Pineal melatonin rhythms and the timing of puberty in mammals

The direction of change in daylength provides the seasonal time cue for the timing of puberty in many mammalian species. The pattern of melatonin secretion from the pineal gland transduces the environmental light-dark cycle into a signal influencing the neuroendocrine control of sexual maturation. The change in duration of nocturnal melatonin secretion is probably the key feature of the melatonin signal which conveys daylength information. This information may also be used by neuroendocrine axes controlling seasonal changes in pelage colour, growth and metabolism. The mechanism of action of melatonin on neuroendocrine pathways is unknown. Although the ability to synthesize and secrete melatonin in a pattern that reflects the duration of the night may not occur until the postnatal period, the rodent and ovine foetus has the ability to respond in utero to photoperiodic cues to which its mother is exposed in late gestation. Transplacental passage of maternal melatonin is likely to be the mechanism by which photoperiodic cues reach the foetus. Species which do not exhibit seasonal patterns of puberty, such as the human, also secrete melatonin in a pattern which reflects the environmental light-dark cycle, but they do not respond reproductively to the seasonal melatonin information.     

The melatonin rhythm: both a clock and a calendar

The paper briefly reviews the data which shows that the circadian production and secretion of melatonin by the pineal gland can impart both daily, i.e., clock, and seasonal, i.e., calendar, information to the organism. The paper summarizes the 3 patterns of nocturnal melatonin production that have been described. Clearly, regardless of the pattern of nocturnal melatonin production a particular species normally displays, the duration of nightime elevated melatonin is proportional to the duration of the night length. Since daylength under natural conditions changes daily the melatonin rhythm, which adjusts to the photoperiod sends time of year information to the organism. The melatonin receptors which subserve the clock message sent by the pineal gland in the form of a melatonin cycle may reside in the biological clock itself, namely, the suprachiasmatic nuclei (SCN). The melatonin receptors that mediate seasonal changes in reproductive physiology are presumably those that are located on the pars tuberalis cells of the anterior pituitary gland. Besides these receptors which likely mediate clock and calendar information, melatonin receptors have been described in other organs. Interestingly, the distribution of melatonin receptors is highly species-specific. Whereas the clock and calendar information that the melatonin cycle imparts to the organism relies on cell membrane receptors, a fact that is of some interest considering the high lipophilicity of melatonin, recent studies indicate that other functions of melatonin may require no receptor whatsoever.     

Neural systems underlying photoperiodic time measurement: a blueprint

This paper briefly reviews the formal properties of the photoperiodic time measurement apparatus of mammals and presents a hypothetical model for the operation of the neural systems responsible for reading and responding to the nocturnal pineal melatonin signal. The primary melatonin readout mechanism is held to be common to all species responsive to melatonin. It seems likely that this mechanism responds to relative changes in the duration and amplitude of the melatonin signal, rather than the absolute levels of melatonin encountered. A series of neural systems which exploit the calendar information provided by the primary readout is envisaged to vary between and within species, depending upon the neuroendocrine response under consideration. Of particular importance is a mechanism for comparing the relative duration of successive melatonin signals. These more complex elements are responsible for phenomena such as the effects of photoperiodic history and photorefractoriness. The brain may be able to encode an accumulated memory of melatonin signals and thereby define longer term intervals within the annual cycle. A series of response elements within the hypothalamus are engaged by the appropriately processed photoperiodic stimuli. For all elements of this model, their anatomical representations are poorly understood or, in certain cases, completely unknown.     

Neural systems underlying photoperiodic time measurement: A blueprint

Summary This paper briefly reviews the formal properties of the photoperiodic time measurement apparatus of mammals and presents a hypothetical model for the operation of the neural systems responsible for reading and responding to the nocturnal pineal melatonin signal. The primary melatonin readout mechanism is held to be common to all species responsive to melatonin. It seems likely that this mechanism responds to relative changes in the duration and amplitude of the melatonin signal, rather than the absolute levels of melatonin encountered. A series of neural systems which exploit the calendar information provided by the primary readout is envisaged to vary between and within species, depending upon the neuroendocrine response under consideration. Of particular importance is a mechanism for comparing the relative duration of successive melatonin signals. These more complex elements are responsible for phenomena such as the effects of photopheriodic history and photorefractoriness. The brain may be able to encode an accumulated memory of melatonin signals and thereby define longer term intervals within the annual cycle. A series of response elements within the hypothalamus are engaged by the appropriately processed photoperiodic stimuli. For all elements of this model, their anatomical representations are poorly understood or, in certain cases, completely unknown.     

Seasonal pattern of melatonin excretion in humans: relationship to daylength variation rate and geomagnetic field fluctuations

In order to investigate the influence of various environmental parameters on melatonin excretion, the night-time urinary melatonin excretion of 16 healthy volunteers was measured in samples collected monthly over a period of one year. No significant interindividual differences were detected in the monthly rate of change of melatonin excretion. A seasonal bimodal pattern did, however, emerge. Peak values were observed in June and November. In these months a combination of high daylength stability and low values of the vertical component of the geomagnetic field was recorded. Trough values were found in April and August–October when low daylength stability was combined with high values of the vertical component of the geomagnetic field. We propose that the daylength variation rate, and the fluctuations of the vertical component of the geomagnetic field, interact to induce the changes in melatonin secretion which signalize the different seasons in humans.     

Mammalian pineal melatonin: a clock for all seasons

The central role of the pineal gland and its hormone melatonin (MEL) in mammalian photoperiodic responses is discussed in terms of: 1) evidence for the involvement of MEL in photoperiodism, 2) which feature of the MEL secretion profile might be most important for regulating photoperiodic responses, 3) evidence for the modulation of responses to changes in daylength based on previous photoperiod exposure (i.e., photoperiodic history) and 4) how the MEL signal might be processed at its target sites to elicit physiological responses.     

Mammalian pineal melatonin: A clock for all seasons

Summary The central role of the pineal gland and its hormone melatonin (MEL) in mammalian photoperiodic responses is discussed in terms of: 1) evidence for the involvement of MEL in photoperiodism, 2) which feature of the MEL secretion profile might be most important for regulating photoperiodic responses, 3) evidence for the modulation of responses to changes in daylength based on previous photoperiod exposure (i.e., photoperiodic history) and 4) how the MEL signal might be processed at its target sites to elicit physiological responses.     

Some reflections on the phylogeny and function of the pineal

The pineal gland is a universal feature of vertebrate organization and has been implicated in the control of rhythmic adaptations to daily and seasonal cycles. This paper considers three aspects of pineal function; the generation of a rhythmical endocrine signal (the nocturnal synthesis of melatonin) and the use of the signal in the regulation of circadian and photoperiodic functions. The shape of the nocturnal signal is determined by an interaction of afferent neural control and biochemical processes intrinsic to the pinealocyte. The nature of the effect of the signal upon circadian systems is unclear, and in adult mammals may not be a specific, direct influence upon the entrainment pathways of the oscillator. In the foetus, strong evidence exists for a physiological role of the maternal melatonin signal as a true internal zeitgeber, remnants of which may persist in the adult. Photoperiodic time measurement in adult and foetal mammals is critically dependent upon the melatonin signal. Indirect evidence indicates that several neural systems may be involved in the response to melatonin and consistent with this, a variety of central melatonin binding sites have been identified in the brain and pituitary. The intra-cellular actions of melatonin and the properties of melatonin responsive neural systems have yet to be identified, but in the context of photoperiodic time measurement, it is clear that the neural responses to melatonin are not dependent upon the circadian clock. The two central effects of melatonin; photoperiodic time measurement and circadian entrainment are probably mediated through completely separate mechanisms.     

Some reflections on the phylogeny and function of the pineal

Summary The pineal gland is a universal feature of vertebrate organization and has been implicated in the control of rhythmic adaptations to daily and seasonal cycles. This paper considers three aspects of pineal function; the generation of a rhythmical endocrine signal (the nocturnal synthesis of melatonin) and the use of the signal in the regulation of circadian and photoperiodic functions. The shape of the nocturnal signal is determined by an interaction of afferent neural control and biochemical processes intrinsic to the pinealocyte. The nature of the effect of the signal upon circadian systems is unclear, and in adult mammals may not be a specific, direct influence upon the entrainment pathways of the oscillator. In the foetus, strong evidence exists for a physiological role of the maternal melatonin signal as a true internal zeitgeber, remnants of which may persist in the adult. Photoperiodic time measurement in adult and foetal mammals is critically dependent upon the melatonin signal. Indirect evidence indicates that several neural systems may be involved in the response to melatonin and consistent with this, a variety of central melatonin binding sites have been identified in the brain and pituitary. The intra-cellular actions of melatonin and the properties of melatonin responsive neural systems have yet to be identified, but in the context of photoperiodic time measurement, it is clear that the neural responses to melatonin are not dependent upon the circadian clock. The two central effects of melatonin; photoperiodic time measurement and circadian entrainment are probably mediated through completely separate mechanisms.The Editors wish to thank Dr M. Hastings for coordinating this multi-author review.     

Persistent 24-h variations of urinary 6-hydroxy melatonin sulphate and cortisol in Antarctica

Bright light (2000-3000 lux) of sufficient intensity to suppress human melatonin secretion, acts as a strong zeitgeber in the entrainment of circadian rhythms in man. In polar conditions, light of this intensity is not experienced for several weeks during the winter. The entrainment of human circadian rhythms, in particular that of melatonin, is clearly of interest in these circumstances. Urinary 6-hydroxy melatonin sulphate (aMT6s) is a good index of melatonin secretion in man. In a limited study of seven male volunteers living on an Antarctic base the overall 24-h rhythm of aMT6s excretion was maintained at four different times of year (spring, summer, autumn and winter) and no significant seasonal effects were noted. Cortisol excretion, appeared to be markedly affected by the season although other factors such as social and environmental stress cannot be discounted. These observations suggest that in the absence of a strong light-dark cycle melatonin production may be entrained by other factors.     

Persistent 24-h variations of urinary 6-hydroxy melatonin sulphate and cortisol in Antarctica

Summary Bright light (2000–3000 lux) of sufficient intensity to suppress human melatonin secretion, acts as a strong zeitgeber in the entrainment of circadian rhythms in man. In polar conditions, light of this intensity is not experienced for several weeks during the winter. The entrainment of human circadian rhythms, in particular that of melatonin, is clearly of interest in these circumstances. Urinary 6-hydroxy melatonin sulphate (aMT6s) is a good index of melatonin secretion in man. In a limited study of seven male volunteers living on an Antarctic base the overall 24-h rhythm of aMT6s excretion was maintained at four different times of year (spring, summer, autumn and winter) and no significant seasonal effects were noted. Cortisol excretion, appeared to be markedly affected by the season although other factors such as social and environmental stress cannot be discounted. These observations suggest that in the absence of a strong light-dark cycle melatonin production may be entrained by other factors.     

Melatonin: presence and formation in invertebrates

In vertebrates, it is now clearly demonstrated that the pineal gland is implicated in conveying photoperiodic information via the daily pattern of melatonin secretion. Invertebrates, like vertebrates, use photoperiodic changes as a temporal cue to initiate physiological processes such as reproduction or diapause. How this information is integrated in invertebrates remains an unsolved question. Our review will be an attempt to evaluate the possible role of melatonin in conveying photoperiodic information in invertebrates. It is now well demonstrated in both vertebrates and invertebrates that melatonin as well as its precursors or synthesizing enzymes are present in various organs implicated in photoreceptive processes or in circadian pacemaking. Melatonin, serotonin or N-acetyltransferase have been found in the head, the eyes, the optic lobe and the brain of various invertebrate species. In some species it has also been shown that melatonin is produced rhythmically with high concentrations reached during the dark period. Moreover, the physiological effects of melatonin on various periodic processes such as rhythmic contractions in coelenterates, fissioning of asexual planarians or reproductive events in flies have been reported in the literature. All these results support the hypothesis (refs 36, 37) that melatonin is not solely a pineal hormone but that it may be an evolutionary conservative molecule principally involved in the transduction of photoperiodic information in all living organisms.     

Structures and molecules involved in generation and regulation of biological rhythms in vertebrates and invertebrates

Melatonin from the retina and the pineal gland functions in neuroendocrine hierarchies. Photoreceptors — eyes and extraretinal — detect light. Oscillators — pineal and suprachiasmatic nuclei — act as pacemakers. Driven neuroendocrine rhythms carry temporal hormone signals throughout the body. Light controls melatonin: light sets the phase of the melatonin rhythm and determines the duration of melatonin synthesis. By these means, circadian rhythms (e.g. in locomotor activity and body temperature) and seasonal rhythms (e.g. in reproduction) are controlled.     

Indoleamines and the UV-light-sensitive photoperiodic responses of the melanocyte network: a biological calendar?

The pineal, serotoninergic and pigmented neurons are associated with light-dependent sleep/arousal, serving as a biological clock with a circadian rhythm. This rhythm is maintained by melatonin which serves to recognise the dark phase. The neural network that responds to seasonal variations in day/night length has not been identified. The present study demonstrates that melanocytes in human skin respond to changes in the duration of UV exposure, and can serve as a biological calendar. These responses are mediated by two indoleamines, serotonin and melatonin. Higher melatonin levels correspond to long nights and long days (short UV pulse), while high serotonin levels in the presence of melatonin reflect short nights and long days (long UV exposure). This response recapitulates the sleep/arousal patterns in animals exposed to large variations in day/night cycle that cause changes in coat colour from pure white in winter to complete repigmentation in summer.     

Aging alters resynchronization of the circadian system in rats after a shift of the light-dark cycle

Four days following an 8-h advance of the light-dark cycle, the circadian rhythms in the pineal N-acetyltransferase activity and melatonin content reappeared in 7-week-old rats, but were still abolished in 24-month-old animals.     

Aging alters resynchronization of the circadian system in rats after a shift of the light-dark cycle

Summary Four days following an 8-h advance of the light-dark cycle, the circadian rhythms in the pineal N-acetyltransferase activity and melatonin content reappeared in 7-week-old rats, but were still abolished in 24-month-old animals.     

Melatonin and circadian control in mammals

Summary Although pinealectomy has little influence on the circadian locomotor rhythms of laboratory rats, administration of the pineal hormone melatonin has profound effects. Evidence for this comes from studies in which pharmacological doses of melatonin are administered under conditions of external desynchronization, internal desynchronization, steady state light-dark conditions, and phase shifts of the zeitgeber. Taken together with recent findings on melatonin receptor concentration in the rat hypothalamus, particularly at the level of the suprachiasmatic nuclei, these results suggest that melatonin is a potent synchronizer of rat circadian rhythms and has a direct action on the circadian pacemaker. It is possible, therefore, that the natural role of endogenous melatonin is to act as an internal zeitgeber for the total circadian structure of mammals at the level of cell, tissue, organ, whole organism and interaction of that organism with environmental photoperiod changes.     

Melatonin and circadian control in mammals

Although pinealectomy has little influence on the circadian locomotor rhythms of laboratory rats, administration of the pineal hormone melatonin has profound effects. Evidence for this comes from studies in which pharmacological doses of melatonin are administered under conditions of external desynchronization, internal desynchronization, steady state light-dark conditions, and phase shifts of the zeitgeber. Taken together with recent findings on melatonin receptor concentration in the rat hypothalamus, particularly at the level of the suprachiasmatic nuclei, these results suggest that melatonin is a potent synchronizer of rat circadian rhythms and has a direct action on the circadian pacemaker. It is possible, therefore, that the natural role of endogenous melatonin is to act as an internal zeitgeber for the total circadian structure of mammals at the level of cell, tissue, organ, whole organism and interaction of that organism with environmental photoperiod changes.