Pioglitazone Metformin Complex Improves Polycystic Ovary Syndrome Comorbid Psychological Distress via Inhibiting NLRP3 Inflammasome Activation: A Prospective Clinical Study

Abstract

Objective. This study aimed at investigating the therapeutic effect and mechanism of pioglitazone metformin complex preparation (PM) in polycystic ovary syndrome (PCOS) comorbid psychological distress. Methods. Seventy-five patients with PCOS comorbid psychological distress were randomly allocated into the PM, metformin, and placebo groups. The primary efficacy measure was the change from baseline to week 12 on the Symptom Checklist 90-R (SCL-90-R) scores. NLRP3 inflammasome, IL-1β, IL-6, TNF-α, and biochemical parameters were determined at baseline and at week 12. The participants were required to meet the criteria for PCOS (Rotterdam, NIH) and psychological distress (any factor scores of SCL−90−R>2). Results. The participants had significantly high scores on the SCL-90-R scales of anxiety and depression. PM significantly decreased anxiety and depression symptom severity (from 2.31±0.75 to 1.65±0.38, p<0.001, and from 2.08±0.74 to 1.61±0.46, p=0.010, at week 12, respectively). PM significantly decreased the expression of NRPL3 and caspase-1. Patients in the PM group experienced a significant reduction in IL-1β (from 98.42±14.38 to 71.76±13.66, p=0.02), IL-6 (from 87.51±8.74 to 71.98±15.87, p=0.02), and TNF-α (from 395.33±88.55 to 281.98±85.69, p=0.04). PM was superior to metformin in reducing total testosterone (2.24±0.74 versus 3.06±0.83, p=0.024, at week 12).Conclusions. This study is the first to reveal that PM alleviates psychological distress via inhibiting NLRP3 inflammasome and improves several markers, including total testosterone.

Interference With the AMPKα/mTOR/NLRP3 Signaling and the IL-23/IL-17 Axis Effectively Protects Against the Dextran Sulfate Sodium Intoxication in Rats: A New Paradigm in Empagliflozin and Metformin Reprofiling for the Management of Ulcerative Colitis

“…The superiority of metformin over empagliflozin in suppressing mTOR activity could be due to its role in inhibiting mTOR via AMPK-independent mechanisms such as Rag GTPases-dependent suppression of mTORC1 signaling ( Kalender et al, 2010 ). Concerning their effect on NLRP3 inflammasome, it was previously reported that metformin had a significant inhibitory effect on NLRP3 ( Bullón et al, 2016 ; Yang et al, 2019 ; Guo et al, 2020 ), which is opposite to our findings; in which metformin had an insignificant effect on the NLRP3 on the protein and the gene expression levels. In our study, individual administration of both drugs showed minimal inhibitory effect on NLRP3 inflammasome and the subsequent inhibition of caspase-1 activation, IL-1β, and IL18.…”

Leptin Signalling in the Ovary of Diet-Induced Obese Mice Regulates Activation of Nod-Like Receptor Protein 3 Inflammasome

“…Certainly, our hypothesis of NLRP3 inflammasome involvement in inflammatory response in the ovary of obese mothers seems to be supported also by earlier reports showing NLRP3 inflammasome activation during development and treatment of PCOS (Guo et al 2020;F. Wang et al 2017).…”

The effect of polycystic ovarian syndrome on the mental health of women of reproductive age

“…1 The most common of these symptoms are depression and anxiety while others include bipolar disorder, schizophrenia spectrum disorder, eating disorder, personality disorder, sleeping disorder, and psychosis. 15,18,19 The exact pathophysiology of these conditions however is not yet fully understood. 20 Alexithymia, a personality trait characterized with difficulty to identify and distinguish emotions from bodily sensations, difficulty to describe and verbalize emotions, externally oriented thinking style, poverty of fantasy life or imaginative ability, and poor empathy is a risk factor for various physical and mental health problems including anxiety, depression, compulsive or addictive behaviours, physical symptoms, and potentially psychosomatic diseases.…”