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Free access

Maya Barake, Anne Klibanski and Nicholas A Tritos

Dopamine agonists (DAs) represent a cornerstone in the management of patients with hyperprolactinemia and have an important role in the treatment of neurologic disorders, including Parkinson’s disease and restless legs syndrome. A growing body of evidence has identified impulse control disorders (ICDs) as possible adverse effects of DA therapy. A variety of ICDs may occur in patients treated with DA, including compulsive shopping, pathologic gambling, stealing, hypersexuality and punding (repetitive performance of tasks, such as collecting, sorting, disassembling and assembling objects). These behaviors can have devastating effects on patients’ life and family. In the present review article, we summarize available data on ICDs in patients with hyperprolactinemia as well as other disorders. Possible risk factors for the emergence of ICDs in patients treated with DA are discussed and the putative pathophysiologic mechanisms underlying the development of ICDs in this setting are reviewed. In addition, strategies for the early identification and management of ICDs in patients on DA are discussed. In conclusion, a wide variety of ICDs can occur in patients treated with DA, including those with hyperprolactinemia. The development of ICDs can have serious implications for patients’ well-being and family. Endocrinologists and other physicians involved in the care of patients on DA therapy must be aware of this potential adverse effect, counsel patients regarding pertinent symptoms and regularly evaluate treated patients for the development of ICDs. Early detection of ICDs and discontinuation of DA therapy can mitigate the potential harms associated with ICDs in these patients.

Free access

Brandon P Galm, E Leonardo Martinez-Salazar, Brooke Swearingen, Martin Torriani, Anne Klibanski, Miriam A Bredella and Nicholas A Tritos

Background

There are limited predictors of prognosis in patients with clinically non-functioning pituitary adenomas (NFPAs). We hypothesized that MRI texture analysis may predict tumor recurrence or progression in patients with NFPAs undergoing transsphenoidal pituitary surgery (TSS).

Objective

To characterize texture parameters on preoperative MRI examinations in patients with NFPAs in relation to prognosis.

Methods

Retrospective study of patients with NFPAs who underwent TSS at our institution between 2009 and 2010. Clinical, radiological and histopathological data were extracted from electronic medical records. MRI texture analysis was performed on coronal T1-weighted non-enhanced MR images using ImageJ (NIH). MRI texture parameters were used to predict tumor recurrence or progression. Both logistic regression and Cox proportional hazard analyses were conducted to adjust for potential confounders.

Results

Data on 78 patients were analyzed. On both crude and multivariable-adjusted analyses, mean, median, mode, minimum and maximum pixel intensity were associated with the risk of pituitary tumor recurrence or progression after TSS. Patients whose tumor mean pixel intensity was above the median for the population had a hazard ratio of 0.44 (95% CI: 0.21–0.94, P = 0.034) for recurrence or progression in comparison with tumors below the median.

Conclusions

Our data suggest that MRI texture analysis can predict the risk of tumor recurrence or progression in patients with NFPAs.

Free access

Nicholas A Tritos, Philippe Chanson, Camilo Jimenez, Donna King, Peter J Jönsson, Anne Klibanski and Beverly M K Biller

Objective

To examine the effectiveness and safety of primary pegvisomant monotherapy.

Design

Retrospective analysis of data extracted from ACROSTUDY (global observational outcomes study of patients with acromegaly treated with pegvisomant).

Methods

The earliest time to insulin-like growth factor 1 (IGF-1) normalization on pegvisomant monotherapy was determined. Both the proportion of patients who achieved IGF-1 normalization and the time to IGF-1 normalization on pegvisomant monotherapy were assessed.

Results

Eligible patients included 28 subjects on primary medical therapy (PT) and 176 controls on adjunctive pegvisomant therapy treated postoperatively, including 43 who were naïve to medical therapy (NMT) and 133 who were previously treated medically and were washed out (WASH). IGF-1 normalization occurred in 76.9% (PT), 85.2% (NMT) and 78.3% (WASH) patients (P = NS). Median times to IGF-1 normalization were 0.5 year (PT), 0.7 year (NMT) and 0.6 year (WASH), P = NS. On survival analysis, the fraction of patients controlled on pegvisomant monotherapy was not different between groups. Higher baseline IGF-1 levels, obtained at study entry, predicted a lower likelihood of IGF-1 normalization on monotherapy (P = 0.012). Safety data include low prevalence of skin rashes, injection site reactions and reversible transaminase elevations. There was one patient (NMT) with a verified increase in tumor size.

Conclusions

Pegvisomant monotherapy, administered either as primary medical therapy or as adjunctive therapy according to local practice, led to IGF-1 normalization in >75% of patients. Pegvisomant monotherapy had a favorable safety profile, consistent with previous observations. Prospective data are needed to further evaluate the role of primary pegvisomant monotherapy in acromegaly.

Free access

Nicholas A Tritos, Amir H Hamrahian, Donna King, Susan L Greenspan, David M Cook, Peter J Jönsson, Michael P Wajnrajch, Maria Koltowska-Häggstrom and Beverly M K Biller

Objective

Childhood-onset GH deficiency (COGHD) is associated with low bone mineral density (BMD). Adults with persistent COGHD may be at risk for insufficient bone accrual or bone loss during adulthood. The purpose of this study was to identify BMD predictors and to characterize the effects of GH replacement on BMD in COGHD adults with persistent GHD.

Design

Retrospective analysis of the KIMS database.

Methods

Variables predicting standardized BMD (sBMD) were identified. The effect of GH replacement (3 years) on BMD was examined.

Results

Three hundred and fourteen COGHD adults (148 women, 166 men; 62 non-naïve, 178 semi-naïve, and 74 true naïve, depending on length and timing of previous GH replacement), who had BMD measured in lumbar spine (LS) and femoral neck (FN) at study entry.

In semi-naïve subjects, a longer gap in GH replacement between childhood and adulthood was predictive of lower sBMD in the FN (r=−0.18, P=0.038). TSH deficiency predicted lower sBMD in the LS (r=−0.16, P=0.052). In true naïve patients, a longer gap between onset of pituitary disease and study entry (r=−0.35, P=0.012), and female gender (r=−0.27, P=0.043) independently predicted lower sBMD in the FN. There were no differences in BMD increases between non-naïve, semi-naïve, and true naïve subjects on GH replacement.

Conclusions

In semi-naïve subjects a longer interval off GH replacement was associated with lower sBMD in the FN. Among true naïve patients, a longer gap between the onset of pituitary disease and GH replacement, and female gender predicted lower sBMD in the FN.

Restricted access

Nicholas A Tritos, Anders F Mattsson, Greisa Vila, Beverly M K Biller, Anne Klibanski, Srinivas Valluri, Judith Hey-Hadavi, Nicky Kelepouris and Camilo Jimenez

Objective

To examine all-cause mortality rates in patients with acromegaly on pegvisomant and identify pertinent risk factors, including insulin-like growth factor I (IGF-I).

Design

Retrospective cohort analysis of data from ACROSTUDY (global surveillance study of patients with acromegaly treated with pegvisomant).

Methods

Kaplan–Meier analyses and Cox regression techniques were used to examine survival rates. Standardized mortality ratios (SMR) with reference to general population (WHO GBD 2016) were estimated. Multiplicative multiple Poisson regression models were used to characterize the association between SMR, IGF-I, and other risk factors associated with mortality risk.

Results

The study consisted of 2077 subjects who were followed for a median interval of 4.1 years, contributing to 8957 patient-years. Higher on-treatment IGF-I (P = 0.0035), older attained age (P < 0.0001), and longer duration of acromegaly (>10 years) before starting pegvisomant (P = 0.05) were associated with higher mortality rates. In reference to general population rates, higher SMR (1.10, 1.42, and 2.62, at attained age 55 years) were observed with higher serum IGF-I category (SMR trend: 1.44 (44%)/per fold level of IGF-I/ULN (95% CI: 1.10, 1.87), P = 0.0075). SMR increased per year of younger attained age (1.04 (1.02–1.04), P < 0.0001) and were higher for longer disease duration (>10 years) before starting pegvisomant (1.57 (1.02, 2.43), P = 0.042). Serum IGF-I levels within the normal range during pegvisomant therapy were associated with all-cause mortality rates that were indistinguishable from the general population.

Conclusions

Higher on-treatment IGF-I, older attained age, and longer duration of acromegaly before starting pegvisomant are associated with higher all-cause mortality rates. Younger patients with uncontrolled acromegaly have higher excess all-cause mortality rates in comparison with older patients.

Free access

Paula P B Silva, Fatemeh G Amlashi, Elaine W Yu, Karen J Pulaski-Liebert, Anu V Gerweck, Pouneh K Fazeli, Elizabeth Lawson, Lisa B Nachtigall, Beverly M K Biller, Karen K Miller, Anne Klibanski, Mary Bouxsein and Nicholas A Tritos

Context

Both acromegaly and adult growth hormone deficiency (GHD) are associated with increased fracture risk. Sufficient data are lacking regarding cortical bone microarchitecture and bone strength, as assessed by microfinite element analysis (µFEA).

Objective

To elucidate both cortical and trabecular bone microarchitecture and estimated bone strength in men with active acromegaly or GHD compared to healthy controls.

Design and subjects

Cross-sectional study at a clinical research center, including 48 men (16 with acromegaly, 16 with GHD and 16 healthy controls).

Outcome measures

Areal bone mineral density (aBMD), cortical and trabecular bone microarchitecture and estimated bone strength (µFEA) at the radius and tibia.

Results

aBMD was not different between the 3 groups at any skeletal site. At the radius, patients with acromegaly had greater cortical area (P < 0.0001), cortical thickness (P = 0.0038), cortical pore volume (P < 0.0001) and cortical porosity (P = 0.0008), but lower trabecular bone density (P = 0.0010) compared to controls. At the tibia, patients with acromegaly had lower trabecular bone density (P = 0.0082), but no differences in cortical bone microstructure. Compressive strength and failure load did not significantly differ between groups. These findings persisted after excluding patients with hypogonadism. Bone microarchitecture was not deficient in patients with GHD.

Conclusions

Both cortical and trabecular microarchitecture are altered in men with acromegaly. Our data indicate that GH excess is associated with distinct effects in cortical vs trabecular bone compartments. Our observations also affirm the limitations of aBMD testing in the evaluation of patients with acromegaly.

Open access

Zhaoyun Zhang, Qin Li, Wenqiang He, Huijia Qiu, Hongying Ye, Yongfei Wang, Ming Shen, Min He, Yifei Yu, Xuefei Shou, Chuanxin Huang, Huan Yu, Guoqian Huang, Weijun Tang, Daoying Geng, Chaowei Fu, Congjin Liu, Zengyi Ma, Zhao Ye, Qilin Zhang, Yichao Zhang, Yue Shen, Yeping Yang, Meng Wang, Xingdang Liu, Yun Lu, Renming Hu, Ying Mao, Liangfu Zhou, Yiming Li, Shiqi Li, Nicholas A Tritos and Yao Zhao

Context

Chronic excess of growth hormone (GH) often leads to systemic complications. The reversibility of these complications after GH resolution is not fully understood.

Objective

To investigate when and to what extent will the comorbidities be ameliorated.

Design

We conducted a prospective study comprising 24 patients with acromegaly, who achieved remission after transsphenoidal surgery. The dynamic changes of endocrine, cardiovascular, respiratory, sleep, bone and morphology parameters were evaluated at enrollment and 1 week, 1 month, 3 months, 6 months and 12 months after surgery.

Results

Random GH dropped by 98.4% at the first day postoperatively. IGF-I index dropped by 50% and 64% at 1 week and 1 month respectively and remained unchanged onwards. Glucose metabolism improved significantly at 1 week and stabilized at 1 month. Testosterone in male patients recovered to normal range since 1 month. Systolic blood pressures dropped markedly at 3 months while diastolic blood pressures fell mildly at later visits. Abnormal lung function showed no improvement. The decrease of bone formation and resorption markers occurred at 1 week and 3 months, respectively. At 1 month, the tongue area declined while the airway volume increased significantly, accompanied with improved obstructive sleep apnea syndrome. Extremities, lips and nasal ala became smaller since 1 week. Liver, kidney and spleen volumes declined by 6.4, 15.9, 9.2%, respectively at 1 month. The volumes of pancreas and adrenal showed no change.

Conclusions

The rapid resolution of excessive GH led to the reversible changes of systemic comorbidities in a time-dependent and organ-specific manner.