The cohort was divided into females and males, and all data were analyzed to assess differences between sexes. Continuous data were presented as mean ± standard deviation (SD) if normally distributed, otherwise as median and range. Shapiro – Wilks test was used to assess normal distribution. For continuous variables, unpaired t-tests were applied when normality was met, and the Mann-Whitney U test was used otherwise. Categorical data were presented as a count (n) and percentage (%). If the analysis included missing values, the total sample size and corresponding percentages were reported. Comparisons of categorical variables were performed using Fisher’s exact test. Kaplan-Meier estimates were employed for time-to-event analyses.

Statistical significance was defined as P < 0.05. All statistical analyzes were conducted using R, version 4.4.2 (Vienna, Austria. URL: https://www.R-project.org/).

Parameters related to surgery and preoperative treatment are shown in Table 1 . Prior to surgery, the majority of patients underwent initial treatment with alpha-blockers, mostly doxazosin or phenoxybenzamine, and one with phentolamine. Of the remaining cases not receiving alpha-blockers, four were discovered during surgery for suspected alternative tumors, two had died before treatment initiation, one was managed palliatively with no PPGL symptoms, and the remaining five were not treated due to mild biochemical and asymptomatic disease or patient refusal. The median duration of preoperative alpha-blocker therapy was 46.5 days (range: 0–360) in females and 60 days (range: 0–330) in males (P = 0.89). Alpha-blockers were used in 94.4% of females and 93.2% of males (P = 0.77). The majority of these patients were treated with doxazosin (82.4% of females vs 78.4% of males, P = 0.59). Patients who were treated more than two decades ago primarily received preoperative therapy with phenoxybenzamine (12.0% of females vs 13.6% of males P = 0.83). The mean dose of doxazosin was 22.3 ± 13.6 mg for females and 26.0 ± 13.9 mg for males (P = 0.07). In the group of phenoxybenzamine, the mean dose was 50.8 ± 19.8 mg for females and 87.5 ± 75.7 mg for males (P = 0.04). Eight patients (4.1%) did not undergo surgery due to the following reasons: two patients refused surgery, two had PPGL with extensive metastases, one presented with widespread adenocarcinoma, one was treated palliatively for multiple morbidities and two died before surgery. Where feasible, these patients were managed with alpha-blockers. Among those not having surgery, three (2.8%) were female, and five (5.7%) were male (P = 0.47).

Females underwent laparoscopic surgery less frequently than males (55.2% vs 71.1%, P = 0.03). In instances where laparoscopic surgery was initiated but could not be completed due to encountered intraoperative challenges, the operating surgeon could opt for conversion to open surgery. Conversions were required in eight females (7.6%) and four males (4.8%) (P = 0.55). Open surgery was performed in cases where other minimally invasive surgical approaches were deemed not to be suitable. A total of 39 (37.1%) females and 20 (24.1%) males underwent open surgery (P = 0.06). Tumor sizes were similar between females and males (49.1 ± 27.6 vs 48.1 ± 27.4 mm, P = 0.50).

The data regarding complications during surgery showed no difference between sexes (17.1% vs 25.3%, P = 0.21). Likewise, length of stay after surgery (LOS) showed no difference between females and males (4 [2-44] vs 5 [2-75] days, P = 0.24).

Associations between sex and glycemic disturbances are presented in Table 2 . At diagnosis, Secondary/T2DM was present in a similar proportion in females and males (28.7% vs 23.9%, P = 0.52). When all glucose abnormalities – including patients with prediabetes, Secondary/T2DM and one patient with type 1 diabetes mellitus– were assessed, prevalence between females and males was also similar (38.9% vs 37.5%, P = 1).

Postoperatively, females demonstrated a non-significant lower prevalence of Secondary/T2DM than males (5.6% vs 12.9%, P = 0.12). Females achieved Secondary/T2DM remission at a higher rate than males (23.4% vs 11.8%, P = 0.04). Measuring overall glucose improvement, females and males were quite similar (24.3% vs 18.8%, P = 0.39).

Blood pressure parameters are presented in Table 3 . Preoperative systolic and diastolic blood pressure (SBP and DBP) was similar between sexes ( Table 3 ). Postoperative SBP had a tendency to be lower in females than in males (122.8 ± 15.3 vs 126.3 ± 14.1, P = 0.06). Postoperative DBP showed similar levels between sexes. SBP and DBP decrease after surgery were similar between sexes.

Improved blood pressure, defined as a postoperative reduction of SBP and DBP of at least 10mmHg and/or a reduction in antihypertensive medication, was comparable between females and males (83.8% vs 84.9%, P = 1). Regarding antihypertensive medication use, females and males exhibited similar results, preoperatively (1.66 ± 1.06 vs 1.73 ± 1.07, P = 0.86) and postoperatively (0.52 ± 0.83 vs 0.57 ± 0.96, P = 0.97). The mean reduction of antihypertensive medications was similar between sexes (1.16 for females vs 1.21 for males, P = 0.86).

Follow-up time was similar between females and males (11.2 ± 9.1 vs 10.7 ± 8.3 years, P = 0.75). There was no difference in the number of patients developing PPGL metastases in females (10.2%) and in males (10.2%) (P = 1). Also, metastases developed at approximately the same time following surgery (4.26 ± 3.45 in females vs 5.91 ± 3.86 years in males, P = 0.36). In cases of metastasis, patients were primarily treated with alpha-blockers, surgery and/or peptide receptor radionuclide therapy (PRRT) with either lutetium or meta-iodobenzylguanidine (MIBG). In total, 20.4% of patients died (15.7% of females vs 26.1% of males, P = 0.08). Two male patients died prior to surgery due to PCC complications and to cardiomyopathy secondary to myeloma respectively. The remaining deaths occurred years later. Among all reported deaths, the cause of death was identified in 36 cases. Deaths attributed to by PPGLs were similar between sexes (25.0% of female deaths and 15.0% of male deaths, P = 0.68) ( Table 1 ). A Kaplan-Meier survival analysis was used to evaluate survival following diagnosis between sexes ( Figure 1 ). The survival curve demonstrated no statistically significant difference between sexes (P = 0.59).

The final dose of phenoxybenzamine was higher in males than in females. In addition, males tended to need higher final doses of doxazosin. It can be viewed as a limitation that not all patients were treated with the same alpha-blockage. If all patients with phenoxybenzamine had been treated with doxazosin, the current preferred choice of alpha-blocker due to fewer side-effects (1), a significant difference in dose between female and male patients might have been observed. While no study have discussed potential differences in dose of alpha-blockage between sexes, females have been found to be more sensitive to alpha-adrenergic receptor stimulation (20). Moreover, females using anti-hypertensive medications achieved greater blood pressure control than males at the same dose, potentially due to natural differences in pharmacokinetics and pharmacodynamics (21). We hypothesize that this applies to alpha-blockers as well.

Our study found that a quarter of patients had preoperative Secondary/T2DM, with no significant sex-specific difference, which is also observed in most other studies (22, 23), but not all (4). However, there is a great variation in Secondary/T2DM prevalence as some studies have reported preoperative Secondary/T2DM to be existent in up to 50% of PPGLs cases (24). Interestingly, although we could not find any sex difference in the overall glucose improvement, females displayed a significantly higher rate of Secondary/T2DM remission after surgery. Studies have shown higher preoperative metanephrine concentrations and older age to be risk factors for persistent diabetes after surgery (25–27). Furthermore, lower body mass index and a duration of disease shorter than 3 years were predictive factors for Secondary/T2DM remission (27). To our knowledge, none has shown sex being a factor.

Our findings are interesting when considering potential complications after surgery. Araki et al. showed that 21% out of 49 patients undergoing surgery for PPGL, experienced severe post-excisional hypoglycemia (28). This considered, we can speculate that females may be more likely to suffer severe hypoglycemia after tumor removal, due to the recovery of insulin secretion after tumor surgery (23). However, our data did not support this, as we observed similar complication risk after surgery between sexes, also supported by others (29). Nevertheless, clinicians need to be aware of hypoglycemia as a complication after surgery, maybe particularly among female patients.

PPGL is considered a potentially curable cause of secondary hypertension (7). We observed a dramatic decrease in blood pressure in both sexes. No significant difference was observed between females and males in any blood pressure measurements, which is in accordance with others (30).

No sex difference was found in the long-term risk of developing PPGL recurrence or metastases with 10.2% of both females and males developing PPGL metastases with time. This finding is consistent with the estimated overall metastasis risk shown in previous research stating that approximately 10-20% of all patients with PPGLs develop metastases (31). Genetic predisposition is a well-established predictor of PPGL recurrence (32); however, the prevalence of positive genetic panels and the mean follow-up time were comparable between sexes in our cohort, thereby effectively ruling out genetic predisposition and follow-up time as potential confounders influencing risk of metastasis (32). Hamidi et al. also found similar risk of metastasis between sexes (33). Furthermore, a multicenter observational study conducted by Bechmann et al. showed that 6.7% of patients with PCC had developed distant metastasis with no sex difference (34). A review article comparing different cohorts also described absence of sex-related differences in long-term outcome of PPGLs, even when considering primary malignant or recurrent PCCs (35). In contrast, Plouin et al., comparing 129 patients, showed that metastatic PPGLs were more prevalent in males preoperatively, however, the risk of subsequent recurrence was not found to be associated with sex (30).

PGLs have been found to have more than double the metastatic potential compared to PCCs (36). Thus, having more females with PGLs in our study, one might have expected a higher incidence of metastases amongst females. This may suggest that other factors beyond tumor type and genetic variants influence metastatic potential. Future research aimed at assessing metastatic potential individually between PCC and PGL comparing sex may be relevant.

Mortality was found to be higher than that reported in some long-term follow-up studies (37, 38). This may be explained by the higher mean age at diagnosis, larger tumor size, as well as a higher frequency of metastasis in our study than those compared. Survival among patients with PPGL was similar between the sexes. In our study, age at diagnosis and follow-up time were similar between sexes with some being followed for up to 20 years. The similar survival is particularly interesting, considering males have a shorter average lifespan (39). Therefore, it would be possible to expect that males with PPGL would have a shorter survival compared to female patients. In contrast, our findings may suggest a potential for higher mortality in females with PPGL. This observation possibly reflects females being more likely to have PGLs in our study, which have been shown to harbor a more malignant potential and be more difficult to surgically excise (9). However, a retrospective single center study by Raber et al., found that females with PPGLs had longer survival (40). Moreover, Plouin et al. demonstrated that sex was not associated to the PCC-free survival (30).

This study has several strengths with the most notable one being that it is the first study to compare sexes in management and outcome in patients with PPGL. With PPGLs being particularly rare diseases, gathering a cohort of this size from a single center is difficult. However, the main limitation lies in its retrospective design, introducing potential biases, including selection bias due to the exclusion of patients with substantial missing data. Retrospective studies are also prone to confounders that can only be acknowledged and addressed in the discussion. Although this cohort is large relative to the topic, it may still have power issues in some analyses. Furthermore, having the strength of being the first study to address the topic of sex differences in management and outcomes also limits the critical depth since there will be absence of comparable studies. Another shortcoming of this study, related to it being retrospective, was that a small proportion of patients had missing data in certain parameters which were impossible to collect in hindsight.

Moreover, with this study being single center, we reduced confounders such as variability in clinical protocol, enhancing the reliability of all patients having similar prerequisites for management and treatment. Conversely, this acts as a limitation since we are unable to prove that it is applicable to a broader population. Finally, many of our patients with PPGLs missed genetic results. This is partially explained by a stricter indication to evaluate the genetics in PPGLs previously but also partially explained by the fact that many of our patients had been included in a study of genetics in PPGLs and the samples had not been analyzed at the time of the analysis of this cohort.