Glucocorticoid replacement therapy after retroperitoneal laparoscopic unilateral adrenal adenoma resection in patients with non-cortisol secreting tumors: a retrospective cohort study
Introduction
In recent years, the prevalence of hypertension and the detection rate of adrenal tumors have increased, a trend further amplified since 2020 by the use of chest computed tomography (CT) for investigating coronavirus disease 2019 (COVID-19) (1-3). Cushing syndrome and primary hyperaldosteronism are common adrenal diseases, while adrenal cortical carcinoma, and pheochromocytoma are less common. Adrenal Cushing’s syndrome is caused by an adrenal tumor that produces hypercortisolism and requires glucocorticoid supplementation following resection of the tumour to prevent adrenal insufficiency, condition associated with significant morbidity (4,5).
The indication for steroid replacement in patients undergoing unilateral adrenalectomy for non-cortisol-secreting adrenal tumors remains unclear (6). Few studies have examined whether glucocorticoid replacement (GR) therapy is required after laparoscopic adrenocortical adenoma resection, or whether there is any correlation between preoperative biochemical indicators and postoperative cortisol function (7,8). Thus, this study sought to evaluate the incidence of postoperative adrenal insufficiency in patients with unilateral adrenocortical adenoma, and the need for GR therapy. The preoperative clinical characteristics and the secretion parameters of adrenal biochemical examinations before and after surgery may be used to predict decreases in postoperative cortical function, avoid postoperative cortisol over replacement, and identify patients who require early treatment for adrenal cortical insufficiency. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-24-469/rc).
Methods
Clinical data
From January 2020 to January 2022, 65 patients who underwent retroperitoneal laparoscopic adrenal adenoma resection at the Department of Urology, Shanxi Bethune Hospital, were analyzed and followed up for 2 months. All patients were monitored for signs and symptoms of hypocortisolism in the immediate and delayed post operative phase. In total, 35 patients were included in the final cohort of this study.
Based on their follow-up results, the patients were allocated to the no GR group, which comprised 28 patients, and the GR group, which comprised 7 patients. During the postoperative follow-up, 7 patients were given hormone supplementation. The criteria for inclusion in the GR group were the presence of adrenal insufficiency and treatment with glucocorticoids within one month after surgery. Before surgery, the antihypertensive drugs of 35 patients were changed to calcium channel blockers or alpha-adrenergic receptors that do not interfere with the renin-angiotensin-aldosterone system. The study was approved by the Ethics Committee of the Shanxi Bethune Hospital (approval notice number: YXLL-2021–066) and informed consent was obtained from all the patients (or their relatives). The research complies with the provisions of the Declaration of Helsinki (as revised in 2013).
Inclusion criteria
To be eligible for inclusion in this study, the patients had to meet the following inclusion criteria: (I) have non-functional adrenal adenomas or primary hyperaldosteronism, primary aldosteronism diagnosis was based on the last international guidelines of primary aldosteronism (9). Non-functional adrenal adenoma was defined as a benign tumor of the adrenal gland that do not secrete active hormones (such as aldosterone, cortisol, etc.); (II) have normal blood and urinary catecholamine assay results; (III) have CT scan results showing homogeneous and low-density adrenal masses, which is consistent with the imaging features of adrenal cortical adenoma; (IV) have histopathological confirmation of adrenal adenoma; (V) have no signs or symptoms of hypercortisolism preoperatively; and (VI) 1 mg low-dose dexamethasone suppression test was negative (≤1.8 µg/dL).
Exclusion criteria
Patients were excluded from the study if they met any of the following exclusion criteria: (I) had abnormal blood and urinary catecholamine assay results; (II) had multiple adrenal nodules, bilateral adrenal disease, pheochromocytoma, hypercortisolism, adrenocortical carcinoma, pituitary adenoma, or abnormal cortisol rhythm; (III) mild autonomous cortisol secretion (MACS), MACS is defined as a condition characterized by the autonomous secretion of cortisol that is insufficient to produce overt Cushing’s syndrome but may still have clinical implications (dexamethasone suppression test >1.8 µg/dL); (VI) had incomplete data; (V) were taking medication, or had a disorder that affects cortisol metabolism or cortisol secretion (e.g., thyroid disease, chronic renal failure, chronic liver disease, depression, alcoholism, rheumatism, or a blood disorder); and/or (VI) had pathological findings indicating adrenal cysts, adrenal metastases, teratomas, myeloid lipomas, adrenal tuberculosis, etc.
Observation indicators
The following preoperative patient data were collected: gender, age, tumor side, maximum diameter of the tumor, hypertension (yes/no), diabetes (yes/no), and heart rate. Biomedical evaluations, included those of the eosinophil percentage, eosinophil count, serum potassium, serum sodium, cortisol levels at 8 am, 4 pm, and 12 am, adrenocorticotropic hormone (ACTH) level, and renin-angiotensin II-aldosterone (recumbent/standing position), were also conducted. Postoperative data, included the serum cortisol level at 8 am, plasma ACTH level at 8 am, the percentage of eosinophils, and the number of eosinophils and for 3 days after surgery, was collected. For testing, samples were collected according to standard procedures. In terms of quality control, the quality of sample collection, processing and storage was reliable. The internal quality control of detection was guaranteed by quality control materials and instrument calibration maintenance, and the external quality control was guaranteed by external quality assessment activities.
Statistical analysis
All statistical analyses were performed using SPSS software version 25.0 (IBM Corp., Armonk, NY, USA). A P value <0.05 was considered statistically significant. Continuous variables are expressed as the mean ± standard deviation. The independent sample t test was used to compare ratios between the two groups, and the chi-squared test was used to compare the rates. Repeated-measures analysis of variance was used for the repeated measurement data of the two groups. First, a spherical test was performed. A P<0.05 indicated that the measured values at each time point did not meet the spherical test. To test the within-subject effect, Greenhouse-Geisser correction was needed to correct the results; a P>0.05 indicated that the measured values at each time point met the sphericity test, and the results of the sphericity test were used in the within-subject effect test; a simple effect analysis was performed when there was an interaction; a least significant difference test was used for pairwise comparisons at different levels. The graphing software used was GraphPad Prism software. All the tests were two-sided, with a significance level set at P<0.05.
Results
Clinical characteristics
In total, 35 patients were evaluated and followed up for 2 months, of whom 12 were male and 23 were female. None of the patients had surgical complications, received blood transfusions, or underwent conversion to open surgery. In addition, none of the patients received cortisol hormone treatment during surgery or for 3 days after surgery. The patients were divided into two groups: the no GR group, which comprised 28 patients; and the GR group, which comprised 7 patients. The patients in the GR group displayed hypocortisolemic symptoms in the clinic and were treated with GR therapy as shown in Table 1. Of these 7 patients, 1 had hyperkalemia, 2 had postoperative hypotension, 3 had gastrointestinal symptoms, and 1 had facial and lower extremities edema.
Table 1
| Clinical manifestation symptoms | GR group (7 cases) | Glucocorticoid time after surgery |
|---|---|---|
| Hyperkalemia | One case | 30 days |
| Hypotension | Two cases | 4 days |
| Nausea and anorexia | Two cases | 15 days |
| Edema with face and lower limbs | One case | 6 days |
| Nausea, fatigue and diarrhea | One case | 15 days |
GR, glucocorticoid replacement.
Comparison of the clinical data obtained from the two groups before surgery
In this study, except for the ACTH level which showed a statistically significant difference between the two groups (P=0.04), there were no statistically significant differences between the two groups in terms of their preoperative laboratory data, including the maximum tumor diameter, hypertension, diabetes, heart rate, eosinophil percentage, eosinophil count, serum potassium, serum sodium, cortisol levels at 8 am, 4 pm, and 12 am, and renin-angiotensin II-aldosterone (as assessed in the recumbent/standing position) (P>0.05). The results are shown in Table 2.
Table 2
| Basic preoperative data | No GR group (n=28) | GR group (n=7) | Reference range | χ2/t | P |
|---|---|---|---|---|---|
| Gender (female:male) | 17:11 | 6:1 | 1.553 | 0.21 | |
| Age (years) | 48.96±13.09 | 53.85±8.55 | −0.935 | 0.36 | |
| Functional adenoma:non-functional adenoma | 10:18 | 2:5 | 0.127 | 0.72 | |
| Side parting (left:right) | 19:9 | 6:1 | 0.875 | 0.35 | |
| Tumor maximum diameter (cm) | 2.44±1.13 | 2.21±0.82 | 0.321 | 0.75 | |
| Number of hypertension cases | 19 | 5 | 0.033 | 0.86 | |
| Number of diabetes cases | 6 | 2 | 0.162 | 0.69 | |
| Systolic blood pressure (mmHg) | 146.14±16.54 | 146.65±19.21 | 0.02 | 0.98 | |
| Diastolic blood pressure (mmHg) | 92.17±22.39 | 93.42±20.36 | −0.243 | 0.81 | |
| Heart rate (sub/min) | 78.01±14.37 | 74.14±16.32 | 0.656 | 0.52 | |
| Eosinophils (%) | 2.91±1.43 | 1.08±0.49 | 0.4–6.0 | 1.59 | 0.12 |
| Eosinophils (109/L) | 0.17±0.06 | 0.06±0.02 | 0.02–0.52 | 1.524 | 0.14 |
| Blood potassium (mmol/L) | 3.71±1.32 | 3.65±0.85 | 3.5–5.3 | 0.314 | 0.76 |
| Blood sodium (mmol/L) | 135.89±23.88 | 141.35±21.36 | 137–147 | −0.598 | 0.55 |
| Cortisol 8:00 am (μg/dL) | 11.76±3.87 | 14.55±4.61 | 6.7–22.4 | −1.643 | 0.11 |
| Cortisol 4:00 pm (μg/dL) | 6.91±3.27 | 8.71±2.75 | <10 | −1.331 | 0.19 |
| Cortisol 12:00 am (μg/dL) | 3.35±1.52 | 5.73±2.33 | <10 | −1.978 | 0.056 |
| ACTH (pg/mL) | 39.20±16.46 | 22.18±10.94 | 7.2–63.4 | 2.151 | 0.04 |
| Renin supine position (pg/mL) | 4.07±1.86 | 6.63±2.48 | 4–24 | −1.597 | 0.12 |
| Renin standing position (pg/mL) | 13.01±6.56 | 18.15±8.01 | 4–38 | −0.857 | 0.40 |
| Aldosterone supine position (pg/mL) | 153.17±70.56 | 165.67±65.32 | 10–160 | −0.285 | 0.78 |
| Aldosterone standing position (pg/mL) | 192.48±72.73 | 271.62±80.45 | 40–310 | −1.178 | 0.25 |
| Aldosterone renin ratio supine position | 38.44±18.64 | 27.16±11.32 | 1.263 | 0.22 | |
| Aldosterone renin ratio standing position | 21.61±8.92 | 19.26±9.63 | 0.276 | 0.79 | |
| Angiotensin II standing position (pg/mL) | 116.99±50.32 | 83.85±27.96 | 49–252 | 0.578 | 0.57 |
| Angiotensin II supine position (pg/mL) | 97.49±34.65 | 121.02±40.41 | 25–129 | 0.649 | 0.52 |
Continuous variables are presented as mean ± standard deviation. GR, glucocorticoid replacement; ACTH, adrenocorticotropic hormone.
Comparison of the laboratory data between the two groups following surgery
The postoperative data, including the serum cortisol level at 8 am, plasma ACTH level at 8 am, eosinophil percentage, and eosinophil count, of the patients in the two groups were collected on the first day, second day and third day after surgery. All the data were subjected to statistical analysis (Table 3, Figure 1).
Table 3
| Observational indicators | Groups | Preoperative | Day 1 after surgery | Day 2 after surgery | Day 3 after surgery | F value | P value |
|---|---|---|---|---|---|---|---|
| Cortisol 8 am (μg/dL) | No GR group | 11.77±3.87 | 7.48±2.95 | 11.92±4.62 | 13.46±5.06 | 8.778* | <0.001 |
| GR group | 14.56±4.61 | 4.26±1.05 | 2.07±0.71 | 3.1±1.23 | |||
| F value | 25.037* | 8.225# | <0.001 | ||||
| P value | <0.001 | ||||||
| ACTH (pg/mL) | No GR group | 33.68±11.37 | 21.97±9.78 | 17.59±5.07 | 29.12±10.04 | 3.439* | 0.04 |
| GR group | 22.18±8.94 | 6.88±2.49 | 7.99±3.79 | 8.13±4.22 | |||
| F value | 12.033* | 0.469# | 0.64 | ||||
| P value | 0.001 | ||||||
| Eosinophils (%) | No GR group | 1.78±0.69 | 0.24±0.09 | 0.37±0.18 | 1.36±0.51 | 12.14* | <0.001 |
| GR group | 1.14±0.46 | 0.35±0.11 | 0.58±0.17 | 1.67±0.76 | |||
| F value | <0.001* | 1.392# | 0.25 | ||||
| P value | 0.99 | ||||||
| Eosinophils (109/L) | No GR group | 0.17±0.06 | 0.03±0.01 | 0.04±0.01 | 0.12±0.04 | 9.151* | 0.001 |
| GR group | 0.06±0.02 | 0.04±0.01 | 0.04±0.02 | 0.21±0.09 | |||
| F value | 0.006* | 4.182# | 0.02 | ||||
| P value | 0.94 | ||||||
*, F statistic and P value for main effect; #, F statistic and P value for interaction effect. GR, glucocorticoid replacement; ACTH, adrenocorticotropic hormone.
Compared to the preoperative levels, significant differences were observed in the postoperative cortisol levels at 8 am on the first day, second day and third day after surgery between the two groups (F=8.778, P<0.001). In the no GR group, the postoperative cortisol level decreased on the first day after surgery; however, their cortisol levels gradually increased on the second and third days after surgery. The cortisol levels of the GR group showed a downward trend for 3 days after surgery. The postoperative cortisol levels of the GR group were significantly lower than those of the no GR group for 3 days after surgery (F=25.037, P<0.001). There was an interaction effect between the time factor and the grouping factor (F=8.225, P<0.001) ( Figure 1A).
Compared to the preoperative levels, significant differences in the postoperative ACTH levels at 8 am were observed between the two groups on the first day, second day, and third day after surgery (F=3.439, P=0.04). The postoperative ACTH levels of the no GR group were decreased on the first day and second day after surgery, and began to increase on the third day. The ACTH levels of the GR group showed a downward trend over the 3 days following surgery, with no significant upward trend. The postoperative ACTH levels of the GR group were significantly lower than those of the no GR group for 3 days after surgery (F=12.033, P=0.001). There was no interaction between the time factor and the grouping factor (F=0.469, P=0.64) (Figure 1B).
In relation to the eosinophil percentage and eosinophil count, the level of both these indicators differed significantly preoperatively and postoperatively (F=12.14, P<0.001, F=9.151, P=0.001). However, no significant differences were observed in the postoperative eosinophil percentages and counts between the no GR and GR groups (F<0.001, P=0.99, F=0.006, P=0.94). In addition, no interaction between the time factor and the grouping factor was observed in terms of the eosinophil percentage (F=1.392, P=0.25), but an interaction was observed in terms of the eosinophil count (F=4.182, P=0.02) (Figure 1C,1D).
Discussion
The most important findings from the study include that cortisol levels tend to be low immediately following surgery following adrenalectomy, but return to normal in a couple of days, in patients with low cortisol supplemental glucocorticoids may be necessary to prevent any symptoms of adrenal insufficiency, and a mild increase in the percentage and count of eosinophils when the cortisol level was lower.
The most dangerous medical complication of adrenal surgery is adrenal crisis due to insufficient cortisol. If not diagnosed and treated, hypocortisolism can be life threatening. GR therapy is the standard treatment for hypercortisolism and cortical cancer after surgery, especially if the hypothalamic-pituitary-adrenal axis is abnormal. Hypocortisolism has also been observed in some patients who undergo unilateral adrenal adenoma surgery, but it is difficult to identify which of these patients will require GR therapy postoperatively (7).
Routine GR therapy can be administered postoperatively to patients with unilateral adrenalectomy to reduce the incidence of hypocortisolism; however, GR therapy can cause certain complications and have adverse effects in the clinic, including hyperglycemia, neuropsychiatric symptoms, osteoporosis, elevated glucose, and cardiovascular disease (10-12). GR therapy can also adversely affect the immune system by regulating the function of natural killer cells, leading to increased infection rates (10,13). Meanwhile, withdrawal syndrome due to GR therapy withdrawal may be related to glucocorticoid overdose, and the non-specific symptoms of withdrawal syndrome include anorexia, weight loss, nausea and vomiting, headache, lethargy, fever, myalgia, arthralgia, skin desquamation, and orthostatic hypotension (14,15). This study sought to identify which patients require GR therapy to avoid glucocorticoid overdose after surgery. We found that patients with postoperative hypocortisolism had lower cortisol levels at 8 am and plasma ACTH levels.
Generally, the low-dose ACTH stimulation test or insulin hypoglycemia test is considered the “gold standard” for the diagnosis of adrenal insufficiency (16). Serum cortisol levels at midnight or the cortisol and ACTH levels after stimulus with corticotropin-releasing hormone can be used to evaluate postoperative adrenal function (17). However, most diagnostic indicators cannot be widely used due to a lack of operational consistency and accuracy in the results. Patients’ postoperative basal cortisol levels (at 8 am) and symptoms after surgery had been proven to be predictors of adrenal insufficiency (18,19), but the ability of basal cortisol levels alone to detect adrenal insufficiency has been shown to be limited (20). In this study, both the serum cortisol levels at 8 am and the ACTH levels after surgery were significantly lower in the patients who needed GR therapy (F=25.037, P<0.001; F=12.033, P=0.001).
The symptoms of hypocortisolism include fatigue, anorexia, gastrointestinal symptoms, such as nausea and diarrhea, hyponatremia, weight loss, myopathy, neuropsychiatric symptoms, hypotension, hypoglycemia, eosinophilia, hyperkalemia, acidosis, and hypercalcemia (20-23). The eosinophil count in blood is often used as a marker of the biological effects of glucocorticoids and adrenal cortical function; an increased level of eosinophils might represent a slight decrease in the adrenal cortical reserve (21,24). The results of this study showed that while there was no significant difference in the percentage and count of eosinophils between the two groups, a mild increase in the percentage and count of eosinophils was observed in the GR group when the cortisol level was lower. These statistical results had poor sensitivity, but had a certain specificity. Thus, further research should be conducted to determine if the percentage and count of eosinophils could serve as auxiliary observation indicators.
This study had certain limitations. First, due to the strict inclusion and exclusion criteria, the sample size was small. Second, the follow-up time of the study was short. Thus, larger sample size studies with longer follow-up times need to be conducted at multi-centers to validate the results of this study.
Conclusions
This study preliminarily showed that postoperative cortisol and ACTH levels can be used to identify patients at an increased risk of hypocortisolism after unilateral adrenal adenoma surgery, and to guide the use of GR therapy. Patients’ postoperative cortisol levels at 8 am and plasma ACTH levels may play an important role in predicting hypocortisolism after unilateral adrenal adenoma surgery.
Acknowledgments
The authors would like to thank the Department of Urology at the Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, for providing the original data.
Funding: None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-24-469/rc
Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-469/dss
Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-469/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-469/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Ethics Committee of the Shanxi Bethune Hospital (approval notice number: YXLL-2021–066). The research complies with the provisions of the Declaration of Helsinki (as revised in 2013). All patients (or their relatives) provided written informed consent for the inclusion of their data in this research.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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(English Language Editor: L. Huleatt)
