Malaria drug shows early potential as polycystic ovary syndrome treatment in rodents and people

Malaria drug shows early potential as polycystic ovary syndrome treatment in rodents and people

Ancient plant compounds called artemisinins were the original anti-malaria heroes, but new research suggests drugs based on them may have the potential to treat a different condition entirely: polycystic ovary syndrome (PCOS).

In a study published June 14 in Science, a research team from Fudan University in Shanghai explained how they found that an artemisinin derivative improved symptoms in mouse and rat models of PCOS by repressing a key disease mechanism. A 12-week clinical trial in human patients had the same effects.

“This advance not only underscores the versatility of artemisinins but also has great potential to improve the quality of life of millions of affected women, representing an important advance in reproductive medicine,” Elisabet Stener-Victorin, Ph.D., a professor at Sweden’s Karolinska Institute who was not affiliated with the study, concluded in an accompanying perspective article.

PCOS affects between 8% and 13% of women and people with ovaries during their reproductive years, according to the WHO. Up to 70% of cases go undiagnosed, namely on account of the vague but burdensome constellation of symptoms the disease causes. PCOS is characterized by abnormally high levels of sex hormones called androgens—the most famous of which is testosterone—that can lead to ovarian cysts, acne, ovulation problems and excessive hair growth on the chest, back and face. It’s also associated with infertility, metabolic disease and mental health problems.

While researchers still don’t understand exactly what causes PCOS, they do know that it’s linked to excessive production of androgens by enzymes in ovarian cells called theca cells, as Stener-Victorin explained in her article. This has a domino effect on other processes in the ovary, pituitary gland, pancreas and other organs, sparking a feedback loop that leads to even more androgen production. Treatment aims to reduce androgen levels, first via hormonal birth control then antiandrogen drugs as a last resort.

The new study stemmed from earlier findings by the Fudan University team that showed artemisinins could improve insulin sensitivity by activating adipocytes, or fat cells, and prevent obesity in mice. (And yes, they are indeed being studied as anti-obesity drugs.) Given the mechanistic links between metabolic disorder and PCOS, the researchers wondered if the drugs might be able to protect against PCOS too.

To find out, they started by creating mouse models of the condition by giving female mice the hormone DHEA, which induces testosterone production. In one group, they administered the artemisinin derivative artemether (ATM). The animals that received DHEA without ATM developed cysts on their ovaries and other signs of estrous cycle disruption, while those that were given the drug did not. Additional experiments with higher doses of ATM showed that the drug was inhibiting testosterone production.

The researchers then developed a rat model of PCOS, this time using insulin and human chorionic gonadotropin injections to increase androgen production. Just as it had in mice, ATM treatment prevented them from developing PCOS symptoms, including in this case lowering testosterone levels and improving fertility.

Next, the team looked more closely at the mechanisms by which ATM was working. They found that it lowered androgen production by reducing enzyme activity in the theca cells, acting specifically on interactions between an enzyme called CYP11A1 and a protein called LONP1.

Given that artemisinin drugs are already used to treat malaria, the researchers moved to testing their findings in humans. They gave 19 people with symptomatic PCOS 40 milligram doses of the malaria drug dihydroartemisinin (DHA) three times a day for 12 weeks. The treatment restored menstrual cycle regularity in 12 of the patients and decreased levels of hormones associated with the condition, including testosterone. None of the participants experienced side effects.

“This discovery opens up avenues for controlling ovarian androgen synthesis by targeting the LONP1-CYP11A1 interaction,” the scientists wrote in their paper.

The researchers noted that there may be a link between the antimalarial and anti-PCOS functions of artemisinin drugs and suggested that future studies should test whether they have effects on a hormone called pregnenolone, an androgen precursor. They also cautioned that using artemisinin-based antimalarial drugs to treat PCOS could accelerate resistance to them, a challenge that’s already well-documented.

The study has limitations, too, both the team and Stener-Victorin noted. For example, it wasn’t possible with the rodent models the researchers used to study the way artemisinin derivatives affect testosterone production within adipose tissue and their impact on insulin sensitivity, an important consideration given that people with PCOS are known to have adipose tissue dysfunction. The researchers will also need to understand the long-term effects of the drugs and how to optimize dosing.

Concerns aside, “the discovery of artemisinins as effective remedies for PCOS nonetheless represents a promising new approach for the development of specific therapies that will potentially change the landscape of PCOS treatment,” Stener-Victorin wrote.

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