The primary research question guiding this scoping review was: “How do hormonal changes in pre- and post-menopausal women influence the ADC values of benign, malignant, and fibroglandular breast tissues as measured by Diffusion-Weighted Imaging?”

This question was developed through an iterative process involving discussions among the research team and preliminary literature searches. The question was designed to be broad enough to capture the range of relevant literature while maintaining a clear focus on the relationship between hormonal status and ADC values in breast tissues.

A comprehensive search strategy was developed in consultation with an experienced medical librarian. The following electronic databases were searched: Scopus, Embase, and PubMed. The search was limited to studies published between January 2000 and December 2021, reflecting the period during which DWI became increasingly used in breast imaging.

The search strategy included a combination of controlled vocabulary (MeSH terms) and free-text terms. Key search terms included: -

“Diffusion Weighted Imaging” OR “DWI” OR “Diffusion Weighted MR Imaging”

Inclusion criteria

The inclusion criteria for this study encompassed several specific requirements. Only studies utilizing 1.5 Tesla MRI scanners and focusing exclusively on female subjects were considered. Additionally, the research had to employ Diffusion-Weighted Imaging sequences and report Apparent Diffusion Coefficient (ADC) values for benign and/or malignant lesions and/or fibroglandular tissue. Studies that took into account pre- and/or post-menopausal status were also included. Lastly, the review was limited to peer-reviewed articles published in English. These criteria were designed to ensure a focused and relevant selection of studies for analysis.

Exclusion criteria

Studies using 3 Tesla MRI scanners were excluded to maintain consistency in imaging parameters across the reviewed research. Any studies involving subjects undergoing neoadjuvant treatment were also omitted from consideration. The review excluded studies that did not report separate mean ADC values for benign and malignant lesions, as well as those not directly related to the diagnostic performance of Diffusion-Weighted Imaging (DWI). To focus on primary research findings, the review also excluded preclinical studies, case reports, letters, review articles, and unpublished articles. These exclusion criteria were implemented to ensure a more homogeneous and relevant dataset for analysis, focusing on studies that directly addressed the research question using comparable methodologies.

The study selection process was conducted in two phases. In the first phase, two reviewers independently screened the titles and abstracts of all retrieved articles against the inclusion and exclusion criteria. In the second phase, the full texts of potentially eligible articles were obtained and independently reviewed by the same two reviewers. Any disagreements were resolved through discussion, with a third reviewer consulted when necessary.

The study selection process followed the PRISMA guidelines. Initially, database searches yielded 487 records. After removing duplicates, 342 unique articles remained for screening. The titles and abstracts of these articles were reviewed, resulting in the exclusion of 314 articles that did not meet the inclusion criteria. The remaining 28 articles were assessed for eligibility through full-text review. During this stage, 22 articles were excluded for various reasons, such as irrelevant outcomes, inappropriate study design, or use of 3T MRI. Ultimately, 6 studies met all inclusion criteria and were included in the qualitative synthesis for this scoping review. No additional studies were identified through other sources. This systematic approach ensured a comprehensive and unbiased selection of relevant studies for the review.

A standardized data charting form was developed in Microsoft Excel to systematically extract relevant information from the included studies. This form was initially piloted on a sample of five studies and subsequently refined based on team discussions to ensure its effectiveness and comprehensiveness.

The data extraction process captured a wide range of information, including study characteristics (author, year, country, and study design), participant characteristics (sample size, age range, and menopausal status), and MRI characteristics (scanner manufacturer and b-values used). Detailed information about ADC measurement techniques, such as regions of interest and measurement methods, was also collected.

Importantly, the form captured quantitative data on ADC values, including mean and standard deviation for benign lesions, malignant lesions, and normal fibroglandular tissue. Any reported relationships between hormonal status and ADC values were noted, along with key findings and conclusions from each study.

To ensure accuracy and completeness, two reviewers independently extracted data from each included study. The extracted data were then cross-checked, providing a robust and reliable dataset for subsequent analysis.

The extracted data were analysed using a narrative synthesis approach. We organized the findings according to key themes and concepts that emerged from the data. Quantitative data (e.g., ADC values) were summarized using descriptive statistics where appropriate. We also created tables and figures to present the key characteristics and findings of the included studies.

In synthesizing the results, we focused on identifying patterns and trends in the relationship between hormonal status and ADC values, as well as highlighting any inconsistencies or gaps in the current evidence base. The PRISMA-ScR check list was used for reporting the data. ¹⁵

The initial database search yielded a total of 487 articles. After removing duplicates, 342 unique articles remained for title and abstract screening. Based on the screening, 28 articles were selected for full-text review. After applying the inclusion and exclusion criteria to the full texts, 6 studies were ultimately included in this scoping review. The study selection process is illustrated in Figure 1 (PRISMA flow diagram).

The six included studies were published between 2001 and 2018, representing a span of nearly two decades of research in this area. All studies used 1.5 Tesla MRI scanners, as per our inclusion criteria. The studies were conducted in various countries: two from the United States, two from South Korea, one from Italy, and one from the United Kingdom. The total number of participants across all studies was 612, with individual study sample sizes ranging from 6 to 288 participants. Table 1 provides the summary of the articles reviewed for this study.

3.2.1 Menstrual Cycle, Menopausal Status and ADC Values

All studies examined the relationship between hormonal status (either menstrual cycle phase or menopausal status) and ADC values. The findings showed some consistencies but also notable variations: 1.

Menopausal Status: -

Horvat et al. (2018) found no significant difference in ADC sensitivity or specificity between pre- and post-menopausal groups.

All studies examined the relationship between menopausal status and ADC values, while three studies also investigated the influence of menstrual cycle phases:

Horvat et al. (2018) found no significant difference in ADC sensitivity or specificity between pre- and post-menopausal groups, with mean ADC values for benign lesions being 1.541 ± 0.256 × 10 ⁻³ mm ²/s in premenopausal women and 1.515 ± 0.272 × 10 ⁻³ mm ²/s in postmenopausal women. Kim et al. (2016) reported significantly lower ADC values in postmenopausal women compared to premenopausal women for both normal fibroglandular tissue (1.60 ± 0.30 vs. 1.75 ± 0.27 × 10 ⁻³ mm ²/s, p < 0.05) and malignant lesions (0.91 ± 0.18 vs. 1.06 ± 0.35 × 10 ⁻³ mm ²/s, p < 0.05). Similarly, Shin et al. (2015) observed lower ADC values in postmenopausal women for normal fibroglandular tissue (1.480 vs. 1.640 × 10 ⁻³ mm ²/s, p < 0.001) and malignant lesions (0.648 vs. 0.644 × 10 ⁻³ mm ²/s, p = 0.031). Additionally, O’Flynn et al. (2012) reported significantly lower mean ADC values in postmenopausal breasts compared to premenopausal breasts for normal fibroglandular tissue (1.46 ± 0.3 vs. 1.84 ± 0.26 × 10 ⁻³ mm ²/s, p < 0.001). While Iacconi et al. (2014) primarily focused on premenopausal women, they also noted that postmenopausal status was associated with lower ADC values in normal breast tissue.

Regarding menstrual cycle influences, Partridge et al. (2001) found no significant variations in ADC values across different phases of the menstrual cycle in their study of six premenopausal volunteers. O’Flynn et al. (2012) reported no significant difference in ADC values between follicular and luteal phases in premenopausal women. Kim et al. (2016) observed slightly higher ADC values in the second half of the menstrual cycle for both normal fibroglandular tissue and breast lesions, but these differences were not statistically significant.

The consistency in findings across these studies, despite variations in sample sizes and specific ADC values, suggests a trend towards lower ADC values in postmenopausal women, particularly in normal fibroglandular tissue. This trend was observed in both benign and malignant lesions, although the difference was more pronounced and consistent for normal tissue. In contrast, the influence of menstrual cycle phases on ADC values appears to be minimal or inconsistent across studies.

The consistency in findings across these studies, despite variations in sample sizes and specific ADC values, suggests a trend towards lower ADC values in postmenopausal women, particularly in normal fibroglandular tissue. This trend was observed in both benign and malignant lesions, although the difference was more pronounced and consistent for normal tissue. In contrast, the influence of menstrual cycle phases on ADC values appears to be minimal, with most studies reporting no significant variations across different phases.

Several studies investigated additional factors that might influence ADC values in breast tissues: 1.

Background Parenchymal Enhancement (BPE): Horvat et al. (2018) investigated the impact of BPE on ADC values and found no significant influence on the sensitivity or specificity of ADC in distinguishing between benign and malignant lesions. This suggests that BPE, despite its known association with hormonal status, may not significantly affect the diagnostic performance of DWI.

The review revealed several technical factors that could contribute to variability in ADC measurements across studies: 1.

b-values: The studies used different b-values for DWI acquisition, ranging from 0 and 600 s/mm ² (Horvat et al., 2018) to 0 and 1000 s/mm ² (Kim et al., 2016). This variation in b-values could potentially affect the calculated ADC values and their sensitivity to tissue microstructure.

Despite the potential influences of hormonal status and other factors on ADC values, several studies reported on the overall diagnostic performance of ADC in differentiating between benign and malignant lesions: 1.

Horvat et al. (2018) found that ADC demonstrated high sensitivity (84%) and specificity (84%) in distinguishing between benign and malignant lesions, regardless of BPE, FGT, or menopausal status.

These findings suggest that while hormonal status may influence absolute ADC values, the diagnostic performance of ADC in differentiating between benign and malignant lesions remains robust across different hormonal states when appropriate cutoff values are used.

Only one study, Partridge et al. (2001), attempted to track longitudinal changes in ADC values across the menstrual cycle. Despite the small sample size, this study provided valuable insights into the potential for cyclic variations in ADC values. The observed minimal fluctuations suggest that the timing of DWI examinations within the menstrual cycle may not significantly impact diagnostic accuracy. However, more extensive longitudinal studies are needed to confirm this finding.

None of the included studies directly measured hormone levels and correlated them with ADC values. The assessment of hormonal status was primarily based on self-reported menstrual history or menopausal status. This represents a significant gap in the current literature, as direct correlations between specific hormone levels and ADC values could provide more precise insights into the relationship between hormonal status and diffusion properties of breast tissues.

In summary, the results of this scoping review reveal a complex relationship between hormonal status and ADC values in breast tissues. While there is evidence suggesting lower ADC values in postmenopausal women, particularly in normal fibroglandular tissue, the impact of menstrual cycle phases appears minimal. The influence of other factors such as BPE and FGT on ADC values adds further complexity to the interpretation of DWI results. Despite these variations, the diagnostic performance of ADC in differentiating between benign and malignant lesions appears to remain robust across different hormonal states, suggesting its potential as a valuable tool in breast cancer diagnosis.

One of the most consistent findings across the reviewed studies was the tendency for lower ADC values in postmenopausal women compared to premenopausal women, particularly in normal fibroglandular tissue. This trend was observed in four out of five studies that examined menopausal status, ^{3 – 6} with only Horvat et al. (2018) ¹⁴ reporting no significant difference.

The lower ADC values in postmenopausal breast tissue can be explained by the physiological changes that occur during menopause. The decline in estrogen levels leads to a reduction in breast tissue vascularity and an increase in fatty tissue replacement of glandular tissue (involution). These changes could result in decreased water diffusivity, manifesting as lower ADC values.

However, it’s important to note that while the trend was consistent, the magnitude of the difference varied across studies. This variability could be attributed to differences in study populations, imaging protocols, or measurement techniques. Moreover, the study by Horvat et al. (2018), which had the largest sample size, found no significant difference in ADC values between pre- and postmenopausal women. This discrepancy highlights the need for larger, standardized studies to definitively establish the relationship between menopausal status and ADC values.

In contrast to the findings on menopausal status, the evidence for menstrual cycle-related changes in ADC values was less conclusive. The three studies that examined this relationship (Kim et al., 2016; Partridge et al., 2001; O’Flynn et al., 2012) consistently found minimal or no significant variations in ADC values across different phases of the menstrual cycle.

This lack of significant menstrual cycle-related changes is somewhat surprising, given the known cyclic changes in breast tissue due to fluctuating levels of estrogen and progesterone. These hormonal fluctuations lead to changes in breast volume, water content, and vascularity throughout the menstrual cycle. The absence of corresponding changes in ADC values suggests that these cyclic variations may not substantially affect water diffusivity at the microstructural level detectable by current DWI techniques.

However, it’s important to note that the studies examining menstrual cycle effects had relatively small sample sizes and may have lacked the statistical power to detect subtle changes. Furthermore, the timing of MRI examinations in relation to menstrual cycle phases was based on self-reported menstrual history rather than direct hormonal measurements, which could introduce inaccuracies.

Despite the observed variations in ADC values related to menopausal status, the diagnostic performance of ADC in differentiating between benign and malignant lesions appears to remain robust. Several studies (Horvat et al., 2018; Kim et al., 2016; Shin et al., 2015) reported high sensitivity and specificity for ADC in distinguishing malignant from benign lesions, regardless of menopausal status.

This maintained diagnostic performance suggests that while absolute ADC values may vary with hormonal status, the relative difference between benign and malignant lesions remains sufficiently large for accurate differentiation. However, the optimal ADC cutoff values for diagnosing malignancy may differ between pre- and postmenopausal women, as demonstrated by Kim et al. (2016) and Shin et al. (2015). This finding underscores the importance of considering menopausal status when interpreting ADC values in clinical practice.

The review highlighted several other factors that may influence ADC values, including the amount of fibroglandular tissue (FGT) and background parenchymal enhancement (BPE). The study by Iacconi et al. (2014) found that breasts with higher amounts of FGT tended to have higher ADC values, an effect that was more pronounced in premenopausal women. This finding suggests that breast composition, which is influenced by hormonal status, can affect ADC measurements independently of the presence or absence of lesions.

Interestingly, Horvat et al. (2018) found that BPE did not significantly impact the diagnostic performance of ADC. This is noteworthy because BPE is known to be influenced by hormonal status and has been associated with breast cancer risk. The lack of significant impact on ADC performance suggests that DWI may offer advantages in terms of consistent diagnostic accuracy across varying levels of BPE.

The review revealed considerable variability in technical aspects of DWI acquisition and ADC measurement across studies. Differences in b-values, ROI selection methods, and scanner manufacturers could all contribute to variations in reported ADC values. This lack of standardization presents a challenge for comparing results across studies and for establishing universal ADC thresholds for clinical use.

Future research should aim to standardize DWI protocols and ADC measurement techniques to improve the comparability and reproducibility of results. This standardization should include consensus on optimal b-values, ROI selection methods, and strategies for minimizing the impact of scanner variability.

Several limitations in the current body of evidence were identified: 1.

Limited direct measurement of hormone levels: None of the reviewed studies directly measured hormone levels and correlated them with ADC values. Future studies incorporating direct hormonal measurements could provide more precise insights into the relationship between specific hormone levels and breast tissue diffusivity.