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control_of_hypercortisolism_in_acc

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Control of Hypercortisolism in ACC

Endocrine Supportive Management

Control of hypercortisolism in adrenocortical carcinoma (ACC) refers to the medical and supportive treatment of cortisol excess caused by a functioning adrenal malignancy. Within ACC care, it is part of endocrine supportive management and is usually delivered alongside surgery, locoregional treatment, or systemic anticancer therapy rather than instead of them.123 This distinction is clinically important because cortisol excess may itself produce immediate morbidity, including hypertension, hypokalemia, diabetes, myopathy, psychiatric symptoms, impaired wound healing, infection susceptibility, and thromboembolic complications, sometimes before tumor burden becomes the dominant short-term threat.45

Functional ACC commonly presents with overt steroid excess, and cortisol secretion is one of its major hormonal phenotypes.67 In many cases, cortisol excess is accompanied by androgen excess or secretion of steroid precursors, which may complicate diagnosis and biochemical follow-up.78 Retrospective data also suggest that hypercortisolism is associated with worse outcomes, although the independent contribution of cortisol excess is difficult to separate from tumor stage and aggressive disease biology.53

The evidence base for cortisol control in ACC is limited. Most data derive from retrospective cohorts, small case series, mixed-cause Cushing syndrome studies, and case reports, with few ACC-specific prospective comparisons of available drugs or treatment sequences.239 Reported response rates therefore require cautious interpretation because definitions of biochemical control vary, combination therapy is common, and endocrine improvement does not necessarily indicate meaningful antitumor effect.1011

Even with these limitations, reviews and accumulated clinical experience broadly support early recognition and prompt treatment of severe hypercortisolism in ACC. The main practical rationale is to reduce endocrine complications and to improve the safety and feasibility of surgery, chemotherapy, and palliative care.41213

Diagnostic and clinical context

Most cortisol-secreting ACC causes ACTH-independent hypercortisolism, but the syndrome may be more biochemically complex than benign adrenal Cushing syndrome because malignant tumors can secrete multiple steroids simultaneously.78 As a result, reliance on a single cortisol measurement may understate ongoing hormonal activity, particularly in metastatic or highly secretory disease. This broader principle is reasonably consistent across reviews and case-based reports, although optimal monitoring panels are not standardized.73

Clinical presentation ranges from classic Cushingoid features to rapidly progressive metabolic decompensation. Severe cases may show hypokalemic alkalosis, difficult hypertension, uncontrolled diabetes, proximal weakness, edema, and opportunistic infection with relatively muted inflammatory signs.14151617 These complications are reliably recognized manifestations of severe cortisol excess; by contrast, clinical features alone do not reliably distinguish ACC from other causes of endogenous Cushing syndrome.

Diagnostic attribution is often straightforward when a cortisol-secreting adrenal mass is present, but unusual endocrine patterns can occur. Rare reports of mixed endocrine syndromes or persistent cortisol excess despite apparently targeted treatment mainly serve as cautionary examples that discordant biochemical and imaging findings should prompt reassessment of source attribution.18192021 These atypical reports have limited generalizability, but their practical implication is that unexpected treatment failure should trigger renewed diagnostic review rather than automatic escalation of the same strategy.

Pharmacologic approaches

Once hypercortisolism is identified, management usually shifts from diagnosis to rapid biochemical control and stabilization for definitive cancer care.

Steroidogenesis inhibitors

Steroidogenesis inhibition is the principal medical strategy for ACC-related hypercortisolism. Metyrapone and ketoconazole are the oral agents most commonly used for initial control, especially when rapid reduction in cortisol is needed before surgery, chemotherapy, or delayed mitotane activity.221023 Retrospective and case-based data suggest that these drugs may improve cortisol levels as well as potassium, glucose, and blood pressure over days to weeks, but incomplete control remains common in advanced disease and efficacy is variable between patients.2425

Combination oral therapy is frequently used in severe presentations. The most consistent signal is that metyrapone plus ketoconazole may achieve faster control than either drug alone when life-threatening hypercortisolism requires urgent stabilization, although this conclusion still rests on small noncomparative series.1026 Clinically, this supports early escalation in unstable patients rather than prolonged single-agent titration.

Mitotane has a dual role as an ACC-directed therapy and an adrenal steroid-lowering agent, but its onset is usually too slow for emergency endocrine control.212 It is therefore commonly combined with faster-acting steroidogenesis inhibitors at treatment initiation.233 Older agents such as aminoglutethimide and amphenone established the principle that malignant steroidogenesis can be pharmacologically suppressed, but their current role is mainly historical because of toxicity and limited practicality.272829

More recent reports suggest that osilodrostat may also be active in ACC-associated hypercortisolism.30911 The evidence is encouraging but still limited, and adverse events, including adrenal insufficiency and electrolyte disturbances, appear common enough to require close monitoring and individualized dosing.3111 Its practical role is therefore that of a promising option in selected patients rather than an established standard.

Glucocorticoid receptor blockade

Mifepristone has been used when biochemical suppression is inadequate, poorly tolerated, or when rapid reversal of cortisol-mediated clinical effects is prioritized.3213 Its main limitation is that cortisol concentrations remain elevated, so response and emerging adrenal insufficiency must be judged clinically rather than with conventional hormone targets.32 This may make symptomatic benefit possible in refractory cases, but it also makes treatment less predictable than direct steroidogenesis inhibition.

Intravenous rescue therapy

Etomidate is the principal parenteral option for emergency control of severe hypercortisolism. Available reports suggest that it may lower cortisol rapidly when oral therapy is not possible, is ineffective, or is too slow, including in intensive care or perioperative settings.43334 This emergency role is reasonably well established in endocrine practice, but ACC-specific evidence remains sparse and administration generally requires ICU-level monitoring because sedation and abrupt adrenal insufficiency are important risks.254

Complications, monitoring, and pitfalls

The case for rapid cortisol control is strongest when systemic complications are already present. Across reviews and case reports, the most consistently described risks are infection, sepsis, thromboembolism, metabolic decompensation, cardiovascular instability, and skeletal fragility.1551735 The association between severe hypercortisolism and these complications is reliable; what remains uncertain is how much any specific drug regimen reduces downstream event rates beyond improving biochemical control.

Perioperative risk appears higher in functional than in nonfunctional ACC, which supports attempts at endocrine stabilization before adrenalectomy when feasible.36 Retrospective cohorts also report substantial postoperative venous thromboembolism burden, leading many authors to support careful thromboprophylaxis and, in selected patients, consideration of extended prophylaxis.3738 The exact candidates and duration remain uncertain, but hypercortisolemic ACC is generally treated as a high-risk perioperative state.

Treatment-induced adrenal insufficiency is a central hazard of successful cortisol lowering. Rapid reduction may cause steroid withdrawal or frank hypoadrenalism, and case-based experience supports dose adjustment, temporary glucocorticoid replacement, or block-and-replace strategies in selected patients.282431 This principle is consistent across agents, even though replacement protocols are not standardized.

Monitoring becomes particularly difficult during mitotane therapy. Mitotane increases cortisol-binding globulin and accelerates cortisol metabolism, so total serum cortisol may be misleading and glucocorticoid replacement requirements are often higher than expected.39404142 Free cortisol assessment, ACTH trends, and clinical evaluation may therefore be more informative than total cortisol alone, although the best monitoring approach has not been fully validated.403

Mitotane also introduces broader endocrine toxicities relevant to long-term supportive care, including delayed adrenal recovery, central hypothyroidism, dyslipidemia, hypogonadism, menstrual disturbance, and fertility-related complications.4344454647 These effects are not direct measures of cortisol control, but they may mimic treatment failure, add symptom burden, and complicate survivorship or palliative management.

Role in multidisciplinary ACC care

After immediate stabilization, control of hypercortisolism is integrated with oncologic treatment planning. It may improve fitness for adrenalectomy, permit systemic therapy to proceed, and reduce short-term mortality from endocrine complications even when overall cancer prognosis remains poor.12133 This role is supported mainly by expert review and retrospective experience rather than trial evidence, but the underlying clinical rationale is consistent.

For metastatic or refractory disease, endocrine palliation remains distinct from tumor control. Some interventions, including mitotane and selected locoregional treatment of hormonally active metastases, may reduce both tumor activity and cortisol burden, but rapid symptomatic improvement usually reflects endocrine rather than antineoplastic effect.4849 The practical implication is that biochemical improvement should not be interpreted as evidence of meaningful tumor response without separate oncologic assessment.

Research gaps remain substantial. Comparative ACC-specific data for metyrapone, ketoconazole, osilodrostat, mifepristone, etomidate, and mitotane-based combinations are limited, and optimal sequencing, monitoring, and prophylactic supportive measures are not well defined.3911 Nevertheless, the available literature consistently supports one broad conclusion: severe hypercortisolism in ACC is a medical priority that should be addressed promptly and in parallel with cancer-directed care.14

Included Articles

  • PMID 479738: In vitro study of two cortisol-secreting adrenocortical carcinomas found that o,p’-DDD, aminoglutethimide, and SKF 12185 inhibited steroidogenesis variably, with strong suppression of 11β-hydroxylase and 18-hydroxylase pathways by some agents but persistent cortisol production in a clinically nonresponsive pediatric case.50
  • PMID 519871: In vitro study of Cushing-type adrenal tissues, including one adrenocortical carcinoma, found that direct addition of o,p’-DDD did not reduce 18-hydroxy-11-deoxycorticosterone synthesis, while prior in vivo o,p’-DDD exposure lowered this steroid only in some glands when cortisol synthesis was also markedly suppressed.51
  • PMID 993360: This case series and review describes aminoglutethimide as a steroidogenesis inhibitor that can palliate hypercortisolism in ACC, including metastatic adrenocortical carcinoma, with associated improvement in hypokalemia, hyperglycemia, and Cushingoid features. The report also notes its use as preoperative medical control of severe cortisol excess, while adverse effects such as sedation, rash, and gastrointestinal symptoms were common.27
  • PMID 1161676: This case of cortisol-secreting metastatic ACC reports that o,p’-DDD reduced steroid excretion but caused substantial gastrointestinal and central nervous system toxicity, while added aminoglutethimide had little additional biochemical effect. The authors emphasize maintaining corticosteroid replacement throughout treatment with these steroid-lowering agents.52
  • PMID 1657460: In a mixed Cushing’s syndrome cohort that included six adrenocortical carcinomas, metyrapone rapidly lowered cortisol and achieved biochemical control in most patients with adrenocortical tumors, supporting its use as ancillary therapy before definitive treatment or for palliation in severe hypercortisolism.22
  • PMID 1828976: In a prospective series of seven ACC patients receiving mitotane, six developed prolonged bleeding time within one week, and several showed platelet aggregation abnormalities consistent with an aspirin-like platelet function defect despite normal platelet counts and coagulation studies. The report highlights a clinically relevant treatment toxicity that may matter before surgery or invasive procedures.53
  • PMID 1903011: In three patients with adrenocortical carcinoma, long-term mitotane markedly increased cortisol-binding globulin and other hormone-binding proteins, rapidly altering circulating hormone binding. These changes can make total serum hormone measurements misleading and may help explain the need for higher glucocorticoid replacement during mitotane therapy.39
  • PMID 2031446: A case of virilizing ACC with mild Cushing syndrome describes preoperative ketoconazole use to reduce operative risk and improve metabolic control, with marked decreases in hyperandrogenism and normalization of hypercortisolism before resection.54
  • PMID 2538676: A small clinical study of Cushing’s syndrome found ketoconazole inhibited adrenal steroidogenesis, but the single ACC case showed only slight short-term cortisol reduction and no marked rise in precursor steroids. The report frames ketoconazole as cortisol-lowering supportive therapy with variable efficacy depending on ACTH feedback context.55
  • PMID 2743227: A case of hormonally active ACC with severe hypercortisolism, androgen excess, and elevated aldosterone showed short-term preoperative improvement with ketoconazole, including normalization of urinary free cortisol, improved blood pressure, and reduced plethora before surgical resection under glucocorticoid coverage.56
  • PMID 2773622: A case report describes high-dose ketoconazole used preoperatively in virilizing adrenocortical carcinoma to rapidly suppress tumoral androgen and cortisol production, with concurrent improvement in hypertension and hyperglycemia. The report emphasizes the risk of early hypoadrenalism and the need for prompt steroid replacement during treatment.57
  • PMID 3441014: A case report describes primary hypogonadism developing during high-dose mitotane therapy, with low testosterone, elevated gonadotropins, testicular atrophy, and biopsy showing seminiferous tubular maturation arrest with preserved Leydig cells. Partial recovery of libido and gonadal function occurred over several years after stopping mitotane.58
  • PMID 3564003: In a metastatic cortisol-secreting ACC case treated with low-dose o,p’-DDD, tumor regression and falling urinary 17-OHCS occurred despite persistent or rising plasma cortisol and ongoing hypertension, hypokalemia, and hyperglycemia. The report suggests monitoring multiple steroids, including mineralocorticoid precursors, rather than relying on cortisol alone during therapy.8
  • PMID 4290376: A small early series reported that aminoglutethimide rapidly suppressed cortisol secretion and urinary steroid excretion in ACTH-independent adrenal cortical tumors, including one metastatic adrenocortical carcinoma, with only partial suppression in bilateral hyperplasia. The findings suggest a medical option for short-term control of tumorous steroid excess.59
  • PMID 4877990: In a patient with cortisol-secreting adrenocortical carcinoma, SK&F-12185 produced marked clinical improvement in Cushing’s manifestations and diabetes while reducing urinary tetrahydrocortisol and increasing tetrahydro S, consistent with steroidogenesis inhibition. Tumor progression was not clearly affected, highlighting endocrine palliation rather than antitumor control.48
  • PMID 7716730: In patients undergoing adrenalectomy for endogenous hypercortisolism, this retrospective series found low operative mortality and limited wound complications despite traditional concern about impaired healing, infection, and thromboembolic risk from cortisol excess. The report highlights perioperative morbidity patterns relevant to managing cortisol-related surgical risk.60
  • PMID 8043488: This review summarizes steroidogenesis inhibitors for hypercortisolism in Cushing’s syndrome and notes that cortisol excess from adrenocortical carcinoma was only rarely controlled with ketoconazole, with remission reported in 1 of 5 cases. It also outlines drug-specific limitations and toxicities, including ketoconazole-associated liver toxicity and the intravenous, sedating constraints of etomidate.25
  • PMID 8191081: A case report describes ketoconazole as a short preoperative medical therapy for hormonally active ACC with severe hypercortisolism and hyperandrogenism. Within days at 600 mg/day, it was associated with improved blood pressure, reduced steroid excess, and marked improvement in polycythemia before surgical resection.61
  • PMID 10448470: A case of cortisol-secreting metastatic ACC showed persistent severe hypercortisolism despite surgery, metyrapone, aminoglutethimide, mitotane, chemotherapy, and a trial of octreotide. The report suggests octreotide has unestablished benefit for secretory symptom control in functional metastatic ACC and should be discontinued promptly if clinical and biochemical improvement are absent.62
  • PMID 11281374: In the NCI-h295 adrenocortical carcinoma cell line, etomidate was the most potent adrenostatic agent for suppressing steroidogenesis and also showed antiproliferative effects at clinically relevant concentrations. Aminoglutethimide and metyrapone additionally reduced ACTH receptor expression, supporting a broader endocrine control role beyond enzyme inhibition in cortisol-producing ACC contexts.63
  • PMID 13130667: This case report describes metastatic cortisol-secreting adrenocortical carcinoma causing severe Cushing’s syndrome with hypertension, hypokalemia, diabetes, and persistent steroid excess. Pituitary-directed suppression and total hypophysectomy did not reduce steroid production, supporting autonomous hormonal secretion by metastatic ACC.64
  • PMID 13297151: A case of metastatic cortisol-secreting adrenocortical carcinoma showed that amphenone markedly suppressed urinary 17-hydroxycorticoid excretion and sharply improved hyperglycemia and insulin requirement. Rapid steroid reduction was associated with symptoms interpreted as acute steroid withdrawal, suggesting the need for gradual hormone control and possible replacement support.28
  • PMID 13575511: In five patients with adrenocortical carcinoma, amphenone treatment reduced some or all measured steroid metabolites and consistently lowered hydrocortisone-derived ketosteroids, while effects on other adrenal secretory components were variable. The report suggests neoplastic adrenal steroid biosynthesis can be differentially suppressed pharmacologically.29
  • PMID 14071312: A case report of metastatic cortisol-secreting adrenocortical carcinoma found that oral metopirone suppressed excessive glucocorticoid production over seven weeks, with marked reduction in 11-oxo(y)-17-OHCS and a fall in the 11-oxo(y)-17-OHCS to 11-desoxy-17-OHCS ratio from 1.7 to 0.1. Clinical benefit could not be determined because the disease progressed rapidly.65
  • PMID 16522701: In patients with endogenous hypercortisolism, including mixed-secreting adrenal carcinoma, vertebral fractures were highly prevalent at diagnosis and lumbar spine bone mineral density best predicted fracture risk. The excerpt also notes that androgen excess in adrenal carcinoma may partly offset spinal bone loss, while gonadal status in women did not materially change fracture prevalence.66
  • PMID 16924084: In a retrospective adrenalectomy series, postoperative steroid replacement was needed for patients with overt or subclinical Cushing syndrome and for bilateral adrenalectomy, but not for unilateral non-Cushing adrenal tumors, including nonfunctioning ACC. Delayed adrenal insufficiency could still occur months to years after surgery in cortisol-secreting cases.67
  • PMID 19289534: This retrospective multicenter series suggests mifepristone can provide rapid symptomatic control of severe hypercortisolism in advanced ACC when surgery is unsuccessful or impossible and prior anticortisolic drugs are ineffective or poorly tolerated. Use requires close clinical monitoring because hypokalemia, hypertension, and clinically assessed adrenal insufficiency can be substantial.32
  • PMID 19473175: In ACC patients receiving mitotane, serum total cortisol can be unreliable because mitotane raises corticosteroid-binding globulin. This pilot study suggests serum free cortisol may better inform glucocorticoid replacement follow-up, particularly when ACTH is suppressed by prior or persistent hypercortisolism, though larger studies are needed.40
  • PMID 19667279: This review emphasizes that uncontrolled hormone excess in ACC, especially severe hypercortisolism, is itself a life-threatening malignant manifestation requiring aggressive treatment. It supports use of steroidogenesis inhibitors such as mitotane, ketoconazole, metyrapone, and etomidate alone or in combination, alongside supportive measures including thrombosis prophylaxis when indicated.1
  • PMID 22171014: This case report describes metastatic ACC causing IGF2-mediated non-islet-cell tumor hypoglycemia, supported by severe hypoinsulinemic hypoglycemia and a markedly elevated IGF-2:IGF-1 ratio. Glucocorticoids and growth hormone provided only temporary benefit, octreotide and everolimus were ineffective, and continuous glucose infusion was ultimately required.68
  • PMID 23038793: In human adrenocortical primary cultures and ACC cell lines, fluconazole dose dependently inhibited cortisol production in vitro, likely through 11β-hydroxylase and 17-hydroxylase inhibition, though it was less potent than ketoconazole. These findings suggest a possible alternative medical option for controlling hypercortisolism, while raising concern for adrenal insufficiency during fluconazole exposure.69
  • PMID 23781302: Mitotane in ACC markedly alters cortisol metabolism, increasing 6β-hydroxylated polar metabolites and suppressing 5α- and 20β-reduction, which helps explain reduced cortisol bioavailability and higher hydrocortisone replacement requirements. The study also notes that standard cortisol monitoring is less useful during mitotane therapy, with ACTH and selected free cortisol assessment being more informative.41
  • PMID 24470886: This case report highlights that severe cortisol-producing ACC can cause profound immunosuppression with invasive fungal infections, including disseminated cryptococcosis and candidiasis. It supports early suspicion of occult infection in marked endogenous hypercortisolism, use of fungal diagnostic assays, aggressive antifungal treatment, and prompt cortisol-lowering therapy.15
  • PMID 24486453: This preclinical study suggests mitotane can directly impair pituitary gonadotroph viability and reduce LH and FSH secretion, offering a mechanistic explanation for hypogonadism and blunted LH response observed in men receiving adjuvant mitotane for ACC.70
  • PMID 24627099: In mitotane-treated ACC, glucocorticoid replacement is difficult to assess because mitotane increases cortisol-binding globulin and CYP3A4-mediated cortisol metabolism. This small study found hair cortisol was frequently elevated despite replacement therapy, suggesting possible long-term hydrocortisone over-substitution and a potential monitoring role for hair cortisol.71
  • PMID 24802156: This review addresses acute hypercortisolism in ACC as an emergency syndrome requiring rapid stabilization, correction of metabolic derangements, and multidisciplinary specialist care. It highlights limits of medical cortisol-lowering therapy, the emergency use of etomidate, and perioperative measures such as infection prophylaxis, thromboembolism prevention, and steroid replacement.4
  • PMID 25411236: In premenopausal women receiving mitotane, ovarian macrocysts, menstrual abnormalities, pelvic pain, and rare surgical complications were observed, alongside reduced androgens and increased LH, FSH, estradiol, and SHBG. These findings support gynecologic and reproductive endocrine monitoring as part of mitotane supportive care.46
  • PMID 25624013: In patients with severe cortisol-secreting ACC and life-threatening hypercortisolism, combined oral metyrapone and ketoconazole produced rapid biochemical control within 1 week and frequent normalization by 1 month, with parallel improvement in hypokalemia, glycemia, and blood pressure and limited short-term toxicity.10
  • PMID 26353009: In a retrospective multicenter cohort of Cushing’s syndrome that included 10 ACC cases, metyrapone provided biochemical improvement and was commonly used to control severe hypercortisolemia, including in palliation of aggressive malignancy. Adverse effects were usually early, mild, and reversible, with hypoadrenalism managed by dose reduction or block-and-replace glucocorticoid therapy.24
  • PMID 26660146: This review emphasizes that hormonally functioning ACC requires parallel oncologic and endocrine control, especially for cortisol excess, which increases risks of infection and venous thromboembolism. It summarizes medical options for hormonal control, including mitotane, ketoconazole, metyrapone, mifepristone, etomidate, and mineralocorticoid receptor blockade, often before surgery or chemotherapy.2
  • PMID 26833215: This review frames severe hypercortisolism, including cases caused by ACC, as an emergency requiring immediate stabilization and rapid cortisol lowering. It highlights metyrapone and ketoconazole as key oral agents, intravenous etomidate when parenteral therapy is needed, supportive management of hypokalemia, thrombosis, infection, and consideration of bilateral adrenalectomy if medical therapy fails.26
  • PMID 27869874: This review notes that adrenocortical carcinoma frequently presents with clinically overt hypercortisolism and that steroidogenesis inhibitors such as metyrapone and ketoconazole can be used to control metabolic complications of cortisol excess. It also states that mitotane is used for severe Cushing syndrome as well as in ACC treatment.6
  • PMID 28859919: In a nationwide inpatient analysis of 2,199 adrenalectomy cases for ACC, functional tumors, predominantly hypercortisolemic, were associated with greater preoperative comorbidity and higher rates of wound complications, adrenal insufficiency, acute kidney injury, and longer hospital stay than nonfunctional tumors. The authors conclude that these patients need careful preoperative medical optimization before adrenalectomy.36
  • PMID 28968221: This case report describes refractory hypoinsulinemic hypoglycemia in metastatic ACC associated with a high IGF2/IGF1 ratio and hypokalemia, consistent with non-islet cell tumor hypoglycemia. Supportive control included carbohydrate-rich fractionated diet, glucose infusion, high-dose dexamethasone, and diazoxide, with corticosteroids emphasized as the most effective symptomatic therapy.72
  • PMID 29019062: In a three-patient case series of advanced cortisol-secreting ACC treated with EDP plus mitotane, adding metyrapone was associated with rapid biochemical and clinical improvement of Cushing’s syndrome, dose tapering over weeks, and no unexpected added toxicity. The report emphasizes the need for prompt cortisol control because mitotane has a delayed onset.23
  • PMID 29192420: A case report describes severe menorrhagia with simple endometrial hyperplasia during adjuvant mitotane therapy for nonfunctional ACC, attributed to altered peripheral steroid metabolism and possible coagulopathy. A levonorgestrel-releasing intrauterine device controlled bleeding over four years without observed reduction in mitotane effectiveness or tolerance.73
  • PMID 29506536: This case report describes postoperative secondary acute adrenal hypofunction after radical resection of adrenocortical carcinoma, presenting with intermittent fever and rash and confirmed by low serum cortisol levels. Symptoms resolved with hydrocortisone, which was tapered and discontinued within 1 month.74
  • PMID 29754634: This review notes that patients with Cushing’s syndrome from ACC have among the worst survival outcomes and that deaths are commonly related to cardiovascular events, infection or sepsis, and thromboembolism. It emphasizes prompt treatment of hypercortisolism and active monitoring and management of related comorbidities to reduce mortality burden.5
  • PMID 29754640: This review emphasizes that hypercortisolism in ACC is common, often accompanied by excess steroid precursors or androgens, and can complicate diagnosis, perioperative care, and prognosis. It highlights the need to recognize autonomous cortisol secretion preoperatively and provide postoperative glucocorticoid replacement after resection of cortisol-secreting tumors.7
  • PMID 30800267: This case series includes a patient with metastatic cortisol-secreting ACC and severe hypercortisolaemia in whom ketoconazole, metyrapone, and mitotane were ineffective, while low-dose intravenous etomidate rapidly lowered cortisol and enabled temporary clinical stabilization and chemotherapy initiation. The review frames etomidate as an emergency bridge therapy when oral agents are ineffective, too slow, or not tolerated.33
  • PMID 31967042: This case report highlights that severe cortisol-producing ACC can cause profound immunosuppression with disseminated invasive aspergillosis, which may mimic metastatic disease and present with minimal inflammatory signs. It emphasizes the need for early recognition and treatment of hypercortisolism and heightened suspicion for opportunistic infection.16
  • PMID 32282928: In reproductive-age women receiving adjuvant mitotane for ACC, treatment was associated with recurrent benign ovarian cysts and amenorrhea that resolved after drug cessation, with return of normal menses and preserved fertility in observed cases. Experimental data suggested mitotane suppresses ovarian steroidogenesis and granulosa-cell proliferation.75
  • PMID 32747211: This case report highlights that severe cortisol excess from ACC-associated Cushing syndrome can predispose to masked, potentially fatal opportunistic infections such as disseminated cryptococcosis. It emphasizes maintaining high suspicion for infection and considering prevention or early intervention strategies in markedly hypercortisolemic patients.17
  • PMID 32784266: A retrospective single-center cohort found a high postoperative venous thromboembolism rate after ACC surgery, with pulmonary embolism in 23.5% within 6 months, most events occurring within 10 weeks and mainly in advanced-stage disease. The authors suggest considering prolonged postoperative thromboprophylaxis, potentially beyond standard durations.37
  • PMID 32869552: This case report describes cortisol-secreting ACC with severe hypercortisolemia complicated by multiple simultaneous opportunistic and bacterial infections during chemotherapy, highlighting profound infection risk in endogenous Cushing syndrome. It emphasizes considering infection prophylaxis, risk stratification before chemotherapy, and cortisol-lowering therapy such as mitotane to help reduce infectious complications.76
  • PMID 33251784: This infant ACC case describes etomidate as rescue medical therapy for severe metastatic hypercortisolemia after surgery failed to control cortisol excess. In a 2-month-old with hypertension and hypertrophic cardiomyopathy, restarting etomidate without a bolus at 0.03 mg/kg/hour reduced cortisol into the target range within 36 hours, with ICU-level monitoring recommended to avoid adrenal insufficiency.34
  • PMID 33471735: In this long-term ectopic ACTH syndrome series, some patients required adrenalectomy to control severe hypercortisolism when the ACTH source remained occult, and most patients with identified lesions received preoperative ketoconazole. The report also describes a mixed corticomedullary adrenal tumor containing an ACTH-secreting pheochromocytoma intermingled with a cortisol-secreting adrenocortical carcinoma.18
  • PMID 33978483: This case report highlights metastatic cortisol-secreting ACC complicated by rare IGF-2-mediated paraneoplastic hypoglycemia despite hypercortisolism. It describes supportive endocrine management using metyrapone for hypercortisolism and hydrocortisone, octreotide, dextrose, and cornstarch for refractory hypoglycemia when resection was not feasible.77
  • PMID 34815159: This case report describes persistent ovarian dysfunction after long-term adjuvant mitotane for ACC, with prolonged amenorrhea, low sex steroids, high gonadotropins, and poor response to ovarian stimulation despite preserved antral follicles. In-vitro maturation enabled a live birth, highlighting fertility preservation and reproductive endocrine management as relevant supportive issues during prolonged mitotane exposure.78
  • PMID 34905500: A seven-patient case series suggests osilodrostat can rapidly control ACC-related hypercortisolism, with biochemical normalization and improvement in Cushingoid symptoms, blood pressure, potassium, and glucose parameters. The report recommends close cortisol monitoring, relatively higher starting doses in severe cases, and consideration of block-and-replace strategies when antineoplastic therapy is started.30
  • PMID 35567656: This review emphasizes supportive endocrine and toxicity management during first-line EDP-mitotane for advanced ACC, including urgent pre-chemotherapy control of cortisol excess with steroidogenesis inhibitors, recognition of mitotane-related hypoadrenalism as a cause of nausea or asthenia, and glucocorticoid supplementation when indicated.12
  • PMID 35900357: In patients with endogenous hypercortisolism, leukocytosis with neutrophilia and reduced lymphocyte and eosinophil counts correlated with cortisol excess, and these abnormalities improved within 3 months after remission. The findings support awareness of immune dysfunction and infection risk in cortisol-secreting ACC.79
  • PMID 36497381: This review emphasizes early integration of supportive and palliative care in advanced ACC, with particular attention to rapid control of severe hypercortisolism using steroidogenesis inhibitors or glucocorticoid receptor antagonism alongside mitotane and oncologic therapy. It also summarizes mitotane toxicity, plasma-level monitoring, and the need for glucocorticoid replacement during treatment.13
  • PMID 36856782: In mitotane-treated ACC patients from two referral-center cohorts, new-onset central hypothyroidism occurred in 95.5%, usually within the first year but sometimes after 12 months, and thyroid function partially or fully recovered in many patients after drug discontinuation. The study supports systematic monitoring of TSH and free T4 during treatment and after stopping mitotane.44
  • PMID 37130722: A case-based report illustrates use of metyrapone for symptomatic cortisol control in adrenocortical carcinoma, with accompanying reductions in serum cortisol and blood pressure over time while mitotane was also being given.80
  • PMID 37370841: This preclinical study reports that mitotane can impair male gonadal function, with reduced testosterone, Leydig cell-associated steroidogenic markers, seminiferous tubule damage, and lower sperm concentration and quality in mice. The findings support attention to hypogonadism, fertility counseling, and possible sperm cryopreservation in men receiving mitotane for ACC.47
  • PMID 38101790: In ACTH-independent adrenal Cushing syndrome, patients showed a hypercoagulable profile versus nonfunctional adrenal adenoma, with shorter PT and APTT and higher D-dimer and fibrin degradation products. Higher cortisol exposure and HbA1c were independent risk factors, supporting attention to thrombosis risk and perioperative venous thromboembolism prophylaxis considerations in cortisol-secreting adrenal tumors, including ACC.35
  • PMID 38190848: This review and case series describes mitotane as a pharmacologic option to control severe hypercortisolemia from ectopic ACTH syndrome, with rapid cortisol normalization and durable maintenance at low doses in advanced pancreatic neuroendocrine tumors. It also summarizes why steroidogenesis blockade is clinically important when life-threatening cortisol excess drives morbidity.81
  • PMID 38236710: This retrospective ACC study reports that mitotane therapy is associated with increased cortisol-binding globulin and higher total serum cortisol, while therapeutic and supra-therapeutic mitotane levels were also linked to reduced free thyroxine. The findings reinforce that total cortisol can be misleading on mitotane and support close endocrine monitoring with glucocorticoid replacement awareness.42
  • PMID 38244214: In ACC patients stopping adjuvant mitotane, adrenal recovery occurred in most cases but was often delayed, with a median of 26 months, while a minority had persistent insufficiency beyond 5 years. Higher mitotane peak levels were linked to slower recovery, and prolonged drug elimination supports extended glucocorticoid management and close endocrine follow-up.43
  • PMID 38726272: This review describes menorrhagia as a clinically important adverse effect of adjuvant mitotane in menstruating women with ACC, sometimes appearing months after treatment initiation and causing severe iron-deficiency anemia. It suggests gynecologic monitoring and reports continuous gestagen therapy, including levonorgestrel intrauterine device use, as helpful management.82
  • PMID 41459168: This case report highlights severe cortisol-secreting ACC causing Cushing syndrome with hypernatremia, hypokalemia, metabolic alkalosis, hyperglycemia, heart failure, and arrhythmias. It emphasizes preoperative cortisol control with metyrapone and postoperative hydrocortisone replacement with close electrolyte, endocrine, and cardiac monitoring.83
  • PMID 39896957: This case report describes off-label osilodrostat for severe hypercortisolism from metastatic ACC after mitotane intolerance, with successful cortisol control using a block-and-replace strategy after treatment-induced adrenal insufficiency. It also highlights monitoring for mineralocorticoid and androgen precursor excess during steroidogenesis inhibition.31
  • PMID 40736645: This review emphasizes that cortisol excess in ACC is a medical priority because severe hypercortisolism worsens prognosis and can cause life-threatening complications before cancer-directed therapy. It outlines rapid control strategies using steroidogenesis inhibitors, cautions about mitotane-related assay interference, and recommends close clinical and biochemical monitoring in expert centers.3
  • PMID 41001067: A veterinary case report describes metastatic functional adrenocortical carcinoma with excess production of multiple steroid hormones and short-term symptomatic improvement on trilostane, including reduction in polyuria, polydipsia, pot-bellied appearance, and several circulating steroid levels before later progression.84
  • PMID 41026626: A single-center retrospective ACC cohort found a high venous thromboembolism burden, with 13.5% of patients experiencing pulmonary embolism and 3.3% developing VTE within 6 months after adrenalectomy. No specific risk factors, including cortisol-producing disease, were identified, supporting continued peri-operative thromboprophylaxis and consideration of extended prophylaxis when additional risks are present.38
  • PMID 41260612: A multicenter real-world study of nonpituitary Cushing syndrome included 19 patients with ACC and found that osilodrostat rapidly lowered cortisol, with 4 of 6 evaluable ACC patients achieving urinary cortisol normalization at 12 weeks. Use was individualized, sometimes in block-and-replace regimens, with adrenal insufficiency and hypokalemia as common adverse events.9
  • PMID 41440228: In ACC patients receiving mitotane for at least six months, central hypothyroidism developed in half of those with normal baseline thyroid function and dyslipidemia in 40% without prior lipid abnormalities, with sex-specific patterns and earlier onset of dyslipidemia. The study supports routine thyroid and lipid monitoring during mitotane therapy and notes preference for non-CYP3A4-metabolized statins such as rosuvastatin or pravastatin.45
  • PMID 41694287: This case report describes relapse of preexisting immune thrombocytopenia during rapid cortisol reduction from metyrapone and again after adrenalectomy with steroid taper in cortisol-secreting ACC. It highlights the need for careful monitoring and individualized exogenous steroid management when correcting hypercortisolism in patients with coexisting autoimmune disease.85
  • PMID 41705522: In hospitalized ACC patients receiving cisplatin, doxorubicin, and etoposide with high-dose dexamethasone, real-time continuous glucose monitoring detected substantially more steroid-induced hyperglycemia than point-of-care testing and was associated with improved glycemic control across chemotherapy cycles.86
  • PMID 41822462: In a small mixed-tumor case series that included metastatic ACC, liver-directed embolization of hormonally active hepatic metastases produced rapid biochemical improvement in severe Cushing syndrome, sometimes causing transient adrenal insufficiency and permitting reduction of steroidogenesis-inhibiting therapy. The report supports embolization as a palliative multidisciplinary option when surgery is not feasible and liver-dominant metastases are driving hypercortisolism.49
  • PMID 41824768: This multicenter retrospective study included 16 patients with ACC and adrenal Cushing syndrome and found osilodrostat produced biochemical cortisol responses in a majority of evaluable cases, with associated reductions in systolic blood pressure and body weight. Adverse events were common enough to cause treatment discontinuation in over half of affected patients.11
  • PMID 10319177: A retrospective veterinary series found that concurrent pituitary and adrenal tumors could produce mixed endocrine and imaging results in hypercortisolism, complicating diagnostic classification. Although indirect to human ACC, it adds a cautionary point about atypical or discordant testing patterns when assigning the source of cortisol excess.19
  • PMID 2370223: A veterinary study found that oral ketoconazole reduced circulating cortisol within hours and lowered ACTH-stimulated cortisol during continued treatment in dogs with hyperadrenocorticism, including adrenocortical tumor cases. For ACC, this provides indirect historical support for ketoconazole as a steroidogenesis inhibitor rather than new human-specific outcome data.87
  • PMID 40090760: A 2025 veterinary case report described a dog with adrenal-dependent Cushing syndrome caused by adrenocortical carcinoma who developed diffuse low bone density and multiple pathological rib fractures. Its relevance to human ACC is indirect, but it adds supportive context for skeletal fragility as a potential consequence of severe cortisol excess.88
  • PMID 7559048: A veterinary series of adrenalectomy for feline hyperadrenocorticism, including one adrenocortical carcinoma case, reported substantial postoperative morbidity and occasional thromboembolic, septic, and adrenal-insufficiency-related deaths despite clinical improvement in survivors. Its ACC relevance is indirect but it reinforces the note’s emphasis on perioperative monitoring and endocrine replacement during correction of severe cortisol excess.89
  • PMID 8454518: A canine case series described bilateral functional adrenocortical neoplasia, including one case of bilateral adrenocortical carcinoma, showing that ACTH-independent hypercortisolism may arise from bilateral adrenal tumors and can be incompletely characterized by imaging alone. This is only indirectly relevant to human ACC, but it adds a diagnostic caution about persistent cortisol excess and adrenal localization.20
  • PMID 14001467: A 1963 study in lung cancer found higher basal adrenocortical steroid measures than in non-neoplastic controls, with anxiety not significantly accounting for this difference and hostility showing only limited correlation. Although indirect and not ACC-specific, it cautions against explaining cancer-associated cortisol elevation mainly by psychological distress.90
  • PMID 1633931: A 1992 comparative series of 41 patients with Cushing syndrome, including one adrenal carcinoma case, reported frequent hypertension, bruising, osteoporosis, leukocytosis, hypernatremia, hypokalemia, and impaired glucose tolerance or diabetes. Although not ACC-specific, it usefully reinforces the general complication profile and monitoring priorities associated with severe cortisol excess.14
  • PMID 17804949: A non-ACC case report showed that severe malignant hypercortisolism can mimic ordinary cardiometabolic syndrome, potentially delaying recognition until marked hypokalemia, hypertension, and other Cushingoid features emerge. Its relevance to ACC is indirect but supports vigilance when metabolic abnormalities appear unusually severe or rapidly progressive.91
  • PMID 2421511: An older prostate cancer study found that oestrogen therapy could modestly raise total serum cortisol and cyproterone acetate could lower it without clear impairment of hypothalamic-pituitary-adrenal feedback or clinical adrenal toxicity. Although indirect to ACC, it adds nuance to cortisol monitoring by showing that drug-related changes in total cortisol may not reflect true hypercortisolism or adrenal failure.92
  • PMID 25022661: A case report in metastatic medullary thyroid carcinoma with ectopic ACTH syndrome described initial cortisol control with metyrapone followed by sustained ACTH/UFC normalization and partial tumor response on sunitinib. Although not specific to ACC, it adds an indirect oncologic parallel in which tumor-directed therapy and control of hypercortisolism appeared to converge.93
  • PMID 31113567: A veterinary retrospective study of canine hepatocellular carcinoma found that concurrent hyperadrenocorticism was significantly more frequent than in the reference population and remained associated on multivariable analysis, though causality was uncertain. Its relevance to ACC is indirect and mainly supports a broader research perspective on links between cortisol excess and malignancy outside the adrenal setting.94
  • PMID 6532790: A 1984 comparative study found that routine chemistry abnormalities in Cushing syndrome differed in several respects from biopsy-proven fatty liver, including lower protein and albumin, higher glucose and cholesterol, and absence of the decreased GOT/GPT ratio typical of fatty liver. One autopsied case of adrenocortical carcinoma with Cushing syndrome showed no fatty change in nonmetastatic liver tissue, making the ACC relevance supportive but indirect.95
  • PMID 37519993: A veterinary case report of metastatic cortisol-secreting ACC described ACTH-independent hypercortisolism and use of metanephrine testing plus imaging to distinguish ACC from pheochromocytoma; its relevance to human ACC is indirect but supports broader diagnostic caution in complex adrenal tumors.21

References

Footnotes

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