Pasireotide-Induced Shrinkage in GH and ACTH Secreting Pituitary Adenoma

Introduction: Pasireotide (PAS) is a novel somatostatin receptor ligands (SRL), used in controlling hormonal hypersecretion in both acromegaly and Cushing’s Disease (CD). In previous studies and meta-analysis, first-generation SRLs were reported to be able to induce significant tumor shrinkage only in somatotroph adenomas. This systematic review and meta-analysis aim to summarize the effect of PAS on the shrinkage of the pituitary adenomas in patients with acromegaly or CD.

Materials and methods: We searched the Medline database for original studies in patients with acromegaly or CD receiving PAS as monotherapy, that assessed the proportion of significant tumor shrinkage in their series. After data extraction and analysis, a random-effect model was used to estimate pooled effects. Quality assessment was performed with a modified Joanna Briggs’s Institute tool and the risk of publication bias was addressed through Egger’s regression and the three-parameter selection model.

Results: The electronic search identified 179 and 122 articles respectively for acromegaly and CD. After study selection, six studies considering patients with acromegaly and three with CD fulfilled the eligibility criteria. Overall, 37.7% (95%CI: [18.7%; 61.5%]) of acromegalic patients and 41.2% (95%CI: [22.9%; 62.3%]) of CD patients achieved significant tumor shrinkage. We identified high heterogeneity, especially in acromegaly (I2 of 90% for acromegaly and 47% for CD), according to the low number of studies included.

Discussion: PAS treatment is effective in reducing tumor size, especially in acromegalic patients. This result strengthens the role of PAS treatment in pituitary adenomas, particularly in those with an invasive behavior, with progressive growth and/or extrasellar extension, with a low likelihood of surgical gross-total removal, or with large postoperative residual tissue.

Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022328152, identifier CRD42022328152

Introduction

Pasireotide (PAS) is a novel somatostatin receptor ligand (SRL) with a high affinity for the somatostatin receptor (SSR) type 5 (12). Somatotroph adenomas are usually responsive to first-generation SRLs (octreotide and lanreotide), as they are able to reduce growth hormone (GH) secretion through SSR type 2 (3). In the flow-chart of acromegaly treatment, PAS is suggested in case of resistance to first-generation SRLs, as SSR type 5 is also abundantly expressed in GH-secreting adenomas (3). A phase III study with PAS long-acting release (LAR) proved its efficacy in first-generation SRLs-resistant acromegalic patients after 6 months (4). In the extension study (Colao A et al.), 37% of patients achieved normalization of insulin-like growth factor 1 (IGF-1) and/or GH levels <1 µg/L, considering both those performing the extension treatment and those crossing over from the first-generation SRL-control group to the PAS LAR group. Nearly two-thirds of responses were achieved after at least 6 months of treatment. Up-titration of the dose from 40 to 60 mg monthly enriched the number of responders, suggesting that the PAS LAR effect may be both time- and dose-dependent (5). Concomitant improvement in signs and symptoms has also been confirmed in other series (69).

SSR type 5 is the predominant isoform in human corticotroph adenomas, since it is not down-regulated by high cortisol levels, as SSR type 2 does. Therefore, PAS is the only SRL available in patients with Cushing’s Disease (CD) (2). In a phase III study, subcutaneous (s.c.) PAS proved to be effective in normalizing urinary free cortisol (respectively in 13% and 25% of patients taking 600 µg or 900 µg bis-in-die for 12 months) (10), achieving significant clinical improvement (11). In the same clinical setting, PAS LAR showed similar efficacy and safety profiles (12). These benefits could be maintained for up to 5 years in an extension study (1314). In a recent meta-analysis, PAS treatment provided disease control in 44% of 522 patients with CD (15). Patients harbouring USP-8 mutations demonstrated an increased SSR type 5 expression in the corticotroph adenoma, increasing the likelihood of a positive response to PAS therapy (16). The safety profile of PAS is similar to that of first-generation SRLs, except for a significant worsening in glucose homeostasis (17).

Despite the normalization of hormonal excess, another goal of the medical treatment in GH-secreting pituitary adenomas is the reduction of the size of the adenoma (18). First-generation SRLs proved to be effective in achieving tumor shrinkage in acromegaly: Endocrine Society clinical practice guidelines suggested their role as primary therapy in poor surgical candidates and in those with extrasellar extension without chiasmal compression (18). Cozzi et al. reported in a large prospective cohort of acromegalic patients a significant Octreotide-induced tumor shrinkage in 82% of those receiving SRL as first-line treatment; most of them exhibited an early shrinkage with a progressive trend in reduction later on (19). A meta-analysis of 41 studies reported a significant tumor shrinkage in 50% of included patients (20). Data from the primary treatment with once-monthly lanreotide in surgical naïve patients demonstrated its efficacy in reducing tumor volume, achieving significant tumor shrinkage in 63% of them (21). Hypo-intensity on T2-weighted sequences at baseline magnetic resonance imaging (MRI) seems to predict tumor volume reduction during first-generation SRLs treatment (22). Regarding patients with CD, most patients presented a microadenoma, usually not aggressive or invasive: only in selected cases tumor shrinkage is an aim to achieve in patients with corticotropinoma.

As available data are scarce (or limited to selected studies), and the issue of pituitary adenoma shrinkage is of primary importance in the management of tumors that cannot be addressed through surgery, the aim of this systematic review and meta-analysis is to summarize available data regarding the effect of PAS on tumor size.

Materials and Methods

We used the Population-Intervention-Comparison-Outcome (PICO) model to formulate the research questions for the systematic review (23), as summarised in Figure 1. The systematic review and meta-analysis were conducted and are reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis of Diagnostic Test Accuracy Studies (PRISMA-DTA) statement (24). We registered the protocol on the International Prospective Register of Systematic Reviews database (PROSPERO, https://www.crd.york.ac.uk/PROSPERO, number CRD42022328152).

Figure 1
www.frontiersin.orgFIGURE 1 PICO (Population-Intervention-Comparison-Outcome) model design to our study.

Search Strategy

An extensive Medline search was performed for the research question by two of the authors (F.C. and A.M.) independently, discrepancies were resolved by discussion. The literature search was performed up to January 2022, no language restriction was applied. Research included the following keywords: 1) (“acromegalies” [All Fields] OR “acromegaly”[MeSH Terms] OR “acromegaly”[All Fields]) AND (“pasireotide”[Supplementary Concept] OR “pasireotide”[All Fields]); 2) (“pituitary ACTH hypersecretion”[MeSH Terms] OR (“pituitary”[All Fields] AND “ACTH”[All Fields] AND “hypersecretion”[All Fields]) OR “pituitary ACTH hypersecretion”[All Fields]) AND (“pasireotide”[Supplementary Concept] OR “pasireotide”[All Fields]).

Inclusion and exclusion criteria were specified in advance and protocol-defined, in order to avoid methodological bias for post-hoc analysis. The searches were designed to select all types of studies (retrospective, observational, controlled, randomized, and non-randomized) conducted in patients with acromegaly or CD treated with PAS as monotherapy; the assessment of the proportion of significant tumor shrinkage was an inclusion criterion. Search terms were linked to Medical Subject Headings when possible. Keywords and free words were used simultaneously. Additional articles were identified with manual searches and included a thorough review of other meta-analyses, review articles, and relevant references. Consolidation of studies was performed with Mendeley Desktop 1.19.8.

Study Selection

We included all original research studies conducted in adult patients that underwent PAS treatment used as monotherapy (s.c. bis-in-die and intramuscular once/monthly), that provided sufficient information about tumor size reduction during treatment. In case of overlapping cohorts of patients (as clinical trials with core and extension phases), we included only the extension study, in order to select those patients with measurable tumor shrinkage after long-term treatment. Local reports regarding patients involved in multicenter trials were excluded from the analysis, as they had been already considered in the larger series. Reviewers were not blinded to the authors or journals when screening articles.

Data Extraction and Quality Assessment

Two authors (F.C. and A.M.) read the included papers and extracted independently relevant data, any disagreements were resolved by discussion. If data were not clear from the original manuscript, the authors of the primary study were contacted to clarify the doubts.

Contents of data extraction in the selected paper included: name of the first author, year of publication, setting (referral centre, academic hospital, mono- or multi-centric collection), type of treatment, its dose schedule and duration, pituitary imaging method during follow- up, the endpoint type regarding adenoma size analysis (i.e. primary vs exploratory). When data were reported for each patient or for subgroups, a global percentage of significant tumor shrinkage was calculated considering all subjects involved in the study.

To assess the risk of bias in the included studies, the critical appraisal tool from Joanna Briggs’s Institute (JBI) was adapted to evaluate those considered in our metanalysis (25). Among the items proposed, we selected the most appropriate to our setting: 1. Were the inclusion criteria clearly identified? 2. Were diagnostic criteria for acromegaly or CD well defined? 3. Were valid methods applied to evaluate tumor shrinkage? 4. Was the inclusion of participants consecutive and complete? 5. Was the reporting of baseline participants’ features (demographic and clinical) complete? 6. Was the report of the outcomes clear? 7. Was the report of demographics of the involved sites complete? 8. Was statistical analysis appropriate? For each aspect we assigned as possible choices of answer: yes, no or unclear.

Data Synthesis and Analysis

A qualitative synthesis was performed summarizing the study design and population characteristics (age, male to female ratio, macro- to micro-adenoma ratio, prior treatments).

A random-effect model was used to estimate pooled effects. Forest plots for percentages of significant tumor size reduction were generated to visualize heterogeneity among the studies. In order to assess publication bias, despite the low number of articles considered, we performed funnel plot and asymmetry analysis adjusted for the low number of studies (an Egger’s regression test and a three-parameter selection model where two tailed p < 0.05 was considered statistically significant). The I2 test was conducted to analyze the heterogeneity between studies: an I2 >50% indicated a between-study heterogeneity.

Statistical analyses were performed with R: R-4.1.2 for Windows 10 (32/64 bit) released 2021-11-01 and R studio desktop RStudio Desktop 1.4.1717 for Windows 10 64 bit (R Foundation for Statistical Computing, Vienna, Austria, URL https://www.R-project.org/).

Results

Study Selection

The study selection process for acromegaly is depicted in Figure 2. The electronic search revealed 179 articles, with one duplicate (N = 178). After the first screening, 141 articles did not meet the eligibility criteria and were discarded. The full-text examination of the remaining studies excluded additional 31 articles: 27 did not provide adequate data about tumor size, two represented the core phase of an extension study, another one referred to a subset of patients from a larger study, and the last one did not provide sufficient data about the percentage of tumor size reduction. Thus, six studies fulfilling eligibility criteria (reported in Tables 12), were selected for data extraction and analysis.

Figure 2
www.frontiersin.orgFIGURE 2 Search strategy for acromegaly. * Petersenn S, 2010 (PAS sc, phase II) and Colao A, 2014 (PAS LAR). ** Shimon I, 2015 (PAS LAR). *** Tahara S, 2019 (PAS LAR, phase II). PAS, pasireotide, sc, subcutaneous, LAR, long-acting release.

Table 1
www.frontiersin.orgTABLE 1 Studies considered for the metanalysis in acromegaly.

Table 2
www.frontiersin.orgTABLE 2 Studies considered for the metanalysis in acromegaly.

The study selection process for CD is depicted in Figure 3. The electronic search revealed 122 articles; an additional one had been included post-hoc, through reference analysis of selected articles (N = 123). After the first screening, 91 articles did not meet the eligibility criteria and were discarded. The full-text examination of the remaining studies excluded 29 more articles: 23 did not provide sufficient data on tumor shrinkage, two of them represented the core phase of extension studies, two referred to subsets of patients included in a larger study and two did not provide sufficient data regarding the percentage of tumor size reduction. Thus, three studies fulfilling eligibility criteria (reported in Tables 34) were selected for data extraction and analysis.

Figure 3
www.frontiersin.orgFIGURE 3 Search strategy for Cushing’s Disease. * Lacroix A, 2018 (PAS LAR, phase III) and Lacroix A, 2020 (PAS sc, phase III post-hoc analysis). ** Simeoli C, 2014 (PAS sc) and Colao A 2012 (PAS sc, phase III). *** Daniel E, 2018 (PAS sc and LAR) and Trementino L, 2016 (PAS sc). PAS, pasireotide, sc, subcutaneous, LAR, long acting release.

Table 3
www.frontiersin.orgTABLE 3 Studies considered for the metanalysis in Cushing’s Disease.

Table 4
www.frontiersin.orgTABLE 4 Studies considered for the metanalysis in Cushing’s Disease.

Study Characteristics

Four multi- and two mono-centric studies in patients with acromegaly were considered and analyzed, all presenting a prospective design. Tumor size analysis was not one of the primary endpoints in any of the considered studies; from an initial overall recruitment of 358 patients, only 265 were included for tumor size reduction analysis. Most patients had previously undergone different treatments (Table 1). All studies, except one, used PAS LAR, dose titration was allowed in all trials. Median follow-up ranged from 6 to 25 months; MRI was performed to evaluate tumor size reduction and the criteria for considering it significant was mainly based on tumor volume analysis, except for Lasolle H et al. which considered median height reduction (26). Data from the PAOLA study provided separate percentages of significant tumor shrinkage for PAS at 40 mg or 60 mg once monthly; considering that respectively 12 and 7 patients showed a reduction >25%, a significant shrinkage was reported in 19 out of 79 considered cases (24%) (4). Stelmachowska-Banás et al. described one patient with McCune-Albright’s syndrome presenting with pituitary hyperplasia, without a visible adenoma at MRI; as its pituitary volume decreased during treatment, the patient was included in the group with significant tumor shrinkage (27). No study provided information about macro- to micro-adenoma ratio. Data regarding age and male to female ratio are also reported in Table 2.

Three studies including patients with CD met the eligibility criteria (Tables 34); all of them presented a multicentre prospective design, recruiting 139 patients, most of them assuming PAS as a second-line treatment, after a surgical failure. For tumor shrinkage analysis, a subgroup of 34 patients was considered, taking s.c. PAS bis-in-die in two studies and PAS LAR in the third; in all cases titration was admitted. Tumor size analysis was a secondary endpoint in all three studies. Follow-up ranged from 6 to 60 months; tumor size assessment was performed with pituitary MRI. Only Pivonello et al. evaluated maximum diameter, instead of tumor volume changes (28). The population analyzed for tumor shrinkage mainly presented with a microadenoma. Data regarding age and gender are reported in Table 4. In the trial reported by Petersenn S et al., we arbitrarily fixed the criterion to define a significant tumor volume reduction (at least 25% of the baseline size of the pituitary adenoma), and the proportion of responders was calculated from the supplementary materials accordingly (3/6 = 50%) (13). Pivonello et al. separated patients exhibiting mild-moderate from those with severe hypercortisolism; we considered them together for tumor size analysis obtaining an overall proportion of significant size reduction of 21.4% (3 out of 14 subjects) (28).

Risk of Bias

The evaluation of the risk of bias performed with the adapted JBI tool is reported in Table 5. All studies presented clear diagnostic and inclusion criteria, except that of Lasolle H et al. (26). Although all papers reported a valid tool for tumor shrinkage analysis (MRI), two of them did not analyse tumor volume and did not provide a clear definition of significant size reduction (2628). Regarding other items, the majority of the considered studies did not appear to present a clear source of bias.

Table 5
www.frontiersin.orgTABLE 5 Evaluation of the risk of bias performed with the adapted Joanna Briggs’s Institute (JBI) tool.

Meta-Analysis

In the six studies considered for acromegaly, 37.7% (95%CI: [18.7%; 61.5%]) of patients demonstrated a significant tumor size reduction (Figure 4). As expected, heterogeneity in tumor reduction between studies was high (I2 = 90%). We attempted to address publication bias despite the low-number of studies (Figure 6A): Egger’s regression test did not indicate the presence of funnel plot asymmetry (intercept = -3.15 with 95%CI: [-10.17; 3.85], t = -0.883, p = 0.427) and the three-parameter selection model performed for p < 0.05 (and p < 0.1 as a sensitivity analysis) suggested absence of publication bias (28).

Figure 4
www.frontiersin.orgFIGURE 4 Pooled effect for the proportion of responders (i.e. presenting significant tumor shrinkage) in acromegaly. CI, confidence interval.

In the three studies considered for CD, 41,2% (95%CI: [22.9%; 62.3%]) of patients overall demonstrated a significant tumor size reduction (Figure 5). The heterogeneity in tumor reduction between the studies represented by I2 amounted to 47%. Publication bias analysis (Figure 6B) was performed using Egger’s regression test (intercept = -1.828 with 95%CI: [-14.53; 10.88], t = -0.282, p = 0.825) without evidence of asymmetry. The three-parameter selection model on the contrary could not be performed due to the small number of studies.

Figure 5
www.frontiersin.orgFIGURE 5 Pooled effect for the proportion of responders (i.e. presenting significant tumor shrinkage) in Cushing’s Disease. CI, confidence interval.

Figure 6
www.frontiersin.orgFIGURE 6 (A) Funnel plot assessing publication bias for Acromegaly. (B) Funnel plot assessing publication bias for Cushing’s Disease.

Discussion

The biochemical efficacy of medical treatment with PAS in GH- or ACTH-secreting pituitary adenomas has been described in previous metanalyses for acromegaly (2930) and CD (15), the latter also exploring the clinical benefit. In addition to these reports, this meta-analysis shows that PAS treatment can induce an additional clinically significant tumor shrinkage in approximately 40% of patients.

Acromegaly

Overall, PAS treatment provided tumor shrinkage in 37.7% of the considered patients. A previous metanalysis on octreotide in acromegaly provided a higher percentage of tumor size reduction (over 50%) (20). Nevertheless, since PAS treatment is usually considered as a second- or third-line treatment in the therapeutic flow-chart of acromegaly, the population recruited is mainly composed of patients with first-generation SRL-resistant somatotroph adenomas. This bias in recruited populations of acromegalic patients may explain this difference in the outcome. In a direct comparison, although PAS LAR seemed more effective in achieving biochemical control, both the SRLs, the first- and the second-generation types, achieved similar percentages of tumor shrinkage (67). Moreover, in the crossover extension, the switch from octreotide to PAS was more effective than the reverse schedule, achieving a slightly higher percentage of further significant tumor shrinkage (8). Lasolle et al. reported that the expression of SSR type 5 and the granulation pattern are of limited value for the prediction of PAS responsiveness: 5 out of 9 somatotropinomas in their series were densely granulated (two did not respond to PAS), and the expression of SSR type 5 was modest in one controlled patient (26).

Other than SRLs, a further therapeutic option targeting the somatotroph adenoma is cabergoline, either as monotherapy in mild cases or as an add-on treatment for resistant adenomas (18). In a previous metanalysis, cabergoline in monotherapy resulted less effective than SRLs, achieving tumor shrinkage in about one third of the enrolled patients (31). It should also be mentioned that some studies reported an escape phenomenon from its treatment efficacy (32).

Data coming from the combination of PAS LAR and pegvisomant in acromegaly were not considered in our metanalysis, due to inclusion criteria and variable combination therapy of the two drugs (33). Since some cases of adenoma growth had been reported during pegvisomant use (3435), this combination therapy represents a rational approach, but tumor volume analysis is less reliable, given the purpose of our study. Despite concerns regarding tumor growth, pegvisomant effectiveness in acromegaly is well documented (1829), although the cost of this combination treatment can limit its applicability in real-life practice. Moreover, it is worth mentioning Coopmans and collaborators’ follow-up analysis, suggesting a PAS mediated anti-tumoral effect in acromegaly. During treatment, patients exhibited a significant increase in T2-weighted sequences signal at MRI; moreover, patients exhibiting this MRI characteristic in their adenomas showed a more evident decrease in IGF-1 levels, but not a similar pattern in reduction of pituitary adenoma size (36). This finding may be related to cell degeneration or tumor cell necrosis, without necessarily determining significant tumor size reduction. Further studies, probably with more data coming from histological reports, may be necessary to better understand these findings.

Cushing’s Disease

Overall, PAS treatment provided significant tumor shrinkage in 41.2% of CD patients. Regarding pituitary-directed drugs, at this moment available for CD treatment, the efficacy of cabergoline has been proven in vitro studies, but its efficacy in clinical trials is still debated (1537). In a previous prospective study, cabergoline induced significant tumor shrinkage (defined as tumor volume reduction >20%) in 4 out of 20 (20%) of the patients recruited after 24 months (38). PAS is the only pituitary-directed treatment for this condition approved by Drug Agencies. Although few studies have been considered in this metanalysis, due to the strict inclusion criteria, PAS appears more effective in tumor size reduction versus cabergoline, resulting in a better choice in CD therapy when aiming to control the pituitary adenoma.

In contrast to acromegaly, the majority of CD patients present a microadenoma, suggesting that tumor size might be a less relevant issue during medical treatment, even if the “cure” of the disease may forecast the resolution of the adenoma. Besides, up to 30% of CD patients, depending also on MRI accuracy and neuro-radiologist’s expertise, may present with negative imaging that prevents any evaluation of tumor shrinkage (39). In spite of that, endocrinologists, not so infrequently, deal with aggressive corticotroph adenomas, characterized by invasive local growth and/or resistance to conventional therapies. This challenging entity often requires multidisciplinary expertise to suggest different approaches, including PAS treatment (40). It should be mentioned that some non-pituitary targeting drugs, as inhibitors of cortisol synthesis, have been associated with tumor growth, due to cortisol-ACTH negative feedback. In particular, during osilodrostat treatment in a phase III study, four recruited patients discontinued osilodrostat after a significant increase in tumor volume (two with micro- and two with macro-adenomas 41), and this growth had also been described during ketoconazole and mitotane treatments (42). Thus, it may be speculated that PAS could provide a rational approach as an combination treatment with steroidogenesis inhibitors. Moreover, after bilateral adrenalectomy, pituitary adenoma tumor size is of the utmost importance, as patients may be at risk of developing a progression of the adenoma, the so-called Nelson’s syndrome. In a prospective study from Daniel E et al., PAS proved to be also effective in this setting, reducing ACTH levels and stabilizing the residual tumor over a treatment period of 7 months (43). Further studies, with longer treatment observation, may reveal whether PAS may achieve significant tumor shrinkage in these patients, as suggested by previous case reports in literature (4445).

Conclusion

The main limitation of our study resides in the scarce literature provided up to now (260 patients with acromegaly and 34 with CD), in the different therapy schedules and different criteria for tumor shrinkage in the selected study (largest tumor diameter vs a selected percentage of reduction). Moreover, in none of the study tumor reduction was one of the primary endpoints, and surgery was performed before PAS in most patients (78-88% of CD and 43-96% of acromegaly).

PAS is a novel compound, with a rising role in the treatment of secreting pituitary adenomas. Thus, this topic might be amplified with more data coming from further clinical studies, as real-life studies, possibly also addressing markers predictive of response to this treatment (e.g., expression of SSR type 2 and type 5 or somatic mutations in USP8 at tissue level of ACTH-secreting adenomas). Nevertheless, we can already state that PAS treatment is effective in reducing tumor size, especially in acromegaly. Our results strengthen the role of PAS treatment in somatotroph and corticotroph adenomas, especially when tumor volume is a relevant issue (i.e. tumor progression, extrasellar invasion) (1839), as a neoadjuvant treatment before surgery or as tailored treatment, alone or in combination, in persistent disease or when surgery is not feasible. Future research aiming to characterize markers predictive of response could help to identify optimal candidates for this treatment.

Data Availability Statement

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.

Ethics Statement

Informed consent was obtained from all subjects participating in the studies analyzed.

Author Contributions

Authors involved contributed to research as reported: literature search (FC, AM), preparation of original draft (FC, AM, MB, LD), literature review (CS, FC, AM, MF), manuscript editing (CS, FC, AM, MB, LD, MF) and supervision (RM, CS). All authors approved the final version of the paper.

Conflict of Interest

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

Publisher’s Note

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

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Keywords: pasireotide, cushing, acromegaly, tumor volume, tumor size

Citation: Mondin A, Manara R, Voltan G, Tizianel I, Denaro L, Ferrari M, Barbot M, Scaroni C and Ceccato F (2022) Pasireotide-Induced Shrinkage in GH and ACTH Secreting Pituitary Adenoma: A Systematic Review and Meta-Analysis. Front. Endocrinol. 13:935759. doi: 10.3389/fendo.2022.935759

Received: 04 May 2022; Accepted: 06 June 2022;
Published: 01 July 2022.

Edited by:

Mohammad E. Khamseh, Iran University of Medical Sciences, Iran

Reviewed by:

Rosa Paragliola, Catholic University of the Sacred Heart, Rome, Italy
Marek Bolanowski, Wroclaw Medical University, Poland
Adriana G Ioachimescu, Emory University, United States

Copyright © 2022 Mondin, Manara, Voltan, Tizianel, Denaro, Ferrari, Barbot, Scaroni and Ceccato. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Filippo Ceccato, filippo.ceccato@unipd.it

ORCID: Alessandro Mondin, orcid.org/0000-0002-6046-5198
Renzo Manara, orcid.org/0000-0002-5130-3971
Giacomo Voltan, orcid.org/0000-0002-3628-0492
Irene Tizianel, orcid.org/0000-0003-4092-5107
Luca Denaro, orcid.org/0000-0002-2529-6149
Marco Ferrari, orcid.org/0000-0002-4023-0121
Mattia Barbot, orcid.org/0000-0002-1081-5727
Carla Scaroni, orcid.org/0000-0001-9396-3815
Filippo Ceccato, orcid.org/0000-0003-1456-8716

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

From https://www.frontiersin.org/articles/10.3389/fendo.2022.935759/full

Hypercortisolemic Cushing’s Patients Possess a Distinct Class of Hematopoietic Progenitor Cells Leading to Erythrocytosis

Abstract

Although human cultures stimulated with dexamethasone suggest that the glucocorticoid receptor (GR) activates stress erythropoiesis, the effects of GR activation on erythropoiesis in vivo remains poorly understood.

We characterized the phenotype of a large cohort of patients with Cushing’s Disease, a rare condition associated with elevated cortisol levels. Results from hypercortisolemic patients with active Cushing’s were compared with those obtained from eucortisolemic patients after remission and from non-diseased volunteers. Active Cushing’s patients exhibit erythrocytosis associated with normal hemoglobin F levels. In addition, their blood contained elevated numbers of the GR-induced CD163+ monocytes and a unique class of CD34+ cells expressing CD110, CD36, CD133 and the GR-target gene CXCR4.

When cultured, these CD34+ cells generated similarly large numbers of immature erythroid cells in the presence and absence of dexamethasone, with raised expression of the GR-target gene GILZ. Of interest, blood from Cushing’s patients in remission maintained high numbers of CD163+ monocytes and, although their CD34+ cells had a normal phenotype, these cells were unresponsive to added dexamethasone.

Collectively, these results indicate that chronic exposure to excess glucocorticoids in vivo leads to erythrocytosis by generating erythroid progenitor cells with a constitutively active GR.

Although remission rescues the erythrocytosis and the phenotype of the circulating CD34+ cells, a memory of other prior changes is maintained in remission.

From https://haematologica.org/article/view/haematol.2021.280542

Subclinical Hemorrhage of ACTH-secreting Pituitary Adenomas in Children and Adolescents Changes Their Biochemical Profile

Journal of the Endocrine Society, Volume 6, Issue 7, July 2022, bvac080, https://doi.org/10.1210/jendso/bvac080

Abstract

Context

Subclinical pituitary hemorrhage, necrosis, and/or cystic degeneration (SPH) presents mainly in large tumors and prolactinomas. The characteristics of patients with Cushing disease (CD) and SPH are not known.

Objective

To determine if SPH affects the presentation and biochemical profile of young patients with CD.

Methods

Pediatric and adolescent patients who were diagnosed with CD between 2005 and 2021 and available magnetic resonance imaging images were evaluated for SPH. The clinical and biochemical characteristics of patients with and without SPH were compared.

Results

Evidence of possible SPH was present in 12 out of 170 imaging studies (7.1%). Patients with and without SPH had similar age at diagnosis and sex distribution but differed in disease duration (median duration: 1.0 year [1.0-2.0] in the SPH group vs 2.5 years [1.5-3.0] in the non-SPH group, P = .014). When comparing their biochemical evaluation, patients with SPH had higher levels of morning adrenocorticotropin (ACTH) (60.8 pg/mL [43.5-80.3]) compared to patients without SPH (39.4 pg/mL [28.2-53.2], P = .016) and the degree of cortisol reduction after overnight high dose (8 mg or weight-based equivalent) dexamethasone was lower (–58.0% [–85.4 to –49.7]) compared to patients without SPH (85.8 [–90.5 to –76.8], P = .035). The presence of SPH did not affect the odds of remission after surgery or the risk of recurrence after initial remission.

Conclusion

SPH in ACTH-secreting pituitary adenomas may affect their biochemical response during endocrine evaluations. They may, for example, fail to suppress to dexamethasone which can complicate diagnosis. Thus, SPH should be mentioned on imaging and taken into consideration in the work up of pediatric patients with CD.

Acute hemorrhage or necrosis of pituitary adenomas (PAs), defined as pituitary apoplexy, is a rare life-threatening condition that requires emergent neurosurgical evaluation [1]. However, subclinical hemorrhage, necrosis, intratumor cystic degeneration, and/or infarct of PAs, herein all events included in the term subclinical pituitary hemorrhage (SPH) for brevity, may occur in up to 7% to 22% of all pituitary tumors [2-9]. SPH is not associated with significant clinical symptoms and is often discovered at the time of routine diagnostic evaluation [2-9].

Previous studies suggested that SPH is more common in large tumors, prolactin-secreting or nonfunctioning PAs, while other factors, such as initiation or withdrawal of treatment with dopamine agonists, use of anticoagulants and others, have also been hypothesized to be involved in this process [56]. Overall, adrenocorticotropin (ACTH)-secreting PAs represent small percentage of SPH (0%-3.2% of cases reported) [3568]. Although pituitary apoplexy is associated with pituitary hormone deficiencies, SPH has a lower if any effect on the function of the remaining pituitary gland when it occurs in nonfunctioning adenomas [34].

The diagnosis of Cushing syndrome (CS) involves elaborate and time-dependent tests that are based on cortisol secretion and its regulation by ACTH [10]. Furthermore, the differential diagnosis of ACTH-dependent causes between ACTH-secreting PAs (Cushing disease, CD) and ectopic ACTH secretion is based on several dynamic tests, such as corticotropin-releasing hormone (CRH) stimulation and dexamethasone suppression [11]. The biochemical profile of corticotropinomas with SPH to both baseline and dynamic endocrine tests is not known.

Materials and Methods

Participants

Individuals enrolled under the protocol 97-CH-0076 (ClinicalTrials.gov identifier NCT00001595) at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), from 2005 to 2020 with confirmed diagnosis of CD, were screened for eligibility in the study. Pediatric and adolescent patients (diagnosis age < 21 years) with imaging studies available before any surgical intervention were included in the analysis. Patients with previous surgery of the pituitary gland or who were evaluated during recurrence were excluded from the study since postoperative changes make imaging findings difficult to distinguish from true SPH, and biochemical presentation at recurrence often differs in severity from initial diagnosis. CS diagnosis was based on criteria defined by the Endocrine Society guidelines and adjusted for the pediatric and adolescent population as needed (abnormal measurements in at least 2 of the following criteria: elevated 24 hour urinary free cortisol [UFC], elevated midnight serum cortisol [> 4.4 mcg/dL in children or > 7.5 mcg/dL for patients age > 18 years], and/or failure to suppress cortisol to 1 mg [or weight-based equivalent dose] overnight dexamethasone suppression test [postdexamethasone cortisol > 1.8 mcg/dL]). CD diagnosis was based on postoperative histologic confirmation of ACTH-secreting PA in most cases, or remission after pituitary surgery even if histologic report failed to identify a PA in the studied material. Remission was defined as postoperative cortisol nadir of less than 2 mcg/dL and/or clinical/biochemical remission during follow-up.

Informed consent was obtained from parents and assent from patients if developmentally appropriate. Study procedures were approved by the NICHD and/or central National Institutes of Health Institutional Review Board.

Magnetic Resonance Imaging Scans

SPH was defined as minimal or no clinical symptoms reported by the patients (apart from those commonly associated with hypercortisolemia) and magnetic resonance imaging (MRI) findings consistent with hemorrhage, intratumor infarction, and/or intratumor cyst formation (suggesting old infarcts) based on the radiologist and the principal investigator’s (C.A.S.) assessment [1213]. MRI scans were performed based on standard clinical protocols as previously described [14]. Briefly, MRIs at the National Institutes of Health were performed before and after intravenous administration of gadolinium contrast material, with a gradient echo sequence and thin slices (≤ 1.5 mm). MRIs were performed in either a 1.5 Tesla or 3 Tesla MR machine from various manufacturers over time.

Clinical and Biochemical Data

Clinical and biochemical data were extracted from electronic medical records. Tumor size was recorded as the maximum dimension retrieved from the histology report. In cases where histologic report was not available, failed to identify a PA in the studied material, or if the histology report recorded only dimensions on fragments of the tumor, the maximum dimension was retrieved from the MRI images. If the MRI was negative and the histology was negative (but the patient achieved remission after surgery), the tumor size was recorded as missing.

Serum cortisol and plasma ACTH levels were calculated as the average value of the corresponding levels performed at 23:30 h and 00:00 h (reported as midnight values) and 07:30 h and 08:00 h (reported as morning values). Twenty-four–hour UFC was calculated as the average of the first 2 or 3 samples reported in the electronic medical records. Given the possible differences in the assays and reported reference range for UFC, we calculated the increase of UFC based on the upper limit of normal according to the following formula: UFC fold change = UFC/upper limit of the reference range. Serum cortisol was measured with solid-phase, competitive chemiluminescent enzyme immunoassay on a Siemens Immulite 2500 analyzer. Plasma ACTH was measured with a chemiluminescence immunoassay on a Siemens Immulite 200 XPi analyzer. UFC was measured with a chemiluminescent enzyme immunoassay until 2011 and with high-performance liquid chromatography–tandem mass spectrometry since 2011. High-dose dexamethasone suppression test was performed as previously described. Briefly, oral dexamethasone (120 mcg/kg, max 8 mg) was administered at 23:00 and cortisol was measured before (8 AM the day of administration) and after (9 AM the day after dexamethasone administration). The change of cortisol was calculated as: 100* [(postdexamethasone cortisol – predexamethasone cortisol)/predexamethasone cortisol]. Levels of cortisol lower than the lower limit of detection of the assay (< 1 mcg/dL) were substituted with the intermediate value (0.5) for all analyses. CRH stimulation test was performed as previously described. Briefly, an intravenous catheter was placed in the forearm the night before testing; the patient was fasting and lying in bed, and ovine CRH (oCRH) was administered (1 mcg/kg, max 100 mcg). Samples for cortisol and ACTH were taken at –5, 0, 15, 30, and 45 minutes after the administration of oCRH. The response to the last was expressed as the percentage change from baseline by subtracting the pretest cortisol and ACTH values from the posttest values and dividing by the former. The mean cortisol increase was estimated at 30 and 45 minutes from baseline. For ACTH the mean increase was estimated at 15 and 30 minutes after the administration of oCRH. CRH stimulation test was not performed after the discontinuation of oCRH by the company in November 2020.

Statistical Analysis

Categorical data are described as counts (proportions) and were compared between groups using the Fisher exact test. Fisher odds ratio (OR) was used to assess the odds of remission based on the presence of SPH and is presented as OR and 95% CI.

Continuous data were checked for normality and not normally distributed data are presented as median (first quartile to third quartile) and were compared between 2 groups using Wilcoxon rank-sum test. The Cox proportional hazards test was used to assess the risk of recurrence based on the presence of SPH and is presented as hazard ratio (HR) and 95% CI. Statistical analyses were performed in R.

Results

Clinical Data

Out of 170 patients with available MRI before first surgery, 12 patients had evidence of possible SPH (7.1%) (Table 1). Various MRI findings were noted (Fig. 1), most commonly hyperintense lesions in T1 and T2 precontrast images (Fig. 1A and 1B), while some patients had intratumor heterogeneity suggestive of cystic formation (Fig. 1C-1F). As expected, the tumor size of patients with SPH as noted in histology reports or MRI images was higher than that in patients without SPH (median size: 8.5 mm [7.0-11.25] in the SPH group vs 5.4 mm [4-8] in the non-SPH group; P < .001).

 

Table 1.

Characteristics of patients with and without subclinical pituitary hemorrhage, necrosis, and/or cystic degeneration

No SPH (N = 158) SPH (N = 12) P
Age at diagnosis, y 13.0 (10.6 to 15.4) 12.5 (10.6 to 15.6) .95
Sex
 Female 89 (56.3%) 5 (41.7%) .49
 Male 69 (43.7%) 7 (58.3%)
Disease duration, y 2.50 (1.5 to 3.0)
n = 138
1.00 (1.0 to 2.0)
n = 10
.014
Morning cortisol, mcg/dL 16.2 (12.6 to 20.4)
n = 139
18.4 (13.7 to 27.5)
n = 10
.28
Midnight cortisol, mcg/dL 14.0 (10.7 to 19.7)
n = 133
16.3 (11.0 to 23.0)
n = 9
.52
UFC fold change 4.89 (2.51 to 8.50)
n = 131
8.81 (6.86 to 9.42)
n = 9
.18
Morning ACTH, pg/mL 39.4 (28.2 to 53.2)
n = 143
60.8 (43.5 to 80.3)
n = 10
.016
Cortisol change during CRH stimulation test, % 68.7 (33.3 to 111)
n = 128
46.0 (–7.46 to 90.7)
n = 8
.22
ACTH change during CRH stimulation test, % 145 (59.6 to 260)
n = 127
103 (–5.75 to 278)
n = 8
.55
Cortisol change during high-dose dexamethasone suppression test, % –85.8 (–90.5 to –76.8)
n = 120
–58.0 (–85.4 to –49.7)
n = 9
.035
Remission
 Yes 127 (80.4%) 10 (83.3%) .99
 No 25 (15.8%) 2 (16.7%)

Number in each cell reports the number of patients with available results.

Abbreviations: ACTH, adrenocorticotropin; CRH, corticotropin-releasing hormone; SPH, subclinical pituitary hemorrhage, necrosis, and/or cystic degeneration; UFC, urinary free cortisol.

 

Figure 1.

Imaging findings in patients with subclinical pituitary hemorrhage, necrosis, and/or cystic degeneration. A, T1, and B, T2 magnetic resonance imaging (MRI) scans of the same patient showing area of high intensity inside the tumor suggesting acute/subacute episode. C, T2, and D, T1 MRI scans of the same patient showing heterogeneity in a large tumor with high-intensity areas suggesting blood-filled cavities and/or necrosis. E, T1, and F, T2 MRI scans of the same patient showing fluid inside the tumor.

Imaging findings in patients with subclinical pituitary hemorrhage, necrosis, and/or cystic degeneration. A, T1, and B, T2 magnetic resonance imaging (MRI) scans of the same patient showing area of high intensity inside the tumor suggesting acute/subacute episode. C, T2, and D, T1 MRI scans of the same patient showing heterogeneity in a large tumor with high-intensity areas suggesting blood-filled cavities and/or necrosis. E, T1, and F, T2 MRI scans of the same patient showing fluid inside the tumor.

Patients with and without SPH were similar in age (median age: 12.5 years [10.6-15.6] in the SPH group vs 13.0 years [10.6-15.4] in the non-SPH group; P = .95) and sex distribution (n of female = 5 (41.7%) in the SPH group vs 89 (56.3%) in the non-SPH group; P = .49). Patients with SPH had a shorter duration of disease as noted by changes in their growth chart parameters (median duration: 1.0 [1.0-2.0] year in the SPH group vs 2.5 [1.5-3.0] years in the non-SPH group; P = .014).

Patients in the 2 groups did not differ on their anthropometric characteristics, including height and body mass index z scores(P > .05). They also had similar blood pressure parameters and did not differ in terms of the frequency of hypertension diagnosis. No patient was on anticoagulation treatment nor had received radiation at the time of the MRI. One patient in the SPH group had a history of lower leg deep vein thrombosis and was previously on low-heparin therapy, but he had stopped treatment at least 6 months before the MRI.

Biochemical Evaluation of Hypercortisolemia

Morning and midnight serum cortisol and 24-hour UFC levels were similar in both groups, but patients with SPH had higher levels of morning ACTH (60.8 pg/mL [43.5-80.3]) compared to patients without SPH (39.4 pg/mL [28.2-53.2]; P = .016). Changes in cortisol and ACTH levels during the CRH stimulation test were similar between the 2 groups, but patients with SPH who underwent the overnight high-dose dexamethasone suppression test (n = 8) had lower suppression of cortisol after dexamethasone (–58.0% [–85.4 to –49.7]) compared to patients without SPH (n = 120) (–86.0% [–90.5 to –76.7]; P = .035) (Fig. 2). When the cutoff of suppression of more than 69% was considered, patients with SPH had a lower chance of suppressing more than 69% compared to patients without SPH (OR: 0.18; 95% CI, 0.03-0.95).

 

Figure 2.

Cortisol levels before and after high-dose dexamethasone suppression test in patients with and without subclinical pituitary hemorrhage, necrosis, and/or cystic degeneration (SPH).

 Cortisol levels before and after high-dose dexamethasone suppression test in patients with and without subclinical pituitary hemorrhage, necrosis, and/or cystic degeneration (SPH).

Remission After Surgical Treatment and Risk for Recurrence

The chance of immediate postoperative remission after surgery was similar in patients with and without SPH. For patients with initial remission and follow-up of at least 3 months, analysis of the risk of recurrence did not show a difference in recurrence rate between the 2 groups (HR: 1.12; 95% CI, 0.13-9.4, in the SPH group compared to the non-SPH group, adjusting for the neurosurgeon).

Discussion

SPH is often an incidental finding in the imaging evaluation of patients with PAs. The frequency of SPH in patients with CD is low (7.1% in our study) but these patients may differ in terms of their history of shorter duration of symptoms and the biochemical evaluation. More specifically, patients with CD and SPH showed higher ACTH levels and lower suppression of cortisol to high-dose dexamethasone. This, however, did not affect their prognosis in terms of immediate postoperative remission and long-term risk of recurrence.

SPH has been mainly studied in cohorts of patients with various types of PAs. From these studies important conclusions have been made suggesting that the risk of SPH is higher in patients with large nonfunctioning PAs or prolactinomas. Other risk factors for pituitary apoplexy are thought to be size of the adenoma, change in size, initiation, and withdrawal of dopamine agonists, type of dopamine agonist, use of anticoagulants, diabetes mellitus, hypertension, head trauma, radiotherapy, and preceding dynamic endocrine testing.

Patients with CD often represent a small portion of these cohorts, and to our knowledge there is no study to investigate how these patients respond to stimulation/suppression tests. For that reason, we evaluated these findings in our cohort of only patients with ACTH-secreting adenomas. As most of our referrals involve pediatric patients, we limited our cohort only to patients diagnosed at younger than 21 years to have a more homogeneous group.

The pathogenesis of pituitary apoplexy has been hypothesized to lie in more friable vessels in PAs, which, while the tumor increases in size, are more susceptible to rupture or cause surrounding feeding vessels to extend and bleed [715]. CS, because of the coexisting hypercortisolemia, leads independently to endothelial dysfunction and coagulation defects, which are often apparent as easy bruising, thrombotic events, and other signs. However, review of the literature and the estimated frequency of SPH in our cohort suggest that patients with CD are not at increased risk for SPH, potentially related to the relatively small adenomas present in these patients [1617].

The main difference of patients with CD and SPH compared to those without lies in their biochemical testing, more characteristically in lower suppression to dexamethasone. The overnight high-dose dexamethasone suppression test was originally designed to differentiate various types of CS [18]. Although originally described as a highly accurate test, in clinical practice, cutoffs of 50% to 80% have shown variable sensitivity and specificity and certain centers opt not to use this test unless all other diagnostic evaluations yield confounding results [19-21]. In previous studies a threshold of suppression of more than 69% showed the highest accuracy (sensitivity: 71%, specificity: 100%), and we have incorporated this in our diagnostic algorithm (acknowledging the limitations of the test) [2223]. In our analysis, patients with SPH had lower suppression of cortisol under the effect of high-dose dexamethasone and a higher chance of not passing the aforementioned threshold. The mechanism for the lower suppression to dexamethasone of these tumors may be due to lower vascular circulation of dexamethasone at the level of the tumor, and/or the lower sensitivity of necrotic cells to the negative feedback by circulating glucocorticoids.

A limitation of this study was that the diagnosis of SPH was based on MRI findings. However, MRI sequences and machines differed between patients and over time. Thus, although large hemorrhagic/necrotic lesions are probably accurately identified, it is possible that smaller lesions are misclassified as negative; the effect of smaller hemorrhagic areas to the biochemical testing may however be smaller as well. Further, the MRIs were not read by a central radiologist, but rather from the radiologist on call at each time point, and this could lead to discrepancies in readings. In addition, our cohort’s data may not be generalized to the pediatric or adult CD population, as often our referrals consist of patients with difficult to treat, small, or otherwise unusual tumors.

In conclusion, SPH may be incidentally identified in up to 7% of patients with CD. Patients with CD and SPH may differ in terms of their response to endocrine tests, and this finding should be incorporated in their evaluation.

Abbreviations

 

  • ACTH

    adrenocorticotropin

  • CD

    Cushing disease

  • CRH

    corticotropin-releasing hormone

  • CS

    Cushing syndrome

  • HR

    hazard ratio

  • MRI

    magnetic resonance imaging

  • NICHD

    Eunice Kennedy Shriver National Institute of Child Health and Human Development

  • OR

    odds ratio

  • PA

    pituitary adenoma

  • SPH

    subclinical pituitary hemorrhage

  • UFC

    urinary free cortisol

Financial Support

This work was supported by the intramural research program of the Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD 20892, USA.

Disclosures

Dr Stratakis holds patents on the function of the PRKAR1APDE11A, and GPR101 genes and related issues; his laboratory has also received research funding on the GPR101 gene, and on abnormal growth hormone secretion and its treatment by Pfizer, Inc. He is currently employed by ELPEN, SA and has been consulting for Lundbeck Pharmaceuticals and Sync, SA. The other authors have nothing to disclose.

Data Availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but may be available from the corresponding author on reasonable request.

Published by Oxford University Press on behalf of the Endocrine Society 2022.
This work is written by (a) US Government employee(s) and is in the public domain in the US.
Published by Oxford University Press on behalf of the Endocrine Society 2022.

Successful Immunomodulatory Treatment of COVID-19 in a Patient With Severe ACTH-Dependent Cushing’s Syndrome

Introduction: Patients with Cushing’s syndrome (CS) represent a highly sensitive group during corona virus disease 2019 (COVID-19) pandemic. The effect of multiple comorbidities and immune system supression make the clinical picture complicated and treatment challenging.

Case report: A 70-year-old female was admitted to a covid hospital with a severe form of COVID-19 pneumonia that required oxygen supplementation. Prior to her admission to the hospital she was diagnosed with adrenocorticotropic hormone (ACTH)-dependent CS, and the treatment of hypercortisolism had not been started yet. Since the patient’s condition was quickly deteriorating, and with presumend immmune system supression due to CS, we decided on treatement with intraveonus immunoglobulins (IVIg) that enabled quick onset of immunomodulatory effect. All comorbidities were treated with standard of care. The patient’s condition quickly stabilized with no direct side effects of a given treatment.

Conclusion: Treatment of COVID-19 in patients with CS faces many challenges due to the complexity of comorbidity effects, immunosupression and potential interactions of available medications both for treatment of COVID-19 and CS. So far, there are no guidelines for treatment of COVID-19 in patients with active CS. It is our opinion that immunomodulating therapies like IVIg might be an effective and safe treatment modality in this particularly fragile group of patients.

Introduction

Dealing with corona virus disease 2019 (COVID-19) focused medical attention on several sensitive population groups. While the knowledge is still improving, some of the recognized risk factors for severe form of the disease are male sex, older age, obesity, hypertension, diabetes mellitus, and cardio-vascular disease (1). This constellation of morbidities is particularly intriguing from endocrine point of view, since they are all features of patients with Cushing’s syndrome (CS). Another relevant feature of CS is a propensity for infections due to profound immune suppression, with prevalence of 21-51%; even more so, infections are the second cause of death (31%) in CS after disease progression, and are the main cause of death (37%) in patients who died within 90 days of diagnosis (2).

Immune system alterations in CS lead to depression of both innate and adaptive immune responses, favoring not only commonly acquired but also opportunistic bacterial infections, fungal infections, and severe, disseminated viral infections (3). Susceptibility to infections directly positively correlates with cortisol level, and is more frequent in ectopic ACTH secretion (EAS). Hypercortisolism hampers the first-line response to external agents and consequent activation of the adaptive response (3). Consequently, there is a decrease in total number of T-cells and B-cells, as well as a reduction in T-helper cell activation, which might favor opportunistic and intracellular infections. On the other hand, an increase in pro-inflammatory cytokine secretion, including interleukine-6 (IL-6) and tumor necrosis factor-α (TNF-α) leads to persistent, low-grade inflammation. It is important to note that immune system changes are confirmed both during the active phase and while in remission of CS (3).

In view of the aforementioned data, a few topics emerge regarding patients with CS and COVID-19. Initial clinical presentation may be altered – low-grade chronic inflammation and poor immune reaction might limit febrile response in the early phase of infection, aggravating timely diagnosis (4). Increased cytokine levels may put patients with CS at increased risk of severe course and progression to acute respiratory distress syndrome (ARDS). On the other hand, the rise in cytokine levels associated with exposure to external agents is significantly hampered, probably because of persistently elevated pro-inflammatory cytokine secretion (45). Patients with CS have a possibility for prolonged duration of viral infections and risk for superinfections leading to sepsis and increased mortality risk; this is especially relevant for hospitalized patients and mandates empirical prophylaxis with broad-spectrum antibiotics (6). Both COVID-19 and CS individually represent disease states of increased thromboembolic (TE) risk, requiring additional care (6).

Due to very limited data, it is still not possible to address these topics with certainty and make recommendations for optimal management of these patients. Current clinical practice guidance for management of CS during COVID-19 commissioned by the European Society of Endocrinology (ESE) emphasizes prompt and optimal control of hypercortisolism and adequate treatment of all comorbidities (7). Although individual circumstances must always be considered, we need more direct clinical experience, especially regarding the actual treatment of COVID-19 in this sensitive group. So far, there are only five published case studies of patients with CS and COVID-19, with eight patients in total (812). In this study, we present a patient with newly diagnosed ACTH-dependent CS who was diagnosed with COVID-19 before the initiation of specific medical treatment.

Case Report

A 70-year-old female was admitted to our Covid hospital due to bilateral interstitial pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Six days before she was discharged from endocrinology department of another hospital where she was hospitalized due to newly diagnosed diabetes mellitus. Her personal history was unremarkable, and she was vaccinated with two doses of inactivated COVID-19 vaccine Sinopharm BBIBP. During this hospitalization Cushingoid features were noted (moon face, centripetal obesity, thin extremities with multiple hematomas, bilateral peripheral edema), as well as diabetes mellitus (HbA1c 8.7%), arterial hypertension (BP 180/100 mmHg), hypokalemia (2.0 mmol/L), mild leukocytosis (WBC 12.9x10e9/L) with neutrophilia, and mildly elevated CRP (12.3 mg/L). Hormonal functional testing confirmed ACTH-dependent Cushing’s syndrome: morning ACTH 92.6 pg/mL (reference range 10-60 pg/mL), morning serum cortisol 1239 nmol/L (reference range 131-642 nmol/L), midnight serum cortisol 1241 nmol/L, lack of cortisol suppression in overnight dexamethasone suppression test (978 nmol/L). Pituitary MRI was unremarkable other than empty sella, and CT scan of thorax normal other than left adrenal hyperplasia. Diabetes mellitus was successfully controlled with metformin, hypertension with ACE-inhibitor, Ca-channel blocker and beta-blocker, and hypokalemia with potassium supplementation along with spironolactone. Steroidogenesis inhibitors were not available in this institution, but before referral to a tertiary care hospital she was tested for SARS-CoV-2, and the test came back positive (sample was obtained by nasopharyngeal swab). Since she was asymptomatic, with normal thoracic CT scan and stabile CRP level (9.1 mg/L), she was discharged with detailed recommendations for conduct in case of progression of COVID symptoms.

Next day she started feeling malaise with episodes of fever (up to 38.2°C). Symptomatic therapy was advised in an outpatient clinic (no antiviral therapy was recommended), but 5 days later respiratory symptoms ensued. During examination, the patient was weak, with dyspnea and tachypnea (RR 22/min), afebrile (36.9°C) and with oxygen saturation (SO2) of 85% measured by pulse oximeter. Chest X-ray confirmed bilateral interstitial pneumonia with parenchymal consolidation in the right lower lung lobe, so she was referred to the COVID hospital.

Laboratory analyses upon admission are presented in the Supplementary Table 1. In addition to her previous testing, elevated chromogranin A (CgA) level was verified (538.8 ng/mL, reference range 11-98.1). The patient was treated with supplemental oxygen with maximal flow of 13 l/min. For the reason of previously confirmed severe endogenous hypercortisolism, glucocorticoids were not administered. Due to limited therapeutic options and presumed further clinical deterioration, we decided to treat the patient with intravenous immunoglobulins (IVIg) 30 g iv for 5 days, starting from the 2nd day of hospitalization. We did not observe any side effects of a given treatment. In parallel, the patient received broad-spectrum antibiotics (ceftazidime and levofloxacin), proton pump inhibitor, LMWH in prophylactic dose, oral and parenteral potassium supplementation along with spironolactone. She continued with her previous antihypertensive therapy with good control of blood pressure. While the patient was on oxygen supplementation, glycaemia was controlled with short acting insulin before meals. Following given treatment, we observed clinical, biochemical (Supplementary Table 1.) and radiological improvement (Supplementary Figure 1). Oxygen supplementation was gradually discontinued. With regard to D-dimer levels and risk factors for TE events due to COVID-19 and CS, we performed color Doppler scan of lower extremities veins, and CT pulmonary angiography, but there were no signs of thrombosis. During hospital stay, there were no signs of secondary infection and cotrimoxazole was not added to the current treatment. The patient was discharged with advice to continue her prior medical therapy along with increased dose of spironolactone and initiation of rivaroxaban. She was referred to the tertiary institution for the initiation of steroidogenesis inhibitor and further diagnostics.

Discussion

Endogenous Cushing’s syndrome is a rare disease with an incidence of 0.7-2.4 million person-years in European population-based studies (13). Significant morbidity yields a standard mortality ratio of 3.7 (95%CI 2.3–5.3), with the highest mortality during the first year after initial presentation. COVID-19 pandemic imposes additional challenge to this fragile group of patients. Due to lack of solid experience, it is still difficult to define potential clinical course and outcome of patients with CS and COVID-19. In addition, currently there are no guidelines for management of SARS-CoV-2 infection in patients with active CS.

So far, only two small case series followed patients with Cushing’s disease (CD) in various disease stages (not all were active) during COVID-19 pandemic (912). Small number of SARS-CoV-2 positive cases (3/22 and 2/61) is clearly biased by shortness of analyzed period (one and a half, and three and a half months). Additionally, a small number of patients was actually tested by nasopharyngeal swab for SARS-CoV-2 even in the presence of indicative symptoms, albeit mild. Nevertheless, all these limitations included, it seems that the prevalence of COVID-19 might be greater in patients with CD than in general population (12). This is accordant with studies on patients on exogenous glucocorticoid (GC) treatment. Overall, there is a growing body of evidence that patients on chronic GC therapy are at higher risk for SARS-CoV-2 infection and a severe course of disese, regardless of age and comorbidities (14). In many studies patients on high-dose GC therapy were at particularly high risk for a severe course of disease, so it is reasonable to assume that there is a dose-dependent effect (14).

All patients except one with endogenous CS and COVID-19 presented in literature were hospitalized, with majority of them requiring oxygen supplementation, which classified them as serious cases of disease (812). Parameters of inflammation (namely CRP) were highly variable (from normal to elevated) and did not seem to reflect severity of COVID-19 consistently. Two patients had fatal outcome; one with postoperative hypocortisolism that required stress doses of hydrocortisone, and with terminal kidney failure as significant comorbidity; the other with suspected EAS who developed ARDS in contrast to normal CRP and absence of fever (912). Based on reported cortisol levels in these patients, it seems that the severity of COVID-19 pneumonia depended on severity of hypercortisolism (812). A patient with probable EAS even developed ARDS, which adds to ongoing controversy regarding the risk of ARDS due to SARS-CoV-2 in patients with CS (315). We ourselves have treated a severely obese female patient with active CD on pasireotide, who developed ARDS despite addition of high doses of methylprednisolone (unpublished data). Additional risk imposed by comorbidities cannot be underestimated (1516). This is particularly relevant for obesity, that not only hampers immune system (leading to increased levels of IL-1, IL-6, and TNF-α), but adipocytes represent a reservoir of SARS-CoV-2 thanks to ACE2 receptor, crucial for virus attachment (15).

Majority of depicted patients with active CS were already medically treated for hypercortisolism but with various compliance (sometimes very poor), and two young patients have just started steroidogenesis inhibitors (metyrapone/ketoconazole). Infection with SARS-CoV-2 was treated by national protocols that were mostly based on supportive care. These protocols changed over time, so a few patients received antiviral therapy (favipiravir), and one young patient with suspected EAS was treated with methylprednisolone along with high doses of ketoconazole (10). Treatment was complicated with adrenal insufficiency (AI) in three patients (81112).

We have presented a patient with CS and rapid development of serious case of COVID-19 pneumonia that required hospital admission and oxygen support. She was febrile and had positive laboratory parameters of inflammation. Her CS was active, with very high cortisol levels, no prior medical treatment and with clinical suspicion of EAS (ACTH-dependent disease of short duration, severe hypercortisolism, hypokalemia, very high CgA, no visible pituitary tumor). With this in mind, and with regard to rapid progression of COVID-19 pneumonia, it was our opinion that the patient required treatment with quick onset and presumable immune system modulation.

A logical approach to treatment of CS during COVID-19 pandemic includes meticulous therapy for comorbidities (namely antihypertensives, anti-diabetic drugs, low molecular weight heparin, etc.), and steroidogenesis inhibitors for treatment for hypercortisolemia (7). While some of these drugs demonstrate quick onset of action regarding normalization of cortisol level (and hence improve clinical comorbidities), rapid effects on immune system responses are not likely, which might be of great relevance in case of acute infection. Secondly, adrenolytic therapy increases a risk of AI, which can be even more perilous than CS in case of infection or other stress situations (8121516). A modified “block and replace” approach may be considered, where addition of hydrocortisone could diminish the risk of AI (7). Still, there are a few potential pitfalls with this regimen as well. Some people fail to respond to high doses of adrenal-blocking agents due to genetic differences in the steroidogenic enzymes, since therapeutic responses to metyrapone and ketoconazole in patients with CS are associated with the polymorphism in the CYP17A1 gene (17). Additionally, there are not enough data about possible interactions between adrenolytic drugs (majority of them being metabolized through the CYP450/CYP3A4 pathway) and medications used to treat COVID-19, most of which are only just emerging (18). Special concerns, amplified with similar potential effects of SARS-CoV-2 itself as well as specific therapies are liver dysfunction (metyrapone, ketoconazole), hypokalemia (metyrapone, ketoconazole), QT-interval prolongation (ketoconazole, osilodrostat), gastrointestinal distress (mitotane, osilodrostat, etomidate) (18). Metyrapone may cause accumulation of androgenic precursors secondary to the blockade of cortisol synthesis, that can virtually enhance expression of transmembrane protease serine 2 (TMPRSS2), found to be essential to activate the viral spikes, induce viral spread, and pathogenesis in the infected hosts (19). Another important issue concerns biochemical estimation of disease control (and hence risk for AI), since most commercially available assays can overestimate cortisol level in patients treated with metyrapone due to cross-reactivity with the precursor 11-deoxicortisol (715). Mass spectrometry is a method of choice to overcome this problem, but it is not available in many centers. Some centers advocate titration and/or temporary halting medical therapies in the treatment of patients with CS in the context of COVID-19 infection (20). Treatement was stopped in a few patients with severe COVID-19 symptoms who were then given high dose GC for a few days with no long-term complications, and with full recovery (20).

There are no data about the effect of anti-viral drugs in patients with CS and COVID-19. A special concern refers to adipose tissuse, as adipose tissue is difficult for antiviral drugs to reach. It cannot be excluded that the constant release of viral replicas from the adipose tissue reservoir may interfere with COVID-19 infection treatment, delaying its resolution and favoring a worse prognosis (15). If antiviral drugs are started, it is suggested that immunocompromised patients may require prolonged therapy (18). However, the timing is difficult in practice and candidates for antivirals are limited.

Since the clinical course of COVID-19 only initially depends on viral replication, immunomodulatory therapy emerged as a valuable treatment option to control the host immune response. This became apparent ever since RECOVERY trial proved efficacy of glucocortiods (21). But this therapeutic option is fairly inapplicable in patients with active CS, since glucocorticoid treatment in chronic hypercortisolism seems to enhance immune system alterations (22). In parallel with the development of new agents, it is prudent to study the efficacy of existing therapeutic options with acceptable safety profile (20). Beside glucocorticoids, inflammation blockers, intravenous immunoglobulin and convalescent plasma were used in various settings (23).

Intravenous immunoglobulin (IVIg) is a blood product prepared from the serum pooled from thousands of healthy donors, containing a mixture of polyclonal IgG antibodies, mostly IgG1 and IgG2 subclasses (2425). Initial rationale for its use was immunodefficiency due to hypoglobulinemia. Since then it has been shown that IVIg exerts pleiotropic immunomodulating action involving both innate and adaptive immunity and it has been used in a variety of diseases (26). In previous studies on MERS (Middle East Respiratory Syndrome) and SARS (Severe Acute Respiratory Syndrome) using IVIg showed beneficial clinical effects (25). Although pathogenesis of COVID-19 has not be fully elucidated, there is a consensus that immune-mediated inflammation plays an important role in the progression of this disease, just as it did in prior coronavirus infections (27). In this context, the actual role of IVIg in COVID-19 patients might be not to boost the immune system, but through its immunomodulatory effect to suppress a hyperactive immune response that is seen in some patients (28). So far, a limited number of studies, case series and meta-analyses demonstrate a promising potential of IVIg in patients with COVID-19. The effect was demonstrated in terms of mortality, improvement of clinical symptoms, laboratory examinations, imaging and length of hospital stay, especially in patients with moderate/severe form of the disease, and with emphasis on early administration (within 3 days of admission) (24252731). A recent double blind, placebo-controlled, phase 3, randomized trial tested hyperimmune intravenous immunoglobulin (hIVIg) to SARS-CoV-2 derived from recovered donors with no demonstrated effect compared with standard of care, but therapy was administered in patients symptomatic up to 12 days (32). Additional clinical trials are underway, hopefully with more guidance for proper selection of patients that might benefit from this type of treatment.

Conclusion

To our knowledge, this is the first case of IVIg treatment in a COVID-19 patient with CS. It is our opinion that immune-modulating properties of IVIg might present an attractive treatment option, especially in those CS patients that show rapid clinical progression and positive laboratory parameters of inflammation. While we await for new therapeutic modalities for COVID-19 and while some of the modalities remain not widely available, IVIg is more accessible, safe method, which could be rescuing in carefully selected patients. Of note, we consider our patient’s vaccinal status as an unquestionable positive contributor to the favorable outcome

Data Availability Statement

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

Ethics Statement

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author Contributions

BP, AS, JV, TG, MJ-L, JV, VS, ZG and TA-V analyzed and interpreted the patient data. BP, AP, DI, and DJ were major contributors in writing the manuscript. All authors contributed to the article and approved the submitted version.

Conflict of Interest

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

Publisher’s Note

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

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2022.889928/full#supplementary-material

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Keywords: Cushing’s syndrome, COVID-19, IVIg, hypercortisolism, immunomodulation, immunosuppression

Citation: Popovic B, Radovanovic Spurnic A, Velickovic J, Plavsic A, Jecmenica-Lukic M, Glisic T, Ilic D, Jeremic D, Vratonjic J, Samardzic V, Gluvic Z and Adzic-Vukicevic T (2022) Successful Immunomodulatory Treatment of COVID-19 in a Patient With Severe ACTH-Dependent Cushing’s Syndrome: A Case Report and Review of Literature. Front. Endocrinol. 13:889928. doi: 10.3389/fendo.2022.889928

Received: 04 March 2022; Accepted: 17 May 2022;
Published: 22 June 2022.

Edited by:

Giuseppe Reimondo, University of Turin, Italy

Reviewed by:

Nora Maria Elvira Albiger, Veneto Institute of Oncology (IRCCS), Italy
Miguel Debono, Royal Hallamshire Hospital, United Kingdom

Copyright © 2022 Popovic, Radovanovic Spurnic, Velickovic, Plavsic, Jecmenica-Lukic, Glisic, Ilic, Jeremic, Vratonjic, Samardzic, Gluvic and Adzic-Vukicevic. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Bojana Popovic, popbojana@gmail.com

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

From https://www.frontiersin.org/articles/10.3389/fendo.2022.889928/full

Eyelid Edema Due to Cushing’s Syndrome

Abstract

Cushing’s syndrome (CS) shows diverse signs such as centripetal obesity, moon face, and buffalo hump, which can complicate the diagnosis. Facial features including eyelid edema, as an underrecognized sign, can be diagnostic clues for an excess of corticoids in a CS patient.

A 49-year-old woman presented with amenorrhea and weight gain that had continued for 2 years. Her medical history was dyslipidemia, hypertension, and osteoporosis. Physical examination revealed eyelid edemas (Figure 1A), moon face, buffalo hump, abdominal purple striae, and centripetal obesity (body mass index (BMI), 30.8 kg/m2). Basal plasma adrenocorticotropin was undetectable and serum cortisol level was high (16.9 μg/dl) without circadian rhythms. Free cortisol level in a 24-h urine collection was elevated (158.7 μg/day). Overnight administration of dexamethasone (1 mg) did not reduce serum cortisol level (17.4 μg/dl). Magnetic resonance imaging suggested bilateral adenomas. We made a diagnosis of adrenal Cushing’s syndrome (CS). Since 131l-adosterol scintigraphy showed specific uptake in the left adrenal gland, left adrenalectomy was laparoscopically performed. Histopathology of the tumor was compatible with adrenocortical adenoma. Three months after surgery, her BMI decreased to 25.0 kg/m2 and eyelid edemas were ameliorated (Figure 1B).

Details are in the caption following the image

(A) Bilateral eyelid edemas due to Cushing’s syndrome are shown. (B) These findings were improved three months after surgery for left adrenal adenomas

Eyelid edema, in addition to centripetal obesity, moon face, and buffalo hump, is also a significant sign of CS; however, it has scarcely been reported in countries other than Japan.12 Increased capillary permeability, insufficient venous return due to muscle atrophy, and sodium retention due to mineralocorticoid actions conceivably cause edema in CS.

AUTHORS’ CONTRIBUTIONS

KY wrote the first draft and managed all the submission processes. KO and KH contributed to the clinical management of the patient. FO organized the writing the manuscript.

ACKNOWLEDGMENT

None.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

ETHICAL APPROVAL

Written informed consent was obtained from the patient to publish this case report.

  • 1Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet. 2015; 386: 913- 927.
  • 2Komiya I, Takasu N, Ohara N, et al. Forty-one cases of Cushing’s syndrome: a comparison between Cushing’s syndrome (adrenal adenoma) and Cushing’s disease (adrenal hyperplasia). Nihon Naibunpi Gakkai Zasshi. 1992; 68: 607- 622.

https://doi.org/10.1002/ccr3.5940

From https://onlinelibrary.wiley.com/doi/10.1002/ccr3.5940

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