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The study covered in this summary was published on Research Square as a preprint and has not yet been peer reviewed.

Key Takeaways

• Adding a corticotropin-releasing hormone (CRH) stimulation test immediately following a 2-day low-dose dexamethasone suppression test (LDDST) ― what's known as a Dex-CRH test and was first introduced in 1993 ― identified Cushing disease in 5 of 65 people (7.7%) with a confirmed diagnosis but who had previously shown normal cortisol levels on a conventional LDDST.

• However, the Dex-CRH test also resulted in one (2.5%) false positive case compared with an LDDST alone.

• Measuring serum dexamethasone levels further improved the diagnostic accuracy of the Dex-CRH test.

Why This Matters

• It can be challenging to diagnose Cushing syndrome and to differentiate Cushing disease from nonneoplastic physiologic hypercortisolism caused by conditions that can present with Cushing syndrome–like clinical features, such as diabetes and obesity.

• The Dex-CRH test, first described in 1993, initially appeared superior to an LDDST alone for ruling out nonneoplastic hypercortisolism, with a report of 100% sensitivity, specificity, and diagnostic accuracy. However, subsequent studies that used different protocols and in which dexamethasone was not measured had results that called into question the accuracy, sensitivity, and specificity of the Dex-CRH test.

• This study reports the accuracy, sensitivity, and specificity of the Dex-CRH test for diagnosing Cushing disease, performed as first described, in 107 patients, including 74 for whom dexamethasone was also measured.

Study Design

• The researchers analyzed data from 107 patients with suspected Cushing disease who underwent a Dex-CRH test during 2002–2014 at the Cleveland Clinic.

Key Results

• Sixty-five people received a confirmed diagnosis of Cushing disease and underwent follow-up for a median of 66 months. Cushing disease was not confirmed in 42 patients who were followed for a median of 52 months.

• The median age of the 107 patients was 40 years, and 82% to 88% were women. The median body mass index for these patients was 34–37 kg/m².

• Among the 65 patients with confirmed Cushing disease, five patients (7.7%) had a suppressed cortisol level no greater than 1.4 μg/dL after the LDDST but were appropriately classified as having Cushing disease with a cortisol level that surpassed 1.4 μg/dL by 15 minutes after CRH stimulation.

• In contrast, 3 of 42 patients (7.1%) in the group without confirmed Cushing disease had an abnormal Dex-CRH test result. For one of these three patients, the LDDST result was borderline normal, with a cortisol level post-DEX of 1.4 μg/dL that increased to 3.1 μg/dL by 15 minutes after CRH stimulation, which resulted in this patient receiving a false positive diagnosis.

• A cortisol threshold value of more than 1.4 μg/dL during the Dex-CRH test was diagnostic of Cushing disease with sensitivity of 100%, specificity of 93%, and diagnostic accuracy of 97%.

• Among the 74 patients with dexamethasone measurements, the sensitivity of the Dex-CRH test was unchanged, but the specificity and diagnostic accuracy increased to 97% and 99%, respectively.

Limitations

• The study was retrospective.

• Not all patients underwent measurement of dexamethasone level.

• No uniform protocol existed for the diagnostic work-up and follow-up of patients suspected of having Cushing disease.

Disclosures

• The study did not receive commercial funding.

• The authors had no financial disclosures.

This is a summary of a preprint research study , "The Addition of Corticotropin-Releasing Hormone to 2-Day Low Dose Dexamethasone," written by researchers primarily from the Cleveland Clinic and Johns Hopkins University School of Medicine, published on Research Square, and provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on research square.com.

From https://www.medscape.com/viewarticle/985984

Abstract

Cortisol production in the adrenal gland is regulated by the hypothalamus-pituitary-adrenal (HPA) axis. Subclinical hypercortisolism is a status characterized by the alteration of HPA axis secretion without typical signs or symptoms of overt hypercortisolism (eg, moon face, truncal obesity, easy bruising, thin extremities, proximal myopathy, cutaneous purple striae) [1, 2]. Although overt hypercortisolism can be detected by its clinical presentations or severe complications, it is sometimes challenging for clinicians to appropriately diagnose subclinical hypercortisolism because of the absence of such clinical presentations [2]. The 1-mg overnight dexamethasone suppression test (1-mg DST) measures the response of the adrenal glands to ACTH through the HPA axis and therefore has been widely used for screening and diagnosis of subclinical hypercortisolism [1, 3]. The European Society of Endocrinology Guideline has defined a partial suppression of the HPA axis (ie, serum cortisol levels after 1-mg DST [F-DST] > 1.8 µg/dL [50 nmol/L]) without clinical signs of overt cortisol hypersecretion as “possible autonomous cortisol secretion” and recommended screening these patients for metabolic disorders including hypertension and type 2 diabetes mellitus to offer appropriate treatment of these comorbidities [4].

Hypertension is one of the most common and distinguishing clinical features in patients with subclinical hypercortisolism [2] as well as overt hypercortisolism [5]. Although hypertension can be triggered by excess cortisol levels [5, 6], it is still unclear whether even slightly elevated cortisol levels among individuals with subclinical hypercortisolism contribute to the occurrence of hypertension. This raises another potential mechanism to cause hypertension such as the coexistence of hyperaldosteronism (ie, excess aldosterone that is an essential steroid hormone for sodium reabsorption, water retention, and blood pressure control) [7]. Previous studies have reported that 10% to 20% of primary aldosteronism is accompanied by cortisol-producing adenoma [8-10], and autonomous cortisol secretion was decreased after the resection of the aldosterone-producing adenoma (a subtype of primary aldosteronism) [11]. Furthermore, a previous mass spectrometry-based analysis revealed that cortisol secretion was frequently found in patients with primary aldosteronism [12]. Although these studies have examined cortisol biosynthesis in primary aldosteronism [13], evidence about whether aldosterone plays a role in the occurrence of hypertension among people with subclinical hypercortisolism is limited.

To address this knowledge gap, we performed a cohort study examining the association between aldosterone and hypertension among patients with adrenal tumor and F-DST >1.8 µg/dL, stratified by whether patients had clinical signs of Cushing syndrome or not. We first analyzed the cross-sectional association between aldosterone and blood pressure at baseline. Then, we analyzed the longitudinal association between aldosterone at baseline and the improvement rate of hypertension after the adrenalectomy. Last, to further clarify the role of aldosterone in the regulation of blood pressure in subclinical hypercortisolism, we described the difference in aldosterone response to ACTH after the adrenalectomy according to the postoperative improvement of hypertension.

Materials and Methods

Data Sources and Study Participants

A retrospective cohort study was designed to assess the clinical characteristics (focusing on aldosterone) among patients with hypercortisolism at the Yokohama Rosai Hospital from 2008 to 2017. We enrolled 89 patients with adrenal tumor and F-DST > 1.8 µg/dL (50 nmol/L) [3, 4, 14]. We then categorized them into 2 groups: (1) overt hypercortisolism (F-DST > 5.0 µg/dL [138 nmol/L]) and having clinical signs of Cushing syndrome (moon face, central obesity, dorsocervical fat pad [buffalo hump], purple striae, thin skin, easy bruising, and proximal myopathy] [15]) and (2) subclinical hypercortisolism (not having such clinical signs). All patients with overt hypercortisolism in this study showed F-DST > 5.0 µg/dL (138 nmol/L). The study was approved by the research ethics committee of the Yokohama Rosai Hospital, and all participants provided written informed consent.

Measurements

Demographic characteristics were self-reported, and body mass index (BMI) was calculated using measured weight and height. Systolic blood pressure was measured in the sitting position using a standard upper arm blood pressure monitor after a 5-minute rest in a quiet place [16]. The mean of 2 measurements was recorded. If the measurement was done only once on a given occasion, the level obtained was recorded. When the patients were already taking antihypertensives at enrollment, they were asked to report their blood pressure levels at the diagnosis of hypertension (ie, systolic blood pressure before starting antihypertensives). Blood samples were collected at 8:00 AM after the patient had rested in the supine position for 30 minutes. We measured F (µg/dL, × 27.6 for nmol/L) and ACTH (pg/mL, × 0.220 for pmol/L) using chemiluminescent enzyme immunoassay and electrochemiluminescent immunoassay, respectively. Plasma aldosterone concentrations (PACs; ng/dL, × 27.7 for pmol/L) and plasma renin activities (PRAs; ng/mL/h) were measured using radioimmunoassay. Any antihypertensive drugs were replaced with calcium channel antagonists (including dihydropyridine calcium channel antagonists) and/or α blocker several weeks before the measurement of PACs and PRAs according to the clinical guideline of the Japan Endocrine Society [17]. We also measured urine aldosterone (µg/day × 2.77 for nmol/d) and urine cortisol (µg/day, × 2.76 for nmol/d) using radioimmunoassay. The tumor size was estimated using contrast-enhanced thin-section computed tomography scans of the adrenal glands.

To evaluate whether the patients had autonomous cortisol secretion, we performed 1-mg DST, in which dexamethasone (1 mg) was administered at 11:00 PM, and blood samples were drawn at 8:00 AM the following morning. F and ACTH were measured in 1-mg DST.

The total or partial adrenalectomy was performed in all cases with overt hypercortisolism. For patients with subclinical hypercortisolism, the adrenalectomy was recommended to those who showed F-DST > 5.0 µg/dL (138 nmol/L) accompanying metabolic disorders [3]. It was also recommended to those who were expected to improve their clinical symptoms and/or metabolic disorders by the tumor resection, which included patients with hypertension possibly resulting from autonomous aldosterone secretion as well as autonomous cortisol secretion from the adrenal gland. The adrenalectomy was conducted when patients agreed with the treatment plan through informed consent. To evaluate whether patients had autonomous aldosterone secretion, we used the screening criterion of primary aldosteronism (ie, PAC/PRA ratio; aldosterone-to-renin ratio [ARR] > 20), followed by the confirmatory tests of primary aldosteronism that included the saline infusion test, captopril challenge, and/or furosemide stimulation test [17].

For patients who were considered to receive a benefit by the adrenalectomy and who agreed with the examination, we performed the segment-selective adrenal venous sampling to assess the laterality of hyperaldosteronism [18-20]. First, blood samples were collected from the bilateral central adrenal veins before ACTH stimulation. Then, we collected samples from the superior, lateral, and inferior tributaries of the right central adrenal vein and the superior and lateral tributaries of the left central adrenal vein after ACTH stimulation. Aldosterone excess (ie, hyperaldosteronism) was considered when the effluent aldosterone concentrations were > 250 ng/dL before ACTH stimulation and 1400 ng/dL after ACTH stimulation, respectively [18-20]. We used the absolute value instead of the lateralization index because individuals included in our study had elevated cortisol concentrations given the inclusion criteria (ie, F-DST >1.8 µg/dL [50 nmol/L]). For 9 patients with subclinical hypercortisolism who showed bilateral adrenal nodules, the side of adrenalectomy was determined by the nodule size and the results of adrenal venous sampling (ie, laterality of hyperaldosteronism). The adrenalectomy was conducted when patients agreed with the treatment plan through informed consent. Immunohistochemical evaluation of aldosterone synthase cytochrome P450 (CYP11B2) was conducted for some resected nodules.

To evaluate the postoperative cortisol responsiveness to ACTH, we performed an ACTH stimulation test a year after the adrenalectomy, in which blood samples were collected and PAC and F were measured 30 and 60 minutes after ACTH administration. Postoperative improvement of hypertension was defined as blood pressure <140/90 mmHg without antihypertensives or the reduction of the number of antihypertensives to maintain blood pressure <140/90 mmHg after the adrenalectomy.

Statistical Analyses

We describe the demographic characteristics and endocrine parameters at baseline comparing patients with overt hypercortisolism and those with subclinical hypercortisolism using the Fisher exact test for categorical variables and Mann-Whitney U test for continuous variables. Second, for each group, we investigated the association between the baseline characteristics and systolic blood pressure using ordinary least-squares regression models. The model included age, sex, BMI, serum potassium levels, estimated glomerular filtration rate, tumor size, and F and PAC at 8:00 AM. Third, we estimated the risk difference and 95% CI of the improvement rate of hypertension after the adrenalectomy according to these baseline characteristics (including systolic blood pressure) using a modified least-squares regression model with a Huber-White robust standard error [21]. Last, to evaluate whether the improvement of hypertension is related to postoperative cortisol and aldosterone secretion, we compared PAC and F responsiveness to ACTH from peripheral blood samples between patients who improved hypertension and those who did not using the Mann-Whitney U test. The longitudinal and postoperative analyses were performed among patients with subclinical hypercortisolism because only 2 cases with overt hypercortisolism failed to show the improvement of hypertension after the adrenalectomy.

To assess the robustness of our findings, we conducted the following 2 sensitivity analyses. First, we replaced F at 8:00 AM with F after DST in our regression models. Second, we estimated the risk difference of the improvement rate of hypertension after the adrenalectomy according to the postoperative F and PAC levels after ACTH stimulation, adjusting for the baseline characteristics included in our main model.

We also conducted several additional analyses. First, to investigate the relationship of change in PAC after adrenalectomy with the improvement rate of hypertension, we included decrease in PAC between before and after adrenalectomy instead of PAC at baseline in the model. Second, to assess the relationship between aldosterone and hypertension among patients with subclinical hypercortisolism without primary aldosteronism, we reran the analyses excluding patients who met the diagnostic criteria of primary aldosteronism. Third, to understand the overall association, we reran the analyses using all samples as a single group to assess the relationship among people with overall (ie, overt and subclinical) hypercortisolism. Last, we compared PAC and F responsiveness with ACTH during adrenal venous sampling between patients with and without postoperative improvement of hypertension. All statistical analyses were performed using Stata, version 15.

Results

Among the 89 enrolled patients, 21 showed clinical signs of overt Cushing syndrome and 68 did not. The flow of the study population is shown in Fig. 1. Among 21 patients with overt hypercortisolism, 19 patients had hypertension. All patients underwent adrenalectomy, and 16 patients showed improved hypertension levels after the surgery (1 patient was referred to another hospital; therefore, no information is available). Among 68 patients with subclinical hypercortisolism, 63 had hypertension. After the evaluation of autonomous aldosterone secretion as well as autonomous cortisol secretion, of 33 patients who underwent adrenalectomy, 23 (70%) showed improved hypertension levels after the adrenalectomy (10 patients in the surgery group decided not to undergo adrenalectomy). Patients with subclinical hypercortisolism who underwent adrenalectomy showed lower PRA and higher ARR than those without adrenalectomy (Supplementary Table S1) [22].

Figure 1.

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Enrollment and follow-up of the study population after the adrenalectomy. ^aThe prevalence of patients with overt hypercortisolism and hypertension among this study population may be higher than in the general population and therefore needs to be carefully interpreted given that the study institute is one of the largest centers for adrenal diseases in Japan. ^bAll patients in this category showed autonomous cortisol secretion (ie, serum cortisol levels >5.0 µg/dL [138 nmol/L] after a 1-mg dexamethasone suppression test). ^cOne case underwent adrenalectomy at another hospital and therefore no information was available after the adrenalectomy. ^dThe adrenalectomy was performed for 33 patients who were expected to improve their clinical symptoms and/or metabolic disorders, including hypertension. This assessment was mainly based on autonomous cortisol secretion evaluated by a 1-mg dexamethasone suppression test, complicated metabolic disorders, and autonomous aldosterone secretion evaluated by adrenal venous sampling for patients who were positive for the screening and confirmatory tests of primary aldosteronism. Details in the assessment can be found in the Methods section or elsewhere [18-20].

Demographic Characteristics and Endocrine Parameters Among Patients With Overt and Subclinical Hypercortisolism

The median age (interquartile range) was 51 years (46, 62 years), and 72% were female. Patients with overt hypercortisolism were relatively younger and showed a higher estimated glomerular filtration rate and larger tumor size compared with patients with subclinical hypercortisolism (Table 1). Other demographic characteristics were similar between these groups. Patients with overt hypercortisolism showed higher F with undetected low ACTH, higher F after DST, and higher urine cortisol levels compared with those with subclinical hypercortisolism who instead showed higher PAC and ARR. Among patients with subclinical hypercortisolism, 9/68 (13.2%) showed undetectable ACTH levels and 25/68 (36%) were positive for PA screening criterion (ie, ARR > 20) followed by at least 1 positive confirmatory test. Based on the results of adrenal venous sampling of these cases, 9 showed aldosterone excess in the right nodules, 6 showed aldosterone excess in the left nodules, and 7 showed aldosterone excess on both sides, respectively (3 cases did not show aldosterone excess on both sides). Immunohistochemical evaluation of CYP11B2 was examined for 6 resected adrenal glands, and all of them showed positive expression.

Association of Demographic Characteristics and Endocrine Parameters With Systolic Blood Pressure

Among patients with overt hypercortisolism, we did not find a significant association of demographic characteristics and endocrine parameters with systolic blood pressure (Table 2). However, among patients with subclinical hypercortisolism, we found that higher PACs at 8:00 AM were significantly associated with systolic blood pressure (adjusted coefficient [95% CI] = +0.59 [0.19-0.99], P = 0.008). The results did not change when we used F after DST instead of F at 8:00 AM (Supplementary Table S2) [22].

Association of Demographic Characteristics and Endocrine Parameters With Hypertension Improvement After the Adrenalectomy Among Patients With Subclinical Hypercortisolism

Among 33 patients with subclinical hypercortisolism and hypertension who underwent the adrenalectomy, we found that age and higher PAC were significantly associated with a higher improvement rate of hypertension after the adrenalectomy (age, adjusted risk difference [95% CI] = +2.36% [1.08-3.64], P = 0.001; PAC, adjusted risk difference [95% CI] = +1.45% [0.35-2.55], P = 0.01; Table 3). The results did not change when we used F after DST instead of F at 8:00 AM (Supplementary Table S3) [22]. Patients with improved hypertension after the surgery showed significantly lower PACs 60 minutes after a postoperative ACTH stimulation test than those without the improvement of hypertension (P = 0.05), although F and PAC/F ratio were not significantly different between these 2 groups (Table 4). The association between lower PACs after postoperative ACTH stimulation and higher improvement rate of hypertension was also found in the multivariable regression analysis adjusting for baseline characteristics (adjusted risk difference [95% CI] = −1.08% [−1.92 to −0.25], P = 0.01; Supplementary Table S4) [22].

Additional Analyses

Decreased PAC between before and after adrenalectomy was significantly associated with hypertension improvement (Supplementary Table S5) [22]. When we restricted samples to those without primary aldosteronism, PACs at baseline tended to be associated with systolic blood pressure but the 95% CI included the null (Supplementary Table S6) [22]. Decreased PAC after adrenalectomy was associated with hypertension improvement after the adrenalectomy, whereas PAC at baseline was not associated with that outcome (Supplementary Table S7) [22]. When we analyzed the entire sample (ie, both overt and subclinical hypercortisolism), PAC at baseline was associated with systolic blood pressure at baseline (Supplementary Table S8) [22] and hypertension improvement after the adrenalectomy (Supplementary Table S9) [22]. We also found the higher median value of PAC response to ACTH during adrenal venous sampling at the remained (ie, not resected by the adrenalectomy) side of adrenal gland among patients whose hypertension did not improve compared with those whose hypertension improved after the surgery, but the difference was not statistically significant (Supplementary Table S10) [22].

Discussion

In this retrospective cohort study, we found that higher aldosterone levels were associated with higher systolic blood pressure among patients with possible autonomous cortisol secretion and without clinical signs of overt Cushing syndrome (ie, subclinical hypercortisolism). In this group, higher aldosterone before the adrenalectomy was associated with the postoperative improvement of hypertension. Moreover, we found that patients with postoperative improvement of hypertension showed lower aldosterone response to ACTH after the adrenalectomy compared with those without the improvement of hypertension. Decrease in PACs after the adrenalectomy was associated with improved hypertension even among patients with subclinical hypercortisolism who did not have primary aldosteronism at baseline, whereas baseline PAC was not associated with that outcome. We found no evidence that aldosterone is associated with systolic blood pressure among patients with overt hypercortisolism. These findings indicate that elevated aldosterone may contribute to the presence of hypertension and its improvement rate after the adrenalectomy for patients with subclinical hypercortisolism.

To the best of our knowledge, this is one of the first studies to assess the potential role of aldosterone in hypertension among patients with overt and subclinical hypercortisolism, during both pre- and postoperative phases. Since aldosterone- and cortisol-producing adenoma was reported in 1979 [23, 24], several studies have assessed the cortisol production in aldosterone-producing adenoma clinically and histologically [8-10, 25] and showed the correlation between the degree of glucocorticoid excess levels and metabolic markers including BMI, waist circumference, blood pressure, insulin resistance, and high-density lipoprotein [12]. Prior research suggested that aldosterone-producing adenoma might produce cortisol as well as aldosterone even when serum cortisol levels after DST is less than 1.8 µg/dL (50 nmol/L) [11]. Although these studies have focused on cortisol synthesis among patients with aldosterone-producing adenoma, little is known about aldosterone synthesis among patients with cortisol-producing adenoma. Given that patients with hypercortisolism tend to have therapy-resistant hypertension and electrolyte disorders [8], our findings may generate the hypothesis that aldosterone contributes to the incidence and severity of hypertension in patients with possible autonomous cortisol secretion; this warrants further investigation.

There are several mechanisms by which cortisol excess leads to hypertension, such as regulating endothelial nitric oxide synthase expression modulated by 11β-hydroxysteroid dehydrogenases [26], activating the mineralocorticoid receptor [27] and upregulating vascular endothelin-1 [28]. Moreover, hypercortisolism impairs the production of endothelial vasodilators, including prostacyclin, prostaglandins, and kallikreins [29]. Despite these potential mechanisms, the direct effect of cortisol may not be sufficient to explain hypertension in patients with hypercortisolism, particularly subclinical hypercortisolism, and the presence of cortisol and aldosterone coproducing adenoma indicates another potential pathway to induce hypertension through aldosterone excess. Aldosterone is a steroid hormone not only promoting sodium reabsorption and volume expansion but also activating the mineralocorticoid receptor in the kidney and nonepithelial tissues (eg, adipose tissue, heart, endothelial cells, and vascular smooth muscle cells) [30]. It also induces oxidative stress, inflammation, fibrosis, vascular tone, and endothelial dysfunction [31]; therefore, aldosterone excess could induce hypertension even when it is slightly elevated [32]. A recent multiethnic study showed that aldosterone levels within the reference range were associated with subclinical atherosclerosis partially mediated through elevated blood pressure [33]. These mechanisms support our results indicating the potential contribution of aldosterone to hypertension among patients with subclinical hypercortisolism.

This study had several limitations. First, we did not have information on the duration of cortisol excess and therefore the estimated effect of cortisol on hypertension in our study might have been underestimated. The duration of exposure to mild hypercortisolism may be one of the important drivers of cardiovascular and metabolic disorders including irreversible vasculature remodeling in patients with subclinical hypercortisolism [2]. Second, we did not have the genetic information of adrenal tumors including aldosterone-producing adenoma. Given the heterogeneity of aldosterone responsiveness to ACTH [34] and postoperative hypertension resolution rate across genetic mutations (eg, KCNJ5, ATP1A1, ATP2B3, CACNA1D, CTNNB1) [35], such information might affect our findings. Third, because of the nature of an observational study, we cannot rule out the unmeasured confounding. Fourth, because aldosterone and cortisol levels were measured at a single point, we may have a risk of mismeasurement. Moreover, when evaluating aldosterone levels, we used dihydropyridine calcium channel blockers to control hypertension based on the clinical guideline of primary aldosteronism in Japan; this might lower serum aldosterone levels. Fifth, because the present study was conducted at a single center, selection bias is inevitable [13]. Given that primary aldosteronism—one of the major causes of secondary hypertension—has still been underdiagnosed, partially because of insufficient recognition of clinical guidelines [36], our findings may indicate the importance of considering aldosterone when evaluating patients with subclinical hypercortisolism accompanied by hypertension. However, we need to carefully interpret the observed “prevalence” in this study because individuals potentially having subclinical hypercortisolism were likely to come to our hospital, which specializes the adrenal disorders, and thus the numbers do not reflect the prevalence in general population. The small number of resected adrenal glands with the evaluation of CYP11B2 expression in this study cohort also limits the prevalence estimation of primary aldosteronism. Finally, as we only followed up 1 year after the adrenalectomy, we could not evaluate the long-term resolution rate of hypertension. To overcome these limitations and generalize our findings, future molecular studies and multicenter longitudinal studies with sufficient individual datasets and longer follow-up are required.

In conclusion, plasma aldosterone concentrations were associated with systolic blood pressure and improvement rate of hypertension after the adrenalectomy among patients with subclinical hypercortisolism—possible autonomous cortisol secretion without clinical signs of overt Cushing syndrome. Our findings underscore the importance of considering aldosterone when patients have an adrenal tumor with possible autonomous cortisol secretion complicated with hypertension. Future molecular and epidemiological studies are warranted to identify the potential role of aldosterone in hypertension among patients with subclinical hypercortisolism, clarify how often these patients also have primary aldosteronism, and examine the clinical effectiveness of the intervention targeting aldosterone for such patients.

Funding

K.I. was supported by the Japan Society for the Promotion of Science (JSPS; 21K20900 and 22K17392) and The Japan Endocrine Society. Study sponsors were not involved in study design, data interpretation, writing, or the decision to submit the article for publication. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Conflicts of Interest

All of authors confirm that there is no conflict of interest in relation to this work.

Data Availability

Restrictions apply to the availability of some data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.

Abbreviations

• ARR

  aldosterone-to-renin ratio

• BMI

  body mass index

• DST

  dexamethasone suppression test

• F

  serum cortisol level

• HPA

  hypothalamus-pituitary-adrenal

• PAC

  plasma aldosterone concentration

• PRA

  plasma renin activity

1. Introduction

Transsphenoidal pituitary surgery is the primary treatment choice for patients with Cushing’s Disease (CD), which has a reported remission rate of 70% to 90% [1,2]. However, hypercortisolism persists in some of these surgical patients and recurs in 3–29% of patients, even in those who have benefited from remission for more than a decade [3,4].

In cases in which the primary surgery failed, serval treatments are considered, including reoperation, medication, conventional radiotherapy, radiosurgery, and bilateral adrenalectomy [4]. With remission rates as high as 87% [5], reoperation is a feasible option worth considering. Although some studies have concentrated on the risk factors and long-term outcomes of repeated transsphenoidal surgery [6,7], the necessity of reoperation in patients with varied clinical, imaging, and pathological characteristics has not been adequately discussed. Reoperation is considered when lesions remain visible on magnetic resonance imaging (MRI), given that tumor removal will likely lead to remission, even if it is located in the cavernous sinus [8]. Nevertheless, the incidence of positive MRI findings is typically low in CD patients with either recurrent or persistent disease [5,9,10,11]. Furthermore, MRI has limitations in revealing the accurate structures of the operated area due to distorted anatomy related to the formation of granulation tissue and inflammatory changes after the initial surgery [12]. Unlike the considerable remission rate achieved after the first operation despite negative MRI findings [1], the decision to perform a second operation without visible lesions detected on MRI is challenging for neurosurgeons. These uncertainties emphasize the importance of discussing the risk factors and the necessity of repeat surgery, especially for patients with negative radiological results.

Our retrospective study aimed to ascertain the treatment preference for reoperation in patients with persistent and recurrent CD and evaluate the significance of MRI findings for selecting patients that are likely to benefit from reoperation. Furthermore, we aimed to provide a reference for surgeons in making decisions on repeat surgical intervention for patients who are most likely to benefit, thereby improving the remission rates associated with reoperation.

2. Patients and Methods

We retrospectively identified patients with CD treated with repeated transsphenoidal surgery between 2002 and 2021 at our institution. Patients with three or more pituitary surgeries were excluded from the present study. The preoperative and postoperative evaluations of the first surgeries are shown in Table 1. All patients fulfilled the following inclusion criteria: persistent hypercortisolism after initial surgery or recurrence after remission with a period of normocortisolism or adrenal insufficiency.

Table 1. Preoperative characteristics of the initial surgery.

This study included 42 patients aged 44.4 ± 14.6 years at the time of the repeat operation (Table S1). The median interval between the two operations was 43 months (interquartile range [IQR] = 18–90). The median follow-up duration after the second operation was 15.5 months (IQR = 4–59).

2.1. Diagnosis

The diagnostic criteria for recurrence in the present study included new onset or recurrence of symptoms, clinical features, serum cortisol level, 24 h urinary-free cortisol (UFC) level, and biochemical tests (low-dose dexamethasone suppression test and high-dose dexamethasone suppression test (HDDST)), which are frequently used to define CD remission, recurrence, and persistence. An algorithm that is currently used in biochemical assessment and management of recurrent and persistent disease is shown in Figure 1. All tests were performed in a College of American Pathologists-accredited laboratory (No. 7217913). Serum cortisol and UFC were examined using an Access Immunoassay System (Beckman Coulter Inc., Fullerton, CA, USA). The normal ranges were 6.7–22.6 µg/dL and 21–111 µg/24 h, respectively. Plasma adrenocorticotropic hormone (ACTH) levels were measured using an ELSA-ACTH immunoradiometric method (Cisbio Bioassays, Codolet, France). The normal range was 12–78 pg/mL. A serum cortisol value of less than 5 μg/dL was considered to indicate remission. Patients who were not considered to be in remission were discharged and routinely evaluated 6 months after surgery for possible delayed remission. Patients were administered oral cortisone and gradually withdrawn to a physiologic replacement dose after 1 month. The yearly follow-up visit included physical examinations and serum cortisol, UFC, and plasma ACTH assessments. MRI was not performed routinely after surgery unless persistent or recurrent hypercortisolism was confirmed biochemically, as postoperative imaging may not be reliably interpreted for hormone-active pituitary adenoma.

Figure 1. Algorithm of the biochemical assessment and treatment of persistent and recurrent Cushing’s disease.

Contrast-enhanced pituitary MRI at our center was conducted to facilitate diagnosis and surgical planning using a superconducting magnet 1.5/3.0 Tesla scanner (SIGNA; GE Healthcare, Chicago, IL, USA). Before gadolinium injection (0.01 mmol/kg gadopentetate dimeglumine; Magnevist, Berlex Laboratories, Inc., Montville, NJ, USA), T1-weighted spin echo and T2-weighted turbo spin echo images were obtained in the coronal and sagittal planes. Beginning simultaneously with gadolinium injection, coronal and sagittal T1-weighted spin echo images were obtained 2 min after the injection. Imaging studies were independently reviewed by a neuroradiologist, endocrinologist, and the patient’s neurosurgeon. Pituitary imaging prior to the first surgery performed outside of our center was acquired and re-interpreted by the same team. Full agreement was reached on the positive nature of the MRI findings. Otherwise, when MRI findings appeared normal or interpretation was ambiguous, the MRI findings were considered negative.

Meanwhile, bilateral inferior petrosal sinus sampling (BIPSS) with or without vasopressin (available after 2015) stimulation was performed in nine patients who experienced recurrence but lacked initially positive ACTH staining on the first histological examination to reconfirm whether the Cushing’s syndrome diagnosis was pituitary-dependent. Two patients were evaluated by BIPSS, although the initial pathology was positive. Regarding persistent disease, among eight patients without positive ACTH staining in their first pathological assessment, five were confirmed by positive BIPSS results and five were confirmed by visible radiological lesions. Only one patient with negative ACTH-staining adenoma underwent repeat surgery with either negative BIPSS results or negative imaging findings.

2.2. Surgical Procedure

The same surgeon performed surgery on all patients via the mononostril transsphenoidal approach under a microscope or endoscope (available from December 2015). The initial location prior to the first operation did not guide the resection during repeat surgery. For each patient with positive MRI results, the imaging-identified areas for adenoma were biopsied as frozen sections for the initial pathological evaluation. Subsequent resection with a rim of pituitary tissue around the tumor cavity was conducted to confirm neoplasm-free margins. No further exploration was performed before frozen pathology confirmation was available unless the BIPSS result showed an increased ACTH level on the other side.

For invisible tumors on MRI, the dura mater was opened widely to facilitate exploration of the whole gland, starting from the initial location on MRI before the first surgery or the side with the higher ACTH level in the BIPSS, if available. If no obvious tumor was identified on this side by the neurosurgeon intraoperatively, half of the gland was resected using the guidance of BIPSS lateralization.

If a tumor was frozen pathologically and identified after half of the gland was removed, the residual gland remained unresected and was only gently explored and sampled in the most suspected area. In some circumstances in which the frozen section was negative, it was subjected to a subtotal adenohypophysectomy of the intermediate lobe and neurohypophysis.

If invasive adenoma characteristics were also identified, the involved dura and medial wall of the cavernous sinus were resected or coagulated. A sample was collected for postoperative pathological confirmation, if available.

2.3. Outcome

Patients were defined as being in remission with an immediate postoperative serum cortisol nadir <5 μg/dL or 24 h UFC at a normal level [13]. Persistent hypercortisolism was defined as an increased postoperative UFC level, while recurrent hypercortisolism was defined as a reappearance of hypercortisolism after a period of normocortisolism or adrenal insufficiency.

2.4. Statistical Analysis

Descriptive statistics are presented as means ± standard deviations when normally distributed or medians and ranges when not normally distributed to describe patient outcome measures and incidence of remission among the study population. Statistical significance was set at a p value < 0.05. Fisher’s exact test was used to compare proportions of categorical measures between groups. All analyses were conducted using Instat (GraphPad Software, San Diego, CA, USA).

3. Results

3.1. Patient Characteristics

The basic information and perioperative evaluations of the two operations are shown in Table 1 and Table S1. Among all 27 recurrent cases, the preoperative MRI before the first operation showed a definite pituitary adenoma. The other 12 patients with persistent hypercortisolism had positive MRI findings before the first surgery. The remaining three patients with negative radiographic findings were diagnosed with CD and underwent the first transsphenoidal surgery (TSS) based on their endocrinological results.

For patients with confirmed persistent or recurrent CD, the imaging findings prior to the second operation of 14 individuals were negative (no solid evidence of tumors), and 28 clearly had positive results for the presence of a solid lesion. All patients who underwent a second surgery for recurrent or persistent hypercortisolism after the initial surgery were endocrinologically re-evaluated before the repeat surgery. There were 38 cases with positive HDDST results among 42 patients. BIPSS was performed in 18 patients with only one that did not reach the criteria of pituitary origin.

3.2. Outcome

In our study, 29 of 42 patients (69.0%, 22 recurrent and 7 persistent cases of CD) were in remission after the repeat operation without additional therapy during follow-up (Table S1). At follow-up, compared with patients with persistent disease, the recurrence group had a higher remission rate, although the difference was not significant (77.8% [21/27] vs. 57.1% [8/15]; p > 0.05; odds ratio = 2.625, 95% confidence interval = 0.651 to 10.586). Negative preoperative MRI findings were not associated with lower odds of immediate remission after repeat surgery (p > 0.05; odds ratio = 3.667, 95% confidence interval = 0.920 to 14.622; Table 2).

Table 2. The remission rate of the recurrent and persistent hypercortisolism patients with or without positive MRI findings.

3.3. Association between Outcomes and MRI Findings

The remission rates of the persistent and recurrent disease groups with positive and negative MRI findings prior to the second procedure are shown in Table 2. Twenty-nine patients whose MRI findings revealed the existence of pituitary adenomas achieved successful outcomes after reoperation (Representative case, #19, Figure 2). The other seven patients who experienced recurrent or persistent hypercortisolism without clear imaging evidence of tumor appearance also benefited from reoperation (Representative case, #11, Figure 3).

Figure 2. Preoperative and postoperative MR images of the two operations (A–D) demonstrate an in situ relapsed intrasellar mass (yellow arrow). Biochemical results obtained before and after the operations (E) show the tumor-related hormone change. KCZ, ketoconazole; MR, magnetic resonance.

Figure 3. MR images (A) demonstrated a pituitary microadenoma on the left side (yellow arrow) before the first operation but not at the subsequent follow-ups (B,C). The biochemical results obtained before the second operation (D) revealed hypercortisolism indicating relapse without obvious MRI confirmation. MR, magnetic resonance; MRI, magnetic resonance imaging.

3.4. Pathology

Respectively, 15/27 (55.6%) and 7/15 (46.7%) patients with recurrent and persistent hypercortisolism had ACTH-positive staining in the first pathological findings. Among patients who achieved remission after the second operation, 20 of 29 patients had confirmed adenoma with positive ACTH pathological staining, while 3 patients with adenoma were ACTH-negative. There were five patients that did not achieve remission even though they had positive ACTH-staining adenoma in the second pathological examination. Meanwhile, five patients achieved remission, although no adenomas were found in their pathological specimens. Overall, positive pathology after either the initial or repeated surgery was not a significant predictor for remission after the second surgery.

3.5. Complications

Four of forty-two patients experienced major postoperative complications and underwent medical or surgical interventions. Most patients recovered well after the second operation, except in one case with persistent hypercortisolism, where a severe intracranial infection led to death. Another three cases with cerebral spinal fluid leakage related to the second operation were successfully surgically repaired afterwards.

Hypopituitarism was a common complication in this subgroup of CD. All of the patients in remission after the second TSS underwent glucocorticoid replacement therapy (hydrocortisone or cortisone), adjusted according to the 24 h UFC. A total of 20 patients (20/29, 68.9%) underwent thyroxine replacement therapy. Three patients (3/29, 10.3%) had permanent diabetes insipidus. In the non-remission group, five patients (5/13, 38.5%) experienced hypothyroidism, and two patients (2/13, 15.4%) had permanent diabetes insipidus.

4. Discussion

In the present study, we reported outcomes for 42 patients undergoing repeat TSS for recurrent and persistent disease in which an overall remission rate of 69.0% was achieved. Immediate remission rates after reoperation for recurrence have been reported in the literature up to 87% [13,14], which is similar to those of other second-line therapies such as radiation therapy and medical treatment. The CD recurrence rate after the initial TSS is reportedly 10–25% with a follow-up time of 10 years [15,16,17]. Ram et al. reported that surgeons performed a second TSS immediately after the first TSS when the postoperative serum cortisol level did not meet the standard level of remission. With an interval time of 1 to 6 weeks, 71% of patients with persistent disease achieved immediate remission, and 53% (9/17) achieved long-term remission [13]. Another study showed a remission rate of 70% with reoperation performed within 10 days [18]. A second TSS reportedly leads an additional 8% of patients to long-term CD remission [3]. Recurrence groups had slightly higher remission rates, which are insignificant when compared with persistent groups in the present study. Similar findings are demonstrated in the study by Ram et al. implicating that failure of the initial surgery suggested that the patient was more difficult to treat successfully with surgery than most patients with recurrence [13]. Therefore, the selection criteria for potential patients and reoperation strategies require further discussion.

4.1. Surgical Strategy

The surgical strategy for the initial CD surgery varies depending on the major concerns of different pituitary surgeons. Some surgeons intend to preserve more normal gland tissue during surgery while others chase higher remission rates. Selective adenectomy is a reasonable choice for visible tumors. Several authors adopted a slightly extended resection with a rim or sometimes 2–3 mm of like-normal tissue around the tumor, which could be considered a partial hypophysectomy [19,20]. A hemi-hypophysectomy is more common in cases in which no tumor was identified during the operation, and the MRI or BIPSS results indicated remarkable lateralization of the tumor origin [21]. Wide exploration of the contralateral side should also be conducted in cases in which BIPSS results are inconsistent with the MRI findings, which may help identify tiny tumors. More extensive procedures, including subtotal or sometimes total pituitary gland resection, have been performed to maximize remission rates up to 75.9–81.8% [20,22], which may be a reasonable recommendation when imaging/intraoperative findings are not definitive, considering the negative impacts on reoperated patients with persistent hypercortisolism rather than hypopituitarism. Interestingly, pathological confirmation rates are fairly low in cases with extended resection even though they show high remission rates. There seems to be a current trend of surgeons performing a partial hypophysectomy, as a total hypophysectomy can lead to hypopituitarism [5,22,23], given that it may not obviously increase remission rates and may decrease quality of life [24].

4.2. MRI Findings

Regarding radiological findings, we emphasize that negative MRI findings do not necessarily indicate the inexistence of pituitary adenomas or negative pathological results. A number of cases in the study by Wagenmakers et al. showed that remission achieved after repeated transsphenoidal surgery was not predictable by positive MRI findings before the first or second operation [10]. Preoperative MRI provides a reference for the diagnosis of pituitary adenomas, although it has a limited predictive function for patient prognosis [9], especially for the repeat operation in which the original anatomical structure was more or less destroyed in the initial surgery. A positive MRI finding before the second operation should promote confidence in surgeons. The remission rate after reoperation with positive MRI findings was reportedly as high as 72.7% [10]. According to our study, the two positive-MRI groups with different initial surgical outcomes showed higher remission rates, albeit insignificantly. Positive MRI findings suggest better endocrinological outcomes may be achieved by a second operation in both recurrent and persistent disease groups compared with patients with negative imaging findings. An excellent remission rate (more than 80%) was achieved in the recurrent group with positive MRI findings, thus encouraging a repeat TSS. An acceptable remission rate (over 60%) close to those of alternative treatment options was observed in the recurrent group with negative MRI findings, as well as the persistent group with positive MRI findings. We noted that one patient with persistent CD and negative MRI findings achieved remission after reoperation. Therefore, whether a second surgical treatment is beneficial for these patients should be carefully considered.

Regarding the recurrent or persistent cases of CD, patients underwent an initial surgery, and we regarded the MRI findings as a possible method to assist in decision making. A second operation is considered when visible lesions remain on MRI under the assumption that removal of the residual tumor leads to remission of the disease. Meanwhile, some recurrent and persistent patients with negative MRI findings also benefited from reoperation. Furthermore, MRI has its limitations in revealing the accurate structures of the originally operated area. The distortion and cicatrization from the previous operation and material packing in the sellar region lead to confusion [12,25]. Unlike the considerable remission rate achieved after the initial operation despite negative MRI findings, reoperation without certain lesion detection on MRI is associated with dissatisfactory remission rates [1], similar to the results of our study. Nevertheless, Knappe and Lüdecke [9] presented a different opinion regarding the significance of MRI findings and reported that it was not usually helpful for determining therapeutic strategies due to its low incidence of detecting existing microadenomas (missed diagnosis in 38–70% of cases). However, the BIPSS results in these cases in which MRI revealed no definitive information on tumors are therefore critical for surgeons to ascertain the pituitary origin of the disease, although another study suggested that MRI and BIPSS do not help locate recurrent tumors [10]. MRI may not help identify tumors in the cavernous sinus or other parasellar regions.

4.3. Pathology

We compared the pathological results and remission situations of recurrent patients and persistent patients and failed to find any relationship between pathological results and remission expectations. These findings are supported by the findings of Ram et al. [13], in which no tumors were found in 11 of 17 patients during the second procedure, and 6 of 11 patients achieved remission. In a series by Locatelli et al. [11], no tumors were found in 8 of 12 patients during the second operation, and 5 had surgical remissions. Even in cases of remission, the positive rate of pathological exams was not as high as expected. There was no significant difference in remission rates between patients grouped by pathological results or one-to-one correspondence between histopathological confirmation and surgical outcomes [11]. To date, little evidence supports the prediction of reoperation outcomes by either of the two pathology results.

4.4. Other Considerations and Factors

In patients with recurrent and persistent hypercortisolism after their first operation, it was difficult to identify solid lesions on MRI compared with the initial preoperative scans. Notably, BIPSS may provide more information, especially for patients who did not undergo this test before the first operation. Moreover, it may help avoid unnecessary repeat TSS in patients with persistent hypercortisolism by revealing false positives for pituitary ACTH overproduction. BIPSS results have the potential to not only confirm the pituitary origin of the condition (despite the fact that the first histological examination did not show ACTH-positive staining) but also to guide exploration and decision making for a hemi-hypophysectomy or accessing the cavernous sinus, especially for patients without obvious tumors identified intraoperatively. Careful dissection is highly recommended on the side of the obviously lateralized BIPSS results, which sometimes also indicate cavernous sinus invasion not shown on MRI and the necessity of opening the medical wall to achieve extended exploration. The predictive value of BIPSS lateralization in repeated surgery requires further investigation, although it is not optimal in native patients with CD [26].

According to a study by Lonser et al. [27], over 20% of CD patients had cavernous sinus invasion that was confirmed histologically. The authors advocated for complete resection, including the invaded sella dura and medial cavernous sinus wall by an experienced surgeon’s hands. Notably, endoscopy with magnification and lighting provides a panoramic view to facilitate extended exploration of the sella, including the cavernous sinus, compared with the microscope-based approach. Micko et al. demonstrated that an endoscope allows for a radical inspection of the entire medial wall of the cavernous sinus [28] and increases the lateral angle of visualizations to facilitate differentiation between tumor tissues and other tissues. These advantages over the microscopic transsphenoidal approach are critical for recurrent and unremitted cases; however, further studies with larger sample sizes are needed to verify this conclusion.

4.5. Other Adjunctive Treatments to Repeat Surgery

Previous studies have noted that ketoconazole may contribute to enhanced tumor appearance on MRI to facilitate pituitary resection in some circumstances [29]. Castinetti et al. reported that visible lesions may be identified on MRI in one-third of patients who were administered ketoconazole [30].

In the literature, reoperation for persistent cases without visible lesions on MRI is rarely satisfactory [31], although these patients may benefit from radiosurgery using the entire sellar region as the therapeutic target [32]. The hormonal normalization was achieved after radiosurgery in half of the cases, including those with negative MRI findings [33]. In general, the radiosurgery outcomes and the less commonly used radiotherapy are more favorable, particularly in MRI-negative cases with persistent hypercortisolism compared with repeat surgery, with potentially fewer complications and a shorter length of hospital stay [34,35]. Salvage TSS for refractory CD after radiation therapy has rarely been reported [36] owing to the difficulty of disrupting surgical landmarks, the formation of scar tissue, and the effects of preoperative radiotherapy [34].

Bilateral adrenalectomy is generally considered the ultima ratio in patients who fail to respond to other treatment options. However, patients who undergo bilateral adrenalectomy will require lifelong surveillance of the corticotroph tumor’s progression, which may lead to Nelson’s syndrome, via MRI and ACTH measurements. Most experts agree that selective transsphenoidal adenomectomy should be recommended as the first-line therapy in patients with Nelson’s syndrome before extrasellar expansion of the tumor occurs [37].

4.6. Limitations

Similar to previous studies, our sample size was not large enough to conduct powerful statistical analyses. Some patients lost during follow-up limited the evaluation of long-term outcomes in the current study. We observed a trend in the predictable values of positive preoperative MRI findings, which is not enough evidence to support an apparent relationship. A potential weakness of the present study is that the outcome was only focused on the biochemical benefits of remission after surgical intervention, possibly leading to an underestimation of the risks of hypopituitarism and decreased quality of life. Indeed, larger case series are needed to further investigate the potential predictive factors and best surgical strategy.

5. Conclusions

Patients with initial surgical treatment may experience hypercortisolism without positive MRI findings in both recurrent and persistent disease. Our findings suggest that for most patients who experience recurrent or persistent CD, reoperation should be an option even with negative MRI findings. However, further comprehensive investigation on recurrent or persistent CD patients is required. Larger groups of surgically treated CD patients with long follow-up periods should be evaluated to improve reoperation outcomes and determine the appropriate selection criteria for repeat surgery, especially for persistent CD patients.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm11226848/s1, Table S1. Preoperative and postoperative evaluation of the repeated surgery of 42 patients.

Author Contributions

B.W. and Y.S. contributed to the study’s conception and design. S.Z. drafted the manuscript. J.R., Z.Z., H.J., Q.S., T.S. and W.W. contributed to data acquisition, analysis, and interpretation. B.W. and Y.S. critically revised the manuscript for important intellectual content. Y.S. and L.B. accept final responsibility for this article. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported in part by the National Natural Science Foundation of China (82000751) and the Shanghai Sailing Program (20YF1438900).

Institutional Review Board Statement

This study involving human participants was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards and was approved by the Ruijin Hospital Ethics Committee of Shanghai Jiao Tong University School of Medicine (approval number 2020-64).

Informed Consent Statement

The need for individual consent was waived by the Ethics Committee owing to the retrospective nature of the study.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further enquiries may be directed to the corresponding authors.

Conflicts of Interest

The authors have no relevant financial or non-financial interests to disclose.

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From https://www.mdpi.com/2077-0383/11/22/6848

• From 

  https://seekingalpha.com/news/3915421-cort-stock-on-watch-after-patent-settlement-with-hikma-for-korlym

The study covered in this summary was published on researchsquare.com as a preprint and has not yet been peer reviewed.

Key Takeaways

• The hypothalamic-pituitary-adrenal (HPA) axis recovered in nearly three quarters of patients with Cushing disease (CD) within 2 years after successful trans-sphenoidal surgery (TSS), with a median recovery time of 12 months.

• Preoperative total triiodothyronine (TT3) level appears to be an independent predictor of central adrenal insufficiency (CAI) in CD patients with biochemical remission post surgery.

Why This Matters

• Transient CAI typically occurs after successful TSS, requiring physiologic hydrocortisone replacement until HPA recovery.

• Inadequate replacement may result in glucocorticoid withdrawal symptoms, including adrenal crisis, while overreplacement could lead to glucocorticoid side effects.

• Findings have been inconsistent regarding recovery time in CD patients and factors predicting HPA axis recovery.

• The new findings could help clinicians predict HPA axis-function recovery time and adjust cortisone replacement treatment in postoperative CD patients.

Study Design

• The retrospective study included 140 patients with biochemical remission following CD surgery at a single institution from 2014–2020.

Key Results

• The HPA axis in 103 patients (73.6%) recovered during 2 years' postsurgical follow-up. In 57 patients (55% of this subgroup), it recovered within 12 months.

• Patients were considered to have recovered if they achieved central adrenal sufficiency (CAS). These patients were significantly younger and had significantly lower midnight levels of adrenocorticotrophic hormone at baseline than those with persistent CAI.

• The researchers found no significant differences in gender, disease duration, maximal tumor diameter, or history of surgery between the two groups at the time of their diagnosis with CD.

• Both TT3 and free triiodothyronine levels were significantly lower in patients with persistent CAI vs CAS.

• There were no significant differences between the two groups in other laboratory parameters, surgical approach, or extended compared with nonextended resection, but more patients in the persistent CAI group underwent partial hypophysectomy.

• In a multiple logistic regression analysis, TT3 levels at diagnosis independently and significantly predicted HPA recovery at 2-year follow-up post surgery after adjustment for gender, age, duration at diagnosis, maximum tumor diameter, history of surgery, surgical approach (endoscopic or microscopic transsphenoidal surgery), adenomectomy range, and the minimal serum cortisol level within the first 7 postoperative days.

• Among the 37 patients with persistent CAI at 2 years, 23 (62%) had multiple pituitary axis dysfunctions, including hypothyroidism (19 patients), hypogonadism (19), and central diabetes insipidus (5).

Limitations

• This retrospective study could not prove the causality of TT3 level for influencing recovery of the HPA axis. However, the number of enrolled patients was relatively large, and follow-up was regular ― factors that make the conclusion credible and representative, the authors said.

Disclosures

• The study received no commercial funding.

• The authors had no disclosures.

This is a summary of a preprint research study, "The Recovery Time of Hypothalamic-Pituitary-Adrenal Axis After Curative Surgery in Cushing’s Disease and Its Predictor," by researchers at Huashan Hospital Fudan University, Shanghai, China, published on Research Square and provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.

Somehow, things don't "count" without a big clinical trial that costs someone $$$.

AARRGGHH!

Have they done multiple tests over many weeks to see if it could be cyclical Cushing's?

Abstract

Introduction

Neuroendocrine carcinomas (NECs) are heterogenous groups of tumors derived from neuroendocrine cells. NECs of the cervix are rare and account for 1-2% of all cervical carcinomas, with the small-cell variant being the most common [1,2]. Small-cell NECs have a high rate of lymphatic and hematogenous metastasis even when the carcinoma is limited to the cervix. Patients usually present at a late stage, with the extra-pelvic disease being apparent at the time of diagnosis [2]. Among the different histologic variants of NEC of the cervix, the small-cell variant has the highest rate of recurrence [3]. Adrenocorticotropic hormone (ACTH)-secreting tumors of the cervix are rare [4]. We present a case of recurrent metastatic NEC of the cervix five years after the original diagnosis of NEC of the cervix, now presenting with Cushing’s syndrome [1,2].

Case Presentation

A 39-year-old female with a history of recurrent small-cell cervical cancer presented to the emergency department (ED) of our hospital with complaints of weight gain, generalized facial edema, lightheadedness, tingling sensation of her entire face, bilateral leg edema, and abdominal distention.

Her problems started a month prior to her ED visit, when she started to complain of abdominal distention. She had a computed tomography (CT) abdomen with contrast, which revealed evidence of metastatic disease, including multiple large liver lesions (Figure 1). Subsequently, she had a positron emission tomography (PET) scan, which confirmed the presence of hypermetabolic lesions in the right peritonsillar tissue, liver, right lower quadrant of the abdomen, and bilateral pulmonary nodules with lymphadenopathy in the left hilum (Figure 2). A liver biopsy was done, with the final pathology consistent with recurrent NEC of the cervix. She was started on cisplatin, etoposide, and atezolizumab by gynecologic oncology but started to develop facial swelling and progressive abdominal distention, prompting this ED consult and subsequent admission.

Figure 1: Abdomial CT with contrast done one month prior showed evidence of metastatic disease including multiple large liver lesions.

 

 

Figure 2: PET/CT demonstrated the presence of hypermetabolic lesions in the liver and right lower quadrant of the abdomen.

 

 

She had a significant medical history of being diagnosed with cervical cancer (FIGO stage 1B2 NEC) five years prior by gynecologic oncology, at which time she underwent concurrent chemo-radiation followed by surgical assessment of her pelvic lymph nodes with robotic pelvic lymph node dissection and bilateral ovarian transposition to avoid premature menopause. She was subsequently treated with cisplatin and pelvic radiation. She had a follow-up cervical biopsy several months after chemotherapy, which showed persistent NEC, but her PET scan showed no evidence of metastatic disease. After undergoing a robotic total laparoscopic hysterectomy, the final pathology showed a persistent microscopic focus of NEC of the cervix with negative margins. She received adjuvant chemotherapy with cisplatin and etoposide for six cycles with regular follow-up pap smears and annual PET scans, with no evidence of recurrence for five years.

On admission, her vital signs were: blood pressure = 129/79 mm Hg, pulse rate = 85/min, respiratory rate = 18/min, and temperature = 98.5 °F (36.9 °C). Her physical examination was notable for moon facies (a noticeable change from her pictures as recent as two months prior), supraclavicular and dorsocervical fat pads, multiple bruises on her arms, edema of her face and legs, acne of her face and neck, and hair growth of her chin area. No purple striae were seen on the abdomen.

Laboratory tests revealed leukopenia and thrombocytopenia (which were attributed to her chemotherapy), recently diagnosed diabetes (occasional hyperglycemia and HbA1c 7.7%), and electrolyte imbalances (hypokalemia and hypophosphatemia) (Table 1).

Sodium	142 mEq/L (135–145 mEq/L)
Potassium	2.0 mEq/L (3.5–5.0 mEq/L)
Chloride	98 mEq/L (98–108 mEq/L)
CO2	35 mEq/L (21–32 mEq/L)
Anion gap	9 mEq/L (8–16 mEq/L)
BUN	14 mg/dL (7–13 mEq/L)
Creatinine	1.13 mg/dL (0.6–1.1 mg/dL)
Glucose	460 mg/dL (74–100 mg/dL)
Calcium	7.8 mg/dL (8.5–10.1 mg/dL)
Phosphorous	1.0 mg/dL (2.5–4.5 mg/dL)
Albumin	2.5 mg/dL (3.1–4.5 mg/dL)
AST	43 U/L (15–27 U/L)
ALT	76 U/L (12–78 U/L)
White blood cell count	0.6 k/cmm (4.5–10.0 k/cmm)
Red blood cell count	3.55 million cells/μL (3.7–5 × 2)
Hemoglobin	11.9 g/dL (12.0–16.0)
Hematocrit	34.3% (35.0–47.0)
Platelet	45 k/cmm (150–440 k/cmm)

Table 1: Initial laboratory work showed leukopenia, thrombocytopenia, hyperglycemia, hypokalemia, and hypophosphatemia.

AST: aspartate aminotransferase, CO₂: carbon dioxide, BUN: blood urea nitrogen, ALT: alanine aminotransferase.

 

Her chest X-ray showed bilateral pleural effusions. Magnetic resonance imaging (MRI) of the brain showed no evidence of pituitary masses, abnormalities, or metastatic disease in the brain. A CT of the chest showed new bilateral non-calcified lung nodules when compared to the previous PET scan, pathologic-sized left hilar adenopathy, and multiple peripherally enhancing hepatic nodules and masses (Figure 3). The adrenal glands were unremarkable. Workup for facial swelling and bilateral leg edema showed no evidence of superior vena cava (SVC) syndrome on both her chest CT and transthoracic echocardiogram.

Figure 3: Contrast-enhanced chest CT showing bilateral noncalcified lung nodules.

 

 

She was admitted to the intensive care unit (ICU) and started on empiric antibiotics and filgrastim for neutropenia. Replacement therapy for both hypokalemia and hypophosphatemia was given. After both electrolytes were normalized, the patient was started on basal-bolus insulin therapy.

Based on her clinic presentation of excessive weight gain, new-onset hyperglycemia, hypertension with hypokalemia, and a history of NEC, suspicion of Cushing’s syndrome was high. Further workup showed elevated serum cortisol after 1 mg overnight dexamethasone suppression, elevated 24-hour urine cortisol, and elevated midnight salivary cortisol, which confirmed Cushing’s syndrome (Table 2). ACTH was also elevated, but dehydroepiandrosterone sulfate (DHEAS) was normal. Thyroid function tests showed a slightly low free thyroxine, but this was attributed to an acute illness.

HgbA1C	7.7%	(4.0-6.0%)
ACTH	1207 pg/mL	(7.2–63.3 pg/mL)
24-hour urine cortisol	7070 μg/24 hr	(6–42 μg/24 hr)
Salivary cortisol	>1.000 μg /dL	(0.025–0.600 μg/dL)
Serum cortisol after 1 mg overnight dexamethasone suppression	143.0 μg/dL	(3.1–16.7 μg/dL)
Total testosterone	77 ng/dL	(14–76 ng/dL)
DHEAS	250.0 μg/dL	(57.3–279.2 μg/dL)
Chromogranin A	970.9 ng/mL	(0.0–101.8 ng/mL)
TSH	0.572 mIU/L	(0.358–3.74mIU/L)
Free T4	0.70 ng/dl	(0.76–1.46) ng/dl

Table 2: Work up showed elevated ACTH, elevated 24-hour urine cortisol, elevated salivary cortisol, and elevated serum cortisol after 1 mg overnight dexamethasone suppression test.

HgbA1C: hemoglobin A1C; ACTH: adrenocorticotropic hormone; DHEAS: dehydroepiandrosterone sulfate; TSH: thyroid stimulating hormone; free T4: free thyroxine.

 

A diagnosis of Cushing's syndrome due to metastatic small-cell neuroendocrine carcinoma of the cervix was assumed. A bilateral adrenalectomy, which is the definitive treatment of hypercortisolism when surgical removal of the source of excess ACTH is done, was not done because gynecologic oncology wanted to treat her with chemotherapy urgently due to her metastases and the nature of the disease and felt that surgery and recovery would delay the start of chemotherapy. Ketoconazole was felt to be a poor choice in the setting of liver metastases with worsening liver function tests. The patient was thus started on mifepristone 300 mg daily, as it is indicated for hypercortisolism secondary to endogenous Cushing’s syndrome with diabetes. Nephrology was consulted, and potassium supplementation was transitioned to oral potassium chloride 40 meq tablets four times a day; spironolactone 50 mg twice daily was added for the hypokalemia and hypertension, which occurred after the patient started bevacizumab. Hypokalemia is a common side effect of mifepristone therapy due to the glucocorticoid receptor blockade, which leads to cortisol's spillover effect on unopposed mineralocorticoid receptors. She was discharged home with a basal-bolus insulin regimen.

Her posthospitalization course was complicated by compression fractures of her lumbar spine one week after discharge with no history of falls. An MRI of the spine showed chronic compression fractures of the T11-L3 vertebral bodies with no evidence of osseous metastatic disease. Dual-energy X-ray absorptiometry (DXA) scan interpretation demonstrated osteoporosis. Vertebral fracture assessment showed morphometric fractures in the lower thoracic and upper lumbar vertebrae. She was subsequently treated with IV administration of 5 mg of zoledronic acid. She was also readmitted multiple times after her initial admission due to the patient's developing neutropenic fever, which was treated with filgrastim and antibiotics.

After starting mifepristone, her glycemic control improved to the point that insulin therapy could be subsequently discontinued. Her liver enzymes normalized, and ketoconazole was subsequently added for adjunct therapy to treat hypercortisolism, but the dose could not be optimized due to persistently elevated liver function tests. Hypokalemia management and resistant hypertension were additional challenges encountered by this patient.

At her follow-up visits, she had notably lost weight with the improvement of her leg edema. She continued to follow up with a nephrologist on an outpatient basis, and her normal potassium levels were normal on 40 meq of oral potassium chloride tablets four times a day and spironolactone 150 mg twice a day. She was followed up closely by her gynecologic oncologist and was on bevacizumab, topotecan, and paclitaxel before her unfortunate demise a few months later.

Discussion

Cushing’s syndrome due to ectopic ACTH secretion only represents 9-18% of cases. Most primary endocrine tumors responsible for ectopic ACTH secretion are located in the chest [5]. Abdominal and retroperitoneal neuroendocrine tumors are the second- and third-most reported sites [5]. Neuroendocrine tumors of the cervix are incredibly rare [6-9].

A unique feature of this case is that the patient presented with Cushing’s syndrome due to neuroendocrine tumor metastases found five years after the primary site of the tumor was resected. For this patient, a biopsy of the liver confirmed a metastatic neuroendocrine tumor, but it is unknown if the other sites of metastases are implicated in the production of excess ACTH.

The management of this disease focuses on controlling hypercortisolism, consequent hyperglycemia, and hypokalemia. Surgical excision of ACTH-secreting neuroendocrine tumors is the most effective, but in cases where that is not possible, bilateral adrenalectomy and medical treatment are the next best treatments for this disease entity [10]. For this patient, bilateral adrenalectomy was not done as gynecologic oncology wanted to treat her with chemotherapy urgently due to the metastases and nature of the disease and felt that surgery and recovery would delay the start of chemotherapy.

We provided medical management for the patient’s hypercortisolism. Pharmacological therapy for hypercortisolism can be categorized into immediate-acting steroidogenesis inhibitors (metyrapone, ketoconazole, and etomidate), slow-acting cortisol-lowering drugs (mitotane), and glucocorticoid receptor antagonists (mifepristone) [5]. We initially chose mifepristone because it is indicated in patients with type 2 diabetes mellitus and could be given safely despite the patient’s worsening liver function levels [11].

As demonstrated, the management of recurrent hypokalemia proved challenging in this patient. The phenomenon is well known to be induced by ectopic ACTH. Several mechanisms contribute to this. Activation of renal tubular type 1 (mineralocorticoid) receptors by cortisol is thought to be the mechanism that applies mainly to patients with severe hypercortisolism due to ectopic ACTH secretion. Additionally, there may also be an increase in the production of renin substrate from the liver. The high serum cortisol concentrations may not be completely inactivated by 11β-hydroxysteroid dehydrogenase type 2 in the kidney and overwhelm its ability to convert cortisol to cortisone, resulting in activation of mineralocorticoid receptors resulting in potassium loss in the distal tubules [12]. Hypokalemia may also result from adrenal hypersecretion of mineralocorticoids, such as deoxycorticosterone and corticosterone. This can also be amplified by mifepristone, as it is a glucocorticoid receptor antagonist that increases circulating cortisol levels [12].

Complications such as hypokalemia, hyperglycemia, acute respiratory distress syndrome, infections, muscle wasting, hypertension, and bone fractures can occur and can arise at any time throughout the course of the disease when urine-free cortisol is fivefold or more above the upper limit of normal [5]. Ketoconazole was initially considered for medical treatment, but due to mildly elevated liver enzymes during the initial presentation, we decided to use mifepristone instead. A small cohort study showed that severe hypercortisolism and increased baseline transaminase levels could be due to cortisol-induced hepatic steatosis [13]. Later in her course, ketoconazole was added to her mifepristone therapy to decrease adrenal cortisol production. Unfortunately, her dose could not be increased due to the patient's persistently elevated liver enzymes.

Recurrent pancytopenia due to chemotherapy contributed to the protracted nature of this patient’s clinical course. Due to cortisol's immunosuppressive and anti-inflammatory effects, opportunistic infections can arise [14]. Since her initial hospitalization, she has been readmitted several times due to neutropenic fever, which was treated with filgrastim and antibiotics.

Conclusions

Ectopic Cushing’s syndrome due to metastatic neuroendocrine small-cell carcinoma is a rare condition with a poor prognosis. The options for treatment are few and not necessarily curative. There needs to be increased awareness of this serious and rare complication. Managing the condition can be a challenge and requires a multidisciplinary team approach to improve outcomes.

References

Objective: This extended evaluation (EE) of the SONICS study assessed effects of levoketoconazole for an additional 6 months following open-label, 6-month maintenance treatment in endogenous Cushing’s syndrome.

Design/Methods: SONICS included dose-titration (150–600 mg BID), 6-month maintenance, and 6-month EE phases. Exploratory efficacy assessments were performed at Months 9 and 12 (relative to start of maintenance). For pituitary MRI in patients with Cushing’s disease, a threshold of ≥2 mm denoted change from baseline in largest tumor diameter.

Results: Sixty patients entered EE at Month 6; 61% (33/54 with data) exhibited normal mean urinary free cortisol (mUFC). At Months 9 and 12, respectively, 55% (27/49) and 41% (18/44) of patients with data had normal mUFC. Mean fasting glucose, total and LDL-cholesterol, body weight, body mass index, abdominal girth, hirsutism, CushingQoL, and BDI-II scores improved from study baseline at Months 9 and 12. Forty-six patients completed Month 12; 4 (6.7%) discontinued during EE due to adverse events. The most common adverse events in EE were arthralgia, headache, hypokalemia, and QT prolongation (6.7% each). No patient experienced ALT or AST >3× ULN, QTcF interval >460 msec, or adrenal insufficiency during EE. Of 31 patients with tumor measurements at baseline and Month 12 or follow-up, largest tumor diameter was stable in 27 (87%) patients, decreased in 1, and increased in 3 (largest increase 4 mm).

Conclusion: In the first long-term levoketoconazole study, continued treatment through 12-month maintenance period sustained the early clinical and biochemical benefits in most patients completing EE, without new adverse effects.

Read the whole article at https://eje.bioscientifica.com/configurable/content/journals$002feje$002faop$002feje-22-0506$002feje-22-0506.xml?t%3Aac=journals%24002feje%24002faop%24002feje-22-0506%24002feje-22-0506.xml&body=pdf-45566

What Is the Role of “Growth Hormone” When You Have Stopped Growing?

Growth hormone clearly plays a key role in development during youth, but research in adults implicates it as an agent in cellular aging processes. Shlomo Melmed, MD, ChB, the first recipient of the Transatlantic Alliance Award, co-sponsored by the Endocrine Society and the European Society of Endocrinology, discusses the misconceptions of administering growth hormone in adults.

Children need growth hormone to grow into their adult height, but the hormone’s function among adults is unclear. The pituitary secretes less growth hormone as a person ages, but new research is elucidating a potentially important role for nonpituitary growth hormone generated in the periphery in regulating cellular proliferation associated with aging.

Unraveling the effects of this mysterious hormone has been a focus of the work of Shlomo Melmed, MB ChB, dean of the faculty of medicine at Cedars-Sinai in Los Angeles. Melmed is the inaugural winner of the Transatlantic Alliance Award, an honor co-sponsored by the Endocrine Society and the European Society of Endocrinology to recognize an international leader who has made significant advancements in endocrine research on both sides of the Atlantic. As part of the award, Melmed gave a presentation at both ENDO 2022 in Atlanta in June, and at the European Congress of Endocrinology 2022 in Milan entitled, “Growth Hormone: An Adult Endocrine Misnomer?”

Dangers of Too Little or Too Much

The growth hormone level declines dramatically with age such that it is barely detectable in the circulation by age 80, but even at low levels it is clearly playing an important role. “Adults deficient in pituitary growth hormone have a unique phenotype,” Melmed says. “They develop central obesity and may have high blood pressure and lethargy. Growth hormone in adulthood is needed to maintain body homeostasis, i.e., the appropriate ratio between lean body mass and fat mass. When these GH-deficient adults [receive] very low doses of growth hormone, body changes are recalibrated and homeostatic changes that occur with hormone deficiency may be reversed.”

On the other hand, the deleterious effects of too much growth hormone from an over-secreting pituitary adenoma are well-known. “Patients with acromegaly have phenotypic features often associated with aging,” Melmed says. “They have heart disease, diabetes, hypertension, and osteoporosis, and may develop tumors. Many afflictions of aging are present, and the linkage of too much growth hormone with adverse effects on the aging process is clinically intuitive.”

Nonpituitary Growth Hormone

However, evidence is mounting that growth hormone that originates not from the pituitary but in the periphery could have significant effects. Melmed and others have been conducting cellular, animal, and human studies on the effects of autocrine and paracrine growth hormone.

“We found that growth hormone locally suppresses p53, thereby unleashing the cell to become more pro-proliferative. We performed a series of cellular and animal experiments to show that the molecular profile of aging may be accelerated by increasing growth hormone signaling, and if you block growth hormone action you may suppress deleterious aging effects on the cell cycle, including attenuation of DNA repair.”

Shlomo Melmed, MB ChB, dean, faculty of medicine, Cedars-Sinai, Los Angeles, California

For example, the hormone appears to be produced by the epithelial cells of the colon and neighboring cells, where it acts locally to activate the growth hormone receptor, to engender cell cycle changes and DNA damage, and to promote pro-proliferative changes, Melmed says. One of its most important actions may be to inhibit the tumor suppressor gene p53, which is a powerful constraint on cell proliferation and tumor formation. “We found that growth hormone locally suppresses p53, thereby unleashing the cell to become more pro-proliferative,” Melmed says.

“We performed a series of cellular and animal experiments to show that the molecular profile of aging may be accelerated by increasing growth hormone signaling, and if you block growth hormone action you may suppress deleterious aging effects on the cell cycle, including attenuation of DNA repair,” Melmed says.

For example, their experiments showed that the drug pegvisomant, a growth hormone receptor inhibitor used to treat patients with acromegaly, can elevate p53 levels and enable a protective environment in the colon epithelium. “The role of growth hormone in regulating proliferation of colon cells could explain why patients with acromegaly have an abundance of colon polyps,” he tells Endocrine News.

Evidence from Families

Melmed says that other tantalizing clues implicating growth hormone in aging include the pioneering work of Endocrine Society Koch Awardee Anderzj Bartke, who showed that GH-deficient mice live longer. Furthermore, a Netherlands study of the relatives of centenarians found that these long-lived individuals and their family members have very low growth hormone levels.

There have also been studies of several families around the world who have inactivating growth hormone receptor mutations with short stature and an extremely low incidence of cancer. “We re-introduced a normal growth hormone receptor into the mutated fibroblasts, and down-regulated their high p53 expression, another proof of principle in humans that local growth hormone may enable a pro-proliferative micro-environment,” Melmed says.

“We propose, based upon the body of cellular, animal, and human data that have been generated by other colleagues and ourselves, that blocking growth hormone action may protect from adverse cellular effects of aging. We have no evidence that aging could be reversed, but blocking growth hormone signaling could mitigate pro-proliferative cell cycle events and DNA damage associated with aging,” Melmed says.

“Adults deficient in pituitary growth hormone have a unique phenotype. They develop central obesity and may have high blood pressure and lethargy. Growth hormone in adulthood is needed to maintain body homeostasis, i.e., the appropriate ratio between lean body mass and fat mass. When these GH-deficient adults [receive] very low doses of growth hormone, body changes are recalibrated and homeostatic changes that occur with hormone deficiency may be reversed.”

He notes that these findings have an immediate practical application as a counter to the large illicit market in which people, especially athletes, are taking growth hormone as a performance-enhancing drug “in an attempt to enhance athletic performance or to improve their longevity” when the evidence indicates that “the opposite is true, and growth hormone may in fact be harmful.”

Seaborg is a freelance writer based in Charlottesville, Va. He wrote about the Endocrine Society’s latest Clinical Practice Guideline, “Management of Hyperglycemia in Hospitalized Adult Patients in Non-Critical Care Settings: An Endocrine Society Guideline,” in the July issue.

From https://endocrinenews.endocrine.org/an-adult-endocrine-misnomer/?fbclid=IwAR0EIssqVRbv9SYloB5tHVIqIeQ6J7xjYYFgbszWVTX4eWS0uUWJShWPVKA

Study Design

 

Go to  

More info at https://clinicaltrials.gov/ct2/show/record/NCT05307328

Tumor samples from prior surgeries were available from one TP53 mutant case (#8, Table 1). This male patient had his first pituitary surgery for CD when he was 30 years old and was treated with γ-knife one year later. He then underwent two more pituitary surgeries and BADX until the age of 35. He developed CTP-BADX/NS with para- and retrosellar tumor extension along with panhypopituitarism and underwent two more pituitary surgeries before dying at the age of 38 due to complications of the disease. We detected the TP53 variant c.1009C > G (p.Arg337Gly) in all available tumor specimens, including his first and latest surgeries (Additional file 1: Supplementary Fig. 1B).

No statistical association was found between clinical data and any of the 8 common variants.

Characteristics of TP53 mutant corticotroph tumors

All TP53 mutations were found in macroadenomas (9/66; Table 3). TP53 mutant tumors were larger that TP53/USP8 wild type (mm median [IQR] 20.0 [14.0] vs. 15.0 [14.3]), but this did not reach statistical significance (Table 3). Multiple comparison analysis showed that the difference in tumor size is significant only comparing TP53 mutant with USP8 mutant (median [IQR] 23.3 [14.0] vs. 14 [7.3] mm; Kruskal–Wallis P = 0.019; Bonferroni corrected P = 0.018).

Parasellar invasion was reported in 34 out of 64 cases, for which this information was available, and it was more common in TP53 mutant tumors (100% vs. 53% and 55% for TP53/USP8 wild type and USP8 mutant, respectively; Fischer exact test P = 0.006). TP53 mutant tumors had higher Knosp grade (Kruskal–Wallis P = 0.011) with the majority being Knosp 4 (Table 3, Additional file 1: Supplementary Table 4).

Ki67 proliferation index was available for 36 cases (6 TP53 mutant). Five out of six TP53 mutant tumors had Ki67 ≥ 3% and the overall Ki67 was higher than in the wild type tumors (Kruskal–Wallis P = 0.01; Bonferroni corrected P = 0.008 for TP53/USP8 wild type) (Table 3). Ki67 ≥ 10% was reported in 6 tumors, from which 5 were TP53 mutant (Fischer exact test P < 0.0001; the remaining case was TP53/USP8 wild type).

We had information on p53 immunostaining from 9 cases (all macroadenomas), four of which TP53 mutant: 3 tumors (from patients #5, 6 and 9) showed high p53 immunoreactivity, while the one (from patient #3) carrying a nonsense variant leading to a truncated protein was p53 negative. The five TP53 wild type cases showed isolated nuclear staining in < 1–3% of cells.

Summarizing, TP53 mutations were significantly associated with features related to a more aggressive tumor behavior, such as incomplete tumor resection, more frequent parasellar invasion, higher Knosp grade, and higher Ki67 proliferation index (Table 3; Additional file 1: Supplementary Table 4).

More than 80% of adults with Cushing’s disease receiving osilodrostat had normalized mean urinary free cortisol levels at 72 weeks of treatment, according to findings from the LINC 3 study extension.

“Cushing’s disease is a chronic condition, and many patients require prolonged pharmacological treatment. Therefore, evaluating long-term efficacy and safety of drug therapies in clinical trials is essential,” Maria Fleseriu, MD, FACE, professor of medicine and neurological surgery and director of the Pituitary Center at Oregon Health & Science University in Portland and a Healio | Endocrine Today co-editor, told Healio. “Our findings build on the positive results of the LINC 3 study core phase, and it was reassuring to see that continued treatment with osilodrostat for over 72 weeks provided long-term normalization of cortisol levels. Furthermore, continued treatment with osilodrostat also led to sustained improvements in clinical signs and physical manifestations of hypercortisolism, as well as health-related quality of life, which are all important factors in the management of these patients.”

Fleseriu and colleagues enrolled 106 adults with Cushing’s disease who were responders to osilodrostat (Isturisa, Recordati) at 48 weeks during the LINC 3 core study to enter the extension phase of the trial. Participants continued to receive open-label osilodrostat until 72 weeks or treatment discontinuation. Mean urinary free cortisol was collected every 12 weeks. Physical manifestations of hypercortisolism were rated at 48 and 72 weeks. Participants completed the Cushing’s Quality of Life questionnaire and Beck Depression Inventory II at 48 and 72 weeks. Adults were deemed to have completely responded to treatment if mean urinary free cortisol was less than the upper limit of normal and partially responded to treatment if mean urinary free cortisol was above the upper limit of normal but decreased more than 50% from baseline.

The findings were published in the European Journal of Endocrinology.

Of the 106 participants in the extension study, 98 completed 72 weeks of treatment. At 72 weeks, 81.1% of participants were complete responders to treatment, and reductions in mean urinary free cortisol from the core phase were maintained during the extension.

Improvements in most cardiovascular and metabolic-related parameters from the core study were maintained or improved in the extension phase. The cohort also had increases in quality of life score and improvements in Beck Depression Inventory II scores.

The proportion of participants with improvements in physical manifestation of hypercortisolism were maintained or improved in all areas at 72 weeks. For hirsutism in women, 86.4% had an improved or stable severe score at 72 weeks. Improved scores were observed in participants with mild, moderate and severe physical manifestations at baseline with few adults experiencing worse manifestations at the end of the extension study.

There were no new safety signals reported in the extension study. Of the extension study participants, 11.3% discontinued osilodrostat due to adverse events, a similar percentage to the 10.9% discontinuation rate during the core phase of the study.

Several hormone concentrations, including mean adrenocorticotropic hormone, 11-deoxycortisol and plasma aldosterone, stabilized during the extension phase after changes were observed in the core study compared with baseline. Mean testosterone in women decreased from 2.6 nmol/L at 48 weeks to 2.1 nmol/L at 72 weeks. There were no changes observed in mean testosterone levels for men.

“Patients should be regularly monitored and osilodrostat dose titrated as necessary, alongside adjustment of concomitant medications, to optimize outcomes,” the researchers wrote. “Taken together, these findings support osilodrostat as an effective and well-tolerated long-term treatment option for patients with Cushing’s disease.”

For more information:

Maria Fleseriu, MD, FACE, can be reached at fleseriu@ohsu.edu.

From https://www.healio.com/news/endocrinology/20220914/osilodrostat-normalizes-urinary-free-cortisol-in-cushings-disease-for-most-at-72-weeks

Pseudo-Cushing’s syndrome is when symptoms are similar to those of Cushing’s syndrome, but further tests show that the syndrome is not present.

Common causes include consuming too much alcohol, obesity, persistently high blood glucose levels, pregnancy, and depression.

Cortisol isn’t bad; you need it to help regulate your responses to life. Regulation involves a very complex interplay of feedback loops between the hypothalamus, pituitary gland, and adrenal glands, says Dr. Singh.

“In general, cortisol levels tend to peak in the late morning and gradually decline throughout the day,” he explains. “When a stressful event occurs, the increased cortisol will work alongside our ‘fight or flight’ mechanisms to either upregulate or downregulate bodily functions. [Affected systems include] the central nervous system, cardiovascular system, gastrointestinal system, or immune system.”

In addition to normal processes that trigger or suppress cortisol release, levels can also be affected by different medical conditions, Dr. Singh says. For example, if someone has abnormally high levels of cortisol, this is called Cushing’s syndrome, which is typically caused by a tumor affecting any of the glands that take part in the process of cortisol production.

When people suffer from abnormally low levels of cortisol, it’s called Addison’s disease. It generally occurs due to adrenal gland dysfunction, but could also be the result of abnormal functioning of any of the other glands in the cortisol production process.

Finally, if you use corticosteroid medications such as prednisone or dexamethasone, prolonged use will result in excessive cortisol production, Dr. Singh says.

“If the medication is not adequately tapered down when discontinued, the body’s ability to create cortisol can become permanently impaired,” he says.

From https://www.yahoo.com/lifestyle/manage-pesky-stress-hormone-cortisol-184900397.html