Treatment of Primary Pigmented Nodular Adrenocortical Disease.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS), which mainly occurs in children and young adults. Treatment options with proven clinical efficacy for PPNAD include adrenalectomy (bilateral or unilateral adrenalectomy) and drug treatment to control hypercortisolemia. Previously, the main treatment of PPNAD is bilateral adrenal resection and long-term hormone replacement after surgery. In recent years, cases reports suggest that unilateral or subtotal adrenal resection can also lead to long-term remission in some patients without the need for long-term hormone replacement therapy. Medications for hypercortisolemia, such as Ketoconazole, Metyrapone and Mitotane et.al, have been reported as a preoperative transition for in some patients with severe hypercortisolism. In addition, tryptophan hydroxylase inhibitor, COX2 inhibitor Celecoxib, somatostatin and other drugs targeting the possible pathogenic mechanisms of the disease are under study, which are expected to be applied to the clinical treatment of PPNAD in the future. In this review, we summarize the recent progress on treatment of PPNAD, in which options of surgical methods, research results of drugs acting on possible pathogenic mechanisms, and the management during gestation are described in order to provide new ideas for clinical treatment.

Diurnal Plasma Cortisol Measurements Utility in Differentiating Various Etiologies of Endogenous Cushing Syndrome.

Cortisol diurnal variation may be abnormal among patients with endogenous Cushing syndrome (CS). The study objective was to compare the plasma cortisol AM/PM ratios between different etiologies of CS. This is a retrospective cohort study, conducted at a clinical research center. Adult patients with CS that underwent adrenalectomy or trans-sphenoidal surgery (n=105) were divided to those with a pathologically confirmed diagnosis of Cushing disease (n=21) and those with primary adrenal CS, including unilateral adrenal adenoma (n=28), adrenocortical hyperplasia (n=45), and primary pigmented nodular adrenocortical disease (PPNAD, n=11). Diurnal plasma cortisol measurements were obtained at 11:30 PM and midnight and at 7:30 and 8:00 AM. The ratios between the mean morning levels and mean late-night levels were calculated. Mean plasma cortisol AM/PM ratio was lower among CD patients compared to those with primary adrenal CS (1.4±0.6 vs. 2.3±1.5, p<0.001, respectively). An AM/PM cortisol ratio≥2.0 among patients with unsuppressed ACTH (>15 pg/ml) excludes CD with a 85.0% specificity and a negative predictive value (NPV) of 90.9%. Among patients with primary adrenal CS, an AM/PM cortisol≥1.2 had specificity and NPV of 100% for ruling out a diagnosis of PPNAD. Plasma cortisol AM/PM ratios are lower among patients with CD compared with primary adrenal CS, and may aid in the differential diagnosis of endogenous hypercortisolemia.

The role of unilateral adrenalectomy in corticotropin-independent bilateral adrenocortical hyperplasias.

BACKGROUND: The objective of the present study was twofold: to demonstrate our experience with unilateral adrenalectomy in the treatment of adrenocorticotropic hormone (ACTH)-independent Cushing syndrome (CS) caused by bilateral adrenocortical hyperplasias, and to evaluate the long-term results as evidenced by the main laboratory and clinical findings. METHODS: From February 2000 to August 2009, unilateral adrenalectomy was performed on 27 patients with ACTH-independent CS and bilateral adrenocortical hyperplasias, including 14 patients with ACTH-independent macronodular adrenal hyperplasia (AIMAH) and 13 patients with primary pigmented nodular adrenocortical disease (PPNAD). Signs and symptoms of CS, endocrine examinations, and radiographic imaging were evaluated preoperatively and postoperatively. RESULTS: At a median follow-up of 69 months (range: 23-120 months) for AIMAH and 47 months (range: 16-113 months) for PPNAD, 25 patients were cured by unilateral adrenalectomy. Serum cortisol level, daily urinary free cortisol (UFC), and plasma ACTH regained the normal range in both AIMAH and PPNAD patients at monthly follow-up visits; the circadian serum cortisol rhythm returned to normal, and a normal responsiveness to overnight low-dose dexamethasone administration (LDDST) became obvious. Both systolic and diastolic blood pressure (BP) levels were significantly reduced: 85 % of patients recovered normal BP levels, and the remaining patients need antihypertensive drugs, but at a reduced dose. No surgery-related morbidity occurred, and there was no sign of further enlargement of the residual adrenal gland after successful unilateral adrenalectomy. One patient with PPNAD and another patient with AIMAH with similar weights and sizes of the bilateral adrenals needed contralateral adrenalectomy. CONCLUSIONS: Unilateral adrenalectomy may be the suitable treatment for selected patients with AIMAH and PPNAD. It can achieve long-term remission of CS and improve glycemic control and BP values.

An unusual presentation of Carney complex with diffuse primary pigmented nodular adrenocortical disease on one adrenal gland and a nonpigmented adrenocortical adenoma and focal primary pigmented nodular adrenocortical disease on the other.

A 24-year-old female patient with cushingoid appearance was admitted in May 2000. The endocrine studies showed ACTH-independent Cushing's syndrome. A 2-day high-dose dexamethasone suppression test (HDDST) revealed paradoxical increase of 24 h urinary free cortisol (UFC). Abdominal computed tomography demonstrated a left adrenal nodule (3 x 2 cm in diameter). An adrenal scintigram with ¹³¹I-6ß-iodomethyl-19-norcholesterol showed uptake of the isotope in the left adrenal gland and non-visualization in the right adrenal gland throughout the examination course. A retroperitoneoscopic left total adrenalectomy was performed in July 2000. The cut surface of the left adrenal was yellow-tan grossly. Microscopically, the left adrenal nodule contained a nonpigmented adrenocortical adenoma (NP) and another focal primary pigmented nodular adrenocortical disease (PPNAD, FP) mixed lesion. The immunohistochemical studies of CYP17 demonstrate positive in NP and FP of the left adrenal gland. Very low baseline morning plasma cortisol (0.97 µg/dL) and subnormal ACTH (8.16 pg/mL) levels were measured 1.5 months after left adrenalectomy. Right adrenal gland recovered its function 6 months after left adrenalectomy. Plasma cortisol could be suppressed to 3.47 µg/dL by overnight low-dose dexamethasone suppression test 65 months after left adrenalectomy. Cushingoid features still did not appear 122 months after left adrenalectomy. In May 2011, this patient was readmitted due to cushingoid characteristics. Paradoxical rise of 24-h UFC to 2-day HDDST was demonstrated. Ultrasonography of thyroid showed bilateral thyroid cysts. Subtotal right adrenalectomy about 80% of right adrenal was performed. Diffuse PPNAD of the right adrenal was proved pathologically. Immunohischemical stain for CYP17 is positive in the right adrenal gland but weaker positive than that in the left adrenal gland. The genetic study of the peripheral blood, left adrenocortical nodule, and right PPNAD all showed p.R16X (c.46C>T) mutation of the PRKAR1A gene.

[Post-resuscitation syndrome. Role of inflammation after cardiac arrest]. / Postreanimationssyndrom. Rolle der Entzündung nach Herz-Kreislauf-Stillstand.

Cardiac arrest with subsequent cardiopulmonary resuscitation causes an ischemic reperfusion syndrome of the whole body resulting in localized damage of particularly sensitive organs, such as the brain and heart, together with systemic sequelae. The main factor is a generalized activation of inflammatory reactions resulting in symptoms similar in many aspects to those of sepsis. Systemic inflammation strengthens organ damage due to disorders in the macrocirculation and microcirculation due to metabolic imbalance as well as the effects of direct leukocyte transmitted tissue destruction. The current article gives an overview on the role of inflammation following cardiac arrest and presents in detail the underlying mechanisms, the clinical symptoms and possible therapeutic approaches.

Children with Cushing's syndrome: Primary Pigmented Nodular Adrenocortical Disease should always be suspected.

Primary Pigmented Nodular Adrenocortical Disease (PPNAD) is a rare form of bilateral adrenocortical hyperplasia that is inherited in an autosomal dominant manner and leads to ACTH-independent Cushing's syndrome (CS). PPNAD may be isolated or associated with Carney Complex (CNC). For the diagnosis of PPNAD and CNC, in addition to the hormonal and imaging tests, searching for PRKAR1A mutations may be recommended. The aims of the present study are to discuss the clinical and molecular findings of two Brazilian patients with ACTH-independent CS due to PPNAD and to show the diagnostic challenge CS represents in childhood. Description of two patients with CS and the many sequential steps for the diagnosis of PPNAD is provided. Sequencing analysis of all coding exons of PRKAR1A in the blood, frozen adrenal nodules (patients 1 and 2) and testicular tumor (patient 1) is performed. After several clinical and laboratory drawbacks that misled the diagnostic investigation in both patients, the diagnosis of PPNAD was finally established and confirmed through pathology and molecular studies. In patient 1, sequencing of PRKAR1A gene revealed a novel heterozygous 10-bp deletion in exon 3, present in his blood, adrenal gland and testicular tumor. The etiologic diagnosis of endogenous CS in children is a challenge that requires expertise and a multidisciplinary collaboration for its prompt and correct management. Although rare, PPNAD should always be considered among the possible etiologies of CS, due to the high prevalence of this disease in this age group.

Update on primary micronodular bilateral adrenocortical diseases.

PURPOSE OF REVIEW: Primary micronodular bilateral adrenocortical hyperplasias (MiBAH) are rare challenging diseases. Important progress in understanding its pathophysiology and genetics occurred in the last two decades. We summarize those progress and recent data on investigation and therapy of MiBAH focusing on primary pigmented nodular adrenocortical disease (PPNAD). RECENT FINDINGS: Larger recent cohorts of PPNAD patients from various countries have confirmed their variable Cushing's syndrome phenotypes. Age of onset is earlier than other ACTH-independent Cushing's syndrome causes and the youngest case have now occurred at 15 months. Two retrospective studies identified an increased risk of osteoporotic fractures in PPNAD as compared with other Cushing's syndrome causes. The utility of 6-day oral dexamethasone test to produce a paradoxical increase of urinary-free cortisol in PPNAD was confirmed but the mean fold of increase was of 48%, less than previously suggested. Several new genetic variants of the PRKAR1A gene have been reported in PPNAD or Carney complex (CNC). Remission of Cushing's syndrome with unilateral adrenalectomy was reported in a few patients with PPNAD. SUMMARY: MiBAH, PPNAD and CNC are rare challenging diseases, but with combined expert clinical and genetic approaches a comprehensive investigation and prevention strategy can be offered to affected patients and families.

Adrenocortical hyperplasia: A multifaceted disease.

Adrenocortical hyperplasia may develop in different contexts. Primary adrenal hyperplasia may be secondary to primary bilateral macronodular adrenocortical hyperplasia (PBMAH) or micronodular bilateral adrenal hyperplasia (MiBAH) which may be divided in primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease (i-MAD). Both lead to oversecretion of cortisol and potentially to Cushing's syndrome. Moreover, adrenocortical hyperplasia may be secondary to longstanding ACTH stimulation in ACTH oversecretion as in Cushing's disease, ectopic ACTH secretion or glucocorticoid resistance syndrome and congenital adrenal hyperplasia secondary to various enzymatic defects within the cortex. Finally, idiopathic bilateral adrenal hyperplasia is the most common cause of primary aldosteronism. We will discuss recent findings on the multifaceted forms of adrenocortical hyperplasia.

Chronic exposure of rats to occupational textile noise causes cytological changes in adrenal cortex.

Chronic exposure to industrial noise and its effects on biological systems. Occupational exposure to noise may result in health disorders. Our aim was to evaluate the effects of chronic exposure to high-intensity noise of textile industry cotton rooms on the adrenal morphology. The environmental noise of a cotton-mill room from a large textile factory of Northern Portugal was recorded and reproduced by an adopted electroacoustic setup in a sound-insulated animal room where the rats were housed. The sounds were reproduced at the original levels of approximately 92 dB, which was achieved by equalization and distribution of sound output in the room. Wistar rats were submitted to noise exposure, in the same time schedule as employed in textile plants. After one, three, five, and seven months, the adrenals were collected and analyzed by light microscopy. Analyzed by multivariate analysis of variance and post hoc Bonferroni correction for multiple comparisons of the means between the groups. Noise exposure induced time-dependent changes in adrenal cortex, with decrease of zona fasciculata (ZF) and increase of zona reticularis volumes, together with a significant depletion of lipid droplet density in ZF cells of exposed rats, in comparison to control rats. Chronic exposure of rats to textile industry noise triggers cytological changes in the adrenals that suggest the existence of a sustained stress response.

Acute adrenal cortex injury during cardiopulmonary bypass in a canine model.

OBJECTIVE: Cardiopulmonary bypass (CPB) might induce systemic inflammatory responses that cause acute injuries to multiple organs. However, no direct evidence exists to determine whether CPB leads to adrenal cortex injury or to describe its underlying mechanism. METHODS: Twelve healthy adult beagles were randomly assigned into control and CPB groups. After cannulation, mild hypothermia CPB was performed in the CPB group but not in the control group. The serum concentrations of various cytokines, cortisol, and aldosterone were assessed. Adrenal cortex injuries were evaluated using standard histological methods. Steroidogenic enzymes and the nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome pathway were detected using quantitative polymerase chain reaction and Western blot analysis. RESULTS: During CPB, serum interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor α, cortisol, and aldosterone levels were significantly higher in the CPB group. The pathologic study revealed higher injury scores (3.6 ± 0.6 vs 0.7 ± 0.7) and significantly more severe edema, inflammatory cell infiltration (lymphocytes and neutrophils), and apoptosis in the CPB group. The electron microscopic examination showed swollen mitochondria, ruptured mitochondrial cristae, reduced lipid droplets, and increased secondary lysosomes in the CPB group. The mRNA expression levels of NLRP3 and the protein levels of 17α-hydroxylase and IL-1ß in adrenal tissue were significantly upregulated in the CPB group. CONCLUSIONS: CPB induces significant systemic and local inflammation in the adrenal cortex and results in cytological architectural and ultrastructural alterations in adrenocorticocytes. In addition, the NLRP3 inflammasome pathway might promote adrenal gland injury during CPB and might represent a novel potential therapeutic target.

Stimulation of gonadal steroid synthesis by chronic excess of adrenocorticotropin in patients with adrenocortical insufficiency.

Analysis of 24-h urinary steroid excretion was performed by capillary gas chromatography in six patients (five men, one woman) with adrenocortical insufficiency. Ten healthy subjects (five men, five women) served as controls. A complete absence of all 21-hydroxylated steroid metabolites was seen in patients with adrenocortical insufficiency, whereas the excretion of several steroids lacking hydroxylation in the 21-position (pregnenolone, pregnenetriol, and 11-ketoandrosterone) was markedly increased. In addition, the presence of 11 beta-hydroxyandrosterone was confirmed by mass-spectrometry in the urine of three patients. This pattern of steroid excretion was unchanged in patients with adrenocortical insufficiency, both after stimulation by 1-24 adrenocorticotropin (ACTH) and after short-term (3-d) suppression with dexamethasone. We conclude that patients with adrenocortical insufficiency present a pattern of steroid excretion characterized by the absence of 21-hydroxylated metabolites. In the absence of functional adrenocortical tissue, long-term pathologically elevated concentrations of ACTH apparently stimulate early steps of steroid synthesis, most likely in the gonads. In addition, the presence of 11-hydroxylated steroid metabolites (11-ketoandrosterone, 11 beta-hydroxyandrosterone) in the urine of patients with adrenocortical insufficiency demonstrates that chronic ACTH excess in this disorder may induce some activity of 11 beta-hydroxylase, an enzyme not found in the gonads under physiological conditions.

Premature pubarche: etiological heterogeneity.

Premature pubarche is characterized by pubic hair, adult type body odor, acne, and axillary hair before 8 yr of age in girls and 9.5 yr of age in boys. Causes of this premature virilization include premature adrenarche, mild errors of steroidogenesis, precocious puberty, and adrenal and gonadal tumors. To determine whether any clinical parameters are helpful in distinguishing which children should undergo further evaluation for mild congenital adrenal hyperplasia, we performed ACTH stimulation tests in 69 children with premature pubarche and 8 pubertal controls. Patients were categorized as having typical (pubic hair with or without axillary hair and body odor) or atypical (pubic hair and genital enlargement) premature pubarche. Blood samples, before and 30 min after iv bolus administration of synthetic ACTH, were obtained for progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, 11-deoxycortisol, and cortisol measurements. The patients were divided into 4 groups based on their individual responses to ACTH stimulation: premature adrenarche (no apparent defect in steroidogenesis), possible decreased 21-hydroxylase activity, possible decreased 3 beta-hydroxysteroid dehydrogenase activity, and indeterminate responses. Five of 11 (45%) children with atypical premature pubarche and 7 of 58 (12%) children with typical premature pubarche were found to have evidence of mild defects in steroidogenesis. Similar to previous reports in postpubertal women, only responses to ACTH stimulation allowed accurate classification of these patients.

Bilateral massive adrenal hemorrhage. Assessment of putative risk factors by the case-control method.

Case reports and case series have identified putative risk factors for the development of bilateral massive adrenal hemorrhage (BMAH) in humans. The anatomy and physiology of the adrenal gland allow development of a model to fit the pathophysiology behind these risk factors. Until now, these risk factors were not systematically tested using analytical epidemiologic studies. A case-control study was undertaken using sources of cases and controls from multiple teaching hospitals in Ontario, Canada. The results of multivariate logistic regression indicated that thrombocytopenia (odds ratio [OR] = 14.6, 95% confidence intervals [CI] = 3.0-70.1, p < 0.001), heparin exposure of any route or type beyond 3 days (4-6 days: OR = 17.0, CI = 1.9-154.6; > 6 days: OR = 33.5, CI = 4.3-262.6; p < 0.001), and sepsis (OR = 6.3, CI = 1.2-32.2, p = 0.019) were most strongly and independently associated with development of BMAH. Another weaker positive association included invasive radiologic procedure (OR = 4.4, CI = 0.9-22.1, p = 0.055). Neither major surgery or duration of hospitalization were independent risk factors. Although coronary artery disease and possibly diabetes and hypertension appeared to be markers for lower risk of BMAH, this may be a result of bias introduced by using hospital controls ("Berkson bias"), as the effect was not explained by a protective effect of vasoactive medications. Thus, a picture of the high-risk patient should include a patient who has been treated with heparin (any route or type) beyond 3 days and has had thrombocytopenia (not necessarily induced by heparin) during the course of an illness. If the setting includes unexplained abdominal, chest, or back pain; fever; confusion; hypotension or shock; abrupt anemia; or electrolyte disorders, clinicians should not hesitate to cover empirically with lifesaving glucocorticoids while awaiting results of confirmatory tests.

Adrenal hemorrhage in the adult.

Bilateral adrenal gland hemorrhage was found in 22 of 2,000 (1.1%) consecutive general hospital autopsies. Clinical features of these 22 patients with diffuse or focal bilateral adrenal hemorrhage have been analyzed and compared with previous series. In our experience, patients with this postmortem finding rarely manifest features of adrenocortical insufficiency and appear instead to die as a consequence of concomitant overwhelming illness, such as septicemia, body surface burns or cardiovascular catastrophe. Two-thirds of the current series had impaired renal function at the time of adrenal hemorrhage and three patients had pituitary gland necrosis. Experimental and clinical observations indicate that the "stressed" adrenal gland--under substantive endogenous or exogenous ACTH stimulation--is unusually susceptible to hemorrhage. While our own experience indicates that bilateral adrenal hemorrhage can infrequently be implicated as a factor contributing to patients' death, the possibility of adrenocortical insufficiency must be considered in patients at risk for adrenal hemorrhage. Such patients are those who are azotemic and have bacteremia, burns, or recent cardiovascular catastrophe, particularly when the latter is managed with anticoagulant administration. In these patients, unexplained clinical deterioration or the appearance of findings consistent with adrenocortical insufficiency mandate measurement of serum cortisol concentration and institution of stress-level corticosteroid replacement therapy until a diagnosis of acute adrenocortical insufficiency can be established or refuted.

Bilateral massive adrenal haemorrhage complicating anaphylactic shock: a case report.

A case of bilateral adrenal haemorrhage complicating anaphylactic shock is reported. Hypovolemic shock related to peritoneal haemorrhage was the main feature landing to laparotomy. Ultrasonographic examination was not contributive, but CT scan easily documented the adrenal haemorrhage and must be considered a valuable diagnostic tool when adrenal haemorrhage is suspected.

Juxta-adrenal cortical cell nests or nodular formation in the younger generation: what does it mean?

The number and size of juxta-adrenal cortical cell nests or nodular formation (JACN) and their histology were examined in autopsy material from 255 successive subjects of various ages (from fetuses to elderly patients). The study of number and size showed that JACN occurred significantly more frequently among subjects aged 0-year-old (0Y0) to 10Y0 (p < 0.01) than among other age groups. The study of numbers within each nodular size range (large nodular formations [LNF; nodules with a minor axis measuring 0.25 mm or more] and small nodular formations [SNF; smaller than LNF]) showed that the number of SNF and the SNF to LNF ratio decreased according to age, while the number of LNF remained relatively constant. Immunohistochemical examination of proliferating adrenal cortical cells using the mouse anti-human antibody MIB-1 demonstrated many positive cells in subjects with many JACN. No nodular proliferation of adrenocorticotrophic hormone positive cells occurred in the adenohypophysis. Fibrous thickening of the adrenal capsule increased gradually with age or medication. JACN was very frequently observed among subjects with conditions such as asplenic syndrome, acute lymphocytic leukemia and Down's syndrome. These data suggest that JACN might be an anatomic variant but that certain factors could increase the size and number of JACN after birth.

Adrenocortical hemorrhagic necrosis: the role of catecholamines and retrograde medullary-cell embolism.

We investigated the pathogenesis of adrenal necrosis using animal models of the disease (induced by administration of acrylonitrile, cysteamine, or pyrazole) and human cases. Results of electron-microscopic and histochemical time-response studies with rat models revealed an early, retrograde embolization of medullary cells and cell fragments in the cortical capillaries that showed prominent endothelial injury. The experimental adrenal lesions were prevented by surgical removal of the medulla one month before administration of adrenocorticolytic chemicals, or by the administration of the alpha-adrenergic antagonist phenoxybenzamine hydrochloride. Histochemical staining for medullary (argyrophil) granules in human cases of adrenal necrosis demonstrated tissue fragments that stained positively for silver in vascular cortical spaces in nine of ten autopsy specimens and in all four surgical cases we reviewed. Thus, catecholamines released from the adrenal medulla and from the retrograde medullary emboli in the cortex may have a role in the pathogenesis of adrenocortical necrosis.

Microcysts of the permanent adrenal cortex in perinates and infants,.

Microscopic cysts in the permanent cortices of adrenal glands were studied in a series of 274 infants, some of whom had been stillborn and none of whom were more than 12 months old. After correction for length of gestation, there were no significant relationships between the occurence and number of microcysts and various maternal, placental, and perinatal diseases. A significant direct correlation was demonstrated statistically with shorter gestational period and shorter survival time after birth. We concluded that the adrenal microcysts are either a developmental feature or the result of a greater susceptibility to stress in the fetus and newborn than in older infants.

Diseases of the adrenal cortex.

The adrenal cortex is functionally a three-dimensional gland that secretes glucocorticoids, mineralocorticoids, and sex steroids. Of these three classes of steroids only the gluco- and mineralocorticoid hormones are necessary to sustain life. The availability of sensitive and specific radioimmunoassays has permitted accurate measurement of practically every steroid hormone secreted by the adrenal cortex. As in other endocrinopathies, suppression studies are employed when hyperfunction is suspected, while provocative tests are used to detect hypofunction. These dynamic studies enable the clinician to evaluate the functional status of the adrenal cortex. The anatomic configuration of the adrenal cortices is delineated by high-resolution computed tomography (and magnetic resonance imaging), obviating the need for invasive procedures such as venography or arteriography. The disorders of the adrenal cortex can be viewed from the dual perspectives of hyperfunction and hypofunction. Clinical expressions of hyperfunctional adrenocortical syndromes include Cushing's syndrome, primary hyperaldosteronism, and the adrenogenital syndrome. The expressions of hypofunctional syndromes include Addison's disease and selective hypoaldosteronism. The diagnosis and treatment of these disorders are outlined in this issue.

Subcapsular cell hyperplasia and mast cell infiltration in the adrenal cortex of mice: comparative study in 7 inbred strains.

Subcapsular cell hyperplasia (SCH) in the adrenal cortex of aged mice (13-15 months old) was frequent in both sexes of BALB/c, C3H/He, DBA/2J and IQI/Jic mice and in the females of A/J and C57BL/6, although the incidence and severity of SCH were considerably different among mouse strains. Mast cells were closely associated with SCH in the A/J, BALB/c, C57BL/6, DBA/2J and IQI/Jic mice, but not in the C3H/He strain. Compared with other strains, IQI/Jic mice had a significantly larger number of mast cells in the adrenal glands. Our findings suggest that mast cells may participate in the development of SCH, and IQI/Jic would be suitable for studying the pathogenesis of SCH and the role of mast cells in this lesion.