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J Womens Health (Larchmt). 2016 Sep 1; 25(9): 865–874.
Published online 2016 Sep 1. doi: 10.1089/jwh.2015.5529
PMCID: PMC5311461
PMID: 27135720

The Association of Inflammation with Premenstrual Symptoms

Abstract

Background: About 80% of women experience premenstrual symptoms (PMSx), and about 50% of women seek medical care for them, posing a large medical care burden. However, despite women's use of anti-inflammatory agents for relief from these symptoms, and the fact that anti-inflammatory agents provide relief from some PMSx, the relationship of inflammation to PMSx has not been well investigated.

Methods: We, therefore, undertook the present cross-sectional analyses using baseline data from the longitudinal Study of Women's Health Across the Nation (SWAN), a racially/ethnically diverse cohort of midlife women (n = 2939), to determine if a biomarker of inflammation, high-sensitivity C-reactive protein (hs-CRP), was associated with PMSx. We performed factor analyses with Varimax rotations to determine five groupings of eight symptoms to develop a parsimonious set of outcome variables. We conducted backward stepwise multiple logistic regression models for each grouping, eliminating non-significant (p > 0.05) covariates.

Results: Having an hs-CRP level >3 mg/L was significantly positively associated with premenstrual mood symptoms (adjusted odds ratio [aOR] = 1.27, 95% confidence interval [95% CI] 1.02–1.58), abdominal cramps/back pain (aOR = 1.40, 95% CI 1.09–1.80), appetite cravings/weight gain/bloating (aOR = 1.41, 95% CI 1.04–1.89), and breast pain (aOR = 1.26, 95% CI 1.02–1.55). Elevated hs-CRP level was not associated with premenstrual headaches or reporting three or more PMSx.

Conclusions: The significant relationships of specific groups of PMSx with elevated hs-CRP levels have potential clinical implications for treatment and possibly for prevention by advising women about the factors associated with inflammation and the potential for treatment with anti-inflammatory agents.

Introduction

Premenstrual symptoms (PMSx) include mood, physical, and cognitive symptoms that begin in the luteal phase of the menstrual cycle and end with, or shortly after, the onset of menstruation.1 The frequency, type, severity, and combination of symptoms that comprise PMSx vary.2 The most frequently reported symptoms are irritability, depression, fatigue, water retention, weight gain, breast tenderness, headaches, abdominal cramps, and mood swings.3 About 80% of women may experience PMSx,4 and about 50% of women seek medical care for them,5–7 thus posing a large medical care burden.

The etiology of PMSx may be related to ovarian function, as suppression of ovarian hormone secretion markedly attenuates PMSx,8 although differences in ovarian steroid hormones have not been consistently observed between symptomatic and asymptomatic women. Biologic, social, demographic, and behavioral factors have been inconsistently associated with PMSx.2,9–12

High-sensitivity C-reactive protein (hs-CRP) is an acute phase inflammatory marker that has been associated with cardiovascular disease risk13 and is an outcome associated with menopausal vasomotor symptoms.14 It has also been associated with some of the risk factors for PMSx, such as smoking, depressive symptoms, increasing age, and increased body mass index (BMI).14 While some studies have investigated the associations of inflammation with PMSx, most of these have had relatively small samples of young (e.g., ages 18–30 years) white women,15,16 and have found suggestive, but not always significant differences in inflammation between women reporting and women not reporting emotional or physical PMSx.

Furthermore, anti-inflammatory agents have been found to provide relief from some PMSx.17 It is thus possible that inflammation is the mechanism by which these factors increase the risk of PMSx. Therefore, establishing the role of inflammation in different types of PMSx in a large diverse sample of women would be informative in understanding the potential physiologic mechanisms involved in PMSx. We undertook these cross-sectional analyses of PMSx among a racially/ethnically diverse cohort of midlife women to determine if inflammation, as measured by hs-CRP, was associated with PMSx.

Methods

Study participants

This cross-sectional study used data on PMSx, health, reproductive, demographic, and lifestyle factors from the baseline questionnaires of the Study of Women's Health Across the Nation (SWAN), a longitudinal, multicenter, multiracial/-ethnic study of midlife women. SWAN is following a cohort of women (N = 3302 at baseline) from five racial/ethnic groups, at seven clinical sites located nationwide.18 We recruited community-based cohorts of Caucasians and one non-Caucasian group at each site: African Americans in Pittsburgh, Boston, Detroit, and Chicago; Hispanics (Puerto Rican, Dominican, Cuban, Central and South American) in Newark, New Jersey; Japanese in Los Angeles; and Chinese in the Oakland, California area.

Participants were eligible for inclusion in the cohort if they were aged 42–52 years and pre- or early perimenopausal, had not undergone a hysterectomy or bilateral oophorectomy, were not pregnant, and were not using menopausal hormone therapy or oral contraceptives at baseline. In addition, participants were required to be able to speak English, Spanish, Cantonese, or Japanese, and to provide informed consent to participate and comply with the study protocol. All instruments and the study protocol were approved by the institutional review boards at all sites, and signed, written informed consent was obtained from all study participants.

From the total baseline sample of 3302 women, 57 were excluded for missing C-reactive protein (CRP) data; 129 additional women were excluded for missing data on PMSx; and an additional 2 women were excluded for missing information on whether the symptoms disappeared within 3 days of onset of their menstrual period.

Data collection

All SWAN participants completed a self-administered and interviewer-administered questionnaire at baseline.

Outcomes

These analyses included data from the baseline visit (administered during 1996–1997) at which participants indicated yes or no in response to the following question for each of eight symptoms: “During the last year, have you had any of the following during at least half of your menstrual periods or in the week before them?” The eight symptoms included the following: abdominal cramps/pain, breast pain/tenderness, weight gain/bloating, mood changes/suddenly sad, increase in appetite or cravings, anxious/jittery/nervous, back/joint/muscle pain, and severe headaches.

If a participant answered yes to any one of the symptoms, she was also asked the following question: “Did this/these characteristic(s) usually (more than half of the time) disappear within 1–3 days after your period started?” Answering “yes” to this question was used as the criterion for a symptom to be considered premenstrual in the present multivariate analyses. Those who answered “no” or “don't know” were excluded from multivariate analyses (an additional 175 who reported symptoms answered no or don't know to whether the symptoms disappeared within 3 days of onset of their menstrual periods; so, the total number excluded = 363 when using this more conservative definition of PMSx, but only 188 were excluded if the more expanded criteria were used of reporting the symptom, but saying no or don't know in response to whether the symptom disappeared within 3 days of onset of their menstrual periods).

Independent variable

hs-CRP assays were performed at baseline using an ultrasensitive rate immunonephelometry (hs-CRP on BN100; Dade-Behring, Marburg, Germany). The method is based on monitoring light scattering during agglutination of CRP to polystyrene particles coated with monoclonal antibodies to CRP. The sensitivity of the assay (lowest detectable concentration) was 0.03 mg/dL. The interassay coefficients of variation at CRP concentrations of 0.05 and 2.2 mg/dL were 10%–12% and 5%–7%, respectively. Although hsCRP level is a continuous variable, a cutoff for elevated hsCRP has been established for clinical use19 and was used to categorize hsCRP into elevated (>3 mg/L) and nonelevated (≤3 mg/L) for analyses.

Covariates

Age at baseline was analyzed as a continuous variable. Annual household income was self-reported and evaluated using a three-level categorical variable based on tertiles of total income reported <$35,000, $35,000–$75,000, and >$75,000. A binary categorical variable was used for the proportion of women with a college education. Race/ethnicity was self-identified as Caucasian, African American, Hispanic, Chinese, or Japanese and included both US-born and foreign-born women.

Menopausal status at baseline was defined using a dichotomous variable: (1) premenopausal (menstrual period in the prior 3 months with no change in regularity of periods) or (2) early perimenopausal (menstrual period in the prior 3 months with change in regularity of periods) without use of hormone therapy. Parity was self-reported and analyzed as a categorical variable.

Weight and height were measured using a calibrated balance beam scale and stadiometer, respectively. BMI (weight in kilograms/[height in meters]2) was computed and analyzed as a four-level categorical variable: low (<18.5), normal (18.5–24.9), overweight (25–29.9), or obese (≥30). Comorbidity consisted of reporting of 1 or more of 10 chronic health conditions (heart disease, arthritis, high blood pressure, diabetes, high cholesterol, stroke, anemia, migraines, angina, and osteoporosis) during the past year and was treated as a categorical variable. Use of anti-inflammatory medications was assessed by self-reported use in the prior month of such prescription and nonprescription medications as assessed by SWAN pharmacologists, independent of report of PMSx.

Active smoking status was assessed by standard questions.20 Passive smoke exposure was assessed by the validated instrument of Coghlin et al.21 Never smokers with no passive smoke exposure were used as the referent group. Physical activity was measured by a composite score based on the Kaiser Permanente Activity Score,22 a modification of the Baecke scale23 assessing three domains: sports, leisure, and household activities. Usual servings of alcoholic beverages per week were analyzed as none, ≤1, and >1 (one serving = 12 oz. beer, 5 oz. wine, or 1.5 oz hard liquor).

Social support was assessed by a summed scale of how often four types of needed emotional and instrumental supports were available, with responses ranging from 0 = none of the time to 4 = all of the time24 and analyzed by quartiles of the total score in the SWAN baseline cohort. A measure of the symptom sensitivity trait was measured at follow-up visit 01 using a summed score (degree of awareness of loud noise, hot or cold, hunger, pain, and things happening in one's body, with responses ranging from 1 = not at all true to 5 = extremely true)25 and analyzed dichotomously as at or above versus below 15, the median for the SWAN cohort. Depressive symptoms were assessed by the Center for Epidemiologic Studies Depression (CES-D)26 scale (score ≥16 on a 20-item scale of the extent to which each item was experienced in the previous week).

Data analyses

This was a cross-sectional analysis, using only data from the baseline visit. Descriptive statistics were computed using bivariate analyses for each symptom grouping (as described below), each independent variable, and each covariate. Categorical variables were analyzed using chi-square tests or Fisher's exact test for comparison of proportions, and t-tests and analysis of variance (ANOVA) were used for comparisons involving continuous variables. Unadjusted odd ratios (ORs) were computed for each symptom group by each independent variable.

We conducted factor analyses with Varimax rotations to determine appropriate groupings of the eight symptoms so that a parsimonious set of outcome variables could be evaluated. To determine whether to retain a particular symptom in a symptom grouping, we used factor loadings of 0.40 or more. If items loaded on more than one factor, the item with the highest loading was retained. Factors were accepted with an eigen value of 1.0 or greater. As in our prior work,12 the five resulting PMSx groupings were as follows: (1) anxiety/jittery/nervous and mood changes, (2) abdominal cramps and back/joint/muscle pain, (3) increased appetite/craving and weight gain/bloating, (4) breast pain/tenderness, and (5) headaches. Because women often reported more than one symptom, associations of the independent variables with the total number of these five symptom groupings (>3 vs. ≤3) were also estimated.

To assess potential confounding variables, we calculated unadjusted odds ratios (ORs) and 95% confidence intervals (95% CIs), one variable at a time. To adjust simultaneously for confounding variables, multiple logistic regression models were developed for each PMSx grouping. Covariates that were associated (at p < 0.15) in unadjusted analyses were entered into backward stepwise multiple logistic regression models for each PMSx grouping with elimination of variables found not to be significant (p > 0.05). The independent variable, elevated hsCRP (>3 mg/L vs. ≤3 mg/L), was forced into all multiple logistic regression models. AIC goodness of fit test criteria were used for multiple logistic regression models. Interactions with race-ethnicity and menopause status were evaluated to determine if any relationships observed differed by these variables.

Results

The unadjusted proportion of women who reported each PMSx, except breast pain or headaches, was significantly increased for women who had hs-CRP values >3 mg/L (Table 1). In addition, mean age was significantly lower among women who reported all PMSx except for those reporting premenstrual breast pain. All symptoms were reported by significantly more Hispanics and early perimenopausal women and by significantly less Chinese and Japanese than Caucasian or premenopausal women. Most symptoms (except changes in appetite/weight/bloating and breast pain) were reported by fewer women with more than a high school education, higher annual income, and lower symptom sensitivity scores compared to those with a high school education or less, lower annual income, and higher symptom sensitivity.

Table 1.

Distributions of Baseline Characteristics by Symptom Reporting

 MoodCramps/back painAppetite/weight/bloatBreast painHeadachesTotal no. of symptoms
 NoYesNoYesNoYesNoYesNoYes<3>3
Independent variables and covariatesn or Mean% or SDn or Mean% or SDn or Mean% or SDn or Mean% or SDn or Mean% or SDn or Mean% or SDn or Mean% or SDn or Mean% or SDn or Mean% or SDn or Mean% or SDn or Mean% or SDn or Mean% or SD
Age,a (mean, SD)46.82.846.22.646.72.846.22.6447.02.746.22.646.42.746.32.746.42.746.22.646.62.846.12.6
hs-CRPa (mg/L)
 ≤352226.9141973.151926.7142273.333817.4160382.662132.0132068.0145474.948725.199451.294748.8
 >319619.680280.416416.483483.610410.489489.631331.468568.671571.628328.441841.958058.1
Race/ethnicityb
 African American21225.362574.714617.469182.69811.773988.328934.554865.561974.021826.039146.744653.3
 Caucasian28720.8109179.231022.5106877.515711.4122188.640729.597170.5102774.535125.561544.676355.4
 Chinese8237.813562.29845.211954.88840.612959.49141.912658.117681.14118.915872.85927.2
 Hispanic4316.821383.23413.322286.73312.922387.14919.120780.914958.210741.88031.217668.8
 Japanese9338.914661.19138.114861.96527.217472.89539.814460.218979.15020.916267.87732.2
Educationc
 ≤High School37422.6128277.432319.5133380.525915.6139784.451030.8114669.2117771.147928.974945.290754.8
 >High School34027.191572.935428.290171.817914.3107685.741533.184066.997077.328522.764851.660748.4
Annual household incomed
 <$35,00018220.570479.517619.971080.113315.075385.027631.261068.861469.327230.739344.449355.6
 $35–75,00029925.388274.727223.090977.018115.3100084.738732.879467.289275.528924.557748.960451.1
 >$75,00021927.557772.521426.958273.111514.468185.625031.454668.660776.318923.740350.639349.4
Menopausal statuse
 Premenopause44829.0109971.040726.3114073.726016.8128783.253034.3101765.7119677.335122.782253.172546.9
 Early perimenopause25619.4106480.625719.5106380.516812.7115287.338329.093771.092369.939730.155542.076558.0
BMI (kg/m2)f
 <18.53721.513578.53922.713377.34023.313276.75230.212069.812069.85230.28147.19152.9
 18.5–24.933926.793273.335628.091572.024219.0102981.039531.187668.995675.231524.864851.062349.0
 25–29.918924.956975.117022.458877.69612.766287.323430.952469.156374.319525.735747.140152.9
 >3015220.957479.111415.761284.3638.766391.325034.447665.652171.820528.232044.140655.9
Parityg
 None14128.036372.011122.039378.06512.943987.115430.635069.439177.611322.424448.426051.6
 1–349024.2153875.848924.1153975.932215.9170684.163731.4139168.6150474.252425.898048.3104851.7
 4+8621.331878.78220.332279.75413.435086.614034.626465.427267.313232.718646.021854.0
Smoke exposureh
 Never smoker/no passive39526.9107473.139426.8107573.227018.4119981.647732.599267.5110675.336324.775851.671148.4
 Never smoker/some passive4321.315978.74421.815878.23818.816481.26130.214169.813968.86331.29145.011155.0
 Former smoker/no passive13922.049478.013922.049478.06910.956489.119030.044370.047074.216325.828144.435255.6
 Former smoker/any passive2018.29081.82926.48173.687.310292.73632.77467.37669.13430.95045.46054.6
 Current smoker11422.938477.17314.742585.35611.244288.816232.533667.535871.914028.122144.427755.6
Alcohol servings/weeki
 None37325.8107474.234924.1109875.923716.4121083.648033.296766.8104372.140427.970348.674451.4
 1 or less15222.851477.215523.351176.78412.658287.420731.145968.948773.117926.932348.534351.5
 More than 119123.462676.617721.764078.312014.769785.324429.957370.163177.218622.838246.843553.2
Physical activityj (mean, SD)9.52.09.42.29.62.19.42.29.32.09.52.29.42.19.52.29.52.19.32.39.52.09.42.3
Sx sensitivity scorek
 <1532930.774469.331129.076271.020318.987081.136834.370565.782176.525223.559955.847444.2
 ≥1530120.8114479.230220.9114379.119513.5125086.544931.199668.9105472.939127.165045.079555.0
CES-D scorel
 <1665629.2158870.858526.1165973.937816.8186683.274833.3149666.7174177.650322.4119953.4104546.6
 ≥16628.963391.19814.159785.9649.263190.818626.850973.242861.626738.421330.648269.4
Social support scorem
 <1112417.857482.215321.954578.110815.559084.524334.845565.247968.621931.430243.339656.7
 11–1213721.450378.613721.450378.68212.855887.219129.844970.248776.115323.929846.634253.4
 13–1416324.949175.116024.549475.59714.855785.220831.844668.248273.717226.332549.732950.3
 15+29431.165268.923324.671375.415516.479183.629130.865569.272176.222523.848751.545948.5
Anti-inflammatory medicationsn
 No49326.4137773.650226.8136873.232917.6154182.461132.7125967.3145878.041222.097452.189647.9
 Yes22521.084479.018116.988883.111310.695689.432330.274669.871166.535833.543841.063159.0
No. of comorbiditieso
 None22028.156471.922128.256371.815519.862980.227034.451465.663480.915019.142854.635645.4
 125325.175474.925925.774874.316716.684083.432232.068568.076175.624624.449849.450950.6
 215324.247875.813220.949979.18313.254886.819731.243468.845772.417427.628845.634354.4
 3+9217.842582.27113.744686.3377.248092.814528.037272.031761.320038.719838.331961.7
Diabetesp
 No68324.9205775.163323.1210776.941715.2232384.886531.6187568.4202073.772026.3131648.0142452.0
 Yes2617.612282.43624.311275.71912.812987.25637.89262.211376.43523.67248.67651.4
High blood pressureq
 No57124.4176575.656324.1177375.936915.8196784.273631.5160068.5174774.858925.2112848.3120851.7
 Yes13624.641775.410619.244780.86611.948788.118533.436866.638970.316429.726147.229252.8
Osteoporosisr
 No70324.7214875.366723.4218476.643315.2241884.891132.0194068.0210873.974326.1137748.3147451.7
 Yes721.22678.826.13193.926.13193.9927.32472.72472.7927.31133.32266.7
Arthritiss
 No63126.2177973.860725.2180374.838916.1202183.979533.0161567.0180174.760925.3120850.1120249.9
 Yes7816.240383.86313.141886.9479.843490.212826.635373.433569.614630.418237.829962.2
Fibroidst
 No57825.1172474.955824.2174475.836715.9193584.175132.6155167.4170374.059926.0112849.0117451.0
 Yes13122.744777.310818.747081.36611.451288.616728.941171.142573.515326.525844.632055.4
Canceru
 No70024.7213375.365923.3217476.742815.1240584.990231.8193168.2209774.073626.0136348.1147051.9
 Yes1017.54782.51119.34680.7814.04986.01933.33866.73866.71933.32645.63154.4
Heartv
 No70024.7213575.366623.5216976.543015.2240584.890632.0192968.0209673.973926.1136848.2146751.8
 Yes1019.24280.847.74892.3611.54688.51528.83771.23873.11426.92140.43159.6
Anemiaw
 No48625.3143474.747424.7144675.333617.5158482.562732.7129367.3144975.547124.595249.696850.4
 Yes23022.877977.220720.580279.510210.190789.930532.770435.271570.929429.145745.355254.7
High cholesterolu
 No60025.2178374.856323.6182076.436415.3201984.776031.9162368.1177774.660625.4115948.6122451.4
 Yes11621.342978.711821.642778.47814.346785.717031.237568.838470.516129.524845.529754.5
Migrainesx
 No62825.4184874.661825.0185875.039916.1207783.980332.4167367.6195478.952221.1125850.8121849.2
 Yes8919.536780.56514.239185.8429.241490.813028.532671.521146.324553.715233.330466.7
Strokeu
 No71224.5219475.567623.3223076.744015.1246684.992631.9198068.1214873.975826.1139848.1150851.9
 Yes618.82681.2721.92578.126.23093.8825.02475.02062.51237.51443.81856.3
Thyroid diseasey
 No68624.7209075.364723.3212976.741815.1235884.988832.0188868.0205374.072326.0134748.5142951.5
 Yes3119.512880.53622.612377.42213.813786.24628.911371.111270.44729.66339.69660.4

Reported having symptom during menstrual period or in week prior and that it disappeared in 3 days after start of menstruation.

aAll significant differences at p < 0.0001 except breast pain not significant and headaches significant at p = 0.048.
bAll significant differences at p < 0.0001.
cAll significant differences at p ≤ 0.005 except appetite cravings/weight gain/bloating and breast pain.
dAll significant differences at p ≤ 0.03 except appetite cravings/weight gain/bloating, breast pain, and >3 symptoms.
eAll significant differences at p < 0.0003.
fOnly significant differences for abdominal cramps/back pain and appetite cravings/weight gain/bloating at p < 0.0001 and >3 symptoms at p = 0.025.
gOnly headaches significant at p = 0.0018.
hOnly abdominal cramps/back pain and appetite cravings/weight gain/bloating significant differences at p < 0.0001, mood at p = 0.027 and >3 symptoms at p = 0.0058.
iOnly significant difference for headaches at p = 0.026.
jOnly significant differences for abdominal cramps/back pain and headaches at p ≤ 0.013.
kSignificant differences for mood, abdominal cramps/back pain, appetite cravings/weight gain/bloating, and >3 symptoms at p ≤ 0.0002 and headaches at p = 0.042.
lAll significant differences at p ≤ 0.0012.
mOnly significant difference for mood, headaches, and >3 symptoms s at p ≤ 0.0069.
nAll significant differences at p ≤ 0.0013 except breast pain.
oAll significant differences at p ≤ 0.0004 except breast pain.
pOnly significant difference for mood at p = 0.043.
qOnly significant differences for abdominal cramps/back pain, appetite cravings/weight gain/bloating, and headaches at p ≤ 0.032.
rOnly significant difference for abdominal cramps/back pain at p = 0.019.
sAll significant differences at p ≤ 0.0062 except headaches at p = 0.020.
tOnly significant differences for abdominal cramps/back pain at p = 0.0046 and appetite cravings/weight gain/bloating at p ≤ 0.0065.
uAll differences nonsignificant.
vOnly significant difference for abdominal cramps/back pain at p = 0.0075.
wSignificant differences for mood, abdominal cramps/back pain, appetite cravings/weight gain/bloating, headaches, and >3 symptoms at p ≤ 0.027.
xAll significant differences at p ≤ 0.0076 except breast pain.
yOnly significant difference for >3 symptoms at p = 0.029.

BMI, body mass index; CES-D, Center for Epidemiologic Studies Depression; hs-CRP, high-sensitivity C-reactive protein; SD, standard deviation.

Most symptoms (except for breast pain or headaches) were reported by significantly more obese women, those with active or passive smoke exposure, and by women with elevated depressive symptom scores (for all symptoms) than normal weight women, women without active or passive smoke exposure, or women with lower depressive symptom scores. Parity, physical activity, hypertension, arthritis, and anemia were significantly positively and alcohol consumption was significantly negatively related to headaches. However, most of the differences were relatively small and likely significant because of the large sample size. Diabetes, cancer, high cholesterol, stroke, and thyroid disease were not significantly related to any symptoms, nor was heart disease except for a significant relationship to abdominal cramps and pain.

Unadjusted analyses

In unadjusted analyses, hs-CRP levels >3 mg/L were significantly associated with premenstrual mood symptoms, regardless of whether the conservative definition (symptom disappeared within 3 days of onset of menses) was used (OR = 1.46, 95% CI 1.22–1.75) or if the symptom did not disappear within 3 days of onset of menses (OR = 1.74, 95% CI 1.17–2.58) (Table 2). Similarly, in unadjusted analyses, hs-CRP levels >3 mg/L were significantly associated with premenstrual abdominal cramps/pain, regardless of whether the conservative definition was used (OR = 1.84, 95% CI 1.52–2.23) or if the symptom did not disappear within 3 days of onset of menses (OR = 2.36, 95% CI 1.61–3.46). Also, in unadjusted analyses, hs-CRP levels >3 mg/L were significantly positively associated with premenstrual appetite cravings/weight gain/bloating, regardless of whether the conservative definition (OR = 1.78, 95% CI 1.42–2.22) or less conservative definition (OR = 2.30, 95% CI 1.54–3.42) was used.

Table 2.

Unadjusted Odds Ratios and 95% Confidence Intervals for Association of Elevated High-Sensitivity C-Reactive Protein with Each Premenstrual Symptom, SWAN Baseline

 Reported had symptom and that it disappeared within 3 days of onset of menses, n = 2978–3044Reported had symptom, but not that it disappeared within 3 days of onset of menses, n = 3114
Premenstrual symptomOR95% CIpOR95% CIp
Mood1.461.22–1.75<0.00011.741.17–2.580.0062
Abdominal cramps/back pain1.841.52–2.23<0.00012.361.61–3.46<0.0001
Appetite cravings/weight gain/bloating1.781.42–2.22<0.00012.301.54–3.42<0.0001
Breast pain0.990.85–1.170.941.020.68–1.530.92
Headaches1.160.98–1.380.0841.110.68–1.830.68

95% CI, 95% confidence interval; OR, odds ratio; SWAN, Study of Women's Health Across the Nation.

An elevated hs-CRP level was not associated with reporting premenstrual breast pain or headaches in unadjusted analyses. Other factors related to each symptom group were similar to those we found previously12 (data not shown).

We also examined the unadjusted mean hs-CRP by number of symptom groups reported and found a trend of increasing means (from 3.11 ± 7.78 mg/L for none, 3.18 ± 9.12 mg/L for one, 3.06 ± 4.76 for two, 3.51 ± 5.31 mg/L for three, 4.25 ± 6.52 mg/L for four to 4.22 ± 5.38 mg/L for five symptoms) with increasing number of symptom groups, which was significant in ANOVA (p = 0.026), but the trend was not monotonic. However, because the distribution of hs-CRP was skewed to the right, we examined median hs-CRP by number of symptom groups reported and found that the median increased monotonically from 1.0 mg/L for none to 2.1 mg/L for five symptoms reported. Further, the unadjusted ORs for the association of elevated hs-CRP with number of symptoms reported also increased monotonically from 0.90 (95% CI 0.51–1.60) for one symptom to 2.21 (95% CI 1.35–3.62) for five symptoms reported; all 95% CIs for these ORs included 1.0 until four or more symptoms were reported.

Multivariable models

In backward stepwise multiple logistic regression models, removing variables not significant (p > 0.05), having an hs-CRP level >3 mg/L remained significantly positively associated with premenstrual mood symptoms (adjusted OR [aOR] = 1.27, 95% CI 1.02–1.58), using the conservative definition of the symptom disappearing within 3 days of onset of menses, after adjustment for age, race/ethnicity, blood draw within cycle days 2–5, menopausal status, CES-D ≥16, symptom sensitivity score ≥15, parity, social support, and comorbidities (Table 3). Having an hs-CRP level >3 mg/L also remained significantly positively associated with premenstrual abdominal cramps/back pain (aOR = 1.40, 95% CI 1.09–1.80) after adjustment for age, race/ethnicity, blood draw within cycle days 2–5, menopausal status, BMI category, CES-D ≥16, symptom sensitivity ≥15, use of anti-inflammatory medications in the past month, and education.

Table 3.

Odds Ratios and 95% Confidence Intervals from Multiple Logistic Regression Models for Association of hs-CRP >3 mg/L with Each Premenstrual Symptom, Adjusted for Covariates, SWAN Baseline, n = 2939

 MoodOR (95% CI)Cramps/painOR (95% CI)Appetite/weight/bloatOR (95% CI)Breast painOR (95% CI)HeadachesOR (95% CI)3 or more SxOR (95% CI)
hs-CRP >3 mg/L1.27a (1.02–1.58)1.40a (1.09–1.80)1.41a (1.04–1.89)1.26a (1.02–1.55)0.91 (0.73–1.12)1.15 (0.95–1.40)
Age per year0.90a (0.87–0.93)0.91a (0.88–0.95)0.87a (0.83–0.90)0.96a (0.93–1.00)0.96a (0.92–0.99)0.91a (0.88–0.94)
Race/ethnicity (ref: Caucasian)
 African American0.60a (0.47–0.77)1.29 (0.99–1.68)0.71a (0.52–0.97)0.85 (0.69–1.05)0.93 (0.73–1.18)0.78a (0.63–0.96)
 Chinese0.55a (0.39–0.77)0.42a (0.30–0.59)0.27a (0.19–0.38)0.60a (0.44–0.81)0.98 (0.66–1.47)0.38a (0.27–0.54)
 Hispanic0.96 (0.63–1.48)1.52 (0.96–2.40)1.01 (0.62–1.65)1.52a (1.05–2.20)2.39a (1.69–3.38)1.46a (1.02–2.09)
 Japanese0.51a (0.37–0.71)0.67a (0.49–0.93)0.51a (0.35–0.73)0.68a (0.50–0.92)1.08 (0.75–1.57)0.50a (0.36–0.69)
Early peri- versus premenopause1.68a (1.37–2.04)1.45a (1.19–1.78)1.40a (1.11–1.77)1.37a (1.16–1.63)1.44a (1.18–1.75)1.50a (1.29–1.83)
Blood not drawn within cycle days 2–50.75a (0.60–0.96)0.79 (0.62–1.01)0.99 (0.74–1.31)0.84 (0.68–1.04)0.71 (0.55–0.91)0.76 (0.61–0.95)
BMI, kg/m2 (ref: 18.5–24.9)   
 <18.5 0.56a (0.36–0.87)0.44a (0.28–0.70)0.60a (0.40–0.89)  
 25–29.9 0.99 (0.77–1.27)1.41a (1.04–1.90)0.88 (0.70–1.09)  
 30+ 1.16 (0.85–1.58)1.33 (0.92–1.93)0.64a (0.49–0.82)  
CES-D score ≥16 versus <162.65a (1.96–3.60)1.47a (1.12–1.92)1.51a (1.10–2.08)1.69a (1.35–2.12)1.93a (1.55–2.42)
Symptom sensitivity score ≥15 versus <151.61a (1.32–1.95)1.32a (1.08–1.60)1.33a (1.06–1.66)1.38a (1.16–1.65)
Use of anti-inflammatory medications in past month1.57a (1.26–1.94)1.29a (1.00–1.67)1.55a (1.27–1.89)1.32a (1.10–1.58)
Parity (ref: 0) 
 1–31.35a (1.05–1.74)     
 4+1.51a (1.04–2.18)     
College education or more (ref: less than college)0.77a (0.63–0.95) 
Social support (ref: <11) 
 11–121.04 (0.76–1.43)     
 13–140.78 (0.58–1.06)     
 15+0.60a (0.45–0.80)     
No. of comorbidities (ref: none)    
 11.21 (0.95–1.54) 1.05 (0.80–1.38) 1.38a (1.05–1.80)1.21 (0.96–1.51)
 21.23 (0.93–1.61) 1.38a (0.99–1.92) 1.44a (1.07–1.94)1.28a (0.99–1.64)
 ≥31.57 (1.14–2.16) 2.01a (1.34–3.03) 2.65a (1.94–3.60)1.73a (1.30–2.30)
Physical activity score1.09a (1.03–1.15)

Using definition that reported premenstrual symptom disappeared within 3 days of onset of menses.

aRemained significantly associated using the less conservative definition of symptom not disappearing within 3 days of onset of menses.

In addition, having an hs-CRP level >3 mg/L also remained significantly positively associated with reporting premenstrual appetite cravings/weight gain/bloating (aOR = 1.41, 95% CI 1.04–1.89) after adjustment for age, race/ethnicity, blood draw within cycle days 2–5, menopausal status, BMI category, physical activity score, CES-D ≥16, symptom sensitivity ≥15, use of anti-inflammatory medication, comorbidities, and physical activity. Having an hs-CRP level >3 mg/L also remained significantly positively associated with reporting premenstrual breast pain (aOR = 1.26, 95% CI 1.02–1.55) after adjustment for age, race/ethnicity, blood draw within cycle days 2–5, menopausal status, and BMI category.

Mood symptoms, abdominal cramps/back pain, appetite cravings/weight gain/bloating, and breast pain also remained significantly positively related to elevated hs-CRP, with similar magnitude of association, in adjusted models using the less conservative definition of not reporting disappearance of the symptom within 3 days of onset of menses. An elevated hs-CRP was not significantly related to premenstrual headache (aOR = 0.91, 95% CI 0.68–1.14) or to having three or more PMSx (aOR = 1.15, 95% CI 0.95–1.40) in multivariable models, regardless of definition used regarding disappearance of symptoms within 3 days of onset of the menstrual period and adjusted for age, race/ethnicity, blood draw within cycle days 2–5, menopausal status, CES-D ≥16, use of anti-inflammatory medications in the past month, and comorbidities.

We also computed adjusted ORs using the conservative definition for symptoms, but with a criterion of >5 mg/L for the elevation of hs-CRP, and found nearly identical results to those above for the lower cutoff except that the associations were somewhat stronger for abdominal cramps/back pain (aOR 1.56, 95% CI 1.15–2.10), weight gain/bloating (aOR 1.52, 95% CI 1.07–2.15), and reporting 3+ symptoms (aOR 1.50, 95% CI 1.18–1.89).

In addition, in multivariable models for each symptom, we tested interaction of elevated hs-CRP with race/ethnicity and separately with menopausal status and found none of the interaction terms to be statistically significant. This indicated that the relationship of elevated hs-CRP to each symptom did not vary by menopausal status or across racial/ethnic groups, although the sample sizes in some racial/ethnic subgroups were probably too small to provide adequate statistical power to detect some meaningful differences as statistically significant. We also computed adjusted ORs for number of symptoms in relationship to hs-CRP >3 mg/L and found a trend of increasing adjusted ORs with increasing number of symptoms reported (from 0.66, 95% CI 0.64–1.30 for one symptom to 1.21, 95% CI 0.67–2.18 for five symptoms) (data not shown), although the 95% CIs were overlapping and none excluded 1.0.

Furthermore, because of the documented relationship of inflammation and depressive symptoms,27,28 we reran all analyses for Table 3 excluding women with CES-D ≥16, and the adjusted ORs remained at a similar magnitude, although some 95% CIs included 1.0 due to the reduced sample size (data not shown). We also reran analyses, adjusting for currently taking “medications for a nervous condition such as tranquilizers, sedatives, sleeping pills, or antidepression medication,” which resulted in little change in adjusted ORs (data not shown). Interactions of each symptom group with the use of such medications were all nonsignificant.

Discussion

In our cross-sectional study, elevated hs-CRP (>3 mg/L), an acute phase biomarker of inflammation, was significantly related to a 26%–41% increased odds of reporting of premenstrual mood symptoms, abdominal cramps/back pain, appetite cravings/weight gain/bloating, and breast pain, but not headache, after adjusting for confounding variables. The results also revealed that the relationship of other risk factors to the different symptoms was not uniform across PMSx, suggesting different mechanisms for the occurrence of the different symptom groups. However, several factors (younger age, being in the early perimenopause, having an elevated depressive symptom score, and increased symptom sensitivity score) were associated with most symptoms with similar magnitudes of association.

The significant relationships of these PMSx with elevated hs-CRP levels have potential clinical implications for the treatment of these symptoms and possibly for prevention by advising women about the factors (e.g., smoking, overweight, and obesity) that are associated with inflammation, as well as suggesting avenues for future mechanistic and epidemiologic research.

To date, little literature has focused on the relationship of inflammation to PMSx, despite the fact that some women use anti-inflammatory medications to treat these frequently occurring symptoms. The observation of significant relationships of inflammation with some PMSx suggests that inflammation may be involved in the occurrence of these symptoms, although this requires future investigation using longitudinal data to establish the temporal sequence.

Our results are consistent with those of some prior studies that have found suggestive, but not always significant differences in inflammation between women reporting and women not reporting emotional or physical PMSx. However, most of these studies have included relatively small samples and have studied young (e.g., ages 18–30 years) white women.15,16 The present results are a unique contribution in that these frequently occurring PMSx were examined in a large sample of midlife (not young) women from a diverse sample that included five racial/ethnic groups.

Strengths and limitations

This study had several significant strengths. First, the sample comprised a large, racially/ethnically diverse, community-based sample of midlife women. Thus, we had good statistical power to detect meaningful associations, and the results are likely to have fairly good generalizability. Second, the assessment of hs-CRP used a high-quality laboratory measure, risk factors were assessed using standardized validated instruments, and both types of assessments were made independently of symptom reporting, thus reducing bias and misclassification. Third, we simultaneously statistically controlled for a number of potential risk factors so that we could assess the independent effects of elevated hs-CRP and each risk factor while controlling for the effects of others, thus minimizing the likelihood of residual confounding.

However, the study also had some limitations. First, multiple statistical comparisons were made; so, some of the observed associations may have occurred by chance or represent markers for other uncontrolled factors; thus, caution must be used for interpreting marginally significant results as well as for significant results for modestly strong associations. Second, the study was cross-sectional; thus, the temporal relationships to symptom reporting could not be adequately assessed, and some associations may have resulted from some factors being used for self-medication or be a consequence of symptoms rather than being causally related (e.g., anti-inflammatory medications, physical activity, and depressive symptoms). A longitudinal study is needed to resolve the temporal sequence of the associations observed here.

Third, all of the factors examined were recalled by participants and thus may lack accuracy of recall, although recall was unlikely to differ by hs-CRP status. Fourth, we did not have information on the presence of infection in participants at the time of blood draw, which could have influenced the results, although was unlikely to differ by symptom reporting. Fifth, due to time limitations for administration of the study instruments, we were not able to include an exhaustive list of symptoms so that some, such as irritability, were not included. Furthermore, the outcomes were not rare so that the ORs may have overestimated risk. Also, our sample sizes in some racial/ethnic groups may have been too small to detect interaction with elevated hs-CRP as statistically significant. Finally, we examined premenstrual symptoms; so, our findings may not apply to premenstrual syndrome.

Conclusions

Premenstrual mood symptoms, abdominal cramps/back pain, appetite cravings/weight gain/bloating, and breast pain, but not headache, appear to be significantly and positively related to elevated hs-CRP levels, a biomarker of inflammation, although with modestly strong associations, even after adjustment for multiple confounding variables. The results also suggest that the factors associated with each premenstrual symptom are complex, suggesting potentially different mechanisms for the etiologies of some symptoms. These results suggest that inflammation may play a mechanistic role in most PMSx, although further longitudinal study of these relationships is needed. However, recommending to women to avoid behaviors that are associated with inflammation may be helpful for prevention, and anti-inflammatory agents may be useful for treatment of these symptoms.

Acknowledgments

The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR), and the NIH Office of Research on Women's Health (ORWH) (Grant Nos. U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, and U01AG012495). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH, or the NIH. Clinical centers: University of Michigan, Ann Arbor–Siobán Harlow, PI 2011–present, MaryFran Sowers, PI 1994–2011; Massachusetts General Hospital, Boston, MA–Joel Finkelstein, PI 1999–present; Robert Neer, PI 1994–1999; Rush University, Rush University Medical Center, Chicago, IL–Howard Kravitz, PI 2009–present; Lynda Powell, PI 1994–2009; University of California, Davis/Kaiser–Ellen Gold, PI; University of California, Los Angeles–Gail Greendale, PI; Albert Einstein College of Medicine, Bronx, NY–Carol Derby, PI 2011–present, Rachel Wildman, PI 2010–2011; Nanette Santoro, PI 2004–2010; University of Medicine and Dentistry–New Jersey Medical School, Newark–Gerson Weiss, PI 1994–2004; and the University of Pittsburgh, Pittsburgh, PA–Karen Matthews, PI. NIH program office: National Institute on Aging, Bethesda, MD–Winifred Rossi 2012–present; Sherry Sherman 1994–2012; and Marcia Ory 1994–2001; National Institute of Nursing Research, Bethesda, MD–Program Officers. Central laboratory: University of Michigan, Ann Arbor–Daniel McConnell (Central Ligand Assay Satellite Services). Coordinating center: University of Pittsburgh, Pittsburgh, PA–Maria Mori Brooks, PI 2012–present; Kim Sutton-Tyrrell, PI 2001–2012; and New England Research Institutes, Watertown, MA–Sonja McKinlay, PI 1995–2001. Steering Committee: Susan Johnson, Current Chair and Chris Gallagher, Former Chair. We thank the study staff at each site and all the women who participated in SWAN.

Author Disclosure Statement

No competing financial interests exist.

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