Shift work and circadian dysregulation of reproduction

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Over the years, many studies have noted that either the onset of labor or birth occurs more often at certain times of the day than others. For example, the onset of labor and spontaneous membrane rupture peaks at night between midnight and 4:00 a.m. ( 74 – 76 ). Several factors such as bacterial inflammation of fetal membranes (chorioamnionitis), time between membrane rupture and labor onset, as well as primiparous versus multiparous mothers, can modulate the timing of labor or membrane rupture. For example, if labor occurs within 3 h of spontaneous membrane rupture, labor is more likely to begin earlier in the day ( 75 ). In addition, labor onset in first pregnancies is more likely to occur either in the early evening (i.e., 8:00 p.m.) or early morning (i.e., 8:00 a.m.), and this time-of-day labor onset bimodal rhythm appears to be absent in multiparous pregnancies ( 77 ). In contrast to labor onset timing, which is most likely to begin during the night, the timing of births peak during the day around 1:00–2:00 p.m. for primiparous births and slightly earlier for multiparous births (i.e., early morning) ( 78 ). Finally, there may be seasonal rhythms – for example, one study noted that births are more common from September to November compared to the winter months (December to February) ( 78 ). Given these temporal differences in parturition, it is not surprising that several studies have found that some interventions during labor are more successful at certain times of the day than others. For example, one study conducted a nested, randomized, controlled clinical trial comparing morning (8:00 a.m.) versus evening (8:00 p.m.) administration of prostaglandin and its success rate in inducing labor. While there were no differences in whether or not birth occurred within 24 h of induction or whether or not a cesarean delivery was used, morning inductions required less oxytocin, had a shorter induction to birth interval, and were less likely to result in instrumental vaginal births for women in their first pregnancies ( 79 ). However, it is important to note that a recent meta-analysis of perinatal mortality found no overall difference between morning and evening prostaglandin application or oxytocin-delivery in either maternal or neonatal outcomes ( 80 ). The day/night profile of melatonin secretion is one putative underlying mechanism for time-of-day differences in labor and delivery or in the success rate of labor intervention. A recent review highlights this potential role for melatonin, noting that melatonin and oxytocin work in concert to induce contraction of smooth muscle myometrial cells in the uterus ( 81 ). In people, sleep and circadian disruption induced by shift work can affect labor and pregnancy outcome. For example, severely disrupted sleep during late pregnancy is more likely to result in cesarean delivery, and even sleep restriction to less than 6] per night is sufficient to increase the risk of long labor and cesarean delivery. Interestingly, fatigue during labor and delivery is not an underlying factor ( 82 ). In addition, pregnant Chinese textile workers who work rotating shifts are more likely to give birth at younger gestational ages and to infants with a low birth weight ( 83 ), consistent with the Swedish Midwife Study, which found that night work is significantly associated with pre-term birth and small for gestational age births ( 84 ). Overall, this link between shift work and pregnancy outcome is consistent with findings in mice with genetic knockout of the Clock gene. Only 57% of these mutant mice deliver viable pups and the rest either reabsorb their pups or go into a long, extended labor that does not end in delivery ( 85 ). Finally, even after birth, shift work can impact new moms’ ability to breastfeed. One study found that breastfeeding rates among night shift workers are reduced at 1 month and 2 months after birth ( 16 ).

In summary, there is a growing amount of evidence supporting the notion that the circadian clock is involved in regulation of nearly every part of the reproductive pathway. For example, circadian clock-gene expression has been localized to neuroendocrine centers in the brain (e.g., hypothalamic GnRH neurons and pituitary cells) and reproductive tissues (e.g., ovary, fallopian tube, uterus), and shown to be necessary for the proper regulation of prolactin, gonadotropins (e.g., LH and FSH), and the GnRH-receptor. Moreover, day-night variation in blood pressure during pregnancy, and timing of labor and/or birth suggest the involvement of the circadian clock. Thus, it is conceivable that perturbations of the circadian system misalign hormones and gonadotropins during the reproductive cycle in a shift work environment. In turn, this can lead to interference with menstrual cycles, pregnancy, and parturition, resulting in increased risk of infertility, spontaneous abortions, pre-term births, low birth weights, and difficulty breastfeeding (Figure 2 ). While documenting these hazards of shift work is an important ongoing mission, it is now imperative for future studies to empirically show how shift work creates circadian misalignment of gonadotropins and other endocrine hormones in humans. The ultimate goal is to determine how to reduce this misalignment and the consequential pathologies. Given that many shift workers revert to nocturnal sleep patterns on days-off ( 34 ), entrainment of endocrine rhythms to night shift is not likely a viable solution. Attention to off-shift behavioral sleep strategies and determination of which strategies produce the least amount of misalignment of circadian clock-controlled rhythms (including reproductive hormones) could lead to potential solutions to the reproductive hazards of shift work. For example, in our study of nurses on night shift, we identified five different sleep/wake schedules that nurses had themselves selected (described in Figure 1 ). Based on self-reported adaptation and performance, we suggest that strategies such as “Incomplete Shifter” or “Switch Sleeper” be implemented to minimize the loss of performance due to sleep deprivation. Tests of these sleep/wake strategies for their impact on the reproductive system could identify schedules that minimize the shift work-induced disruptions in the reproductive axis reviewed in this paper. Circadian regulation of reproduction and impairment associated with shift work . Evidence suggests that the circadian clock regulates each part of the reproductive axis from timing of neuronal activity in hypothalamic neurons to the day-night variation in the release of pregnancy hormones. Dysregulation of circadian rhythms, as often occurs with shift work, results in increased risk of adverse consequences at each step of the reproductive pathway. See text for references. GnRH, gonadotropin releasing hormone; LH, luteinizing hormone; FSH, follicle stimulating hormone; ACTH, adrenocorticotropic hormone.

The National Sleep Foundation 2008 poll estimates that ∼7% of American workers are shift workers ( 1 ), and the U.S. Bureau of Labor Statistics estimates that nearly 15% of the workforce is employed on an alternative work schedule such as evening, night, or rotating shift work ( 2 ). Shift work is associated with an increased risk of developing cardiovascular/metabolic/gastrointestinal disorders, some types of cancer, and mental disorders including depression and anxiety ( 3 – 5 ). In women, shift workers have a higher incidence of obesity and high blood pressure ( 6 ), breast cancer ( 7 ), and reproductive issues ( 8 – 10 ). For example, shift work has been associated with an increased risk of irregular menstrual cycles ( 11 ), endometriosis ( 12 ), miscarriage ( 13 ), low birth weight or pre-term delivery ( 14 , 15 ), and reduced incidence of breastfeeding ( 16 ). The purpose of this review is to highlight the role of circadian clock in regulating human reproductive physiology and shift work-induced pathology within each step of the reproductive axis. The circadian clock allows organisms to anticipate regular and daily repeating events that occur at approximately the same time of day, and this anticipation enables upregulation of key physiological pathways so that an appropriate physiological or behavioral response can be elicited at the correct time. In mammals, these 24-h rhythms in physiology are orchestrated by a primary clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN coordinates other central circadian oscillators (e.g., the hypothalamus and pituitary gland) that drive rhythms in peripheral tissues ( 17 ), including endocrine tissues such as the adrenal gland, thyroid gland, adipocytes, pancreas, and gonads ( 18 ). (For an overview of basic human reproductive endocrinology, see Box 1 ). Within both the central clocks in the brain and peripheral oscillators, the 24-h timing mechanism appears to be the same and is composed of a set of genes (clock genes) and respective proteins that form a feedback loop [for review see ( 19 )] which rhythmically regulates many output genes (clock-controlled genes or ccg’s) as detailed in Box 2 . For the purpose of this review, we will focus on the circadian clock genes CLOCK , NPAS2 , BMAL1 (a.k.a. ARNTL ), PER1 , and PER2 . Female mammals exhibit a cyclical flux of hormones controlling follicular maturation and ovulation. The approximately 28-day menstrual cycles of women are tightly orchestrated by the HPG axis, which coordinates peripheral organs with the central nervous system (CNS). The primary signal from the CNS is GnRH, which is secreted in short pulses averaging once every 90 min. GnRH also stimulates the anterior pituitary to release FSH and LH, which promote follicular development. Estradiol is produced by developing follicles in the ovaries; its synthesis is a carefully regulated system that is coordinated by feedback mechanisms between the hypothalamus, anterior pituitary, and ovaries. The release of estradiol from developing ovarian follicles stimulates proliferation of the uterine endometrium and negatively regulates the further release of GnRH and FSH. One follicle outgrows all of the others which undergo atresia. As estradiol concentrations peak, they trigger the surge release of GnRH into the hypophyseal portal blood system. This GnRH surge triggers a surge of LH which acts on the ovary and induces ovulation. The follicle releases the ovum as it ruptures and undergoes luteinization. During this, the secretory cycle stage, large amounts of progesterone and estradiol are secreted by the corpus luteum. The secretory phase lasts for 10–16 days in women. During this phase the endometrium becomes increasingly thicker as endometrial glands and blood vessels become increasingly tortuous in preparation for implantation of a fertilized ovum. Simultaneously, estrogen in particular and progesterone to a lesser extent negatively feed back to the anterior pituitary and maintain low secretory rates of LH and FSH. In the absence of pregnancy, involution of the corpus luteum usually occurs after the 12th day. The sudden cessation of its inhibitory effect on the anterior pituitary allows for the renewed release of LH and FSH to begin a new ovarian cycle. At the same time, paucity of secretion of progesterone and estradiol lead to the breakdown of endometrial lining and menstruation. (A) The 24-h timing of the molecular clock is orchestrated by a set of clock genes and proteins that form a positive feedback loop when CLOCK dimerizes with BMAL1 and binds to the E-box elements of PER and CRY genes, activating transcription. Negative control of transcription occurs when PER/CRY dimerize, and this complex translocates into the nucleus where it inhibits the transcription of its own genes, through inhibition of BMAL1 and CLOCK transcription. Circadian clock-gene expression is rhythmic in peripheral tissues, including in human PBMCs ( 49 – 52 ) with hPER1/2 peaking at the sleep-to-wake transition and hBMAL1 peaking at the end of the wake period ( 53 ). (B) Circadian clock-gene expression has been reported in a majority of neuroendocrine tissues ( 86 ). The neural timing of the SCN is believed to signal to neuroendocrine cells (e.g., hypothalamic GnRH neurons) which in turn (via GnRH) drive the rhythmic secretion of pituitary LH and subsequent ovulation. Rhythms of clock-gene expression have in fact been reported in many brain regions involved in controlling the HPG axis, such as the hypothalamus and the pituitary gland, the latter being the earliest and best described circadian oscillator in the HPG axis ( 21 , 87 , 88 ). Several peripheral mammalian reproductive tissues in both male [e.g., extra-testicular ducts ( 89 )] and female [e.g., ovary, uterus, and oviducts ( 45 , 90 – 94 )] rodents have also been shown to exhibit 24-h oscillations in circadian clock-gene expression and circadian clock-controlled gene expression rhythms [for review, see ( 23 )]. For example, in the ovary, the transcriptional rhythms of the circadian clock genes per1/2 and bmal1 peak around light offset and onset, respectively, regardless of ovarian cycle stage ( 8 , 23 ). The circadian rhythms of clock-gene expression observed in reproductive brain areas suggest that this neural timing system drives and orchestrates neuroendocrine events ultimately leading up to the pre-ovulatory luteinizing hormone (LH) surge and ovulation [reviewed by ( 18 )]. The SCN has been shown to be necessary for normal functioning of the hypothalamic pituitary gonadal (HPG) axis, and rhythms of clock-gene expression have been recorded in brain regions controlling both the HPG and hypothalamic-pituitary-adrenal (HPA) axes. The earliest and best described circadian oscillator in the HPG axis is the pituitary gland ( 18 ). Here, rhythmic gene expression of prolactin and gonadotropin releasing hormone (GnRH) receptors has been shown to be mediated via clock-gene regulatory elements [i.e., E-Boxes; ( 20 , 21 )]. Furthermore, GnRH secreted by the hypothalamus appears to activate clock-gene expression in pituitary gonadotrophs through the same intracellular mechanism used to drive LH gene expression ( 22 ). In the more distally located ovarian clock, CLOCK and BMAL1 transcriptionally regulate a clock-controlled gene whose protein product is a key transcription factor (COX2) involved in prostaglandin synthesis ( 23 ). This growing body of work linking circadian and reproductive systems supports the notion that the coordinated timing of circadian clocks in reproductive brain areas such as the hypothalamus, forebrain, and pituitary and more peripheral circadian oscillators in the gonads may not only facilitate but be a prerequisite for establishment and maintenance of reproductive health. Endogenous rhythmicity must be entrained or synchronized to the environment, and this process primarily occurs through photic input to the SCN from the retina. Specifically, environmental light is detected in intrinsically photoreceptive, melanopsin-containing retinal ganglion cells, which transmit this information directly to the SCN via the dedicated retinohypothalamic tract ( 24 ). Through a multi-synaptic pathway, the SCN drives 24-h rhythms in the production of the pineal hormone melatonin and is also critical for acute, light-induced suppression of melatonin synthesis at night ( 25 , 26 ). Other environmental stimuli including exercise and feeding behavior can also entrain circadian rhythmicity. For example, when rodents consume food 12 h out of phase with activity rhythms, the rhythmic clock-gene expression in the SCN remains the same while clock-gene expression shifts in the liver, kidney, heart, and pancreas, leading to a state of internal desynchronization ( 27 , 28 ). In addition, transient internal desynchronization induced by a 6-h delay of the light-dark cycle in rats alters sleep architecture ( 29 ). In fact, even a simple 6-h shift in the light-dark cycle takes 6–12 days for clock-gene expression rhythms to completely adjust, with different peripheral tissues requiring varying amounts of time to shift ( 30 , 31 ). Detailed investigation of the effects of a 6 h advance of the light-dark cycle on ovarian rhythmic phase has revealed that the ovarian clock is not fully shifted by 6 days, but phase synchrony is fully restored by 12 days. Moreover, endocrine signals from the pituitary [LH and follicle stimulating hormone (FSH)] are capable of resetting the ovarian clock phase ( 31 ). In addition to transient desynchronization, chronic internal desynchronization using repeated, weekly 6 h advances in the light-dark cycle in rodents, can result in greatly increased mortality in aged or immune-challenged animals ( 32 , 33 ). Given that shift workers commonly prefer to shift back to night-sleep on days-off ( 34 ), a better understanding of the internal desynchronization of endocrine tissues induced by frequent shifts in sleep/wake behavior is critically important to finding solutions to the reproductive health hazards of shift work.