Humanin: A Potential Treatment for PCOS?

Advancements in the management of polycystic ovary syndrome (PCOS) have proven to be difficult given the heterogeneity of the disorder and the fact that the cause of PCOS remains elusive. Further understanding of the underlying cause(s) of PCOS is essential for the future development of treatments that effectively alleviate PCOS symptoms. Although diagnosis of PCOS is based on reproductive and endocrinological traits, associated metabolic features of the condition have become more recognized as key PCOS features; therefore, new interventions that target metabolic PCOS traits are needed. A recent publication, by Wang et al (1) highlights the potential involvement of a mitochondria-derived peptide, humanin, in the pathology of PCOS, and how a humanin analogue, HNG, could be a prospective treatment to alleviate the insulin resistance (IR) associated with PCOS.

Humanin, is reported to be involved in metabolic processes, such as diabetes and more recently PCOS (2). Wang et al (1), report a decrease in humanin concentrations in follicular fluid from women with PCOS who also display IR, but not in non-PCOS or control patients with IR, suggesting an association between humanin, IR, and PCOS. It is unclear if the decrease in humanin is a consequence of the PCOS phenotype or if it plays a role in the development of PCOS. However, the authors have carried out initial experiments that point to a potential role of humanin in the pathology of PCOS, although further work is needed to determine if humanin has an initiating role. To investigate if increasing humanin levels could alleviate PCOS features, the authors tested humanin supplementation using the humanin analogue HNG, in a PCOS rat model. They found that HNG attenuated the elevated fasting glucose, fasting insulin, and HOMA-IR levels experienced by PCOS rats to levels comparable to controls (1). The authors concluded from these studies that HNG is able to improve systemic IR.

Metformin is recommended in the 2018 guidelines for the management of PCOS-associated metabolic features, however the effectiveness of metformin varies across patient cohorts (3, 4). Myo-inositol is also reported to improve IR in some PCOS patients (5); however both metformin and myo-inositol have not consistently been shown to improve other associated metabolic PCOS features (4, 5). Lifestyle interventions, including exercise, are recommended as first-line treatment for women with PCOS, as weight loss has been demonstrated to improve PCOS features. Interestingly, mitochondrial-derived peptides, like humanin, activate similar signaling pathways to exercise, therefore are thought to act as an exercise mimetic (6). Hence, the use of humanin may be a useful therapeutic to improve IR in PCOS patients and could potentially have downstream positive effects similar to exercise.

In a previous publication by the same group, HNG supplementation was observed to decrease body weight gain and improve ovarian morphology in a dehydroepiandrosterone (DHEA)-induced PCOS rat model (2). In the most recent publication (1), the authors report a link between humanin levels and IR in the same DHEA-induced PCOS rats. However, further research is needed in other PCOS animal models, as a recent review by experts in the field reported that the DHEA rat model used is not an ideal model to study PCOS because, besides displaying PCOS-like traits, they also present other PCOS-excluding endocrinopathies (7). Therefore, additional studies using other rodent models of PCOS, such as the testosterone or dihydrotestosterone induced PCOS rats and mice, should be performed, as well as studies in sheep and/or primate models of PCOS, to determine if the effects of HNG are replicable. Additionally, further basic research should be conducted on the safety of HNG long-term effects, so that future clinical trials can be conducted in PCOS patients.

To elucidate the mechanism by which HNG improves IR, Wang et al (1) analyzed granulosa cells from PCOS rats treated with HNG. They observed that PCOS rats treated with HNG displayed an upregulation of phosphorylation of insulin receptor substrate 1 (IRS1), phosphoinositide-3-kinase (PI3K), and protein kinase B (AKT), which was downregulated in PCOS rats not treated with HNG. Phosphorylation of IRS1, PI3K and AKT meant that the reduction in signal transduction pathways in PCOS rat granulosa cells were activated by HNG treatment, thus HNG improved glucose uptake in these cells. This improvement in glucose uptake was also demonstrated by in-vitro studies in which combined HNG and insulin treatment increased glucose consumption, and IRS1 and AKT expression in normal COV434 cells and COV434 cells where humanin was knocked down (1). The authors also reported that GLUT4 expression was downregulated in PCOS rats, but HNG supplementation attenuated this effect and promoted GLUT4 translocation from the cytoplasm to the membrane, implying that humanin had an effect on glucose transport and thus could potentially improve glucose homeostasis and consequently IR. Insulin-mediated glucose uptake has been reported to be abnormal in granulosa cells from anovulatory PCOS patients (8), therefore it would be interesting to investigate if decreased humanin levels are also associated with anovulation in PCOS. These findings from Wang et al support further research into glucose metabolism in PCOS ovaries and the role of humanin in ovarian IR.

This study advances current research pursuing the identification of novel and effective new treatments for ameliorating PCOS. The potential role of humanin in PCOS pathogenesis is an exciting discovery that adds a new piece of the puzzle to unraveling the cause of PCOS, but also raises further important questions. Wang et al (1) provide insight into the possible importance of humanin in the development of ovarian IR in PCOS. However, further studies on the effects of HNG supplementation on oocyte quality are needed to understand the effects on oocyte development, fertility, and potential transgenerational effects. This knowledge is essential for the safe use of HNG and future translation of this research to PCOS patients. Additionally, it is important to understand why IR-PCOS patients present with decreased levels of humanin in follicular fluid and to determine if this can be prevented. In summary, this study by Wang et al (1) has highlighted a novel new potential role for humanin in PCOS. Further research into the mechanisms by which humanin is potentially involved in causing IR in PCOS will reveal if humanin is an appropriate target for the development of future mechanism-based therapies for women with PCOS.