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The Journal of Clinical Endocrinology and Metabolism logoLink to The Journal of Clinical Endocrinology and Metabolism
. 2021 Jun 22;106(11):e4542–e4553. doi: 10.1210/clinem/dgab461

Breast Cancer Risk Factors and Circulating Anti-Müllerian Hormone Concentration in Healthy Premenopausal Women

Tess V Clendenen 1,1, Wenzhen Ge 1,1, Karen L Koenig 1, Yelena Afanasyeva 1, Claudia Agnoli 2, Elizabeth Bertone-Johnson 3, Louise A Brinton 4, Farbod Darvishian 5,6, Joanne F Dorgan 7, A Heather Eliassen 8, Roni T Falk 4, Göran Hallmans 9, Susan E Hankinson 3,8, Judith Hoffman-Bolton 10, Timothy J Key 12, Vittorio Krogh 2, Hazel B Nichols 13, Dale P Sandler 14, Minouk J Schoemaker 15, Patrick M Sluss 16, Malin Sund 17, Anthony J Swerdlow 15,18, Kala Visvanathan 10,11, Mengling Liu 1,6,2, Anne Zeleniuch-Jacquotte 1,6,2,✉
PMCID: PMC8530718  PMID: 34157104

Abstract

Context

We previously reported that anti-Müllerian hormone (AMH), a marker of ovarian reserve, is positively associated with breast cancer risk, consistent with other studies.

Objective

This study assessed whether risk factors for breast cancer are correlates of AMH concentration.

Methods

This cross-sectional study included 3831 healthy premenopausal women (aged 21-57, 87% aged 35-49) from 10 cohort studies among the general population.

Results

Adjusting for age and cohort, AMH positively associated with age at menarche (P < 0.0001) and parity (P = 0.0008) and inversely associated with hysterectomy/partial oophorectomy (P = 0.0008). Compared with women of normal weight, AMH was lower (relative geometric mean difference 27%, P < 0.0001) among women who were obese. Current oral contraceptive (OC) use and current/former smoking were associated with lower AMH concentration than never use (40% and 12% lower, respectively, P < 0.0001). We observed higher AMH concentrations among women who had had a benign breast biopsy (15% higher, P = 0.03), a surrogate for benign breast disease, an association that has not been reported. In analyses stratified by age (<40 vs ≥40), associations of AMH with body mass index and OCs were similar in younger and older women, while associations with the other factors (menarche, parity, hysterectomy/partial oophorectomy, smoking, and benign breast biopsy) were limited to women ≥40 (P-interaction < 0.05).

Conclusion

This is the largest study of AMH and breast cancer risk factors among women from the general population (not presenting with infertility), and it suggests that most associations are limited to women over 40, who are approaching menopause and whose AMH concentration is declining.

Keywords: anti-Müllerian hormone, breast cancer risk factors, AMH correlates

Epidemiological studies, including our pooled analysis of data from 10 prospective cohorts, have consistently reported a positive association between the concentration of anti-Müllerian hormone (AMH), produced in ovarian follicles and a marker of ovarian reserve, and risk of breast cancer (1-4). It is therefore of interest to examine the association of AMH concentration with known breast cancer risk factors. Reports of associations of AMH with parity (4-8), age at menarche (4-6), body mass index (BMI) (4-7, 9-12), and oral contraceptive (OC) use (5, 13-24) have provided inconsistent results. Limited data are available about the association of AMH with family history of breast cancer (4) and gynecological surgeries such as partial oophorectomy and hysterectomy (25-27). To our knowledge, no study has examined whether a history of breast biopsy that did not result in a diagnosis of breast cancer (referred to as benign breast biopsy hereafter) is associated with AMH concentration. While a number of studies have examined the association of AMH concentration with reproductive and lifestyle factors, these have primarily focused on women experiencing infertility (14, 28). Few large studies have assessed AMH correlates in women from the general population (5, 6, 9). We assessed the relationship between breast cancer risk factors and AMH concentrations in women who were presumed healthy in a large international collaborative study including 10 prospective cohorts.

Methods

The majority (81.5%) of women included in this cross-sectional analysis were controls from nested case-control studies of AMH and risk of breast cancer (1, 2, 4, 29) in 10 cohorts (the Generations Study, CLUE II, Columbia MO Serum Bank, Guernsey Study, Nurses’ Health Study [NHS], Nurses’ Health Study II [NHSII], Northern Sweden Mammography Screening Cohort, New York University Women’s Health Study, Study of Hormones and Diet in the Etiology of Breast Tumors, and the Sister Study). The NHSII cohort also provided samples from 2 other studies of AMH, one in relation to early menopause and the other to race/ethnicity. For all studies except the race/ethnicity study, controls were selected using individual matching (with cases defined as women diagnosed with breast cancer or women with early menopause), with matching factors including cohort, age, and date of blood draw. The race/ethnicity study selected women from 3 race/ethnicity categories: African American, Asian, and Caucasian, as described in (30). Only women who provided blood samples before menopause were eligible. We excluded women who reported use of menopausal hormone replacement therapy at blood draw.

We assessed the association of AMH concentrations with BMI, smoking status, OC use, hysterectomy, partial oophorectomy, age at menarche, parity, age at first full-term pregnancy, first-degree family history of breast cancer, and history of benign breast biopsy. Variables were self-reported by participants at the time of, or on the questionnaire that was closest in time to, the blood draw. Weight and height were self-reported in most studies but were measured by study personnel in 3 cohorts (Guernsey, Study of Hormones and Diet in the Etiology of Breast Tumors [ORDET], and Sister Study). All variables were harmonized across contributing studies (1).

Laboratory Measurement

AMH was measured using the picoAMH assay (Ansh Labs, Webster, TX) for all cohorts except the NHSII race/ethnicity study, which used the AMH Gen II ELISA kit (Beckman Coulter) and a subset of the Sister Study, which used a combination of the Ultrasensitive AMH and picoAMH ELISA kits (Ansh Labs) (2). Details about the assays and their detection limits for each study have been described previously (1, 2, 29).

Statistical Analysis

AMH concentrations below the lowest detectable value of the assay were assigned the midpoint between zero and the lowest detectable value of the assay used for that cohort. AMH concentration was log2-transformed to normalize its distribution. The strong association between AMH and age is well documented (31) and we planned, a priori, to adjust all analyses for age. Specifically, we adjusted for both age and age-squared (age2), which provided a good fit to the data (see Supplemental Figure 1 (32)) and has been used by others to capture the age-AMH association (29, 33, 34). We observed a strong R2 (0.45) and an almost complete overlap of the locally-estimated-scatterplot-smoothing (LOESS) (35) and quadratic curves, further confirming that a quadratic function appropriately captures the age-AMH association.

AMH geometric means were calculated for each of the categories of the potential correlates, adjusting for age, age2, and cohort. F-tests from the analysis of variance were used to assess heterogeneity across the categories for each variable. We assessed the trend in AMH concentration across categories of age at menarche, parity, and age at first full-term pregnancy by modeling these as ordered categorical variables. Tests for heterogeneity between cohorts were conducted by comparing models including/excluding a cohort-by-variable interaction term. All variables that were individually associated with AMH were included simultaneously in an analysis of variance model to calculate multivariable-adjusted AMH geometric means. AMH-covariate associations were also assessed in age subgroups by stratifying by age <40 vs ≥40 years at the time of blood draw. All analyses were performed using SAS v9.4 and R software. A 2-sided P value < 0.05 was considered statistically significant.

Results

A total of 3831 premenopausal women were included in this cross-sectional analysis. Most (75.9%) were over age 40 (Table 1). About 90% of women were White, 6% Black/African American, and 3% Asian. Most had a BMI < 25 kg/m2 (59%), though 25% were overweight (BMI 25-29.9 kg/m2), and about 16% were obese (BMI ≥ 30 kg/m2). Few women reported current use of OCs at blood draw (5%), which was expected since this was an exclusion criterion for most cohorts. About 26% had a first-degree family history of breast cancer, although after excluding the Sister Study, in which all participants have a family history by design, this proportion was 11.5%. Approximately 17% of women had a history of benign breast biopsy and about 11% were current smokers at the time of blood donation. Distributions of breast cancer risk factors by cohort are shown in Supplemental Table 1 (32).

Table 1.

Descriptive characteristics

N %
3831
Age at blood draw, years
 21-35 134 3.5%
 35-39 789 20.6%
 40-44 1365 35.6%
 45-49 1183 30.9%
 50-57 360 9.4%
Race/ethnicity
 White 3313 89.8%
 Black/African American 218 5.9%
 Asian 120 3.3%
 Other 39 1.1%
 Missing 141
BMI, kg/m 2
 <18.5 69 1.8%
 18.5-24.9 2197 57.7%
 25-29.9 944 24.8%
 30-34.9 345 9.1%
 35+ 255 6.7%
 Missing 21
Age at menarche, years
 9-10 305 8.0%
 11 581 15.2%
 12 1016 26.7%
 13 1099 28.8%
 14 459 12.0%
 15+ 351 9.2%
 Missing 20
Parity
 Nulliparous 865 23.0%
 1 514 13.7%
 2 1404 37.4%
 3 709 18.9%
 4+ 266 7.1%
 Missing 73
Age at first full-term pregnancy, years
 Nulliparous/missing 938
 <20 254 6.6%
 21-24 939 24.5%
 25-29 1066 27.8%
 30-34 484 12.6%
 35+ 150 3.9%
Oral contraceptive use
 Never user 911 24.4%
 Former user 2639 70.7%
 Current user 184 4.9%
 Missing 97
Hysterectomy and/or partial oophorectomy
 No 3576 93.7%
 Hysterectomy without oophorectomy 107 2.8%
 Partial oophorectomy with or without hysterectomy 133 3.5%
 Missing 15
Family history of breast cancer
 No 2830 73.9%
 Yes 1001 26.1%
Benign breast biopsy
 No 3128 83.2%
 Yes 633 16.8%
 Missing 70
Smoking status a
 Never 2340 63.9%
 Former 912 24.9%
 Current 412 11.2%
 Missing 167
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Abbreviation: BMI, body mass index.

a Variable was reported as ever/never in 2 cohorts (Northern Sweden Mammography Screening Cohort and Northern Sweden Mammography Screening Cohort). “Ever” was set to missing as these individuals could not be distinguished as former vs current (n = 54)

AMH geometric means are shown in Fig. 1 for each variable, in models adjusted for cohort, age, and age-squared. In women with BMI ≥ 18.5 kg/m2, AMH concentration decreased with increasing BMI (Ptrend < 0.0001). The AMH geometric mean was lower among women who were underweight than for women with BMI of 18.5-25 kg/m2. AMH concentrations increased with increasing age at menarche (P < 0.0001) and with increasing parity (Ptrend = 0.02 and for parous vs nulliparous P = 0.03, data not shown). We did not observe an association of AMH with age at first full-term pregnancy (Ptrend = 0.84). Current OC users had lower AMH geometric mean than former and never users (P < 0.0001). Women who had had a simple hysterectomy or a partial oophorectomy had lower geometric mean AMH than women without these surgeries (P = 0.0008). Family history of breast cancer was not associated with AMH concentration (P = 0.73), including in analyses that excluded the Sister Study (data not shown). AMH concentrations varied by smoking status: current smokers had the lowest AMH geometric mean, and former smokers had a geometric mean intermediate between current smokers and nonsmokers (P = 0.01). History of benign breast biopsy was associated with a higher AMH geometric mean (P = 0.03). There was no evidence of heterogeneity by cohort for any of the AMH associations with these variables.

Figure 1.

Figure 1.

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Age- and cohort-adjusted geometric mean AMH concentration (pmol/L) by individual characteristics. Note: P values are from the ANOVA F-tests for differences across categories. Ptrend for ordered categories are shown for BMI, age at menarche, parity, and age at first full-term pregnancy. All models are adjusted for age, age-squared, and cohort.

Table 2 shows age- and cohort-adjusted, as well as multivariate-adjusted, AMH geometric means. The first 2 columns show that age- and cohort-adjusted results were similar in analyses including all participants and in analyses limited to participants without missing data for any of the variables included in the multivariate model. The last 2 columns show that all variables that were associated with AMH in the model adjusting only for age and cohort remained associated with AMH in the multivariate model.

Table 2.

Geometric mean AMH concentration (pmol/L) adjusted for risk factors by which AMH concentrations vary across levels

Age- and cohort-adjusteda Age- and cohort-adjusted in dataset with no missing covariatesb Fully adjusted for each of the other covariates, age, and cohortc
N Geo mean 95% CI P value N Geo mean 95% CI P value N Geo mean 95% CI P value
Body mass index, kg/m2 <0.0001 <0.0001 <0.0001
 <18.5 69 1.98 (1.42-2.77) 62 2.35 (1.66-3.31) 62 2.20 (1.58-3.08)
 18.5-24.9 2197 2.79 (2.62-2.97) 2057 2.88 (2.71-3.08) 2057 2.83 (2.65-3.01)
 25-29.9 944 2.75 (2.49-3.03) 881 2.80 (2.53-3.09) 881 2.85 (2.57-3.15)
 30-34.9 345 2.18 (1.85-2.58) 325 2.20 (1.85-2.62) 325 2.31 (1.95-2.75)
 35+ 255 1.72 (1.39-2.13) 243 1.87 (1.51-2.31) 243 1.97 (1.59-2.43)
Age at menarched <0.0001 <0.0001 0.0002
 9-10 305 1.98 (1.65-2.37) 280 2.02 (1.67-2.44) 280 2.09 (1.73-2.52)
 11 581 2.53 (2.24-2.87) 559 2.63 (2.32-2.99) 559 2.71 (2.39-3.07)
 12 1016 2.39 (2.17-2.62) 949 2.43 (2.21-2.68) 949 2.44 (2.22-2.70)
 13 1099 2.78 (2.55-3.04) 1025 2.86 (2.61-3.14) 1025 2.86 (2.61-3.13)
 14 459 3.21 (2.81-3.68) 429 3.35 (2.91-3.85) 429 3.25 (2.83-3.73)
 15+ 351 2.89 (2.46-3.39) 326 3.09 (2.63-3.63) 326 2.98 (2.53-3.51)
Parityd 0.0008 0.0037 0.0284
 Nulliparous 865 2.32 (2.10-2.56) 809 2.45 (2.22-2.72) 809 2.52 (2.27-2.79)
 1 514 2.44 (2.12-2.80) 491 2.49 (2.16-2.86) 491 2.52 (2.19-2.90)
 2 1404 2.68 (2.48-2.91) 1340 2.75 (2.54-2.99) 1340 2.74 (2.53-2.97)
 3 709 2.88 (2.57-3.22) 678 2.95 (2.63-3.31) 678 2.90 (2.59-3.25)
 4 or more 266 2.96 (2.45-3.57) 250 3.06 (2.52-3.71) 250 2.94 (2.43-3.55)
Hysterectomy and/or oophorectomy 0.0008 0.0066 0.0084
 No 3576 2.69 (2.56-2.83) 3349 2.76 (2.62-2.90) 3349 2.76 (2.62-2.90)
 Hysterectomy without oophorectomy 107 1.78 (1.22-2.59) 96 1.83 (1.24-2.70) 96 1.86 (1.26-2.74)
 Partial oophorectomy 133 1.89 (1.42-2.50) 123 2.12 (1.58-2.84) 123 2.13 (1.60-2.85)
Oral contraceptive use <0.0001 <0.0001 <0.0001
 Never 911 2.65 (2.40-2.93) 854 2.77 (2.50-3.07) 854 2.75 (2.49-3.04)
 Former 2639 2.72 (2.57-2.88) 2521 2.78 (2.62-2.95) 2521 2.78 (2.63-2.95)
 Current 184 1.60 (1.26-2.03) 172 1.61 (1.26-2.06) 172 1.60 (1.24-2.06)
Benign breast disease 0.0314 0.0201 0.0193
 No 3128 2.55 (2.42-2.69) 2934 2.63 (2.49-2.78) 2934 2.63 (2.49-2.77)
 Yes 633 2.94 (2.60-3.33) 603 3.08 (2.71-3.49) 603 3.08 (2.71-3.49)
Smoking 0.0103 0.0087 0.0058
 Never 2340 2.78 (2.62-2.96) 2275 2.84 (2.67-3.02) 2275 2.85 (2.68-3.04)
 Former 912 2.52 (2.27-2.79) 894 2.59 (2.34-2.87) 894 2.55 (2.31-2.82)
 Current 412 2.21 (1.92-2.55) 399 2.23 (1.93-2.58) 399 2.24 (1.94-2.59)
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a Model adjusted for age, age-squared, and cohort only

b Subjects with missing data on any of the covariates were excluded from this analysis.

c Model adjusted for age, age-squared, and cohort in addition to all other variables in the table.

d Ordered categories of age at menarche and parity were used to estimate P values

The associations of AMH with age at menarche, parity, hysterectomy and/or partial oophorectomy, smoking, and benign breast disease were primarily limited to women 40 years of age and over, while the associations of AMH with BMI and OCs were similar for women aged <40 and ≥40 (Supplemental Table 2 (32)).

Discussion

We observed the well-known relationship of decreasing AMH with increasing age, with the greatest AMH decrease after age 40, as ovarian function declines. Overall, we observed positive associations of AMH with age at menarche, parity, and history of benign breast biopsy, and inverse associations with obesity, history of hysterectomy and/or partial oophorectomy, current OC use, and current or former smoking. These associations were independent of each other, as they were observed in a multivariate-adjusted model. BMI and OCs were the only 2 variables whose association with AMH was similar in women <40 and ≥ 40 years of age. For all other variables, the association was observed only in older women. We did not observe an association of AMH with family history of breast cancer or age at first full-term pregnancy.

Our observation that AMH concentration was lower in women who had had a partial oophorectomy than in women with both ovaries intact was consistent with expectation, given the reduction in number of follicles following partial oophorectomy. The only other study to examine the effect of partial oophorectomy on AMH concentrations found an increase in AMH concentrations, but it included only 19 women with partial oophorectomy (36). We also observed that women who had undergone hysterectomy without oophorectomy had lower AMH concentration than women who had not had any of these surgeries. This observation is consistent with several previous studies which reported that hysterectomy in premenopausal women results in reductions in AMH compared with the concentration observed prior to surgery (25-27, 37-39), though not all studies agreed (40, 41). Such an effect could be due to reduced blood flow to the ovaries or altered signaling from the uterus following surgery (26, 42), a hypothesis supported by some (26, 43, 44), though not all (40), studies. Another possible explanation is that the pathology leading to hysterectomy was a cause of early ovarian failure and thus, lower AMH concentration. However, in the studies that observed a decline in AMH concentrations after hysterectomy, AMH concentrations prior to hysterectomy were similar to those of women who did not have the surgery (26, 27).

We observed a higher mean AMH concentration in parous than in nulliparous women, and a trend of increasing AMH with increasing parity. The largest study to date (n = 2320), like ours, observed higher concentrations of AMH in parous women than in nulliparous women (5). One smaller study also found a positive association with parity (8), while others found no association (7, 18, 19), and one study of young women (n = 294 women, ages 20-22) reported an inverse association (21). These discrepant results could be due to the differences in age distribution among studies. Because AMH increases until ages 20 to 25 and decreases thereafter (33, 45), the association of parity with AMH may differ in younger women compared with women close to menopause. We were not able to directly examine this hypothesis, as there were only very few women below the age of 25 in our study. However, we note that we observed a positive association between AMH and parity among women ≥40 years of age, but not among women younger than 40 years. AMH concentration has been shown to decrease during pregnancy; it is about 50% lower by the third trimester than in the nonpregnant state (46, 47). This suggests that primary recruitment of follicles is reduced during pregnancy and, as a result, there is slower depletion of the pool of primordial follicles. A larger pool of remaining primordial follicles in parous women compared with nulliparous women of the same age may be associated with greater number and quality of pre-antral and small antral follicles, which are the source of AMH. However, another possible explanation for the association we observed between parity and AMH is that nulliparous women include women with infertility problems, some of which are associated with low AMH concentrations. We were not able to disentangle the roles of parity and infertility because data on infertility are not available from most of the cohorts included in this study. The trend we observed of increasing AMH geometric means with parity in analyses limited to parous women, though, suggests that the association we observed cannot be fully explained by the inclusion of infertile women in the group of nulliparous women.

Use of OCs was also associated with AMH concentration; while there was no difference between never and past users, the geometric mean AMH concentration among current users of OCs was substantially lower than in the 2 other groups. Our finding of reduced AMH concentration in current, but not past, users of OCs is consistent with most (5, 13-21, 48, 49), though not all (22-24), studies. It is also consistent with the observation that the number of follicles measured by ultrasound, which includes the small growing follicles that secrete AMH, is reduced in women using OCs (14-16). It is of interest that, though the lower AMH concentrations observed during pregnancy and OC use appears to have a similar cause, that is, a smaller number of growing follicles; pregnancy has a long-term effect (since parity is positively associated with AMH), while the effect of OC use appears transient (since AMH is not related to past use).

We found a trend of increasing AMH with increasing age at menarche. Two studies (n = 671, P = 0.04 and n = 2320, P = 0.09) reported a similar trend (5, 6), while a third study (n = 204) did not observe any association (4). Furthermore, 2 studies (n < 300 women per study) found an inverse association (20, 21). Participants in these 2 latter studies were women in their early 20s (20, 21), which is younger than the participants in our study. Our results showed that age at menarche was positively associated with AMH in women over 40 but was not associated with AMH concentration in women who were younger than age 40. Differences in age distributions across studies may, therefore, explain the inconsistent results. There is a negative correlation between AMH and follicular recruitment between the ages of 15 and 25 because AMH increases as a greater proportion of follicles reach later stages of development. After age 25, both AMH and follicular recruitment begin to decline as a reflection of declining ovarian reserve (50). AMH concentrations are thus thought to reflect different reproductive processes before and after age 25 (51, 52).

In the studies that examined the relationship between BMI and AMH among healthy women (ie, not among women with infertility), observations are mixed, with studies reporting both inverse (9-11, 48, 53-55) and null associations (4-7, 18, 19, 56). The largest studies that did not report any association included few obese women (5, 6). Most studies did not assess AMH concentrations among underweight women separately (4-7, 9-11, 18, 19, 48, 53-56), or like our study, had a small number of underweight women (5, 6), and associations were mixed across studies. Obesity can result in follicular atresia through the damaging effects of insulin resistance on granulosa cells, as a result of obesity-associated polycystic ovarian syndrome, or through altered hormone signaling due to leptin and adiponectin dysregulation (57, 58). Underweight (59, 60), and obesity, in some (59), but not all (60) studies, have been associated with risk of early menopause, consistent with our observations of lower AMH among women with low or high BMI.

Similar to several prior studies, we observed that current, and to a lesser extent, former smoking was associated with lower AMH concentrations than never smoking (5, 48, 61, 62). Studies that did not find an association of smoking with AMH included mostly younger women (ages 20-40) (7, 10, 63), in agreement with our observation that the smoking-AMH association was limited to women over age 40 (see Supplemental Table 2 (32)). The association we observed with smoking is supported by literature that has demonstrated earlier age at menopause among women who smoke cigarettes (64), as smoking is thought to reduce ovarian follicle density (65).

Higher AMH is a predictor of later age at menopause (29, 66), which could explain the AMH-breast cancer risk association, since age at menopause is a risk factor for breast cancer (67). Late age at menopause is thought to be associated with an increased risk of breast cancer because it reflects longer exposure to sex hormones. Longer exposure to sex hormones is also thought to explain, in part, the association of younger age at menarche with breast cancer risk (67). Similarly, premenopausal obesity, which is associated with reduced breast cancer risk (68, 69), is associated with anovulation and younger age at menopause, both of which are thought to be associated with reduced exposure to sex hormones. The directions of the associations between premenopausal obesity, AMH, and risk of breast cancer are consistent (premenopausal obesity is associated with lower AMH concentration, and both premenopausal obesity and lower AMH are inversely associated with risk of breast cancer). On the other hand, the association between age at menarche and AMH is not consistent with the direction of their associations with breast cancer risk (higher age at menarche is associated with higher AMH concentration, which is associated with increased risk of breast cancer, while higher age at menarche is associated with decreased risk). Thus, while the association between AMH and premenopausal obesity might help explain the association of premenopausal obesity with breast cancer risk, the association of AMH with age at menarche does not help explain the association of age at menarche with risk of breast cancer.

The association between parity and breast cancer risk is complex, as each full-term pregnancy results first in an increase, followed by a long-term decrease, in risk (70). A large consortium study recently reported that the initial increase in breast cancer risk is observed up to 24 years after the most recent full-term pregnancy (71). The positive association we observed between AMH and parity is consistent with this initial positive association of parity with breast cancer risk.

A novel finding in our study is that women with a history of benign breast biopsy, a surrogate for benign breast disease, had higher AMH concentrations than women without previous biopsy. The AMH-breast biopsy association was restricted to women who were over age 40, suggesting that a slower decline in ovarian function among women approaching menopause may co-occur with benign breast disease (72-74). Among women <40, we found some suggestion that benign breast biopsy was associated with lower AMH concentration. We note that the number of women <40 was small and the majority likely underwent mammography for clinical reasons (ie, strong family history of breast cancer, identification of a palpable mass or other symptoms), while women over 40 could be referred to breast biopsy for any of the same reasons but are also part of the broader screening population. The reason for the positive association observed in women ≥ 40 is unclear. Since this is the first study reporting an association of AMH with history of breast biopsy and we were not able to examine the association by type of benign breast disease, additional studies are needed.

This study had several strengths. Women included in this study were not selected for history of infertility or other pathology. The large sample size of this study allowed us to detect clear trends of AMH with several variables (BMI, age at menarche, and parity) because we were able to use finer categorization than previous studies. Further, we had enough data to assess whether AMH-risk factor associations varied according to age at blood donation (<40 vs ≥40). Finally, AMH was measured for a majority of the participants (75%) using the same high sensitivity picoAMH assay.

Our study also had several limitations. Because of its cross-sectional design, the temporal relationship between breast cancer risk factors and AMH concentration could not be assessed. The cross-sectional design also prevented us from assessing the AMH-age at menopause association. Over 80% of the women included in the study were controls who were individually selected to match to cases of breast cancer using incidence density sampling and thus are not a random sample of the cohorts and the cohorts themselves are not a random sample of the general population. We confirmed, though, several associations of AMH with age, smoking, oral contraceptive use, and hysterectomy/oophorectomy that other large studies have reported, giving credibility to our other results. In addition, though the characteristics of the populations of the 10 cohorts were quite different, there was no evidence of heterogeneity between cohorts, which also supports the generalizability of our results. We therefore believe our results to be generalizable to healthy premenopausal women. Only 24% of the women were less than 40 years of age, which could explain why we observed fewer associations in this group than in the group of older women. We note that sample handling and processing procedures varied across cohorts and there remained some variability in AMH concentration by cohort after controlling for technical sample handling variables (1). To eliminate this nuisance effect, we controlled all analyses for cohort. Although we only had a single AMH measurement from each woman, we and others have observed that temporal reproducibility is high over a period of a few months to a few years (3, 75, 76). Finally, we did not have breast biopsy results and thus could not examine whether the association we observed between breast biopsy and AMH concentration was specific to some benign breast disease diagnoses. We used benign breast biopsy because it was available from the majority of participating cohorts and because it is a clearly defined event, which women are likely to remember and report accurately, while they may not remember the results of the biopsy beyond its benign characteristic.

In a large study of premenopausal women aged 30 to 57, we observed that lower AMH concentrations were associated with obesity, younger age at menarche, parity, hysterectomy and partial oophorectomy, current OC use, and current and former smoking. This is the largest study of the association of AMH with breast cancer risk factors in women from the general population, who were not selected based on fertility status. Our results help to clarify associations with several hormone- and reproduction-related risk factors and AMH that were previously inconsistent across studies with smaller sample size. It also supports that the associations of AMH with reproductive and lifestyle variables are different in late premenopausal women than in women in the early and middle stages of reproductive life. History of benign biopsy, a surrogate for benign breast disease, was associated with higher AMH in women over age 40. Since this is the first study to report the association with benign breast biopsy, it requires confirmation.

Acknowledgments

We thank the NCI Cohort Consortium. CLUE authors would like to thank the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries of the Centers for Disease Control and Prevention for the funds that helped support the collection and availability of the cancer registry data. The CLUE authors would also like to thank the CLUE participants and staff at the George W. Comstock Center for Public Health Research and Prevention. NHS authors thank the participants and staff of the NHS and NHSII for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.

Financial Support: This work was supported by grant National Institutes of Health (NIH) R01 CA178949. Support for the individual cohorts included: The Generations Study: This work was supported by Breast Cancer Now and The Institute of Cancer Research, United Kingdom. We acknowledge National Health System funding to the Royal Marsden and The Institute of Cancer Research NIHR Biomedical Research Centre. Columbia, MO Serum Bank: This research was supported by the Intramural Research Program of the NIH, National Cancer Institute (NCI), and the Department of Defense Breast Cancer Research Program (BC062367). Guernsey cohort: Cancer Research United Kingdom C570/A16491. Availability of data and materials: Data access policies for the Guernsey study are available on the Cancer Epidemiology Unit website at https://www.ceu.ox.ac.uk/policies2. Nurses Health Study: NCI UM1 CA186107; R01 CA49449. Nurses’ Health Study II (NHSII): NCI UM1 CA176726; R01 CA67262. New York University Women’s Health Study (NYUWHS): NIH R01 CA098661, UM1 CA182934 and center grants P30 CA016087 and P30 ES000260. Sister Study: This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005) to D.P. Sandler and the Avon Foundation (02-2012-085) to H.B. Nichols and D.P. Sandler.

Glossary

Abbreviations

AMH

anti-Müllerian hormone

BMI

body mass index

NHS

Nurses’ Health Study

NHSII

Nurses’ Health Study II

OC

oral contraceptive

Additional Information

Disclosures: The authors have nothing to disclose. The authors do not declare any conflicts of interest.

Data Availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Supplementary information and tables are available online at (32).

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Supplementary information and tables are available online at (32).

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