Which gland influences the sleep wakefulness cycle

Watch this video to view an animation describing the function of the hormone melatonin. What should you avoid doing in the middle of your sleep cycle that would lower melatonin? Interestingly, children have higher melatonin levels than adults, which may prevent the release of gonadotropins from the anterior pituitary, thereby inhibiting the onset of puberty.

Finally, an antioxidant role of melatonin is the subject of current research. Jet lag occurs when a person travels across several time zones and feels sleepy during the day or wakeful at night.

Traveling across multiple time zones significantly disturbs the light-dark cycle regulated by melatonin. It can take up to several days for melatonin synthesis to adjust to the light-dark patterns in the new environment, resulting in jet lag. Some air travelers take melatonin supplements to induce sleep. The pineal gland is an endocrine structure of the diencephalon of the brain, and is located inferior and posterior to the thalamus.

It is made up of pinealocytes. These cells produce and secrete the hormone melatonin in response to low light levels.

High blood levels of melatonin induce drowsiness. Jet lag, caused by traveling across several time zones, occurs because melatonin synthesis takes several days to readjust to the light-dark patterns in the new environment. If the egg is not fertilized, sex hormone levels drop at the end of the LP and trigger the shedding of the uteral lining menstruation [ 34 ]. Hormone changes across the menstrual cycle result in altered body temperature.

Skin temperature and vascular blood flow, which are important thermoregulatory responses, are affected by the menstrual cycle. Increased threshold for sweating [ 39 , 40 ] and for vasodilation [ 39 — 41 ] as well as decreased thermal conductance and skin blood flow [ 42 ] is observed during the LP compared to the FP. This upward shift in the thermoregulatory set-point is most likely due to progesterone, which possesses thermogenic properties [ 36 , 43 ], and was shown to increase the firing rate of cold-sensitive i.

A relatively limited number of studies have addressed sleep-wake patterns across the menstrual cycle in healthy women. These have indicated that while sleep homeostasis [ 49 , 51 , 55 ] and quality [ 43 , 49 , 52 ] remain stable at different menstrual phases, there are observable changes in sleep architecture [ 49 , 51 — 53 ] summarized in Table 1.

Interestingly, women often report subjective complaints of disturbed sleep during the late-LP and premenstrual days, though polysomnography- PSG- based estimates indicating disrupted sleep during this time are less frequent [ 22 ]. Since most studies compared sleep at only two menstrual phases e. In the first systematic study of sleep EEG across the menstrual cycle in healthy women, nocturnal sleep was recorded in the laboratory every other night throughout a full cycle [ 49 ].

In a later study focusing on sleep-disordered breathing and the menstrual cycle, Driver et al. Across three phases, REM sleep min was significantly reduced during the mid-LP compared to the mid-FP, latency to stage 3 sleep was significantly reduced during the mid-LP compared to menses, and there were no significant changes observed for stage 2 sleep min or SWS [ 51 ].

The results from eighteen healthy controls studied by Parry et al. Two investigations studied PSG sleep across four phases of the menstrual cycle [ 45 , 47 ]. The first, which included eight healthy participants at the early-FP, the late-FP, the early-LP and the late-LP, found significant menstrual phase variations for stage 3 sleep min , with a trough at the late-LP, and intermittent awakenings, with a peak at the late-LP [ 45 ].

The second, which included recordings of seven healthy females at menses, the late-FP, the early-LP and the late-LP, only found a significant variation for SWS min , which, like the aforementioned study [ 45 ], was lowest during the LP compared to the late-FP and menses [ 47 ]. Interested in studying the effects of the menstrual cycle on the circadian variation of sleep propensity, Shibui et al. Sleep propensity defined in the study as the sum of the duration of stages 2, 3, 4 and REM sleep occurring at each minute nap trial varied significantly across the circadian day, but did not differ between menstrual phases.

Their main finding was that from to , the number of naps containing SWS was increased during the LP compared to the FP [ 37 ]. It should be noted, however, that their participants were sleep-deprived for 24 hours preceding the start of the ultra-rapid sleep-wake cycle, creating a situation that could have increased the homeostatic pressure for SWS propensity, thus potentially confounding these results.

The effects of menstrual phase on quantitative sleep EEG have been investigated by a few groups, yet results indicate a very consistent pattern of findings, making the prominent increase in SFA during the LP the most characteristic menstrual cycle associated sleep change [ 48 , 49 , 55 ] Table 1. The sleep of five healthy young women was recorded by Ishizuka et al.

Defining a sleep spindle as activity within the Similarly, in the aforementioned study by Driver et al. Maximum menstrual phase variation was observed within the Finally, in the recent study by Baker et al.

Most studies agree with the absence of changes in homeostatic sleep mechanisms i. Methodological differences between the various studies might contribute to these discrepancies. For example, menstrual phase delineation and the number of sleep recordings across the cycle is often different between studies, and menstrual phase status is not uniformly confirmed with hormonal assays.

Stabilization of sleep-wake patterns before lab entry is not always done, even though it is recommended to ensure a proper alignment of sleep and circadian rhythms.

The changing sex hormone profile across the menstrual cycle may play a role in producing these LP-specific sleep alterations. Specifically, progesterone, as well as its neuroactive metabolites, can affect sleep architecture, as was illustrated by the findings that exogenous progesterone [ 69 ] or megestrol acetate, a progesterone-receptor agonist [ 70 ], reduced REM sleep in male participants.

Furthermore, progesterone likely affects the sleep system through another indirect means, namely by increasing body temperature during the LP. Sleep architecture, like the timing of sleep propensity, is under a circadian regulation, with highest REM sleep occurring at times corresponding with the nadir of body temperature [ 72 ].

The finding of reduced REM sleep during the LP, when nocturnal body temperature is significantly elevated compared to the FP, is therefore interesting. The LP-associated increase in SFA is most likely a result of the neuroactive metabolites of progesterone acting as agonistic modulators of central nervous system G A B A A -receptors in a benzodiazepine-like manner [ 49 , 71 ].

Indeed, progesterone administration enhanced spindle activity in the rat [ 71 ] and in male participants particularly those who experienced an early allopregnanolone peak in response to exogenous progesterone treatment during the first two hours of sleep [ 69 ].

Since sleep spindles are thought to have a sleep-protecting effect via their blockage of information processing to the cortex [ 74 ], increased SFA may be the mechanism through which sleep quality is maintained at a good level despite the changing physiological and hormonal profile associated with different menstrual cycle phases.

It has been proposed that the menstrual cycle could form a backdrop on which daily circadian rhythms are expressed [ 22 ], and as such, circadian physiology can be altered as a function of the changing hormone profile associated with different menstrual phases see Table 2 for a summary.

It was proposed that one implication of the altered circadian rhythms observed during the menstrual cycle is the production of a stable intrauterine environment [ 35 ]. Specifically, the authors point to the reduced efficacy of melatonin function during the LP, which results in a blunted nocturnal decline of CBT and reduced circadian CBT amplitude, as a stabilizing factor which would encourage proper implantation and development of a fertilized egg [ 35 ].

However, these effects may also contribute to the increased incidence of subjective sleep complaints during the LP. PRL showed either a trend for increased amplitude during the LP compared to the FP [ 64 ] or no change across the menstrual cycle [ 60 ]. Since limited number and inconsistencies once again characterize these data, it is important to replicate these studies using highly controlled experimental conditions and adequate sample sizes.

Melatonin is known to play a role in reproductive physiology see [ 75 ] for a review. Studying menstrual-related changes in melatonin secretion has been a topic of interest, though findings remain equivocal Table 2. An early study sampling plasma melatonin every four hours during the FP and LP reported a significant increase in the total amount of secretion in 24 hours during the LP compared to the FP [ 58 ].

This result was supported by the finding that nocturnal urinary immunoreactive melatonin concentration sampled nightly over an entire menstrual cycle was significantly increased during the LP compared to the FP [ 59 ]. However, in a well-controlled study sampling every hour during the FP and LP under constant conditions, the hour area under the curve AUC for plasma melatonin was significantly decreased during the LP, though other timing measures were unaffected [ 37 ].

On the other hand, in an important study outlining the role of melatonin on body temperature changes during the LP, Cagnacci et al. Most other studies have found no change in the patterns of melatonin secretion including onset, offset, duration, midpoint, and AUC across the menstrual cycle in healthy women [ 47 , 60 — 62 , 65 , 67 ].

Furthermore, strengths of these studies were that they actually sampled melatonin across the menstrual cycle i. Evidence indicates that the pineal melatonin system and the reproductive system interact, as was illustrated by a variation in the number of cerebral and caudal arterial melatonin binding sites in the rat throughout the estrous cycle [ 76 ].

An interaction between the melatonin system and sex hormones may have an influence on sleep and body temperature rhythms across the menstrual cycle. Further support for such an interaction comes from the colocalization of melatonin receptors with estrogen and progesterone receptors throughout the brain and periphery.

Specifically, considering areas involved with the reproductive cycle, melatonin binding sites were found at human [ 77 ] and rat [ 78 , 79 ] granulosa cells, and melatonin was found in human ovarian follicular fluid [ 80 ]. Furthermore, various sources indicate that receptors for melatonin, progesterone, and estrogen can all be found at the SCN [ 81 , 82 ], POAH [ 82 , 83 ], and pineal gland [ 84 , 85 ]. Evidence of a functional interaction between melatonin and sex hormones was presented by Cagnacci et al.

While this appears to support a functional antagonism between melatonin and progesterone, there is also evidence for a positive relationship between the two. Exogenous synthetic progestins in the form of oral contraceptives have a tendency to increase melatonin secretion [ 58 , 59 , 67 ], and melatonin treatment can enhance human chorionic gonadotropin-stimulated progesterone production from human granulosa cells [ 86 ].

Conversely, estrogen appears to negatively influence melatonin. For example, a low-estrogen environment was associated with increased melatonin levels in menopausal women, which was suppressed after exogenous estrogen administration, and oopherectomy in premenopausal women results in a significant increase in melatonin secretion [ 87 ].

Estrogen treatment also reduced melatonin binding in the rat ovary [ 78 ] and reduced melatonin synthesis in rat pinealocytes [ 88 ]. Most studies which sampled hormones at different menstrual phases did not do so under controlled conditions, which are advised to limit the confounding effects of environmental factors notably ambient light exposure, posture changes, and the sleep-wake cycle , something which likely contributes to these discrepancies [ 90 ].

Again, differences in the methods of dividing the menstrual cycle as well as sampling frequency both across 24 hours and the menstrual cycle are likely to contribute to inconsistencies in the literature. More studies need to be conducted before definitive conclusions can be made regarding the circadian variation of different hormone secretions across the menstrual cycle. As is implied by its name, the occurrence of PMDD is defined by its timing within the context of the menstrual cycle.

Symptoms typically begin during the late-LP and remit after menses, with a complete absence of symptoms during the FP. While the exact causes of PMDD are still unknown, a variety of hypotheses have been proposed which implicate endocrine or other neurotransmitter systems. An altered sex hormone profile in PMDD has been reported, with lower progesterone levels found in patients compared to controls [ 93 , 94 ] as well as decreased levels of the anxiolytic progesterone metabolite allopregnanolone during the LP in patients [ 94 , 95 ].

Results of prior drug trials have found the most effective treatment of PMDD to date to be selective serotonin reuptake inhibitors SSRIs and they have become the most common clinical treatment for the disorder [ ]. Experimental evidence implicating the serotonergic system includes findings of reduced plasma- [ ] and whole-blood [ ] serotonin levels in patients compared to controls.

This raises the question of whether low serotonin levels could alter the production of melatonin by the pineal gland, since serotonin is a precursor for melatonin synthesis. Interestingly, PMDD patients experience alterations in the timing and amount of nocturnal melatonin secretion see Section 8. Although disrupted sleep is a characteristic symptom of PMDD, results of sleep studies in these women have been limited and inconsistent Table 1. A preliminary study comparing six healthy controls and three patients with PMS defined as a set of emotional, physical, and behavioral symptoms that occur with similar timing, but less severity, as PMDD failed to detect significant differences in any sleep parameter [ 50 ].

A larger study with 23 PMDD patients and 18 controls also showed no intergroup differences, though significant menstrual phase effects were noted.

Results from this comparative study showed that women with severe PMS and healthy controls both experienced similar increases in WASO min and microarousals per hour during the late-LP compared to the FP. A significant menstrual cycle variation of stage 3 sleep was observed, and two other studies found decreased SWS or stage 3 sleep during the LP Table 1. It remains unclear what could be causing PMDD-specific sleep changes, and further studies should address the relationships between sleep and parameters which are known to be altered in the PMDD patients, like CBT, melatonin concentration, and circadian phase.

Important methodological issues should be addressed in these studies as well, including in addition to those mentioned previously the high degree of patient heterogeneity and diagnostic criteria used in these investigations. Finally, a nonsignificant trend for a phase-advanced temperature minimum in PMDD patients compared to controls was observed across the entire menstrual cycle [ 45 ].

Differences in experimental techniques and data collection methods are likely contributors to inconsistencies in the aforementioned studies. Furthermore, patient diagnostic criteria, sample size, and the frequency of temperature recordings throughout the menstrual cycle all varied between the studies.

Future research should consider these methodological issues. A deficient or altered circadian rhythm of melatonin secretion Table 2 was proposed as a mechanism causing excessive daytime sleepiness and depressed mood in PMDD.

Some evidence supporting this notion, such as decreases in amplitude, AUC, and mean levels, a phase-advance, and a shorter duration of melatonin secretion in PMDD patients compared to controls were reported [ 62 , 65 ].

Additionally, when comparing across the menstrual cycle within PMDD patients, onset time was delayed, off-set time was advanced, and duration of secretion was decreased in the LP compared to the FP [ 65 ]. The peak time and acrophase of TSH secretion was significantly phase-advanced in patients compared to controls, without any changes in concentration [ 64 ].

Throughout the menstrual cycle, amplitude and peak of PRL were higher in PMDD patients compared to controls [ 63 , 64 ], with a phase-advanced acrophase also detected in these women [ 64 ].

In both of these studies, sleep patterns and light-dark exposure were controlled for and stabilized. Nevertheless, TSH and PRL profiles, both of which are affected by the sleep-wake cycle [ 14 ], were not obtained under constant conditions including sleep deprivation ; so masking effects cannot be excluded.

The major findings regarding altered hormone patterns in PMDD include decreased melatonin secretion AUC and amplitude Table 2 , which is reminiscent of findings in patients with major depressive disorder MDD [ ]. Lending further support to the idea that PMDD women experience a phase-advance of circadian rhythms similar to what is observed in MDD [ ], these women also experienced a tendency for phase-advanced CBT rhythms as well as significantly advanced melatonin and TSH when compared with controls Table 2.

Since this altered circadian physiology can contribute to an internal desynchrony, resulting in poor sleep quality and mood symptoms, more studies conducted under strict constant routine conditions are necessary. A better understanding of disturbed circadian rhythms in these women may lead to improved chronotherapeutic techniques, which, while similar to those already used in MDD and seasonal affective disorder [ ], can be specialized to treat PMDD women. Treatments of PMDD that target and correct circadian rhythm abnormalities may be an effective alternative to drug-based therapies and may function via a realignment of biological rhythms with the sleep-wake cycle.

Since PMDD patients seem to experience a phase-advance of biological rhythms [ 45 , 62 , 64 ], it was hypothesized that light therapy, particularly in the evening, could have therapeutic effects.

Indeed, studies have found that light therapy was effective in significantly reducing depressive symptoms in PMDD patients [ — ]. While an initial study by Parry et al.

As the authors point out, a placebo effect cannot be excluded. A study by Lam et al. This improvement may be achieved via a resynchronization or phase-shift of biological rhythms, since, compared to neutral-dim red light, bright evening light therapy was shown to delay the onset and offset of melatonin [ 65 ], increase the midpoint concentration of melatonin [ 65 ], delay cortisol acrophase [ 63 ], and increase TSH nadir [ 63 ] in PMDD patients during the LP. In a series of studies, Parry et al.

These changes, particularly the phase-delays achieved in CBT and TSH, as well as amplitude changes produced in CBT and PRL, indicate, that like light therapy, SD might achieve its mood elevating effects by targeting and correcting abnormal circadian rhythms. A study by Parry et al. The authors concluded that these therapeutic effects were accomplished, at least partially, via a correction of altered circadian rhythms which affect the sleep-wake cycle.

The therapeutic effects of SD, however, were only studied during experimental nights and at a single recovery night [ 52 ]; therefore the duration of improvement in response to such a treatment is unknown.

These results are quite promising, though, so more studies should be carried out along these lines to determine the duration of such positive responses. Unlike MDD, however, in which morning bright light had the greatest antidepressant effects [ ], two studies demonstrated the most mood improvement after evening bright light.

PMDD patients responded with mood improvements after both partial and total SD, and interestingly these treatments often resulted in favorable shifts of circadian physiology. Based on the single study discussed above [ 52 ], both early- and late-SD produced improvements in objective sleep parameters in PMDD patients, though future laboratory studies in this direction should address how long these improvements persist beyond a night of recovery sleep. Preliminary results from our study investigating the effects of exogenous melatonin taken prior to nocturnal sleep periods during the LP indicate that melatonin may be beneficial in alleviating sleep disruptions in PMDD women [ ].

Evidence from a variety of sources indicates that the menstrual cycle interacts with circadian processes to alter the expression of hormonal rhythms and sleep organization at different menstrual phases. The most consistently observed menstrual cycle-related changes in the sleep profile of healthy women are a reduction of REM sleep [ 49 , 51 — 53 , 56 ], with a maintenance of homeostatic sleep mechanisms throughout the cycle [ 90 ], and a robust variation of SFA across the menstrual cycle [ 48 , 49 , 55 ], which increases in association with progesterone during the LP.

The circadian variation of CBT is altered by the menstrual cycle in both groups of women. Mean levels are increased particularly during night time hours [ 35 , 36 ] and the circadian amplitude is reduced [ 35 — 38 ] during LP.

Generally, circadian hormone rhythms are not significantly altered across the menstrual cycle see Table 2 , though variable results including both increases [ 58 , 59 ] and decreases [ 37 ] in melatonin as well as changes in the timing of hormones [ 35 ] have been described.

Finally, nonpharmacological therapies for PMDD symptoms which target the sleep-wake cycle and circadian rhythms, such as phototherapy [ — ] and sleep deprivation [ 52 , 65 , , ], are often effective in improving mood and sleep quality in these patients.

Because of the persistent inconsistencies in the literature, however, it is necessary to conduct more investigations of circadian rhythm changes across the menstrual cycle. These should make efforts to assay sex hormone levels, utilize constant conditions, control for light exposure, and record sleep at numerous points throughout the menstrual and circadian cycles.

In light of the present discussion, it is critical that researchers who are interested in including female participants in studies on sleep and circadian rhythms always make efforts to control for and document menstrual cycle phase. Investigations focusing on the interaction between circadian physiology, sex hormones, and the sleep-wake cycle in women across the lifespan will be important to understand the role age-related neuroendocrine changes play in the regulation of sleep and circadian rhythms.

This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Special Issues. Ari Shechter 1,2 and Diane B. Academic Editor: Barbara L. Received 13 Aug Accepted 16 Oct Published 18 Jan Abstract A relationship exists between the sleep-wake cycle and hormone secretion, which, in women, is further modulated by the menstrual cycle.

Introduction A variety of hormones, including melatonin, cortisol, thyroid stimulating hormone TSH , and prolactin PRL , vary across the hour day and are highly regulated by the circadian and sleep-wake cycles. Hormones and the Sleep-Wake and Circadian Cycles 2.

Circadian and Homeostatic Regulation of the Sleep-Wake Cycle The sleep-wake cycle is regulated by an interaction between homeostatic process S and circadian process C processes [ 10 ].

Figure 1. From [ 8 ]. Figure 2. Pathways involved in the hypothalamic control of the circadian rhythms of sleep, wakefulness and body temperature. Modified with permission from [ 9 ]. Figure 3. The relationship between melatonin secretion, body temperature and sleepiness. The onset of melatonin secretion during the early night causes an increase in heat loss at the extremities i.

From [ 21 ]. Figure 4. The variation of gonadotropic and sex steroid hormones, and the subsequent changes in daily body temperature across the full menstrual cycle.

During the pre-ovulatory FP, estrogen levels are high. During the post-ovulatory LP, increasing levels of circulating progesterone are observed, along with increased daily body temperature. From [ 22 ], as adapted from [ 23 ]. Table 1. Table 2. The variation of hormonal rhythms across the menstrual cycle. References C. Manber and R. View at: Google Scholar S. Hurt, P. Schnurr, S.

Severino et al. View at: Google Scholar K. Spiegel, E. Tasali, R. Leproult, and E. Meerlo, A. Sgoifo, and D. Riemann and U.

Piccinelli and G. Dijk and D. Turek and P. Zee, Eds. View at: Google Scholar C. Saper, G. Cano, and T. Dijk and P. Kryger, T. In children, while the hormonal system is still developing, bedwetting may be partly influenced by low levels of antidiuretic hormone.

Hormone levels also influence the timing of when we feel sleepy and awake — our body clock or sleep-wake cycle. This is why being around too much bright light before bed can affect our sleep as it can stop the release of melatonin.

Levels of the hormone cortisol dip at bedtime and increase during the night, peaking just before waking. This acts like a wake-up signal , turning on our appetite and energy.

So increased cortisol levels and hunger may occur at inappropriate times of the day. The relationship between hormones and the sleep-wake cycle in women is further influenced by the menstrual cycle. This is the stage of sleep when most of our dreams occur. For women with severe premenstrual symptoms reduced levels of melatonin before bedtime just before their menstrual period can cause poor sleep, including night-time awakenings or daytime sleepiness.

Changes in hormone levels also contribute to sleeping difficulties during pregnancy. Increased progesterone levels can cause daytime sleepiness, particularly in the first trimester. High levels of oestrogen and progesterone during pregnancy can also cause nasal swelling and lead to snoring. During menopause , low levels of oestrogen may contribute to sleeping difficulties.

Changes in hormone levels mean that body temperature is less stable and there may be increases in adrenaline levels, both of which can affect sleep.