Reconstructive Liposuction for Residual Lipodystrophy After Remission of Cushing’s Disease

Posted on July 3, 2025 by MaryO

​Abstract

Cushing’s syndrome (CS) is often presented due to an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, characterized by high chronic cortisol levels. Surgical resection of the pituitary adenoma is the primary treatment, but long-term metabolic and physical sequelae can persist, affecting psychological well-being and social functioning. Glucocorticoids are directly involved in alterations of fat metabolism, favoring centripetal adiposity. Even after hormonal normalization, patients may experience residual lipodystrophy. Impairment of body image may cause psychological distress and social isolation. The objective is to illustrate the potential therapeutic value of reconstructive liposuction in restoring body image and psychological well-being in a patient with persistent lipodystrophy after Cushing’s disease remission.

We report a case of a 16-year-old female with recurrent Cushing’s disease secondary to a pituitary microadenoma, confirmed by elevated urinary free cortisol and magnetic resonance imaging (MRI). It was initially treated with transsphenoidal resection in 2019; disease recurrence was confirmed and again treated in 2024. Despite intervention, the prolonged hypercortisolism developed into secondary lipodystrophy, leading to severe body image dissatisfaction and social withdrawal. Thyroid function remained euthyroid, ruling out metabolic contributors. Because of the psychological distress caused by persistent fat redistribution, the patient underwent elective liposuction in 2025. Postoperative follow-up revealed reduced psychological distress and improved well-being and self-esteem. Reconstructive liposuction can play a key role in the treatment and management of persistent post-CS lipodystrophy, contributing significantly to psychological recovery. Prospective studies evaluating surgical criteria and long-term psychosocial outcomes are needed to define eligibility criteria and assess outcomes, leading to the development of clinical guidelines for aesthetic interventions in post-CS recovery.

Introduction

Corticotroph pituitary adenomas (corticotropinomas) are pituitary tumors that secrete excess adrenocorticotropic hormone (ACTH), causing endogenous Cushing’s syndrome (CS). Most of these adenomas are sporadic and monoclonal, although in some rare cases, they are associated with germline mutations (e.g., in USP8) or genetic syndromes [1,2]. Clinically, excess ACTH causes a classic presentation with centripetal obesity, purple striae, muscle asthenia, hypertension, and emotional disturbances such as depression or anxiety [3-5]. Chronically elevated cortisol levels promote fat deposition in central body regions – face, neck, torso, and abdomen – at the expense of relative thinning of the limbs [3], leading to lipodystrophy that can seriously affect the patient’s quality of life.

At the molecular level, glucocorticoids stimulate the differentiation of preadipocytes into mature adipocytes and enhance lipoprotein lipase activity in peripheral fat tissues [6], thereby increasing the uptake of circulating fatty acids and the storage of triglycerides. At the same time, they increase hepatic lipogenesis and modulate cortisol receptor homeostasis (e.g., 11β-HSD1 in adipose tissue), favoring visceral fat distribution [6]. Although glucocorticoids can induce acute lipolysis, they exert chronic lipogenic effects – especially in subcutaneous adipose tissue – which promotes fat accumulation in the face, neck, and trunk [6]. This central adiposity, characteristic of CS, is further enhanced by increased hepatic lipogenesis and the overexpression of 11β-HSD1 in adipose tissue, which amplifies the local action of cortisol [6].

Case Presentation

In 2019, a 16-year-old female patient was initially diagnosed with a 4 × 3 mm pituitary microadenoma (Figure 1), following clinical suspicion of Cushing’s disease. The diagnosis was confirmed through imaging studies and endocrinological testing, which revealed consistently elevated urinary free cortisol levels ranging from 459 to 740.07 µg/24 hours (normal range: <50 µg/24 hours), indicative of endogenous hypercortisolism. No dynamic load tests (such as dexamethasone suppression or ACTH stimulation) were performed, as the diagnosis was supported by the clinical context and laboratory findings. Moreover, no clinical or biochemical evidence of adrenal insufficiency was observed during follow-up.

T1-weighted-sagittal-MRI-scan-showing-a-corticotroph-pituitary-microadenoma-(4-×-3-mm)-circled-in-red
Figure 1: T1-weighted sagittal MRI scan showing a corticotroph pituitary microadenoma (4 × 3 mm) circled in red

The lesion is localized within the anterior pituitary gland, consistent with an ACTH-secreting adenoma causing Cushing’s disease in the patient.

MRI, magnetic resonance imaging; ACTH, adrenocorticotropic hormone

The patient underwent transsphenoidal endonasal resection of the pituitary tumor in 2019. Although initially successful, disease recurrence was confirmed, and a second endonasal transsphenoidal surgery was performed in 2024. Despite these interventions, the prolonged hypercortisolism led to the development of secondary lipodystrophy, manifesting as centripetal fat accumulation, a dorsal fat pad, and disproportionate truncal adiposity (Figure 2). These physical alterations had a significant psychosocial impact, as reported by the patient during follow-up visits, resulting in body image dissatisfaction, low self-esteem, and social withdrawal. No formal psychometric scales were administered.

Preoperative-and-intraoperative-images-of-the-patient
Figure 2: Preoperative and intraoperative images of the patient

A and B panels show the anterior and posterior views prior to liposuction, demonstrating centripetal adipose accumulation characteristic of Cushing’s syndrome. The C panel shows the intraoperative stage following abdominal and flank liposuction, with placement of drainage tubes, and visible reduction in subcutaneous fat volume.

A thyroid function panel revealed a slightly elevated thyroid-stimulating hormone (TSH) level (4.280 μUI/mL; reference range: 0.270-4.200), with total and free T3 and T4 values within normal limits, ruling out clinically significant hypothyroidism as a confounding factor for her phenotype. The biochemical profile suggested a euthyroid state, despite borderline TSH elevation, which was interpreted as a subclinical or adaptive response to chronic cortisol excess (Table 1).

Parameter Normal Range Patient’s Value
Cortisol (µg/24 hour) 58.0 – 403.0 459.5 – 740.07
TSH (µUI/mL) 0.270 – 4.200 4.280
Total T3 (ng/mL) 0.80 – 2.00 1.02
Free T3 (pg/mL) 2.00 – 4.40 3.33
Total T4 (µg/dL) 4.50 – 12.00 8.63
Free T4 (ng/dL) 0.92 – 1.68 1.36
Table 1: Comparison between the patient’s hormone levels and standard reference ranges

A persistently elevated 24-hour urinary cortisol range is observed, consistent with endogenous hypercortisolism. The thyroid profile remains within normal limits, with a mildly elevated TSH in the absence of overt thyroid dysfunction. These findings support the functional and metabolic profile characteristic of Cushing’s syndrome.

TSH, thyroid-stimulating hormone

The procedure targeted lipodystrophic regions identified through clinical examination and patient concerns, rather than formal imaging or anthropometric measurements. It aimed to restore body contour, alleviate somatic distress, and improve her overall self-perception and quality of life. Postoperative follow-up revealed patient-reported improvements in body image and psychological well-being. While these outcomes were not evaluated with formal instruments, the clinical improvement was evident and significant from the patient’s perspective, highlighting the role of plastic surgery not only as a reconstructive tool, but also as a therapeutic strategy for restoring dignity and social functioning in patients recovering from CS.

Discussion

After successful treatment of the pituitary adenoma, many metabolic parameters improve; however, fat distribution usually only partially reverses. Longitudinal studies show that, in the medium term, weight and abdominal circumference decrease, and there is some redistribution of fat toward the limbs following cortisol remission [3].

For example, Bavaresco et al. (2024) observed that, after hormone levels normalized, total fat was reduced and part of it shifted from the visceral area to the legs [3]. Nevertheless, their review highlights that a significant proportion of patients continue to present with residual visceral adiposity and moderate obesity (body mass index, or BMI >25), despite hormonal control [7]. In our case, truncal adiposity persisted based on clinical assessment, though no formal anthropometric measurements were performed.

Although liposuction is not traditionally considered first-line therapy for cortisol-induced lipodystrophy secondary to Cushing’s disease, increasing evidence from related lipodystrophic syndromes supports its clinical utility. For instance, in human immunodeficiency virus (HIV)-associated cervicodorsal lipodystrophy, Barton et al. (2021) conducted a 15-year retrospective analysis comparing liposuction and excisional lipectomy, finding that 80% of patients undergoing liposuction alone experienced recurrence, while none of the patients treated with excisional lipectomy showed recurrence – albeit with a higher risk of postoperative seroma formation [7]. These findings underscore that, while liposuction may be less durable than excision, it remains a viable option for selected cases, especially when used for contouring or as an adjunct [7]. Similarly, the Endocrine Society guidelines on lipodystrophy management emphasize the importance of personalized approaches, particularly when localized adipose accumulation contributes to persistent metabolic dysfunction or psychological distress [8]. Akinci et al. (2024) also highlight that, even in partial or atypical lipodystrophy syndromes, patients often report substantial impairment in quality of life due to disfiguring fat redistribution [9]. In this context, liposuction should not be dismissed as merely cosmetic but considered part of a functional and psychosocial rehabilitation strategy. The present case exemplifies this rationale, as the patient – despite biochemical remission of Cushing’s disease – continued to experience debilitating body image disturbances and emotional distress, which were ameliorated following targeted liposuction. This supports the integration of body-contouring procedures into multidisciplinary care protocols for endocrine-related lipodystrophies, especially when residual physical stigma persists after hormonal normalization [7-9].

Body image disorders, such as those secondary to CS or lipodystrophy, significantly impact self-perception, self-esteem, and social functioning. For example, a study by Alcalar et al. (2013) reported that patients with active Cushing’s disease had significantly lower SF-36 scores – particularly in emotional role functioning and mental health domains – compared to controls [10]. Similarly, Akinci et al. (2024) described that patients with partial lipodystrophy demonstrated marked reductions in EQ-5D index values and visual analog scale (VAS) scores, indicating impaired health-related quality of life [9]. These findings underscore that fat redistribution disorders can substantially compromise psychosocial well-being, even after endocrine remission.

This is especially relevant in women, where sociocultural stereotypes surrounding female physical appearance reinforce thinness, symmetry, and youthfulness as standards of personal value and social acceptance [1]. This societal context amplifies body dissatisfaction when visible physical changes occur, even after the clinical remission of endocrine diseases, often leading to social withdrawal, anxiety, or depression [3,10]. Within this framework, plastic surgery – such as reconstructive liposuction – has proven to be a valuable therapeutic tool, offering physical restoration that can enhance self-confidence and promote social reintegration [4]. Postoperative follow-up in our case revealed patient-reported improvements in body image and psychological well-being. While these outcomes were not assessed using formal psychometric tools, the clinical benefit was evident from the patient’s perspective. This aligns with prior findings demonstrating the psychosocial value of reconstructive surgery, which can enhance self-esteem and social reintegration after physical disfigurement [11,12]. These observations underscore the role of plastic surgery not only as a reconstructive intervention, but also as a therapeutic strategy for restoring dignity and quality of life in patients recovering from CS.

Although validated psychometric instruments such as the Body Image Quality of Life Inventory (BIQLI) and the Dysmorphic Concern Questionnaire (DCQ) are available to assess body image disturbances, these were not applied in our case. Nonetheless, they represent useful tools for evaluating subjective impact in both clinical practice and research settings. The BIQLI evaluates the effect of body image on various aspects of life – social interactions, self-worth, sexuality, and emotional well-being – using a Likert scale ranging from -3 (very negative impact) to +3 (very positive impact), providing a quantifiable assessment of its influence on quality of life [5]. The DCQ, on the other hand, identifies dysfunctional concerns about perceived physical flaws by assessing behaviors such as avoidance, mirror checking, and concealment; higher scores are associated with suspected body dysmorphic disorder (BDD) [6]. These tools are useful for initial diagnosis, surgical candidate selection, and postoperative follow-up, as they objectively measure subjective changes related to body image. Their advantages include ease of use, clinical validity, and applicability in research settings. However, they also have limitations: they do not replace comprehensive psychological evaluation, may be influenced by cultural context, and do not detect deeper psychiatric comorbidities. Therefore, a multidisciplinary and ethically grounded approach – integrating plastic surgery, endocrinology, and psychology – is essential to ensure safe and patient-centered treatment planning.

Aesthetic liposuction is associated with significant improvements in perceived body image and patient quality of life [11]. For example, Papadopulos et al. (2019) observed statistically significant increases in perception of one’s own body appearance and high satisfaction with postoperative results [12]. These aesthetic gains were accompanied by psychological improvements: the same study documented an increase in emotional stability and a reduction in postoperative anxiety [12]. Similarly, Kamundi (2023) found that nearly all assessed dimensions of quality of life improved after liposuction (p < 0.05 in most of them). Altogether, these findings suggest that liposuction not only corrects physical alterations typical of CS, but also strengthens self-esteem and psychological well-being by substantially improving satisfaction with one’s body image [11].

Moreover, self-esteem influences adherence to medical treatments and lifestyle changes. By improving self-image through reconstructive surgery, it is plausible that the patient feels more motivated to maintain healthy habits, such as diet and regular exercise, that prevent metabolic relapse [12,13].

Nonetheless, it is important to emphasize that liposuction, in this context, should be viewed as a reconstructive complement, not a primary treatment. There are no established protocols or formal guidelines that explicitly include plastic surgery in the care of cured CS; the decision is personalized, based on the residual functional and psychological impact.

Conclusions

Reconstructive plastic surgery, though not a primary therapeutic approach for CS, plays a key role in enhancing patients’ quality of life following remission. Liposuction, in particular, offers a safe and effective solution for persistent lipodystrophy, providing aesthetic benefits with minimal scarring, rapid recovery, and low complication rates in properly selected patients.

This case underscores the importance of addressing both physical and psychosocial sequelae after endocrine stabilization. A multidisciplinary approach – encompassing endocrinology, neurosurgery, and plastic surgery – not only restores physical appearance but also contributes to emotional recovery, self-esteem, and overall patient satisfaction.

References

  1. Tatsi 😄 Cushing syndrome/disease in children and adolescents. Endotext [Internet]. Feingold KR, Ahmed SF, Anawalt B, et al. (ed): MDText.com, Inc., South Dartmouth (MA); 2000.
  2. Mir N, Chin SA, Riddell MC, Beaudry JL: Genomic and non-genomic actions of glucocorticoids on adipose tissue lipid metabolism. Int J Mol Sci. 2021, 22:8503. 10.3390/ijms22168503
  3. Bavaresco A, Mazzeo P, Lazzara M, Barbot M: Adipose tissue in cortisol excess: what Cushing’s syndrome can teach us?. Biochem Pharmacol. 2024, 223:116137. 10.1016/j.bcp.2024.116137
  4. Nieman LK: Molecular derangements and the diagnosis of ACTH-dependent Cushing’s syndrome. Endocr Rev. 2022, 43:852-77. 10.1210/endrev/bnab046
  5. Patni N, Chard C, Araujo-Vilar D, Phillips H, Magee DA, Akinci B: Diagnosis, treatment and management of lipodystrophy: the physician perspective on the patient journey. Orphanet J Rare Dis. 2024, 19:263. 10.1186/s13023-024-03245-3
  6. Peckett AJ, Wright DC, Riddell MC: The effects of glucocorticoids on adipose tissue lipid metabolism. Metabolism. 2011, 60:1500-10. 10.1016/j.metabol.2011.06.012
  7. Barton N, Moore R, Prasad K, Evans G: Excisional lipectomy versus liposuction in HIV-associated lipodystrophy. Arch Plast Surg. 2021, 48:685-90. 10.5999/aps.2020.02285
  8. Brown RJ, Araujo-Vilar D, Cheung PT, et al.: The diagnosis and management of lipodystrophy syndromes: a multi-society practice guideline. J Clin Endocrinol Metab. 2016, 101:4500-11. 10.1210/jc.2016-2466
  9. Akinci B, Celik Gular M, Oral EA: Lipodystrophy syndromes: presentation and treatment. Endotext [Internet]. Feingold KR, Anawalt B, Boyce A, et al. (ed): MDText.com, Inc., South Dartmouth (MA); 2024.
  10. Alcalar N, Ozkan S, Kadioglu P, Celik O, Cagatay P, Kucukyuruk B, Gazioglu N: Evaluation of depression, quality of life and body image in patients with Cushing’s disease. Pituitary. 2013, 16:333-40. 10.1007/s11102-012-0425-5
  11. Kamundi RK: Determining the Impact of Liposuction on Patient Satisfaction of Quality of Life and Body Image: A Prospective Study in Nairobi, Kenya. University of Nairobi, Nairobi; 2023.
  12. Papadopulos NA, Kolassa MJ, Henrich G, Herschbach P, Kovacs L, Machens HG, Klöppel M: Quality of life following aesthetic liposuction: a prospective outcome study. J Plast Reconstr Aesthet Surg. 2019, 72:1363-72. 10.1016/j.bjps.2019.04.008
  13. Saariniemi KM, Salmi AM, Peltoniemi HH, Charpentier P, Kuokkanen HOM: Does liposuction improve body image and symptoms of eating disorders?. Plast Reconstr Surg Glob Open. 2015, 3:461. 10.1097/GOX.0000000000000440

From https://www.cureus.com/articles/376886-reconstructive-liposuction-for-residual-lipodystrophy-after-remission-of-cushings-disease-a-case-report#!/

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Double Synchronous Functional Pituitary Adenomas Causing Acromegaly and Subclinical Cushing Disease

Posted on July 1, 2025 by MaryO

Abstract

Double pituitary adenomas with growth hormone (GH) and adrenocorticotropic hormone (ACTH) secretion are very rare. They are responsible for acromegaly with hypercortisolism. Subclinical corticotropic adenomas are exceptional.
Herein, we report the case of a patient with double functional pituitary adenomas causing acromegaly and subclinical Cushing’s disease. A 45-year-old woman was referred to our Department for suspected acromegaly. Her past medical history included diabetes mellitus treated with oral antidiabetic drugs and hypertension.
On physical examination, she had a large prominent forehead, thickened lips, increased interdental spacing, prognathism, and enlarged hands and feet. No signs of hypercortisolism were found. Biological investigations showed an elevated insulin growth factor-1 (IGF-1) level at 555 ng/mL, a GH nadir after 75 g oral glucose tolerance test at 2 ng/mL, a morning cortisol level at 158 ng/mL, an ACTH level at 64 pg/mL, a thyroid stimulating hormone (TSH) level at 2.26 mIU/L, and a free thyroxine (FT4) level at 12.8 pmol/L. Cortisol level after low-dose dexamethasone suppression test was 86 ng/mL.
The diagnosis of acromegaly associated with Cushing’s disease was established. Pituitary magnetic resonance imaging showed a pituitary macroadenoma with no clear limits. The patient underwent transsphenoidal tumor resection. The pathological examination revealed two separate pituitary adenomas. The positivity to ACTH and GH was 100% and 80%, respectively.
This case emphasizes the necessity of an evaluation of all the pituitary axes in case of adenoma in order not to miss a double hormonal secretion or more even in the absence of suggestive clinical signs.

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Personalized Noninvasive Diagnostic Algorithms Based on Urinary Free Cortisol in ACTH-dependant Cushing’s Syndrome

Posted on November 9, 2024 by MaryO

Julie Lavoillotte, Kamel Mohammedi, Sylvie Salenave, Raluca Maria Furnica, Dominique Maiter, Philippe Chanson, Jacques Young, Antoine Tabarin
The Journal of Clinical Endocrinology & Metabolism, Volume 109, Issue 11, November 2024, Pages 2882–2891
https://doi.org/10.1210/clinem/dgae258

Abstract

Context

Current guidelines for distinguishing Cushing’s disease (CD) from ectopic ACTH secretion (EAS) are questionable, as they use pituitary magnetic resonance imaging (MRI) as first-line investigation for all patients. CRH testing is no longer available, and they suggest performing inferior petrosal sinus sampling (BIPPS), an invasive and rarely available investigation, in many patients.

Objective

To establish noninvasive personalized diagnostic strategies based on the probability of EAS estimated from simple baseline parameters.

Design

Retrospective study.

Setting

University hospitals.

Patients

Two hundred forty-seven CD and 36 EAS patients evaluated between 2001 and 2023 in 2 French hospitals. A single-center cohort of 105 Belgian patients served as external validation.

Results

Twenty-four-hour urinary free cortisol (UFC) had the highest area under the receiver operating characteristic curve for discrimination of CD from EAS (.96 [95% confidence interval (CI), .92–.99] in the primary study and .99 [95% CI, .98–1.00] in the validation cohort). The addition of clinical, imaging, and biochemical parameters did not improve EAS prediction over UFC alone, with only BIPPS showing a modest improvement (C-statistic index .99 [95% CI, .97–1.00]). Three groups were defined based on baseline UFC: < 3 (group 1), 3–10 (group 2), and > 10 × the upper limit of normal (group 3), and they were associated with 0%, 6.1%, and 66.7% prevalence of EAS, respectively. Diagnostic approaches performed in our cohort support the use of pituitary MRI alone in group 1, MRI first followed by neck-to-pelvis computed tomography scan (npCT) when negative in group 2, and npCT first followed by pituitary MRI when negative in group 3. When not combined with the CRH test, the desmopressin test has limited diagnostic value.

Conclusion

UFC accurately predicts EAS and can serve to define personalized and noninvasive diagnostic algorithms.

Read the article here: https://academic.oup.com/jcem/article/109/11/2882/7645065

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Cardiac Magnetic Resonance Reveals Biventricular Impairment In Cushing’s Syndrome

Posted on June 4, 2024 by MaryO

Purpose

Cushing’s syndrome (CS) is associated with severe cardiovascular (CV) morbidity and mortality. Cardiac magnetic resonance (CMR) is the non-invasive gold standard for assessing cardiac structure and function; however, few CMR studies explore cardiac remodeling in patients exposed to chronic glucocorticoid (GC) excess. We aimed to describe the CMR features directly attributable to previous GC exposure in patients with cured or treated endogenous CS.

Methods

This was a prospective, multicentre, case-control study enrolling consecutive patients with cured or treated CS and patients harboring non-functioning adrenal incidentalomas (NFAI), comparable in terms of sex, age, CV risk factors, and BMI. All patients were in stable condition and had a minimum 24-month follow-up.

Results

Sixteen patients with CS and 15 NFAI were enrolled. Indexed left ventricle (LV) end-systolic volume and LV mass were higher in patients with CS (p = 0.027; p = 0.013); similarly, indexed right ventricle (RV) end-diastolic and end-systolic volumes were higher in patients with CS compared to NFAI (p = 0.035; p = 0.006). Morphological alterations also affected cardiac function, as LV and RV ejection fractions decreased in patients with CS (p = 0.056; p = 0.044). CMR features were independent of metabolic status or other CV risk factors, with fasting glucose significantly lower in CS remission than NFAI (p < 0.001) and no differences in lipid levels or blood pressure.

Conclusion

CS is associated with biventricular cardiac structural and functional impairment at CMR, likely attributable to chronic exposure to cortisol excess independently of known traditional risk factors.

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Introduction

Cushing’s syndrome (CS), or chronic hypercortisolism, is associated with increased mortality mostly due to cardiovascular disease [1, 2], with infectious diseases and coexisting comorbidities also playing a role [1,2,3,4,5,6,7,8,9]. Older age at diagnosis, longer disease activity, uncontrolled hypertension, and diabetes mellitus are the main factors increasing mortality in CS [1, 2].

The higher cardiovascular risk in CS has traditionally been attributed to chronic hypertension, vascular atherosclerosis, and increased thromboembolism [2, 10,11,12,13,14], ultimately leading to an increased risk for myocardial infarction, cardiac failure, and stroke [2, 15].

Prompt and effective treatment of cortisol excess is crucial for reversing comorbidities and reducing the mortality risk associated with CS [1, 2]. However, concomitant treatment for cardiovascular comorbidities should also be provided to mitigate cardiovascular damage [1, 2, 16]. Despite improved treatment modalities, comorbidities can persist in a significant proportion of patients even after remission of CS [2, 17], suggesting that the consequence of prolonged exposure to glucocorticoid (GC) excess can produce irreversible alteration in cardiac structure.

Alterations in cardiac kinetics and structure include abnormal relaxation patterns (decreased systolic strain and impaired diastolic filling) and concentric left ventricle hypertrophy [2, 18,19,20], the latter being more severe in CS patients when compared to hypertensive controls [2, 20]. Increased myocardial fibrosis, caused by enhanced responsiveness to angiotensin II and activation of the mineralocorticoid receptor in response to cortisol excess, further complicates the scenario [2].

Albeit myocardial fibrosis and cardiac abnormalities might improve [21], cardiovascular alterations can persist for up to 5 years since remission of GC excess [2, 22, 23], underscoring the importance of prompt diagnosis and treatment, but also monitoring of increased risk.

Most studies rely on 2D echocardiography to characterize cardiac alterations in patients with CS [24]. Still, cardiac magnetic resonance (CMR) is now the established non-invasive gold standard method for measuring left ventricle (LV) volume, LV mass (LVM), and cardiac function due to its higher accuracy, reproducibility, and lower variability [25]. Few controlled studies assess cardiac dysfunction in CS patients by CMR, with preliminary data confirming the 2D-echocardiography observation of altered LV function and structure [18, 24, 26,27,28,29].

Therefore, our study aims to provide a detailed characterization of cardiac alterations in patients who have been exposed to chronic GC excess using a CMR-based approach and help clarify which are directly attributable to GC excess by matching the CS cohort with randomly selected adrenal patients with proven intact hypothalamic-pituitary-adrenal-axis, but similar traditional cardio-metabolic risk factors.

Materials and methods

Study design and population

We performed a prospective, multicentric, case-control study. From September 2014 to January 2020, consecutive adult (>18 years) patients diagnosed with CS as per current criteria [30] (either cured or with an active drug-treated disease) were recruited from the endocrinology outpatient clinics of the Department of Experimental Medicine at “Sapienza” University of Rome and the Department of Clinical Medicine and Surgery at “Federico II” University of Naples. Disease remission following surgery was defined by urinary free cortisol (UFC) levels per upper limit of normal (ULN) < 1.0 and by serum morning cortisol levels <50 nmol/L following overnight 1 mg dexamethasone suppression, in the absence of any cortisol-lowering treatment. Disease control under chronic medical therapy was defined by UFC xULN <1.0 [16, 31]. Patients with contraindications (or unwilling to undergo) to CMR were excluded from the study. The control group consisted of randomly selected patients with non-functioning adrenal incidentalomas (NFAI) diagnosed according to current criteria [32] undergoing follow-up imaging for the adrenal lesion, comparable with patients in terms of sex, age, BMI, and traditional cardiovascular risk factors. Sixteen patients with CS and 15 NFAI entered the study. All patients must have been in stable condition, including hormonal control, for at least 6 months before entering the study. All patients provided written informed consent after fully explaining the purpose and nature of all procedures used. The study was approved by the Ethical Committee of Policlinico Umberto I (ref. number 4245). The study has been performed according to the ethical standards of the 1964 Declaration of Helsinki and its later amendments. This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting.

Study procedures

Clinical and laboratory assessment

All patients underwent an accurate medical history review, including drugs used, hormonal assessment at diagnosis (UFC xULN, serum cortisol after dexamethasone suppression test), comorbidities (hypertension, glucose metabolism impairment, dyslipidemia, obesity), and cardiovascular risk factors (e.g., smoking habit). Subsequently, they were submitted to physical examination with measurement of anthropometric parameters and vital signs. Blood sampling for the assessment of biochemistry and hormones was performed at the local laboratory of each participating center; to better standardize results about disease activity, UFC levels were normalized by the upper limit of normal of each center’s laboratory. Clinical and laboratory findings and the prevalence of cardiometabolic complications have been compared between patient groups (CS vs NFAI) and cured and drug-treated patients (cured CS vs controlled CS). All patients were followed up for a minimum of 24-month timeframe.

Cardiac evaluation

All subjects underwent cardiac evaluation with CMR imaging performed as previously described [33] with a 1.5-T clinical magnetic resonance imaging system (Avanto, Siemens, Healthcare Solutions, Erlangen, Germany). During the examination, an ECG device was used for cardiac gating, and all acquisitions were made in apnea at the end of inspiration. In all cases, CMR imaging was performed by the same radiologist expert in cardiac imaging (N.G.) using the same acquisition protocol. CMR was performed at study entry, but not earlier than 6 months from any previous severe acute disease, event, or procedure.

T1-mapping for the evaluation of fibrosis

The T1-mapping technique has been used to quantify the degree of myocardial fibrosis non-invasively. The measured extracellular volume fraction (ECV) is highly sensitive and indicates diffuse myocardial fibrosis [34]. T1-mapping is automatically calculated as the average of the intensity of the individual pixels with and without contrast medium in T1 and expressed in msec (CMR 42 SW). The calculation of the ECV has been performed using the mathematical formula using the hematocrit value [DR1 myocardium: (1/T1 myocardial-post) − (1/T1 myocardial-pre); DR1 blood: (1/T1 blood-post) − (1/T1 blood-pre); Myocardial partition coefficient (λ) = (DR1 myocardial/DR1 blood); ECV = (1 − hematocrit) × (λ)]. A cut-off of ECV > 30% was used to identify increased interstitial fibrosis [35].

CMR findings have been compared between patient groups (CS vs NFAI). Moreover, the comparison of cardiac parameters has also been performed in CS patients according to cardiometabolic comorbidities, disease status, and sex.

The main steps of CMR image acquisition are shown in Fig. 1.

Fig. 1

figure 1

Cardiac magnetic resonance image acquisition protocol. T1-weighted, late gadolinium enhancement cardiac MR images of a 71-year-old female patient with Cushing’s disease, cured after successful neurosurgery. A Vertical long axis slice, coronal plane, two-chamber view. B Horizontal long axis slice, axial plane, four-chamber view. C Short-axis slice at the end of the diastole, sagittal plane. Red circle: endocardium; Blue circle: epicardium. LA left atrium, LV left ventricle, RA right atrium, RV right ventricle

Statistical analysis

Continuous variables are expressed as standard deviation (SD), median and 95% confidence interval (95%CI) as per data distribution, assessed through the Shapiro–Wilk test. Dichotomous variables are expressed as frequencies and percentages when relevant. According to variable distribution, the Student’s t-test or the non-parametric Mann–Whitney U test was performed to compare continuous variables between CS and NFAI and between cured and drug-controlled patients. Differences between groups regarding qualitative variables were evaluated by χ2 statistics. Bivariate correlations between numerical variables were analyzed using Pearson’s or Spearman’s correlation test, as appropriate. The statistical significance was set at p < 0.05. Statistical analyses were performed using SPSS 20.0 for MacOS (SPSS Inc.).

Results

Patient characteristics

The cohort characteristics are summarized in Table 1. Sixteen patients with CS (12 females, mean age 47 ± 12 years) and 15 with NFAI (7 females, mean age 55 ± 10 years) were enrolled during the study period. Twelve patients (75%) had been diagnosed with Cushing’s disease (CD), while four (25%) had ACTH-independent CS due to a cortisol-secreting adrenal adenoma.

Table 1 Baseline characteristics of patients with CS

At enrollment, eleven (69%) patients were cured and five (31%) had drug-treated CD. Among patients with CD, nine had previously undergone pituitary surgery, seven (58%) were cured, and five (42%) presented with a biochemically persistent disease. In the latter group, 3 patients had adequate biochemical control under medical therapy, whereas 2 patients were not entirely on target, because of low compliance and intolerance to medical treatments.

All patients with a cortisol-secreting adrenal adenoma had undergone unilateral adrenalectomy and were cured at the time of enrollment.

Table 2 details comorbidities and their therapies for CS and NFAI patients.

Table 2 Biochemical and clinical parameters in CS patients and NFAI

Biochemical and clinical evaluation

The main clinical and biochemical parameters are reported in Table 2. Sex, age, and BMI did not differ between the CS patients and NFAI. The two groups were similar concerning HbA1c, fasting insulin or homeostatic model assessment for insulin resistance, and lipid levels; fasting glucose levels were marginally lower in CS than in NFAI (p < 0.001). No differences were found in systolic and diastolic blood pressure, the prevalence of cardiometabolic complications or drugs (i.e., diagnosis of hypertension, dyslipidemia, obesity, and diabetes or prescriptions needed to control such comorbidities), suggesting that GC excess was resolved (or adequately controlled) at the time of enrollment for the great majority of patients.

Subgroup analysis of cardiac parameters in patients with Cushing’s syndrome

A subgroup analysis was performed to assess possible differences in cardiac parameters when the CS cohort was stratified according to disease status and cardiometabolic comorbidities (i.e., between patients with or without hypertension, glucose metabolism impairment, dyslipidemia, obesity), smoking, sex, and disease status.

Firstly, pharmacologically treated CS exhibited higher systolic and diastolic blood pressure levels than cured CS (p = 0.027), but no other differences were found regarding CMR parameters. Subgroup analysis according to the presence/absence of comorbidities revealed no significant effect on cardiac parameters, except for CS patients with impaired glucose tolerance, who showed a lower RV-EF compared with the remaining CS patients (p = 0.017).

Analyzing sex differences, male CS patients displayed higher RV-EDVi (p = 0.035) and RV-ESVi (p = 0.044), as well as a trend toward higher LV-EDVi (p = 0.067), LV-ESVi (p = 0.053) and LVMi (p = 0.066) compared to females. However, male CS patients only exhibited higher interventricular septum (IVS) thickness (p = 0.001) when compared to male and female reference ranges for the general population, age and sex-matched [36].

Comparison of cardiac parameters between patients and controls

A comparison of the main morphostructural and functional cardiac parameters between CS and NFAI in the left and the right ventricle is reported in Fig. 2 and Fig. 3, respectively. CMR cardiac morphology revealed an increased left ventricle-end systolic volume index (LV-ESVi) (31.0 ± 8.7 vs 24.1 ± 7.4, p = 0.027) in CS compared to NFAI (Fig. 2). Left ventricle mass index (LVMi) was also higher in CS (51.0 ± 11.8 vs 41.8 ± 6.9, p = 0.013) (Fig. 2), albeit none matched the criteria for left ventricular hypertrophy [37]. Regarding cardiac function, a trend toward lower left ventricle-ejection fraction (LV-EF) was measured in CS (57.1 ± 6.3 vs 61.9 ± 7.0, p = 0.056). Mirroring the alterations found in the left ventricle, higher indexed right ventricle-end systolic volume (RV-ESVi) (34.0 ± 7.7 vs 26.3 ± 6.0, p = 0.006) and right ventricle-end diastolic volume (RV-EDVi) (74.8 ± 14.2 vs 64.9 ± 9.3, p = 0.035), as well as lower right ventricle-ejection fraction (RV-EF) (54.6 ± 5.5 vs 59.5 ± 7.1, p = 0.044) were measured in patients with CS (Fig. 3). Dedicated T1 mapping technique did not reveal any difference between CS and NFAI, either before or after contrast administration. No patient had ECV greater than 30%, and no difference in ECV values was observed between groups.

Fig. 2
figure 2

Comparative analysis of left ventricle parameters in Cushing’s syndrome and NFAI patients. Left ventricle morphological and functional cardiac parameters in patients with Cushing’s syndrome (gray bars) and patients with NFAI (black bars). Data are expressed as mean ± SD. *p < 0.05. CS Cushing’s syndrome, CNT NFAI, LV-EDVi Left Ventricle End-Diastolic Volume index, LV-ESVi Left Ventricle End-Systolic Volume index, LV-SVi Left Ventricle Stroke Volume index, LVMi Left Ventricular Mass index, LV-EF Left Ventricle Ejection Fraction

Fig. 3
figure 3

Comparative analysis of right ventricle parameters in Cushing’s syndrome and NFAI patients. Right ventricle morphological and functional cardiac parameters in patients with Cushing’s syndrome (gray bars) and patients with NFAI (black bars). Data are expressed as mean ± SD. *p < 0.05; **p < 0.01; CS Cushing’s syndrome, CNT NFAI, RV-EDVi Right Ventricle End-Diastolic Volume index, RV-ESVi Right Ventricle End-Systolic Volume index, RV-SVi Right Ventricle Stroke Volume index, RV-EF Right Ventricle Ejection Fraction

No significant correlations were found between CMR parameters and UFC x ULN (assessed at diagnosis or date of CMR evaluation), serum cortisol after dexamethasone suppression test (at diagnosis) or disease duration from diagnosis. An explicative summary of cardiac parameters is shown in Table 3.

Table 3 Cardiac parameters in CS patients and NFAI

Discussion

The current study reveals that exposure to endogenous GC excess induces a peculiar early remodeling of affected patients’ left and right ventricles, which can persist after CS remission and is independent of traditional cardiometabolic risk factors. Namely, the higher LV and RV ESVi and EDVi observed in patients exposed to GC excess is accompanied by higher LVMi. However, LV and RV ejection fractions are only mildly reduced, suggesting that a morphological impairment anticipates a performance dysfunction. The fact that such alterations occur rapidly in CS and are partially irreversible after remission advocates the use of CMR to improve the management of fatal cardiac complications in this rare endocrine disease.

Several echocardiographic studies have evaluated cardiac structure and function in patients with CS and found LV systolic and diastolic dysfunction [19, 21, 38,39,40,41]. Albeit cardiac echocardiography is more practical in everyday clinical practice, CMR allows an evaluation of ventricular mass and volumes free of cardiac geometric assumption, ensuring a higher accuracy and reproducibility [29, 42].

Few controlled studies evaluating small cohorts have analyzed patients with CS using CMR [18, 26,27,28]. Kamenicky and coworkers compared 18 patients with active CS with 18 controls matched for age, sex, and BMI and found that patients had lower LV, RV, and left atrium ejection fractions, along with increased left and right ESVi and end-diastolic LV segmental thickness. Of note, successful treatment of CS was associated with an improvement in ventricular and atrial systolic performance [18]. A later study from the same group evaluated 23 patients with active CS and compared them with 27 controls matched for age, sex, and BMI, reporting increased left ventricular wall thickness, and reduced ventricular stroke volumes in patients [28]. A CMR study comparing CS patients with age and sex-matched controls showed that patients with active disease had higher LVMi than controls, as opposed to those in disease remission [27]. In all the studies mentioned above, patients and controls significantly differed in cardiovascular risk factors, with a worse cardiovascular profile in patients than controls. Conversely, our cohorts were largely homogeneous, without any significant difference between patients with CS and NFAI in glycometabolic profile, except for a surprisingly marginally lower fasting glucose levels in CS than in NFAI. This is likely because CS patients were either cured or drug-treated, and NFAI were comparable in terms of BMI and known CV risk factors.

As a result, the two groups did not significantly differ either in systolic and diastolic blood pressure levels or in the overall prevalence of cardiometabolic complications or the drugs prescribed to treat them. Nevertheless, our results confirmed the CMR findings of previous studies regarding higher cardiac volumes and mass and lower ejection fractions in patients with CS than in NFAI, advocating a direct effect of GC excess exposure in cardiac impairment beyond the known cardiovascular risk factors. Moreover, the results of the current study highlight the importance of a biventricular evaluation in this context, as opposed to most 2D-echocardiographic studies. Ultrasound measurement of RV volumes is challenging; therefore, most CS echocardiographic studies have mainly focused on the LV [19, 21, 38,39,40,41], whereas CMR studies suggest an impairment in both left and right ventricles. The RV is anatomically and functionally different from the LV. In the absence of clear alterations in pulmonary resistance, our findings suggest RV involvement is a direct effect of GC excess on cardiomyocytes, whose receptors are equally expressed in left and right ventricles in donor hearts and dilated cardiomyopathy [43].

Cardiac morphological alterations in our cohort were not related to increased myocardial fibrosis, as we did not find any difference between patients and controls in T1 mapping evaluation, probably also due to the superimposable cardiometabolic profile of the two study groups. Albeit patients had non-significantly higher postcontrast T1 values, none had ECV values compatible with fibrosis. Similarly, Roux and coworkers evaluated 10 patients with active CD matched with 10 hypertensive and 10 healthy controls and performed a CMR study using the T1 mapping technique and found increased native myocardial T1 in CD, independently from hypertension, without differences in myocardial partition coefficient (λ) between groups. These results support the hypothesis of a potential role of T1 mapping in identifying early biomarkers of subclinical myocardial fibrosis in this disease [26].

Even though we didn’t find any significant correlation between indicators of hypercortisolism severity (UFC x ULN, disease duration) and CMR parameters, the independency of cardiac alterations from traditional cardiometabolic risk factors, claims a direct role of hypercortisolism on cardiac impairment, acting as a fingerprint of GC excess exposure. Our data point toward a persistent toxic effect on the heart, mediated directly through GC and/or mineralocorticoid receptors [2, 11, 44], that produces changes in cardiac structure that are clinically silent but long-lasting, as if the heart retained a memory of GC excess exposure. The mineralocorticoid pathway increases collagen secretion by activating fibroblasts [45]. In addition, stimulating mineralocorticoid receptors decreases myocyte contractility and stimulates mitosis, resulting in myocardial hypertrophy and dysfunction [46]. However, previous data on mineralocorticoid antagonism in GC-induced hypertension did not prove convincing [47], disclosing the need for direct control of GC receptors (for example, via selective GC receptor antagonists such as relacorilant). Indeed, there is evidence supporting the role of GCs in driving alterations in vasoactive substances, thus impacting the balance between vasoconstriction and vasodilation (including catecholamines, nitric oxide, and atrial natriuretic peptide), as well as the activation of the renin-angiotensin system, leading to cardiac hypercontractility [11, 48].

The present study has shown more structural rather than functional changes at CMR in CS patients without evidence of fibrosis, thus suggesting the latter probably as a late phenomenon.

Additive to the direct role of cortisol, almost 60% of our patients presented hypertension, which could have contributed to the development of cardiac impairment. Similarly, the impact of other CS-related cardiovascular risk factors, such as visceral obesity, glucose intolerance and dyslipidemia, cannot be entirely ruled out.

Finally, our study showed for the first time that sex might affect cardiac morphological changes induced by GC excess. Male CS patients exhibited higher IVS thickness compared to females after adjusting for population age and sex reference ranges, independently from the prevalence of hypertension, supporting sex-related differences as observed in other cardiovascular diseases [49, 50]. Recently, a study by Wolf et al. showed that male sex was an independent predictor of increased epicardial and pericardial fat [28], which may play a role in the pathogenesis of CS cardiomyopathy. However, among CS patients, we did not find any differences in the prevalence of male and female hypogonadism (50% vs 42%, p = 1.000). Still, we can not exclude that estrogen exposure could have protected GC-related cardiomyopathy [51].

Very few studies have evaluated cardiac structure and function in CS using CMR, and this is a strength of the current study. However, it does have some limitations. The cross-sectional design and the lack of sample size in such a small and heterogeneous study population with different etiologies of endogenous CS, including both cured and well-controlled patients, might have underestimated the cardiac impairment. Anyway, considering that CS is a rare disease, we opted for a study design closer to a CS clinic’s real-life setting; this aspect represents a strength of this study. Nevertheless, according to the published evidence, as well as to our results, it is likely that cardiac dysfunction might persist in CS even after disease remission. Indeed, although our CS patients had higher biventricular volumes, the subgroup comparison between surgically cured and drug-treated patients revealed no differences in cardiac morphology or biochemical or cardiometabolic complications prevalence, althoghut the lack of standardization of the evaluation period. A previous paper found a significantly higher LVMi in active patients than in remission [27]. Anyway, longitudinal studies (baseline versus post-treatment) with larger population are needed to better clarify the reversibility of cardiac changes after treatment.

We propose a novel approach to cardiac disease in CS, going beyond the traditional cardiometabolic risk factors and evaluating both ventricles, preferably with CMR. Moreover, the present study highlights the importance of a sex-oriented approach in the management of CS complications, taking into account the sex-related differences in cardiac damage of these patients, for whom cardiac complications still represent the major cause of death, very often occurring during remission [2].

Conclusions

In CS biventricular cardiac remodeling associated with functional impairment, has been ascribed to a multifactorial pathogenesis. Our findings highlight the greater contribution of direct effect of GC excess exposure on myocardium than on cardiovascular risk factors, suggesting a sex-related differences in cardiac impairment. More importantly, the maladaptive change triggered by chronic exposure to GC excess, even if the latter is resolved, is persistent and clinically silent and could be detected though a more sensitive and precise approach with CMR.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the PRecisiOn Medicine to Target Frailty of Endocrine-metabolic Origin (PROMETEO) project (NET-2018-12365454) by the Ministry of Health and the European Union – NextGenerationEU through the Italian Ministry of University and Research under PNRR – M4C2-I1.3 Project PE_00000019 “HEAL ITALIA” to Andrea Isidori CUP B53C22004000006. Open access funding provided by Università degli Studi di Roma La Sapienza within the CRUI-CARE Agreement.

Author information

Author notes

  1. These authors contributed equally: Tiziana Feola, Alessia Cozzolino
  2. These authors jointly supervised this work: Andrea M. Isidori, Elisa Giannetta

Authors and Affiliations

  1. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy

    Tiziana Feola, Alessia Cozzolino, Dario De Alcubierre, Federica Campolo, Andrea M. Isidori & Elisa Giannetta

  2. Neuroendocrinology, Neuromed Institute, IRCCS, Pozzilli, Italy

    Tiziana Feola & Dario De Alcubierre

  3. Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Oxford University Hospitals, NHS Trust, Oxford, UK

    Riccardo Pofi

  4. Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome, Italy

    Nicola Galea & Carlo Catalano

  5. Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Naples, Italy

    Chiara Simeoli, Nicola Di Paola & Rosario Pivonello

  6. Centre for Rare Diseases (ENDO-ERN accredited), Policlinico Umberto I, Rome, Italy

    Andrea M. Isidori

Contributions

A.M.I., E.G., T.F., A.C. contributed to the idea and design of the study, analysis of the data, and writing of the manuscript. D.D.A., R.P., C.S., N.D.P., F.C. and R.P.i. contributed to the design of the study, analysis of the data, and revision of the report. T.F., A.C., D.D.A., N.G. and C.C. analyzed the data. All authors contributed to the interpretation of the data and the writing of the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Andrea M. Isidori or Elisa Giannetta.

Ethics declarations

Conflict of interest

RPi has received research support to Università Federico II di Napoli as a principal investigator for clinical trials from Novartis Pharma, Recordati, Strongbridge Biopharma, Corcept Therapeutics, HRA Pharma, Shire, Takeda, Neurocrine Biosciences, Camurus AB, and Pfizer, has received research support to Università Federico II di Napoli from Pfizer, Ipsen, Novartis Pharma, Strongbridge Biopharma, Merk Serono, and Ibsa, and received occasional consulting honoraria from Novartis Pharma, Recordati, Strongbridge Biopharma, HRA Pharma, Crinetics Pharmaceuticals, Corcept Therapeutics, Pfizer, and Bresmed Health Solutions. AMI has been a consultant for Novartis, Takeda, Recordati, and Sandoz companies and has received unconditional research grants from Shire, IPSEN, and Pfizer. All the other authors have nothing to disclose.

Consent to publish

The authors affirm that human research participants provided informed consent for publication of the images in Fig. 1.

Ethics approval and conset to participate

All patients provided written informed consent after fully explaining the purpose and nature of all procedures used. The study was approved by the Ethical Committee of Policlinico Umberto I (ref. number 4245). The study has been performed according to the ethical standards of the 1964 Declaration of Helsinki and its later amendments.

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Feola, T., Cozzolino, A., De Alcubierre, D. et al. Cardiac magnetic resonance reveals biventricular impairment in Cushing’s syndrome: a multicentre case-control study. Endocrine (2024). https://doi.org/10.1007/s12020-024-03856-7

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Day 6: Cushing’s Awareness Challenge

Posted on April 6, 2024 by MaryO

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The above is the official Cushing’s path to a diagnosis but here’s how it seems to be in real life:

Egads!  I remember the naive, simple days when I thought I’d give them a tube or two of blood and they’d tell me I had Cushing’s for sure.

Who knew that diagnosing Cushing’s would be years of testing, weeks of collecting every drop of urine, countless blood tests, many CT and MRI scans…

Then going to NIH, repeating all the above over 6 weeks inpatient plus an IPSS test, an apheresis (this was experimental at NIH) and specialty blood tests…

The path to a Cushing’s diagnosis is a long and arduous one but you have to stick with it if you believe you have this Syndrome.

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