Scientists show that the anti-malarial drug, Artemisinin, can reduce symptoms of polycystic ovarian syndrome by targeting one of its root causes.
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A tumultuous, roaring river flows by a bank full of stones, some of which are arranged in a precariously balanced and gravity-defying sculpture. A tiny disturbance in the overall equilibrium can send the entire structure tumbling down. Much like this ancient art form of rock stacking, the human endocrine system also relies on a harmonious balance of over 50 different hormones. A tilt in any direction can cause a cascade of effects, resulting in diseases like diabetes, obesity, and polycystic ovarian syndrome (PCOS).
PCOS affects 10 to 13 percent of reproductive-age women, who can experience any of the associated collection of symptoms, such as irregular menstruation, ovarian cysts, obesity, insulin resistance, excessive growth of facial hair, and infertility, among others.1 Current treatments for the disorder include oral contraceptive pills and blood-sugar-controlling medicines. While these help to address certain symptoms, neither target the root cause of PCOS.
Now, Qi-Qun Tang, an adipocyte researcher at Fudan University Shanghai Medical College, and his team showed that anti-malarial drug compounds called artemisinins can ameliorate various symptoms of PCOS by restoring the hormonal imbalance in both rodent models and human patients. “PCOS has so many complicated symptoms. This is the first treatment that can deal with almost all of them,” he said. In doing so, the authors identified molecular targets for developing other therapies for PCOS. Their study was published in the journal Science.2
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“I was impressed that they actually got the idea of looking into this in such detail as they did,” said Elisabet Stener-Victorin, a reproductive endocrinologist at Karolinska Institute, who was not involved in the study. “How did they get the thinking of actually doing this?”
Tang’s venture into PCOS biology was an outcome of a serendipitous finding in a different project. In a screen to identify molecules for treating metabolic disorders like obesity, Tang discovered that artemisinin enhances the function of brown fat.3 Around the same time, another group showed that brown fat is dramatically reduced in PCOS rat models, as compared to healthy animals.4 They also observed a reduction in symptoms when they transplanted brown fat into the rats with PCOS. Based on their combined findings, Tang wondered if artemisinin could help treat PCOS.
From the first experiment, the team saw promising results. One of the main drivers of PCOS is an increase in the levels of a class of sex hormones called androgens, such as testosterone. Therefore, Tang and his colleagues established a PCOS-like mouse model by injecting the animals with androgens. Simultaneously, they treated the mice with a derivative of artemisinin—artemether (ATM)—and observed a dramatic improvement in PCOS symptoms. The drug lowered the elevated levels of serum testosterone, improved the disrupted estrous cycle, and significantly reduced the number of cyst-like follicles in the ovaries, as compared to PCOS-like mice that did not receive the treatment. The researchers wanted to know if these effects translated to the animal’s fertility; they observed that ATM treatment increased the success rate of embryo implantation and the number of pups born. This was a huge improvement in comparison to oral contraceptive pills, which have no impact on ovarian morphology or infertility.
Tang wanted to uncover the cellular pathways responsible for the inhibitory effect of ATM on testosterone levels in PCOS-like mice. In females, ovaries are one of the major sources of androgens, within which, a series of enzymes convert cholesterol to androgens. The team performed a quantitative protein analysis on mouse ovarian cells with and without ATM and observed that ATM significantly diminished the levels of one of these enzymes: cytochrome P450 family 11 subfamily A member 1 (CYP11A1). The ATM-treated cells also had reduced testosterone levels as compared to untreated cells, confirming the link between CYP11A1 and androgen production. Tang and his colleagues saw a similar reduction in CYP11A1 levels in PCOS-like mice that were administered ATM.
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Next, the team wanted to decipher the mechanism by which ATM reduced CYP11A1. The researchers noticed that ATM shortened the half-life of CYP11A1, thus making the enzyme more unstable and easily degradable. To discover the mediators responsible for this effect, they conducted an immunoprecipitation assay and identified two proteins that interacted with CYP11A1. ATM dramatically enhanced the binding of one of these proteins with CYP11A1, lon peptidase 1 (LONP1), a mitochondrial protease that degrades misfolded or oxidized proteins. The authors speculated that ATM acts as a molecular glue, enhancing the association between these two proteins and consequently, the degradation of CYP11A1. When they overexpressed LONP1 in mice ovaries, they observed a drastic drop in CYP11A1, and consequently, testosterone levels.
Researchers have previously shown that expression of CYP11A1 is higher and that of LONP1 is lower in ovarian cells of women with PCOS, as compared to normal ovarian cells.5 So, Tang and his team performed a pilot clinical study to determine if ATM can treat PCOS in human patients as well. They recruited 19 individuals with PCOS and treated them with oral artemisinin for 12 weeks. After the treatment was over, the team observed a significant reduction in serum testosterone levels and improved ovarian morphology among the individuals. Further, 63 percent of them reported that their menstrual cycles became regular after being administered ATM.
Despite the overwhelmingly positive results in patients, Stener-Victorin cautioned that a ton of work needs to be done before artemisinin can be prescribed to people with PCOS. "When it is an uncontrolled study, you have a very strong placebo effect,” she said. “What's needed here is a randomized control placebo control trial,” she said.