Sex-Specific Cardiovascular Risks and Mortality in Patients with Panhypopituitarism: A Nationwide Cohort Study
Article information
Abstract
Background
Panhypopituitarism is a condition of combined deficiency of multiple pituitary hormones, which requires lifelong hormone replacement therapy. Hormone deficiency or inadequate hormone replacement may contribute to cardiovascular disease. Here, we aimed to investigate the burden of cardiovascular, cerebrovascular diseases and mortality in patients with panhypopituitarism.
Methods
A total of 5,714 patients with panhypopituitarism were enrolled in the Korean National Health Insurance Service database from 2003 to 2020. Panhypopituitarism was defined according to the International Classification of Diseases, 10th Revision (ICD- 10) codes for hypopituitarism, pituitary adenoma, or craniopharyngioma and the continuous prescription of thyroid hormone and glucocorticoids. The risks of all-cause mortality, coronary artery disease (CAD), heart failure (HF), ischemic stroke, and intracranial hemorrhage were compared between patients with panhypopituitarism and age-, sex-, and index year-matched controls.
Results
The mean age of patients with panhypopituitarism and matched controls was 55.1 years, and men accounted for 51.5%. Patients with panhypopituitarism showed significantly higher all-cause mortality compared to matched controls after adjustment for covariates (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.95 to 2.43 in men and HR, 3.09; 95% CI, 2.78 to 3.44 in women). Additionally, there were higher risks of CAD, HF, ischemic stroke, and intracranial hemorrhage in both sexes, except for CAD in men.
Conclusion
Patients with panhypopituitarism have elevated risks of cardiovascular and cerebrovascular diseases as well as increased mortality. These risks are particularly prominent for all-cause mortality in women. Therefore, proactive monitoring for cardiovascular and cerebrovascular complications is required in patients with panhypopituitarism.
INTRODUCTION
Hypopituitarism is characterized by a partial or complete hormone deficiency in the anterior or posterior pituitary gland. The prevalence of hypopituitarism is not well established; however, it is approximately 290 to 455 cases per million individuals, with an incidence of approximately 42.1 cases per million [1]. Gonadotropin deficiency is the most common (87% of cases), followed by growth hormone (GH) deficiency (61%), adrenocorticotropic hormone deficiency (62%), and thyroid-stimulating hormone deficiency (64%) [1]. Panhypopituitarism, specifically, is indicated in the case of all pituitary hormone deficiencies. Panhypopituitarism has various etiologies including pituitary tumors such as pituitary adenomas and craniopharyngiomas, which account for approximately 60%–76% of cases. Peripituitary tumors, surgery, radiation, head trauma, autoimmune diseases, and genetic mutations can lead to a broad spectrum of hormonal deficiencies [2,3].
Among the complications of panhypopituitarism, the increased risk of cardiovascular diseases and an elevated mortality rate are of the greatest concern. Patients with hypopituitarism have a 1.2–4.5 times higher risk of all-cause mortality than the general population [3-5]. Cardiovascular and cerebrovascular diseases are leading risk factors for increased mortality rates in these patients [4-6]. However, the effects of panhypopituitarism on cardiovascular outcomes and mortality have not been comprehensively evaluated in large population-based studies.
Hypopituitarism predisposes individuals to cardiovascular diseases through several mechanisms. GH deficiency leads to an increase in fat content and a decrease in muscle mass, adversely affecting the lipid profile and leading to an increased risk of cardiovascular and cerebrovascular diseases [7,8]. Estrogen deficiency is associated with increased metabolic risks, such as alterations in lipid profiles, and is known to affect endothelial function [9,10]. Low testosterone levels are associated with reduced muscle mass, increased fat mass, and increased insulin resistance [11]. Thyroid hormone levels are directly related to cardiac contractility, and hypothyroidism is associated with changes in lipid profiles such as hypercholesterolemia [12].
The sex-specific impact on cardiovascular outcomes in these patients remains to be elucidated. The impact of sex hormones on cardiovascular health in hypopituitary patients is not fully understood. Estrogen and testosterone can affect cardiovascular risk factors differently, but their specific roles in these patients need further investigation. The interaction between sex and other cardiovascular risk factors such as diabetes mellitus, hypertension, ad dyslipidemia in hypopituitary patients is not wellcharacterized [13]. Generally, women have a higher average life expectancy and relatively lower cardiovascular risk compared to men. However, several studies showed that the increased risk was higher in female patients compared to male patients with hypopituitarism [3-5,14-16].
To address these gaps, we conducted a nationwide, population-based study using data from the Korean National Health Insurance Service (NHIS). Our aims were to (1) delineate the specific cardiovascular outcomes and all-cause mortality attributable to panhypopituitarism; (2) elucidate the sex-specific differences in these risks; and (3) identify the risk factors for cardiovascular outcomes and all-cause mortality in patients with panhypopituitarism. By leveraging a large representative cohort with a long follow-up period and robust statistical methods, we aimed to provide a more comprehensive and contemporary understanding of the cardiovascular and mortality risks associated with panhypopituitarism. These findings may guide the development of tailored risk-management strategies for this patient population.
METHODS
Study design and population
This nationwide, population-based, retrospective cohort study used data from the Korean NHIS. The NHIS is a mandatory health insurance system that covers approximately 97% of the South Korean population and provides comprehensive information on demographic characteristics, disease diagnoses, procedures, surgery, and drug prescription records [17].
Adult patients aged ≥19 years diagnosed with panhypopituitarism were included. For each patient with panhypopituitarism, 10 age-, sex-, and index year-matched controls (n=57,140) were randomly selected from among individuals without International Classification of Diseases, 10th Revision (ICD-10) codes for pituitary disease from 2002 to 2020. A flow diagram of the study participants is shown in Fig. 1. Using the NHIS database, we screened 216,065 individuals diagnosed with pituitary disease between 2003 and 2020. First, we screened patients with pituitary diseases having at least two registrations of ICD-10 codes and special V-codes for rare and intractable disease, irrespective of the type, for panhypopituitarism (E23, E23.0–E23.7), pituitary tumors (D352, D443, C751), craniopharyngiomas (D353, D444, C752), postoperative panhypopituitarism (E893), benign neoplasm of the pituitary gland (D35.2, V162), and Sheehan syndrome (E23.0, V165). Patients diagnosed with hyperpituitarism, acromegaly (ICD-10 code E22), and Cushing disease (ICD-10 code E240) were excluded. Finally, we enrolled 5,714 patients who met the following criteria: (1) patients who received thyroid hormone and glucocorticoid medications for ≥ 180 days within 1 year from the last prescription date and patients who were prescribed glucocorticoid medications for ≥ 335 days annually; (2) patients who received prescriptions for thyroid hormone or glucocorticoids after or within 30 days before the ICD-10 diagnosis of panhypopituitarism; and (3) patients for whom the initial prescription of glucocorticoids and thyroid hormone was within a 180-day interval.
Flow diagram of study subjects. E23- and E22- denote E23 and E22 and their subordinate codes, respectively.
We established a comparison group using a matching methodology. For each identified case of panhypopituitarism, we selected 1:10 age-, sex-, and index year-matched controls from the general population who had undergone appendectomy (Q2861–2863) without any pituitary diseases, yielding a total of 57,140 control subjects. Ethical approval for this study was granted by the Institutional Review Board of Seoul National University Hospital (IRB No. E-2406-062-1543), which waived the requirement for informed consent given the retrospective nature of the study and the use of anonymized data.
Definition of study outcomes
The outcomes of this study were newly diagnosed cardiovascular disease, cerebrovascular disease, and all-cause mortality. Coronary artery disease was defined by the presence of the ICD-10 codes I20–I25 at least once during hospitalization and a record of coronary artery angiography (procedure codes HA607, E0721, E0723, O1640, O1641, O1642, O1647, O1648, O1649, OA640, OA641, OA642, OA647, OA648, OA649, M6551, M6552, M6553, M6554, M6561, M6562, M6563, M6564, M6565, M6566, M6567, M6571, and M6572). Heart failure was defined by the presence of the ICD-10 codes I50, I42, and I43 more than twice in an outpatient setting or at least once during hospitalization. Ischemic stroke and intracranial hemorrhage were defined by the presence of ICD-10 codes (I63–I66 for ischemic stroke and I60–I62 for intracranial hemorrhage) at least once during hospitalization and records of least one brain imaging study or procedure (codes HE101, HE102, HE135, HE136, HE201, HE202, HE235, HE236, HE301, HE302, HE501, HE502, HE535, and HE536). Composite cardiovascular outcome was defined as a combination of coronary artery disease, ischemic stroke, intracranial hemorrhage, and heart failure.
The index date was established as the earliest date on which either thyroid hormone or glucocorticoid hormone treatment was initiated. After a 1-year washout period, we collected outcome data from the index date until December 31, 2020, or the date of death. The follow-up duration was defined as the index date to the date of onset of cardiovascular outcomes, date of death, or December 31, 2020, whichever came first.
Data collection
Baseline demographic and clinical characteristics including age, sex, income level, and comorbidities were analyzed. Hypertension was defined by the presence of the ICD-10 code I10 more than twice in outpatient settings or at least once during hospitalization and prescriptions of antihypertensive drugs for >180 days. Dyslipidemia was defined by the presence of the ICD-10 codes E78 more than twice in an outpatient setting or at least once during hospitalization. Diabetes mellitus was defined by the presence of ICD-10 codes E11–E14 more than twice in outpatient settings or at least once during hospitalization and a prescription of antidiabetic agents or insulin for >180 days.
Brain surgery was defined by at least one record of a surgical procedure code for a craniotomy or transsphenoidal approach (S4631–4639, S4743). Radiation therapy was defined by a record of a procedure code for brain radiotherapy (HD051–059). Similarly, radiosurgery was defined by at least one record of a procedure code for stereotactic radiosurgery of the brain (HD113–114).
Individuals were classified as users of GH, sex hormones (estrogen for females and testosterone for males), and desmopressin if they had a minimum of two prescriptions for these medications recorded within 365.25 days from the index date.
Statistical analyses
The baseline characteristics were compared between the panhypopituitarism and control groups. Continuous variables were presented as mean±standard deviation, whereas categorical variables were presented as number (%). For comparing the continuous and categorical variables, Student t-test and chi-square test was used, respectively.
The incidence rates of cardiovascular disease and all-cause mortality were calculated by dividing the number of events by the total person-years of follow-up. The risks of mortality and new onset cardiovascular outcomes were analyzed using the Cox proportional hazards model. Hazard ratios (HRs) and 95% confidence intervals (CIs) were presented for heart failure, coronary artery disease, ischemic stroke, and intracranial hemorrhage. Initially, adjustments were made for age and index year through inverse probability of treatment weighting (IPTW) (Model 1). Subsequently, additional adjustments were made to model 1 to include baseline hypertension, dyslipidemia, diabetes mellitus, and income (model 2) to enhance the comprehensiveness of the risk analysis. Univariate and multivariate analyses were conducted using the Cox proportional hazards model to determine the impact of various risk factors on cardiovascular outcomes and all-cause mortality in patients with panhypopituitarism. The cumulative incidence of coronary artery disease, heart failure, ischemic stroke, intracranial hemorrhage, composite outcome of cardiovascular disease, and mortality were analyzed using the Kaplan–Meier survival analysis and the log-rank test.
Subgroup analyses were performed to investigate potential effect modifiers, including sex and age (≥40 or <40 years). Sensitivity analyses were performed to assess the robustness of the findings.
All statistical analyses were conducted using R version 4.1 (Foundation for Statistical Computing, Vienna, Austria). Statistical significance was set at P<0.05.
RESULTS
Baseline characteristics
The baseline characteristics of the patients with panhypopituitarism and their age-, sex-, and index year-matched controls are presented in Table 1. A total of 5,714 patients with panhypopituitarism (2,945 men and 2,769 women) were matched with 57,140 controls. The mean age was 55.1±15.1 years, and men accounted for 51.5% in both groups. The panhypopituitarism group showed a higher prevalence of several comorbidities including hypertension (36.5% vs. 31.3%), dyslipidemia (56.4% vs. 41.2%), and diabetes mellitus (17.7% vs. 10.7%) (all P<0.001). Regarding treatment modalities, approximately half (47.7%) of the patients with panhypopituitarism underwent brain surgeries such as transsphenoidal surgery and craniotomy. A smaller proportion of patients underwent radiation therapy (3.2%) or radiosurgery (9.9%). Among patients with panhypopituitarism, 1.9% used GHs; 8.2%, sex hormones; and 31.7%, desmopressin.
Comparison of Baseline Characteristics between Patients with Panhypopituitarism and Matched Controls
Cardiovascular outcomes and all-cause mortality
The HRs for cardiovascular diseases and mortality in patients with panhypopituitarism compared with matched controls are presented in Tables 2, 3. During the median follow-up period of 93.6 months for patients with panhypopituitarism and 105.0 months for controls, the composite cardiovascular outcome was observed in 691 patients with hypopituitarism and 4,590 controls. Among men, the HR for the composite cardiovascular outcome was 1.87 (95% CI, 1.66 to 2.12; P<0.001), after adjusting for age, index year, baseline hypertension, dyslipidemia, diabetes mellitus, and income. Men with panhypopituitarism had increased risks of individual cardiovascular events, including heart failure (HR, 1.30; 95% CI, 1.09 to 1.54; P=0.004), ischemic stroke (HR, 3.36; 95% CI, 2.86 to 3.96; P<0.001), and intracranial hemorrhage (HR, 3.28; 95% CI, 2.10 to 5.11; P<0.001), with the exception of coronary artery diseases (Table 2, Fig. 2).
The Hazard Ratios for Cardiovascular Disease and Mortality in Patients with Panhypopituitarism Compared to Matched Controls: Male
The Hazard Ratios for Cardiovascular Disease and Mortality in Patients with Panhypopituitarism Compared to Matched Controls: Female
Cumulative incidence curves for (A) coronary artery disease, (B) heart failure, (C) ischemic stroke, (D) intracranial hemorrhage, (E) composite cardiovascular outcome, and (F) all-cause mortality in male patients with panhypopituitarism. Cumulative incidence curves represent the proportion of individuals in each group (patients with panhypopituitarism and matched controls) experiencing coronary artery disease, heart failure, ischemic stroke, intracranial hemorrhage, composite cardiovascular outcomes, and all-cause mortality.
Similarly, female patients with panhypopituitarism faced a higher risk of the composite cardiovascular outcome (HR, 1.58; 95% CI, 1.41 to 1.78; P<0.001) and individual events such as coronary artery disease (HR, 1.79; 95% CI, 1.23 to 2.61; P=0.002), heart failure (HR, 1.46; 95% CI, 1.26 to 1.70; P<0.001), ischemic stroke (HR, 1.51; 95% CI, 1.25 to 1.81; P<0.001), and intracranial hemorrhage (HR, 2.33; 95% CI, 1.45 to 3.73; P=0.001) (Table 3, Fig. 3).
Cumulative incidence curves for (A) coronary artery disease, (B) heart failure, (C) ischemic stroke, (D) intracranial hemorrhage, (E) composite cardiovascular outcome, and (F) all-cause mortality in female patients with panhypopituitarism. Cumulative incidence curves represent the proportion of individuals in each group (patients with panhypopituitarism and matched controls) experiencing coronary artery disease, heart failure, ischemic stroke, intracranial hemorrhage, composite cardiovascular outcomes, and all-cause mortality.
During the follow-up period, mortality was reported in 865 patients with panhypopituitarism and 4,018 controls. The risk of all-cause mortality was higher in both male (HR, 2.18; 95% CI, 1.95 to 2.43) and female (HR, 3.09; 95% CI, 2.78 to 3.44) patients with panhypopituitarism compared to that in the matched controls (Tables 2, 3).
In a sensitivity analysis conducted in patients aged ≥40 years (Supplemental Tables S1, S2), the findings were consistent with those of the main analysis, demonstrating a significantly increased risk of the composite cardiovascular outcome and all-cause mortality in patients with panhypopituitarism compared with that in controls.
Risk factors of composite cardiovascular outcome and all-cause mortality
We further investigated factors contributing to composite cardiovascular outcomes and all-cause mortality in patients with panhypopituitarism. In men, age (adjusted HR, 1.03; 95% CI, 1.02 to 1.04), diabetes mellitus (adjusted HR, 1.48; 95% CI, 1.12 to 1.95), and hypertension (adjusted HR, 1.42; 95% CI, 1.11 to 1.81) were found to significantly increase the risk of cardiovascular disease (Table 4). Similarly, in women, age (adjusted HR, 1.04; 95% CI, 1.03 to 1.05), diabetes mellitus (adjusted HR, 1.35; 95% CI, 1.02 to 1.77), and hypertension (adjusted HR, 1.59; 95% CI, 1.25 to 2.01) were significant risk factors for cardiovascular disease, whereas GH therapy (adjusted HR, 0.29; 95% CI, 0.09 to 0.92) reduced this risk (Table 5).
In men, significant risk factors for all-cause mortality included age (adjusted HR, 1.06; 95% CI, 1.05 to 1.07) and radiation therapy (adjusted HR, 3.77; 95% CI, 2.32 to 6.12), whereas pituitary surgery was associated with a significantly reduced risk (adjusted HR, 0.70; 95% CI, 0.57 to 0.85) (Table 6). Conversely, in women, age (adjusted HR, 1.06; 95% CI, 1.05 to 1.07), radiation therapy (adjusted HR, 3.54; 95% CI, 2.18 to 5.75), and desmopressin use (adjusted HR, 1.52; 95% CI, 1.23 to 1.89) were significant factors for all-cause mortality (Table 7).
Risk Factors to All-Cause Mortality in Male with Panhypopituitarism
Risk Factors to All-Cause Mortality in Female with Panhypopituitarism
DISCUSSION
The present nationwide cohort study demonstrated that Korean patients with panhypopituitarism had increased risks of cardiovascular outcomes and mortality compared to age-, sex-, and index year-matched controls. During a median follow-up duration of 7.8 years, both male and female patients with panhypopituitarism had elevated risks of coronary artery disease, heart failure, ischemic stroke, and intracranial hemorrhage compared to their matched controls, except for coronary artery disease in men. In addition, the risk of all-cause mortality was higher in patients with panhypopituitarism than in matched controls, and it was more noticeable in women than in men.
In the present study, both male and female patients with panhypopituitarism exhibited increased risks of heart failure, ischemic stroke, and intracranial hemorrhage compared with controls. Classic risk factors for cardiovascular and cerebrovascular diseases, such as hypertension, diabetes mellitus, and dyslipidemia, were significantly more prevalent in patients with panhypopituitarism. However, this finding persisted after adjusting for major cardiovascular risk factors such as hypertension, diabetes mellitus, and dyslipidemia. Inadequate hormone replacement and newly developed risk factors may contribute to the elevated risk of cardiovascular outcomes. Moreover, this risk may be attributable to body composition changes such as lower lean mass, higher fat mass, endothelial dysfunction, and elevated inflammatory markers in patients with panhypopituitarism, which were not assessed in our study [18-20].
Notably, panhypopituitarism was associated with a strikingly elevated risk of ischemic and hemorrhagic stroke in both men and women. The HRs for ischemic stroke were 3.37 and 1.52 in men and women, whereas those for intracranial hemorrhage were 3.31 and 2.20, respectively. These results align with those of previous studies suggesting that panhypopituitarism may predispose individuals to cerebrovascular events, likely through the aforementioned mechanisms [14,21,22]. Furthermore, intracranial radiation is a well-known risk factor for cerebrovascular diseases [6,14,23]. Intriguingly, the increased risk of stroke was more pronounced in men than in women. Further, the proportion of men who underwent intracranial irradiation was 3.9% (114/2,945), which was approximately 1.5 times higher than the 2.6% (71/2,769) in women (Supplemental Table S3). At baseline, the prevalence of stroke was significantly higher in men than in women, even though the age of men was lower than that of women, and both groups had a similar prevalence of hypertension, dyslipidemia, and diabetes mellitus (Supplemental Table S3). Therefore, there may be other unmeasured risk factors such as smoking, alcohol consumption, body composition, or genetic predisposition.
Intriguingly, the risk of coronary artery disease was higher in female patients with pan-hypopituitarism than in male patients. This pattern of elevated cardiovascular risk among women aligns with previously reported trends [6,13,24]. The lack of protective effect of estrogen against cardiovascular disease in female patients with panhypopituitarism may have significantly contributed to the observed sex discrepancies. Women in the menopausal state demonstrated a higher risk of coronary artery disease than those in the premenopausal state [25], and this risk was mitigated by sex hormone replacement therapy [26]. In this study, sex hormone supplementation was identified as a significant factor for improving composite cardiovascular outcomes in women in the univariate analysis. However, its effect was attenuated in the multivariate analysis, and it did not demonstrate statistically significant results. Further research is needed to evaluate the impact of sex hormone replacement on mortality and composite cardiovascular outcomes in female patients with panhypopituitarism.
On the other hand, the effect of testosterone on cardiovascular outcomes in men remains controversial. Lincoff et al. [27] reported that the effect of testosterone replacement therapy on cardiovascular safety is not inferior to that of a placebo. Paradoxically, this suggests that gonadotropin deficiency in men may have a neutral effect on coronary artery disease, contrary to its effects in women. In addition, a higher risk of ischemic and hemorrhagic stroke in men with panhypopituitarism may be a competing risk factor that prevents them from developing or being diagnosed with coronary artery disease due to increased mortality from stroke events.
Patients with hypopituitarism had an approximately 2-fold higher risk for all-cause mortality than the general population [4-6,14,28,29]. The mortality risks were higher in both men and women with panhypopituitarism than those in their matched controls. Notably, the increased mortality risk was more prominent in women than in men. A meta-analysis reported a standard mortality ratio of 1.33 (95% CI, 0.95 to 1.86) for men and 2.09 (95% CI, 1.51 to 2.89) for women with hypopituitarism [30]. Similarly, female patients with hypopituitarism had a more pronounced mortality risk than male patients [3-6,14,15,31]. This finding may be related to the fact that, in the general population, women have a relatively lower mortality rate than men. Furthermore, the lack of sex hormones in female patients with panhypopituitarism may offset the benefit of a longer life expectancy that women have over men. In the present study, estrogen replacement possibly reduced the risk of cardiovascular complications in the univariate analysis, supporting the aforementioned hypothesis. This outcome has also been consistently observed in other studies, further corroborating these findings [4,32-34]. Moreover, other studies have reported underdiagnosis and undertreatment of hypopituitarism in women as a possible explanation [3,35,36].
Transcranial surgery [4], radiation therapy [4,37], hypogonadism [14], GH deficiency [6,15], craniopharyngioma [4], and arginine vasopressin (AVP) deficiency [37] are associated with increased mortality in patients with hypopituitarism. Certain types of brain surgery, such as the transcranial approach, increase the risk of mortality compared to the transsphenoidal approach [4,30]. However, studies specifically examining the overall risk associated with brain surgery are limited. Brain surgery is associated with reduced mortality in male patients with panhypopituitarism. Patients who undergo brain surgery may have better prognostic profiles than those with unresectable or metastatic pituitary gland tumors. Similar to other studies, we also observed that radiation therapy was a risk factor for increased all-cause mortality. Conversely, sex hormone replacement tended to lower the risk of the composite cardiovascular outcome, although the effect was not statistically significant. This supports the hypothesis that a reduction in female sex hormones contributes to an increase in cardiovascular disease and mortality in patients with panhypopituitarism, thereby creating differences between the sexes. Whether GH supplementation in patients with GH deficiency improves cardiovascular outcomes and mortality remains controversial [28,38-41]. Notably, GH supplementation reduced the risk of adverse cardiovascular outcomes in female patients with panhypopituitarism. While GH supplementation did not show significant effects on cardiovascular outcomes in men, the relatively lower proportion of GH supplementation in men (1.6%) compared to women (2.3%) may have limited our ability to evaluate the impact of GH supplementation on cardiovascular outcomes in the male population. The use of desmopressin, the primary treatment for AVP deficiency, was associated with an increased risk of all-cause mortality in female patients with panhypopituitarism. This finding is consistent with previous studies reporting heightened mortality rates in patients with AVP deficiency [30]. However, the effect of desmopressin on all-cause mortality was not significant in male patients. Notably, desmopressin use was significantly higher in men (37.4%) than that in females (25.6%). Desmopressin use in conditions other than AVP deficiency, such as benign prostatic hyperplasia in men, may mitigate the detrimental effects of AVP deficiency on all-cause mortality.
This study has several strengths. First, we used a large sample of 5,714 patients with panhypopituitarism from the Korean National Cohort NHIS database to analyze the effects of panhypopituitarism on cardiovascular complications and all-cause mortality. Second, age-, sex-, and index year-matched controls were established, allowing for a fully adjusted analysis of the available confounding factors using IPTW. Third, to exclusively identify complications attributable to panhypopituitarism, patients with functional pituitary tumors were excluded. Additionally, for a more accurate assessment of comorbidities, procedure and medication codes were also included along with the ICD-10 diagnostic codes. Fourth, this study compared the effects of pan-hypopituitarism on cardiovascular outcomes in a sex-specific manner. Finally, the robustness of our findings was enhanced by the relatively long median follow-up period of 7.8 years.
This study has several limitations. First, despite adjusting for the major cardiovascular risk factors, the possibility of residual confounding factors could not be excluded. Unmeasured or imperfectly measured confounders, such as lifestyle factors (e.g., diet and physical activity) and body composition, may have influenced the observed associations. Second, the definition of hypopituitarism was based on the operational definitions of prescribed hormone medications, as the NHIS database does not include the results of hormone tests. Accordingly, we restricted patients with hypopituitarism to those who were using glucocorticoids and levothyroxine simultaneously, which corresponded to patients with panhypopituitarism. Third, because of the reliance on claims data to assess medication utilization, accurately capturing the prescriptions of medications not covered by national insurance, such as testosterone or oral contraceptives, is challenging. This difficulty is compounded by the lack of analysis of medication dosages. Consequently, the effects of sex hormone replacement therapy on cardiovascular outcomes and mortality have not been fully evaluated. Fourth, the exact causes of death could not be determined. Therefore, it was challenging to confirm whether an increase in cardiovascular risk directly contributed to an increase in mortality. Finally, the generalizability of the findings to other populations or healthcare systems may be limited, considering the potential differences in genetic backgrounds, environmental factors, and healthcare delivery models.
In conclusion, this nationwide population-based study provides compelling evidence that panhypopituitarism is associated with an increased risk of cardiovascular and cerebrovascular diseases as well as all-cause death. A notable sex-specific trend was observed in patients with panhypopituitarism. Male patients were more prone to ischemic and hemorrhagic stroke, whereas female patients had a higher likelihood of coronary artery disease and a greater overall mortality risk. To mitigate the high morbidity and mortality observed in patients with panhypopituitarism, it is crucial to effectively manage cardiovascular risk factors and optimally replace deficient hormones. Future research should further elucidate the underlying mechanisms contributing to the observed sex disparities, paving the way for personalized precision medicine approaches to optimize outcomes in patients with panhypopituitarism.
Supplementary Material
Supplemental Table S1.
The Hazard Ratio for Cardiovascular Disease and Mortality in Male Patients ≥40 Years with Panhypopituitarism Compared to Controls (n=2,395)
Supplemental Table S2.
The Hazard Ratio for Cardiovascular Disease and Mortality in Female Patients ≥40 Years with Panhypopituitarism Compared to Controls (n=2,383)
Supplemental Table S3.
Comparison of Baseline Characteristics between Male and Female Patients with Panhypopituitarism
Notes
CONFLICTS OF INTEREST
Jung Hee Kim is a deputy editor of the journal. But she was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
AUTHOR CONTRIBUTIONS
Conception or design: C.H.A., K.K., J.H.K. Acquisition, analysis, or interpretation of data: S.S.P., H.J., C.H.A., M.J.P., Y.H.K., K.K., J.H.K. Drafting the work or revising: S.S.P., M.J.P., Y. H.K., K.K., J.H.K. Final approval of the manuscript: K.K., J. H.K.
Acknowledgements
This study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare of the Republic of Korea (Project No. HI22C0049).
This research was conducted using a customized database provided by the Korean National Health Insurance Service (KNHIS). We express our gratitude to KNHIS for the access to the data, which enabled this study.