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Let there be light: does circadian rhythm disruption cause polycystic ovary syndrome?

      In 1959, Franz Halberg coined the term circadian from the Latin words circa (about) and dies (day). Circadian rhythms are endogenous, entrainable processes that repeat roughly every 24 hours, corresponding to the rotation of the Earth. In the time since, much progress has been made in delineating the molecular mechanisms controlling circadian rhythms, thereby advancing the study of our biological clocks. The suprachiasmatic nucleus of the hypothalamus, known as the master mammalian circadian clock, is activated when light hits the melanopsin photoreceptors in the eye, resulting in rhythm-establishing effects including the suppression of melatonin production by the pineal gland.
      However, the suprachiasmatic nucleus is far from the only molecular clock that matters; these “timekeepers” are pervasive throughout the peripheral tissues. Composed of transcriptional and translational feedback loops, the basis of these molecular clocks lies in the transcription factors CLOCK and BMAL1 promoting rhythmic transcription of the period and cryptochrome genes. In the reproductive realm, research within the past 15 years has expanded upon the dogma of neuroendocrine control of ovarian function by demonstrating the presence of peripheral cell-autonomous clock genes and clock-controlled gene expression in the ovary (
      • Sen A.
      • Sellix M.T.
      The circadian timing system and environmental circadian disruption: from follicles to fertility.
      ). Given these scientific advances, the inevitable question of whether circadian rhythm disruptions contribute to the pathogenesis of ovarian disease has arisen.
      In this issue of Fertility and Sterility, Wang et al. (
      • Wang F.
      • Xie N.
      • Wu Y.
      • Zhang Q.
      • Zhu Y.
      • Dai M.
      • et al.
      Association between circadian rhythm disruption and polycystic ovary syndrome.
      ) engaged in clinical and laboratory investigations to examine circadian rhythm disruption and polycystic ovary syndrome (PCOS). First, they conducted a multicenter survey in China including 436 women with PCOS and 715 women as controls to assess the association between night-shift work and PCOS. Participants who had ever engaged in night-shift work had nearly double the odds of having PCOS compared with that of those who had never engaged in night-shift work. When further subgroup analyses were performed, this association only remained statistically significant for the night-shift workers who had worked rotating (vs. permanent) night shifts and had worked night shifts for ≥2 years or more (vs. <2 years). A portion of the survey participants had morning follicular phase melatonin levels drawn with no significant differences seen between the results in women with PCOS and the women in the control group.
      For the second component of their investigation, the researchers utilized a PCOS rat model established with testosterone propionate to explore potential circadian disturbances in PCOS. In these studies, the hormone levels were repeatedly measured in the rats over 24 hours to assess for circadian variation. Again, there were no significant differences in melatonin levels at any time point, but corticotropin-releasing hormone and adrenocorticotropic hormone levels both peaked and were significantly higher than those in the control group at 6 AM. Finally, in a third experiment, luteinized human granulosa cells were collected during oocyte retrieval from three women with PCOS with infertility and three control women with tubal infertility. Ex vivo studies were performed on the granulosa cells, which were cultured in a circadian fashion. Messenger ribonucleic acid extracted over the course of 24 hours for analysis demonstrated genome-wide alteration in rhythmic expression patterns at the different time points in the PCOS women compared with results in the control women.
      This multifaceted study should be applauded for its contribution to what is currently a very small body of literature addressing the circadian rhythm gene expression in women with PCOS. However, the study is not without limitations. Despite the reasonably large survey sample size, the actual number of night-shift workers in each group was relatively small with 47 (6.6%) and 49 (11.2%) night-shift workers in the PCOS and control groups, respectively, thus increasing the likelihood of a positive finding because of chance. In contrast, the only other comparable epidemiological study did not find any associations between night-shift work and PCOS features (
      • Lim A.J.
      • Huang Z.
      • Chua S.E.
      • Kramer M.S.
      • Yong E.L.
      Sleep duration, exercise, shift work and polycystic ovarian syndrome-related outcomes in a healthy population: a cross- sectional study.
      ).
      Furthermore, the cross-sectional nature of the study precludes any ability to draw causal relationships. Although a combination of genetic and environmental factors is believed to contribute to the pathogenesis of PCOS, night-shift work by default is limited to the adult population and would not explain earlier-onset disease. However, there is certainly a biological plausibility for circadian rhythm disruption caused by night-shift work to drive hyperinsulinemia and hyperandrogenism, and as indicated by the results of the subgroup analysis, the effect may be dose-dependent. The degree to which night-shift work might either initiate or, more likely, exacerbate the PCOS phenotype is certainly a worthwhile topic of investigation in future longitudinal studies in women with PCOS.
      The exploratory ex vivo human granulosa cell genetic studies were also hampered by a small sample size, and the investigators acknowledge the limitations of using luteinized and stimulated granulosa cells, as the ovarian circadian clock has been shown to be affected by exogenous gonadotropins. However, the differences in the clock gene expression in PCOS women seen in this study are supported by another recent rat study that showed constant darkness led to decreased expression of BMAL1 and period, giving rise to metabolic and reproductive PCOS features including polycystic ovaries. Improvement of the PCOS features with melatonin and restoration of normal light/dark exposure suggest a potential therapeutic target (
      • Li S.
      • Zhai J.
      • Chu W.
      • Geng X.
      • Chen Z.J.
      • Du Y.
      Altered circadian clock as a novel therapeutic target for constant darkness-induced insulin resistance and hyperandrogenism of polycystic ovary syndrome.
      ). Without a doubt, further study of circadian rhythm disruption in PCOS has exciting translational potential that may improve clinical care in the future.

      References

        • Sen A.
        • Sellix M.T.
        The circadian timing system and environmental circadian disruption: from follicles to fertility.
        Endocrinology. 2016; 157: 3366-3373
        • Wang F.
        • Xie N.
        • Wu Y.
        • Zhang Q.
        • Zhu Y.
        • Dai M.
        • et al.
        Association between circadian rhythm disruption and polycystic ovary syndrome.
        Fertil Steril. 2021; 115: 771-781
        • Lim A.J.
        • Huang Z.
        • Chua S.E.
        • Kramer M.S.
        • Yong E.L.
        Sleep duration, exercise, shift work and polycystic ovarian syndrome-related outcomes in a healthy population: a cross- sectional study.
        PLoS One. 2016; 11e0167048
        • Li S.
        • Zhai J.
        • Chu W.
        • Geng X.
        • Chen Z.J.
        • Du Y.
        Altered circadian clock as a novel therapeutic target for constant darkness-induced insulin resistance and hyperandrogenism of polycystic ovary syndrome.
        Transl Res. 2020; 219: 13-29

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