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Risk Factors Associated with Severe Macromastia among Adoles… : Plastic and Reconstructive Surgery


Macromastia (benign breast hypertrophy) is a common condition, with well-documented negative physical and psychosocial effects, including impaired physical functioning; difficulty exercising; and diminished mental health, social functioning, and self-esteem.1,2 Macromastia typically arises during adolescence.3 Most cases are idiopathic and pathophysiology is normally attributed to increased end-organ (i.e., glandular) sensitivity to the circulating gonadal hormones estrogen and progesterone.4–6 Despite the widespread prevalence and profound effects of this condition among adolescents,1,2 there is scant literature examining the clinical risk factors associated with macromastia severity in this age group.

This study is the first to explore clinical risk factors associated with macromastia severity in adolescents using a robust sample size and standardized clinical assessment. By determining potential risk factors, we aim to equip physicians with a means to identify patients at greater risk for developing more severe macromastia; address modifiable risk factors to prevent progression to more severe disease, with the potential to obviate the future need for reduction mammaplasty in certain individuals; and use macromastia consultation as a screening opportunity to identify other comorbid conditions.

PATIENTS AND METHODS

Patients

From 2008 through 2018, patients between 12 and 21 years of age with bilateral macromastia were prospectively enrolled into the study at initial consultation. A diagnosis of macromastia was established using a combination of symptoms, physical examination, and the modified Schnur criteria.7,8 All patients included in the study underwent reduction mammaplasty. Patients were excluded if they had a history of breast or chest surgery. Patients were evaluated and managed by a single pediatric plastic surgeon (B.I.L.).

The study was approved by the authors’ institutional committee of clinical investigation (protocol X08-10-0492). Written informed consent was provided by all participants or a parent or guardian if the participant was younger than 18 years.

Demographics and Medical History

Standardized intake forms were administered by the clinical team at the initial consultation. These forms collected information regarding breast symptoms, pubertal history (including age at thelarche and menarche), and family history of breast disease, specifically inquiring about macromastia, reduction mammaplasty, and breast cancer. Patient charts were also reviewed to collect demographic data and the total mass of the resected breast tissue (in grams).

Clinical Presentation and Biometrics

Clinical staff recorded height and weight for each patient at each office visit. For patients 20 years and older, body mass index category was determined using the Centers for Disease Control and Prevention Adult BMI Calculator.9 Patients were categorized by body mass index, as follows: underweight (<18.5 kg/m2), healthy weight (between 18.5 and 24.9 kg/m2), overweight (between 25 and 29.9 kg/m2), or obese (>30 kg/m2).

Body mass index percentiles accounting for age and sex were used to categorize patients younger than 20 years. This calculation was facilitated by the Centers for Disease Control and Prevention Child and Teen BMI Calculator, which defined body mass index categories as follows: underweight (less than fifth percentile), healthy weight (between the fifth and 84th percentiles), overweight (between the 85th and 94th percentiles), and obese (greater than the 95th percentile).10

Macromastia Severity Value

Using the method developed by Nuzzi et al.,11 the total breast resection mass (in grams) recorded intraoperatively at the time of surgery was divided by each patient’s body surface area (m2) to yield a macromastia severity value (g/m2). This effectively normalizes measurements of breast hypertrophy with respect to patient body habitus. Body surface area was derived using the formula devised by DuBois and DuBois.12

Patients were placed into two groups based on severity. Patients with a macromastia severity value greater than the sample median were categorized as having more severe breast hypertrophy; those with less than the sample median were considered to have less severe hypertrophy.

Defining Variables

Age at the time of surgical intervention was normally distributed and was dichotomized by categorizing patients as older or younger than the cohort mean. (See Table, Supplemental Digital Content 1, which defines variables, https://links.lww.com/PRS/F455.) Body mass index category was also dichotomized as healthy weight versus overweight or obese because there were no underweight patients in our sample. During their initial consult, patients were asked to self-identify their race from the following categories: White, Black, Asian, Native American/Pacific Islander, other, or prefer not to answer. Patients were also asked to identify their ethnicity as Hispanic or non-Hispanic. For analyses, race and ethnicity were collapsed into binary variables of “White, non-Hispanic” or “racial or ethnic minority.” Patients whose race or ethnicity was unknown or undisclosed were excluded from analyses concerning this variable.

Gynecologic and endocrine complaints and diagnoses were recorded in the medical record and included in our analyses. These included polycystic ovarian syndrome, precocious puberty requiring intervention, endometriosis, irregular periods, dysmenorrhea, menorrhagia, amenorrhea, and dysfunctional uterine bleeding.

The occurrence of early breast development (precocious puberty) and early menarche were assessed. Using established pediatric guidelines, precocious puberty was defined as the development of breast buds (thelarche) before 8 years of age.13–15 Because no patients in the sample met criteria for precocious menarche, a definition of early menarche was set within the sample (i.e., age at menarche at the 25th percentile or younger within the study cohort). Patient-reported prescription or over-the-counter medication use (within the 3 months preceding surgical consultation), smoking or tobacco use status, alcohol consumption, and recreational drug use were captured.

Data Management and Statistical Methods

Data were collected and stored using the secure, electronic REDCap database (Research Electronic Data Capture).16 Analyses were conducted using IBM SPSS Statistics for Windows, version 2.0 (IBM Corp., Armonk, N.Y.). Frequency distributions were tabulated and means and medians were calculated, as appropriate. Univariate logistic regressions were run with various demographic and clinical variables as predictors of macromastia severity. A multivariate logistic regression model was fit to determine the key predictors of macromastia severity using covariates that had a two-tailed value of p < 0.2 on univariate analysis. The performance of this model was assessed with a receiver operating characteristic curve. Mean (SD) was used to report normally distributed variables and median (interquartile range) to report nonnormally distributed variables. Odds ratios and 95 percent confidence intervals were calculated as appropriate. A missing data threshold of 20 percent was set and a p value less than 0.05 was considered statistically significant for all analyses.

RESULTS

Participant Characteristics

A total of 375 participants with a mean ± SD age at surgery of 18.1 ± 1.7 years were included in our study. The majority of the sample self-identified as non-Hispanic White [n = 200 (53.3 percent)], declined or were unable to answer or unknown [n = 83 (22.1 percent)], or self-identified as Black or African American [n = 56 (14.9 percent); Table 1]. Two-thirds of the cohort was overweight or obese [n = 248 (66.1 percent)]. Patients reached thelarche and menarche at a mean ± SD age of 11.2 ± 1.9 years and 11.9 ± 1.5 years, respectively. More than 3 percent (n = 13) of participants experienced precocious puberty. The median (interquartile range) macromastia severity value was 714.9 g/m2 (560.5, 921.3 g/m2). All patients were nulliparous at the time of surgery.


Table 1. -
Patient Demographics
*


















Characteristics Patients with Macromastia (n = 375)
Age at surgery, yr 18.1 ± 1.7
Race
 White, non-Hispanic 200 (53.3)
 Black or African American 56 (14.9)
 Hispanic or Latino 21 (5.6)
 Other 15 (4.0)
 Declined, unable to answer, or unknown 83 (22.1)
Body mass index category
 Healthy 127 (33.9)
 Overweight 114 (30.4)
 Obese 134 (35.7)
Pubertal milestones
 Precocious puberty 13 (3.5)
 Age at thelarche, yr 11.2 ± 1.9
 Age at menarche, yr 11.9 ± 1.5
  25th percentile 11.0
  50th percentile 12.0
  75th percentile 13.0
Macromastia severity value, g/m2 714.9 (560.5, 921.3)

*Values are expressed as n (%), mean ± SD, or median (interquartile range).

n = 362 as thelarche data were unreported for 13 subjects.

Univariate Analyses

Patients who were overweight or obese (OR, 3.72; 95 percent CI, 2.35 to 5.90; p < 0.001), were a racial or ethnic minority (OR, 3.21; 95 percent CI, 1.91 to 5.39; p < 0.001), or achieved early menarche (occurring before 11 years of age; OR, 3.16; 95 percent CI, 1.78 to 5.62; p < 0.001) were twice as likely to have severe macromastia. [See Table, Supplemental Digital Content 2, which demonstrates univariate analyses of factors associated with macromastia severity (n = 375), https://links.lww.com/PRS/F456.] The presence of patient-reported gynecologic or endocrine complaints also increased the likelihood of having more severe macromastia by 69 percent (OR, 1.69; 95 percent CI, 1.08 to 2.64; p = 0.02). However, there was no association between macromastia severity and presence of a formal gynecologic or endocrine diagnosis, precocious puberty, or patient age at time of surgery (all p > 0.05).

Family history of macromastia or breast cancer, as well as having a first-degree relative with macromastia or breast cancer, were not significant predictors of macromastia severity (all p > 0.05). Any recreational drug use (OR, 0.45; 95 percent CI, 0.27 to 0.76; p = 0.003) and specifically alcohol use (OR, 0.37; 95 percent CI, 0.19 to 0.70; p = 0.002) were associated with less severe breast hypertrophy. Marijuana and tobacco use were not significant predictors of macromastia severity (both p > 0.05). Any medication use up to 3 months before surgical consultation was not associated with breast hypertrophy severity (all p > 0.05).

Multivariate Analyses

When combined into a single model, patient-reported gynecologic or endocrine complaints, racial or ethnic minority status, overweight or obese status, and early menarche persisted as significant risk factors for the development of more severe macromastia (all p < 0.05; Fig. 1). Receiver operating characteristic analysis demonstrated an area under the curve value of 0.74, indicating accuracy of this model. After controlling for the above variables, recreational drug use and alcohol use were no longer significant predictors of less severe macromastia (both p > 0.05).

Fig. 1.:

Odds ratios calculated from multivariate analyses of factors associated with macromastia severity (n = 375).

DISCUSSION

Adolescent macromastia is common and associated with deficits in health-related quality of life, including increased prevalence of anxiety, depression, disordered eating, and negative self-image, which persist throughout adolescence.1,2 Despite the known adverse effects of macromastia, there exists a paucity of literature regarding the risk factors for severe macromastia in young women. This study is the first known cohort study to assess these risk factors. Overweight or obesity, racial or ethnic minority status, early menarche, and patient-reported gynecologic or endocrine complaints were all found to be independent predictors of more severe breast hypertrophy among our sample of adolescents undergoing bilateral breast reduction.

Overweight or obesity, the strongest of these risk factors, has been identified in previous literature, particularly epidemiologically, demonstrating a correlation between the rise of childhood and adolescent obesity and increased prevalence of macromastia and associated demand for reduction mammaplasty.17 Some have postulated that adipose tissue itself may contribute significantly to breast size, but our institution’s analysis of reduction mammaplasty specimens, specifically glandular tissue, does not support this theory.18 RNA sequencing data from these specimens has demonstrated inflammatory transcriptional changes among obese adolescents that may potentiate estrogen action in the immature breast microenvironment.18 Moreover, our macromastia severity value calculation normalizes breast resection mass to body surface area, and therefore minimizes the likelihood of large body habitus confounding our assessment of hypertrophy severity.11

The role of adipose tissue as an important endocrine organ cannot be discounted. Research investigating gynecomastia (male breast hypertrophy) demonstrates that increased amounts of adipose tissue may lead to excess aromatization of androgens and a downstream elevation of local estrogen production, stimulating mammary glandular proliferation.19,20 Leptin production by adipocytes may also contribute; leptin has been shown to increase aromatization activity in the breast and also increase breast sensitivity to estrogen, producing a synergistic proliferative effect in mammary tissue.21 These mechanisms are consistent with our current understanding of the pathogenesis of idiopathic macromastia, which is that affected patients typically have normal levels of circulating hormones, have no concurrent abnormalities in secondary sexual characteristics, and likely exhibit an enhanced end-organ (glandular) sensitivity to gonadal hormones.4–6 The precise mechanisms remain unconfirmed and much of our understanding of macromastia etiology in this young age group is tangentially derived from other forms of breast hypertrophy, notably virginal hypertrophy and gynecomastia.20,21

The association between overweight or obesity and severe breast hypertrophy is epidemiologically, genetically, hormonally, and now clinically significant, in that this is the only readily modifiable independent risk factor identified in the current study. Weight management, good nutrition, and the promotion of an active lifestyle early in life may assist with the prevention of more severe breast hypertrophy. For prepubertal patients or those in early breast development, these measures may ultimately obviate the need for reduction mammaplasty later in life. This finding underscores the importance of a multidisciplinary approach to patients with adolescent macromastia, where the availability of integrated pediatric, nutrition, physical therapy, and endocrine services may benefit patients’ general health as well as macromastia. Macromastia may be among the first serious medical consequences of obesity encountered by a young individual; intervention of weight-related issues at this point may confer additional long-term cardiovascular and metabolic benefits.

Patient-reported gynecologic and endocrine complaints (e.g., menstrual irregularities) and early menarche were risk factors for the more severe macromastia encountered by our group. In contrast, physician-diagnosed gynecologic or endocrine conditions did not positively associate with macromastia severity. This disconnect between patient symptoms and diagnosis may indicate undiagnosed or undertreated gynecologic or endocrine disease in this age group. This is potentially a consequence of the stigma surrounding reproductive health issues and may indicate a lack of screening for or the ability to diagnose these disorders. Polycystic ovarian syndrome, for instance, is reportedly underdiagnosed because of the diversity of presentation and a tendency for only those with a severe phenotype to consult their physician; polycystic ovarian syndrome and other gynecologic or endocrine conditions that arise during adolescence often go undetected until adulthood.22,23 Given the established interplay between the endocrine system and breast development, the presence of this risk factor is not necessarily surprising. However, in the same way that symptomatic macromastia can represent an opportunity to intervene for weight management, macromastia consultation is a potential avenue for surgeons to refer their adolescent patients hesitant to seek reproductive health care for necessary gynecologic and endocrine screening.

Patients self-identifying as racial or ethnic minorities experienced greater odds of developing severe macromastia when compared with their non-Hispanic White peers. There are possible confounding variables at play, including national and state data demonstrating higher rates of overweight or obesity among Black or African American and Hispanic children, as well as the earlier occurrence of pubertal milestones in Black or African American and Hispanic American girls.24–26 Multivariate analyses in the current study demonstrated a persistent effect of race or ethnicity on macromastia severity, even when controlling for body mass index category and the timing of pubertal milestones. Minority representation of patients in the current study was closely aligned proportionally with national statistics for breast reduction.27 However, a weakness of this study is the small sample size of non-White patients, compounded by the fact that a notable proportion of patients listed their race as “declined/unable to answer” or “unknown” [n = 83 (22.1 percent)]. As a result, racial and ethnic minorities were collapsed into a single category for the purpose of statistical analysis. With a greater sample size, we may be able to stratify by race and ethnicity in future analyses to better characterize the risk of severe breast hypertrophy in specific groups.

Family history of macromastia was not associated with macromastia severity. There are a few important considerations when interpreting this result. First, the self-reported nature of the clinic intake forms may result in underreporting of frequency of family history of macromastia, given that some young patients may be unaware of familial presence of this condition. Furthermore, although our data do not demonstrate family history as a risk factor for macromastia severity (among a cohort already diagnosed with macromastia), a positive family history may very well remain a risk factor for the development of macromastia not captured in this analysis. This merits further investigation to elucidate how familial genetics may contribute to macromastia.

Additional limitations of this study must also be discussed. First, although resection mass is commonly used in clinical research as a proxy for macromastia severity, it is an imperfect measure and is often influenced by patients’ goals for postoperative breast size. However, unlike many previous investigators, we mitigate this bias by normalizing resection masses to body habitus to yield a macromastia severity score. In addition, all patients in this sample underwent the same surgical technique by a single surgeon to reduce potential variability. Our patient sample is also relatively young among the patient population seeking breast reduction; mean age for this operation is typically reported to occur in the fifth decade of life.28 As a result, our analyses do not capture the effects of age-related weight gain, pregnancy, and lactation on breast morphology and growth. While the scope of the current study focused on those aged 12 to 21 years, these factors would warrant exploration in a sample inclusive of postpartum individuals. The role of chronic comorbid conditions and long-term medication or drug use and their effects on breast hypertrophy also cannot be assessed properly in such a young cohort.

Self-reported smoking, alcohol intake, and drug use is likely underreported because of stigma associated with these actions. Patients typically attend surgical consultation and complete intake forms with at least one parent or guardian present. Presence of a parent or guardian has been shown to increase patient-reported information censorship.29 Age at time of thelarche is also particularly vulnerable to recall bias given that it is a relatively difficult pubertal milestone to pinpoint (especially in contrast to menarche, which is often a singular memorable event). Finally, we did not evaluate the effects of hormonal contraception in the current study, as this was explored in detail by our team in a previous investigation.30

CONCLUSIONS

Macromastia is a common condition among female adolescents and young women and is associated with significant emotional, psychosocial, and physical detriment. In the current study, overweight or obesity, racial or ethnic minority status, early menarche, and patient-reported gynecologic or endocrine complaints were all identified as independent risk factors for macromastia severity in adolescents and young women. Many of the factors responsible for breast development are inextricably linked, and a combination of additional translational and clinical research is indicated to better understand the causes of severe breast hypertrophy. Awareness of these risk factors can empower physicians to identify patients at greater risk for developing severe macromastia early in life and attempt to address modifiable factors before or early in breast development. Furthermore, severe macromastia in younger patients should prompt providers to inquire into gynecologic or endocrine complaints and provide allied health referrals as indicated.

ACKNOWLEDGMENT

This work was supported in part by the Plastic Surgery Foundation (grant 192776; July of 2011). The Plastic Surgery Foundation had no involvement in the study design; collection, analysis, or interpretation of data; writing of this manuscript; or the decision to submit this manuscript for publication.

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