Suppression Of Cortisol Secretion Research Articles

Reduction of SGLT2 protein levels inhibits cortisol secretion through regulation of cytokine secretion

Reduction of SGLT2 protein levels inhibits cortisol secretion through regulation of cytokine secretion

Phase 2 randomised placebo-controlled trial of spironolactone and dexamethasone versus dexamethasone in COVID-19 hospitalised patients in Delhi

BackgroundIn this phase 2 randomised placebo-controlled clinical trial in patients with COVID-19, we hypothesised that blocking mineralocorticoid receptors using a combination of dexamethasone to suppress cortisol secretion and spironolactone is safe and may reduce illness severity.MethodsHospitalised patients with confirmed COVID-19 were randomly allocated to low dose oral spironolactone (50 mg day 1, then 25 mg once daily for 21 days) or standard of care in a 2:1 ratio. Both groups received dexamethasone 6 mg daily for 10 days. Group allocation was blinded to the patient and research team. Primary outcomes were time to recovery, defined as the number of days until patients achieved WHO Ordinal Scale (OS) category ≤ 3, and the effect of spironolactone on aldosterone, D-dimer, angiotensin II and Von Willebrand Factor (VWF).ResultsOne hundred twenty patients with PCR confirmed COVID were recruited in Delhi from 01 February to 30 April 2021. 74 were randomly assigned to spironolactone and dexamethasone (SpiroDex), and 46 to dexamethasone alone (Dex). There was no significant difference in the time to recovery between SpiroDex and Dex groups (SpiroDex median 4.5 days, Dex median 5.5 days, p = 0.055). SpiroDex patients had significantly lower D-dimer levels on days 4 and 7 (day 7 mean D-dimer: SpiroDex 1.15 µg/mL, Dex 3.15 µg/mL, p = 0.0004) and aldosterone at day 7 (SpiroDex 6.8 ng/dL, Dex 14.52 ng/dL, p = 0.0075). There was no difference in VWF or angiotensin II levels between groups. For secondary outcomes, SpiroDex patients had a significantly greater number of oxygen free days and reached oxygen freedom sooner than the Dex group. Cough scores were no different during the acute illness, however the SpiroDex group had lower scores at day 28. There was no difference in corticosteroid levels between groups. There was no increase in adverse events in patients receiving SpiroDex.ConclusionLow dose oral spironolactone in addition to dexamethasone was safe and reduced D-dimer and aldosterone. Time to recovery was not significantly reduced. Phase 3 randomised controlled trials with spironolactone and dexamethasone should be considered.Trial registrationThe trial was registered on the Clinical Trials Registry of India TRI: CTRI/2021/03/031721, reference: REF/2021/03/041472. Registered on 04/03/2021.

Bakuchiol and Ethyl (Linoleate/Oleate) Synergistically Modulate Endocannabinoid Tone in Keratinocytes and Repress Inflammatory Pathway mRNAs

The endocannabinoid (eCB) system plays an active role in epidermal homeostasis. Phytocannabinoids such as cannabidiol modulate this system but also act through eCB-independent mechanisms. This study evaluated the effects of cannabidiol, bakuchiol (BAK), and ethyl (linoleate/oleate) (ELN) in keratinocytes and reconstituted human epidermis. Molecular docking simulations showed that each compound binds the active site of the eCB carrier FABP5. However, BAK and ethyl linoleate bound this site with the highest affinity when combined 1:1 (w/w), and invitro assays showed that BAK+ ELN most effectively inhibited FABP5 and fatty acid amide hydrolase. In TNF-stimulated keratinocytes, BAK+ ELN reversed TNF-induced expression shifts and uniquely downregulated type I IFN genes and PTGS2 (COX2). BAK+ ELN also repressed expression of genes linked to keratinocyte differentiation but upregulated those associated with proliferation. Finally, BAK+ ELN inhibited cortisol secretion in reconstituted human epidermis skin (not observed with cannabidiol). These results support a model in which BAK and ELN synergistically interact to inhibit eCB degradation, favoring eCB mobilization and inhibition of downstream inflammatory mediators (e.g., TNF, COX-2, type I IFN). A topical combination of these ingredients may thus enhance cutaneous eCB tone or potentiate other modulators, suggesting novel ways to modulate the eCB system for innovative skincare product development.

Geongangbuja-Tang Decoction and Its Active Ingredient, Aconiti Lateralis Radix Preparata, Exerts Inhibitory Effects on Heat Stress-Induced Inflammation in Mice

Heat stress induces the hypothalamic-pituitary-adrenal (HPA) axis activation, influences biological responses, and reduces energy metabolism. Geongangbuja-tang (GBT) and its components, Zingiberis Rhizoma (ZOR) and Aconiti Lateralis Radix Preparata (ALRP) have been used to induce energy metabolism; however, the effects of GBT and its ingredients on heat-induced inflammatory responses have not yet been investigated. In this study, we performed an open-field test to evaluate locomotor activity in mice. To assess the effects of GBT and its ingredients on inflammation, the protein levels of c-fos, pro-inflammatory cytokines, and cortisol were measured in the mouse hypothalamus and serum. The results showed that GBT alleviated locomotive activity and reduced c-fos levels in a dose-dependent manner under the heat exposure. After investigating the active constituent of GBT, we found that compared to GBT and ZOR, ALRP significantly suppressed c-fos expression under heat stress. Subsequently, ALRP decreased the expression of pro-inflammatory cytokines, such as interleukin-9 and -13 and prostaglandin, under the heat stress in the mouse hypothalamus. Moreover, treatment with ALRP inhibited cortisol secretion in the mouse serum following heat exposure. These results indicate that GBT and its active component, ALRP, could be the thermoregulatory agents that regulate the HPA axis.

A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks.

Stress activates a complex network of hormones known as the hypothalamic–pituitary–adrenal (HPA) axis. The HPA axis is dysregulated in chronic stress and psychiatric disorders, but the origin of this dysregulation is unclear and cannot be explained by current HPA models. To address this, we developed a mathematical model for the HPA axis that incorporates changes in the total functional mass of the HPA hormone‐secreting glands. The mass changes are caused by HPA hormones which act as growth factors for the glands in the axis. We find that the HPA axis shows the property of dynamical compensation, where gland masses adjust over weeks to buffer variation in physiological parameters. These mass changes explain the experimental findings on dysregulation of cortisol and ACTH dynamics in alcoholism, anorexia, and postpartum. Dysregulation occurs for a wide range of parameters and is exacerbated by impaired glucocorticoid receptor (GR) feedback, providing an explanation for the implication of GR in mood disorders. These findings suggest that gland‐mass dynamics may play an important role in the pathophysiology of stress‐related disorders.

Insuffisance surrénale secondaire aux opioïdes : rapport de cas et synthèse de la littérature

IntroductionOpioid therapy for pain relief is associated with several adverse effects. Herein, we report the potential consequences of opioid use on the adrenal function. ObservationA 49-year-old woman with sickle cell anemia (Hemoglobin SS) was admitted for the treatment of a vaso-occlusive crisis. Morphine was used for pain management, provided by intravenous intermittent dosing (patient-controlled analgesia). She developed during the hospitalization low blood pressure, due to secondary adrenal insufficiency (cortisol 74 nmol/L; ACTH 2.9pmol/L). Pituitary gland was normal on brain magnetic resonance imaging and adrenal function recovered after morphine discontinuation. ConclusionOpioids suppress cortisol secretion, primarily mediated by direct negative effect on hypothalamus and pituitary gland. Further studies are needed to define the incidence and the clinical significance of opioid-induced adrenal insufficiency, as well as the need for hormone replacement.

Foetal exposure to mitotane/Op'DDD: Post-natal study of four children.

Mitotane/Op'DDD is used in the treatment of adrenocortical carcinoma and for other causes of hypercortisolism. Mitotane inhibits cortisol secretion and displays adrenolytic and antitumor actions. This compound is a metabolite of the pesticide and endocrine disruptor DDT (dichlorodiphenyltrichloroethane) and is classified among teratogenic compounds worldwide. However, little is known about its effects on human development. The outcome of four children exposed to mitotane during their intrauterine life was examined. Patients having conceived while taking mitotane, or with detectable mitotane plasma levels, were retrospectively recruited via the French COMETE and FIRENDO networks. Mitotane in maternal plasma, adrenocortical hormones in children. Three women treated with mitotane gave birth to four children. During early pregnancy, all patients had detectable mitotane plasma levels (0.9, 2.4 and 6.7 mg/L, respectively). During pregnancy, no foetal malformations were detected. The four exposed newborns presented at birth with apparently normal adrenal function and genitalia. One twin female had a low birthweight. Evaluation at birth and after 3 months, 2 years and 7 years of follow-up showed no significant neurological abnormality. Evaluation of adrenocortical functions showed no cortisol deficiency. Unexpectedly, exposure of these four children to mitotane during foetal life seemed to have no clear teratogenic effect. However, considering the sub-therapeutic mitotane concentrations used here, the small number of cases, and because long-term follow-up is unknown, we strongly advise not to take mitotane during pregnancy and still recommend avoiding pregnancy, at least as long as mitotane plasma levels remain detectable.

Impact of Electrical Stimulation on Cortisol Secretion in Rat Adrenal Gland

Cortisol is the primary hormone responsible for the undesirable effects of stress. This study aimed to understand how electrical stimulation influences cortisol secretion, which can be advantageous for designing future implantable electrical devices, to monitor and control the cortisol level. Acutely prepared adrenal gland slices of Sprague-Dawley rats were electrically stimulated at various frequencies, in the presence and absence of adrenocorticotropic hormone (ACTH) and the resultant cortisol levels determined. Electrical stimulation at ≥5 Hz frequency inhibited ACTH-induced cortisol secretion, but electrical stimulation alone did not have any effect. Furthermore, when applied in the presence of TTA-P2, a T-type Ca2+ channel inhibitor, electrical stimulation presented no influence on ACTH-induced cortisol secretion. Our results suggest that the inhibition of the T-type Ca2+ channels by electrical stimulation may contribute to its suppression of cortisol secretion.

Effects of oral megestrol acetate administration on the hypothalamic-pituitary-adrenal axis of male bottlenose dolphins (Tursiops truncatus).

OBJECTIVE To evaluate the impact of oral megestrol acetate (MA) administration on adrenal function in male bottlenose dolphins (Tursiops truncatus). DESIGN Serial cross-sectional study. ANIMALS 8 adult male dolphins, all of which were receiving MA at various daily doses (range, 0 to 60 mg, PO) for the control of reproductive behavior. PROCEDURES Blood samples were collected every 2 weeks for 1 year from dolphins trained to voluntarily provide them. Cortisol, ACTH, and other hormone concentrations were measured in serum or plasma via radioimmunoassay or ELISA. Fecal samples, also provided by dolphins voluntarily, were assayed for glucocorticoid metabolite concentrations. Effects of daily MA dose on hormone concentrations were evaluated. RESULTS Daily MA doses as low as 10 mg strongly suppressed cortisol secretion in nearly all dolphins, and except for a single measurement, no dolphin had measurable serum concentrations at doses ≥ 20 mg. Variations in serum cortisol concentration were unrelated to season but were directly related to ACTH concentrations, suggesting primary effects upstream of the adrenal gland. Cessation of MA administration resulted in almost immediate restoration of measurable serum cortisol concentrations, although concentrations continued to rise in a few dolphins over the following weeks to months. CONCLUSIONS AND CLINICAL RELEVANCE Caution should be exercised when administering MA to control reproductive behavior in male dolphins. Because the hypothalamic-pituitary-adrenal axis appeared to be sensitive to even small doses of MA in dolphins, duration of treatment may be the most critical consideration.

A Refill for the Brain Mineralocorticoid Receptor: The Benefit of Cortisol Add-On to Dexamethasone Therapy.

Some serious medical conditions require life-saving treatment with high doses of synthetic glucocorticoids such as dexamethasone. A substantial number of patients subjected to this treatment develops psychosis, mood disturbances, or sleep problems. A recent clinical trial demonstrated that dexamethasone therapy for young patients with acute lymphoblastic leukemia caused severe adverse psychological effects and sleep disturbances in about 30% of these patients. These side effects were ameliorated by coadministration of a low dose of the naturally occurring glucocorticoid hormone cortisol. This paradoxical finding was predicted by the idea that the synthetic glucocorticoid targets the glucocorticoid receptor, causing suppression of cortisol secretion and, thus, depletion of the brain mineralocorticoid receptor (MR) of its endogenous ligand. The refill of the unoccupied brain MR with physiological amounts of cortisol ameliorates the dexamethasone-induced psychological side effects. In the present report, we discuss the mechanistic underpinning of the MR refill concept in glucocorticoid therapy.

Cushing’s disease, pseudo-Cushing states and the dexamethasone test: a historical and critical review

The dexamethasone (DXM) test has been widely used for diagnosing Cushing's disease (CD). The purpose of this paper is to review its diagnostic merit based on calculation of data extracted from earlier publications. Studies presenting individual values for patients with CD and normal subjects were identified through PubMed searches and references in pertinent studies. Calculation of the retrieved data demonstrated huge variation in the relative suppressibility, negative suppression being common. Furthermore, in almost each study retrieved, the pre and post DXM values were closely correlated. Finally, the generally accepted view that DXM causes less suppression in Cushing's disease than in euadrenal controls appears unfounded. A central issue in the definition of so-called "pseudo-Cushing's states" is failure to suppress cortisol secretion with DXM. From analysis of the literature it appears quite possible that this does not reflect a specific endocrine deficit, but a physiological "stress" reaction. The above issues question the diagnostic value of the test, in particular in clinically and biochemically borderline cases.

Cortisol-mediated downregulation of the serotonin 1A receptor subtype in the Gulf toadfish, Opsanus beta

In both mammals and teleost fish, serotonin stimulates cortisol secretion via the 5-HT1A receptor. Additionally, a negative feedback loop exists in mammals whereby increased circulating levels of cortisol inhibit 5-HT1A receptor activity. To investigate the possibility of such a feedback mechanism in teleosts, plasma cortisol levels and signaling in Gulf toadfish (Opsanus beta) were manipulated and the role of cortisol in the control of 5-HT1A evaluated. Despite a significant 4-fold increase in plasma [cortisol], crowded toadfish expressed similar amounts of 5-HT1A mRNA transcript as uncrowded toadfish; whereas, cortisol-implanted fish possessed 41.8% less 5-HT1A mRNA transcript compared to vehicle-implanted controls. This cortisol effect appeared to be reversed in RU486-injected fish, which blocks glucocorticoid receptors, as these fish expressed nearly twice as much 5-HT1A receptor transcript as the vehicle-injected fish despite significantly elevated cortisol levels. The binding affinity for the 5-HT1A receptor in the brain did not vary between any groups; however, maximum binding was significantly higher in uncrowded toadfish compared to crowded, and the same significant difference was observed between the maximum binding of vehicle and cortisol-implanted fish. The opposite trend was seen in RU486-injected and vehicle-injected fish, with RU486-injected fish having significantly higher maximal binding compared to vehicle-injected controls. Injection with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin revealed an inhibition of cortisol secretion that was independent of 5-HT1A transcript and protein binding. These results suggest that cortisol plays a role in regulating the 5-HT1A receptor via GR-mediated pathways; however, further study is necessary to elucidate how and where this inhibition is mediated.

A phenomenological model for circadian and sleep allostatic modulation of plasma cortisol concentration

Both circadian rhythmicity and sleep play significant roles in the regulation of plasma cortisol concentration by the hypothalamo-pituitary-adrenal (HPA) axis. Numerous studies have found links between sleep and changes in cortisol concentration, but the implications of these results have remained largely qualitative. In this article, we present a quantitative phenomenological model to describe the effects of different sleep durations on cortisol concentration. We constructed the proposed model by incorporating the circadian and sleep allostatic effects on cortisol concentration, the pulsatile nature of cortisol secretion, and cortisol's negative autoregulation of its own production and validated its performance on three study groups that experienced four distinct sleep durations. The model captured many disparate effects of sleep on cortisol dynamics, such as the inhibition of cortisol secretion after the wake-to-sleep transition and the rapid rise of cortisol concentration before morning awakening. Notably, the model reconciled the seemingly contradictory findings between studies that report an increase in cortisol concentration following total sleep deprivation and studies that report no change in concentration. This work provides a biomathematical approach to combine the results on the effects of sleep on cortisol concentration into a unified framework and predict the impact of varying sleep durations on the cortisol profile.

Acute administration of alprazolam, a benzodiazepine activating GABA receptors, inhibits cortisol secretion in patients with subclinical but not overt Cushing’s syndrome

The purpose of this study is to verify whether acute pre-treatment with alprazolam (ALP), a benzodiazepine that inhibits HPA secretion in normal subjects, could better characterize patients with subclinical Cushing's syndrome (SCS) than the 1-mg dexamethasone test (DST). In 22 patients with SCS, 10 with overt Cushing's syndrome (CS), 11 with non-functioning adrenal incidentalomas (NF) and 14 normal subjects (NS) we studied the effect of ALP (1 mg, p.o. at 2300 hours) on cortisol levels after 1-mg DST. Cortisol levels (mean ± SEM) after DST were lower (P = 0.012) in SCS (3.9 ± 0.3 μg/dl) than in overt CS (10.4 ± 1.9 μg/dl), while they were higher (P = 0.0005) than in NF (1.1 ± 0.1 μg/dl) and NS (1.5 ± 0.1 μg/dl). After ALP pre-treatment, cortisol levels further decreased (P = 0.004) in SCS (3.0 ± 0.3 μg/dl), but neither in CS (9.3 ± 1.3 μg/dl) nor in NF (1.3 ± 0.1 μg/dl) and in NS (1.3 ± 0.1 μg/dl). In SCS, cortisol levels after ALP + 1-mg DST persisted lower (P = 0.0005) than those in CS, but higher (P = 0.0005) than those in NF and NS. Considering individual cases, ALP pre-treatment reduced cortisol levels < 3 and < 1.8 μg/dl in 50 and 23 % of SCS patients, respectively. ALP amplifies the cortisol inhibition exerted by 1-mg DST in patients with SCS but not in those with CS. The clinical usefulness of ALP to increase the sensitivity of 1-mg DST to identify true autonomous cortisol release in patients with adrenal incidentalomas as well as to predict different clinical outcomes remains to be clarified.

Pituitary-directed medical therapy with pasireotide for a corticotroph macroadenoma: pituitary volume reduction and literature review

Hypercortisolism due to an ACTH-secreting pituitary adenoma (Cushing's disease) is a chronic condition associated with high morbidity and mortality if inadequately managed. Pasireotide is a multireceptor-targeted somatostatin analogue and is the only approved medical therapy for Cushing's disease that treats the underlying cause of the disorder. This paper reviews the available literature for medical-therapy-induced adenoma volume reduction in patients with Cushing's disease and reports the experience of a 53-year-old surgically, radiologically and medically naïve (de novo) female with a pituitary macroadenoma who declined surgery. This patient was treated with pasireotide as first-line therapy as part of the largest randomized Phase III study evaluating a medical therapy in patients with Cushing's disease (SOM230B2305 trial). Subcutaneous pasireotide significantly decreased tumor volume, suppressed cortisol secretion, and improved clinical signs and symptoms of Cushing's disease in this patient. Based on this experience, first-line pasireotide has the potential to achieve substantial tumor volume reduction in addition to significant improvements in cortisol levels and signs and symptoms in patients with Cushing's disease for whom surgery is not an option.

Are oestrogen receptors and protein tyrosine kinases involved in phytoestrogen-modulated steroid secretion by porcine adrenocortical cells?

The phytoestrogens genistein and daidzein had been found to affect the function of some tissues via oestrogen receptors (ER). In addition, genistein, but not daidzein, is considered to be a protein tyrosine kinase (PTK) inhibitor. Thus, the involvement of oestrogen receptors and PTK in phytoestrogen action on adrenocortical porcine steroidogenesis was examined in this study. The aims of the experiment were to test the effects of (i) ICI 182, 780 (ICI), an ER antagonist, on genistein- and daidzein-modulated cortisol and androstenedione (A4) secretion by adrenocortical cells isolated during the luteal and follicular phases of the porcine oestrous cycle; (ii) tyrphostin AG 957 (TAG), a nonsteroidal PTK inhibitor, on cortisol and A4 secretion by the cells and (iii) the phase of the porcine oestrous cycle on the mechanism of phytoestrogen action. Adrenals were harvested during the luteal (n = 5 animals) and follicular (n = 5 animals) phases of the oestrous cycle from locally slaughtered crossbred gilts. The isolated adrenocortical cells were incubated for 8 h (37 °C, 95% air, 5% CO2) with genistein (5 or 10 μM) or daidzein (5 or 10 μM) in the presence or absence of ICI (0.5 μM) or TAG (5 or 10 μM). Genistein and daidzein inhibited cortisol secretion and stimulated A4 secretion by porcine adrenocortical cells harvested during both the luteal and follicular phases of the oestrous cycle. The ER antagonist ICI did not eliminate phytoestrogen-induced changes in steroidogenesis. In contrast to genistein, TAG reduced the secretion of A4 and did not affect cortisol secretion. There was no observable effect due to the phase of the cycle. It is suggested that the mechanism of genistein and daidzein action in the adrenocortical cells of pigs is independent of ER and PTK. It is possible that PTK are involved in A4 secretion by porcine adrenocortical cells.

The Effect of Modified-Release Ketoconazole on Insulin Resistance in Patients with Severe Metabolic Syndrome

Introduction: The association between metabolic syndrome and cortisol levels has previously been discussed and recent studies have also shown that down-regulation of cortisol improves metabolic and circulatory risk factors in obese patients with the metabolic syndrome. Aim: The primary objectives were to establish the effect of modified-release formulation of ketoconazole, a substance known to inhibit cortisol secretion, on insulin resistance and to establish a suitable dose for further investigation. The secondary objectives were to confirm improvement in other parameters related to metabolic syndrome such as HbA1c, blood pressure, liver enzymes, serum lipids, fasting blood glucose, and 24-hour urinary microalbuminuria. Method: Seventy-two overweight and viscerally obese male and female patients aged 18 to 75 year were included in a randomized, double-blind, placebo-controlled, 3-month study, with a 4 weeks safety follow-up period. They were randomized to receive 200 mg and 400 mg of the modified-release formulation of ketoconazole and placebo with 24 patients in each group. Entry criteria included a diagnosis of type 2 diabetes for at least one year prior to study entry, HbA1c levels ≥ 6.7%, fasting plasma insulin ≥ 15mU/L (ref: ≤ 10mU/L), visceral obesity withwaist to hip ratio of ≥ 0.93 for males and ≥ 0.88 for females, and the presence or history of two or more of the following: hypertension, dyslipidemia and microalbuminuria. Results: Administration of 400mg of the modified-release formulation of ketoconazole improved HbA1c levels, fasting blood glucose and total cholesterol compared to placebo with less consistent effects at 200mg of the modified-release formulation of ketoconazole. Additionally, reductions in systolic and diastolic blood pressure were found, and the study showed reductions in urinary microalbuminuria. Urinary cortisol decreased without signs of cortisol deficiency as measured with the standardized ACTH test. We found small mean increases from baseline in glucose disposal rate (GDR). Conclusion: This study with modified-release ketoconazole, showed improvements in several parameters of the metabolic syndrome, but did not meet the primary efficacy endpoint of improvement in insulin resistance most likely due to the short study period.

Perioperative management of high risk ACTH-independent macronodular adrenal hyperplasia: Report of one case

Objective To improve the diagnosis and treatment of ACTH-independent macronodular adrenal hyperplasia(AIMAH).Methods A 51-year-old female patient with Cushing's syndrome caused by AIMAH was reported.Elevated early morning plasma cortisol levels,increased 24 h urinary free cortisol excretion,and loss of the normal circadian rhythm in cortisol secretion were presented.There was no suppression of cortisol secretion by administration of low-and high-dose overnight dexamethasone suppression test.Cardio-pulmonary function was very bad with the highest blood pressure reaching 300/120 mm Hg( 1 mm Hg=0.133 kPa).Initially,she was treated with mitotane(60 mg/d),but was not effective.After taking ketoconazole (800 mg/d)for 5 days,cardio-pulmonary function was not effectively improved with blood pressure only descending to 180/120 mm Hg.Orthopnoea appeared and Spo2fell once to 75％.The patient had to undergo right total adrenalectomy immediately.Results The mass resected was 10 cm× 10 cm in size and weighted 67.5 g.Histological examination of the removed adrenal revealed nonpigmented macronodular cortical hyperplasia.The patient continued to take ketoconazole (400-800 mg/d)from the 6th day of the operation without steroid replacement therapy in that period.With normal cortisol levels( plasma cortisol at 8:00 was 18.65 μg/dl,24 h urinary free cortisol was 78.75 μmol),she left hospital after the general condition had been improved.During the following updated 10 months follow up,the indexes of her laboratory examination were maintained normal.Conclusion Individualized therapy should be adopted for the patient with AIMAH.The medication is useful to suppress the adrenal gland cortisol production for those with progression of symptoms,very high blood pressure,hypokalemia and hypoproteinemia.Once the cardio-pulmonary function improves,the target organ should be resected as soon as possible.The supplement of cortisol is not appropriate during the perioperative period.The unilateral adrenalectomy is an effective treatment for AIMAH. Key words: ACTH-independent macronodular adrenal hyperplasia; Surgery; Ketoconazole; Plasma cortisol

ACTH-independent macronodular adrenal hyperplasia: report of 12 cases

Objective To explore the diagnosis and treatment of adrenocorticotropin-independent macronodular adrenal hyperplasia (AIMAH). Methods The clinical symptoms, endocrinological and radiological characteristics, treatment modalities, and postoperative clinical course of 12 AIMAH patients were retrospectively reviewed. There were 5 men and 7 women with an average age of 48 years old. Results All cases had some clinical features and biochemical evidence of Cushing's syndrome. The circadian rhythm of serum cortisol was abnormal. Low- and high-dose dexamethasone suppression tests failed to suppress cortisol secretion. CT or MRI scan showed bilateral enlargement of the adrenal glands with multiple macronodules. Bilateral adrenalectomy was performed in three patients and unilateral adrenalectomy combined with contralateral subtotal adrenalectomy was performed in one patient. Seven patients underwent unilateral adrenalectomy of the larger gland. The removed adrenal glands weighted within 8-96 g range and pathologic diagnoses were nodular or adenomatoid hyperplasia of adrenal cortex. The duration of postoperative follow-up was 14 to 124 months. Clinical symptoms of Cushing's syndrome disappeared after surgery in all cases and there was no Nelson's syndrome after bilateral adrenalectomy. Urinary free cortisol and serum cortisol were within normal ranges. No further enlargement of the contralateral gland has been noticed in patients who received unilateral adrenalectomy during the follow-up.Conclusions AIMAH had unique endocrinological and pathological features. Unilateral adrenalectomy appears to be an effective and safe alternative treatment for AIMAH. Bilateral adrenalectomy or unilateral adrenalectomy combined with contralateral subtotal adrenalectomy may be performed if the symptoms had not been improved or recurred after unilateral adrenalectomy. Key words: Cushing's syndrome; Corticotropin; Macronodular adrenal hyperplasia

Long-term Efficacy of Trilostane for Cushing's Syndrome due to Adrenocorticotropin-Independent Bilateral Macronodular Adrenocortical Hyperplasia

A 66-year-old man with Cushing's syndrome due to adrenocorticotropin-independent bilateral macronodular adrenocortical hyperplasia (AIMAH) was treated for 7 years with trilostane, a 3β-hydroxysteroid dehydrogenase inhibitor. Administration of trilostane reduced the serum cortisol level to around the upper limit of normal for 7 years, and symptoms of excessive glucocorticoid production (such as moon face and obesity) were gradually improved. On the other hand, the size of both adrenal glands gradually increased despite treatment with trilostane. Though trilostane therapy could not prevent adrenal growth, it did suppress cortisol secretion over the long term, so it might be a reasonable option for AIMAH in addition to adrenalectomy.