SYSTEMATIC REVIEW published: 31 March 2022 doi: 10.3389/fendo.2022.846865 11-Deoxycorticosterone Producing Adrenal Hyperplasia as a Very Unusual Cause of Endocrine Hypertension: Case Report and Systematic Review of the Literature Queralt Asla 1,2,3, Helena Sardà 1,2,4, Enrique Lerma 2,4,5, Felicia A. Hanzu 6,7,8, Marı́a Teresa Rodrigo 7,9, Eulàlia Urgell 2,10, José Ignacio Pérez 2,11, Susan M. Webb 1,2,4,12 and Anna Aulinas 1,2,3,12* 1 Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 2 Sant Pau Biomedical Research Institute (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 3 Department of Medicine, University of Vic-Central University of Catalonia, Vic, Spain, 4 Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain, 5 Department of Pathological Anatomy, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, Edited by: 6 Department of Endocrinology and Nutrition, Hospital Clı´nic, Barcelona, Spain, 7 Institut d’Investigacions Biomèdiques Elena Aisha Azizan, August Pi i Sunyer, Barcelona, Spain, 8 Department of Medicine, Faculty of Medicine and Health Sciences, University of National University of Malaysia, Barcelona, Barcelona, Spain, 9 Department of Pathological Anatomy, Hospital Clı´nic, Barcelona, Spain, 10 Department of Malaysia Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 11 Department of General and Digestive Surgery, Reviewed by: Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 12 Centro de Investigación Biomédica en Red de Enfermedades GianLuca Colussi, Raras (CIBER-ER, Unit 747), Instituto de Salud Carlos III (ISCIII), Madrid, Spain University of Udine, Italy Akira Sugawara, Tohoku University, Japan Background and Objectives: 11-deoxycorticosterone overproduction due to an *Correspondence: adrenal tumor or hyperplasia is a very rare cause of mineralocorticoid-induced Anna Aulinas hypertension. The objective is to provide the most relevant clinical features that aaulinas@santpau.cat clinicians dealing with patients presenting with the hallmarks of hypertension due to 11- This article was submitted to Adrenal Endocrinology, deoxycorticosterone-producing adrenal lesions should be aware of. a section of the journal Frontiers in Endocrinology Design and Methods: We report the case of a patient with an 11-deoxycorticosterone- producing adrenal lesion and provide a systematic review of all published cases (PubMed, Specialty section: Web of Science and EMBASE) between 1965 and 2021. Received: 31 December 2021 Accepted: 23 February 2022 Results: We identified 46 cases (including ours). Most cases (31, 67%) affected women Published: 31 March 2022 with a mean age of 42.9 ± 15.2 years and presented with high blood pressure and Citation: hypokalemia (average of 2.68 ± 0.62 mmol/L). Median (interquartile range) time from onset Asla Q, Sardà H, Lerma E, Hanzu FA, Rodrigo MT, Urgell E, Pérez JI, of first suggestive symptoms to diagnosis was 24 (55) months. Aldosterone levels were Webb SM and Aulinas A (2022) 11- low or in the reference range in 98% of the cases when available. 11-deoxycorticosterone Deoxycorticosterone Producing levels were a median of 12.5 (18.9) times above the upper limit of the normal reference Adrenal Hyperplasia as a Very Unusual Cause of Endocrine range reported in each article and overproduction of more than one hormone was seen in Hypertension: Case Report and 31 (67%). Carcinoma was the most common histological type (21, 45.7%). Median tumor Systematic Review of the Literature. Front. Endocrinol. 13:846865. size was 61.5 (60) mm. Malignant lesions were larger, had higher 11-deoxycorticosterone doi: 10.3389/fendo.2022.846865 levels and shorter time of evolution at diagnosis compared to benign lesions. Frontiers in Endocrinology | www.frontiersin.org 1 March 2022 | Volume 13 | Article 846865 Asla et al. DOC-Producing Adrenal Lesions Conclusions: 11-deoxycorticosterone-producing adrenal lesions are very rare, affecting mostly middle-aged women with a primary aldosteronism-like clinical presentation and carcinoma is the most frequent histological diagnosis. Measuring 11-deoxycorticosterone levels, when low aldosterone levels or in the lower limit of the reference range are present in hypertensive patients, is advisable. Systematic Review Registration: Open Science Framework, 10.17605/OSF.IO/ NR7UV. Keywords: mineralocorticoid hypertension, mineralocorticoid excess, 11-deoxycorticosterone (DOC), DOC- producing adrenal tumor, adrenal hyperplasia, adrenocortical carcinoma, adrenal adenoma INTRODUCTION reports and abstracts presented at scientific meetings to expand the initial search. Most cases of hypertension are essential or idiopathic (primary hypertension) although 5–10% of hypertensive Study Selection and Data Extraction patients present an identifiable cause (secondary hypertension) A DOC-producing adrenal lesion was defined as either an (1). Primary aldosteronism (PA) is a mineralocorticoid- adrenal tumor or hyperplasia together with elevated DOC induced hypertension due to an excess of aldosterone (ALD) concentrations in peripheral and/or adrenal vein blood and/or production. PA is the most frequent endocrine cause of increased DOC or tetra-hydro-DOC (THDOC) concentrations secondary high blood pressure (BP) (2) and the main clinical in urine, supported when available by altered enzyme presentation includes hypertension of variable degree, but immunoreactivity of the mineralocorticoid pathway and/or hypokalemia only in 9–37% of the cases (3). However, there elevated DOC levels in adrenal tissue. are other less common non-ALD-dependent causes We considered the following exclusion criteria: of mineralocorticoid hypertension with a clinical presentation a. Diagnosis other than adrenal carcinoma, adrenal adenoma or similar to PA, du e to overproduction of different non-congenital adrenal hyperplasia. mineralocorticoid precursors like 11-deoxycorticosterone b. Diagnosis of adrenal carcinoma, adrenal adenoma or non- (DOC) or other intermediate steroids (4). A small number of congenital adrenal hyperplasia without any major clinical case reports on adrenal lesions (either adenoma, carcinoma or sign of mineralocorticoid excess (high BP and/or hyperplasia) producing mineralocorticoid intermediate hypokalemia). metabolites have been reported, although some are probably c. Diagnosis of adrenal carcinoma, adrenal adenoma or non- overlooked, since intermediate measurements of steroids are not congenital adrenal hyperplasia with significant elevation of available in clinical practice in the majority of centers. other steroid intermediates considered to be responsible for We present a case of DOC-producing adrenal hyperplasia the clinical presentation of mineralocorticoid excess. with a life-threatening clinical presentation and a comprehensive d. Significant unavailable information, defined as missing data review of DOC-producing adrenal lesions described in the in more than four of the following eight relevant variables: literature. This review is intended to provide insights on the sex, age at diagnosis, time of suggestive symptoms until most relevant reported clinical, radiological and pathological diagnosis, overproduction of other hormones different from features of DOC-producing adrenal lesions that might be DOC, serum DOC levels, serum potassium levels, tumor size useful for clinicians dealing with patients with rare causes of and histological diagnosis. secondary hypertension with low or normal ALD levels. Two investigators (QA, HS) independently reviewed all articles retrieved, identified those potentially eligible for inclusion in the review and performed data extraction. In case METHODS of disagreement a third investigator was consulted (AA) and the question was solved by a consensus. Duplicated cases were Search Strategy excluded. A dataset was designed prior to data collection of the A systematic search was performed to identify potential relevant following items: clinical cases in the following electronic databases: PubMed, Web of Science and EMBASE with the MeSH terms: 1. Paper meta-data: first name of author, year of publication, (deoxycorticosterone OR DOC) AND (adrenal tumor OR country of origin. adrenal hyperplasia). There were no language and year 2. Baseline characteristics: gender, age at diagnosis, time of restrictions. All case reports published between 1965 and suggestive symptoms. October 2021 were considered. The literature search was 3. Characteristics of the DOC-producing adrenal lesion: serum supplemented with listed references from the selected case potassium, ALD levels, renin levels and DOC levels, Frontiers in Endocrinology | www.frontiersin.org 2 March 2022 | Volume 13 | Article 846865 Asla et al. DOC-Producing Adrenal Lesions biochemical production other than DOC, tumor size and Serum 17-hydroxy-progesterone was measured by enzyme histological diagnosis. linked immunosorbent assay (DRG instruments GmbH, Germany) with a LOQ of 0.47 nmol/L and intra-interassay CV of <4% and <6.3%. Quality Assessment The present systematic review is based only on clinical cases Statistical Analysis reported in the literature of DOC-producing adrenal lesions. We For descriptive analysis, quantitative data were expressed as included all cases found in the literature search. We carefully mean ± SD or median (interquartile range) according to data excluded those cases with significant missing information (more distribution and categorical data as absolute frequencies and than four of the items included) to minimize any information percentages. Distribution of continuous data was tested for bias. Importantly, case reports were excluded if a concomitant normality by the Shapiro–Wilk test. Means across groups hormone hypersecretion considered to be more clinically (malignant vs benign behavior) were compared using Student’s relevant than DOC overproduction was present, according to t-test or Wilcoxon’s rank-sum test accordingly, and Fisher’s the authors. exact test was performed to compare categorical variables. For The study was registered on the Open Science Framework reporting, the Preferred Reporting Items for Systematic Reviews (https://doi.org/10.17605/OSF.IO/NR7UV) and approved by the and Meta-Analyses (PRISMA) statement (see Supplementary local Ethics Committee. Written informed consent was obtained Material: Tables 1, 2) was used (5). STATA software, version from the patient for publication of the case report. 14.2 (StataCorp LLC, College Station, TX) was used for statistical analysis. Hormone Measurements Biochemical and blood parameters were analyzed using routine laboratory methods. All hormonal measurements were performed in our laboratory except 17-hydroxy-pregnenolone, CASE PRESENTATION DOC and 11-deoxycortisol that were measured in an external laboratory (Reference Laboratory); 11-deoxycortisol by A 53-year-old Caucasian woman without any previous history of radioimmunoassay (DIAsource ImmunoAssays, Belgium; limit hypertension consulted the Primary Care Emergency Department of quantification (LOQ) of 0.10 ng/ml and intra and interassay for a one-week history of self-measured high BP (up to 190/100 coefficients of variation (CV) of 7.7 and 15.1%), and by liquid mmHg), muscle aches and stiffness. A blood test showed serum chromatography-tandem mass spectrometry (LC–MS/MS) potassium (K+) of 1.73 mmol/L. When reviewing previous blood (1290 LC-6430 QQQ Agilent; LOQ of 0.10 ng/ml, intra and tests, K+ was in the normal range with the exception of the interassay CV <6.7% and <8%); DOC and 17-hydroxy- immediately preceding level five months before with a result of pregnenolone by LC–MS/MS (1290 LC-6430 QQQ Agilent; 3.18 mmol/L. An angiotensin-converting enzyme inhibitor (enalapril LOQ of 1 ng/dl and 0.10 ng/ml, intra and interassay CV <6% 20 mg/24 h orally) and K+ supplements (50 KCl mEq/24 h orally) and <6.7%, <6.8% and <8.1%, respectively). were initiated. Nevertheless, during follow-up BP was not controlled, Steroid hormones, serum testosterone and urinary cortisol and K+ levels did not improve (2.13 mmol/L). Four weeks later, she (extracted with dichloromethane) concentrations were was admitted to the Intensive Care Unit (ICU) for uncontrolled determined by an electrochemiluminescent immunoassay hypertension (BP of 200/120 mmHg), severe hypokalemia (1.80 (cobas e601; Roche Diagnostics GmbHm, Manheim, mmol/L), metabolic alkalosis (pH 7.52, HCO3− 43.5 mmol/L) Germany). Testosterone LOQ was 0.416 nmol/L and urinary (Table 1) and changes in the electrocardiogram, namely, QT cortisol LOQ was 0.5 nmol/L. Intra-interassay CV were <4.4% interval prolongation, a visible U wave and T wave flattening. In and <5.9% for testosterone and <1.1% and <1.7% for urinary the ICU she required high doses of both intravenous and oral K+ (up cortisol. Serum estradiol and cortisol were measured by to 176 mEq KCl/24 h). Because of initial difficulties in raising serum chemiluminescent microparticle immunoassay (Alinity, Abbott K+ levels despite high supplements, access to the bathroom was Laboratories, IL60064, USA). The LOQ and the intra-interassay banned and a psychiatric consultation ruled out self-induced CV were 0.088 nmol/L, <7.2% and <7.7% for serum estradiol and vomiting. Her BP was finally controlled with two oral drugs (the 27.6 nmol/L, <4.3% and <5.1% for serum cortisol. ALD and calcium channel blocker amlodipine 10 mg/24 h and the peripheral plasma renin activity (PRA) were determined by vasodilator hydralazine 25 mg/8 h) and serum K+ levels were radioimmunoassay (DRG GmbH, Germany and Beckman maintained with in the lower limit of the normal range with oral Coulter, Immunotech Czech Republic respectively). The LOQ 72 mEq/24 h of KCl. and the intra-interassay CV were 79 pmol/L, <11.92% and After her hemodynamic and biochemical situation <10.15% for ALD and 0.20 µg/L/h, <11.25% and <20.9% for normalized, she was transferred to the hospitalization ward PRA. Progesterone, dehydroepiandrosterone sulfate (DHEAS) for diagnostic workup of suspected secondary hypertension. and androstendione were measured by chemiluminiscent Her family history was irrelevant for hypertension or any immunometric assay (Immulite 1000, Siemens Healthcare other endocrine disease. Besides high BP, physical examination Diagnostics, Llanberis, UK), with a LOQ of 1.46 nmol/L, 0.08 was normal with no signs of hypercortisolism, hirsutism µmol/L and 1.0 nmol/L and intra-interassay CV of <12.5% and or virilization. Biochemical and hormone data are shown in <13.2%, <9.5% and <15% and <9.1% and <15.2%, respectively. Table 1. Plasma metanephrines, 1 mg overnight dexamethasone Frontiers in Endocrinology | www.frontiersin.org 3 March 2022 | Volume 13 | Article 846865 Asla et al. DOC-Producing Adrenal Lesions TABLE 1 | Summary of biochemistry results before (during and after the first hospitalization) and after surgery. Laboratory test During first hospitalization After first hospitalization After surgery Reference range pH 7.52 7.40 – 7.35–7.45 pCO2 (mmHg) 53 45.7 – 38–45 HCO3- (mmol/L) 43.5 26 – 22–25 Base excess (mmol/L) 18 5.4 – −2–2 K+ (mmol/L) 1.80 3.71 5.08 3.50–5.10 Cl- (mmol/L) 93.4 107 – 98–107 Na+ (mmol/L) 145 143 141 136–145 Renal function (ml/min/1.73 m2) >90 >90 >90 >90 Urine K+ (mmol/L) 28 – – 17–83 Urine Na+ (mmol/L) 113 – – 25–150 Cortisol (nmol/L) 648 – – 171–680 Dexamethasone suppression test (nmol/L) 50.98 – – <50 Urine cortisol (nmol/24 h) 262.86 – – 100–379 ALD (pmol/L) with normal K+ level <79 81.94 696.86 187–930 PRA (µg/L/h) with normal K+ level <0.20 <0.20 1.27 0.6-4.18 DOC (ng/ml) – 35.8 19.6 2-15 11-deoxycortisol (ng/ml) – 4.3 (RIA) 0.54 (LC–MS/MS) After first hospitalization: ≤7.2 After surgery: ≤0.79 17-OH-pregnenolone (ng/ml) – 4.77 – ≤4.55 17-OH-progesterone (nmol/L) – 2.99 – <4.80 ACTH (pmol/L) – 12.3 – 1.6–13.9 LH (UI/L) – 33.1 – 10.4–64.6 FSH (UI/L) – 50.4 – 26.7–133.4 Estradiol (nmol/L) – <0.09 – <0.10 Progesterone (nmol/L) – 1.1 – <3.2 Testosterone (nmol/L) – 0.43 – 0.22–2.90 DHEAS (µmol/L) – 2.4 – 0.7–5.4 Androstendione (nmol/L) – 6.3 – 3.5–11.4 Plasma free metanephrines (nmol/L) Metanephrine – 0.10 – <0.45 Normetanephrine – 0.38 – <0.74 3-metoxitiramine – 0.04 – <0.11 TSH (mUI/L) 1.84 – 1.73 0.3–5.0 pCO2, partial pressure of carbon dioxide; HCO3-, bicarbonate; K+, potassium; Cl−, chloride; Na+, sodium; ALD, aldosterone; PRA, plasma renin activity; RIA, radioimmunoassay; LC–MS/ MS, liquid chromatography-tandem mass; DOC, 11-deoxycorticosterone; 17-OH-pregnenolone, 17-hydroxy-pregnenolone; 17-OH-progesterone, 17-hydroxy-progesterone; ACTH, adrenocorticotropic hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; DHEAS, dehydroepiandrosterone sulfate; TSH, thyroid stimulating hormone. suppression test, thyroid function and the rest of biochemical With the diagnostic suspicion of a functional adrenal mass due and hematological findings were normal; PRA and ALD were to non-ALD-dependent mineralocorticoid secretion, namely, undetectable. Adrenal computed tomography (CT) showed two excessive DOC production, a laparoscopic left adrenalectomy was calcifications in the right adrenal gland and two adrenal nodules performed. Macroscopy revealed a 6 × 2 × 2 cm left adrenal gland suggestive of adenomas in the left adrenal gland, the largest of with cortical adenomatous hyperplasia and several soft and 12.3 × 10 × 14 mm. Both nodular adrenal lesions presented −2 yellowish nodules, the largest being 12 × 12 mm and the rest (the largest) and 5.4 Hounsfield Units and absolute and relative were less than 1 cm and less defined (Figure 1). On microscopic percentages of washout at 15 min of 70% and 79%, suggestive of examination, the larger nodule had no capsule and its margins were benign lesions. Abdominal and renal ultrasonography did not not clear (Figure 2A). Two main types of cells were identified: large reveal any abnormal finding. cells disposed in irregular nests with vacuolated cytoplasm and At follow-up in the Endocrinology Department after small, round nuclei with inconspicuous nucleoli and, among these hospitalization, new blood tests after adjusting antihypertensive nests, a second cell population of smaller cells with eosinophilic drugs and maintaining oral K+ supplementation showed serum cytoplasm (Figure 2B). No atypia, mitosis or necrosis was detected K+ levels in the lower normal range (3.43 mmol/L), undetectable and the Ki67 index was positive in less than 1% of cells (Figure 2C). PRA (<0.20 µg/L/h; reference range 0.6–4.18 µg/L/h) and low Immunohistochemical analysis of steroidogenic enzymes, namely, ALD (81.94 pmol/L; reference range 187–930 pmol/L). Further CYP11B2 (cytochrome P450 family 11, subfamily B, member 2) testing evidenced elevated DOC (35.8 ng/dl; reference range 2– immunostaining (11b-hydroxylase, 18-hydroxylase and 18-oxidase 15 ng/dl) and normality of the rest of the hormonal profile activities) and CYP11B1 (cytochrome P450 family 11, subfamily B, (Table 1). All other potential causes of non-ALD-dependent member 1) immunostaining (11b-hydroxylase activity) was mineralocorticoid excess were excluded by clinical history, performed (Figure 3). In the zona glomerulosa of the physical examination and/or biochemical results. adenomatous hyperplasia, there was a sparse expression of Frontiers in Endocrinology | www.frontiersin.org 4 March 2022 | Volume 13 | Article 846865 Asla et al. DOC-Producing Adrenal Lesions FIGURE 1 | Macroscopic image of the excised adrenal gland (6 × 2 × 2 cm) with a visible multi-nodular pattern. The larger nodule was round, measured 12 mm in diameter and was composed by a bright-yellow soft tissue. Other less defined nodules were found. CYP11B2, highlighting only two isolated clusters of ALD- RESULTS OF THE SYSTEMATIC REVIEW producing cells in the outer margin of the subcapsular area (Figure 3A). Immunoreactivity for CYP11B1 was fundamentally Study Selection expressed in the zona fasciculata (Figure 3B) as expected. These The results of the search process are summarized in a flowchart findings suggested an overproduction of DOC by hyperplasic (Figure 5 and Supplementary Material: Table 3). The initial adrenal cells, leading to a suppression of ALD levels (Figure 4). search identified 839 papers. Of these 808 did not meet the After surgery, K+ levels normalized, and K+ supplementation could eligibility criteria. Thirty-one manuscripts describing one or be withdrawn immediately. BP remained elevated but to a lesser more case reports on DOC-adrenal producing lesions were degree, suggestive of co-diagnosis of primary hypertension. She included (6–40). Seven additional manuscripts (including one required hypotensive therapy (angiotensin II receptor antagonist case each) were found from the listed references of the articles losartan 25 mg/24 h) at hospital discharge achieving a previously retrieved or from abstracts presented at scientific satisfactory BP control. Postoperative serum PRA and ALD levels endocrine meetings (41–47). Finally, five additional cases were were normal, while postoperative serum DOC levels practically identified from two articles with a review of the literature in 1993 normalized (Table 1). and 1995 (29). In summary, 46 cases including ours were included. A B C FIGURE 2 | Microscopic images of the left adrenal gland. (A) Panoramic microscopic image of the larger nodule (Hematoxylin–Eosin; magnification ×4). Lack of capsule and fear delimitation of the normal cortex (arrows). (B) Representative histologic section of the adenomatous left adrenal hyperplasia, showing two types of cell population. No atypia, mitosis or necrosis was detected (Hematoxylin–Eosin; magnification ×20). (C) Positive Ki-67 immunohistochemical staining in less than 1% of adrenal cells (magnification ×20). Frontiers in Endocrinology | www.frontiersin.org 5 March 2022 | Volume 13 | Article 846865 Asla et al. DOC-Producing Adrenal Lesions A B FIGURE 3 | Immunohistochemical analysis of steroidogenic enzymes. (A) Sparse expression of CYP11B2 immunoreactivity in the zona glomerulosa. Only two clusters of ALD-producing cells stained (arrows) in the outer margin of the subcapsular zona glomerulosa (magnification ×4). (B) Normal expression of CYP11B1 in the zona fasciculata (magnification ×4). Characteristics of DOC-Producing (67%) affected adult women (31 females and 15 males) with a Adrenal Lesions mean age of 42.9 ± 15.2 years (range: 10.5–74 years). The most To the best of our knowledge, a total of 46 cases (including ours) of frequent clinical presentation did not differ from PA and DOC overproduction due to an adrenal lesion (tumor or frequently included high BP, moderate to severe hypokalemia hyperplasia) have been reported in the medical literature. Of (average of 2.68 ± 0.62 mmol/L, ranging from 1.5 to 3.8 mmol/L), note, half (23, 50%) were published by Japanese authors, while and/or non-specific symptoms mostly related to hypokalemia the others came from the United States (11, 24.9%), United (muscle weakness, paraesthesia). Of note, five cases presented Kingdom (5, 10.9%), Spain (2, 4.3%) and France, Germany, with extremely low serum K+ levels <2 mmol/L (19, 33, 42, 46 and Italy, The Netherlands and Brazil (each with 1 case, 2.2%). ours) and two cases did not have overt high BP (29, 41). Five cases Table 2 summarizes the main characteristics of the published presented with large malignant adrenal masses with abdominal cases of DOC overproduction by an adrenal lesion. The majority (18, 22, 25, 38) or lumbar (47) compression symptoms. Median FIGURE 4 | Steroid hormone metabolism pathways. (−) and (+) represent diminished and increased enzyme activity respectively detected during intratumoral analysis of steroidogenic enzymes of nine case reports (including ours). 3b-HSD, 3b-hydroxysteroid dehydrogenase; 18-OH-corticosterone, 18-hydroxy- corticosterone; 17-OH-pregnenolone, 17-hydroxy-pregnenolone; 17-OH-progesterone, 17-hydroxy-progesterone, 17b-HSD, 17b-hydroxysteroid dehydrogenase. Frontiers in Endocrinology | www.frontiersin.org 6 March 2022 | Volume 13 | Article 846865 Asla et al. DOC-Producing Adrenal Lesions FIGURE 5 | Flowchart of the literature review. time from onset of the first suggestive symptom to date of lesions were larger (tumor size of 97, (70) vs 40 (28) mm, p = diagnosis was 24 (55) months (range: 0 to 240 months). By 0.0001), with higher DOC levels (20.3 (14.1) vs 7.4 (17.8) times definition, serum DOC concentrations were elevated in all, with above the upper limit of normal, p = 0.036) and a shorter time of wide variability from mildly to hugely elevated (from 1.5 up to 79 evolution of symptoms (11 (35) vs 42 (74) months, p = 0.029). times above the upper limit of normal reference range). Of those Malignant lesions in comparison with benign lesions were not reported, ALD and renin (concentration or activity) levels were significantly different in gender distribution (malignant: men 10 mostly low or in the reference range (40/41, 98%) and decreased (45%)/women 12 (55%) vs benign: men 5 (22%)/women 18 (78%), (30/34, 88%), respectively. On average, DOC levels were reported a p = 0.092), K+ levels (2.69 ± 0.14 vs 2.67 ± 0.14 mmol/L, p = 0.936) median of 12.5 (18.9) times above the upper limit of normal. or existence of concomitant hormone overproduction (17 (85%) vs Overproduction of other hormones different from DOC was seen 14 (67%), p = 0.172). in 31 cases (67%), while only in 11 cases (24%) was DOC hormone solely produced and in 4 (9%) these data were not available. The most common histological types were carcinoma (21, DISCUSSION 45.7%) and adenoma (19, 41.3%). Other less frequent pathological types when reported were adrenal hyperplasia (4, 8.9%) and a To our knowledge, this is the forty-sixth DOC overproduction due neoplasm of uncertain malignant potential (2.2%) and no available to an adrenal lesion published so far worldwide. This case is information in one case (2.2%). Excluding DOC-producing adrenal remarkable for the rapid and severe clinical presentation, despite hyperplasia, median calculated tumor size based on the maximum the relatively small size of the adenomatous adrenal hyperplasia diameter reported was 61.5 (60) mm (range: 11–240 mm). When (the largest nodule of 12 mm) and mildly elevated DOC levels comparing by histological behavior, malignant compared to benign compared to the majority of cases reported. Our literature review Frontiers in Endocrinology | www.frontiersin.org 7 March 2022 | Volume 13 | Article 846865 Asla et al. DOC-Producing Adrenal Lesions TABLE 2 | Clinical characteristics and biochemical, imaging and histological findings of DOC-producing adrenal tumors or hyperplasia. Literature review and report of a new case. Author Sex Age, Time of Serum K+ ALD levels Renin DOC Overproduction ≥1 Tumor Histological (year), (F/M) years suggestive levels levels levels*** adrenal hormone size diagnosis country symptoms* (mmol/L)** (PRA/PRC) other than DOC (mm)a Marquezy F 15 11 months 2.7 Only NA Only available 17-ketosteroids (DHEA), NA Carcinoma et al. (1965), available in in urine 10 17- France (6) urine: <2 µg/L hydroxycorticosteroids mg/24 h and estriol Biglieri F 39 9 months 2.0 Only NA Only available No, however micrograms NA Bilateral gross (1965), USA available in in plasma quantities of a steroid nodular (41) urine: 109 from adrenal were found in the urine of hyperplasia (100–205 vein (0.18 µg/ the patient mg/24 h) ml) and adrenal gland tissue (0.81 µg/g wet weight). THDOC excretion in urine 300– 600 (5–30 µg/24 h) Solomon M 31 14 months NA Only NA Only available Estrogens 60–70 Carcinoma et al. (1968), available in in urine 609 USA (7) urine 18 (50–180 µg/ (60–180 µg/ 24 h) 24 h) Powell- F 64 36 months 2.2 12.8 (4–18 NA 535 (4.1– No 94 × 77 × Carcinoma Jackson ng/100 ml) 17.2 ng/100 58 et al. (1974), ml) UK (8) Kondo et al. F 35 72 months 2.2 2.5 (3.0- <0.5 (1.2– 121 (2.0–8.0 No 95 × 85 × Adenoma (1976)/ (preeclampsia 10.0 ng/100 2.1 ng/ml/h) ng/100 ml) 55 Saruta et al. during prior ml) (1977)/Aiba pregnancy, et al. (1985), persisting Japan (9–11) hypertension and proteinuria after delivery) Tan et al. M 10 ½ 1 month 2.0 Low NA 1,560 (10– 17-OH-progesterone, 11- NA Carcinoma (1977), USA excretion in 180 pg/ml) deoxycortisol and cortisol (12) urine Hogan et al. M 45 12 months 3.7 on 14.2 (2–14 0.75 (2–12 126.1 (5–15 Corticosterone, 50 Adenoma (1977), USA supplements ng/dl) ng/ml/3h) ng/dl) tetrahydrocorticosterone, (13) tetrahydro-11- deoxycortisol and cortisol Davies et al. F 51 18 months 2.9 192 (100– <0.5 (1–6 12,400 (100– Progesterone NA Carcinoma (1980)/Kelly 500 pmol/L) ng/ml/h) 500 pmol/L) et al. (1982), UK (14, 15) Kojima M 56 NA NA NA NA NA 15 × 15 × Adenoma (1984), 30 Japan (29) Honjo M 44 NA NA NA NA NA 180 × 155 Carcinoma (1987)/Miki × 120 (1988), Japan (29) Isles et al. F 47 Several years 2.8 800 (<500 <1 (9–50 5,117 (120– Corticosterone, 18-OH- 56 × 30 × Carcinoma (1987), UK pmol/L) µU/L) 480 pmol/L) corticosterone and ALD 36 (16) Makino F 25 60 months 3.7 12.0 (5.6– 0.1 (0.3–3.2 244 (1–30 Pregnenolone, 35 × 30 × Carcinoma et al. (1987), 16.4 ng/dl) ng/ml/h) ng/dl) progesterone, 18-OH- 35 Japan (17) DOC, corticosterone, 18- (Continued) Frontiers in Endocrinology | www.frontiersin.org 8 March 2022 | Volume 13 | Article 846865 Asla et al. DOC-Producing Adrenal Lesions TABLE 2 | Continued Author Sex Age, Time of Serum K+ ALD levels Renin DOC Overproduction ≥1 Tumor Histological (year), (F/M) years suggestive levels levels levels*** adrenal hormone size diagnosis country symptoms* (mmol/L)** (PRA/PRC) other than DOC (mm)a OH-corticosterone, 17- OH-pregnenolone and 17-OH-progesterone Irony et al. F 31 60 months 2.3 <83 (205 ± 0.03 (0.61 ± 5,659 (148– 18-OH-DOC and 60 Adenoma (1987), USA 25 pmol/L) 0.08 ng/L·s) 178 pmol/L) corticosterone (18) F 55 1 month 2.8 144 (205 ± 0.11 (0.61 ± 14,010 (148– 18-OH-DOC, NA Carcinoma 25 pmol/L) 0.08 ng/L·s) 178 pmol/L) corticosterone and 18- (biopsy) OH-corticosterone Ishikawa F 52 48 months 2.2 0.12 (0.03– 0.08 (0.3– 1.13 (0.06– Corticosterone 15 Adenoma et al. (1988), 0.18 nmol/L) 2.9 ng/ml/h) 0.23 nmol/L) Japan (19) F 62 24 months 1.7 0.04 (0.03– 0.10 (0.3– 1.47 (0.06– Corticosterone and 11- CT scan Adrenal 0.18 nmol/L) 2.9 ng/ml/h) 0.23 nmol/L) deoxycortisol did not hyperplasia? show an adrenal tumor Konta et al. F 33 84 months 2.1 60 (50–360 0.1 ng/ml/h 9.68 (0.034– 11-deoxycortisol 21 × 15 Adenoma (1989)/ pmol/L) 0.325 ng/ml) Osanai et al. (1990), Japan (20, 21) Sakurai M 40 60 months 3.8 65 (10.9– 0.2 (0.3–2.9 3.360 (0.08– Pregnenolone, 90 × 70 × Carcinoma et al. (1989), 62.7 pg/ml) ng/ml/h) 0.278 ng/ml) progesterone and ALD 50 Japan (22) Road/Okano M 28 NA 3.1 NA NA NA 68 × 73 × Carcinoma (1989), 50 Japan (29) Imada/ F 33 NA 3.1 NA NA NA 21 × 15 × Adenoma Terayama/ 11 Komatsu (1989–1990), Japan (29) Saha et al. F 39 NA 3.0 3 (3–10 ng/ 0 (1.2–2.1 1.16 (0.03– No 48 Adenoma (1990), dl) ng/ml/h) 0.33 ng/ml) Japan (23) Yoshitomi F 74 NA NA NA NA No 40 NA (1990), Japan (29) White et al. F 43 48 months 3.0 444 (83–694 0.03 (0.08– 7,260 (61– Progesterone, 18-OH- 50 Adenoma (1992), USA pmol/L) 0.53 ng/L/s) 580 pmol/L) DOC, corticosterone and (24) 11-deoxycortisol Bijl et al. M 73 0 month 2.8 0.19 (0.14– 0.30 (0.30– 9.5 (<3.0 Progesterone and 17- 200 Carcinoma (1992), (hospital 0.22 nmol/L) 0.60 nmol/L) nmol/L) OH-progesterone Netherlands admission) (25) Matsumoto M 43 36 months NA Low in 0.6 (0.3–3.0 0.26 (<0.13 18-OH-DOC, 30 × 30† Adenoma et al. (1993), plasma and ng/ml/h) ng/ml) corticosterone and 18- Japan (26) in urine <2 OH-corticosterone (2–14 ng/dl) Yamamoto, M 66 4 months 2.6 47 (35.7– Suppressed 17.10 (0.08– Progesterone and 18- 100 × 80 Carcinoma et al. (1993), 240 pg/ml) (<0.1 ng/ml/ 0.278 ng/ml) OH- DOC × 45 Japan (27) h) Komura F 55 Several 2.8 98 (37.5– 0.2 (0.3–2.9 1.0 (<0.130 18-OH-DOC 40 × 20† Adenoma et al. (1993), months 240 pg/ml) ng/ml/h) ng/ml) Japan (28) Furuse et al. M 39 0 month 3.2 6.5 (2–12 NA 4.86 (0.08- Pregnenolone, 110 × 60 Carcinoma (1995), (hospital ng/dl) 0.28 ng/ml) progesterone, 11- × 50 Japan (29) admission) deoxycortisol and androstenedione (Continued) Frontiers in Endocrinology | www.frontiersin.org 9 March 2022 | Volume 13 | Article 846865 Asla et al. DOC-Producing Adrenal Lesions TABLE 2 | Continued Author Sex Age, Time of Serum K+ ALD levels Renin DOC Overproduction ≥1 Tumor Histological (year), (F/M) years suggestive levels levels levels*** adrenal hormone size diagnosis country symptoms* (mmol/L)** (PRA/PRC) other than DOC (mm)a Wada et al. F 29 3 months 2.5 45.2 (50– 0.01 (0.2– 11.6 (0.03– 18-OH-DOC, 28 × 44† Adenoma (1995), 150 pg/ml) 2.0 ng/ml/h) 0.33 ng/ml) corticosterone, 11- Japan (30) deoxycortisol and cortisone Nitta et al. M 58 84 months 3.0 98.2 (47– 0.33 (0.5– 1.69 (0.08– Corticosterone Right Bilateral (1996), 131 ng/ml) 2.0 ng/ml/h) 0.278 ng/ml) adrenal adenoma Japan (31) tumor: 22 × 20 Left adrenal tumor:10 × 10 Toyoda F 55 120 months 2.5 98 (37.5– 0.2 (0.3–2.9 2.82 (<0.13 18-OH-DOC 40 Adenoma et al. (1996), 240 pg/ml) ng/ml/h) ng/ml) Japan (32) Limone F 23 6 months 3.6 Only NA NA in serum. No NA (micro- Micronodular et al. (1997), available in THDOC adenomas) hyperplasia Italy (33) urine excretion in (normal) urine 78 (25– 60 µg/24 h) Egoshi et al. F 60 240 months 1.6 Normal 6.64 (<0.3 11-deoxycortisol 110 × 85 Carcinoma (1998), ng/ml) × 45 Japan (34) Soranno F 14 36 months 3.4 <30 (50– 0.15 (0.20– 5.7 (0.05– 17-OH-pregnenolone, 50 Adenoma et al. (1999), 250 pmoL/ 1.60 ng/ml/ 0.26 nmol/L) 17-OH-progesterone, 11- USA (35) L) h) deoxycortisol, DHEA, DHEAS, A4- androstenedione and testosterone Nagai et al. F 31 11 months 1.9 62 (35.7– 0.1 (0.3–2.9 1.68 (0.03– No 11 × 9 × 8 Adenoma (1999), 240 pg/ml) ng/ml/h) 0.33 ng/ml) Japan (42) Müssig et al. M 37 Some weeks 3.4 43 (10–160 0.2 (0.12– 347.2 (2–15 17-OH-pregnenolone 140 × 90 Carcinoma (2005), pg/ml) 1.59 ng/ml/ ng/dl) and 11-deoxycortisol × 70 Germany h) (36) Messer F 42 5 months 2.3 <1 (1–16 2.35 (4.0– 385 (2–19 17-OH-progesterone, 80 × 55 × Carcinoma et al. (2007), ng/dl) 7.7 ng/ml/h) ng/dl) cortisol, 35 USA (37) androstenedione, testosterone and estradiol Sone et al. F 27 0 month 2.3 66 (30–159 0.1 (0.2–2.7 8.04 (0.03– Pregnenolone, 170 × 110 Carcinoma (2009), (hospital pg/ml) ng/ml/h) 0.33 ng/ml) progesterone 18-OH- × 78 Japan (38) admission) DOC and 17-OH- progesterone Gupta et al. F 35 216 months 3.1 Suppressed <0.6 (0.6– 65 (1.6–5.6 Cortisol 53 × 45 × Adenoma (2010), USA (<4.0 ng/dl) 4.0 ng/ml/h) ng/dl) 70† (43) Freel et al. M 42 NA 2.3 Suppressed NA Corticosterone and 11- 120 × 80 Carcinoma (2014), UK deoxycortisol (44) Oyama et al. M 59 120 months 3.0 154 (29.9– 0.2 (0.3–2.9 1.52 (0.08– ALD 25 × 25 Macroadenoma (2014), 159 pg/ml) ng/ml/h) 0.28 µg/ml) producing DOC Japan (39) and microadenomas producing ALD Paja et al. F 29 12 months 3.1 Normal to Suppressed 237.9 (<15 No 65 Adenoma (2017), Spain low (7.3 ng/ (<0.2 ng/ml/ ng/dl) (45) dl) h) Goodale F 53 60 months 1.5 4 (4–31 ng/ 2.0 (0.5–4.0 62.60 (<19 No 63 × 34 × Carcinoma et al. (2018), dl) ng/ml/h) ng/dl) 52† USA (46) (Continued) Frontiers in Endocrinology | www.frontiersin.org 10 March 2022 | Volume 13 | Article 846865 Asla et al. DOC-Producing Adrenal Lesions TABLE 2 | Continued Author Sex Age, Time of Serum K+ ALD levels Renin DOC Overproduction ≥1 Tumor Histological (year), (F/M) years suggestive levels levels levels*** adrenal hormone size diagnosis country symptoms* (mmol/L)** (PRA/PRC) other than DOC (mm)a Marques F 35 120 months Long 224 (330– 0.01 (0.15– 9,741 (121– No 110 × 75 Neoplasm of et al. (2019), standing 830 pmol/L) 2.10 pmol/ 514 pmol/L) × 60 uncertain UK (40) hypokalemia ml/h) malignant 3.7 on potential supplements Scaranello F 61 36 months 2.4 Suppressed 654 (<25 ng/ Progesterone and 11- 240 × 130 Carcinoma et al. (2020), dl) deoxycortisol × 130 Brazil (47) The current F 53 1 month 1.7 <79 (187– <0.2 (0.6– 35.8 (2–15 No The Unilateral case 930 pmol/L) 4.18 mg/L/h) ng/ml) biggest adenomatous reported adrenal hyperplasia (2022), Spain nodule 12 × 12 Summary/ 31 F 42.9 24 (55) 2.68 ± 0.62 25 in the 30 12.5 (18.9) 31 yes (67%), 11 no 61.5 (60) 21 (45.7%) Total# (67%), ± reference decreased (24%), 4 not reported ACC 19 15 M 15.2 range (65.2%) 4 (9%) (41.3%) benign (33%) (54.3%) 15 in range 4 (8.7%) decreased (8.7%) 12 hyperplasia 1 (32.6%) 1 not (2.2%) elevated reported uncertain (2.2%) 5 (26.1%) malignant not potential 1 reported (2.2%) not (10.9%) reported *The estimation has been made considering the onset of symptoms (hypertension and/or symptoms of hypokalemia) until the patient was referred or admitted to a medical centre. ** The minimum K+ level is reported. *** Median (IQR) times above the upper limit of normal range of serum DOC levels reported in each article and in parentheses the normal reference values. a Average tumor size was calculated based on the maximum diameter reported. †Size information obtained from CT scan and/or MRI. #Quantitative data are expressed as the mean SD (Gaussian distribution) or median (interquartile range) (non-Gaussian distribution) and categorical data as absolute frequencies and percentages. F, female; M, male; K+, potassium; ALD, aldosterone; PRA, plasma renin activity; PRC, plasma renin concentration; DOC, 11-deoxycorticosterone; NA, not available; DHEA, dehydroepiandrosterone; THDOC, tetra-hydro-11- deoxycorticosterone; 17-OH-progesterone, 17-hydroxy-progesterone; 18-OH-corticosterone, 18-hydroxy-corticosterone; 18-OH-DOC, 18-hydroxy-11-deoxycorticosterone; 17-OH- pregnenolone, 17-hydroxy-pregnenolone; CT, computed tomography; DHEAS, dehydroepiandrosterone sulphate; ACC, adrenocortical carcinoma; SD, standard deviation; MRI, magnetic resonance imaging. revealed a female predominance, average age of presentation in the excess with low ARP and ALD levels: congenital adrenal fourth decade, a median tumor size of around 62 mm and a benign hyperplasia (CAH) due to 11b-hydroxylase and 17a- behavior in roughly half of the DOC-producing adrenal lesions hydroxylase deficiency, DOC-producing adrenal tumors, (including adrenal adenomas and hyperplasia). This review adds primary cortisol resistance and apparent mineralocorticoid knowledge in the limited body of literature on this extremely rare excess (AME) syndrome due to acquired or genetic 11b- functional adrenocortical lesion and is intended to raise awareness dehydrogenase type 2 dysfunction. An algorithm for the of the possibility of a DOC-producing adrenal lesion in the differential diagnosis of non-ALD-dependent mineralocorticoid presence of low serum ALD levels despite hypertension hypertension (also known as pseudohyperaldosteronism) is shown presumed to be due to excessive mineralocorticoid secretion. in Figure 6. An accurate diagnosis is crucial since appropriate Mineralocorticoids are, together with glucocorticoids and sex treatment differs substantially among each clinical entity. In our steroids, the three different adrenal steroid hormones produced in case, CAH was rapidly ruled out since the patient did not have any the adrenal cortex (Figure 4). ALD is the final and most potent sign or symptom of hirsutism or virilization, nor relevant family mineralocorticoid hormone, representing 90% of mineralocorticoid history or consanguinity and the 5th decade is not a common age activity (48). However, other mineralocorticoid products have been of presentation for CAH. Genetic AME syndrome, an autosomal isolated from the adrenal cortex (48). These are usually secreted in recessive inherited disease usually presents in childhood, was small amounts and have a weaker mineralocorticoid activity (48). excluded and also acquired causes (i.e., liquorice root intake and Thus, it seems plausible that only high levels of mineralocorticoid Cushing’s syndrome). Moreover, DOC concentrations might precursors different from ALD could produce a clinically relevant increase in patients receiving 11 b-hydroxylase inhibitors such hypermineralocorticoid state. as metyrapone or mitotane, which was not the case. Furthermore, DOC is an ALD precursor with a 1/20 (38) to 1/30 (48) of the the CT scan revealed an adrenal mass, increasing suspicion of a mineralocorticoid activity of ALD. It is synthesized from DOC-producing adrenal lesion. progesterone by the 21a-hydroxylase enzyme in the adrenal The first evidence of adrenal tumor DOC production emerged in cortex and converted to corticosterone by the 11b-hydroxylase the sixties (49, 50) and was published in 1965 by Marquezy et al. and enzyme (Figure 4). Four uncommon situations generate DOC Biglieri (6, 41). Overproduction of DOC was determined by an Frontiers in Endocrinology | www.frontiersin.org 11 March 2022 | Volume 13 | Article 846865 Asla et al. DOC-Producing Adrenal Lesions excess of DOC and its metabolite THDOC excreted in 24 h urine (6, intravenous and oral K+ supplements, leading to the suspicion of an 41) and by an increased content of DOC in adrenal tissue and underlying psychiatric disorder despite not having any previous adrenal venous plasma (41). Two main factors can mask the history of mental diseases. The combination of severe hypokalemia, diagnosis and contribute to underestimating its incidence. On the metabolic alkalosis, critical hypertension and the presence of two left one hand, DOC assay is not readily available in many routine adrenal adenomas were highly suggestive of mineralocorticoid clinical centers (40). On the other hand, some cases of PA might hypertension, yet ARP and ALD levels were repeatedly very low, occur simultaneously with DOC overproduction (16, 39), implying excluding PA, while elevated serum DOC led to the diagnosis of a that DOC is not searched for since ALD is not suppressed. DOC-producing adrenal neoplasm (Figure 6). Our case report shows several singularities. One was the As reported, very high DOC plasma levels are to be expected, suddenness of the life-threatening clinical presentation that took the highest published up to eighty times above the upper normal the patient to the ICU in less than a month since high BP was limit (18). However, in our case, DOC levels only doubled the detected, while most of the previously published cases presented normal range. Similarly, Matsumoto et al. (26) reported a case of months or years before diagnosis (16, 20, 31, 32, 34, 39, 40, 43). weak mineralocorticoid-producing benign adrenal tumor with a Additionally, initial serum hypokalemia was resistant despite high doubling of serum DOC levels. The authors hypothesized that FIGURE 6 | Algorithm for the diagnostic approach of patients with non-ALD-dependent mineralocorticoid hypertension. BP, blood pressure; ALD, aldosterone; PRA, plasma renin activity; DOC, 11-deoxycorticosterone; 19-Nor-DOC, 19-Nor-deoxycorticosterone; 18-OH-DOC, 18-hydroxy-deoxycorticosterone; CT, computed tomography; ACTH, adrenocorticotropic hormone. Frontiers in Endocrinology | www.frontiersin.org 12 March 2022 | Volume 13 | Article 846865 Asla et al. DOC-Producing Adrenal Lesions another mineralocorticoid intermediate different from DOC, 18- and hormonal improvement after surgery, led to confirm the hydroxy-deoxycorticosterone (18-OH-DOC, a hydroxylated diagnosis of DOC overproduction due to unilateral adenomatous metabolite of DOC), that was above the normal value, might adrenal hyperplasia. We might have not identified all cases be responsible for the hypertensive state of that patient (26). In reported and cannot rule out the possibility that some addition to 18-OH-DOC, other mineralocorticoid precursor unpublished cases of interest may have been missed. related to DOC, such as 19-Nor-DOC, can cause overt Nevertheless, we collected an important number of cases of hypertension (51), especially in patients with slightly elevated this very rare disease to provide enough accurate data to DOC levels. Unfortunately, we could not measure 18-OH-DOC summarize its main characteristics and increase the knowledge or 19-Nor-DOC. Although in the presented patient of DOC-producing adrenal lesions. Besides, we had limited postoperative hormone levels almost normalized, supporting access to case reports written in Japanese, but all cases found the indubitable participation of DOC overproduction, it is were computed and the scant information available possible that other metabolites of DOC with a known was included. hypertensive and salt-retaining activity were also involved. In conclusion, DOC overproduction due to adrenal lesions mostly Regarding histological behavior, malignant DOC-producing affects middle aged women with a PA-like presentation and time to adrenal lesions were larger (about 2.5 times more) and had diagnosis of several months. Nearly half of the cases demonstrated higher DOC levels (about 3 times higher) in comparison to malignant behavior and adrenal hyperplasia was exceptional. benign lesions; without differences in gender distribution, age Reduced 11b-hydroxylase and 17a-hydroxylase enzyme activities and K+ levels. Thus, the benign behavior of our case with a were the most frequent immunohistochemical findings. relatively small tumor size and mildly elevated DOC levels could be expected based on the review of DOC-producing adrenal lesions published so far. First physiopathological reports on the mechanisms involved DATA AVAILABILITY STATEMENT in DOC-producing adrenal tumors showed a relative 11b- hydroxylation deficiency in an adrenal carcinoma tissue of a The raw data supporting the conclusions of this article will be deceased patient (50). Since then, intratumoral analysis of made available by the authors, without undue reservation. steroidogenic enzymes (Figure 4) revealed a reduced 11b- hydroxylase and 17a-hydroxylase enzyme activities in all instances (23, 27, 30, 32, 34, 38, 39 and our case), suggestive of an autonomous DOC overproduction by adrenal neoplastic cells. AUTHOR CONTRIBUTIONS Recently, LC–MS/MS metabolite steroid profiling in urine AA planned the concept of this review. QA and HS carried out followed by machine learning analysis have evidenced a panel of the literature research, manuscript selection and data extraction. nine steroids as a highly discriminative tool in differentiating AA performed the analysis. QA and AA drafted the manuscript. adrenocortical carcinoma from adenoma (52), being tetra- EU performed the laboratory analysis. EL provided the hydro-11-deoxycortisol (a metabolite of 11-deoxycortisol) the macroscopic and microscopic images and MR performed the most distinguishable biomarker. This panel also included immunohistochemical analysis. All authors listed have made a THDOC, a metabolite of DOC, which was significantly substantial, direct, and intellectual contribution to the work and increased in patients with adrenocortical carcinoma (52). approved it for publication. Similarly, urine metabolite steroid profiling of DOC-producing adrenal tumors could permit to better differentiate the behavior of these lesions. Some limitations need to be considered. Unfortunately, we SUPPLEMENTARY MATERIAL were not able to measure DOC intermediate products. However, the PA-like clinical presentation, the biochemical and hormonal The Supplementary Material for this article can be found online at: profile at diagnosis, the immunohistochemical analysis in the https://www.frontiersin.org/articles/10.3389/fendo.2022.846865/ surgical specimen together with the marked clinical, biochemical full#supplementary-material 4. Young WF Jr, Hogan MJ. Renin-Independent Hypermineralocorticoidism. Trends REFERENCES Endocrinol Metab (1994) 5(3):97–106. doi: 10.1016/1043-2760(94)90090-6 1. Rimoldi SF, Scherrer U, Messerli FH. Secondary Arterial Hypertension: 5. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, When, Who, and How to Screen? Eur Heart J (2014) 35(19):1245–54. et al. The PRISMA 2020 Statement: An Updated Guideline for Reporting doi: 10.1093/eurheartj/eht534 Systematic Reviews. BMJ (2021) 372:n71. doi: 10.1136/bmj.n71 2. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 6. 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Desoxycorticosterone Synthesis by Human Adrenal Adenoma. J Clin Endocrinol Metab (1962) 22:481–9. Publisher’s Note: All claims expressed in this article are solely those of the authors doi: 10.1210/jcem-22-5-481 and do not necessarily represent those of their affiliated organizations, or those of 50. West CD, Kumagai LF, Simons EL, Dominguez OB, Berliner DL. the publisher, the editors and the reviewers. Any product that may be evaluated in Adrenocortical Carcinoma With Feminization and Hypertension this article, or claim that may be made by its manufacturer, is not guaranteed or Associated With a Defect in 11-Beta-Hydroxylation. J Clin Endocrinol endorsed by the publisher. Metab (1964) 24:567–79. doi: 10.1210/jcem-24-7-567 51. Griffing GT, Dale SL, Holbrook MM, Melby JC. 19-Nor-Deoxycorticosterone Copyright © 2022 Asla, Sardà, Lerma, Hanzu, Rodrigo, Urgell, Peŕ ez, Webb and Excretion in Primary Aldosteronism and Low Renin Hypertension. J Clin Aulinas. This is an open-access article distributed under the terms of the Creative Endocrinol Metab (1983) 56(2):218–21. doi: 10.1210/jcem-56-2-218 Commons Attribution License (CC BY). The use, distribution or reproduction in other 52. Chortis V, Bancos I, Nijman T, Gilligan LC, Taylor AE, Ronchi CL, et al. forums is permitted, provided the original author(s) and the copyright owner(s) are Urine Steroid Metabolomics as a Novel Tool for Detection of Recurrent credited and that the original publication in this journal is cited, in accordance with Adrenocortical Carcinoma. J Clin Endocrinol Metab (2020) 105(3):e307–18. accepted academic practice. No use, distribution or reproduction is permitted which doi: 10.1210/clinem/dgz141 does not comply with these terms. Frontiers in Endocrinology | www.frontiersin.org 15 March 2022 | Volume 13 | Article 846865