It seems that many bodily organs and systems operate with fixed, time-related rhythms that have a wide variety of paces. Virtually all biological processes in the body are modulated by an internal circadian clock which optimizes physiological and behavioral performance according to the changing demands of the external 24-h world. In mammals, the circadian clock is intimately involved in the control of metabolic and physiological processes and its disruption can be either the cause or the effect of various disorders including metabolic syndrome  or cancer predisposition . To note, the ability of living systems to sustain 24-h rhythms in the absence of environmental cues shows that most daily oscillations are generated by an internal clock. This is a hierarchal, very complex system which is regulated by a set of core ‘clock’ genes (such as PER1 and BMAL1) through a master circadian pacemaker located in the suprachiasmatic nucleus (SCN) in the hypothalamus . Neural and endocrine/hormonal pathways then deliver the downstream signals to their targets. In the case of a 24-h cycle, the link between the internal pacemaker and the external environment involves the daily light–dark cycle.
Sex differences in circadian mechanisms occur at several levels . At the SCN they include variances in morphology, electrical activity and gonadal steroid receptors. Outside the SCN there are dissimilarities in other brain areas, such as the pineal body (melatonin excretion) and the hypothalamic–pituitary–peripheral axes. Apart from the above gender issues, another major factor seems to be age, since the circadian clock undergoes significant changes throughout the life span, at both the physiological and molecular levels . Perhaps the best and most disturbing example would be the change in sleep patterns with early waking and associated daily tiredness and napping [6, 7]. Needless to mention that sleep disturbances are a mainstay of the menopause symptomatology, and that any deviation from a normal wake–sleep circadian pattern may carry untoward outcomes . Perhaps the most investigated issue in this respect is the circadian rhythm of melatonin release from the pineal gland, which is highly synchronized with the habitual hours of sleep [7, 9]. Endogenous secretion of melatonin decreases with aging across genders, and, among women, menopause is associated with a significant reduction of melatonin levels, affecting sleep . Nocturnal hot flushes are certainly a significant factor in sleep quality. A circadian rhythm was detected in the daily pattern of hot flushes, with a peak in the afternoons [11, 12]. Although it might seem that hot flushes and melatonin secretion are likely related, there are not enough data to support such a hypothesis. A small (n = 20), randomized, placebo-controlled study looked into the effect of melatonin on luteinizing hormone in postmenopausal women . The results were consistent with other studies that pointed at suppression of luteinizing hormone (LH) by melatonin. It was assumed that the same hypothalamic pulse generator may trigger the pulsatile release of gonadotropin releasing hormone and LH as well and cause hot flushes. Thus, if melatonin suppressed this pulse generator in postmenopausal women, it might relieve hot flushes. Such an effect, however, was not found in this study. Another randomized, placebo-controlled trial of melatonin on breast cancer survivors (n = 96) reached similar conclusions since subjects randomized to melatonin experienced significantly greater improvements in subjective sleep quality, but there were no significant differences in measures of hot flushes .
There is already robust evidence that genetics plays a major role in the circadian rhythm. Even a single nucleotide polymorphism may lead to a different pattern of the circadian rhythm and the ensuing wake–sleep cycle . Many studies have concluded that postmenopausal women exhibit loss of circadian robustness and an increase in sleep abnormalities compared with premenopausal women . This cyclical physiological process is very complex and multifactorial, may be associated with metabolic alterations and development of cancer, and in fact is still largely not well understood.
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel