Antimalarial drug inhibits testosterone production in ovaries

Some 10 to 13 per cent of women of reproductive age struggle with polycystic ovary syndrome (PCOS), a hormonal disorder in which the excessive formation of follicles or cysts in the ovaries impedes ovulation and thereby leads to reduced fertility. Women with PCOS have too little follicle-stimulating hormone (FSH), whilst levels of luteinising hormone (LH) and testosterone are too high. This hormonal imbalance means the condition is also associated with a disrupted metabolism, abnormal and excessive hair growth on the body and face, and a higher risk of developing type 2 diabetes.

Despite its high prevalence, there is as yet no curative treatment for this condition, but that may now be about to change. Chinese researchers describe in Science on 13 June last the therapeutic potential of artemether (ATM), a derivative of the antimalarial drug artemisinin, to influence testosterone production in the ovaries. This occurs via an indirect route. ATM stimulates the breakdown of the enzyme CYP11A1 (cytochrome P450 family 11 subfamily A member 1), which catalyses the conversion of cholesterol to pregnenolone — the first step in the biosynthesis of testosterone.

Androgenic hormones

Women with PCOS have markedly elevated levels of this enzyme, as well as of other key enzymes involved in the production of androgenic, ‘male’, hormones. ATM acts specifically on lon peptidase 1 (LONP1), an ATP-dependent serine protease that hydrolyses peptide bonds to break down misfolded or oxidised proteins within the mitochondria. By binding to LONP1, the artemisinin derivative stimulates the interaction between CYP11A1 and LONP1, triggering the LONP1-catalysed degradation of the CYP11A1 protein. Less CYP11A1 means a declining production of male hormones in the ovaries.

Notably, an induced increase in LONP1 production also led to lower levels of male hormones. Conversely, it was found that once the researchers restored androgen production to levels characteristic of PCOS, the binding between LONP1 and CYP11A1 diminished. The amount of LONP1 decreased, whilst that of CYP11A1 rose again.

Clinical study

The inhibitory effect of ATM proved dependent on direct binding to the proteolytic domain of LONP1, and was moreover dose-dependent. The researchers tested ATM as a therapy for PCOS in rodent models and in an initial pilot clinical trial with 19 PCOS patients. This group was administered dihydroartemisinin, the active metabolite of all artemisinin variants, over a period of 12 weeks. The typical symptoms of PCOS diminished: testosterone levels fell and fewer follicles were visible in the ovaries. In 12 of the 19 women, the menstrual cycle normalised as well. The drug produced no side effects.

‘Although further studies are needed to fully understand the long-term effects and to optimise the dosage for the best therapeutic outcome, the discovery of artemisinins as a treatment for PCOS nonetheless represents a promising new approach that will transform the therapeutic landscape,’ writes Elisabet Stener-Victorin of the Swedish Karolinska Institute in a related perspective. She further notes that follow-up research is also desirable to elucidate other effects of artemisinins on PCOS symptoms. PCOS is also associated, for instance, with aberrant fat metabolism and insulin sensitivity.

The same team previously discovered that artemisinin and its derivatives ATM, artesunate (ATS) and SM934 are also capable of activating brown adipose tissue. The energy expenditure and insulin sensitivity of the brown fat cells increase as a result, meaning these compounds may potentially offer protection against obesity and metabolic disease. However, what effect they have on the adipose tissue and glucose metabolism of women with PCOS has yet to be established. Furthermore, the researchers looked only at the effect of ATM on testosterone synthesis in the ovaries, whilst male hormones are also produced in the adrenal glands.

Yang Liu, et al., Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction, Science (2024), doi:10.1126/science.adk5382

Elisabet Stener-Victorin, Remedy hope for polycystic ovary syndrome, Science (2024), doi:10.1126/science.adq0328