Unilateral Adrenalectomy for Primary Bilateral Macronodular Adrenal Hyperplasia: Analysis of 71 Cases

Abstract Objective Primary bilateral macronodular adrenal hyperplasia (PBMAH) is characterized by benign bilateral enlarged adrenal masses, causing Cushing’s syndrome (CS). The aim of the current article is to define the role of unilateral adrenalectomy (UA) in treating patients with CS related to PBMAH. Methods A PubMed database search was conducted to identify articles reporting UA to treat PBMAH. We also report cases of PBMAH from our medical center treated by UA. Results A total number of 71 cases of PBMAH (62 cases reported in the literature and 9 cases from our center) are presented. Most patients were women (73.2%) and most UA involved the left side (64.3%). In most cases, the resected gland was the larger one. Following UA, 94.4% of cases had remission of hypercortisolism. Recurrence rate of CS was 19.4% and hypoadrenalism occurred in 29.6%. After UA, when the size of the remained adrenal gland was equal or greater than 3.5 cm, CS persisted in 21.4% of cases, and recurrence occurred in 27.3% of cases (after 20±9.2 months). However, when the size of the remained gland was less than 3.5 cm, CS resolved in all cases and recurrence occurred in 21.2% of cases after a long period (65.6±52.1 months). High levels of urinary free cortisol (UFC) were not correlated with post-surgical CS recurrence or persistence. Conclusions UA leads to beneficial outcomes in patients with CS related to PBMAH, also in cases with pre-surgical elevated UFC or contralateral large gland.

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Diagnosis and management of primary bilateral macronodular adrenal hyperplasia

Endocrine Related Cancer ◽

10.1530/erc-19-0240 ◽

2019 ◽

Vol 26 (10) ◽

pp. R567-R581 ◽

Cited By ~ 4

Author(s):

Dimitra A Vassiliadi ◽

Stylianos Tsagarakis

Keyword(s):

Genetic Defect ◽

Urinary Free Cortisol ◽

Distinct Pattern ◽

Cortisol Secretion ◽

Adrenal Hyperplasia ◽

Unilateral Adrenalectomy ◽

Steroid Dependency ◽

Downstream Signaling ◽

Free Cortisol ◽

Hormonal Evaluation

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a highly heterogeneous entity. The incidental identification of an increasing number of cases has shifted its clinical expression from the rarely encountered severe forms, regarding both cortisol excess and adrenal enlargement, to mild forms of asymptomatic or oligosymptomatic cases with less impressive imaging phenotypes. Activation of cAMP/PKA pathway, either due to alterations of the different downstream signaling pathways or through aberrantly expressed G-protein-coupled receptors, relates to both cortisol secretion and adrenal growth. Germline ARMC5 mutations are a frequent genetic defect. The diagnostic approach consists of both imaging and hormonal characterization. Imaging characterization should be done separately for each lesion. Endocrine evaluation in cases with clinically overt Cushing’s syndrome (CS) is similar to that applied for all forms of CS. In incidentally detected PBMAH, hormonal evaluation includes testing for primary aldosteronism, pheochromocytoma and evaluation for autonomous cortisol secretion, using the 1 mg overnight dexamethasone suppression test. Midnight cortisol or 24-h urinary free cortisol may aid in establishing the degree of cortisol excess. In patients with hypercortisolism, ACTH levels should be measured in order to establish ACTH independency. At variance with other forms of CS, PBMAH may be characterized by a distinct pattern of inefficient steroidogenesis. The appropriate management of PBMAH remains controversial. Bilateral adrenalectomy results in lifetime steroid dependency and is better reserved only for patients with severe CS. Unilateral adrenalectomy might be considered in selected patients. In cases where the regulation of cortisol secretion is mediated by aberrant receptors there is some potential for medical therapy.

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Epinephrine to the Rescue: Identifying the Offending Side in Bilateral (B/L) Macronodular Adrenal Hyperplasia (BMAH) With Cushing Syndrome (CS) and Hyperaldosteronism

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.263 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A130-A131

Author(s):

Tarunya Vedere ◽

Parvathy Madhavan ◽

Carl D Malchoff

Keyword(s):

Cortisol Level ◽

Adrenal Vein ◽

Serum Cortisol Level ◽

Plasma Epinephrine ◽

Adrenal Hyperplasia ◽

Unilateral Adrenalectomy ◽

Free Cortisol ◽

Adrenal Masses ◽

The Right ◽

Cortisol Ratio

Abstract Management of ACTH-independent CS in the setting of B/L adrenal masses can be challenging. We present a patient with concomitant cortisol and aldosterone hypersecretion and B/L adrenal masses who was treated with unilateral adrenalectomy (UA) based on simultaneous B/L adrenal vein sampling (AVS) results normalized to plasma epinephrine levels, to correct for flow and dilution. A 60-year-old lady presented for evaluation of incidentally discovered B/L adrenal masses. CT abdomen with contrast revealed B/L lobulated adrenal glands measuring 3.4 x 5.5 x 4.1 cm on the right and 3.8 x 4.2 x 2 cm on the left (pre contrast density of 37 and 44 Hounsfield Units respectively). She had a recent diagnosis of HTN and prediabetes. She reported fatigue, easy bruising, and muscle weakness. Family history was notable for a sister with CS and B/L adrenal masses who was successfully treated with UA. On physical examination her BP was 160/94 mm Hg and she did not have an obvious cushingoid appearance. Laboratory testing included an elevated AM serum cortisol level of 16.6 mcg/dL following 1 mg of dexamethasone given at 11 pm the previous night. ACTH was <1.0 pg/mL consistent with ACTH-independent CS. She had a serum aldosterone level of 26.6 ng/dL(4.0 - 31.0 ng/dL),simultaneous plasma renin activity of 0.5 ng/ml/hr (0.5–4 ng/ml/hr) and serum potassium level of 4.4 mmol/l. She underwent B/L simultaneous AVS. Given concomitant hyperaldosteronism, plasma epinephrine levels were measured to determine successful catheter placement and to correct for flow and dilution between the adrenal veins. Right adrenal vein to peripheral vein cortisol ratio was 9.27 (> 6.5) consistent with cortisol hypersecretion. The right to left cortisol ratio was 2.3 (>/= 2.3), consistent with right sided predominance. Right to left ratio of the epinephrine corrected cortisol level was 2.7. She underwent right adrenalectomy, and pathology showed macronodular adrenal hyperplasia. Postoperatively, she had resolution of HTN and normalization of 24 hour urine free cortisol. UA is increasingly becoming recognized as a successful treatment for BMAH due to lower risk of adrenal crisis when compared to B/L adrenalectomy. In a recent publication, remission from CS was seen in 94.4 % of patients with BMAH following UA, with recurrence in 19% of patients. The mean time to recurrence was 5 years. We utilized cutoff values that were previously reported for cortisol lateralization in interpreting AVS. Our patient attained remission of CS 9 months post UA. Epinephrine levels were not significantly different between the adrenal veins, possibly due to simultaneous AVS, so we were also able to calculate epinephrine corrected cortisol ratios. Simultaneous B/L AVS with epinephrine to localize autonomous hypercortisolism in the setting of concomitant hyperaldosteronism can be beneficial in guiding surgical management of patients.

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Post-surgical hypocortisolism after removal of an adrenal incidentaloma: is it predictable by an accurate endocrinological work-up before surgery?

Acta Endocrinologica ◽

10.1530/eje-09-0775 ◽

2010 ◽

Vol 162 (1) ◽

pp. 91-99 ◽

Cited By ~ 47

Author(s):

Cristina Eller-Vainicher ◽

Valentina Morelli ◽

Antonio Stefano Salcuni ◽

Massimo Torlontano ◽

Francesca Coletti ◽

...

Keyword(s):

Hpa Axis ◽

Adrenal Incidentaloma ◽

Serum Cortisol ◽

Urinary Free Cortisol ◽

Tolerance Test ◽

Surgical Removal ◽

Acth Stimulation ◽

Unilateral Adrenalectomy ◽

Free Cortisol ◽

Few Data

ObjectiveFew data are available regarding the need of steroid substitutive therapy after unilateral adrenalectomy for adrenal incidentaloma (AI). It is unknown whether, before surgery, the hypothalamic–pituitary–adrenal (HPA) axis secretion parameters can predict post-surgical hypocortisolism.AimThis study aimed to evaluate whether, in AI patients undergoing unilateral adrenalectomy, post-surgical hypocortisolism could be predicted by the parameters of HPA axis function.DesignProspective, multicenter.MethodsA total of 60 patients underwent surgical removal of AI (surgical indication: 29 subclinical hypercortisolism (SH); 31 AI dimension). Before surgery, SH was diagnosed in patients presenting at least three criteria out of urinary free cortisol (UFC) levels>60 μg/24 h, cortisol after 1-mg dexamethasone suppression test (1 mg-DST)>3.0 μg/dl, ACTH levels<10 pg/ml, midnight serum cortisol (MSC)>5.4 μg/dl.Two months after surgery, HPA axis function was assessed by low dose ACTH stimulation test or insulin tolerance test when needed: 39 patients were affected (Group B) and 21 were not affected (Group A) with hypocortisolism. The accuracy in predicting hypocortisolism of pre-surgical HPA axis parameters or their combinations was evaluated.ResultsThe presence of >2 alterations among 1 mg-DST>5.0 μg/dl, ACTH<10 pg/ml, elevated UFC and MSC has the highest odds ratio (OR) for predicting post-surgical hypocortisolism (OR 10.45, 95% confidence interval, CI 2.54–42.95, P=0.001). Post-surgical hypocortisolism was predicted with 100% probability by elevated UFC plus MSC levels, but not ruled out even in the presence of the normality of all HPA axis parameters.ConclusionPost-surgical hypocortisolism cannot be pre-surgically ruled out. A steroid substitutive therapy is indicated after unilateral adrenalectomy for SH or size of the adenoma.

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MON-LB44 Cushing’s Syndrome and Illegal Receptors

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.2203 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Caroline Poku ◽

Randa Sharag Eldin ◽

Abubakr Hassab Elrasoul Babiker Mohamed ◽

Sadiq Sobia

Keyword(s):

Cushing’S Syndrome ◽

Hormone Receptors ◽

Age Distribution ◽

Cushing's Syndrome ◽

Endocrine Surgery ◽

Adrenal Hyperplasia ◽

Unilateral Adrenalectomy ◽

Production Studies ◽

Bilateral Adrenal Hyperplasia ◽

Adrenal Masses

Abstract Case presentation: A 48-year-old female with HTN presented to the endocrinology clinic for the evaluation of incidental bilateral adrenal masses noted on chest CT for dyspnea workup. At the time of the presentation, she reported generalized fatigue, significant weight gain in the past year and shortness of breath. Her physical exam was remarkable for central obesity. Lab work showed elevated cortisol after 1 mg dexamethasone suppression test x 2 and elevated 24- hour urine cortisol. Plasma free metanephrine levels and aldosterone/ renin ratio were normal. MRI abdomen was done and showed bilateral adrenal masses (left: 5.6 cm, right: 3.2 cm). Patient was diagnosed with Cushing’s syndrome secondary to primary bilateral adrenal hyperplasia and was referred to endocrine surgery who recommended unilateral adrenalectomy. The decision was made to remove the larger left side adrenal mass. On post-operative day one her am cortisol decreased to 2.1 and she was started on hydrocortisone 20 mg in the morning and 10 mg in the evening. Discussion: Primary bilateral adrenal hyperplasia is a rare cause (< 2 %) of endogenous Cushing’s syndrome, usually occurs in a bimodal age distribution, in childhood and in the fifth- sixth decades. Presentation is variable with most patients having no symptoms or subclinical Cushing’s. The theory is the larger nodule size corelates with the higher cortisol production. Studies have shown between 60-70% of cases has aberrant ectopic hormone receptors which leads to increased cortisol production not only from ACTH but also from other ligands such as serotonin and vasopressin. Aberrant receptor testing examines whether cortisol or other steroid production increases in response to either physiologic or pharmacologic stimulus. Multiple genetic mutations have been associated, the most frequent is mutations in the Armadillo repeat- containing 5 gene identified in 2013. Treatment can either be medical or surgical. Medical therapy can be initiated if testing for an aberrant receptor is positive. In recent years there has been a trend towards doing unilateral adrenalectomy instead of bilateral, with initial remission of symptoms reported in about 84% of cases after unilateral adrenalectomy although there is a small risk of recurrence. Post operatively after unilateral adrenalectomy patients should be monitored for adrenal insufficiency. Our patient declined aberrant receptor testing and opted for surgery and is doing well post operatively. Conclusion: Primary bilateral adrenal hyperplasia is a rare cause of endogenous Cushing’s syndrome which can be treated either medically or surgically.

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MON-LB035 Adrenal Venous Sampling in the Lateralization of Acth-Independent Cushing Syndrome With Bilateral Adrenal Masses: A Case With a 5-Year Follow-Up

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.2191 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Yu Mi Kang ◽

Sachin Majumdar

Keyword(s):

Cushing Syndrome ◽

Urine Volume ◽

Adrenal Vein ◽

Adrenal Venous Sampling ◽

Venous Sampling ◽

Unilateral Adrenalectomy ◽

Free Cortisol ◽

Adrenal Masses ◽

The Common ◽

The Right

Abstract Background Nearly 25% of adrenal Cushing syndrome (CS) patients with bilateral adrenal masses have unilateral hypercortisolism, making localization crucial for surgical planning. Since there is no standardized protocol for adrenal venous sampling (AVS) in lateralizing adrenal hypercortisolism, we share our experience with a case of CS with bilateral adrenal masses in which lateralization via AVS permitted unilateral adrenalectomy. Clinical Case A 59-year-old woman with hypertension, hyperlipidemia, and prediabetes was hospitalized for worsening back pain and hypertension. Her BMI was 26.5 kg/m2, BP 173/93 mmHg, HR 73/min, she was anxious, diaphoretic, and hirsute. Glucose was 118 mg/dL and HbA1c 6.6%. Abdominal computed tomography revealed a type B aortic dissection with both right (6.1 x 3.1cm and 3.6 x 2.4cm), and left (largest 1.7 cm) sided adrenal masses. Plasma and 24 hour-urine metanephrine, normetanephrine and catecholamines, as well as plasma renin and aldosterone levels, were normal. AM cortisol on three different occasions was 21.30, 20.70, and 21.30 mcg/dL. Midnight cortisol was 17.8 mcg/dL, and 24-hour urine free cortisol on two occasions was 163 mcg (urine volume 3.4L with creatinine 1.14) and 99.2 mcg (urine volume 1.15L). After 1mg dexamethasone her AM ACTH and cortisol were <5 and 18.70 mcg/dL, respectively. Preoperative AVS was performed and 8mg of dexamethasone was administered the night prior to ensure ACTH suppression during the procedure, and epinephrine was measured to ascertain adequate adrenal vein cannulation. Cortisol levels (in mcg/dL) from the common iliac, right and left adrenal veins were 14.7, 61.5, and 23.5 at 0 minute and 15.2, 61.0, and 22.7 at 2 minutes, respectively. Epinephrine levels (in pg/dL) from the common iliac, right and left adrenal veins were 42, 577, and 3225 at 0 minutes, and 46, 718, and 2989 at 2 minutes. Despite higher epinephrine levels from the left adrenal, the cortisol ratio of the right adrenal vein to peripheral vein was 4.18 with the right-to-left ratio of 2.59 and 2.68 at 0 and 2 minutes, suggesting hypersecretion of cortisol from the right adrenal gland. Unilateral right adrenalectomy revealed a 5.6 cm adrenal adenoma arising in a background of adrenal cortical hyperplasia. Morning postoperative cortisol was 2.2 mcg/dL. She was placed on hydrocortisone and tapered over a 10-month period with remission maintained for more than 3.5 years post-operatively. Conclusion This case demonstrates the safety, usefulness, and necessity, of AVS in localizing cortisol production when bilateral adrenal masses are present. In addition, this case suggests that the use of high dose dexamethasone and measurement of catecholamines may be helpful for more accurate interpretation. More data on AVS in CS patients with bilateral adrenal masses is needed so a well-validated and standardized CS-specific ACS protocol can be developed.

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Defining Nonfunctioning Adrenal Adenomas on the Basis of the Occurrence of Hypocortisolism after Adrenalectomy

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa079 ◽

2020 ◽

Vol 4 (8) ◽

Cited By ~ 1

Author(s):

Cristina Eller-Vainicher ◽

Valentina Morelli ◽

Carmen Aresta ◽

Antonio Stefano Salcuni ◽

Alberto Falchetti ◽

...

Keyword(s):

Serum Cortisol ◽

Urinary Free Cortisol ◽

Tolerance Test ◽

Cortisol Secretion ◽

Unilateral Adrenalectomy ◽

Insulin Tolerance ◽

Free Cortisol ◽

Suppression Test ◽

Dexamethasone Suppression ◽

Rule Out

Abstract Background In patients with adrenal incidentalomas (AIs), there is uncertainty on how to rule out hypercortisolism. The occurrence of postsurgical (unilateral adrenalectomy) hypocortisolism (PSH) has been proposed as a proof of the presence of presurgical hypercortisolism in AI patients. The aim of this study was to define the thresholds of cortisol level after the 1 mg overnight dexamethasone suppression test (F-1mgDST), urinary free cortisol (UFC), midnight serum cortisol (MSC), and adrenocorticotropin (ACTH) to predict the absence of PSH in AI patients undergoing surgery. Methods In 60 patients who underwent AI excision, cortisol secretion was assessed by a low-dose corticotropin stimulation test or insulin tolerance test when needed. We searched for the lowest presurgical value of F-1mgDST, UFC, and MSC and the highest value for ACTH in AI patients with PSH as indexes of normal cortisol secretion. Results The lowest values of F-1mgDST, UFC, and MSC and the highest value for ACTH in PSH patients were 1.2 µg/dL (33 nmol/L), 10.4 µg/24 hours (29 nmol/24 hours), 1.2 µg/dL (33 nmol/L), and 26.9 pg/mL (6 pmol/L), respectively, but only F-1mgDST <1.2 µg/dL (33 nmol/L) was able to predict the absence of PSH. Among AI patients with F-1mgDST <1.2 µg/dL (33 nmol/L) no subjects had diabetes mellitus and/or metabolic syndrome, and these subjects tended to have a better metabolic profile than those with F-1mgDST ≥1.2 µg/dL (33 nmol/L) Conclusion In AI patients a F-1mgDST <1.2 µg/dL (33 nmol/L) rules out PSH and could be used to exclude hypercortisolism in AI patients.

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Bilateral Adrenal Hyperplasia: Pathogenesis and Treatment

Biomedicines ◽

10.3390/biomedicines9101397 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1397

Author(s):

Benjamin Chevalier ◽

Marie-Christine Vantyghem ◽

Stéphanie Espiard

Keyword(s):

Carney Complex ◽

Current Data ◽

Adrenal Hyperplasia ◽

Systematic Screening ◽

Unilateral Adrenalectomy ◽

Paracrine Regulation ◽

Causal Genes ◽

Bilateral Adrenal Hyperplasia ◽

Pka Pathway

Bilateral adrenal hyperplasia is a rare cause of Cushing’s syndrome. Micronodular adrenal hyperplasia, including the primary pigmented micronodular adrenal dysplasia (PPNAD) and the isolated micronodular adrenal hyperplasia (iMAD), can be distinguished from the primary bilateral macronodular adrenal hyperplasia (PBMAH) according to the size of the nodules. They both lead to overt or subclinical CS. In the latter case, PPNAD is usually diagnosed after a systematic screening in patients presenting with Carney complex, while for PBMAH, the diagnosis is often incidental on imaging. Identification of causal genes and genetic counseling also help in the diagnoses. This review discusses the last decades’ findings on genetic and molecular causes of bilateral adrenal hyperplasia, including the several mechanisms altering the PKA pathway, the recent discovery of ARMC5, and the role of the adrenal paracrine regulation. Finally, the treatment of bilateral adrenal hyperplasia will be discussed, focusing on current data on unilateral adrenalectomy.

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Role of Ketoconazole Treatment in Urinary-Free Cortisol-to-Cortisone and Tetrahydrocortisol-to-Tetrahydrocortisone Ratios in Nonectopic Cushing's Syndrome

Endocrine ◽

10.1385/endo:18:3:279 ◽

2002 ◽

Vol 18 (3) ◽

pp. 279-284 ◽

Cited By ~ 7

Author(s):

Pablo Stiefel ◽

José S García-Morillo ◽

Luis Jimenez ◽

Encarnación Pamies ◽

María Luisa Miranda ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Urinary Free Cortisol ◽

Cushing's Syndrome ◽

Free Cortisol

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Aberrant Membrane Hormone Receptors in Incidentally Discovered Bilateral Macronodular Adrenal Hyperplasia with Subclinical Cushing’s Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.11.8062 ◽

2001 ◽

Vol 86 (11) ◽

pp. 5534-5540 ◽

Cited By ~ 2

Author(s):

Isabelle Bourdeau ◽

Pierre D’Amour ◽

Pavel Hamet ◽

Jean-Marie Boutin ◽

André Lacroix

Keyword(s):

Cushing’S Syndrome ◽

Plasma Cortisol ◽

Hormone Receptors ◽

Gastric Inhibitory Polypeptide ◽

Urinary Free Cortisol ◽

Cushing's Syndrome ◽

Cortisol Secretion ◽

Adrenal Hyperplasia ◽

Free Cortisol ◽

Cortisol Levels

Cortisol secretion in adrenal Cushing’s syndrome can be regulated by the aberrant adrenal expression of receptors for gastric inhibitory polypeptide, vasopressin, catecholamines, LH/human CG (LH/hCG), or serotonin. Four patients with incidentally discovered bilateral macronodular adrenal hyperplasia without clinical Cushing’s syndrome were evaluated for the possible presence of aberrant adrenocortical hormone receptors. Urinary free cortisol levels were within normal limits, but plasma cortisol levels were slightly elevated at nighttime and suppressed incompletely after dexamethasone administration. Plasma ACTH was partially suppressed basally but increased after administration of ovine CRH. A 51-yr-old woman had ACTH-independent increases of plasma cortisol after 10 IU AVP im (292%), 100 μg GnRH iv (184%), or 10 mg cisapride orally (310%); cortisol also increased after administration of NaCl (3%), hCG, human LH, and metoclopramide. In a 61-yr-old man, cortisol was increased by AVP (349%), GnRH (155%), hCG (252%), and metoclopramide (191%). Another 53-yr-old male increased plasma cortisol after AVP (171%) and cisapride (142%). Cortisol secretion was also stimulated by vasopressin in a 54-yr-old female. This study demonstrates that subclinical secretion of cortisol can be regulated via the aberrant function of at least V1-vasopressin, LH/hCG, or 5-HT4 receptors in incidentally identified bilateral macronodular adrenal hyperplasia.

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