Time To Cycle Regularity and Health Risks

Abstract

Purpose of Review:

Adolescents often have irregular menstrual cycles after menarche until the reproductive axis fully matures. This review explores how menstrual regularity is established and the health risks associated with prolonged time to cycle regularity in adolescents.

Recent Findings:

Cross-sectional studies show an association between prolonged time to cycle regularity and increased risks for ongoing menstrual dysfunction, cardiometabolic disorders, cancers, and overall mortality. Importantly, some of these cardiometabolic associations are independent of PCOS status.

Summary:

The menstrual cycle can be used as a vital sign for assessing overall health. While further longitudinal studies are needed to establish causal relationships, these findings highlight a crucial window for early intervention in adolescents with prolonged time to cycle regularity to mitigate future risks.

Introduction

The menstrual cycle is considered a vital sign in females, providing insight into overall health status. Adolescent females often have irregular menstrual cycles after the onset of menarche until the full maturation of the reproductive axis, a process that typically takes one to two years. While menstrual irregularities in adult women are known to have health consequences, including metabolic and cardiovascular disorders, their implications during adolescence remain unclear. The prolonged time to cycle regularity is often overlooked in this critical stage of development, typically regarded as a part of physiologic maturation. This review aims to understand the mechanisms of establishing menstrual regularity and explore recent literature examining the association between a longer time to cycle regularity in adolescents and potential health risks.

Physiology of menarche

Menstrual cycle regularity depends on a series of puberty maturation steps, and abnormalities in this process can disrupt both the timing and regularity of menstrual cycles. Puberty begins with the pulsatile GnRH secretion, regulated by coordinated changes in inhibitory and excitatory neuro-signaling within the hypothalamus [1]. GnRH stimulates pituitary gonadotrophs to produce LH and FSH. In the earlier stages, serum LH rises disproportionately to FSH, and this disparity is more evident during sleep [2]. As puberty progresses, LH and FSH levels continue to increase throughout the day until the diurnal rhythm is diminished [2,3]. LH and FSH act on ovarian theca and granulosa cells, respectively, resulting in ovarian production of androgens and estradiol. High estradiol levels exert negative feedback on the gonadotropic axis to suppress it, resulting in cyclic estrogen levels and uterine bleeding [4].

Menarche and ovulation represent distinct phases in the menstrual cycle maturation process. While menarche marks the onset of menstruation, it does not signify full maturation of the HPO axis since it initially involves only estrogen-withdrawal bleeding [1]. Ovulation, on the other hand, occurs following the establishment of the positive feedback mechanism of the mid-cycle LH surge in response to estradiol produced by the dominant ovarian follicle. LH surge allows mature follicle to pass through and cause the formation of corpus luteum which is responsible for progesterone synthesis.

The precise maturational changes that occur within the reproductive axis as a girl begins to establish ovulatory cycles are variable and not well understood. This transition is not smooth and stepwise, as it is not uncommon for a normal ovulatory cycle to be followed by regression to an anovulatory cycle [5]. There is a general progression of an increase in gonadotropins with follicular growth, increase in estradiol and progesterone secretion, and an extended luteal phase, reflecting growing HPO reproductive maturity [5,6].

Menstrual cycle pattern of adolescent females

Menarche is a significant milestone in the development of females. The median age of menarche in females in the US is 12.43 years, based on data from the Third National Health and Nutrition Examination Survey (NHANES III) [7]. While there was a substantial decline in menarche age from the early 1800s to the mid-1950s, this trend has stabilized over the past 50 years. A comparison of US NHANES II (1963–1970) and III (1988–1994) shows that the mean age at menarche for U.S. girls declined by only 2.3 months [8,9,10]. Despite a small change in the median age of menarche, recent data from the Apple Women’s Health Study shows an almost two-fold increase in the percentages of women experiencing early (<11 years) and very early (<9 years) menarche from 1950 to 2005 [11].

Most studies on menstrual cycle pattern in adolescent females referenced in literature and ACOG/AAP guidelines are from before the 1990’s [12,13,14,15]. The recent emergence of menstrual tracking apps allows epidemiologic studies in large populations (11,16,17,18) that confirm the findings of older, small sample size studies and fill in trends since the 1960s. There is a consensus among all studies on menstrual cycle length in adolescents typically ranging from 21 to 45 days, even in the first gynecological year. As individuals progress from menarche, there is a trend toward shorter menstrual cycle lengths. By the third year after menarche, approximately 60% to 80% of cycles fall within the range of 21 to 34 days (13,14,19). Data from the Clue App (18) did not show variation in average cycle length with increasing age, which could be due to small sample size in early gynecological years and potential measurement errors, like missed cycle tracking.

The terminology of cycle regularity is inconsistent in the literature, defined as atypical cycle length (<21 days, >45 days) and/or atypical inter-month variability. Most studies indicate that a regular menstrual pattern is established within 1–2 years after menarche (6,11,20,21). However, some older studies report a longer interval of up to 5 years (15,22). The discrepancy in the studies can be partly explained by differences in study populations, methodologies, definition criteria, and confounding factors influencing cycle regularity. Menstrual regularity itself does not necessarily indicate ovulatory cycles, as half of the menstrual cycles are anovulatory in the first two post-menarcheal years, even if some of these cycles are within the 21–45 days range (22,23,24).

The temporal trend in time to cycle regularity over the past 50 years was evaluated in Apple Woman Health Study, with the mean time to cycle regularity increasing from 1.27 to 1.40 years. The percentage of individuals reaching regularity within 2 years declined from 76.3% to 56.0% (11). This similar trend of delayed onset of cycle regularity was also observed in French E3N (25) and Japanese (26) cohort populations.

Factors affecting menstrual cycle characteristics

The establishment of menstrual regularity is influenced by both time since menarche and age at menarche. Younger gynecologic age is associated with a higher likelihood of irregular cycles. Apter and Vihko found in their longitudinal study of 200 girls that when menarche occurs before age 12, 50% of cycles are ovulatory in the first gynecologic year. However, it takes much longer for girls with late menarche to experience ovulatory cycles (27,28). A recent study from the Clue app also showed that older age at menarche is associated with increased odds of cycle variability, even after accounting for gynecologic age (18). Interestingly, despite this association, younger generations show a decrease in the age of menarche and a delay in cycle regularity (11,26) suggesting other common factors influence both.

Ethnic and racial differences also play a role in the onset of menstrual cycle regularity. Harlow et al. (29) found that European-American adolescents have longer menstrual cycles than African American adolescents, while Wang et al. 11) reported higher rates of irregularity among Hispanic individuals compared to their non-Hispanic White peers. These racial/ethnic differences could be the direct or indirect effects of various geographic, socioeconomic, environmental, cultural, and lifestyle factors (30). For instance, environmental factors such as exposure to air pollution (31) and endocrine-disrupting chemicals (32) may increase the odds of menstrual irregularity. Dossus et al. (33) found that both a larger body silhouette at menarche and excessive physical activity independently delayed the onset of cycle regularity in their study of the French E3N cohort. However, the Apple Women’s Health Study (11) did not find that BMI at menarche significantly mediated the temporal trends in time to regularity. These findings highlight the need for further longitudinal research to elucidate the complex interplay of biological, environmental, and lifestyle factors in menstrual cycle regulation.

Time to cycle regularity and health risks

The impact of time to cycle regularity on specific health outcomes is elucidated in the following studies.

Menstrual Dysfunction

There is association between menstrual irregularity in adolescents and increased risk for ongoing menstrual dysfunction in late-adolescence and adulthood (28,35,36,37,38,39). In Apple Women Health Study (39), individuals who took longer to establish regular cycles had 2.66 times higher odds of irregular cycles in adulthood, and 3.53 times higher odds of having PCOS compared to those who achieved regularity within 1 year after menarche. In a population-based study (40), it was found that 51% of oligomenorrheic adolescents at age 15 continued to experience oligomenorrhea at age 18. The risk for ongoing anovulation was greater with high BMI, LH and testosterone levels.

The diagnosis of PCOS in adolescents is both controversial and challenging due to the overlap of normal pubertal physiological changes with PCOS diagnostic criteria. Limited data suggest that half of hyperandrogenism in adolescent anovulatory cycles is from neuroendocrine immaturity, that resolve during adolescence (28,38). There is a paucity of reliable norms for androgen levels in adolescents. Moreover, accurate determination of testosterone concentration is often problematic due to poor reliability of assays (41). Reassessment at the time of full reproductive maturity, i.e. 2 years from post-menarche, is particularly important to assess for persisting PCOS features (42,43).

Cardiometabolic Conditions

The relationship between menstrual irregularity and cardiometabolic outcomes has been studied in adults (44,45,46); however, few studies specifically address this link during early adolescence.

A significant study, a cross-sectional analysis of 60789 of study participants from the Apple Women’s Health Study (39), found that 26.3% had a prolonged time to regularity (not spontaneously establishing regularity within five years of menarche), and 12.3% reported a diagnosis of PCOS. Prolonged time to regularity was associated with a higher prevalence of several metabolic conditions, including obesity, diabetes, hyperlipidemia, hypertension, as well as several cardiovascular conditions. Interestingly, some of these positive associations, including type 1 diabetes, type 2 diabetes, hypertension, arrythmia and TIA, persisted even after accounting for PCOS status. Women with prolonged time to cycle regularity also tended to be younger at the diagnosis of several cardiometabolic conditions.

In another study, Nurses’ Health Study II cohort (47), which is a prospective cohort study of 116,429 female registered nurses enrolled in 1989 at ages 25 to 42, women with always irregular or no periods from ages 14 to 17 had a hazard ratio for cardiovascular events of 1.16 compared to women with very regular cycles, even when adjusted for age at menarche, BMI, and family history of CVD. However, the results were not significant when adjusted for behavioral factors. The study also found an increased association in females of this age group who reported using oral contraceptives, which might reflect confounding by indications for use, such as PCOS or endometriosis.

In Pittsburgh Girls Study cohort (48), a longitudinal community-based study primarily involving Black young women, those experiencing menstrual irregularities at age 15 were associated with elevated levels of insulin, glucose, triglycerides, systolic and diastolic blood pressure, and clinical markers of cardiometabolic risk in early adulthood (ages 22–25 years).

While a plausible explanation for the association of menstrual irregularity in adolescents has often been underlying PCOS, the Apple Women’s Health Study has been crucial in establishing an increased risk even in individuals without PCOS. This suggests that menstrual irregularities in adolescents might be associated with a spectrum of conditions, such as depleted ovarian reserve, chronic diseases (e.g., type 1 diabetes), eating disorders, endometriosis, or other hormonal issues, which may contribute to the cardiometabolic associations.

Furthermore, hormonal dysregulation during anovulatory cycles contributes to metabolic disturbances such as insulin resistance, elevated androgen levels, and increased adiposity accumulation, thereby increasing the risk of cardiometabolic diseases. These study designs do not allow establishing the direction of this association, as data on cardiometabolic indicators during adolescence were unavailable. It is plausible that these cardiometabolic changes preceded the observed menstrual cycle disruptions.

Another key limitation of these studies is the potential for recall bias and misclassification, as menstrual cycle data in adolescence is collected retrospectively. Additionally, these study cohorts, comprising health-conscious users who use mobile apps and healthcare professionals, could limit generalizability to the general population. Further longitudinal studies are needed to establish causal relationships and better characterize these associations.

Time to pregnancy

In the pre-conception prospective cohort studies in Northern American (49) and Danish women (50), time to menstrual cycle regularity after menarche, was not appreciably associated with fecundability (the cycle-specific probability of conception). However, shorter menstrual cycle length was associated with delayed time to pregnancy.

Cancer

The preliminary data from Apple Women Health Study shows that individuals with prolonged time to cycle regularity more than 5 years, had more than twice the risk of endometrial hyperplasia and more than 3.5 times the risk of uterine cancer, compared to those who reported their cycles took less than one year to reach regularity.

In Nurses’ Health Study II (51), individuals with irregular menstrual cycles at age 14–17 years, had increased cancer risk during follow-up. This association was driven by obesity-related cancers, particularly colorectal, thyroid, post-menopausal breast and endometrial cancer. They did not observe evidence of a statistically significant effect modification by BMI, suggesting that the associations may reflect a shared hormonal milieu between obesity and irregular cycles. The authors explain the link between obesity-related cancers and irregular menstrual cycles through the hormonal interactions involving sex steroids, insulin, and IGF (52). The association with endometrial cancer is attributed to chronic unopposed estrogen exposure resulting from anovulatory cycles.

Mortality

A prospective cohort study of Mexican teachers found that women who took three or more years to achieve menstrual regularity had a higher risk of all-cause mortality compared to those who took less, even after adjusted for age of menarche and body silhouette before menarche. (53). Similarly in the Nurses’ Health Study II cohort, women with irregular or long menstrual cycles had a higher crude cumulative incidence of premature mortality (<70 years) across all age groups, including adolescents, compared to those with regular or short cycles (54). There was a higher risk of cancer mortality among women who used oral contraceptives, which might represent confounding by indication. These associations remained largely unchanged after adjusting for time-varying dietary and lifestyle factors.

Conclusion

The time to menstrual cycle regularity in adolescents is a critical aspect of women’s health with significant implications for long-term well-being. Achieving regular menstrual cycles reflects the maturation of the hypothalamic-pituitary-ovarian axis and is influenced by factors such as age at menarche, BMI, and environmental exposures. This review highlights that a prolonged time to cycle regularity is linked to increased risks of ongoing menstrual dysfunction, cardiometabolic conditions, and certain cancers. While some of these associations can be attributed to early signs of PCOS, they also exist independently of PCOS. Further longitudinal studies are needed to fully understand the causal relationships and to elucidate the developmental progression of these potentially interconnected risk factors.

Healthcare providers should monitor menstrual patterns in adolescents closely, considering the time to cycle regularity as a vital sign indicative of broader metabolic and reproductive health. Attention should be given to consider a diagnostic workup if menstrual cycle length or regularity during adolescence falls outside the statistically driven normal range. Early intervention research is crucial to developing strategies aimed at mitigating long-term health risks.

Key Points:

• Most adolescent’s female establishes regular menstrual cycles within 1 to 2 years after menarche.

• Time to cycle regularity is influenced by age of menarche, ethnicity and environmental factors.

• Prolonged time to cycle regularity has associations with increased risk for cardiometabolic disorders, cancers, and overall mortality.

• Future research is necessary to establish causal relationships and to develop early intervention strategies in adolescents to mitigate future health risks.