Adrenal-Directed Treatment Options for Cushing’s Disease

Abstract Purpose Recurrence after pituitary surgery in Cushing’s disease (CD) is a common problem ranging from 5% (minimum) to 50% (maximum) after initially successful surgery, respectively. In this review, we give an overview of the current literature regarding prevalence, diagnosis, and therapeutic options of recurrent CD. Methods We systematically screened the literature regarding recurrent and persistent Cushing’s disease using the MESH term Cushing’s disease and recurrence. Of 717 results in PubMed, all manuscripts in English and German published between 1980 and April 2020 were screened. Case reports, comments, publications focusing on pediatric CD or CD in veterinary disciplines or studies with very small sample size (patient number < 10) were excluded. Also, papers on CD in pregnancy were not included in this review. Results and conclusions Because of the high incidence of recurrence in CD, annual clinical and biochemical follow-up is paramount. 50% of recurrences occur during the first 50 months after first surgery. In case of recurrence, treatment options include second surgery, pituitary radiation, targeted medical therapy to control hypercortisolism, and bilateral adrenalectomy. Success rates of all these treatment options vary between 25 (some of the medical therapy) and 100% (bilateral adrenalectomy). All treatment options have specific advantages, limitations, and side effects. Therefore, treatment decisions have to be individualized according to the specific needs of the patient.

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MANAGEMENT OF ENDOCRINE DISEASE: The burden of Cushing's disease: clinical and health-related quality of life aspects

Acta Endocrinologica ◽

10.1530/eje-11-1095 ◽

2012 ◽

Vol 167 (3) ◽

pp. 311-326 ◽

Cited By ~ 134

Author(s):

R A Feelders ◽

S J Pulgar ◽

A Kempel ◽

A M Pereira

Keyword(s):

Quality Of Life ◽

Cushing’S Disease ◽

Treatment Options ◽

Current Treatment ◽

Cushing's Disease ◽

Health Related Quality ◽

Time To Diagnosis ◽

Related Quality ◽

Health Related

ObjectiveCushing's disease (CD) is a rare endocrine disorder characterized by excess secretion of ACTH due to a pituitary adenoma. Current treatment options are limited and may pose additional risks. A literature review was conducted to assess the holistic burden of CD.DesignStudies published in English were evaluated to address questions regarding the epidemiology of CD, time to diagnosis, health-related quality of life (HRQoL), treatment outcomes, mortality, prevalence of comorbidities at diagnosis, and reversibility of comorbidities following the treatment.MethodsA two-stage literature search was performed in Medline, EMBASE, and Science Citation Index, using keywords related to the epidemiology, treatment, and outcomes of CD: i) articles published from 2000 to 2012 were identified and ii) an additional hand search (all years) was conducted on the basis of bibliography of identified articles.ResultsAt the time of diagnosis, 58–85% of patients have hypertension, 32–41% are obese, 20–47% have diabetes mellitus, 50–81% have major depression, 31–50% have osteoporosis, and 38–71% have dyslipidemia. Remission rates following transsphenoidal surgery (TSS) are high when performed by expert pituitary surgeons (rates of 65–90%), but the potential for relapse remains (rates of 5–36%). Although some complications can be partially reversed, time to reversal can take years. The HRQoL of patients with CD also remains severely compromised after remission.ConclusionsThese findings highlight the significant burden associated with CD. As current treatment options may not fully reverse the burden of chronic hypercortisolism, there is a need for both improved diagnostic tools to reduce the time to diagnosis and effective therapy, particularly a targeted medical therapy.

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Cardiovascular risk in patients with Cushing’s disease – an interdisciplinary problem

Pediatria i Medycyna Rodzinna ◽

10.15557/pimr.2021.0045 ◽

2021 ◽

Vol 17 (3) ◽

pp. 197-202

Author(s):

Agnieszka Jurek ◽

◽

Paweł Krzesiński ◽

Grzegorz Gielerak ◽

Beata Uziębło-Życzkowska ◽

...

Keyword(s):

Quality Of Life ◽

Cardiovascular Risk ◽

Cushing’S Disease ◽

Treatment Options ◽

Pituitary Tumour ◽

Cushing's Disease ◽

Entire Body ◽

Systemic Complications ◽

Cardiovascular Assessment

Cushing’s disease is a chronic endogenous hypercortisolaemia associated with overproduction of adrenocorticotropic hormone by a pituitary adenoma, leading to multiple systemic complications that significantly increase morbidity and mortality, as well as reduce the quality of life as a result of prolonged tissue exposure to excess cortisol. Hypercortisolaemia in Cushing’s disease is associated with significant functional and constitutional disorders of the entire body. The consequences of chronic hypercortisolaemia include haemodynamic disorders associated with excessive vascular contraction and increased blood pressure, obesity, carbohydrate metabolism disorders, dyslipidaemia, and coagulopathies, which may contribute to significant cardiovascular remodelling. Cardiovascular disorders have a particular impact on long-term prognosis and quality of life in Cushing’s disease. If left untreated, Cushing’s disease significantly increases the cardiovascular risk and limits the treatment options for secondary organ complications. Cardiovascular mortality (myocardial infarction, heart failure, stroke) is several times higher in patients with Cushing’s disease than in the general population. Early diagnosis of the corticotropic pituitary tumour, as well as a thorough morphological and functional cardiovascular assessment seem essential in risk stratification. Normalisation of cortisol levels after combined neurosurgical and/or pharmacological treatment reduces mortality and the risk of cardiovascular and respiratory complications. The aim of this study is to present the complexity of clinical problems in patients with Cushing’s disease, who are in a particular need of interdisciplinary care.

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Melanocortin 2 Receptor Antagonists in Canine Cushing’s Disease: In Vitro Studies

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1654 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A812-A812

Author(s):

Karin Sanders ◽

Adri Slob ◽

Steven F Betz ◽

Hans S Kooistra ◽

Sara Galac

Keyword(s):

Cell Viability ◽

Mrna Expression ◽

Cell Cultures ◽

Cushing’S Disease ◽

Treatment Options ◽

Cushing's Disease ◽

Maximal Concentration ◽

Adrenocortical Cell ◽

Adrenocortical Hormone

Abstract Melanocortin 2 receptor antagonists in canine Cushing’s disease: in vitro studies Cushing’s disease (CD), caused by an ACTH-secreting pituitary adenoma, is one of the most common endocrinopathies in dogs. The current medical treatment options involve adrenocortical steroid synthesis inhibitors, but a selective targeted approach to block ACTH receptor at its receptor would be much more attractive. The objective of this study was to preclinically investigate the effect of MC2R antagonists on adrenocortical hormone production, cell viability, and mRNA expression of steroidogenic enzymes in canine primary adrenocortical cell cultures from adrenal glands of healthy dogs. Three different MC2R antagonists were used: CRN.1, CRN.2, and CRN.4. Canine primary adrenocortical cell cultures (n = 8) were incubated with 50 nM ACTH for 24h, to mimic CD. Thereafter, 10 nM (IC50) and 2 μM (maximal concentration) of CRN.1, CRN.2, and CRN.4 were added. The two concentrations were established based on preliminary studies. After 24 hours of incubation, adrenocortical hormone concentrations were measured in the culture medium using liquid chromatography-mass spectrometry. RNA was isolated from the cells using the RNeasy Microkit (Qiagen) for subsequent real-time quantitative PCR analysis. Cell viability was assessed after 24 hours of incubation using alamarBlue™ Cell Viability Reagent. All CRN compounds effectively inhibited cortisol concentrations, while leaving aldosterone concentrations unaffected. In incubations with a maximal concentration of the three compounds, cortisol concentration decreased to undetectable levels. The mRNA expression levels of steroidogenic enzymes StAR, CYP11A1, CYP17A1, HSD3B2, CYP21, and CYP11B were significantly inhibited in most conditions when compared to the ACTH-stimulated control. The mRNA expression of melanocortin 2 receptor accessory protein (MRAP) was suppressed as well. Cell viability was not affected by CNR.1 or CNR.4, but was slightly inhibited by CRN.2. In summary, canine adrenocortical cell culture is a useful model system for drug testing. Incubation with MC2R antagonists demonstrated the potential of CNR.1 and CNR.4 as new treatment options for CD. Future in vivo studies in dogs with spontaneous CD are indicated.

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Treatment Options in Cushing's Disease

Clinical Medicine Insights Oncology ◽

10.4137/cmo.s6198 ◽

2012 ◽

Vol 6 ◽

pp. CMO.S6198 ◽

Cited By ~ 11

Author(s):

Ahmed Rizk ◽

Juergen Honegger ◽

Monika Milian ◽

Tsambika Psaras

Keyword(s):

Pituitary Adenoma ◽

Medical Therapy ◽

Treatment Option ◽

Cushing’S Disease ◽

Treatment Options ◽

Bilateral Adrenalectomy ◽

Metabolic Effects ◽

Cushing's Disease ◽

Line Treatment ◽

Second Line

Endogenous Cushing's syndrome is a grave disease that requires a multidisciplinary and individualized treatment approach for each patient. Approximately 80% of all patients harbour a corticotroph pituitary adenoma (Cushing's disease) with excessive secretion of adrenocorticotropin-hormone (ACTH) and, consecutively, cortisol. The goals of treatment include normalization of hormone excess, long-term disease control and the reversal of comorbidities caused by the underlying pathology. The treatment of choice is neurosurgical tumour removal of the pituitary adenoma. Second-line treatments include medical therapy, bilateral adrenalectomy and radiation therapy. Drug treatment modalities target at the hypothalamic/pituitary level, the adrenal gland and at the glucocorticoid receptor level and are commonly used in patients in whom surgery has failed. Bilateral adrenalectomy is the second-line treatment for persistent hypercortisolism that offers immediate control of hypercortisolism. However, this treatment option requires a careful individualized evaluation, since it has the disadvantage of permanent hypoadrenalism which requires lifelong glucocorticoid and mineralocorticoid replacement therapy and bears the risk of developing Nelson's syndrome. Although there are some very promising medical therapy options it clearly remains a second-line treatment option. However, there are numerous circumstances where medical management of CD is indicated. Medical therapy is frequently used in cases with severe hypercortisolism before surgery in order to control the metabolic effects and help reduce the anestesiological risk. Additionally, it can help to bridge the time gap until radiotherapy takes effect. The aim of this review is to analyze and present current treatment options in Cushing's disease.

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The New Genetic Landscape of Cushing’s Disease: Deubiquitinases in the Spotlight

Cancers ◽

10.3390/cancers11111761 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1761 ◽

Cited By ~ 5

Author(s):

Silviu Sbiera ◽

Meik Kunz ◽

Isabel Weigand ◽

Timo Deutschbein ◽

Thomas Dandekar ◽

...

Keyword(s):

Cushing’S Disease ◽

Somatic Mutations ◽

Therapeutic Potential ◽

Meta Analysis ◽

Treatment Options ◽

Rare Condition ◽

Cushing's Disease ◽

High Morbidity ◽

Sequencing Data ◽

Pathogenic Variants

Cushing’s disease (CD) is a rare condition caused by adrenocorticotropic hormone (ACTH)-producing adenomas of the pituitary, which lead to hypercortisolism that is associated with high morbidity and mortality. Treatment options in case of persistent or recurrent disease are limited, but new insights into the pathogenesis of CD are raising hope for new therapeutic avenues. Here, we have performed a meta-analysis of the available sequencing data in CD to create a comprehensive picture of CD’s genetics. Our analyses clearly indicate that somatic mutations in the deubiquitinases are the key drivers in CD, namely USP8 (36.5%) and USP48 (13.3%). While in USP48 only Met415 is affected by mutations, in USP8 there are 26 different mutations described. However, these different mutations are clustering in the same hotspot region (affecting in 94.5% of cases Ser718 and Pro720). In contrast, pathogenic variants classically associated with tumorigenesis in genes like TP53 and BRAF are also present in CD but with low incidence (12.5% and 7%). Importantly, several of these mutations might have therapeutic potential as there are drugs already investigated in preclinical and clinical setting for other diseases. Furthermore, network and pathway analyses of all somatic mutations in CD suggest a rather unified picture hinting towards converging oncogenic pathways.

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Highly Aggressive and Radiation-Resistant, “Atypical” and Silent Pituitary Corticotrophic Carcinoma: A Case Report and Review of the Literature

Case Reports in Oncology ◽

10.1159/000496019 ◽

2019 ◽

Vol 12 (1) ◽

pp. 139-146 ◽

Cited By ~ 1

Author(s):

Laura Flores ◽

Richard Sleightholm ◽

Beth Neilsen ◽

Michael Baine ◽

Andjela Drincic ◽

...

Keyword(s):

Radiation Therapy ◽

Cushing’S Disease ◽

Treatment Plan ◽

Treatment Options ◽

Pituitary Tumors ◽

Response To Therapy ◽

Cushing's Disease ◽

Ki 67 ◽

Radiation Resistant ◽

Metastatic Sites

Background: Pituitary tumors typically remain silent unless interaction with nearby structures occurs. Rare subsets of pituitary tumors display aggressive phenotypes: highly mitotic, locally invasive, metastatic, chemotherapy and radiation resistant, etc. Disease progression and response to therapy is ill-defined in these subtypes, and their true prognostic potential is debated. Thus, identifying tumor characteristics with prognostic value and efficacious treatment options remains a challenge in aggressive pituitary tumors. Case Presentation: A 45-year-old female presented with a nonfunctioning corticotropic pituitary macroadenoma with biomarkers suggestive of an “atypical” subtype: Ki-67 of 8–12%, increased mitosis, and locally invasive. Despite resections and radiation, growth continued, eventually affecting her vision. Although histologically ACTH positive, the patient remained clinically asymptomatic. Twelve months later, an episode of Cushing’s disease-induced psychosis prompted a PET-CT scan, identifying sites of metastasis. Temozolomide was added to her medical regimen, and her metastatic liver lesions and boney metastases were treated with radiofrequency ablation and stereotactic body radiation therapy, respectively. Systemic treatment resulted in a drop in her ACTH levels, with her most recent scans/labs at 12 months following RFA suggesting remission. Conclusions: This is a unique presentation of a pituitary tumor, displaying characteristics of both clinically silent corticotropic and “atypical” macroadenoma subtypes. Although initially ACTH positive while clinically silent, the patient’s disease ultimately recurred metastatically with manifestations of Cushing’s disease and psychosis. With the addition of temozolomide to her treatment plan, her primary and metastatic sites have responded favorably to radiation therapy. Thus, the addition of temozolomide may be beneficial in the treatment of aggressive pituitary tumors.

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THERAPY OF ENDOCRINE DISEASE: Outcomes in patients with Cushing's disease undergoing transsphenoidal surgery: systematic review assessing criteria used to define remission and recurrence

Acta Endocrinologica ◽

10.1530/eje-14-0883 ◽

2015 ◽

Vol 172 (6) ◽

pp. R227-R239 ◽

Cited By ~ 57

Author(s):

Stephan Petersenn ◽

Albert Beckers ◽

Diego Ferone ◽

Aart van der Lely ◽

Jens Bollerslev ◽

...

Keyword(s):

Cushing’S Disease ◽

Transsphenoidal Surgery ◽

Treatment Options ◽

Management Strategies ◽

Cushing's Disease ◽

Surgical Experience ◽

Endocrine Disease ◽

Number Of Factors ◽

Clinically Significant

ObjectiveA number of factors can influence the reported outcomes of transsphenoidal surgery (TSS) for Cushing's disease – including different remission and recurrence criteria, for which there is no consensus. Therefore, a comparative analysis of the best treatment options and patient management strategies is difficult. In this review, we investigated the clinical outcomes of initial TSS in patients with Cushing's disease based on definitions of and assessments for remission and recurrence.MethodsWe systematically searched PubMed and identified 44 studies with clear definitions of remission and recurrence. When data were available, additional analyses by time of remission, tumor size, duration of follow-up, surgical experience, year of study publication and adverse events related to surgery were performed.ResultsData from a total of 6400 patients who received microscopic TSS were extracted and analyzed. A variety of definitions of remission and recurrence of Cushing's disease after initial microscopic TSS was used, giving broad ranges of remission (42.0–96.6%; median, 77.9%) and recurrence (0–47.4%; median, 11.5%). Better remission and recurrence outcomes were achieved for microadenomas vs macroadenomas; however, no correlations were found with other parameters, other than improved safety with longer surgical experience.ConclusionsThe variety of methodologies used in clinical evaluation of TSS for Cushing's disease strongly support the call for standardization and optimization of studies to inform clinical practice and maximize patient outcomes. Clinically significant rates of failure of initial TSS highlight the need for effective second-line treatments.

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