Long-term environmental exposure of darkness induces hyperandrogenism in PCOS via melatonin receptor 1A and aromatase reduction

Abstract

Polycystic ovary syndrome (PCOS) is a common and complex disorder impairing female fertility, yet its etiology remains elusive. It is reported that circadian rhythm disruption might play a crucial role in PCOS pathologic progression. Here, in this research, we investigated the effect of environmental long-term circadian rhythm dysfunction and clarified its pathogenic mechanism in the development of PCOS, which might provide the targeted clinical strategies to patients with PCOS. Female SD rats were used to construct a circadian rhythm misalignment model with constant darkness (12/12-h dark/dark cycle), and the control group was kept under normal circadian rhythm exposure (12/12-h light/dark cycle) for 8 weeks. We measured their reproductive, endocrinal, and metabolic profiles at different zeitgeber times (ZTs). Different rescue methods, including melatonin receptor agonist and normal circadian rhythm restoration, and in vitro experiments on the KGN cell line were performed. We found that long-term darkness caused PCOS-like reproductive abnormalities, including estrous cycle disorder, polycystic ovaries, LH elevation, hyperandrogenism, and glucose intolerance. In addition, the expression of melatonin receptor 1A (Mtnr1a) in ovarian granulosa cells significantly decreased in the darkness group. Normal light/dark cycle and melatonin receptor agonist application relieved hyperandrogenism of darkness-treated rats. In vitro experiments demonstrated that decreased MTNR1A inhibited androgen receptor (AR) and CYP19A1 expression, and AR acted as an essential downstream factor of MTNR1A in modulating aromatase abundance. Overall, our finding demonstrates the significant influence of circadian rhythms on PCOS occurrence, suggests that MTNR1A and AR play vital roles in pathological progression of hyperandrogenism, and broadens current treatment strategies for PCOS in clinical practice.

Essential Role of Granulosa Cell Glucose and Lipid Metabolism on Oocytes and the Potential Metabolic Imbalance in Polycystic Ovary Syndrome

“…Immature follicles in people with PCOS secrete anti-Mullerian hormone (AMH), which inhibits FSH-induced aromatase activity [147]. An important endogenous hormone, melatonin, is present in the body; long-term exposure to dark environments significantly reduces the granulosa cell surface expression of the melatonin receptor (Mtnr1a), and this decreases the ability of melatonin in regulating glucose metabolism, and also inhibits the expression of the androgen receptor (AR) and CYP19A1, thus reducing the output of aromatase in granulosa cells, hyperandrogenism can occur [148,149]. People with PCOS often experience abnormal adipokine metabolism; this mainly manifests as high levels of leptin and low levels of adiponectin.…”

The specificities, influencing factors, and medical implications of bone circadian rhythms

“…129 Other studies showed that the rhythms of serum melatonin levels in the constant dark environment persisted in both diurnal (rhesus monkeys) and nocturnal (rats) species. [130][131][132] This might be related to vitamin D as lack of light affects the synthesis of vitamin D and affects its role in the metabolism of calcium and bone minerals. In the absence of light, a study shows that only a diet rich in vitamin D is not enough to maintain the optimal level of vitamin D metabolites in the serum of mice.…”

“…It has been reported that there is a much higher incidence of spinal deformities in the cichlid A. citrinellus raised in permanent darkness than those raised under normal light conditions 129 . Other studies showed that the rhythms of serum melatonin levels in the constant dark environment persisted in both diurnal (rhesus monkeys) and nocturnal (rats) species 130–132 . This might be related to vitamin D as lack of light affects the synthesis of vitamin D and affects its role in the metabolism of calcium and bone minerals.…”

Androgen excess: a hallmark of polycystic ovary syndrome

“…Interestingly, prolonged darkness would lead to HA and IR in PCOS rat models. Downregulated melatonin receptor 1A disturbs AR expression and downstream CYP19A1 transcription ( 134 ). Another study revealed that the dysregulation of some core clock gene expression is closely associated with HA.…”