Fluctuating oestrogen levels in women may significantly influence how efficiently drugs designed to target the brain reach their intended destination, according to recent research. This discovery could revolutionise the development and administration of treatments for neurological conditions, particularly by addressing previously overlooked sex-specific differences in drug response.
The findings emerged from a re-evaluation of the experimental drug davunetide, which was initially halted over a decade ago after a late-stage clinical trial for progressive supranuclear palsy (PSP) appeared to show no overall benefit. However, upon closer inspection, scientists found that davunetide may have been effective in women. Led by Illana Gozes at Tel Aviv University, the researchers delved deeper, revealing a potential link between varying oestrogen levels and the drug's access to the brain.
Davunetide, derived from a naturally occurring brain protein, was designed to reinforce microtubules – a crucial part of the brain's cellular transport system – to help prevent the build-up of abnormal tau proteins, which are implicated in conditions like Alzheimer's and PSP. The initial 2014 trial, which used an intranasal formulation, did not demonstrate a clear effect across the entire study group.
Prompted by earlier studies that showed sex differences in results, Gozes and her team re-analysed davunetide data, separating findings by sex. They observed that in women with PSP, the drug seemed to slow disease progression and offer protection against symptoms related to brain damage, such as difficulties with swallowing and speaking. Subsequent experiments with fluorescently labelled davunetide in mice showed that more of the drug reached the heads of female mice when their oestrogen levels were at their peak. A small human study involving six women and two men also indicated that women tended to have higher peak concentrations of the drug in their circulating plasma.
Experts suggest that oestrogen's influence on blood flow, drug metabolism, and the permeability of the blood-brain barrier could explain these observed differences in drug absorption. Jens Pahnke from the University of Oslo, who was not involved in the research, highlighted that brain diseases are often regulated by steroid hormones, a factor frequently overlooked in drug development. He described this oversight as a "massive problem," underscoring the need for greater consideration of hormonal influences in future research and clinical trials.