Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Patients With Cushing Syndrome, Does Not Cause Prolongation of the Cardiac QT Interval.

OBJECTIVE: To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate-corrected QT interval (QTc). METHODS: Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling. RESULTS: Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc. CONCLUSION: At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.

Mass spectrometry-based steroid profiling in primary bilateral macronodular adrenocortical hyperplasia.

Biochemical characterization of primary bilateral macronodular adrenocortical hyperplasia (PBMAH) by distinct plasma steroid profiles and its putative correlation to disease has not been previously studied. LC-MS/MS-based steroid profiling of 16 plasma steroids was applied to 36 subjects (22 females, 14 males) with PBMAH, 19 subjects (16 females, 3 males) with other forms of adrenal Cushing's syndrome (ACS), and an age and sex-matched control group. Germline ARMC5 sequencing was performed in all PBMAH cases. Compared to controls, PBMAH showed increased plasma 11-deoxycortisol, corticosterone, 11-deoxycorticosterone, 18-hydroxycortisol, and aldosterone, but lower progesterone, DHEA, and DHEA-S with distinct differences in subjects with and without pathogenic variants in ARMC5. Steroids that showed isolated differences included cortisol and 18-oxocortisol with higher (P < 0.05) concentrations in ACS than in controls and aldosterone with higher concentrations in PBMAH when compared to controls. Larger differences in PBMAH than with ACS were most clear for corticosterone, but there were also trends in this direction for 18-hydroxycortisol and aldosterone. Logistic regression analysis indicated four steroids - DHEA, 11-deoxycortisol, 18-oxocortisol, and corticosterone - with the most power for distinguishing the groups. Discriminant analyses with step-wise variable selection indicated correct classification of 95.2% of all subjects of the four groups using a panel of nine steroids; correct classification of subjects with and without germline variants in ARMC5 was achieved in 91.7% of subjects with PBMAH. Subjects with PBMAH show distinctive plasma steroid profiles that may offer a supplementary single-test alternative for screening purposes.

[Nutrition of horses with equine pituitary pars intermedia dysfunction ("Cushing's syndrome") treated with pergolid - A field study]. / Ernährung von Pferden mit Equine Pituitary Pars Interme dia Dysfunction ("Cushing-Syndrom") unter Pergolidtherapie.

OBJECTIVE AND AIM: The nutritional status of 36 patients with equine pituitary pars intermedia dysfunction (PPID) under pergolide treatment was investigated. ANIMALS, MATERIALS AND METHODS: The body condi tion score (BCS) and feeding were determined at the beginning of the study and after 60 and 120 days. Sampled blood for control of pergolid therapy were used for insulin and glucose measurement. A standardized questionnaire regarding the symptoms of the disease, including hypertrichosis and weight change, was completed by the owners. RESULTS: The mean BCS (scale of 1 = cachexia to 9 = grossly obese) was 3.1 ± 0.8 (large horses 2.7 ± 0.8, ponies 3.5 ± 0.8). The mean energy requirement of the large horses was estimated to be 74 ± 10 MJ of metabolizable energy, but the intake amounted only to 65 ± 15 MJ. There was a significant correlation between the BCS and the estimated energy intake in percent of requirements in the large horses. The energy requirements of the ponies were generally met. The patients were fed a mean of 2.0 ± 0.7 meals of roughage per day (total roughage intake per day 0.2-2.1 kg/100 kg body weight) and a maximum of one meal of concentrates. Sixteen ponies and one large horse did not receive any concentrates, whereas five ponies and 14 horses were fed concentrates (mean amount for ponies 0.15 kg and for large horses 0.8 kg). The requirements for zinc, copper, selenium and vitamins A and E were not met in the majority of patients. Blood glucose levels were within the reference range in all samples, but insulin levels were elevated in seven animals at least at one sampling point. The serious underweight of some of the patients was not recognized as a problem by some of the owners. CONCLUSION AND PRACTICAL RELEVANCE: Owners of PPID patients need more guidance on body condition scoring, amount of feed, number of meals, and logistics of feeding to avoid malnutrition of their animals.

Effects of RXR Agonists on Cell Proliferation/Apoptosis and ACTH Secretion/Pomc Expression.

Various retinoid X receptor (RXR) agonists have recently been developed, and some of them have shown anti-tumor effects both in vivo and in vitro. However, there has been no report showing the effects of RXR agonists on Cushing's disease, which is caused by excessive ACTH secretion in a corticotroph tumor of the pituitary gland. Therefore, we examined the effects of synthetic RXR pan-agonists HX630 and PA024 on the proliferation, apoptosis, ACTH secretion, and pro-opiomelanocortin (Pomc) gene expression of murine pituitary corticotroph tumor AtT20 cells. We demonstrated that both RXR agonists induced apoptosis dose-dependently in AtT20 cells, and inhibited their proliferation at their higher doses. Microarray analysis identified a significant gene network associated with caspase 3 induced by high dose HX630. On the other hand, HX630, but not PA024, inhibited Pomc transcription, Pomc mRNA expression, and ACTH secretion dose-dependently. Furthermore, we provide new evidence that HX630 negatively regulates the Pomc promoter activity at the transcriptional level due to the suppression of the transcription factor Nur77 and Nurr1 mRNA expression and the reduction of Nur77/Nurr1 heterodimer recruiting to the Pomc promoter region. We also demonstrated that the HX630-mediated suppression of the Pomc gene expression was exerted via RXRα. Furthermore, HX630 inhibited tumor growth and decreased Pomc mRNA expression in corticotroph tumor cells in female nude mice in vivo. Thus, these results indicate that RXR agonists, especially HX630, could be a new therapeutic candidate for Cushing's disease.

Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing's syndrome.

CONTEXT: Mitotane is highly effective in the long-term management of Cushing's syndrome but has a slow onset of action. Mitotane combined with fast-acting steroidogenesis inhibitors might avoid the need for emergency bilateral adrenalectomy in patients with severe hypercortisolism. OBJECTIVE: Our objective was to assess the efficacy and safety of combination therapy with mitotane, metyrapone, and ketoconazole in severe ACTH-dependent Cushing's syndrome. PATIENTS, DESIGN, AND SETTING: Eleven patients with severe Cushing's syndrome participated in this follow-up study in a tertiary referral hospital. INTERVENTIONS: High-dose therapy combining mitotane (3.0-5.0 g/24 h), metyrapone (3.0-4.5 g/24 h), and ketoconazole (400-1200 mg/24 h) was initiated concomitantly. Twenty-four-hour urinary free cortisol (UFC) excretion (normal values 10-65 µg/24 h) was monitored. RESULTS: Data are reported as medians (range). All 11 patients experienced a marked clinical improvement. UFC excretion fell rapidly from 2737 µg/24 h (range 853-22,605) at baseline to 50 µg/24 h (range 18-298) (P = 0.001) within 24-48 h of treatment initiation and remained low to normal on the combination therapy. In seven patients, metyrapone and ketoconazole were discontinued after 3.5 months (range 3.0-6.0) of combination therapy, and UFC excretion remained controlled by mitotane monotherapy (UFC 17 µg/24 h, range 5-85; P = 0.016). Five patients became able to undergo etiological surgery and are presently in remission. Four of them recovered normal adrenal function after mitotane discontinuation. Adverse effects were tolerable, consisting mainly of gastrointestinal discomfort and a significant rise in total cholesterol and γ-glutamyl transferase levels (P = 0.012 and P = 0.002, respectively). CONCLUSIONS: When surgical treatment for severe ACTH-dependent Cushing's syndrome is not feasible, combination therapy with mitotane, metyrapone, and ketoconazole is an effective alternative to bilateral adrenalectomy, a procedure associated with significant morbidity and permanent hypoadrenalism.

Preventive action of Panax ginseng roots in hypercortisolism-induced Impairment of hippocampal neurons in male C57BL/6N mice.

An increasing number of people suffering from hypercortisolism are at risk of developing hippocampus impairment and mental disorders. The aim of this study was to investigate whether the water extract of Panax ginseng roots (GWE) could prevent hypercortisolism-induced adverse consequences. Hypercortisolism was experimentally induced by repeated corticosterone injection in male mice. Treatment with corticosterone alone resulted in a significant decrease in hippocampus neurofilament light chain (NF-L) protein expression and induced depression-like behavior. Serum corticosterone was significantly increased in the corticosterone-treated mice. Treatment with GWE (800 and 400 mg/kg) during corticosterone treatment reduced or partially antagonized the effects induced by corticosterone toward the normal values of the controls; however, it failed to normalize increased corticosterone levels in corticosterone-treated mice. Overall, ginseng conclusively exhibited a protective action against hypercortisolism-induced impairment of hippocampal neurons.

Resistant hypertension in an aged woman presenting with clinical features simulating ectopic ACTH syndrome--response to spironolactone--.

A 91-year-old depressed woman had resistant hypertension despite a triple combination of anti-hypertensives, including a Ca-antagonist, an angiotensin receptor blocker, and a thiazide diuretic at optimal doses. She had hypokalemic metabolic alkalosis, elevated plasma cortisol and ACTH, and elevated urinary cortisol. The high-dose dexamethasone did not suppress the elevated ACTH and cortisol. The addition of spironolactone to her previous medications controlled and normalized hypertension, hypokalemia, and hormonal abnormalities within 4 months. Her blood pressure, serum electrolytes, and the hormonal states remained normalized for more than a year thereafter. Her depressed mental state also improved after spironolactone.

Pasireotide for the treatment of Cushing's disease.

IMPORTANCE OF THE FIELD: It is important to treat patients with Cushing's disease as rapidly as possible to limit both the mortality and morbidity of the disease. Pituitary surgery remains the treatment of choice, but the rate of cure at long-term follow-up is suboptimal and recurrence rates are high. If surgery fails or relapse occurs, no treatment has proven to be fully satisfactory. Currently available medical therapies are considered a transient and palliative treatment. However, recently there has been renewed interest in medical therapy due to new insights in pathogenetic mechanisms of corticotroph pituitary tumors. AREAS COVERED IN THIS REVIEW: We summarize the pharmacodynamics and possible mechanism of action of pasireotide (SOM230), a novel multireceptor-targeted somatostatin analogue. Pasireotide has a unique binding profile, with high affinity for four of the five somatostatin receptors, especially SSTR(5), the receptor most prevalent in corticotroph tumors. WHAT THE READER WILL GAIN: The reader should gain an understanding of preclinical and clinical data supporting the potential use of pasireotide in patients with Cushing's disease. TAKE HOME MESSAGE: Preliminary data suggest that pasireotide shows promise as a tumor-targeted medical therapy in patients with Cushing's disease. If the efficacy of pasireotide is confirmed by larger studies, this compound may be a useful treatment option not only in patients with severe Cushing's disease, but also in patients with mild hypercortisolism where its efficacy might be more evident.

A case of human intramuscular adrenal gland transplantation as a cure for chronic adrenal insufficiency.

Intramuscular endocrine gland transplantation has been well described as it pertains to parathyroid autotransplantation; however, transplantation of the adrenal gland is less well characterized. While adrenal autotransplantation in the setting of Cushing's disease has been described, intramuscular adrenal allotransplantation as a cure for adrenal insufficiency to our knowledge has not been previously carried out. Current treatment for adrenal insufficiency leaves patients without diurnal variation in cortisol release and susceptible to the detrimental effects of chronic hypercortisolism. We describe here the case of a 5-year-old girl with renal failure who had adrenal insufficiency following fulminant meningococcemia that led to requirements for both stress-dose steroid and mineralocorticoid replacement. Ten months after the onset of her disease, she received a simultaneous renal and adrenal gland transplant from her mother. The adrenal gland allograft was morselized into 1 mm(3) segments and implanted into three 2 cm pockets created in her rectus abdominis muscle. Three years after surgery, her allograft remains fully functional, responding well to adrenocorticotropin hormone stimulation and the patient does not require any steroid or mineral-corticoid supplementation. We believe this case represents the first description of successful functional intramuscular adrenal allograft transplantation with long-term follow up as a cure for adrenal insufficiency.

Weekly clodronate treatment prevents bone loss and vertebral fractures in women with subclinical Cushing's syndrome.

INTRODUCTION: Chronic mild endogenous glucocorticoid excess has been shown to cause bone loss and to increase fracture risk in both post-menopausal and premenopausal women. Currently, it is unclear if patients with subclinical Cushing's syndrome (SCS) with osteoporosis or osteopenia may benefit from antiresorptive treatment and the type of therapy to be given. OBJECTIVE: This pilot randomized study was aimed at evaluating the effects of 12-month im administration of clodronate (100 mg every week) on vertebral and femoral bone mineral density (BMD), bone turnover markers and on subjective pain in premenopausal women with SCS due to adrenal incidentalomas. METHODS: Forty-six women (age, 43.1+/-7.7 yr) with SCS due to adrenal incidentaloma and osteoporosis/osteopenia were randomized to receive clodronate plus supplement of Calcium (500 mg daily) and Vitamin D3 (800 mg daily) (group 1, no.=23) or supplements only (group 2, no.=23). Both groups were similar in terms of age, body mass index, cortisol levels, BMD values, and bone turnover markers. All of the women were re-evaluated after 12 months. RESULTS: After 12 months of treatment, in group 1, a significant increase in lumbar BMD occurred (p=0.04), while bone turnover markers decreased by about one third (p<0.05). In group 2, bone turnover markers did not change and BMD values slightly decreased (p=ns). The differences in bone turnover markers and in lumbar BMD between the two groups were significant (p<0.05, all). No new vertebral fracture occurred in group 1, while in group 2 the spine radiographies revealed 2 new fractures and a worsening of two pre-existent fractures. An improvement in subjective back pain, assessed by visual analogue scale pain score was observed in group 1 (from 4.3+/-2.7 to 2.9+/-2.0; p<0.05) but not in group 2 (from 4.4+/-3.1 to 4.2+/-3.4; p=ns). No significant changes occurred in cortisol secretion or clinical picture of the SCS during the study. CONCLUSIONS: Intramuscular administration of clodronate effectively increased lumbar BMD values, preserved bone mass at the femoral neck, stabilized vertebral fracture index, and decreased subjective back pain in pre-menopausal women with SCS. Since the untreated group continued to lose bone, antiresorptive treatment should be considered in patients with SCS, according to the prevision of surgical treatment, prevalent fractures, BMD values, age, concomitant morbidities, and desire for pregnancy.

Mineralocorticoid effects due to cortisol inactivation overload explain the beneficial use of hydrocortisone in septic shock.

The role of corticosteroids in septic shock remains controversial despite their use for over 50 years. Large prospective trials of their use continue with the aim of resolving the controversy. These may well remain indecisive if basic endocrine principles are ignored. Review of the available evidence suggests that use of synthetic glucocorticoids is harmful but hydrocortisone beneficial. Consideration of the basic properties of the corticosteroids used and their receptors suggest an explanation for their differing therapeutic effects. The harmful synthetic glucocorticoids have no or reduced mineralocorticoid effects in contrast with the significant mineralocorticoid effects of hydrocortisone at the doses which have been found to be beneficial. The potent synthetic mineralocorticoid fludrocortisone is well recognised to raise peripheral resistance by sensitising the resistance vessels to endogenous or exogenous catecholamines and also causes metabolic alkalosis. We provide evidence to support our hypothesis that at the doses of hydrocortisone used, cortisol inactivation overload is the basis of the beneficial effect. The consequent mineralocorticoid effects result in increased sensitivity of the resistance vessels to endogenous and exogenous catecholamines with an increase in peripheral resistance correcting shock. In addition the metabolic alkalotic component of mineralocorticoid effect would tend to correct the prevailing metabolic acidosis. Hydrocortisone also has an attenuating, as opposed to the suppressing effect of synthetic glucocorticoids on the immune response which is also regarded as beneficial.

Ketoconazole therapy: an efficacious alternative to achieve eucortisolism in patients with Cushing's syndrome.

Cushing's syndrome (CS) is a serious condition requiring drug management in diverse clinical settings. Fifty four patients (44 females, 10 males) with CS, aged 14-63, received ketoconazole (KTZ) prior to surgery (n= 27), as complementary therapy after surgery and/or radiotherapy (n= 16), or as primary treatment (n= 11). It was given at a 600 (500 - 600) mg/day (median - Cl195) maintenance dose for periods ranging from 15 days to 13 years. Clinical signs, hepatic enzymes and urinary free cortisol (UFC) were evaluated before and during KTZ treatment. UFC normalised or decreased to subnormal values in 85% of the patients, in 5 to 150 days after starting treatment; although failing to normalise, UFC decreased to 12-48% of pre-treatment values in the remaining patients. Clinical signs improved throughout. Side effects were adrenal insufficiency (18.5%), reversible hepatic toxicity (11%), allergic skin rash (5.5%) and gastric intolerance (3.7%); in 11% of patients, an "escape phenomenon" was observed. Twenty-four out of the total (44.4%) were treated for prolonged periods, from one up to 13 years. In conclusion, this study confirms that KTZ is an effective and generally well tolerated treatment for CS particularly: a) shortly before surgery, b) because of persistent hypercortisolism after surgery or awaiting the results of radiotherapy, c) as a reasonable option in patients with CS of unknown aetiology and, d) as long-term therapy in any case of unsolved hypercortisolism after failure of current treatments.

Ketoconazole therapy: an efficacious alternative to achieve eucortisolism in patients with Cushing's syndrome

El síndrome de Cushing (SC) es un trastorno grave que requiere frecuentemente tratamiento medicamentoso. Cincuenta y cuatro pacientes (44 mujeres, 10 varones) de 14-63 años de edad con SC, recibieron ketoconazol (KTZ) previo a cirugía (n=27), como complemento luego de cirugía y/o radioterapia (n=16), o como tratamiento primario (n=11). La dosis de mantenimiento fue de 600 (500 - 600) mg/día (mediana-IC95) durante 15 días a 13 años. Los signos clínicos, hepatograma y cortisol libre urinario (CLU) fueron evaluados antes y durante tratamiento con KNZ. El CLU cayó a valores normales o subnormales en 85% de los pacientes, 5 a 150 días luego de iniciar el tratamiento; aún sin normalizar, el CLU disminuyó a 12-48% de los valores pre-tratamiento en el resto de los pacientes acompañándose de mejoría de los signos clínicos. Los efectos colaterales fueron: insuficiencia adrenal (18.5%), toxicidad hepática reversible (11%), "rash" cutáneo (5.5%) e intolerancia gástrica (3.7%); en 11% de los pacientes se observó un fenómeno de "escape". Veinticuatro pacientes (44.4%) fueron tratados por períodos prolongados, de uno a trece años. Este estudio confirma que el KTZ constituye un tratamiento eficaz y generalmente bien tolerado del SC, en particular: a) como preparación para cirugía b) en casos de hipercortisolismo residual luego de cirugía o en espera de resultados de radioterapia, c) como una alternativa razonable en pacientes con SC de origen desconocido y, d) como tratamiento crónico en casos de hipercortisolismo no resuelto luego de fracaso de las terapéuticas habituales.

Cushing's syndrome (CS) is a serious condition requiring drug management in diverse clinical settings. Fifty four patients (44 females, 10 males) with CS, aged 14-63, received ketoconazole (KTZ) prior to surgery (n= 27), as complementary therapy after surgery and/or radiotherapy (n= 16), or as primary treatment (n= 11). It was given at a 600 (500 - 600) mg/day (median - CI95) maintenance dose for periods ranging from 15 days to 13 years. Clinical signs, hepatic enzymes and urinary free cortisol (UFC) were evaluated before and during KTZ treatment. UFC normalised or decreased to subnormal values in 85% of the patients, in 5 to 150 days after starting treatment; although failing to normalise, UFC decreased to 12-48% of pre-treatment values in the remaining patients. Clinical signs improved throughout. Side effects were adrenal insufficiency (18.5%), reversible hepatic toxicity (11%), allergic skin rash (5.5%) and gastric intolerance (3.7%); in 11% of patients, an "escape phenomenon" was observed. Twenty-four out of the total (44.4%) were treated for prolonged periods, from one up to 13 years. In conclusion, this study confirms that KTZ is an effective and generally well tolerated treatment for CS particularly: a) shortly before surgery, b) because of persistent hypercortisolism after surgery or awaiting the results of radiotherapy, c) as a reasonable option in patients with CS of unknown aetiology and, d) as long-term therapy in any case of unsolved hypercortisolism after failure of current treatments.

Ketoconazole therapy: an efficacious alternative to achieve eucortisolism in patients with Cushings syndrome

El síndrome de Cushing (SC) es un trastorno grave que requiere frecuentemente tratamiento medicamentoso. Cincuenta y cuatro pacientes (44 mujeres, 10 varones) de 14-63 años de edad con SC, recibieron ketoconazol (KTZ) previo a cirugía (n=27), como complemento luego de cirugía y/o radioterapia (n=16), o como tratamiento primario (n=11). La dosis de mantenimiento fue de 600 (500 - 600) mg/día (mediana-IC95) durante 15 días a 13 años. Los signos clínicos, hepatograma y cortisol libre urinario (CLU) fueron evaluados antes y durante tratamiento con KNZ. El CLU cayó a valores normales o subnormales en 85% de los pacientes, 5 a 150 días luego de iniciar el tratamiento; aún sin normalizar, el CLU disminuyó a 12-48% de los valores pre-tratamiento en el resto de los pacientes acompañándose de mejoría de los signos clínicos. Los efectos colaterales fueron: insuficiencia adrenal (18.5%), toxicidad hepática reversible (11%), "rash" cutáneo (5.5%) e intolerancia gástrica (3.7%); en 11% de los pacientes se observó un fenómeno de "escape". Veinticuatro pacientes (44.4%) fueron tratados por períodos prolongados, de uno a trece años. Este estudio confirma que el KTZ constituye un tratamiento eficaz y generalmente bien tolerado del SC, en particular: a) como preparación para cirugía b) en casos de hipercortisolismo residual luego de cirugía o en espera de resultados de radioterapia, c) como una alternativa razonable en pacientes con SC de origen desconocido y, d) como tratamiento crónico en casos de hipercortisolismo no resuelto luego de fracaso de las terapéuticas habituales.(AU)

Cushings syndrome (CS) is a serious condition requiring drug management in diverse clinical settings. Fifty four patients (44 females, 10 males) with CS, aged 14-63, received ketoconazole (KTZ) prior to surgery (n= 27), as complementary therapy after surgery and/or radiotherapy (n= 16), or as primary treatment (n= 11). It was given at a 600 (500 - 600) mg/day (median - CI95) maintenance dose for periods ranging from 15 days to 13 years. Clinical signs, hepatic enzymes and urinary free cortisol (UFC) were evaluated before and during KTZ treatment. UFC normalised or decreased to subnormal values in 85% of the patients, in 5 to 150 days after starting treatment; although failing to normalise, UFC decreased to 12-48% of pre-treatment values in the remaining patients. Clinical signs improved throughout. Side effects were adrenal insufficiency (18.5%), reversible hepatic toxicity (11%), allergic skin rash (5.5%) and gastric intolerance (3.7%); in 11% of patients, an "escape phenomenon" was observed. Twenty-four out of the total (44.4%) were treated for prolonged periods, from one up to 13 years. In conclusion, this study confirms that KTZ is an effective and generally well tolerated treatment for CS particularly: a) shortly before surgery, b) because of persistent hypercortisolism after surgery or awaiting the results of radiotherapy, c) as a reasonable option in patients with CS of unknown aetiology and, d) as long-term therapy in any case of unsolved hypercortisolism after failure of current treatments.(AU)

Development of test systems for the discovery of selective human aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1) inhibitors. Discovery of a new lead compound for the therapy of congestive heart failure, myocardial fibrosis and hypertension.

Two key players in adrenal steroid hormone biosynthesis are the human mitochondrial cytochrome P450 enzymes CYP11B1 and CYP11B2 that catalyze the final steps in the biosynthesis of cortisol and aldosterone, respectively. Overproduction of both hormones contributes to a number of severe diseases, as illustrated by the association of elevated aldosterone levels with hypertension and higher mortality in congestive heart failure, and by Cushing's syndrome as the clinical correlate of chronic hypercortisolism. Thus, CYP11B1 and CYP11B2 comprise new targets for drug treatment and selective inhibitors of both enzymes are of high pharmacological interest. To facilitate the search for such compounds, we have established novel test procedures using recombinant fission yeast strains that stably express these enzymes. The aim of this study was to compare the inhibition profiles displayed by these enzymes in established mammalian cell culture test systems to those obtained with the new fission yeast assays, and to evaluate the usefulness of the Schizosaccharomyces pombe strains as screening systems for the identification of novel lead compounds. Using these test systems, we were able to identify a new and very selective CYP11B2 inhibitor (SIAS-1) that displayed no detectable interference with CYP11B1 activity.

Síndrome de Cushing subclínico / Subclinical Cushing´s syndrome

La aplicación de técnicas de imagen de alta definición como la tomografía axial computarizada o la resonancia magnética ha hecho posible que la identificación de masas adrenales incidentales sea cada vez más frecuente. El estudio funcional de los incidentalomas adrenales permite comprobar que un porcentaje significativo de ellos se comporta de forma autónoma en lo que respecta a la secreción de cortisol, que se muestra independiente del control de las concentraciones de corticotropina. La aplicación de diferentes protocolos diagnósticos está permitiendo caracterizar mejor los incidentalomas adrenales desde el punto de vista funcional, lo que favorece la tipificación de situaciones de autonomía adrenocortical o síndrome de Cushing subclínico. Aun cuando son necesarios más estudios para establecer el impacto del hipercortisolismo subclínico sobre la esperanza de vida, existen evidencias de que se asocia con factores de riesgo cardiovascular y con el desarrollo de osteoporosis, lo que recalca la importancia de su detección, valoración y tratamiento. El desarrollo de la vía laparoscópica en el abordaje quirúrgico de las masas adrenales ofrece una opción terapéutica factible para el tratamiento de las masas adrenales hiperfuncionantes. Establecer qué casos de síndrome de Cushing subclínico son susceptibles de intervención terapéutica es uno de los retos actuales en la patología de la glándula suprarrenal (AU)

Successful long-term treatment of refractory Cushing's disease with high-dose mifepristone (RU 486).

An extremely ill patient, with Cushing's syndrome caused by an ACTH-secreting pituitary macroadenoma, experienced complications of end-stage cardiomyopathy, profound psychosis, and multiple metabolic disturbances. Initially treated unsuccessfully by a combination of conventional surgical, medical, and radiotherapeutic approaches, he responded dramatically to high-dose long-term mifepristone therapy (up to 25 mg/kg x d). Treatment efficacy was confirmed by the normalization of all biochemical glucocorticoid-sensitive measurements, as well as by the significant reversal of the patient's heart failure, the resolution of his psychotic depression, and the eventual unusual return of his adrenal axis to normal. His 18-month-long mifepristone treatment course was notable for development of severe hypokalemia that was attributed to excessive cortisol activation of the mineralocorticoid receptor, which responded to spironolactone administration. This case illustrates the efficacy of high-dose long-term treatment with mifepristone in refractory Cushing's syndrome. The case also demonstrates the potential need for concomitant mineralocorticoid receptor blockade in mifepristone-treated Cushing's disease, because cortisol levels may rise markedly, reflecting corticotroph disinhibition, to cause manifestations of mineralocorticoid excess.

Cushing's disease: a new approach to therapy in equine and canine patients.

Forty-one cases of Cushing's Disease affecting both equine and canine patients were treated with an identical mixture of two homeopathically prepared remedies (ACTH 30c and Quercus robur 30c), and the clinical improvements seen in the cases assessed. Homeopathy has been described as a medicine that can only be prescribed on the basis of individual symptoms shown, fitting the remedy to the patient, not the disease. The aim of this study was to define whether a standardised approach, using homeopathically prepared remedies, was a valid system of therapy for this disease, and if so, whether results were repeatable between species. The overall success rate for the therapy was 80% and results were broadly similar between the two species, indicating that homeopathy lends itself to the treatment of Cushing's Disease, and also to both cohort studies and group medicine.

Adrenal cortical carcinoma.

Adrenal cortical carcinoma is a rare endocrine tumor, and complete surgical resection is the only potentially curative treatment. Accurate preoperative biochemical and radiographic evaluation of the patient who presents with an adrenal mass optimizes patient management and facilitates a complete margin-negative resection of the primary tumor--the most important prognostic variable for long-term survival. Response to mitotane or chemotherapy is modest in patients with advanced disease. It is hoped that an improved understanding of the molecular pathogenesis of this challenging tumor will lead to the development of novel treatment strategies.