Associations Between Earlier Menarche and Fibroid Severity in Individuals Seeking Hysterectomy

Abstract

Objective:

Early menarche is associated with uterine fibroid risk, but the association between menarcheal timing and fibroid severity remains to be explored. Given the hormonal dependence of fibroids, earlier menarche may increase physical burden (e.g., number of fibroids) and/or symptoms (e.g., heavy menstrual bleeding), though the two are not always correlated. We hypothesized that individuals with earlier menarche are more likely to have severe fibroids.

Design:

We analyzed observational data using linear regression models to examine the association between earlier age at menarche and fibroid severity.

Subjects

: Individuals seeking hysterectomy (n = 110) for fibroid management at a hospital in Washington, D.C. from 2014 to 2021 as part of the Fibroids, Observational Research on Genes and the Environment study.

Exposure:

Participants recalled age at menarche during adulthood. We modeled age at menarche continuously, and we defined early menarche as menarche before 12 years in descriptive analyses.

Main Outcome Measures:

We evaluated three types of fibroid severity outcomes: self-reported symptoms using validated scales, clinical parameters (e.g., fibroid number and size), and age at hysterectomy.

Results:

In our predominantly Black sample, early menarche (i.e., <12 years) was reported by 25.5% (28/110) of participants. In adjusted linear models, earlier menarche was associated with increased symptom severity [b = −3.3 (95% CI: −6.05, −0.56)], younger age at hysterectomy [b = 0.8 (95% CI: 0.2, 1.41)], and uterine weight over 250 g (compared with ≤250 g) [b = −0.05 (95% CI: −0.11, −0.00)], but not with other measures of physical fibroid burden.

Conclusion:

Earlier menarche was associated with measures of fibroid severity. Prolonged exposure to estrogen via early menarche may accelerate the tumorigenesis process. Patient-reported symptoms as well as measures of physical burden should be considered when investigating the etiology of fibroid-related morbidity.

Introduction

The development of uterine leiomyoma (fibroids) across the reproductive lifespan is common, occurring in 70–80% of those with uteruses.¹ These estrogen-dependent, noncancerous tumors have a wide range of health consequences: while they are asymptomatic for many, others experience severe pain, bleeding, adverse pregnancy outcomes, and infertility due to fibroids. A range of characteristics including age, race, exposure to endocrine-disrupting chemicals (EDCs), obesity, and hormonal and reproductive factors are associated with increased risk of fibroid development;^2,3 nevertheless, it is poorly understood why age of onset, burden, and symptom severity vary significantly between individuals.

Earlier menarche has been associated in multiple studies with fibroid development.^4

–7 The leading hypothesis for this finding is that earlier menarche results in prolonged estrogen exposure that may increase the risk of fibroid formation. Several studies have examined earlier menarche and clinical parameters including fibroid subtype, size, and number as captured by ultrasound.^6,8 However, fibroid characteristics may not directly correlate with patient-reported symptom severity.⁹ To date, no study has examined associations between earlier menarche and symptom severity, which is often a driver of medical and surgical treatment options.¹⁰

In the United States, fibroids are more common and occur earlier with more severe symptoms among Black individuals.^1,11,12 The increased risk of fibroids among Black individuals is sometimes attributed in part to Black individuals having an earlier average age at menarche;⁶ however, earlier menarche and higher overall fibroid risk have also been found in the Black Women’s Health Study,¹³ and early menarche and increased fibroid risk have been found among both Black and White women in the Right From The Start cohort.⁶ The objective of our present study is to examine the association of menarche with physical fibroid burden and symptom severity in a predominantly Black sample of individuals seeking hysterectomy, further clarifying the impact of early menarche on later development of disruptive and disabling uterine pathologies across the life course.

Materials and Methods

Description of FORGE study

The Fibroids, Observational Research on Genes and the Environment (FORGE) study has been described in detail elsewhere.^14,15 Briefly, individuals who were intending to have a hysterectomy or a myomectomy at the George Washington University Hospital (GWUH) were recruited from the Minimally Invasive Gynecology Division of the Medical Faculty Associates in Washington, D.C from 2014 to 2021. Eligible patients were 18 years of age or older, premenopausal, and English-or Spanish-speaking with no cancer or precancer diagnosis. The George Washington University Institutional Review Board approved the study.

The majority of patients sought hysterectomy with a uterine fibroid diagnosis; several patients sought hysterectomy with an endometriosis or adenomyosis diagnosis, but upon surgical confirmation also had fibroids. Patients undergoing hysterectomy for other reasons (i.e., gender affirming care, endometriosis, or adenomyosis with no fibroid co-diagnosis) were excluded. Those undergoing myomectomy were also excluded as they were missing age at hysterectomy (as they did not undergo this procedure at the time of this study) and post-hysterectomy pathology reports. The majority of multiple uterine comorbidities in this sample were discovered as a result of pathology reports indicating a missed diagnosis of endometriosis. Participants without available menarche data were excluded from the analysis. Our final analytic sample included 110 cis-gender women with fibroids.

Age at menarche

Age at menarche was self-reported by participants in integers (10 years, 11 years, etc.). Participants who reported menarche <10 years old were coded as reaching menarche at age 9; participants who reported menarche >15 years were coded as reaching menarche at age 16. Age at menarche was analyzed as a continuous variable in regression models (Table 3). For descriptive comparisons, age at menarche was categorized into three groups: before 12 years, 12–13 years, and 14 years or older (Tables 1 and 2). The categorization of early menarche as before 12 years is consistent with other research on age at menarche.¹⁶

Table 1.

Demographic Characteristics Stratified by Age at Menarche, FORGE Study

Demographic characteristics	Age at menarche			p-value/ F-value^a
Demographic characteristics	<12 years	12–13 years	≥ 14 years	p-value/ F-value^a
Overall prevalence (%/n) (n = 110)	25.5 (28)	41.8 (46)	32.7 (36)	0.11
Race/ethnicity (%/n)				0.05
Black	92.9 (26)	69.6 (32)	69.4 (25)
White	3.6 (1)	19.6 (9)	25.0 (9)
Asian/Pacific Islander	0.0 (0)	8.7 (4)	2.8 (1)
Latina	3.6 (1)	0.0 (0)	2.8 (1)
Multiple race/ethnicity	0.0 (0)	2.2 (1)	0.0 (0)
Education (%/n) (n = 108)				<0.01
Some college or less	71.4 (20)	37.8 (17)	37.1 (13)
Bachelor’s/graduate degree	28.6 (8)	62.2 (28)	62.9 (22)
Insurance (%/n)				<0.01
Government or public	78.6 (22)	34.8 (16)	38.9 (14)
Private	21.4 (6)	65.2 (30)	61.1 (22)
Body mass index (mean/sd)	34.7 (7.4)	31.9 (7.9)	29.8 (5.6)	0.03
Reproductive history (mean/sd)
Pregnancies	3.0 (2.1)	2.3 (2.7)	2.6 (2.9)	0.55
Miscarriages	1.0 (1.3)	1.0 (1.8)	1.0 (2.2)	0.99
Living children	2.1 (2.0)	1.3 (1.4)	1.6 (1.5)	0.15

P values from chi-square/Fisher’s exact tests performed on categorical variables, F-values from ANOVA tests performed on continuous variables.

ANOVA, analysis of variance; FORGE, Fibroids, Observational Research on Genes and the Environment.

Table 2.

Measures of Physical Fibroid Burden and Fibroid Symptoms, FORGE Study

Clinical characteristics	Age at menarche			p value/ F-value^d
Clinical characteristics	<12 years	12–13 years	≥ 14 years	p value/ F-value^d
Overall prevalence (%/n) (n = 110)	25.5 (28)	41.8 (46)	32.7 (36)	0.11
Age at hysterectomy (mean/sd)	43.5 years (4.6 years)	43.9 years (5.5 years)	46.8 years (5.1 years)	0.02
Multiple uterine pathologies (%/n)	64.3 (18)	39.1 (18)	55.6 (20)	0.09
Submucosal fibroid(s) (n = 92)	30.4 (7)	29.3 (12)	32.1 (9)	0.97
Uterine volume (n = 108)	598 g (598)	818 g (992)	590 g (464)	0.31
Uterine weight				0.64
≤ 250 g	35.7 (10)	34.8 (16)	44.4 (16)
>250 g	64.3 (18)	65.2 (30)	55.6 (20)
Number of fibroids (n = 100)	3.1 (1.7)	3.5 (2.1)	3.4 (2.3)	0.34
Size of largest fibroid (n = 97)	6.3 (2.8)	7.6 (3.6)	7.3 (3.6)	0.32
Menstrual bleeding severity^a (mean/sd) (n = 79)	35.3 (10.4)	30.4 (14.8)	33.7 (17.6)	0.46
Average pain (mean/sd) (n = 89)	52.7 (28.8)	49.5 (31.3)	49.6 (30.9)	0.91
Worst pain (mean/sd) (n = 91)	72.6 (31.9)	73.9 (26.7)	78.3 (29.0)	0.73
Symptoms severity (mean/sd) (n = 109)^b	74.4 (17.9)	59.9 (26.1)	55.6 (28.2)	0.01
Uterine Fibroid Quality of Life Score (UFS-QOL)^c (mean/sd)	37.6 (20.0)	44.4 (27.7)	41.1 (26.8)	0.55
UFS-QOL subdomains^b (mean/sd)
Concern	24.3 (20.3)	42.2 (32.5)	35.3 (36.2)	0.07
Activities	37.4 (25.3)	46.0 (29.7)	41.0 (28.2)	0.43
Energy/mood	41.4 (25.9)	41.5 (31.5)	43.3 (31.5)	0.96
Control	40.0 (26.3)	49.1 (31.4)	46.2 (29.1)	0.45
Self-conscious	42.3 (28.8)	40.2 (31.5)	38.5 (31.0)	0.89
Sexual function	45.4 (33.8)	48.1 (35.6)	40.1 (37.5)	0.61

Measured using the Menstrual Bleeding Questionnaire; a higher score indicates a higher negative impact of menstrual bleeding on quality of life.

Measured using the UFS-QOL; a higher score means more severe symptoms.

A higher score in the UFS-QOL indicates a higher quality of life.

P values from chi-square/Fisher’s exact tests performed on categorical variables, and F-values from ANOVA tests performed on continuous variables.

ANOVA, analysis of variance; FORGE, Fibroids, Observational Research on Genes and the Environment; sd, standard deviation.

Table 3.

Effect Estimates from Adjusted Linear Regression Models in the FORGE Cohort (n = 110)

Outcome	Effect estimate (β [95% CI])
Symptom severity	−3.3 (−6.05, −0.56)
Uterine Fibroid Quality of Life Score	0.03 (−2.89, 2.95)
Menstrual bleeding	−0.18 (−2.15, 1.79)
Size of largest fibroid	0.17 (−0.25, 0.58)
Number of fibroids	0.12 (−0.13, 0.37)
Uterine volume	−18.34 (−105.45, 68.78)
Uterine weight (>250 g vs. ≤ 250 g)	−0.05 (−0.11, −0.00)
Multiple uterine pathologies	−0.02 (−0.08, 0.04)
Age at hysterectomy^b	0.8 (0.2, 1.41)

Associations between age at menarche and physical fibroid burden, fibroid symptoms, and multiple uterine pathologies.a Effects estimated are per year of age at menarche.

Adjusted for education and race/ethnicity.

Also adjusted for insurance type.

CI, confidence interval; FORGE, Fibroids, Observational Research on Genes and the Environment.

Outcome assessment

We obtained data from diagnostic imaging reports and post-surgical pathology reports to confirm fibroid diagnosis and to obtain information on fibroid characteristics including number, location, and size. When multiple data sources were available, we preferenced magnetic resonance imaging (MRI) data over ultrasound (US) data and US data over pathology reports as MRI is considered the gold standard for fibroid detection and measurement.¹⁷ MRI data were available for 29% of patients. US data were available for 84% of patients, with 67% of patients having only US data. Ultrasounds were performed using a transabdominal and transvaginal approach. All participants underwent minimally invasive hysterectomies thus larger specimens were manually morcellated, precluding the pathologists’ ability to accurately measure fibroid and uterine dimensions. We categorized those with endometriosis/adenomyosis on post-surgical pathology reports (in addition to fibroids, which were confirmed in all participants) as having multiple uterine comorbidities.

Physical burden measurements

Clinical characteristics included largest fibroid, number of fibroids, uterine volume, location within the uterus (fundus, body, lower uterine segment, or cervix), and subtype (submucosal, intramural, or subserosal). A subset of participants’ (n = 37) ultrasounds had been conducted at the GWUH medical center, which allowed a radiologist on our study team with expertise in ultrasound imaging to review the static images and cine clips. We preferenced the radiologist’s findings over the imaging reports. We also compared the radiologist’s findings with the imaging reports within the subset across the different clinical characteristics. We found that the data on number of fibroids were subject to a large amount of measurement error. Many imaging reports stated the number of fibroids as “2 or more,” “3 or more,” or “10 or more,” while others reported the actual number of fibroids ranging from 1 to 9. Given this, some recoding of data was required for the ultrasounds not conducted at GWUH (and thus not available for review). When the number of fibroids was recorded as “2 or more” or “3 or more,” values were recoded as the number stated (“2” or “3”). Although this method of recoding is imperfect, we lack further information on the ultrasounds conducted at other institutions that would allow us to adopt a more precise approach. We did not find discrepancies between the radiologist’s findings and imaging reports for other clinical characteristics.

Uterine volume was calculated using the equation: Π (diameter 1*diameter 2*diameter 3)/6. Fibroid size (in centimeters [cm]) was reported in up to three dimensions, and the largest recorded dimension was used. Uterine weight was obtained from postoperative surgical notes because a different billing code is used when the uterus weighs over 250 g, this documentation was consistent across providers, and we dichotomized uterine weight accordingly (over 250 g vs. less than or equal to 250 g).

Symptom measurements

Symptom severity was measured using several validated scales. The Uterine Fibroids Quality of Life (UFS-QoL) survey is a 37-item questionnaire that includes questions on symptom severity as well as six health-related quality of life subdomains related to living with uterine fibroids.¹⁸ The symptom severity subset of questions in the UFS-QoL is composed of 8 questions that are scored on a five-level Likert scale, with a lowest possible raw score of 8 and a highest possible raw score of 40. In accordance with the UFS-QoL scoring guidelines, this raw score is then transformed to a scale ranging from 0 to 100. A higher score corresponds to worse symptoms including tightness or pressure in the pelvic area, frequent urination, fatigue, irregular menstrual cycle and period lengths, and heavy bleeding and blood clots during menstrual periods. The health-related quality of life subdomains capture how often symptoms related to uterine fibroids have occurred over the last three months, grouped into the following subdomains: concern (e.g., How often have your symptoms related to uterine fibroids made you concerned about soiling bed linens?), activities (e.g., How often have your symptoms related to uterine fibroids interfered with your physical activities?), energy/mood (e.g., How often have your symptoms related to uterine fibroids caused you to feel tired or worn out?), control (e.g., How often have your symptoms related to uterine fibroids made you feel less productive?), self-conscious (e.g., How often have your symptoms related to uterine fibroids made you feel conscious about the size and appearance of your stomach?), and sexual function (e.g., How often have your symptoms related to uterine fibroids caused you to avoid sexual relations?). Each subdomain is scored separately and then summed to obtain the health-related quality of life score; a higher score corresponds to a better quality of life, with a lowest possible score of 29 and a highest possible score of 145.

We measured menstrual bleeding severity using the Menstrual Bleeding Questionnaire (MBQ), which includes questions on amount of bleeding, pain associated with menstruation, and social impact of bleeding.¹⁹ We measured pain using the Visual Analogue Pain Scale (VAS), a measure of pain intensity.²⁰ We also considered age at hysterectomy as an outcome related to symptom severity. Uterine-sparing procedures as treatment for fibroids are currently recommended by clinicians unless other options have been exhausted,²¹ and a preference for uterine-sparing producers has been documented among Black women.²² Given this, we consider age at hysterectomy an important indicator of symptom severity and/or the impact of fibroids on the daily life of participants. Age at hysterectomy was calculated based on date of birth from medical charts.

Sociodemographic covariates

Insurance and body mass index (BMI) were abstracted from electronic medical records. Insurance was dichotomized into two categories: private insurance versus government and public insurance together. Educational attainment, race/ethnicity, and reproductive history data were collected as part of an interview-administered questionnaire. Education was dichotomized into two categories: those with less than a college education vs. those with at least a bachelor’s degree.

Statistical methods

Adjusted generalized linear models were performed to examine the relationship between early menarche and fibroid outcomes. All analyses were carried out using SAS 9.4. Confounders were chosen according to a search of the literature^11,23 and by using directed acyclic graphs (see Supplementary Appendix SA1). We controlled for education and race/ethnicity, although educational attainment at adulthood generally occurs after menarche, educational attainment is a proxy for lifetime socioeconomic status, which is a proxy for childhood socioeconomic status. We also controlled for insurance type when analyzing the association of earlier menarche and age at hysterectomy as insurance type influences health care decisions. We did not include age as a confounder as we believe it to be a collider in this context (see Supplementary Appendix SA1).

We also conducted a sensitivity analysis in a subsample restricted to Black women (74.5% of the cohort, see Supplementary Appendix SA1), and we conducted analyses of nonlinearity modeling menarche as a categorical variable with age 12–13 as the reference group (see Supplementary Appendix SA1).

Results

In this sample, 75% of individuals self-identified as Black, 17% self-identified as White, and 7% self-identified as Asian/Pacific Islander, Latina, or multiple race. The majority (54%) had a bachelor’s or graduate degree. One-quarter (25.5%) reported menarche before age 12 (Table 1). Those reporting early menarche were more likely to self-identify as Black, have some college or less education, and have government or public insurance. In addition, those reporting early menarche had a higher average BMI. Reproductive history including number of pregnancies, miscarriages, and living children did not significantly vary with age at menarche.

Those with early menarche reported worse uterine fibroid symptoms (on the UFS-QoL symptom severity subscale) and an earlier age at hysterectomy (mean = 43.5 years [sd = 4.6] for menarche < age 12 compared with mean = 46.8 years [sd = 5.1] for menarche ≥ age 14) (Table 2). Early menarche was not associated with physical measures of fibroid burden including uterine volume, uterine weight, number of fibroids, and the size of the largest fibroid. Multiple uterine pathologies, presence of submucosal fibroid(s), and health-related quality of life were not associated with early menarche. Symptoms measured using scales developed for the general population including menstrual bleeding severity (on the MBQ), average pain, and worst pain (on the VAS) were also not associated with early menarche.

In adjusted regression models, earlier menarche was associated with increased symptom severity (b = −3.3 (95% CI: (−6.05, −0.56), younger age at hysterectomy (b = 0.8 (95% CI: 0.2, 1.41), and uterine weight over 250 g (compared with ≤250 g) (b = −0.05 ((95% CI: −0.11, −0.00), but not with other measures of physical fibroid burden (Table 3). Age at menarche was not associated with menstrual bleeding severity, size of largest fibroid removed, number of fibroids, or uterine volume, nor was it associated with health-related quality of life on the UFS-QoL. A nonlinear relationship showing increased likelihood of multiple uterine pathologies for those with earlier (<12 years) or later (≥14 years) menarche compared with those with menarche at 12–13 years was observed (see Supplementary Tables SA1–SA3 in Supplementary Appendix SA1).

We performed a sensitivity analysis restricting the sample to Black women (n = 83) and found consistent results between early menarche and measures of fibroid severity, with the exception of uterine weight over 250 g, which was not significantly associated with earlier menarche within the subset (see Supplementary Appendix SA1).

Discussion

In this study of predominantly Black women seeking hysterectomy for fibroid management, earlier menarche was associated with fibroid symptom severity. With the exception of uterine weight over 250 g, we found no association between earlier menarche and physical measures of fibroid burden including uterine volume, presence of submucosal fibroid(s), number of fibroids, and the size of the largest fibroid, nor did we find an association with patient-reported menstrual bleeding severity or pain when using scales developed for the general population. In contrast, earlier menarche was associated with fibroid symptom severity using the UFS-QoL, which includes fibroid-specific symptoms such as tightness or pressure in the pelvic area and frequent urination as well as fatigue, blood clots, and heavy bleeding. It was also associated with younger age at hysterectomy, another indicator of the impact of fibroids on the daily life of participants.

Our findings are consistent with results from the prospective Black Women’s Health study¹³ that reported an association between early menarche and increased fibroid risk, and with results from the multiethnic Right From the Start cohort that systematically screened for fibroids during early pregnancy, finding associations between both early menarche and fibroids as well as between early menarche and multiple fibroids (compared with no fibroids).⁶ Our comprehensive symptom data add to this evidence base, as we found that even within a population of individuals with fibroids (i.e., FORGE cohort study participants), those with earlier menarche had more severe fibroid symptoms and earlier age at hysterectomy. The relationship between earlier menarche and younger age at hysterectomy has been documented elsewhere and found most strongly among women undergoing hysterectomy due to symptomatic fibroids.²⁴ In addition, while we were not powered to test for effect modification, in line with results from the Right From the Start cohort, we found no evidence that age at menarche and fibroid severity varies by race in our sensitivity analyses.

The drivers of earlier menarche include nutrition, EDCs, stress, and possible genetic factors.²⁵ The association between childhood sexual abuse and early menarche has been widely documented though not fully understood, although elevated androgen levels (metabolic precursors to estrogens) in reaction to stress may play a role.²⁶ While medical intervention to prevent or induce menarche is not typical except in the case of gender affirmation or stunted growth, in a clinical setting, early menarche may be a useful marker of high risk or vulnerable populations for symptomatic fibroids and a useful data point for constructing patient risk profiles when screening for fibroids and other hormonally driven pathologies.

The current understanding of the mechanism between early menarche and fibroid risk points to the increased lifetime exposure to hormonal peak during ovulatory cycles. Each ovulatory cycle involves increases in estrogen and progesterone as well as cell proliferation in the myometrium that occurs during the luteal phase of the menstrual cycle when the endometrium thickens.²³ Estrogen regulates inflammation, oxidative stress, and DNA instability in the myometrium, and earlier estrogen exposure may accelerate these processes. Consistent with this understanding, parity is negatively associated with fibroid risk,²⁷ as pregnancy results in fewer ovulatory cycles. There is, however, mixed evidence that irregular and longer menstrual cycles are negatively associated with fibroid risk,^28,29 which would be expected if cumulative exposure to ovulatory cycles influences fibroid risk.

While the mechanisms that result in fibroid development remain to be fully understood, improved clinical parameters that are more reflective of patient symptoms and experience are needed to understand the etiological underpinnings of severe fibroid symptoms. Our results suggest that early hormonal processes may result in severe fibroid symptoms years later, and severe symptoms may not be accurately captured by physical measures of fibroid burden.

Strengths and limitations

In this study, we were able to measure fibroid severity using a variety of indicators including patient-reported symptoms and clinical parameters of physical burden. The use of the UFS-QoL, the MBQ, and the VAS together with imaging and pathology reports allowed us to achieve a more complete picture of fibroid severity with respect to early menarche than has been done elsewhere.

We are aware of several limitations in our study. Because menarche was retrospectively reported by participants during adulthood, we expect there is some error in its measurement. Nevertheless, because reliability studies of middle-aged recall of menarche have generally found nondifferential misclassification (i.e., no systematic over- or underreporting)³⁰ that tends to bias effect estimates towards the null, our results may be underestimating the relationship between earlier menarche and severe symptomatic fibroids.

We also expect there to be some measurement error in both the physical burden and symptom measures used. Because ultrasounds were not conducted specifically for research purposes, and imaging was performed at different institutions with different ultrasound technicians and equipment, there is inherent variation in the measurement, as ultrasound is an operator-dependent imaging exam. This likely creates error in some endpoints of physical fibroid burden, particularly in measuring number of fibroids, especially because different levels of specificity were used by technicians, with some reporting a max of 2 or 3 or more fibroids, and other reporting a max of 10 or more. The uterine weight measure was also less precise given that the data available was dichotomized due to limitations in available documentation.

At the same time, other measures of physical fibroid burden like size of largest fibroid, type of fibroid, and uterine volume are less subject to operator interpretation, and the results were consistent. In terms of symptoms measures, while there is potential for recall bias using the UFS-QoL, MBQ, and VAS, these measures have been widely used to quantify patient experience and are the only way to capture patient pain and discomfort. In our case, and in the case of any study that does not conduct ultrasounds for research purposes with the same technician, the symptom measures are likely subject to less bias than the physical measures of fibroid burden as they are consistent across all participants.

Finally, our population of hysterectomy patients is not generalizable to the wider population of individuals with uteruses or even the population of individuals with fibroids, as hysterectomy is unlikely to be recommended or preferred for individuals with fibroids that are less symptomatic. At the same time, while we conceptualize age at hysterectomy as a measure of severity, we recognize that many other factors influence the decision of if and when to have a hysterectomy. Patient age/parity (younger patients and those who have not yet had children may prefer treatments that preserve fertility), patient race (Black women are more likely to prefer uterine-sparing treatments),²² patient preference for a curative treatment option (hysterectomy being the only one currently available), and provider training and institutional norms^21,31 may all factor into this decision.

Conclusions

The processes that result in fibroids may begin early in life, and prolonged exposure to estrogen via early menarche may accelerate the tumorigenesis process. Patient-reported symptoms as well as measures of physical burden should be considered when investigating the etiology of fibroid-related morbidity. This study highlights the importance of early menarche as a patient characteristic that could be important for clinical histories as an upstream risk factor for severe fibroid symptoms in adulthood. Future research may include exploring early menarche as a mediator of early life exposures that are connected with severe fibroids later in life (e.g., prenatal EDC exposure and adverse childhood exposures). Clarifying the etiology of severe fibroid symptoms, while also applicable to understanding general fibroid etiology, is of vital importance given the severe toll symptomatic fibroids exact on patients.

Footnotes

Authors’ Contributions

E.L.S.: conceptualization, formal analysis, methodology, visualization, writing—original draft, and writing—review and editing. B.V.: investigation and writing—review and editing. L.H.: methodology and writing—review and editing. A.A.-H.: methodology and writing—review and editing. N.K.: investigation, methodology, and writing—review and editing. C.Q.M.: investigation, methodology, resources, and writing—review and editing. A.R.Z.: conceptualization, funding acquisition, investigation, methodology, resources, supervision, and writing—review and editing.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by the Eunice Kennedy Shriver National Institutes of Child Health and Development (R21HD096248), National Institute of Environmental Health Sciences (P30 ES009089), National Center for Advancing Translational Sciences (UL1TR001876, KL2TR001877), California Breast Cancer Research Program (B28TP5728, 23UB-6511), The George Washington University Milken School of Public Health, and The George Washington University Office of the Vice President for Research (Cross-disciplinary Research Fund).

Disclaimer

The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding agencies.

Supplementary Material

Supplementary Appendix SA1

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

References

Baird

, Dunson

, Hill

, et al. High cumulative incidence of uterine leiomyoma in black and white women: Ultrasound evidence. Am J Obstet Gynecol, 2003; 188(1):100–107; doi: 10.1067/mob.2003.99

Pavone

, Clemenza

, Sorbi

, et al. Epidemiology and risk factors of uterine fibroids. Best Pract Res Clin Obstet Gynaecol, 2018; 46:3–11; doi: 10.1016/j.bpobgyn.2017.09.004

Laughlin

, Schroeder

, Baird

. New directions in the epidemiology of uterine fibroids. Semin Reprod Med, 2010; 28(3):204–217; doi: 10.1055/s-0030-1251477

Marshall

, Spiegelman

, Goldman

, et al. A prospective study of reproductive factors and oral contraceptive use in relation to the risk of uterine leiomyomata. Fertil Steril, 1998; 70(3):432–439; doi: 10.1016/s0015-0282(98)00208-8

Templeman

, Marshall

, Clarke

, et al. Risk factors for surgically removed fibroids in a large cohort of teachers. Fertil Steril, 2009; 92(4):1436–1446; doi: 10.1016/j.fertnstert.2008.08.074

Velez Edwards

, Baird

, Hartmann

. Association of age at menarche with increasing number of fibroids in a cohort of women who underwent standardized ultrasound assessment. American Journal of Epidemiology, 2013; 178(3):426–433; doi: 10.1093/aje/kws585

, Wei

, Hu

, et al. Investigation on factors related to uterine fibroids in rural women of northern Anhui province. J Obstet Gynaecol Res, 2021; 47(9):3279–3287; doi: 10.1111/jog.14899

Dragomir

, Schroeder

, Connolly

, et al. Potential risk factors associated with subtypes of uterine leiomyomata. Reprod Sci, 2010; 17(11):1029–1035; doi: 10.1177/1933719110376979

Divakar

. Asymptomatic uterine fibroids. Best Pract Res Clin Obstet Gynaecol, 2008; 22(4):643–654; doi: 10.1016/j.bpobgyn.2008.01.007

10.

VanNoy

, Bowleg

, Marfori

, et al. Black women’s psychosocial experiences with seeking surgical treatment for uterine fibroids: Implications for clinical practice. Womens Health Issues, 2021; 31(3):263–270; doi: 10.1016/j.whi.2021.01.001

11.

Faerstein

, Szklo

, Rosenshein

. Risk factors for uterine leiomyoma: A practice-based case-control study. I. African-American heritage, reproductive history, body size, and smoking. Am J Epidemiol, 2001; 153(1):1–10; doi: 10.1093/aje/153.1.1

12.

Stewart

, Nicholson

, Bradley

, et al. The burden of uterine fibroids for African-American women: Results of a national survey. J Womens Health (Larchmt), 2013; 22(10):807–816; doi: 10.1089/jwh.2013.4334

13.

Wise

, Palmer

, Harlow

, et al. Reproductive factors, hormonal contraception, and risk of uterine leiomyomata in African-American women: A prospective study. Am J Epidemiol, 2004; 159(2):113–123; doi: 10.1093/aje/kwh016

14.

Zota

, Geller

, Calafat

, et al. Phthalates exposure and uterine fibroid burden among women undergoing surgical treatment for fibroids: A preliminary study. Fertil Steril, 2019; 111(1):112–121; doi: 10.1016/j.fertnstert.2018.09.009

15.

Zota

, Chu

, Marfori

, et al. Adverse childhood experiences and health-related quality of life among women undergoing hysterectomy for uterine leiomyoma. Am J Obstet Gynecol, 2022; 227(2):351–353.e5; doi: 10.1016/j.ajog.2022.04.028

16.

Ibitoye

, Choi

, Tai

, et al. Early menarche: A systematic review of its effect on sexual and reproductive health in low-and middle-income countries. PLoS One, 2017; 12(6):e0178884; doi: 10.1371/journal.pone.0178884

17.

Levens

, Wesley

, Premkumar

, et al. Magnetic resonance imaging and transvaginal ultrasound for determining fibroid burden: Implications for research and clinical care. Am J Obstet Gynecol, 2009; 200(5):537.e1–e1; doi: 10.1016/j.ajog.2008.12.037

18.

Spies

, Coyne

, Guaou

, et al. The UFS-QOL, a new disease-specific symptom and health-related quality of life questionnaire for leiomyomata. Obstet Gynecol, 2002; 99(2):290–300; doi: 10.1016/s0029-7844(01)01702-1

19.

Matteson

, Scott

, Raker

, et al. The menstrual bleeding questionnaire: Development and validation of a comprehensive patient‐reported outcome instrument for heavy menstrual bleeding. BJOG, 2015; 122(5):681–689; doi: 10.1111/1471-0528.13273

20.

Price

, McGrath

, Rafii

, et al. The validation of visual analogue scales as ratio scale measures for chronic and experimental pain. Pain, 1983; 17(1):45–56; doi: 10.1016/0304-3959(83)90126-4

21.

Leyland

, Leonardi

, Murji

, et al. A call-to-action for clinicians to implement evidence-based best practices when caring for women with uterine fibroids. Reprod Sci, 2022; 29(4):1188–1196; doi: 10.1007/s43032-022-00877-3

22.

Wegienka

, Stewart

, Nicholson

, et al. Black women are more likely than white women to schedule a uterine-sparing treatment for leiomyomas. J Womens Health (Larchmt), 2021; 30(3):355–366; doi: 10.1089/jwh.2020.8634

23.

Wise

, Laughlin-Tommaso

. Epidemiology of uterine fibroids–from menarche to menopause. Clinical Obstetrics and Gynecology, 2016; 59(1):2–24; doi: 10.1097/GRF.0000000000000164

24.

Cooper

, Hardy

, Kuh

. Timing of menarche, childbearing and hysterectomy risk. Maturitas, 2008; 61(4):317–322; doi: 10.1016/j.maturitas.2008.09.025

25.

Canelón

, Boland

. A systematic literature review of factors affecting the timing of menarche: The potential for climate change to impact women’s health. Int J Environ Res Public Health, 2020; 17(5):1703; doi: 10.3390/ijerph17051703

26.

Houghton

, Knight

, Wei

, et al. Association of prepubertal and adolescent androgen concentrations with timing of breast development and family history of breast cancer. JAMA Netw Open, 2019; 2(2):e190083; doi: 10.1001/jamanetworkopen.2019.0083

27.

Baird

, Dunson

. Why is parity protective for uterine fibroids? Epidemiology, 2003; 14(2):247–250; doi: 10.1097/01.EDE.0000054360.61254.27

28.

Terry

, De Vivo

, Hankinson

, et al. Reproductive characteristics and risk of uterine leiomyomata. Fertil Steril, 2010; 94(7):2703–2707; doi: 10.1016/j.fertnstert.2010.04.065

29.

Marino

, Eskenazi

, Warner

, et al. Uterine leiomyoma and menstrual cycle characteristics in a population-based cohort study. Hum Reprod, 2004; 19(10):2350–2355; doi: 10.1093/humrep/deh407

30.

Cooper

, Blell

, Hardy

, et al. Validity of age at menarche self-reported in adulthood. J Epidemiol Community Health, 2006; 60(11):993–997; doi: 10.1136/jech.2005.043182

31.

Stewart

, Laughlin-Tommaso

, Catherino

, et al. Uterine fibroids. Nat Rev Dis Primers, 2016; 2:16043–16048; doi: 10.1038/nrdp.2016.43

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