The Menstrual Cycle and Sleep

INTRODUCTION

From menarche or first menstrual period, to menopause that signals the end of reproduction, women experience monthly variations in hormones that regulate reproduction. These hormones have widespread effects outside their direct reproductive functions, including influences on regulating mood, body temperature, respiration, autonomic nervous system, and sleep. This review updates a prior review from 2018,¹ delving into the complex relationship between the menstrual cycle and sleep, focusing on perceived sleep quality, objective measures of sleep continuity and sleep architecture, as well as sleep-related physiological changes in homeostatic and circadian regulation of body temperature and heart rate, at different phases of the menstrual cycle. We discuss sleep disturbances in the context of the menstrual cycle across the reproductive years, and also consider relationships between sleep and infertility, use of oral contraceptives, and menstrual-associated disorders, including polycystic ovary syndrome, premenstrual dysphoric disorder, and dysmenorrhea.

DEFINITIONS AND MENSTRUAL CYCLE PHYSIOLOGY

Most women have menstrual cycle lengths between 21-30 days, with menses lasting <7days.² The menstrual cycle is divided into a pre-ovulatory follicular phase and post-ovulatory luteal phase, with onset of menstrual flow marking the beginning of a new cycle (Day 1) (Figure 1).

Figure 1:

Schematic representation of changes in hormones and termperature across a typical 28-day ovulatory menstrual cycle, where 1 represent the first day of bleeding and 14 the day of ovulation.

During the follicular phase, follicle-stimulating hormone and luteinizing hormone (LH) are released from the anterior pituitary and act on the ovaries to initiate development of several primary follicles, which produce estrogens, principally estradiol. At the end of the follicular phase, estrogen levels rise, triggering a peak in LH. Ovulation occurs 12-16 hours later, around day 14. Following ovulation, the corpus luteum develops, producing progesterone and estrogen, which peak 5-7 days after ovulation before declining (in the absence of implantation), resulting in endometrial breakdown and menstruation.

Estrogen and progesterone receptors are widely distributed throughout the central nervous system (CNS), including the basal forebrain, hypothalamus, dorsal raphe nucleus, and locus coeruleus.^3,4 These areas are also involved in sleep regulation, and fluctuations in ovarian steroids across the menstrual cycle can modulate sleep. Indeed, work in rodents shows that sleep patterns fluctuate in concert with natural fluctuations of ovarian steroids and ovariectomy eliminates these fluctuations in sleep, with effects dependent on time of day.^5,6 While ovarian steroids’ mechanisms of action on sleep regulation are not completely clear, both sleep- and wake-promoting areas of the CNS are sensitive to the effects of estrogen. Ovarian steroids can also influence circadian rhythms, including of sleep-wake activity, through direct or indirect effects on the master pacemaker – the suprachiasmatic nucleus. The mechanistic framework is therefore in place for menstrual cycle-related changes in reproductive hormones to influence sleep and circadian rhythms.

SLEEP AND MENARCHE

Women are at higher risk than men of suffering from insomnia symptoms and disorder,⁷ due to many factors. Menarche is a critical time window for the emergence of a sex difference in insomnia – which persists throughout adulthood,⁸ and fluctuations and transitions in gonadal hormones in women could be one factor that leads them to be vulnerable to insomnia across their reproductive life. After menarche, as menstrual cycles become established, menstrual pain becomes highly prevalent, affecting 84,1% of young women,⁹ and is a leading cause of recurrent short-term school absenteeism.¹⁰ There is limited work investigating sleep quality in the context of the menstrual cycle and menstrual-associated symptoms in adolescents, however, evidence suggests that menstrual pain is commonly associated with sleep disturbances, which could in turn negatively affect academic performance.¹¹ Irregular menstrual cycles are also associated with sleep disturbances (insomnia symptoms),¹² as well as daytime sleepiness.¹³ On the other hand, a longer sleep duration is associated with a lower prevalence of menstrual cycle irregularity.¹⁴ This body of research about sleep quality in the context of adolescent menstrual health has mostly relied on retrospective questionnaires and further research is needed to evaluate how menstrual cycle features and sleep correlate, what might be the directionality of this relationship, and to what extent this interaction affects academic performance and wellbeing during the teenager years. Effective interventions for the management of menstruation, including menstrual pain and menstrual hygiene, have been successfully applied in girls from low- and middle-income countries,^15,16 with the aspiration of benefitting academic performance, improving school attendance and wellbeing. Effectiveness of such interventions for better sleep quality, which in turn could contribute to better educational outcomes, remains to be seen.

SLEEP AND CIRCADIAN RHYTHMS ACROSS THE MENSTRUAL CYCLE

Self-reported sleep quality

Collectively, studies in adult women show that sleep disturbances are more commonly reported around the time of menstruation, encompassing the last few premenstrual days (late luteal phase) and first few days of menstrual bleeding (early follicular phase).^17-20 However, not all studies find a menstrual cycle effect on sleep quality^21,22 or find only small effects,²³ possibly reflecting between-individual variability in the relationship between sleep and menstrual cycle phase. Van Reen and Kiesner²⁴ identified three different patterns of variation in self-reported sleep difficulty across the menstrual cycle among their 213 participants: one group (46%) showed no relationship, a second group (25%) showed a mid-cycle increase in difficulty sleeping, and a third group (29%) showed a perimenstrual increase in difficulty sleeping. Psychological and vegetative symptoms (e.g., anxiety, depression, headaches, cramps, and breast tenderness) significantly predicted difficulty sleeping.²⁴ The extent that ovarian hormones directly contribute to perceived sleep disturbance, versus other factors that vary with the menstrual cycle, remains unclear. Changes in progesterone and estrogen, rather than absolute levels, in the late-luteal phase may be a critical factor for sleep quality. Menstrual cycle characteristics are also relevant: women with irregular cycles report more sleep difficulties than women with regular cycles, even when controlling for age, body mass index (BMI), dysmenorrhea and premenstrual complaints.²⁵ Irregular menstrual cycles and heavy bleeding were associated with poor sleep (i.e., shorter sleep duration, poorer sleep quality, and fatigue) and poor mental health (stress and depression) in a racially and socioeconomically diverse community sample of women aged 22–60 years.²⁶

Objective sleep measures

Sleep across the menstrual cycle has been studied objectively with research-grade actigraphy, wearable sleep technology, and polysomnography (PSG). Actigraphy and consumer wearables can be easily used to track changes in daily sleep-wake activity in a large number of participants, however, few studies have investigated menstrual cycle-related patterns in sleep using these devices. In a small study of 19 women (18-43 years), actigraphy-measured sleep efficiency (SE) was positively associated with 1-day lagged estrogen metabolites and negatively with 1-day lagged progesterone metabolites, although effects were weak and self-reported sleep was unassociated with hormone metabolites.²² The Study of Women Across the Nation (SWAN), which is tracking women as they transition from late-reproductive stage to post-menopause, has included actigraphy in a sub-sample of the group,²⁷ representing the largest sample of women in whom objective sleep measures are available across the menstrual cycle. In this group of 163 late-reproductive aged women (age range: 48-59 years), there was a significant decline in SE and total sleep time (TST) in the premenstrual week relative to the prior week, with greater effects associated with obesity, financial strain, smoking, and a greater apnea hypopnea index.²⁷ In a more recent study, the Oura ring was used to track physiological changes across the ovulatory menstrual cycle in 26 early reproductive (18-35 years old) women.²¹ No significant variation across the menstrual cycle was found in sleep continuity measures, in agreement with the women’s self-reported sleep quality. Importantly, this group of women had no to low premenstrual symptoms and their mood symptoms remained stable across the cycle. In a study specifically focused on collegiate female athletes (n=45), at-home EEG monitoring was used to examine differences in sleep on the first and and second nights after menses onset compared with one night between the 7^th -10^th night after menses (mid-follicular phase).²⁸ Women had a shorter TST and a longer sleep onset latency on the second night of menstruation (but not on the first night of menses) compared with the mid-follicular phase. However, these results need to be interpreted cautiously since they refect a particular sub-group of women (i.e., athletes) and authors did not control for the presence of menstrual pain, which was reported in 60% of the sample.

Laboratory-based PSG has been used in small numbers of women to compare sleep between discrete menstrual cycle phases, such as mid-follicular versus mid-luteal phase. Major findings for PSG measures in these two phases are summarized in Table 1. A foundational study by Driver and colleagues²⁹ tracked changes in PSG measures of sleep recorded every second night across an entire menstrual cycle in 9 young women, with phases carefully characterized. They found that sleep onset latency (SOL), wakefulness after sleep onset (WASO), and SE were stable across the menstrual cycle.³⁰ N2 sleep was increased and REM sleep tended to decline in the luteal phase relative to the follicular phase, however, there was no change in the amount of slow wave sleep (SWS) or slow wave activity (SWA) across the menstrual cycle,²⁹ indicating no change in this marker of sleep homeostasis across the menstrual cycle. Analysis of SWA by sleep cycle, did reveal subtle changes however: higher slow wave activity was found in the first NREM sleep episode and lower activity in the second NREM episode in the mid-luteal phase compared with mid-follicular phase.³⁰

Table 1:

Summary of evidence comparing objective sleep and related physiological measures during the luteal phase relative to the follicular phase of the natural menstrual cycle.

	Variable	Luteal (relative to follicular)
Sleep continuity
	Total Sleep Time (TST)	No change in young women / Decreased actigraphic TST in late-reproductive women – but only when comparing the premenstrual week vs the prior weeka
	Sleep onset latency (SOL)	No change
	Sleep efficiency (SE)	No change in young women / Decreased actigraphic SE in late-reproductive women – but only when comparing the premenstrual week vs the prior weeka
	Wakefulness and awakenings (WASO)	Most studies show no change in young women / More PSG awakenings in late-reproductive womenb
Sleep architecture	Slow wave sleep and slow wave EEG activity	No change in young women / Decreased in late-reproductive womena
	REM sleep	Decrease in duration of REM sleep episodes
	Sigma EEG activity (spindle frequency range)	Increased activity, associated with increased spindle density and duration
	N2 sleep	Most studies find no change
Sleep-related features	Body temperature	Increased body temperature rhythm, with reduced amplitude due to blunted nocturnal decline. No change in circadian phase
	Melatonin	No change in circadian phase or amplitude
	Heart rate	Increased (~4 bpm) - associated with decreased vagal activity
	Upper airway resistance	Lowerc

^adata available from only one study⁵⁵

^bdata available from only one study⁴⁰

^cdata available from only one study¹²¹

Other studies have mostly confirmed no difference in SWS or SWA between follicular and luteal phases in young women, although inconsistencies remain (See reviews^30,31). Others have also found variability in REM sleep with menstrual cycle phase: REM sleep had an earlier onset³² and REM sleep episodes were shorter,^30,33 with amount of REM sleep negatively correlating with progesterone and estradiol levels in the luteal phase.³³ Using a careful ultra-rapid sleep-wake cycle procedure, Shechter and Boivin¹⁷ also found that REM sleep was decreased (at circadian phase 0° and 30°) in the luteal phase compared with follicular phase. This reduction in REM sleep may relate to the raised body temperature in the luteal phase since heat loss mechanisms are inhibited during REM sleep.³⁴

Finally, most studies support Driver and colleagues’²⁹ findings of no menstrual cycle variability in sleep continuity PSG measures in young women, although two studies found more wakefulness/awakenings in the late luteal phase^35,36 and one study found that a steeper rise in progesterone from follicular to early-mid luteal phase was associated with WASO in the luteal phase.³⁷ Inconsistencies in PSG findings could reflect the individual variability in effects of the menstrual cycle on sleep and reflect methodological challenges with in-lab studies, such as small sample sizes, differences in sampling times across the menstrual cycle (occuring at discrete intervals), as well as differences in menstrual cycle characteristics and demographic factors like age. As for self-reported sleep, there may be clusters of women, some who may have changes in sleep continuity at transitions between the follicular and luteal phase (i.e. around ovulation) and/or premenstrualy or during menses, potentially in association with mood and physical symptoms. Laboratory based PSG studies and even the few studies with wearables, actigraphy, or home-based EEG measures have had small samples or have not examined if there are different clusters of women who show variability in menstrual cycle effects on sleep.

The most dramatic and consistent menstrual cycle change in sleep is in EEG activity in the 14.25-15.0 Hz (sigma) band corresponding to the upper frequency range of sleep spindles, which is significantly increased in the luteal compared to the follicular phase.^29,33,38,39 This increase in spindle frequency activity is associated with increased spindle density and duration.⁴⁰ The mechanism for luteal phase increases in spindle activity is unknown, however, it may involve modulation of GABA-A receptors by progesterone metabolites.²⁹ Given the supposed sleep-protective function of spindles,⁴¹ increased spindles may function to maintain sleep quality in the presence of luteal phase hormonal changes.³¹ Some studies have explored the functional relevance of increased sleep spindle activity in the luteal phase, given their role in sleep-dependent memory consolidation.⁴² During sleep, the brain replays and strengthens memories that were acquired during the day, a process that is essential for solidifying new memories. Spindles are thought to be involved in this process of transfering information from short-term to long-term memory storage. Studies that have investigated menstrual cycle related modulation of sleep-dependent memory consolidation have shown poorer consolidation during menses or early follicular phase than other times of the menstrual cycle.^43,44 Genzel and colleagues assessed motor and declarative performance on a memory task following a nap in men and in women at two time points of their cycle: early follicular (first week of the cycle) and luteal phase (third week of the cycle).⁴³ While men performed better after a nap, women only benefitted from a nap in the luteal phase of their cycle. Critically, women in the luteal phase and men experienced a significant increase in spindle activity after learning – an effect not seen in women in the early follicular phase of the menstrual cycle. Estradiol levels correlated with spindle density and frequency in women.⁴³ These data show that hormonal and associated changes in spindle activity across the menstrual cycle are linked with changes in declarative memory consolidation during sleep.

Circadian Rhythms

Hormonal variations across the menstrual cycle are also associated with changes in circadian rhythms. Body temperature is increased by about 0.4°C⁴⁵ due to the thermogenic action of progesterone and has a smaller amplitude due to a blunted nocturnal decline, in the luteal phase compared to follicular phase.³⁵ (see ⁴⁶ for a review). Using an ultra-short sleep-wake cycle procedure to control for light, posture and food intake, Shechter and colleagues⁴⁷ confirmed a reduced amplitude and found no difference in phase for core temperature rhythms in the luteal phase. In freely living women, a menstrual cycle related change in skin temperature is detectable with a wearable device: Alzueta and colleagues found that distal skin temperature measured with the Oura ring increased in the post-ovulation luteal phase relative to menses and peri-ovulatory phases in a group of healthy young women.²¹ There was also a smaller-magnitude peri-ovulatory drop in skin temperature, which corresponds to the phase when estrogen surges. This work supports other studies examining changes in temperature across the cycle using weareables^48-50 and together, data suggest that the ovulatory period can be identified with skin temperature measurement, a relevant finding in the context of fertility prediction.

Melatonin plays an important role in reproduction (e.g., oocyte maturation, fertilization and embryonic development),⁵¹ and it may have a role in the regulation of the menstrual cycle through interactions with the frequency of gonadotropin-releasing hormone pulses.⁵² Studies that have examined melatonin circadian rhythms in controlled conditions (e.g., forced desynchrony protocols) found that melatonin acrophase, onset, and offset did not differ between the follicular and luteal phases of the menstrual cycle of young women.^47,53,54 Two of these studies also found no menstrual-cycle differences in amplitude of the melatonin rhythm.^47,54 While melatonin rhythm characteristics do not differ across the cycle, studies of melatonin levels in uncontrolled conditions have found variation across the cycle, which could reflect it’s role in reproductive function. For example, in a cross-sectional SWAN study of 20 peri-menopausal (i.e., still menstruating) women, Greendale and colleagues analyzed overnight urinary levels of a melatonin metabolite, aMT6, and metabolites of estrogen and progesterone across the menstrual cycle.⁵⁵ They identified a cyclic rise in aMT6 in the late-luteal phase of the menstrual cycle. A luteal rise in a metabolite of progesterone (PdG) predicted the aMT6 rise, suggesting that the late-luteal melatonin peak might be signaled by progesterone. In the longitudinal portion of this study, the aMT6 excretion patterns when women were no longer menstruating (i.e., postmenopause) showed no organized pattern. Further, the total amount of aMT6s excretion declined by 30% in the postmenopausal collections compared to the premenopausal ones, an effect that could be due to chronological and/or reproductive aging (menopause).

SLEEP AND POLYCYSTIC OVARY SYNDROME

The most common endocrine disorder for reproductive-age women is polycystic ovary syndrome (PCOS). PCOS affects 5-20% of women, depending on age, type of epidemiological survey, and diagnostic criteria.⁵⁶ High testosterone levels, clinical signs of hyperandrogenism, and irregular or absent (i.e., anovulation) menstrual cycles may occur, and polycystic ovaries may or may not be present. PCOS is associated with important cardiovascular and metabolic comorbidities such as obesity and insulin resistance,^57,58 and psychological distress.⁵⁹ Between 50-60% of women with PCOS are obese⁶⁰ and are at increased risk for sleep-disordered breathing (SDB) particularly when of older age.⁶¹ Treatments for PCOS includes hormonal treatment to lower testosterone levels.⁶² Oral contraceptives are effective in managing menstrual cycle irregularity, acne, and hirsutism. Metformin is indicated for weight reduction and insulin resistance as well as hirsutism.⁶³

Women diagnosed with PCOS often experience sleep problems. They are significantly more likely to report difficulty falling sleep, even after adjusting for factors such as BMI and depressive symptoms.^64,65 Also, the prevalence of insomnia is higher in women with PCOS (10.5% scored > 14 on the insomnia severity index, reflecting insomnia) compared to healthy controls.⁶⁰ Daytime sleepiness would be an expected outcome of poor sleep, but findings are mixed when women with PCOS are compared to controls. Franik and colleagues⁶⁰ found no difference in rate of daytime sleepiness. Conversely, Vgzontzas and colleagues⁶² found a high prevalence of daytime sleepiness in women with PCOS (80.4%) compared to controls (27%).

PCOS has also been linked to differences in sleep architecture, with obese adolescents and adult women with PCOS experiencing a longer time to fall asleep, lower sleep efficiency, and less time in REM sleep than controls. Yet, these findings may be influenced by factors such as SDB. Women with PCOS are at increased risk of SDB during their reproductive years and are more likely to report excessive daytime sleepiness (80% vs 27% in controls).⁶⁶ It is likely that excessive weight, specifically central obesity contributes to high risk for SDB in women with PCOS.⁶⁷ Severity of SDB has been found to be connected to issues with glucose tolerance and insulin resistance in women with PCOS, indicating that SDB may play a role in the metabolic irregularities in these women (see ⁶⁶ for a review). Beyond affecting insulin sensitivity, it is still uncertain if sleep disturbances have other effects on the development of PCOS. One study used frequent blood sampling and PSG to examine the relationship between sleep architecture and LH pulse initiation in women with PCOS.⁶⁸ In healthy women, in the mid- to late-follicular phase, LH pulses were more likely to occur after/during wake epochs and less likely to occur after/during REM epochs. However, in women with PCOS, the interaction between sleep architecture and LH pulses differed, with LH pulses more likely to occur after/during SWS and no evidence of a relationship between LH pulses and REM sleep. Authors suggest that the lack of appropriate inhibition of LH pulse initiation in REM sleep in PCOS may contribute to high sleep LH pulse frequency, and thus ovarian hyperandrogenemia and ovulatory dysfunction.⁶⁸

Finally, it has been proposed that dysrhythmia (abnormal or irregular rhythm of certain physiological processes) affects the function of the ovaries and is one of the underlying causes of PCOS.^69,70 As a systemic hormone modulator, melatonin may play a role in this process although it is unclear if there are abnormalities in melatonin secretion in women with PCOS.⁷¹ Local melatonin levels in the ovary may be more relevant: Li and colleagues examined levels of melatonin in the ovarian micro-environment in women receiving in-vitro fertilization treatment for PCOS and non-PCOS reasons; melatonin levels in follicular fluid were lower in women with PCOS compared to other women.⁷²

SLEEP AND PREMENSTRUAL SYNDROME

Premenstrual syndrome (PMS) is characterized by emotional, behavioral, and physical symptoms that manifest almost exclusively in the late-luteal (premenstrual) phase, with resolution soon after onset of menses. While many women experience some symptoms premenstrually, up to 18% have severe symptoms that impact daily function.⁷³ Premenstrual dysphoric disorder (PMDD), is a severe form of PMS evident in 3-8% and classified as a depressive disorder in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5).⁷³ A PMDD diagnosis requires the occurrence of five specified symptoms, of which at least one must be a mood-related symptom experienced in the late-luteal phase, documented for at least two consecutive cycles. One of these symptoms is sleep disturbance (insomnia or hypersomnia). Etiology of PMDD remains unclear although symptoms are effectively managed with selective serotonin reuptake inhibitors, anxiolytics, and ovulation-suppressing agents.^74,75

Perceived sleep quality and daytime sleepiness

Several studies have found that women with PMS report a poorer sleep quality than other women overall, based on retrospective sleep quality assessments (i.e. not considering menstrual cycle phase). PMS has been associated with a two-fold higher risk for poor sleep.⁷⁶ Similarly, in a study of female university students (67 with severe PMS/PMDD symptoms and 195 controls), the PMS/PMDD group was more likely than controls to report poor sleep quality based on a score of greater than 5 on the PSQI (80.5% vs. 56.4%).⁷⁷ Sleep disturbance, daytime dysfunction, and use of sleep medications, were all more prevalent in the PMS/PMDD group, although self-reported sleep duration, sleep onset latency, and sleep efficiency did not significantly differ between groups. There may be both trait (across the menstrual cycle) and state (in conjunction with other symptoms) differences in women with PMS/PMDD compared with controls.⁷⁸ Trait-like symptoms may then magnify in the presence of the hormonal changes associated with the premenstrual phase. Women with severe PMS frequently report late-luteal phase sleep symptoms, including insomnia, disturbing dreams, poor sleep quality, daytime sleepiness and fatigue.^78-80 One laboratory-based study found that women with PMS/PMDD reported more awakenings and felt less refreshed on awakening compared with controls in both the follicular and late-luteal phases, and also reported worse sleep quality in their late-luteal phase relative to their own follicular phase.³³

A few researchers have investigated the second type of sleep disturbance (hypersomnia) listed in the DSM-5 for diagnosis of PMDD. Mauri⁸¹ found that PMS clinic patients reported greater daytime sleepiness in luteal and menstruation phases than other times of the menstrual cycle. Similarly, women with PMS symptoms were sleepier and less alert in late-luteal phase than in follicular phase, an effect not found in controls in another study.⁸² In a survey of 269 young women, women with PMS were more likely to report daytime sleepiness and fatigue premenstrually than controls.⁸⁰ Based on objective measures, women with PMS showed psychomotor slowing, with increased lapses and slower reaction times, corresponding with their perceived greater late-luteal levels of sleepiness and fatigue compared with their follicular phase and compared with controls.⁸³ However, waking EEG measures of alertness and cognitive processing, as well as sleep onset latency on the maintenance of wakefulness task, did not differentiate PMS women when symptomatic, although there were some trait differences.⁸³

Objective sleep and potential sleep-related treatments

Despite evidence of perceived poor sleep quality and greater daytime sleepiness in the late-luteal phase in women with PMS/PMDD, laboratory studies show little evidence of disturbed PSG sleep parameters specific to this phase. Most studies show no change in sleep effciency, arousals, sleep onset latency, or sleep EEG in late-luteal phase relative to follicular phase.^31,33,78 Perception of poor sleep quality in late-luteal phase may be a component of the symptom profile of PMS in the absence of actual sleep disruption, as sleep quality correlated with anxiety in women with PMS/PMDD in late-luteal phase.³³ On the other hand, two studies^33,84 found increased SWS in PMS and PMDD subjects in both the follicular and luteal phase of the menstrual cycle compared to controls. Differences found in PSG measures at both phases of the menstrual cycle suggest trait differences in sleep, although the nature of these differences varies between studies.^31,78 Age may influence the severity of sleep disruption in association with symptoms; findings indicate that women over 40 years old with PMS report more frequent awakenings than younger women,⁸⁵ however, PSG studies have not been powered to investigate age-PMS interactions.

Shechter and colleagues have gone further to examine abnormalities in melatonin secretion in women with PMDD. They found that women with PMDD had lower nocturnal melatonin levels under controlled conditions at both menstrual phases compared to controls, suggesting a trait difference,⁸⁶ which could underlie the higher SWS found in PMDD.⁸⁴ A decreased melatonin amplitude in the symptomatic luteal phase was also evident, suggesting an additional sensitivity to the altered ovarian hormone environment (i.e. state difference) in PMDD.⁸⁶ Parry and colleagues⁸⁷ also found disturbances in melatonin rhythms and timing of rhythms for cortisol and thyroid stimulating hormone, suggesting that circadian regulation disturbances may be a factor in PMDD. Melatonin therefore has been proposed as a potential treatment to modulate PMS/PMDD symptoms. In a recent study, Moderie and colleagues⁸⁸ investigated the efficacy of exogenous melatonin on sleep in five women with PMDD. Melatonin administration in the luteal phase during three consecutive cycles led to a reduction of SWS together with a reduction in PMDD symptoms. Importantly, these changes were independent from melatonin effects on circadian phase, temperature, or steroidogenesis. Also, light therapy in women with and without PMDD has been investigated with positive outcomes for mood.⁸⁹ Further clinical trials in larger samples are needed to establish the role of disturbed melatonin function in PMDD as well as the potential efficacy of circadian-related treatments, including light therapy, for PMDD.

SLEEP AND DYSMENORRHEA

Dysmenorrhea, defined as painful menstrual cramps of uterine origin, is either primary (menstrual pain without organic disease that typically emerges in adolescence) or secondary (associated with conditions such as endometriosis and pelvic inflammatory disease). The relationship between primary dysmenorrhea and sleep is detailed elsewhere in a prior review (Shaver and Iacovides, 2018). Briefly, evidence indicates that when severe, dysmenorrhea negatively impacts sleep, daytime function, and mood^90-92,12 and PSG studies also indicate sleep disturbances (lower SE) in association with painful menses.^93,94 Sleep and pain share a reciprocal relationship.⁹⁵ Breaking this pain-sleep cycle could be critical for long-term health of women with primary dysmenorrhea who show increased pain sensitization.⁹⁶ One study showed promising effects of a non-steroidal anti-inflammatory drug that alleviated nocturnal pain and restored sleep quality in women with primary dysmenorrhea.⁹⁴ Also, exercise therapy has been shown to be effective in reducing pain severity and improving sleep quality in women with dysmenorrhea.⁹⁷

SLEEP AND HORMONAL CONTRACEPTIVES

Combined oral contraceptives (OCs) contain ethinyl estradiol and a synthetic progestin taken for 21 days, and a placebo taken for 7 days. During the 21-day period, hypothalamic pituitary ovarian axis activity is suppressed and endogenous estradiol and progesterone levels are low, similar to levels in follicular phase for non-users.⁹⁸ Across most of the 7-day placebo period, estrogen levels remain suppressed. New formulations contain the minimum steroid doses necessary to inhibit ovulation.⁹⁹ As such, levels of estrogen and progestin in today’s OCs are lower than in older formulations, which needs to be considered when comparing studies.

The few studies that have examined PSG measures in women taking OCs have not found increased sleep disruption or poorer sleep quality, however, sleep architecture is altered. Women had about 12% more N2 sleep on a night during the 21-day period of active pill compared with a night in the 7-day placebo period.¹⁰⁰ They also have more N2 sleep and less N3 (SWS) than naturally-cycling women in luteal phase,^100-102 and possibly a shorter REM onset latency.¹⁰² One study also examined effects of OC use on the sleep EEG, showing that use of a synthetic progestin (medroxyprogesterone) was associated with increased upper spindle frequency activity and greater sleep spindle density in women,¹⁰³ similar to natural luteal phase effects. Hachul and colleagues²⁵ found that women using OCs had a lower apnea hypopnea index,¹⁰⁴ as well as shorter latency to REM sleep and fewer arousals.²⁵ From this work, it could be hypothesized that taking OCs might have a beneficial effect on sleep. However, as shown in a recent meta-analysis, the use of OCs seems to have minimal benefit on the main features of sleep.¹⁰⁵

Other effects of OC use include raised 24-hour body temperature profiles, similar to the natural luteal phase, probably due to progestin. This increased temperature profile persists during the 7-day placebo period,¹⁰¹ which contrasts with the rapid decline in temperature as progesterone levels decline before menstruation in ovulatory cycles. OCs may also influence the melatonin profile, although findings are inconsistent.³⁵ In one study using a modified constant routine procedure, melatonin levels did not differ between naturally-cycling women and women taking OCs, although there was a trend for increased melatonin in the latter part of the night in the OC group.⁵⁴

In summary, OCs alter aspects of sleep architecture as well as body temperature, although their impact on sleep quality appears to be minimal. Given the lower doses of hormones in current OCs, it remains to be seen if their effects on sleep architecture and temperature differ from that of prior formulations.

IMPACT OF SLEEP ON REPRODUCTIVE FUNCTION

Sleep duration, timing, and quality can influence the reproductive system and particular sleep stages are also important for reproductive maturity: During puberty, LH is released in a pulsatile fashion during N3, playing a critical role in reproductive regulation.^106,107 In adultood, the direction of this relationship changes in the early follicular phase, with sleep inhibiting LH secretion, which may be necessary for recruitment of ovarian follicles.¹⁰⁸

Shiftwork and menstrual cycle rhythms

There are reports of associations between short sleep duration and altered menstrual cycles. Women reporting < 6 h sleep were more likely to report abnormal (short or long) menstrual cycle lengths¹⁰⁹. There has been a larger body of work investigating the impact of shiftwork on reproductive function in women, given the typical disrupted sleep and circadian patterns in this group, as reviewed in detail elsewhere.¹¹⁰ In general, observational studies have provided evidence for reproductive disturbances such as menstrual irregularity and subfertility in women shift workers.¹¹¹ For example, a 2014 meta-analysis of 4 studies involving 28,479 women suggested that shift workers experience higher rates of infertility.¹¹² Similarly, a meta-analysis of 4 studies involving 71,681 women suggested that shift workers experience higher rates of menstrual disruption (cycles less than 25 days or greater than 31 days) compared to non-shift workers.¹¹² Some evidence suggests that shift work, particularly night-shift work, may lead to fertility problems and increased risk for miscarriage, however the effect size is uncertain.¹¹³ Meta-analyses of the literature investigating the association between various working conditions and fetal and maternal health concluded that shiftwork poses minimal risk to the female reproductive system¹¹⁴ and that there is insufficient evidence for clinicians to advise restricting shiftwork in reproductive-age women.¹¹² However, several professional bodies on health and safety state that shift work, particularly night shift work, may increase risk for menstrual cycle disruption or pregnancy complications. The nature of the relationship between shiftwork and reproductive health remains unclear, but it could relate to increased stress, disrupted circadian rhythms and/or sleep, which influence reproductive hormone secretion, particularly LH and FSH.

Sleep during in vitro fertilization

In vitro fertilization (IVF) is a widely used assisted reproductive technology, as it offers a solution for infertility and other reproductive issues. Emerging work has begun to examine the impact of sleep on IVF outcomes since sleep can affect various physiological processes that play a role in the success of the treatment, such as hormone regulation, immune function, and stress levels. Sleep disturbances are commonly reported throughout the IVF treatment process.¹¹⁵ A pilot study of 22 women that used subjective and objective measures found that almost half of the group has short actigraphic TST (< 7 hours) at baseline, and this percentage remained high across IVF treatment until post-embryo transfer. Daytime sleepiness was also common in the group and increased significantly from baseline to stimulation.¹¹⁶ There was a trend for a positive association of TST with oocytes retrieved in this small sample, suggesting that sleep duration may be an important factor for IVF success. Another study using actigraphy¹¹⁷ showed an association between shorter sleep duration and higher rates of implantation failure. Poor sleep quality may be a risk factor for adverse IVF embryo transfer,¹¹⁸ while good sleep quality has been associated with successful outcomes in IVF treatments, including higher rates of clinical pregnancy and live birth.¹¹⁸ It should be acknowledged, however, that the association between sleep and reproductive function may be bidirectional. Disturbed sleep may interfere with fertility but, the distress associated with infertility can also contribute to a poor sleep quality and shorter sleep.¹¹⁹ Reschini and colleagues¹²⁰ examined sleep quality and psychological health (i.e., infertility related distress and symptoms of anxiety and depression) in women undergoing IVF treatment. While results showed that only sleep quality was linked with IVF treatment success, they concluded the association between poor sleep quality and lower chances of pregnancy were mediated by a poorer psychological health. Further longitudinal studies of larger samples of women preparing for and undergoing IVF are required to fully understand the role of sleep in the success of IVF outcomes.

SLEEP AND LATE-REPRODUCTIVE STAGE

Women show a dramatic increase in sleep disturbance when they approach menopause (i.e., during the transition to peri-menopause to menopause) (Baker et al 2018). Self-reported sleep complaints in the midlife years are more likely during the premenstrual week and during the first few days of menstruation compared to other times of the cycle. For example, the Study of Women’s Health Across the Nation (SWAN), which included women in their late reproductive years and women entering the menopausal transition, reported that self-report sleep disturbance varied with cycle phase, being more likely to occur during the late luteal and early follicular phases of the menstrual cycle.¹⁸ After controlling for cycle day and other confounders, poorer sleep quality was associated with hormonal factors, although relationships differed depending on reproductive stage: higher levels of a progesterone metabolite, pregnanediol glucuronide, in urine were related to more trouble sleeping in the perimenopausal group, and higher urine FSH levels were related to more sleeping complaints in the premenopausal group.¹⁸

Menstrual cycle-related changes may impact sleep more prominently with advancing age: although hormone levels were not measured, a large actigraphy study of late-reproductive aged women in SWAN, found a 5% decline in sleep efficiency and a 25-minute decrease in total sleep time in the premenstrual week relative to the prior week²⁷ and a small PSG study found that women in the menopausal transition who were still cycling had more awakenings and arousals, as well as less N3 sleep in the luteal phase compared to the follicular phase⁴⁰ - effects that are not observed in most studies of younger women. While there was no change in slow wave EEG activity, the upper frequency range of sleep spindles significantly increase in the luteal phase compared with the follicular phase.⁴⁰ Interestingly, midlife women with insomnia showed a blunted rise in sigma EEG activity in the luteal phase, possibly reflecting a weaker influence of the menstrual cycle on sleep EEG in the presence of insomnia.⁴⁰ Further investigation is necessary to examine distinct trajectories of sleep disturbance across the menstrual cycle in the context of sex hormone levels, menopausal symptoms, and age.

CONCLUSION

Aspects of sleep and circadian rhythms are altered in association with the hormonal changes of the menstrual cycle, with negative effects on sleep most evident in the presence of menstrual-associated disorders. The magnitude of effect varies, particularly for self-reported sleep quality, which worsens in some, but not all, women when premenstrual symptoms emerge. For research purposes, effects of menstrual cycle phase should be kept in mind when data are collected, and ideally, phase should be documented. There are diverse menstrual cycle profiles such that inter-subject variability needs to be accounted when studing sleep. When comparing women with men, women of reproductive age should be studied in the follicular phase before there is potential influence from the rise in progesterone. Women's lives are marked by significant hormomal fluctuations during (i.e., menstrual cycle) and across (i.e., puberty, menopause) their reproductive years that affect sleep, which can have consequences for their physical, mental and emotional wellbeing. Sleep is an essential behavior that needs to be prioritized in the context of women´s health. Providing women with menstrual health education, necessary resources, and psychosocial support to manage the effects of hormonal changes can help them navigate potential challenges to sleep that may accompany these transformative phases.

Key Points.

1. Self-reported sleep disturbance can emerge during premenstrual and menstruation phases of the menstrual cycle, particularly in women with moderate-severe premenstrual symptoms (PMS/PMDD), irregular cycles, or painful menstrual cramps (dysmenorrhea).

2. Objective measures of sleep continuity show no significant variation across the cycle in young women without menstrual-related complaints, however, peri-menstrual sleep disturbances (e.g., poorer sleep efficiency or more awakenings) may emerge in women in the late-reproductive years.

3. There is a marked menstrual cycle related change in sleep spindle activity in the electroencephalogram, which is increased in the luteal relative to the follicular phase, possibly due to an effect of progesterone and/or its metabolites.

4. While sleep can be affected by reproductive hormone variations, the reverse relationship is also evident such that sleep disturbance and/or altered sleep timing is associated with altered reproductive function.

Synopsis.

Aspects of sleep change occur across the menstrual cycle in some women. Poorer sleep quality in the premenstrual phase and menstruation is common in women with premenstrual symptoms or painful menstrual cramps. While objective sleep continuity remains unchanged across the regular, asymptomatic menstrual cycle, activity in the sleep electroencephalogram varies, with a prominent increase in sleep spindle activity in the post-ovulatory luteal phase, when progesterone is present, relative to the follicular phase. Luteal phase changes in physiology are also clearly evident during sleep, with a raised nocturnal body temperature rhythm of smaller amplitude (due to a blunted nocturnal decline) accompanied by a faster heart rate. Sleep duration and quality may influence reproductive health, with short sleep duration and/or shifted sleep timing being associated with altered reproductive function. Menstrual cycle phase, reproductive stage, and menstrual-related disorders should be considered when assessing women’s sleep complaints.