ResearchPad - pituitary-tumors-ii Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[MON-303 Giant Growth Hormone Secreting Pituitary Adenomas: A Single Institution Case Series]]> The prevalence of growth hormone (GH)-secreting pituitary adenoma is around 11-13% of all pituitary adenomas. Giant GH-secreting pituitary adenomas (≥ 4 cm) are rare tumors, and its prevalence of among acromegalic patients is <5%.

This is a retrospective cohort study including patients with giant GH-secreting pituitary adenomas. The study population consisted of 10 patients (5 M/5 F). The mean age at diagnosis was 33.0±12.9 yrs (11-55 yrs). The mean delay between first symptom onset and diagnosis was 2.9 years. The most frequent symptoms were acral enlargement and facial changes (80%), followed by headache (70%) and visual deterioration (50%). One patient had epilepsy. Amenorrhea was presented in three females but obvious galactorrhea in two. The mean adenoma diameter was 42.6±4.7 mm (40-51 mm) at diagnosis. The vast majority of adenomas presented suprasellar extension (100%) or cavernous sinus invasion (80%). Cystic adenomas accounted for 50%. At presentation, mean GH and IGF-1 levels were 40.0±21.4 ng/mL (14.8-51.0) and 2.62±1.09 x ULN (1.08-3.96), respectively. Six patients presented with PRL cosecretion. At diagnosis maximal tumor diameter was not correlated with GH or IGF-1 levels.

All patients underwent pituitary surgery as first-line treatment. Three cases were treated with an endoscopic approach and four cases with a microscopic approach. Transcranial approach was also employed in three cases. Postoperative mean GH and IGF-1 levels were 14.9±16.1 ng/mL (0.6-51.0) and 2.25.±0.82 x ULN (1.48-3.74), respectively. After first surgery, only one patient had more than 50% reduction in IGF-1 levels. Five patients (50%) underwent repeat surgery on two to three procedures because remission was not achieved. Postoperative somatostatin receptor ligands (SRLs) were used by all patients. Six patients were treated with dopamine agonist in combination with SRL. Six patients (60%) received postoperative radiotherapy.

The mean follow-up period was 12.6±5.3 yrs (4-21 yrs). The mean GH and IGF-1 levels were 1.47±1.54 ng/mL (0.08-5.25) and 0.73±0.44 x ULN (0.08-1.56), respectively at the last visit. Residual adenoma was present at the last MRI in eight patients (mean diameter 9.0±3.6 mm). Panhypopituitarism rose from 10% at baseline to 30% at the last visit. During follow-up, one patient diagnosed breast cancer, while another diagnosed thyroid papillary cancer.

Giant GH-secreting pituitary adenomas can have a clinically aggressive behavior with mass effect. Moreover, treatment in patients with giant GH-secreting pituitary adenoma is complex and multimodal therapy is necessary.

<![CDATA[MON-318 Acute, Life-Threatening and Perioperative Complications in Cushing’s Syndrome: Predictors and Outcomes]]> Introduction

Cushing’s syndrome is associated with significant chronic and acute comorbidities including acute thromboembolic and cardiovascular events. To date, there are no data on the prevalence and predictors of acute and perioperative complications in patients with active Cushing’s syndrome.


In a single-center cohort analysis we evaluate predictors and outcomes of acute, life-threatening and perioperative complications in patients with active biochemically verified Cushing’s syndrome attending our endocrine department between 1978 and 2016. Any medical complications necessitating hospitalization, including admission to intensive care units (ICUs), from the time of appearance of first symptoms of hypercortisolism until one year after biochemical remission by surgery (or where surgical remission was not achieved, during continuing follow-up) were recorded and classified. Baseline factors related to and predicting acute complications were tested using uni- and multivariate analysis.


The study included 242 patients (m/f n=54/188) with Cushing’s syndrome (pituitary n=99, adrenal n=116, ectopic n=27), 14.0% of which had malignant disease.

At least one acute complication was observed in 54.5% of patients; these included electrolyte disturbances (24.4%), infections (27.7%), thromboembolic events (14.9%), cardiac arrhythmias necessitating medical intervention (5.4%), hypertensive crises (8.7%), acute coronary events (3.3%) and cerebrovascular events (4.1%). At least one ICU admission (excluding post-surgical observance) was required in 13.2% of patients. The majority of complications occurred prior to surgery (60-90%); infections occurred pre- and postoperatively (51.7% vs 48.3%, respectively).

Patients with ectopic Cushing’s syndrome demonstrated a higher likelihood of infection (p<0.001), hypokalemia (p<0.001) and ICU stays (p=0.009) compared to patients with pituitary or adrenal Cushing’s syndrome. Patients with diabetes mellitus at diagnosis (n=81) had a significantly higher frequency of infection (p<0.001), hypokalemia (p<0.001), hypertensive crises (p=0.004), acute coronary events (p=0.029), arrhythmias (p=0.025) and a higher likelihood of an ICU stay (p<0.001).

The total number of acute complications and the number of days at ICU correlated positively with parameters of cortisol excess including urinary free cortisol and the time of hypercortisolism.


This cohort analysis identifies a significantly high prevalence of acute and perioperative complications in Cushing’s syndrome, with one in eight patients suffering a life-threatening situation necessitating ICU admission. These acute complications are positively predicted by the degree of hypercortisolism, emphasizing the necessity for acute interventions aiming to reduce cortisol excess even before definitive disease cure is achieved.

<![CDATA[MON-310 Factors Associated with Remission After Surgery for Acromegaly]]> Background: Acromegaly is a disorder characterized by excessive growth hormone (GH) secretion, which, in most cases, is caused by a GH secreting adenoma. Surgical removal of the tumor via a transsphenoidal approach is the first choice treatment for most patients. The remission rate after an initial resection is 80 to 90 percent for microadenomas and less than 50 percent for macroadenomas.

Objective: To analyze predictive factors of remission in acromegaly patients who underwent transsphenoidal surgery for GH secreting adenoma.

Methods: From January 2006 to October 2019, 75 patients with GH secreting pituitary adenoma were evaluated at our center. Patients who had undergone medical treatment or radiotherapy as first treatment were excluded. A total of 60 patients were included in the analysis. Remission was defined as normal serum insulin-like growth factor-1 (IGF-1) age and sex adjusted and a random serum GH less than 1 ng/mL and/or nadir GH during oral glucose tolerance test <0.4 ng/mL.

Results: We evaluated 60 patients (41 females and 19 males), with a mean age at diagnosis of 49.6 (ranged from 23 to 77 years). Mean initial IGF-1 was 905.3 ng/mL (range 100-324) and mean initial GH was 25.0 ng/mL (<2.5). Macroadenomas were more common than microadenomas (48 vs 12). The average maximum tumor diameter was 15.6 mm and 21 patients were graded as Knosp 3 or 4, which indicated cavernous sinus invasion. Patients were follow for 11.8 years. Overall, the remission rate was 50.0% after surgery. Mean age of patients in surgical remission (51.6 years) was higher than those patients not in remission (47.5 years) (p=0.439). Remission rates for microadenomas and macroadenomas were 75.0% and 44.9%, respectively (p=0.04). Patients who achieved remission had smaller tumors compared with those who failed to attain remission (mean diameter 11.6mm versus 17.8 mm). Using the Knosp classification system and preoperative magnetic resonance images to determine cavernous sinus invasion, Knosp grade 3 to 4 tumors were found in 5 patients in remission and in 16 patients with persistence of disease (p=0.003). Patients who achieved remission had a significantly lower preoperative IGF-1 level (650.5 ng/mL) compared with those who did not (1211.0 ng/mL) (p=0.04). Preoperative GH levels were lower for the patients who achieved remission (18.7 ng/mL) than for those who did not (32.5 ng/mL, p=0.006).

Conclusions: In our study, predictors of biochemical remission after surgery were smaller tumor size, lower Knosp grade, and lower preoperative GH and IGF-1 levels.

<![CDATA[MON-LB46 Thyrotropinoma and Pregnancy]]> Thyrotropinomas (TSHomas) are rare pituitary tumours, comprising 1-2% of all pituitary adenomas. Thyrotropinomas in pregnancy are exceedingly rare and management of these in pregnancy can be challenging due to the potential for maternal and foetal harm. We report the case of a 35 year old woman who was found to have a pituitary macroadenoma on imaging whilst being evaluated for headaches and sinusitis. She had felt more stressed than usual but no other overt thyrotoxic symptoms. There were no visual field abnormalities or symptoms to suggest other endocrine hypo or hypersecretion. Pituitary MRI revealed a macroadenoma and biochemistry demonstrated raised free T4 24 pmol/L and free T3 6.8 pmol/L and inappropriately elevated TSH of 4.2 mIU/L, in keeping with secondary hyperthyroidism. She was scheduled for transsphenoidal (TSA) pituitary surgery, however on review she had naturally fallen pregnant. After a multi-disciplinary discussion, it was decided that surgery should be deferred and close observation be undertaken under the care of a multidisciplinary team. During the first half of pregnancy she suffered hyperemesis gravidarum with ongoing thyrotoxicosis but declined carbimazole. Her visual fields were normal throughout pregnancy. She delivered vaginally at 38 weeks, weight 3.395kg and had no malformations. Post birth was complicated by post-partum haemorrhage requiring multiple blood transfusions and intensive care. One week later after recovering, she was able to commence breastfeeding. She went on to TSA at 6months post partum with complete tumour resection. This case demonstrates the complexity of managing TSHomas in pregnancy and the potential cross reactivity of the early hCG rises with the already elevated TSH levels, likely exacerbating her hyperemesis gravidarum.

<![CDATA[MON-299 Risk Factors of Re-Growth of Non-Functional Pituitary Adenomas]]> The aim of investigation to determine clinical aggressiveness diagnostic markers in patients with non-functional pituitary adenomas (NFPA) in the formation of gravity neuroendocrine disease symptoms. Material and Methods: We observed in 87 patients (including man - 44 women -43) of which have a verified diagnosis of NFPA after surgery - 31 which were subjected transnasal adenomectomy of the pituitary (TAG). Further analysis was performed on these patients, who were followed from 1 to 3 years. Results. After the analysis of the frequency of remission and relapse NFPA data selectively in patients we studied the correlation between various parameters and the frequency of relapses. NFPA developed the scale of aggressiveness allowed to identify the risk factors of markers on the 3rd degrees, allowing to create a set of measures of tumor growth relapse prevention. According to MRI data of the brain and pituitary gland, in 15 patients an endosellar tumor was found, in 16 - an endo-extrasellar tumor. In an MRI study, the structure of the NFPA had a predominantly soft tissue (n = 16) and cystic (n = 11) structure. In 4 cases (13%), the structure of the NFPA was represented by a hemorrhagic component, and in 2 (6.4%) of them, both cystic and hemorrhagic components were present. In 18 patients, microadenoma was revealed, in 12 - pituitary macroadenoma and in 1 - a giant pituitary adenoma. The developed scale of aggression markers of NFPA allowed identifying factors by 3 degrees, which allows developing a complex of measures for the prevention of tumor growth recurrence. Conclusions. 1) According to our data, the number of patients with large-cell chromophobic pituitary adenoma predominated - 24 (77.5%). In 2nd place were patients with small cell NFPA - 6 cases (19.3%). And only in 1 case was observed (3.2%) a giant malignant pituitary macroadenoma with recurrence of growth and metastasis in the brain of a teenage girl, in which dark-cell pituitary adenoma was histologically determined, 2) According to our preliminary data, the markers of aggressiveness of the course of NFPA are: young patient age, first symptoms of the disease manifest, large tumor size, asymmetry and deformation of the pituitary gland, signs of tumor invasion into adjacent tissues / arteries / cavernous sinus, presence of small cell and / or dark extracellular chromophobic adenomas, STH hypopituitarism, panhypopituitarism.

<![CDATA[MON-323 IGF-I Variability and Its Association with Demographic and Clinical Characteristics in Patients with Acromegaly Treated with Injectable Somatostatin Receptor Ligands (SRLS); Results from an International Prospective Phase III Study]]> Background: In clinical practice, most patients responding to injectable somatostatin receptor ligands exhibit IGF-I variability around the upper limit of normal (ULN) during long-term follow up. These fluctuations are thought to result from various factors such as assay variability, nutrition, comorbid conditions, concomitant medications and other unknown factors. The magnitude of this variability, and the factors affecting it, is not well understood in patients with acromegaly treated with injectable SRLs. Methods: IGF-I levels of patients responding to and stably treated with injectable SRLs were measured over time in the CHIASMA OPTIMAL phase III study. Two time periods were assessed - Period 1, three assessments during screening phase before randomization to octreotide capsules (N=56), and Period 2 - multiple assessments up to week 36, in patients rescued with SRL injections for at least 12 weeks (N=21). The time from the last injection to each of the 3 assessments in period 1 [Screening visits 1 and 2 (SV1 & SV2), and Baseline (BL)], was on average 6.8 ± 10.7 (SD), 15.8 ± 2.7, and 29.0 ± 1.8 days respectively. Correlation with various demographics and Baseline characteristics, including age, gender, weight, BMI and residual tumor size to IGF-I variability was assessed. Percent change for each individual patient from Minimal to Maximal IGF-I values within each period was computed and the overall population mean was calculated (lowest value was used as the denominator and all other values were expression as a positive % above this value). Results: The overall mean within-patient percent change of IGF-I levels during Period 1 was 20.48 ± 15.56 (range: 0.6-81). Mean IGF-I levels for SV1, SV2 and BL were 0.78 ± 0.18, 0.79 ± 0.18, and 0.85 ± 0.22 x ULN respectively. The overall increase in mean IGF-I levels from SV1 to BL (longest time interval) was statistically significant (p=0.0002; paired T-test). Analysis of IGF-I levels in patients during Period 2, revealed that the overall mean within-patient percent change of IGF-I levels was 15.27 ± 12.20 (range: 0-41.5). The mean duration of follow up during this period, after patients were already treated for ≥12 weeks with injectable SRL, was 1.72 (± 1.29) months. The variability observed in Period 2 was similar to that observed in the entire sample evaluated in Period 1. No significant differences were found in the mean IGF-I percent change between any demographic or baseline characteristic subgroup examined. Conclusion: IGF-I levels fluctuate in patients with acromegaly who are responsive to injectable SRLs. These fluctuations are wide and can be up to 81% higher than the lowest (most controlled) value, with an average increase of approximately 20%. Significant IGF-I increases were observed at the end of the long acting SRL injection interval.

Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

<![CDATA[MON-LB49 Atypical Presentation for a 5.5-cm Macroprolactinoma: Unilateral Visual Loss and Only Partial Hypopituitarism; Asymptomatic Hypogonadism]]> Background: Macroprolactinoma is an uncommon pituitary tumor which presents mainly in males. The usual presentation is headache, bitemporal hemianopia, and signs/symptoms of hypogonadism. Ours is a case report of 5.5 –cm macroprolactinoma presented with unilateral optic nerve atrophy and asymptomatic hypogonadism.

Clinical case: A 50-year-old male with past medical history of type 2 diabetes mellitus and essential hypertension presented with progressive blurred vision of the left eye for 6 months. He was able to perceive color but had difficulty reading. There was occasional headache with left periorbital pain. He was seen by an optometrist and was found to have left optic disc atrophy with suspicion of glaucoma. Subsequent visual field test showed entire left and right superior temporal loss. MRI of the pituitary showed 5.5 x 5.6 x 5.3 cm enhancing mass centered in the sellar/suprasellar region. There was significant mass effect with compression of the optic chiasm, temporal lobe and brainstem. The patient reported mood changes, normal libido, but loss of morning erection. He has family history of pituitary macroadenoma with left optic nerve compression. On physical examination, there were left visual field defect and decreased visual acuity. There were no signs of Cushing’s syndrome, hypothyroidism, acromegaly, or hypogonadism. Laboratory tests showed prolactin of >200 ng/ml and 16,610 ng/ml after dilution (male <13), total testosterone 92 ng/dl (240-950) and free testosterone 1.20 mg/dl (4.26-16.40). Surprisingly, other pituitary hormones were normal: AM cortisol 20.3 µg/dl (6-27), GH 0.24 ng/ml (0.01-0.97), IGF-1 58 ng/ml (40-259), FSH 4 IU/l (1-18), LH 3 IU/l (1.3-9.6), TSH 1.38 µIU/ml (0.34-3), and free T4 0.8 ng/dl (0.6-1.6). The patient underwent surgery with partial resection. Pathology revealed lactotroph adenoma. Postoperative prolactin level was 11,900 ng/ml. Medical treatment with cabergoline 0.25 mg twice weekly has been started.

Conclusion: Even though profoundly hypogonadal by labs, the presentation for this 5.5-cm prolactinoma was acute vision loss. The highly elevated prolactin level correlates with the size of macroadenoma. The typical presentation of local mass effect is bitemporal hemianopia, but in our case the patient presented with unilateral optic nerve atrophy. Despite a 5.5-cm lesion, there is partial hypopituitarism; hypogonadism. Based on the size, one would have expected panhypopituitarism. Given a family history of macroadenoma, there might be genetic predisposition. Molecular testing is planned.

<![CDATA[MON-297 Withdrawal from Long-Acting Somatostatin Receptor Ligand Injections in Adult Patients with Acromegaly: Results from the Phase 3, Randomized, Double-Blind, Placebo-Controlled CHIASMA OPTIMAL Study]]> Data on the impact of withdrawal from long-acting somatostatin receptor ligand (SRL) injections on disease activity in patients with acromegaly are limited. The phase 3 Octreotide capsules versus Placebo Treatment In MultinationAL centers (OPTIMAL) study assessed the efficacy and safety of oral octreotide capsules in adult patients with acromegaly responding to injectable SRL therapy. The placebo-controlled arm of this study allowed for assessment of acromegaly biochemical and disease activity in patients after withdrawal from SRL treatment. A multinational, randomized, placebo-controlled study was conducted in 56 adult patients with active acromegaly. Patients were ≥ 18 years of age, had evidence of active disease (defined as IGF-I ≥1.3 x ULN after last pituitary surgery), and an average IGF-I ≤ 1.0 x ULN in response to a stable dose of SRL injection. Patients were randomized, 1 month following their last injection, to octreotide capsule or placebo for 36 weeks, with an option to enroll in an open-label extension. The primary aim was to determine the proportion of patients maintaining biochemical response, defined as IGF-I ≤1.0 x ULN (average of week 34 and 36). The trial met the primary endpoint, with 58% (16/28) of patients receiving octreotide capsules maintaining IGF-I response vs 19% (5/28) receiving placebo (P=0.008). The median time to loss of response (2 criteria evaluated: IGF-I >1.0 and ≥ 1.3 x ULN for 2 consecutive visits) was 16 weeks in the placebo group, while it was not reached in the octreotide capsule group. Of the 5 patients in the placebo group who maintained their biochemical response at 36 weeks, only 2 (7% of placebo group) did not meet loss of response criteria. When IGF-I values for any 2 consecutive visits were analyzed for patients receiving placebo, 93% (26/28) lost response based on IGF-I > 1 x ULN and 79% (22/28) lost response based on IGF-I ≥ 1.3 x ULN. Irrespective of biochemical control of acromegaly, 26/28 patients receiving placebo experienced active disease-related symptoms reported as AEs of special interest (AESIs). Most common AESIs (≥ 5%) included arthralgia/arthritis (60.7%), soft tissue swelling (35.7%), headache (32.1%), hyperhidrosis (25%), carpal tunnel (14.3%), musculoskeletal pain (14.3%), weight increased (7.1%) and tongue disorders (7.1%). The 5 patients receiving placebo with controlled IGF-I at 36 weeks received active medical treatment in the open label extension by decision of their study PIs, as they were deemed to have either lost their response during the study or had continuing active acromegaly symptoms. 93% of patients receiving placebo lost response following withdrawal of injectable SRLs, with a median duration of 16 weeks. All 5 patients receiving placebo who met the primary endpoint criteria at the end of the study were assessed clinically to have active disease and were continued on oral SRL treatment in the open label extension.

<![CDATA[MON-321 AgRP and Food Cravings Decrease with Treatment of Cushing’s Disease]]> Cushing’s disease (CD) is characterized by chronic exposure to excess glucocorticoids due to an ACTH-producing tumor. Obesity is a prominent feature of CD, although the mechanisms of weight gain have not been completely elucidated. In some patients, obesity persists despite appropriate medical or surgical treatment of CD and normalization of cortisol levels (1). Few studies have followed patients prospectively to understand the effect of CD remission and cortisol normalization on appetite and body weight. Previous studies have not shown a correlation between appetite or food cravings and circulating total peptide YY (PYY), ghrelin, or leptin concentrations, leading to interest in other hormones which may regulate appetite in CD (2). One of these is the neuropeptide Agouti-related protein (AgRP). AgRP is known to promote appetite and decrease energy expenditure by acting as a melanocortin antagonist at the level of the hypothalamus. Plasma AgRP may be elevated in patients with active CD and decreases with normalization of cortisol levels (3). We sought to determine if AgRP may play a role in regulating appetite or food cravings in CD. Plasma AgRP was measured before and prospectively after treatment in 19 patients with CD. Patients completed surveys on appetite and food cravings at these same time points. As expected, AgRP significantly decreased following treatment for CD, with mean AgRP before treatment 128.72 pg/mL (SD 55.41) and mean AgRP after treatment 75.23 pg/mL (SD 23.46). Using a paired t-test, the mean difference of 53.5 pg/mL was significant (p=0.0006). In addition, there were significant decreases in BMI, weight, and waist circumference with CD treatment. We found that plasma AgRP concentrations did not correlate with an 8-question visual analogue scale (VAS) used to assess hunger and satiety. However, treatment of CD significantly reduced Trait Food Craving Questionnaire scores in parallel with circulating AgRP levels using a one-way analysis of variance (p=0.004). Our data suggest that AgRP may play a role in food craving, rather than appetite, in patients with CD. Further research may clarify the relationship between AgRP and food cravings in CD patients before and after treatment. References:

1. Geer et al. Endocrinol Metab Clin North Am. 2014; 43: 75-102.

Geer et al. Pituitary. 2016; 19: 117-126.Page-Wilson et al, J Clin Endocrinol Metab. 2019; 104 (3): 961-969.

<![CDATA[MON-317 Prognostic Factors and Mortality According to the Structural and Functional Classification of Acromegaly]]> Background: acromegaly is a systemic disorder caused by overproduction of growth hormone (GH) where most common cause is a pituitary somatotroph adenoma. Different prognostic factors have been previously reported, such as adenoma granulation, and p21 and somatostatin receptor type 2 (SSTR2) immunohistochemistry expression. Considering these factors, three different acromegaly subtypes were proposed. Type 1 tumors are dense granulated microadenomas with higher expression of p21 and SSTR2, with better prognosis. In contrast, type 3 are sparsely granulated, highly invasive macroadenomas, with less expression of SSTR2 and p21, and worst prognosis with less responsiveness to treatment. Type 2 adenomas showed intermediate prognosis. Objective: to determine independent prognostic factors according to somatotroph adenoma subtypes in patients with acromegaly.

Material and methods: this is a comparative, observational, longitudinal study. We classified patients according to p21, SSTR and tumor granulation as previously reported. Then, bivariate and multivariate using binary logistic and Cox-regression analyses were performed. Results: 222 patients (52% women and 48% men, mean age 40+-13 years old) with confirmed diagnosis of acromegaly were classified in the three acromegaly types. Mean age at diagnosis was significantly different among groups, with 45, 41 and 38 years old, in types 1 to 3, respectively (p 0.010). All patients with type 1 (n=47) showed microadenomas, and type 2 (n=72) and 3 (n=103) macroadenomas (p <0.001). Invasiveness was present in 11% in type 1, 0% in type 2, and 100% in type 3 (p <0.001). GH and the upper limit number IGF-1 index was significantly higher in in type 3 vs. type 1 (p <0.001). Hypertension (43% vs. 34% vs. 23%), cardiovascular/cerebrovascular disease (44% vs. 28% vs. 28%), diabetes (47% vs. 29% vs. 24%), hypertriglyceridemia (54% vs. 24% vs. 22%), and high LDL-c (43% vs. 30% vs. 27%) were significantly higher in type 3 vs. type 2 vs type 1 acromegaly patients, respectively (all p<0.05). Using multivariate Cox regression analysis (adjusted for neurosurgery and radiotherapy) we identified that type 3 acromegaly showed worst prognosis with higher probability of remaining active (2LogR=652.6, chi square=17.7, p=0.001), and higher mortality (2LogR=489, chi square=43, p<0.001) than type 2 vs. type 1 acromegaly patients at last follow-up. Independent parameters related with disease activity were acromegaly types 2 and 3 (OR=2.7; IC95% 1.9-6.7, p=0.005), and radiotherapy (OR=0.36, 0.18-0.70, p=0.003). Conclusions: Type 3 acromegaly patients showed higher frequency of comorbidities, disease activity, and risk of mortality, adjusted for treatment, than type 2 and type 1 patients.



Cuevas-Ramos, D., Carmichael, J. D., Melmed, S. (2015). A Structural and Functional Acromegaly Classification. JCEM, 100(1), 122–131.doi:10.1210/jc.2014-2468

<![CDATA[MON-326 Non Functioning Pituitary Adenomas (NFPA): Sex Related Differences in Presentation, Clinical Features and Outcomes]]> INTRODUCTION: NFPA are characterized as tumors without a typical hormonal hypersecretion syndrome. They are frequently diagnosed in the sixth decade, by visual field defects, hypopituitarism or incidentally. PATIENTS AND METHODS: retrospective and observational study that included 103 patients with NFPA (60 females) who were seen between 1999 and 2019 in our hospital. We compared and analyzed patients characteristics by sex: reason for consultation, hormonal status at diagnosis, invasiveness of the tumor through MRI, treatments and outcomeRESULTS: out of 103 patients, 58,2% were women (W). Men (M) were significantly older than women (56 vs. 45 yold. p=0,002). The presence of a macroadenoma was similar in both sexes (93%W vs. 94,7% M), however tumor invasiveness was more frequent in men (50% vs. 24,6%). Most men consulted for incidental finding (47,4% vs. 29,8%); most women consulted for symptoms related to the tumor(70% vs 52%): hypogonadism 31,6% W, 13% M; galactorrhea 17% W; visual field defects 21,7% W, 23,7%M, pituitary apoplexy 11,6% M. At baseline hormonal assessment hyperprolactinemia was more frequent (50,9% vs 42%) and higher in women (mean PRL levels 75 ng/ml vs. 37 ng/ml). Hypogonadism was more frequent in men (54% vs 42%) as well as hypopituitarism (15% vs. 10,5%). Surgery was the most used therapy in both sexes (69% M vs. 73%W) but males required more frequently second surgery and radiotherapy than females (15% vs. 5% and 10% vs. 5% respectively). Gonadotropin secreting adenoma was diagnosed in 62% of men and 37,5% by tumor immunohistochemistry, in the 45% of women who presented negative immunostaining the presence of a gonadotrophic lineage is not ruled out, median Ki-67 labeling was low in both sexes (2%). After surgery 66% of men and 37% of women showed tumor remnant > 1cm (p=0,001), tumor regrowth was seen in 38,4% men and 10,4% women (p=0,03). Hypogonadism was greater in men than in women (56% vs 39%). Ninety two percent of men and 60,9% of women developed some degree of pituitary deficiency after surgery (P<0,001). Men showed a higher degree of complete hypopituitarism compared to women (pretreatment 15% vs 10,5%, post treatment 32% vs 13%). CONCLUSION: NFPA in men are usually diagnosed incidentally at an older age, are more invasive at presentation with a higher incidence of pituitary dysfunction. Moreover, they presented with greater rate of tumor regrowth and hypopituitarism after surgery. NFPA in women are diagnosed earlier due to endocrine symptoms, had lower degree of invasiveness with better outcomes after treatment. Sex related differences in NFPA may be associated with the delay in diagnosis, although a more aggressive biology cannot be discarded.

<![CDATA[MON-328 Disorders of Glucose Metabolism in Cushing Syndrome in Uzbekistan]]> Relevance. Cushing’s Syndrome (CS) is a serious risk factor for developing impaired glucose tolerance disorder (GTD) and a manifestation of secondary diabetes mellitus (DM). On the other hand, the development of impaired glucose metabolism affects not only the course but also the outcome of SC. Moreover, their frequency varies from 10% to 45% of all cases of SC. The aim of investigation - to evaluate the frequency of various forms of impaired glucose metabolism in patients with SC according to the national registry in the Republic of Uzbekistan. Materials and methods. The object of the study was 264 patients included in the register, 182 women (68.9%); men 82 (31.1%) aged 16 to 49 years. Including ACTH dependent CS (ACTH-DS) 219 (82.9%), ACTH independent CS (ACTH-IS) 41 (15.5%), ACTH ectopic CS (ACTH-ES) 4 (1.5%). The levels of ACTH, cortisol, insulin, glucose, glycated hemoglobin were studied, tests with dexamethasone and an oral glucose tolerance test (OGTT) were performed; MSCT of the adrenal gland and MRI of the pituitary gland. Fasting glucose (IH), NTG and diabetes were determined according to international criteria (EASD 2019, IDF 2018) Results. It was found that out of 264 patients with SC, 136 (51.5%) had various disorders of carbohydrate metabolism (CM), including diabetes in 32.6 ± 2.9% (86 bp), GTD in 18, 6 ± 2.4% (49 bp) and NGN - in 0.4 ± 0.4% (1 bp). At the same time, diabetes developed in 33.3% of cases in patients with ACTH-DS, 24.4% of ACTH-IS and 75% with ACTH-ESC (p˂ 0.01; p˂ 0.001). Cases of prediabetes were mainly found in the form of NTG in 17.4% of ACTH-DS and 26.8% in ACTH-IS. Conclusions. In the Republic of Uzbekistan, CM took place in the overwhelming majority of patients with CS (51.5%) and clearly depended on the type of CS (ACTH-ES, AKTG-DS, AKTG-IS) and correlated with the degree of hypercortisolism.

<![CDATA[MON-300 AIP Gene Germline Mutations in Non-Selected Patients with Apparently Sporadic Pituitary Macrodenomas]]> Up to 5% of all pituitary tumors are hereditary (e.g. due to menin or AIP genes germline mutations). AIP gene mutations are more common in subjects with acromegaly, less than 30 years old at the onset of disease, and with FIPA family history.

The study was aimed at the assessment of the frequency and characteristics of AIP-mutation related tumors in non-selected patients with pituitary macroadenomas.

Material and methods. The study included subsequent 131 patients (57 males, 74 females; median age 42 years (IQR 25 years) diagnosed with pituitary macroadenomas, and with a negative family history of FIPA or MEN1 syndromes. The following tumors were identified: 11 ACTH-secreting, 49 GH-secreting (including 7 pluri-hormonal ones), 6 gonadotropinomas, 23 prolactinomas, 1 TSH-oma, and 43 non-secreting adenomas. Sanger sequencing was used for the assessment of AIP gene variants. The study was approved by the Ethics Board of JUMC.

Results. An AIP mutation was identified in five of 131 included subjects (3.8%): one diagnosed with Cushing’s disease, two with acromegaly, and two with non-secreting adenomas. In two patients, the identified mutation usually predisposes to ACTH-secreting adenomas, in two patients - mutations of unknown clinical significance were found (usually connected with pituitary adenomas), and the mutation detected in one patient was described as benign. Patients harboring hereditary AIP gene variations did not differ from the rest of the study group in median age at diagnosis (41 vs. 42.5 years, p=0.8), median largest tumor diameter (25 vs. 24 mm, p=0.6), gender distribution (60% of females vs. 56.3%, p=0.8), secreting tumor frequency (60% vs. 67.5%, p=0.7), or acromegaly diagnosis frequency (40% vs.37.3%, p=0.9). 2 of the 5 patients with identified AIP gene mutations agreed for their families to be offered AIP genetic testing: (1) An AIP mutation was found in the asymptomatic mother of one acromegalic female patient. (2) The AIP mutation of unknown clinical significance was detected in the son of a male acromegalic patient with acromegaly, clinically unscreened yet.

Conclusions. In our series of apparently sporadic pituitary macroadenomas, AIP gene mutation carriers did not differ substantially from patients with negative genetic testing. A risk factor-centered approach to AIP genetic screening may result in missing germline mutations, therefore, there is a need to establish if such a situation negatively impacts a patient’s and his/her family outcomes.

<![CDATA[MON-314 Analysis of Adverse Events in Adult Patients with Acromegaly Receiving Oral Octreotide Capsules: Results from the Phase 3, Randomized, Double-Blind, Placebo-Controlled CHIASMA OPTIMAL Study]]> Distinguishing non-specific signs and symptoms of acromegaly from treatment emergent adverse events (TEAEs) in patients treated with somatostatin receptor ligands has proven difficult given limited data from placebo-controlled studies. The phase 3 Octreotide capsules versus Placebo Treatment In MultinationAL centers (OPTIMAL) study provides a novel data set to evaluate the incidence of adverse events from patients randomized to octreotide capsules or placebo. A multinational, randomized, placebo-controlled study was conducted in 56 adult patients with active acromegaly. Eligible patients were ≥18 years of age, had active disease (IGF-I ≥1.3 x ULN after last pituitary surgery), and an average IGF-I ≤1.0 x ULN in response to a stable dose of somatostatin receptor ligand injection. Patients were randomized to octreotide capsule or placebo (28 per group) for 36 weeks, followed by an optional open-label extension for up to 1 year. Safety and tolerability were evaluated based on incidence of AEs, including incidence of new or worsening adverse events of special interest (AESIs). In this study, the safety profile of octreotide capsules was consistent with the known safety profile of injectable octreotide (Melmed et al 2015). No new or unexpected safety signals were detected. Nearly all patients (55/56) experienced a TEAE (28 patients [100.0%] in the octreotide capsule group and 27 patients [96.4%] in the placebo group). Thirty-three patients (58.9%) experienced a TEAE considered to be related to study drug by the blinded PI (64.3% of the octreotide capsule group [18 patients, 40 events] and 53.8% of the placebo group [15 patients, 41 events]). TEAEs with an incidence ≥5% that were more common in the octreotide capsule group vs placebo group included GI disorders, increased blood glucose, sinusitis, osteoarthritis, and cholelithiasis. TEAEs with an incidence ≥5% that were more common in the placebo group vs octreotide capsule group included arthralgia, headache, fatigue, hyperhidrosis, and peripheral swelling. GI disorders were the most common TEAE, reported in 64% of all patients (36/56) and at similar rates between octreotide capsule (68%) and placebo groups (61%). AESIs (defined as new or worsening signs of acromegaly) were observed in 15 patients (53.6%, 34 events total) in the octreotide capsule group and more frequently in 26 patients (92.9%, 82 events total) in the placebo group. In this study, the safety profile of octreotide capsules was consistent with the known safety profile of injectable octreotide. Most patients receiving octreotide capsules or placebo demonstrated TEAEs, although the profile of most common TEAEs varied between groups. TEAEs observed in the placebo group may be indicative of underlying disease activity. Further analysis may elucidate the difference between treatment related AEs and signs/symptoms of active disease in acromegaly.

<![CDATA[MON-311 Glucose Metabolism in Acromegaly Patients Resistant to First Generation Somatostatin Receptor Ligands Treated with Pegvisomant And/Or Pasireotide Lar]]> Introduction: Acromegaly (Acro) is a systemic disease characterized by high growth hormone (GH) and insulin like growth factor-I (IGF-I), insulin resistance, glucose intolerance (IGT) and higher diabetes mellitus (DM) risk in 15% - 38% of patients (pts). Moreover, different medical therapies of Acro are reported to have variable effects on glucose metabolism. An association between blood glucose (BG) and serum IGF-I levels in patients with DM and Acro has been suggested, while IGF-I levels and hemoglobin A1c (HbA1c) correlation is still controversial because of the multifactorial influence.Study aim: to investigate glucose metabolism in pts with Acro resistant to 1st gen somatostatin receptor ligands (SRLs) treated with Pegvisomant (Peg) or Pasireotide LAR (Pasi). Patients and Methods: Retrospective, international, multicenter study; consecutive pts enrolled according to following inclusion criteria for at least 6 consecutive months: (1) resistant to 1st gen SRLs, (2) treated with Pasi or Peg for active Acro. Patients with concomitant treatments with known action on glucose metabolism were excluded, with the exception of glucocorticoid replacement for central hypoadrenalism. Results: 72 pts with active Acro, mean age at study entry 37 ±15 yrs, 47 females (65.3%). 28 (38.9%) pts were treated with Pasi and 44 pts with Peg (61.1%). Peg was monotherapy in 18 pts (40.9%) and in combo with first generation SRLs for 26 pts (59.1%). The number of pts with IGT and DM2 was superimposable between the 2 groups (Pasi and Peg). In Pasi group, 19 pts had Acro control (67.9%); glucose metabolism worsened in 16 pts (57.1%). Worsening of glucose metabolism occurred most frequently in pts with persistently active Acro (62.5%) and in pts with higher BG and HbA1c values at study start. Similarly, HbA1c was higher in pts with active Acro, although HbA1c worsened during Pasi treatment both in euglycemic and IGT at study entry, regardless of Acro control. In Peg group, 31 pts reached Acro control (73%); glucose metabolism worsened in 12 (27.3%) but improved in 5 pts (11.4%). All pts who experienced glucose metabolism improvement had controlled Acro, regardless of the use of a combo with first generation SRL. Among the 13 pts with active Acro after Peg, BG worsened in 5 cases (38.4%). Moreover, we found that pts with worsening BG control had higher HbA1c (p=0.03) and required higher Peg doses (mean ±SD 25 ±10 mg/day; p=0.04). Patients with higher HbA1c had higher IGF-I, both at study entry and at study end and were treated with higher Peg dose (mean 25 mg/day). Conclusion: Impaired glucose metabolism was more frequent after Pasireotide treatment and in patients of both Pasireotide and Pegvisomant groups with altered pre-treatment glucose and persistently active disease. Therefore, in such acromegaly patients close monitoring of glucose status is recommended during treatment.

<![CDATA[MON-330 Cancer Incidence in 1,296 Patients with Acromegaly Is Not Increased: A Nationwide Population-Based Study]]> Background: Single- and multi-center studies have shown an increased incidence of malignancies in patients with acromegaly. These findings may be affected by selection bias. Our aim was therefore to investigate the incidence of malignancies in a nationwide unselected cohort of patients with acromegaly.

Methods: Adult patients diagnosed with acromegaly due to a pituitary tumor between 1987 and 2017 were identified in the Swedish National Patient Registry. All malignancies following the diagnosis of acromegaly were identified in the Swedish Cancer Registry that has a coverage of over 96%. Standardized incidence ratios (SIRs) for malignancies, with 95% confidence intervals (CI), were calculated by using the Swedish general population as a reference. Incidence of malignancies was also analyzed in sub-groups of patients treated with radiotherapy and in those having diabetes mellitus and hypopituitarism.

Results: A total of 1,296 patients with acromegaly were included (621 men, 675 women). The mean age (±SD) at diagnosis was 51.6±14.7 years. The mean follow-up was 12.7±8.3 years, with a total of 16,395 person years at risk. Pituitary surgery was performed in 842 (65%) patients and radiation therapy in 152 (12%) patients. The diagnosis of hypopituitarism and diabetes mellitus was recorded in 29% and 16% of patients, respectively. Overall, 186 malignancies were identified in patients with acromegaly as compared to 179 expected malignancies in the general population (SIR 1.04; 95% CI 0.90-1.20). Incidence of malignancies was similar in men and women [SIR 1.08 (95% CI 0.88-1.32) vs 1.00 (95% CI 0.80-1.23)]. Incidence of colorectal cancer (SIR 1.12; 95% CI 0.75-1.62) or malignancies of the respiratory system (SIR 1.22; 95% CI 0.76-1.84) was not increased. Incidence of kidney and ureter cancer (n=17) was, however, increased (SIR 3.81; 95% CI 2.22-6.11). In the entire study cohort, only three cases of thyroid cancer were recorded. SIR for malignancies in patients treated with radiotherapy (1.12; 95% CI 0.56-2.01) and in patients with hypopituitarism (SIR

0.91; 95% CI 0.68-1.18) or diabetes (SIR 1.08; 95% CI 0.78-1.45) did not differ from the general population.

Conclusions: This large nationwide population-based study showed that the overall incidence of malignancies in patients with acromegaly was not different from the general population. In particular, incidence of colorectal and thyroid cancer was not increased. Incidence of malignancies of the urinary tract was, however, increased.

<![CDATA[MON-332 Safety and Efficacy of Levoketoconazole in the Treatment of Endogenous Cushing’s Syndrome (LOGICS): A Double-Blind, Placebo-Controlled, Withdrawal Study]]> Endogenous Cushing’s syndrome (CS) is a rare, serious disorder caused by chronically elevated cortisol. A phase 3, open-label study (SONICS) of levoketoconazole in adults with CS and mean urinary free cortisol (mUFC) ≥1.5 × upper limit of normal (ULN) at baseline demonstrated normalization of mUFC in 62% of those completing 6 months of maintenance treatment (Fleseriu M, et al. Lancet Diabetes Endocrinol. 2019;7[11]:855-865). LOGICS is an ongoing, phase 3, double-blind, placebo-controlled, randomized-withdrawal study further investigating the safety and efficacy of levoketoconazole in patients who completed the SONICS study, or patients with CS who are levoketoconazole treatment-naive ( identifier: NCT03277690). The primary objective of LOGICS is to evaluate the effect of withdrawing levoketoconazole treatment to placebo, versus continuing treatment with levoketoconazole, on the cortisol therapeutic response established during open-label levoketoconazole therapy. The study includes (1) a screening phase (up to 13 weeks to allow for washout of CS medications); (2) a dose titration-maintenance phase (150-600 mg BID [dosed as needed to target mUFC normalization]) of ≥14 weeks, with at least the final 4 weeks demonstrating mUFC normalization prior to advancing to the randomized-withdrawal (R-W) phase; (3) a double-blind, placebo-controlled R-W phase (levoketoconazole or placebo; up to 8 weeks); and (4) a double-blind restoration phase (levoketoconazole and placebo; 8 weeks). Patients are randomized 1:1 in the R-W phase to continue their therapeutic dose of levoketoconazole, established during the dose titration-maintenance phase, or to receive an equivalent number of placebo tablets. Up to ~54 subjects are targeted for randomization. The primary efficacy endpoint, assessed at the completion of R-W phase, is the proportion of patients with loss of therapeutic response to levoketoconazole (mUFC ≥1.5x ULN, >40% above baseline if baseline value is >ULN [SONIC-completer cohort only], or early rescue criterion met) upon withdrawing to placebo, compared with continuing treatment with levoketoconazole, during the R-W phase. Secondary endpoints include changes from baseline to all postbaseline visits in R-W phase for mUFC, late-night salivary cortisol, CS cardiovascular biomarkers (fasting glucose, fasting insulin, hemoglobin A1c, homeostatic model assessment-insulin resistance, total and LDL cholesterol, high-sensitivity C-reactive protein), CS clinical signs and symptoms (acne, hirsutism [women only], and peripheral edema scores), and patient-reported outcomes of QoL (Cushing QoL questionnaire score) and depression (Beck Depression Inventory II). Potential liver toxicity, QT prolongation, and adrenal insufficiency are prespecified adverse events of special interest.

<![CDATA[MON-306 Acromegaly Comorbidity Costs, Quality of Life, and Mortality: Lifetime Comparisons for Controlled Acromegaly, Uncontrolled Acromegaly, and the General US Population]]> Acromegaly is a rare, chronic disorder characterized by hypersecretion of growth hormone (GH) that stimulates the production of insulin-like growth factor 1 (IGF-1). In addition to the physical manifestations, such as acral soft-tissue enlargement and maxillofacial changes, patients may develop a number of comorbidities, often prior to diagnosis. The goal of acromegaly treatment is to achieve biochemical control (normalization of GH and IGF-1 levels), which may resolve or prevent worsening of comorbid conditions. The objective of this study was to quantify the economic burden of comorbidities associated with acromegaly, including diabetes, hypertension, colon cancer, sleep apnea, and hypopituitarism. Comparisons were made between patients with acromegaly and biochemical control, patients with acromegaly without biochemical control, and the general population. Literature was reviewed to identify the prevalence of comorbidities among the groups, as well as the influence of each comorbidity on healthcare costs, quality of life, and mortality. Inputs from the literature were synthesized using a decision-analytic cohort model with a starting age of 55 years old and 55% female and extrapolated over a lifetime. Acromegaly-associated morbidity and mortality were not modeled due to possible double counting between acromegaly and other comorbidities. The average comorbidity count measure (range from 0 to 5) was a sum across all 5 comorbidity prevalence rates for all those living in the cohort per year of survival. Comorbidity prevalence was higher among acromegalic patients vs the general population for all comorbidities. Within acromegaly, uncontrolled disorder was associated with a higher prevalence of diabetes, hypertension, and sleep apnea. Lifetime discounted comorbidity costs were ~$121,000, ~$313,000, and ~$406,000 in the general population, acromegaly controlled, and acromegaly uncontrolled populations, respectively. Lifetime discounted life years were 17.6, 16.9, and 16.7 in the general population, acromegaly controlled, and acromegaly uncontrolled populations, respectively. Lifetime discounted quality-adjusted life years were 14.6, 11.7, and 10.4 in in the general population, acromegaly controlled, and acromegaly uncontrolled populations, respectively. Lifetime discounted average comorbidity count was 0.8, 1.9, and 2.4 in each group, respectively. Compared with controlled acromegaly, uncontrolled disorder resulted in $93,000 additional comorbidity-related costs, 1.3 fewer years of perfect health, and 0.5 more comorbidities across the remaining lifespan. This simulation model suggests achieving biochemical control seems to be associated with improvements in cost, quality of life, and mortality. A multimodal treatment strategy including biochemical control and management of comorbidities is necessary to promote optimal patient outcomes.

<![CDATA[MON-304 Prolactin as a Surrogate Marker to Predict Long Term Postoperative Hypopituitarism After Transsphenoidal Resection of Pituitary Adenomas]]> Transsphenoidal surgery (TSS) is the first line treatment for pituitary adenoma. A well-known complication of TSS is hypopituitarism with a reported risk of 5-25% after resection of pituitary adenomas. A decrease in postoperative prolactin concentration was shown to be associated with postoperative hypopituitarism in a previous report. We hypothesized that in addition to clinical factors (preoperative hypofunction and adenoma size), biochemical factors (change in prolactin concentration and immediate post-operative hypofunction) can aid in predicting long term hypopituitarism as defined as ≥1 biochemically confirmed hypofunctioning pituitary axes 3 years after resection. A retrospective analysis of all patients undergoing TSS for both functioning and non-functioning pituitary adenomas at a tertiary center from January 2013 through December 2015 was performed. Prolactinomas were excluded. Of the 75 patients included, 21.3% (n=16) had at least one pituitary axis requiring replacement at 3 years post operatively. Mean age at presentation was 55 ± 16 years, 55% were female and 81% were Caucasian. Mean adenoma size was no different between normal pituitary function and hypopituitary groups (24.0 ± 11.9 mm versus 25.3 ± 10, p=0.7). Factors associated with long term hypopituitarism were older age (mean age 64 ± 4 years versus 53 ± 2 years, p = 0.02), preoperative secondary adrenal insufficiency (AM cortisol 6.4 ± 3.7 vs 12.0 ± 6.5 µg/dL; p = 0.03), preoperative secondary hypothyroidism (0.8 ± 0.2 vs 12.0 ± 6.5 ng/dL; p < 0.01), low immediate postoperative cortisol (5.3±3.1 vs 26.1±18.3 µg/d; p<0.01), and persistence of adrenal insufficiency (10.7% vs 2.7%; p<0.01) and secondary hypothyroidism (13.3% vs 5.3%; p<0.01) at 3 months. Change in prolactin concentration from preoperative to postoperative day 1-7 was not significantly different between groups (p=0.09) due to the higher variability in the hypopituitary group (median 0.2 ng/mL, IQR -0.5 - 0.8 ng/mL) compared to the normal pituitary function group (median 0.7 ng/mL, IQR 0.5-0.8 ng/mL). Adenoma size, optic chiasm and cavernous sinus involvement were not associated with long term hypopituitarism. In patients who developed postoperative hypopituitarism, there was a higher frequency of adenoma persistence or recurrence (20% vs 47%). There was a high rate of patients lost to follow up (56%). Older age, the presence of preoperative secondary adrenal insufficiency and hypothyroidism, and low day 1-7 postoperative cortisol concentration are factors that can be used to deem a patient high risk for future hypopituitarism. These patients should have close follow up with continued screening postoperatively. Contrary to prior reports, adenoma size and parasellar involvement were not associated which may be suggestive of surgical expertise. Prolactin concentrations proved not to be a good surrogate marker to predict long term hypopituitarism.

<![CDATA[MON-296 Craniopharyngiomas Presenting as Incidentalomas: Results of Kraniopharyngeom 2007]]>