Objective: To describe the long term safety and efficacy of pegvisomant (PEGV), and the predictors of treatment response in patients with acromegaly in the real life setting. Subjects and methods: We retrospectively reviewed the clinical, hormonal and radiological data of acromegalic patients treated with PEGV in 17 Argentine centers. Results: Seventy-five patients (age range 22-77, 51 females) with acromegaly have been treated with PEGV for up to 118 months (median 27 months). Before PEGV, 97.3% of patients had been treated with medical therapy, surgery and/or radiotherapy, two patients had no previous treatment. At that time, all patients had an IGF-1 above the upper normal limit (ULN) (mean 2.4 x ULN ± 0.98, range 1.25-7). At diagnosis of acromegaly 84% presented macroadenomas, prior to PEGV only 23,5% of patients remained with tumor remnant > 1 cm, the remaining showed normal or less than 1 cm images. Disease control (IGF-1 ≤ 1.2 x ULN) was achieved in 62.9% of patients with a mean dose of 11.8 mg/day. Thirty-four patients (45%) received PEGV monotherapy, while 41 (55%) received combined therapy with either somatostatin analogues and/or cabergoline. Adverse events related to PEGV were: local injection site reaction in 5.3%, elevated liver enzymes in 9.3%, and tumor size growth in 9.8%. Pre-PEGV IGF-I level was the only predictor of treatment response: 2.1 x ULN vs 2.8 x ULN in controlled and uncontrolled patients respectively (p < 0.001). Conclusion: this long term experience indicates PEGV treatment was highly effective and safe in our series of Argentine patients with acromegaly refractory to standard therapies. Arch Endocrinol Metab.

No abstract

Background Acromegaly is associated with higher morbidity and mortality mainly due to cardiovascular disease. Data on the incidence and evolution of thyroid cancer in acromegaly are controversial. Our objective was to describe the characteristics of a group of acromegalic patients with differentiated thyroid carcinoma (DTC) and analyze their evolution. Methods This is a retrospective multicenter study of 24 acromegalic patients with DTC. The AJCC Staging System 8th Edition was used for TNM staging, and the initial risk of recurrence (RR), initial response and response at the end of follow-up (RFU) were defined according to the 2015 ATA Guidelines. As a control group, 92 patients with DTC without acromegaly were randomly included. Statistical analyses were done using SPSS Statistics 20.0. Results Median age of patients at diagnosis of acromegaly was 49.5 years (range 12–69). The median delay in diagnosis of acromegaly was 3 years (range 0.5–23). Mean baseline IGF-1 level was 2.9 ± 1.1 ULN. Median age at DTC diagnosis was 51.5 years (18–69). At the moment of diagnosis of DTC, 58.3% of the patients had active acromegaly. Median time from DTC diagnosis to acromegaly control was 1.25 years (0.5–7). Mean DTC tumor diameter of the biggest lesion was 14.6 ± 9.2 mm, being multifocal in 37.5%. All tumors were papillary carcinomas, two cases being of an aggressive variety. Lymph node dissection was performed in 8 out of 24 patients and 62.5% had metastases. Only one patient had distant metastases. Radioiodine ablation was given to 87.5% of patients. Nineteen patients (79%) were stage I, four (17%) stage II and one (4%) stage IVb. Initial RR was low in 87% (21/24), intermediate in 9% (2/24) and high in 4% (1/24) patient. RFU was: 83% (19/23) patients with no evidence of disease, 9% (2/23) with indeterminate response, 4% (1/23) with biochemical incomplete response and 4% (1/23) with structural incomplete response, at a median time of FU of 36.5 months. When comparing RFU between acromegalics and controls no statistically significant differences were found. Conclusions Patients with acromegaly and DTC mostly had a low initial RR. When compared with the control group, we found that DTC patients with acromegaly did not have a worse evolution.

Cushing’s disease (CD) is an endocrine disorder originated by a corticotroph tumor. It is linked with high mortality and morbidity due to chronic hypercortisolism. Treatment goals are to control cortisol excess and achieve long-term remission, therefore, reducing both complications and patient’s mortality. First-line of treatment for CD is pituitary’s surgery. However, 30% of patients who undergo surgery experience recurrence in long-term follow-up. Persistent or recurrent CD demands second-line treatments, such as pituitary radiotherapy, adrenal surgery, and/or pharmacological therapy. The latter plays a key role in cortisol excess control. Its targets are inhibition of adrenocorticotropic hormone (ACTH) production, inhibition of adrenal steroidogenesis, or antagonism of cortisol action at its peripheral receptor. Retinoic acid (RA) is a metabolic product of vitamin A (retinol) and has been studied for its antiproliferative effects on corticotroph tumor cells. It has been shown that this drug regulates the expression of pro-opiomelanocortin (POMC), ACTH secretion, and tumor growth in corticotroph tumor mouse cell lines and in the nude mice experimental model, via inhibition of POMC transcription. It has been shown to result in tumor reduction, normalization of cortisol levels and clinical improvement in dogs treated with RA for 6 months. The orphan nuclear receptor COUP-TFI is expressed in normal corticotroph cells, but not in corticotroph tumoral cells, and inhibits RA pathways. A first clinical human study demonstrated clinical and biochemical effectiveness in 5/7 patients treated with RA for a period of up to 12 months. In a recent second clinical trial, 25% of 16 patients achieved eucortisolemia, and all achieved a cortisol reduction after 6- to 12-month treatment. The goal of this review is to discuss in the context of the available and future pharmacological treatments of CD, RA mechanisms of action on corticotroph tumor cells, and future perspectives, focusing on potential clinical implementation.

Pregnancy is associated with a physiological GH excess, where maternal pituitary GH is suppressed by effect of placental GH on the hepatic receptor, increasing IGF-1 serum levels1. However, it is also described that estrogens and progesterone are responsible for reduction in IGF-1 by direct hepatic action through the inhibition of the JAK-STAT pathway that results in GH resistance, being more clear at the beginning of pregnancy.2 Acromegaly is a rare disorder in which GH axis is deregulated and IGF-1 is the most reliable biochemical marker for diagnosis and monitoring. It is know that secondary hypogonadism associated with these pathology decreases fertility rates. Nonetheless, improvement of acromegaly treatment and greater access to assisted reproductive technology increase pregnancy rates in this population. The follow-up of pregnant acromegalic women acquires relevance for the comorbidities of this association and depends on the adequate interpretation of the IGF-1 values. Then, due to changes in concentration and action of IGF-1 during pregnancy3, it is important that each laboratory establish their specific reference values. For that reason we analyzed serum samples from 80 healthy pregnant women living in the Metropolitan Area of Buenos Aires (AMBA): 22 were in the 1st trimester (1T), 29 in the 2nd (2T) and 29 in the 3rd (3T). All women were between 30 and 40 years old, had no endocrinopathies or metabolic diseases. Serum IGF-1 was measured by Immulite 2000 Siemens, and Prism8 GraphPad was used for statistical analysis, calculating ranges for each trimester defined as 2,5 and 97,5 percentiles. Ranges obtained were: 64,5-165,0 ng/ml, 78,9-201,0 ng/ml and 96,1-344,0 ng/ml for 1T, 2T and 3T, respectively. Significant differences were observed between 3T and the other trimesters (1T and 2T). We also compared these ranges with our reference values from healthy non-pregnant women in the same age, and found that 3T has significantly higher values ​​of IGF-1 (55,8-188,4 ng/ml vs. 96,1-344,0 ng/ml respectively). In conclusion, IGF-1 levels during the first two trimesters of pregnancy remain within the normal range, and there is a significant increase during the third trimester. Given that IGF-1 plays an essential role during pregnancy, it is important to report ranges in healthy pregnant women to contribute in the follow-up of patients with acromegaly who get pregnant. Although our results are in agree with the available literature, it is necessary to increase the number of healthy pregnant women to establish reference values of IGF-1. 1Frankenne et al (1988). The physiology of growth hormones in pregnant women and partial characterization of the placental GH variant. Journal of Clinical Endocrinology and Metabolism 66:1171-1180 2Leung et al (2004). Estrogen regulation of growth hormone action. Endocrine Reviews 25:693-72 3Muhammad et al (2017). Pregnancy and acromegaly. Pituitary 20:179-184

No abstract

Introduction: Pituitary Metastases (MTS) are infrequently seen in clinical practice. The incidence ranges from 0.14 to 28%. Breast and lung cancer are the primary sites that most frequently metastasize to sellar region, between the sixth and seventh decades of life. Most cases are diagnosed in patients with advanced malignant disease, however, in 20-30%, symptoms of pituitary involvement can precede the diagnosis of the primary tumor. Objectives: To evaluate symptoms at presentation, hormonal, radiological and histological findings, management and outcome of a series of patients with pituitary MTS. Patients and methods: medical records of 16 patients from eight Endocrine Centers were reviewed. Ten patients had histological confirmation of the pituitary MTS, 6 were not operated, being the diagnostic criteria the presence of sellar mass associated with diabetes insipidus (DI) and / or sudden-onset of neuro-ophthalmological symptoms in patients with confirmed primary neoplasia. Results: The median age was 54 years (range 35-70), 9 women (56.2%). The sites of the primary tumor were: 7 lung (44%), 5 breast (32%), 1 follicular thyroid carcinoma (6%), 1 Hodgkin lymphoma (6%), 1 poorly differentiated carcinoma (6%), and 1 clear cell renal carcinoma (6%). The median time between the diagnosis of the primary neoplasm and the occurrence of the pituitary MTS was 12 months (range: 3-120). In 9 patients (56.2%), the diagnosis of the primary neoplasm was made after the finding of the symptomatic sellar mass. DI was found in 14 patients (87.5%), adenohypophyseal deficit in 12 (75%), visual disorders in 10 (62.5 %), headache in 6 (37.5%) and cranial nerve deficits in 6 (37.5%). In 68.7% (11 patients), other MTS were detected. Fifteen patients were evaluated by MRI and one by CT: 13 (81.3%) harbored supra / parasellar masses, and the remaining 3 had lesions limited to the pituitary gland, with stalk thickening and lack of spontaneous neurohypophysis hyperintensity in 2 of them. In all cases diffuse gadolinium uptake was present. Fourteen patients died (87.5%), with a median survival time of 6,5 months (range: 1-36); the remaining 2 are still alive with a follow-up period of 4 and 12 months respectively. Conclusions: In this series of 16 patients with pituitary MTS, the most frequent primary neoplasms were lung and breast. Median age was lower than in published series. DI was the most common condition at presentation, followed by hypopituitarism and visual disorders. The short survival was related to the extent of the disease at the time of diagnosis. In more than half of the cases the diagnosis of primary neoplasia was made through the symptomatic pituitary mass. In the presence of a pituitary lesion with diffuse gadolinium uptake, associated with DI and / or acute visual deficit, pituitary MTS should be suspected even in patients without a history of oncological disease.

Introduction Acromegaly is associated with higher morbidity and mortality due to malignant neoplasms. However, data on the incidence and evolution of thyroid cancer in acromegaly is controversial. Objectives: To describe the clinical and biochemical characteristics of a group of acromegalic patients with differentiated thyroid carcinoma (DTC). Identify any predicting factor for DTC evolution. Analyze risk of recurrence (RR), initial response to treatment and response at the end of follow-up (RFU), comparing the outcomes with non-acromegalic patients with DTC. Patients and methodsRetrospective, multicenter study of 16 acromegalic patients with DTC. Acromegaly control or remission was defined with an IGF-1 ≤1 ULN with or without medical treatment (MT) respectively. AJCC Staging System 8th Edition was used for TNM staging, and the initial RR, initial response and RFU were defined according to ATA Guidelines 2015. As a control group, 56 patients with DTC without acromegaly were selected. Statistical analyses were done using SPSS Statistics 2.0. Results Median age of patients at the diagnosis of acromegaly was 44 years (range 12-69). Delay in diagnosis of acromegaly was a median of 2.5 years (range 0.5-10). Basal mean IGF-1 level was 3.2 ± 1.2 xULN. Surgery was performed in 85.7%. Post surgically, the best mean IGF-1 was 1.24 ± 0.34 xULN. Control with MT was achieved in 80%, with a median time to control since diagnosis of 21 months (6-132). Mean age at CDT diagnosis was 46.5 years (18-69). No patient had personal history of cervical irradiation. Most patients (86.7%) had normal thyroid function tests At the moment of diagnosis of DTC 62.5% of the patients had active acromegaly, IGF-1 of 2.5 ± 1.4 xULN. Median time from CDT diagnosis to acromegaly control was 1 year (0.5-7). Mean DTC tumor diameter of the bigger lesion was 13.7 ± 7.4 mm, being multifocal in 40% of the cases. All were papillary carcinoma, one case an aggressive variety. In 6/15 lymph node dissection was done, 50% with metastasis. One patient had distant metastasis. Radioiodine ablation was given to 87.5%, mean dose 115 ± 64.5 mCi. Twelve of the patients were stage I, 3 stage II and 1 IVb. Initial RR was low in 14/16, intermediate in 1 and high in 1 patient. RFU was: 13/15 with no evidence of disease, 1 patient with biochemical incomplete response and 1 with structural incomplete response, on average at 47.7 ± 33.3 months of FU. No statistically significant correlations were found between characteristics of the acromegalics and DTC outcomes. When comparing response on FU between acromegalics and controls no statistically significant differences were found. Conclusions The acromegalics with DTC had a low initial RR, that could be related to an early diagnosis of DTC (anticipated bias). We did not find any predisposing factor for unfavorable evolution. When comparing with the control group, we can conclude that DTC in acromegaly does not have a worse evolution.