High Recovery Rate of Adrenal Function After Successful Surgical Treatment of Cushing’s Syndrome

Posted on April 23, 2025 by MaryO

Abstract

Context

Successful first-line treatment of Cushing’s syndrome by resection of the underlying tumor is usually followed by adrenal insufficiency.

Purpose

The aims of this study were to determine the recovery rate and time to recovery of adrenal function after treatment for different forms of endogenous Cushing’s syndrome and to identify factors associated with recovery.

Methods

In this retrospective study of 174 consecutive patients with Cushing’s syndrome, the recovery rate and time to recovery of adrenal function after surgery were assessed.

Results

The 1-year, 2-year and 5-year recovery rates of patients with Cushing’s disease were 37.8, 70.1 and 81.1%, respectively. For patients with adrenal Cushing’s syndrome, the 1-year, 2-year and 5-year recovery rates were higher: 49.3, 86.9 and 91.3%, respectively. Median time to recovery for patients with Cushing’s disease and adrenal Cushing’s syndrome was 13.9 and 12.1 months, respectively. The median time to recovery of adrenal function in patients with Cushing’s disease with and without recurrence was 9.9 versus 14.4 months, respectively. Higher age was associated with a lower probability of recovery of adrenal function: HR 0.83 per decade of age (95% CI 0.70–0.98).

Conclusion

The recovery rate of adrenal function after successful surgery as first-line treatment in patients with Cushing’s syndrome is high. However, it may take several months to years before recovery of adrenal function occurs. In case of early recovery of adrenal function, clinicians should be aware of a possible recurrence of Cushing’s disease.

Introduction

Cushing’s syndrome (CS) is characterized by chronic exposure to an excess of glucocorticosteroids (1). Endogenous hypercortisolism is a rare disorder with an estimated incidence of 0.2–5 patients per million per year (1). CS can cause severe, disabling signs and symptoms and is associated with significantly increased morbidity and mortality. In approximately 70% cases, endogenous CS is caused by an ACTH-producing pituitary adenoma, also known as Cushing’s disease (CD). In 15–25% cases, an ACTH-independent form of CS is caused by a unilateral adrenal adenoma, adrenal carcinoma or bilateral micro- or macronodular hyperplasia (adrenal CS). An ACTH-producing ectopic tumor is a rare cause of CS. First-line treatment of CS is surgical removal of the pituitary, adrenal or ectopic tumor (1, 2).

Successful first-line treatment by resection of the underlying tumor is usually followed by adrenal insufficiency (AI) due to suppression of the hypothalamic–pituitary–adrenal axis after prolonged exposure to high concentrations of cortisol (3, 4, 5). Theoretically, one would expect that the hypothalamic–pituitary–adrenal axis recovers over time and that the substitution of glucocorticosteroids can slowly be reduced and stopped as long as there is no irreversible damage to the remaining adrenal or pituitary tissue. However, in clinical practice, AI is not always transient. In a subset of patients, this is caused by permanent AI due to perioperative damage to the pituitary gland or irreversible atrophy of the contralateral adrenal gland. In other cases, tapering the dosage of glucocorticosteroids is not possible because this causes worsening of symptoms. Despite the glucocorticoid replacement therapy, patients often experience symptoms resembling AI, such as fatigue, myalgia, arthralgia, depression, anxiety and decreased quality of life, also known as glucocorticoid withdrawal syndrome (GWS) (6). GWS is caused by dependence on supraphysiologic glucocorticoid concentrations after chronic exposure to high concentrations of glucocorticoids, which can complicate and delay the withdrawal of exogenous steroids. As a result, patients and physicians often struggle with a dilemma: on the one hand, lowering the cortisol substitution is necessary to enable functional recovery of the hypothalamic–pituitary–adrenal axis. On the other hand, lowering the substitution therapy often causes worsening of symptoms. In clinical practice, it is not always possible to completely taper the substitution of steroids due to GWS, even in spite of intensive guidance and support by the treating physician, specialized nurse and other healthcare professionals. Moreover, in patients remaining on glucocorticoid replacement, it is not always clear whether the failure to recover from AI is caused by the irreversible damage of the remaining pituitary or adrenal tissue or the failure to overcome the GWS. The time after which adrenal function recovers and substitution therapy can be tapered off varies largely between patients but may take several years (7).

A recent survey among patients with CS highlighted the need of patients for better information about the difficult post-surgical course (8). However, scientific data about this post-operative period, particularly regarding the recovery rate and time to recovery from AI are scarce (9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20). Because of the rarity of CS, most studies are hampered by a limited number of patients. The reported recovery rates of adrenal function after first-line treatment for CS vary widely, between 37 and 93% for CD (9, 10, 11, 12, 13) and between 38 and 93% for overt adrenal CS (10, 12, 14, 15, 16, 17).

The reported duration to recovery of the hypothalamic–pituitary–adrenal axis after CD and adrenal CS also varies widely, between 13 and 25 months after CD (9, 10, 11, 13, 19) and between 11 and 30 months in overt adrenal CS (10, 14, 15, 16, 18, 20).

Factors which influence the recovery rate and the duration to recovery of adrenal function are not entirely clear. A few studies reported a lower chance of recovery and a longer duration to recovery of adrenal function in patients who are younger, have more severe hypercortisolism, and longer duration of symptoms before diagnosis, whereas other studies could not confirm these findings (10, 13, 21). By contrast, other studies reported a higher chance of recovery in younger patients (21). Identification of these factors may help provide patients with more information about the expected post-surgical course.

Therefore, the aims of the present study were to assess the recovery rate and time to recovery of adrenal function after successful first-line treatment in the different subtypes of CS in a large series of consecutive patients treated at a tertiary referral center and to identify factors associated with recovery.

Methods

Patients

The medical records of adult and pediatric patients treated for CS at Radboud University Medical Center, Nijmegen, between 1968 and 2022 were examined retrospectively. This is a tertiary referral hospital where practically all cases of CS from the large surrounding geographic area are managed. All patients with CD, adrenal CS and ectopic CS who were in remission and developed AI after first-line surgical treatment were included. Exclusion criteria were bilateral adrenalectomy as first-line treatment, adrenocortical carcinoma, radiotherapy of the pituitary gland before surgery, pituitary carcinoma and the therapeutic use of corticosteroids for conditions other than AI. Data were collected on age, sex, body mass index (BMI), duration of CS symptoms, comorbidities, the use of medication, biochemical results at diagnosis and during follow-up, preoperative imaging, surgical treatment and histology.

The study was assessed by the Committee for Research with Humans, Arnhem/Nijmegen Region and the need for written approval by individual patients was waived since this study did not fall within the remit of the Medical Research Involving Human Subjects Act (WMO). The study has been reviewed by the ethics committee on the basis of the Dutch Code of conduct for health research, the Dutch Code of conduct for responsible use, the Dutch Personal Data Protection Act and the Medical Treatment Agreement Act. The ethics committee has passed a positive judgment on the study. The procedures were conducted according to the principles of the Declaration of Helsinki.

Diagnostics and definitions

Patients were diagnosed with CS according to the guidelines available at the time, i.e., the presence of signs and symptoms of hypercortisolism in combination with confirmatory biochemical tests, including the 1 mg dexamethasone suppression test (DST), 24-h urine free cortisol (UFC), late-night salivary cortisol concentrations and/or hair cortisol. The cutoff value for adequate cortisol suppression after the DST was <50 nmol/L (22). For UFC, the times upper limit of normal was calculated because several assays with different reference values were used over time.

First-line treatment consisted of pituitary surgery in patients with CD and unilateral adrenalectomy in patients with ACS. In patients with bilateral macronodular hyperplasia, adrenalectomy of the largest adrenal was performed after carefully outweighing the risks and benefits of surgery together with the patient, taking into account factors such as age, severity of symptoms, comorbidities associated with hypercortisolism (e.g., diabetes mellitus type 2, cardiovascular disease, osteoporosis) and the severity of the hypercortisolism (2).

Peri- and postoperatively, all patients received glucocorticoid stress dosing, which was tapered off within a few days after surgery. Adrenal function was initially evaluated with a postoperative morning fasting cortisol concentration, measured at least 24 h after the last dose of hydrocortisone or cortisone acetate, within 7 days after surgery. If the postoperative morning fasting cortisol was <200 nmol/L, the patient was considered to have AI and glucocorticoid replacement therapy was continued. The starting dose was usually hydrocortisone 30 mg once daily (or an equivalent dose of cortisone acetate in the early years). For children, the dose was weight-based. Afterwards, the dose was slowly tapered off according to the symptoms/well-being of the patient and fasting cortisol values. During follow-up, the dose was usually divided into two or three doses a day.

Remission of CS after treatment was defined as either a morning cortisol of ≤50 nmol/L, adequate cortisol suppression after DST or a late-night salivary cortisol concentration within the reference range. Duration of AI was defined as the time between surgery and discontinuation of glucocorticoid replacement therapy. Complete recovery of adrenal function was assessed by spontaneous fasting cortisol concentration, an insulin tolerance test or a 250 μg ACTH stimulation test after discontinuation of glucocorticoid replacement therapy. In cases where fasting morning cortisol ≥520 nmol/L, adrenal function was considered as completely recovered. For the dynamic tests, assay-dependent cutoff values were used according to the guidelines available at the time. The dynamic tests were not performed routinely in all patients until 1999. In patients for whom no dynamic tests (results) were available, complete recovery of AI was defined as complete discontinuation of replacement therapy. Recurrence of CS was defined as the presence of signs and symptoms of hypercortisolism in combination with confirmatory biochemical tests, including the 1 mg DST, 24-h UFC, late-night salivary cortisol concentrations and/or hair cortisol.

Statistical analysis

Continuous data were expressed as mean ± SD or median + interquartile range (IQR), and categorical data were presented as frequency (n) and percentage (%). We produced Kaplan–Meier curves to determine the unadjusted probability of recovery of adrenal function over time. Patients that tapered off and completely stopped the glucocorticoid replacement therapy were assigned in the survival analyses as having an event (=recovery of adrenal function). The date of the last follow-up visit was assigned in the survival analyses as the last date and patients that were lost to follow-up or developed a recurrence before stopping the glucocorticoid replacement therapy were censored. In order to identify factors associated with recovery of adrenal function, we compared Kaplan Meier curves between several subgroups of patients: CD versus adrenal CS versus ectopic CS, age (at diagnosis) groups of ≤35 versus 36–55 versus ≥56 years old, patients with or without postoperative pituitary deficiencies, patients with or without recurrence of CS during follow-up, patients with or without preoperative medical treatment (PMT), patients operated before versus after 2010 and patients with a low versus slightly higher post-operative morning cortisol (<100 nmol/L versus 100–200 nmol/L), measured within 7 days after surgery. The Kaplan–Meier curves of the subgroups were compared using the two-sided log-rank test. The P-value ≤0.05 was considered statistically significant. The Kaplan–Meier curves provided the 1-year, 2-year and 5-year recovery rates and the median time to recovery of the adrenal gland. We used Cox proportional hazards models to calculate hazard ratios (HRs) with a 95% confidence interval (CI) of the probability of recovery of adrenal function over time in order to identify factors associated with recovery of adrenal function (univariate analyses). Cox proportional hazards models with multivariate analyses were performed to calculate the adjusted HRs with 95% CI. The model of multivariate analysis for the whole group included the variables: etiology of CS, age, sex, BMI, duration of symptoms before diagnosis, UFC and postoperative cortisol 0.10–0.20 versus <0.10 mcmol/L. The model of multivariate analysis for the patients with CD only included the variables: etiology of CD, age, sex, BMI, duration of symptoms before diagnosis, UFC, post-operative cortisol 0.10–0.20 versus <0.10 mcmol/L, PMT, hormonal deficiencies of the anterior pituitary gland other than AI and micro/macroadenoma. A 95% CI not including 1 was considered statistically significant.

All statistical analyses were performed using STATA version 11 (StataCorp, USA).

Results

In total, 174 patients were included in the analysis. The assessment of eligibility, the number of patients excluded from this study and the reasons for exclusion are shown in Fig. 1. The baseline characteristics are described in Table 1. The median follow-up was 6.8 years (IQR: 2.2–12.6). In 69.6% (94/135) of all patients who discontinued their glucocorticoid replacement therapy, the recovery of adrenal function was confirmed with a dynamic test or a morning cortisol concentration ≥520 nmol/L.

Figure 1View Full Size
Figure 1
Flowchart showing the assessment for eligibility, the number of patients excluded from the study and the reasons for exclusion.

Citation: Endocrine Connections 14, 5; 10.1530/EC-24-0612

Table 1Baseline characteristics.

Variable All patients CD Adrenal CS
Participants (n) 174 135 35
Female (%) 135/174 (77.6%) 102/135 (75.6%) 32/35 (91.4%)
Median age at diagnosis (y) 44 (35–55) 43 (32–55) 47 (36–54)
Median BMI at diagnosis (kg/m2) 28.3 (24.7–32.4) 28.6 (24.7–32.9) 28.0 (26.0–31.8)
Median duration of symptoms before diagnosis of CS (years) 3.0 (1.0–5.6) 3.0 (1.0–6.0) 3.5 (1.5–5.6)
Median times upper limit of normal UFC at diagnosis 3.7 (1.9–5.8) 3.9 (2.0–6.4) 2.4 (1.4–4.1)
Median cortisol after DST (nmol/L) 480 (320–630) 460 (290–620) 550 (330–710)
Median salivary cortisol at diagnosis (nmol/L) 8.6 (5.4–15.4) 10.1 (5.9–18.0) 6.1 (4.0–8.9)
Median follow up (years) 6.8 (2.2–12.6) 8.4 (3.0–13.5) 2.2 (1.2–4.7)
Preoperative medical therapy* (n) 120/174 (69%) 106/135 (78.5%) 10/35 (28.6%)
Pituitary microadenoma/macroadenoma/no adenoma detected on MRI scan (n) – 64/27/28** –
Bilateral disease (n) – – 7/35 (20.0%)

CD, Cushing’s disease; CS, Cushing’s syndrome; BMI, body mass index; UFC, 24-h urine free cortisol; DST, 1 mg dexamethasone suppression test. Continuous data are summarized as median and interquartile ranges. Categorical data are presented as frequencies and percentages.

*Cortisol-lowering medication, either metyrapone or ketoconazole.

**Missing data on MRI in 16 patients.

Recovery rates and recovery times of adrenal function

The probability of recovery of AI for CD, adrenal CS and ectopic CS are depicted in Fig. 2. The 1-year, 2-year and 5-year recovery rates of adrenal function for the entire cohort were 40.1, 73.4 and 83.3%, respectively. The median time to recovery of adrenal function was 13.9 months. The 1-year, 2-year and 5-year recovery rates of patients with CD were 37.8, 70.1 and 81.1%, respectively. The median recovery time was 13.9 months for patients with CD. For patients with adrenal CS, the 1-year, 2-year and 5-year recovery rates were higher: 49.3, 86.9 and 91.3%, respectively (two-sided log-rank test: P = 0.14). The median recovery time for patients with adrenal CS was 12.1 months. Seven out of the 35 patients with adrenal Cushing had bilateral disease. The median time to recovery in patients with bilateral disease was 17.5 versus 11.0 months in patients with unilateral disease.

Figure 2View Full Size
Figure 2
Cumulative probability of recovery of adrenal function in CD (n = 135), adrenal CS (n = 35) and ectopic Cushing (n = 4).

Citation: Endocrine Connections 14, 5; 10.1530/EC-24-0612

Of the 15 evaluated patients with ectopic CS, only four patients underwent successful resection of the ectopic tumor and were included in our study. All four patients had a neuroendocrine tumor of the lung and recovered from AI. The time to recovery of adrenal function was known in three patients: 5.7, 7.9 and 14.5 months.

Factors associated with recovery of adrenal function

Age at diagnosis

Figure 3 shows the Kaplan–Meier curves of three different age groups (group 1: 0–35 years old, group 2: 36–55 years old and group 3: 56–100 years old). The 1-year recovery rates of patients aged between 0–35, 36–55 and 56–100 years old were 54.6, 37.2 and 31.4%, respectively. The 2-year recovery rates were 79.3, 72.6 and 68.4%, respectively and the 5-years recovery rates were 89.6, 83.8 and 75.1%, respectively. The median times to recovery of adrenal function of patients aged between 0–35, 36–55 and 56–100 years old were 11.2, 13.4 and 17.6 months, respectively. The probability of recovery of AI was higher in young patients (0–35 years old) (two-sided log-rank test: P = 0.05).

Figure 3View Full Size
Figure 3
Cumulative probability of recovery of adrenal function by age groups.

Citation: Endocrine Connections 14, 5; 10.1530/EC-24-0612

Recurrence after primary treatment

In total, 17.8% patients with CD (24/135) had developed a recurrence during follow-up. Figure 4 shows the Kaplan–Meier curves with the probability of recovery of AI of the groups with and without recurrence during follow-up in patients with CD. The probability of recovery of AI was higher in patients with a recurrence (two-sided log-rank test: P-value = 0.02). In patients with a recurrence, the 1-, 2- and 5-year recovery rates of AI were 60.9, 78.3 and 87.0%, respectively. In patients without a recurrence, the 1-, 2- and 5-years recovery rates of AI were 32.6, 68.3 and 79.7%, respectively. The median time to recovery of adrenal function in patients with CD with and without recurrence was 9.9 versus 14.4 months, respectively.

Figure 4View Full Size
Figure 4
Cumulative probability of recovery of adrenal function by recurrence during follow-up in patients with CD.

Citation: Endocrine Connections 14, 5; 10.1530/EC-24-0612

There was only one patient with adrenal CS with a recurrence. This was a patient with bilateral macronodular hyperplasia. During the first surgery, the largest adrenal was removed. However, 3 years later, the contralateral adrenal was also removed because of the recurrence of CS.

Hypopituitarism after pituitary surgery

In patients with CD, we performed a sub-analysis based on the presence of anterior pituitary deficiencies after pituitary surgery for CD, besides AI. Antidiuretic hormone (ADH) deficiency was not included in this analysis. As expected after pituitary surgery and in line with the literature, temporary ADH deficiency occurred in a substantial part of the patients after surgery (23). Therefore, only central hypothyroidism, hypogonadotropic hypogonadism and growth hormone deficiency were taken into account (Fig. 5). The probability of recovery of AI was lower in patients with one or more pituitary deficiencies versus patients with intact pituitary function after surgery (two-sided log-rank test: P-value = 0.05). In patients with anterior pituitary deficiencies, the 1-, 2- and 5-years recovery rates of AI were 35.6, 60.4 and 67.6%, respectively. In patients without anterior pituitary deficiencies, the 1-, 2- and 5-years recovery rates of AI were 39.2, 76.0 and 89.1%, respectively. The median time to recovery of adrenal function in patients with CD with and without anterior pituitary deficiencies was 15.9 versus 13.4 months, respectively. Figure 6 shows the Kaplan–Meier curves by the number of hormonal deficiencies of the anterior pituitary gland, other than AI. Although statistical significance was not reached, there is a trend showing that the more postoperative hormonal deficiencies present, the lower the probability of recovery of AI is (two-sided log-rank test: P-value = 0.15).

Figure 5View Full Size
Figure 5
Kaplan–Meier curve by the presence/absence of hormonal deficiencies of the anterior pituitary gland (other than AI) after surgery in patients with CD.

Citation: Endocrine Connections 14, 5; 10.1530/EC-24-0612

Figure 6View Full Size
Figure 6
Kaplan–Meier curve by the number of hormonal deficiencies of the anterior pituitary gland after surgery in patients with CD.

Citation: Endocrine Connections 14, 5; 10.1530/EC-24-0612

Preoperative cortisol-lowering medical therapy, year of surgery and fasting cortisol concentration at the initial postoperative evaluation

Sub-analyses regarding patients who received PMT versus patients without PMT did not show any difference in the probability of recovery. In patients without PMT, the 1-, 2- and 5-years recovery rates of AI were 42.6, 77.6 and 85.2%, respectively. In patients with PMT, the 1-, 2- and 5-years recovery rates of AI were 41.6, 73.7 and 82.3%, respectively. The median time to recovery of adrenal function in patients without PMT and with PMT was 14.1 versus 13.5 months, respectively.

Sub-analyses regarding patients operated on before versus after 2010, regarding the results of the 1 mg dexamethasone suppression test at diagnosis and regarding patients with a low versus slightly higher postoperative morning cortisol within 7 days after surgery (<100 versus 100–200 nmol/L) also did not show any difference in the probability of recovery of adrenal function.

Table 2 shows HRs of univariate and multivariate Cox regression analyses. Adrenal CS and ectopic CS were associated with a higher probability of recovery of AI in comparison with patients with CS. Higher age was associated with a lower probability of recovery of AI.

Table 2Uni- and multivariate Cox regression analyses.

Variable Univariate Cox regression Multivariate Cox regression
HR 95% CI P value HR 95% CI P value
Etiology of CS (CD/adrenal CS/ectopic) 1.44 1.00–2.08 0.05 1.76 1.11–2.80 0.02
Etiology of CS (CD/adrenal CS) 1.42 0.91–2.22 0.12
Age (decades) 0.81 0.71–0.93 0.002 0.83 0.70–0.98 0.03
Sex (male/female) 1.02 0.68–1.55 0.92 0.74 0.46–1.20 0.22
BMI (kg/m2) 1.00 0.97–1.02 0.81 1.01 0.97–1.05 0.61
Duration of symptoms before diagnosis (years) 0.95 0.90–1.01 0.08 0.95 0.89–1.01 0.09
UFC (ULN) 1.03 0.99–1.07 0.15 1.01 0.97–1.05 0.57
Post-operative cortisol 0.10–0.20 versus <0.10 mcmol/L 0.92 0.56–1.50 0.73 1.16 0.58–2.30 0.67
In patients with CD only
PMT (no/yes) 1.23 0.75–2.02 0.40 1.26 0.53–3.02 0.60
Hormonal deficiencies of the anterior pituitary gland, other than AI (no/yes) 0.65 0.43–0.99 0.05 0.67 0.40–1.11 0.12
Micro/macroadenoma 1.13 0.70–1.83 0.62 1.42 0.79–2.52 0.24

PMT, preoperative medical treatment; HR, hazard ratio; CI, confidence interval; CS, Cushing’s syndrome; CD, Cushing’s disease; BMI, body mass index; UFC (ULN), times upper limit 24-h urine free cortisol; AI, adrenal insufficiency. The model of multivariate analysis for the whole group included the variables: etiology of CD, age, sex, BMI, duration of symptoms before diagnosis, UFC and postoperative cortisol 0.10–0.20 versus <0.10 mcmol/L. The model of multivariate analysis for the patients with CD only included the variables: etiology of CD, age, sex, BMI, duration of symptoms before diagnosis, UFC, postoperative cortisol 0.10–0.20 versus <0.10 mcmol/L, preoperative medical treatment, hormonal deficiencies of the anterior pituitary gland other than AI and micro/macroadenoma.

Discussion

In this study, we investigated the recovery rate of adrenal function and time to recovery after first-line treatment in patients with CS. The main finding is that the recovery rates of adrenal function are high. However, it may take several months to years before recovery of adrenal function occurs.

Patients with adrenal CS had higher recovery rates than patients with CD. This can be explained by the fact that the cortisol excess is generally less severe in adrenal CS and the fact that one adrenal gland remains completely intact after unilateral adrenalectomy. By contrast, patients who undergo pituitary surgery are at risk of developing new pituitary hormone deficiencies, including corticotrope deficiency, due to permanent structural damage to the pituitary gland. Our finding that patients with additional pituitary deficiencies after surgery for CD had lower recovery rates of adrenal function supports this hypothesis.

The recovery rates of adrenal function in CD, as well as in adrenal CS, are higher than what was reported in some previous studies (10, 11, 12), but are similar to other reports (13, 15, 17, 18). As shown in Table 3, it is difficult to compare previous studies because they all differ in design, study population and inclusion and exclusion criteria. For example, Berr et al. and Klose et al. used a different cutoff value of postoperative cortisol (<100 nmol/L) than we did (<200 nmol/L) to define initial AI shortly after surgery. However, only 25 patients in our cohort had a postoperative morning cortisol between 100 and 200 nmol/L and sub-analysis of patients with a morning cortisol <100 nmol/L versus patients with a morning cortisol between 100 and 200 nmol/L did not show any difference in recovery rate or time. Another difference between studies is the strategy for tapering off and stopping glucocorticoids in the postoperative period. In our study, patients started with 30 mg hydrocortisone per day after surgery. One might expect that a higher dose of hydrocortisone leads to a longer time to recovery of adrenal function. However, there are no data or evidence-based guidelines regarding the best strategy for tapering off and stopping glucocorticoids in the postoperative period.

Table 3Overview of previous studies regarding recovery of adrenal function after surgery in patients with CS.

Author n, etiology Recovery rate AI Time to recovery, years Follow up years Definition of AI/remission Substitution therapy (start doses) Recurrence rate (CD)
Alexandraki, 2013 (8) 131 CD 49/81 (60.5%) during follow up Median 1.5 years Minimum 6 years, mean 15.9 ± 6 years Postoperative cortisol ≤50 nmol/L Prednisolone 5 + 2 mg or HC 20 mg in divided doses 22.7% (microadenoma) 33.3% macroadenoma
Berr, 2015 (9) 5-year: Median: Mean 8.2 years Morning cortisol ≤100 nmol/L HC 40–50 mg/day
54 CD CD: 58% CD: 1.4 years CD: 7.0 years
26 ACS ACS: 38% ACS: 2.5 years ACS: 8.5 years
11 ECS ECS: 82% ECS: 0.6 years ECS: 13.5 years
Serban, 2019 (12) 61 CD 5-year: Median 1.6 years Minimum 3 years, median 6 years Morning cortisol ❤ μg/dL or cortisol after 250 μg synacthen test <18 μg/dL Cortisone acetate 25 mg, divided in 2–3 doses 16.4%
Persistent remission: 55.8% 2.1 years
Recurrence: 100% 1.0 years
Ciric 2012 (10) 86 CD 59.3% during follow up Mean 1.1 years Minimum 0.5 years, mean 5.7 years Drop in immediate postoperative cortisol, range <0.5–5.3 µg/dL and symptoms No specific unified algorithm 9.7%
Klose, 2004 (11) 2-year: Median: Post-operative cortisol <100 nmol/L and/or UFC <50 nmoL/24h Hydrocortisone 20–30 mg/day
18 CD CD: 67% CD: 2 years CD: 22.2%
14 ACS ACS: 79% ACS: 2 years ACS: 0%
Prete, 2017 (18) Median: Minimum 2 years Postoperative morning serum cortisol <5 μg/dL/138 nmol/L Hydrocortisone 20–30 mg/day in divided in 2–3 doses Patients with recurrence were excluded
15 CD CD: 1.3 years CD: median 5.8 years
31 ACS ACS: 0.8 years ACS: Median 4.0 years
 14 overt ACS Overt ACS: 1.5 years
 17 subclinical ACS Subclinical ACS: 0.5 years
Hurtado, 2018 (14) 81 ACS 87.8% during follow up Median ACS: 0.4 years Median ACS: 1.2 years Postoperative morning (day 1) serum cortisol <10 μg/dL/276 nmol/L or hemodynamic instability or received perioperative GC due to anticipated AI after unilateral adrenalectomy Prednisone or hydrocortisone, median hydrocortisone-equivalent dose 40 mg/day
 27 severe CS Severe: 1.0 years Severe: 1.0 years
 24 moderate CS Moderate: 0.2 years Moderate: 1.0 years
 30 MACE MACE: 0.2 years MACE: 1.5 years
Dalmazi, 2014 review on adrenal function after adrenalectomy for subclinical CS, 28 studies (17) ACS: 376 overt ACS 141 subclinical ACS Overt ACS: 93.4% subclinical ACS: 97.9% Mean overt ACS: 0.9 years subclinical ACS 0.5 years

CD, Cushing’s disease; ACS, adrenal Cushing’s syndrome; ECS, ectopic Cushing’s syndrome; AI, adrenal insufficiency; Subclin: subclinical; MACE, mild autonomous cortisol excess.

One might also hypothesize that the studies reporting high recurrence rates are related to higher recovery rates in CD patients. In our study, the recurrence rate was 17.8%, which is in line with previous studies (9, 13, 24). The establishment of recovery of adrenal function in patients with a recurrence later on is a difficult matter: despite the exclusion of patients with immediate obvious persistent disease in our study, recovery of glucocorticoid secretion in patients who developed a recurrence later on could be an early manifestation of recurrence instead of true recovery of physiological adrenal function. A striking finding in this study, in line with the aforementioned hypothesis, was the considerably higher 1-year recovery rate and the shorter time to recovery of patients with a recurrence in comparison to patients without a recurrence. Recovery of adrenal function is more rapid in patients with recurrences (13, 25). These findings imply that in case of an early recovery of adrenal function, clinicians should be aware of a possible recurrence of CD.

Another difference between studies is the inclusion or exclusion of patients with mild autonomous cortisol secretion (MACS), formerly known as subclinical CS. Previous studies have shown that patients with subclinical CS have a higher probability of recovery and a shorter duration of AI (14, 15, 16, 18). In our study, only two patients were diagnosed with subclinical CS (in this study characterized as inadequate suppression after DST in combination with values of UFC within the reference range) and therefore subgroup analysis was not possible.

In the present study, a rather high number of patients received PMT in comparison to other studies. In our institution, it was common practice to start PMT 3 months before pituitary surgery in patients with CD with the aim to improve hemostasis and other Cushing-related comorbidities, although the benefit of PMT has not yet been well established by randomized controlled trials. At the liberty of the treating physician, the dose of ketoconazole or metyrapone was titrated with the aim to normalize the 24-h UFC excretion. The doses needed to achieve normal 24-h UFC and the time to normalization of 24-h UFC varied between patients.

One could hypothesize that lowering cortisol levels during the weeks to months before surgery may result in a faster recovery of adrenal function. However, this was not the case in this study.

Overall, the present study shows a high recovery rate of adrenal function after treatment for CS. The time until recovery is partly dependent on the strategy and success of tapering off of glucocorticoids replacement and therefore may be very long because of GWS. These are meaningful findings. Tapering glucocorticoid substitution in parallel with the recovery of cortisol secretion after surgery for CS is often a challenging and lengthy trajectory for both patients and physicians. The lack of standardization of the follow-up and of the tapering protocols, the need for constant shared decision-making and personalized support for patients, particularly of those who are also confronted with severe associated comorbidities and unpredictable withdrawal symptoms, may discourage patients and physicians from proceeding in this endeavor. Given the rarity of the disease, knowledge on this topic is scarce. Previous, mainly smaller studies reported a wide range of recovery rates of adrenal function after first-line treatment for CS (varying between 37 and 93% for CD, and for overt adrenal CS between 38 and 93%) (10, 11, 12, 13, 15, 17, 18). The rather low percentages of recovery of adrenal function in some of these previous studies could discourage patients and physicians to persevere the attempt to taper off hydrocortisone. Our findings in a large cohort of patients with CS, including a sizable subgroup of patients with CD, allow us to deepen the multivariate analysis to uncover factors that are associated with a better chance of recovery. The data indicate that in this real-life setting, despite the long time to achieve recovery, the recovery rates are high and while this occurs for most of the patients within 1–2 years after treatment, recovery is still possible even after a longer follow-up. Moreover, this study showed that the recovery rate is higher in patients with adrenal CS versus CD, in younger patients and in patients with CD with preserved pituitary function after pituitary surgery. These findings are very important for clinical practice. They highlight the importance of continuing to taper off the glucocorticoids, if necessary slowly and steadily, in the years after surgery. They also help us better inform the patients beforehand and to improve the management and the expectations of both patients and physicians to motivate them to persevere in tapering of the glucocorticosteroids while considering the factors such as those identified to influence the chance of recovery during their personalized counseling and guidance of the patients in this often very difficult and lengthy period.

In our institution, it is common practice to counsel and provide guidance intensively to patients in this difficult period, both by the treating physician and a specialized nurse, as we consider this coordinated guidance of utmost importance. Moreover, all patients are provided with contact details so that they can reach to us for advice 24 h a day, either by phone or by secure email throughout this process. When indicated, patients are referred to other healthcare professionals such as psychologists, physical therapists, social workers and other specialists.

One important strength of our study is the large size of our single-center cohort, considering the rarity of the disease. This has also allowed us to do subgroup analyses and assess factors associated with recovery from postoperative AI. The limitations include the retrospective character of this study and the fact that patients were included over a long period of time (1968 to 2022) during which diagnostic tools and management protocols for CS have somewhat changed over this period of time. We have tried to mitigate the limitations that are inevitable with a retrospective study by being thorough and extensive in the quality and amount of data that we were able to collect. In addition to that, the diagnostic assessment and the treatment of the patients followed very strict and uniform protocols in conformity with the internationally recognized clinical guidelines available at the time. On the other hand, the fact that this represents a real-life study renders the results more relatable for clinical practitioners and strengthens its impact.

We collected data from medical records regarding the duration of CS-related signs and symptoms before diagnosis, as mentioned by the patient during history taking. We are well aware that these data are rather subjective and dependent on the accuracy of the recollection of the patient. However, this is the only way to assess the duration of symptoms before diagnosis. In our opinion, these data still could be very valuable.

In conclusion, our study shows that the large majority of patients with CS recover their adrenal function after first-line surgical treatment, even though the time to recovery may take several months to years. Informing patients beforehand and providing support, encouragement and guidance in this process is therefore paramount. Herewith, one could consider factors such as the age of the patient, the etiology of CS and the presence of additional pituitary deficiencies after pituitary surgery. In case of an early recovery of adrenal function, clinicians should be aware of a possible recurrence of CD. Future studies should establish the optimal postoperative management for CS to improve the chance for success of recovery of adrenal function.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

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First-Episode Psychosis and Cushing Syndrome

Posted on March 28, 2025 by MaryO

Cushing syndrome, a state of hypercortisolism, has multiple etiologies, including ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS). EAS is a frequently severe emergency related to the degree of hypercortisolism. Neuropsychiatric symptoms of Cushing syndrome are well documented, including irritability, anxiety, depressed mood, and cognitive impairment.1 A few prior case reports have described first episode psychosis associated with Cushing syndrome,2 sometimes leading to delayed or misdiagnosis of Cushing syndrome.

Here, we report a case of a 72-year old man diagnosed with EAS caused by excessive ACTH secretion by a metastatic neuroendocrine tumor. Our report aims to add to the body of evidence indicating that Cushing associated psychosis can cause acutely severe paranoia and delusions that significantly impact management.

Case Report

Mr A, a 72-year-old retired physician with no prior psychiatric history, was diagnosed with new-onset psychosis in the setting of hypercortisolism. He initially presented with weakness secondary to hypokalemia and was found to have Cushing syndrome. On psychiatric evaluation, he demonstrated paranoia and delusions as well as illogical, concrete, and limited thought content. Laboratory workup, neurocognitive examination, and collateral history ruled out delirium or dementias. His morning cortisol levels were up to 162 μg/dL, and ACTH levels were greater than 2,000 pg/mL.

Mr A’s cortisol levels were not suppressed with a high-dose dexamethasone test, supporting ectopic ACTH production. He was found to have a metastatic ACTH secreting large cell neuroendocrine tumor, responsible for his hypercortisolism. Magnetic resonance imaging of his brain demonstrated a pituitary mass, and a bilateral adrenalectomy revealed a small focus of neuroendocrine carcinoma on his left adrenal gland.

Mr A was treated with haloperidol for hallucinations, delusional features, and paranoia; ramelteon for delirium prophylaxis; and suvorexant for sleep initiation. His endocrinology team ultimately started him on osilodrostat (decreases cortisol synthesis via 11 β-hydroxylase inhibition), which led to improvements in his cortisol levels, and his psychotic features subsequently diminished and resolved by the fourth day. All medications for psychiatric symptoms were successfully discontinued without symptom recurrence.

Discussion

Hypothalamic-pituitary-adrenal axis abnormalities, including hypercortisolism, have been well documented in first-episode psychosis cases.3 This includes increased morning cortisol levels in the blood in individuals with first-episode psychosis and increased baseline cortisol levels in the saliva for individuals at a clinical high risk of psychosis.4 There are multiple proposed mechanisms for how excess exposure to cortisol leads to psychosis. Theories include structural and chemical changes such as abnormal regulation of neurotransmitters, impaired neurogenesis, decreased brain volume in the hippocampus, abnormal loss of synapses, and dendritic atrophy. However, these changes are typically in the setting of prolonged exposure to high levels of cortisol.

There are a limited number of case reports regarding Cushing syndrome and acute psychosis.2 Past case reports that have described Cushing syndrome and acute onset of psychosis endorse severely high levels of cortisol, which may be a driving factor, and patients presented with less profound delusional and paranoid content.2 In this case, the patient presented with severe paranoia and delusions in the setting of excess cortisol and metastatic malignancy. Similar cases have been reported and focus on reducing cortisol levels to help manage the psychiatric symptoms.2,5,6 Psychotropic management can assist with symptoms; however, the ultimate treatment remains to address the endocrinologic abnormality. While most cases have reported improvement of neuropsychiatric symptoms with resolution of hypercortisolism, others have described persisting or even exacerbation of psychiatric symptoms even after resolution of the high cortisol levels.5–7 Most importantly, we must recognize Cushing syndrome and its hormonal derangements as a possible underlying etiology of psychosis to guide effective diagnostics and therapeutic management.

Article Information

Published Online: March 25, 2025. https://doi.org/10.4088/PCC.24cr03886
© 2025 Physicians Postgraduate Press, Inc.
Prim Care Companion CNS Disord 2025;27(2):24cr03886
Submitted: November 4, 2024; accepted January 3, 2025.
To Cite: Gunther M, Jiang S. First-episode psychosis and Cushing syndrome. Prim Care Companion CNS Disord 2025;27(2):24cr03886.
Author Affiliations: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California (Gunther); Department of Psychiatry, University of Florida, Gainesville, Florida (Jiang).
Corresponding Author: Matthew Gunther, MD, MA, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Rd, Palo Alto, CA 94304 (guntherm@stanford.edu).
Relevant Financial Relationships: None.
Funding/Support: None.
Patient Consent: Consent was received from the patient to publish the case report, and information has been de-identified to protect anonymity.

References:

  1. Santos A, Resmini E, Pascual JC, et al. Psychiatric symptoms in patients with Cushing’s syndrome: prevalence, diagnosis and management. Drugs. 2017;77(8):829–842. CrossRef
  2. Okumura T, Takayama S, Nishio S, et al. ACTH producing thymic neuroendocrine tumor initially presenting as psychosis: a case report and literature review. Thorac Cancer. 2019;10(7):1648–1653. CrossRef
  3. Misiak B, Pruessner M, Samochowiec J, et al. A meta-analysis of blood and salivary cortisol levels in first-episode psychosis and high-risk individuals. Front Neuroendocrinol. 2021;62:100930. CrossRef
  4. Chaumette B, Kebir O, Mam-Lam-Fook C, et al. Salivary cortisol in early psychosis: new findings and meta-analysis. Psychoneuroendocrinology. 2016;63:262–270. CrossRef
  5. Al-Harbi SD, Mashi AH, AlJohani NJ. A case of Cushing’s disease presenting with isolated suicidal attempt. Clin Med Insights Case Rep. 2021;14:11795476211027668.
  6. Mokta J, Sharma R, Mokta K, et al. Cushing’s disease presenting as suicidal depression. J Assoc Physicians India. 2016;64(11):82–83.
  7. Pivonello R, Simeoli C, De Martino MC, et al. Neuropsychiatric disorders in Cushing’s syndrome. Front Neurosci. 2015;9:129.

From https://www.psychiatrist.com/pcc/first-episode-psychosis-cushing-syndrome/

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Leukocytosis in Cushing’s Syndrome Persists Post-Surgical Remission and Could Predict a Lower Remission Prognosis in Patients with Cushing’s Disease

Posted on March 21, 2025 by MaryO

Abstract

Context

Leukocytosis frequently noted in Cushing’s syndrome (CS), along with other blood cell changes caused by direct and indirect cortisol effects.

Objective

Assess baseline white blood cell (WBC) profile in CS patients compared to controls and WBC changes pre- and post-remission after surgical treatment for CS.

Design

A comparative nationwide retrospective cohort study.

Setting

Data from Clalit Health Services database.

Patients

297 patients (mean age 51 ± 16.1 years, 73.0% women) with CS and 997 age-, sex-, body mass index-, and socioeconomic status-individually matched controls. Ectopic CS or adrenal cancer patients were excluded.

Main outcome measure

Mean WBC, neutrophils, and neutrophil-to-lymphocyte ratio (NLR) two-years before and after pituitary or adrenal surgery. WBC and neutrophils are expressed as Kcells/µl.

Results

At baseline, leukocytosis was observed in 21.5% of patients with CS vs. 8.9% of controls (P < 0.001). Patients with CS had significantly higher WBC (8.8 ± 2.88 vs. 7.54 ± 2.45, p < 0.0001), neutrophils (5.82 ± 2.38 vs. 4.48 ± 1.97, p < 0.0001), and NLR (3.37 ± 2.63 vs. 2.27 ± 1.86, p < 0.0001) compared to controls, regardless of pituitary or adrenal source of hypercortisolemia. Post-surgery, patients with CS experienced significant decreases in mean WBC (-0.57 ± 2.56, p < 0.0001), neutrophils (-0.84 ± 2.55, p < 0.0001), and NLR (-0.63 ± 2.7, p < 0.0001). Despite achieving disease remission, patients with CS still had higher WBC (8.11 ± 2.4 vs. 7.46 ± 2.17, p = 0.0004) and neutrophils (4.71 ± 2.10 vs. 4.41 ± 1.87, p = 0.03) compared to controls. Patients with CD and baseline leukocytosis had lower remission rate than those with normal WBC (36.7% vs. 63.9%, p = 0.01).

Conclusions

At diagnosis, CS patients have elevated WBC, neutrophils, and NLR compared to controls. Remission does not normalize WBC levels in all patients, and baseline leukocytosis predicts a poorer remission prognosis in CD.

From https://link.springer.com/article/10.1007/s40618-025-02535-2

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A Rare Case of PRKACA Duplication–Associated Childhood-Onset Primary Pigmented Nodular Adrenocortical Disease

Posted on March 19, 2025 by MaryO

Abstract

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare but important cause of adrenocorticotropic hormone (ACTH)-independent Cushing syndrome (CS). It usually presents as cyclical CS in young adults. Childhood onset of PPNAD is exceedingly rare. About 90% of cases of PPNAD are associated with Carney complex (CNC). Both PPNAD and CNC are linked to diverse pathogenic variants of the PRKAR1A gene, which encodes the regulatory subunit type 1 alpha of protein kinase A (PKA). Pathogenic variants of PRKACA gene, which encodes the catalytic subunit alpha of PKA, are extremely rare in PPNAD. We report a case of a female child, aged 8 years and 3 months, who presented with features suggestive of CS, including obesity, short stature, hypertension, moon facies, acne, and facial plethora but without classical striae or signs of CNC. Hormonal evaluation confirmed ACTH-independent CS. However, abdominal imaging revealed normal adrenal morphology. Genetic analysis identified a duplication of the PRKACA gene on chromosome 19p, which is linked to PPNAD. The patient underwent bilateral laparoscopic adrenalectomy, and histopathological study confirmed the PPNAD diagnosis. Postoperative follow-up showed resolution of cushingoid features and hypertension. To our knowledge, this is the first reported case of a female child with PRKACA duplication presenting as CS due to PPNAD.

PPNAD, PRKACA, Carney complex, Cushing syndrome
Issue Section:

Case Report

Introduction

Endogenous Cushing syndrome (CS) is a multisystem disorder caused by excessive production of cortisol. It can result from either adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent etiologies. The incidence of endogenous CS is estimated to be 0.7 to 2.4 cases per million annually, with 10% of cases occurring in children [1]. Adrenal causes account for 65% of endogenous CS in children and 2% of these are due to primary pigmented nodular adrenocortical disease (PPNAD) [2]. PPNAD is associated with Carney complex (CNC) in 90% of patients, while the remaining 10% occur as isolated cases [3]. CNC is an autosomal dominant disorder characterized by spotty skin pigmentation, mesenchymal tumors, peripheral nerve tumors, and various other neoplasms [2].

The PRKAR1A gene on chromosome 17 is most commonly implicated in CNC and PPNAD. It encodes the regulatory subunit type 1 alpha of protein kinase A (PKA) [4]. Pathogenic variants in the PDE11A gene, encoding phosphodiesterase 11A, are the second most common genetic abnormality in PPNAD [4]. PRKACA gene on chromosome 19 encodes the catalytic subunit alpha of PKA. Pathogenic variants in the PRKACA gene are rarely reported in PPNAD [5]. To date, only 3 cases of pathogenic variants in PRKACA have been reported as a cause of PPNAD, with 1 case occurring in childhood [6‐8]. We report a rare case of PPNAD in a female child, caused by a duplication of the PRKACA gene.

Case Presentation

A female child aged 8 years and 3 months presented with a 1-year history of acne, poor linear growth, and a weight gain of 9 kg over the past 6 months. She was the first-born child of non-consanguineous parents and had an uneventful perinatal and postnatal history until the age of 7 years. There were no episodes of vomiting, seizures, headache, visual disturbances, flushing, or abdominal pain. The family history was unremarkable with no similar symptoms reported in either siblings or parents. Auxological evaluation was carried out at the age of 8 years and 3 months, and it revealed a height of 114.5 cm, which was 2 SD below the mean for her age. The parental target height was 148.56 cm, which was 1.6 SD below the mean for adult height (Fig. 1). Her weight was 37 kg and body mass index (BMI) was 28.22 kg/m2, which was above the 95th percentile, categorizing her as obese. Tanner pubertal staging showed breast stage B1 bilaterally, pubic hair stage P1, and absent axillary hair. Physical examination revealed grade 3 acanthosis nigricans, moon facies, facial plethora, acne on the face, and a dorsocervical fat pad (Fig. 2). However, there were no characteristic wide purple striae, easy bruisability, or hyperpigmentation of the skin. Signs of hyperandrogenism, such as hirsutism or clitoromegaly were absent, except for facial acne. Cutaneous examination showed no features of CNC, such as spotty skin pigmentation, blue nevi, or cutaneous myxomas. Her blood pressure was 160/100 mm of Hg, exceeding the 99th percentile for her age and height, without a postural drop. Systemic examination was unremarkable, with no breast masses, nerve thickening, or other stigmata of CNC.

Growth chart by the Indian Academy of Pediatrics [9] illustrating the patient's progression. At baseline, the patient's height was 114.5 cm, placing her below the 3rd percentile for her age, while her weight was 37 kg, corresponding to the 75th to 90th percentile range. Five months after bilateral adrenalectomy, she exhibited a 9-cm increase in height and a 10-kg reduction in weight.

Figure 1.

Growth chart by the Indian Academy of Pediatrics [9] illustrating the patient’s progression. At baseline, the patient’s height was 114.5 cm, placing her below the 3rd percentile for her age, while her weight was 37 kg, corresponding to the 75th to 90th percentile range. Five months after bilateral adrenalectomy, she exhibited a 9-cm increase in height and a 10-kg reduction in weight.

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A and B, clinical signs of Cushing syndrome observed during physical examination: moon facies, dorsocervical fat pad, generalized obesity, short stature, and facial acne. C, Follow-up photograph taken 5 months after bilateral adrenalectomy, showing a reduction in weight, resolution of facial acne and acanthosis, and an increase in height.

Figure 2.

A and B, clinical signs of Cushing syndrome observed during physical examination: moon facies, dorsocervical fat pad, generalized obesity, short stature, and facial acne. C, Follow-up photograph taken 5 months after bilateral adrenalectomy, showing a reduction in weight, resolution of facial acne and acanthosis, and an increase in height.

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Diagnostic Assessment

Biochemical investigations revealed dyslipidemia, while fasting plasma glucose, 2-hour post-glucose plasma glucose, liver function tests, and renal function tests were within normal limits. Hematological evaluation showed neutrophilic leukocytosis. Fasting serum insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) were elevated, signifying marked insulin resistance (Table 1). Serum cortisol levels measured at 08:00 hours, 16:00 hours, and midnight were elevated, indicating a loss of the normal diurnal cortisol rhythm (Table 2). Serum cortisol levels following the overnight dexamethasone suppression test (ONDST), low-dose dexamethasone suppression test (LDDST), and high-dose dexamethasone suppression test (HDDST) were non-suppressible, confirming the presence of endogenous CS. There was no paradoxical rise in serum cortisol following HDDST. Serum ACTH levels were suppressed both at 08:00 hours and at midnight, indicating an ACTH-independent etiology of hypercortisolism (Table 2). The levels of androgens such as serum testosterone and dehydroepiandrosterone sulfate were within normal limits. Plasma aldosterone concentration (PAC), plasma renin activity (PRA) and PAC to PRA ratio were all within the normal range as shown in Table 2.

Table 1.
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Results of biochemical and hematological testing

Parameter (reference range) Value (baseline) Value (5 months postsurgery)
Fasting plasma glucose
(70-100 mg/dL; 3.9-5.6 mmol/L)		 81 mg/dL(4.4 mmol/L) 63 mg/dL (3.5 mmol/L)
2-hour post-glucose plasma glucose
(70-100 mg/dL (3.9-7.8 mmol/L)		 110 mg/dL (6 mmol/L) 79 mg/dL (4.4 mmol/L)
Serum insulin (3-35 mU/L; 21.5-251 pmol/L) 44.6 mU/L (319.6 pmol/L) 14 mU/L (100.3 pmol/L)
HbA1c
(4-5.6%; 20-38 mmol/mol)		 5.5% (37 mmol/mol) 5.5% (37 mmol/mol)
HOMA-IR
(0.5-1.4)		 8.9 2.2
Serum total cholesterol
(<200 mg/dL; <5.2 mmol/L)
Age 0-19 years:
(<170 mg/dL; 4.3 mmol/L)		 188 mg/dL (4.9 mmol/L) 130 mg/dL (3.4 mmol/L)
Serum LDL
(<100 mg/dL; <2.6 mmol/L)		 123 mg/dL (3.2 mmol/L) 85 mg/dL (2.2 mmol/L)
Serum HDL
Males: (>40 mg/dL; >1 mmol/L)
Females: (>50 mg/dL; >1.3 mmol/L)
Age 0-19 years:
(>45 mg/dL; >1.2 mmol/L)		 46 mg/dL (1.2 mmol/L) 23 mg/dL (0.6 mmol/L)
Serum triglyceride
(<150 mg/dL; <1.7 mmol/L)
Age 0-9 years:
(<75 mg/dL; <1.0 mmol/L)		 93 mg/dL (1.0 mmol/L) 85 mg/dL (0.9 mmol/L)
Hemoglobin
(11-16 g/dL; 6.8-9.9 mmol/L)		 13.6 g/dL (8.4 mmol/L) 12.7 g/dL (7.8 mmol/L)
Total leukocyte count
(4000-11 000 cells/µL)		 16 170 cells/µL 6550 cells/µL
Total platelet count
(1.5–4×105 cells/µL)		 4.79×105 cells/µL 2.00×105 cells/µL
Differential count
Neutrophils
(40%-75%)
Lymphocytes
(20%-45%)
Eosinophils
(1%-6%)
Monocytes
(2%-10%)
Basophils
(0%-0.5%)		 71.8%
24%
1.2%
3%
0%		 41%
52%
5%
2%
0%

Abbreviations: HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; LDL, low-density lipoprotein.

Table 2.

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Results of dynamic testing of serum cortisol, serum ACTH, and other hormonal assessment

Parameter (reference range) Value
Serum cortisol
0800 Am (5-25 µg/dL; 138-690 nmol/L) 28.5 µg/dL (786.6 nmol/L)
0400 Pm (3-10 µg/dL; 82.8-276 nmol/L) 24.9 µg/dL (686.1 nmol/L)
Midnight (awake) (<7.5 µg/dL; <207 nmol/L) 25.9 µg/dL (714.6 nmol/L)
Post ONDST (<1.8 µg/dL; <50 nmol/L) 31.9 µg/dL (879.8 nmol/L)
Post LDDST (<1.8 µg/dL; <50 nmol/L) 24.7 µg/dL (680.6 nmol/L)
Post HDDST (<1.8 µg/dL; <50 nmol/L) 25 µg/dL (690 nmol/L)
Serum ACTH
Midnight (5-22 pg/mL; 1.1-4.8 pmol/L) 1.5 pg/mL (0.34 pmol/L)
0800 Am (10-60 pg/mL; 2.3-13.6 pmol/L) 1.2 pg/mL (0.27 pmol/L)
Androgens
Serum DHEAS (10-193 µg/dL; 0.27-5.23 µmol/L) 13.6 µg/dL(0.37 µmol/L)
Serum testosterone (5-13 ng/dL; 0.17-0.45 nmol/L) 11.41 ng/dL(0.39 nmol/L)
Renin-aldosterone axis
PAC (<40 ng/dL; <1100 pmol/L) 8 ng/dL (220 nmol/L)
PRA (0.8-2.0 ng/mL/h; 10.24-25.6 pmol/L/min) 1.2 ng/mL/h (15.36 pmol/L/min)
PAC to PRA ratio (<30 ng/dL per ng/mL/h; <60 pmol/L per pmol/L/min) 6.67 ng/dL per ng/mL/h (14.3 pmol/L per pmol/L/min)

Abbreviations: ACTH, adrenocorticotropic hormone; DHEAS, dehydroepiandrosterone sulfate; HDDST, high-dose dexamethasone suppression test; LDDST, low-dose dexamethasone suppression test; ONDST, overnight dexamethasone suppression test; PAC, plasma aldosterone concentration; PRA, plasma renin activity.

Adrenal imaging with both computed tomography (CT) and magnetic resonance imaging (MRI) showed no abnormalities in either adrenal gland (Fig. 3). Based on these clinical findings, hormonal profile, and normal imaging results, PPNAD was suspected.

Adrenal computed tomography (CT) showing normal adrenals bilaterally (white arrows).

Figure 3.

Adrenal computed tomography (CT) showing normal adrenals bilaterally (white arrows).

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Blood was collected in an EDTA vial, and DNA was extracted for targeted gene capture using a custom kit. Sequences were aligned to the human reference genome (GRCh38) using BWA aligner (Sentieon, PMID: 20080505). Variants were identified with Sentieon haplotype caller, and copy number variants were detected using ExomeDepth (PMID: 22942019) method. This identified a heterozygous exonic duplication ∼24.97 Kb at genomic location chr19:g.(? 14092580)(14117547_? )dup on chromosome 19p13, which comprises the PRKACA gene. This was a heterozygous autosomal dominant variant and confirmed the diagnosis of PPNAD.

Treatment

The child was started on antihypertensive therapy, requiring a combination of 3 medications; amlodipine, enalapril, and spironolactone to achieve adequate blood pressure control. She subsequently underwent bilateral laparoscopic adrenalectomy at our institute. During the procedure, she received steroid coverage with a continuous infusion of hydrocortisone at 4 mg per hour, which was maintained for 48 hours postoperatively. This was followed by oral hydrocortisone replacement therapy at a dose of 15 mg/m²/day in 3 divided doses along with oral fludrocortisone at 100 µg/day. The intraoperative and postoperative periods were uneventful.

On gross examination, the excised adrenal glands appeared unremarkable (Fig. 4A). However, histopathological examination using hematoxylin and eosin (H&E) staining revealed multiple round-to-oval nodules within the adrenal cortex of both glands (Fig. 4B and 4C). Nodules were well-defined but unencapsulated. These nodules were composed of large polygonal lipid-poor cells with abundant eosinophilic granular cytoplasm containing lipofuscin granules. The peri-nodular cortex showed compression atrophy. These findings were consistent with a diagnosis of PPNAD [10].

A, Gross image of the excised adrenal glands B, Histopathological findings of adrenal tissue stained with hematoxylin and eosin (H&E) stain, showing nonencapsulated micronodules (green arrows) with internodular cortical atrophy. C, Magnified image of a single cortical nodule showing an unencapsulated nodule composed of large polygonal lipid-poor cells with abundant eosinophilic granular cytoplasm with lipofuscin granules. Nuclei show prominent nucleoli. Peri-nodular cortex shows compression atrophy (H&E stain, 400X).

Figure 4.

A, Gross image of the excised adrenal glands B, Histopathological findings of adrenal tissue stained with hematoxylin and eosin (H&E) stain, showing nonencapsulated micronodules (green arrows) with internodular cortical atrophy. C, Magnified image of a single cortical nodule showing an unencapsulated nodule composed of large polygonal lipid-poor cells with abundant eosinophilic granular cytoplasm with lipofuscin granules. Nuclei show prominent nucleoli. Peri-nodular cortex shows compression atrophy (H&E stain, 400X).

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Outcome and Follow-Up

By postoperative day 7, the patient’s blood pressure had normalized, allowing discontinuation of antihypertensive medications. She was initially started on hydrocortisone in 3 divided doses which was later converted to 2 divided doses. She was stable and reported no adrenal crises during the follow-up period of 5 months. Throughout this period, she demonstrated consistent clinical improvement, with resolution of acne, improvement in cushingoid facies, and sustained normotension without the need for antihypertensive medications. At 5 months after surgery, she showed significant clinical recovery, evidenced by a weight loss of 10 kg, a height gain of 9 cm, and a reduction in BMI from 28.22 to 16 kg/m², as shown in Figs. 1 and 2. Biochemical analysis at this stage revealed normalization of serum insulin levels, a reduction in HOMA-IR, and a normalized lipid profile.

Discussion

The diagnosis of PPNAD is often challenging in the absence of characteristic features of CNC. Approximately 90% of PPNAD cases occur as part of CNC. CNC is associated with typical manifestations such as spotty skin pigmentation, blue cutaneous nevi, cardiac myxomas, and tumors at various sites [2, 3]. PPNAD typically presents in young adults, often as cyclical CS and less frequently as classical CS [11]. Childhood onset of PPNAD is exceedingly rare [12]. In the absence of CNC, certain diagnostic indicators, such as a paradoxical rise in serum cortisol following a HDDST, may serve as important clues for diagnosing PPNAD. However, no paradoxical rise was observed in our case. The utility of imaging in diagnosing PPNAD is limited, as adrenal CT scans are often unremarkable [13]. A case series of 88 patients with confirmed PPNAD reported normal-appearing adrenals in 45% of cases, while bilateral adrenal nodularity or enlargement was identified in only 12% and 27% of cases, respectively [14]. MRI adds minimal diagnostic value. Given these limitations, a high index of clinical suspicion and genetic analysis are crucial for establishing a definitive diagnosis of PPNAD. Genetic confirmation is particularly important, as bilateral adrenalectomy, which is curative, requires lifelong steroid replacement therapy. Pathogenic variants in the PRKAR1A gene are the most common genetic abnormality in PPNAD, found in 79.5% of cases. Pathogenic variants in the PDE11A gene are the second most common and are found in 26.5% cases [15].

PKA is a heterotetramer composed of 2 regulatory subunits and 2 catalytic subunits. Four regulatory subunits (RIα, RIβ, RIIα, and RIIβ) and 4 catalytic subunits (Cα, Cβ, Cγ and Prkx) have been identified [15]. In its inactive state, the regulatory subunits are bound to the catalytic subunits, maintaining the complex in an inhibited configuration. Under normal physiological conditions, ACTH binds to the melanocortin-2 receptor (MC2R) on zona fasciculata cells of the adrenal cortex, activating adenylate cyclase. Adenylate cyclase enhances the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) [15]. Increased intracellular cAMP induces a conformational change in PKA, resulting in the release of the catalytic subunits. The liberated catalytic subunits phosphorylate downstream targets, such as cAMP–response element-binding protein (CREB), which in turn drives the transcription of genes involved in cortisol synthesis and adrenocortical cell proliferation. Duplication of PRKACA gene results in constitutive activation of the catalytic subunit alpha of PKA [16]. This aberrant activation enhances downstream signaling pathways of PKA, leading to increased cortisol biosynthesis and adrenocortical cell proliferation, ultimately culminating in PPNAD.

Pathogenic variants of the PRKACA gene causing PPNAD are exceedingly rare, with only 3 cases reported in the literature to date (Table 3) [6‐8]. To the best of our knowledge, the present case is the first reported female patient with PPNAD caused by a pathogenic variant of PRKACA gene, presenting in the first decade of life. This case highlights that PPNAD caused by pathogenic PRKACA variants can manifest as an isolated condition in childhood without other features of CNC.

Table 3.

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Previously reported cases of PPNAD with pathogenic variants of PRKACA

S. No. Age (years) Gender PRKACA defect Clinical features Authors (year of reporting)
1. 22 Female Copy number gain variation of size 431 kb spanning genomic region 19p13.13p13.12, which contains the PRKACA gene PPNAD with Cushing syndrome and features of CNC Wang-Rong Yang et al (2024) [6]
2. 8 Male Copy number duplication in PRKACA gene PPNAD with Cushing syndrome, without any features of CNC Xu Yuying et al (2023) [8]
3. 21 Female Point mutation in PRKACA gene at 95th nucleotide, substituting Adenine with Thymine (c.95 A > T) PPNAD with Cushing syndrome, without any features of CNC Wan Shuang et al (2022) [7]
4.
(current case)		 8 Female Heterozygous duplication of size 24.9 kb, spanning genomic location chr19:g.(?_14092580)_(14117547_?)dup, comprising the PRKACA gene PPNAD with Cushing syndrome, without any features of CNC

Abbreviations: CNC, Carney complex; PPNAD, primary pigmented nodular adrenocortical disease; PRKACA, catalytic subunit alpha of protein kinase A.

Learning Points

  • PRKACA duplication is a rare but important cause of PPNAD and should be considered during genetic testing, especially in the absence of pathogenic variants of PRKAR1A gene and classical CNC features.

  • Normal adrenal imaging and absence of CNC manifestations do not exclude the diagnosis of PPNAD, emphasizing the importance of comprehensive clinical evaluation and genetic testing.

  • The potential genotypic correlation between pathogenic variants of the PRKACA gene and CNC remains uncertain and requires further research.

Acknowledgments

We acknowledge the contributions of the Departments of Urology, Paediatric Surgery, Anaesthesiology and Paediatrics at our institute for surgical management and postoperative care of the reported case. We extend our sincere gratitude to Dr. Manoj Kumar Patro for his significant contributions to the histopathological evaluation of the case.

Contributors

All authors made individual contributions to authorship. P.R.K., D.K.D., D.P., B.D., J.K.M., and B.S.D. were involved in the diagnosis, management, and manuscript submission. All authors reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

None declared

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient’s relatives or guardians.

Data Availability Statement

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Abbreviations

 

    • ACTH

      adrenocorticotropic hormone

 

    • BMI

      body mass index

 

    • cAMP

      cyclic adenosine monophosphate

 

    • CNC

      Carney complex

 

    • CS

      Cushing syndrome

 

    • CT

      computed tomography

 

    • HOMA-IR

      homeostatic model assessment of insulin resistance

 

    • HDDST

      high-dose dexamethasone suppression test

 

    • LDDST

      low-dose dexamethasone suppression test

 

    • MRI

      magnetic resonance imaging

 

    • ONDST

      overnight dexamethasone suppression test

 

    • PAC

      plasma aldosterone concentration

 

    • PKA

      protein kinase A

 

    • PPNAD

      primary pigmented nodular adrenocortical disease

 

  • PRA

    plasma renin activity

© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.
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From Weight Gain To Diabetes

Posted on March 10, 2025 by MaryO
Cushing’s syndrome happens when the body has too much cortisol, the stress hormone. It can cause weight gain, high blood pressure, and diabetes. So how to keep your health in check and what are the treatment options available? In an exclusive interview with Times Now, an Endocrinologist explains its symptoms, causes, and treatments.
We often blame stress for everything—from sleepless nights to stubborn weight gain. But did you know your body’s stress hormone, cortisol, could be at the root of more serious health issues like high blood pressure and diabetes? Yes, you read that right! But how? We got in touch with Dr Pranav A Ghody, Endocrinologist at Wockhardt Hospital, Mumbai Central, who explains how excessive cortisol levels can lead to a condition known as Cushing’s Syndrome.
What Exactly is Cortisol, and Why is it Important?
Hormones are the body’s chemical messengers, travelling through the bloodstream to regulate essential functions. Among them, cortisol, produced by the adrenal glands (tiny glands sitting above the kidneys), plays a crucial role in controlling blood pressure, blood sugar, energy metabolism, and inflammation. The pituitary gland, located at the base of the brain, regulates cortisol through another hormone called Adrenocorticotropic Hormone (ACTH).
Often referred to as the “stress hormone,” cortisol spikes when we’re under stress. However, when levels remain high for too long, it can lead to Cushing’s Syndrome, a disorder first identified in 1912 by Dr Harvey Cushing.

What Causes Cushing’s Syndrome?

Dr Ghody explains that Cushing’s Syndrome occurs when the body is exposed to excessive cortisol, which can happen in two ways:

1. Exogenous (External) Cushing’s Syndrome
This is the most common form and results from prolonged use of steroid medications (such as prednisone) to treat conditions like asthma, rheumatoid arthritis, and lupus, or to prevent transplant rejection. Since steroids mimic cortisol, long-term use can disrupt the body’s hormone balance.
2. Endogenous (Internal) Cushing’s Syndrome
This occurs when the body produces too much cortisol due to a tumour in the pituitary gland, adrenal glands, or other organs (lungs, pancreas, thymus). While rare—affecting about 10 to 15 people per million annually—it’s more common in women between 20 and 50 years old. When caused by a pituitary tumour, it’s specifically called Cushing’s Disease.

Symptoms: How To Recognize Signs Of Cushing’s Syndrome

Excess cortisol affects multiple organs, leading to a variety of symptoms. This includes:

– Weight gain around the belly (central obesity)
– Rounded, puffy face (moon face)
– Excess facial and body hair (hirsutism)
– Fat accumulation on the upper back (buffalo hump)
– Thin arms and legs
– Dark red-purple stretch marks on the chest and abdomen
– Extreme fatigue and muscle weakness
– Depression or anxiety
– Easily bruising with minimal trauma
– Irregular menstrual cycles in women
– Reduced fertility or low sex drive
– Difficulty sleeping
High blood pressure and newly diagnosed or worsening diabetes are also common red flags.

Why is Cushing’s Syndrome Often Misdiagnosed?

Dr Ghody explains that while severe cases of Cushing’s Syndrome are easier to identify, milder forms can often be missed or mistaken for conditions like obesity, diabetes, or polycystic ovary syndrome (PCOS).

Diagnosing Cushing’s Syndrome involves:
1. Measuring cortisol levels in the blood, urine, or saliva.
2. Identifying the source through ACTH hormone testing, MRI/CT scans, and advanced techniques like Inferior Petrosal Sinus Sampling (IPSS) or nuclear medicine scans
Treatment Options: How is Cushing’s Syndrome Managed?
Once diagnosed, the treatment depends on the cause:
– If due to steroid medication, the dosage is gradually reduced under medical supervision.
– If caused by a tumour, surgery is the primary treatment. Some patients, especially those with pituitary tumours, may require repeat surgery, gamma knife radiosurgery, or medications to control cortisol levels.

Can You Prevent Cushing’s Syndrome?

While complete prevention isn’t always possible, Dr Ghody shares some key strategies to reduce risk:

– Use steroids cautiously – If prescribed, take the lowest effective dose for the shortest time. Never stop abruptly without consulting a doctor.
– Genetic screening for people at risk – If you have a family history of pituitary or adrenal tumours, regular monitoring can help with early detection.
– Maintain a healthy lifestyle – A diet rich in fresh vegetables, and fruits, low sodium intake, adequate calcium, and vitamin D can help manage the metabolic effects of excess cortisol.
– Avoid alcohol and tobacco – These can further disrupt hormone balance and overall health.
“Cushing’s Syndrome can be life-threatening if left untreated, but early diagnosis and proper management can significantly improve quality of life. So if you experience unexplained weight gain, blood pressure spikes, or other symptoms, consult an endocrinologist to manage hormonal imbalances,” he said.

Filed under: Cushing's, Diagnostic Testing, symptoms, Treatments | Tagged: , , , , , | Leave a comment »

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