s authors and a professor of pharmaceutical chemistry at the University of Jena in Germany.

Men, for example, are less likely to suffer from inflammatory diseases like asthma, psoriasis or rheumatoid arthritis than women. It’s thought this may be because the male sex hormone, testosterone, has a protective effect with these disorders.

Werz and his colleagues used high resolution microscopes to observe how testosterone interacts with immune cells and the molecules they produce in response to inflammatory diseases -- known as leukotrienes , which cause some of the symptoms. The researchers used specialized high-resolution and time-resolved microscopy -- a technique that can create images detailed enough to discern biochemical processes at a cellular level. The scientists also looked at the biochemical relationship between testosterone and five anti-inflammatory drugs that interfere with leukotriene production.

The female blood samples were shown to have higher levels of leukotrienes than the male samples, but that was no surprise since it was already known that testosterone downregulates the molecule’s synthesis. “But we also wondered if the drugs that block leukotrienes are more efficient in females than males,” said Werz.

That’s exactly what Werz and his colleagues found; testosterone made the drugs less effective, which created a significant difference in drug potency between sexes. One of the drugs tested, MK886, was close to eight times more effective at reducing leukotrienes in blood samples collected from women compared to men. Another, sulindac sulfide, had almost no effect in male blood samples at all, but was effective in the female samples.

Not knowing about the sex-specific potency of these drugs may have prevented women who suffer from these diseases from accessing potentially helpful medicines. Three of the five drugs that Werz tested -- including MK866 -- were not approved for use because they were shown to be ineffective. That judgement was based on clinical trials during the 1980s and 1990s in which women were not properly included, said Werz.

“I’m sure that researchers in the past would have seen these differences if they’d considered males and females in their experimental designs,” said Werz.

The study has impressed Garth Maker, a biochemistry researcher at Murdoch University in Australia, who argues that drug companies should be creating gender-specific versions of their products. “They got some compelling data. There are definitely different mechanisms going on in men and women for these diseases and it warrants further investigation.”

The biochemical differences between men and women extend far beyond the reproductive organs. The levels of hormones, notably testosterone and estrogen differ, but males and females are also genetically distinctive. That means men and women are different on a cellular level and there is no reason to blindly believe these differences don’t affect the potency of different drugs until we check, said Maker.

According to Maker, the number of studies which suggest drugs behave differently depending on gender is on the rise, but still lacking.

To continue with a one-size-fits-all policy for drug development means the therapeutic power of medicines will not reach their full potential -- for either sex, said Maker.

Paula Johnson , president of Wellesley College and chief of the Division of Women’s Health at Harvard Medical School, has been working for years to raise awareness of how diseases and drugs act differently in men and women. She has often pointed out how we know more about men’s health than women’s because of the gender makeup of clinical trial participants.

“The authors of this important study again clearly demonstrate that consideration of sex in biomedical research is important to the accuracy and integrity of science and medicine,” she wrote in an email. “It can help us to better determine how therapies may differ by sex.”

For drugs to be designed with gender in mind, the scientific community needs to continue producing evidence, but Werz said it won’t be easy to convince pharmaceutical companies that it’s worth the investment because approaching drug design in a sex-specific way could increase the cost. It would necessitate additional clinical trials if there were to be male and female versions of one drug. In addition to that, any one sex-specific drug may have lower sales.

“It’s not in the economic interest of the drug companies. It’s more cost effective to have one drug that fits all,” said Werz. “It’s a major problem.”

Multiple drug companies contacted by Inside Science declined to comment.

There’s also a question of how to best accommodate the transgender community; hormonally they are likely to be similar to their chosen gender, but genetically they remain as their original sex.

“If we’re going to potentially divide our health system along gender lines then it creates a gap in the middle where some trans people might be left with less than optimal care options,” said Maker, “It’s a complicated situation. It strikes me that you’d have to respond in an individualized way because they’d probably be in a unique position biochemically.”

But for the moment, researchers such as Werz say they will continue their work to help ensure that gender is at least considered in the drug-making process.