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 »

Resolution of pituitary microadenoma after coronavirus disease 2019: a case report

Posted on November 6, 2021 by MaryO

This article was originally published here

J Med Case Rep. 2021 Nov 1;15(1):544. doi: 10.1186/s13256-021-03127-3.

ABSTRACT

BACKGROUND: This report describes the case of a patient whose pituitary microadenoma resolved after he contracted coronavirus disease 2019. To our knowledge, this is one of the first reported cases of pituitary tumor resolution due to viral illness. We present this case to further investigate the relationship between inflammatory response and tumor remission.

CASE PRESENTATION: A 32-year-old man in Yemen presented to the hospital with fever, low blood oxygen saturation, and shortness of breath. The patient was diagnosed with coronavirus disease 2019. Past medical history included pituitary microadenoma that was diagnosed using magnetic resonance imaging and secondary adrenal insufficiency, which was treated with steroids. Due to the severity of coronavirus disease 2019, he was treated with steroids and supportive care. Three months after his initial presentation to the hospital, brain magnetic resonance imaging was performed and compared with past scans. Magnetic resonance imaging revealed changes in the microadenoma, including the disappearance of the hypointense lesion and hyperintense enhancement observed on the previous scan.

CONCLUSIONS: Pituitary adenomas rarely undergo spontaneous resolution. Therefore, we hypothesized that tumor resolution was secondary to an immune response to coronavirus disease 2019.

PMID:34724974 | DOI:10.1186/s13256-021-03127-3

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

« Previous Page — Next Page »