Long-term Discontinuation of Dopamine Agonist Treatment in Patients with Prolactinomas Revisited.

The most common type of functioning pituitary adenomas is prolactinomas; unlike other types, they are treated medically with dopamine agonists (DA). This treatment aims to normalize PRL levels and decrease tumor size by 50% or more. These objectives are typically achieved by 90% of patients with microprolactinoma, two-thirds of those with macroprolactinomas, and about half of those with giant prolactinomas. Life-long pharmacological treatment implies costs, discomfort, and the possibility of side effects, therefore, it has been suggested that DA discontinuation could be attempted in some patients. Long-term remission seems more likely in who, after 2 years of therapy achieve clinical, biochemical, and imaging remission criteria: no evidence of hypogonadism, a normal PRL level (preferably <5 ng/mL), and a >50% of tumor size reduction. Long-term remission seems to be more likely if the patient has been treated with cabergoline (CBG) for a minimum of 2 years, the PRL levels have normalized, tumor size has decreased by at least 50%, and the DA dose can gradually be tapered down to 0.25-0.5 mg per week. After treatment withdrawal, about 65% of patients experience a recurrence of hyperprolactinemia within the first 12 months of DA discontinuation. Although in most patients in whom DA discontinuation has been attempted, the hyperprolactinemia will recur, not all of them will require re-initiation of treatment. A good clinical judgement is crucial to identify those patients who need life-long treatment.

Non-Invasive Biochemical Testing of ACTH-dependent Cushing's Disease: Do We Still Need Petrosal Sinus Sampling?

Differentiating between a pituitary from an ectopic source of ACTH could be a real one of the major challenges of clinical endocrinology. The Bilateral inferior petrosal sinus sampling (BIPSS) is considered the gold standard for identifying the source of ACTH; however, is not available worldwide. After the SARS-CoV-2 pandemic, algorithms that include biochemical and imaging tests have gained importance as an alternative to BIPSS. This review summarizes the drawbacks in the differential diagnosis of ACTH-dependent Cushing; the evolution of diagnostic tests, and the evidence that exists on their performance. As well as a comparison between the advantages and disadvantages of invasive and non-invasive tests.

Efficiency and Safety of CyberKnife Robotic Radiosurgery in the Multimodal Management of Patients with Acromegaly.

OBJECTIVE: To analyze, in a cohort of acromegalic patients, the results of the efficiency and safety of radiosurgery (CyberKnife), as well as the prognostic factors associated with disease remission. MATERIAL AND METHODS: Observational, retrospective, longitudinal, and analytical study that included acromegalic patients with persistent biochemical activity after initial medical-surgical treatment, who received treatment with CyberKnife radiosurgery. GH and IGF-1 levels at baseline after one year and at the end of follow-up were evaluated. RESULTS: 57 patients were included, with a median follow-up of four years (IQR, 2-7.2 years). The biochemical remission rate was 45.6%, 33.33% achieved biochemical control, and 12.28% attained biochemical cure at the end of follow-up. A progressive and statistically significant decrease was observed in the comparison of the concentrations of IGF-1, IFG-1 x ULN, and baseline GH at one year and at the end of follow-up. Both cavernous sinus invasion and elevated baseline IGF-1 x ULN concentrations were associated with an increased risk of biochemical non-remission. CONCLUSION: Radiosurgery (CyberKnife) is a safe and effective technique in the adjuvant treatment of GH-producing tumors. Elevated levels of IGF x ULN before radiosurgery and invasion of the cavernous sinus by the tumor could be predictors of biochemical non-remission of acromegaly.

Risk factors associated with thyroid nodular disease in acromegalic patients: A case-cohort study in a tertiary center.

INTRODUCTION: Goiter is very common in patients with acromegaly; its development is correlated to the duration of the disease. Thyroid cells express the IGF-1 receptor and the TSH/IGF-1 interaction has been demonstrated to have a synergistic effect in thyroid cell growth. There is a correlation between IGF-1 levels and the thyroid volume of patients with acromegaly. The aim of this study was to evaluate, in a retrospective case-cohort study of patients with acromegaly, the associated risk factors for thyroid nodules disease in this population. METHODS: This was a case-cohort study matched by age, gender, and growth hormone at diagnosis. Cases consisted of acromegalic patients that developed thyroid nodules during the follow up, and controls consisted in acromegalic patients without thyroid nodules. A Cox proportional hazard estimation was carried out for measure the associated risk factors for thyroid nodules disease in acromegalic patients. A nodular thyroid disease-free survival analysis was estimated using the Kaplan-Meier analysis. RESULTS: We recruited 49 cases and 56 controls. In a multivariate Cox proportional hazard analysis age and IGF-1 ≥ 2.2 x ULN were significantly related with the presence of thyroid nodules [HR of 2.21 (95% CI; 1.15-4.25, p = 0.01)]. Nodularity-free survival rates in patients who had an IGF-1 X ULN ≥ 2.2 was found to be lower in comparison to those who had IGF-1 X ULN < 2.2, according to a Kaplan-Meier survival analysis. CONCLUSIONS: Our findings support that exist more probability to develop thyroid nodular disease in patients with acromegaly that present IGF-1 X ULN ≥ 2.2, suggesting a possible direct effect between the time of exposure to the IGF-1 axis hyperactivity and the genesis of thyroid nodules.

Surgical and Pharmacological Outcomes in Acromegaly: Real-Life Data From the Mexican Acromegaly Registry.

CONTEXT: Acromegaly registries constitute a valuable source of therapeutic outcome information in real-life. OBJECTIVE: The objective of this work is to analyze surgical and pharmacological outcomes in the Mexican Acromegaly Registry (MAR). DESIGN AND METHODS: Data were extracted from the MAR informatic platform. Surgical remission was defined by a postoperative postglucose (GH) of less than 1 ng/mL and an insulin-like growth factor 1 (IGF-1) of less than 1.2 × upper limit of normal (ULN). Pharmacological remission was defined by a basal GH of less than 1 ng/mL and an IGF-1 of less than 1.2 × ULN. RESULTS: A total of 650 surgical outcomes were analyzed (94.6% transsphenoidal). Surgical remission was achieved in 40.15%, whereas 44.15% remained biochemically active. Persistently active disease after surgery was significantly associated with harboring an invasive macroadenoma, a basal GH of greater than 10 ng/mL, and/or an IGF-1 of greater than 2 × ULN at diagnosis on bivariate and multivariate analysis. The outcome of monotherapy with first-generation somatostatin analogs (SSAs) was evaluated in 267 patients (adjunctive in 65%), of whom 28.4% achieved remission. Persistently active disease was significantly associated with harboring an invasive macroadenoma as well as with pretreatment basal GH and IGF-1 levels of greater than 10 ng/mL and greater than 2 × ULN, respectively, on bivariate and multivariate analysis. Combined therapy with SSA and cabergoline was analyzed in 100 patients, of whom 19% achieved remission and 44% remained active; in this subset of patients, only a pretreatment IGF-1 of greater than 2 × ULN was significantly associated with persistent disease activity. CONCLUSION: Surgical and pharmacological outcomes in acromegaly are highly dependent on tumor size/invasiveness as well as on the degree of hypersomatotropinemia.

High biochemical recurrence rate after withdrawal of cabergoline in prolactinomas: is it necessary to restart treatment?

PURPOSE: Treatment with dopamine agonists (DA) is highly effective in patients with prolactinomas. In selected patients, discontinuation of DA after several years of successful treatment is possible, however, hyperprolactinemia recurs in 60-80% of them. It is unclear what is the clinical significance of these recurrences and hence, whether or not reinitiation of therapy is necessary. OBJECTIVES: To evaluate the recurrence rate in prolactinoma patients after DA withdrawal and the necessity to restart treatment. METHODS: Patients with >2 years of treatment with cabergoline (CBG) who achieved normoprolactinemia and a > 50% reduction in tumor size were included. DA dose was down titrated until withdrawal. Basal tumor size, as well as PRL and gonadal steroid levels were recorded at diagnosis, at withdrawal of DA and every 3-6 months for 1-3 years. RESULTS: Fifty patients were included (38 women, 34 macroprolactinomas). After withdrawal, 34 (68%) presented recurrence of hyperprolactinemia. PRL levels <5 ng/mL at the time of withdrawal predicted remission (sensitivity 76%, specificity of 63%). CBG was restarted in eight patients (23%) because of the presence of hypogonadism. CBG was withheld in the remaining 26, based on the following arguments: (1) premenopausal women without biochemical hypogonadism, (54%); (2) asymptomatic men under 65 without biochemical hypogonadism (19%); (3) asymptomatic postmenopausal women (19%); (4) asymptomatic men over 65 (8%). After a median follow-up of 30 months, no increase in PRL levels or tumor growth was documented. CONCLUSIONS: Biochemical recurrence in prolactinomas is very frequent, however, in only a few of these patients reinitiation of DA is necessary.

Are there really any predictive factors for a successful weight loss after bariatric surgery?

BACKGROUND: Currently, bariatric surgery is the most effective treatment for severe obesity and its metabolic complications; however, 15-35% of the patients that undergo bariatric surgery do not reach their goal for weight loss. The aim of this study was to determine the proportion of patients that didn't reach the goal of an excess weight loss of 50% or more during the first 12 months and determine the factors associated to this failure. METHODS: We obtained the demographic, anthropometric and biochemical information from 130 patients with severe obesity who underwent bariatric surgery in our institution between 2012 and 2017. We used self-reports of physical activity, caloric intake and diet composition. An unsuccessful weight loss was considered when the patient lost < 50% or more of the excess weight 12 months after surgery. We compared the characteristics between the successful and unsuccessful groups in order to find the factors associated with success. RESULTS: We included 130 patients (mean age 48 ± 9 years, 81.5% were women). One year after surgery, 26 (20%) had loss < 50% EBW. Unsuccessful surgery was associated with an older age, previous history of hypertension, abdominal surgery or depression/anxiety, also the number of comorbidities and unemployment affected the results. These patients loss enough weight to improve some of their comorbidities, but they are more prone to regain weight 2 years after surgery. CONCLUSIONS: A fifth of the patients undergoing bariatric surgery may not lose enough weight to be considered successful by current standards. Some patients may benefit from the surgery in the short term, but they are more likely to regain weight after 2 years. The factors influencing this result are still controversial but may be population-specific. Early detection of the patients that are more likely to fail is imperative to establish additional therapeutic strategies, without denying them the opportunity of surgery or waiting for weight re-gain to occur.

Prevalence, Clinical and Biochemical Spectrum, and Treatment Outcome of Acromegaly With Normal Basal GH at Diagnosis.

Context: The term micromegaly has been used to describe a subset of patients who have elevated IGF-1 levels but apparently normal basal GH (bGH) concentrations and often a glucose-suppressed GH of <1 ng/mL. Objective: To evaluate the prevalence, clinical spectrum, and therapeutic outcome of acromegaly with normal bGH at diagnosis. Design and Methods: Retrospective analysis of a cohort of patients with acromegaly diagnosed and treated at a tertiary care center. Results: A cohort of 528 patients with acromegaly was stratified according to bGH at diagnosis: group 1, <2 ng/mL, n = 16; group 2, 2 to 9.9 ng/mL, n = 202; group 3, 10 to 99 ng/mL, n = 294; and group 4, ≥100 ng/mL, n = 16. Patients in group 1 (normal bGH) constituted 3% of the total cohort and were significantly older and more likely to be male than patients in the other groups. The frequency of acromegalic symptoms, signs, and comorbidities was similar between the four patient groups. Patients in group 1 more often harbored microadenomas (75%) and had significantly lower median IGF-1 and postglucose GH levels. Surgical success rates were similar between patients from groups 1 (53.8%), 2 (54.1%), and 3 (36.9%), whereas only 13.3% of patients in group 4 achieved remission. Conclusion: Normal bGH acromegaly is uncommon in real life. These patients have some distinctive features that argue against this being simply acromegaly in its early stages.

Treatment of multiresistant prolactinomas with a combination of cabergoline and octreotide LAR.

BACKGROUND AND OBJECTIVES: Dopamine agonist (DA)-resistant prolactinomas are rare but they constitute a real challenge, since there are few therapeutic alternatives left for these patients. DESIGN AND SETTING: Proof-of-concept study at a tertiary care, referral center. PATIENTS AND METHODS: The studied population consisted of five patients (one female and four males, mean age at diagnosis 23.5 ± 19) with macroprolactinomas with persistent hyperprolactinemia and/or tumor mass despite high doses of cabergoline (CBG) and pituitary surgery, to whom 20 mg monthly of octreotide LAR was added for 6-13 months. Response was evaluated by measuring prolactin (PRL) levels and by magnetic resonance imaging. Immunohistochemistry (IHC) for pituitary hormones, Ki-67, and somatostatin receptor subtypes 2 and 5 was (SSTR2 and 5) was available in two of the subjects. RESULTS: The addition of octreotide LAR to ongoing CBG treatment had no effect on either PRL levels or tumor size in three patients. In two of the five patients, combination treatment resulted in a significant reduction in PRL concentrations (from 7643 to 200 ng/mL and from 2587 to 470 ng/mL) as well as in adenoma size (93% reduction). IHC evaluation of tumor samples from two patients (a responder and a non-responder) revealed positive immunostaining for PRL and SSTR5 but not for other pituitary hormones or for SSTR2. CONCLUSIONS: The addition of a somatostatin analog to ongoing CBG treatment may be effective in some patients with DA-resistant macroprolactinomas, independently of the adenoma's SSTR expression profile.

LONG-TERM OUTCOME OF THE DIFFERENT TREATMENT ALTERNATIVES FOR RECURRENT AND PERSISTENT CUSHING DISEASE.

OBJECTIVE: Treatment alternatives for persistent and recurrent Cushing disease (CD) include pituitary surgical re-intervention, radiation therapy (RT), pharmacotherapy, and bilateral adrenalectomy (BA). The decision of which of these alternatives is better suited for the individual patient rests on clinical judgment and the availability of resources. This retrospective cohort study was performed at a referral center to evaluate the long-term efficacy of different secondary interventions for persistent and recurrent CD. METHODS: We evaluated the hospital charts of 84 patients (77 female, median age 34 years, median follow up 6.3 years) with CD diagnosed, treated, and followed at our multidisciplinary clinic according to a pre-established protocol. RESULTS: Of the 81 patients who were initially treated with transsphenoidal surgery (TSS), 61.7% had a long-lasting remission, 16% had persistent disease, and 22% achieved remission but relapsed during follow-up. The most frequently used secondary treatment was pituitary re-intervention, followed by ketoconazole, RT, and BA. Early remissions were observed in 66.6% of the re-operated and in 58.3% of the radiated patients; long-lasting remission was achieved in 33.3% and 41.6% of these patients, respectively. Nelson syndrome developed in 41.6% of the patients who underwent BA. Upon last follow-up, 88% of all the patients are in remission, and 9.5% are biochemically controlled with ketoconazole. CONCLUSION: The efficacy of treatment alternatives for recurrent or persistent CD varies considerably among patients and multiple interventions are often required to achieve long-lasting remission. ABBREVIATIONS: ACTH = adrenocorticotrophic hormone; BA = bilateral adrenalectomy; CBG = cabergoline; CD = Cushing disease; CV = coefficient of variation; DXM = dexamethasone; IQR = interquartile range; RT = radiation therapy; SRS = stereotactic radiosurgery; TSS = transsphenoidal surgery; UFC = urinary free cortisol; ULN = upper limit of normal.

[Anxiety and depression in asthmatic adults in comparison to healthy individuals]. / Ansiedad y depresión en asmáticos adultos en comparación con sujetos sanos.

BACKGROUND: Asthmatic patients present different degrees of anxiety and depression, being psychiatric pathologies the most frequent alterations related to this illness. In this country there is available information of asthma in children but just a few about adult patients. OBJECTIVES: To know the frequency of anxiety and depression in adult asthmatic patients, compare them with healthy individuals and determine their relationship with the severity of illness. PATIENTS AND METHODS: There were included asthmatic adults (GINA 2002) and as control group healthy individuals, using the HAD scale (Hospital Anxiety and Depression Scale) to determine the presence of anxiety and depression RESULTS: 120 patients participated, 60 in each group with a mean age of 34 years old in the group 1 (asthmatic) and 31 years old in group 2 (healthy individuals). The HAD scale results in group 1 showed that 30% of patients presented anxiety, and 8% showed depression; in group 2 18% had anxiety and 3% depression. There are more anxiety and depression in asthmatic patients than in healthy individuals, p < 0.05, correlation between depression and severity of asthma is r = 0.288. CONCLUSIONS: Anxiety is frequent in asthmatic patients, being less common the presence of depression but related with asthma severity. These results contrast with available information where up to 54% of asthmatic patient present anxiety and 30% depression, using the same scale HAD. It is necessary to identify these problems, with the object to give an integral an accurate treatment to the patient.