Prevalence of Nelson’s Syndrome After Bilateral Adrenalectomy in Patients with Cushing’s Disease

Eleni PapakokkinouMarta PiaseckaHanne Krage CarlsenDimitrios ChantzichristosDaniel S. OlssonPer DahlqvistMaria PeterssonKatarina BerinderSophie BensingCharlotte HöybyeBritt Edén EngströmPia BurmanCecilia FollinDavid PetranekEva Marie ErfurthJeanette WahlbergBertil EkmanAnna-Karin ÅkermanErik SchwarczGudmundur JohannssonHenrik Falhammar & Oskar Ragnarsson

Abstract

Purpose

Bilateral adrenalectomy (BA) still plays an important role in the management of Cushing’s disease (CD). Nelson’s syndrome (NS) is a severe complication of BA, but conflicting data on its prevalence and predicting factors have been reported. The aim of this study was to determine the prevalence of NS, and identify factors associated with its development.

Data sources

Systematic literature search in four databases.

Study Selection

Observational studies reporting the prevalence of NS after BA in adult patients with CD.

Data extraction

Data extraction and risk of bias assessment were performed by three independent investigators.

Data synthesis

Thirty-six studies, with a total of 1316 CD patients treated with BA, were included for the primary outcome. Pooled prevalence of NS was 26% (95% CI 22–31%), with moderate to high heterogeneity (I2 67%, P < 0.01). The time from BA to NS varied from 2 months to 39 years. The prevalence of NS in the most recently published studies, where magnet resonance imaging was used, was 38% (95% CI 27–50%). The prevalence of treatment for NS was 21% (95% CI 18–26%). Relative risk for NS was not significantly affected by prior pituitary radiotherapy [0.9 (95% CI 0.5–1.6)] or pituitary surgery [0.6 (95% CI 0.4–1.0)].

Conclusions

Every fourth patient with CD treated with BA develops NS, and every fifth patient requires pituitary-specific treatment. The risk of NS may persist for up to four decades after BA. Life-long follow-up is essential for early detection and adequate treatment of NS.

Introduction

Cushing´s disease (CD) is a rare disorder associated with excess morbidity and increased mortality [12]. Previously, bilateral adrenalectomy (BA) was the mainstay treatment for CD. During the last decades, however, other treatment modalities have emerged, including pituitary surgery, radiotherapy and medical treatments. Despite this, BA is still considered when other treatment options have failed to achieve remission, or when a rapid relief of hypercortisolism is necessary [3].

BA is considered to be a safe and effective treatment for CD [4], especially after the laparoscopic approach was introduced during the 1990s [5]. There are, however, significant drawbacks with BA, mainly the unavoidable chronic adrenal insufficiency, as well as the risk for Nelson’s syndrome (NS), i.e., growth of the remaining pituitary tumor and excessive production of ACTH, that may cause optic nerve or chiasmal compression and mucocutaneous hyperpigmentation [6].

The prevalence of NS varies between studies, mainly due to a lack of consensus on the definition and diagnostic criteria for the syndrome [78]. Previously published studies are also inconsistent as to whether factors such as previous radiotherapy, age at BA, gender and duration of CD, may affect the risk of developing NS. Furthermore, high ACTH concentrations after BA have been suggested as a risk factor for developing NS [9,10,11,12].

Thus, the primary aim of this systematic review and meta-analysis was to estimate the prevalence of NS after BA for CD, both the total prevalence of NS as well the prevalence of NS requiring treatment with pituitary surgery and/or radiotherapy. The secondary aim was to investigate risk factors associated with development of NS.

Methods

A systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [13]. The PICO process was applied for the definition of the research question and eligibility criteria for the literature search. The protocol of this review was registered in the PROSPERO database (CRD42020163918).

Search strategy

We searched PubMed, Embase, Cochrane Library and Web of Science on February 25th 2020, with no start date restriction, for relevant articles by using the following terms: “Cushing´s syndrome” or “Cushing´s disease” or “Hypercortisolism” or “Pituitary ACTH hypersecretion” or “corticotroph tumor” or “corticotroph tumors” or “corticotroph adenoma” or “corticotroph adenomas” or “corticotropinoma” or “corticotropinomas” or “corticotrophinoma” or “corticotrophinomas” or “ACTH pituitary adenoma” or “ACTH pituitary adenomas” or “adrenocorticotropin pituitary adenoma” or “adrenocorticotropin pituitary adenomas” AND “bilateral adrenalectomy” or “bilateral adrenalectomies” or “total adrenalectomy” or “total adrenalectomies”. A detailed description of the search strategy is given in the Supplementary. Also, references of the included studies and relevant review articles were checked manually for additional articles. A new search was performed on January 12th 2021, prior submission, to identify any new publications.

Study selection and eligibility criteria

Eligible studies were observational studies (cohort or cross-sectional studies) reporting the prevalence of NS in adult patients with CD treated with BA. Studies including only children (age < 18 years), review articles, letters, commentaries and meeting abstracts were excluded. Moreover, case reports, case-series and studies with a population of fewer than 10 cases were excluded. Also, studies written in languages other than English were not considered for inclusion.

Data collection process and data extraction

Titles and abstracts from all identified articles were screened for eligibility and further full-text assessment by three independent investigators (EP, MP, OR). Discrepancies were resolved through discussion and consensus. Duplicate articles and studies with overlapping populations were excluded. In the latter case, the publication with the largest population, more comprehensive information on relevant clinical variables and/or lowest risk of bias was included.

Full-text assessment and data extraction were conducted independently by the same investigators as above. Data on the following predefined variables were extracted: first author, year of publication, region/hospital, study period, characteristics of the study population (number of patients, gender, follow-up, age at CD, age at BA, previous treatment with radiotherapy and/or pituitary surgery, ACTH concentrations at BA, MRI findings at CD and at BA), intervention (BA as primary or secondary treatment, remission status) and outcome (criteria for NS, number of patients with NS, age at NS, time from BA to NS, ACTH concentrations one year after BA, number of patients treated for NS, type of treatment; pituitary radiotherapy and/or pituitary surgery).

One of the studies included in the meta-analysis is our nationwide Swedish study on CD [2]. Additional clinical data, not provided in the original publication, was retrieved and used in the current analysis (Table 1).Table 1 Characteristics of the included studiesFull size table

Risk of bias assessment

The Newcastle–Ottawa Scale [14], modified to suit the current study, was used for assessment of risk of bias of all included studies. Three investigators (EP, MP, OR) assessed the studies independently, and any disagreements were resolved by discussion. Selection, comparability and outcome were assessed through predefined criteria. All studies that provided information on NS as outcome, and/or corticotroph tumor progression, were included, and the definition as well as the treatment of NS were recorded (Table 1 and Table S1). A clear definition of NS and information on treatment were considered to be two of the most important components of the quality assessment. We considered the definition of NS to be clear when it included either a new visible pituitary tumor or progression of a pituitary tumor remnant following BA, alone, or in combination with high ACTH concentrations and/or hyperpigmentation. Detailed description of the criteria for the risk of bias assessment is provided in the Supplementary file. Studies with an overall score ≥ 5 (max overall grade 8) and a clear definition of NS, were considered to have a low risk of bias.

Data synthesis and statistical analysis

Primary endpoints were the prevalence of NS, as well as the prevalence of pituitary-specific treatment for NS. Descriptive data are presented as median (range or interquartile range; IQR). Meta-analysis was performed by using the meta package in R (version 4.0.3) [15]. Statistical pooling was performed according to random-effects model due to the clinical heterogeneity among the included studies [16]. For all analyses, indices of heterogeneity, I2 statistics and Cochrane’s Q test, are reported. For the primary outcomes we estimated pooled prevalence with 95% confidence intervals (95% CI). Statistical significance was defined as P < 0.05. The possibility of publication bias was assessed by visual inspection of funnel plots as well as with the Egger’s test [17].

Sensitivity analyses were performed by excluding studies with an overall risk of bias < 5, and studies where information on diagnostic criteria for NS was lacking. By choosing the overall risk of bias < 5, all studies without adequate follow-up were also excluded (Table S2). Also, another sensitivity analysis was performed by including all studies reporting the number of patients with NS who received treatment for NS (Table 1).

Subgroup analyses were performed to investigate factors that may affect the prevalence of NS, namely pituitary radiotherapy prior to BA, prophylactic pituitary radiotherapy, overall radiotherapy (prior to BA or prophylactic), pituitary surgery (transcranial or transsphenoidal surgery) prior to BA, and BA as primary or secondary treatment. For these outcomes, we estimated relative risks (RRs), or pooled prevalence, with 95% CIs. Also, in a subgroup analysis, the prevalence (with 95% CI) of NS and treatment for NS were estimated in studies where MRI was used at diagnosis and during follow-up.

Uni- and bivariate meta-regression was used to investigate whether the prevalence of NS was influenced by median follow-up time or age at BA. The meta-analysis was performed by using the Metareg command in R. The estimated association is reported as β coefficient.

Role of funding source

The funding source had no role in the design and conduction of the study; i.e., collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Results

Identification and description of included studies

After removal of duplicates, 1702 articles were identified (Fig. 1). Three additional articles were found after checking the reference lists of identified articles and review papers. After reviewing titles, abstracts and full-text articles, 48 articles were considered eligible for further analysis. Of these, however, 11 articles were excluded due to overlapping or identical patient cohorts. Thus, 37 studies published between 1976 and 2020, were included in the current meta-analysis (Fig. 1). All studies had a retrospective observational design. Characteristics of the included studies are presented in Table 1. Two of the included studies had an overlapping cohort where one was used for the main outcome [18] and one [19] for the subgroup analyses on the influence of radiotherapy on the development of NS. An overview of risk of bias assessment of the eligible studies is provided in Table S2.

figure1
Fig. 1

In total, 1316 patients with CD treated with BA were included. The median follow-up after BA was 7 years (23 studies, range 3.3–22). Median age at BA in patients with NS was 31 years (13 studies, IQR 26–34). Median time from BA to the diagnosis of NS was 4 years (19 studies) with the shortest reported time being 2 months [20] and the longest 39 years [2]. At diagnosis of NS, hyperpigmentation was reported in 155 of 188 (82%) patients (19 studies) and chiasmal compression in 24 of 129 (19%) patients [11 studies].

Prevalence of NS

Thirty-six of 37 studies, with total 1316 patients with CD treated with BA, were included [21820,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53]. Reported prevalence of NS ranged from 4 to 60%. The mean pooled prevalence was 26% (95% CI 22–31%) with a moderate to high heterogeneity (I2 67%, P < 0.01) (Fig. 2). The Egger’s test was statistically significant (P = 0.01), but visual inspection showed no obvious asymmetry. The significant Egger’s test indicates publication bias, probably explained by the fact that case reports and cohorts with fewer than 10 participants were excluded (Fig. S1).

figure2
Fig. 2

In a sensitivity analysis, excluding all studies with high risk of bias (overall score < 5) and no clear definition of NS, the pooled prevalence was 31% (95% CI 24–38%; I2 76%, 17 studies, 822 patients; P < 0.01) (Fig. S2). In a subgroup analysis, the prevalence of NS in studies where MRI was used at diagnosis and during follow-up was 38% (Fig. 3; 95% CI 27–50%; I2 71%, 7 studies, 280 patients; P < 0.01).

figure3
Fig. 3

Prevalence of treated NS

The pooled prevalence of treatment for NS was 21% (95% CI 18–26%; I2 52%, P < 0.01) (Table 1; 29 studies with 1074 patients). Thus, the pooled prevalence was slightly lower, compared to the pooled prevalence of NS in total, as well as the heterogeneity (Fig. S3). The funnel plot showed no asymmetry and Egger’s test was not statistically significant, indicating low possibility of publication bias (Fig. S4). In a subgroup analysis, the prevalence of treated NS in studies where MRI was used at diagnosis and during follow-up was 25% (95% CI 17–35%; I2 61%, 7 studies; P = 0.02).

The indication for treatment was progression of the pituitary tumor in 23 out of 28 patients (82%, five studies), optic chiasmal compression in 11 out of 91 patients (12%, 11 studies), while four patients out of 14 (one study) had both these indications for treatment. Twenty-six studies provided information on treatment modalities (pituitary surgery and/or radiotherapy). Seventy-three out of 201 patients with NS (36%) were treated with pituitary surgery, 86 (43%) with radiotherapy and 41 (20%) received both treatments.

Radiotherapy

Nineteen studies provided information on radiotherapy prior to BA. However, nine studies had no events and no patients in one of the arms (radiotherapy or no radiotherapy) (Table S3). Thus, ten studies were eligible for further estimation, showing that the risk for NS in patients treated with radiotherapy prior to BA was comparable to the risk in patients not treated with radiotherapy (RR 0.9, 95% CI 0.5–1.6; 10 studies with 564 patients) (Fig. 4).

figure4
Fig. 4

Thirteen studies provided information on prophylactic radiotherapy. However, only one study provided applicable data for calculating RR, thus subgroup analysis was not performed (Table S4). In that study [20], none of the seventeen patients who received prophylactic radiotherapy developed NS, while 11 of 22 patients without radiotherapy developed NS after a mean follow-up of 4.4 years (range 10–16 years).

By using studies with information on either previous or prophylactic radiotherapy (11 studies with 603 patients; Table S5), the pooled RR was 0.8 (95% CI 0.5–1.5).

Pituitary surgery prior to BA

Of 21 studies with information on pituitary surgery prior to BA (Table S6), only ten provided information for estimation of RR. A pooled RR of 0.6 (10 studies with 430 patients; 95% CI 0.4–1.0) was found (Fig. 5), indicating that the risk for developing NS was not influenced by previous pituitary surgery.

figure5
Fig. 5

BA as primary or secondary treatment for CD

Information on whether patients with NS were treated primarily with BA or not, was provided in ten and nine studies, respectively (Fig. S5 and S6). The pooled prevalence of NS was 26% (95% CI 20–33%) for patients treated primarily with BA and 22% (95% CI 15–31%) for patients who had been treated with pituitary surgery and/or radiotherapy prior to BA.

ACTH concentrations one year after BA

Four studies provided information on ACTH concentrations during the first year after BA [45495253]. In a study by Assié et al. the median ACTH concentration in patients who developed NS was 301 pmol/L, compared to 79 pmol/L in patients without NS (upper range of limit; URL 13 pmol/L) [52]. The median ACTH concentration in a study by Cohen et al. was 105 pmol/L in the NS group compared to 18 pmol/L in patients without NS (P = 0.007) (URL 10 pmol/L) [49]. Also, in a study by Das et al., there was a statistically significant difference in ACTH concentrations one year after BA between patients with and without NS (110 vs 21 pmol/L respectively; P = 0.002) [53]. On the contrary, Espinosa-de-Los-Monteros et al.found no difference in ACTH concentrations between the patients with NS and those without NS [45]. Thus, three of four studies found that high ACTH concentrations one year after BA were associated with the development of NS. However, since the ACTH assays and the conditions when ACTH was collected were different in these studies (Table S7), further comparison or a meta-analysis on ACTH levels after BA was not considered feasible.

Influence of age at BA and duration of follow-up on prevalence of NS

In a meta-regression analysis, age at BA (β-coefficient = – 0.03, P = 0.4; Fig. 6) and median duration of follow-up (β-coefficient = 0.01, P = 0.7; Fig. S7) were not associated with prevalence of NS. After adjustment for follow-up, age at BA was still not associated with prevalence of NS (β-coefficient = -0.03, P = 0.4).

figure6
Fig. 6

Discussion

In this study we have for the first time evaluated the pooled prevalence of NS by using a meta-analysis on data from 36 studies, including more than 1300 patients with CD treated with BA. The overall prevalence of NS was 26% and the median time from BA to diagnosis of NS was 4 years, ranging from 0.2 to 39 years. The prevalence of patients requiring pituitary-specific treatment for NS was 21%. Furthermore, radiotherapy and pituitary surgery prior to BA, as well as age at BA, did not seem to affect the risk of developing NS.

Various definitions have been used for NS over the past decades [12]. Historically, the diagnosis was based on clinical findings related to mucocutaneous hyperpigmentation and chiasmal compression, together with signs of an enlarged sella turcica on skull radiography [6]. Since then, the diagnosis of NS in most studies has been based on (i) radiological evidence of a pituitary tumor that becomes visible, or a progression of a preexisting tumor, (ii) “high” ACTH concentrations, and (iii) hyperpigmentation [54]. In the studies with the highest prevalence of NS [4546], the diagnosis was based on rising ACTH concentrations and an expanding pituitary mass, where 2 mm increment in tumor size on MRI was considered to be a significant growth. On the contrary, the criteria for NS in studies with the lowest prevalence were based on hyperpigmentation, often but not always combined with a pituitary tumor responding to radiotherapy and/or a radiographic evidence of pituitary tumor on skull radiography [2123]. Thus, the great variance in the prevalence of NS between studies can, at least partly, be explained by the different definitions of NS. Consequently, in an expert opinion published in 2010, it was suggested that the diagnosis of NS should be based on an elevated level of ACTH >500 ng/L (110 pmol/L) in addition to rising levels of ACTH on at least three consecutive occasions and/or an expanding pituitary mass on MRI or CT following BA [54]. Similarly, in a recently published expert consensus recommendation, based on a systematic review, it was suggested that NS should be defined as radiological progression or new detection of a pituitary tumor on a thin-section MRI [55]. Furthermore, the authors recommend active surveillance with MRI three months after BA, and every 12 months for the first 3 years, and every 2–4 years thereafter, based on clinical findings. The meta-regression of the current analysis did not show an association between median follow-up time and prevalence of NS. Nevertheless, NS occurred as early as 2 months [20], and up to 39 years after BA [2], supporting that life-long surveillance after BA is necessary for patients with CD.

Active surveillance with MRI was more common in studies published during the last two decades. In fact, the use of MRI in recent studies resulted in earlier detection of a growing pituitary adenoma and, subsequently, contributed to a higher prevalence of NS. Namely, the seven studies including patients treated with BA after 1990 and using MRI reported higher prevalence of NS, both overall NS and treated NS.

Whether factors such as pituitary radiotherapy affects the risk for development of NS has been evaluated in several studies. Some studies have shown that radiotherapy prior to BA, or administrated prophylactically, can prevent or delay the development of NS [2039]. On the contrary, other studies have not demonstrated a protective effect of radiotherapy prior to BA [1837] and, moreover, one study found an association with tumor progression [46]. Nevertheless, the current meta-analysis indicates that radiotherapy prior to BA does not decrease the risk of developing NS. Neither did previous pituitary surgery affect the risk for NS.

Elevated ACTH concentrations during the first year after BA have been considered to be a strong predictor of NS [4952]. In fact, seven studies in the current analysis included cut-off levels for ACTH concentration, arbitrarily defined, for the diagnosis of NS [18253436414549]. Due to the different ACTH assays, and different conditions when ACTH was collected, no further analysis on ACTH levels was performed. Nevertheless, four studies [45495253] reported ACTH concentrations one year after BA in both patients with and without NS. Three of these studies found that high ACTH concentrations one year after BA [495253] were associated with pituitary tumor progression. Thus, these findings support the suggestion that ACTH should be monitored following BA in patients with CD [5455].

The prevalence of treatment for NS (21%), and the heterogeneity index (52%), were slightly lower than in the analysis of total prevalence of NS (26%, I2 67%). The majority of the patients was treated with radiotherapy, followed by pituitary surgery and combination of pituitary surgery and radiotherapy. Today, surgical removal of the pituitary tumor is considered to be the first-line therapy of NS whereas radiotherapy is considered if surgery has failed or is not possible [125456]. In a large multi-center study by Fountas et al., the 10-year progression-free survival rates after surgery alone, or with radiotherapy, for patients with NS was 80% and 81%, respectively [57]. In comparison, progression-free survival rate in patients who did not receive treatment was 51%. Reports on the efficacy of medical therapy for NS have shown inconsistent results [56].

Strengths and limitations

This is the largest systematic review, and the first meta-analysis, on NS published to date. However, some limitations have to be acknowledged. Most important are the different diagnostic methods used to detect NS, and the different definitions of the syndrome between the studies. The majority of the studies have used the combination of hyperpigmentation, high ACTH concentrations and radiological findings for the diagnosis of NS. Notwithstanding these common criteria, there were still differences in the cut-offs of ACTH levels, the use of different radiological modalities over time as well as the radiological definition of progress of pituitary tumors. Moreover, in some studies radiological findings were used solely or in combination with either hyperpigmentation and/or bitemporal hemianopsia, ACTH concentrations or response to treatment of NS. Furthermore, in several studies a clear definition of NS was not provided. Nevertheless, we consider our attempt to address the heterogeneity of the included studies, through systematic review, quality assessment, and sensitivity and subgroup analyses to be a strength.

Conclusions

The risk of NS after BA in patients with CD is considerable and may first become clinically evident many decades later. Thus, life-long close follow-up is necessary for an early detection of a growing pituitary tumor, and adequate treatment when needed. Although this meta-analysis did not find prior surgery or radiotherapy to be associated with risk of NS, the findings are based on a limited number of studies. Thus, in order to individualize the treatment for patients with CD, further studies are needed where these and other factors possibly associated with risk of NS are evaluated.

Data availability

The data generated or analyzed during this study are included in this published article or in the Supplementary file.

Abbreviations

CD:

Cushing’s diseaseBA:

Bilateral adrenalectomyNS:

Nelson’s syndromeACTH:

Adrenocorticotropic hormoneRR:

Relative riskMRI:

Magnet resonance imagingCT:

Computer tomography

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Acknowledgements

We would like to thank Therese Svanberg, librarian at the Medical Library at Sahlgrenska University Hospital for her expert assistance with the literature search.

Funding

Open access funding provided by University of Gothenburg. The study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-593301) and a grant from the Gothenburg Society of Medicine.

Author information

Affiliations

  1. Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, 413 45, Gothenburg, SwedenEleni Papakokkinou, Marta Piasecka, Dimitrios Chantzichristos, Daniel S. Olsson, Gudmundur Johannsson & Oskar Ragnarsson
  2. The Department of Endocrinology, Sahlgrenska University Hospital, Blå stråket 5, 413 45, Gothenburg, SwedenEleni Papakokkinou, Marta Piasecka, Dimitrios Chantzichristos, Daniel S. Olsson, Gudmundur Johannsson & Oskar Ragnarsson
  3. Department of Environmental and Occupational Health School of Public Health and Community Medicine, University of Gothenburg, 4053, Gothenburg, SwedenHanne Krage Carlsen
  4. Department of Public Health and Clinical Medicine, Umeå University, 901 87, Umeå, SwedenPer Dahlqvist
  5. Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176, Stockholm, SwedenMaria Petersson, Katarina Berinder, Sophie Bensing, Charlotte Höybye & Henrik Falhammar
  6. Department of Endocrinology, Karolinska University Hospital, 171 76, Stockholm, SwedenMaria Petersson, Katarina Berinder, Sophie Bensing, Charlotte Höybye & Henrik Falhammar
  7. Department of Endocrinology and Diabetes, Uppsala University Hospital, and Department of Medical Sciences, Endocrinology and Mineral Metabolism, Uppsala University, 751 85, Uppsala, SwedenBritt Edén Engström
  8. Department of Endocrinology, Skåne University Hospital, University of Lund, 205 02, Malmö, SwedenPia Burman
  9. Department of Endocrinology, Skåne University Hospital, 222 42, Lund, SwedenCecilia Follin, David Petranek & Eva Marie Erfurth
  10. Department of Endocrinology and Department of Medical and Health Sciences, Linköping University, 581 83, Linköping, SwedenJeanette Wahlberg & Bertil Ekman
  11. Department of Internal Medicine, School of Health and Medical Sciences, Örebro University, 702 81, Örebro, SE, SwedenJeanette Wahlberg, Anna-Karin Åkerman & Erik Schwarcz

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Correspondence to Oskar Ragnarsson.

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Papakokkinou, E., Piasecka, M., Carlsen, H.K. et al. Prevalence of Nelson’s syndrome after bilateral adrenalectomy in patients with cushing’s disease: a systematic review and meta-analysis. Pituitary (2021). https://doi.org/10.1007/s11102-021-01158-z

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Keywords

  • Bilateral adrenalectomy
  • Cushing’s disease
  • Corticotroph adenoma
  • Nelson’s syndrome

From https://link.springer.com/article/10.1007/s11102-021-01158-z

Chronic Insomnia Can Be Sign of Cushing’s

Abstract

Background: Cushing’s syndrome is a condition caused by excessive glucocorticoid with insomnia as one of its neuropsychiatric manifestation. Cushing’s syndrome may be caused by excessive adrenocorticotropin hormone (ACTH-dependent), for example from ACTH producing pituitary tumors, or by overproduction of cortisol by adrenocortical tumors. In this report, we presented a case with Cushing’s syndrome manifesting as chronic insomnia with adrenal cortical adenoma and pituitary microadenoma.

Case presentation: A 30-year-old woman was consulted from the Neurologic Department to the Internal Medicine Department with the chief complaint of insomnia and worsening headache for 6 months prior to the admission. She had undergone head MRI and abdominal CT scan previously and was found to have both pituitary microadenoma and left adrenal mass. From the physical examination she had clinical signs of Cushing’s syndrome like Cushingoid face and purplish striae on her stomach. Midnight cortisol serum examination was done initially and showed high level of cortisol. High dose dexamethasone suppression test or DST (8 mg overnight) was later performed to help determine the main cause of Cushing’s syndrome. The result failed to reach 50% suppression of cortisol serum, suggestive that the Cushing’s syndrome was not ACTH-dependent from the pituitary but potentially from overproduction of cortisol by the left adrenal mass. Therefore, left adrenalectomy was performed and the histopathological study supported the diagnosis of adrenal cortical adenoma.

Conclusion: Chronic insomnia is a very important symptoms of Cushing’s syndrome that should not be neglected. The patient had both microadenoma pituitary and left adrenal mass thus high dose DST test (8 mg overnight) needed to be performed to differentiate the source of Cushing’s syndrome. The result showed only little suppression therefore the pituitary microadenoma was not the source of Cushing’s syndrome and more suggestive from the adrenal etiology.

Keywords: Cushing’s syndrome; insomnia; adrenal cortical adenoma; pituitary microadenoma; dexamethasone suppression test

Permalink/DOI: https://doi.org/10.14710/jbtr.v7i1.9247I

Read the entire article here: https://ejournal2.undip.ac.id/index.php/jbtr/article/view/9247/5440

Home cortisol tests: 3 of the best

Please note that if you buy through links in this article, Medical News Today may earn a small commission. Here’s their process.

Cortisol is a hormone with various functions throughout the body. However, if a person’s body cannot regulate their cortisol levels, it could lead to a serious health condition. In these cases, home cortisol tests may be useful to indicate when someone might need medical attention.

A person sitting at a desk, holding an at-home cortisol test tube, typing on a laptop.

This article discusses:

  • what cortisol is
  • what a home cortisol test is
  • why a person might buy a home cortisol test
  • some home cortisol tests to purchase online
  • when to see a doctor

What is cortisol?

Cortisol is the stress hormone that affects several systems in the body, including the:

The adrenal glands produce cortisol. Most human body cells have cortisol receptors, and the hormone can help in several ways, including:

  • reducing inflammation
  • regulating metabolism
  • assisting with memory formation
  • controlling blood pressure
  • developing the fetus during pregnancy
  • maintaining salt and water balance in the body
  • controlling blood sugar levels

All these functions make cortisol a vital part of maintaining overall health. If the body can no longer regulate cortisol levels, it can lead to several health disorders, such as Cushing’s syndrome and Addison’s disease. Without treatment, these conditions could cause life threatening complications.

The body requires certain cortisol levels during times of stress, such as:

  • in the event of an injury
  • during illness
  • during a surgical procedure

What are home cortisol tests? 

A cortisol test usually involves a blood test. However, some may require saliva and urine samples instead.

There are several home cortisol tests available to purchase over the counter or online. These allow a person to take a sample of blood, urine, or saliva before sending it off for analysis.

After taking a home cortisol test, people can usually receive their results within 2–5 days online or via a telephone call with a healthcare professional.

However, there are currently no studies investigating the reliability of these home cortisol tests. Therefore, people should follow up on their test results with a healthcare professional.

Why and when do people need them? 

A person should take a home cortisol test if they feel they may have a cortisol imbalance.

If cortisol levels are too high, a person may notice the following:

  • rapid weight gain in the face, chest, and abdomen
  • high blood pressure
  • osteoporosis
  • bruises and purple stretch marks
  • mood swings
  • muscle weakness
  • an increase in thirst and need to urinate

If cortisol levels are too low, a person may experience the following symptoms:

  • fatigue
  • loss of appetite
  • unintentional weight loss
  • muscle weakness
  • abdominal pain

Additionally, low cortisol levels may lead to:

A test can help individuals check their cortisol levels. If the test results show these levels are too high or too low, people should seek medical advice.

A cortisol imbalance may be a sign of an underlying condition, which can lead to serious complications without treatment.

If a person cannot carry out a home cortisol test, they should speak to a medical professional who can arrange a cortisol test at a healthcare facility.

What to look for in a home cortisol test

At a clinic or hospital setting, a medical professional will usually take a blood sample and analyze it for an individual’s cortisol levels.

Home cortisol tests involve a person taking a sample of blood, urine, or saliva. There are currently no studies investigating the accuracy of these results.

However, home cortisol tests may be faster and more convenient than making an appointment with a doctor to take a sample.

People may consider several factors when deciding to purchase a home cortisol test, including:

  • Sample type: Some tests require a blood sample, while others need a sample of urine or saliva. With this in mind, a person may wish to buy a product that uses a testing method they are comfortable providing.
  • Test analysis: A person may wish to purchase a product from a company that sends tests to Clinical Laboratory Improvement Amendments (CLIA)-certified labs for analysis. The Food and Drug Administration (FDA), Center for Medicaid Services, and the Centers for Disease Control and Prevention (CDC) regulate these labs to help ensure safety and accuracy.
  • Accuracy: Individuals may wish to speak to a pharmacist or other healthcare professional before purchasing to ensure the test is reliable and accurate.

Products

Several online retailers offer home cortisol tests. It is important to follow all test instructions to ensure a valid result.

Please note, the writer has not tested these products. All information is research-based.

LetsGetChecked – Cortisol Test

This cortisol test uses the finger prick method to draw blood for the sample.

Here are the steps to take and send off a blood sample:

  1. Individuals fill in their details on the collection box and activate their testing kit online at the LetsGetChecked website.
  2. People need to wash their hands with warm soapy water before using an alcohol swab to clean the finger that they will prick.
  3. Once the finger is completely dry, individuals pierce the skin using the lancet in the test kit. A person must wipe away the first drop of blood before squeezing some into the blood collection tube.
  4. After closing the tube, individuals must invert it 5–10 times before placing it in the included biohazard bag, which they then place in the box.

After following these steps, people can send the sample back to LetsGetChecked using the kit’s prepaid envelope. Test results usually come back within 2–5 days.

LetsGetChecked tests samples in the same labs that primary care providers, hospitals, and government schemes use. These labs are CLIA-certified and CAP-accredited.

The company also has a team of nurses and doctors available 24 hours a day, 7 days a week, to offer ongoing support. These healthcare professionals are on hand to discuss a person’s results with them over the phone.

Everlywell At-Home Cortisol Levels Test Kit – Sleep & Stress Test

This Everlywell product uses a urine sample to test a person’s cortisol levels.

The test measures the levels of three hormones in a person’s body: cortisol, cortisone, and melatonin. It also measures a person’s creatinine levels.

There are three steps with this test:

  1. Individuals register their testing kit on Everlywell’s website.
  2. A person follows the instructions carefully to take their urine sample.
  3. Once they have their urine sample, they place it in the prepaid package and send it off to Everlywell’s labs.

Within a few days, individuals will receive their results digitally via the Everlywell website. Medical professionals can also offer helpful insights via their secure platform.

As well as sending a personalized report of each marker, Everlywell also sends detailed information about what the results mean.

The labs where Everlywell tests samples all carry certification with CLIA. The company also ensures that all results are reviewed and certified by independent board-certified physicians within the person’s specific state.SHOP NOW

Healthlabs Cortisol, AM & PM Test

Healthlabs offers a cortisol test that tests a person’s cortisol levels twice — once in the morning and once in the evening.

The company says they do this because a person’s cortisol levels fluctuate throughout the day. Therefore, by testing twice, they can gather information on this fluctuation.

This test uses a blood sample, which a person takes once in the morning and once in the afternoon. They must follow the instructions clearly to ensure they take suitable samples.

The manufacturer says that people should collect a morning sample between 7–9 a.m. and an evening sample between 3–5 p.m.

They then need to send off their sample for analysis. After testing is complete at a CLIA-certified lab, a person will receive their results, which usually takes between 1–2 days. SHOP NOW

When to speak with a doctor

A person should undergo a cortisol test if they believe they may have high or low cortisol levels.

They can do this at home or speak with a medical professional who can carry out the test for them.

People may also wish to seek medical help if they show signs of too much or too little cortisol. This could indicate a potentially serious underlying health issue.

Summary

Cortisol is an important hormone that affects almost all parts of the body. It has many functions, including reducing inflammation, regulating metabolism, and controlling blood pressure.

If a person believes they have high or low cortisol levels, they may wish to take a cortisol test. Usually, these tests take place at a medical practice. However, several home cortisol tests are available to purchase.

A person can take these tests at home by providing a urine, blood, or saliva sample. Once a lab analyzes the test, people usually receive their results within a few days. Individuals should follow up any test results with a healthcare professional. No clinics, no stress. Test your cortisol levels from home

Test your cortisol level from home with LetsGetChecked. Get free shipping, medical support, and results from accredited labs within 2–5 days. Order today for 30% off. LEARN MORE

Last medically reviewed on April 29, 2021 at https://www.medicalnewstoday.com/articles/3-of-the-best-home-cortisol-tests

How does COVID-19 impact the adrenal gland?

This month marks a little over one year since the first surge of COVID-19 across the United States. April is also Adrenal Insufficiency Awareness month, a good time to review the data on how COVID-19 infection can impact the adrenal glands.

The adrenal glands make hormones to help regulate blood pressure and the ability to respond to stress. The hormones include steroids such as glucocorticoid (cortisol), mineralocorticoid (aldosterone), and forms of adrenaline known as catecholamines (norepinephrine, epinephrine, and dopamine). The activity of the adrenal gland is controlled through its relationship with the pituitary gland (the master regulator of hormones in the body).

Some common adrenal diseases include the following:

  • Addison’s Disease (where the body attacks the adrenal glands making them dysfunctional)
  • Hyperaldosteronism
  • Cushing’s Syndrome
  • Pheochromocytoma
  • Adrenal Nodules/Masses (termed incidentaloma)
  • Congenital adrenal hyperplasia

COVID-19 was found in the adrenal and pituitary glands of some patients who succumbed to the illness, suggesting that these organs might be among the targets for infection.  One of the first highly effective therapies for COVID-19 infection was the use of IV steroid (dexamethasone) supplementation in hospitalized patients in patients requiring oxygen.

A focused search of COVID-19-related health literature shows 85 peer-reviewed papers that have been published in medical literature specifically on the adrenal gland and COVID-19. This literature focuses on three phases of COVID infection that may impact the adrenal gland: the acute active infection phase, the immediate post-infection phase, and the long-term recovery phase.

Medical research has identified that during the acute active infection, the adrenal system is one of the most heavily affected organ systems in the body in patients who have COVID-19 infection requiring hospitalization. In these cases, supplementation with the steroid dexamethasone serves as one of the most powerful lifesaving treatments.

Concern has also been raised regarding the period of time just after the acute infection phase – particularly, the development of adrenal insufficiency following cases of COVID-19 hospitalizations. Additionally, some professional societies recommend that for patients who have adrenal insufficiency and are on adrenal replacement therapy, they be monitored closely post-COVID-19 vaccine for the development of stress-induced adrenal insufficiency.

In mild-to-moderate COVID-19 cases, there does not seem to be an effect on adrenaline-related hormones (norepinephrine, epinephrine, dopamine). However, in cases of severe COVID-19 infection triggering the development of shock, patients will need supplementation with an infusion of catecholamines and a hormone called vasopressin to maintain their blood pressure.

Finally, some studies have addressed the concern of adrenal insufficiency during the long-term recovery phase. Dr Sara Bedrose, adrenal endocrine specialist at  Baylor College of Medicine, indicates that studies which included adrenal function in COVID survivors showed a large percentage of patients with suboptimal cortisol secretion during what is called ACTH stimulation testing.

Results indicated that most of those cases had central adrenal insufficiency. It was concluded that adrenal insufficiency might be among the long-term consequences of COVID-19 and it seemed to be secondary to pituitary gland inflammation (called hypophysitis) or due to direct hypothalamic damage. Long-term follow-up of COVID 19 survivors will be necessary to exclude a gradual and late-onset adrenal insufficiency.

Some patients who have COVID-19 will experience prolonged symptoms. To understand what is happening to them, patients may question whether or not they have a phenomenon called adrenal fatigue. This is a natural question to ask, especially after having such a severe health condition. A tremendous amount of resources are being developed to investigate the source and treatment of the symptoms, and this work has only just begun.

However, adrenal fatigue is not a real medical diagnosis. It’s a term to describe a group of signs and symptoms that arise due to underactive adrenal glands. Current scientific data indicate that adrenal fatigue is not in and of itself a medical disease – although a variety of over-the-counter supplements and compounded medications may be advocated for in treatment by alternative medicine/naturopathic practitioners.

My takeaway is that we have learned a great deal about the effects COVID-19 infection has on the adrenal glands. Long-term COVID-19 remains an area to be explored –  especially in regards to how it may affect the adrenal glands.

-By Dr. James Suliburk, associate professor of surgery in the Division of Surgical Oncology and section chief of endocrine surgery for the Thyroid and Parathyroid Center at Baylor College of Medicine

From https://blogs.bcm.edu/2021/04/22/how-does-covid-19-impact-the-adrenal-gland/

Cushing Death Rate ‘Unacceptable,’ Triple That of General Population

Excess mortality among people with endogenous Cushing syndrome (CS) has declined in the past 20 years yet remains three times higher than in the general population, new research finds.

Among more than 90,000 individuals with endogenous CS, the overall proportion of mortality ― defined as the ratio of the number of deaths from CS divided by the total number of CS patients ― was 0.05, and the standardized mortality rate was an “unacceptable” three times that of the general population, Padiporn Limumpornpetch, MD, reported on March 20 at ENDO 2021: The Endocrine Society Annual Meeting.

Excess deaths were higher among those with adrenal CS compared to those with Cushing disease. The most common causes of death among those with CS were cardiovascular diseases, cerebrovascular accident, infection, and malignancy, noted Limumpornpetch, of Songkla University, Hat Yai, Thailand, who is also a PhD student at the University of Leeds, Leeds, United Kingdom.

“While mortality has improved since 2000, it is still significantly compromised compared to the background population…. The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, infection control, and a normalized cortisol level,” she said.

Asked to comment, Maria Fleseriu, MD, told Medscape Medical News that the new data show “we are making improvements in the care of patients with CS and thus outcomes, but we are not there yet…. This meta-analysis highlights the whole spectrum of acute and life-threatening complications in CS and their high prevalence, even before disease diagnosis and after successful surgery.”

She noted that although she wasn’t surprised by the overall results, “the improvement over time was indeed lower than I expected. However, interestingly here, the risk of mortality in adrenal Cushing was unexpectedly high despite patients with adrenal cancer being excluded.”

Fleseriu, who is director of the Pituitary Center at Oregon Health and Science University, Portland, Oregon, advised, “Management of hyperglycemia and diabetes, hypertension, hypokalemia, hyperlipidemia, and other cardiovascular risk factors is generally undertaken in accordance with standard of clinical care.

“But we should focus more on optimizing more aggressively this care in addition to the specific Cushing treatment,” she stressed.

In addition, she noted, “Medical therapy for CS may be needed even prior to surgery in severe and/or prolonged hypercortisolism to decrease complications…. We definitely need a multidisciplinary approach to address complications and etiologic treatment as well as the reduced long-term quality of life in patients with CS.”

Largest Study in Scale and Scope of Cushing Syndrome Mortality

Endogenous Cushing syndrome occurs when the body overproduces cortisol. The most common cause of the latter is a tumor of the pituitary gland (Cushing disease), but another cause is a usually benign tumor of the adrenal glands (adrenal Cushing syndrome). Surgery is the mainstay of initial treatment of Cushing syndrome. If an operation to remove the tumor fails to cause remission, medications are available.

Prior to this new meta-analysis, there had been limited data on mortality among patients with endogenous CS. Research has mostly been limited to single-cohort studies. A previous systematic review/meta-analysis comprised only seven articles with 780 patients. All the studies were conducted prior to 2012, and most were limited to Cushing disease.

“In 2021, we lacked a detailed understanding of patient outcomes and mortality because of the rarity of Cushing syndrome,” Limumpornpetch noted.

The current meta-analysis included 91 articles that reported mortality among patients with endogenous CS. There was a total of 19,181 patients from 92 study cohorts, including 49 studies on CD (n = 14,971), 24 studies on adrenal CS (n = 2304), and 19 studies that included both CS types (n = 1906).

Among 21 studies that reported standardized mortality rate (SMR) data, including 13 CD studies (n = 2160) and seven on adrenal CS (n = 1531), the overall increase in mortality compared to the background population was a significant 3.00 (range, 1.15 – 7.84).

This SMR was higher among patients with adrenal Cushing syndrome (3.3) vs Cushing disease (2.8) (= .003) and among patients who had active disease (5.7) vs those whose disease was in remission (2.3) (< .001).

The SMR also was worse among patients with Cushing disease with larger tumors (macroadenomas), at 7.4, than among patients with very small tumors (microadenomas), at 1.9 (= .004).

The proportion of death was 0.05 for CS overall, with 0.04 for CD and 0.02 for adrenal adenomas.

Compared to studies published prior to the year 2000, more recent studies seem to reflect advances in treatment and care. The overall proportion of death for all CS cohorts dropped from 0.10 to 0.03 (P < .001); for all CD cohorts, it dropped from 0.14 to 0.03; and for adrenal CS cohorts, it dropped from 0.09 to 0.03 (P = .04).

Causes of death were cardiovascular diseases (29.5% of cases), cerebrovascular accident (11.5%), infection (10.5%), and malignancy (10.1%). Less common causes of death were gastrointestinal bleeding and acute pancreatitis (3.7%), active CS (3.5%), adrenal insufficiency (2.5%), suicide (2.5%), and surgery (1.6%).

Overall, in the CS groups, the proportion of deaths within 30 days of surgery dropped from 0.04 prior to 2000 to 0.01 since (P = .07). For CD, the proportion dropped from 0.02 to 0.01 (P = .25).

Preventing Perioperative Mortality: Consider Thromboprophylaxis

Fleseriu told Medscape Medical News that she believes hypercoagulability is “the least recognized complication with a big role in mortality.” Because most of the perioperative mortality is due to venous thromboembolism and infections, “thromboprophylaxis should be considered for CS patients with severe hypercortisolism and/or postoperatively, based on individual risk factors of thromboembolism and bleeding.”

Recently, Fleseriu’s group showed in a single retrospective study that the risk for arterial and venous thromboembolic events among patients with CS was approximately 20%. Many patients experienced more than one event. Risk was higher 30 to 60 days postoperatively.

The odds ratio of venous thromoboembolism among patients with CS was 18 times higher than in the normal population.

“Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in all patients with Cushing syndrome and balanced with individual bleeding risk,” Fleseriu advised.

A recent Pituitary Society workshop discussed the management of complications of CS at length; proceedings will be published soon, she noted.

Limumpornpetch commented, “We look forward to the day when our interdisciplinary approach to managing these challenging patients can deliver outcomes similar to the background population.”

Limumpornpetch has disclosed no relevant financial relationships. Fleseriu has been a scientific consultant to Recordati, Sparrow, and Strongbridge and has received grants (inst) from Novartis and Strongbridge.

ENDO 2021: The Endocrine Society Annual Meeting: Presented March 20, 2021

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape. Other work of hers has appeared in the Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She can be found on Twitter @MiriamETucker.

From https://www.medscape.com/viewarticle/949257

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