Impact of Female Sex and Mild Cortisol Secretion on Coagulation Profile in Adrenal Incidentalomas

Abstract

Context

Studies describing the coagulation profile in adrenal adenomas still need to be added.

Objective

We explored how sex and mild autonomous cortisol secretion (MACS) affect coagulation parameters in patients with adrenal adenomas.

Design

Cross-sectional study.

Methods

From January 2019 until April 2023, participants in the Impact of Adrenal IncidenTalomas and Possible Autonomous Cortisol Secretion on Cardiovascular and Metabolic Alterations trial (NCT04127552) diagnosed with adrenal adenoma were categorised according to the 1 mg overnight dexamethasone-suppression test (1 mg-DST). Coagulation parameters were evaluated, and two-way ANOVA was used to elucidate the cortisol-by-sex interaction.

Results

Of 153 patients screened, 90 were enrolled (62.2% female, mean age 62 ± 10 years): 41 with non-functioning adrenal tumour (1 mg-DST ≤ 1.8 µg/dL), and 49 with a MACS (1 mg-DST > 1.8 µg/dL). Platelet counts were higher in the MACS group (P = .01). Regression analysis identified female sex (B = 36.603, P = .011), 1mg-DST (B = 0.238, P = .042), and younger age (B = −1.452, P = .038) as independent predictors for elevated platelet count. In patients with MACS, women exhibited higher levels of procoagulant factors fibrinogen (P = .004) and factor VIII (P < .001), and coagulation inhibitors protein C (P = .003) and antithrombin III (P = .005) than males. No differences were observed in the non-functioning adrenal tumour group, providing a cortisol-by-sex interaction regarding fibrinogen (P = .047), factor VIII (P = .046), and protein C (P = .028).

Conclusion

Our findings revealed a worse coagulation profile in women with MACS, underscoring the need for a sex-specific approach in clinical practice to manage thrombotic risks effectively. Dedicated prospective studies are needed to validate and integrate these findings into clinical strategies for thromboprophylaxis.

Nowadays adrenal incidentalomas are increasingly detected due to the widespread use of high-resolution imaging techniques, with a prevalence of 5% to 7% in adults, increasing with age [1-6]. The majority of these lesions are benign adenomas originating from the adrenal cortex. Adrenal adenomas are classified based on morning serum cortisol levels following 1 mg overnight dexamethasone-suppression test (1 mg-DST) and, remarkably, up to 50% exhibit mild autonomous cortisol secretion (MACS), defined as 1 mg-DST > 1.8 µg/dL (50 nmol/L) [7, 8]. While often asymptomatic, MACS is linked to an elevated risk of morbidity, mortality, and, importantly, cardiovascular complications and thromboembolic events [9-18]. The latter association is especially pronounced in the context of overt hypercortisolism, where patients with Cushing's syndrome (CS) exhibit a significantly heightened risk of venous thromboembolic events (VTE) due to hypercoagulability [19-27]. However, despite that a recent study revealed a nonnegligible prevalence of thromboembolic events among individuals with MACS, the impact of MACS on coagulation parameters has been relatively underexplored [10]. The interplay between sex differences and cardiovascular health outcomes is increasingly recognized as a pivotal area of medical research [28, 29], particularly regarding hypercoagulability and thrombotic events [28, 30-32], highlighting the necessity for gender medicine to tailor personalized, effective treatments [33]. Notably, women, especially those under 65 with MACS, face worse outcomes compared to men, underscoring a complex interplay of sex, hormonal levels, and hypercortisolism [10]. Nevertheless, the specific impact of mild hypercortisolism on coagulation parameters and the extent to which sex-specific differences contribute are yet to be fully clarified. This underscores the critical need to further deepen the mechanisms driving these sex differences to inform risk assessment and personalized management strategies in patients with mild hypercortisolism.

This study aims to bridge this knowledge gap by examining coagulation parameters in asymptomatic patients with adrenal adenoma, focusing on the contributions of MACS and investigating potential sex-specific differences.

Material and Methods

Patient Selection

This is a prospective observational study (Impact of Adrenal IncidenTalomas and Possible Autonomous Cortisol Secretion on Cardiovascular and Metabolic Alterations, NCT04127552) on consecutive patients aged 18 to 80 years diagnosed with adrenal incidentaloma and referred to the endocrine outpatient clinic of the Department of Experimental Medicine, Policlinico Umberto I, Sapienza University of Rome. Only patients with adrenal adenoma were included in the study. Exclusion criteria included a confirmed diagnosis of overt CS, defined according to the guidelines as the presence of hypercortisolism (evaluated by the 1 mg-DST, 24 hours urinary free cortisol (UFC), and/or late-night salivary cortisol) along with specific clinical signs of cortisol excess (eg, easy bruising, facial plethora, and proximal myopathy) [34, 35]. Patients with a diagnosis of adrenal masses other than nonaldosterone-secreting adrenocortical adenomas, such as primary aldosteronism, pheochromocytoma, adrenocortical carcinoma, adrenal metastasis, myelolipoma, congenital adrenal hyperplasia, and other rare adrenal diseases were excluded, along with patients using drugs or affected by diseases known to impact on corticosteroid metabolism or cortisol secretion (ie, glucocorticoids, hormone replacement therapy or hormonal contraceptive, thyrotoxicosis, bowel diseases, chronic renal failure, chronic hepatic disease, depression, alcoholism, eating disorders, rheumatologic and hematological diseases). Postmenopausal women receiving any form of estrogen replacement therapy were excluded from the study. Moreover, patients taking anticoagulants with a history of thrombosis or myocardial infarction and an active malignancy were also excluded from the study. In accordance with the most recent European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors [10], all patients were stratified for cortisol secretion as follows: patients with 1 mg-DST above 1.8 µg/dL (>50 nmol/L) were labeled as MACS, whereas those 1 mg-DST ≤ 1.8 µg/dL (≤50 nmol/L) were classified as non-functioning adrenal tumors (NFATs). In all patients with MACS, the diagnosis of overt CS was excluded based on physical examination and at least 2 repeated UFC measurements. Therefore, UFC values were calculated as the mean of at least 2 independent measurements.

Anthropometric measurements included body mass index (BMI), calculated by dividing weight (in kg) by squared height (in m²). Arterial hypertension was defined by systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg on repeated evaluations and/or by the reported use of antihypertensive medication [36]. Type 2 diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance were diagnosed according to fasting glucose or hemoglobin A1c as per European Society of Cardiology/European Association for the Study of Diabetes guidelines or reported use of antidiabetic drugs [37]; insulin resistance (IR) was defined by the Homeostasis Model Assessment of Insulin Resistance ≥ 2.5 [38]. Dyslipidaemia was diagnosed according to lipid profile as per European Society of Cardiology/European Association for the Study of Diabetes guidelines or reported use of hypolipidemic drugs [37]. As smoking is a well-established thromboembolic risk factor, with an immediate increase in the risk of thrombosis for current smokers and a gradual decrease over time for former smokers, we have taken these variables into account and defined “current smoker” as an individual who was smoking any tobacco at the time of the study and “former smoker” as an individual who had quit smoking although they had smoked in the past [39-41]. Adrenal lesions were discovered by computed tomography or magnetic resonance imaging, and all of them were larger than 10 mm and displayed magnetic resonance or computed tomographyCT features consistent with benign adenoma. When bilateral adenomas were found, the diameter of the largest adenoma was considered. This study was approved by the Local Ethics Committee of Sapienza University in Rome (reference number 5279) and was conducted in accordance with the Declaration of Helsinki (1964) and its subsequent amendments. All enrolled patients provided their written informed consent to participate in the study.

Laboratory Analyses

All biochemical tests were performed locally at the study center. Serum cortisol was measured by radioimmunoassay, using Beckman Coulter reagents (ref. IM1841, RRID: AB_2894408). The measurement range (from analytical sensitivity to the highest calibrator) is 8.60 to 2000 nM. The high specificity of the assay was confirmed by extremely low or undetectable cross reactivity against other naturally occurring steroids (aldosterone, corticosterone, cortisone, 11-desoxycortisol, progesterone, etc.) or therapeutic drugs that may be present in patient samples (eg, prednisolone, prednisone, spironolactone). Complete blood count, coagulation markers factor V (FV), factor VII (FVII), factor VIII (FVIII), fibrinogen, prothrombin time (PT), international normalization ratio (INR), activated partial thromboplastin time (aPTT) and coagulation inhibitors such as antithrombin III (ATIII), protein C anticoagulant (protein C), and protein S were performed. PT, aPTT, and INR were measured by standard methods. Standard 1-stage clotting assays using a specific factor-deficient plasma as substrate were used to determine FV, FVII, and FVIII (Siemens Medical Solutions Diagnostics). AT III and protein C activity were quantified by chromogenic determination (Siemens Medical Solutions Diagnostics). Protein S activity was quantified with a clotting assay (Siemens Medical Solutions Diagnostics).

Statistical Analysis

Distribution of continuous variables was assessed with the Shapiro–Wilk test; linearity was established by visual inspection of a scatterplot. Categorical variables are expressed as percentage and frequency; continuous variables are reported as mean and SD or median and interquartile range (IQR, 25th-75th percentile) as appropriate per distribution of data. For group comparisons unpaired Student's t-test, Mann–Whitney, χ², or Fisher's exact test were used as appropriate. A backward stepwise predictor selection was applied to the linear regression analysis, starting with a full model and gradually eliminating any predictor that was not significant to the model. Multiple regression analysis was run to test the effects of variables selected based on the known association with increased VTE [42] (1 mg-DST, sex, BMI, age, smoking habits) on the likelihood of predicting coagulation parameters showing significant group differences. Multicollinearity among the predictor variables was identified by assessing the values of tolerance and variance inflation factor. Two-way ANOVA was conducted to assess the main effects of the 2 independent variables (cortisol secretion, based on 1 mg-DST, and sex) and their interaction effect on the dependent variable (coagulation parameters) and was interpreted as significant at P-value <.05 and possible for .05 ≤ P-value <.10. Post hoc analyses (Bonferroni correction) were performed to compare specific levels of the independent variables, when adequate. A log transformation or reciprocal transformation was used for skewed data, as appropriate. Outliers, constituting less than 2% of the sample, were detected using the IQR method in the boxplot and removed to ensure more accurate ANOVA results. Homogeneity of variances was assessed by Levene's test. Statistical analyses were performed using SPSS, version 29 (IBM, Chicago, IL) and GraphPad Prism 10.0 software package (GraphPad Software, La Jolla, CA).

Results

Characteristics of the Whole Cohort

Between September 2019 and April 2023, out of 153 patients with adrenal incidentaloma referred to our department, 90 qualified for the coagulation study inclusion criteria (Fig. 1). The mean age of the participants was 62 ± 10 years, with a median BMI of 25.7 kg/m² (IQR 23.6-29.9). In our cohort, all patients indicated that their gender corresponded to their sex registered at birth; all were Caucasian. Among these, 56 (62.2%) were female, aged between 49 and 71 years; all were postmenopausal with a median estradiol 10 pg/mL (IQR 10-17) and a mean FSH 51.1 ± 8.7 mIU/mL, and none were on hormone replacement therapy. All males were eugonadal with mean testosterone levels of 18.7 ± 1.5 nmol/L. According to BMI, 36.7% presented with overweight and 23.3% presented with obesity. The overall prevalence of cardiovascular comorbidities was 60% for arterial hypertension and 59% for dyslipidemia. Impaired glucose metabolism was found in 47 patients (52%), including 8.9% with type 2 diabetes mellitus and 43.3% with either impaired fasting glucose, impaired glucose tolerance, or insulin resistance. The maximum diameter of the adrenal lesion was 20.0 mm (IQR 14.0-31.0). According to the number of adrenal lesions, 21 (23.3%) had bilateral adenomas, of which 6 (28.6%) had more than 2 nodules on at least 1 side. A summary of characteristics of the whole cohort is shown in Table 1.

Subgroup Analysis According to 1 mg-DST

Forty-one patients were classified as NFAT (45.5%) and 49 as MACS (54.5%). Both groups were comparable in terms of sex, age, BMI, and smoking habits (current/former smokers) distributions. There were no significant differences in the frequency of comorbidities between groups. Notably, MACS had larger adrenal lesions (27.0 mm, IQR 19.0-37.5) compared to NFAT (16.5 mm, IQR 12.0-21.5; P < .001), lower ACTH levels (16.6 pg/mL, IQR 11.2-20.9 vs 20.3 pg/mL IQR 15.6-34.5, P = .009), and a higher prevalence of bilateral lesions compared to NFAT (32.7% vs 12.2%, P = .043), as shown in Table 1. UFC levels were below the upper limit of normal (ULN) in both groups, with no significant differences observed (0.60 × ULN [0.40-0.70] vs 0.55 × ULN [0.46-0.66], P = .675). Additionally, no correlation between age and the 1 mg-DST was observed (r = 0.144, P = .182). No differences in coagulation markers and inhibitors were found between MACS and NFAT, except for the platelets count, which was higher in the MACS compared to the NFAT group (242 ± 72 × 10⁹/L vs 209 ± 54 × 10⁹/L, P = .01), as shown in Table 2. Additionally, a univariate analysis across the whole cohort identified a positive relationship between 1 mg-DST and platelet count (r = 0.223; P = .038), as shown in Fig. 2.

To ascertain if a set of clinically and biochemically important parameters could independently predict total platelet count, a backward linear regression analysis was performed. The analysis included factors considered potentially associated with increased risk for VTE (ie, 1 mg-DST, sex, BMI, age, smoking habits) [42]. The model was significant (r² = 0.169, P = .009) revealing that female sex had the most substantial influence (B = 36.603, P = .011) on total platelet count. Additionally, a higher 1 mg-DST (B = 0.238, P = .042) and a younger age (B = −1.452, P = .038) were also identified as significant, albeit less influential, predictors. Notably, smoking habits or BMI did not appear to contribute to platelet total count. All coefficients and complete results are reported in Table 3. No differences in coagulation parameters were observed between patients with unilateral lesion and those with bilateral lesions.

Subgroup Analysis According to sex

We therefore sought to analyze sex differences across the entire cohort. Despite both groups being comparable in terms of age, BMI, smoking habits (current/former smokers) distributions, prevalence of MACS, and bilateral adenomas, females displayed a less favorable coagulation profile than males, characterized by a higher platelets count (242 ± 59 ×10⁹/L vs 202 ± 71 × 10⁹/L, P = .003), fibrinogen (3.4 g/L [IQR 3.0-3.9] vs 3.0 g/L [IQR 2.7-3.7], P = .043), FV (132 ± 30% vs 119 ± 25%, P = .044), FVII (130% [IQR 104-174] vs 107% [IQR 93-126], P = .002), and ATIII (104% [IQR 93-116] vs 93% [IQR 87-100], P = .006), and lower INR (0.96 ± 0.05 vs 0.99 ± 0.06, P = .023) and aPTT (28.4 second [IQR 26.5-30.5] vs 30.4 second [IQR 27.9-32.4], P = .017) (Table 4).

Noteworthy, a further stratification by sex within the MACS and NFAT groups revealed significant differences in the MACS group alone, where females confirmed a less favorable coagulation profile than males, as detailed in Supplementary Table S1 [43]. Conversely, no sex differences in the coagulation profile were observed in the NFAT group.

Interaction of Cortisol Secretion and sex on the Coagulation Profile of Adrenal Adenomas

To elucidate the potential interaction between the effects of cortisol secretion excess, based on 1 mg-DST, and sex (cortisol-by-sex interaction) on coagulation parameters, a 2-way ANOVA was performed. As opposed to patients with NFAT (Fig. 3 and Table 5), the analysis showed that, in patients with MACS, women exhibited higher levels of both procoagulant factors, including fibrinogen [females 3.58 ± 0.76 g/L vs males 2.85 ± 0.24 g/L; Δ_Sex 0.73 g/L, 95% confidence interval (CI) 0.24 to 1.22; P = .004] and FVIII (females 147 ± 1% vs males 117 ± 1%; Δ_Sex 1.26%, 95% CI 1.11 to 1.42; P < .001) and coagulation inhibitors, such as protein C (females 128 ± 1% vs males 99 ± 1%; Δ_Sex 1.28%, 95% CI 1.09 to 1.50; P = .003) and ATIII (females 105 ± 1% vs males 93 ± 1%; Δ_Sex 1.1%, 95% CI 1.0 to 1.2; P = .005), compared to males (Fig. 3 and Table 5). This resulted in a cortisol-by-sex interaction on fibrinogen (P = .047), FVIII (P = .046), and protein C (P = .028) and a possible interaction for ATIII, which approached statistical significance (P = .060). Other parameters, including platelets count, PT, INR, aPTT, FV, FVII, and protein S did not show significant differences (Supplementary Fig. S1 [44] and Table 5).

Discussion

This study investigates coagulation parameters in a homogeneous cohort of patients with adrenal adenomas, exploring the influence of sex and cortisol levels on hemostasis. While the presence of mild hypercortisolism on its own may not markedly alter the coagulation system, a distinct sex-related difference is observed within the MACS group, with females presenting a worse profile compared to their male counterparts.

Previous research has established a link between hypercortisolism and an enhanced coagulation system, particularly evident in CS, which typically involves an alteration of the intrinsic coagulation pathway, in particular an increase in FVIII, and increased levels of coagulation inhibitors (ie, ATIII, protein C, and protein S) as a compensatory response [22]. In line with this, the most recent consensus on the diagnosis and management of CS suggests that clinicians and surgeons should be aware of the altered coagulation profile in patients with CS for up to 1 year following surgical remission and should consider administering anticoagulation therapy on a case-by-case basis [45].

A recent meta-analysis on more than 7,000 subjects with CS revealed a substantially increased risk (OR 18) of VTE compared to the general population. As expected, the majority of the subjects were female (78%), yet no direct link was found between the severity of hypercortisolism and VTE incidence or coagulation profiles. Notably, this analysis did not explore differences in outcomes based on the interaction between sex and cortisol levels [23]. On the contrary, results from the ERCUSYN study indicated that both male sex [hazards ratio (HR) 2.11] and higher UFC levels (HR 1.06) significantly increased the risk of VTE occurrence. However, data on UFC levels in patients with VTE were only available in 50% of patients, and, importantly, men exhibited higher UFC levels than women [19]. Nevertheless, nowadays it is recognized that MACS and CS are distinct entities, with the transition from MACS to CS a rare occurrence [7, 46-49]. However, both conditions share increased cardiovascular and metabolic risk compared to NFAT, suggesting that even a mild cortisol excess might contribute to these risks.

In our cohort, the significant difference in platelet counts between MACS and NFAT groups, despite remaining within the normal range, points toward a potential elevated thrombotic risk associated with the former, albeit this interpretation warrants dedicated studies to confirm any clinically significant implications. However, the absence of significant differences in other coagulation markers implies that mild hypercortisolism alone may not drastically alter coagulation function. Our regression analysis, which considered variables typically associated with hypercoagulability, such as age, sex, BMI, smoking habits, and 1 mg-DST, specifically highlighted that younger (albeit postmenopausal) women with MACS presented with higher platelet counts, independent of typical risk factors like obesity or smoking habits. Several studies have reported a reduction in platelet counts with aging [50, 51]. Our analysis confirms these findings, showing that for every year of decrease in age, there was an average increase of 1.5 × 10⁹/L in platelet count. Additionally, each 10 nmol/L (∼0.4 µg/dL) increase in 1 mg-DST was associated with a rise of 2.5 × 10⁹/L in platelet count. Notably, females had approximately 40 × 10⁹/L more platelets than their male counterparts, suggesting that female sex may be the most significant factor influencing platelet count in our study. Our results align with a retrospective study on over 300 patients with adrenal adenomas including NFA, MACS, and CS that found that women had higher platelet counts compared to men. However, the authors did not observe any difference across the spectrum of cortisol secretion [52]. Importantly, in this study, the groups differed in terms of age, with patients diagnosed with CS being on average 20 years younger than those with MACS and NFAT. Unfortunately, the analysis was not corrected by age [52]. Therefore, our finding underscores the nuanced relationship between cortisol levels and coagulation, suggesting that specific demographic and clinical features, including sex, age, and mild cortisol secretion, might contribute to an adverse coagulation profile. This complexity suggests the need for additional research to explore whether healthcare providers should develop personalized treatment plans for patients with these specific risk factors, aiming for more precise and effective care.

Following the latest guidelines by the European Society of Endocrinology/European Network for the Study of Adrenal Tumors on adrenal incidentalomas management, interpreting the 1-mg DST results as a spectrum rather than a binary outcome emphasizes the nuanced impact of cortisol levels on thrombotic risk [7]. Our study reinforces the concept that the degree of hypercortisolism, rather than the mere diagnosis of MACS, should be considered an additional risk factor for an altered coagulation profile, especially in women. This highlights the importance of thorough thrombotic risk assessments in patients with adrenal adenoma, and especially females, eligible for adrenalectomy [53] to potentially guide the implementation of perioperative anticoagulation strategies aimed at minimizing surgical thrombotic complications.

Our results complement and potentially elucidate the observation from the NAPACA outcome study [10]. In this large retrospective study with a 7-year median follow-up duration, the authors confirmed cardiovascular comorbidities to be more frequently observed in patients with MACS than in NFAT. Notably, there was a nonnegligible proportion of venous thrombosis and pulmonary embolism, suggesting the presence of a prothrombotic risk in this population. Importantly, the study found that the increase of all-cause mortality and a high prevalence of associated cardiometabolic comorbidities in patients with MACS was sex- and age-dependent [10]: women younger than 65 years of age with MACS had the worst outcomes (HR 4.39) suggesting a sexual dysmorphism among adrenal adenomas [29].

Aligned with these findings, our study further enriches the discussion on sex disparities in patients with adrenal incidentaloma. Our analysis reveals a distinct coagulation profile in females with MACS, despite remaining within the normal range, marked by elevated levels of fibrinogen, FVIII, protein C, and ATIII, and their male counterparts underscoring the critical role of sex in modulating coagulative risks. Notably, such distinctions were not evident in the NFAT group, emphasizing the predominant influence of cortisol levels on coagulation dynamics and suggesting an intricate interplay between cortisol secretion and sex. Determining whether the observed alterations in coagulation patterns in our cohort translates into a clinically significant increase in the incidence of VTE requires confirmation through dedicated prospective studies. However, several reports demonstrated a correlation between increased plasma concentrations of both FVIII and fibrinogen with increase of VTE risk [54-58]. A case-control study involving more than 300 participants revealed that subjects with FVIII levels above 150% experienced a nearly 5-fold increase in the risk of VTE compared to those with normal levels. Additionally, the study estimated that each 1% increase in FVIII levels over the normal range raised the odds ratio for VTE by 1.9% [54]. This finding extends to the recurrence of VTE [56]. Applying these insights to our cohort, a 34% difference in FVIII levels between females and males in the MACS group (Supplementary Table S1 [43]) suggests a 65% heightened risk of VTE in women with MACS compared to their male counterparts. These findings highlight the clinical significance of our data and support a refined sex-specific approach in assessing and managing the coagulation risks in patients with adrenal incidentaloma. This could potentially guide the integration of these findings into clinical strategies for thromboprophylaxis.

Previous research has reported sex-related disparities in coagulation markers, often linking differences in platelet activity to sex hormones [59-61]. Estrogens have been shown to stimulate prostacyclin production, leading to higher nitric oxide levels and reduced platelet aggregation [60, 62]. However, our study exclusively included postmenopausal women, indicating that the differences observed in coagulation parameters between females with MACS and those with NFAT could stem from other complex sex-specific interplays between cortisol and coagulation factors, beyond the hormonal changes observed in menopause. The precise mechanisms underlying these observations remain to be fully elucidated, calling for additional studies.

Although our study provides valuable insights, it is important to acknowledge its limitations, including a relatively small sample size and the lack of a control group (patients without adrenal adenomas), which makes it challenging to provide definitive data. In this study, we evaluated the contribution of major general thromboembolic risk factors such as smoking, sex, and BMI, as well as population-specific factors like the degree of hypercortisolism. However, several studies highlight that lifestyle factors, particularly dietary habits, can also influence coagulation status [63-65]. Therefore, the lack of investigation into this aspect represents an additional limitation of the study. Moreover, individual variations in drug metabolism or biological response may affect responses to the 1 mg-DST, and thus, the unavailability of dexamethasone serum concentrations represents another limitation of our study [66]. Additionally, being a single time point evaluation, we are unable to capture changes over time and demonstrate if the observed relationships among variables are constant over time (ie, after adrenalectomy, medical treatment, active follow-up). Therefore, further prospective studies are necessary to confirm whether sex differences in coagulation profiles among patients with adrenal adenomas lead to an increased incidence of VTE. Identifying additional thromboembolic risk scores that account for these differences could be beneficial, as current risk assessment models used in clinical practice primarily apply to hospitalized patients, exhibiting weak predictive accuracy for VTE [67]. Despite these limitations, our study provides a detailed analysis of coagulation parameters in patients with adrenal adenoma, representing a pioneering exploration of the potential for sex-based differences in this context. This aspect carries clinical implications, as it opens the possibility of the inclusion of this condition among known risk factors for VTE (ie, smoking, hormone replacement therapy or hormonal contraceptive, etc). Our data suggest redefining antithrombotic prophylaxis with a sex-specific approach and considering MACS in females as an additional risk factor warranting intervention in specific settings (ie, long flights or periods of immobilization). This lays the groundwork for further studies aimed at understanding whether patients with adrenal adenomas may benefit from antithrombotic prophylaxis and whether it requires greater attention compared to the general population.

Conclusions

While coagulation function in CS has been extensively investigated, there remains a paucity of data on the coagulation status in patients diagnosed with adrenal incidentaloma. Generally, patients with adrenal adenomas, encompassing both NFAT and MACS, do not exhibit clinically significant alterations in coagulation parameters. However, considering sex differences, females diagnosed with MACS exhibit a worse coagulation profile. Nowadays, the consideration of sex dimorphism should be a key factor in personalized management strategies in patients diagnosed with adrenal incidentaloma. Such an approach has the potential not only to minimize the rising healthcare costs associated with this condition but also to underscore the importance of incorporating sex as a crucial factor in the assessment and management of adrenal incidentalomas and potentially integrate these findings into clinical strategies for thromboprophylaxis. Further prospective studies involving larger cohorts are essential to thoroughly elucidate the relationship between hypercortisolism and hypercoagulability in patients diagnosed with adrenal incidentaloma.

Funding

The research leading to these results has received funding from the European Union Next Generation EU through the Italian Ministry of University and Research under PNRR M4C2 I1.3 Project PE_00000019 “HEAL ITALIA” to A.M.I., CUP (B53C22004000006) and by the Precision Medicine to target Frailty of Endocrine-metabolic Origin (PROMETEO) project (NET-2018-12365454) by the Italian Ministry of Health. The views and opinions expressed are those of the authors only and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the European Commission can be held responsible for them.

Author Contributions

R.P., M.M., and I.B. contributed to the study conception and design. I.B., A.T., D.F., D.D.A., and V.H. contributed to material preparation and data collection. R.P. and I.B. performed statistical analysis. The first draft of the manuscript was written by I.B. and reviewed by M.M., R.P., and A.M.I. All the other authors reviewed, edited, and commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Disclosures

A.M.I. discloses principal investigator role in sponsored trials and consultancies for Recordati, Corcept, HRA pharma, Neurocrine. All the other authors have no relevant financial or nonfinancial interests to disclose.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Consent to Participate

The study was conducted in accordance with the Declaration of Helsinki, and all participants gave their written informed consent.

Ethical Approval and Research Involving Human Participants

The study was approved by the Ethics Committee of Sapienza University in Rome (reference number 5279).

References

Abbreviations

 
• 1 mg-DST

  1 mg overnight dexamethasone-suppression test

 
• aPTT

  activated partial thromboplastin time

 
• ATIII

  antithrombin III

 
• BMI

  body mass index

 
• CI

  confidence interval

 
• CS

  Cushing's syndrome

 
• FV

  factor V

 
• FVII

  factor VII

 
• FVIII

  factor VIII

 
• HR

  hazards ratio

 
• INR

  international normalization ratio

 
• IQR

  interquartile range

 
• MACS

  mild autonomous cortisol secretion

 
• NFAT

  nonfunctioning adrenal tumor

 
• protein C

  protein C anticoagulant

 
• PT

  prothrombin time

 
• UFC

  urinary free cortisol

 
• ULN

  upper limit of normal

 
• VTE

  venous thromboembolic events

Author notes