Breast tenderness and swelling experiences related to menstrual cycles and ovulation in healthy premenopausal women: Secondary analysis of the 1-year “Prospective Ovulation Cohort”

Mary Wood; Sonia Shirin; Azita Goshtasebi; Jerilynn C Prior

doi:10.1371/journal.pone.0321205

. 2025 May 12;20(5):e0321205. doi: 10.1371/journal.pone.0321205

Breast tenderness and swelling experiences related to menstrual cycles and ovulation in healthy premenopausal women: Secondary analysis of the 1-year “Prospective Ovulation Cohort”

Mary Wood ¹, Sonia Shirin ^2,³, Azita Goshtasebi ^2,^3,⁴, Jerilynn C Prior ^2,^3,^4,^5,^*

Editor: Patrick Ifeanyi Okonta⁶

PMCID: PMC12068584 PMID: 40354418

Abstract

Breast tenderness and swelling are associated with premenstrual symptoms but are not well described in healthy women. In this 1-year prospective observational study, we examined daily breast tenderness and swelling to determine whether differences existed between normally ovulatory and ovulatory disturbed (short luteal phase and anovulatory) cycles in a cohort of community dwelling, non-smoking, healthy premenopausal women. Enrolment required two consecutive normal-length and normally ovulatory cycles by Quantitative Basal Temperature© analysis. Women (n = 53) ages 20–41 recorded their daily breast experiences in the Menstrual Cycle Diary© across an average of 13.6 cycles. In all 720 cycles, the median breast tenderness was 1.4 (on a 0–4 scale, range 0.0–3.0), in cycles with a mean length of 28.1 days (95% CI 27.5–28.8). Comparison of breast tenderness and breast size (changes from usual) parameters between all normally ovulatory cycles and all ovulatory disturbed cycles in the whole cohort showed significantly higher levels in normally ovulatory (luteal length ≥10 days) in both Breast Tenderness Score [intensity X duration in days; 6.0 (range 1.0–14.0) vs. 3.0 (0.0–11.0) (P=.005)] and breast size [4.0 (2.0–4.0) vs. 4.0 (0.0–4.0) (P=.034]). However, within-woman in the forty-seven women with both normally ovulatory and ovulatory disturbed cycles, breast tenderness (intensity, duration, and Breast Tenderness Score), did not differ between normally ovulatory cycles and cycles with ovulatory disturbances. This study also demonstrated that in all ovulatory cycles, the timing of breast tenderness increased in parallel with breast swelling; the maximum for both was in the late luteal phase.

Introduction

Breast tenderness associated with the menstrual cycle is commonly reported as noted by 68% of a random sample of ~900 premenopausal women [1]; it often co-occurs with breast swelling [2,3]. Breast tenderness is likely ‘normal’ when women experience it for fewer than five days/cycle prior to flow and if it decreases with the onset of flow [2–4].

Although there is no clear etiology for these cyclical breast changes, several physiological mechanisms are possible. These include increased dietary fat intake’ [5]; higher prolactin levels leading to fluid retention in the breast [6]; imbalance in estradiol and progesterone activities on breast proliferation, differentiation, and maturation [7]; and’anovulatory cycles’ [8].

However, most menstrual studies do not assess ovulatory status or use non-valid methods [9,10]. Thus, there has yet been no accurate assessment of breast tenderness and swelling experiences related to ovulatory status [9]. Previous studies that have confirmed ovulation had durations of only 1–2 cycles [11–13], often used retrospectively reported data [12,14], or included only clinical participants [2,10,14].

Both women and clinicians need to know what is expected or ‘normal’ for menstrual cycle-related breast swelling and tenderness. We also need to know if breast changes across a cycle reflect ovulatory status. Given the long-term consequences associated with anovulation, including decreased bone and cardiovascular health [7], breast experiences might allow for the identification of women with predictable, month-apart cycles who have ovulatory disturbances (called Subclinical Ovulatory Disturbances, SOD). These women may benefit from consideration of cyclic progesterone therapy [15,16].

The primary objective of this study was to determine whether prospectively recorded breast tenderness differed between normally ovulatory and ovulatory-disturbed cycles within-woman in a cohort of healthy, community dwelling women with ~month-apart and luteal phase length- (LL) documented cycles. We hypothesized that there would be an increase in the intensity and duration of breast tenderness in cycles with SOD given their relative or absolute absence of progesterone [7].

Methods

Participants

These data were prospectively collected between 1984 and 1986 for a primary study, published in 1990 whose outcome was spinal bone change [16]. To enrol, women needed two consecutive normal-length (21–36 day) [17] and normally ovulatory (LL ≥10 days by Quantitative Basal Temperature© [QBT©]) cycles [16].

This cohort of community dwelling, premenopausal women were between ages 20–41 years, with body mass indexes (BMI) between 18.5–24.9, and were in overall good physical and emotional health [16], non-smoking and had not taken any form of hormonal contraception within 6 months [16].

The 66 women who completed the initial trial became the “Prospective Ovulation Cohort” (POC). Data from those 53 with complete menstrual cycle experience records (the Menstrual Cycle Diary©, MCD, was optional in the original study) plus cycle and ovulation documentation over ≥8 (mean=13) cycles were analyzed.

Menstrual Cycle Diary^© (MCD^©) and Quantitative Basal Temperature^© (QBT^©) analysis

All in the POC were asked to record the start of each cycle. The MCD^© [18] recording daily cycle and general experiences, was completed before bed, and included breast tenderness and change from usual in breast size by ordinal scales [18].

Assessments of ovulation and LL used the Quantitative Basal Temperature^© (QBT^©) analysis of first morning temperatures recorded in the MCD^©. QBT^© has been twice blindly validated: against the serum luteinizing hormone (LH) peak, and versus a within-cycle three-fold rise in the follicular-to-luteal urinary progesterone metabolite level [19,20]. All thermometers were from a single batch and women recorded to the nearest 0.05°C (Becton Dickinson No. 4009) [16]; they also noted external factors that could have affected their first-morning temperatures.

By QBT^©, cycles were categorized as being either normally ovulatory (LL≥10 days), short luteal phase (<10 days) or anovulatory (no significant temperature rise or for <4 days).

Breast experiences - Breast tenderness and swelling

Using the MCD^©, breast tenderness intensity was recorded on a five-point ordinal scale (0 = None, 1 = Minimal, 2 = Moderate, 3 = Moderately Intense, and 4 = Very Intense) [16]. A Breast Tenderness Score was derived by multiplying this intensity by its duration in days. We calculated mean breast tenderness per woman over all cycles and the number of days of an intensity > 0.

Breast size changes were also recorded in relation to ‘usual’ which was the mid-point on a five-point scale. These data were collected by capital letters with U = usual (3), and two letters above and below. Letters were converted into numbers: 1 = much less, 2 = a little less, 3 = usual, 4 = a little increased, and 5 = much increased [17]. Mean change in breast size from each woman’s perceived usual (including days with MCD© data <3 or >3), and days of size change were evaluated across all cycles for the entire cohort and within-woman between normally ovulatory and SOD.

Statistical analysis

Demographic, anthropomorphic, exercise, menstrual and reproductive health variables for all women were assessed for distribution and described as mean (95% confidence interval) or median, range across two groups split according to the median intensity of breast tenderness.

Based on data distribution (normally vs. non-normally distributed), statistical analysis used either ANOVA or a Mann-Whitney U tests to identify differences between breast tenderness groups.

Mean breast tenderness and changes in breast size were compared between all normally ovulatory cycles (LL≥ 10) and SOD cycles with QBT© data in the 53 women using a Mann-Whitney U test.

Forty-seven cohort women experienced both normally ovulatory and SOD cycles during ~1-year. We used Wilcoxon Signed Rank Test to compare median breast tenderness intensity, duration and Breast Tenderness Score, plus breast size changes and days of change from usual, in a within-woman comparison of normally ovulatory versus SOD cycles.

A multiple linear regression assessed demographic, anthropomorphic, exercise, menstrual and reproductive health variables for all 53 women related to continuous documentation of breast tenderness. In addition, breast tenderness and size changes were both described graphically in all ovulatory cycles oriented to the QBT© day of ovulation. Breast tenderness and size correlations were examined by Pearson correlation coefficient. Statistical analyses were performed with SPSS (version 29; Armonk, NY: IBM Corp) and R version 4.3.0.v with probabilities of <.05 considered likely important.

Ethics approval

The original study, with data collected approximately between 1984 and 1986, was approved by the Research Office of the University of British Columbia in 1984 (#C84-007). An overarching protocol and ethics proposal to analyze previously collected, unanalyzed data was subsequently approved for the ‘Menstrual Cycle and Ovulation-Related Experiences in Healthy Premenopausal Women: the 1-year Prospective Ovulation Cohort (POC)’ (#H21-03130) [21] as well as for this discrete breast-focussed project of the POC study (#H22-00695). The de-identified data were released for statistical analysis on May 5, 2022. Participants were not financially compensated for study participation but learned their own results and the whole study’s findings before publication [16].

Participant consent

All study participants were community dwelling women, not patients, and provided written informed consent to the original study protocol.

Results

Women participants averaged age 34 years (95% CI 32.4, 35.4), BMI 22.0 (95% CI 21.4, 22.5) and mean age at menarche, 11.5 years (95% CI 11.1, 11.8) years. In the 53 women in the Prospective Ovulation Cohort, breast experiences related to the menstrual cycle were analyzed within all 720 cycles, 97% of which were of normal lengths (21–36 days). We also analyzed them separately in the 694 of these cycles with documentable ovulatory status (Fig 1).

Fig 1 — Flow of participants from the original POC to the 53 whose Diary data were analyzed for this breast tenderness and swelling study.

By QBT© analysis, 495 cycles were normally ovulatory (71%), 181 had short LL (<10 days, 26%), and 18 (3%) were anovulatory (SOD 199, 29%). Mean cycle lengths in all normally ovulatory cycles (495) and all anovulatory cycles (18) were also not different: 28.5 (95% 28.2, 28.7) and 27.8 (95% CI 25.8, 29.8), respectively. Of 53 participants, 47 women recorded both normally ovulatory and short luteal and anovulatory (SOD) cycles.

Breast tenderness parameters

The mean intensity of breast tenderness in 53 women across all 720 cycles is shown in Fig 2 by quartiles of frequency distribution. The median breast tenderness was 1.4 (range, 0.0, 3.0) intensity in cycles of 28.1 days (95% CI 27.5, 28.8) long.

As shown in Table 1. no baseline data were different by median split of breast tenderness. All breast tenderness occurred in the luteal or premenstrual phase.

Table 1. Demographics for all 53 POC Women. Demographic, anthropomorphic, exercise, reproductive and menstrual health characteristics of 53 women (720 cycles) from the Prospective Ovulation Cohort reported by a median split of the intensity of breast tenderness.

Characteristic	n = 53	Intensity of Breast Tenderness		P value
Characteristic	n = 53	Mild (<1.4) n = 30	Moderate to Intense (≥ 1.4) n = 23	P value
†Mean and (95% confidence interval)
Age (in years)	33.9 (32.4-35)	35.4 (33.5-37.3)	32.6 (30.3 -35.0)	.066
Height (in cm)	162.5 (160.8-164.3)	163.8 (161.1-166.5)	161.3 (159.0-163.7)	.158
Weight (kg)	58.1 (56.2-60.0)	59.5 (57.4-61.5)	56.9 (53.8-59.9)	.165
Body Mass Index (BMI) (kg/m²)	22.0 (21.4-22.6)	22.2 (21.3-23.1)	21.8 (21.0-22.6)	.449
Age at Menarche (in years)	11.5 (11.1-11.8)	11.6 (11.2-12.0)	11.3 (10.8-11.8)	.392
Total Cycle #	720	357	363	–
Cycle (mean #/women)	13.6 (12.8-14.4)	14.3 (13.1-15.4)	13.0 (11.9-14.1)	.093
Cycle lengths (days)	28.1 (27.5-28.8)	27.9 (27.0-28.8)	28.4 (27.4-29.3)	.444
‡Median and (range)
Average duration of running (minutes/cycle)	310.7 (0.0-1572.5)	336.4 (0.0-1191.7)	231.3 (0.0-1572.5)	.548
Moderate-strenuous exercise^ (minutes/cycle)	82.2 (0.0-854.2)	59.1(0.0-477.1)	104.4 (0.0-854.2)	.218
	*n = 44*	*n = 20*	*n = 24*
Lifetime # of months on CHC^*	42.0 (2.0-156.0)	42.0 (2.0-143.0)	42.0 (3.0-156.0)	.637
	*n = 29*	*n = 13*	*n = 16*
Lifetime months of pregnancy	20.0 (2.0-40.0)	20.0 (3.0-30.0)	15.0 (2.0-40.0)	.619

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*CHC means combined hormonal contraception.

^ i.e., aerobics, swimming, skiing, fast walking, playing tennis, dancing.

P values are from either †ANOVA or ‡Mann-Whitney U Test.

A multiple linear regression analysis yielded no significant associations for relationships between breast tenderness and baseline variables.

Breast tenderness parameters for all normally ovulatory versus SOD cycles showed that mean breast tenderness intensity and duration were significantly greater in normally ovulatory cycles (Table 2). The median Breast Tenderness Score was 6.0 (range 1.0–14.0) in the 495 normally ovulatory cycles versus 3.0 (0.0–11.0) for the 199 cycles with SOD (P =.005).

Table 2. Breast Tenderness and Size Change Parameters for all 53 POC Women. Breast Tenderness and Breast Size Change Parameters between Normally Ovulatory and Ovulatory Disturbed Cycles by Quantitative Basal Temperature© from the Prospective Ovulation Cohort in all 53 Women.

Characteristic Median (IQR^Ɉ)	All 53 Women n = 694 cycles	Normally Ovulatory (Luteal Length ≥ 10 days) n = 495 cycles	Ovulatory Disturbances (Short Luteal phase & Anovulatory Cycles) n = 199 cycles	P Value^*
Mean Intensity of Breast Tenderness (0–4 scale)	1.0 (0.0 - 1.5)	1.0 (1.0 - 1.5)	1.0 (0.0 - 1.4)	.005
Duration of Breast Tenderness (days/cycle)	4.0 (0.0–9.0)	4.0 (1.0–9.0)	2.0 (0.0–8.0)	.001
Breast Tenderness Score	5.0 (0.0–12.0)	6.0 (1.0–14.0)	3.0 (0.0–11.0)	.001
	n = 690 cycles	n = 491 cycles	n = 199 cycles
Mean Change in Breast Size from Usual (per cycle)	4.0 (0.0 - 4.0)	4.0 (2.0–4.0)	4.0 (0.0 - 4.0)	.034
Duration of breast size change from usual (days/cycle)	4.0 (0.0–10.0)	5.0 (1.0–11.0)	3.0 (0.0–7.0)	.002

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*Mann-Whitney U Test ^ɈIQR= Interquartile Range.

Breast size changes

Changes in breast size from “usual” in the 711 cycles with this record were 4.0 (range 0.0–5.0). Breast size changes from usual were present for a mean of 4.0 (range 0.0–27.0) days/cycle and all occurred only in the luteal phase or premenstrually. Both increase in usual in breast size and its duration were significantly greater in normally ovulatory cycles (491) compared to SOD cycles (199). Breast swelling was scored (4.0 [2.0–4.0] vs. 4.0 [0–4.0]) (P =.034) and the days of breast enlargement 5.0 (1.0–11.0) vs. 3.0 (0–7.0) (P =.002) respectively (Table 2).

Breast tenderness and breast size change parameters within-woman

We compared breast tenderness and size experiences related to ovulation status within-woman in 47 women (Table 3). Breast Tenderness Score for 420 normally ovulatory cycles was median 5.9 (0–33.0) for, and for the 199 SOD cycles was 5.7 (0–34.3). In normally ovulatory cycles the intensity of breast tenderness tended to be greater (1.24 vs 1.21, P =.089), and the duration of swelling (4.5 days vs 4.3) was significantly greater (P =.034).

Table 3. Within-woman Comparison of Breast Tenderness and Breast Size Change. Within-woman comparison of Breast Tenderness Intensity, Duration, Breast Tenderness Score, and Mean Change in Breast Size (from usual = 3) and Number of Days of Breast Size Changes across all cycles in 47 women from the Prospective Ovulation Cohort who experienced both normally ovulatory cycles and subclinical ovulatory disturbances (anovulatory and cycles with luteal phase length <10 days).

Characteristic Median (range)	Normally Ovulatory Cycles (LL ≥ 10) n = 420	Subclinical Ovulatory Disturbances (LL < 10) n = 199	Mean Positive Ranks	P Value^a
Intensity of Breast Tenderness (0–4 scale)	1.2 (0.0-2.3)	1.21 (0.0-2.3)	21.81	.089
Duration of Breast Tenderness (days/cycle)	3.9 (0.0-16.0)	4.3 (0.0-15.5)	21.32	.266
Breast Tenderness Score	5.9 (0.0-33.0)	5.7 (0.0-34.3)	20.29	.268
	n = 416	n = 199
Mean Change in Breast Size from Usual (per cycle)	4.0 (0.0-4.4)	4.0 (0.0-4.6)	–	.124
Duration of breast size change from usual (days/cycle)	4.5 (0.0-20.6)	4.3 (0.0-19.0)	–	.034

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^aWilcoxon Signed Rank Test was used for these within-woman analyses.

Breast tenderness and breast swelling temporal association in ovulatory cycles

In all ovulatory cycles aligned by QBT© ovulation day, we could integrate the cycle timing and both types of breast experiences by plotting mean breast tenderness and breast size changes per cycle day for the 676 cycles from 53 women (Fig 3). Tenderness and swelling were parallel in timing and positively correlated (r = 0.315, P =.001). The late luteal phase showed maximal values for timing of both breast characteristics.

Fig 3 — Mean Breast Tenderness and Change from Usual in Breast Size (with 3 = usual) (95% CI) for 53 women (676 cycles) from the Prospective Ovulation Cohort are reported around the temperature shift day (ovulation = day ‘0’) by Quantitative Basal Temperature© analysis.

Discussion

These comprehensive 1-year healthy community cohort data described breast tenderness and breast swelling increases in the days before flow across menstrual cycles in 53 healthy, initially normally ovulatory women with the greatest changes being within normally ovulatory cycles. Mild breast tenderness is common and lasts 2–5 days. These data confirm previous literature about premenstrual breast tenderness and swelling but do not confirm our hypothesis that SOD cycles would be more symptomatic. We also showed a positive, significant correlation between breast tenderness and swelling.

It is accepted that regular, month-apart menstrual cycles are ovulatory [22,23]. We have recently shown that this is often untrue [24]. It is proposed that premenstrual experiences including breast tenderness and fluid retention relate to ovulation; they are thus unlikely to be reported in anovulatory cycles [8]. These ideas explained improved PMS on combined hormonal contraceptives (CHC) [8]. However, spontaneous ovulatory disturbances including anovulation (SOD) occur in up to one third of regular, normal-length menstrual cycles [16,23,25]. Population-based data in a previous study showed that cycles without ovulation by a cycle-timed serum progesterone level <9.5 nmol/L had both significantly lower progesterone and estradiol levels [23]. Although progesterone levels were 84% lower, estradiol was decreased by only 20% [23]. Based on the results of our study, it is possible that even this minimal decrease in estradiol was sufficient to result in a perceivable decrease in breast tenderness and swelling.

Few studies have previously sought to characterize menstrual cycle breast tenderness and size changes related to known ovulatory status [10–12] and no published study to date, has compared these in normally ovulatory vs. short luteal and anovulatory cycles within premenopausal women. In a study by Laessle et al. (1990) [11] data from prospective daily diary logs were used to analyze breast tenderness over a single cycle in 30 volunteer women (mean age 24) with confirmed ovulation by serum progesterone and known luteal phase lengths [11]. Our data confirm their observation of an increased breast tenderness later in the luteal phase [11]. They did not assess changes in breast size.

Our centre, while evaluating women aged in their 40s with regular cycles also experiencing night sweats (clinically in perimenopause), found breast tenderness increased premenstrually in both anovulatory and ovulatory cycles [26]. In ovulatory cycles, alone, breast tenderness was also found to peak during the window of ovulation [26]. This temporal pattern was not present in our premenopausal cohort.

It is thought that high estradiol levels, combined with lower-than-normal levels of progesterone, are associated with increased breast tenderness [7,23,26]. Population data showed a higher estradiol/progesterone ratio that could result in proliferation of breast epithelial cells [27]. By contrast, the entire data set of our study documented that breast tenderness intensity and duration were increased in normally ovulatory cycles compared to cycles with disturbed ovulation.

Given the few (n =18) anovulatory cycles in our dataset, we had insufficient power to assess breast tenderness and size changes with anovulation. Further research is needed to relate estradiol and progesterone levels with breast tenderness and size changes.

Our secondary objective was to characterize the timing and variation of normal breast size changes associated with the menstrual cycle. There are studies examining breast changes in clinical populations and in women with ‘clinical cyclical mastalgia’ [1,28], but these experiences cannot be generalized to represent typical breast changes experienced over a normal menstrual cycle [10].

We also examined changes from each woman’s perceived usual in breast size as well its relationship with breast tenderness [3,9]. Morphological changes in breast tissue during the luteal phase, including stromal edema, inflammatory cell infiltrates, and increased mitotic figure counts described by Ramakrishnan et al. [29], likely explain the significant association we found for breast swelling with breast tenderness. The extended exposure to luteal phase progesterone levels driving these morphological changes may also explain the increased days of breast swelling in normally ovulatory vs. SOD cycles.

Our study is limited as a secondary analysis of previously collected data. Direct measurements of estradiol and progesterone would have been ideal [7]. Funding insufficiency and study burden prohibited this. We also had few anovulatory cycles which likely limited our ability to show a within-woman difference in breast tenderness results.

Our study’s strengths are prospectively reported data, minimizing recall bias, and characterizing diverse daily cycle experiences [1,2,14]. Its approximately 1-year duration also increases its validity versus many existing shorter studies [9,11,12]. Another strength is that all women on two consecutive cycles were initially normally cycling and ovulatory based on QBT© prior to enrollment. These breast experiences may be expected for healthy, initially ovulatory, premenopausal women.

Conclusion

This one-year prospective observational cohort study in 53 healthy, normally cycling, and ovulatory women evaluated breast experiences recorded daily in 720 cycles. Results showed that mild breast tenderness and swelling occurred before flow in cycles with normal ovulation; these were totally absent during the follicular phase. Further research is needed on premenopausal normal breast experiences related to ovarian hormone levels.

Acknowledgments

We thank the women who conscientiously kept daily records in the Prospective Ovulation Cohort. We also appreciate all those whose efforts contributed to the digitization and data management, including Yvette M. Vigna for review and documentation of the QBT© data. We thank Dr. Sewon Bann (working with co-author, Azita Goshtasebi) who determined that MCD© records in the POC were best evaluated in the 53 women with ≥8 menstrual cycle records/person (mean = 13).

Data Availability

We have uploaded the study data to Borealis, UBC's research data repository. Here is the link: https://borealisdata.ca/privateurl.xhtml?token=c9a3da20-83f4-4a8b-b3f2-eda631b29a2a Data requests can be made to Dr. Eugene Barsky or the UBC Research Data Team research.data@ubc.ca

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. 2025 May 12;20(5):e0321205. doi: 10.1371/journal.pone.0321205.r001

Author response to Decision Letter 0

27 Nov 2024

PLoS One. doi: 10.1371/journal.pone.0321205.r002

Decision Letter 0

Patrick Okonta

29 Dec 2024

PONE-D-24-53242Breast Experiences related to Menstrual Cycles and Ovulation in Healthy Premenopausal Women: the 1-year “Prospective Ovulation Cohort”PLOS ONE

Dear Dr. Prior,

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Reviewer #2: Partly

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Reviewer #1: The authors has looked into an aspect of medicine that has been assumed, their study is therefore opening new grounds for other researchers to look into.

But 40 years before the data was analyzed may be a drawback, I recommend a recent study can be done to evaluate the same breast changes.

The statistical analysis is appropriate.

The language was standard English and written in an intelligible fashion.

The conclusion is supported by the data.

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Reviewer #2: Yes: OSAJI NICOLE EVELYN CHIUDE

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Attachment

Submitted filename: PEER REVIEW COMMENTS.pdf

pone.0321205.s001.pdf^{(34KB, pdf)}

PLoS One. 2025 May 12;20(5):e0321205. doi: 10.1371/journal.pone.0321205.r003

Author response to Decision Letter 0

24 Feb 2025

February 11, 2025

Dear Dr. Patrick Ifeanyi Okonta,

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf<.https://track.editorialmanager.com/CL0/https:%2F%2Fjournals.plos.org%2Fplosone%2Fs%2Ffile%3Fid=ba62%2FPLOSOne_formatting_sample_title_authors_affiliations.pdf/1/010f0194149fe789-71bb2081-c775-402b-af26-b5b01e31d061-000000/Q8tPGFu9EXaoIM_gHIxp6uE6Q9jJ-zPEhRCjHu34xnA=190>

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2. In this instance it seems there may be acceptable restrictions in place that prevent the public sharing of your minimal data. However, in line with our goal of ensuring long-term data availability to all interested researchers, PLOS’ Data Policy states that authors cannot be the sole named individuals responsible for ensuring data access (http://journals.plos.org/plosone/s/data-availability#loc-acceptable-data-sharing-methods).

We agree that institutional management is more reliable. As the senior author, I am now almost 82 years old!

We are in the process of depositing our de-identified data for this analysis into a University of British Columbia “dataverse” instrument (Borealis) that will be accessible, if appropriate, through non-author university employees.

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Detailed responses to reviewers including identification of manuscript changes

Reviewer 1

The authors has looked into an aspect of medicine that has been assumed, their study is therefore opening new grounds for other researchers to look into. But 40 years before the data was analyzed may be a drawback, I recommend a recent study can be done to evaluate the same breast changes.

The statistical analysis is appropriate. The language was standard English and written in an intelligible fashion. The conclusion is supported by the data.

Thank you for your positive assessments of the statistics, language and conclusion.

Unfortunately, at this time funding is not available to collect new data and repeat the initial study which included MCD© and QBT© data over the course of a year for 53 women. We do not believe that is necessary. There is no reason to think that contemporary data collection with repeated analysis would alter our findings. It is unlikely that spontaneously recorded breast tenderness and swelling experiences in relation to ovulatory status would have changed over a 40-year period. When looked at that way, we trust you will agree.

Reviewer 2

1.Cohort study done using previous secondary data is called a retrospective cohort study or historical cohort study. Secondary data cannot be utilized to carry out a prospective cohort study.

Thank you for your careful and comprehensive review.

You are quite correct that this is a secondary analysis. However, it is an analysis of prospectively collected data and thus still considered to have a prospective cohort design. The Menstrual Cycle Diary© (MCD©) data were collected prospectively during the initial study (Prior, 1990, New England J Med). In that investigation we used the MCD© for cycle length timing and as a form for recording first morning temperatures used in the Quantitative Basal Temperature© [QBT©] analysis.

However, most MCD data items were not reported until we determined the protocol for secondary analysis of these diary data in the Prospective Ovulation Cohort study analyzing and reporting the MCD©-recorded experiences of the 53 women with at least 8 consecutive cycles (mean 13.6). That published open-access protocol is accessible here http://hdl.handle.net/2429/80682.

This is a prospective study because the participants were followed prospectively (over time into the future) and as stated by Klebanoff & Snowden (2018). It is the timing of data collection with respect to when the follow up/observed outcome takes place that makes a study prospective vs. retrospective, not the timing of the analysis, nor the year when the data were collected.

Klebanoff MA, Snowden JM. Historical (retrospective) cohort studies and other epidemiologic study designs in perinatal research. American Journal of Obstetrics & Gynecology. 2018;219(5):447-50.

ABSTRACT

2. Title should contain “A secondary data analysis “

Thank you for that suggestion. We have added it (Line 4).

3. A standard definition of the population used which falls into the pre- menopausal age group bracket. Your population was 20-40 years are they pre-menopausal? Insert your reference.

The participants included in this study were deemed premenopausal. They had predictable normal length (21-36 day) menstrual cycles with two consecutive normally ovulatory cycles prior to study enrolment. Normal ovulatory status was proven with QBT© determined luteal phase lengths of 10 or more days. Based on the STRAW+10 criteria (Harlow et al., 2012), they would only be considered perimenopausal if they had persistent variability in cycle lengths by 7 days or more in consecutive cycles.

Harlow SD, Gass M, Hall JE, Lobo R, Maki P, Rebar RW, et al. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. Menopause. 2012;19(4):387-95.

4. Title is vague should have indicated the specific breast experiences which will be the dependent variable or outcome. As prospective cohort studies must have a timeline for follow up, which indicates the time to develop the outcome (and exemplified as per person per year) not any arbitrary time frame.

Thank you for that suggestion. We have added “breast tenderness and swelling” to the title (Line 3).

5. For range in the statement (Line 26), the comma should be changed to hyphen “the median breast tenderness was 1.4 (on a 0-4 scale, range 0.0, 3.0)”.

We generally prefer a comma between ranges to ensure that a hyphen is not interpreted as a negative number. However, we have accepted your suggestion. See (Line 28)

6. For CI in the statement ( line 27 ) “ in cycles with a mean length of 28.1 days (95% CI 27.5, 28.8)”. The comma should be changed to hyphen.

We have again accepted your suggestion. See (Line 29)

7. Explain how the within woman finding of no statistical significance in breast tenderness impacts on your primary objective of your study and its conclusion. Your conclusion in the abstract should be in line with the objectives, this enables relay a snapshot summary.

We respectfully disagree with the suggestion to describe the primary outcome first.

Given that there is reason to suspect more accuracy of a self-reported experience within- than between women, that the within-woman outcome was our primary objective, and that our within-woman and between women results differed, we believe that our within-woman findings are important to report in the abstract. We had only 18 anovulatory cycles in this database given that all women were initially normally cycling and ovulatory. These results highlight the need for future research with more anovulatory cycles for direct comparison to further evaluate our primary objective.

8. The study design utilized is limited when temporality needs to be established hence conflicting with your statement in line 52-54 which states “Both women and clinicians need to know what is expected or ‘normal’ for menstrual cycle related breast swelling and tenderness. We also need to know if breast changes across a cycle reflect ovulatory status”, cannot be investigated extensively with regard to casualty.

You are right that we cannot assess causality. We are only attempting to describe breast tenderness and swelling experiences as well as when within the menstrual cycle the breast experience changes occurred (temporality).

Our study prospectively followed 53 previously healthy and normally cycling women with self-reported breast experiences (tenderness and size changes) over at least 8 consecutive cycles (mean 13). We were able to show the general trends and characterization of breast changes experienced across cycles that were proven to be ovulatory based on QBT© data, as well as the relationship and cycle phase timing of breast tenderness and swelling throughout all ovulatory cycles.

Given the extensive screening, and the healthy nature of the participants, these findings can be extrapolated to similar populations as a reflection of expected menstrual cycle experience changes.

INTRODUCTION

A. This statement should be referenced “However, most menstrual studies do not assess ovulatory status or use non-valid methods”.

We agree that this statement should be referenced. We have added two references, (Lines 51-52)

B. The normal menstrual cycle length is 21-35 days. Reference this statement “To enrol, women needed two consecutive normal-length (21-36 day)

You are right to call this out.

In the late 1970s when planning was underway for data collection, the upper length of the normal menstrual cycle was considered 36 by experts like Dr. Abraham. We’ve referenced a review of his (Line 73).

C. Line 6. How did you account for differential pain perception- minimal pain documented by a respondent may be maximal to respondent (confounding/ propensity scoring)

Pain scales are entirely subjective, and as you correctly identified, respondents have different pain thresholds and tolerance levels. We were assessing breast tenderness that we expected to be and was usually mild (as the median was 1.4 on a 0-4 scale shows).

We simply scored breast tenderness with the same scale as we used for other things like frustration or sleep problems. Our MCD© data were to evaluate trends and variations in reported experiences throughout an individual’s cycle to assess patterns with regards to ovulatory status.

D. Line 108: Delete this ( ) from the range and insert a comma, in the statement “as mean (95% confidence interval) or median (range) across two groups”. It is a distinct statistical term, a measure of dispersion not a measure of central tendency.

We have followed your suggestion—see (Lines 112-113)

E. Line 110: correct analysis in the statement “Based on data distribution (normally vs. non-normally distributed), statistical analyses” analysis is singular while analyses is plural.

Thank you. We have changed ‘analyses’ to ‘analysis’ (Line 114)

G. Line 112-113: You used Man Whitney U test {which is utilized for non- parametric data }to compare the mean (a parametric data ).

In summarizing, I guess our statistical analysis plan became unclear.

We have indicated that we used a non-parametric test for data (such as the ordinal and not interval data in which breast tenderness was scored) that were not normally distributed.

H. Line 115-118: What objective are you analyzing using Wilcoxon Signed Rank Test, when you compared the constructed composite “breast tenderness score” with the other parameters in both groups?

Thank you for this question. In Table 3 we should have made it clear that our non-parametric but paired analysis of breast experience parameters used this test for within-woman analysis. We’ve added a footnote to Table 3 to indicate the use of the Wilcoxon Signed Rank Test for these data.

I. Line 122-123: What objective did breast tenderness and size correlations answer. Always do the statistical analysis which are pertinent to your study objectives.

Thank you for the important reminder to make sure that data analysis responds to stated study objectives.

One of our secondary objectives was to characterize the timing and variation of normal breast size changes associated with the menstrual cycle (Lines 301-302). As a component of this analysis, we examined the timing and pattern of both breast tenderness and change in size across a normally ovulatory cycle. These two breast experiences were found to be positively correlated, both increasing towards the end of the luteal phase prior to the onset of menses.

Knowing that increased breast tenderness and increased breast size or swelling, which can contribute to perceived breast tenderness, is a normal premenstrual experience across an ovulatory cycle is valuable information to both clinicians and premenopausal women in the context of menstrual health evaluation.

ETHICAL APPROVAL

A. Line 133-134: This statement is not necessary “These data were de-identified so that the identities of the participants were not known to the researchers analyzing the data”.

We have taken this statement out (see Line 142) but referred to de-identified data elsewhere as our ethics confidentiality guideline require.

B. This statement should be under the section on ethical approval “ They were not financially compensated for study participation”.

We have moved the place in the document in which this is mentioned, as you requested. (Lines 140-142)

C. Insert the appropriate flow diagram for the study.

We have inserted the Flow Diagram early in the results to orient the reader to what data we are analyzing (see Lines 168-171)

RESULTS

Documentation should chronologically reflect your objectives to reduce ambiguity.

Thank you for your perspective.

Before the objectives can be understood and data presented, we believe it is important to first introduce the participants in a trial, to show the flow of participants and data through the study, to show the distribution of the major factor of interest (breast tenderness) and to first provide complete baseline data stratified by the median breast tenderness.

We then show the primary parameters for breast tenderness and size changes for all women, examining

Attachment

Submitted filename: POC breast-Responses to Editor and Reviewers Feb 11 - Final.pdf

pone.0321205.s003.pdf^{(409KB, pdf)}

PLoS One. doi: 10.1371/journal.pone.0321205.r004

Decision Letter 1

Patrick Okonta

3 Mar 2025

Breast Tenderness and Swelling Experiences Related to Menstrual Cycles and Ovulation in Healthy Premenopausal Women: secondary analysis of the 1-year “Prospective Ovulation Cohort”

PONE-D-24-53242R1

Dear Dr. Prior,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Patrick Ifeanyi Okonta, MBBCh, MPH, FWACS, FMCOG, MD, DRH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0321205.r005

Acceptance letter

Patrick Okonta

PONE-D-24-53242R1

PLOS ONE

Dear Dr. Prior,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

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on behalf of

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Academic Editor

PLOS ONE

Associated Data

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

Supplementary Materials

Attachment

Submitted filename: PEER REVIEW COMMENTS.pdf

pone.0321205.s001.pdf^{(34KB, pdf)}

Attachment

Submitted filename: POC breast-Responses to Editor and Reviewers Feb 11 - Final.pdf

pone.0321205.s003.pdf^{(409KB, pdf)}

Data Availability Statement

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PERMALINK

Breast tenderness and swelling experiences related to menstrual cycles and ovulation in healthy premenopausal women: Secondary analysis of the 1-year “Prospective Ovulation Cohort”

Mary Wood

Sonia Shirin

Azita Goshtasebi

Jerilynn C Prior

Roles

Abstract

Introduction

Methods

Participants

Menstrual Cycle Diary© (MCD©) and Quantitative Basal Temperature© (QBT©) analysis

Breast experiences - Breast tenderness and swelling

Statistical analysis

Ethics approval

Participant consent

Results

Fig 1. Participant flow in the Prospective Ovulation Cohort (POC).

Breast tenderness parameters

Fig 2. Frequency distribution of breast tenderness.

Table 1. Demographics for all 53 POC Women. Demographic, anthropomorphic, exercise, reproductive and menstrual health characteristics of 53 women (720 cycles) from the Prospective Ovulation Cohort reported by a median split of the intensity of breast tenderness.

Table 2. Breast Tenderness and Size Change Parameters for all 53 POC Women. Breast Tenderness and Breast Size Change Parameters between Normally Ovulatory and Ovulatory Disturbed Cycles by Quantitative Basal Temperature© from the Prospective Ovulation Cohort in all 53 Women.

Breast size changes

Breast tenderness and breast size change parameters within-woman

Breast tenderness and breast swelling temporal association in ovulatory cycles

Fig 3. Temporal pattern of mean breast tenderness and breast size change related to the day of ovulation.

Discussion

Conclusion

Acknowledgments

Data Availability

Funding Statement

References

Author response to Decision Letter 0

Decision Letter 0

Patrick Okonta

Roles

Author response to Decision Letter 0

Decision Letter 1

Patrick Okonta

Roles

Acceptance letter

Patrick Okonta

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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Menstrual Cycle Diary^© (MCD^©) and Quantitative Basal Temperature^© (QBT^©) analysis