Ultrasound Assessment and Sexual Dimorphism of Thyroid Nodules: Bringing Gender Medicine to Clinical Practice
by
,
Marina Valenzano
1,*
,
Ruth Rossetto Giaccherino
2,
Loredana Pagano
2,
Sara Garberoglio
2 and
Roberto Garberoglio
2 1
Division of Diabetology, Local Health Service TO4, 10034 Chivasso, Italy
2
Division of Endocrinology and Metabolic Disorders, Città della Salute e della Scienza Hospital, 10126 Torino, Italy
*
Author to whom correspondence should be addressed.
Endocrines 2025, 6(2), 15; https://doi.org/10.3390/endocrines6020015
Submission received: 29 December 2024
/
Revised: 17 February 2025
/
Accepted: 10 March 2025
/
Published: 1 April 2025
(This article belongs to the Section Thyroid Endocrinology)
Abstract
:Background/Objectives: Understanding sex-based differences in both the pathophysiology and clinical presentation of diseases is necessary to improve health care towards precision medicine. The endocrine system is deeply involved in human health, and endocrine diseases may be influenced by steroidal hormone exposure. Thyroid nodular disease and differentiated thyroid cancer, in particular, show a high prevalence in the female sex; however, little is known about sex-related differences in risk factors and clinical presentation. This study aims to assess whether morphological differences, which can be detected by ultrasound examination, can be related to sex in order to refine diagnostic approaches and oncological risk classification. Methods: A retrospective observational study on 1355 ultrasound images of thyroid nodules obtained from 2017 to 2020 at a single university center was conducted. The images were reviewed by a single observer blinded to the patient’s sex and the cytological nature of the nodules. The qualitative description, size, anatomical location and oncological risk classification were assessed. Results: A taller-than-wide shape (anteroposterior/craniocaudal axis ratio > 1) was found to be more frequent in men than in women (6.7% vs. 3.6%, p = 0.027); the nodular volume was significantly larger in males (p << 0.01) than in females. Significant tropism for the upper lobe and isthmus was described in women (26% vs. 16.5%, p = 0.011) and for medium–lower thyroid lobes in men (83.5% vs. 73.8%, p = 0.011). Background thyroiditis was more common in women, while the number of cytological diagnoses of malignant or likely malignant nodules was higher than expected in men (9% vs. 6%, p = 0.01). Conclusions: Thyroid nodules show different distributions, in terms of a larger volume, more frequent taller-than-wide shape and lobular caudal location, in men vs. women. These results should be confirmed by further investigations, and the underlying mechanism should be clarified. However, our explorative research is of interest due to its novelty and possible future clinical implications.
1. Introduction and Objectives
Sex-based and gender-based differences may influence people’s health, and there is a growing interest in the field of gender medicine in understanding the underlying mechanisms of diseases, which can ultimately lead to more precise and appropriate management of diseases [1].
Thyroid disease, in general, has a higher prevalence (5–8 times higher) in female patients, and differentiated thyroid cancer, which is the commonest endocrine neoplasm, shows 3 to 4 times higher incidence in women than in men [2], although the exact reasons remain unclear, and feminine sex is only recognized as a risk factor for recurrence by the ATA guidelines [3].
Previous epidemiological work is controversial, with two main trains of thought appearing plausible: on the one hand, selection bias may often interfere in prevalence assessment, while, on the other hand, oncogenic insults may be modulated by sex (i.e., through different steroidal hormones exposure or different immune system regulation and escape strategies held by women vs. men) [4]. Conversely, clinical practice rarely discriminates according to sexual or gender, and it is unknown if a sex-based approach is truly needed.
A recent extended review [5] confirms the epidemiological prevalence of differentiated thyroid cancer through different populations (with the female/male ratio ranging from 2:1 to 3:1 in different geographical areas), with larger incidence in younger multiparous women (<40 years old) [2]. Additional sex-related risk seems to be limited to the commonest histological subtypes (papillary and follicular carcinoma) [6], while not affecting medullary and anaplastic incidence [7], although data regarding rare subtypes are scarce. These findings are not supported by studies on autopsy examinations: a recent meta-analysis concluded, for a female/male ratio of 1.07:1 (95% confidence interval CI = 0.8–1.42) of papillary thyroid cancer prevalence [8], that is more coherent with the risk of selection bias than a sex-related oncogenic effect. The impact of gender and, in particular, of male sex on risk of disease recurrence has also been questioned [9].
Dealing with pathogenesis, some investigational preclinical and clinical studies have suggested a potential role of pregnancy and, in particular, of the human chorionic gonadotropin (hCG) on nodular enlargement, even if it is not associated with malignant transformation [10,11,12]. Other authors have also tested the hypothesis of trophic stimulation by thyrotropin stimulating hormone (TSH) [13,14,15], although the role of clinical values of IGF-1 and IGF-BP-3 showed a more solid relationship with goiter development [16,17]. The presence of estrogen receptors on normal and cancerous thyrocytes has been ascertained [2,4,7], though α and β receptors are likely to act in opposite ways (the former activating pro-oncogenic pathways and the latter having a protective effect).
Thyroid ultrasound represents the first-line investigation for nodular disease, but no risk scores have included sexual differentiation to date [3,18,19]. Previous research examined the ultrasound presentation of Hashimoto’s thyroiditis in relation to both thyroid function and autoimmunity [20]. The correlation between the classical ultrasound presentation (hypoechoic, inhomogeneous structure) and the presence of thyroid autoantibodies was stronger in women, though nodular disease was excluded from the assessment. However, a recent study shows that thyroiditis is associated with increasing odds of thyroid cancer [21], but the correlation has already been debated [22,23,24].
Our research aims to investigate whether sexual dimorphisms are present and can be detected by ultra-sonographic assessment and/or cytological examination on fine-needle aspiration (FNA) samples. In particular, we are interested in discovering if some kind of association exists between sex and any of the most significant echography image characteristics and/or cytological classification results. To the best of our knowledge, no previous studies published in the literature have explicitly addressed this point, and we hope that the findings of this work could be a first step in driving further investigations and possibly taking into consideration some redefinitions of risk stratification tools.
2. Materials and Methods
A single-center retrospective observational study was conducted at the Division of Endocrinology and Metabolic Diseases, “Le Molinette” University Hospital of Turin. Ultrasound nodular assessment of nodules referred for FNA was performed using Esaote MyLabTM Twice echography and digital images stored in the hospital database. Because of the very large number of images in the archive, the indication for FNA was adopted as a selection criterion in order to obtain a set of clinically relevant data of manageable size. The local archive was then queried from 1 January 2017 to 31 December 2020 to extract the images of interest, together with the cytological classification results. The COVID-19 pandemic period was excluded from this research project, since emergency procedures affected both the work volume and selection criteria for accessing the ultrasound examination. Images of thyroid nodules were included if a complete ultrasonographic evaluation was available, that is, it involved at least two pictures for antero-posterior, transversal and longitudinal axis measurement, strain elastography and EcoColorDoppler pattern assessment, together with cytological classification according to the SIAPEC-IAP/AIT/AME/SIE guidelines [25].
For the purpose of this study, a single endocrinologist, with experience in neck diagnostic and interventional ultrasound, re-examined the selected images after their retrieval from the hospital archive. It is worth noting that, before being entered into the hospital database, all ultrasound exams were evaluated and reported by medical staff and specialized technicians.
Typical descriptive (and corresponding categorical variables) and measurable elements for imaging review were then assessed, including the following:
- Structure;
- Echogenicity;
- Margins;
- Punctuated endonodal hyperechoic spots or “foci” (PEF);
- Taller-than-wide nodular presentation in the longitudinal axis;
- Nodular vascularization pattern;
- Stiffness;
- Subcapsular extension;
- Side;
- Position;
- Nodular volume.
The taller-than-wide shape was assessed in longitudinal scans of nodules and defined as the antero-posterior/cranio-caudal ratio > 1, as shown in Figure 1. A longitudinal rather than transverse assessment allows for more strict definition of the taller-than-wide shape, since possible interference from rigid or bulky structures, such as trachea cartilage or supra-aortic vessels, which could lead to anteroposterior axis overestimation, is eliminated.
Other anatomical data were also obtained, that is, the intra-lobular collocation of nodules, closeness to the thyroid capsule and laterality. Sufficiently wide images also allowed for a qualitative assessment of background thyroiditis, defined as hypoechoic and/or inhomogeneous tissue texture.
The continuous variables considered in the study were the nodular volume (NV) and the antero-posterior/cranio-caudal (AP/CC) ratio, whose main descriptive statistical measures are reported in Table 1.
The nodular volume was estimated as per ellipsoidal bodies with the simple geometric equation
where and are the cranio-caudal, antero-posterior and transversal diameters, respectively.
The NV and AP/CC variable distributions were also checked for normality. A statistical analysis carried out via a Shapiro–Wilk test formally proved that both the NV and AP/CC samples did not have a normal distribution, as shown in Table 2, for the different subgroups.
Starting from ultrasound qualitative image description, each patient was assigned a risk class evaluated and stratified according to the AACE/ACE/AME 2016 categories (low/intermediate/high suspicion of malignancy) [26]. The AACE/ACE/AME ultrasound classification was chosen for its simplicity and wide adoption in regional endocrine services, and also because it is similar to the ATA 2015 risk classification [3]. Both tools are considered to perform well in populations with a high prevalence of goiter.
Finally, we also analyzed the assignments to the cytological risk categories, according to the Italian Consensus for the Classification and Reporting of Thyroid Cytology (ICCRTC) [25], which includes six categories: TIR 1/1C, TIR 2, TIR 3A, TIR 3B, TIR 4, and TIR 5 from the lowest to the highest risk of malignity, respectively.
The examiner was blinded to the sex of the analyzed patients and the cytological nature of the nodules, which were matched after the process of imaging review.
To establish whether or not an association exists between sex and any of the categorial variables (that is, any sonographic characteristic except for the nodular volume and the AP/CC ratio), a χ2 statistical test was adopted, while a Wilcoxon signed rank test was used to investigate whether the nodular volumes and the antero-posterior/cranio-caudal ratios of men and women belong to the same populations, since the observed values proved not to be normally distributed in both cases and a parametric test could not be adopted in this condition.
A subgroup analysis was also planned, with a specific focus on younger women of childbearing age. Since data on the gonadal function and fertility status of participants were not available, an empirical cut-off age of 45 years was chosen in order to select a reasonable time frame for probable higher estrogen exposure.
All statistical analyses were performed using the R open-source software package https://www.r-project.org/ [27]. The hypothesis of different ultrasound descriptive elements, distributions of volumes, AP/CC ratios, risk categories and cytological classifications for the two sexes was tested at a statistical significance level α = 0.05 [28].
All procedures involving humans in our study were performed in accordance with the Italian national ethical standards and with the 1964 Helsinki Declaration and its later amendments. Moreover, informed consent for treatment and permission to publish the study results were obtained from the patients.
3. Results
3.1. Sample Demographic Characteristics
A set of 1355 suitable images were obtained by querying the database: 1157 images were selected and 198 discarded because of a lack of adherence to some inclusion criteria. The selected images belonged to 1157 patients: 267 (23%) male and 890 (77%) female.
The mean age μ of the overall sample was 56 years (standard deviation σ = 14), with only a slight difference between males (μ = 59 years, σ = 12) and females (μ = 55 years, σ = 14). The subgroup of younger women (age < 46) consisted of 235 patients (26%), while the number of women older than 45 was 655 (74%).
3.2. Categorical Ultrasound Element Assessment
The percentage values observed for each ultrasound element considered in this study are shown in Table 3. The two columns in the middle concern the whole male and female groups, while the two leftmost columns refer to the younger and older women subgroups, respectively.
Only a few ultrasound aspects of nodules were found to have a statistically significant association with sex: Table 4 summarizes the results of the analysis, also showing the p-values in the different cases.
In particular, the taller-than-wide shape showed higher prevalence in the male group compared to females and their subgroups, though it appeared to be significant at the α = 0.05 level only when men were compared to the whole group of women (6.74% vs. 3.60%, p = 0.027, respectively) and the older women subgroup (6.74% vs. 3.36%, p = 0.02, respectively).
Women, in particular the younger subgroup, also showed a higher proportion of altered nodular margins, either indistinct or lobulated, when compared to men (14.47% vs. 8.61%, p = 0.04).
When the nodular placement was considered, differences in tropism were detected, with a higher distribution of caudal nodes in the male subgroup and upper or isthmic nodes for women (25.57% vs. 20.50%, p = 0.011), caudal nodes in men vs. women (10.02% and 16.10% upper and isthmic nodes, respectively, for women vs. 6.39% and 10.15% in men, p = 0.011), with no difference in right- and left-side localization (distribution was similar, with roughly half of nodules placed on each side for both sexes). In this case, the results were also statistically significant when males were compared to each female subgroup, as shown in Table 4.
Finally, background thyroiditis was detectable in 673 subjects, of which 80% were female patients. The differences were found to be significant between the male and female groups, except when younger women were compared to men, as the fourth-to-last row in Table 4 shows.
3.3. Nodular Volume and AP/CC Ratio Assessment
The nodular volume and AP/CC ratio were computed for 1070 patients (831 women and 239 men). The NV mean value and standard deviation were μm = 108 cm3, σm = 157 cm3 for males and μw = 63 cm3, σw = 83 cm3 for females, respectively.
The values obtained for the AP/CC ratio were μm = 0.69, σm = 0.18 for males and μw = 0.65, σw = 0.18 for females, as already shown in Table 1.
As mentioned before, the nodular volumes and AP/CC ratios were formally proven not to be normally distributed using a Shapiro–Wilk test, so a Wilcoxon signed-rank test was chosen for comparisons between sexes, because it is non-parametric and does not rely on any assumption of normality [28].
With and denoting the median of the nodular volume distribution for men and women, respectively, the test was applied taking as null hypothesis , and as alternate hypothesis either (two-tailed test) or (one-tailed test). The alternate hypotheses, respectively, check whether the medians of the men’s and women’s volume distributions significantly differed, and if the median of the women’s volume distribution was significantly lower than the median of the men’s distribution. The test revealed a very significant statistical difference (p << 0.01) of the volume distribution medians, as shown in Table 5, when all males and females were considered, leading us to reject the null hypotheses in both the two-tailed and one-tailed test conditions. The higher values in men vs. women were thus confirmed to be significant, and the same occurred when males were compared to the two female subgroups.
Similar reasoning was then applied to analyze the AP/CC ratio behavior, and the Wilcoxon test confirmed a statistically significant shift in distributions for all the subgroups considered, as shown in the last two rows in Table 5.
The medians and interquartile ranges (IQRs) of the nodular volumes for the different subgroups are highlighted by the notched boxplot in Figure 2. The boxes show that value distributions are right-skewed in all groups and that the variance in men is larger than in the other groups. The notches (that is, the 95% confidence intervals for the medians) of the groups of men and women are not overlapped: this confirms that there is strong evidence that the shift in volumes is significant when sex is considered. The same occurs when men are compared to the two rightmost boxes in Figure 2, as the data samples come from the same population of women.
In the analysis of the AP/CC ratio, we also remarked a slighter but tangible left shift in the distribution when males were compared to the different subgroups of women. As for NV, the notched boxplots in Figure 3 are a graphical representation of the median and IQR for AP/CC. However, in this case, the boxes do not appear significantly skewed, and the variance for men and women is similar, while the 95% confidence intervals for the medians (notches) do not overlap, thus providing further evidence of the statistical significance of the AP/CC distribution shift.
3.4. Sonographic Risk Classification
A malignity risk class value (low, medium, high) was assigned to each patient according to the AACE/ACE/AME 2016 categories [26], which are based on the co-presence of the following qualitative sonographic signs:
- (1)
- Low-risk class (expected risk of malignancy 1%): cystic or spongiform structure;
- (2)
- Medium-risk class (expected risk of malignancy of 5–15%): mixed or solid structure, lack of strongly hypoechoic echogenicity, lack of PEF with microcalcifications, regular margins, missing taller-than-wide shape, lack of strongly intranodal vascular pattern, elastic or intermediate/in-band stiffness;
- (3)
- High-risk class (expected risk of malignancy of 50–90%): mixed or solid structure, strongly hypoechoic echogenicity, PEF with microcalcifications, irregular margins, taller-tan-wide shape, strongly intranodal vascular pattern, rigid stiffness.
The risk class categorical variables were then analyzed to establish possible distribution differences between men and women. In both the male and female groups, there was a large prevalence of intermediate risk category nodules, as summarized in Table 6. The high-risk category was attributed to 28% of nodules and low-risk to 11% when men were considered. Table 6 also shows that the proportions are not very different in the case of women, with only a slight increment in the intermediate-risk class (63%) and a concomitant reduction in the high-risk class (25%) concerning the older female subgroup. However, none of these differences were found to be statistically significant (third-to-last row in Table 4).
3.5. Cytological Category Matches
A subset of 280 nodule images (24% of the whole sample) that were selected for fine-needle aspiration biopsy did not result in diagnostic judgment (TIR1/1C category) because of an inadequate sampling or a cystic nature. The percentage distributions of the resulting cytological category assignments for the different groups are shown in Table 7.
The benign (TIR2) risk category was attributed to 41% of the examined population, and it was more frequent than expected (43%) in the female group, while the opposite (33%) occurred in the male group. Contrarily, cytological abnormalities, indicating a high probability of malignant neoplasms (TIR4 + TIR5 classes), were more common than expected in the male subgroup (about 9% vs. 6%).
The differences in the TIR2, TIR4 and TIR5 category assignments reported above proved to be statistically relevant (p = 0.01) when assessed by the χ2 test, as shown in the last row of Table 4. Statistical significance was also confirmed (p = 0.02) when all TIR classes were considered (second-to-last row in Table 4).
Finally, in the indetermined class of cytological results (TIR3A + TIR3B), the differences between males and females were much smaller, as shown in Table 7, at least when subgroups were not considered, and were not found to be statistically significant.
4. Discussion
Considering the overall sample, we acknowledge that female sex is far more represented in our study; however, this mirrors the real frequency of access to our thyroid ultrasound service. Although the image database was searched retrospectively to select only nodules that were referred for fine-needle aspiration biopsy, thus involving potential selection biases, the result is worth noting. In fact, gender disparities may affect access to diagnostic examination [29] and other management or procedural aspects, together with dimorphic biological presentation at the time of assessment.
Nevertheless, statistical tests accounted for the initial disproportion between sexes.
Images of patients with low- or intermediate-risk class nodules who did not undergo fine-needle aspiration biopsy were not considered, possibly limiting the applicability and generalizability of the study. However, in our region, benign goiter disease is widely present, often leading to the excessive use of ultrasound investigation and overdiagnosis, while clinically relevant malignancies are not so frequent. Invasive investigations should be avoided if discomfort and procedural risks are not outweighed by the expected benefits. Moreover, in limiting the analysis to suspicious nodules and having a cytological confirmation of each nodule’s nature, we aimed to provide valuable information to implement ultrasound assessment practice and discrimination criteria beyond scientific interest.
The similar distributions between sexes, observed in terms of ultrasound risk classification, confirm that clinical management and referral to cytological examination by physicians were not influenced by gender considerations, but only by nodular morphological presentation. The monocentric design of this study may also be considered a methodological limitation; however, we believe that our sample is representative of the regional population since our university center guarantees full access to patients from different regional and extra-regional provenance. Moreover, inter-operator variability was avoided through the choice of a single observer for all ultrasound images revisions.
The strengths of our study comprise the novelty of the research aim, the vast population recruited and the richness of the ultrasonographic details which were assessed, considering not only B-mode images, but also Color Doppler and elastography assessment, although these techniques did not prove to perform differently in the two sexes in our sample. Furthermore, we believe that the subgroup analysis regarding women of childbearing age is extremely specific for the purpose of this study and cannot easily be found across available evidence and previous studies.
Unfortunately, anthropometric data were not available, and volume values could not be corrected for the body mass index of subjects. The anatomical peculiarities of the male neck, with a narrower angle of the thyroid cartilage, and the propensity for a taller distribution in men might be associated with the taller-than-wide shape, which was more frequently observed in the male group. However, this descriptive sign is quite rare and extremely specific for malignancies. In fact, our study confirmed a higher frequency of nodes classified as either probably or highly probably malignant in men, and this finding seems to be consistent with the ultrasound description mentioned above.
Conversely, younger women, who are likely to be exposed to estrogens, showed larger nodules than their older and (likely) peri- or post-menopausal counterparts did. This observation is coherent with previous studies highlighting the effect of pubertal growth spurts [30] on nodule enlargement, which is more evident in the feminine sex, as well as the similar hormonal effect during pregnancy.
Finally, another hypothesis involves the timing of the first ultrasound assessment and nodular detection. Since usually, women undergo examinations when planning to become pregnant and are more concerned with aesthetical issues, thyroid ultrasound is likely performed more frequently and earlier than in men, thus justifying the earlier detection of smaller nodules. Also, as our sample shows, men are less represented, and ultrasound assessment is probably offered only when symptoms (i.e., compression exerted by nodular enlargement) become present.
The findings regarding nodular margin alterations also point to a possible female peculiarity, especially in the younger subgroup; however, the role of this descriptive element is poorly relatable to the other observations. Nodular enlargement may be associated with indefinite or lobular margins, but the relationship between single descriptive elements was not analyzed since it was not a goal of this study.
In general, we observed significant morphological discrepancies between sexes in terms of the volume and shape of thyroid nodules.
Our findings of a different tropism for nodular collocation in the two sexes are innovative. In fact, to the best of our knowledge, no previous studies have described the relationship between the cranio-caudal spatial location of nodules and patient gender. Upper nodules have been reported to be at high risk of oncogenic shift, because of less efficient venous drainage and higher exposure to reactive oxygen species [31,32]. However, our investigations suggest that men are prone to developing thyroid nodules in the medium–lower part of both thyroid lobes, which are at higher risk of malignant evolution with respect to observations in the female group, regardless of age and childbearing potential. This aspect can likely be explained by the higher prevalence of papillary carcinoma among thyroid-differentiated cancer subtypes, which are known to affect lymphatic dissemination rather than venous. Overall, conclusions cannot be but explorative in this field, and further ad hoc investigations are required to confirm our findings and shed more light on the possible relationships between nodular volume, shape, location and risk of malignancy in men.
Unlike for nodular disease, the relationship between thyroiditis and patients’ gender has already been described in the available literature, with a higher proportion of female subjects who proved to be affected. In this context, the obtained results align with previous data and confirm the representativeness of our sample, although a regional difference in terms of nodular disease epidemiology could still be possible.
A limit of the present study consists in the lack of data about autoimmunity, which could have been of help to confirm diagnoses. However, Hashimoto’s disease is characterized by anti-thyroid peroxidase and/or anti-thyroglobulin antibodies, but the antibody titer cannot always be detected in all forms of inflammatory disease. Thyroiditis could complicate ultrasound nodular assessment when considering specific signs (i.e., echogenicity), and this aspect has to be taken into account. Nevertheless, we did not find significant sex-related differences in the sonographic descriptive assessment, which, in principle, could have been affected by the higher female distribution of background thyroiditis.
5. Conclusions
We conducted a retrospective observational study on thyroid nodule ultrasound presentation in order to identify possible morphological differences in the two sexes, which could correlate with steroidal hormone exposure and the risk of malignant neoplastic evolution.
Our statistical analysis revealed significant differences between the two sexes in terms of nodular volume (higher in males than in females and in men than in childbearing-age women). Nodular shape also provided different distributions: although rare, the taller-than-wide shape was more frequent in men. This finding was evident and statistically significant when considered as either a categorical (taller-than-wide) or as a continuous (AP/CC ratio) variable. In fact, a slight but tangible shift in the AP/CC ratio distribution towards higher values was observed in the male group.
In terms of nodular location, different tropism was detected, with a tendency to involve the medium and lower parts of the thyroid lobe in men, while the upper lobe and isthmus were more affected by nodular disease in women. Finally, although all the examined nodules reported a similar distribution of global sonographic risk classification and were referred for fine-needle aspiration biopsy, the cytological results showed a higher propensity for a malignant nature in men than in women. These findings are explorative and should be confirmed by prospective ad hoc investigations. However, gender’s influence on thyroid nodular disease has been poorly studied, and a deeper knowledge of biological dimorphisms may be useful to improve the available risk scores and endocrine clinical practice.
Author Contributions
Conceptualization, M.V., R.R.G. and R.G.; methodology and formal analysis, M.V.; investigation and resources, M.V., R.R.G., L.P. and S.G.; writing and original draft preparation, M.V.; writing and review and editing, L.P.; supervision, R.G. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
This study was conducted in accordance with the Declaration of Helsinki and approved by the Interorganizational Ethics Committee Città della Scienza e della Salute Torino—AO Ordine Mauriziano Torino—ASL Città di Torino, Torino, Italy, reg. Number 0109911, 5 November 2018.
Informed Consent Statement
Informed consent was obtained from all subjects involved in this study.
Data Availability Statement
The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.
Conflicts of Interest
The authors declare no conflicts of interest.
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Figure 1.
Example of taller-than-wide nodular shape, presented in ultrasound longitudinal scan (left side) and transverse scan (right side) of a thyroid lobe. The antero-posterior (vertical) axis (1) is superior in length to the longitudinal (horizontal) axis (2) of the nodular lesion.
Figure 1.
Example of taller-than-wide nodular shape, presented in ultrasound longitudinal scan (left side) and transverse scan (right side) of a thyroid lobe. The antero-posterior (vertical) axis (1) is superior in length to the longitudinal (horizontal) axis (2) of the nodular lesion.
Figure 2.
Medians and interquartile ranges of nodular volume distributions for males, females, females of childbearing age and post-menopausal females.
Figure 2.
Medians and interquartile ranges of nodular volume distributions for males, females, females of childbearing age and post-menopausal females.
Figure 3.
Medians and interquartile ranges of the AP/CC distributions for males, females, females of childbearing age and post-menopausal females.
Figure 3.
Medians and interquartile ranges of the AP/CC distributions for males, females, females of childbearing age and post-menopausal females.
Table 1.
Central tendency and variability measures of nodular volume and anteroposterior/craniocaudal (AP/CC) ratio.
Table 1.
Central tendency and variability measures of nodular volume and anteroposterior/craniocaudal (AP/CC) ratio.
| Variable | Index | Men | Women (All) | Women (Age < 46) | Women (Age > 45) |
|---|---|---|---|---|---|
| NV (cm3) | Mean (μ) | 108 | 62.78 | 61.58 | 63.22 |
| Standard deviation (σ) | 157.45 | 82.79 | 78.06 | 87.14 | |
| Median (M) | 49.56 | 31.83 | 35.21 | 31.2 | |
| Interquartile range (IRQ) | 118.37 | 69.01 | 75.04 | 66 | |
| AP/CC | Mean (μ) | 0.69 | 0.65 | 0.64 | 0.65 |
| Standard deviation (σ) | 0.18 | 0.18 | 0.19 | 0.17 | |
| Median (M) | 0.68 | 0.63 | 0.61 | 0.64 | |
| Interquartile range (IRQ) | 0.22 | 0.19 | 0.19 | 0.19 |
Table 2.
The statistical significance of the Shapiro–Wilk test for the normality of the NV and AP/CC samples in the different subgroups.
Table 2.
The statistical significance of the Shapiro–Wilk test for the normality of the NV and AP/CC samples in the different subgroups.
| Men | Women (All) | Women < 46 | Women > 45 | |
|---|---|---|---|---|
| NV normal distribution | no (p << 0.01) | no (p << 0.01) | no (p << 0.01) | no (p << 0.01) |
| AP/CC normal distribution | no (p << 0.01) | no (p << 0.01) | no (p << 0.01) | no (p << 0.01) |
Table 3.
Percentage values of ultrasound descriptive elements observed in study population.
| Element | Value | Men | Women (All) | Women (Age < 46) | Women (Age > 45) |
|---|---|---|---|---|---|
| Structure | cystic | 7.87 | 5.73 | 5.53 | 5.81 |
| spongiform | 3.75 | 5.17 | 4.26 | 5.5 | |
| mixed | 19.85 | 22.59 | 23.83 | 22.13 | |
| solid | 68.53 | 66.51 | 66.38 | 66.56 | |
| Echogenicity | iso/hyperechoic | 58.43 | 62.59 | 62.13 | 62.75 |
| hypoechoic | 30.71 | 29.21 | 29.79 | 29 | |
| strongly hypoechoic | 3.37 | 2.81 | 2.98 | 2.75 | |
| anechoic | 7.49 | 5.39 | 5.11 | 5.5 | |
| Margins | regular | 91.39 | 89.33 | 85.53 | 90.69 |
| indistinct or lobulated | 8.61 | 10.67 | 14.47 | 9.31 | |
| PEF | none/macrocalcification | 96.25 | 93.48 | 91.92 | 94.05 |
| yes (microcalcification) | 3.75 | 6.52 | 8.08 | 5.95 | |
| Taller than wide | no | 93.26 | 96.4 | 95.74 | 96.64 |
| yes | 6.74 | 3.6 | 4.26 | 3.36 | |
| Vascular pattern | none | 8 | 5.98 | 6.64 | 5.74 |
| peripheral | 44 | 43.02 | 37.61 | 44.98 | |
| peripheral and intranodal | 42 | 44.43 | 46.9 | 43.54 | |
| strongly intranodal | 6 | 6.57 | 8.85 | 5.74 | |
| Stiffness | intermediate/in-band | 79.52 | 78.53 | 72.73 | 80.74 |
| rigid | 19.28 | 20.75 | 27.27 | 18.27 | |
| elastic | 1.2 | 0.72 | 0 | 0.99 | |
| Extension | extra-thyroid extension | 0.37 | 0.45 | 0.85 | 0.31 |
| subcapsular | 11.99 | 13.93 | 14.47 | 13.74 | |
| none | 87.64 | 85.62 | 84.68 | 85.95 | |
| Side | left | 45.42 | 46.83 | 46.81 | 46.84 |
| right | 54.58 | 53.17 | 53.19 | 53.16 | |
| Position | isthmus | 10.15 | 16.1 | 19.15 | 15.01 |
| upper third | 6.39 | 10.02 | 10.64 | 9.8 | |
| middle third | 57.89 | 53.28 | 50.21 | 54.52 | |
| lower third | 25.57 | 20.5 | 20 | 20.67 | |
| Thyroiditis | yes | 50.94 | 60.34 | 48.51 | 64.58 |
| no | 49.06 | 39.66 | 51.49 | 35.42 |
Table 4.
Statistical significance (α = 0.05) of sex association with considered echography characteristics, nodular malignity and cytological risk classes.
Table 4.
Statistical significance (α = 0.05) of sex association with considered echography characteristics, nodular malignity and cytological risk classes.
| Element | Men–Women (All) | Men–Women < 46 | Men–Women > 45 |
|---|---|---|---|
| Structure | no (p = 0.52) | no (p = 0.72) | no (p = 0.55) |
| Echogenicity | no (p = 0.47) | no (p = 0.68) | no (p = 0.52) |
| Margins | no (p = 0.33) | yes (p = 0.04) | no (p = 0.73) |
| PEF | no (p = 0.23) | no (p = 0.06) | no (p = 0.39) |
| Taller than wide | yes (p = 0.027) | no (p = 0.22) | yes (p = 0.02) |
| Vascularity | no (p = 0.65) | no (p = 0.33) | no (p = 0.66) |
| Stiffness | no (p = 0.67) | no (p = 0.09) | no (p = 0.77) |
| Extension | no (p = 0.41) | no (p = 0.39) | no (p = 0.47) |
| Side | no (p = 0.68) | no (p = 0.75) | no (p = 0.70) |
| Position | yes (p = 0.011) | yes (p = 0.005) | yes (p = 0.04) |
| Thyroiditis | yes (p = 0.006) | no (p = 0.58) | yes (p << 0.01) |
| Nodular malignity risk class | no (p = 0.90) | no (p = 0.38) | no (p = 0.68) |
| Cytology (all TIR classes) | yes (p = 0.02) | no (p = 0.09) | yes (p << 0.01) |
| Cytology (TIR2, 4, 5 only) | yes (p = 0.01) | no (p = 0.94) | yes (p << 0.01) |
Table 5.
Statistical significance of NV and AP/CC distribution shifts with respect to sex obtained with Wilcoxon signed-rank test.
Table 5.
Statistical significance of NV and AP/CC distribution shifts with respect to sex obtained with Wilcoxon signed-rank test.
| Variable | H | Men–Women (All) | Men–Women < 46 | Men–Women > 45 |
|---|---|---|---|---|
| Nodular volume | H1 | yes (p << 0.01) | yes (p = 0.0012) | yes (p << 0.01) |
| H2 | yes (p << 0.01) | yes (p = 0.006) | yes (p << 0.01) | |
| AP/CC ratio | H1 | yes (p << 0.01) | yes (p << 0.01) | yes (p = 0.0012) |
| H2 | yes (p << 0.01) | yes (p << 0.01) | yes (p << 0.006) |
Table 6.
Percentage distribution of ultrasound malignity risk classes in groups and subgroups of study population.
Table 6.
Percentage distribution of ultrasound malignity risk classes in groups and subgroups of study population.
| Malignity Risk Class | Men | Women (All) | Women (Age < 46) | Women (Age > 45) |
|---|---|---|---|---|
| Low | 11.61 | 10.90 | 9.79 | 11.30 |
| Intermediate | 60.30 | 61.46 | 56.60 | 63.21 |
| High | 28.09 | 27.64 | 33.62 | 25.50 |
Table 7.
Percentage values of cytological categories observed in study population.
| Category | Whole Sample | Men | Women (All) | Women (Age < 46) | Women (Age > 45) |
|---|---|---|---|---|---|
| TIR1/1C | 24.13 | 28.84 | 22.72 | 18.38 | 24.27 |
| TIR2 | 41 | 32.96 | 43.42 | 40.17 | 44.58 |
| TIR3A + TIR3B | 28.55 | 29.59 | 28.23 | 31.2 | 27.18 |
| TIR4 | 1.99 | 2.62 | 1.81 | 2.99 | 1.37 |
| TIR5 | 4.33 | 5.99 | 3.82 | 7.26 | 2.6 |
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Valenzano, M.; Giaccherino, R.R.; Pagano, L.; Garberoglio, S.; Garberoglio, R. Ultrasound Assessment and Sexual Dimorphism of Thyroid Nodules: Bringing Gender Medicine to Clinical Practice. Endocrines 2025, 6, 15. https://doi.org/10.3390/endocrines6020015
AMA Style
Valenzano M, Giaccherino RR, Pagano L, Garberoglio S, Garberoglio R. Ultrasound Assessment and Sexual Dimorphism of Thyroid Nodules: Bringing Gender Medicine to Clinical Practice. Endocrines. 2025; 6(2):15. https://doi.org/10.3390/endocrines6020015
Chicago/Turabian StyleValenzano, Marina, Ruth Rossetto Giaccherino, Loredana Pagano, Sara Garberoglio, and Roberto Garberoglio. 2025. "Ultrasound Assessment and Sexual Dimorphism of Thyroid Nodules: Bringing Gender Medicine to Clinical Practice" Endocrines 6, no. 2: 15. https://doi.org/10.3390/endocrines6020015
APA StyleValenzano, M., Giaccherino, R. R., Pagano, L., Garberoglio, S., & Garberoglio, R. (2025). Ultrasound Assessment and Sexual Dimorphism of Thyroid Nodules: Bringing Gender Medicine to Clinical Practice. Endocrines, 6(2), 15. https://doi.org/10.3390/endocrines6020015
