Paraneoplastic Cushing Syndrome in Gastrointestinal Neuroendocrine Tumour

Posted on November 17, 2021 by MaryO

Abstract

Ectopic production of adrenocorticotropic hormone (ACTH) by gastrointestinal neuroendocrine tumours (NETs) is relatively uncommon. We report a rare case of a liver metastatic G1 low-grade NET of the intestine that induced hypercortisolism after surgical resection. A 50-year-old man was admitted for an intestinal obstruction caused by a tumour of the intestine. Paraneoplastic Cushing syndrome was diagnosed more than a year later following the appearance of cushingoid symptoms, despite stable disease according to RECIST criteria but chromogranin A increase. Ketoconazole and sandostatin medical treatment and liver chemoembolization never managed to control the hypercortisolism unlike the bilateral adrenalectomy. The identification and effective management of this uncommon statement of ectopic ACTH secretion is important to improve the patient’s prognosis and quality of life.

© 2021 The Author(s). Published by S. Karger AG, Basel

Introduction

Neuroendocrine tumours (NETs) are a relatively rare and heterogeneous tumour type, comprising about 2% of all malignancies [1]. The gastrointestinal (GI) and pancreatic tract and lungs are the most common primary tumour sites, with 62%–67% and 22%–27%, respectively, and within the GI tract, most of them occurs in the small bowel or the appendix [2, 3]. Since 2010 and the latest version of the WHO classification, GI and pancreatic NETs are subdivided according to their mitotic count or Ki67 index, associated with cellular proliferation. Well-differentiated NETs are relatively low-aggressive tumours, with a rather indolent disease course and a good prognosis in most patients. Nevertheless, some NETs with a low-grade histologic appearance may behave aggressively with rapid growth and metastasis proliferation [4, 5]. Because of this low incidence, tumour heterogeneity, lack of awareness, and non-uniform classifications, GI and pancreatic NETs remain a poorly understood disease, and delayed diagnosis is common among these [6, 7].

Paraneoplastic Cushing syndrome (PCS) represents approximately 10% of all Cushing syndrome and is frequently caused by NETs [8, 9]. While PCS is common with lung NETs (>50% of PCS), this paraneoplastic syndrome is relatively uncommon associated with GI NETs and only described in isolated case reports. Nevertheless, knowing the indolent course of low-grade NETs and the clinical symptoms of cushingoid appearance resulting from prolonged exposure to excessive glucocorticoids, PCS is typically present before cancer detection [8], and surgery is curative in >80% of patients [10, 11]. For the remaining 20%, effective management is necessary, given the risk of infections and thromboembolic events due to the immunosuppressive effect and the hypercoagulable state [11]. For patients with medically unmanageable hypercortisolism, synchronous bilateral adrenalectomy is an effective and safe treatment [12]. We describe a case of typical metastatic intestinal NETs associated with a late ectopic Cushing syndrome, which was managed with synchronous bilateral adrenalectomy.

Case Presentation

We describe the case of a 50-year-old man admitted to the emergency department for an intestinal obstruction caused by an intestinal tumour. Anatomopathological analysis of the resected specimen and lymph nodes revealed an NET. Three nodes out of 12 removed were positive for cancer localization. The tumour presented serosa infiltration and perineural, vascular and lymphatics vessel invasion. The primary location could not be confirmed histologically between the ileum and appendix. Our diagnosis was pT3N1 according to the American Joint Committee on Cancer (AJCC) classification. An immunohistochemistry analysis revealed a Ki-67 expression <2%. Mitotic count/10 was 2 × 10 high-power fields, and cells showed well differentiation. So, according to the WHO classification, this tumour was classified as G1 NET. 111In-Octreoscan (Octreoscan) revealed lymph node and multifocal liver metastases.

After discussion with a multidisciplinary team, the patient was started treatment with somatostatin analogue. Twelve months later, although computerized tomography (CT) scan showed stable disease, patient physical examination revealed facial puffiness with fatty tissue deposits in the face, generalized oedema, muscle weakness, and wasting. He also reports polydipsia, insomnia, and balance disorders. We noted however a discreet increase in the chromogranin A (CgA) value, from 55 ng/mL to 199 ng/mL (with a diagnostic value of 1,700 ng/mL) without an increase in the urinary 5-HIAA level.

Laboratory tests revealed an 8.00 a.m. cortisol level of 888 nmol/L, an adrenocorticotropic hormone (ACTH) level of 96.5 pg/mL, and 24-h urine free cortisol of 1,494 μg. A high-dose dexamethasone suppression test showed no cortisol suppression. The patient was diagnosed with ACTH-dependent Cushing syndrome. Magnetic resonance imaging (MRI) of the brain showed a normal pituitary gland, confirming the PCS diagnosis. Ketoconazole treatment associated with sandostatin alleviated hypercortisolism within a month, with a cortisol level within normal laboratory ranges. Two months later, secondary diabetes mellitus was discovered and managed effectively with insulin glargine.

Four months later and despite stable disease according to RECIST criteria, cortisol levels increased considerably, with cortisol values similar to diagnosis without ketoconazole increased response. Moreover, diabetes became complicated to manage. Also we noted an increase in CgA value, from 165 ng/mL to 393 ng/mL. Chemoembolization was performed on liver metastases without any effectiveness on hypercortisolism. Adding targeted therapy with mTOR inhibitor (everolimus) was considered. Nevertheless, given the magnitude of drug interaction, the use of everolimus should be avoided in ketoconazole-treated patients, or vice versa.

Considering the risks for the patient and expected benefits, synchronous bilateral adrenalectomy was performed. It resolved hypercortisolism and permitted to stabilize diabetes (shown in Fig. 1). Everolimus treatment has been started 1 month after the surgery. Twelve months after everolimus initiation, the patient CT scan still showed stable disease, according to RECIST criteria and a stable CgA value.

Fig. 1.

Histogram of 8:00 a.m. plasmatic cortisol, ACTH, 24-h urinary cortisol, and CgA levels from Cushing syndrome diagnosis to bilateral adrenalectomy. ACTH, adrenocorticotropic-hormone; ULN, upper limit of normal; 8:00 a.m. cortisol normal ranges (172–497) nmol/L; ACTH normal ranges (7–63) ng/L; 24-h urinary cortisol normal ranges (20–50) µg/24 h; CgA normal ranges (27–94) ng/mL. ACTH, adrenocorticotropic hormone; CgA, chromogranin A.

/WebMaterial/ShowPic/1364794

Discussion

Approximately 10% of Cushing syndrome is paraneoplastic and may result in many tumours, preferentially lung cancer (50–60% of time), with 1–2% of lung NET and about 5% of small-cell lung cancer associated with Cushing syndrome [8, 11, 13]. Others reported sites of malignancy include the thymus, thyroid, pancreas, and adrenals. Except for the pancreas, PCS secondary to GI NET (appendix, duodenum, ileum, colon, and anal canal) is extremely rare, and only isolated case reports have described this syndrome.

In paraneoplastic endocrine syndrome cases, symptoms are due to secretion of hormones by malignant cells or secondary to the impact of neoplastic cell antibodies on normal cells. PCS arises from tumour secretion of ACTH or CRH, resulting in production and release of cortisol from the adrenal glands. Unlike paraneoplastic endocrine syndromes that present most of the time after cancer diagnosis, PCS typically appears before cancer detection and similarly relapse may herald tumour recurrence [11, 14]. In our case, no symptoms related to hypercortisolaemia led the patient to consult before obstructive syndrome. The occurrence of hypercortisolaemia 12 months after diagnosis was not linked to imaging progression according to RECIST criteria. However, concurrent CgA increase should be noted.

Commonly measured tumour markers in NETs include serum CgA and 5-HIAA, the final secreted product of serotonin, levels in a 24-h urine sample. Elevated levels of circulating of CgA have been associated with almost all types of NETs, including those arising from GI tract but also pheochromocytomas [15]. The clinical sensitivity of CgA has been demonstrated to depend on the threshold cut-off, on NET primary location, and on the spread of the disease, especially the existence of liver metastases [16]. Indeed, a higher sensitivity was found in patients with midgut NETs and liver metastases, as in our patient. Moreover, with our cut-off level (94 ng/mL) approximately the same as used in 2 studies [16, 17], sensitivity was 62%–67% and specificity was 96%. Furthermore, Korse et al. [18]. postulated that serum CgA was superior to urinary 5-HIAA concerning the prognostic relevance in the follow-up of metastatic midgut NETs. These data are consistent with our patient outcomes for which 5-HIAA was not increased unlike CgA. However, although CgA is currently the best available tumour marker indicating tumour recurrence [19], there are many comorbidities and drugs that may increase CgA levels and lead to false-positive results. As a result, it is questionable whether the CgA increase in our patient was not rather secondary to cardiovascular or GI disorders, inflammatory diseases, diabetes, or even food intake before CgA measurement [16, 20, 21]. Similarly, many drugs, foods, natural stimulants, and comorbidities may alter the level of 24-h urinary 5-HIAA, positively or negatively.

Cushing syndrome is due to hypercortisolism. Two-thirds of endogenous elevated cortisol is caused by ACTH-secreting pituitary tumours, 15% by primary adrenal glands and 15% by ectopic PCS [22]. The first step is laboratory tests with cortisol and ACTH levels to differentiate ACTH-dependent or ACTH-independent Cushing syndrome. When ACTH-dependent Cushing syndrome is confirmed, differentiation between PCS and Cushing disease can be difficult. The high-dose dexamethasone suppression tests help distinguish Cushing disease from PCS, as in our presented case. Indeed, no decrease in blood cortisol during the high-dose test and high ACTH levels are consistent with PCS. Nevertheless, 21–26% of ectopic ACTH secretions have a positive suppression, about one-third of MRI scans for pituitary adenoma exclusion are false-negative, and occult ectopic ACTH-secreting tumours have been described in about 15% of adult patients [23–26]. In our patient, both MRI and high-dose dexamethasone suppression test are consistent with PCS. The gold standard diagnosis – inferior petrosal sinus sampling – that demonstrates gradient in ACTH concentration between the affected side sinus and the periphery in pituitary lesions, whereas the absence of this gradient in PCS was not performed because of its invasiveness and its neurological accident risks [27]. Note however although the ACTH level at diagnosis suggests ACTH-dependent Cushing syndrome, the occurrence of adrenal metastasis few months after the diagnosis and explaining the sudden deregulation could be possible and consistent with the CgA increase but refuted by adrenal gland histology.

Clinical features of PCS depend on the source of production and rate of ACTH synthesis. Characteristically, these patients have severe hypercortisolaemia, leading to low serum potassium levels, diabetes, generalized infections, hypertension, and psychosis. To confirm whether rapidly growing tumours produce sudden onset of symptoms, gradual physical signs are noticed in slower growing tumours [28], as for our patient for whom we suppose that liver metastases started to produce ACTH ectopically. An option for non-resectable neuroendocrine liver lesions, given that the majority of them are hypervascular, is hepatic directed procedures, which include ablative therapy, transarterial embolization, transarterial chemoembolization, and selective internal radiation therapy with yttrium-90 microspheres [29]. Hepatic artery chemoembolization for the treatment of liver metastases from NETs is useful for tumour size reduction and symptom palliation and can be associated with prolonged survival [30]. Nevertheless, chemoembolization on NET liver metastasis-producing ACTH is not well documented. Given the fact that hepatic metastasis chemoembolization was ineffective on hypercortisolism and despite Octreoscan results, there is still a small chance that he harbours somewhere else metastasis-producing ACTH. Indeed, PET-CT imaging with 68Gallium-DOTATATE has recently replaced Octreoscan as the new gold standard with a higher detection rate in GI NETs [31].

Hypercortisolism requires a prompt therapeutic management to reduce the risk of development of a potentially fatal emergency. Synchronous bilateral adrenalectomy is an effective and safe treatment for patient with unmanageable ACTH-dependent hypercortisolism [12]. Taking account of the risks to the patient and the lack of effective medical therapeutic possibilities, we have chosen to perform this surgery.

According to the recent consensus guidelines for digestive NETs of the jejunum and ileum, the 5-year survival rate is 36% in patients with distant metastases [32]. Several analyses suggest a significant survival benefit in patients who received surgery for the primary tumour even in the presence of metastasis [33]. Moreover, the impact of liver resection or liver-directed therapies on the survival of patients with liver metastasis is unclear with conflicting results [33]. PCS can cause a poor clinical outcome due to various complications with an increase in susceptibility to infection and GI ulceration. Indeed, for small-cell lung cancer and gynaecological malignancies, PCS is associated with accelerated decompensation and poorer response to chemotherapy (Mitchell et al. [14]). Whether these findings can be extrapolated to other malignancies is unknown. However, an early diagnosis and a prompt management can improve patient outcomes through earlier cancer diagnosis or relapse and thus earlier administration of treatment, as was the case with our patient.

Conclusion

We report an uncommon case with PCS due to a GI NET. The identification of this rare cause of ectopic ACTH secretion can be challenging, but aggressive management is critical to prevent or decelerate the acute decompensation of cancer patients and prolong overall survival. In this context, synchronous bilateral adrenalectomy may be the unique answer.

Statement of Ethics

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor-in-chief of this journal.

Conflict of interest Statement

The authors have no conflict of interest to declare.

Funding Sources

No funding was received for this study.

Author Contributions

L.M. conceived the study and participated in data collection. L.V. performed the literature search and wrote the manuscript. L.M. and R.B. critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript version.

Data Availability Statement

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

From https://www.karger.com/Article/FullText/518316

Filed under: Cushing, Cushing's, Rare Diseases | Tagged: , , , | Leave a comment »

Updated Cushing’s disease guideline highlights new diagnosis, treatment ‘roadmap’

Posted on November 15, 2021 by MaryO

An updated guideline for the treatment of Cushing’s disease focuses on new therapeutic options and an algorithm for screening and diagnosis, along with best practices for managing disease recurrence.

Despite the recent approval of novel therapies, management of Cushing’s disease remains challenging. The disorder is associated with significant comorbidities and has high mortality if left uncontrolled.

Adrenal transparent _Adobe
Source: Adobe Stock

“As the disease is inexorable and chronic, patients often experience recurrence after surgery or are not responsive to medications,” Shlomo Melmed, MB, ChB, MACP, dean, executive vice president and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, and an Endocrine Today Editorial Board Member, told Healio. “These guidelines enable navigation of optimal therapeutic options now available for physicians and patients. Especially helpful are the evidence-based patient flow charts [that] guide the physician along a complex management path, which usually entails years or decades of follow-up.”

Shlomo Melmed

The Pituitary Society convened a consensus workshop with more than 50 academic researchers and clinical experts across five continents to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, participants reviewed data from January 2015 to April 2021 on screening and diagnosis; surgery, medical and radiation therapy; and disease-related and treatment-related complications of Cushing’s disease, all summarized in recorded lectures. The guideline includes recommendations regarding use of laboratory tests, imaging and treatment options, along with algorithms for diagnosis of Cushing’s syndrome and management of Cushing’s disease.

Updates in laboratory, testing guidance

If Cushing’s syndrome is suspected, any of the available diagnostic tests could be useful, according to the guideline. The authors recommend starting with urinary free cortisol, late-night salivary cortisol, overnight 1 mg dexamethasone suppression, or a combination, depending on local availability.

If an adrenal tumor is suspected, the guideline recommends overnight dexamethasone suppression and using late-night salivary cortisol only if cortisone concentrations can also be reported.

The guideline includes several new recommendations in the diagnosis arena, particularly on the role of salivary cortisol assays, according to Maria Fleseriu, MD, FACE, a Healio | Endocrine Today Co-editor, professor of medicine and neurological surgery and director of the Pituitary Center at Oregon Health & Science University in Portland.

Maria Fleseriu

“Salivary cortisol assays are not available in all countries, thus other screening tests can also be used,” Fleseriu told Healio. “We also highlighted the sequence of testing for recurrence, as many patients’ urinary free cortisol becomes abnormal later in the course, sometimes up to 1 year later.”

The guideline states combined biochemical and imaging for select patients could potentially replace petrosal sinus sampling, a very specialized procedure that cannot be performed in all hospitals, but more data are needed.

“With the corticotropin-releasing hormone stimulation test becoming unavailable in the U.S. and other countries, the focus is now on desmopressin to replace corticotropin-releasing hormone in some of the dynamic testing, both for diagnosis of pseudo-Cushing’s as well as localization of adrenocorticotropic hormone excess,” Fleseriu said.

The guideline also has a new recommendation for anticoagulation for high-risk patients; however, the exact duration and which patients are at higher risk remains unknown.

“We always have to balance risk for clotting with risk for bleeding postop,” Fleseriu said. “Similarly, recommended workups for bone disease and growth hormone deficiency have been further structured based on pitfalls specifically related to hypercortisolemia influencing these complications, as well as improvement after Cushing’s remission in some patients, but not all.”

New treatment options

The guideline authors recommended individualizing medical therapy for all patients with Cushing’s disease based on the clinical scenario, including severity of hypercortisolism. “Regulatory approvals, treatment availability and drug costs vary between countries and often influence treatment selection,” the authors wrote. “However, where possible, it is important to consider balancing cost of treatment with the cost and the adverse consequences of ineffective or insufficient treatment. In patients with severe disease, the primary goal is to treat aggressively to normalize cortisol concentrations.”

Fleseriu said the authors reviewed outcomes data as well as pros and cons of surgery, repeat surgery, medical treatments, radiation and bilateral adrenalectomy, highlighting the importance of individualized treatment in Cushing’s disease.

“As shown over the last few years, recurrence rates are much higher than previously thought and patients need to be followed lifelong,” Fleseriu said. “The role of adjuvant therapy after either failed pituitary surgery or recurrence is becoming more important, but preoperative or even primary medical treatment has been also used more, too, especially in the COVID-19 era.”

The guideline summarized data on all medical treatments available, either approved by regulatory agencies or used off-label, as well as drugs studied in phase 3 clinical trials.

“Based on great discussions at the meeting and subsequent emails to reach consensus, we highlighted and graded recommendations on several practical points,” Fleseriu said. “These include which factors are helpful in selection of a medical therapy, which factors are used in selecting an adrenal steroidogenesis inhibitor, how is tumor growth monitored when using an adrenal steroidogenesis inhibitor or glucocorticoid receptor blocker, and how treatment response is monitored for each therapy. We also outline which factors are considered in deciding whether to use combination therapy or to switch to another therapy and which agents are used for optimal combination therapy.”

Future research needed

The guideline authors noted more research is needed regarding screening and diagnosis of Cushing’s syndrome; researchers must optimize pituitary MRI and PET imaging using improved data acquisition and processing to improve microadenoma detection. New diagnostic algorithms are also needed for the differential diagnosis using invasive vs. noninvasive strategies. Additionally, the researchers said the use of anticoagulant prophylaxis and therapy in different populations and settings must be further studied, as well as determining the clinical benefit of restoring the circadian rhythm, potentially with a higher nighttime medication dose, as well as identifying better markers of disease activity and control.

“Hopefully, our patients will now experience a higher quality of life and fewer comorbidities if their endocrinologist and care teams are equipped with this informative roadmap for integrated management, employing a consolidation of surgery, radiation and medical treatments,” Melmed told Healio.

From https://www.healio.com/news/endocrinology/20211029/updated-cushings-disease-guideline-highlights-new-diagnosis-treatment-roadmap

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

Innovative One-Visit Adrenal Tumor Diagnosis and Treatment Program Begins in Tampa

Posted on November 10, 2021 by MaryO

TAMPA, Fla., Nov. 3, 2021 /PRNewswire/ — The Carling Adrenal Center, a worldwide destination for the surgical treatment of adrenal tumors, becomes the first center to offer adrenal vein sampling and curative surgery in one visit.

The novel protocol and diagnostic method for adrenal tumors will condense a 2–4-week process of localization of hyper-secreting adrenal tumors and subsequent curative surgery down to just one day. The innovative approach combines highly specialized adrenal vein sampling with rapid adrenal hormone lab testing and then consultation with the world’s highest volume adrenal surgeon. If appropriate, a patient may even complete their mini-surgery during that same visit.

Established by Dr. Tobias Carling in 2020, the Carling Adrenal Center located at the Hospital for Endocrine Surgery in Tampa FL, is the highest volume adrenal surgical center in the world. The Center now averages nearly 20 adrenal tumor patients every week that could benefit from this novel diagnostic and treatment approach to address a decades-long problem for patients with adrenal tumors.

The Endocrine Society Clinical Practice Guideline recommends adrenal vein sampling (AVS) as the preferred method to select patients with primary hyperaldosteronism for an adrenalectomy.

“The difficulty and complexity of testing and diagnosing adrenal tumors secreting excess aldosterone is the primary reason why less than 5% of these adrenal tumors are diagnosed and treated,” says Dr. Carling. “By combining expertise in interventional radiology for adrenal vein sampling and rapid laboratory measurements of adrenal hormones with our unique international consulting capability, we can determine which adrenal gland is bad and whether or not the patient needs that adrenal gland removed.”

Adrenal vein sampling is performed through small catheters placed in very specific veins where blood samples are obtained from both adrenal veins and the inferior vena cava. In experienced centers, the bilateral adrenal veins are catheterized and sampled with a success rate exceeding 90%. Technical success is directly associated with operator experience, leading to the recommendation that the procedure only be performed by true experts or the test will very likely be of no help.

Dr. Carling’s very high volume of adrenal surgery for many years has allowed him to publish scientific studies demonstrating that in aldosterone-producing adenomas, there is a strong correlation between the imaging phenotype (i.e., what the tumor looks like on a CT scan), histology (what the tumor looks like under the microscope) and genotype (what gene is mutated in the tumor).

This knowledge allows Dr. Carling and his team at the Hospital for Endocrine Surgery to predict who can go straight to surgery with an excellent outcome, and who may first need adrenal vein sampling to determine which adrenal gland is over-producing the hormone causing significant morbidity and mortality.

With adrenal vein sampling proving lateralization, the next step is surgical removal of the adrenal tumor. Dr. Carling has more experience with all types of adrenal surgery than any surgeon in the United States, but especially with advanced, minimally invasive adrenal operations which are the best options for aldosterone-secreting adrenal tumors. A fellow of the American College of Surgeons, Dr. Carling is a member of both the American Association of Endocrine Surgeons (AAES) and the International Association of Endocrine Surgeons (IAES).

Dr. Carling moved his world-renowned adrenal surgery program from Yale University to Tampa, Florida in early 2020 to start the Carling Adrenal Center. Here, patients needing adrenal surgery have access to the best practices and best techniques the world has to offer.

In January 2022, the Carling Adrenal Center will unite with the Norman Parathyroid Center, the Clayman Thyroid Center and the Scarless Thyroid Surgery Center at the brand-new Hospital for Endocrine Surgery located in Tampa, Florida.

About the Carling Adrenal Center: Founded by Dr. Tobias Carling, one of the world’s leading experts in adrenal gland surgery, the Carling Adrenal Center is a worldwide destination for the surgical treatment of adrenal tumors. Dr. Carling spent nearly 20 years at Yale University, including 7 as the Chief of Endocrine Surgery before leaving in 2020 to open to Carling Adrenal Center, which performs more adrenal operations than any other hospital in the world. More about adrenal vein sampling for adrenal tumors can be found at the Center’s website www.adrenal.com and here. (813) 972-0000.

Contact:
Julie Canan, Director of Marketing
Carling Adrenal Center
juliec@parathyroid.com

SOURCE Carling Adrenal Center

From https://www.prnewswire.com/news-releases/innovative-one-visit-adrenal-tumor-diagnosis-and-treatment-program-begins-in-tampa-301414465.html

Filed under: adrenal, Cushing's, Treatments | Tagged: , , , , , | Leave a comment »

Cushing Disease Treated Successfully with Metyrapone During Pregnancy

Posted on November 9, 2021 by MaryO
https://doi.org/10.1016/j.aace.2021.10.004Get rights and content
Under a Creative Commons license
open access

Highlights

•

Cushing’s Disease (CD) in pregnancy is rare, but poses many risks to the mother and fetus

•

Although surgery is still considered first line, this CASE highlights the successful use of metyrapone throughout pregnancy to manage CD in patients where surgery is considered high risk or low likelihood of cure

•

The dose of metyrapone can be titrated to a goal urinary free cortisol of < 150 ug/24 hours given the known rise in cortisol during gestation

•

Though no fetal adverse events have been reported, metyrapone does cross the placenta and long-term effects are unknown.

ABSTRACT

Background

Cushing Disease (CD) in pregnancy is a rare, but serious, disease that adversely impacts maternal and fetal outcomes. As the sole use of metyrapone in the management of CD has been rarely reported, we describe our experience using it to treat a pregnant patient with CD.

Case Report

34-year-old woman with hypertension who was diagnosed with adrenocorticotropic hormone-dependent CD based on a urinary free cortisol (UFC) of 290 μg/24hr (reference 6-42μg/dL) and abnormal dexamethasone suppression test (cortisol 12.4 μg/dL) before becoming pregnant. She conceived naturally 12 weeks post-transsphenoidal surgery, and was subsequently found to have persistent disease with UFC 768μg/dL. Surgery was deemed high risk given the proximity of the tumor to the right carotid artery and high likelihood of residual disease. Instead, she was managed with metyrapone throughout her pregnancy and titrated to goal UFC of <150μg/24hr due to the known physiologic rise in cortisol during gestation. The patient had diet-controlled gestational diabetes, and well-controlled hypertension. She gave birth at 37 weeks gestation to a healthy baby boy, without adrenal insufficiency in the baby or mother.

Discussion

This CASE highlights the successful use of metyrapone throughout pregnancy to manage CD in patients where surgery is considered high risk or low likelihood of cure. While metyrapone is effective, close surveillance is required for worsening hypertension, hypokalemia, and potential adrenal insufficiency. Though no fetal adverse events have been reported, this medication crosses the placenta and long-term effects are unknown.

Conclusion

We describe a CASE of CD during pregnancy that was successfully treated with metyrapone.

Key words

Cushing disease
metyrapone
pregnancy
cortisol

INTRODUCTION

Cushing disease (CD) is caused by endogenous overproduction of glucocorticoids due to hypersecretion of adrenocorticotropic hormone (ACTH) by a pituitary adenoma. CD in pregnancy is very rare, and when it occurs, it is considered a high-risk pregnancy with many potential adverse outcomes for both the mother and fetus.1 Infertility is common in CD due to cortisol and androgen excess leading to hypogonadotropic hypogonadism.1 Due to the rarity of CD in pregnancy, there is little guidance in terms of treatment for this patient population. Similar to non-pregnant patients, the first-line treatment is transsphenoidal pituitary adenoma resection, with medical therapy as a second-line treatment option. This report presents a CASE that highlights the use of metyrapone, a steroidogenesis inhibitor, as a sole therapy in cases where surgery is deemed to be high risk and unlikely curative due to location of the tumor.

CASE REPORT

A 34-year-old woman with a past medical history of hypertension and infertility for six years presented to endocrinology for evaluation. Aside from difficulty conceiving, her only complaints were nausea and easy bruising. On exam she did not have clinical features of CD –abdominal violaceous striae, moon facies or a dorsocervical fat pad were absent. Her laboratory results revealed an elevated prolactin level (50-60ng/mL, reference range 1.4-24), an elevated ACTH level (61 pg/mL, reference range 0-46), and low FSH and LH levels (1.7mIU/mL and 1.76mIU/mL, respectively). Further testing demonstrated an elevated urinary free cortisol level (UFC) (290μg/24 hour, reference range 6-42) and her cortisol failed to suppress on a 1mg dexamethasone suppression test (cortisol 12.4μg/dL). Magnetic resonance imaging (MRI) of the pituitary with and without contrast showed a T2 hyperintense, hypoenhancing lesion within the right side of the sella touching the right cavernous internal carotid artery measuring 8x8x9 mm consistent with a pituitary adenoma (Figure 1).

  1. Download : Download high-res image (247KB)
  2. Download : Download full-size image

Figure 1. Caption: T1 weighted post gadolinium coronal image of the pituitary gland with a small hypoenhancing lesion within the right side of the sella.

After the presumed diagnosis of CD was made, she was referred to neurosurgery for transsphenoidal resection of the adenoma, which she underwent a few months later. Intra-operatively, a white friable tumor was found, and otherwise the surgery was uneventful. Three months later, however, she was found to have a persistent 8x8x9mm hypoenhancing lesion extending laterally over the right cavernous carotid artery on MRI. The mass approximated but did not contact the right intracranial optic nerve. The pathology from resected tissue was consistent with normal pituitary tissue with staining for growth hormone (80%), ACTH (30%), prolactin (40%), follicle stimulating hormone (5%), luteinizing hormone (40%) and thyroid stimulating hormone (15%), proving the surgery to have been unsuccessful.

Twelve weeks post-operatively, the patient discovered she was pregnant. At 12 weeks gestation, her UFC was 768μg/24h and two midnight salivary cortisol levels were elevated at 0.175 and 0.625μg/dL (reference <0.010-0.090). She was experiencing easy bruising and taking labetalol 400 mg twice daily for hypertension. She had gained 10 pounds by 12 weeks gestation.

A second transsphenoidal surgery during pregnancy was deemed high risk, with a high likelihood of residual disease due to the proximity of the tumor to the right carotid artery. The decision was made to treat the patient medically with metyrapone which was started at 250 mg twice per day at 12 weeks gestation and was eventually uptitrated based on UFC levels every 3-4 weeks (goal of <150μg /24h) to 1000 mg three times per day by the time of delivery with an eventual UFC level of 120μg/24h (Figure 2) . Morning ACTH and serum cortisol levels were monitored for potential adrenal insufficiency.

  1. Download : Download high-res image (375KB)
  2. Download : Download full-size image

Figure 2. Caption: This figure depicts the patient’s 24 hour urinary cortisol levels over time as well as the titration of metyrapone dosage in mg/day.

Her hypertension was well controlled throughout pregnancy on labetalol with the addition of nifedipine XL 30mg daily in the second trimester. She remained normokalemic with potassium ranging from 3.8-4.1mEq/L. She was diagnosed with gestational diabetes at 24 weeks by an abnormal two-step oral glucose tolerance test, which was diet-controlled. The patient was induced at 37 weeks gestation due to cervical insufficiency with cerclage in place, and was given stress dose steroids along with metyrapone. She delivered a healthy baby boy vaginally without complications. His Apgar scores were 9 and 9 and he weighed 6 pounds and 5 ounces. At the time of delivery and one week later, the baby’s cortisol levels were normal (6 μg/dL, normal 4-20), without evidence of adrenal insufficiency.

The patient’s metyrapone dose was reduced to 500mg three times a day after pregnancy and her 2 month postpartum 24 hour UFC was 42μg/24hr. The patient stopped the metyrapone on her own four months later and her UFC was found to be elevated at 272ug/24hr (normal 6-42μg/24hr). An MRI one year postpartum revealed a 10x10x9 mm adenoma in the right sella with some suprasellar extension without compression of the optic chiasm, but with abutment of the right carotid artery. Due to the persistently elevated cortisol, large size of the tumor, and potential for cure, especially if followed by radiation therapy, a second transsphenoidal surgery was recommended. However, due to the COVID-19 pandemic the patient underwent a delayed surgery 1.5 years postpartum. The pathology was consistent with a pituitary adenoma that stained strongly and diffusely for ACTH and synaptophysin, only. Her postoperative day 2 cortisol was 1.1μg/dL (reference range 6.7-22.6) and hydrocortisone 20mg in the morning and 10mg in the afternoon was started. She remains on hydrocortisone replacement and went on to conceive again, one month after her second surgery.

DISCUSSION

We describe a patient with pre-existing CD who became pregnant and was managed successfully with metyrapone throughout her pregnancy.

Although CD is rare in pregnancy, it can occur, and poses risks to both the mother and fetus.1,2 Potential maternal complications include hypertension, preeclampsia, diabetes, fractures and more uncommonly, cardiac failure, psychiatric disorders, infection and maternal death.1,2 There is also increased fetal morbidity including prematurity, intrauterine growth retardation and less commonly CD can lead to stillbirth, spontaneous abortion, intrauterine death and hypoadrenalism.1,2

It is, therefore, imperative that these patients receive prompt care to control cortisol levels. The treatment of CD in pregnancy is challenging as there are no large research trials studying the efficacy and safety of medications in CD during pregnancy. Pituitary surgery is first-line recommendation and should be done late in the first trimester or in the second trimester to prevent spontaneous pregnancy loss.3 In this CASE, however, it was felt that a second surgery would be high-risk given the proximity of the tumor to the right carotid artery and possibly not curative, and thus surgery was not a feasible option. She was therefore successfully managed with medical therapy with metyrapone alone throughout her pregnancy.

Metyrapone use in pregnancy has been previously reported in the literature and has been shown to be effective in reducing cortisol levels.4,5,6 Although not approved for use in pregnancy, this steroidogenesis inhibitor is the most commonly used medication to treat Cushing’s syndrome in pregnant women.3,5 Due to metyrapone’s inhibition of 11-beta-hydroxylase, there is a buildup of steroidogenesis precursors such as 11-deoxycorticosterone, which can worsen hypertension, increase frequency of preeclampsia, and cause hypokalemia.3 Metyrapone also leads to elevation of adrenal androgens, which in conjunction with accumulation of 11-deoxycorticosterone, can cause hirsutism and virilization. 8

Though the use of Cabergoline has been reported in cases with Cushing disease during pregnancy, no long term safety data is available regarding it effects on pregnancy as well as the fetus. Moreover, studies assessing the effect of cabergoline in persistent or recurrent CD show a response rate of 20-30% only in cases with mild hypercortisolism. 9

There is no consensus on how to medically treat patients with CD during pregnancy. We chose a goal UFC of <150μg/24 hours because of the physiological rise of cortisol to two to three times the upper limit of normal during pregnancy.3,7 During pregnancy, there is an increase in corticotropin-releasing hormone from the placenta, which is identical in structure to the hypothalamic form.7 This leads to increased levels of ACTH which stimulates the maternal adrenal glands to become slightly hypertrophic and accounts for the rise in serum cortisol levels in pregnancy.7 Corticosteroid-binding globulin also increases in pregnancy, along with serum free cortisol, leading to urinary free cortisol increasing to 3-fold the normal range.7 We therefore aimed to keep our patient’s urinary free cortisol approximately 3 times the upper limit of normal on our assay, to maintain normal cortisol levels for pregnancy.

Close surveillance of patients is required for worsening hypertension, hypokalemia, and potential adrenal insufficiency.3 Although no fetal adverse events from metyrapone have been reported, the medication does cross the placenta, leading to the potential for fetal adrenal insufficiency, and long-term effects are unknown.3

CONCLUSION

This CASE demonstrates the successful use of metyrapone alone to treat CD throughout pregnancy resulting in the birth of a healthy baby without adrenal insufficiency. These cases are particularly challenging given the lack of FDA-approved therapies and the lack of consensus on directing titration of medications and the duration of therapy.

Uncited reference

4., 6..

REFERENCES:

Clinical Relevance: Cushing’s Disease (CD) in pregnancy is a rare, but serious, disease that has potential adverse effects on maternal and fetal health. Surgery is considered first line therapy, and there is little consensus on medical treatment of CD in pregnancy. This CASE demonstrates the successful use and titration of metyrapone throughout pregnancy.

From https://www.sciencedirect.com/science/article/pii/S2376060521001164

Filed under: Cushing's, Rare Diseases, Treatments | Tagged: , , , , | Leave a comment »

Acute severe Cushing’s disease presenting as a hypercoagulable state

Posted on November 8, 2021 by MaryO

This article was originally published here

Proc (Bayl Univ Med Cent). 2021 Jul 29;34(6):715-717. doi: 10.1080/08998280.2021.1953950. eCollection 2021.

ABSTRACT

Cushing’s disease (CD) is the most common cause of endogenous cortisol excess. We discuss the case of a 60-year-old woman with recurrent venous thromboembolism, refractory hypokalemia, and lumbar vertebrae compression fractures with a rapidly progressive disease course.

Ectopic hypercortisolism was suspected given the patient’s age and rapid onset of disease. Investigations revealed cortisol excess from a pituitary microadenoma.

This case demonstrates that CD can present with severe findings and highlights the increased risk of venous thromboembolism in hypercortisolism, especially in CD.

PMID:34732999 | PMC:PMC8545141 | DOI:10.1080/08998280.2021.1953950

Filed under: Cushing's, symptoms | Tagged: , , , , , , | Leave a comment »

« Previous Page — Next Page »