in mammals , the 24-hour clock mechanism , or circadian oscillator , is critical for the function and coordination of a broad range of biological processes , from hormone secretion to locomotor activity . animals are more likely to gain mating opportunities if they coordinate their sexual behavior with that of their potential partners . females benefit from synchronizing the timing of pregnancy to seasons with favorable food and weather conditions , and it is advantageous for an animal to give birth at a time of day when it is most likely to be in a safe place such as a burrow rather than out foraging . a mounting body of evidence indicates that disruptions in normally synchronized , or entrained , biological rhythms are associated with a broad range of pathologies including reproductive dysfunction in females . this review will describe how the endogenous timing system interacts with the hypothalamic - pituitary - gonadal axis to regulate female reproductive cyclicity . i will address how disruptions in the alignment of these rhythms , as occurs in shift work or jet lag , are strongly associated with reproductive dysfunction in women . i will lastly address how  clock genes  , the genetic components underlying the circadian mechanism , relate to reproductive function , and how hormone secretion in turn can alter clock gene rhythmicity . the bureau of labor statistics reported that in 2004 over 27 million americans had flexible or shift work schedules . shift work is defined as any employment after 7  pm and before 9  am . shift work is found in services such as healthcare , military , and protection ( police , firefighters ) . shift - workers tend to have activity , body temperature , and hormonal rhythms that are out of phase with environmental cues and often the behavioral rhythms of their family and friends . some workers are able to adapt or synchronize their rhythms ( sleep schedules , melatonin secretion patterns ) to an alternative work schedule . even so , adapting to a shift work schedule can be hindered when workers have weekends off and encounter a world operating on a standard schedule . a number of individuals are never able to adjust to shift work .   jet lag is caused by shifts in the environmental light : dark cycle , or photic phase , that result in an organism 's internal rhythms becoming transiently out of phase with the environment and each other . similar to shift work , jet lag also causes a myriad of physical , emotional , and psychiatric problems in humans [ 47 ] . it is likely that these disruptions in circadian rhythms are even more extreme for transmeridian travelers than those of shift workers . these individuals do not have a regular schedule to enable entrainment , they travel through different time zones which provide constantly changing light : dark schedules , and they experience light exposure at times when their internal clock mechanism indicates it should be night . all of these signals can continuously reset and disrupt internal circadian rhythms ( e.g. , sleep patterns ) . shift work , jet lag , and other forms of circadian disruption including sleep deprivation increase the risk of individuals acquiring a disease or exacerbate the symptoms of a preexisting condition . shift - work , jet lag , and sleep deprivation have been associated with an increased risk of mood disorders , depression , cardiovascular disease , endometriosis , dysmenorrhea , as well as an increased incidence and risk of breast cancer     [ 811 ] . shift workers and transmeridian travelers report increased fatigue and sleep disturbances relative to individuals working daytime shifts . women with chronic sleep deprivation or insomnia are more likely to have circadian rhythm disruptions and clinical depression . sleep disturbance in late pregnancy is associated with increased labor duration and increased likelihood of requiring medical intervention such as cesarean section . these relationships between work schedules and health have gained considerable attention from society and the scientific community . the american academy of sleep medicine recognizes jet lag as a sleep disorder typified by excessive daytime sleepiness and associated physiological impairments . in 2007 , night shift work was reclassified from a possible to a probable human carcinogen ( class 2a ) by the international agency for research on cancer . in fact , this ruling formed the basis for a recent decision by a danish industrial injuries board to award compensation to women shift workers . these women had worked more than 20 years as a shift worker and developed cancer . the most - studied animal models of female reproductive cyclicity are laboratory muroid rodents ( i.e. , rat , hamster , mouse ) , which have an estrous cycle characterized by a short total duration ( 4 - 5 days ) , spontaneous follicular development and spontaneous ovulation . the menstrual cycles of women and the estrous cycles of these rodents have several features in common including a series of tightly orchestrated events that result in increased activity in gonadotropin releasing hormone ( gnrh ) neurons , a hormone surge , and ovulation ( figure 1 ) . during the follicular phase of the cycle , maturing follicles in the ovary release increasing levels of estradiol . when estradiol concentrations reach a threshold , a surge of gnrh is released from cells in the hypothalamus into the hypophyseal portal blood system . this surge of gnrh triggers a surge of luteinizing hormone ( lh ) from the anterior pituitary , and this hormone acts on the ovary to induce ovulation . following ovulation the follicles rupture then are luteinized . during this cycle stage progesterone rats and mice have corpora lutea that function for 13 days but do not have a true extended luteal phase without coitus or vaginal stimulation .   in rodents these reproductive events occur in a cyclical and circadian manner . in rats gnrh neurons become active just before lights - off as indicated by the presence of the immediate early gene fos within the nucleus . this rhythm is endogenous , as ovariectomized rats given steroid hormones only have a rise in gnrh cell activation at one time of day , and this rhythm persists in animals housed in constant darkness . the lh surge is concurrent with the gnrh cell activation and occurs just before lights - off . for example , in hamsters housed in a light : dark cycle , the estrous cycle occurs every 96 hours ( 4 periods of 24  hours ) . when animals are housed in constant conditions this rhythm continues ( range 95.3597.54  h ) , indicating that an endogenous circadian mechanism ( rather than the environmental light : dark cycle ) is regulating the estrous cycle . rodents also exhibit a daily rhythm in the timing of mating behavior ; typically this occurs around the onset of their active period     [ 21 , 22 ] .   in laboratory rodents the precise timing of this cascade of estrous cycle events is regulated by a small number of cells located in a brain region called the suprachiasmatic nucleus ( scn ) . the scn contains the primary circadian mechanism and regulates the timing of central and peripheral oscillators . rats and hamsters with bilateral scn lesions lack a rhythm in sexual behavior , the preovulatory lh surge , corticosteroid rhythms , and a consistently functional estrous cycle     [ 2428 ] . transplants of fetal scn tissue restore some behavioral rhythms but do not restore estrous rhythms , indicating that synaptic inputs from the circadian clock are critical for mediating these systems . women also exhibit daily rhythms in the timing of reproductive cycle events and hormone secretion patterns . a second study examining the timing of the lh surge in 155 cycles ( from 35 women ) found that 48% of the surges occurred between 4 and 8 am and 37% of the surges occurred between midnight and 4 am . in women , the precise timing of ovulation has not been determined but is estimated to occur 2440  h later     [ 19 , 30 , 31 ] . in humans , the lh surge occurs before the active period ( daytime ) as is the case for other day - active or diurnal species . in nocturnal rodents , these events also occur just before their active period at the time of lights - off . there is diurnal variation in the pattern of pulsatile lh secretion ; this rhythm of peaks and troughs remains evident even in the reduction or absence of ovarian hormones , as is seen in hypogonadal women . the timing of the onset of labor and the timing of birth also exhibit strong diurnal rhythmicity with respect to time of day . a study of over 17,000 term singleton deliveries found the majority of women going into labor between midnight and 8  am with 01:45 am as the peak time of labor onset . in a second study of over 15,000 women , the onset of labor had a 24-hour rhythm , with a nadir in the middle of the day and peaks around dawn and dusk . the timing of birth typically occurs in the middle of the afternoon . in two retrospective studies ( 6608 and 15,000 women , resp . ) , the majority of births following a spontaneous onset of labor occurred between 1 and 2  pm [ 36 , 37 ] . interestingly , multiparous women were more likely to deliver babies earlier in the morning , between 8 and 11  am when compared to nulliparous mothers , the authors speculated this difference may be related to the timing of fetal and maternal hormone secretions . a clinical study was conducted to determine if this diurnal rhythm in the onset of labor was also important to women in whom labor was induced . women which had labor induced in the morning required less uterine stimulation ( i.e. , oxytocin ) , had a shorter interval from induction to birth , and were less likely to require operative assistance with the delivery when compared to women that had their labor induced in the evening hours .   these reproductive events in women occur with a diurnal rhythmicity ; however , it remains possible that the circadian system does not control the timing of reproductive events in humans as tightly as it does in rodents . for example , humans and primates are able to copulate throughout the ovarian cycle and are not limited to a particular time of day or specific duration of exposure to steroid hormones . in primates a surge in lh can be induced at any time of day with the proper strength and interval of steroid hormone treatment . this does not eliminate the possibility that appropriate and successful reproduction in women is regulated by the light : dark cycle and/or a circadian timing mechanism . nearly all of the available data indicate that alteration of the phase relationship between an animal , human or otherwise , and the light : dark cycle has adverse effects on the physiology of the affected organism . in support of this hypothesis , alterations or disruptions in the daily ( and potentially circadian ) rhythms of women women working an evening shift , night shift , or have irregularly scheduled shifts ( such as days - off or flexible schedules ) report altered menstrual cycle length ( both increases and decreases ) , increased menstrual pain , and changes in the duration and amount of menstrual bleeding     [ 41 , 42 ] . these symptoms are accompanied by changes in patterns of ovarian and pituitary hormone secretion , such as an increase in follicular stage length and changes in follicular stimulating hormone ( fsh ) concentrations     [ 8 , 10 , 42 , 43 ] . these effects are apparent even when the studies controlled for health , lifestyle , or job environment ( i.e. , stress ) . female shift workers have a higher risk of producing premature and/or low birth weight babies , spontaneous abortion and subfecundity     [ 10 , 44 ] . flight attendants who worked while they were pregnant were twice as likely to have a spontaneous abortion when compared to flight attendants who did not work during their pregnancy . some studies on pregnancy outcomes in flight attendants indicate that this risk of miscarriage is moderate compared to the general population of women     [ 45 , 46 ] . in a mouse model of shift work , there was a significant reduction in the percent of animals that mated when they were housed in a 22  hours ( 11  h light  : 11  h dark ) or 26 hours ( 13  h light  : 13  h dark ) light - dark cycles for 2 or more weeks prior to mating . interestingly , if pregnant animals were taken from a 24 hours light : dark cycle and moved to a 22 or 26  hours light : dark cycle there was very little effect on the pregnancy outcomes . entrainment to the light : dark cycle in women and rodents may be essential for successful copulation and conception , however , once pregnancy is achieved , female hormonal secretion patterns may be less sensitive to environmental changes .   shift work and jet lag may exert their effects on health and physiology by reducing the total amount of sleep for an individual . women working the night shift or experiencing transmeridian travel report a decrease in the amount of sleep and an increase in fatigue and insomnia     [ 13 , 41 ] . this reduction in sleep duration is not trivial as it has an effect on hormone secretion patterns . for example women with less than 8 hours of sleep secrete 20% less fsh compared to women with longer sleep durations . total or partial sleep deprivation increases lh amplitude , estradiol and fsh concentrations in normal cycling women . increased estrogen is associated with an increased risk of breast cancer ( discussed below ) . it is possible that the altered menstrual cycle physiology associated with circadian misalignment is due to a direct effect of sleep state on ovarian and pituitary hormone secretion . it remains to be eluciated if circadian disruption , while significant to emotional well being and other physiological aspects , is a critical mechanism underlying the reproductive dysfunctions . in the last decade there has been a strong link between shift work and incidence of breast cancer . as a number of recent reviews discuss this issue in depth , this topic will only be highlighted here     [ 50 , 51 ] . there is a substantial literature which links light exposure at night , shift work or transmeridian travel , and an increased risk of breast cancer     [ 9 , 5154 ] . one report examining over 85,000 women enrolled in the nurses ' health study found that a woman 's relative risk of getting breast cancer was amplified if she worked the night shift or had rotating shifts     [ 52 , 55 ] . animal cancer models indicate that altered circadian function exacerbates cancer symptomology . in a series of elegant studies , filipski et al . disrupted circadian rhythms in mice either through scn ablation or jet - lag schedules ( repeated advances of the light : dark cycle ) . mice experiencing this desynchrony had significantly accelerated growth of inoculated tumor cells     [ 5658 ] . one hypothesis which addresses the mechanism underlying this risk of breast cancer in shift workers is the  light at night theory  . this postulates that the increased exposure to light during evening working hours decreases melatonin secretion . melatonin is a pineal hormone that is secreted during the dark phase of the light : dark cycle and is suppressed when an individual is exposed to light including artificial light . melatonin concentration , diurnal pattern of melatonin secretion , and the relationship of this pineal hormone rhythm to other physiological rhythms are altered in shift workers compared to daytime employees . when compared to day - shift workers , women working the second or third shift have altered melatonin rhythms as measured by the urinary melatonin breakdown product 6-hydroxymelatonin sulfate . this hormone has a protective effect against cancer , and can inhibit the growth of metastatic cells . in in vitro studies melatonin can suppress the growth of malignant breast cancer cells ( reviewed in ) . melatonin - rich blood ( collected at night from healthy women ) suppresses tumor growth in immunodeficient rats carrying a human breast cancer xenograft . when these animals were given the melatonin rich blood and a melatonin receptor inhibitor , or blood collected during the day , the tumor suppressive effects were eliminated . there is a strong link between light at night , melatonin , and breast cancer risk however , shift work or sleep deprivation may not be the direct cause of cancer . rather the exposure to light at night suppresses the oncostatic hormone melatonin and accelerates the development of cancer symptoms . additionally , as mentioned above , sleep deprivation can alter gonadal and pituitary hormone secretion patterns which may influence tumor cell growth . it is clear that shift work , jet lag , and sleep disturbances put a woman at increased risk for acquiring this pathology and this will require additional research to determine the causal relationships . the link between circadian rhythms and reproductive function also functions at the molecular level . in the last decade a family of  clock  gene and protein transcription and translation feedback loops have been identified . these clock genes play a role in an individual 's rhythmicity , entrainment and responsiveness to light [ 6062 ] . in mammals , the proteins clock and bmal1 form heterodimers . this complex then activates the transcription of thee period genes known as per1 , per2 , and per3 . this clock / bmal1 heterodimer also turns on the transcription of two cryptochome genes known as cry1 and cry2 . the protein products of the per and cry genes heterodimerize , then act as repressors and turn off the transcription of clock and bmal1 . a second protein , npas2 also forms heterodimers with bmal and this protein complex also initiates per and cry transcription . the initial identification of rhythmic expression of clock gene transcription and translation was within individual cells of the scn . these molecular rhythms have also been found in peripheral organs including female reproductive tissues such as the ovary     [ 64 , 65 ] , uterus [ 6668 ] , and oviducts   ( figure 1 ) . daily rhythms in clock gene expression have been found in an additional component of the hpg system ; the gnrh neurons themselves . in cell cultures of gnrh gt1 - 7 cells , mrna of clock , bmal1 , per1 and per2 , and the protein bmal1 have a diurnal pattern of expression     [ 70 , 71 ] . transfecting these cells with an altered clock protein ( clock ) or the addition of the cry protein to the culture alters the amplitude and frequency of gnrh pulsatility . the exact role of the molecular clock within these neuroendocrine cells has not been determined . it is possible that this is a mechanism which alters cellular activity of gnrh neurons , or modifies their sensitivity to estradiol . further evidence that clock gene rhythmicity is critical for reproductive function is seen in knock out or transgenic animal models . disruptions in known circadian clock genes disrupts reproductive processes in female rodents ; several detailed reviews have been published recently     [ 19 , 73 ] . in knock - out mice missing either the per1 or per2 gene , estrous cycles are irregular or absent , and animals have decreased fertility . mice compared to young mice , suggesting that mutations in this gene accelerate ageing at least with respect to reproductive function . bmal1 knock - out female mice are able to mate but are not able to produce young . mice expressing a homozygous genotype of a mutated clock protein ( clock ) have a dampened lh surge , disrupted and irregular estrous cycles and difficulties with pregnancy . not all clock genes have an equal effect on reproduction as mice lacking , per3 , cry1 , or cry2 ( or combinations of these genes ) are able to breed and reproduce .   fertility and reproductive cyclicity may depend upon the precise phase relationship between the  master  clock contained in the scn and the clocks contained within reproductive tissues and gnrh neurons . the peak expression of bmal1 in the rat ovary is about 4 hours delayed relative to the acrophase of bmal1 mrna in the scn . similarly , the per2 rhythm in the ovary peaks 4 hours after lights off , whereas it peaks 6 hours earlier in the scn . if a female experiences a shift in the light : dark cycle , it is unknown how long it takes the circadian clock genes in the scn , ovary and uterus to resynchronize to one another . it is known that in mice experiencing a phase advance , per1 mrna rhythms in the scn rapidly readjust to the new light : dark cycle but the peripheral organs ( liver , lung , muscle ) take nearly 6 times as long as the scn to recover . rhythms in clock gene expression thus adjust to jet lag at different rates relative to one another , and relative to the peripheral organs . it is this mismatch of rhythms within the body that may underlie the reproductive deficits experienced by women experiencing disrupted biological rhythms     [ 77 , 78 ] .   the relationship between clock genes and female health has not yet been examined closely in women ; however , several studies have correlated circadian clock gene polymorphisms with reproductive disorders . the expression of three different polymorphisms of the npas2 gene was examined in control ( n = 476 ) and breast cancer cases ( n = 431 ) . a significant association was found between breast cancer risk and one of the heterozygous gene polymorphisms ( compared to homozygous genotype ) . this same research group also found a 1.7 fold increased risk of breast cancer in women with a heterozygous genotype for a per3 length polymorphism compared to women with a homozygous genotype . in contrast no link was found between endometriosis , shift work , and the expression of a polymorphism of the clock gene ( ht3111c ) in humans . this gene is correlated with mood disorders and in clock mutant mice estrous cyclicity is impaired [ 76 , 80 ] . despite these data , the authors did find that women working the night shift had a nearly doubled increase in risk of endometriosis and this was further increased if women had altered sleep rhythms on their days off . circadian gene markers may provide a valuable tool for identifying individuals in shift work environments that may be particularly susceptible to developing diseases . these markers may also help identify those individuals that may be better able to adapt to or accommodate a changing work schedule . as described above , the timing of estrus - related events including hormone secretion is regulated in part by the scn and circadian system . ovarian hormones in turn influence the behavioral and molecular circadian rhythms     [ 81 , 82 ] . on the day of sexual receptivity ( estrus ) , female rats , hamsters , and degus ( octodon degus , an hystricomorph rodent ) advance the onset of their daily activity rhythms     [ 8385 ] . ovariectomized female hamsters and rats have given a capsule containing estrogen similarly advance the onset of their activity rhythms and have a shorter free running period when compared to control animals     [ 86 , 87 ] . ovarian hormones appear to have a similar effect in women as diurnal and circadian rhythms including sleep - wake cycles and endocrine rhythms ( cortisol , melatonin ) change between the follicular and luteal phases of the reproductive cycle     [ 8890 ] . there are relatively few studies that have examined these rhythms in a controlled environment but one generalization is that ovarian hormones modify the amplitude but not the phase of various physiological rhythms . for example , humans have a daily rhythm in the fluctuation of body temperature , the nadir occurs after lights - off , and the temperature remains relatively low until the time of lights - on . in females , this general pattern remains consistent across the menstrual cycle but the amplitude of the rhythm is reduced during the luteal compared to follicular phase . similarly , when women were studied in an ultrashort sleep - wake protocol ( which separates the endogenous rhythms from the influence of the environmental cues ) the daily rhythm in cortisol was blunted during the luteal compared to follicular phase     . ovarian hormones also influence the expression of circadian clock genes both within and outside of the scn . importantly , the effects of estrogen on the rhythm of clock gene expression are both tissue and gene specific . in ovariectomized female rats , chronic estrogen treatment significantly phase advances the acrophase of per2 mrna expression , but not that of per1 , in the scn . an injection with estrogen significantly decreases the amount of cry2 mrna within the scn , but does not change the amount of cry1 mrna . in the uterus , estradiol treatment results in bimodal per1 and per2 expression whereas control animals had a single peak and estrogen shortens the period of per2 expression [ 67 , 93 ] . on the day of proestrus ( high estradiol ) data on clock gene expression in reproductive tissue of women is limited ; breast and endometrial cancer lines and tissue from breast cancer patients express clock genes and their protein products [ 94 , 95 ] . additionally , per2 expression inhibits the expression of estrogen receptors in breast cancer cell lines . lastly , it is possible for estrogen to have a direct effect on the circadian timing system as estrogen receptors have been detected in the human scn .   in rodent studies , changing concentrations of estradiol , either though the endogenous estrous cycle , or though disrupted ovarian function can phase shift or desynchronize circadian genes in both a tissue specific and clock gene specific manner . this perturbation in the steroid hormone signal can lead to a change in the expression of circadian clock genes both within the scn and in peripheral tissues including female reproductive organs . it will be important to determine if these factors also play a role in human reproductive health and disease . the general mechanisms by which the scn and circadian system regulate the physiological rhythms are still being elucidated . the investigation of specific central ( scn ) or peripheral oscillators that regulate rhythms in the well - described hypothalamic - pituitary - gonadal system will provide a more general understanding of how the circadian clock mechanism regulates rhythmic outputs . future work will also clarify the relationship between the circadian timing system and the contribution of other factors that impact women 's reproductive health . life or work stressors , sleep deprivation and fatigue , smoking habits , age , weight , and environmental conditions such as exposure to solvents all impact female reproductive function . the circadian timing system and scn regulate the onset of the preovulatory lh surge , ovulation , and mating behavior in rodents . rhythmic clock gene expression within the scn and peripheral reproductive tissues in females , and the relationship of these rhythms to one another , may be critical for successful reproduction . i hypothesize those disruptions in the endogenous circadian timing mechanism underlie reproductive deficits . in animal models , disruptions in these rhythms , as seen in transgenic and knockout mice , scn lesioned animals , or individuals experiencing changes in the light : dark cycle , lead to changes in estrous cyclicity and altered patterns of hormonal secretion . the desynchrony of gene expression within a tissue and between central and peripheral tissues may also impact upon an individual 's ability to establish phase relationships to environmental cues . in women , perturbations in daily rhythms , as occurs in shift work , jet lag , and sleep deprivation is associated with an increased menstrual cycle irregularity , increased risk of miscarriage , difficulty in conceiving , and a higher risk of breast cancer . females ' health and physiology may be particularly vulnerable to circadian disruption as the resulting changes in steroid hormones secretion patterns can further alter clock gene rhythms . further investigations are needed to examine how reproductive cycles are regulated in women , the impact of disturbed biological rhythms on reproductive physiology , and how to reduce the health risks associated with altered rhythms .
circadian rhythms and  clock gene  expression are involved in successful reproductive cycles , mating , and pregnancy . 
 alterations or disruptions of biological rhythms , as commonly occurs in shift work , jet lag , sleep deprivation , or clock gene knock out models , are linked to significant disruptions in reproductive function . 
 these impairments include altered hormonal secretion patterns , reduced conception rates , increased miscarriage rates and an increased risk of breast cancer . 
 female health may be particularly susceptible to the impact of desynchronizing work schedules as perturbed hormonal rhythms can further influence the expression patterns of clock genes . 
 estrogen modifies clock gene expression in the uterus , ovaries , and suprachiasmatic nucleus , the site of the primary circadian clock mechanism . 
 further work investigating clock genes , light exposure , ovarian hormones , and reproductive function will be critical for indentifying how these factors interact to impact health and susceptibility to disease .