Biological rhythms in female reproduction: a link with clinical data, uterine receptivity and implantation

Abstract

Many aspects of physiological function are strongly circadian. Disturbance of these intrinsic modulators is implicated in disease states, but the role of biological rhythmic control in the context of reproduction is still largely unknown. The circadian network is apparent in all aspects of reproductive functioning; from menstruation to implantation and pregnancy. Endometrial dysfunction may occur if regulatory processes do not happen, with a disruptive effect on the synchronisation of implantation. Whether this dysregulation happens at the level of the endometrium, at the embryo-endometrial interface or at the level of clock genes is not known.

This work has investigated the role these biological rhythms, in particular those pertaining to that of uterine receptivity and implantation. By a systematic review and a meta-analysis of shift workers, a population being at risk of adverse early reproductive outcomes was identified. The link between experiencing poor early reproductive outcomes and sleep and activity was further investigated and it was shown that sleeping and activity patterns are different in reproductive pathology as compared with fertile healthy women.

The molecular basis of observed relationships between sleep and reproductive difficulty was investigated by examination of the uterine environment. Human samples were compared in-vivo, and with in-vitro culture models in unstimulated, normal menstrual cycles. This was to examine whether the difference in the circadian rhythm, which leads to deleterious effects in other pro-inflammatory disease, could be linked to the uterine environment of women with reproductive pathology. The immunomodulatory uterine secretome profile in women suffering from recurrent implantation failure (RIF) was shown to be different from fertile women.

The expression of core clock genes within the uterus was shown to be cyclical in a circadian manner. The effect of decidualisation appeared to effect the phase, but not the period of this expression. The distinct pattern of endometrial secretions in each group of women (RIF and fertile controls) was compared with the reciprocal core clock gene expression, and was shown to be correlated with a four-hour time lag. The geneimmunomodulator association was effected by decidualisation, more so in the women suffering from RIF than the controls. The addition of melatonin to the cell culture model made the RIF endometrium respond more like the control endometrium. After treatment with melatonin, cells from women with RIF had a more similar geneimmunomodulator profile to the control women. This effect was more noticeable after decidualisation. Whether or not this can be considered a beneficial alteration has not been ascertained.

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ORCID for Ying Cheong: orcid.org/0000-0001-7687-4597

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