Treatment Patterns, Adherence, Persistence, and Health Care Resource Utilization in Acromegaly: A Real-World Analysis.

Context: Treatment of acromegaly is multimodal for many patients, and medical treatments include somatostatin receptor ligands (SRLs), dopamine agonists (DAs), and growth hormone receptor antagonists (GHRAs). However, recent real-world evidence on treatment patterns for patients with acromegaly is limited. Objective: This study evaluated medication usage, treatment changes, adherence, persistence, comorbidities, and health care resource utilization using deidentified data from MarketScan, a US claims database. Methods: Eligible patients (n = 882) were those receiving monotherapy or combination therapy for ≥90 days without treatment gaps. Results: Mean age at diagnosis was 48.6 years; 50.1% of patients were female. Over half (59.4%) had 1 line of treatment (LOT); 23.1% had 2 LOTs; 17.5% had at least 3 LOTs. Most patients (94.6%) initiated treatment with monotherapies. The most common first-line monotherapy treatments were cabergoline (DA, 36.8%), octreotide long-acting release (first-generation SRL, 29.5%), and lanreotide depot (first-generation SRL, 22.5%). Adherence for first-line treatments (proportion of days covered) was higher for first-generation SRLs (lanreotide depot: 0.8) compared with DAs (0.7). Treatment persistence (time between the first treatment record and a change in LOT/censoring) in LOT 1 was higher for GHRAs (24.8 months) and first-generation SRLs (20.0 months) compared with DAs (14.4 months). Female patients and those diagnosed at a younger age were more likely to have shorter treatment persistence. The most prevalent comorbidities were hyperlipidemia, essential hypertension, and sleep apnea. Conclusion: Patients with more comorbidities had more health care visits during the first year after diagnosis, suggesting increased disease burden. Real-world evidence on treatment patterns provides insights into recommendations for individualized therapy.

Prevalence of comorbidities and concomitant medication use in acromegaly: analysis of real-world data from the United States.

PURPOSE: Patients receiving treatment for acromegaly often experience significant associated comorbidities for which they are prescribed additional medications. We aimed to determine the real-world prevalence of comorbidities and concomitant medications in patients with acromegaly, and to investigate the association between frequency of comorbidities and number of concomitantly prescribed medications. METHODS: Administrative claims data were obtained from the IBM® MarketScan® database for a cohort of patients with acromegaly, identified by relevant diagnosis codes and acromegaly treatments, and a matched control cohort of patients without acromegaly from January 2010 through April 2020. Comorbidities were identified based on relevant claims and assessed for both cohorts. RESULTS: Overall, 1175 patients with acromegaly and 5875 matched patients without acromegaly were included. Patients with acromegaly had significantly more comorbidities and were prescribed concomitant medications more so than patients without acromegaly. In the acromegaly and control cohorts, respectively, 67.6% and 48.4% of patients had cardiovascular disorders, the most prevalent comorbidities, and 89.0% and 68.3% were prescribed > 3 concomitant medications (p < 0.0001). Hypopituitarism and hypothalamic disorders, sleep apnea, malignant neoplasms and cancer, and arthritis and musculoskeletal disorders were also highly prevalent in the acromegaly cohort. A moderate, positive correlation (Spearman correlation coefficient 0.60) was found between number of comorbidities and number of concomitant medications in the acromegaly cohort. CONCLUSION: Compared with patients without acromegaly, patients with acromegaly have significantly more comorbidities and are prescribed significantly more concomitant medications. Physicians should consider the number and type of ongoing medications for individual patients before prescribing additional acromegaly treatments.

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

The WHO Classification of Endocrine Tumours designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.

The Use of Recombinant Human Growth Hormone to Protect Against Muscle Weakness in Patients Undergoing Anterior Cruciate Ligament Reconstruction: A Pilot, Randomized Placebo-Controlled Trial.

BACKGROUND: Anterior cruciate ligament (ACL) tears are common knee injuries. Despite undergoing extensive rehabilitation after ACL reconstruction (ACLR), many patients have persistent quadriceps muscle weakness that limits their successful return to play and are also at an increased risk of developing knee osteoarthritis (OA). Human growth hormone (HGH) has been shown to prevent muscle atrophy and weakness in various models of disuse and disease but has not been evaluated in patients undergoing ACLR. HYPOTHESIS: Compared with placebo treatment, a 6-week perioperative treatment course of HGH would protect against muscle atrophy and weakness in patients undergoing ACLR. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: A total of 19 male patients (aged 18-35 years) scheduled to undergo ACLR were randomly assigned to the placebo (n = 9) or HGH (n = 10) group. Patients began placebo or HGH treatment twice daily 1 week before surgery and continued through 5 weeks after surgery. Knee muscle strength and volume, patient-reported outcome scores, and circulating biomarkers were measured at several time points through 6 months after surgery. Mixed-effects models were used to evaluate differences between treatment groups and time points, and as this was a pilot study, significance was set at P < .10. The Cohen d was calculated to determine the effect size. RESULTS: HGH was well-tolerated, and no differences in adverse events between the groups were observed. The HGH group had a 2.1-fold increase in circulating insulin-like growth factor 1 over the course of the treatment period (P < .05; d = 2.93). The primary outcome measure was knee extension strength, and HGH treatment increased normalized peak isokinetic knee extension torque by 29% compared with the placebo group (P = .05; d = 0.80). Matrix metalloproteinase-3 (MMP3), which was used as an indirect biomarker of cartilage degradation, was 36% lower in the HGH group (P = .05; d = -1.34). HGH did not appear to be associated with changes in muscle volume or patient-reported outcome scores. CONCLUSION: HGH improved quadriceps strength and reduced MMP3 levels in patients undergoing ACLR. On the basis of this pilot study, further trials to more comprehensively evaluate the ability of HGH to improve muscle function and potentially protect against OA in patients undergoing ACLR are warranted. REGISTRATION: NCT02420353 ( ClinicalTrials.gov identifier).

Growth hormone therapy in adults with growth hormone deficiency: a critical assessment of the literature.

PURPOSE: Growth hormone (GH) therapy has been studied as treatment for clinical manifestations of adult-onset growth hormone deficiency (AO-GHD), including cardiovascular risk, bone health, and quality of life. Patients with AO-GHD typically also have significant history of pituitary pathology and hypopituitarism, which raises the question of what proportion of their clinical presentation can be attributed to GHD alone. Currently, much of the existing data for GH therapy in AO-GHD come from uncontrolled retrospective studies and observational protocols. These considerations require careful reassessment of the role of GH as a therapeutic agent in adult patients with hypopituitarism. METHODS: We contrast results from placebo-controlled trials with those from uncontrolled and retrospective studies for GH replacement in patients with hypopituitarism. We also examine the evidence for the manifestations of AO-GHD being attributed to GHD alone, as well as the data on adults with congenital, life-long untreated isolated GHD. RESULTS: The evidence for increased morbidity and mortality in hypopituitary patients with GHD, and for the benefits of GH therapy, are conflicting. There remains the possibility that the described clinical manifestations of AO-GHD may not be due to GHD alone, but may also be related to underlying pituitary pathology, treatment history and suboptimal hormone replacement. CONCLUSIONS: In the setting of inconsistent data on the benefits of GH therapy, treatment of AO-GHD remains an individualized decision. There is a need for more randomized, placebo-controlled studies to evaluate the long-term outcomes of GH therapy in adults with hypopituitarism.

Pituitary Dysfunction after Radiation for Anterior Skull Base Malignancies: Incidence and Screening.

Background Management of anterior cranial base malignancies requires multidisciplinary care. Radiation therapy remains a mainstay of definitive or adjuvant treatment. Apart from primary hypothyroidism, the effects of radiation on the hypothalamic-pituitary axis after high-dose treatment of head and neck malignancies remain poorly described. We describe a comprehensive screening protocol for surveillance and characterize the incidence of pituitary dysfunction after radiation for anterior cranial base malignancies. Methods A review of patients prospectively enrolled in a skull base registry at an academic center was performed. Included patients had a history of anterior skull base malignancy and external beam radiation to the primary site, with comprehensive post-treatment pituitary serologies and at least 1 year of post-radiation follow-up. Routine hormonal screening was initiated during the study period for all patients with anterior skull base irradiation. Results Eighty-one patients met inclusion. Fifty-eight patients (71%) demonstrated some laboratory abnormality. Thirty patients (37%) demonstrated evidence of hypopituitarism. Twenty-four (29%) demonstrated central hypogonadism, and 16% of patients showed central hypothyroidism. Ten patients (12%) displayed central adrenal insufficiency with six patients demonstrating panhypopituitarism. Primary tumor location and maximum dose of radiation to the gland appeared to correlate with incidence of hypopituitarism. Conclusion Radiation for malignancies of the anterior skull base resulted in a 37% incidence of hypopituitarism in our study. Given the potential morbidity of hypopituitarism, we recommend annual post-treatment screening in these patients. We describe a comprehensive set of serologies that can be utilized, and recommend updating clinical guidelines to reflect the necessity of this screening.

A Consensus on the Diagnosis and Treatment of Acromegaly Comorbidities: An Update.

OBJECTIVE: The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013. PARTICIPANTS: The Consensus Group, convened by 11 Steering Committee members, consisted of 45 experts in the medical and surgical management of acromegaly. The authors received no corporate funding or remuneration. EVIDENCE: This evidence-based consensus was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence following critical discussion of the current literature on the diagnosis and treatment of acromegaly comorbidities. CONSENSUS PROCESS: Acromegaly Consensus Group participants conducted comprehensive literature searches for English-language papers on selected topics, reviewed brief presentations on each topic, and discussed current practice and recommendations in breakout groups. Consensus recommendations were developed based on all presentations and discussions. Members of the Scientific Committee graded the quality of the supporting evidence and the consensus recommendations using the GRADE system. CONCLUSIONS: Evidence-based approach consensus recommendations address important clinical issues regarding multidisciplinary management of acromegaly-related cardiovascular, endocrine, metabolic, and oncologic comorbidities, sleep apnea, and bone and joint disorders and their sequelae, as well as their effects on quality of life and mortality.

Interpretation of common endocrine laboratory tests: technical pitfalls, their mechanisms and practical considerations.

Pitfalls in hormonal assays are commonly seen in clinical practice and may lead to erroneous clinical impressions and treatments. In this article, we address common laboratory pitfalls encountered during evaluation of patients with real or presumed endocrine disorders including high dose hook effect and falsely normal prolactin in cases of macroprolactinomas, macroprolactinemia and falsely elevated prolactin, macrothyrotropinemia and falsely elevated TSH, heterophile antibodies leading to false elevation of hormonal concentration, biotin interference with different hormonal assays, cross-reactivity of steroid hormones immunoassays, and others. We describe the mechanisms of such laboratory pitfalls, review clinical scenarios in which they might occur, and discuss the ways to resolve such conundrums. The aim of this article is to present a learning material for the endocrine trainees and practitioners.

A machine learning approach to predict early outcomes after pituitary adenoma surgery.

OBJECTIVEPituitary adenomas occur in a heterogeneous patient population with diverse perioperative risk factors, endocrinopathies, and other tumor-related comorbidities. This heterogeneity makes predicting postoperative outcomes challenging when using traditional scoring systems. Modern machine learning algorithms can automatically identify the most predictive risk factors and learn complex risk-factor interactions using training data to build a robust predictive model that can generalize to new patient cohorts. The authors sought to build a predictive model using supervised machine learning to accurately predict early outcomes of pituitary adenoma surgery.METHODSA retrospective cohort of 400 consecutive pituitary adenoma patients was used. Patient variables/predictive features were limited to common patient characteristics to improve model implementation. Univariate and multivariate odds ratio analysis was performed to identify individual risk factors for common postoperative complications and to compare risk factors with model predictors. The study population was split into 300 training/validation patients and 100 testing patients to train and evaluate four machine learning models using binary classification accuracy for predicting early outcomes.RESULTSThe study included a total of 400 patients. The mean ± SD patient age was 53.9 ± 16.3 years, 59.8% of patients had nonfunctioning adenomas and 84.7% had macroadenomas, and the mean body mass index (BMI) was 32.6 ± 7.8 (58.0% obesity rate). Multivariate odds ratio analysis demonstrated that age < 40 years was associated with a 2.86 greater odds of postoperative diabetes insipidus and that nonobese patients (BMI < 30) were 2.2 times more likely to develop postoperative hyponatremia. Using broad criteria for a poor early postoperative outcome-major medical and early surgical complications, extended length of stay, emergency department admission, inpatient readmission, and death-31.0% of patients met criteria for a poor early outcome. After model training, a logistic regression model with elastic net (LR-EN) regularization best predicted early postoperative outcomes of pituitary adenoma surgery on the 100-patient testing set-sensitivity 68.0%, specificity 93.3%, overall accuracy 87.0%. The receiver operating characteristic and precision-recall curves for the LR-EN model had areas under the curve of 82.7 and 69.5, respectively. The most important predictive variables were lowest perioperative sodium, age, BMI, highest perioperative sodium, and Cushing's disease.CONCLUSIONSEarly postoperative outcomes of pituitary adenoma surgery can be predicted with 87% accuracy using a machine learning approach. These results provide insight into how predictive modeling using machine learning can be used to improve the perioperative management of pituitary adenoma patients.

Decreased quality of life (QoL) in hypopituitary patients: involvement of glucocorticoid replacement and radiation therapy.

PURPOSE: Hypopituitary patients are assumed to have decreased QoL due to GHD. However, in placebo controlled trials, the effects of GH replacement are no different from placebo. Hydrocortisone dose > 20 mg/day and pituitary radiation are independently associated with poorer QoL. We assessed QoL in panhypopituitary GH- deficient patients never treated with GH. METHODS: Study group was divided into: (a) surgery followed by radiation (n = 21) and (b) surgery alone (n = 32). Mean duration of GHD was 71.4 ± 7.8 months and mean daily hydrocortisone dose was 15 ± 0.7 mg. Control group had transnasal surgery for benign sinus conditions (n = 54). RESULTS: AGHDA scores were significantly worse in the entire study group compared to controls (8.1 ± 1.0 vs. 5.1 ± 0.9, p = 0.03). In patients with history of radiation therapy AGHDA scores were significantly worse than in controls (9.1 ± 1.5, p = 0.02) and SNOT-22 (Sino-Nasal Outcome Test) scores were also significantly worse (15.8 ± 2.0 vs. 23.2 ± 3.5, p = 0.04). However, AGHDA scores in patients without history of radiation and on "physiological" dose of hydrocortisone were similar to those in controls (5.1 ± 0.9 vs. 7.3 ± 1.3, p = 0.17). CONCLUSIONS: Replacement with hydrocortisone doses not exceeding 20 mg/day and avoidance of radiation therapy was accompanied by normal QoL in patients not replaced with GH. Thus, we suggest that the decreased QoL in hypopituitary patients may not be due to GH deficiency per se, but rather to high hydrocortisone doses and to aftereffects of cranial radiation.

Correction to: Criteria for the definition of Pituitary Tumor Centers of Excellence (PTCOE): A Pituitary Society Statement.

The original version of this article unfortunately contained an affiliation error in 'Collaborators for The Pituitary Society, Expert Group on Pituitary Tumors' section. Dr. Misa Pfeifer is affiliated with Medical Faculty, University of Ljubljana, Slovenia and the correct email address to contact is misa.pfeifer@gmail.com.

Biochemical efficacy of long-acting lanreotide depot/Autogel in patients with acromegaly naïve to somatostatin-receptor ligands: analysis of three multicenter clinical trials.

PURPOSE: In clinical research involving acromegalic patients naïve to somatostatin-receptor ligands (SRLs), 19 and 31% of those receiving the SRLs octreotide LAR and pasireotide LAR, respectively, achieved GH < 2.5 ng/mL + normalized IGF-1 concentrations. The proportions achieving control appeared higher in the post-surgery compared with the de-novo setting with pasireotide, but more similar with octreotide. Using pooled data from multicenter clinical trials, we examined the biochemical efficacy of lanreotide depot/Autogel in similar settings. METHODS: Inclusion criteria: Ipsen-sponsored, 48-52-week trials in SRL-naïve acromegalic populations receiving lanreotide depot (60-120 mg); patients were included if de novo (no prior acromegaly treatment) or post-surgery (no medical treatment; radiotherapy allowed unless within previous 3 years). Efficacy endpoints included normalized IGF-1 levels and GH < 2.5 ng/mL + normalized IGF-1 at study end/last value available. ANALYSES: all patients (analysis #1) and subset with baseline GH > 5 ng/mL (analysis #2). RESULTS: Three studies were included. Analysis #1: normalized IGF-1 was achieved by 42% (71/171) of patients overall (post-surgery, 46% [21/46]; de-novo, 40% [50/125]); GH < 2.5 ng/mL + normalized IGF-1 was achieved by 35% (59/171) (39% [18/46] and 33% [41/125], respectively). Analysis #2: normalized IGF-1 levels, 39% (46/118) (post-surgery, 40% [10/25]; de-novo, 39% [36/93]); GH < 2.5 ng/mL + normalized IGF-1, 31% (36/118) (28% [7/25] and 31% [29/93], respectively). CONCLUSION: In these pooled analyses of SRL-naïve patients receiving lanreotide depot, 39-42% achieved IGF-1 control and 31-35% achieved GH and IGF-1 control. Control rates within post-surgery cohorts did not differ markedly from those in corresponding de-novo cohorts.

Korsakoff syndrome from retrochiasmatic suprasellar lesions: rapid reversal after relief of cerebral compression in 4 cases.

Korsakoff syndrome is a chronic memory disorder caused by a severe deficiency of thiamine that is most commonly observed in alcoholics. However, some have proposed that focal structural lesions disrupting memory circuits-in particular, the mammillary bodies, the mammillothalamic tract, and the anterior thalamus-can give rise to this amnestic syndrome. Here, the authors present 4 patients with reversible Korsakoff syndromes caused by suprasellar retrochiasmatic lesions compressing the mammillary bodies and adjacent caudal hypothalamic structures. Three of the patients were found to have large pituitary macroadenomas in their workup for memory deficiency and cognitive decline with minimal visual symptoms. These tumors extended superiorly into the suprasellar region in a retrochiasmatic position and caused significant mass effect in the bilateral mammillary bodies in the base of the brain. These 3 patients had complete and rapid resolution of amnestic problems shortly after initiation of treatment, consisting of resection in 1 case of nonfunctioning pituitary adenoma or cabergoline therapy in 2 cases of prolactinoma. The fourth patient presented with bizarre and hostile behavior along with significant memory deficits and was found to have a large cystic craniopharyngioma filling the third ventricle and compressing the midline diencephalic structures. This patient underwent cyst fenestration and tumor debulking, with a rapid improvement in his mental status. The rapid and dramatic memory improvement observed in all of these cases is probably due to a reduction in the pressure imposed by the lesions on structures contiguous to the third ventricle, rather than a direct destructive effect of the tumor, and highlights the essential role of the caudal diencephalic structures-mainly the mammillary bodies-in memory function. In summary, large pituitary lesions with suprasellar retrochiasmatic extension and third ventricular craniopharyngiomas can cause severe Korsakoff-like amnestic syndromes, probably because of bilateral pressure on or damage to mammillary bodies, anterior thalamic nuclei, or their major connections. Neuropsychiatric symptoms may rapidly and completely reverse shortly after initiation of therapy via surgical decompression of tumors or pharmacological treatment of prolactinomas. Early identification of these lesions with timely treatment can lead to a favorable prognosis for this severe neuropsychiatric disorder.

Ventriculoscopic Surgery for Cystic Retrochiasmatic Craniopharyngiomas: Indications, Surgical Technique, and Short-Term Patient Outcomes.

BACKGROUND: Attempted gross-total resection for the management of cystic retrochiasmatic craniopharyngiomas can cause severe hypothalamic dysfunction and decrease overall survival. Ventriculoscopic surgery is a minimally invasive alternative; however, potential indications and technique have not been well defined. OBJECTIVE: To present our indications and technique for the ventriculoscopic treatment of cystic retrochiasmatic craniopharyngiomas. METHODS: We evaluated all patients with retrochiasmatic craniopharyngiomas for ventriculoscopic surgery. Indications and operative technique were developed to minimize operative morbidity, relieve mass effect, and optimize functional outcome. Cyst size and functional outcomes were statistically evaluated to determine radiographic and short-term clinical outcome. RESULTS: Indications for ventriculoscopic surgery included (1) radiographic evidence of hypothalamic involvement and (2) major cystic component. Ten patients met indications, and mean follow-up was 2.5 ± 1.6 yr. The surgical technique included wide cyst fenestration at the foramen of Monro, and fenestration of inferior cyst wall/third ventriculostomy ("through-and-through" technique). Preoperative Karnofsky performance status was 70 ± 15 and was inversely correlated with preoperative cyst size (13 ± 13 cm3). A statistically significant reduction in cyst size was found on early postoperative imaging (2.1 ± 4.3 cm3). Seven patients received postoperative radiotherapy. Postoperative performance scores (81 ± 8.3) had improved; no patient suffered functional decline. Pre- and postoperative body mass indices were similar. No patient had short-term hypothalamic obesity. CONCLUSION: Ventriculoscopic surgery, with or without adjuvant treatments, can reduce early postoperative tumor volume and improve short-term functional status in cystic retrochiasmatic craniopharyngiomas with hypothalamic involvement; it should be considered a minimally invasive option in the multimodal treatment of craniopharyngiomas. Further studies are needed to determine long-term efficacy.