key: cord-1006464-ql5fphz7
authors: Campbell, Lily R.; Scalise, Ariel L.; DiBenedictis, Brett T.; Mahalingaiah, Shruthi
title: Menstrual cycle length and modern living: a review
date: 2021-10-04
journal: Curr Opin Endocrinol Diabetes Obes
DOI: 10.1097/med.0000000000000681
sha: 1d68a2d231b7507720975dea473d94f1eef6c9f4
doc_id: 1006464
cord_uid: ql5fphz7

PURPOSE OF REVIEW: The aim of this review is to evaluate biological, life history, environmental, and lifestyle factors and exposures that cause variability in menstrual cycle length (MCL). RECENT FINDINGS: Recent literature has detailed a number of factors that influence MCL, with particular emphasis placed on novel environmental exposures, such as air pollution and endocrine disrupting chemicals. SUMMARY: MCL varies widely in response to intrinsic and extrinsic inputs and is a useful predictor of reproductive health and fecundability. VIDEO ABSTRACT:

Menstrual cycle length (MCL) is a relevant indicator of cycle regularity and reproductive health [1] . MCL is sensitive to inputs from the environment and varies within and between individuals [2] , though a length between 24 and 38 days is considered normal [3] . Several factors cause MCL variability, including ovarian biomarkers [4] and lifestyle-based exposures [5] . Environmental exposures, such as air pollutants and endocrine disrupting chemicals (EDCs) pose a unique threat, as many are ubiquitous, persistent, and detrimental to reproductive health and MCL [6, 7] . This review aims to discuss recent literature evaluating MCL variation in response to common and novel variables in modern life. We will also discuss MCL as an indicator or predictor of outcomes, such as endometriosis, polycystic ovary syndrome (PCOS), age at menopause, and fecundability.

A literature search was conducted using PubMed to identify studies evaluating MCL and a number of biological, life history, environmental, and lifestyle exposures (shown as inputs in Fig. 1 ). Factors were identified using clinical and professional knowledge of prior literature. Novel exposures included air pollution and EDCs. Outputs (Fig. 1) were not included as search terms.

Search strategies are reported in Supplemental Table 1 (see Table, Supplemental Digital Content 2, http://links.lww.com/COE/A29, which lists queries used in the literature search). Searches used the terms 'menstrual cycle length' and 'cycle length' with one of the input variables in Fig. 1 , using MeSH and non-MeSH terms. Search strategies excluded articles discussing MCL in populations with polycystic ovarian syndrome (PCOS). A limited number of relevant studies were published between 2020 and 2021, so inclusion criteria were expanded to include those with a publication date from 2016 to 2021. Most searches excluded studies not performed with human participants, though five necessitated the removal of this filter because of erroneous exclusion of relevant articles.

The searches yielded 268 results after duplicates were removed. Six additional articles were identified via citation searching and two were identified from knowledge of existing literature. Articles were excluded if they were not in English, were not primary studies, or were conducted in individuals with a reproductive disorder. Articles were excluded if they did not evaluate the association between MCL and variables included in the search strategies, or if they were not conducted using human participants. One article using a nonhuman primate model to study the effect of marijuana use on MCL was included because of its relevance to the scope of the review and the lack of literature in humans. The screening process (Fig. 2 ) yielded a total of 38 relevant studies. The distribution of relevant studies by publication date is shown in Fig. 3 .

Intrinsic factors affecting MCL are presented first and include the following biological and life history factors of age, BMI and body weight, ovarian variables, genetics, age at menarche, and parity and breastfeeding. Extrinsic factors consist of the following environmental and lifestyle exposures: air pollution, EDCs, shift work, exercise, alcohol intake, smoking, and marijuana use.

The way in which MCL and cycle length variability changes across the reproductive lifespan is well documented. Although most studies demonstrate a decrease in MCL during an individual's 30s and 40s [4, 9, 10 ]. However, results on this topic are inconsistent. Bull et al. [9] found no association between BMI and MCL, though they were limited by the exclusion of nonovulatory cycles and a population not reflective of global obesity rates. Similar results were reported Reports not retrieved (n = 5)

Reports assessed for eligibility (n = 50) Reports excluded: Out of scope (n = 10) Not primary study (n = 7) Wrong study population (n = 1)

Records identified from: Prior knowledge (n = 2) Citation searching (n = 6)

Reports assessed for eligibility (n = 8)

Studies included in review (n = 37) Reports of included studies (n = 1)

Reports sought for retrieval (n = 8)

Reports not retrieved (n = 0) Identification Screening Included FIGURE 2. PRISMA flow diagram describing the selection of articles included in this review. Data from [8] . For more information, visit http://www.prisma-statement.org/. propose that hormonal markers, such as sex hormone-binding globulin (SHBG), estrone (E1), and insulin may be partially mediating the interaction between measurements of weight and MCL. The underlying inconsistencies are likely because of cohort characteristics, study population, the assumption of ovulatory cycles for all episodes of bleeding, and varying definitions of MCL variability and irregularity.

Ovarian characteristics, such as anti-M€ ullerian hormone (AMH), ovarian volume, and antral follicle count (AFC) are associated with MCL. AMH, in particular, is the primary ovarian predictor of MCL and has a strong positive correlation with cycle length [4,18 & ,19 ]. Zhu et al. [4] propose that AMH elongates follicular phase lengths by suppressing FSH-stimulated estradiol production from the antral follicles during folliculogenesis. A trend of increasing MCL was also seen with diminishing AMH, which is inversely correlated with increasing age [20] . Ovarian reserve and AFC are also both associated with AMH and MCL, though not to the same degree as AMH alone with MCL [4] . This association is likely because of the secretion of AMH by antral follicles and a proportional relationship between ovarian reserve and AMH.

Three studies evaluate the genetic determinants of MCL. One reported that a polymorphism in the FSHB promoter (rs10835638; c.-211G>T) lowers folliclestimulating hormone (FSH) levels and is associated with longer MCL [21] . As a threshold of FSH must be met for follicular recruitment, establishment of the dominant follicle, and ovulation to occur, the authors propose an association between the genetic determinants of FSH levels, ovulation, and parity, such that decreased FSH levels in individuals with the polymorphism undergo ovulation less frequently, and therefore, have lower fecundability [21] . A genome-wide association study subsequently confirmed the association between the FSHB locus and MCL and highlighted four other loci of importance: NR5A2, DOCK5/GNRH1, IGF2, AND PGR [22] . These loci are involved in steroidogenesis, FSH/luteinizing hormone (LH) release, folliculogenesis, and progesterone signaling, respectively. Although a third study found the FSHB promoter polymorphism to be associated with significantly higher serum concentrations of FSH and LH, no significant association was found between the polymorphism and MCL [23] . However, the authors note their study was underpowered to assess this association.

Whitcomb et al. [19] demonstrated that cycle lengths in individuals aged 18-22 years increased with later age at menarche. Conversely, data from a preconception cohort indicates that MCL is longer in individuals who reach menarche at a younger age [24] . Others have found no appreciable association between the two [4] . Conflicting results may be because of differences in study populations (Nurses' Health Study II [19] vs. preconception pregnancy planners [24] vs. healthy individuals recruited from a single site [4] ), age at which MCL was evaluated (18-22 [19] vs. 21-45 years [4, 24] , and potential misclassification of MCL and age at menarche because of reliance upon patient self-report.

Parity may be related to shorter MCL [11 & ,24] , though this association is sometimes weak [19] or nonexistent [4] . Additionally, breastfeeding appears to affect MCL. Najmabadi and colleagues [11 & ] report that individuals experienced shorter mean MCL (29.6 vs. 31.0 days), shorter follicular phases (18.5 vs. 19.1 days), and shorter luteal phases (11.0 vs. 11.7 days) when partially breastfeeding. Models used were stratified by age and parity but this study was limited by homogenous cohorts and lacked data regarding metabolic variables and lifestyle behaviors. Conversely, short MCL is associated with a shorter duration of breastfeeding in a model stratified by age [19] .

Mahalingaiah et al. [7] found that individuals exposed to total suspended particulate in air have slightly increased odds of cycle irregularity and increased time to cycle regularity after menarche. Furthermore, sulfur dioxide and particulate matter smaller than 10 mmol/l (PM 10 ) are associated with decreased luteal phase length [25] . In a separate study, levels of nitrogen dioxide (NO 2 ) and particulate matter smaller than 2. 5 mmol/l are associated with increased follicular phase length, though neither NO 2 nor PM 10 are associated with increased luteal phase length [26 & ]. These results indicate that exposure to particulates released by fuel combustion may alter HPO signaling via endocrine disruption, thereby affecting MCL, possibly through lengthened follicular phases or luteal phase deficiency [6] .

Studies have reported concerning associations between EDC exposure and MCL. Notably, many are limited by small sample size. Three prospective cohort studies reported variability in MCL following exposure to perfluoroalkyl substances (PFAS) [10, 27, 28] . Though Singer et al. [27] found no association between PFAS concentrations and MCL, subgroup analyses linked decreased perfluoroheptane sulfonate and perfluorooctane sulfonate (PFOS) levels to short MCL in parous individuals, and increased perfluorononanoic acid (PFNA) and perfluoroundecanoic acid levels to long MCL in individuals who had used oral contraceptives in the previous year. Interestingly, higher perfluorooctanoic acid (PFOA) concentrations are associated with decreased MCL in one study [10] but increased levels of PFOA, PFNA, perfluorohexane sulfonate, and PFOS are associated with MCL more than 35 days in another [28] .

The impact of organohalogen exposure on MCL has likewise been of interest. A prospective cohort study showed no significant association between prenatal exposure to persistent organochlorine pollutants or polychlorinated biphenyls and MCL but did find that other aspects of reproductive health were impacted [29] . Recently, a study demonstrated that long and irregular cycles were common in Latinx child and adolescent farmworkers exposed to pesticides, including pyrethroids, organochlorines, and organophosphates [30 & ]. The study detected pesticide exposure using wristbands but the results are limited as wristbands were worn for 1 day. Conversely, increasing concentrations of persistent organohalogens and elements, particularly polybrominated diphenyl ethers, cadmium, and selenium, are associated with decreasing MCL, whereas increased MCL is associated with higher concentrations of copper [31] .

Remaining studies evaluate MCL following exposure to several other EDCs. A prospective cohort study reported increasing average MCL with increased exposure to polybrominated biphenyls (PBBs), though this was not statistically significant [32] . Moreover, a study linked shorter MCL and higher urinary concentrations of parabens, which are used as preservatives in personal care products and demonstrate estrogenic activity [33] . A similar association was reported between shorter luteal phases and higher urinary concentrations of phthalates and bisphenol A in a prospective cohort study, though no associations were found with follicular phase length [34] . Conversely, in a cross-sectional study assessing exposure to n-hexane, a volatile organic compound, 79% of exposed individuals demonstrated MCL more than 35 days vs. 20% in the control group (

Finally, a prospective cohort study evaluated the effect of dietary phytoestrogens and found that, though phytoestrogens were not associated with MCL, they may be associated with cycle regularity [36] .

Whether a relationship exists between stress and MCL remains unclear, likely in part because studies rely on self-reports of perceived stress levels. Of note, physical stress from exercise or caloric restriction is not included in this conceptualization of stress. Nonetheless, among those that are still menstruating and not affected by stress-induced hypothalamic amenorrea, increased perceived stress (noted on a questionnaire) is associated with shorter MCL [13 && ] and increased MCL irregularity [37] . The latter result is supported by Phelan et al. [38 & ], who assessed how stress associated with the COVID-19 pandemic impacted menstrual characteristics. Cycle length, however, was not found to change significantly before and during the pandemic [38 & ], and a separate study similarly reported no significant relationship between MCL and perceived stress [4] .

Although one study found no significant association between average hours of sleep, shift work, and MCL [4] , others indicate that MCL is impacted by disrupted circadian rhythm [5,39,40 & ]. The frequency of night shifts is associated with shortened MCL and shift work schedules are associated with increased likelihood of cycle irregularity in a study containing both cross-sectional and nested case-control components [39] . Particularly concerning is that these changes had not recovered 2 years later [39] . Another crosssectional study similarly found that rotating shifts were associated with MCL irregularity [40 & ]. Sleeping for fewer than 6 h per night is also significantly associated with short MCL (OR ¼ 3.7; 95% CI 1.1-12.7) and nonsignificantly associated with long MCL (OR ¼ 1.7, 95% CI 0.8-3.7) in a prospective cross-sectional study, leading the authors to suggest a causal association between insufficient sleep and metabolic abnormalities [5] .

Three studies evaluated MCL and exercise frequency but did not differentiate between types of exercise. Of these, two found that exercise frequency did not significantly change MCL [4, 5] . The third showed that individuals with short cycles were more likely to report no regular exercise than those with normal or long MCL [13 && ]. One prospective cohort study utilized the frequency of different exercise types to assess metabolic expenditure, concluding that individuals with shorter cycles had higher metabolic equivalent task-hours per week than individuals with MCLs between 26 and 31 days [19] .

Two studies evaluated the influence of diet on MCL within the review period. A cross-sectional study found that individuals with a low adherence to a Mediterranean diet had longer MCL than those whose regular diet more closely resembled a Mediterranean diet (P < 0.01) [41 & ]. A second study reported moderate differences in MCL associated with dietary factors, including dietary percentage of vegetable protein, vitamin D, energy, and dairy [19] .

Most studies show no association [4, 13 && ] or a weak association [19] between MCL and alcohol consumption. One cross-sectional study found a positive correlation between the daily quantity of alcohol consumed and MCL in individuals aged 18-35 (r ¼ 0. [4] , and blood concentration of nicotine biomarkers [10] ) may explain the contrasting results.

One study evaluated how marijuana use affects MCL in humans, and a second study using a nonhuman primate model was identified through outside knowledge. A randomized controlled trial found individuals co-using marijuana and tobacco experience a significantly shorter luteal phase [11.4 days AE 2.2 (SD)] than participants who only use tobacco [16.8 days AE 11.3 (SD); P ¼ 0.002] [42]. However, the authors reported no differences in follicular phase length or overall MCL, and conclusions were limited by lack of information regarding the frequency and quantity of marijuana used and combined use of tobacco and marijuana. Conversely, average MCL increased in a dose-dependent manner (4 days for each mg/7 kg/day of tetrahydrocannabinol (THC)) (95% CI 1.4-6.6 days; P ¼ .002) in rhesus macaques given chronic, heavy doses of THC edibles [43 & ].

Though only one blood sample was taken at each dose increase, the frequency and quantity of THC ingested were closely controlled.

These studies are evidence of the extent to which MCL is sensitive to internal biological factors and external exposures. The purpose of this review is to provide an update to factors, which have been the subject of publications in recent years, including novel exposures, such as air pollution and EDCs. Literature published prior to the review period has documented MCL varying in response to factors not discussed here, such as caffeine intake [44] , oral contraceptive use and cessation [45] , miscarriages [45] , and race and ethnicity [46] . Studies identified within this review serve to further document the response of MCL to everyday life. Of particular importance are those which evaluate the association between MCL and novel environmental and lifestyle exposures. It is likely that, as individuals experience increased cumulative exposures to air pollution and EDCs and increased availability and accessibility of marijuana, MCL disturbances may become more common.

Furthermore, MCL serves as an indicator of general and reproductive health. MCL has previously been associated with differences in reported menstrual cycle symptom patterns [47] , postmenopausal fracture risk [48] , and mental illness [49] . In the context of reproductive health, MCL is an indicator of cumulative hormone exposure [50] and a predictor of age at menopause [19] . Indeed, individuals who experience cycle lengths less than 25 days at ages 18-22 years are at a higher risk of early menopause, suggesting accelerated oocyte depletion as the cause [19] . MCL can also be assessed as both a risk factor and a symptom of gynecologic disease. For example, short MCL increases an individual's risk for endometriosis because of more frequent exposure to retrograde menstruation [51] . MCL is also associated with PCOS, such that longer MCLs are considered a symptom of the disorder [52] and the ovarian variables that are significantly associated with MCL are strongly linked to the pathophysiology of PCOS [4] .

One of the most impactful applications of the presented information pertains to fecundability. Intervals of 27-29 [24] , 30-31 [53] , and 32-33 days [54] have the highest fecundability among MCLs within the normal range within a population of women of childbearing age or those attempting conception. Moreover, MCL is strongly correlated with successful in-vitro fertilization treatments [55] . These findings highlight the value of using MCL as a predictor of fecundability in a clinical context.

Notably, there are cautions to be taken when assessing studies on MCL, many of which rely on self-reporting to determine menstrual characteristics. Moreover, comparing data between studies is complicated by inconsistent definitions of normal, short, or long MCLs (e.g. long MCL being !32 days [15 & ] vs. >45 days [30 & ]) and MCL variability. Researchers have previously proposed that some factors affect MCL more dramatically in individuals predisposed to shorter or longer cycles, therefore, complicating the ability to draw broad conclusions about how a given factor affects an entire population [56] .

This review demonstrates how MCL varies in response to a number of biological, life history, environmental, and lifestyle factors in a way that impacts reproductive health. With the rise in cycle tracking apps, it is likely that population-level data will become available as large datasets that are used to obtain broader MCL patterns. Further research will elucidate the physiological mechanisms underlying these changes and further our understanding of topics that are new (like the genetic determinants of MCL) or underrepresented in research (like the effect of marijuana on reproductive health). This study analyzes data from six million menstrual cycles entered into a reproductive health app by women living in Japan. Results support previously established relationships between age and menstrual cycle length, though no association was found between cycle length and seasonality. 13.

Grieger JA, Norman RJ. Menstrual cycle length and patterns in a global cohort of women using a mobile phone app: retrospective cohort study. J Med Internet Res 2020; 22:e17109. This study utilizes data from 1.5 million menstrual tracking app users to characterize global patterns in menstrual cycle length. Age, BMI, stress, and exercise were found to impact cycle length and variability, whereas alcohol consumption and smoking status were not. This study demonstrates an association between high body fat percentile and longer menstrual cycle lengths. The authors further propose that a mechanism involving sex hormone-binding globulin, estrone, and insulin partially underlies this relationship. Though the primary focus of this study is the association between menstrual cycle characteristics and risk of type 2 diabetes, it found associations between cycle length irregularity and high BMI, as well as short cycle length and active smoking status. 18. 

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Can we achieve international agreement on terminologies and definitions used to describe abnormalities of menstrual bleeding?

Antim€ ullerian hormone, antral follicle count and ovarian volume predict menstrual cycle length in healthy women

Sleep duration, exercise, shift work and polycystic ovarian syndrome-related outcomes in a healthy population: a cross-sectional study

Environmental toxicant exposure and menstrual cycle length

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Perfluoroalkyl chemicals, menstrual cycle length, and fecundity: findings from a prospective pregnancy study

Ovarian reserve biomarkers and menstrual cycle length in a prospective cohort study

This study highlights the role of anti-M€ ullerian hormone as the primary ovarian predictor of menstrual cycle length

Menstrual cycle characteristics in adolescence and early adulthood are associated with risk of early natural menopause

Antral follicle count (AFC) and serum anti-M€ ullerian hormone (AMH) are the predictors of natural fecundability have similar trends irrespective of fertility status and menstrual characteristics among fertile and infertile women below the age of 40 years

Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health

Large-scale meta-analysis highlights the hypothalamic-pituitary-gonadal axis in the genetic regulation of menstrual cycle length

FSHB -211 G>T is a major genetic modulator of reproductive physiology and health in childbearing age women

Menstrual cycle characteristics and fecundability in a North American preconception cohort

Effect of air pollution on menstrual cycle length-a prognostic factor of women's reproductive health

Menstrual cycle patterns and irregularities in hired Latinx child farmworkers

This study analyzes the effect of pesticide exposure on the menstrual cycle in Latinx child and adolescent farmworkers and found increased cycle irregularities in those predominantly exposed to pyrethroids, organochlorines, and organophosphates

Menstrual cycle perturbation by organohalogens and elements in the Cree of James Bay

Polybrominated biphenyl exposure and menstrual cycle function

Association between paraben exposure and menstrual cycle in female university students in Japan

Urinary concentrations of phthalate metabolites and bisphenol A and associations with follicular-phase length, luteal-phase length, fecundability, and early pregnancy loss

Possible role of n-hexane as an endocrine disruptor in occupationally exposed women at reproductive age

Urinary phytoestrogens and relationship to menstrual cycle length and variability among healthy, eumenorrheic women

Mental health, psychotropic medication use, and menstrual cycle characteristics

The effects of delta-9-tetrahydrocannabinol exposure on female menstrual cyclicity and reproductive health in rhesus macaques

Correlates of menstrual cycle characteristics among nulliparous Danish women

Lifestyle and reproductive factors associated with follicular phase length

Factors affecting menstrual cycle characteristics

Characterizing physiological and symptomatic variation in menstrual cycles using self-tracked mobile-health data

Long-term effects of reproductive-age menstrual cycle patterns on peri-and postmenopausal fracture risk

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The utility of menstrual cycle length as an indicator of cumulative hormonal exposure

Length of menstrual cycle and risk of endometriosis: a meta-analysis of 11 case-control studies

The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited

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We would like to thank Dr. James F. A. Traniello (Boston University) for his mentorship and guidance.Financial support and sponsorship None.

There are no conflicts of interest.

Papers of particular interest, published within the annual period of review, have been highlighted as: