Antimalarial Compounds Show Promise in Treating PCOS

A new study, published in Science, investigates the therapeutic potential of antimalarial compounds for polycystic ovary syndrome (PCOS).

The lack of available PCOS treatments

PCOS affects 10–13% of women worldwide. Yet, despite the condition's prevalence, the molecular mechanisms underpinning the disease are still unknown.

PCOS is characterized by elevated levels of male sex hormones called androgens. The reproductive disorder is associated with fertility issues, metabolic dysfunction and impaired ovulation. Most of the current treatments for PCOS focus on managing symptoms rather than treating the disorder, leaving women worldwide to struggle with their condition. Controlling excess androgen levels is essential for effective PCOS treatment.

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Artemisinins, derived from Artemisia plants, are best known for their treatment of malaria. The plant-derived compound, and its derivatives, have previously been shown to promote energy expenditure and insulin sensitivity through the activation of thermogenic adipocytes. In this same study, artemisinins were also highlighted for their potential in treating PCOS due to their ability to strongly inhibit ovarian androgen synthesis, reduce immature follicles and improve the estrous cycle in rodents and humans.

Analyzing artemisinins in rodent models

In the new Science study, researchers used both in vitro and in vivo approaches to investigate the effect of artemisinins on the development of PCOS. Rodent models were injected with dehydroepiandrosterone (DHEA), a hormone produced by the body's adrenal glands, to increase serum testosterone levels and promote irregular estrous cycles and polycystic ovarian morphology, establishing PCOS-like profiles.

To evaluate the protective effects of artemisinins against the development of PCOS, animal models were injected with the compound artemether (ATM) and DHEA simultaneously. A second experimental group was treated with ATM after establishing the PCOS-like profile to investigate its therapeutic effects.

When ATM was administered simultaneously with DHEA, the elevated serum testosterone in the DHEA-treated mice was ablated, thereby reducing PCOS-like traits. Disrupted estrous cycles were improved in the treatment group and the ovaries of the mice also exhibited normal morphology, suggesting ATM’s potential for preventing PCOS development.

In the rodent group that investigated ATM’s therapeutic effects, dose-dependent administration decreased serum testosterone, recovered normal estrous cycles and dramatically reduced cystic follicles in the ovaries.

Relative quantitative proteomics analysis showed the decrease in ovarian androgen synthesis was due to enhanced degradation of CYP11A1, a key enzyme in androgen production, resulting from increased interactions with the protease LONP1.

Pilot trial yields promising results

The researchers also studied the compound's effects in humans.  In a pilot study, including 19 women diagnosed with PCOS, participants were administered oral dihydroartemisinin 3 times daily for 12 weeks. Testosterone and anti-Müllerian hormone (AMH) levels were measured before and after the 12-week trial. Ovarian antral follicles were also evaluated by transvaginal ultrasounds, and menstrual cycles were recorded for 24 weeks before the trial and 24 weeks after the trial was complete.

All patients exhibited a significant decrease in serum testosterone and AMH levels, improved polycystic ovarian morphology and regular menstruation was restored in 12 out of 19 patients. The drug was found to substantially reduce key PCOS biomarkers without any side effects.

“Although further studies will be needed to fully understand the long-term effects and to optimize dosing strategies to maximize therapeutic outcomes, 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,” said [RLS2] Dr. Elisabet Stener-Victorin, who was not involved in the original study, in a related Perspective paper.  Stener-Victorin is a professor of reproductive physiology in the Department of Physiology and Pharmacology at the Karolinska Institute.

Reference: Liu Y, Jiang J, Du S, et al. Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction. Science. 2024. doi: 10.1126/science.adk5382

This article is a rework of a press release issued by The American Association for the Advancement of Science. Material has been edited for length and content.