[Clinically active pituitary tumors]. / Klinisch aktive Hypophysentumoren.

The widespread use of diagnostic imaging has led to an increase in the incidence of pituitary tumors. The majority of incidentalomas are hormone-inactive (HI) pituitary microadenomas. The most common clinically relevant pituitary adenomas are prolactin-secreting, followed by HI, and far less common are growth hormone (GH)-, adrenocorticotropic hormone (ACTH)- and thyroid-stimulating hormone (TSH)-secreting adenomas. Pituitary adenomas are usually benign, although aggressive growth and invasion occurs in individual cases. Very rarely, they give rise to metastases and are then termed pituitary carcinomas. All pituitary tumors require endocrine testing for pituitary hormone excess. In addition to the medical history and clinical examination, laboratory diagnostics are very important. Symptoms such as irregular menstruation, loss of libido or galactorrhea often lead to the timely diagnosis of prolactinomas, and hyperprolactinemia can easily confirm the diagnosis (considering the differential diagnoses). Diagnosis is more difficult for all other hormone-secreting pituitary adenomas (acromegaly, Cushing's disease, TSHoma), as the symptoms are often non-specific (i.e., headaches, weight gain, fatigue, joint pain). Furthermore, comorbidities such as hypertension, diabetes, and depression are such widespread diseases that pituitary adenomas are rarely considered as the underlying cause. Timely diagnosis and appropriate treatment have a significant impact on morbidity, mortality, and quality of life. Therefore, the role of primary care physicians is very important for achieving an early diagnosis. In addition, patients with pituitary adenomas should always be referred to endocrinologists to ensure optimal diagnosis as well as treatment.

From Knee Pain Consultation to Pituitary Surgery: The Challenge of Cushing Disease Diagnosis.

Cushing syndrome (CS) is a rare endocrinological disorder resulting from chronic exposure to excessive cortisol. The term Cushing disease is used specifically when this is caused by excessive secretion of adrenocorticotropic hormone (ACTH) by a pituitary tumor, usually an adenoma. This disease is associated with a poor prognosis, and if left untreated, it has an estimated 5-year survival rate of 50%. We present the case of a 66-year-old female patient who received a referral to endocrinology for an evaluation of obesity due to right knee arthropathy. Taking into consideration her age, she was screened for osteoporosis, with results that showed diminished bone density. Considering this, combined with other clinical features of the patient, suspicion turned toward hypercortisolism. Laboratory findings suggested that the CS was ACTH-dependent and originated in the pituitary gland. After a second look at the magnetic resonance imaging results, a 4-mm lesion was identified on the pituitary gland, prompting a transsphenoidal resection of the pituitary adenoma.

Leukocyte transcriptome of Cushing's disease are associated with nerve impairment and psychiatric disorders.

INTRODUCTION: The hypothalamus-pituitary-adrenal (HPA) axis and its end product cortisol is a major response mechanism to stress and plays a critical role in many psychiatric disorders. Cushing's disease (CD) serves as a valuable in vivo "hyperexpression" model to elucidate the effect of cortisol on brain function and mental disorders. Changes in brain macroscale properties measured by magnetic resonance imaging (MRI) have been detailed demonstrated, but the biological and molecular mechanisms underlying these changes remain poorly understood. MATERIAL AND METHODS: Here we included 25 CD patients and matched 18 healthy controls for assessment, and performed transcriptome sequencing of peripheral blood leukocytes. Weighted gene co-expression network analysis (WGCNA) was performed to construct a co-expression network of the relationships between genes and we identified a significant module and hub gene types associated with neuropsychological phenotype and psychiatric disorder identified in enrichment analysis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis preliminarily explored the biological functions of these modules. RESULTS: The WGCNA and enrichment analysis indicated that module 3 of blood leukocytes was enriched in broadly expressed genes and was associated with neuropsychological phenotypes and mental diseases enrichment. GO and KEGG enrichment analysis of module 3 identified enrichment in many biological pathways associated with psychiatric disorders. CONCLUSION: Leukocyte transcriptome of Cushing's disease is enriched in broadly expressed genes and is associated with nerve impairment and psychiatric disorders, which may reflect some changes in the affected brain.

Sensitivity of Different ACTH and Cortisol Concentration Values in Corticotropin-Releasing Hormone Based Tests in Cushing's Disease.

PURPOSE: In Cushing's disease (CD) patients, the aim of the present study is to confirm sensitivity of several ACTH and cortisol concentration values in different time points, during corticotropin-releasing hormone (CRH) stimulation test and during CRH stimulation following dexamethasone suppression (DEX-CRH) test. METHODS: We retrospectively analyzed cortisol and ACTH concentration increment during CRH and DEX-CRH tests in 23 patients with confirmed CD. Cortisol and ACTH concentrations were determined immediately before, 15 min and 30 min after CRH stimulation. We evaluated the sensitivity of different cutoff values including those reported in previous studies, in the diagnosis of CD. RESULTS: During DEX-CRH test, 15 min serum cortisol concentration of 1.4 µg/dl (38 nmol/L) had a sensitivity of 90.9%, and serum cortisol concentration ≥1.27 µg/dl (35 nmol/L) had a sensitivity of 100%. For plasma ACTH, sensitivity of 100% was obtained using ACTH ≥3.5pmol/L (16 pg/ml) at 30 min. During CRH test, 35% increase from baseline in ACTH concentration had a sensitivity of 72.7%. Twenty percent increase in cortisol 30 minutes after stimulation yielded a sensitivity of 85.7%. The best sensitivity of ACTH and cortisol increment was obtained 15 min after stimulation, using 19% and 9% increase, respectively (sensitivity of 100% and 92.8%, respectively). CONCLUSION: During CRH and DEX-CRH tests, the study findings agree with the good sensitivity of ACTH and cortisol cutoff values suggested in previous studies; yet, other cutoff values may give a higher diagnostic sensitivity.

Thrombosis in Cushing's disease; raising the flag of concern.

Cushing's disease (CD) is associated with an increased risk of venous thromboembolic events. The purpose of this review is to discuss preventive strategies for post-operative thrombosis in CD patients and their impact on patient outcomes. A systematic review under PRISMA guidelines was conducted within PubMed, Embase, Web of Science, and Cochrane databases through July 2022. Of the 3207 papers retrieved, seven articles were included in this systematic review. Four hundred forty-eight patients were presented in the reviewed studies and the overall reported mortality was 2.67% (12/448). Three studies utilized prophylaxis methods including graduated compression stockings (GCS) and early ambulation (EA) while the remaining four studies only used anticoagulation medicine. Only 20 patients received pre-operative prophylactic treatment, while 366 patients received post-operative prophylaxis which was delivered either immediately after surgery or at different time intervals within 2 days following the surgery. Thrombotic events mainly occurred within two to 3 months after surgery. Overall, a higher frequency of thromboembolic events and mortality was observed in the control groups in comparison to groups receiving prophylaxis. A combination of anticoagulation, EA, and GCS might reduce thrombotic events and mortality in CD patients after treatment. Although the early commencement of a prophylactic anticoagulation regimen on the same day of surgery and continuing up to 3 months seems beneficial, the application of a prophylactic regimen should be utilized with caution since the number of included studies was insufficient to draw a strong conclusion, as well as neither prospective study nor randomized controlled trials existed.

Hipercortisolismo severo e hipocalemia recurrente / Severe hypercortisolism and recurring hypocalemia

RESUMEN El síndrome de Cushing endógeno deriva de un aumento crónico, inapropiado y sostenido de glucocorticoides principalmente como respuesta al exceso en las concentraciones séricas elevadas de la hormona adrenocorticotropa (ACTH) desde un tumor adenohipofisiario, enfermedad de Cushing; o producida de forma ectópica por tumores neuroendocrinos. El Cushing suprarrenal se origina por tumores de la corteza adrenal que producen de forma autónoma cortisol y es independiente de ACTH. El curso clínico, tratamiento, pronóstico y posibles complicaciones dependen de identificar de forma correcta la lesión desencadenante; situación que en múltiples ocasiones resulta en una experiencia retadora para los clínicos. Se presenta el caso de una mujer de 62 años, ingresada por síntomas constitucionales con hipocaliemia severa de difícil corrección e hipercortisolismo severo.

ABSTRACT Endogenous Cushing syndrome derives from a chronic, inappropriate, and sustained increase in glucocorticoids, mainly in response to remarkably high serum concentrations of adrenocorticotropic hormone (ACTH) secreted from an adenohypophyseal tumor, Cushing's disease, or due to ectopic production by neuroendocrine tumors. Adrenal Cushing's disease is caused by tumors of the adrenal cortex that autonomously produce cortisol and this is independent from ACTH action. Clinical course, treatment, prognosis, and possible complications depend on correctly identifying the triggering lesion; this situation frequently becomes a challenging experience for clinicians. We present the case of a 62-year-old woman, admitted for constitutional symptoms with severe hypokalemia that was difficult to correct and severe hypercortisolism.

Diagnostic Power of Bilateral Inferior Petrosal Sinus Sampling with Desmopressin in Paediatric Cushing's Disease

Objective: The aim of this study was to evaluate the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS) with desmopressin for pediatric Cushing's disease (CD). Methods: We reviewed studies performed in children that evaluated the accuracy of BIPSS with desmopressin. Results: All included studies were case series of children with adrenocorticotropin hormone (ACTH)-dependent Cushing's syndrome. The overall accuracy of BIPSS before stimulation was 84.1% (37/44), and after stimulation it was 92.3% (36/39). The overall lateralizing accuracy of BIPSS was 50.0%. Conclusion: Considering that available evidence is limited, it appears that BIPSS with desmopressin stimulation is accurate for the diagnosis of pediatric CD, but its lateralizing accuracy is probably not suitable for pediatric clinical practice.

MRI-Negative Cushing's Disease: A Review on Therapeutic Management.

OBJECTIVES: In this systematic review and meta-analysis, we review the literature regarding patients with Cushing's disease (CD) with negative or inconclusive magnetic resonance imaging (MRI). METHODS: A quantitative systematic review was performed. Article selection was performed by searching MEDLINE (using PubMed), EMBASE, and Cochrane electronic bibliographic databases. RESULTS: 28 articles described surgical management of inconclusive MRI or MRI-negative CD. A total of 858 patients underwent surgery for their Cushing adenoma. Different types of surgery, including endoscopic endonasal transsphenoidal surgery (EETS) (190 cases) and microscopic endonasal transsphenoidal surgery (METS) (488 cases), were performed on patients with MRI-negative CD. 7 studies, which included 164 patients, did not describe any surgery. EETS and METS are conducted to achieve selective adenomectomy (231 cases), partial adenomectomy (80 cases), total adenomectomy (13 cases), hemihypophysectomy (15 cases), or enlarged adenomectomy (48 cases). Based on available data on these studies, the remission rate, persistence rate, and recurrence rate after different types of surgeries on patients with MRI-negative CD were 72.97%, 27.03%, and 12.05%, respectively. There was no statistically significant difference between EETS and METS in the subanalysis regarding recurrence rate, remission rate, and persistence rate. However, the recurrence rate in the METS group is almost 3 times higher than in the EETS group. CONCLUSIONS: Surgery has a good prognosis in patients with MRI-negative CD in terms of remission, and EETS has a lower rate of disease recurrence than METS; therefore, EETS seems to be the potential recommended treatment technique, while to confirm the therapeutic method of choice, further investigations should be done.

Contrast-enhanced 3D-T2-weighted SPACE sequence for MRI detection and localization of adrenocorticotropin (ACTH)-secreting pituitary microadenomas.

OBJECTIVE: Cushing disease is a potentially fatal endocrine disorder caused by adrenocorticotropin (ACTH)-secreting microadenomas in the pituitary gland. Accurate detection and localization of the adenomas is the key to clinical treatment. This study analysed the value of contrast-enhanced Sampling Perfection with Application-optimized Contrasts using different flip angle Evolutions (SPACE) sequence in magnetic resonance imaging (MRI) assessment of ACTH-secreting pituitary microadenomas. DESIGN AND PATIENTS: We carried out a retrospective study in which 45 patients with ACTH-secreting pituitary microadenomas were enrolled. Dynamic contrast-enhanced (DCE) coronal T1-SE sequence was performed. A contrast-enhanced coronal SPACE sequence was added immediately after DCE MRI finished. Two independent observers assessed the tumour existence and location, then the results were compared with surgical findings. RESULTS: Twenty-four lesions (53.3%) were detected by the DCE T1-SE sequence alone, while 35 lesions (80.0%) were detected with the addition of contrast-enhanced SPACE sequence. The sensitivity (58.5% vs. 85.3%; p < .05) and best diagnostic accuracy (62.0% vs. 84.4%; p < .05) were significantly better for addition with SPACE sequence than DCE-SE images alone in detection of ACTH-secreting pituitary microadenomas. For lesions <5 mm, the detected numbers were 4 (16.6%) versus 10 (27.8%) by DCE T1-SE sequence and combined DCE T1-SE with SPACE sequence. CONCLUSIONS: A combination of contrast-enhanced SPACE with DCE T1-SE sequence could improve the detection of ACTH-secreting pituitary microadenomas. Contrast-enhanced SPACE sequence could be a supplementary sequence for imaging of ACTH-secreting pituitary adenomas when T1-SE sequence provides negative or equivocal findings.

Assessment of Vitamin D Metabolism in Patients with Cushing's Disease in Response to 150,000 IU Cholecalciferol Treatment.

In this study we aimed to assess vitamin D metabolism in patients with Cushing's disease (CD) compared to healthy individuals in the setting of bolus cholecalciferol treatment. The study group included 30 adults with active CD and the control group included 30 apparently healthy adults with similar age, sex and BMI. All participants received a single dose (150,000 IU) of cholecalciferol aqueous solution orally. Laboratory assessments including serum vitamin D metabolites (25(OH)D3, 25(OH)D2, 1,25(OH)2D3, 3-epi-25(OH)D3 and 24,25(OH)2D3), free 25(OH)D, vitamin D-binding protein (DBP) and parathyroid hormone (PTH) as well as serum and urine biochemical parameters were performed before the intake and on Days 1, 3 and 7 after the administration. All data were analyzed with non-parametric statistics. Patients with CD had similar to healthy controls 25(OH)D3 levels (p > 0.05) and higher 25(OH)D3/24,25(OH)2D3 ratios (p < 0.05) throughout the study. They also had lower baseline free 25(OH)D levels (p < 0.05) despite similar DBP levels (p > 0.05) and lower albumin levels (p < 0.05); 24-h urinary free cortisol showed significant correlation with baseline 25(OH)D3/24,25(OH)2D3 ratio (r = 0.36, p < 0.05). The increase in 25(OH)D3 after cholecalciferol intake was similar in obese and non-obese states and lacked correlation with BMI (p > 0.05) among patients with CD, as opposed to the control group. Overall, patients with CD have a consistently higher 25(OH)D3/24,25(OH)2D3 ratio, which is indicative of a decrease in 24-hydroxylase activity. This altered activity of the principal vitamin D catabolism might influence the effectiveness of cholecalciferol treatment. The observed difference in baseline free 25(OH)D levels is not entirely clear and requires further study.

Descriptive Epidemiology and Survival Analysis of Prolactinomas and Cushing's Disease in Korea.

BACKGROUND: Only a few studies have established the epidemiology of prolactinoma and Cushing's disease in Korea. Furthermore, the incidence of these disease are increasing than before associated with the development of technologies. This study was designed to evaluate the epidemiology of prolactinoma and Cushing's disease and their survival analysis according to treatment. METHODS: The nationwide, population-based study evaluated incidence and prevalence of prolactinoma and Cushing's disease using de-identified claims data in The Korean Health Insurance Review and Assessment Service database between 2013 and 2017. The survival analysis investigated regarding treatment over a period of 6 years. A log-rank test and Cox proportional hazard regression analysis were used. RESULTS: The 6,056 patients with newly diagnosed prolactinoma and 584 patients with Cushing's disease were recorded between 2013 and 2017. The annual incidence of prolactinoma was 23.5 cases per million, and its prevalence was 82.5 cases per million, and 2.3 cases per million/year and 9.8 cases per million for Cushing's disease. The survival benefit was insignificant in prolactinoma according to treatment, but treatment of Cushing's disease ameliorated the survival rate significantly. CONCLUSION: Overall, the incidence of prolactinoma and Cushing's disease was similar with those found previously, but the prevalence of two diseases were inconsistent when compared with the early studies. The present study also proposed necessity of treatment in Cushing's disease for improving the survival rate.

Early post-natal life stress induces permanent adrenocorticotropin-dependent hypercortisolism in male mice.

PURPOSE: It has been hypothesized that specific early-life stress (ES) procedures on CD-1 male mice produce diabetes-like alterations due to the failure of negative feedback of glucocorticoid hormone in the pituitary. The aim of this study is to investigate the possible mechanism that leads to this pathological model, framing it in a more specific clinical condition. METHODS: Metabolic and hypothalamic-pituitary-adrenal-related hormones of stressed mice (SM) have been analyzed immediately after stress procedures (21 postnatal days, PND) and after 70 days of a peaceful (unstressed) period (90 PND). These data have been compared to parameters from age-matched controls (CTR), and mice treated during ES procedures with oligonucleotide antisense for pro-opiomelanocortin (AS-POMC). RESULTS: At 21 PND, SM presented an increased secretion of hypothalamic CRH and pituitary POMC-derived peptides, as well as higher plasmatic levels of ACTH and corticosterone vs. CTR. At 90 PND, SM showed hyperglycemia, with suppression of hypothalamic CRH, while pituitary and plasmatic ACTH levels, as well as plasma corticosterone, were constantly higher than in CTR. These values are accompanied by a progressive acceleration in gaining total body weight, which became significant vs. CTR at 90 PND together with a higher pituitary weight. Treatment with AS-POMC prevented all hormonal and metabolic alterations observed in SM, both at 21 and 90 PND. CONCLUSIONS: These findings show that these specific ES procedures affect the negative glucocorticoid feedback in the pituitary, but not in the hypothalamus, suggesting a novel model of ACTH-dependent hypercortisolism that can be prevented by silencing the POMC gene.

Medical therapy in severe hypercortisolism.

Severe hypercortisolism is characterized as a life-threatening endocrine condition in patients with Cushing syndrome, usually related to the concomitant onset of one or more comorbidities, requiring rapid normalization of cortisol concentrations and aggressive treatment of associated complications. It is mainly, but not exclusively, caused by ectopic ACTH syndrome, and the diagnosis of severity is more accurate when is based on simultaneous evaluation of the clinical course and manifestations of the disease, cortisol levels and systematic search of comorbidities. Once the severity and imminent risk to life are established, urgent therapeutic measures must be taken and etiological investigation postponed until the patient is stabilized. Adrenal steroidogenesis inhibitors (mainly etomidate, ketoconazole, and metyrapone), alone or in combined therapy, are commonly the first-line treatment for severe hypercortisolemia due to their rapid action, good efficacy and safety profile. The new drug osilodrostat is a future potential candidate to be included in the list. The glucocorticoid receptor antagonist mifepristone has also a rapid action, but its use has been limited due to difficulties to monitor its efficacy and safety. Other slow-acting cortisol-lowering drugs (mainly mitotane, cabergoline, and pasireotide) might be included in the therapeutic scheme to synergize and overcome a possible escape phenomenon frequently observed with the fast-acting drugs in the prolonged follow-up. When medical therapies fail, are unavailable or contra-indicated, bilateral adrenalectomy should be indicated as a life-saving measure. Adrenal arterial embolization is rarely encountered in routine clinical practice, being a last alternative in specialized centers when all other options fail or are contra-indicated.

Comparative analysis of rhinologic outcomes in Cushing disease and non-functioning pituitary adenoma in patients submitted to endoscopic endonasal transsphenoidal surgery.

PURPOSE: Adrenocorticotropic hormone (ACTH) secreted by pituitary tumors lead to changes in nasal cavity anatomy and physiology. As a consequence of hormonal alteration, there is an abnormal soft tissue and an increased capillary fragility, inducting to a thinner mucosa that acts in the healing process. We compared post-operative nasal alterations in patients with Cushing's disease versus patients with non-functioning macroadenomas who underwent endoscopic endonasal transsphenoidal surgery. METHODS: A retrospective study with 14 patients with Cushing's disease who underwent initial transsphenoidal endonasal surgery for an ACTH-secreting adenoma was conducted. Forty-two patients who underwent the same surgery for non-functioning adenomas were selected as controls. The following data were collected: operative technique, endoscopic alterations in late post-operative period and post-operative nasal complaints. RESULTS: There were 13/14 (92.9%) females with Cushing disease versus 23/42 (54.8%) in the non-functioning adenoma group. Surgical approach was similar in both groups, with no differences in flap usage, turbinectomies or ethmoidectomies. No difference occurred concerning endoscopic alterations or nasal complaints in post-operative period. CONCLUSIONS: Post-operative results are similar, and healing could be expected to be equal.

Prediction of recurrence and remission within 3 years in patients with Cushing disease after successful transnasal adenomectomy.

BACKGROUND: Some laboratory and clinical features are associated with a probability of recurrence after transnasal adenomectomy for Cushing disease (CD). However, there is no consensus on a set of predictors. Rules for prediction of recurrence were not proposed earlier. AIM: To develop prediction model of recurrence/remission after successful neurosurgical treatment for CD. METHODS: Retrospective single-site comparative study included 349 patients (52 men and 297 women) with a verified diagnosis of CD who underwent effective endoscopic transsphenoidal adenomectomy between 2007 and 2014. Clinical and laboratory parameters were evaluated. Laboratory tests were performed using immunochemiluminescent method. Time-to-event analysis and ROC-analysis were applied. Multivariate models were developed using logistic regression and artificial neural network (ANN). RESULTS: Postoperative cortisol and ACTH levels and their combinations cannot be used for prediction of recurrence. ANN for prediction of recurrence within 3 years after successful surgery was developed. Input variables are age, duration of the disease, MRI data on adenoma, morning postoperative levels of ACTH and cortisol, output variable is binary (recurrence/remission). Predictive value for remission is 93%, 95% CI [89%; 96%], and predictive value for recurrence is 85%, 95% CI [71%; 94%]. Web-calculator based on the model is developed and free for use. CONCLUSION: Effective method for prediction of recurrence and long-term remission within 3 years after successful endoscopic transsphenoidal adenomectomy is proposed.

Long Term Follow-up after Endoscopic Endonasal Approach for the Treatment of Cushing's Disease.

Introduction Surgery has been the standard treatment for Cushing's disease. Currently, the endoscopic endonasal approach (EEA) is the most widely used technique. However, among some endocrinologists and neurosurgeons used to the microscope assisted technique, there are still questions about the effectiveness and safety of transitioning to the EEA. We aim to show our initial experience with such transition. Method Retrospective review of medical records of patients, who underwent EEA in our center as a first treatment for Cushing's disease, and with a minimum 18 months of follow-up, from March 2004 to March 2014 Results Our cohort had 16 patients (14 females and 2 males), with a mean age of 33.7 years. The mean follow-up was 52.0 months. Magnetic resonance imaging (MRI) identified an adenoma in 93.8% of the patients (56.2% microadenomas and 37.5% macroadenomas). Postoperative cerebrospinal fluid (CSF) leak was observed in two patients (12.5%). No new neurological deficits were present after surgery. The early remission and sustained remission rates after a single procedure were 87.5 and 68.75%, respectively. Weight reduction, improved control of blood pressure, and lower serum glucose levels were documented in 68.75, 60, and 55.5% of patients, respectively, after remission. Conclusion Despite the need for specialized training, equipment and team building by ENT (Ear, Nose and Throat) and neurosurgery, the transition from microscope assisted pituitary surgery to endoscopic endonasal approach is possible and safe. The clinical outcomes, even in the early years, are similar to the previous microscope assisted treatment, and over time, with greater experience and knowledge, there is a tendency for improvement.

Fluconazole as a Safe and Effective Alternative to Ketoconazole in Controlling Hypercortisolism of Recurrent Cushing's Disease: A Case Report.

INTRODUCTION: Ketoconazole has long been the first-line medical therapy for controlling hypercortisolism secondary to either pituitary or adrenal pathology. However, it is largely unavailable in most countries. As a result, we have turned to fluconazole as a viable alternative in view of its favourable safety profile. CASE PRESENTATION: A 50-year-old lady developed recurrent Cushing's disease after being in remission following transsphenoidal surgery (TSS) for a left pituitary microadenoma 16 years ago. The repeat MRI showed a right pituitary microadenoma (1.7 mm × 1.3 mm) for which she underwent a second TSS. However, she continued to have persistent hypercortisolism despite repeated MRIs showing absence of tumour recurrence. She refused bilateral adrenalectomy and external radiotherapy. Ketoconazole was commenced at 200 mg twice daily for disease control but this was hindered by intolerable side effects including pruritus and skin exfoliation. In the meantime, she suffered a right hypertensive basal ganglia hemorrhage. Treatment was subsequently switched to cabergoline and the dose titrated to 0.5 mg daily. Fluconazole 400 mg daily was later added to control the persistent disease. Her clinical and biochemical parameters improved markedly three months after the addition of fluconazole. No adverse event was reported. Her disease has remained stable for the last 15 months up until the time of the recent clinic review. CONCLUSIONS: This case demonstrates the long-term efficacy of fluconazole in tandem with cabergoline for the control of recurrent Cushing's disease.

Remisión espontánea de acromegalia y enfermedad de Cushing en adultos mayores: casos clínicos / Spontaneous remission of acromegaly and Cushing's disease in older patients: report of two cases

Pituitary diseases such as acromegaly and Cushing's disease require surgical or medical therapy. In some functioning pituitary tumors, a spontaneous remission of hormonal hypersecretion is observed, mainly associated to apoplexy or pituitary infarction. We report the evolution of two female patients older than 70 years at the time of diagnosis, with multiple comorbidities. In case 1, acromegaly was diagnosed at 74 years of age. Sellar CT scan showed a 10-mm adenoma. During her follow-up, IGF1 levels remained normal. Nine years later, a magnetic resonance (MR) showed a 7-mm adenoma. In case 2, clinical and biochemical diagnosis of Cushing's disease was done being 71 years old. Sellar MR showed a 6-mm adenoma. Three years later, urinary cortisol normalized with no changes in adenoma at MR. Seven years later, she remains without clinical or biochemical signs of hypercortisolism. In both cases, no signs of hemorrhage were observed at MR.

Recent Progress in the Medical Therapy of Pituitary Tumors.

Management of pituitary tumors is multidisciplinary, with medical therapy playing an increasingly important role. With the exception of prolactin-secreting tumors, surgery is still considered the first-line treatment for the majority of pituitary adenomas. However, medical/pharmacological therapy plays an important role in controlling hormone-producing pituitary adenomas, especially for patients with acromegaly and Cushing disease (CD). In the case of non-functioning pituitary adenomas (NFAs), pharmacological therapy plays a minor role, the main objective of which is to reduce tumor growth, but this role requires further studies. For pituitary carcinomas and atypical adenomas, medical therapy, including chemotherapy, acts as an adjuvant to surgery and radiation therapy, which is often required to control these aggressive tumors. In the last decade, knowledge about the pathophysiological mechanisms of various pituitary adenomas has increased, thus novel medical therapies that target specific pathways implicated in tumor synthesis and hormonal over secretion are now available. Advancement in patient selection and determination of prognostic factors has also helped to individualize therapy for patients with pituitary tumors. Improvements in biochemical and "tumor mass" disease control can positively affect patient quality of life, comorbidities and overall survival. In this review, the medical armamentarium for treating CD, acromegaly, prolactinomas, NFA, and carcinomas/aggressive atypical adenomas will be presented. Pharmacological therapies, including doses, mode of administration, efficacy, adverse effects, and use in special circumstances are provided. Medical therapies currently under clinical investigation are also briefly discussed.

Recent Progress in the Medical Therapy of Pituitary Tumors

Management of pituitary tumors is multidisciplinary, with medical therapy playing an increasingly important role. With the exception of prolactin-secreting tumors, surgery is still considered the first-line treatment for the majority of pituitary adenomas. However, medical/pharmacological therapy plays an important role in controlling hormone-producing pituitary adenomas, especially for patients with acromegaly and Cushing disease (CD). In the case of non-functioning pituitary adenomas (NFAs), pharmacological therapy plays a minor role, the main objective of which is to reduce tumor growth, but this role requires further studies. For pituitary carcinomas and atypical adenomas, medical therapy, including chemotherapy, acts as an adjuvant to surgery and radiation therapy, which is often required to control these aggressive tumors. In the last decade, knowledge about the pathophysiological mechanisms of various pituitary adenomas has increased, thus novel medical therapies that target specific pathways implicated in tumor synthesis and hormonal over secretion are now available. Advancement in patient selection and determination of prognostic factors has also helped to individualize therapy for patients with pituitary tumors. Improvements in biochemical and “tumor mass” disease control can positively affect patient quality of life, comorbidities and overall survival. In this review, the medical armamentarium for treating CD, acromegaly, prolactinomas, NFA, and carcinomas/aggressive atypical adenomas will be presented. Pharmacological therapies, including doses, mode of administration, efficacy, adverse effects, and use in special circumstances are provided. Medical therapies currently under clinical investigation are also briefly discussed.