tretinoin and Pituitary-ACTH-Hypersecretion

Cushing's syndrome is associated with multisystem morbidity and, when suboptimally treated, increased mortality. Medical therapy is an option for patients if surgery is not successful and can be classified into pituitary-directed drugs, steroid synthesis inhibitors, and glucocorticoid receptor antagonists. In the last decade there have been new developments in each drug category. Targeting dopamine and somatostatin receptors on corticotroph adenomas with cabergoline or pasireotide, or both, controls cortisol production in up to 40% of patients. Potential new targets in corticotroph adenomas include the epidermal growth factor receptor, cyclin-dependent kinases, and heat shock protein 90. Osilodrostat and levoketoconazole are new inhibitors of steroidogenesis and are currently being evaluated in multicentre trials. CORT125134 is a new selective glucocorticoid receptor antagonist under investigation. We summarise the drug therapies for various forms of Cushing's syndrome and focus on emerging drugs and drug targets that have the potential for new and effective tailor-made pharmacotherapy for patients with Cushing's syndrome.

Topics: ACTH Syndrome, Ectopic; ACTH-Secreting Pituitary Adenoma; Adenoma; Adrenal Gland Neoplasms; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Cabergoline; Cushing Syndrome; Dopamine Agonists; ErbB Receptors; Gefitinib; Hormones; Humans; Imidazoles; Isoquinolines; Molecular Targeted Therapy; Pituitary ACTH Hypersecretion; Pyrazoles; Pyridines; Receptors, Glucocorticoid; Roscovitine; Somatostatin; Temozolomide; Tretinoin

The most frequent cause of endogenous hypercortisolism is Cushing disease (CD), a devastating condition associated with severe comorbidities and high mortality. Effective tumor-targeting therapeutics are limited.. Search in PubMed with key words "corticotroph" and "Cushing's disease" plus the name of the mentioned therapeutic agent and in associated references of the obtained papers. Additionally, potential therapeutics were obtained from ClinicalTrials.gov with a search for "Cushing disease.". At present, the tumor-targeted pharmacological therapy of CD is concentrated on dopamine agonists (cabergoline) and somatostatin analogs (pasireotide) with varying efficacy, escape from response, and considerable side effects. Preclinical studies on corticotroph pathophysiology have brought forward potential drugs such as retinoic acid, silibinin, and roscovitine, whose efficacy and safety remain to be determined.. For many patients with CD, effective tumor-targeted pharmacological therapy is still lacking. Coordinated efforts are pivotal in establishing efficacy and safety of novel therapeutics in this rare but devastating disease.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Antineoplastic Agents; Cabergoline; Clinical Trials as Topic; Corticotrophs; Humans; Pituitary ACTH Hypersecretion; Roscovitine; Silybin; Somatostatin; Treatment Outcome; Tretinoin

Transsphenoidal surgery remains the first line therapy in Cushing's disease, but a large number of patients will not be cured or disease will recur over time. Repeat pituitary surgery, bilateral adrenalectomy, and radiation have limitations with respect to efficacy and/or side effects. Therefore, there is a clear need for an effective medical treatment. The studies reviewed here suggest a role for pituitary-directed therapies, applying multireceptor ligand somatostatin analogs like pasireotide or second-generation dopamine agonists. Retinoic acid has been also studied in a small prospective study. These compounds target ACTH-secretion at the pituitary level and possibly inhibit corticotrope proliferation. Specific side effects of these compounds need to be considered, especially when used as long-term therapy. These novel approaches could provide options for treatment of patients in whom surgery has failed or is not possible, and while awaiting effects of radiation therapy. Preoperative use to decrease cortisol excess, potentially reducing perioperative complications, needs to be further studied.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Antineoplastic Agents; Dopamine Agonists; Humans; Pituitary ACTH Hypersecretion; Pituitary Gland; Somatostatin; Treatment Outcome; Tretinoin

Hypercortisolism induced by Cushing disease causes high morbidity and mortality. The treatment of choice is pituitary surgery, but it often fails to achieve cure, and other treatment modalities (radiotherapy, bilateral adrenalectomy) may therefore be required. If these treatments are not effective or while waiting for their results, hypercortisolism should be controlled with drugs. The classical drug treatments are those that act by inhibiting cortisol secretion by the adrenal gland (ketoconazole, metyrapone, mitotane, etomidate). The preliminary results of a new drug (LCI699) which is a potent enzyme inhibitor of cortisol secretion have been reported. A clinical trial of the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, has just been published. The drugs deserving more attention today are those with a direct action on the tumor by inhibiting ACTH secretion: somatostatin analogues (pasireotide), dopamine agonists (cabergoline), PPAR-γ, and retinoic acid. A special review is made of the available clinical trials with pasireotide and cabergoline.

Topics: Adenoma; Adrenocorticotropic Hormone; Animals; Cabergoline; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Drug Evaluation, Preclinical; Ergolines; Etomidate; Humans; Hydrocortisone; Imidazoles; Ketoconazole; Metyrapone; Mice; Mifepristone; Mitotane; Multicenter Studies as Topic; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; PPAR gamma; Pyridines; Rats; Somatostatin; Therapies, Investigational; Tretinoin

Cushing's disease is a severe clinical condition caused by hypersecretion of corticosteroids due to excessive ACTH secretion from a pituitary adenoma. This complex endocrine disorder still represents a major challenge for the physician in terms of efficient treatment. In the last years there was only little progress in elucidating the molecular mechanisms responsible for the constitutive and autonomous ACTH secretion of pituitary corticotrophinomas. As a consequence, no effective drug therapy is currently available, particularly if surgical excision is not successful. In the present article we examine recent studies that have investigated the therapeutic potential of retinoic acid receptors as nuclear receptor targets for the treatment of Cushing's disease. Retinoic acid is an efficient drug used for the treatment of different types of cancers and it proved to act in animal models of Cushing's disease. The efficiency of this treatment in patients with this disorder still needs to be tested in clinical trials.

Topics: ACTH-Secreting Pituitary Adenoma; Animals; Antineoplastic Agents; Humans; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; Tretinoin

Cushing disease, which is caused by the excessive production of ACTH, is a rare and complex endocrine disorder that still represents a major challenge for the physician in terms of accurate diagnosis and efficient treatment. Diagnosing Cushing syndrome and its etiology is an elaborate procedure and no single test is sensitive and specific enough to provide sufficient accuracy. Therefore, an ordered cascade of tests is necessary recommended by a consensus statement in 2002. The proposed diagnostic algorithm will be summarized in the following section. In the absence of efficient drug therapy, transsphenoidal resection of the pituitary adenoma is the treatment of choice for the reduction of ACTH secretion. However, not all patients can be cured by surgery. In the present article, we examine recent studies that have investigated the therapeutic potential of new generations of drugs for the treatment of Cushing disease such as cabergoline and SOM230. The role of nuclear receptors: retinoic acid receptors and peroxisome proliferator-activated receptor-gamma as new approaches for treating pituitary tumors is also discussed.

Topics: Algorithms; Animals; Diagnosis, Differential; Dopamine Agonists; Humans; Ligands; Pituitary ACTH Hypersecretion; PPAR gamma; Somatostatin; Tretinoin

Topics: Antineoplastic Agents; Chromans; Humans; Ligands; Pituitary ACTH Hypersecretion; PPAR gamma; Receptors, Retinoic Acid; Thiazolidinediones; Tretinoin; Troglitazone

Cushing's disease, i.e. cortisol excess due to an ACTH-secreting pituitary adenoma, is a rare disorder with considerable morbidity and mortality but no satisfactory medical treatment as yet. Experimental data have recently shown that retinoic acid restrains ACTH secretion by tumoral corticotropes.. Our objective was to evaluate the efficacy and safety profile of retinoic acid treatment in patients with Cushing's disease.. This is a prospective, multicenter study. Seven patients with Cushing's disease (three men, four postmenopausal women) were started on 10 mg retinoic acid daily and dosage increased up to 80 mg daily for 6-12 months. ACTH, urinary free cortisol (UFC), and serum cortisol as well as clinical features of hypercortisolism and possible side effects of retinoic acid were evaluated at baseline, during retinoic acid administration, and after drug withdrawal.. A marked decrease in UFC levels was observed in five patients; mean UFC levels on retinoic acid were 22-73% of baseline values and normalization in UFC was achieved in three patients. Plasma ACTH decreased in the first month of treatment and then returned to pretreatment levels in responsive patients whereas no clear-cut pattern could be detected for serum cortisol. Blood pressure, glycemia, and signs of hypercortisolism, e.g. body weight and facial plethora, were ameliorated to a variable extent on treatment. Patients reported only mild adverse effects, e.g. xerophthalmia and arthralgias.. Long-term treatment with retinoic acid proved beneficial and well tolerated in five of seven patients with Cushing's disease. This represents a novel, promising approach to medical treatment in Cushing's disease.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Adolescent; Adrenocorticotropic Hormone; Adult; Antineoplastic Agents; Female; Humans; Hydrocortisone; Male; Middle Aged; Pituitary ACTH Hypersecretion; Prospective Studies; Treatment Outcome; Tretinoin; Young Adult

Cushing's disease is almost always caused by an ACTH-secreting pituitary tumor, but effective medical therapy is currently limited. Because retinoic acid has been shown to be potentially useful in decreasing corticotroph secretion and proliferation in rodent models, we have studied its action in dogs with Cushing's disease. A randomized treatment with retinoic acid (n = 22) vs. ketoconazole (n = 20) in dogs with Cushing's disease was assigned for a period of 180 d. Clinical signs, plasma ACTH and alpha-MSH, the cortisol/creatinine urine ratio, and pituitary magnetic resonance imaging were assessed and compared at different time points. We recorded a significant reduction in plasma ACTH and alpha-MSH, and also in the cortisol/creatinine urine ratio, of the dogs treated with retinoic acid. Pituitary adenoma size was also significantly reduced at the end of retinoic acid treatment. Survival time and all the clinical signs evaluated showed an improvement in the retinoic-acid-treated dogs. No adverse events or signs of hepatotoxicity were observed, suggesting that the drug is not only effective but also safe. Retinoic acid treatment controls ACTH and cortisol hyperactivity and tumor size in dogs with ACTH-secreting tumors, leading to resolution of the clinical phenotype. This study highlights the possibility of using retinoic acid as a novel therapy in the treatment of ACTH-secreting tumors in humans with Cushing's disease.

Topics: Adenoma; Adrenocorticotropic Hormone; alpha-MSH; Animals; Body Weight; Creatinine; Dog Diseases; Dogs; Female; Hydrocortisone; Ketoconazole; Magnetic Resonance Imaging; Male; Pituitary ACTH Hypersecretion; Pituitary Gland; Pituitary Neoplasms; Survival Rate; Tretinoin

La enfermedad de Cushing (EC) es rara durante el embarazo y se asocia con complicaciones maternas y fetales significativas. El objetivo fue reportar el caso de una paciente con EC que logró embarazo y parto sin complicaciones tras el tratamiento con dosis bajas de cabergolina.. Mujer de 29 años con diagnóstico de EC (macroadenoma secretor de ACTH que produce desplazamiento del quiasma óptico, infiltra el seno cavernoso derecho y engloba la arteria carótida interna). Se somete a cirugía transesfenoidal con resección tumoral incompleta. Luego de un año de estabilidad clínica, reaparecen los síntomas por lo que se instaura tratamiento médico con cabergolina. Durante el tratamiento la paciente concibe embarazo y se suspende la medicación.. En el primer trimestre, los parámetros clínicos y bioquímicos indican EC activa, por lo que se decide reinstaurar Cabergolina a dosis bajas durante el resto de la gestación. Con el agonista dopaminérgico se alcanza normalizar parámetros clínicos y de laboratorio y la paciente dio a luz una niña sana a las 38 semanas, dentro de percentiles normales y sin complicaciones.. El embarazo es un evento raro en pacientes con EC. Sin embargo, las consecuencias de la exposición materno-fetal al hipercortisolismo pueden ser graves. Nuestra experiencia con el uso de cabergolina a dosis bajas en una embarazada con EC, aporta datos favorables a los escasos reportes bibliográficos existentes, sumando evidencia sobre el perfil de seguridad del fármaco en esta población de pacientes.. Cushing's disease (CD) is rare during pregnancy and is associated with significant maternal and fetal complications. The aim was to report the case of a patient with CD who achieved pregnancy and delivery without complications after treatment with low doses of cabergoline.. A 29-year-old woman diagnosed with CD (ACTH-secreting macroadenoma that produces displacement of the optic chiasm, infiltrates the right cavernous sinus and includes the internal carotid artery). She undergoes transsphenoidal surgery with incomplete tumor resection. After a year of clinical stability, the symptoms reappeared, so medical treatment with cabergoline was established.. At the first trimester, clinical and biochemical parameters indicate active CD, so it was decided to readminister Cabergoline at low doses for the rest of the pregnancy. The response to dopaminergic agonists was excellent, and the laboratories were normalized, and the disease was controlled. The patient delivered a healthy girl at 38-week-old, with normal percentiles and without complications.. Pregnancy is rare in patients with CD. However, the consequences of maternal-fetal exposure to hypercortisolism can be serious. Our experience with the use of low-dose cabergoline in a pregnant woman with CD provides favourable data to the few existing bibliographic reports, adding evidence on the safety profile of the drug in this group of patients.

Topics: Cabergoline; Colectomy; Female; Humans; Pituitary ACTH Hypersecretion; Pregnancy; Retrospective Studies; Tretinoin

Introducción: La enfermedad de Cushing (EC) es rara durante el embarazo y se asocia con complicaciones maternas y fetales significativas. El objetivo fue reportar el caso de una paciente con EC que logró embarazo y parto sin complicaciones tras el tratamiento con dosis bajas de cabergolina. Métodos: Mujer de 29 años con diagnóstico de EC (macroadenoma secretor de ACTH que produce desplazamiento del quiasma óptico, infiltra el seno cavernoso derecho y engloba la arteria carótida interna). Se somete a cirugía transesfenoidal con resección tumoral incompleta. Luego de un año de estabilidad clínica, reaparecen los síntomas por lo que se instaura tratamiento médico con cabergolina. Durante el tratamiento la paciente concibe embarazo y se suspende la medicación. Resultados: En el primer trimestre, los parámetros clínicos y bioquímicos indican EC activa, por lo que se decide reinstaurar Cabergolina a dosis bajas durante el resto de la gestación. Con el agonista dopaminérgico se alcanza normalizar parámetros clínicos y de laboratorio y la paciente dio a luz una niña sana a las 38 semanas, dentro de percentiles normales y sin complicaciones. Conclusión: El embarazo es un evento raro en pacientes con EC. Sin embargo, las consecuencias de la exposición materno-fetal al hipercortisolismo pueden ser graves. Nuestra experiencia con el uso de cabergolina a dosis bajas en una embarazada con EC, aporta datos favorables a los escasos reportes bibliográficos existentes, sumando evidencia sobre el perfil de seguridad del fármaco en esta población de pacientes.

Topics: Cabergoline; Colectomy; Female; Humans; Pituitary ACTH Hypersecretion; Pregnancy; Retrospective Studies; Tretinoin

Retinoids play a pivotal role in adrenal development and differentiation. Recent clinical trials revealed therapeutic potential of both all-trans and 9-cis retinoic acid in patients with cortisol excess due to a pituitary ACTH-secreting adenoma and indicated that retinoids might act also on the adrenal. Aim of the present study was to evaluate the effect of 9-cis retinoic acid on adrenals from patients with ACTH-dependent Cushing's syndrome. Adrenal specimens from six patients with Cushing's disease were incubated with 10 nM-1 µM 9-cis retinoic acid with and without 10 nM ACTH. Cortisol secretion was measured by immunoassay and expression of genes involved in steroidogenesis as well as retinoic acid action were evaluated by real-time RT-PCR. Incubation with 10-100 nM 9-cis retinoic acid increased spontaneous cortisol secretion and expression of STAR and CYP17A. On the other hand, in wells treated with ACTH, 9-cis retinoic acid markedly diminished ACTH receptor upregulation and no stimulatory effect on cortisol secretion or steroidogenic enzyme synthesis was observed. ACTH itself increased ligand-induced retinoic acid receptor expression, possibly enhancing sensitivity to retinoic acid. Our findings indicate that the effect of 9-cis retinoic acid in presence of ACTH is distinct from unchallenged wells and support the hypothesis of a direct adrenal action in patients with Cushing's disease.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Alitretinoin; Cushing Syndrome; Humans; Hydrocortisone; Pituitary ACTH Hypersecretion; Receptors, Retinoic Acid; Translational Research, Biomedical; Tretinoin

Cushing's disease (CD) is a rare condition in which hypercortisolemia is secondary to excessive ACTH release from a pituitary corticotroph adenoma. CD is associated with significant morbidity and mortality, and a safe therapy that effectively targets the pituitary tumor is still lacking. Retinoic acid (RA) and dopamine agonists (DAs) have recently been considered as monotherapy in CD patients, and satisfactory results have been reported, albeit in a limited number of patients. Given the permissive role of RA on the dopamine receptor type-2 (DRD2), the aim of the present study was to see whether a combination of 9-cis RA and the DA bromocriptine (Br) might represent a possible treatment for CD. Here we show that 9-cis RA induces a functional DRD2 in the pituitary corticotroph cell line AtT20, and increases cell sensitivity to Br via a mechanism only partially related to corticotroph-to-melanotroph transdifferentiation. In addition, 9-cis RA and Br act synergistically to modulate cell viability, with favorable implications for clinical use. In nearly 45% of corticotropinoma-derived primary cultures, the combined administration of 9-cis RA and Br lowered the steady-state level of the ACTH precursor proopiomelanocortin (POMC) more efficiently than either of the drugs alone. In conclusion, the effects of a combination of 9-cis RA and Br on ACTH synthesis/secretion and cell viability in AtT20, and on POMC transcriptional activity in human corticotropinomas might represent a suitable starting point for assessing the potential of this treatment regimen for ACTH-secreting pituitary adenomas. This study thus has potentially important implications for novel therapeutic approaches to CD.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Animals; Cell Proliferation; Cell Transdifferentiation; Corticotrophs; Humans; Male; Melanotrophs; Mice; Middle Aged; Models, Biological; Pituitary ACTH Hypersecretion; Promoter Regions, Genetic; Receptors, Dopamine D2; Tretinoin; Up-Regulation; Young Adult