Longterm-Outcomes In Patients With Cushing’s Disease vs. Non-Functioning Pituitary Adenoma After Pituitary Surgery: An Active-Comparator Cohort Study

Posted on July 22, 2024 by MaryO

Abstract

Objective

There is increasing evidence that multisystem morbidity in patients with Cushing’s disease (CD) is only partially reversible following treatment. We investigated complications from multiple organs in hospitalized patients with CD compared to patients with non-functioning pituitary adenoma (NFPA) after pituitary surgery.

Design

Population-based retrospective cohort study using data from the Swiss Federal Statistical Office between January 2012 and December 2021.

Methods

Through 1:5 propensity score matching, we compared hospitalized patients undergoing pituitary surgery for CD or NFPA, addressing demographic differences. The primary composite endpoint included all-cause mortality, major adverse cardiac events (i.e., myocardial infarction, unstable angina, heart failure, cardiac arrest, ischemic stroke), hospitalization for psychiatric disorders, sepsis, severe thromboembolic events, and fractures in need of hospitalization. Secondary endpoints comprised individual components of the primary endpoint and surgical reintervention due to disease persistence or recurrence.

Results

After matching, 116 patients with CD (mean age 45.4 years [SD, 14.4], 75.0% female) and 396 with NFPA (47.3 years [14.3], 69.7% female) were included and followed for a median time of 50.0 months (IQR 23.5, 82.0) after pituitary surgery. CD presence was associated with a higher incidence rate of the primary endpoint (40.6 vs. 15.7 events per 1,000 person-years, HR 2.75; 95% CI, 1.54 to 4.90). CD patients also showed increased hospitalization rates for psychiatric disorders (HR 3.27; 95% CI, 1.59 to 6.71) and a trend for sepsis (HR 3.15; 95% CI, 0.95 to 10.40).

Conclusions

Even after pituitary surgery, CD patients faced a higher hazard of complications, especially psychiatric hospitalizations and sepsis.

Accepted manuscripts
Accepted manuscripts are PDF versions of the author’s final manuscript, as accepted for publication by the journal but prior to copyediting or typesetting. They can be cited using the author(s), article title, journal title, year of online publication, and DOI. They will be replaced by the final typeset articles, which may therefore contain changes. The DOI will remain the same throughout.
This content is only available as a PDF.
© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/pages/standard-publication-reuse-rights)

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

Unveiling the Uncommon: Cushing’s Syndrome (CS) Masquerading as Severe Hypokalemia

Posted on July 2, 2024 by MaryO

Abstract

Cushing’s syndrome (CS) arises from an excess of endogenous or exogenous cortisol, with Cushing’s disease specifically implicating a pituitary adenoma and exaggerated adrenocorticotropic hormone (ACTH) production. Typically, Cushing’s disease presents with characteristic symptoms such as weight gain, central obesity, moon face, and buffalo hump.

This case report presents an unusual manifestation of CS in a 48-year-old male with a history of hypertension, where severe hypokalemia was the primary presentation. Initial complaints included bilateral leg swelling, muscle weakness, occasional shortness of breath, and a general feeling of not feeling well. Subsequent investigations revealed hypokalemia, metabolic alkalosis, and an abnormal response to dexamethasone suppression, raising concerns about hypercortisolism. Further tests, including 24-hour urinary free cortisol and ACTH testing, confirmed significant elevations. Brain magnetic resonance imaging (MRI) identified a pituitary macroadenoma, necessitating neurosurgical intervention.

This case underscores the rarity of CS presenting with severe hypokalemia, highlighting the diagnostic challenges and the crucial role of a collaborative approach in managing such intricate cases.

Introduction

Cushing’s syndrome (CS), characterized by excessive cortisol production, is well-known for its diverse and often conspicuous clinical manifestations. Cushing’s disease is a subset of CS resulting from a pituitary adenoma overproducing adrenocorticotropic hormone (ACTH), leading to heightened cortisol secretion. The classic presentation involves a spectrum of symptoms such as weight gain, central obesity, muscle weakness, and mood alterations [1].

Despite its classic presentation, CS can demonstrate diverse and atypical features, challenging conventional diagnostic paradigms. This case report sheds light on a rare manifestation of CS, where severe hypokalemia was the primary clinical indicator. Notably, instances of CS prominently manifesting through severe hypokalemia are scarce in the literature [1,2].

Through this exploration, we aim to provide valuable insights into the diagnostic intricacies of atypical CS presentations, underscore the significance of a comprehensive workup, and emphasize the collaborative approach essential for managing such uncommon hormonal disorders.

Case Presentation

A 48-year-old male with a history of hypertension presented to his primary care physician with complaints of bilateral leg swelling, occasional shortness of breath, dizziness, and a general feeling of malaise persisting for 10 days. The patient reported increased water intake and urinary frequency without dysuria. The patient was diagnosed with hypertension eight months ago. He experienced progressive muscle weakness over two months, hindering his ability to perform daily activities, including using the bathroom. The primary care physician initiated a blood workup that revealed severe hypokalemia with a potassium level of 1.3 mmol/L (reference range: 3.6 to 5.2 mmol/L), prompting referral to the hospital.

Upon admission, the patient was hypertensive with a blood pressure of 180/103 mmHg, a heart rate of 71 beats/minute, a respiratory rate of 18 breaths/minute, and an oxygen saturation of 96% on room air. Physical examination revealed fine tremors, bilateral 2+ pitting edema in the lower extremities up to mid-shin, abdominal distension with normal bowel sounds, and bilateral reduced air entry in the bases of the lungs on auscultation. The blood work showed the following findings (Table 1).

Parameter Result Reference Range
Potassium (K) 1.8 mmol/L 3.5-5.0 mmol/L
Sodium (Na) 144 mmol/L 135-145 mmol/L
Magnesium (Mg) 1.3 mg/dL 1.7-2.2 mg/dL
Hemoglobin (Hb) 15.5 g/dL 13.8-17.2 g/dL
White blood cell count (WBC) 13,000 x 103/µL 4.5 to 11.0 × 109/L
Platelets 131,000 x 109/L 150-450 x 109/L
pH 7.57 7.35-7.45
Bicarbonate (HCO3) 46 mmol/L 22-26 mmol/L
Lactic acid 4.2 mmol/L 0.5-2.0 mmol/L
Table 1: Blood work findings

In order to correct the electrolyte imbalances, the patient received intravenous (IV) magnesium and potassium replacement and was later transitioned to oral. The patient was also started on normal saline at 100 cc per hour. To further investigate the complaint of shortness of breath, the patient underwent a chest X-ray, which revealed bilateral multilobar pneumonia (Figure 1). He was subsequently treated with ceftriaxone (1 g IV daily) and clarithromycin (500 mg twice daily) for seven days.

A-chest-X-ray-revealing-(arrows)-bilateral-multilobar-pneumonia
Figure 1: A chest X-ray revealing (arrows) bilateral multilobar pneumonia

With persistent abdominal pain and lactic acidosis, a computed tomography (CT) scan abdomen and pelvis with contrast was conducted, revealing a psoas muscle hematoma. Subsequent magnetic resonance imaging (MRI) depicted an 8×8 cm hematoma involving the left psoas and iliacus muscles. The interventional radiologist performed drainage of the hematoma involving the left psoas and iliacus muscles (Figure 2).

Magnetic-resonance-imaging-(MRI)-depicting-an-8x8-cm-hematoma-(arrow)-involving-the-left-psoas-and-iliacus-muscles
Figure 2: Magnetic resonance imaging (MRI) depicting an 8×8 cm hematoma (arrow) involving the left psoas and iliacus muscles

In light of the concurrent presence of hypokalemia, hypertension, and metabolic alkalosis, there arose concerns about Conn’s syndrome, prompting consultation with endocrinology. Their recommended workup for Conn’s syndrome included assessments of the aldosterone-renin ratio and random cortisol levels. The results unveiled an aldosterone level below 60 pmol/L (reference range: 190 to 830 pmol/L in SI units) and a plasma renin level of 0.2 pmol/L (reference range: 0.7 to 3.3 mcg/L/hr in SI units). Notably, the aldosterone-renin ratio was low, conclusively ruling out Conn’s syndrome. The random cortisol level was notably elevated at 1334 nmol/L (reference range: 140 to 690 nmol/L).

Furthermore, a low-dose dexamethasone suppression test was undertaken due to the high cortisol levels. Following the administration of 1 mg of dexamethasone at 10 p.m., cortisol levels were measured at 9 p.m., 3 a.m., and 9 a.m. the following day. The results unveiled a persistently elevated cortisol level surpassing 1655 nmol/L, signaling an abnormal response to dexamethasone suppression and raising concerns about a hypercortisolism disorder, such as CS.

In the intricate progression of this case, the investigation delved deeper with a 24-hour urinary free cortisol level, revealing a significant elevation at 521 mcg/day (reference range: 10 to 55 mcg/day). Subsequent testing of ACTH portrayed a markedly elevated level of 445 ng/L, distinctly exceeding the normal reference range of 7.2 to 63.3 ng/L. A high-dose 8 mg dexamethasone test was performed to ascertain the source of excess ACTH production. The baseline serum cortisol levels before the high-dose dexamethasone suppression test were 1404 nmol/L, which decreased to 612 nmol/L afterward, strongly suggesting the source of excess ACTH production to be in the pituitary gland.

A CT scan of the adrenal glands ruled out adrenal mass, while an MRI of the brain uncovered a 1.3×1.3×3.2 cm pituitary macroadenoma (Figure 3), leading to compression of adjacent structures. Neurosurgery was consulted, and they recommended surgical removal of the macroadenoma due to the tumor size and potential complications. The patient was referred to a tertiary care hospital for pituitary adenoma removal.

Magnetic-resonance-imaging-(MRI)-of-the-brain-depicting-a-1.3x1.3x3.2-cm-pituitary-macroadenoma-(star)
Figure 3: Magnetic resonance imaging (MRI) of the brain depicting a 1.3×1.3×3.2 cm pituitary macroadenoma (star)

Discussion

CS represents a complex endocrine disorder characterized by excessive cortisol production. While the classic presentation of CS includes weight gain, central obesity, and muscle weakness, our case highlights an uncommon initial manifestation: severe hypokalemia. This atypical presentation underscores the diverse clinical spectrum of CS and the challenges it poses in diagnosis and management [1,2].

While CS typically presents with the classic symptoms mentioned above, severe hypokalemia as the initial manifestation is exceedingly rare. Hypokalemia in CS often results from excess cortisol-mediated activation of mineralocorticoid receptors, leading to increased urinary potassium excretion and renal potassium wasting. Additionally, metabolic alkalosis secondary to cortisol excess further exacerbates hypokalemia [3,4].

Diagnosing a case of Cushing’s disease typically commences with a thorough examination of the patient’s medical history and a comprehensive physical assessment aimed at identifying characteristic manifestations such as central obesity, facial rounding, proximal muscle weakness, and increased susceptibility to bruising. Essential to confirming the diagnosis are laboratory examinations, which involve measuring cortisol levels through various tests, including 24-hour urinary free cortisol testing, late-night salivary cortisol testing, and dexamethasone suppression tests. Furthermore, assessing plasma ACTH levels aids in distinguishing between pituitary-dependent and non-pituitary causes of CS. Integral to the diagnostic process are imaging modalities such as MRI of the pituitary gland, which facilitate the visualization of adenomas and the determination of their size and precise location [1-4].

Treatment for Cushing’s disease primarily entails surgical removal of the pituitary adenoma via transsphenoidal surgery, with the aim of excising the tumor and restoring normal pituitary function. In cases where surgical intervention is unsuitable or unsuccessful, pharmacological therapies employing medications such as cabergoline (a dopamine receptor agonist) or pasireotide (a somatostatin analogue) may be considered to suppress ACTH secretion and regulate cortisol levels. Additionally, radiation therapy, whether conventional or stereotactic radiosurgery, serves as a supplementary or alternative treatment approach to reduce tumor dimensions and mitigate ACTH production [5,6]. To assess the effectiveness of treatment, manage any problem, and assure long-term illness remission, diligent long-term follow-up and monitoring are essential. Collaborative multidisciplinary care involving specialists such as endocrinologists, neurosurgeons, and other healthcare professionals is pivotal in optimizing patient outcomes and enhancing overall quality of life [2,4].

The prognosis of CS largely depends on the underlying cause, stage of the disease, and efficacy of treatment. Early recognition and prompt intervention are essential for improving outcomes and minimizing long-term complications. Surgical resection of the adrenal or pituitary tumor can lead to remission of CS in the majority of cases. However, recurrence rates vary depending on factors such as tumor size, invasiveness, and completeness of resection [2,3]. Long-term follow-up with endocrinologists is crucial for monitoring disease recurrence, assessing hormonal function, and managing comorbidities associated with CS.

Conclusions

In conclusion, our case report highlights the rarity of severe hypokalemia as the initial presentation of CS. This unique presentation underscores the diverse clinical manifestations of CS and emphasizes the diagnostic challenges encountered in clinical practice. A multidisciplinary approach involving endocrinologists, neurosurgeons, and radiologists is essential for the timely diagnosis and management of CS. Early recognition, prompt intervention, and long-term follow-up are essential for optimizing outcomes and improving the quality of life for patients with this endocrine disorder.

References

  1. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-40. 10.1210/jc.2008-0125
  2. Newell-Price J, Bertagna X, Grossman AB, Nieman LK: Cushing’s syndrome. Lancet. 2006, 367:1605-17. 10.1016/S0140-6736(06)68699-6
  3. Torpy DJ, Mullen N, Ilias I, Nieman LK: Association of hypertension and hypokalemia with Cushing’s syndrome caused by ectopic ACTH secretion: a series of 58 cases. Ann N Y Acad Sci. 2002, 970:134-44. 10.1111/j.1749-6632.2002.tb04419.x
  4. Elias C, Oliveira D, Silva MM, Lourenço P: Cushing’s syndrome behind hypokalemia and severe infection: a case report. Cureus. 2022, 14:e32486. 10.7759/cureus.32486
  5. Fleseriu M, Petersenn S: Medical therapy for Cushing’s disease: adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers. Pituitary. 2015, 18:245-52. 10.1007/s11102-014-0627-0
  6. Pivonello R, De Leo M, Cozzolino A, Colao A: The treatment of Cushing’s disease. Endocr Rev. 2015, 36:385-486. 10.1210/er.2013-1048

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

The Efficacy Of Bisphosphonates For Osteoporosis In Young Cushing’s Disease Patients With Biochemical Remission

Posted on June 24, 2024 by MaryO

Background: Patients with Cushing’s disease (CD) often experience slow recovery of bone mineral density (BMD), and the effectiveness of anti-osteoporosis drugs in young CD patients who have achieved biochemical remission after surgery is not well understood. Therefore, we aimed to explore whether bisphosphonates could help accelerate the recovery of osteoporosis in young CD patients with remission.

Methods: We retrospectively enrolled 34 young patients with CD who achieved postoperative biochemical remission. All patients suffered from osteoporosis before surgery and were divided into postoperative bisphosphonate treatment group (16 cases) and without bisphosphonate treatment group (18 cases). Clinical data, BMD (Z Value), and bone turnover markers were collected at the time of diagnosis and one year after successful tumor resection.

Results: The Z values in the lumbar spine showed slight improvement in both groups at follow-up compared to baseline, but this improvement was not statistically significant. There was no significant difference observed between the two groups at follow-up. One year after operation, bone formation markers (OC and P1NP) were significantly higher than those at baseline in both groups. However, OC and P1NP in the bisphosphonate treatment group were lower than those in control group at one year follow-up. In without bisphosphonate treatment group, β-CTX from follow-up visit was higher than that at baseline, while no significant difference was observed in the bisphosphonate treatment group before and after surgery.

Conclusion: Young patients with Cushing’s disease combined with osteoporosis might not benefit from bisphosphonate therapy for osteoporosis recovery in the first year after achieving biochemical remission.

Introduction

Osteoporosis is one of common complications of Cushing’s syndrome (CS). 40–78% of CS patients have osteopenia at diagnosis and 22–57% have osteoporosis (1). Previous studies reported non-violent fractures in 16–50% of patients with CS at diagnosis (1–5).

The pathophysiological mechanism of glucocorticoid (GC)-induced osteoporosis is very complex. The main feature is a persistent decrease in bone formation accompanied by an early transient increase in bone resorption, which directly acts on osteoblasts, osteoclasts, and osteocytes (6–9). In addition, GC also can lead to bone loss through indirect effects, mainly including decreased sex hormone levels, intestinal and renal calcium absorption and reabsorption, muscle mass and mechanical sensitivity and increased parathyroid hormone levels, etc. (10).

Prevention strategies for osteoporosis in patients treated with long-term exogenous hormones were relatively mature, and drugs promoting bone formation or inhibiting bone resorption should be used. However, osteoporosis was often ignored in patients with Cushing’s syndrome. Previous studies had shown that BMD of patients with CS improved after achieving biochemical remission (11), but some patients still had osteoporosis for several years after remission, even though their BMD were improved compared to preoperative levels (1). A study showed that BMD increased due to high turnover of bone after CS remission, and no additional anti-osteoporotic treatment was considered (12). However, till now it remained unclear whether anti-osteoporosis treatment could help accelerate the recovery of osteoporosis in young CD patients with biochemical remission after surgery.

Therefore, the aim of this study was to determine the efficacy of bisphosphonates for osteoporosis in young Cushing’s disease (CD) patients with biochemical remission.

Materials and methods

Subjects

This study was a retrospective cohort study and was approved by the Human Investigation Ethics Committee at Huashan Hospital (No.2017M011). Thirty-four young CD patients combined with osteoporosis at diagnosis who were hospitalized in the Department of Endocrinology, Huashan Hospital, Fudan University from January 2010 to February 2021 were included. Patients’ selection was shown in Figure 1.

Figure 1

www.frontiersin.org

Figure 1 Research flow chart.

Inclusion criteria were as follows: 1) the diagnostic criteria for Cushing’s disease were met, and the pituitary ACTH adenoma was confirmed by surgical pathology, 2) men ≥18 years old but younger than 50 years old at diagnosis; premenopausal women ≥ 18 years old and young women(<50 years old) with menstrual abnormalities which were associated with CD, 3) Z-score of BMD in lumbar spine or femoral neck ≤-2.0 at diagnosis of Cushing’s disease or with a history of fragility fractures, 4) attaining biochemical remission after transsphenoidal surgery, 5) receiving regular follow-up and bone mineral density was measured in our hospital at diagnosis and one year follow-up.

Enrolled patients were divided into two groups based on whether using bisphosphonates treatment after surgery or not. Biochemical remission of Cushing’s disease was defined as morning serum cortisol <2μg/dL (<55nmol/L) within the week after surgery and although serum cortisol at 8:00 a.m. was≥2 µg/dl or back to normal range immediate after surgery, it became hypocortisolemic at subsequent evaluation(s) and without relapse during the follow-up (13–15). Meanwhile, relapse was excluded by cortisol value < 1.8 µg/dL after 1-mg dexamethasone suppression test (DST) and 24-hour urinary free cortisol (UFC) in normal range (13).

Exclusion criteria included: 1) having comorbidities affecting BMD (e.g., hyperparathyroidism, hyperthyroidism, primary hypogonadism, rheumatic immune disease, gastric bypass, inflammatory bowel disease, etc.), 2) long-term use of glucocorticoid drugs for the treatment of immune related diseases (except for hypopituitarism hormone replacement therapy) or other drugs that significantly affect bone metabolism, 3) use of anti-osteoporosis drugs before surgery, 4) postoperative treatment with anti-osteoporotic drugs other than bisphosphonate, 5) Cushing’s syndrome other than pituitary origin, 6) loss of follow up, 7) uncured or relapse of CD during the follow up.

Clinical and biochemical methods

We collected data on demographic characteristics, duration of CD-related signs and symptoms, comorbidities, medications, laboratory tests, and bone mineral density.

Endocrine hormones included cortisol (F), 24-hour urinary free cortisol (24hUFC), adrenocorticotropic hormone (ACTH); growth hormone (GH), insulin-like growth factor (IGF-1), prolactin (PRL), luteinizing hormone (LH), follicle stimulating hormone (FSH), estrogen (E2), progesterone (P), testosterone (T), thyroid stimulating hormone (TSH), and free thyroxine (FT4). Hormonal measurements were carried out by chemiluminescence assay (Advia Centaur CP). Bone metabolism markers included osteocalcin (OC), type I procollagen amino-terminal peptide (P1NP), type I collagen C-terminal peptide degradation product (CTX), parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)VD], and they were measured in a Roche Cobas e411 analyzer using immunometric assays (Roche Diagnostics, Indianapolis, IN, USA).

Bone mineral density was measured by dual-energy X-ray absorptiometry of American HOLOGIC company Discovery type W in all patients at diagnosis of CD and one year follow-up after surgery. Z value was used for young CD patients and Z value = (measured value – mean bone mineral density of peers)/standard deviation of BMD of peers. In this study, osteoporosis was defined as a Z-value of -2.0 or lower or with a history of fragility fractures.

All patients were administered with 20mg of hydrocortisone 3 times daily after surgery to avoid steroid withdrawal syndrome, with a 10-day taper afterward. When hydrocortisone was reduced to 10mg once a day for 10 days, the patient was followed up for the first time after surgery. Then the hormone replacement dose was adjusted based on the patient’s blood level obtained before that day’s glucocorticoid intake and urine cortisol level. All patients were administered with calcium carbonate D3 tablet (one tablet a day, consisting of calcium 600mg and D3 125U) and vitamin D (0.25ug a day) at diagnosis of osteoporosis till the last follow-up.

Statistical analyses

Normal distributed continuous variables were expressed as mean values ± standard deviation (s.d.). Median, 25th percentile, and 75th percentile (Median [P25, P75]) for variables without a normal distribution. Independent t-tests for normally distributed continuous variables and non-parametric tests for variables without a normal distribution were used to compare data between groups. SPSS 20.0 (SPSS) was used. A two-tailed P value <0.05 was considered statistically significant.

Results

Patients’ characteristics at baseline

418 CD patients were hospitalized in the Department of Endocrinology, Huashan Hospital from January 2010 to February 2021. A total of 34 patients were included in our study, with an average age of 33.06 ± 7.37 years, 13 males (38.24%) and 21 females (61.76%). Sixteen patients were treated with bisphosphonates postoperatively (bisphosphonate group, including zoledronic acid and alendronate sodium), and eighteen patients were not treated with bisphosphonates postoperatively (without bisphosphonate group). Characteristics of the two groups were summarized in Table 1. Although there was a significant different in disease duration, there were no differences in age, gender, BMI, the proportion of hypertension, diabetes, dyslipidemia, liver function, kidney function, serum calcium, PTH, vitamin D level, bone metabolism markers, cortisol level, thyroid function, and growth hormone level between the two groups at baseline. Meanwhile, there was no significant difference in Z score of lumbar vertebra and femoral neck between two groups, -2.49 ± 0.56 (CV%=22.49%) vs-2.85 ± 0.61 (CV%=21.40%) and -1.74 ± 0.78 (CV%=44.83%) vs -1.93 ± 0.80 (CV%=41.45%) respectively. Therefore, the impact of different disease duration on the results was relatively small.

Table 1

www.frontiersin.org

Table 1 Clinical Baseline Characteristics of Patients in two groups.

One year after achieving biochemical remission, BMD improved in both groups; however there was no significant difference between the two groups

For these patients with osteoporosis secondary to Cushing’s disease, the most important work was to remove the cause. Patients with a history of fragility fractures didn’t receive bisphosphonate after surgery partly because they refused to use it. As shown in Table 2, Figures 2A, B, there were no significant differences in the Z Score of lumbar vertebra and femoral neck between the two groups at baseline. The Z values in lumbar spine at one year follow-up of both groups were slightly improved but not significantly compared to baseline respectively. There was no significant difference in the Z score of lumbar vertebra [-2.40 ± 0.617 (CV%=25.71%) vs -2.81 ± 0.771 (CV%=27.44%), p=0.0766] or femoral neck [-1.9 ± 0.715 (CV%=37.63%) vs -2.01 ± 0.726 (CV%=36.12%), p=0.6378] between two groups at one year follow-up.

Table 2

www.frontiersin.org

Table 2 Changes in bone mineral density and bone turnover markers before and 1 year after remission in the two groups.

Figure 2

www.frontiersin.org

Figure 2 Comparison of BMD and bone turnover markers at baseline and one year after remission between bisphosphonate-treated and non-bisphosphonate-treated groups. (A) Z Score of lumbar vertebra; (B) Z Score of femoral neck; (C) levels of OC; (D) levels of P1NP; (E) levels of β-CTX. *P < 0.05, **P < 0.01, ***P < 0.001.

At one year follow-up, bone formation markers increased obviously in both groups compared to those at diagnosis, and they increased higher without bisphosphonate treatment

As shown in Table 2, Figures 2C–E, there were no significant differences in bone turnover markers including OC, P1NP, and β-CTX between the two groups at baseline. Serum OC levels were significantly higher than those before surgery in both groups at one year follow-up after achieving remission respectively (5.90 (2.40–8.03) ng/ml vs 46.7 (23.25–83) ng/ml in control group, p<0.0001, and 6.80 (4.50–8.60) ng/ml vs 33.8 (14.46–49.27) ng/ml in treatment group, p=0.009). However, the serum OC level in the control group at follow-up was significantly higher than that in the treatment group [46.7 (23.25–83) ng/ml vs 33.8 (14.46–49.27) ng/ml, p=0.0381]. Serum P1NP levels were also significantly higher than those before surgery in both groups at follow-up after achieving remission of Cushing’s disease respectively (34.72 (23.22–41.79) ng/ml vs 353.5(124.9–501.2) ng/ml in control group, p=0.003, and 22.57 (15.93–30.53) ng/ml vs 181.1(65.46–228.75) ng/ml in treatment group, p=0.001). Similarly, the serum P1NP level at follow-up in the control group was significantly higher than that in the treatment group [353.5 (124.9–501.2) vs 181.1 (65.46–228.75) ng/ml, p=0.0484].

In the group without bisphosphonate treatment, β-CTX at one year after remission was higher than that before surgery [0.97 (0.83–1.57) vs 0.42 (0.16–0.66) ng/ml, p=0.006]. However, there was no significant difference in the bisphosphonate treatment group between baseline and follow-up [0.59 (0.27–0.90) vs 0.72(0.47–1.50) ng/ml, p=0.115]. No significant difference was seen for β-CTX level at follow-up between the two groups [0.97 (0.83–1.57) vs 0.72(0.47–1.50) ng/ml, p=0.409].

Discussion

Osteoporosis is one of common complications of Cushing’s disease and the recovery of bone mineral density after remission is a slow process. An important clinically question is whether young patients with CD after remission would benefit from anti-osteoporotic drugs such as bisphosphonates. To our knowledge, this study was the first well-powered retrospective cohort study of the efficacy of bisphosphonates for osteoporosis in young CD patients with biochemical remission. Our data showed that BMD improved slowly in young CD patients with remission at the first- year follow-up regardless of whether bisphosphate was used or not, and no significant difference in BMD improvement was observed between two groups at follow-up.

It was well known that after cure of Cushing’s syndrome, there was a long recovery period for BMD. It had been shown that full recovery from BMD in cured adult CS patients could take up to a decade or more (1, 16). However, Hermus (17) had shown that some patients had a 2% or more reduction in BMD in the short term after surgery, especially in the first 6 months after surgery, and did not show consistent BMD increases until 24 months after surgery. It also showed that there was a highly significant inverse correlation between age and increase of BMD in the lumbar spine after surgery (17). The lack of significant improvements in BMD in our results might be related to the short duration of follow-up.

Current studies of endogenous Cushing’s syndrome had shown that bone metabolism was characterized by decreased bone formation and increased bone resorption, consistent with the classical effects of glucocorticoids (11). Successful treatment of endogenous Cushing’s syndrome resulted in a strong activation of bone turnover, characterized by increased bone formation and resorption. A retrospective study by Pepijn van Houten showed that sustained improvement in BMD continued for up to 20 years after CD treatment, and a large proportion of patients in this cohort were treated with anti-osteoporotic drugs (1). The study also showed that patients not receiving anti-osteoporosis drugs experienced significant spontaneous improvement in mean BMD. However, this retrospective study could not be used to answer the clinical question of whether anti-osteoporotic therapy was beneficial due to selection bias in enrolled patients. Leah T Braun showed that within 2 years of successful surgical remission in patients with Cushing’s syndrome, markers of bone formation suggested a high rate of bone turnover, resulting in a significant net increase in BMD in the majority of patients. The results strongly suggested that an observational approach to bone phenotype was justified as long as CS remission was assured (12). However, this retrospective study mentioned a significant mismatch in baseline BMD between the two groups (anti-osteoporotic medication group and without anti-osteoporotic medication group) and did not describe the type of anti-osteoporosis drugs (promoting bone formation or inhibiting bone resorption or both). Somma’s prospective study showed that a significant increase in lumbar and femoral BMD was observed in 21 CD patients who achieved remission after surgery and were either treated with alendronate for 12 months or not (18). It should be noted that this study included postmenopausal women, and there were no direct comparisons of clinical data, bone mineral density, and bone turnover markers at baseline and follow-up between the two groups.

Our study also showed that even bone formation markers increased at follow-up in bisphosphonate group, they were significantly lower compared to non- bisphosphonate users. Since bone metabolism was in a state of high turnover in the initial stage of biochemical remission from Cushing’s disease, our results indicated that bisphosphonates might affect bone formation in the first year after remission and was not conductive to the improvement of BMD. The mechanism of bisphosphonates in the treatment of osteoporosis lied in their high affinity with skeletal hydroxyapatite, allowing them to specifically bind to actively remodeling bone surface and inhibit the function of osteoclasts, thereby inhibiting bone resorption. Studies had shown that while bisphosphonates strongly inhibited bone resorption, they also significantly reduced bone formation. This reduced formation was often attributed to mechanisms that maintained the resorption/formation balance during remodeling (19).

There are evidence-based guidelines available for assessing fracture risk during long-term exogenous glucocorticoid(GC) therapy in adults, as well as for initiating and selecting anti-osteoporosis therapy. Specifically, for patients at risk of fracture taking GC ≥2.5 mg/day for >3 months, treatment options include bisphosphonates, denosumab, or PTH analogs. Although there is currently no definitive evidence-based treatment regarding the choice and efficacy of anti-osteoporosis after glucocorticoid withdrawal, it is widely accepted that treatment should be continued based on bone density and fracture risk assessment. For patients at a high fracture risk level (T≤-2.5), it is recommended to either continue their current anti-osteoporosis treatment or switch to an alternative medication. The main challenge faced by individuals with endogenous glucocorticoid induced osteoporosis (GIOP) is that exogenous GIOP is not exactly the same as endogenous GIOP. Therefore, it is not appropriate to apply the same strategies of exogenous GIOP for CD patients with remission. The findings of this study indicated that bisphosphonate therapy might not be beneficial for osteoporosis recovery in CD patients achieving biochemical remission (20).

Our study, limited by retrospective clinical studies, a small sample size, and a short follow-up duration, might not optimally answer the question of whether patients with CD achieving remission would benefit from bisphosphonate therapy, although it was a relatively well-designed retrospective cohort study and reached the maximum number after strict inclusion criteria and matching baseline characteristics as much as possible. Therefore, prospective randomized controlled clinical trials with longer duration were needed in the future.

In conclusion, our study suggested that young patients with Cushing’s disease combined with osteoporosis might not benefit from bisphosphonate therapy for osteoporosis recovery in the first year after achieving biochemical remission.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving humans were approved by the Human Investigation Ethics Committee at Huashan Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

Author contributions

QS: Writing – original draft. WS: Writing – original draft, Formal analysis, Data curation. HY: Writing – review & editing, Supervision, Resources. SZ: Writing – review & editing, Supervision.

Funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The present study was supported by grants from initial funding of Huashan Hospital (2021QD023).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. van Houten P, Netea-Maier R, Wagenmakers M, Roerink S, Hermus A, van de Ven A. Persistent improvement of bone mineral density up to 20 years after treatment of Cushing’s syndrome. Eur J Endocrinol. (2021) 185:241–50. doi: 10.1530/EJE-21-0226

CrossRef Full Text | Google Scholar

2. Ohmori N, Nomura K, Ohmori K, Kato Y, Itoh T, Takano K. Osteoporosis is more prevalent in adrenal than in pituitary Cushing’s syndrome. Endocr J. (2003) 50:1–7. doi: 10.1507/endocrj.50.1

CrossRef Full Text | Google Scholar

3. Valassi E, Santos A, Yaneva M, Tóth M, Strasburger CJ, Chanson P, et al. The European Registry on Cushing’s syndrome: 2-year experience. Baseline demographic and clinical characteristics. Eur J Endocrinol. (2011) 165:383–92. doi: 10.1530/EJE-11-0272

CrossRef Full Text | Google Scholar

4. Zhou J, Zhang M, Bai X, Cui S, Pang C, Lu L, et al. Demographic characteristics, etiology, and comorbidities of patients with cushing’s syndrome: A 10-year retrospective study at a large general hospital in China. Int J Endocrinol. (2019) 2019:7159696. doi: 10.1155/2019/7159696

CrossRef Full Text | Google Scholar

5. Kristo C, Jemtland R, Ueland T, Godang K, Bollerslev J. Restoration of the coupling process and normalization of bone mass following successful treatment of endogenous Cushing’s syndrome: a prospective, long-term study. Eur J Endocrinol. (2006) 154:109–18. doi: 10.1530/eje.1.02067

CrossRef Full Text | Google Scholar

6. O’Brien CA, Jia D, Plotkin LI, Bellido T, Powers CC, Stewart SA, et al. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology. (2004) 145:1835–41. doi: 10.1210/en.2003-0990

CrossRef Full Text | Google Scholar

7. Liu Y, Porta A, Peng X, Gengaro K, Cunningham EB, Li H, et al. Prevention of glucocorticoid-induced apoptosis in osteocytes and osteoblasts by calbindin-D28k. J Bone Miner Res. (2004) 19:479–90. doi: 10.1359/JBMR.0301242

CrossRef Full Text | Google Scholar

8. Yun SI, Yoon HY, Jeong SY, Chung YS. Glucocorticoid induces apoptosis of osteoblast cells through the activation of glycogen synthase kinase 3beta. J Bone Miner Metab. (2009) 27:140–8. doi: 10.1007/s00774-008-0019-5

CrossRef Full Text | Google Scholar

9. Pereira RC, Delany AM, Canalis E. Effects of cortisol and bone morphogenetic protein-2 on stromal cell differentiation: correlation with CCAAT-enhancer binding protein expression. Bone. (2002) 30:685–91. doi: 10.1016/S8756-3282(02)00687-7

CrossRef Full Text | Google Scholar

10. Buckley L, Humphrey MB. Glucocorticoid-induced osteoporosis[J]. N Engl J Med. (2018) 379:2547–56. doi: 10.1056/NEJMcp1800214

CrossRef Full Text | Google Scholar

11. Mancini T, Doga M, Mazziotti G, Giustina A. Cushing’s syndrome and bone. Pituitary. (2004) 7:249–52. doi: 10.1007/s11102-005-1051-2

CrossRef Full Text | Google Scholar

12. Braun LT, Fazel J, Zopp S, Benedix S, Osswald-Kopp A, Riester A, et al. The effect of biochemical remission on bone metabolism in cushing’s syndrome: A 2-year follow-up study. J Bone Miner Res. (2020) 35:1711–7. doi: 10.1002/jbmr.4033

CrossRef Full Text | Google Scholar

13. Fleseriu M, Auchus R, Bancos I, Ben-Shlomo A, Bertherat J, Biermasz NR, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. (2021) 9:847–75. doi: 10.1016/S2213-8587(21)00235-7

CrossRef Full Text | Google Scholar

14. Dutta A, Gupta N, Walia R, Bhansali A, Dutta P, Bhadada SK, et al. Remission in Cushing’s disease is predicted by cortisol burden and its withdrawal following pituitary surgery. J Endocrinol Invest. (2021) 44:1869–78. doi: 10.1007/s40618-020-01495-z

CrossRef Full Text | Google Scholar

15. Chinese Pituitary Adenoma Cooperative Group. Consensus of Chinese experts on diagnosis and treatment of Cushing’s disease. Natl Med J China. (2016) 96:835–40. doi: 10.3760/cma.j.issn.0376-2491

CrossRef Full Text | Google Scholar

16. Randazzo ME, Grossrubatscher E, Dalino Ciaramella P, Vanzulli A, Loli P. Spontaneous recovery of bone mass after cure of endogenous hypercortisolism. Pituitary. (2012) 15:193–201. doi: 10.1007/s11102-011-0306-3

CrossRef Full Text | Google Scholar

17. Hermus AR, Smals AG, Swinkels LM, Huysmans DA, Pieters GF, Sweep CF, et al. Bone mineral density and bone turnover before and after surgical cure of Cushing’s syndrome. J Clin Endocrinol Metab. (1995) 80:2859–65. doi: 10.1210/jcem.80.10.7559865

CrossRef Full Text | Google Scholar

18. Di Somma C, Colao A, Pivonello R, Klain M, Faggiano A, Tripodi FS, et al. Effectiveness of chronic treatment with alendronate in the osteoporosis of Cushing’s disease. Clin Endocrinol (Oxf). (1998) 48:655–62. doi: 10.1046/j.1365-2265.1998.00486.x

CrossRef Full Text | Google Scholar

19. Russell RG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int. (2008) 19:733–59. doi: 10.1007/s00198-007-0540-8

CrossRef Full Text | Google Scholar

20. Humphrey MB, Russell L, Danila MI, Fink HA, Guyatt G, Cannon M, et al. 2022 American college of rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheumatol. (2023) 75:2088–102. doi: 10.1002/art.42646

CrossRef Full Text | Google Scholar

Keywords: Cushing’s disease, young patients, osteoporosis, bisphosphonates, bone turnover markers

Citation: Sun Q, Sun W, Ye H and Zhang S (2024) The efficacy of bisphosphonates for osteoporosis in young Cushing’s disease patients with biochemical remission: a retrospective cohort study. Front. Endocrinol. 15:1412046. doi: 10.3389/fendo.2024.1412046

Received: 04 April 2024; Accepted: 04 June 2024;
Published: 21 June 2024.

Edited by:

Daniela Merlotti, University of Siena, Italy

Reviewed by:

Catalina Poiana, Carol Davila University of Medicine and Pharmacy, Romania
Ming Chen, Chinese PLA General Hospital, China

Copyright © 2024 Sun, Sun, Ye and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Hongying Ye, janeyhy@163.com; Shuo Zhang, zhangshuo@huashan.org.cn

†These authors share first authorship

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

From https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1412046/full

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

Is Cushing Syndrome More Common in the US Than We Think?

Posted on June 11, 2024 by MaryO

I think members of the Cushing’s Help boards have been saying this forever!  Cushing’s isn’t all that rare.  Just rarely diagnosed,

 

BOSTON — The prevalence of Cushing syndrome (CS) in the United States may be considerably higher than currently appreciated, new data from a single US institution suggest.

In contrast to estimates of 1 to 3 cases per million patient-years from population-based European studies, researchers at the University of Wisconsin, Milwaukee, estimated that the incidence of CS in Wisconsin is a minimum of 7.2 cases per million patient-years. What’s more, contrary to all previous studies, they found that adrenal Cushing syndrome was more common than pituitary adrenocorticotropic hormone (ACTH)– secreting tumors (Cushing disease), and that fewer than half of individuals with adrenal Cushing syndrome had classic physical features of hypercortisolism, such as weight gain, round face, excessive hair growth, and stretch marks.

“Cases are absolutely being missed…. Clinicians should realize that cortisol excess is not rare. It may not be common, but it needs to be considered in patients with any constellation of features that are seen in cortisol excess,” study investigator Ty B. Carroll, MD, Associate Professor of Medicine, Endocrinology and Molecular Medicine, and the Endocrine Fellowship Program Director at Medical College of Wisconsin in Milwaukee, told Medscape Medical News.

There are several contributing factors, he noted, “including the obesity and diabetes epidemics which make some clinical features of cortisol excess more common and less notable. Providers get used to seeing patients with some features of cortisol excess and don’t think to screen. The consequence of this is more difficult-to-control diabetes and hypertension, more advance metabolic bone disease, and likely more advanced cardiovascular disease, all resulting from extended exposure to cortisol excess,” he said.

Are Milder Cases the Ones Being Missed?

Asked to comment, session moderator Sharon L. Wardlaw, MD, professor of medicine at Columbia University College of Physicians and Surgeons, New York City, said “When we talk about Cushing [syndrome], we usually think of pituitary ACTH as more [common], followed by adrenal adenomas, and then ectopic. But they’re seeing more adrenal adenoma…we are probably diagnosing this a little more now.”

She also suggested that the Wisconsin group may have a lower threshold for diagnosing the milder cortisol elevation seen with adrenal Cushing syndrome. “If you screen for Cushing with a dexamethasone suppression test…[i]f you have autonomous secretion by the adrenal, you don’t suppress as much…. When you measure 24-hour urinary cortisol, it may be normal. So you’re in this in-between [state]…. Maybe in Wisconsin they’re diagnosing it more. Or, maybe it’s just being underdiagnosed in other places.”

She also pointed out that “you can’t diagnose it unless you think of it. I’m not so sure that with these mild cases it’s so much that it’s more common, but maybe it’s like thyroid nodules, where we didn’t know about it until everybody started getting all of these CT scans. We’re now seeing all these incidental thyroid nodules…I don’t think we’re missing florid Cushing.”

However, Wardlaw said, it’s probably worthwhile to detect even milder hypercortisolism because it could still have long-term damaging effects, including osteoporosis, muscle weakness, glucose intolerance, and frailty. “You could do something about it and normalize it if you found it. I think that would be the reason to do it.”

Is Wisconsin Representative of Cushing Everywhere?

Carroll presented the findings at the annual meeting of the Endocrine Society. He began by noting that most of the previous CS incidence studies, with estimates of 1.2-3.2 cases per million per year, come from European data published from 1994 to 2019 and collected as far back as 1955. The method of acquisition of patients and the definitions of confirmed cases varied widely in those studies, which reported CS etiologies of ACTH-secreting neoplasms (pituitary or ectopic) in 75%-85% and adrenal-dependent cortisol excess in 15%-20%.

The current study included data from clinic records between May 1, 2017, and December 31, 2022, of Wisconsin residents newly diagnosed with and treated for CS. The CS diagnosis was established with standard guideline-supported biochemical testing and appropriate imaging. Patients with exogenous and non-neoplastic hypercortisolism and those who did not receive therapy for CS were excluded.

A total of 185 patients (73% female, 27% male) were identified from 27 of the total 72 counties in Wisconsin, representing a population of 4.5 million. On the basis of the total 5.9 million population of Wisconsin, the incidence of CS in the state works out to 7.2 cases per million population per year, Carroll said.

However, data from the Wisconsin Hospital Association show that the University of Wisconsin’s Milwaukee facility treated just about half of patients in the state who are discharged from the hospital with a diagnosis of CS during 2019-2023. “So…that means that an actual or approximate incidence of 14-15 cases per million per year rather than the 7.2 cases that we produce,” he said.

Etiologies were 60% adrenal (111 patients), 36.8% pituitary (68 patients), and 3.2% ectopic (6 patients). Those proportions were similar between genders.

On biochemical testing, values for late-night salivary cortisol, dexamethasone suppression, and urinary free cortisol were highest for the ectopic group (3.189 µg/dL, 42.5 µg/dL, and 1514.2 µg/24 h, respectively) and lowest for the adrenal group (0.236 µg/dL, 6.5 µg/dL, and 64.2 µg/24 h, respectively). All differences between groups were highly statistically significant, at P < .0001, Carroll noted.

Classic physical features of CS were present in 91% of people with pituitary CS and 100% of those ectopic CS but just 44% of individuals with adrenal CS. “We found that adrenal-dependent disease was the most common form of Cushing syndrome. It frequently presented without classic physical features that may be due to the milder biochemical presentation,” he concluded.

Carroll reports consulting and investigator fees from Corcept Therapeutics. Wardlaw has no disclosures. 

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker.

1

Credit

Lead image: Designer491/Dreamstime

Medscape Medical News © 2024 WebMD, LLCSend comments and news tips to news@medscape.net.

Cite this: Is Cushing Syndrome More Common in the US Than We Think? – Medscape – June 07, 2024.

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

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.

Similar content being viewed by others

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.

References

  1. R. Pivonello, M. De Leo, A. Cozzolino, A. Colao, The Treatment of Cushing’s Disease. Endocr. Rev. 36, 385–486 (2015). https://doi.org/10.1210/er.2013-1048

    Article CAS PubMed PubMed Central Google Scholar

  2. R. Pivonello, A.M. Isidori, M.C. De Martino, J. Newell-Price, B.M. Biller, A. Colao, Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol. 4, 611–629 (2016). https://doi.org/10.1016/S2213-8587(16)00086-3

    Article CAS PubMed Google Scholar

  3. J. Newell-Price, X. Bertagna, A.B. Grossman, L.K. Nieman, Cushing’s syndrome. Lancet 367, 1605–1617 (2006). https://doi.org/10.1016/S0140-6736(06)68699-6

    Article CAS PubMed Google Scholar

  4. R. Pivonello, M.C. De Martino, M. De Leo, G. Lombardi, A. Colao, Cushing’s Syndrome. Endocrinol. Metab. Clin. North Am. 37, 135–149 (2008). https://doi.org/10.1016/j.ecl.2007.10.010. ix

    Article CAS PubMed Google Scholar

  5. C. Steffensen, A.M. Bak, K.Z. Rubeck, J.O. Jorgensen, Epidemiology of Cushing’s syndrome. Neuroendocrinology 92, 1–5 (2010). https://doi.org/10.1159/000314297

    Article CAS PubMed Google Scholar

  6. R.N. Clayton, P.W. Jones, R.C. Reulen et al. Mortality in patients with Cushing’s disease more than 10 years after remission: a multicentre, multinational, retrospective cohort study. Lancet Diabetes Endocrinol. 4, 569–576 (2016). https://doi.org/10.1016/S2213-8587(16)30005-5

    Article PubMed Google Scholar

  7. E. Valassi, A. Tabarin, T. Brue et al. High mortality within 90 days of diagnosis in patients with Cushing’s syndrome: results from the ERCUSYN registry. Eur. J. Endocrinol. 181, 461–472 (2019). https://doi.org/10.1530/EJE-19-0464

    Article CAS PubMed Google Scholar

  8. V. Hasenmajer, E. Sbardella, F. Sciarra, M. Minnetti, A.M. Isidori, M.A. Venneri, The Immune System in Cushing’s Syndrome. Trends Endocrinol. Metab. 31, 655–669 (2020). https://doi.org/10.1016/j.tem.2020.04.004

    Article CAS PubMed Google Scholar

  9. M. Minnetti, V. Hasenmajer, E. Sbardella et al. Susceptibility and characteristics of infections in patients with glucocorticoid excess or insufficiency: the ICARO tool. Eur. J. Endocrinol. 187, 719–731 (2022). https://doi.org/10.1530/EJE-22-0454

    Article CAS PubMed PubMed Central Google Scholar

  10. M. De Leo, R. Pivonello, R.S. Auriemma et al. Cardiovascular disease in Cushing’s syndrome: heart versus vasculature. Neuroendocrinology 92, 50–54 (2010). https://doi.org/10.1159/000318566

    Article CAS PubMed Google Scholar

  11. A.M. Isidori, C. Graziadio, R.M. Paragliola et al. The hypertension of Cushing’s syndrome: controversies in the pathophysiology and focus on cardiovascular complications. J. Hypertens. 33, 44–60 (2015). https://doi.org/10.1097/HJH.0000000000000415

    Article CAS PubMed PubMed Central Google Scholar

  12. T. Mancini, B. Kola, F. Mantero, M. Boscaro, G. Arnaldi, High cardiovascular risk in patients with Cushing’s syndrome according to 1999 WHO/ISH guidelines. Clin. Endocrinol. 61, 768–777 (2004). https://doi.org/10.1111/j.1365-2265.2004.02168.x

    Article Google Scholar

  13. A.M. Isidori, M. Minnetti, E. Sbardella, C. Graziadio, A.B. Grossman, Mechanisms in endocrinology: The spectrum of haemostatic abnormalities in glucocorticoid excess and defect. Eur. J. Endocrinol. 173, R101–R113 (2015). https://doi.org/10.1530/EJE-15-0308

    Article CAS PubMed Google Scholar

  14. F. Fallo, G. Di Dalmazi, F. Beuschlein et al. Diagnosis and management of hypertension in patients with Cushing’s syndrome: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension. J. Hypertens. 40, 2085–2101 (2022). https://doi.org/10.1097/HJH.0000000000003252

    Article CAS PubMed Google Scholar

  15. O.M. Dekkers, E. Horvath-Puho, J.O. Jorgensen et al. Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J. Clin. Endocrinol. Metab. 98, 2277–2284 (2013). https://doi.org/10.1210/jc.2012-3582

    Article CAS PubMed Google Scholar

  16. L.K. Nieman, B.M. Biller, J.W. Findling et al. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 100, 2807–2831 (2015). https://doi.org/10.1210/jc.2015-1818

    Article CAS PubMed PubMed Central Google Scholar

  17. F.M. van Haalen, L.H. Broersen, J.O. Jorgensen, A.M. Pereira, O.M. Dekkers, Management of endocrine disease: Mortality remains increased in Cushing’s disease despite biochemical remission: a systematic review and meta-analysis. Eur. J. Endocrinol. 172, R143–R149 (2015). https://doi.org/10.1530/EJE-14-0556

    Article CAS PubMed Google Scholar

  18. P. Kamenicky, A. Redheuil, C. Roux et al. Cardiac structure and function in Cushing’s syndrome: a cardiac magnetic resonance imaging study. J. Clin. Endocrinol. Metab. 99, E2144–E2153 (2014). https://doi.org/10.1210/jc.2014-1783

    Article CAS PubMed PubMed Central Google Scholar

  19. M.L. Muiesan, M. Lupia, M. Salvetti et al. Left ventricular structural and functional characteristics in Cushing’s syndrome. J. Am. Coll. Cardiol. 41, 2275–2279 (2003). https://doi.org/10.1016/s0735-1097(03)00493-5

    Article PubMed Google Scholar

  20. A.M. Pereira, V. Delgado, J.A. Romijn, J.W. Smit, J.J. Bax, R.A. Feelders, Cardiac dysfunction is reversed upon successful treatment of Cushing’s syndrome. Eur. J. Endocrinol. 162, 331–340 (2010). https://doi.org/10.1530/EJE-09-0621

    Article CAS PubMed Google Scholar

  21. K.H. Yiu, N.A. Marsan, V. Delgado et al. Increased myocardial fibrosis and left ventricular dysfunction in Cushing’s syndrome. Eur. J. Endocrinol. 166, 27–34 (2012). https://doi.org/10.1530/EJE-11-0601

    Article CAS PubMed Google Scholar

  22. A. Colao, R. Pivonello, S. Spiezia et al. Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure. J. Clin. Endocrinol. Metab. 84, 2664–2672 (1999). https://doi.org/10.1210/jcem.84.8.5896

    Article CAS PubMed Google Scholar

  23. A. Faggiano, R. Pivonello, S. Spiezia et al. Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission. J Clin Endocrinol. Metab. 88, 2527–2533 (2003). https://doi.org/10.1210/jc.2002-021558

    Article CAS PubMed Google Scholar

  24. A. Kanzaki, M. Kadoya, S. Katayama, H. Koyama, Cardiac Hypertrophy and Related Dysfunctions in Cushing Syndrome Patients-Literature Review. J. Clin. Med. 11, 7035 (2022). https://doi.org/10.3390/jcm11237035

    Article CAS PubMed PubMed Central Google Scholar

  25. M. Salerno, B. Sharif, H. Arheden et al. Recent Advances in Cardiovascular Magnetic Resonance: Techniques and Applications. Circ. Cardiovasc. Imaging 10, e003951 (2017). https://doi.org/10.1161/CIRCIMAGING.116.003951

    Article PubMed PubMed Central Google Scholar

  26. C. Roux, N. Kachenoura, Z. Raissuni et al. Effects of cortisol on the heart: characterization of myocardial involvement in cushing’s disease by longitudinal cardiac MRI T1 mapping. J. Magn. Reson. Imaging 45, 147–156 (2017). https://doi.org/10.1002/jmri.25374

    Article PubMed Google Scholar

  27. F. Maurice, B. Gaborit, C. Vincentelli et al. Cushing Syndrome Is Associated With Subclinical LV Dysfunction and Increased Epicardial Adipose Tissue. J. Am. Coll. Cardiol. 72, 2276–2277 (2018). https://doi.org/10.1016/j.jacc.2018.07.096

    Article PubMed Google Scholar

  28. P. Wolf, B. Marty, K. Bouazizi et al. Epicardial and Pericardial Adiposity Without Myocardial Steatosis in Cushing Syndrome. J. Clin. Endocrinol. Metab. 106, 3505–3514 (2021). https://doi.org/10.1210/clinem/dgab556

    Article PubMed Google Scholar

  29. M. Moustaki, G. Markousis-Mavrogenis, A. Vryonidou, S.A. Paschou, S. Mavrogeni, Cardiac disease in Cushing’s syndrome. Emphasis on the role of cardiovascular magnetic resonance imaging. Endocrine 83, 548–558 (2024). https://doi.org/10.1007/s12020-023-03623-0

    Article CAS PubMed Google Scholar

  30. M. Fleseriu, R. Auchus, I. Bancos et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 9, 847–875 (2021). https://doi.org/10.1016/S2213-8587(21)00235-7

    Article PubMed PubMed Central Google Scholar

  31. J.M. Hinojosa-Amaya, D. Cuevas-Ramos, The definition of remission and recurrence of Cushing’s disease. Best. Pract. Res. Clin. Endocrinol. Metab. 35, 101485 (2021). https://doi.org/10.1016/j.beem.2021.101485

    Article PubMed Google Scholar

  32. M. Fassnacht, S. Tsagarakis, M. Terzolo et al. European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur. J. Endocrinol. 189, G1–G42 (2023). https://doi.org/10.1093/ejendo/lvad066

    Article PubMed Google Scholar

  33. R. Pofi, E. Giannetta, N. Galea et al. Diabetic Cardiomiopathy Progression is Triggered by miR122-5p and Involves Extracellular Matrix: A 5-Year Prospective Study. JACC Cardiovasc. Imaging. 14, 1130–1142 (2021). https://doi.org/10.1016/j.jcmg.2020.10.009

    Article PubMed Google Scholar

  34. J.C. Moon, D.R. Messroghli, P. Kellman et al. Myocardial T1 mapping and extracellular volume quantification: a Society for Cardiovascular Magnetic Resonance (SCMR) and CMR Working Group of the European Society of Cardiology consensus statement. J. Cardiovasc. Magn. Reson. 15, 92 (2013). https://doi.org/10.1186/1532-429X-15-92

    Article PubMed PubMed Central Google Scholar

  35. P. Haaf, P. Garg, D.R. Messroghli, D.A. Broadbent, J.P. Greenwood, S. Plein, Cardiac T1 Mapping and Extracellular Volume (ECV) in clinical practice: a comprehensive review. J. Cardiovasc. Magn. Reson. 18, 89 (2016). https://doi.org/10.1186/s12968-016-0308-4

    Article PubMed PubMed Central Google Scholar

  36. N. Kawel-Boehm, S.J. Hetzel, B. Ambale-Venkatesh et al. Reference ranges (“normal values”) for cardiovascular magnetic resonance (CMR) in adults and children: 2020 update. J. Cardiovasc. Magn. Reson. 22, 87 (2020). https://doi.org/10.1186/s12968-020-00683-3

    Article PubMed PubMed Central Google Scholar

  37. R. Janardhanan, C.M. Kramer, Imaging in hypertensive heart disease. Expert Rev. Cardiovasc. Ther. 9, 199–209 (2011). https://doi.org/10.1586/erc.10.190

    Article CAS PubMed PubMed Central Google Scholar

  38. M. Baykan, C. Erem, O. Gedikli et al. Assessment of left ventricular diastolic function and Tei index by tissue Doppler imaging in patients with Cushing’s Syndrome. Echocardiography 25, 182–190 (2008). https://doi.org/10.1111/j.1540-8175.2007.00572.x

    Article PubMed Google Scholar

  39. N.A. Bayram, R. Ersoy, C. Aydin et al. Assessment of left ventricular functions by tissue Doppler echocardiography in patients with Cushing’s disease. J. Endocrinol. Invest. 32, 248–252 (2009). https://doi.org/10.1007/BF03346461

    Article CAS PubMed Google Scholar

  40. P.M. Toja, G. Branzi, F. Ciambellotti et al. Clinical relevance of cardiac structure and function abnormalities in patients with Cushing’s syndrome before and after cure. Clin. Endocrinol. 76, 332–338 (2012). https://doi.org/10.1111/j.1365-2265.2011.04206.x

    Article CAS Google Scholar

  41. F. Tona, M. Boscaro, M. Barbot et al. New insights to the potential mechanisms driving coronary flow reserve impairment in Cushing’s syndrome: A pilot noninvasive study by transthoracic Doppler echocardiography. Microvasc. Res. 128, 103940 (2020). https://doi.org/10.1016/j.mvr.2019.103940

    Article CAS PubMed Google Scholar

  42. A.C. Armstrong, S. Gidding, O. Gjesdal, C. Wu, D.A. Bluemke, J.A. Lima, LV mass assessed by echocardiography and CMR, cardiovascular outcomes, and medical practice. JACC Cardiovasc. Imaging 5, 837–848 (2012). https://doi.org/10.1016/j.jcmg.2012.06.003

    Article PubMed PubMed Central Google Scholar

  43. C. Sylven, E. Jansson, P. Sotonyi, F. Waagstein, T. Barkhem, M. Bronnegard, Cardiac nuclear hormone receptor mRNA in heart failure in man. Life Sci. 59, 1917–1922 (1996). https://doi.org/10.1016/s0024-3205(96)00539-5

    Article CAS PubMed Google Scholar

  44. A.S. Mihailidou, T.Y. Loan Le, M. Mardini, J.W. Funder, Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction. Hypertension 54, 1306–1312 (2009). https://doi.org/10.1161/HYPERTENSIONAHA.109.136242

    Article CAS PubMed Google Scholar

  45. G. Fujisawa, R. Dilley, M.J. Fullerton, J.W. Funder, Experimental cardiac fibrosis: differential time course of responses to mineralocorticoid-salt administration. Endocrinology 142, 3625–3631 (2001). https://doi.org/10.1210/endo.142.8.8339

    Article CAS PubMed Google Scholar

  46. X. Feng, S.A. Reini, E. Richards, C.E. Wood, M. Keller-Wood, Cortisol stimulates proliferation and apoptosis in the late gestation fetal heart: differential effects of mineralocorticoid and glucocorticoid receptors. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R343–R350 (2013). https://doi.org/10.1152/ajpregu.00112.2013

    Article CAS PubMed PubMed Central Google Scholar

  47. P.M. Williamson, J.J. Kelly, J.A. Whitworth, Dose-response relationships and mineralocorticoid activity in cortisol-induced hypertension in humans. J. Hypertens. Suppl. 14, S37–S41 (1996)

    CAS PubMed Google Scholar

  48. S.L. Ong, J.A. Whitworth, How do glucocorticoids cause hypertension: role of nitric oxide deficiency, oxidative stress, and eicosanoids. Endocrinol. Metab. Clin. North. Am. 40, 393–407 (2011). https://doi.org/10.1016/j.ecl.2011.01.010

    Article CAS PubMed Google Scholar

  49. A. De Bellis, G. De Angelis, E. Fabris, A. Cannata, M. Merlo, G. Sinagra, Gender-related differences in heart failure: beyond the “one-size-fits-all” paradigm. Heart Fail. Rev. 25, 245–255 (2020). https://doi.org/10.1007/s10741-019-09824-y

    Article PubMed Google Scholar

  50. R. Pofi, E. Giannetta, T. Feola et al. Sex-specific effects of daily tadalafil on diabetic heart kinetics in RECOGITO, a randomized, double-blind, placebo-controlled trial. Sci. Transl. Med. 14, eabl8503 (2022). https://doi.org/10.1126/scitranslmed.abl8503

    Article CAS PubMed Google Scholar

  51. D. Gianfrilli, R. Pofi, T. Feola, A. Lenzi, E. Giannetta, The Woman’s Heart: Insights into New Potential Targeted Therapy. Curr. Med. Chem. 24, 2650–2660 (2017). https://doi.org/10.2174/0929867324666161118121647

    Article CAS PubMed Google Scholar

Download references

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Cite this article

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

Download citation

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

« Previous Page — Next Page »