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The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPG). Recommendations are based on diligent reviews of clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. The Executive Summary of this 2019 updated guideline contains 58 numbered recommendations: 12 are Grade A (21%), 19 are Grade B (33%), 21 are Grade C (36%), and 6 are Grade D (10%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 357 citations of which 51 (14%) are evidence level (EL) 1 (strong), 168 (47%) are EL 2 (intermediate), 61 (17%) are EL 3 (weak), and 77 (22%) are EL 4 (no clinical evidence). This CPG is a practical tool that practicing endocrinologists and regulatory bodies can refer to regarding the identification, diagnosis, and treatment of adults and patients transitioning from pediatric to adult-care services with growth hormone deficiency (GHD). It provides guidelines on assessment, screening, diagnostic testing, and treatment recommendations for a range of individuals with various causes of adult GHD. The recommendations emphasize the importance of considering testing patients with a reasonable level of clinical suspicion of GHD using appropriate growth hormone (GH) cut-points for various GH-stimulation tests to accurately diagnose adult GHD, and to exercise caution interpreting serum GH and insulin-like growth factor-1 (IGF-1) levels, as various GH and IGF-1 assays are used to support treatment decisions. The intention to treat often requires sound clinical judgment and careful assessment of the benefits and risks specific to each individual patient. Unapproved uses of GH, long-term safety, and the current status of long-acting GH preparations are also discussed in this document. This updated guideline provides evidence-based recommendations regarding the identification, screening, assessment, diagnosis, and treatment for a range of individuals with various causes of adult growth-hormone deficiency (GHD) and patients with childhood-onset GHD transitioning to adult care. The update summarizes the most current knowledge about the accuracy of available GH-stimulation tests, safety of recombinant human GH (rhGH) replacement, unapproved uses of rhGH related to sports and aging, and new developments such as long-acting GH preparations that use a variety of technologies to prolong GH action. Recommendations offer a framework for physicians to manage patients with GHD effectively during transition to adult care and adulthood. Establishing a correct diagnosis is essential before consideration of replacement therapy with rhGH. Since the diagnosis of GHD in adults can be challenging, GH-stimulation tests are recommended based on individual patient circumstances and use of appropriate GH cut-points. Available GH-stimulation tests are discussed regarding variability, accuracy, reproducibility, safety, and contraindications, among other factors. The regimen for starting and maintaining rhGH treatment now uses individualized dose adjustments, which has improved effectiveness and reduced reported side effects, dependent on age, gender, body mass index, and various other individual characteristics. With careful dosing of rhGH replacement, many features of adult GHD are reversible and side effects of therapy can be minimized. Scientific studies have consistently shown rhGH therapy to be beneficial for adults with GHD, including improvements in body composition and quality of life, and have demonstrated the safety of short- and long-term rhGH replacement. = American Association of Clinical Endocrinologists; = American College of Endocrinology; = alpha-2-HS-glycoprotein; = adult-onset growth hormone deficiency; = arginine; = best evidence level; = bone mineral density; = body mass index; = confidence interval; = childhood-onset growth hormone deficiency; = clinical practice guideline; = C-reactive protein; = diabetes mellitus; = dual-energy X-ray absorptiometry; = evidence level; = Food and Drug Administration; = fixed-dose glucagon stimulation test; = Genetics and Neuroendocrinology of Short Stature International Study; = growth hormone; = growth hormone deficiency; = growth hormone-releasing hormone; = glucagon stimulation test; = high-density lipoprotein; = Hypopituitary Control and Complications Study; = insulin-like growth factor-1; = insulin-like growth factor-binding protein; = isolated growth hormone deficiency; = insulin tolerance test; = Kabi International Metabolic Surveillance; = long-acting growth hormone; = low-density lipoprotein; = leukemia inhibitory factor; = multiple pituitary hormone deficiencies; = magnetic resonance imaging; = procollagen type-III amino-terminal pro-peptide; = pituitary hormone deficiencies; = quality of life; = recombinant human growth hormone; = receiver operating characteristic; = relative risk; = subarachnoid hemorrhage; = standard deviation score; = standardized incidence ratio; = secondary neoplasms; = triiodothyronine; = traumatic brain injury; = vitamin D-binding protein; = World Anti-Doping Agency; = weight-based glucagon stimulation test.

Many patients with growth hormone-secreting pituitary adenoma (GHPA) fail to achieve biochemical remission, warranting investigation into epigenetic and molecular signatures associated with tumorigenesis and hormonal secretion. Prior work exploring the DNA methylome showed Myc-Associated Protein X (MAX), a transcription factor involved in cell cycle regulation, was differentially methylated between GHPA and nonfunctional pituitary adenoma (NFPA). We aimed to validate the differential DNA methylation and related MAX protein expression profiles between NFPA and GHPA. DNA methylation levels were measured in 52 surgically resected tumors (37 NFPA, 15 GHPA) at ~100,000 known MAX binding sites derived using ChIP-seq analysis from ENCODE. Findings were correlated with MAX protein expression using a constructed tissue microarray (TMA). Gene ontology analysis was performed to explore downstream genetic and signaling pathways regulated by MAX. GHPA had more hypomethylation events across all known MAX binding sites. Of binding sites defined using ChIP-seq analysis, 1,551 sites had significantly different methylation patterns between the two cohorts; 432 occurred near promoter regions potentially regulated by MAX, including promoters of TNF and MMP9. Gene ontology analysis suggested enrichment in genes involved in oxygen response, immune system regulation, and cell proliferation. Thirteen MAX binding sites were within coding regions of genes. GHPA demonstrated significantly increased expression of MAX protein compared to NFPA. GHPA have significantly different DNA methylation and downstream protein expression levels of MAX compared to NFPA. These differences may influence mechanisms involved with cellular proliferation, tumor invasion and hormonal secretion.

Objective: The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPG). Methods: Recommendations are based on diligent reviews of clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. Results: The Executive Summary of this 2019 updated guideline contains 58 numbered recommendations: 12 are Grade A (21%), 19 are Grade B (33%), 21 are Grade C (36%), and 6 are Grade D (10%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 357 citations of which 51 (14%) are evidence level (EL) 1 (strong), 168 (47%) are EL 2 (intermediate), 61 (17%) are EL 3 (weak), and 77 (22%) are EL 4 (no clinical evidence). Conclusion: This CPG is a practical tool that practicing endocrinologists and regulatory bodies can refer to regarding the identification, diagnosis, and treatment of adults and patients transitioning from pediatric to adult-care services with growth hormone deficiency (GHD). It provides guidelines on assessment, screening, diagnostic testing, and treatment recommendations for a range of individuals with various causes of adult GHD. The recommendations emphasize the importance of considering testing patients with a reasonable level of clinical suspicion of GHD using appropriate growth hormone (GH) cut-points for various GH–stimulation tests to accurately diagnose adult GHD, and to exercise caution interpreting serum GH and insulin-like growth factor-1 (IGF-1) levels, as various GH and IGF-1 assays are used to support treatment decisions. The intention to treat often requires sound clinical judgment and careful assessment of the benefits and risks specific to each individual patient. Unapproved uses of GH, long-term safety, and the current status of long-acting GH preparations are also discussed in this document. LAY ABSTRACT This updated guideline provides evidence-based recommendations regarding the identification, screening, assessment, diagnosis, and treatment for a range of individuals with various causes of adult growth-hormone deficiency (GHD) and patients with childhood-onset GHD transitioning to adult care. The update summarizes the most current knowledge about the accuracy of available GH–stimulation tests, safety of recombinant human GH (rhGH) replacement, unapproved uses of rhGH related to sports and aging, and new developments such as long-acting GH preparations that use a variety of technologies to prolong GH action. Recommendations offer a framework for physicians to manage patients with GHD effectively during transition to adult care and adulthood. Establishing a correct diagnosis is essential before consideration of replacement therapy with rhGH. Since the diagnosis of GHD in adults can be challenging, GH–stimulation tests are recommended based on individual patient circumstances and use of appropriate GH cut-points. Available GH–stimulation tests are discussed regarding variability, accuracy, reproducibility, safety, and contraindications, among other factors. The regimen for starting and maintaining rhGH treatment now uses individualized dose adjustments, which has improved effectiveness and reduced reported side effects, dependent on age, gender, body mass index, and various other individual characteristics. With careful dosing of rhGH replacement, many features of adult GHD are reversible and side effects of therapy can be minimized. Scientific studies have consistently shown rhGH therapy to be beneficial for adults with GHD, including improvements in body composition and quality of life, and have demonstrated the safety of short- and long-term rhGH replacement. Abbreviations: AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; AHSG = alpha-2-HS-glycoprotein; AO-GHD = adult-onset growth hormone deficiency; ARG = arginine; BEL = best evidence level; BMD = bone mineral density; BMI = body mass index; CI = confidence interval; CO-GHD = childhood-onset growth hormone deficiency; CPG = clinical practice guideline; CRP = C-reactive protein; DM = diabetes mellitus; DXA = dual-energy X-ray absorptiometry; EL = evidence level; FDA = Food and Drug Administration; FD-GST = fixed-dose glucagon stimulation test; GeNeSIS = Genetics and Neuroendocrinology of Short Stature International Study; GH = growth hormone; GHD = growth hormone deficiency; GHRH = growth hormone–releasing hormone; GST = glucagon stimulation test; HDL = high-density lipoprotein; HypoCCS = Hypopituitary Control and Complications Study; IGF-1 = insulin-like growth factor-1; IGFBP = insulin-like growth factor–binding protein; IGHD = isolated growth hormone deficiency; ITT = insulin tolerance test; KIMS = Kabi International Metabolic Surveillance; LAGH = long-acting growth hormone; LDL = low-density lipoprotein; LIF = leukemia inhibitory factor; MPHD = multiple pituitary hormone deficiencies; MRI = magnetic resonance imaging; P-III-NP = procollagen type-III amino-terminal pro-peptide; PHD = pituitary hormone deficiencies; QoL = quality of life; rhGH = recombinant human growth hormone; ROC = receiver operating characteristic; RR = relative risk; SAH = subarachnoid hemorrhage; SDS = standard deviation score; SIR = standardized incidence ratio; SN = secondary neoplasms; T3 = triiodothyronine; TBI = traumatic brain injury; VDBP = vitamin D-binding protein; WADA = World Anti-Doping Agency; WB-GST = weight-based glucagon stimulation test

ContextSurgical management of prolactinomas is an important treatment for patients intolerant of dopamine agonist therapy. However, predictors of postoperative outcomes remain unclear. ObjectWhile transsphenoidal surgical resection (TSSR) is important second-line therapy in prolactinoma patients, predictors of surgical cure and biochemical remission following TSSR remain sparse. MethodsA retrospective review of prolactinoma patients undergoing TSSR at the USC Pituitary Center from 1995 to 2020 was conducted. Participants were categorized as surgical cure (normalization of serum prolactin without medical treatment), surgical noncure, biochemical control (prolactin normalization with or without adjuvant therapy), and nonbiochemical control. A systematic review of the outcomes of surgically managed prolactinomas was performed. ResultsThe 40 female and 16 male participants had an average age of 35.6 years. Prior treatment included transsphenoidal resection (6, 11%) and dopamine agonist treatment (47, 84%). The 40 macroadenomas and 15 microadenomas exhibited suprasellar extension (24, 43%) and parasellar invasion (20, 36%). Fifteen (27%) were purely intrasellar. Gross total resection was achieved in 25 patients (45%) and subtotal in 26 (46%). Surgical cure was achieved in 25 patients (46%) and biochemical control in 35 (64%). Surgical cure was more likely in smaller, noninvasive tumors, those that were fully resected, and patients with lower preoperative (< 1000 ng/mL) and immediately postoperative (< 7.6 ng/mL) prolactin levels. Ten of 26 patients (38%) undergoing adjuvant therapy achieved biochemical control, which was less likely in men and those with higher preoperative prolactin or invasive tumors. ConclusionSurgical resection of prolactinomas is a safe procedure that, when offered judiciously, can achieve symptom and/or biochemical control in a majority of patients. A variety of predictors may be useful in advising patients on likelihood of postoperative remission.

Background The study aim was to estimate the proportion of acromegaly patients with various comorbidities and to determine if biochemical control was associated with reduced proportion of cardiovascular risk factors. Methods Data were from a single-center acromegaly registry. Study patients were followed for ≥12 months after initial treatment. Study period was from first to last insulin-like growth factor-I and growth hormone tests. Results Of 121 patients, 55% were female. Mean age at diagnosis was 42.4 (SD: 15.0). Mean study period was 8.8 (SD: 7.2) years. Macroadenomas were observed in 93 of 106 patients (87.7%), and microadenomas in 13 (12.3%). Initial treatment was surgery in 104 patients (86%), pharmacotherapy in 16 (13.2%), and radiation therapy in 1 (0.8%). Of 120 patients, 79 (65.8%) achieved control during the study period. New onset comorbidities (reported 6 months after study start) were uncommon (<10%). Comorbidities were typically more prevalent in uncontrolled versus controlled patients—24 (58.5%) vs. 33 (41.8%) had hypertension, 17 (41.5%) vs. 20 (25.3%) had diabetes, 11 (26.8%) vs. 16 (20.3%) had sleep apnea, and 3 (7.3%) vs. 3 (3.8%) had cardiomyopathy—except for colon polyps or cancer (19.5% vs. 20.3%), left ventricular hypertrophy (9.8% vs. 11.4%), and visual defects (14.6% vs. 17.7%). Conclusions A greater number of comorbidities were observed in biochemically uncontrolled patients with acromegaly compared to their controlled counterparts in this single-center registry. About a third of the patients remained uncontrolled after a mean of >8 years of treatment, demonstrating the difficulty of achieving control in some patients.

Abstract BACKGROUND: Long-term remission rates from endoscopic transsphenoidal surgery for acromegaly and their relationship to prognostic indicators of disease aggressiveness are not well documented. OBJECTIVE: To investigate long-term remission rates in patients with acromegaly after endoscopic transsphenoidal surgery, and correlate this with molecular and radiographic markers of disease aggressiveness. METHODS: We identified all patients undergoing endoscopic transsphenoidal surgery for acromegaly from 2005 to 2013 at Cedars-Sinai Pituitary Center. Hormonal remission was established by normal insulin-like growth factor (IGF)-1, basal serum growth hormone <2.5 ng/mL, and growth hormone suppression to <1 ng/mL following oral glucose tolerance test. Oral glucose tolerance test was performed at 3 months after surgery, and then as indicated. IGF-1 was measured at 3 months and then at least annually. We evaluated tumor granularity, nuclear expression of p21, Ki67 index, and extent of cavernous sinus invasion, and correlated these with remission status. RESULTS: Fifty-eight patients that underwent surgery had follow-up from 38 to 98 months (mean 64 ± 32.2 months). There were 21 microadenomas and 37 macroadenomas. Three months after surgery 40 of 58 patients (69%) were in biochemical remission. Four additional patients were in remission at 6 months after surgery, and 1 patient had recurrence within the first year after surgery. At last follow-up, 43 of 44 (74.1%) of patients remained in remission. Cavernous sinus invasion by tumor predicted failure to achieve remission. CONCLUSIONS: Prognostic markers of disease aggressiveness other than cavernous sinus invasion did not correlate with surgical outcome. Long-term remission after surgery alone was achieved in 74% of patients, indicating long-term efficacy of endoscopic surgery.

Abstract Context Preclinical studies show seliciclib (R-roscovitine) suppresses neoplastic corticotroph proliferation and pituitary adrenocorticotrophic hormone (ACTH) production. Objective To evaluate seliciclib as an effective pituitary-targeting treatment for patients with Cushing disease (CD). Methods Two prospective, open-label, phase 2 trials, conducted at a tertiary referral pituitary center, included adult patients with de novo, persistent, or recurrent CD who received oral seliciclib 400 mg twice daily for 4 consecutive days each week for 4 weeks. The primary endpoint in the proof-of-concept single-center study was normalization of 24-hour urinary free cortisol (UFC; ≤ 50 µg/24 hours) at study end; in the pilot multicenter study, primary endpoint was UFC normalization or ≥ 50% reduction in UFC from baseline to study end. Results Sixteen patients were consented and 9 were treated. Mean UFC decreased by 42%, from 226.4 ± 140.3 µg/24 hours at baseline to 131.3 ± 114.3 µg/24 hours by study end. Longitudinal model showed significant UFC reductions from baseline to each treatment week. Three patients achieved ≥ 50% UFC reduction (range, 55%-75%), and 2 patients exhibited 48% reduction; none achieved UFC normalization. Plasma ACTH decreased by 19% (P = 0.01) in patients who achieved ≥ 48% UFC reduction. Three patients developed grade ≤ 2 elevated liver enzymes, anemia, and/or elevated creatinine, which resolved with dose interruption/reduction. Two patients developed grade 4 liver-related serious adverse events that resolved within 4 weeks of seliciclib discontinuation. Conclusion Seliciclib may directly target pituitary corticotrophs in CD and reverse hypercortisolism. Potential liver toxicity of seliciclib resolves with treatment withdrawal. The lowest effective dose requires further determination.

Background Acromegaly is a rare, slowly progressive disorder resulting from excessive growth hormone (GH) production by a pituitary somatotroph tumor. The objective of this study was to examine acromegaly treatment outcomes during long-term care at a specialized pituitary center in patients presenting with lack of biochemical control. Methods Data came from an acromegaly registry at the Cedars-Sinai Medical Center Pituitary Center (center). Acromegaly patients included in this study were those who presented biochemically-uncontrolled for care at the center. Biochemical control status, based on serum insulin-like growth factor-1 values, was determined at presentation and at study end. Patient characteristics and acromegaly treatments were reported before and after presentation by presenting treatment status and final biochemical control status. Data on long-term follow-up were recorded from 1985 through June 2013. Results Seventy-four patients presented uncontrolled: 40 untreated (54.1%) and 34 (45.9%) previously-treated. Mean (SD) age at diagnosis was 43.2 (14.7); 32 (43.2%) were female patients. Of 65 patients with tumor size information, 59 (90.8%) had macroadenomas. Prior treatments among the 34 previously-treated patients were pituitary surgery alone (47.1%), surgery and medication (41.2%), and medication alone (11.8%). Of the 40 patients without prior treatment, 82.5% achieved control by study end. Of the 34 with prior treatment, 50% achieved control by study end. Conclusions This observational study shows that treatment outcomes of biochemically-uncontrolled acromegaly patients improve with directed care, particularly for those that initially present untreated. Patients often require multiple modalities of treatment, many of which are offered with the highest quality at specialized pituitary centers. Despite specialized care, some patients were not able to achieve biochemical control with methods of treatment that were available at the time of their treatment, showing the need for additional treatment options.

Abstract BACKGROUND Rathke cleft cysts (RCCs) are benign sellar and suprasellar lesions commonly presenting as asymptomatic incidental findings. Rarely, RCCs hemorrhage and mimic pituitary apoplexy on presentation. OBJECTIVE To review a series of hemorrhagic RCCs for physicians encountering this rare presentation. METHODS A database review of >1700 transsphenoidal pituitary operations was performed at the USC Pituitary Center to identify patients with pathologically confirmed RCCs presenting with acute symptoms and evidence of hemorrhage at the time of surgery. Surgical treatment involved transsphenoidal RCC fenestration and drainage. Clinical, endocrine, and imaging outcomes were reviewed. RESULTS A total of 119 RCCs were identified, and 6 (5.0%) presented with hemorrhage mimicking pituitary apoplexy. Presenting symptoms included acute onset headaches (5/6), vision loss (2/6), and oculomotor nerve palsy (n = 1). Endocrine disturbances at presentation included pre-existing amenorrhea in all female patients (3/3), hypothyroidism (n = 2), panhypopituitarism (n = 2), and one with profound hyponatremia (Na 116 meq/L). All patients underwent endonasal transsphenoidal fenestration and drainage with no major complications. Over mean follow-up of 38.4 mo, 2/2 patients with vision loss reported improvement, and 2/5 patients with headaches reported improvement. Although all women resumed menses, patients with preoperative hypopituitarism did not experience pituitary axis improvement. Follow-up magnetic resonance imaging showed no instances of RCC recurrence with a mean imaging follow-up of 38.6 mo. CONCLUSION RCCs occasionally present with hemorrhage and clinical symptoms that may be confused with apoplexy. Outcomes following hemorrhagic RCC treatment are excellent when treated at tertiary pituitary centers. Although hyperprolactinemia often improves following surgery, other pituitary axis deficits typically do not. Graphical Abstract Graphical Abstract

Abstract Background Many women with inflammatory bowel disease (IBD) report changes in symptoms in association with hormonal changes during menses, pregnancy, and hormonal contraceptive use, suggesting a hormonal influence on disease activity. We aimed to identify and characterize IBD symptom fluctuations in women during times of hormonal variation. Methods From June 2012 through September 2012, women enrolled in Crohn's and Colitis Foundation of America Partners , an online Internet cohort of patients with IBD, were invited to participate in this study. Using a 5-point Likert scale, participants were asked to rate symptom changes during their menstrual cycle, pregnancy, the postpartum period, and after menopause. Clinical and demographic differences were assessed using univariate and multivariable methods. Results A total of 1,203 female patients with Crohn's disease (CD) and ulcerative colitis (UC) participated (64% CD, 34% UC). Over half of the women with IBD reported worsening symptoms during menses. Symptom changes were similar between women with CD vs UC, except in pregnancy, where symptom worsening during pregnancy was more commonly seen in UC than CD (P = 0.02). Overall, women reporting symptom worsening were younger at the time of IBD diagnosis (P < 0.01), had lower quality of life (SIBDQ) scores (P < 0.01), and had a higher BMI (25 vs 24) than women without symptom worsening. Conclusions Women with IBD report changes in symptom severity during times of hormone fluctuation. Further clarification of the role of hormones in IBD is warranted in order to understand these relationships and to identify potential management strategies for women with IBD and hormonally sensitive gastrointestinal symptoms. 10.1093/ibd/izx004_video1 izx004.video1 5721589559001