A Preliminary Model to Tailor Osilodrostat In Patients With Adrenocorticotropic Hormone (ACTH)-Dependent Cushing’s syndrome

Posted on October 10, 2025 by MaryO

Abstract

Over the past 10 years, osilodrostat has become one of the most commonly used steroidogenesis inhibitors in patients with Cushing’s syndrome. The starting dose is usually determined based on the product characteristics, the prescriber’s experience, and cortisol levels. However, no study has attempted to determine whether there was a dose–response relationship between osilodrostat and cortisol reduction. In this study, we developed a preliminary kinetic–pharmacodynamic model to tailor osilodrostat in patients with Adrenocorticotropin hormone (ACTH)-dependent Cushing’s syndrome. We first analyzed the decrease in cortisol 48 hours after initiation or dose change of osilodrostat in 18 patients. Simulations were then performed for different doses of osilodrostat to evaluate the variation in cortisol concentrations. Our results report the first dose–response relationship between osilodrostat dose and cortisol levels, which should be helpful in identifying the optimal dosing regimen in patients with Cushing’s syndrome and in individualizing treatment to approximate a nychthemeral rhythm.

osilodrostat, Cushing’s syndrome, Cushing’s disease, cortisol, adrenal insufficiency
Issue Section:

Brief Report

Significance

The current preliminary study is a first step in trying to better understand the effect of osilodrostat on cortisol, which should help determine the optimal dose for each patient.

Introduction

Cushing’s syndrome is a rare condition in which increased cortisol levels lead to a wide range of comorbidities and increased mortality. Surgery is usually regarded as the first-line and most effective treatment.1 In some cases, cortisol-lowering drugs are necessary, mainly after failed surgery.2,3 Among several steroidogenesis inhibitors such as ketoconazole and metyrapone,4,5 osilodrostat, which acts through inhibition of 11β-hydroxylase, is now being considered an effective drug in controlling cortisol hypersecretion. Initially designed as a CYP11B2 inhibitor, the study by Ménard et al.6 involving both animal models and healthy human subjects showed that osilodrostat reduced cortisol levels from a dose of 1 mg/day, while lower doses exerted an anti-aldosterone effect. Since then, several clinical trials and retrospective studies emphasized its efficacy in all etiologies of Cushing’s syndrome.7-9 While the usual recommended starting dose is 2 mg twice a day, precise studies on the short-term effect of osilodrostat on plasma cortisol are lacking. These data could, however, be of interest to tailor the treatment. Moreover, baseline urinary free cortisol (UFC) level is not able to predict response to osilodrostat.10 Taking advantage of serial cortisol measurements performed in inpatient clinics in our center at the time osilodrostat became available, we developed a pharmacokinetic (PK)/pharmacodynamic model of plasma cortisol variation as a function of osilodrostat dose in patients with Adrenocorticotropin-hormone (ACTH)-dependent Cushing’s syndrome.

Patients and methods

Clinical data and hormonal measurements

We retrospectively included patients with ACTH-dependent Cushing’s syndrome, who had serial measurements of plasma cortisol (every 4 hours for 24 hours) before and after the first osilodrostat dose between 2019 and 2024. These measurements were part of our standard of care approach when osilodrostat became available in our tertiary expert center as a thorough evaluation of the efficacy and tolerance of a new drug. The initial dose ranged from 2 to 15 mg/day, depending on the severity of hypercortisolism. Subsequently, osilodrostat dose was gradually adjusted based on the successive cortisol measurements described above. Sex, age at diagnosis, and etiologies were recorded, as well as plasma cortisol measurements 48 hours after the initiation or any change in the osilodrostat dose and time elapsed since change of dose and last administration were recorded. All plasma cortisol measurements were performed with the same Elecsys II Cortisol, Cobas (Roche Diagnostics) assay in the hormonal laboratory of our center; cross-reactivity with 11-deoxycortisol is 4.9%. According to our institutional policy, this retrospective study did not require specific signed informed consent from patients as the data collected were anonymized. It was thus approved by the Ethics Committee of Assistance Publique—Hopitaux de Marseille (RGPD PADS reference RUXXX2). The current study complies with the Declaration of Helsinki.

Pharmacokinetics and statistical analysis

The pharmacodynamic parameters of osilodrostat on cortisol concentrations were analyzed using a kinetic–pharmacodynamic (PD) model in the software Nonlinear Mixed Effects Modeling version 7.4 (NONMEM Icon Development Solutions, Ellicott City, MD, United States). PK analysis from a previously published study6 was used to predict plasma concentration in our patients. The PK parameters were described in the article, and mean concentration values were obtained by digitizing the graph of osilodrostat vs time using the software WebPlotDigitizer version 4.2.11 With these data, a one-compartment population PK model was used to predict osilodrostat concentrations for different dosing regimens. Direct and indirect relationship between osilodrostat-predicted concentration and variation of cortisol concentrations were evaluated to consider a delay. The variation of cortisol concentrations was calculated with reference to a session without treatment. Several functions were tested to describe the relationship such as linear and sigmoidal. Model selection and evaluation were done by the likelihood ratio test (objective function), goodness-of-fit plots (observed vs predicted variation of cortisol concentrations, observed vs individual predictions, normalized prediction distribution errors vs time and variation of cortisol predictions), bootstrap, and visual predictive checks. Graphical analysis was performed with the R software version 4.4.012 using the ggplot2 package.13 Simulations were performed for different doses of osilodrostat to evaluate the variation on cortisol concentrations using the package rxode2.14

Results

Of the patients who were prescribed osilodrostat at least once between 2019 and 2024, 18 were presenting ACTH-dependent Cushing’s syndrome, 12 women (66.6%) and 6 men (33.3%). Mean age was 53.2 ± 15 years. The cause of Cushing’s syndrome was Cushing’s disease in 16 patients (88.9%), ectopic ACTH secretion in 1 patient (5.6%), and ACTH-dependent hypercortisolism of uncertain diagnosis in 1 patient (5.6%). Clinical characteristics are presented in Table 1. It should be noted that none of the patients included were Asian.

 

 

Table 1.

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Clinical characteristics of patients with all included patients and differentiated according to gender.

All patientsa Women Men
Age at diagnosis 53.2 ± 15 54 ± 17.2 51.5 ± 10.5
Weight 81.7 ± 13.7 79.5 ± 12.7 86.2 ± 15.6
% of CD 88.9 83.3 100
ULN of 24 hour UFC 4.4 ± 8.3 5.5 ± 10.3 2.5 ± 1.8
Osilodrostat starting dose 3.3 ± 2.2 3.7 ± 2.4 2.5 ± 1.4
Cortisol before osilodrostat intake 422.9 ± 159.2 414.7 ± 176.6 439.4 ± 130.7
Cortisol 4 hour after osilodrostat 404 ± 165.6 408.2 ± 200.1 395.5 ± 70.8

 

Abbreviations: CD, Cushing’s disease; ULN, upper limit range; UFC, urinary free cortisol.

aOf note, none of the included patients were Asian.

In their article, Ménard et al.6 showed that the dose–exposure relationship was not strictly proportional. A one-compartment model was enhanced by increasing the relative bioavailability with the dose and was estimated that the dose resulting in a 50% increase in bioavailability was 1.06 mg. The PK parameters derived from Ménard et al.6 were fixed and used to predict osilodrostat concentration in our patients. A direct relationship between the predicted osilodrostat concentrations and variation of cortisol concentrations (%) gave a better fit than an indirect model. The drug effect was modeled with the following sigmoidal function (Eq. 1);

(1)

where Imax is the maximal inhibition and IC50 is the apparent half-maximal inhibitory concentration.

The estimated PD parameters were IC50 and Imax. Their values as well as the relative standard errors (RSE%) and the corresponding bootstrap IC50 are shown in Table 2. Final parameters were used to simulate n = 500 profiles following a single dose of osilodrostat.

 

 

 

Table 2.

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Pharmacodynamic parameters of osilodrostat’s effects on the variation of cortisol concentrations.

Parameters Unit Estimation RSE% Bootstrap
0.025 0.975
KA (fixed)a 1/hour 4.03 — — —
CL/F (fixed)a L/hour 18.3 — — —
V/F (fixed)a L 125 — —
Imax % 44.5 18.7 12.51 90.9
IC50 mg/L 0.011 37.4 0.0001 0.10
Interindividual variability (ω)
 Imax 0.40 30.9 0.003 1.86
 IC50 3.78 41.0 0.003 9.22
Residual unexplained variability (σ)
 Additive % 23.8 12.2 18.2 29.9

 

Abbreviations: CL/F, apparent clearance; IC50, osilodrostat concentration associated with half the maximal inhibition of the cortisol variation; Imax, maximum inhibitory effect of osilodrostat on the variation of cortisol; KA, first-order absorption rate constant; RSE, relative standard error; V/F, apparent volume of distribution.

 

aAdapted from Ménard et al.6

The effects on plasma cortisol variation are depicted in Figure 1. Cortisol concentration declines during the first hour after taking osilodrostat, from 24% for a 1 mg dose to over 42% for a 20 mg dose. Thereafter, from the first hour onward, cortisol increases progressively, with loss of treatment efficacy occurring around the 10th-15th hour for 1 and 2 mg, while for doses above 5 mg, a moderate effect persists over the following hours. Figure 2 shows the variation in cortisol concentration for a 2 mg dose, with median decrease in cortisol variation of 31%, ranging from 0% to 67.5%, with, as mentioned above, a maximum effect 1 hour after osilodrostat intake, and a progressive increase in cortisol levels, mainly during the 12 hours following treatment. The same analysis for 10 mg revealed a median reduction in cortisol of 38%, ranging from 5% to 80%. Figure 3 describes the relationship between osilodrostat concentration and cortisol variation, showing that the maximum effect corresponds to the maximum concentration and that a decrease in osilodrostat concentration results in an increase in cortisol level.

Relationship between time since last administration of osilodrostat and cortisol concentrations.

Figure 1.

Relationship between time since last administration of osilodrostat and cortisol concentrations.

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Visual predictive variation on cortisol concentrations following 2 or 10 mg osilodrostat administration.

Figure 2.

Visual predictive variation on cortisol concentrations following 2 or 10 mg osilodrostat administration.

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Relation between osilodrostat concentration and cortisol variation.

Figure 3.

Relation between osilodrostat concentration and cortisol variation.

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Discussion

To the best of our knowledge, this is the first study that attempts to define a dose/efficacy relationship between osilodrostat dose and the variation of plasma cortisol. First, our results suggest that the effect of osilodrostat appears immediately after the peak of concentration, 1 hour after treatment intake, which highlights the parallel evolution of osilodrostat and cortisol concentrations. This is unusual, as typically effect peak takes few hours, following concentration peak.15 The relationship between osilodrostat concentration and the effect on cortisol is not linear but sigmoidal with a rapid increase in concentrations producing a rapid significant effect, leading to a maximal effect. Because elimination is a slower process than absorption, the effect’s decline will also be slower: this means that efficiency remains stable during the first 5 hours, with a further progressive increase of cortisol and a loss of efficiency around 10-15 hours after intake. This confirms the need for two intakes per day, with one early in the morning and the other 12 hours later in the evening. In addition, even if our simulation suggests a wide interindividual variability, we were able to determine the impact of different doses of osilodrostat on the percent decrease in plasma cortisol levels. For instance, 20 mg osilodrostat leads to an estimated 42% decrease in cortisol concentration. Interestingly, Ferrari et al.16 recently showed that patients controlled with two doses of osilodrostat for at least 1 month had the same efficacy with a single intake (combing both doses) at 4 or 7 Pm. This is quite surprising and will need to be evaluated in future studies: our preliminary model could give more precise information on this point.

Cushing’s syndrome is also characterized by a loss of circadian rhythm leading to increased comorbidities such as diabetes, hypertension, and cardiovascular disease.17,18 This is why 24 hour UFC can only be considered an imperfect marker of glucocorticoid overexposure even though it is an easy-to-use marker, as exemplified by its use in all the clinical trials performed on cortisol-lowering drugs.7,8,10,19 Predicting the efficacy of osilodrostat on plasma cortisol might be helpful to tailor the treatment as a titrating approach. Of note, some studies suggested that there might be an inpatient variability of cortisol secretion in Cushing’s syndrome,20 and this might account for a bias in our results. However, none of our patients had cyclical Cushing’s syndrome. Moreover, 12 patients in our cohort had at least two cortisol cycles (every 4 hours during the day) before starting treatment. A comparison of these two cycles using Student’s t-test showed no significant difference (P = .7), indicating no obvious spontaneous variability. Our preliminary report gives interesting insights into the maximal efficacy expected for a single dose of osilodrostat, thus defining the initial dosage needed to rapidly control hypercortisolism, as opposed to the dose currently recommended by the manufacturer (2 mg twice daily). Thus, our results could help define an optimal dose in the morning, but also in the evening, with the aim of re-establishing a circadian profile. This will, however, have to be confirmed on an interventional study focusing on comorbidities, quality of life and their potential improvements while using this PK model.

The main limitation of this proof-of-concept study is the large CI. This may be due to the relatively low number of patients and the fact that cortisol was measured every 4 hours instead of every hour, but also to the large variability in efficacy between subjects. Due to the number of patients included in the analysis, it was not possible to investigate further if a covariate, such as the gender, may explain these differences between individuals. It is important to highlight that although our model predicts cortisol levels 1 hour post intake as the most reliable predictor of future efficacy, cortisol measurements were taken every 4 hours. Thus, this finding should be confirmed in prospective studies with more frequent cortisol measurements, particularly 1 hour after osilodrostat administration. While the kinetic–pharmacodynamic approach used in this study can present with some inherent limitations, this type of approach is regularly used to define the modalities of use for a medication in a new indication. A nonlinear mixed-effects modeling allows the use of data from the routine clinical follow-up of patients. This method is thus effective and particularly well-suited for sparse data. Finally, a larger study could include closer measurements of cortisol. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) is the best method for avoiding cross-reactivity with steroid precursors and could be used for these measurements. However, we used the Elecsys Cortisol II Immunoassay, which shows <5% cross-reactivity with 11-deoxycortisol; thus, our results are credible.

In conclusion, we designed a kinetic–pharmacodynamic model to adapt osilodrostat in patients with ACTH-dependent Cushing’s syndrome. Our model shows that cortisol level 1 hour after treatment is the best indicator of future efficacy. Moreover, depending on the initial cortisol level and the goal to be achieved, different doses should be prescribed. Despite wide inter-patient variability, we believe our model provides insight into the minimal dose necessary to decrease cortisol levels and the maximal efficacy expected for a given dose. Thus, it should help physicians tailor the treatment to reach maximal efficacy in the shortest possible time. The next step will be to analyze whether this percent decrease remains stable on a long-term basis or becomes more important with time, as suggested by some clinical cases showing delayed adrenal insufficiency on stable doses of osilodrostat.21

Authors’ contributions

Cecilia Piazzola (Conceptualization [equal], Formal analysis [equal], Writing—original draft [equal]), Frederic Castinetti (Conceptualization [equal], Formal analysis [equal], Writing—review & editing [equal]), Katharina von Fabeck (Conceptualization [equal], Writing—review & editing [equal]), and Nicolas Simon (Conceptualization [equal], Methodology [equal], Supervision [equal], Validation [equal], Writing—original draft [equal], Writing—review & editing [equal])

Funding

This work received an unrestricted educational grant from Recordati Rare Diseases.

To see the references and the original article, please go here: https://academic.oup.com/ejendo/article/193/4/K11/8255719?login=false

 

Filed under: adrenal crisis, Clinical trials, Cushing's, pituitary, Treatments | Tagged: , , , | Leave a comment »

A Case 0f Hailey–Hailey Disease Accompanied by Cushing’s Syndrome and Adrenal Insufficiency Due to Long-Term Usage of Topical Steroids With Review of Literature

Posted on August 14, 2025 by MaryO
Abstract

Hailey–Hailey disease (HHD), or familial benign chronic pemphigus, is a rare autosomal dominant disorder characterized by recurrent vesicles and erosions in intertriginous areas. Topical corticosteroids are the primary treatment, but their potential systemic side effects are often overlooked. Prolonged use on compromised skin can lead to excessive absorption, increasing the risk of iatrogenic Cushing’s syndrome and adrenal insufficiency.

Here, we report the case of a 50-year-old woman with HHD who had been using topical clobetasol or betamethasone for over 10 years, reaching doses up to 50 g/day.

She developed Cushingoid features, metabolic abnormalities, and suppression of the hypothalamic–pituitary–adrenal (HPA) axis. After tapering off topical corticosteroids, she developed adrenal insufficiency and associated withdrawal symptoms. Following the initiation of hydrocortisone replacement therapy, psychiatric symptoms, impaired glucose tolerance, and osteoporotic fractures emerged, suggesting exacerbation of iatrogenic Cushing’s syndrome.

This case highlights the risk of systemic complications from chronic topical corticosteroid use, particularly in high-absorption areas. Gradual dose reduction, close endocrine monitoring, and individualized tapering strategies are essential to prevent severe outcomes.

Clinicians should be aware of potential adrenal suppression and consider endocrine evaluation in patients receiving prolonged, high-dose topical corticosteroid therapy.

Filed under: adrenal, Cushing's, Rare Diseases | Tagged: , , , , , , | Leave a comment »

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

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

Adrenal Insufficiency May Be Misdiagnosed as Anxiety

Posted on November 23, 2024 by MaryO

The hormone cortisol is produced by the adrenal glands, so adrenal insufficiency (also called Addison’s disease) is caused when the adrenal glands do not produce cortisol normally. Low cortisol can actually cause anxiety and depression, so some patients may really have anxiety — though doctors need to do further testing and/or evaluation to see that it is caused by their hormone levels, not a mental illness.

“I have adrenal insufficiency, which can cause depression and anxiety as a sign and symptom of low cortisol. After attempting hospitalization for depression, we found that I’d been living on almost undetectable cortisol for at least a year,” Sarah Reilley said. “Now that I’m on hydrocortisone replacement, my depression and anxiety are nearly gone and serve to warn me when my cortisol is dangerously low! I’m really lucky to be alive.”

Read about other conditions that may be misdiagnosed as anxiety here: https://themighty.com/topic/chronic-illness/misdiagnosed-anxiety-symptoms/

Filed under: Addison's disease, adrenal, adrenal crisis | Tagged: , , , , | Leave a comment »

Iatrogenic Cushing Syndrome and Adrenal Suppression Presenting as Perimenopause

Posted on November 12, 2024 by MaryO

JCEM Case Reports, Volume 2, Issue 11, November 2024, luae183, https://doi.org/10.1210/jcemcr/luae183

Abstract

Secondary adrenal insufficiency is a life-threatening condition that may arise in the setting of iatrogenic Cushing syndrome. Intra-articular corticosteroid injections (IACs) are a standard treatment for osteoarthritis, and they carry a high risk of secondary central adrenal suppression (SAI). We present the case of a 43-year-old woman who was referred to reproductive endocrinology for evaluation of abnormal uterine bleeding with a provisional diagnosis of perimenopause. She reported new-onset type 2 diabetes mellitus, abdominal striae, hot flashes, and irregular menses. Laboratory evaluation revealed iatrogenic Cushing syndrome and SAI attributable to prolonged use of therapeutic IACs for osteoarthritis. Treatment included hydrocortisone replacement and discontinuation of IACs followed by hydrocortisone taper over the following 16 months that resulted in the return of endogenous ovarian and adrenal function. This case demonstrates the many hazards of prolonged IAC use, including suppression of ovarian and adrenal function and iatrogenic SAI.

Introduction

Intra-articular corticosteroid injections (IACs) are commonly used for the treatment of symptomatic osteoarthritis [1]. Synovial injections carry the highest risk of secondary central adrenal suppression (SAI) [2-5]. Further, exogenous glucocorticoid administration may also result in secondary Cushing syndrome. Symptoms associated with exogenous glucocorticoid administration vary significantly, and misdiagnosis is common [6, 7]. Here, we present a case of exogenous IAC use resulting in SAI and Cushing syndrome in a 43-year-old woman who was referred for evaluation and treatment of abnormal uterine bleeding with a provisional diagnosis of perimenopause.

Case Presentation

A 43-year-old woman with a past medical history of fibromyalgia, osteoarthritis, bursitis, asthma, gastroesophageal reflux, and diabetes was referred to reproductive endocrinology with a chief complaint of hot flashes for over 2 years and a presumptive diagnosis of perimenopause. Approximately 2 years before the onset of her symptoms, she reported irregular menses, followed by 11 months of amenorrhea, then 3 menstrual intervals with prolonged bleeding lasting 45, 34, and 65 days, respectively. She reported menarche at 11 years old, regular menstrual cycles until the last 2 years, and 4 pregnancies that were spontaneously conceived. She delivered 3 liveborn term children and had one spontaneous miscarriage. Her only complication of pregnancy was gestational hypertension during her last pregnancy that occurred 9 years prior when she was 34 years old.

In addition to menstrual irregularity, she also reported hot flashes, increasing truncal weight gain over the last 5 years, new-onset diabetes mellitus, and hypertension. Eighteen months prior to referral, she had an endometrial biopsy, which demonstrated secretory endometrium without hyperplasia, and cervical cancer screening was negative.

She initially reported the following medications: inhaled fluticasone/propionate + salmeterol 232 mcg + 14 mcg as needed and albuterol 108 mcg as needed. Her daily medications were glimepiride 1 mg, furosemide 20 mg, omeprazole 20 mg, montelukast 10 mg, azelastine hydrochloride 137 mcg, ertugliflozin 5 mg, and tiotropium bromide 2.5 mg. Importantly, she did not report IAC treatments.

Diagnostic Assessment

Initial physical examination showed height of 160 cm, weight of 103.4 kg, body mass index (BMI) of 46 kg/m2, and blood pressure (BP) of 128/80. Physical exam was significant for round facies with plethora, bilateral dorsocervical neck fat pads, and violaceous striae on her abdomen and upper arms (Fig. 1). The patient ambulated with a cane and reported severe bilateral proximal leg atrophy and weakness.

 

Abdominal and upper extremity striae prior to treatment with truncal obesity immediately before (A) and 1 year after initial diagnosis (B).

Figure 1.

Abdominal and upper extremity striae prior to treatment with truncal obesity immediately before (A) and 1 year after initial diagnosis (B).

A laboratory evaluation was recommended but was not initially completed. She was scheduled for a transvaginal ultrasound that required prior authorization; the pelvic ultrasound showed a heterogeneous and thickened anterior uterine wall, suggestive of adenomyosis, with a posterior intramural fibroid measuring 15 × 15 mm and an anterior intramural fibroid measuring 15 × 8 mm. Endometrial lining was thin at 5 mm. Both ovaries were small, without masses or antral follicles. Three-dimensional reconstruction showed a normal uterine cavity with some heterogeneity of the endometrial lining but no discrete masses suggestive of polyps or intracavitary fibroids as the cause of irregular bleeding. Upon additional questioning, she acknowledged receiving bilateral shoulder, hip, and knee injections of triamcinolone 80 mg every 2 to 3 months to each joint for about 5 years. Table 1 shows the initial laboratory evaluation and includes age-appropriate low ovarian reserve as evidenced by anti-Müllerian hormone (AMH), secondary hypothalamic hypogonadism, diabetes mellitus, and central adrenal suppression. Of note, the diabetes mellitus developed after 3 years of IAC use. Additional diagnostic assessment for adrenal insufficiency by synacthen testing was scheduled, however, the patient declined further investigation.

Initial laboratory values at presentation

Result Reference range
Basic metabolic panel
 Sodium 141 mEq/L; 141 mmol/L 135 to 145 mEq/L; 135 to 145 mmol/L
 Potassium 3.7 mEq/L; 3.7 mmol/L 3.7 to 5.2 mEq/L; 3.7 to 5.20 mmol/L
 Chloride 104 mEq/L; 104 mmol/L 96 to 106 mEq/L; 96 to 106 mmol/L
 Carbon dioxide 25 mEq/L; 25 mmol/L 23 to 29 mEq/L; 23 to 29 mmol/L
 Creatinine 0.42 mg/dL; 37.14 µmol/L 0.6 to 1.3 mg/dL; 53 to 114.9 µmol/L
 Urea nitrogen 14 mg/dL; 5 mmol/L 6 to 20 mg/dL; 2.14 to 7.14 mmol/L
Adrenal function
 Cortisol 0.8 µg/dL; 22.07 nmol/L 4-22 µg/dL; 138-635 nmol/L
 ACTH <5 pg/mL; <1 pmol/L 6-50 pg/mL; 5.5-22 pmol/L
 DHEAS 8 mcg/dL; 0.02 µmol/L 15-205 mcg/dL; 1.36-6.78 µmol/L
Endocrine function
 HbA1c 8.5% <5.7%
 Random glucose 124 mg/dL; 6.9 mmol/L 80-100 mg/dL; 4.4-5.5 mmol/L
 TSH 1.74 mIU/L 0.5-5 mIU/L
 tT4 10.5 µg/dL; 135.2 nmol/L 5.0-12.0 µg/dL; 57-148 nmol/L
 Free T4 index 2.6 ng/dL; 33.4 pmol/L 0.7-1.9 ng/dL; 12-30 pmol/L
 tT3 165 ng/dL; 2.5 nmol/L 60-180 ng/dL; 0.9-2.8 nmol/L
 TPO antibody Negative n/a
Ovarian function
 FSH 5.6 IU/L 4.5-21.5 IU/L
 LH 2.9 IU/L 5-25 IU/L
 Progesterone <0.5 ng/mL; 1.6 nmol/L Varies
 Estradiol 21 pg/mL; 77.1 pmol/L Varies
 AMH 1.1 ng/mL; 7.9 pmol/L 1.0-3.0 ng/mL; 2.15-48.91 pmol/L

Abbreviations: ACTH, adrenocorticotropic hormone; AMH, anti-Müllerian hormone; DHEAS, dehydroepiandrosterone sulfate; eGFR, estimated glomerular filtration rate; FSH, follicle-stimulating hormone; HbA1c, hemoglobin A1C; LH, luteinizing hormone; TPO antibody, thyroid peroxidase antibody; TSH, thyroid stimulating hormone; tT4, total thyroxine.

Treatment

The patient was immediately started on hydrocortisone 10 mg twice daily for glucocorticoid replacement, which was gradually reduced to 5 mg daily each morning at 16 months. Endocrine function testing was trended over the following months as replacement cortisone therapy was tapered.

Outcome and Follow-Up

Within 6 months of replacement and cessation of IACs, hot flashes ceased, and she reported regular menses. She lost 6.8 kg, her truncal obesity and striae significantly improved (Fig. 1), and she could now ambulate without assistance. Her glycated hemoglobin (HbA1c) level decreased from 8.5% to 6.8%. Fourteen months after her initial diagnosis and cessation of IAC, laboratory studies demonstrated partial recovery of adrenal and ovarian function and improved metabolism, as evidenced by increases in morning cortisol, adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate (DHEAS), and decreased HbA1c. At 16 months, she had a return of ovulatory ovarian function.

Discussion

Cortisol is the main glucocorticoid secreted by human adrenal glands. The secretion pattern is precisely regulated by an integrated limbic-hypothalamic-pituitary (LHP) drive with the physiologic goal of homeostasis [1]. Conditions that result in deviations in glucocorticoid concentrations carry a variety of consequences. Our patient was referred because of a provisional diagnosis of abnormal uterine bleeding and perimenopause, which distracted from recognition of iatrogenic Cushing syndrome and secondary central adrenal suppression. This patient vignette underscores the importance of explicitly asking patients about nonoral medications, as patients may not report their use.

Exogenous administration of long-acting synthetic glucocorticoids may suppress adrenal function via negative feedback at the limbic and hypothalamic levels, which was reflected in this patient by undetectable ACTH and low cortisol levels (Table 1). In addition, excess glucocorticoid levels result in other neuroendocrine concomitants, including suppression of gonadotropin-releasing hormone (GnRH) drive that results in hypothalamic hypogonadism [8, 9], decreased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and anovulation despite AMH levels indicating residual ovarian reserve [10]. The clinical phenotype is variable and reflects individual glucocorticoid receptor sensitivities [9].

Regardless of cause, Cushing syndrome often presents with hallmark features of central obesity, violaceous striae, easy bruising, round facies, and nuchal adiposity with lower limb muscle atrophy and loss of strength [11]. Additionally, glucocorticoid excess causes insulin resistance and metabolic syndrome [8]. Truncal obesity is a common presenting symptom of excess cortisol. Cortisol inhibits metabolic response to insulin centrally and peripherally and increases gluconeogenesis, which together predispose to and cause diabetes [10].

Exogenous use of injectable glucocorticoids carries the highest risk of adrenal suppression when compared to other routes of exogenous steroids [5]. Patients typically report fatigue, malaise, and gastrointestinal complaints. Oligomenorrhea is a common presenting complaint in women, as was the case in our patient. Hyponatremia, water retention, and hypotension may occur in SAI because of endogenous glucocorticoid deficiency. A thorough laboratory evaluation in this patient revealed low LH, FSH, estradiol, and progesterone levels, indicating hypothalamic hypogonadism and not perimenopause/menopause [12] and low levels of cortisol, ACTH, and DHEAS confirmed SIA [10].

Adrenal insufficiency can be a life-threatening condition that requires supplementation with glucocorticoids [10, 13, 14]. A review of patients diagnosed with SAI suggested tapering of hydrocortisone before discontinuing all replacement therapy and revealed most patients recover without the need for exogenous steroids after 2 years from diagnosis [14]. ACTH stimulation testing may indicate the return of adrenal function [14, 15]. Our patient showed increased ACTH, cortisol, and DHEAS at 14 months. Ovulatory ovarian function, indicated by progesterone < 5 ng/mL (< 1.59 nmol/L) (Table 2), returned at 16 months after cessation of IACs. The improvement in adrenal and ovarian function following cessation of IACs and tapering of hydrocortisone replacement therapy was accompanied by decreased HbA1c, weight loss, truncal obesity, and stria, and increased muscle strength scalp hair.

 
Table 2.

Endocrine lab results 7 years prior, at presentation (T0), and over the next 16 months

Analyte Reference range 7 years prior T0 1 month 7 months 13 months 14 months 16 months
DHEAS 15-205 µg/dL; 1.36-6.78 nmol/L — 8 µg/dL; 0.22 nmol/L 5 µg/dL;
0.14 nmol/L		 6 µg/dL;
0.16 nmol/L		 22 µg/dL; 0.59 nmol/L 28 µg/dL; 0.76 nmol/L 24 µg/dL; 0.65 nmol/L
Cortisol 4-22 µg/dL; 138-635 nmol/L — 0.9 µg/dL;
24.83 nmol/L		 5.8 µg/dL;
160.01 nmol/L		 3.0 µg/dL;
82.76 nmol/L		 3.9 µg/dL;
107.59 nmol/L		 11.2 µg/dL;
308.99 nmol/L		 12.6 µg/dL;
347.61 nmol/L
ACTH 6-50 pg/mL; 5.5-22 pmol/L — <5 pg/mL;<1.10 pmol/L <5 pg/mL;<1.10 pmol/L <5 pg/mL;<1.10 pmol/L <5 pg/mL;<1.10 pmol/L 11 pg/mL;
2.42 pmol/L		 10 pg/mL;
2.20 pmol/L
HbA1c <5.7% 5.0% 8.5% 8.5% 7.8% 5.8% 5.7% 5.7%
LH 5-25 IU/L — 5.8 IU/L 2.9 IU/L — 3.3 IU/L 5.2 IU/L 5.7 IU/L
FSH 4.5-21.5 IU/L — 6.2 IU/L 5.6 IU/L — 2.0 IU/L 3.5 IU/L 1.3 IU/L
Estradiol Varies — 21 pg/mL;
77.09 pmol/L		 74 pg/mL;
271.65 pmol/L		 — 101 pg/mL;
370.77 pmol/L		 — 121 pg/mL;
444.19 pmol/L
Progesterone Varies — <0.5 ng/mL;<1.59 nmol/L <0.5 ng/mL;<1.59 nmol/L — <0.5 ng/mL;<1.59 nmol/L — 6.6 ng/mL;
20.99 nmol/L

Abbreviations: ACTH, adrenocorticotropic hormone, DHEAS, dehydroepiandrosterone sulfate, FSH, follicle-stimulating hormone, LH, luteinizing hormone, T0, time at presentation.

In conclusion, exogenous glucocorticoids, specifically intra-articular injections, carry the highest potential for iatrogenic Cushing syndrome and secondary adrenal insufficiency. Glucocorticoid excess has a variable presentation that often obscures diagnosis. As this scenario demonstrates, careful physical and laboratory assessment and tapering of hydrocortisone replacement eventually can lead to restoration of adrenal, ovarian, and metabolic function and improved associated symptoms.

Learning Points

  • Exogenous intra-articular glucocorticoid use may suppress adrenal and ovarian function via central suppression of ACTH and GnRH.
  • Cushing syndrome presents with a broad spectrum of signs and symptoms that may be mistaken for individual conditions, such as perimenopause and isolated diabetes mellitus.
  • Exogenous steroid use may lead to Cushing syndrome and subsequent adrenal insufficiency, which is life-threatening.
  • Treatment of adrenal insufficiency with a long-term exogenous glucocorticoid taper allows for subsequent return of adrenal and ovarian function.

Contributors

All authors contributed to authorship. S.L.B. was involved in the diagnosis and management of the patient, and manuscript editing. S.A. was involved in patient follow-up and manuscript development. J.M.G. was responsible for manuscript development and editing. All authors reviewed and approved the final draft.

Funding

None declared.

Disclosures

S.L.B. reports ClearBlue Medical Advisory Board, 2019—present

Emblem Medical Advisory Board, Amazon Services, 2022—present

Medscape, 2023

Myovant, May 2023

Omnicuris, 2023

Sage Therapeutics and Biogen Global Medical, Zuranolone OB/GYN Providers Advisory Board, Dec 2022, March 2023

Member, Board of Trustees, Salem Academy and College, Salem, NC: 2018-present (Gratis)

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient.

Data Availability Statement

Originally data generated and analyzed in this case are reported and included in this article.

References

1

Johnston
PC

,

Lansang
MC

,

Chatterjee
S

,

Kennedy
L

.

Intra-articular glucocorticoid injections and their effect on hypothalamic-pituitary-adrenal (HPA)-axis function

.

Endocrine

.

2015

;

48

(

2

):

410

‐

416

.

2

Stout
A

,

Friedly
J

,

Standaert
CJ

.

Systemic absorption and side effects of locally injected glucocorticoids

.

PM R

.

2019

;

11

(

4

):

409

‐

419

.

3

Prete
A

,

Bancos
I

.

Glucocorticoid induced adrenal insufficiency

.

BMJ

.

2021

;

374

:

n1380

.

4

Herman
JP

,

McKlveen
JM

,

Ghosal
S

, et al.

Regulation of the hypothalamic-pituitary-adrenocortical stress response

.

Compr Physiol

.

2016

;

6

(

2

):

603

‐

621

.

5

Broersen
LH

,

Pereira
AM

,

Jørgensen
JO

,

Dekkers
OM

.

Adrenal insufficiency in corticosteroids use: systematic review and meta-analysis

.

J Clin Endocrinol Metab

.

2015

;

100

(

6

):

2171

‐

2180

.

6

Tan
JW

,

Majumdar
SK

.

Development and resolution of secondary adrenal insufficiency after an intra-articular steroid injection

.

Case Rep Endocrinol

.

2022

;

2022

:

4798466

.

7

Colpitts
L

,

Murray
TB

,

Tahhan
SG

,

Boggs
JP

.

Iatrogenic cushing syndrome in a 47-year-old HIV-positive woman on ritonavir and inhaled budesonide

.

J Int Assoc Provid AIDS Care

.

2017

;

16

(

6

):

531

‐

534

.

8

Lee
SM

,

Hahm
JR

,

Jung
TS

, et al.

A case of Cushing’s syndrome presenting as endometrial hyperplasia

.

Korean J Intern Med

.

2008

;

23

(

1

):

49

‐

52

.

9

Yesiladali
M

,

Yazici
MGK

,

Attar
E

,

Kelestimur
F

.

Differentiating polycystic ovary syndrome from adrenal disorders

.

Diagnostics (Basel)

.

2022

;

12

(

9

):

2045

.

10

Raff
H

,

Sharma
ST

,

Nieman
LK

.

Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia

.

Compr Physiol

.

2014

;

4

(

2

):

739

‐

769

.

11

Unuane
D

,

Tournaye
H

,

Velkeniers
B

,

Poppe
K

.

Endocrine disorders & female infertility

.

Best Pract Res Clin Endocrinol Metab

.

2011

;

25

(

6

):

861

‐

873

.

12

Peacock
K

,

Carlson
K

,

Ketvertis
KM.

Menopause.

StatPearls

.

StatPearls Publishing, Copyright © 2024, StatPearls Publishing LLC.

,

2024

.

13

Foisy
MM

,

Yakiwchuk
EM

,

Chiu
I

,

Singh
AE

.

Adrenal suppression and Cushing’s syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature

.

HIV Med

.

2008

;

9

(

6

):

389

‐

396

.

14

Draoui
N

,

Alla
A

,

Derkaoui
N

, et al.

Assessing recovery of adrenal function in glucocorticoid-treated patients: our strategy for screening and management

.

Ann Med Surg (Lond)

.

2022

;

78

:

103710

.

15

Joseph
RM

,

Hunter
AL

,

Ray
DW

,

Dixon
WG

.

Systemic glucocorticoid therapy and adrenal insufficiency in adults: a systematic review

.

Semin Arthritis Rheum

.

2016

;

46

(

1

):

133

‐

141

.

Abbreviations

 

  • ACTH

    adrenocorticotropic hormone

  • AMH

    anti-Müllerian hormone

  • DHEAS

    dehydroepiandrosterone sulfate

  • FSH

    follicle-stimulating hormone

  • HbA1c

    glycated hemoglobin

  • IAC

    intra-articular corticosteroid

  • LH

    luteinizing hormone

  • SAI

    secondary central adrenal suppression

Published by Oxford University Press on behalf of the Endocrine Society 2024.
This work is written by (a) US Government employee(s) and is in the public domain in the US. See the journal About page for additional terms.

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