Menstrual cyclicity: Pathogenicity, predictability, and reproducibility

INTRODUCTION

Menarche marks the range of the reproducibility age of Homo sapiens with the beginning of the menstrual cycle in a woman’s reproductive career. It is likely to be linked to acquiring the aid needed for successful reproductive outcomes.^[1] Its proximate cause is an increase in the frequency of the gonadotropin-releasing hormone (GnRH) pulse generator in the hypothalamus.^[2,3] Pubertal events due to the activation of the hypothalamic-pituitary-gonadal (HPG) axis and hypothalamic-pituitary-adrenal axis cluster together and follow a fairly uniform sequence, whose end program is menarche, conform to a biological and timing of maturation.^[4] The HPG axis regulates neuroendocrine function to facilitate the release of GnRH, leading to a rise in pulsatile secretion of gonadotropins such as, follicle-stimulating hormone and luteinizing hormone from the anterior pituitary, activating the onset of ovulatory menstrual cycles.^[5] The ovary’s estrogen and progesterone influence the uterus’s control of each other’s actions through a complex set of negative feedback loops.^[6] Women’s experience of menarche and menstruation is a complex interweaving of their particular physiology,^[7] psychology,^[8] and cultural backgrounds.^[9] A paradigm shift from childhood to womanhood has been subject to extraordinary symbolic elaboration in various cultures. Such representative strength is so frequently ascribed to feminine blood, and the colorful appearance of rules for the direction of discharging ladies has put the monthly cycle in closer view of the anthropological investigations of “taboo”^[10,11] and “contamination.”^[12,13] Concentrating reports in the UK and the USA uncovered that ladies would not talk about their period to anyone. Study reports in the UK and the USA reveal that women would not discuss menstruation with all people.^[14] Laws^[14] called it “menstrual etiquette,” which describes certain boundaries around women’s menstrual behavior.^[14] Understanding the concept of “menstrual etiquette” and its impact on women’s health is crucial for understanding the social and cultural factors that can affect women’s reproductive health.

The widespread occurrence of different menarcheal ages^[15] and their impact on disease onset have spurred researchers to investigate a causal relationship between the downward secular trend^[16] of menarcheal age and the concomitant increase of civilization’s chronic diseases.^[17] Several factors^[18] have been shown to significantly influence the age at menarche, such as programmed patterns of gonadotropin release established during antenatal ontogenesis, genetic parameters,^[19] socioeconomic conditions,^[20] general health and lifestyle,^[21] nutritional status,^[22] seasonality,^[23] physical activity,^[24] and altitude level.^[25,26]

MENARCHE AND RISK OF ENDOMETRIOSIS

Menstruation is the monthly shedding of the endometrium, which occurs naturally during the reproductive age of women. This could be explained by the cyclicity of the endometrial shedding^[27] and the vaginal bleeding.^[27,28] During each cycle, endometrium proliferates, developing a higher secretory capability followed by an extended microvasculature. If implantation and pregnancy do not occur, the extra tissue is reabsorbed or shed with the menses.^[27] Vaginal bleeding,^[27,28] on the other hand, is the external loss of blood and other tissues through the vagina. The capability of endometrial cycles is that they are coupled to ovarian cycles. Regular menstruation is a marker of sterility, not fecundity. The fecund women mostly conceive on one of their postpartum cycles, whereas the less fecund women continue to cycle regularly.^[29]

Menstrual cyclicity is a set of routine patterns that conform to the average length (21–35 days)^[30] of the monthly cycle regulation of four subsequent phases: Follicular phase, ovulatory phase, luteal phase, and menstrual phase. Phasal changes are regulated by the internal production of hormones from the pituitary gland. Thus, due to having an intricacy in the central nervous system involving the ovaries and the uterus, an exposure to menstrual periods occur.^[30] Alteration of any phase due to hormonal imbalance or immunological disorder results in changes in cyclicity and is implicated in reproductive disease. Menstrual cyclicity and prostaglandin-inflammatory dynamics play a plausible role (prostaglandin metabolism, and immunological factors have been suggested) to cause endometriosis potentially. Possible reasons of incessant menstruation are (the factors most consistently associated with) early-age onset with often occurrence of high and low flow during (menarche and long and heavy menstrual cycles reflect increased exposure to reproductive complications) menstruation.^[31] Early menarche is associated with a more rapid onset of ovulatory cycles and the tendency to sustain higher levels of progesterone and estrogen in secretory phase (of luteal phase estradiol and progesterone).^[32,33] Menarche exemplifies the foci of differential menstrual cyclicities as symptoms linked with a possible reproductive disorder such as endometriosis.

Onset of menses begin (menarche typically occurs) within the age range of 9–16 in girls, although the age varies across and within different groups of populations. Widely published literature on early maturation, faces an array of disagreement (having a substantial controversy) pertinent to the upper and lower limit of (over age cutoffs for determining) early menarcheal age. The wide range of early menarche [Table 1] is implicated in early biological maturity. There is a lower limit of ≤8 years^[34] and an upper limit of <12 years^[35] in the category of early menarche. Understanding this age range is crucial, as it can help identify potential health risks and implications for early or late menarche.

It is now readily apparent about consistent age pattern related to the menarche, which varies from ≤8 to <12 years. The consistent controversy surrounding the early age category of menarche may attenuate a reasonable growing potential bias [Table 1] arising from the different studies, either through a universal consensus or by maintaining a strict methodology of clearly mentioning the category to be followed by investigators through cutoff marks. The differential age in the early menarche category is likely to impede the analysis that demands further investigation exploring or analyzing infertile and adolescent populations taking different pathological details of the disease (with endometriosis separately). An early manifestation of maturation occurring at <12 years of age has a possibility of facing reproductive anomaly leading to (associated with a higher risk of) certain health issues, including estrogen-driven disease envisages (endometriosis, and other anomalies) that this concept is crucial for identifying potential health risks associated with early puberty.

The mean onset of period becomes the most important indicator pertinent to the women’s sexual maturity due to the reliability for diagnosis.^[36] Mean onset (average age of menarche) declined from about 17 to 12.8 from 1830 to 1962. The cessation of the drift (trend has stopped) occurs simultaneously with the concomitant progress of cyclicity influences the leveling off at 12.6.^[37]

The majority of the hitherto epidemiologic researches on endometriosis^[38] is centred on menstrual cyclicity^[39] along with allied pathological conditions.^[40] Due to the exposure to menstruation in the entirety of procreative age, all putative menstrual factors could be the plausible exposure to (risk of developing) endometriosis.^[41]

Among 26 studies [Table 1] evaluated from the review of literature, 20 are case-control, one is case-cohort, four are cohort, and one is an observational are accessible on-line have been retrieved from the year 1986 to 2023. Twenty reports collectively demonstrate (case-control studies involving) 9073 diagnosed women as cases versus (cases of laparoscopically diagnosed endometriosis) 4,12,130 controls,^{[36,39,40,42-58]} four cohorts have 201 cases and 7,71,157 controls,^{[34,38,59,60]} one each case-cohort (201 cases vs. 721 controls),^[61] and observational study with 89 cases, respectively, were conducted [Table 1]. The case-control studies were conducted in three in the USA, three in Canada, three in Italy, and rest ten studies were executed in Oceania, central European countries (conducted in Austria, Belgium), Egypt, France, Germany, Iran, Malaysia, Nigeria, Spain, and Sweden. One each case-cohort and observational research had been aimed at UK and India, respectively, and rest four cohort projects had been selected from USA. Study population was predominantly from general (representative of source) population. Above reports belonged to either used population control other than hospital^{[34,40,43,47,55-57,59]} of subjects that are were derived from the same group (sampled from the same cohort)^{[39,44,45,52,53,61]} or from hospitals^{.[37,41,47-49,62,63]} However, four studies^{[38,46,54,60]} had been sampled from controls from large population cohort.

Women under study are by and large under 18–>50 years of age, although two of them were recruited to the tune of 65 years.^[46,54] Among them, five studies^{[39,44,53,55,58]} belonged to sub-fertile, although a single study comprised of infertile women was case–control studies was mentioned on (the impact of) sexual activity for developing excess estrogen exposure among different subgroups are pertinent to the beginning of periods arguably from the age group of 12 onwards.^[48] All but 15 studies^{[36,39,40,42,44-47,49-51,53,56-58]} recruited women over time before (prospectively enrolled women with) laparoscopic diagnosed endometriosis. There are altogether three studies^[38,43,52] which were retrospectively designed. Twenty-one studies were designed taking women experienced exposure to menstruation in advance, which are conducive to (early age at menarche as) variability in six categories such as ≤10 for (years old in) one study;^[56] as <10 in one study;^[38] <12 in six studies;^{[40,45,46,51,57,62]} ≤12 in two studies;^[48,53] ≤11 in nine studies^{;[36,39,43,47,49,50,56,58,59]} and <11 in two studies.^[52,54]

Seven of the 26 studies depicted a positive association with early menarche.^{[38,39,46,55]} Two studies found less exposure to disease in the advancement of (reduced risk of endometriosis with early) menarche.^[49,50] Four studies suggest a statistically significant positive trend of disease (risk of endometriosis with early menarche)^{[36,39,46,55]} and followed by a negative trend (lesser risk in one study) when associated with fertile controls.^[39,49] Two studies pooled data belong to (enrolled women with) the revised American society for reproductive medicine (rASRM) stages I or II.^[44] One study from (recruited women with) rASRM stages III or IV,^[49] one study with endometriosis phenotypes^[64] such as superficial endometriosis (SUP), endometrioma (OMA), and deep infiltrating endometriosis (DIE)^[45] were conducted. It is a sensitive indicator for public health trend analysis, clinical application, geographical location, environmental condition, and a deeper understanding of the socioeconomic inequalities within the country’s population.^[65,66] While describing women living on either side of the equator (a geographic north-south gradient in age at menarche), it reveals^[67] that women beyond the tropic of cancer exposed to advanced onset of period in comparison to the women who live on (girls who live at higher latitudes appear to have an earlier initiation of menses than girls who live closer to the) equator.^[68] Researchers from the The National Health and Nutrition Examination Survey (NHANES) use menarcheal data from the U.S. population to understand pubertal trends in varying populations of girls.^[65] The average age at menarche provides an index of variability in puberty timing and is considered the baseline of demographic variables.^[69] The global-level health facilitates women in the middle-and-low-income countries to avail (and development community would greatly benefit from the increased availability of) qualitative information regarding the comprehensive details of menstrual kinetics and its respective impact on the social dynamics across the globe (data on the average age of menarche facilitates to track trends in socioeconomic and nutritional status in regions around the world).^[65] Although, the improved living and environmental conditions following birth presumably strengthen the early maturation process, they too become held responsible for (or being associated with) many adverse health outcomes.^[70] The evidence-based findings worldwide seem plausible and are in agreement with the evidence on (consistent with the hypothesis that) the early age of menarche that is influenced by programmed patterns of gonadotropin release formed during antenatal ontogenesis.^[17] Hence, seemingly impact on such causal relation between early menarche and a woman’s reproductive career^[71] is likely to being susceptible to chronic diseases later in life.^[17] The phenomena of acceleration of pubertal onset in girls followed by advanced maturation could reasonably support the concerned hypothesis of Developmental Origin of Health and Diseases (DOHaD). ^[72] According to the DOHaD that the advanced onset has been implicated in critical windows of human individual development, which are peri-conceptional context, pertinent to fetal periods, childhood, and until the period of puberty^[73,74] are by and large supposed to be the sensitive to epigenetic changes for programming human development having a probable impact on (in the risk of) chronic diseases in adulthood. This explains the worldwide downward secular trend^[75] in differential onsets of periods vis-à-vis (of age at menarche) on the concomitant rise of estrogen-dependent metabolic diseases,^[31] for instance, estrogenic exposure (such as endometriosis), and breast cancer.^[4]

Emerging evidence suggests that the menarche is the starting point of executing (the evolution of) the spontaneous decidualization process (the “preparation,” i.e., the endometrial part for gestational development [of the endometrium for pregnancy)],^[76] including the monthly the menstrual cycle has far-reaching implications for pathogenic causes of diseases. Shedding of endometrium causes pathogen load to be tightly connected, courtesy of retrograde menstruation.^[77] Every female is born with the potential pathogens load of fibroids and endometriosis, whose trigger is still not being fully identified.^[78] We argue that enough credible evidence exists to substantiate the hypotheses that early, normal, and late menarche have an asymptomatic relationship either between an advanced or late onset of endometriosis.

MENARCHE: THE GATEWAY OF ENDOMETRIOSIS?

Considering restrictions on knowledge of estrogen-caused disorders with underlying pelvic anomalies; requirements of further evidence-based research are a matter of urgency to expedite the cause and effect between menstrual cyclicity and progression of estrogenic responses in the ectopic milieu (having a greater limitation to our current understanding of how endometriosis develops, challenges to reproductive health are being elucidated by several studies highlighting the different reproductive patterns and the associated hormonal cycles). Reflections from population studies state that endometriosis is lately diagnosed, because the onset of the disease is hidden under the guise of “menstrual etiquette.” However, it quietly alternates menstrual cyclicity to be developmentally entrained contingent on pathological risks using draining out the menstrual reflux into an ectopic region (the peritoneal cavity) which may likely to form endometriotic implants either in the early menarche; in the normative menarche; in subsequent phase of (in the late) menarche or where, menarcheal age is not in the etiological route to cause sequence of reactions on the surface of the ectopic region.

Normative menarche

The normative menstrual bleeding in (age at menarche of) 12–13 years is said to cause endometriosis risk. Partial support was demonstrated for the second hypothesis, which conforms to the evidence-based studies. Mahmood and Templeton [Figure 1] found a significant association (<0.05) of disease propensity having an average range, for instance, 12.54 ± 1.53 years in the endometriosis group (n = 227) and 13.07 ± 1.58 years in the no endometriosis group (n = 1315).^[84] In another outcome work retrieving 1282 sub-fertile women from the recorded history (retrospective study of 1282 surgical patients in an infertility institute) in Iran- based hospital within the range from 2011 to 2013^[85] [Figure 2], identified sub-fertile patients (n = 341) diagnosed condition under study with a mean age at menarche of 13.1 ± 1.2 years, along with having sub-fertility (n = 332) (control) with a mean age at menarche of 13.1 ± 1.3 years devoid of pelvic inflammatory disease.

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Figure 1:

Comparison of age at menarche between endometriosis and without endometriosis.

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Figure 2:

Age-wise demographic characteristics of case and comparison groups.

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Late menarche

Women who have endometriosis have variable ages at menarche, ranging from early to normative, and late studies provided partially support third hypothesis. The findings did document that both Lombardy^[49] [Figure 3] and Oxford Endometriosis Gene^[63] studies demonstrated the involvement of early, normative, and late menarcheal age (11–14 years) with endometriosis. Study investigators had further used the rASRM protocol of categorizing disease (classification of endometriosis) (1996) to show different stages of early (stages I and II) and late (stages III and IV) disease stages [Figure 3].^[86] In a large population-based investigation (prospective cohort study), Japan Nurses’ Health Study (JNHS), there was a significant trend towards higher probability of disease (increased risk of endometriosis) present not only at the younger age of menarche (≤11) in diagnosed (surgically confirmed endometriosis) groups (n = 210) but also such risk persisted in other menarcheal ages of 12, 13, and 14 years in the same group.^[87]

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Figure 3:

Percentage of endometriosis, based on disease stage and age at menarche.

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Late menarche is inversely related with (associated with the subsequent risk of) endometriosis (OR = 0.3; 95% CI 0.1–0.6), found in an evidence-based study.^[40] Nevertheless, late menarche is supposed to be a guiding principle to workout both the investigation including treatment (diagnostic and therapeutic) strategy to corroborate the related symptoms warranting endometriosis. The said study^[40] found a significantly decreased chances at later age (≥14 years at menarche) but with a limited clinical findings against the reduced risk associated with the later stage of onset. On the contrary, age at menarche under ≥14 years can be the tool facilitating the (to guide diagnostic and therapeutic) strategy, which provided when allied complications (if any other symptoms) suggest favoring possible outcome (endometriosis as a possible diagnosis).

MENARCHEAL AGE IS NOT IN THE ETIOLOGIC PATHWAY TO ENDOMETRIOSIS

Exposure to the menstruation seems plausible to be not related to develop disease at (women diagnosed with endometriosis) later in life. The following studies are in a position to support this hypothesis. Having probed the putative causes related to cyclicity (while describing the menstrual profile [age at menarche]) [Figure 4] in determining about its ubiquity (the prevalence of endometriosis) between the surgically confirmed Puerto Rican women (n = 57) and general women (n = 1228) population with no endometriosis in Puerto Rico in the Caribbean island. Flores et al.^[34] reported that although this estrogen caused disorder is not severe ailment present in the said Caribbean island, showing the highest percentage (42.10%) [Figure 4] of diseased prone patients (of women with endometriosis) in 12–13 groups of women (age at menarche compared) to their very early and late counterparts. It seems plausible that menstrual characteristics had hardly any impact on endometriosis.^[34]

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Figure 4:

Different menarcheal age with endometriosis in Puerto Rico.

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Percentage in regard to the diagnosed patients (all of them belong to stage III–IV) by revised criteria of the rASRM^[86] pertinent to the incident cases in a prospective matched study reported more reproductive ailments (pelvic pain or dysmenorrhea) in the past year of three categories of menarcheal age [Figure 5] of ≤11 years = 37 (19.9%), 12–13 years = 87 (46.8%), and ≥14 years = 62 (33.3%) in operative cohort of n = 473 compared to ≤11 years = 2 (15.4), 12–13 years = 5 (38.5), and ≥14 years = 6 (46.2) in population cohort of n = 127 having mean±Standard Deviation of 13.0±1.8 years and 13.2±1.5 years, respectively.^[59] Hence, three categories of menarcheal age, along with or without a pedigree depicting the inheritance pattern of disease (family history of endometriosis) are susceptible to endometriosis^[55] but independent of drawing inferences from the etiologic pathway. However, asymptomatic estrogen-dependent fact appears to be the stumbling block in assessing the actual span of reproductive disorder (of the disease), thereby delaying diagnosis and eventually facing in fertility treatment.^[59]

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Figure 5:

Different menarcheal age with endometriosis.

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A well-design case–control study on Iranian infertile women diagnosed with pelvic endometriosis, Moini et al.^[88] reported that the menstrual pattern and amount of menstrual bleeding were significantly different among the control (n = 153), stage I/II (n = 52 and n = 70) along with (n = 122), and stage III/IV (n = 128) groups (P < 0.05), but not to the speak of time of onset of periods pertinent to 13.42 years in control, 13.62 years in early including (stage I/II), and 13.22 years in late as per rASRM classification (in stage III/IV) and dysmenorrhea.^[88] The above findings reveal that menarche at 13.42 and 13.22 increases a woman’s risk for endometriosis in later years.

DISCUSSION

The present study makes an exhaustive effort after having assessed the published works in the context of differential time of pubertal maturation caused disease relationship that offers both quantitative and qualitative argument to systematically deal with the underlying reality involving (the effect of) menarche may precede an exposure to the higher level of estrogen response (against the risk of endometriosis) by not ignoring the putative factors of other menstrual characteristics are alluded to almost all the literature under study. The given case-control studies retrieved from the number of published works (in the meta-analysis)^[89] on pathogenesis of endometriosis in the early and late stage as laid down in the rASRM classification are carefully interpreted about the direct and indirect role of non-modifiable risk factors^[41] rather than analyzing evidence-based and other modifiable risk factors^[36] including delay in diagnosis, infertility, lifestyle, physical activities,^[39] and environmental exposure^[42] along with pelvic abnormality.^[39] Further, identifying menstrual and allied characteristics are stupendous exercise from symptoms of progressive and multicausal^[42] endometriosis, due to have long span within (a range of) 10–19 year age.^[40]

Most of these results have, however, been based on small sample size,^[42] which are devoid of a linear trend,^[54] that bars obtaining comprehensive results on clinical plausibility,^[36] thereby facing obstruction in enrolling cases, since significant linear trend may not always be found.^[40] Furthermore, studies with low statistical power, poorly defined study populations, and inadequate adjustment for confounders may cause hindrance of revealing the results.^[90] Kvaskoff et al.^[46] claimed a kind of limitation in their study design is due to the long time-frame happens between the studied exposures and disease occurrence that poses a question of reliability of data on infertility against controls by virtue of differences in risk profiles. Much later, a remark from (one study in) Sweden^[54] met with some limitations by virtue of the cross-sectional study, where follow-up was not there after 1ong-time collection of information that may affect disease legitimacy in the population. Another study Burghaus et al.^[47] encountered certain limitations in a hospital-based study that may cause the selection bias of both the disease and healthy cohorts (cases and controls) in influencing results. It could be lesser, had it been a population based.

From hitherto findings of overall menstrual characteristics pertinent to the differential onsets of periods, lending an evidential support attributed to Sampson’s argument on reflux (theory of retrograde) menstruation.^[77] It states that menstrual characteristics of women release more menstrual debris covering ectopic cells of outside the uterus (in the peritoneal cavity) is likely to exacerbate (increase the risk of) the progression of endometriosis.^[42] It is further exacerbated by longer periods,^[43,47] short cycle length,^{[36,39,43,55,58]} irregular cycle,^[41,42] and heaviness of flow.^[40] This sparks a question regarding the clarity of association between menstrual characteristics^[44] and endometriosis^[39] that may not support an intricacy concerning (the association between) the overarching cyclicity (age at menarche) per se and endometriosis.^[38] The present study has been dealt with an array of comprehensiveness for (the impact of) the prognostication of disease (exposure to menstruation) met with limitation for not addressing any causality regarding (the effect of) menstrual characteristics other than periodical anomalies^[91] (age at menarche).

CONCLUSION

Before confirming a significant relation with endometriosis, the evidence-based details from the above four hypotheses state that menarche matters to make (is involved in the) initiation related to the pathogenesis (of the disease) directly or indirectly and is unique for its relevance from the onset to developing (diagnosis of the) disease at eventual circumstances in (the onset of the onset of) menstrual life at about the age of <11 years. A girl who has endometriosis either in her adolescence or in her early or mid-20’s has no symptom or symptom of pain or a cascade played at the arrhythmic monthly cycle (of menstrual irregularities). Concurrent pain and other irregularities may be the symptoms that are kept unnoticed by the patient for a longer duration. However, early menarche matches with certain probabilities, (as a risk factor) offers several conclusions postulated in numerous studies, including the possibility of endometriosis.

Onset of puberty ushers in a sexual maturity of woman (Menarche is defined as the first menstrual period in a female adolescent). It happens in early teens with a mean within the range of 12.4 (menarche typically occurs between the ages of 10 and 16, with the average age of onset being 12.4) years is not abstaining to exposure to (from the risk of) endometriosis found in studies? By the proximal end of the early menarche category, it is unclear whether these groups behave as early menarche groups. Mahmood and Templeton’s remark about a “younger group” resonates with this proximity. When preponderance found in (the risk of) endometriosis persists in the early, normative, and late menarche groups, plausibility toward the (the risk of) disease prevalence in advance sexual maturity is (early menarche has) failed to be understood. Nevertheless, the secular trend of early maturation, with evidence of the growing impact on (prevalence of endometriosis in) developed countries and the early age of menarche less then equal of the age of 12 years (as ≤12 years) by some authors, is tantamount to the involvement of menarche in developing the disease.

There is no denying that the great deal of dearth of appropriate clinical markers and pathognomonic signs, it is difficult to locate the endometriosis spot before a confirmed diagnosis. Hence, clinical markers are paramount to facilitating the earlier endometriosis diagnosis.