Cushing’s Disease | CushieBlog

Cushing Disease Clinical Phenotype and Tumor Behavior Vary With Age

Posted on January 24, 2025 by MaryO

Abstract

Context

Little is known about presenting clinical characteristics, tumor biology, and surgical morbidity of Cushing disease (CD) with aging.

Objective

Using a large multi-institutional data set, we assessed diagnostic and prognostic significance of age in CD through differences in presentation, laboratory results, tumor characteristics, and postoperative outcomes.

Methods

Data from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) were reviewed for patients with CD treated with transsphenoidal tumor resection at 11 centers between 2003 and 2023. Outcomes assessed included comorbidities, presenting features, preoperative endocrine evaluations, perioperative characteristics, postoperative endocrine laboratory values, and complications.

Results

Of the 608 patients evaluated, 496 (81.6%) were female; median age at surgery was 44 years (range, 10-78 years). Increasing age was associated with increasing comorbidities, frailty, rates of postoperative thromboembolic disease, Knosp grade, tumor size, and postoperative cortisol and adrenocorticotropin nadirs. Conversely, increasing age was associated with decreased hallmark CD features, preoperative 24-hour urinary free cortisol, Ki-67 indices, and arginine vasopressin deficiency. Younger patients presented more frequently with weight gain, facial rounding/plethora, abdominal striae, hirsutism, menstrual irregularities, dorsocervical fat pad, and acne. Obstructive sleep apnea and infections were more common with increasing age.

Conclusion

There are age-dependent differences in clinical presentation, tumor behavior, and postoperative outcomes in patients with CD. Compared to younger patients, older patients present with a less classic phenotype characterized by fewer hallmark features, more medical comorbidities, and larger tumors. Notably, age-related differences suggest a more indolent tumor behavior in older patients, potentially contributing to delayed diagnosis and increased perioperative risk. These findings underscore the need for tailored diagnostic and therapeutic approaches across age groups, with a focus on managing long-term comorbidities and optimizing surgical outcomes.

Cushing disease, hypercortisolism, elderly, pituitary registry

From https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgae904/7941836?redirectedFrom=fulltext&login=false

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

Management of Diabetes Mellitus in Acromegaly and Cushing’s Disease with Focus on Pasireotide Therapy

Posted on August 2, 2024 by MaryO

Abstract: Patients suffering from acromegaly and Cushing’s Disease (CD) face the risk of several clinical complications. The onset of diabetes mellitus (DM) is among the most important: exposure to elevated growth hormone or cortisol levels is associated with insulin resistance (IR). DM contributes to increasing cardiovascular risk for these subjects, which is higher compared to healthy individuals. Hyperglycemia may also be caused by pasireotide, a second-generation somatostatin receptor ligand (SRLs), currently used for the treatment of these diseases. Accordingly, with 2014 medical expert recommendations, the management of hyperglycemia in patients with CD and treated with pasireotide is based on lifestyle changes, metformin, DPP-4 inhibitors (DPP-4i) and, subsequently, GLP-1 Receptor Agonists (GLP-1 RAs). There is no position for SGLT2-inhibitors (SGLT2-i). However, a very recent experts’ consensus regarding the management of pasireotide-induced hyperglycemia in patients with acromegaly suggests the use of GLP-1 RAs as first line treatment (in suitable patients) and the use of SGLT2-i as second line treatment in patients with high cardiovascular risk or renal disease. As a matter of fact, beyond the hypoglycemic effect of GLP1-RAs and SGLT2-i, there is increasing evidence regarding their role in the reduction of cardiovascular risk, commonly very high in acromegaly and CD and often tough to improve despite biochemical remission. So, an increasing use of GLP1-RAs and SGLT2-i to control hyperglycemia is desirable in these diseases. Obviously, all of that must be done with due attention in order to minimize the occurrence of adverse events. For this reason, large studies are needed to analyze the presence of potential limitations.

Keywords: acromegaly, Cushing’s disease, pasireotide, hyperglycemia, diabetes mellitus, cardiovascular risk

Introduction

Acromegaly and Cushing’s Disease (CD) are rare but weakening endocrine diseases.

Acromegaly is usually caused by a growth hormone (GH)-secreting pituitary adenoma, with subsequent excess of insulin-like growth factor (IGF-1).¹ CD is characterized by hyperproduction of cortisol due to an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma.² Impaired glucose metabolism and the onset of DM are common clinical conditions resulting from these diseases. The worsening of glycemic control might also be caused by treatment with somatostatin receptor analogs, more specifically with pasireotide.

Pasireotide, a second-generation somatostatin receptor ligand (SRLs), is currently used for the treatment of acromegaly and CD.^3,4

In the management of acromegaly, long-acting pasireotide is recommended at a starting dose of 40 mg monthly (potentially up-titrated to 60 mg) in patients with poorly controlled or uncontrolled disease after failure with first generation SRLs. Several Randomized Control Trials (RCTs) have shown better outcomes in achieving biochemical control compared to octreotide and lanreotide, both in parallel arms as well as in a cross-over evaluation.^5,6 In CD, pasireotide is approved for the treatment of persistent hypercortisolism after a surgical procedure or when surgery is not feasible or refused, at a start dose of 0.6 mg twice daily (potentially up titrated to 0.9 mg twice daily).^7,8

Hyperglycemia and Increased Cardiovascular Risk in Acromegaly and CD

Impaired glucose metabolism is one of the comorbidities associated with acromegaly and CD, uniquely linked to the pathophysiology of the diseases. As a matter of fact, in acromegaly, the prevalence of altered basal glucose ranges between 7 and 22%, of altered glucose tolerance between 6 and 45%, and of diabetes between 19 and 56%.⁹ Additionally, disorders of carbohydrate metabolism occur in 14–74% of the patients among the various forms of hypercortisolism while the prevalence of diabetes varies between 21 and 47%.¹⁰

The pathogenesis of insulin resistance (IR) in acromegaly is due to multiple factors: GH exerts its effects both directly by inducing gluconeogenesis, glycogenolysis and lipolysis and promoting IR in the liver and peripheral tissues, as well as indirectly through IGF-1.¹¹ GH stimulates the hydrolysis of triglycerides and the production of free fatty acids from adipose tissue, and this increased synthesis of free fatty acids leads to a decrease in insulin-mediated glucose uptake by inhibiting glucose transporters GLUT-1 and GLUT-4.^12,13 Moreover, GH suppresses key insulin signaling pathways involved in stimulating glucose transport in muscle and adipose tissue and inhibiting glucose production in the liver.¹⁴

The effects of IR secondary to the excess of GH are initially compensated by the increased secretion of insulin from the pancreatic beta cells, which, however, diminishes over time, favoring the onset of prediabetes and diabetes.^15,16 Once the beta cell function is affected, the glucose metabolism disorders persist even after the acromegaly is cured.¹⁷ Although physiologically IGF-1 improves glucose homeostasis, the chronic excess of GH in acromegaly that causes IR greatly exceeds the possible beneficial effects of IGF-1 on insulin sensitivity.¹⁸

Similar to the excess of GH, hypercortisolism affects carbohydrate metabolism mainly in liver, skeletal muscles, and adipose tissue.¹⁹ In the liver, excess glucocorticoids stimulate gluconeogenesis by activating numerous genes involved in the hepatic gluconeogenesis, stimulating lipolysis and proteolysis with increasing substrates for gluconeogenesis, potentiating the action of glucagon and inhibiting glycogenogenesis.²⁰

In the muscle, hypercortisolism induces IR by interfering with different components of the insulin-signaling cascade, as well as by stimulating proteolysis and loss of muscle mass. All this reduces the capacity of the muscle to synthesize glycogen and uptake most of the postprandial glucose from circulation.²¹

Additionally, hypercortisolism causes an increase in visceral obesity and a relative reduction in peripheral adipose tissue, and this “shift” is closely associated with metabolic syndrome and worsens IR. Moreover, the excess of cortisol influences the synthesis and release of hormones from adipose tissue, mainly adipokines, further contributing to the development of IR.²¹

Glucocorticoids inhibit the synthesis and secretion of insulin. Also in CD, there is an initial transient phase characterized by the increase in insulin secretion as an adaptive mechanism to IR, but later the chronic exposure to higher levels of cortisol induces pancreatic beta cell apoptosis, loss of beta cell function and the subsequent development of diabetes.^20,22

The involvement of the bone system in affecting glucose homeostasis has also been found: in fact, long-term exposure to glucocorticoids causes a reduction in circulating osteocalcin that can increase IR.²³

Furthermore, two studies in humans^24,25 suggested that secretion of incretins (glucagon-like peptide-1, GLP-1 and glucose dependent insulinotropic peptide, GIP) was unaffected by dexamethasone administration, but their insulinotropic effects of on beta-cells were reduced.

The worsening of glycemic control and the onset of DM are also important limitations in the management of some patients treated with pasireotide.^26,27 This topic will be further explored in a subsequent paragraph.

As is well known, hyperglycemia contributes to increasing cardiovascular risk, which is already very high in patients with acromegaly or CD.^28,29

Cardiovascular disease is the leading cause of death in 23–50% of patients with acromegaly in different studies.⁹ Hypertension affects about 33% of the patients, ranging from 11 to 54.7%,³⁰ and it is strongly related with typical cardiac implications of acromegaly as valvulopathy, arrhythmias and cardiomyopathy.

In the large Liege Acromegaly Survey database of 3173 acromegalic patients from 10 European countries,³¹ left ventricular hypertrophy was present in 15.5% at time of diagnosis. The most common manifestations of cardiopathy are biventricular hypertrophy, diastolic-systolic dysfunction, and valvular regurgitation.³² Certainly, the severity of cardiac disease is correlated with age, duration of acromegaly, GH and IGF-1 levels (both vascular growth factors which stimulate collagen deposition) and long-standing hypertension.³³ In the worst cases, hypertrophic cardiopathy can evolve into Left Ventricular Systolic Dysfunction (LVSD), the last stage of cardiac disease, with recurring hospitalizations and very high mortality rates.³⁴ Acromegaly is also associated with sleep apnea (ranging from 45 to 80% of the cases).³⁵

Similarly, in CD cardiovascular disease is the leading cause of death: a retrospective study involving 502 patients (83% in remission) with a median follow-up of 13 years³⁶ demonstrated a standardized mortality ratio (SMR) of 3.3 (95% CI 2.6–4.3) for CV disease, in particular 3.6 (95% CI 2.5–5.1) for ischemic cardiac disease and 3.0 (95% CI 1.4–5.7) for stroke. SMR related cardiovascular disease remained higher also after biochemical remission (2.5, 95% CI 1.8–3.4).³⁶ Cardiovascular remodeling caused by hypercortisolism is frequently irreversible: at 5 years post-remission, coronary artery plaques persisted in 27% of subjects vs 3% of control.³⁷ As a result, the risk for ischemic events remains above that of the general population.³⁸

Hypertension is highly prevalent in patients with hypercortisolism: the majority (80–85%) of patients have hypertension at diagnosis and 9% may have required hospital admission because of the hypertension crisis before the diagnosis of hypercortisolism.³⁹ Also, after remission, hypertension results are highly prevalent, as shown in two different studies (50% and 40%, respectively).^40,41 Up to 70% of the patients with active CD present abnormal left ventricular mass parameters, whereas systolic and diastolic function were usually normal. Rarely, patients present dilatative cardiopathy and severe HF.⁴² Moreover, greater incidence of hypokalemia exposes patients to fatal arrhythmias.

Finally, both obesity and dyslipidemia, frequently occurring in these diseases, do not normalize despite biochemical remission.

Mechanisms of Pasireotide-Induced Hyperglycemia

Pasireotide is a multi-receptor targeted SRL, with action on different somatostatin receptors (SSTR). Pasireotide binds with high affinity to SSTR-1, 3 and 5 and lower to SSTR-2 than first generation SSA. More specifically, the affinity for SSTR-5, several times greater than those of octreotide and lanreotide, explains the efficacy of pasireotide: this binding causes the suppression of ACTH and GH, accompanied by tumor volume reduction.^43,44

However, this mechanism causes the alteration of glucose metabolism because the binding is not specific to pituitary cells. Stimulation of pancreatic SSTR-5, expressed more in Langerhans islet beta cells than alfa cells (87% vs 44%), suppresses insulin secretion much more than glucagon secretion.⁴⁵

Pasireotide appears to inhibit the secretion of incretin hormones GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) in health volunteers after oral glucose tolerance test (OGTT),⁴⁶ even if a recent study showed no differences in incretin levels and their response to mixed meal tolerance test (MMTT) in CD patients,⁴⁷ suggesting a main role of direct inhibition of beta-cells activity. However, a reduced intra-islet paracrine effect of GLP-1 cannot be excluded whereas an increased IL-6 mediated GLP-1 secretion in CD may disguise pasireotide inhibitory effect.^47,48 Furthermore, pasireotide has no effect on hepatic and peripheral insulin sensitivity.⁴⁶

Pasireotide-induced hyperglycemia is less pronounced following multiple dosing, and it appears even reversible upon discontinuation of the drug,⁴⁹ as shown in a pharmacokinetic analysis of single-dose administration, in which mean glucose levels increased to 200 mg/dL (11.1 mmol/L) and returned to euglycemia approximately 23 hours later.⁵⁰

Not all patients treated with pasireotide develop impaired glucose tolerance or DM: the prevalence of these conditions in CD is respectively 21–64% and 20–47%,⁵¹ whereas in acromegaly it is 6–45% and 16–65%.⁹ This suggests that glycemic control prior to the treatment and a preceding DM, could be predictive of the extent of hyperglycemia.

In the PAOLA study⁶ a fasting blood glucose (FBG) > 100 mg/dL (5.5 mmol/L) at baseline correlated with higher FBG and higher HbA1c during treatment with pasireotide, while patients with acromegaly < 40 years of age were less likely to experience hyperglycemia than older patients.

Moreover, in acromegalic patients, the up-titration to a dose of 60 mg was associated with a 21–36% increased risk of hyperglycemia.^52,53 Other factors that could increase the risk of hyperglycemia were a Body Mass Index > 30 kg/m², hypertension and dyslipidemia at baseline.⁵⁴

Superimposable results were obtained in another Phase III study,⁵⁵ always performed in subjects with acromegaly: it was reported that up to 45% of patients with baseline FBG between 100 (5.5 mmol/L) and 126 mg/dL (7.0 mmol/L) had FBG levels ≥126 mg/dL (7.0 mmol/L) after 26 months of pasireotide.⁵⁵

Also, in CD, preexisting DM or impaired glucose tolerance increased the risk of hyperglycemia-related adverse events (AEs) with pasireotide, although severe AEs were not reported.⁷

A meta-analysis showed a lower frequency of hyperglycemia-related AEs in acromegalic patients treated with pasireotide monthly (57.3–67.0%) in comparison to those who received it twice daily for CD (68.4–73.0%).²⁷ Also, the rate of discontinuation due to hyperglycemia was higher in CD trials (6.0% and 5.3%) than that in acromegaly trials (3.4% and 4.0%).^5–7,56 The reasons for these findings are unknown.

On the other hand, it has been acknowledged that other drugs, commonly used for the treatment of acromegaly or CD, may affect glucose metabolism leading to clinical benefits, even during pasireotide therapy. In fact, in acromegalic subjects, cabergoline can improve glucose tolerance,⁵⁷ whereas pegvisomant reduces fasting glucose levels and improves insulin sensitivity.^58,59 Similar results have been highlighted for ketoconazole,⁶⁰ metyrapone⁶¹ and osilodostrat⁶² in studies involving patients with CD.

Antidiabetic Drugs with Proven Cardiovascular Benefits

The evidence from Cardio Vascular Outcome Trials with GLP-1 RAs and SGLT2-i have revolutionized the management of Type 2 Diabetes Mellitus (T2DM). As reaffirmed in the recent American Diabetes Association-European Association for the Study of Diabetes (ADA-EASD) Consensus, the treatment approach must be holistic and person-centered, with four main areas of interest: glycemic control, weight loss, CV risk reduction and renal protection.⁶³

In a network meta-analysis of 453 trials assessing glucose-lowering medications from nine drug classes, the greatest reductions in HbA1c were seen with GLP-1 RAs.⁶⁴ Another meta-analysis comparing the effects of glucose-lowering drugs on body weight and blood pressure indicated the greatest efficacy for reducing body weight with GLP-1 RAs, whereas the greatest reduction in blood pressure is seen with the SGLT2-i.⁶⁵

Among GLP-1 RAs, liraglutide (at a dose of 1.8 mg daily),⁶⁶ dulaglutide (at a dose 1.5 mg weekly)⁶⁷ and injectable semaglutide (at a dose of 0.5 and 1 mg weekly)⁶⁸ reduced the incidence of three point-MACE (Major Adverse Cardiovascular Events) and the progression of CKD (Chronic Kidney Disease) through the reduction of albuminuria.

With regard to SGLT2-i, empagliflozin and canagliflozin reduced the incidence of three point-MACE.^69,70 Empagliflozin, dapagliflozin and canagliflozin demonstrated improvement of CKD in trials with specific renal outcomes, and the first two also demonstrated this benefit in patients without T2DM.^71–73 Another significant clinical benefit is the reduction of hospitalization for heart failure (HF), demonstrated also in patients without T2DM for empagliflozin and dapagliflozin, both with reduced ejection fraction (HFrEF)^74,75 and preserved ejection fraction (HFpEF).^76,77

The Current Management of Pasireotide-Induced Hyperglycemia

Several studies, performed with different designs, evaluated the impact of pasireotide on glucose metabolism. The principal results are summarized in Table 1.^{5–8,78–85}

Table 1 Main Studies Regarding the Use of Pasireotide in Acromegaly and in Cushing’s Disease

It’s undeniable that impairment of glucose metabolism occurred: generally, in all studies the number of subjects with diabetes and prediabetes increased, HbA1c levels were higher and anti-hyperglycemic treatments were required. Metformin, DPP-4i and insulin were commonly used to treat hyperglycemia, whereas GLP-1 RAs and SGLT2-i were given only in a small number of cases.

Nevertheless, a recent randomized multicenter study involving 81 patients with acromegaly or CD receiving pasireotide⁸⁶ and uncontrolled hyperglycemia with metformin or other oral antidiabetic medications (acarbose or sulfonylureas), evaluated the effects of two different regimens of treatment (incretin-based therapy vs insulin). All 38 patients randomized to an incretin-based therapy (acromegaly, n = 26; CD, n =12) received sitagliptin; 28 of them switched to liraglutide. Twelve patients (31.6% [CD, n = 6; acromegaly, n = 6]) randomized to incretin-based therapy received insulin as rescue therapy. The results have shown a trend for better control of HbA1c with incretin-based therapy. Furthermore, in the same study, 109 patients who received pasireotide did not develop hyperglycemia requiring antidiabetic treatment.⁸⁶ These findings suggest that impaired glucose metabolism or onset of DM during pasireotide therapy are manageable in most patients, without the need for treatment discontinuation.

Accordingly, given the above-mentioned evidence, glycemia should be monitored in all patients treated with pasireotide in order to intercept an initial alteration of glucose metabolism which could be either prediabetes or DM, according to the indications of ADA.⁸⁷ In patients treated with pasireotide, FBG and HbA1c levels tend to increase during the first 1–3 months of treatment and stabilize thereafter.⁸⁸

Regarding CD, in 2014, a medical expert recommendation on pasireotide-induced hyperglycemia was published.⁸⁹ In this, an HbA1c target value less than 7.0–7.5% (53–58 mmol/L) is established, avoiding as much as possible the risk of hypoglycemia. Patients in euglycemia prior to therapy must be monitored: they should self-check FBG and postprandial glucose (PPG) levels during the day, precisely twice in the first week and once weekly later. Instead, patients with prediabetes and DM must be monitored closely (after 1, 2 and 4 weeks), and they should self-check blood glucose values up to six times per day during the first week, and at least four times per day thereafter.^26,89

Medical treatment should always include dietary modification and exercise. Metformin is the first line-therapy, unless contraindicated or not tolerated. If glycemic control is not reached or maintained with monotherapy, combination therapy with drugs targeting the incretinic axis is recommended:⁸⁹ a Phase I study⁹⁰ in 19 healthy volunteers randomized to pasireotide 600 μg sc bid alone or co-administered with antidiabetic drugs (metformin 500 mg bid, nateglinide 60 mg tid, vildagliptin 50 mg bid and liraglutide 0.6 daily) demonstrated greater effects of vildagliptin and liraglutide in minimizing hyperglycemia.

Therefore, therapy with a DDP-4i is suggested in a first step combination. Only in the case of failure to reach the HbA1c target, the replace of DDP-4i with a GLP-1 RAs is recommended. If pasireotide-induced hyperglycemia remains uncontrolled with combinations containing metformin and DPP-4i or GLP-1 RAs, experts’ recommendations suggest the beginning of basal insulin therapy. If the individual HbA1c targets are not achieved or the postprandial glucose levels remains elevated, prandial insulin can be added.⁸⁹

Instead, in acromegaly, a very interesting experts’ consensus statement regarding the management of pasireotide-induced hyperglycemia has been recently published.⁹¹ It suggests monitoring blood glucose prior to initiation of pasireotide treatment, through the determination of HbA1c or FBG or the execution of OGTT. Patients are divided into three risk categories related to glycemic status: normal glucose tolerance (NGT) patients at low risk, NGT patients at high risk and prediabetic or diabetic patients. In low-risk patients with no worsening of glycemic control, self-measurement of blood glucose (FBG and PPG) once every week is considered sufficient. In high-risk patients who do not have elevated blood glucose levels, weekly self-monitoring (FBG and PPG) is recommended in the first three months. In patients with pre-existing hyperglycemia, daily self-monitoring in recommended with at least one FBG and one PPG, ideally as multiple-point profiles.⁹¹ Further, when possible and economically feasible, high-risk patients should temporarily be equipped with continuous glucose monitors (CGMs) to detect elevated blood glucose levels early and determine deviations from the time in range precisely. During treatment with pasireotide, HbA1c measurements should be routinely performed every three months and at least with each IGF-1measurement.⁹¹

For the treatment of hyperglycemia, this recent experts’ consensus statement represents an important leap forward from a conceptual point of view. As a matter of fact, glycemic targets are not strictly fixed but an individualized approach for each patient is suggested. Moreover, CV risk is introduced as a factor influencing the choice of antidiabetic drugs.

Obviously, lifestyle intervention (physical activity, healthy sleep, high-quality nutrition) is always suggested. Metformin is indicated as a first-line medication but, considering the high CV risk of acromegalic subjects, GLP-1 RAs with proven CV benefits could also be considered as a first-line treatment. DPP-4i are considered a viable alternative to GLP-1 RAs in case of gastrointestinal side-effects.⁹¹

However, studies demonstrated that 10–30% of acromegalic patients show a paradoxical increase in GH (PI-GH) during 75-g OGTT.³ This is probably due to the action of GIP, which is higher in acromegalic patients, particularly in those with hyperglycemia, and that is likely able to increase the secretion of GH.^92,93 As is well known, DPP-4i reduce the incretin-degrading enzyme DPP-4 and thus increase the concentration of active incretins, including GIP. Accordingly, a recent study showed that sitagliptin, administered one hour before 75-g OGTT, increase GH in acromegalic patients, especially in those with PI-GH.⁹⁴ For this reason, acromegalic patients should be carefully monitored for a potential worsening of the underlying disease during treatment with a DPP- 4i.

The use of SGLT2-i is recommended only as second-line treatment for patients with high CV risk and/or renal disease, despite their high prevalence in acromegaly.⁹¹ This is justified by the increased risk of diabetic ketoacidosis (DKA), a severe condition related to treatment with SGLT2-i, in acromegalic subjects.^95–97 However, patients safely treated with pasireotide and SGLT2-i are reported.⁹⁸

The addition of insulin may be considered, but it should ideally be used as an adjunct to metformin and at least one other therapeutic agent.

Obviously, in case of poor glycemic control despite treatment with several anti-hyperglycemic drugs, the dose reduction or even the discontinuation of pasireotide should be considered.

A Potential Change of Perspective and Open Issues

Considering the complex cardiovascular profile of patients with acromegaly and CD, a much greater use of GLP-1 RAs and SGLT2-i might be necessary if DM occurs. There are at least three important aspects that support this consideration: glycemic control, cardiovascular protection, and weight loss.

Accordingly, both in acromegaly and CD, the use of GLP-1 RAs contributes to the achievement of these three main goals, providing an important possibility to enhance the quality of life and to decrease the mortality of patients, with evident advantages compared to DDP-4i and insulin.^86,91,99 In this regard, co-agonists of GLP-1 and GIP, such as tirzepatide, with their extraordinary impact in terms of HbA1c reduction and weight loss, represent a theoretically intriguing therapeutic option for the future, despite the current lack of data in acromegaly and CD.

SGLT2-i are not included in the expert recommendations for the patients with CD.⁸⁹ Currently, there is not enough evidence to support their use, even if their impact on cardiorenal risk might be valuable.

The same reasoning could apply to the acromegalic subjects. In particular, the very favorable benefit of SGLT2-i on HF risk could be extremely crucial.

A proposal for an approach to contrasting hyperglycemia, also taking into account the higher cardio-renal risk, in acromegaly and CD is depicted in Figure 1.

Figure 1 Proposal for a new approach to treat hyperglycemia in patients with acromegaly or Cushing’s Disease, with or without pasireotide treatment. The restoration of euglycemia should be achieved with concomitant reduction in terms of weight and cardiovascular risk, improving quality of life and decreasing mortality.

Notes: The choice of anti-hyperglycemic drugs should be driven by high CV risk and not by the concomitant treatment for acromegaly and CD. In patients with dual therapy at baseline (Metformin + SGLT2-i or GLP-1 RAs) and glycemic control not achieved, follow the same indications reported in the figure. Consider DPP-4i in case of intolerance at SGLT2-i and GLP-1 Ras; Consider BASAL INSULIN as first therapy in case of severe glycometabolic state (HbA1c > 10%, FBG > 300 mg/dL, clinical signs of catabolism). In patients with high risk of ketoacidosis and positive anamnesis for recurrent genitourinary infections, SGLT2-i should be avoided.

Potential limits are higher costs and the risk of AEs. It is well known that the most common AEs of GLP-1 RAs are gastrointestinal (nausea, vomiting, and diarrhea) and tend to occur during initiation and dose escalation, diminishing over time.¹⁰⁰ Same AEs are noted with pasireotide, even if described as non-severe.

Another AE common to both treatments (pasireotide and GLP-1 RAs) are cholelithiasis and gallbladder disease. Different meta-analysis of RCTs confirmed that GLP1-RAs are associated with an increased risk of cholelithiasis, in the absence of any relevant increase in the risk of pancreatitis and pancreatic cancer.^101,102 It is notable that in the study which compared incretin-based and insulin therapy, patients in the latter group had a higher incidence of gallbladder or biliary-related AEs (23.3% vs 13.2%).⁸⁶

Instead, as reported in the recent consensus about the management of hyperglycemia in acromegaly, a potential limit for the use of SGLT2-i is the risk of DKA, a condition characterized by hyperglycemia, metabolic acidosis and ketosis (pH ≤ 7.3, bicarbonate ≤ 15 mmol/L, anion gap > 12 mmol/L), fortunately rare in acromegaly, considering it concerns only 1% of all cases and it often occurs only in the initial disease manifestation.¹⁰³ During treatment with SGLT2-i, DKA occurs in the absence of hyperglycemia, and so it also known as euglycemic diabetic ketoacidosis (EuDKA).¹⁰⁴ The suggested mechanism behind the EuDKA is the reduction of insulin requirement in patient treated with SGLT2-i due to massive glycosuria, with concomitant increased gluconeogenesis (driven by an increase of glucagon), release of free fatty acid and subsequent propensity to ketone production.¹⁰⁵

It is noteworthy that GH and cortisol themselves increase lipolysis, the lipid oxidation rate and so ketone bodies. Moreover, the shift in the insulin/glucagon ratio as observed in pasireotide treatment is thought to be especially prone to this metabolic complication, warranting greater caution.¹⁰³

It’s essential to consider the higher risk of DKA or EuDKA during treatment with SGLT2-i, but it’s equally necessary to specify that their incidence appears significantly lower compared to that of a fatal cardiovascular event, both in acromegaly and CD. As a matter of fact, a multicenter retrospective study, during 2015–2020, in 9940 persons with T2DM treated with SGLT2-i has shown that the overall prevalence of DKA is around 0.43% (with 0.25% for EuDKA).¹⁰⁶ Furthermore, even some real-life evaluations conducted in subjects with Type 1 Diabetes, a clinical condition with a well-known high risk of DKA and in which the use of SGLT2-i is actually contraindicated, have shown similar data: Stougard et al¹⁰⁷ have observed an incidence of DKA equal to 0% in patients treated with SGLT2-i whereas Anson et al¹⁰⁸ have observed a lower risk of DKA and associated hospitalization in subjects treated with SGLT-2i compared to those treated with GLP-1 RAs (obviously, as an adjunct to insulin therapy).

Additionally, in acromegalic subjects treated with pegvisomant, in monotherapy or in combination with pasireotide, the incidence of the EuDKA should be reduced. In fact, a reciprocal positive interaction could be achieved because SGLT2-i attenuate the hyperglycemic effect by decreased insulin secretion, meanwhile pasireotide in combination with pegvisomant mitigates the hyperglucagonemia induced by SGLT2-i. Also, pegvisomant decreases lipid oxidation via extrahepatic suppression of Growth Hormone Receptor in different tissues.¹⁰⁹

Hence, it seems reasonable to encourage the use of SGLT2-i even in acromegalic patients treated with pasireotide, especially in those with well-controlled disease, modest hyperglycemia and undergoing combined treatment with pegvisomant. It should be helpful to advise them to discontinue therapy with SGLT2-i in case of intercurrent illnesses that may cause a reduction in carbohydrates intake and dehydration (eg, infections and gastroenteritis), and to not skip doses in the case of contextual insulin therapy. SGLT2-i should be avoided in patients with poorly controlled disease.

The same considerations could also be applied to patients with poorly controlled CD.

Another potential limit for the use of SGLT2-i, especially in CD patients for the overall increased risk of infection in this disease, is the higher prevalence of genitourinary infections, reported in both clinical trials and real world evidence. These infectious events are usually mild, and their prevalence is related to sex and a prior positive history of genital infections. In fact, the risk appears higher in females, and among them, in those with previous infections.¹¹⁰ Moreover, it is interesting to underline that in the study of McGovern et al¹¹⁰ the use of corticosteroids, a clinical condition similar to CD, higher values of HbA1c were not associated with significant additional infection risk in subjects treated with SGLT2-i.

Therefore, it is good clinical practice to suggest meticulous intimate hygiene to patients treated with SGLT-2i, avoiding the use of this class of drugs in those with positive anamnesis for genitourinary infections, especially for females.

It is also worth noting that neither GLP-1 RAs nor SGLT2-i cause hypoglycemia, another condition that significantly increases cardiovascular risk and mortality, as demonstrated in the ACCORD trial.¹¹¹

Finally, a recent case report¹¹² showed the positive effect of a combined therapy of GLP-1 RAs and SGLT2-i on pasireotide-induced hyperglycemia in a patient with CD. After the failure of metformin and DPP-4i, multiple daily insulin injections and, after two days, dulaglutide 0.75 mg were initiated. After improvement of glycemic control, 10 mg of empagliflozin was started and insulin discontinued. After 3 months, hypercortisolemia and glucose impairment were well-regulated, and the patient’s health improved overall.¹¹²

Despite several limits (not optimal use of insulin, short follow-up, lack of data regarding other parameters), this is an example of a treatment that is not glycemic-centered but focused to prevent and improve hypercortisolemia-related complications.

Needless to say, further investigations are needed to analyze the above-mentioned considerations and to overcome the limited findings available.

Ethics Statement

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution and considerations, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The authors did not receive support from any organization for the submitted work.

Disclosure

The authors declare that they have no competing interests in this work.

References

1. Sanno N, Teramoto A, Osamura RY, et al. Pathology of pituitary tumors. Neurosurg Clin N Am. 2003;14(1):25–39. doi:10.1016/s1042-3680(02)00035-9

2. Tritos NA, Miller KK. Diagnosis and management of pituitary adenomas: a review. JAMA. 2023;239(16):1386–1389. doi:10.1001/jama.2023.5444

3. Katznelson L, Laws ER, Helmed S, et al. Acromegaly: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(11):3933–3951. doi:10.1210/jc.2014-2700

4. Nieman LK, Biller BMK, Findling JW, et al. Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guidelines. J Clin Endocrinol Metab. 2015;100(8):2807–2831. doi:10.1210/jc.2015-1818

5. Colao A, Bronstein MD, Freda P, et al. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J Clin Endocrinol Metab. 2014;99(3):791–799. doi:10.1210/jc.2013-2480

6. Gadelha MR, Bronstein MD, Brue T, et al. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, Phase 3 trial. Lancet Diabetes Endocrinol. 2014;2(11):875–884. doi:10.1016/S2213-8587(14)70169-X

7. Colao A, Petersenn S, Newell-Price J, et al. A 12-month Phase 3 study of pasireotide in Cushing’s disease. N Engl J Med. 2012;366(10):914–924. doi:10.1016/S2213-8587(14)70169-X

8. Lacroix A, Gu F, Gallardo W, et al. Efficacy and safety of once-monthly pasireotide in Cushing’s disease: a 12 month clinical trial. Lancet Diabetes Endocrinol. 2018;6(1):17–26. doi:10.1016/S2213-8587(17)30326-1

9. Pivonello R, Auriemma RS, Grasso LF, et al. Complications of acromegaly, cardiovascular, respiratory and metabolic comorbidities. Pituitary. 2017;20:46–62. doi:10.1007/s11102-017-0797-7

10. Li D, El Kawkgi OM, Henriquez AF, Bancos I. Cardiovascular risk and mortality in patients with active and treated hypercortisolism. Gland Surg. 2020;9(1):43–58. doi:10.21037/gs.2019.11.03

11. Ershadinia N, Tritos NA. Diagnosis and treatment of acromegaly: an update. Mayo Clin Proc. 2022;97:333–346. doi:10.1016/j.mayocp.2021.11.007

12. Ferraù F, Albani A, Ciresi A, Giordano C, Cannavò S. Diabetes secondary to acromegaly, physiopathology, clinical features and effects of treatment. Front Endocrinol. 2018;9:358. doi:10.3389/fendo.2018.00358

13. Dal J, List EO, Jørgensen JOL, Berryman DE. Glucose and fat metabolism in acromegaly: from mice models to patient care. Neuroendocrinology. 2015;103:96–105. doi:10.1159/000430819

14. Del Rincon JP, Iida K, Gaylinn BD, et al. Growth hormone regulation of p85α expression and phosphoinositide 3-kinase activity in adipose tissue. Diabetes. 2007;56:1638–1646. doi:10.2337/db06-0299

15. Moustaki M, Paschou SA, Xekouki P, et al. Secondary diabetes mellitus in acromegaly. Endocrine. 2023;81(1):1–15. doi:10.1007/s12020-023-03339-1

16. Kasayama S, Otsuki M, Takagi M, et al. Impaired β-cell function in the presence of reduced insulin sensitivity determines glucose tolerance status in acromegalic patients. Clin Endocrinol. 2000;52:549–555. doi:10.1046/j.1365-2265.2000.00986.x

17. Kinoshita Y, Fujii H, Takeshita A, et al. Impaired glucose metabolism in Japanese patients with acromegaly is restored after successful pituitary surgery if pancreatic β-cell function is preserved. Eur J Endocrinol. 2011;164:467–473. doi:10.1530/EJE-10-1096

18. Frara S, Maffezzoni F, Mazziotti G, Giustina A. Current and emerging aspects of diabetes mellitus in acromegaly. Trends Endocrinol Metab. 2016;27:470–483. doi:10.1016/j.tem.2016.04.014

19. Popovicu MS, Paduraru L, Nutas RM, et al. Diabetes mellitus secondary to endocrine diseases: an update of diagnostic and treatment particularities. Int J Mol Sci. 2023;24(16):12676. doi:10.3390/ijms241612676

20. Scaroni C, Zilio M, Foti M, Boscaro M. Glucose metabolism abnormalities in Cushing syndrome: from molecular basis to clinical management. Endocr Rev. 2017;38(3):189–219. doi:10.1210/er.2016-1105

21. Barbot M, Ceccato F, Scaroni C. Diabetes mellitus secondary to Cushing’s disease. Front Endocrinol. 2018;5(9):284. doi:10.3389/fendo.2018.00284

22. Pivonello R, De Leo M, Vitale P, et al. Pathophysiology of diabetes mellitus in Cushing’s syndrome. Neuroendocrinology. 2010;92(Suppl 1):77–81. doi:10.1159/000314319

23. Brennan-Speranza TC, Henneicke H, Gasparini SJ, et al. Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism. J Clin Investig. 2012;122:4172–4189. doi:10.1172/JCI63377

24. Eriksen M, Jensen DH, Tribler S, Holst JJ, Madsbad S, Krarup T. Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance. Diabetologia. 2015;58(5):920–928. doi:10.1007/s00125-015-3522-y

25. Jensen DH, Aaboe K, Herniksen JE, et al. Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes mellitus. Diabetologia. 2012;55(5):1406–1416. doi:10.1007/s00125-012-2459-7

26. Vergès B. Effects of anti-somatostatin agents on glucose metabolism. Diabetes Metab. 2017;43(5):411–415. doi:10.1016/j.diabet.2017.05.003

27. Silvertstein JM. Hyperglycemia induced by Pasireotide in patients with Cushing’s disease or acromegaly. Pituitary. 2016;19:536–543. doi:10.1007/s11102-016-0734-1

28. Puglisi S, Ferraù F, Ragonese M, Spagnolo F, Cannavò S. Cardiometabolic risk in acromegaly: a review with a focus on pasireotide. Front Endocrinol. 2020;11:28. doi:10.3389/fendo.2020.00028

29. Coulden A, Hamblin R, Wass J, Karavitaki N. Cardiovascular health and mortality in Cushing’s disease. Pituitary. 2022;25(5):750–753. doi:10.1007/s11102-022-01258-4

30. Puglisi S, Terzolo M. Hypertension and acromegaly. Endocrinol Metab Clin North Am. 2019;48:779–793. doi:10.1016/j.ecl.2019.08.008

31. Petrossians P, Daly AF, Natchev E, et al. Acromegaly at diagnosis in 3173 patients from the Liege Acromegaly Survey (LAS) Database. Endocr Relat Cancer. 2017;24(10):505–518. doi:10.1530/ERC-17-0253

32. Sharma AN, Tan M, Amsterdam EA, Singh GD. Acromegalic cardiomyopathy: epidemiology, diagnosis and management. Clin Cardiol. 2018;41(3):419–425.

33. Colao A, Marzullo P, Di Somma C, Lombardi G. Growth hormone and the heart. Clin Endocrinol. 2001;54(2):137–154. doi:10.1046/j.1365-2265.2001.01218.x

34. Marstrand P, Han L, Day SM, et al. Hypertrophic cardiomyopathy with left ventricular systolic dysfunction: insights from the SHaRe Registry. Circulation. 2020;141(17):1371–1383. doi:10.1161/CIRCULATIONAHA.119.044366

35. Davì MV, Giustina A. Sleep apnea in acromegaly, a review on prevalence, pathogenetic aspects and treatment. Expert Rev Endocrinol Metab. 2012;7:55–62. doi:10.1586/eem.11.82

36. Ragnarsson O, Olsson DS, Papakokkinou E, et al. Overall and disease-specific mortality in patients with Cushing disease: a Swedish nationwide study. J Clin Endocrinol Metab. 2019;104(6):2375–2384. doi:10.1210/jc.2018-02524

37. Colao A, Pivonello R, Spiezia S, et al. Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful care. J Clin Endocrinol Metab. 1999;84(8):2664–2672. doi:10.1210/jcem.84.8.5896

38. Varlamov EV, Langlois F, Vila G, Fleseriu M. Management of endocrine disease: cardiovascular risk assessment, thromboembolism, and infection prevention in Cushing’s syndrome: a practical approach. Eur J Endocrinol. 2021;184(5):R207–R224. doi:10.1530/EJE-20-1309

39. Fallo F, Di Dalmazi G, Beuschlein F, 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. 2022;40(11):2085–2101. doi:10.1097/HJH.0000000000003252

40. Giordano R, Picu A, Marinazzo E, et al. Metabolic and cardiovascular outcomes in patients with Cushing’s syndrome of different aetiologies during active disease and 1 year after remission. Clin Endocrinol. 2011;75(3):354–360. doi:10.1111/j.1365-2265.2011.04055.x

41. Faggiano A, Pivonello R, Spiezia S, 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. 2003;88(6):2527–2533. doi:10.1210/jc.2002-021558

42. Toja PM, Branzi G, Ciambellotti F, et al. Clinical relevance of cardiac structure and function abnormalities in patients with Cushing’s syndrome before and after cure. Clin Endocrinol. 2012;76(3):332–338. doi:10.1111/j.1365-2265.2011.04206.x

43. Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G. SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol. 2002;146(5):707–716. doi:10.1530/eje.0.1460707

44. Moloney KJ, Mercado JU, Ludlam WH, Mayberg MR. Pasireotide (SOM230): a novel pituitary-targeted medical therapy for the treatment of patients with Cushing’s disease. Expert Rev Endocrinol Metab. 2012;7(5):491–502. doi:10.1586/eem.12.49

45. Singh V, Brendel MD, Zacharias S, et al. Characterization of somatostatin receptor subtype-specific regulation of insulin and glucagon secretion: an in vitro study on isolated human pancreatic islets. J Clin Endocrinol Metab. 2007;92:673–680. doi:10.1210/jc.2006-1578

46. Henry RR, Ciaraldi TP, Armstrong D, Burke P, Ligueros-Saylan M, Mudaliar S. Hyperglycaemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J Clin Endocrinol Metab. 2013;98:3446–3453. doi:10.1210/jc.2013-1771

47. Barbot M, Mondin A, Regazzo D, et al. Incretin response to mixed meal challenge in active Cushing’s disease and after pasireotide therapy. Int J Mol Sci. 2022;23:5217. doi:10.3390/ijms23095217

48. Schmid AH, Brueggen J. Effects of somatostatin analogs on glucose homeostasis in rats. J Endocrinol. 2012;212:49–60. doi:10.1530/JOE-11-0224

49. MacKenzie Feder J, Bourdeau I, Vallette S, Beauregard H, Marie LG S, Lacroix A. Pasireotide monotherapy in Cushing’s disease: a single-centre experience with 5-year extension of phase III trial. Pituitary. 2014;17(6):519–529. doi:10.1007/s11102-013-0539-4

50. Golor G, Hu K, Ruffin M, et al. A first-in-man study to evaluate the safety, tolerability, and pharmacokinetics of pasireotide (SOM230), a multireceptor-targeted somatostatin analog, in healthy volunteers. Drug Des Devel Ther. 2012;6:71–79. doi:10.2147/DDDT.S29125

51. Feelders RA, Pulgar SJ, Kempel A, Pereira AM. The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol. 2012;167(3):311–326. doi:10.1530/EJE-11-1095

52. Shen G, Darstein C, Hermosillo Resendiz K, Hu K. Pharmacokinetic and pharmacodynamic analyses of pasireotide LAR and octreotide LAR: randomized, double-blind, phase III study in patients with medically naïve acromegaly. Poster presented at: European congress of endocrinology; May 3–7; 2014; Wroclaw, Poland.

53. Shen G, Darstein C, Hermosillo Resendiz K, Hu K. Analysis of pharmacokinetic (PK) and pharmacodynamic (PD) data for efficacy and safety from a randomized phase III study of pasireotide LAR in patients with acromegaly inadequately controlled on first-generation somatostatin analogs (SSA). Poster presented at: Endocrine society annual meeting; March 5–8; 2015; San Diego, CA.

54. Gadelha MR, Gu F, Bronstein MD, et al. Risk factors and management of pasireotide-associated hyperglycemia in acromegaly. Endocr Connect. 2020;9(12):1178–1190. doi:10.1530/EC-20-0361

55. Sheppard M, Bronstein MD, Freda P, et al. Pasireotide LAR maintains inhibition of GH and IGF-1 in patients with acromegaly for up to 25 months: results from the blinded extension phase of a randomized, double- blind, multicenter, phase III study. Pituitary. 2015;18(3):385–394. doi:10.1007/s11102-014-0585-6

56. Boscaro M, Bertherat J, Findling J, et al. Extended treatment of Cushing’s disease with pasireotide: results from a 2-year, Phase II study. Pituitary. 2014;17(4):320–326. doi:10.1007/s11102-013-0503-3

57. Higham CE, Atkinson AB, Aylwin S, et al. Effective combination treatment with cabergoline and low-dose pegvisomant in active acromegaly: a prospective clinical trial. J Clin Endocrinol Metab. 2012;97:1187–1193. doi:10.1210/jc.2011-2603

58. van der Lely AJ, Hutson RK, Trainer PJ, et al. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet. 2001;358:1754–1759. doi:10.1016/s0140-6736(01)06844-1

59. Schreiber I, Buchfelder M, Droste M, et al. Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: safety and efficacy evaluation from the German Pegvisomant Observational Study. Eur J Endocrinol. 2007;156:75–82. doi:10.1530/eje.1.02312

60. Castinetti F, Guignat L, Giraud P, et al. Ketoconazole in Cushing’s disease: is it worth a try? J Clin Endocrinol Metab. 2014;99(5):1623–1630. doi:10.1210/jc.2013-3628

61. Valassi E, Crespo I, Gich I, Rodrìguez J, Webb SM. A reappraisal of the medical therapy with steroidogenesis inhibitors in Cushing’s syndrome. Clin Endocrinol. 2012;77:735–742. doi:10.1111/j.1365-2265.2012.04424.x

62. Gadelha M, Bex M, Feelders RA, et al. Randomized trial of osilodrostat for the treatment of Cushing’s disease. J Clin Endocrinol Metab. 2022;107(7):e2882–e2895. doi:10.1210/clinem/dgac178

63. Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycemia in type 2 diabetes. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022;45(11):2753–2786. doi:10.2337/dci22-0034

64. Tsapas A, Avgerinos I, Karagiannis T, et al. Comparative effectiveness of glucose-lowering drugs for type 2 diabetes: a systematic review and network meta-analysis. Ann Intern Med. 2020;173:278–286. doi:10.7326/M20-0864

65. Tsapas A, Karagiannis T, Kakotrichi P, et al. Comparative efficacy of glucose-lowering medications on body weight and blood pressure in patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Obes Metab. 2021;23:2116–2124. doi:10.1111/dom.14451

66. Marso SP, Daniels GH, Brown-Frandsen K, et al.; for the LEADER Steering Committe on behalf of the LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–322. doi:10.1056/NEJMoa1603827

67. Gerstein HC, Colhoun HM, Dagenais GR, et al.; for the REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394:121–130. doi:10.1016/S0140-6736(19)31149-3

68. Marso SP, Bain CS, Consoli A, et al.; for the SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Eng J Med. 2016;375:1834–1844. doi:10.1056/NEJMoa1607141

69. Zinman B, Wanner C, Lachin JM, et al.; for the EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;375:2117–2128. doi:10.1056/NEJMoa1504720

70. Neal B, Perkovic V, Mahaffey KW, et al.; for the CANVAS Program Collaborative group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657. doi:10.1056/NEJMc1712572

71. The EMPA-KIDNEY Collaborative group. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023;388:117–127. doi:10.1056/NEJMoa2204233

72. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al.; for the DAPA-CKD Trial committees and investigators.. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436–1446. doi:10.1056/NEJMoa2024816

73. Perkovic V, Jardine MJ, Neal B, et al.; for the CREDENCE Trial investigators. Canagliflozin and renal outcome in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–2306. doi:10.1056/NEJMoa1811744

74. Packer M, Anker SD, Butler J, et al.; for the EMPEROR-Reduced Trial investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–1424. doi:10.1056/NEJMoa2022190

75. McCurray JJV, Solomon SD, Inzucchi SE, et al.; for the DAPA-HF Trial committees and investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995–2008. doi:10.1056/NEJMoa1911303

76. Anker SD, Butler J, Filippatos G, et al.; fort the EMPEROR-Preserved Trial investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385:1451–1461. doi:10.1056/NEJMoa2107038

77. Solomon SD, McMurray JJV, Clagget B, et al.; for the DELIVER Trial committees and investigators. Dapagliflozin in heart failure with mildly reduced of preserved ejection fraction. N Engl J Med. 2022;387:1089–1098. doi:10.1056/NEJMoa2206286

78. Fleseriu M, Rusch E, Geer EB; on behalf of the ACCESS Study Investigators. Safety and tolerability of pasireotide long-acting release in acromegaly-results from the acromegaly, open-label, multicenter, safety monitoring program for treating patients who have a need to receive medical therapy (ACCESS) study. Endocrine. 2017;55:247–255. doi:10.1007/s12020-016-1182-4

79. Lasolle H, Ferriere A, Vasilijevic A, Eimer S, Nunes ML, Tabarin A. Pasireotide-LAR in acromegaly patients treated with a combination therapy: a real-life study. Endocr Connect. 2019;8:1383–1394. doi:10.1530/EC-19-0332

80. Witek P, Bolanowski M, Szamotulska K, Wojciechowska-Luzniak A, Jawiarczyk-Przybylowska A, Kaluzny M. The effect of 6 month’s treatment with pasireotide LAR on glucose metabolism in patients with resistant acromegaly in Real-World clinical settings. Front Endocrinol. 2021;10(12):633944. doi:10.3389/fendo.2021.633944

81. Wolf P, Dormoy A, Maione L, et al. Impairment in insulin secretion without changes in insulin resistance explains hyperglycemia in patients with acromegaly treated with pasireotide LAR. Endocr Connect. 2022;11:e220296. doi:10.1530/EC-22-0296

82. Fleseriu M, Petersenn S, Biller BMK, et al. Long-term efficacy and safety of once-monthly pasireotide in Cushing’s disease: a phase III extension study. Clin Endocrinol. 2019;91:776–785. doi:10.1111/cen.14081

83. Pivonello R, Arnaldi G, Scaroni C, et al. The medical treatment with pasireotide in Cushing’s disease: an Italian multicentre experience based on “real-world experience”. Endocrine. 2019;64:657–672. doi:10.3389/fendo.2020.00648

84. Simeoli C, Ferrigno R, De Martino MC, et al. The treatment with pasireotide in Cushing’s disease: effect of long-term treatment on clinical picture and metabolic profile and management of adverse events in the experience of a single center. J Endocrinol Invest. 2020;43:57–73. doi:10.1007/s12020-015-0557-2

85. Sahin S, Karimova G, Özcan SG, Durcan E, Özkaya HM, Kadıoğlu P. Pasireotide treatment in Cushing’s Disease: a single tertiary center’s experience. Turk J Med Sci. 2022;52:467–476. doi:10.55730/1300-0144.5335

86. Samson SL, Gu F, Feldt-Rasmussen U, et al. Managing pasireotide-associated hyperglycemia: a randomized, open-label, Phase IV study. Pituitary. 2021;24:887–903. doi:10.1007/s11102-021-01161-4

87. ElSayed NA, Aleppo G, Aroda VR, et al. Classification and diagnosis of diabetes: standard of Care in Diabetes- 2023. Diabetes Care. 2023;46(Suppl.1):S19–S40. doi:10.2337/dc23-S002

88. Samson SL. Management of hyperglycemia in patients with acromegaly treated with pasireotide LAR. Drugs. 2016;76(13):1235–1243. doi:10.1007/s40265-016-0615-y

89. Colao A, De Block C, Gaztambide MS, Kumar S, Seufert J, Casanueva FF. Managing hyperglycemia in patients with Cushing’s disease treated with pasireotide: medical expert recommendations. Pituitary. 2014;17:180–186. doi:10.1007/s11102-013-0483-3

90. Breitschaft A, Hu K, Hermosillo Resendiz K, Darstein C, Golor G. Management of hyperglycemia associated with pasireotide (SOM230): healthy volunteer study. Diabet Res Clin Pract. 2014;103:458–465. doi:10.1016/j.diabres.2013.12.011

91. Störmann S, Meyhöfer SM, Groener JB, et al. Management of pasireotide-induced hyperglycemia in patients with acromegaly: an experts’ consensus statement. Front Endocrinol. 2024;15:1348990. doi:10.3389/fendo.2024.1348990

92. Peracchi M, Porretti S, Gebbia C, et al. Increased glucose-dependent insulinotropic polypeptide (GIP) secretion in acromegaly. Eur J Endocrinol. 2001;145:R1–R4. doi:10.1530/eje.0.145r001

93. Shekhawat VS, Bhansali S, Dutta P, et al. Glucose-dependent insulinotropic polypeptide (GIP) resistance and β-cell dysfunction contribute to hyperglycaemia in acromegaly. Sci Rep. 2019;9:5646. doi:10.1038/s41598-019-41887-7

94. Oba-Yamamoto C, Kameda H, Miyoshi H, et al. Acromegaly cases exhibiting increased Growth Hormone levels during oral glucose loading with preadministration of dipeptidyl peptidase-4 inhibitor. Intern Med. 2021;60(15):2375–2383. doi:10.2169/internalmedicine.4755-20

95. Quarella M, Walser D, Brandle M, Fournier JY, Bilz S. Rapid onset of diabetic ketoacidosis after SGLT2 inhibition in a patient with unrecognized acromegaly. J Clin Endocrinol Metab. 2017;102(5):1451–1453. doi:10.1210/jc.2017-00082

96. Yoshida N, Goto H, Suzuki H, et al. Ketoacidosis as the initial clinical condition in nine patients with acromegaly: a review of 860 cases at a single institute. Eur J Endocrinol. 2013;169(1):127–132. doi:10.1530/eje-13-0060

97. Prencipe N, Bioletto F, Bona C, Gatti F, Grottoli S. Diabetic ketoacidosis in acromegaly: a case study-somatostatin analogs adverse event or disease complication? Acta Diabetol. 2020;57(4):491–493. doi:10.1007/s00592-019-01437-z

98. Zaina A, Grober Y, Abid A, Arad E, Golden E, Badarny S. Sodium glucose cotransporter 2 inhibitors treatment in acromegalic patients with diabetes-a case series and literature review. Endocrine. 2021;73(1):65–70. doi:10.1007/s12020-021-02718-w

99. Mehlich A, Bolanowski M, Mehlich D, Witek P. Medical treatment of Cushing’s disease with concurrent diabetes mellitus. Front Endocrinol. 2023;14:1174119. doi:10.3389/fendo.2023.1174119

100. Wharton S, Davies M, Dicker D, et al. Managing the gastrointestinal side effects of GLP-1 receptor agonists in obesity: recommendations for clinical practice. Postgrad Med. 2022;134(1):14–19. doi:10.1080/00325481.2021.2002616

101. He L, Wang J, Ping F, et al. Association of Glucagon-Like Peptide-1 Receptor Agonist use with risk of gallbladder and biliary disease: a systematic review and meta-analysis of Randomized Clinical Trials. JAMA. 2022;182(5):513.519. doi:10.1001/jamainternmed.2022.0338

102. Monami M, Nreu B, Scatena A, et al. Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): data from Randomized Controlled Trials. Diabetes Obes Metab. 2017;19(9):1233–1241. doi:10.1111/dom.12926

103. Zaina A, Prencipe N, Golden E, et al. How to position sodium-glucose co-transporter 2 inhibitors in the management of diabetes in acromegaly patients. Endocrine. 2023;80(3):491–499. doi:10.1007/s12020-023-03352-4

104. Peteres AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic Diabetic Ketoacidosis: a potential complication of treatment with Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015;38(9):1687–1693. doi:10.2337/dc15-0843

105. Sampani E, Sarafidis P, Papagianni A. Euglycaemic diabetic ketoacidosis as a complication of SGLT-2 inhibitors: epidemiology, pathophysiology, and treatment. Expert Opin Drug Saf. 2020;19(6):673–682. doi:10.1080/14740338.2020.1764532

106. Ata F, Yousaf Z, Khan AA, et al. SGLT-2 inhibitors associated euglycemic and hyperglycemic DKA in multicentric cohort. Sci Rep. 2021;11:10293. doi:10.1038/s41598-021-89752-w

107. Stougaard EB, Kristensen PL, Kielgast U, et al. Real life evaluation of sodium-glucose cotransporter 2 inhibition in type 1 diabetes and the risk of diabetic ketoacidosis. Diab Vasc Dis Res. 2022;19:14791641221130043.

108. Anson M, Zhao SS, Austin P, Ibarburu GH, Malik RA, Alam U. SGLT2i and GLP-1 RA therapy in type 1 diabetes and Reno-vascular outcomes: a real-world study. Diabetologia. 2023;66:1869–1881.

109. Adnan Z. Sodium Glucose Co-transporter Inhibitors in patients with acromegaly and diabetes. Trends Endocrinol Metab. 2019;30(2):77–79. doi:10.1016/j.tem.2018.11.007

110. McGovern AP, Hogg M, Shields BM, et al.; BM MASTERMIND consortium. Risk factors for genital infections in people initiating SGLT2 inhibitors and their impact on discontinuation. BMJ Open Diabetes Res Care. 2020;8(1):e001238. doi:10.1136/bmjdrc-2020-001238

111. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–2559. doi:10.1056/NEJMoa0802743

112. Shikata M, Ashida K, Goto Y, et al. Pasireotide-induced hyperglycemia in a patient with Cushing’s disease: potential use of sodium-glucose cotransporter 2 inhibitor and glucagon-like peptide-1 receptor agonist for treatment. Clin Case Rep. 2020;8(12):2613–2618. doi:10.1002/ccr3.3230

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Diagnostic dilemma in Cushing’s syndrome: discrepancy between patient-reported and physician-assessed manifestations

Posted on July 31, 2024 by MaryO

Purpose

Early diagnosis and immediate treatment of Cushing’s syndrome (CS) are critical for a better prognosis but remain a challenge. However, few comprehensive reports have focused on this issue or investigated whether patient-reported manifestations are consistent with physician-assessed symptoms of CS. This study aimed to clarify the differences in patient-reported and physician-assessed manifestations of signs and symptoms of CS that prevent early diagnosis.

Methods

This single-center retrospective study included 52 patients with CS (16 with Cushing’s disease and 36 with adrenal CS). Upon clinical diagnosis, medical records were used to independently review the patient-reported and physician-assessed manifestations of typical (such as purple striae and proximal myopathy) and nonspecific features (such as hirsutism and hypertension). The correlations and differences between the patient-reported and physician-assessed manifestations were then analyzed.

Results

We observed a positive correlation between the total number of manifestations of nonspecific features reported by patients and those assessed by physicians, but not for typical features. Moreover, manifestations reported by the patients were less frequent than those assessed by physicians for typical features, leading to discrepancies between the two groups. In contrast, there were no differences in most nonspecific features between the patient-reported and physician-assessed manifestations. Notably, the concordance between patient-reported and physician-assessed manifestations of typical features was not associated with urinary free cortisol levels.

Conclusion

Regardless of disease severity, patients often do not complain of the typical features of CS that are crucial for formulating a diagnosis.

Introduction

Endogenous Cushing’s syndrome (CS) is caused by chronic and excessive glucocorticoid exposure. This occurs primarily due to adrenocorticotropic hormone (ACTH)-producing pituitary tumors (Cushing’s disease; CD) or cortisol-producing adrenal tumors (adrenal Cushing’s syndrome; ACS) [1]—and has a high mortality rate owing to cardiovascular disease, severe infection, and suicide, even when diagnosed and treated appropriately [1, 2]. Moreover, the prognosis is poor if the disease is not adequately treated or remains undiagnosed [2]. Therefore, early diagnosis and immediate intervention are important, as remission of CS due to surgical and pharmacological treatment can reduce the risk of mortality [3, 4].

CS is a rare disease with a prevalence of 57 per million individuals and an annual incidence of 3.2 per million, and its epidemiology is consistent across various regions worldwide [5, 6]. Most symptoms and signs of CS are common in general metabolic disorders, including obesity, hypertension, osteoporosis, and diabetes mellitus [7]. However, CS should be suspected if these symptoms appear as unusual features for their age [1, 8]. Consequently, the identification of CS is challenging and labor-intensive [1, 9, 10]. In fact, recent research revealed that a definitive diagnosis of CD (the most common form of CS), took an average of 3.8 ± 4.8 years from the onset of symptoms, and patients typically consulted 4.6 ± 3.8 medical professionals before this disease was identified [11]. Typical features of CS include symptoms of moon face, central obesity, or buffalo hump [12], which are similar to other symptoms such as primary obesity and therefore can lead to misdiagnosis. Furthermore, although purple striae or thin skin with an increased propensity for bruising are other typical features of CS [12], these attributes are not commonly acknowledged by the general population [1, 9].

Attempts have been made to diagnose CS early, including the development of scoring systems to estimate the pre-test probability of CS and facial image analysis software to diagnose the specific facial features of CS [13‐15]; however, these have not yet been used widespread or fully and the early diagnosis of CS remains dependent on the experience-based medical skills of the clinical staffs [16].

Additionally, although it is difficult for patients to recognize complex and nonspecific symptoms [17, 18], the significance of patients recognizing their illness has recently been reported for various diseases such as heart failure and malignant carcinoma [19‐21]. It is widely acknowledged that patients’ self-recognition can result in early detection of the disease, reduce its severity and recurrence, and enhance their quality of life [19]. In patients with endocrine diseases, there is increasing focus on issues surrounding self-recognition [22‐24]. For example, a previous study focusing on acromegaly reported a discrepancy between patient-reported and physician-reported manifestations and indicated that resolving this discrepancy could shorten the time to diagnosis [25].

Identifying CS may be challenging for primary care physicians who are yet to specialize. Therefore, endocrinologists with extensive experience in CS have often noticed that patients and these physicians struggle to identify the symptoms of CS; however, few comprehensive reports have focused on this issue or investigated whether patient-reported manifestations are consistent with physician-assessed symptoms of CS.

Therefore, this study aimed to investigate the unreported manifestations of CS among individuals referred to non-specialist healthcare providers, including primary care physicians, and to recognize potential challenges with the current diagnosis of CS with the goal of facilitating early detection.

Materials and methods

Patients, study design, and data collection

This single-center retrospective study was conducted to identify the discrepancies between patient-reported and physician-assessed symptoms and investigate the factors causing these differences.

From September 2004 to December 2022, 199 patients were referred to our department at a tertiary medical institution upon suspicion, evaluation, or follow-up for hypercortisolism. Of these patients, 92 were newly diagnosed with CS (36 with CD, 51 with ACS, and 5 with ectopic ACTH syndrome) based on the diagnostic guidelines [3, 8, 12], with a diagnosis confirmed by pathological evaluation after surgical resection [26]. However, 35 patients were excluded due to a lack of detailed clinical data on the manifestations at diagnosis. Similarly, we excluded individuals diagnosed with ectopic ACTH syndrome because of the lack of comprehensive information on symptoms reported by the patients and primary care physicians due to the rapid progression and severity of this disease. Therefore, 52 patients (16 with CD and 36 with ACS) were enrolled in this study.

Upon clinical diagnosis, the manifestations included in the comprehensive standardized interview at the time of diagnosis and those assessed by the physician through collaborative assessment with multiple board-certified endocrinologists as routine practice were independently reviewed from the medical records. We categorized these manifestations reviewed from the medical records into the following two categories based on the diagnostic guidelines including those of the Japan Endocrine Society: typical features, including moon face, central obesity or buffalo hump, purple striae of ≥1 cm, thin skin and easy bruising, and proximal myopathy; and nonspecific features (shown as atypical in Japan Endocrine Society’s guideline), including hypertension, menstrual abnormalities, acne, hirsutism, peripheral edema, glucose metabolism impairment, osteoporosis, pigmentation (which is not expected in patients with ACS), and mental abnormalities [1, 8, 12]. Central obesity or buffalo hump can also be observed in pseudo CS. However, in this study, features were classified as the same typical feature according to clinical guidelines [12, 27]. We also reviewed the biochemical findings, comorbidities, duration from the initial recognition of CS-related symptoms to diagnosis, and number of medical institutions visited before diagnosis.

The present retrospective study was performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Kobe University Hospital (Approval No. 1351). The patients had the option of an opt-out process, and all procedures were part of routine medical care.

Definition of patient-reported and physician-assessed manifestations

In the context of routine clinical care, physicians asked the patients about the presence or absence of manifestations and comorbidities (e.g., hypertension, menstrual abnormalities, glucose metabolism impairment, osteoporosis, and mental abnormalities), which were documented in the medical records. These reports in the medical records were defined as patient-reported manifestations in this study. In contrast, the manifestations and comorbidities of CS were assessed within several weeks after the patient was referred to our department for suspected CS. Additional diagnostic information on comorbidities is provided in the subsequent section. Physician-assessed manifestations were subsequently defined based on these findings.

Comorbidities of Cushing’s syndrome

All comorbidities were diagnosed according to the appropriate guidelines [28‐30]. For example, hypertension was diagnosed if patients were taking oral antihypertensive medication or had more than grade 1 hypertension (≥140/90 mmHg) in a treatment-naïve state [28]. Moreover, glucose metabolism impairment—including diabetes mellitus, impaired glucose tolerance, and impaired fasting glucose—was diagnosed based on the results of blood glucose levels during fasting and after a 75-g oral glucose tolerance test, as well as hemoglobin A1c (HbA1c) levels [29]. Patients taking medications for diabetes mellitus at the time of CS diagnosis were also categorized as having diabetes.

Other comorbidities included mental abnormalities, menstrual abnormalities, and the presence of osteoporosis. Mental abnormalities were defined as the use of anxiolytic medications, sleeping pills, or antidepressants prescribed by experienced psychologists, and menstrual abnormalities were defined as women with irregular menstrual cycles. Furthermore, the presence of osteoporosis was defined as bone mineral density (BMD) of <–2.5 standard deviations (SD) of the T-score of the lumbar vertebrae (L2–L4), femoral neck, or distal radius measured using dual-energy x-ray absorptiometry (DXA; Horizon A DXA System), and/or an experience of a fragility fracture [30]. As per the specifications of the measurement system employed, L1 was not included in the assessment. The Z-score was also employed as a diagnostic reference among young adults. Patients also diagnosed with osteoporosis who were receiving medications for this disease.

Hormone assay

In this study, blood samples were collected after an overnight fast. Subsequently, serum cortisol levels were measured using a chemiluminescent enzyme immunoassay [CLEIA] (TOSOH, Tokyo, Japan, RRID:AB_3099658) or enzyme immunoassay [EIA] (TOSOH, Tokyo, Japan, RRID:AB_3076600). Similarly, plasma ACTH levels were measured using a CLEIA (TOSOH, Tokyo, Japan, RRID:AB_3099657, or Siemens, Tokyo, Japan, RRID:AB_2909441) and EIA (TOSOH, Tokyo, Japan, RRID:AB_2783633). In both methods, the measurements showed good correlation and no conversion was required [31, 32].

Urinary free cortisol (UFC) levels were also measured using radioimmunoassays (RIA; TFB, Tokyo, Japan, RRID:AB_2894408) or chemiluminescent immunoassays (CLIA; Siemens, Tokyo, Japan, RRID:AB_2893154). Using the following formula, the UFC levels measured by RIA were then corrected to the value measured by CLIA: Y = 0.832X − 4.23 (Y = UFC levels using CLIA, X = UFC levels using RIA) [33].

Statistical analysis

All statistical analyses were performed using SPSS ver. 28.0 software (IBM Corp., Armonk, NY, USA). All continuous variables were analyzed using the Shapiro–Wilk normality test to confirm a normal distribution, whereas Fisher’s exact test was used to analyze categorical data. Between the two groups, differences in normally or non-normally distributed data were compared using the unpaired Student’s t-test or the Mann–Whitney U test, respectively.

Cohen’s kappa coefficient was used to describe the concordance between the patient-reported and physician-assessed manifestations. As previously reported [19, 20, 34], the concordance based on the value of Cohen’s kappa coefficient was rated as follows: 0.00–0.20 for “Slight,” 0.21–0.40 for “Fair,” 0.41–0.60 for “Moderate,” 0.61–0.80 for “Substantial,” and 0.81–1.00 for “Almost Perfect.” For correlation analysis between two variables of non-normally distributed data, we used Spearman’s rank correlation coefficient. Multivariate logistic regression analyses were then performed to investigate variables associated with the discrepancies between patient-reported and physician-assessed manifestations.

The results are presented as mean ± SD for normally distributed data and median [interquartile range] for non-normally distributed data, and differences were considered statistically significant when the P value was <0.05.

Results

Clinical characteristics of the patients

We included 52 patients diagnosed with CS in this study. Their clinical characteristics are presented in Table 1. Notably, this group consisted of 5 males and 47 females, with a mean age of 49.4 ± 15.8 years, median body mass index (BMI) of 23.0 [21.3–28.0] kg/m², and median UFC level of 272.1 [126.0–435.0] µg/day. Of the CS patients, 16 had CD and 36 had ACS, which is consistent with epidemiological data on CS observed in Asians (including Japanese individuals); however, this differed from epidemiological data from Western countries [35, 36]. Regarding comorbidities, 43 patients were diagnosed with hypertension—of which 34 were prescribed antihypertensive medications—with a mean systolic blood pressure (BP) of 136.4 ± 21.5 mmHg and diastolic BP of 83.5 ± 15.0 mmHg. In addition, 44 patients were diagnosed with glucose metabolism impairment—of which, 20 were prescribed oral hypoglycemic agents and/or insulin—with a median fasting serum glucose level of 99.5 [87.3–116.5] mg/dL and median HbA1c level of 6.3% [5.7–7.4]. Moreover, 29 patients were diagnosed with osteoporosis, of which 4 were prescribed antiosteoporosis medication, with BMD T-score SDs of -1.54 ± 1.39, -1.76 ± 1.12, and -0.50 [-1.53–0.50] for the lumber spine, femoral neck, and distal radius, respectively. Notably, the UFC levels were higher in patients with CD than in those with ACS (412.6 [243.2–1,100.3] vs. 215.3 [114.0–387.8] µg/day); however, there were no significant differences attributed to sex, age, BMI, or the proportion of patients with respect to comorbidities, including hypertension and glucose metabolism impairment, between patients with CD and ACS.

Table 1

Clinical characteristics of the patients

	Total	CD	ACS	CD vs. ACS P value
Number of men/women	5/47	1/15	4/32	1.00
Age (years)	49.4 ± 15.8	54.3 ± 19.2	47.2 ± 13.8	0.14
BMI (kg/m²)	23.0 [21.3–28.0]	24.7 [22.2–30.0]	22.8 [20.8–26.4]	0.17
Midnight F (µg/dL)	20.1 [16.0–23.5]	20.2 [13.9–24.7]	20.1 [16.9–23.0]	0.97
F after LDDST (μg/dL)	21.2 ± 6.9	24.2 ± 10.1	19.7 ± 4.2	0.11
UFC (μg/day)	272.1 [126.0–435.0]	412.6 [243.2–1,100.3]	215.3 [114.0–387.8]	0.02
Basal ACTH (pg/mL)	2.0 [0.0–53.9]	83.2 [57.4–169.9]	0.0 [0.0–2.1]	<0.01
Systolic BP (mmHg)	136.4 ± 21.5	140.5 ± 20.7	134.6 ± 21.8	0.36
Diastolic BP (mmHg)	83.5 ± 15.0	83.1 ± 14.3	83.6 ± 15.5	0.90
Use of antihypertensive drugs, n (%)	34 (65)	13 (81)	21 (58)	0.13
FSG (mg/dL)	99.5 [87.3–116.5]	110.0 [102.0–142.8]	92.5 [83.3–114.3]	0.01
HbA1c (%)	6.3 [5.7–7.4]	6.8 [5.9–8.6]	6.0 [5.7–7.1]	0.08
Use of OHA and/or insulin, n (%)	20 (38)	9 (56)	11 (31)	0.12
LS BMD T-score (SD)	−1.54 ± 1.39	−1.00 ± 1.38	−1.79 ± 1.35	0.07
LS BMD Z-score (SD)	−0.78 ± 1.37	0.13 ± 1.11	−1.20 ± 1.28	<0.01
FN BMD T-score (SD)	−1.76 ± 1.12	−1.73 ± 1.54	−1.78 ± 0.88	0.92
FN BMD Z-score (SD)	−0.79 ± 1.01	−0.39 ± 1.10	−0.99 ± 0.92	0.10
Radius BMD T-score (SD)	−0.50 [−1.53–0.50]	−0.30 [−2.50–0.40]	−0.60 [−1.30–0.60]	0.79
Radius BMD Z-score (SD)	0.60 [−0.60–1.50]	1.50[−0.60–1.80]	0.50[−0.50–1.00]	0.33
Use of antiosteoporosis drugs, n (%)	4 (8)	1 (6)	3 (8)	1.00
Time to diagnosis (months)	44.0 [13.3–125.3]	43.0 [15.0–128.3]	47.5 [12.5–125.3]	0.87
Number of medical institutions before diagnosis	3.0 [2.0–5.0]	3.0 [2.0–5.0]	3.0 [3.0–5.8]	0.23

The results are presented as mean ± SD for normally distributed data and median [interquartile range] for non-normally distributed data

CD Cushing’s disease, ACS adrenal Cushing’s syndrome, BMI body mass index, F cortisol, LDDST low-dose dexamethasone suppression test, UFC urinary free cortisol, ACTH adrenocorticotropic hormone, BP blood pressure, FSG fasting serum glucose, HbA1c hemoglobin A1c, OHA oral hypoglycemic agents, BMD bone mineral density, LS lumber spine, FN femoral neck

The median duration from the patients’ initial recognition of CS-related manifestations to diagnosis was 44.0 [13.3–125.3] months, and it took more than 3 years to diagnose CS in 30 patients (58%). Furthermore, the median number of medical facilities visited by patients before diagnosis was 3.0 [2.0–5.0]; however, there were no significant differences in the duration or number of medical institutions between patients with CD and those with ACS.

Frequency and concordance between patient-reported and physician-assessed CS-related manifestations

Each manifestation reported by a patient or assessed by a physician is shown vertically for individual cases in Fig. 1. Compared with nonspecific features, typical features appeared to not be reported by the patients but were only assessed by the physicians. In addition, compared to nonspecific features, there were fewer cases in which the manifestations reported by the patients were consistent with those assessed by physicians for typical features.

Fig. 1

Consistency between patient-reported and physician-assessed manifestations for each individual case. The consistencies or discrepancies between patient-reported and physician-assessed manifestations are shown. Vertical lines represent manifestations in individual patients. CD Cushing’s disease, ACS adrenal Cushing’s syndrome

Consistent with the impact of these visually distinctive presentations shown in Fig. 1, no correlation was observed in the number of typical features between patient-reported and physician-assessed manifestations (r = –0.20, P = 0.16) (Fig. 2A), whereas a positive correlation was found for nonspecific features (r = 0.62, P < 0.01) (Fig. 2B). Moreover, the total number of patient-reported manifestations of typical features was lower than that of physician-assessed manifestations (1.0 [0.0–2.0] vs. 3.5 [3.0–4.0], P < 0.01), and four of the five typical features were reported less frequently by patients than by physicians, except for proximal myopathy (Table 2A). According to Cohen’s kappa coefficient, the concordance between patient-reported and physician-assessed manifestations was marked as “Fair” to “Slight,” indicating a discrepancy for all typical features. Similarly, the total number of patient-reported manifestations of nonspecific features was also lower than that in physicians (2.5 [2.0–3.0] vs. 4.0 [3.0–5.0], P < 0.01). However, except for glucose metabolism impairment or osteoporosis, there were no differences in the frequencies of nonspecific features between patient-reported and physician-assessed manifestations, and the concordance of the nonspecific features between the patient-reported and physician-assessed manifestations was “Almost perfect” for menstrual abnormality and “Substantial” for mental abnormality and hypertension, whereas that for glucose metabolism impairment and osteoporosis was “Fair.” This suggests that the discrepancy between patient-reported and physician-assessed manifestations was more significant for typical than for nonspecific features. However, no differences in these discrepancies were observed between patients with CD and those with ACS (Table 2B, C).

Fig. 2

Correlation between the total number of patient-reported and physician-assessed manifestations. Correlations between the total number of patient-reported and physician-assessed manifestations are shown for typical (A) and nonspecific features (B). CD is plotted by ×, and ACS is plotted by ○. The Spearman’s rank correlation coefficients and P value are presented. CI confidence interval, CD Cushing’s disease, ACS adrenal Cushing’s syndrome

Table 2

Frequencies of patient-reported and physician-assessed manifestations and their concordance. A. All patients (n = 52). B. Patients with CD (n = 16). C. Patients with ACS (n = 36)

	Patient-reported	Physician-assessed	P value of Fisher’s exact test	Concordance with Cohen’s kappa coefficient
A
Typical features
Moon face, n (%)	20 (39)	48 (92)	<0.01	Slight
Central obesity or buffalo hump, n (%)	13 (25)	44 (85)	<0.01	Slight
Purple striae, n (%)	3 (6)	15 (29)	<0.01	Fair
Thin skin and easy bruising, n (%)	15 (29)	43 (83)	<0.01	Slight
Proximal myopathy, n (%)	21 (40)	27 (52)	0.33	Slight
Nonspecific features
Hypertension, n (%)	39 (75)	43 (83)	0.47	Substantial
Menstrual abnormalities, n (%)	11 (21)	11 (21)	1.00	Almost perfect
Acne, n (%)	7 (14)	13 (25)	0.21	Moderate
Hirsutism, n (%)	3 (6)	10 (19)	0.07	Moderate
Peripheral edema, n (%)	24 (46)	28 (54)	0.56	Fair
Glucose metabolism impairment, n (%)	24 (46)	44 (85)	<0.01	Fair
Osteoporosis, n (%)	7 (14)	29 (56)	<0.01	Slight
Pigmentation, n (%)	0 (0)	5 (10)	0.06	–
Mental abnormalities, n (%)	17 (33)	17 (33)	1.00	Substantial
B
Typical features
Moon face, n (%)	6 (38)	14 (88)	0.01	Slight
Central obesity or buffalo hump, n (%)	6 (38)	15 (94)	<0.01	Slight
Purple striae, n (%)	2 (13)	4 (25)	0.56	Moderate
Thin skin and easy bruising, n (%)	4 (25)	13 (81)	0.06	Slight
Proximal myopathy, n (%)	8 (50)	8 (50)	1.00	Slight
Nonspecific features
Hypertension, n (%)	16 (100)	15 (94)	0.78	Slight
Menstrual abnormalities, n (%)	5 (31)	5 (31)	1.00	Almost perfect
Acne, n (%)	1 (6)	3 (19)	0.56	Moderate
Hirsutism, n (%)	2 (13)	4 (25)	0.56	Moderate
Peripheral edema, n (%)	8 (50)	10 (63)	0.56	Slight
Glucose metabolism impairment, n (%)	10 (63)	15 (94)	0.14	Slight
Osteoporosis, n (%)	4 (25)	9 (56)	0.15	Slight
Pigmentation, n (%)	0 (0)	5 (31)	0.14	–
Mental abnormalities, n (%)	5 (31)	6 (38)	0.78	Moderate
C
Typical features
Moon face, n (%)	14 (39)	34 (94)	<0.01	Slight
Central obesity or buffalo hump, n (%)	7 (19)	29 (81)	<0.01	Slight
Purple striae, n (%)	1 (3)	11 (31)	<0.01	Slight
Thin skin and easy bruising, n (%)	11 (31)	30 (83)	<0.01	Slight
Proximal myopathy, n (%)	13 (36)	19 (53)	0.24	Slight
Nonspecific features
Hypertension, n (%)	23 (64)	28 (78)	0.30	Substantial
Menstrual abnormalities, n (%)	6 (17)	6 (17)	1.00	Almost perfect
Acne, n (%)	6 (17)	10 (28)	0.40	Moderate
Hirsutism, n (%)	1 (3)	6 (17)	0.11	Fair
Peripheral edema, n (%)	16 (44)	18 (50)	0.81	Fair
Glucose metabolism impairment, n (%)	14 (39)	29 (81)	<0.01	Fair
Osteoporosis, n (%)	3 (8)	20 (56)	<0.01	Slight
Pigmentation, n (%)	0 (0)	0 (0)	–	–
Mental abnormalities, n (%)	12 (33)	11 (31)	1.00	Almost perfect

The frequencies of patient-reported and physician-assessed manifestations were compared using Fisher’s exact test. The concordance between patient-reported and physician-assessed manifestations was evaluated with Cohen’s kappa coefficient, and its coefficients were defined as follows: 0.00–0.20 for “Slight,” 0.21–0.40 for “Fair,” 0.41–0.60 for “Moderate,” 0.61–0.80 for “Substantial,” and 0.81–1.00 for “Almost perfect”

CD Cushing’s disease, ACS adrenal Cushing’s syndrome

We performed logistic regression analyses using UFC to investigate whether excess cortisol levels influenced the discrepancy between patient-reported and physician-assessed manifestations. Notably, we observed no association between UFC levels and discrepancies between patient-reported and physician-assessed manifestations in the univariate or multivariate logistic regression analyses adjusted for sex and age (Table 3A). In addition, no association was observed after adjusting for other variables such as BMI and disease duration. Similarly, we found that the serum cortisol levels after the low-dose dexamethasone suppression test (LDDST) were not associated with discrepancies between patient-reported and physician-assessed manifestations (Table 3B). Thus, these disparities were shown to be insignificant when directly related to the severity of CS.

Table 3

Logistic regression analyses of the discrepancies between the patient-reported and physician-assessed manifestations. A. Variables associated with UFC levels. B. Variables associated with serum cortisol levels after the LDDST

	Univariate	Multivariate 1 (sex- and age-adjusted)	Multivariate 2 (BMI-adjusted)	Multivariate 3 (disease duration-adjusted)
A
Moon face	1.000 (0.999–1.001)	1.000 (0.999–1.001)	1.000 (0.998–1.002)	1.000 (0.999–1.001)
Proximal myopathy	1.000 (0.999–1.001)	1.000 (0.999–1.001)	1.000 (0.998–1.001)	1.000 (0.998–1.001)
Thin skin and easy bruising	1.000 (0.998–1.001)	1.000 (0.999–1.001)	1.000 (0.999–1.001)	1.000 (0.998–1.001)
Central obesity or buffalo hump	1.001 (1.000–1.003)	1.001 (1.000–1.003)	1.001 (1.000–1.003)	1.001 (1.000–1.003)
Purple striae	1.000 (0.999–1.002)	1.000 (0.998–1.002)	1.001 (0.999–1.003)	1.000 (0.999–1.002)
B
Moon face	0.998 (0.919–1.084)	0.999 (0.919–1.086)	1.000 (0.920–1.088)	0.997 (0.918–1.082)
Proximal myopathy	1.007 (0.925–1.097)	1.007 (0.924–1.097)	1.007 (0.925–1.097)	1.006 (0.924–1.096)
Thin skin and easy bruising	1.022 (0.939–1.112)	1.018 (0.934–1.109)	1.023 (0.940–1.113)	1.019 (0.937–1.109)
Central obesity or buffalo hump	0.979 (0.890–1.078)	0.978 (0.865–1.105)	0.981 (0.875–1.099)	0.978 (0.887–1.078)
Purple striae	0.998 (0.919–1.084)	0.999 (0.919–1.086)	1.000 (0.920–1.088)	0.997 (0.918–1.082)

The results are presented as odds ratios (95% confidence intervals)

UFC urinary free cortisol, BMI Body Mass Index, LDDST low-dose dexamethasone suppression test

Discussion

In the present study, we highlight the challenges associated with the diagnosis of CS—a condition resulting from excessive glucocorticoid exposure—and elucidate the divergence between patient-reported and physician-assessed manifestations. Thus, this study may aid in the early detection of CS by identifying symptoms that patients are unable to recognize based on the disparities between patient-reported and physician-assessed manifestations of CS.

In this study, the number of patient-reported manifestations of both typical and nonspecific features was lower than that of physician-assessed manifestations, suggesting that CS symptoms may have been overlooked by relying solely on patient reports. Additionally, analysis of the concordance between patient-reported and physician-assessed manifestations revealed a tendency for these manifestations to be inconsistent for both typical and nonspecific features, with a tendency to be more significant for typical features. Furthermore, the UFC and serum cortisol levels after the LDDST, which represent the severity of CS, were not associated with the concordance of manifestations between patients and physicians, suggesting that even in cases of severe CS, patients may not recognize their symptoms. These findings imply that typical features, which are essential for diagnosing CS, may be difficult for patients to recognize and poorly identified or conveyed to patients by non-specialist physicians, who are typically the first to interact with individuals with CS. The importance of educating healthcare providers such as primary care physicians, family physicians and gynecologists for early diagnosis of CS should be highlighted.

According to a previous report on the diagnostic history of 176 patients with CD, 83% of the patients visited their family physician for manifestations such as weight gain and hypertension, while 46% visited a gynecologist for menstrual abnormalities before the diagnosis of CD [11]. Thus, the typical features of CS were not recognized. The examination may reveal nonspecific features. However, individuals who are non-specialists may not recognize these features as indications of CS. Therefore, patients are often unaware of the potential complications associated with CS. This is consistent with the results of our study, in which patient-reported and physician-assessed manifestations were more consistent for hypertension and menstrual abnormalities than for other manifestations such as typical features, glucose metabolism impairment, and osteoporosis. This makes diagnosis challenging as non-specialist physicians and, more prominently, patients may not recognize the full range of symptoms associated with CS, especially the typical features with high diagnostic value. In addition, older patients diagnosed with CS present with a lower BMI and waist circumference than younger patients [37], and they typically do not exhibit symptoms commonly associated with CS such as skin alterations, depression, hair loss, hirsutism, and reduced libido. These findings may further complicate the diagnosis of CS in elderly patients.

By evaluating only the patient-reported manifestations, it appears that manifestations such as peripheral edema and proximal myopathy were more common. Possibly, these symptoms were not considered features of CS by physicians, in comparison to the degree of symptoms experienced by the patients. However, this may not necessarily imply diminishing the significance of the patient’s signs and symptoms, as these manifestations can be considered as the unidentified complaints and may result in a postponement of the diagnosis of CS. Patients may be experiencing symptoms that physicians do not perceive, indicating the importance of interview and physical examination. Further investigation is needed to elucidate underlying factors.

Considering the rarity of CS, it is crucial to suspect and diagnose the condition based on clinical symptoms and perform the appropriate screening tests without over- or under-screening [7]. Although CS screening in patients with diabetes mellitus and hypertension has been reported to lead to a diagnosis in only 0–0.7% and 0.1–0.5% of these patients, respectively [38‐41], it is ineffective in terms of false positives and cost [9]. Therefore, patients with typical features that are highly specific for CS, such as purple striae, easy bruising, and proximal myopathy [1, 8, 12], as well as those with obesity, diabetes mellitus, or hypertension in combination with these features, should be screened for CS [7, 27]. However, our results suggest that these symptoms are unlikely to be self-recognized. Therefore, the appropriate screening measures must be implemented to establish an early and effective diagnosis of CS.

In these situations, it is crucial for physicians to utilize their knowledge and experience to suspect CS based on symptoms such as typical features [10]. It has been reported that years of clinical experience in endocrine practice can contribute to the estimation of the pre-test probability of CS [16]. In contrast, non-specialists are less likely to encounter patients with CS in their lifetime, which can make it difficult to properly suspect CS [9]. From this perspective, it is of utmost importance that family physicians and general internists are knowledgeable regarding the manifestations that require screening for CS, as early diagnosis of this uncommon and severe condition is crucial [11]. Therefore, it is important for physicians who routinely treat patients presenting with common symptoms such as obesity, diabetes mellitus, and hypertension to meticulously interview and observe for any indicators of CS, even if the patient does not recognize them. Failure to adopt an appropriate tone in these situations may cause the disease to become undetectable.

In rare disorders such as CS, in addition to enhancing public recognition of the disease, the appropriate sharing of information and provision of specialized care in clinical practice remain important issues [42]. Early identification of such rare diseases can be achieved by promoting an understanding of the disease and its symptoms among family, friends, and patients who may be the first to recognize the signs and symptoms in an individual. In fact, in a questionnaire survey of 340 patients with CS across 30 countries, the diagnosis of CS was made in 5.6% of cases by the patients themselves and in 0.9% by their family or friends [43]. In the present study, we found that it took more than 3 years to diagnose CS in 58% of the cases. If CS and its symptoms are popularized among the public, the typical features of CS could be more readily reported to physicians and the time to diagnosis might be shorter. Furthermore, a primary care physician who is well-educated and knowledgeable is crucial in ensuring that the concerns of such individuals are not overlooked.

This study has some limitations. First, this single-center retrospective study included a relatively small sample size with few male patients. Second, CD and ACS have different pathologies; therefore, the frequencies of several CS-related manifestations will differ depending on their subtypes [3, 44]. However, in this study, there was no difference in the discrepancies between patient-reported and physician-assessed manifestations in patients with CD or ACS. Nonetheless, it is crucial that comprehensive research is conducted in larger patient populations with a focus on employing methods that accurately reflect the pathophysiology of CD and ACS. Third, patient reports may be inaccurate in terms of onset and duration because they depend on the patient’s memory. Fourth, the endocrinologists who examined the patients differed, which may have affected the presence or absence of physician-assessed manifestations. Finally, this study investigated the differences between the manifestations reported by patients and those assessed by endocrinologists, although the evaluations conducted by primary care physicians, which are crucial for the early detection of CS, were not available. Future research is needed to investigate the differences in recognizing manifestations between non-specialist physicians and endocrinologists with extensive experience in CS and to examine the changes before and after education for these non-specialists to determine if they can lead to earlier diagnosis of CS.

In conclusion, endocrinologists have been shown to be aware of CS-related symptoms, especially typical features, whereas patients do not recognize these manifestations, even when the disease is severe. Therefore, the key to the early diagnosis and treatment of CS is a more proactive approach of questioning and examining patients suspected of having the disease.

Acknowledgements

We thank all the physicians and medical assistants who were involved in this study. We are grateful to all the laboratory members for their excellent discussions and fruitful suggestions. We also thank Editage (www.editage.jp) for English language editing.

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests.

Ethics approval

This study conformed to the Declaration of Helsinki guidelines and was approved by the Ethics Committee of Kobe University Hospital (Approval No. 1351).

Informed consent was obtained from all the participants using an opt-out approach.

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From https://www.springermedizin.de/diagnostic-dilemma-in-cushing-s-syndrome-discrepancy-between-pat/27374870

Filed under: adrenal, Cushing's, Diagnostic Testing, pituitary | Tagged: adrenal Cushing's, Cushing's Disease, diagnosis, pituitary | Leave a comment »

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.

Cushing’s disease, longterm-outcome, pituitary surgery, sepsis, psychiatric disorders

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From https://academic.oup.com/ejendo/advance-article-abstract/doi/10.1093/ejendo/lvae069/7701848?redirectedFrom=fulltext&login=false

Filed under: Cushing's, pituitary, symptoms | Tagged: Cushing's Disease, longterm-outcome, pituitary surgery, psychiatric disorders, sepsis | Leave a comment »

Spontaneous Cushing’s Disease Remission Induced by Pituitary Apoplexy

Posted on July 17, 2024 by MaryO

Abstract

Spontaneous remission of Cushing’s disease (CD) is uncommon and often attributed to pituitary tumor apoplexy. We present a case involving a 14-year-old female who exhibited clinical features of Cushing’s syndrome. Initial diagnostic tests indicated CD: elevated 24h urinary cortisol (235 µg/24h, n < 90 µg/24h), abnormal 1 mg dexamethasone overnight test (cortisol after 1 mg dex 3.4 µg/dL, n < 1.8 µg/dL), and elevated adrenocorticotropic hormone concentrations (83.5 pg/mL, n 10-60 pg/mL). A pituitary adenoma was suspected, so a nuclear MRI was performed, with findings suggestive of a pituitary microadenoma. The patient was referred for a transsphenoidal resection of the microadenoma. While waiting for surgery, the patient presented to the emergency department with a headache and clinical signs of meningism. A computed axial tomography of the central nervous system was performed, and no structural alterations were found. The symptoms subsided with analgesia. One month later, she presented again to the emergency department with clinical findings of acute adrenal insufficiency (cortisol level of 4.06 µg/dL), and she was noted to have spontaneous biochemical remission associated with the resolution of her symptoms of hypercortisolism. For that reason, spontaneous CD remission induced by pituitary apoplexy (PA) was diagnosed. The patient has been managed conservatively since the diagnosis and remains in clinical and biochemical remission until the present time, after 10 months of follow-up. There are three unique aspects of our case: the early age of onset of symptoms, the spontaneous remission of CD due to PA, which has been rarely reported in the medical literature, and the fact that the patient presented a microadenoma because there are fewer than 10 clinical case reports of PA associated with microadenoma.

Introduction

Cushing’s disease (CD) is characterized by excessive production of adrenocorticotropic hormone by a pituitary adenoma and represents the most common cause of endogenous Cushing’s syndrome (CS) [1]. CD was first reported in 1912 by Harvey Williams Cushing, and he described 12 cases at the Peter Bent Brigham Hospital in Baltimore [2]. This disease has a global incidence of approximately 2.2 cases per 1,000,000 people and occurs more frequently in women from 20 to 50 years of age [3]. Pituitary apoplexy (PA) is a rare condition that occurs in 2-12% of cases, and it has a high morbidity and mortality rate [4]. We report an interesting case of a woman diagnosed with CD who achieved spontaneous remission of her disease after a PA.

Case Presentation

A 14-year-old female presented with a two-year history of weight gain (32 kg), depression, elevated blood pressure, type 2 diabetes mellitus, and growth failure (height less than the third percentile). Her height was 140 cm, and her BMI was 28.1 (97th percentile). At presentation, she had not yet reached menarche. Physical examination revealed Tanner 2 breast development, acne, hirsutism, moon facies, dorsocervical fat pad, central obesity, and stretch marks. Initial laboratory tests showed hemoglobin A1C of 13%, low-density lipoprotein of 167 mg/dL, triglycerides of 344 mg/dL, high-density lipoprotein of 26 mg/dL, creatinine of 0.4 mg/dL, and elevated liver enzymes. Abdominal ultrasound indicated moderate hepatic steatosis changes.

Given the high suspicion of CS, a hormonal profile was conducted (Table 1), confirming CS and subsequently diagnosing CD. A nuclear MRI revealed a 2.6 × 1.8 mm pituitary lesion (Figure 1), prompting referral for transsphenoidal resection of the pituitary microadenoma.

Laboratories	Reference range	Initial	One month	Three months	Six months
TSH (mUI/L)	0.35-4.94	–	2.17	–	2.01
AM cortisol (µg/dL)	6.02-18.4	17.3	4.06	<0.5	4.7
1 mg DST (µg/dL)	<1.8	3.4	–	–	–
8 mg DST (µg/dL)	<50% suppression	1.9 (78% suppression)	–	–	–
Urine-free cortisol (µg/24h)	<90	235	–	–	–
ACTH (pg/mL)	10-60	83.5	–	19.2	9.7
IGF-1 (ng/mL)	36-300	–	–	–	293

Table 1: Pertinent laboratory investigation at baseline and follow-up with our patient

ACTH, adrenocorticotropic hormone; DST, dexamethasone suppression test; IGF-1, insulin growth factor-1; TSH, thyroid-stimulating hormone

Figure 1: Axial view of a T1 MRI with contrast showing a sellar lesion

The red arrow shows a microadenoma in relation to the normal pituitary gland.

Approximately one month after the suppression tests and while awaiting surgery, the patient presented to the emergency department with a sudden, severe, holocranial headache accompanied by projectile vomiting and diplopia, suggestive of meningism. A computed axial tomography of the central nervous system was conducted, revealing no structural abnormalities. Symptoms resolved with intravenous analgesia within approximately four to six hours. Subsequently, the patient experienced a significant decrease in insulin requirements, ultimately leading to the suspension of insulin therapy due to persistent hypoglycemia.

Weeks after the headache episode, the patient was reevaluated in the emergency department with a three-day history of diffuse abdominal pain, vomiting, asthenia, myalgia, hypotension, tachycardia, orthostatism, and recurrent hypoglycemia despite insulin suspension. Acute adrenal insufficiency was suspected and confirmed by a cortisol level of 4.06 µg/dL. Treatment with intravenous hydrocortisone 50 mg every six hours was initiated, leading to complete resolution of symptoms within 72 hours. The patient was discharged on maintenance therapy with oral hydrocortisone (20 mg in the morning and 10 mg at night). Subsequent follow-ups showed undetectable cortisol levels. Currently, the patient has been followed up for 10 months post-event, showing persistent clinical and hormonal remission of her disease.

Discussion

CD represents approximately 80% of cases of endogenous hypercortisolism, and pituitary microadenomas are the most common cause of CD in all age groups [5]. CD prevalence is 0.3-6.2 cases per 100,000 people [3], which represents 4.4% of all pituitary adenomas [6], and it is up to five times more likely to occur in women than men. Spontaneous remission of CD is rare, and it is mainly due to the apoplexy of a pituitary tumor [7].

PA is a potentially fatal condition resulting from hemorrhage or necrosis of a pituitary adenoma that produces compression of the surrounding structures with symptoms that can be critical and even fatal [8]. PA affects between 2% and 12% of patients with pituitary adenomas, mainly in nonfunctional macroadenomas [9]. Although the main mechanism of PA is hemorrhage, it can also be due to a hemorrhagic infarction or an infarction without hemorrhage; this last scenario is clinically less aggressive [10]. Among the most important precipitating factors are craniocerebral trauma, pregnancy, thrombocytopenia, coagulopathies, pituitary stimulation tests, drugs such as anticoagulants and estrogens, surgeries that are complicated by hypotension, and radiotherapy [4,11,12].

There are three unique aspects of our case. First, the age of onset is 14 years old. This characteristic has been reported in less than 6% of cases of CD, with a mean age of onset between 12.3 and 14.1 years and a slightly higher incidence in men (63%) [13]. In this population, CD is the most common cause of hypercortisolism, accounting for 75-80% of all cases [14]. Furthermore, our patient presented a significant weight gain, severe compromise in her height, hypertension, depression, and diabetes mellitus, which is compatible with the classic profile described for CD in pediatric ages. It is important to clarify that although type 2 diabetes mellitus is common in adults, it is unusual in the pediatric population [13].

Second, spontaneous remission in CD due to apoplexy has been rarely reported in the past; hence, our case is an important addition to the scant literature on this unusual phenomenon. Although there are characteristics suggestive of PA, such as hyperdense lesions within the pituitary gland and the reinforcing ring, a CT scan has a low sensitivity for detecting pituitary hemorrhage (21-46%); therefore, a negative CT scan does not rule out PA in cases where there is infarction without hemorrhage, a situation that could correspond to our case [15].

The third unique feature of our case is that the stroke occurred in the context of a microadenoma, a situation reported in less than 10 cases in the literature. Despite being a microadenoma, the symptoms of PA were severe, with symptoms of meningism, an intense headache, vomiting, and the development of adrenal insufficiency. Taylor et al. [16] reported a similar case of a 41-year-old female with microadenoma whose PA was associated with severe headache and vomiting.

The main differential diagnosis in our case is cyclical CS (CCS), a disorder that occurs in 15% of CS cases, especially in CD [17]. The diagnosis of CCS is classically established with three peaks and two valleys in cortisol secretion, spontaneous fluctuations, and clinical features of CS [7]. The possibility of CCS was ruled out due to the typical presentation of the PA event and the persistence of hypocortisolism.

Finally, several cases of recurrence of their disease have been described after remission of CS due to AP. Those recurrences usually develop in follow-ups of up to seven years [18]. At the time of the last evaluation (10 months post-PA), the patient remained in remission, but long-term follow-up is required to detect both reactivation and hypopituitarism [19].

Conclusions

CD is a rare entity in the pediatric population, usually associated with a pituitary microadenoma. Spontaneous remission of this disease is very uncommon, but when it occurs, it is mainly due to PA. We describe a case with three unique aspects: CD with an early age of onset of symptoms, spontaneous remission of CD due to PA, which has been rarely reported in the medical literature, and the fact that there are less than 10 clinical case reports of PA associated with microadenoma. It is imperative for clinicians to be aware of this possible outcome in patients with CD.

References

Fleseriu M, Auchus R, Bancos I, et al.: Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021, 9:847-75. 10.1016/S2213-8587(21)00235-7
Bray DP, Rindler RS, Dawoud RA, Boucher AB, Oyesiku NM: Cushing disease: medical and surgical considerations. Otolaryngol Clin North Am. 2022, 55:315-29. 10.1016/j.otc.2021.12.006
Giuffrida G, Crisafulli S, Ferraù F, et al.: Global Cushing’s disease epidemiology: a systematic review and meta-analysis of observational studies. J Endocrinol Invest. 2022, 45:1235-46. 10.1007/s40618-022-01754-1
Briet C, Salenave S, Bonneville JF, Laws ER, Chanson P: Pituitary apoplexy. Endocr Rev. 2015, 36:622-45. 10.1210/er.2015-1042
Newell-Price J, Bertagna X, Grossman A, Nieman L: Cushing’s syndrome. Lancet. 2006, 367:1605-17. 10.1016/S0140-6736(06)68699-6
Daly AF, Beckers A: The epidemiology of pituitary adenomas. Endocrinol Metab Clin North Am. 2020, 49:347-55. 10.1016/j.ecl.2020.04.002
Popa Ilie IR, Herdean AM, Herdean AI, Georgescu CE: Spontaneous remission of Cushing’s disease: a systematic review. Ann Endocrinol (Paris). 2021, 82:613-21. 10.1016/j.ando.2021.10.002
Siwakoti K, Omay SB, Inzucchi SE: Spontaneous resolution of primary hypercortisolism of Cushing disease after pituitary hemorrhage. AACE Clin Case Rep. 2020, 6:e23-9. 10.4158/ACCR-2019-0292
Dubuisson AS, Beckers A, Stevenaert A: Classical pituitary tumour apoplexy: clinical features, management and outcomes in a series of 24 patients. Clin Neurol Neurosurg. 2007, 109:63-70. 10.1016/j.clineuro.2006.01.006
Semple PL, De Villiers JC, Bowen RM, Lopes MB, Laws ER Jr: Pituitary apoplexy: do histological features influence the clinical presentation and outcome?. J Neurosurg. 2006, 104:931-7. 10.3171/jns.2006.104.6.931
Turgut M, Ozsunar Y, Başak S, Güney E, Kir E, Meteoğlu I: Pituitary apoplexy: an overview of 186 cases published during the last century. Acta Neurochir (Wien). 2010, 152:749-61. 10.1007/s00701-009-0595-8
Wildemberg LE, Glezer A, Bronstein MD, Gadelha MR: Apoplexy in nonfunctioning pituitary adenomas. Pituitary. 2018, 21:138-44. 10.1007/s11102-018-0870-x
Concepción-Zavaleta MJ, Armas CD, Quiroz-Aldave JE, et al.: Cushing disease in pediatrics: an update. Ann Pediatr Endocrinol Metab. 2023, 28:87-97. 10.6065/apem.2346074.037
Ferrigno R, Hasenmajer V, Caiulo S, et al.: Paediatric Cushing’s disease: epidemiology, pathogenesis, clinical management and outcome. Rev Endocr Metab Disord. 2021, 22:817-35. 10.1007/s11154-021-09626-4
Banerjee AK: Diagnostic imaging: Brain. 2nd edition. Br J Radiol. 2010, 83:450-1.
Taylor HC, McLean S, Monheim K: Resolution of Cushing’s disease followed by secondary adrenal insufficiency after anticoagulant-associated pituitary hemorrhage: report of a case and review of the literature. Endocr Pract. 2003, 9:147-51. 10.4158/EP.9.2.147
Alexandraki KI, Kaltsas GA, Isidori AM, et al.: The prevalence and characteristic features of cyclicity and variability in Cushing’s disease. Eur J Endocrinol. 2009, 160:1011-8. 10.1530/EJE-09-0046
Kamiya Y, Jin-No Y, Tomita K, et al.: Recurrence of Cushing’s disease after long-term remission due to pituitary apoplexy. Endocr J. 2000, 47:793-7. 10.1507/endocrj.47.793
Machado MC, Gadelha PS, Bronstein MD, Fragoso MC: Spontaneous remission of hypercortisolism presumed due to asymptomatic tumor apoplexy in ACTH-producing pituitary macroadenoma. Arq Bras Endocrinol Metabol. 2013, 57:486-9. 10.1590/s0004-27302013000600012

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Cushing Disease Clinical Phenotype and Tumor Behavior Vary With Age

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Management of Diabetes Mellitus in Acromegaly and Cushing’s Disease with Focus on Pasireotide Therapy

Introduction

Hyperglycemia and Increased Cardiovascular Risk in Acromegaly and CD

Mechanisms of Pasireotide-Induced Hyperglycemia

Antidiabetic Drugs with Proven Cardiovascular Benefits

The Current Management of Pasireotide-Induced Hyperglycemia

A Potential Change of Perspective and Open Issues

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Diagnostic dilemma in Cushing’s syndrome: discrepancy between patient-reported and physician-assessed manifestations

Purpose

Methods

Results

Conclusion

Introduction

Materials and methods

Patients, study design, and data collection

Definition of patient-reported and physician-assessed manifestations

Comorbidities of Cushing’s syndrome

Hormone assay

Statistical analysis

Results

Clinical characteristics of the patients

Frequency and concordance between patient-reported and physician-assessed CS-related manifestations

Discussion

Acknowledgements

Compliance with ethical standards

Conflict of interest

Ethics approval

Informed consent

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

Abstract

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Spontaneous Cushing’s Disease Remission Induced by Pituitary Apoplexy

Abstract

Introduction

Case Presentation

Table 1: Pertinent laboratory investigation at baseline and follow-up with our patient

Figure 1: Axial view of a T1 MRI with contrast showing a sellar lesion

Discussion

Conclusions

References

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