Lessons from 50 Years of Study of Laron Syndrome

Objective: To describe the characteristics of untreated and recombinant insulin-like growth factor 1 (IGF-1)- treated patients with the Laron syndrome (LS) as seen in our clinic over a period of over 50 years. In 1966, we reported a new disease, characterized by dwarfism (-4 to -10 height standard deviation score) typical facial features, small head circumference, obesity, and small genitalia. They resembled congenital growth hormone (GH) deficiency but had high levels of serum human GH and low IGF-1. Since then, our cohort grew to 69 patients, consisting of Jews of oriental origin, Muslins, and Christians originating from the Middle East or Mediterranean area. Many belong to consanguineous families.Methods: Molecular genetic investigations revealed that these patients had deletions or mutations in the GH receptor gene, but only individuals homozygous for this defect express the disease, coined “Laron syndrome” (LS; Online Mendelian Inheritance in Man# 262500).Results: During childhood, LS patients grow slowly, have a retarded bone age and sexual development, but reach full sexual development. The treatment of LS is recombinant IGF-1, which stimulates the linear growth but increases the degree of obesity. Adult-age patients with congenital IGF-1 deficiency are protected from cancer but can develop insulin resistance, glucose intolerance, diabetes, and cardiovascular disease. Due to pathologic changes in the brain related to the type of molecular defect in the GH receptor, they vary in their intellectual capacity. A number of LS patients marry, and with help of pregestational genetic diagnosis, have healthy children.Conclusion: LS is a unique disease model presenting a dissociation between GH and IGF-1 activity.Abbreviations:GH = growth hormonehGH = human growth hormoneIGF-1 = insulin-like growth factor 1LS = Laron syndromerIGF-1 = recombinant IGF-1SDS = standard deviation score     

Discordance Between Gh and Igf-1 Levels in Turkish Acromegalic Patients

Objective: Discordance between insulin-like growth factor-1 (IGF-1) and growth hormone (GH) levels is an important problem in the follow-up of patients diagnosed with acromegaly. Our aims were to evaluate the discordance between IGF-1 and GH levels and compare the performance of different cut-off levels for the nadir in GH (GHn) in acromegalic patients.Methods: The study included 63 acromegalic patients in a follow-up at a tertiary care university hospital facility. Levels of IGF-1, IGF binding protein-3 (IGFBP-3), and GH were investigated. The baseline GH and GHn levels were evaluated after an oral glucose tolerance test (cut-offs of 0.4 and 1 ng/mL, respectively). The discordance rates between GHn and IGF-1 levels, and IGF-1/IGFBP-3 ratios were determined.Results: We first adopted a GHn cut-off value of 1 ng/mL and found that 27 patients (42.9%) exhibited biochemical remission (BR) (IGF-1 <95^th percentile, GH <1), and 25 patients (39.7%) had no BR (NBR) (IGF-1 ≥95^th percentile, GH >1).Discordance in the presence of normal IGF-1 and nonsuppressed GH (DC1) occurred in 2 of 63 (3.2%) patients; discordance in the presence of high IGF-1 and suppressed GH (DC2) occurred in 9 of 63 (14.3%) patients. If the GHn cut-off value adopted was 0.4 ng/mL, the distributions were 17 of 63 (27.0%) patients in BR, 29 of 63 (46.0%) patients in NBR, 12 of 63 (19.0%) in DC1, and 5 of 63 (7.9%) patients in DC2. If only the baseline GH values were considered, the distributions were very similar to those with a GHn cut-off value of 0.4 ng/mL. The IGF-1/IGFBP-3 ratio was lowest in the BR group.Conclusion: Adopting a GHn cut-off value of 0.4 ng/mL did not increase the test performance compared with baseline GH only. In contrast, in the follow-up of acromegalic patients, the IGF-1/IGFBP-3 ratio might be a useful measurement when discordance between IGF-1 and GH levels occurs. We propose that these values be considered in clinical practice.Abbreviations:BR = biochemical remissionDC1 = discordance group 1DC2 = discordance group 2DM = diabetes mellitusGH = growth hormoneGHn = nadir in GHIGF-1 = insulin-like growth factor-1IGFBP-3 = IGF binding protein-3LAR = long-acting releaseNBR = not in biochemical remissionOGTT = oral glucose tolerance test     

Significant Elevation of Growth Hormone Level Impacts Surgical Outcomes in Acromegaly

Objective: Transsphenoidal adenomectomy (TSA) is first-line treatment for acromegaly. Our aim was to determine the impact of pre-operative biochemical parameters on the outcomes of surgery.Methods: Retrospective case series of 79 consecutive acromegalics operated between 1994 and 2013. Inclusion criteria were: first TSA, pathology-confirmed growth hormone (GH) adenoma, and follow-up >3 months. Biochemical remission was defined as normal insulin-like growth factor 1 (IGF-1) without adjuvant therapy during follow-up.Results: Median follow-up was 35.4 months (range, 3 to 187 months). Logistic regression analysis showed that the best model to predict long-term remission included the following pre-operative markers: GH, tumor diameter, and cavernous sinus invasion (CSI) (area under the curve, 0.933). A threshold GH of 40 ng/mL was associated with long-term remission (sensitivity, 97%; specificity, 42%). Group A (GH >40 ng/mL) comprised 19 patients (9 men); age, 43 ± 13 years; tumor diameter, 2.7 ± 1.0 cm; 73.7% with CSI; and pre-operative median GH, 77.8 ng/mL (interquartile range [IQR], 66.7 to 107.0 ng/mL). Three patients (15%) in group A achieved remission at 3 months, but 2 patients recurred during follow-up. Group B (GH ≤40 ng/mL) comprised 60 patients (25 men); age, 47 ± 13 years; tumor diameter, 1.6 ± 1.0 cm; 35% with CSI, preoperative median GH, 6.9 ng/mL (IQR, 3.4 to 16.9 ng/mL). Thirty-five patients (58%) in group B achieved remission at 3 months without recurrence during follow-up. Group A had larger tumors and a higher proportion of tumors with CSI (P<.05).Conclusion: Both GH and IGF-1 should be measured pre-operatively, as highly elevated GH levels negatively impact long-term surgical remission. This strategy allows early identification of patients who require adjuvant therapy and may decrease time to biochemical control.Abbreviations: AUC = area under the curve CSI = cavernous sinus invasion GH = growth hormone ICA = internal carotid artery IGF-1 = insulin-like growth factor 1 MRI = magnetic resonance imaging OGTT = oral glucose tolerance test POD2 = postoperative day 2 TSA = transsphenoidal adenomectomy     

Necessity of Multimodal Treatment of Acromegaly and Outcomes

Objective: Uncontrolled acromegaly is associated with increased morbidity and mortality. Despite multimodal therapeutic options, adequate control can be challenging and lead to prolonged exposure to growth hormone excess. The aim of this study was to assess treatment patterns and outcomes in patients with acromegaly following surgery at a single institution.Methods: A retrospective analysis of response to treatment modalities for patients with a new diagnosis of acromegaly at the Mayo Clinic in Rochester, Minnesota, from 1995–2015.Results: A total of 245 patients with newly diagnosed acromegaly (mean age at diagnosis, 47 ± 14 years; mean follow-up, 5.5 ± 5 years) were evaluated. Primary surgical intervention was performed in 236 patients; 117 (54%) did not achieve remission. Among those with ≥3 months follow-up, 76/217 (35%) patients required three or more forms of treatment. Mean tumor size at diagnosis was 1.6 ± 0.8 cm (80% macroadenomas), and 35% (75/217) had cavernous sinus invasion on pre-operative imaging. The most common second-line treatment was radiation treatment (RT) (50%, 59/117). Among those with persistent disease following surgery, a normal insulin-like growth factor 1 (IGF-1) was achieved in 52% (61/117), with a median time to acromegaly control of 4.5 years. The rate of IGF-1 normalization was 2.1-fold higher in those who received RT compared to those who did not.Conclusion: In patients with persistent acromegaly following surgery, multiple treatment modalities, including RT, may be required to achieve remission. Treatment outcome uncertainty and the need for multiple interventions add to the disease burden associated with persistent acromegaly.Abbreviations: CI = confidence interval; GH = growth hormone; IGF-1 = insulin like growth factor-1; KM = Kaplan-Meier; RT = radiation treatment     

Limitations of Current Approaches For The Treatment of Acromegaly

Objective: Acromegaly is a rare disease characterized by hypersecretion of growth hormone (GH), typically from a benign pituitary somatotroph adenoma, that leads to subsequent hypersecretion of insulin-like growth factor 1 (IGF-1). Patients with acromegaly have an increased risk of mortality and progressive worsening of comorbidities. Surgery, medical therapy, and radiotherapy are currently available treatment approaches for patients with acromegaly, with overall therapeutic goals of lowering GH levels and achieving normal IGF-1 levels, reducing tumor size, improving comorbidities, and minimizing mortality risk. Although surgery can lead to biochemical remission in some patients with acromegaly, many patients will continue to have uncontrolled disease and require additional treatment.Methods: We reviewed recently published reports and present a summary of the safety and efficacy of current treatment modalities for patients with acromegaly.Results: A substantial proportion of patients who receive medical therapy or radiotherapy will have persistently elevated GH and/or IGF-1. Because of the serious health consequences of continued elevation of GH and IGF-1, there is a need to improve therapeutic approaches to optimize biochemical control, particularly in high-need patient populations for whom current treatment options provide limited benefit.Conclusion: This review discusses current treatment options for patients with acromegaly, limitations associated with each treatment approach, and areas within the current treatment algorithm, as well as patient populations for which improved therapeutic options are needed. Novel agents in development were also highlighted, which have the potential to improve management of patients with uncontrolled or persistent acromegaly.Abbreviations:AACE = American Association of Clinical EndocrinologistsAE = adverse eventATG = AutogelCFRT = conventional fractionated radiotherapyDA = dopamine agonistENDO = Endocrine SocietyGH = growth hormoneGHRA = growth hormone receptor antagonistIGF-1 = insulin-like growth factor 1LAR = long-acting releaseLFT = liver function testSC = subcutaneousSRS = stereotactic radiosurgerySSA = somatostatin analoguesst = somatostatin receptorsst₂ = somatostatin receptor subtype 2sst₅ = somatostatin receptor subtype 5TSS = transsphenoidal surgery     

A Subcutaneous Octreotide Hydrogel Implant for the Treatment of Acromegaly

ObjectiveTo evaluate the pharmacokinetics, efficacy, and safety of a subcutaneous octreotide hydrogel implant in patients with acromegaly.MethodsIn 2 phase II open-label randomized studies, patients aged ≥ 18 years with confirmed acromegaly and octreotide responsiveness received one or two 52 mg hydrated implants (52 mg study) or a hydrated or nonhy drated 84 mg implant (84 mg study) inserted subcutane ously in the upper arm. Implants were removed after 6 months. The 84 mg study assessed pharmacokinetics in patients with undetectable baseline octreotide concentra tions. Both studies assessed efficacy (serum growth hor mone [GH], insulin-like growth factor 1 [IGF-1]) and safety (adverse events, physical examination, clinical chemistry).ResultsEleven patients received 1 (n = 5) or 2 (n = 6) 52 mg implants; 34 received a hydrated (n = 17 [safety]; n = 16 [efficacy analysis]) or nonhydrated (n = 17) 84 mg implant. With the nonhydrated versus hydrated 84 mg implant, mean maximum serum concen tration (C_max) and mean area under the drug concentration versus time curve from time 0 to 6 months were decreased (P = 0.002 and P = 0.03, respectively) and mean time to C_max was increased (P = 0.002). In both studies, IGF-1 and GH declined in month 1 and were significantly suppressed during the 6-month treatment versus baseline (P < 0.001). With the 52 mg and 84 mg implants, respectively, 3 of 11 patients (27%) and 17 of 33 patients (52%) achieved IGF-1 normalization and 8 of 11 patients (73%) and 13 of 33 patients (39%) exhibited GH < 2.5 ng/mL; 9 of 11 patients (82%) and 11 of 34 patients (32%) experienced treatment related adverse events, which were mainly gastrointestinal.ConclusionOctreotide hydrogel implants were well tolerated and maintained stable octreotide release and sup pression of IGF-1 and GH over 6 months. (Endocr Pract. 2012;18:870-881)     

Adherence to Growth Hormone Therapy: Results of a Multicenter Study

ObjectiveTo evaluate the adherence to growth hormone (GH) therapy and identify the influencing factors and outcomes in children.MethodsA total of 217 GH-naïve patients in 6 pediatric endocrinology clinics were enrolled in the study. Structured questionnaires were filled out and patients were evaluated at the initiation and 3rd, 6th, and 12th months of therapy. Patients were categorized into 4 adherence segments based on percentage of doses omitted at each evaluation period, classified as excellent if 0%, good if 5%, fair if 5 to 10%, and poor if > 10%.Results:There was a decrement in adherence to GH therapy during the study period (P = .006). Patients who showed excellent and good adherence to therapy had better growth velocity and growth velocity standard deviation scores (SDSs) (P = .014 and P = .015, respectively). A negative correlation between growth velocity SDS and number of missed injections was also observed (r = − .412; P = .007). A positive correlation between delta insulin-like growth factor-1 (IGF-1) SDS and growth velocity was demonstrated (r = .239; P = .042). IGF-1 levels were significantly higher in patients who showed excellent and good adherence to therapy (P = .01). Adherence was better in boys than in girls (P = .035), but adherence rates were not associated with age, cause of GH treatment, socioeconomic status, person who administered the injections, type of injection device, or GH product.ConclusionPoor adherence to GH therapy was common in our group of patients and was one of the factors underlying suboptimal growth during therapy. Before considering other problems that can affect growth, clinicians should confirm good adherence to therapy. (Endocr Pract. 2014;20:46-51)     

Endocrine Complications in Patients with Gvhd

Objective: Graft-versus-host disease (GVHD) is an immune phenomenon that occurs in 30 to 70% of patients after allogeneic hematopoietic stem cell transplantation (HST). Chronic GVHD is a state of immune dysregulation wherein, depending on the severity and organ involved, patients may require prolonged treatment with additional or higher corticosteroids and other immunosuppressive agents. The objective of this study was to review the endocrine manifestations following HST that can arise as a consequence of the primary disease or its treatment, including chemotherapeutic agents, corticosteroids, radiation, or GVHD.Methods: We performed a narrative review of GVHD after HST. An English-language search for relevant studies was conducted on PubMed from inception to August 1, 2018, using the following search terms: “endocrine complications,” “bone marrow transplantation,” “graft-versus-host disease,” and “GVHD.” The reference lists of relevant studies were also reviewed.Results: Chronic GVHD may be associated with considerable pediatric growth impairment and may also contribute to thyroid gland dysfunction and thyroid cancer. These patients may also be at increased risk for low bone mineral density, reduced fertility, metabolic syndrome, and suppression of the pituitary-adrenal axis with adrenal insufficiency.Conclusion: This review indicates the importance of monitoring, diagnosing, and properly treating the endocrine complications in this population. More studies are needed to investigate the independent impact of GVHD on the endocrine system and treatment for complications.Abbreviations: BMD = bone mineral density; GH = growth hormone; GVHD = graft-versus-host disease; HST = hematopoietic stem cell transplantation; IGF-1 = insulin-like growth factor 1     

Significance of Elevated Parathyroid Hormone After Parathyroidectomy

ObjectiveTo review the prevalence of parathyroid hormone elevation after parathyroidectomy for primary hyperparathyroidism and to discuss possible mechanisms.MethodsA Medline search of the English-language literature published between 1990 and 2009 was performed using the search terms “elevated PTH after parathyroidectomy.” All of the identified articles reported either prospective or retrospective studies without control groups. Studies that included patients with secondary or tertiary hyperparathyroidism were not reviewed.ResultsWithin 1 week to 5 years after parathyroidectomy, 9% to 62% of patients with a normal serum calcium concentration are reported to have an elevated parathyroid hormone concentration. No evidence suggests that postoperative normocalcemic parathyroid hormone elevation is an indication of surgical failure and recurrent hypercalcemia. Preoperative findings in patients with postoperative parathyroid hormone elevation include lower vitamin D concentration, higher concentrations of bone turnover markers, and higher parathyroid hormone concentration. Potential mechanisms for parathyroid hormone elevation in the setting of normocalcemia include vitamin D deficiency, hungry bone syndrome, and parathyroid hormone resistance. Study findings suggest a possible benefit of postoperative calcium and vitamin D supplementation, but no randomized trials have been done.ConclusionElevation of parathyroid hormone commonly occurs after parathyroidectomy for primary hyperparathyroidism, although the underlying mechanism remains unclear. (Endocr Pract. 2010;16:112-117)     

IGF-1 concentration patterns and their relationship with follicle development after weaning in young sows fed different pre-mating diets

Piglet birth weight and within-litter birth weight variation are important for piglet survival and growth. Pre-mating diets may improve IGF-1 and follicle development during the weaning-to-oestrus interval (WEI) and subsequent piglet birth weight. The objective of this study was to modulate IGF-1 concentration during late lactation and the WEI of young sows by using specific pre-mating diets supplemented with microfibrillated cellulose (MF), l-carnitine (LC) or l-arginine (AR). A further objective was to investigate the relationship between IGF-1 and subsequent follicle development and oestrus and ovulation characteristics. In total, 56 first-parity and 20 second-parity sows in three consecutive batches were used for this experiment. Sows received daily either wheat (CON) or wheat plus MF, LC or AR at one of two supplementation levels (low and high) during last week of lactation and WEI. From weaning onwards, follicle and corpus luteum (CL) diameters were repeatedly measured with ultrasound. Blood samples were collected during the WEI for IGF-1 and on day 21 of pregnancy for progesterone analyses, respectively. Insulin-like growth factor-1 concentration, follicle diameter, oestrus and ovulation characteristics and CL diameter were not affected by pre-mating diets. Low IGF-1 class (≤156 ng/ml, N = 22) sows had smaller follicles at weaning (3.5 v. 3.8 mm, P < 0.05) and a longer weaning-to-ovulation interval (147.2 v. 129.8 h, P < 0.05) than high IGF-1 class sows. In first-parity sows, high loin muscle depth (LM) loss sows (≥8%, N = 28) had lower IGF-1 concentrations at weaning (167 v. 214 ng/ml, P < 0.05) compared to low LM loss sows (<8%, N = 28). However, after weaning, IGF-1 concentrations increased and did not differ between high LM loss and low LM loss sows. In conclusion, the different supplemented compounds in pre-mating diets did not improve IGF-1 concentrations around weaning in young sows. Furthermore, high body condition loss caused lower IGF-1 concentrations at weaning, but these levels rapidly recovered after weaning and were related to follicle development and the interval from weaning to ovulation.     

The Prevalence of Cancer and Its Relation to Disease Activity in Patients With Acromegaly: Two Centers' Experience

ObjectiveAcromegaly is characterized by increased serum concentrations of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). Although animal studies have demonstrated a relationship between these hormones and cancer risk, the results of human studies evaluating cancer prevalence in acromegaly are inconsistent. We aimed to investigate the prevalence of malignant neoplasms in patients with acromegaly.MethodsCancer risk was evaluated in a cohort of 280 patients (male/female: 120/160; mean age: 50.93 ± 12.07 years) with acromegaly. Patients were categorized into 2 groups according to the presence or absence of cancer. Standard incidence ratios were calculated as compared to the general population.ResultsFrom 280 patients, cancer was diagnosed in 19 (6.8%) patients; 9 (47%) of them had thyroid cancer, which was the most common cancer type. Standard incidence ratios of all cancers were 0.8 (95% CI, 0.5-1.1) and 1.0 (95% CI, 0.8-1.3) in men and women, respectively. Compared to patients without cancer, the current age was higher in patients with cancer (59 [49-65] to 51 [42-59], P = .027). In contrast, the age at diagnosis was similar in both groups. Not only was the time to diagnosis and disease duration similar in both groups but also the basal and current GH and IGF-1 levels. The prevalence of active disease was also similar between the groups (32% to 23%, P = .394).ConclusionOur findings were not consistent with the studies suggesting that patients with acromegaly encounter an increased cancer risk. Furthermore, there were similar basal and current GH and IGF-1 levels in patients with acromegaly, both with and without cancer.     

The Effect and Potential Mechanism Analysis of Growth Hormone–Secreting Pituitary Adenomas on Thyroid Function

ObjectiveCurrent studies on the effect of high growth hormone (GH)/insulin-like growth factor (IGF)-1 on thyroid function are inconsistent. The aim was to explore the effect and potential mechanism of high GH/IGF-1 on thyroid function by analyzing the changes of thyroid function in patients with growth hormone–secreting pituitary adenoma (GHPA).MethodsThis was a retrospective cross-sectional study. Demographic and clinical data of 351 patients with GHPA who were first admitted to Beijing Tiantan Hospital, Capital Medical University, from 2015 to 2022 were collected to analyze the relationship between high GH/IGF-1 levels and thyroid function.ResultsGH was negatively correlated with total thyroxine (TT4), free thyroxine (FT4), and thyroid-stimulating hormone (TSH). IGF-1 was positively correlated with total triiodothyronine (TT3), free triiodothyronine (FT3), and FT4 and negatively correlated with TSH. Insulin-like growth factor–binding protein (IGFBP)-3 was positively correlated with TT3, FT3, and FT3:FT4 ratio. The FT3, TT3, TSH, and FT3:FT4 ratio of patients with GHPA and diabetes mellitus (DM) were significantly lower than those with GHPA but without DM. With the increase of tumor volume, thyroid function gradually decreased. GH and IGF-1 were correlated negatively with age in patients with GHPA.ConclusionThe study emphasized the complex interaction between the GH and the thyroid axes in patients with GHPA and highlighted the potential effect of glycemic status and tumor volume on thyroid function.     

American Association of Clinical Endocrinologists and American College of Endocrinology Disease State Clinical Review: A Neuroendocrine Approach to Patients With Traumatic Brain Injury

Objective: Traumatic brain injury (TBI) is now recognized as a major public health concern in the United States and is associated with substantial morbidity and mortality in both children and adults. Several lines of evidence indicate that TBI-induced hypopituitarism is not infrequent in TBI survivors and may contribute to the burden of illness in this population. The goal of this article is to review the published data and propose an approach for the neuroendocrine evaluation and management of these patients.Methods: To identify pertinent articles, electronic literature searches were conducted using the following keywords: “traumatic brain injury,” “pituitary,” “hypopituitarism,” “growth hormone deficiency,” “hypogonadism,” “hypoadrenalism,” and “hypothyroidism.” Relevant articles were identified and considered for inclusion in the present article.Results: TBI-induced hypopituitarism appears to be more common in patients with severe TBI. However, patients with mild TBI or those with repeated, sports-, or blast-related TBI are also at risk for hypopituitarism. Deficiencies of growth hormone and gonadotropins appear to be most common and have been associated with increased morbidity in this population. A systematic approach is advised in order to establish the presence of pituitary hormone deficiencies and implement appropriate replacement therapies.Conclusion: The presence of traumatic hypopituitarism should be considered during the acute phase as well as during the rehabilitation phase of patients with TBI. All patients with moderate to severe TBI require evaluation of pituitary function. In addition, symptomatic patients with mild TBI and impaired quality of life are at risk for hypopituitarism and should be offered neuroendocrine testing.Abbreviations: CBG = corticosteroid-binding globulin DI = diabetes insipidus GH = growth hormone IGF-1 = insulin-like growth factor 1 SIADH = syndrome of inappropriate antidiuretic hormone T₄ = thyroxine TBI = traumatic brain injury TSH = thyroid-stimulating hormone     

Insulin-Like Growth Factor-1 and Anemia in Older Subjects: The Inchianti Study

Objective: Recent studies indicate a role for the age-related decline of anabolic hormones, especially testosterone, in the onset of “anemia of aging.” Some of testosterone's erythropoietic activities are mediated by insulin-like growth factor (IGF)-1, which also seems to have independent erythropoietic effects. However, the associations among IGF-1, anemia, and hemoglobin (Hb) have not been adequately investigated in older populations.Methods: We used data from a representative sample of 953 subjects ≥65 years who participated in the InCHIANTI (Invecchiare in Chianti) Study and were not on growth hormone (GH) or erythropoietin therapy and were not diagnosed with hematologic malignancies or other cancers. Anemia was defined according to the World Health Organization (WHO) criteria by Hb level ≤13 g/dL in males and ≤12 g/dL in females. Backward multiple regression analyses including age, IGF binding protein (IGFBP)-3, testosterone, comorbidities, inflammatory markers, and anemia-related measures were used to address the relationship between IGF-1 and Hb and between IGF-1 and anemia in both sexes.Results: We found that 46/410 (11.2%) males and 71/543 (13.0%) females were defined as anemic. After adjustment for age, anemic males (100 ± 54 vs. 130 ± 56, P<.001) and females (89.1 ± 48 vs. 110 ± 52, P = .001) exhibited lower IGF-1 levels than their nonanemic counterparts. IGF-1 levels were independently and negatively associated with anemia in males (β ± SE = -0.0005 ± 0.0002, P = .04) but not in females (β ± SE = -0.0002 ± 0.0002, P = .40). In both males (β ± SE = 0.002 ± 0.001, P = .03) and females (β ± SE = 0.002 ± 0.0009, P = .03), IGF-1 levels were independently and positively associated with Hb levels.Conclusion: In older males but not in females, IGF-1 levels are negatively associated with anemia. IGF-1 levels are independent and positive determinants of Hb concentration in both sexes.Abbreviations: BMI = body mass index CRP = C-reactive protein CV = coefficient of variation GH = growth hormone Hb = hemoglobin IGF-1 = insulin-like growth factor-1 IGFBP-3 = insulin-like growth factor binding protein-3 IL-6 = interleukin-6 InCHIANTI = Invecchiare in Chianti MDC = minimum detectable concentration sTfr = soluble transferrin receptor WHO = World Health Organization     

Comparison of Cabergoline Versus Raloxifene Add-On Therapy to Long-Acting Somatostatin Analogue in Patients With Inadequately Controlled Acromegaly: A Randomized Open Label Clinical Trial

Objective: The present study aimed to evaluate the efficacy of add-on therapy of cabergoline versus raloxifene to long-acting somatostatin analogues (SAs) in patients with inadequately controlled acromegaly.Methods: This was a prospective, randomized open label clinical trial. Forty-four patients (22 per group) completed the study; where participants received either cabergoline (3 mg/week) or raloxifene (60 mg twice daily) add-on therapy for 12 weeks in a parallel manner. The primary outcome was the rate of reduction in serum insulin-like growth factor 1 (IGF-1) from baseline. Secondary outcomes comprised normalization of serum IGF-1 for age and sex.Results: Serum IGF-1 was significantly decreased in both the cabergoline (40.3 ± 25.6%, P<.001) and raloxifene (31.5 ± 24.6%, P<.001) groups, with no significant difference between arms (P>.05). Normalization in serum IGF-1 values occurred in 40.9% of patients who were on cabergoline compared to 45.5% of those receiving raloxifene (P = .76). The subsequent logistic regression analysis highlighted baseline IGF-1 as a significant predictor of IGF-1 normalization (odds ratio, 0.995; 95% confidence interval, 0.990–0.999; P = .02). Using the receiver operating characteristic (ROC) curve analysis for the entire group, the baseline IGF-1 value of 1.47 the upper limit of normal (ULN) was the best cut-off point to identify patients with normal IGF-1 at the end of the study (sensitivity: 52.6%, specificity: 84.0%, Yoden's index: 0.366). Full biochemical control of acromegaly was achieved in 22.7% of patients in the cabergoline group compared to 13.6% of those in the raloxifene group (P = .43).Conclusion: Cabergoline and raloxifene add-on therapy could effectively decrease serum IGF-1 level in patients with inadequately controlled acromegaly. The efficacy profiles of both drugs are comparable.Abbreviations: DA = dopamine agonist; FBG = fasting blood glucose; GH = growth hormone; IGF1 = insulin-like growth factor-1; IQR = interquartile range; OR = odds ratio; ROC = receiver operating characteristic; SA = somatostatin analogue; SERM = selective estrogen modulator receptor; ULN = upper limit of normal     

Effects of Lanreotide Autogel on Growth Hormone,Insulinlike Growth Factor 1, and Tumor Size in Acromegaly: a 1-Year Prospective Multicenter Study

ObjectiveTo evaluate the safety and effectiveness of lanreotide Autogel on growth hormone and insulinlike growth factor 1 (IGF-1) concentrations and tumor size in patients with acromegaly.MethodsBetween September 2004 and March 2006, patients with active acromegaly who had not previously been treated with somatostatin analogues or received irradiation were enrolled in a 1-year, prospective, open, multicenter study. Lanreotide Autogel was injected subcutaneously starting with 90 mg every 4 weeks for 2 cycles and then individually titrated, aiming for safe growth hormone concentrations (< 2.5 ng/mL) and normal age-matched IGF-1 concentrations. Tumor shrinkage, clinical score, pituitary function, and safety parameters were evaluated.ResultsTwenty-seven patients (15 women, 12 men) were enrolled. One patient withdrew because of treatment intolerance, and 5 proceeded to neurosurgery 6 months into the study. Lanreotide Autogel was the primary treatment in 19 patients (4 with microadenoma, 15 with macroadenoma) and the adjuvant treatment in 8 patients in whom it followed a previous unsuccessful neurosurgery. In the 26 patients, safe growth hormone values were achieved in 11 (42%), normal IGF-1 values in 14 (54%), and both targets were achieved in 10 (38%). Tumors shrank in 16 of the 22 patients (73%) in whom tumor shrinkage could be evaluated. The maximal vertical diameter of the tumor decreased by a mean of 24% (range, 0% to 50%), from 14.4 ± 8.4 mm to 10.4 ± 7 mm, and tumor volume decreased by a mean of 44% (range, 0% to 76%), from 2536 mm³ (range, 115-7737 mm³) to 1461 mm³ (range, 63-6217 mm³) (both P < .015). Symptom scores and lipid levels significantly improved. In the 26 patients, glucose metabolism deteriorated in 3 (12%) and improved in 4 (15%). New biliary alterations appeared in 26%. Pituitary function and safety parameters did not change.ConclusionsLanreotide Autogel treatment, titrated for optimal hormonal control, effectively controls IGF-1 and growth hormone levels, shrinks tumors, reduces acromegalic symptoms, and is well tolerated. (Endocr Pract. 2008;14:846-855)     

American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Growth Hormone Deficiency in Adults and Patients Transitioning from Pediatric to Adult Care

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 ABSTRACTThis 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     

Ectopic Acromegaly due to A Pancreatic Neuroendocrine Tumor Producing Growth Hormone-Releasing Hormone

ObjectiveTo present a case of acromegaly due to ectopic growth hormone-releasing hormone (GHRH) secretion from a pancreatic neuroendocrine tumor in the context of multiple endocrine neoplasia type 1 (MEN 1).MethodsWe describe the clinical, imaging, and pathologic findings of the study patient.ResultsA 46 year old woman presented with clinical and biochemical findings diagnostic of acromegaly. Magnetic resonance imaging showed a 1.2-cm sellar mass. Following resection of the macroadenoma, serum insulinlike growth factor 1 (IGF-1) and growth hormone (GH) levels remained unchanged. Pathologic examination revealed adenomatous changes, including a nonsecretory focus and a prolactin immunopositive area (GH stain negative in both). Octreotide long-acting release was ineffective. Search for an ectopic tumor included normal octreoscan and abdominal computed tomography. GHRH was greater than 1000 pg/mL. Repeated abdominal computed tomography documented a 6.2-cm mass in the tail and body of the pancreas. Distal pancreatectomy revealed a pancreatic neuroendocrine tumor that stained positive for GHRH. Postoperatively, serum GHRH and IGF-1 normalized. Re-evaluation of the initial pituitary pathologic specimen revealed additional somatotroph hyperplasia of the adjacent, normal pituitary gland. Primary hyperparathyroidism was diagnosed, and multigland parathyroid hyperplasia was noted at surgery. Genetic testing was positive for a mutation in the MEN1 gene.ConclusionThis patient’s acromegaly was resistant to somatostatin analogue therapy, reflecting the negative octreoscan imaging. In addition, this case is novel because the patient presented with pituitary adenomatous changes, which were presumably associated with MEN 1 and/or possibly the elevated GHRH levels. (Endocr Pract. 2011; 17:79-84)     

Surgical Reintervention in Acromegaly: is it Still worth trying?

Background and ObjectiveThere has not been a formal evaluation of how frequently and to what extent surgical reintervention in patients with persistently active acromegaly may achieve significant, albeit incomplete, reductions in growth hormone (GH) and insulinlike growth factor-I (IGF-I) levels. Of importance, recent studies suggest that the response to radiotherapy and pharmacotherapy is better with lower degrees of hypersomatotropism. The objective of this study was to evaluate the outcome of surgical reintervention in patients with active acromegaly at our institution between 1995 and 2005.MethodsWe retrospectively evaluated the outcome in 53 patients with active acromegaly (49 with macroadenomas) who underwent a second operation a mean of 24.1 ± 25.2 months after the first intervention. Basal and postglucose GH as well as IGF-I levels were analyzed at diagnosis and after the first and second pituitary procedures.ResultsBasal GH decreased in 38 patients (72%): to < 10 ng/mL in 17 and to < 2.5 ng/mL in 11. The mean IGF- I index and basal GH decreased significantly after surgical reintervention: 1.7 ± 0.4 to 1.4 ± 0.4 (P = .0001) and 13.0 ± 12.8 to 8.3 ± 11.3 ng/mL (P = .0001), respectively. Some decrement in IGF-I was observed after surgical reintervention in 30 patients (57%), being greater than 30% in 9 (17%). Only 5 patients (9%) achieved complete biochemical cure (normal IGF-I and a postglucose GH level of < 1 ng/mL). Reoperation achieved a significant decline in basal and postglucose GH levels as well as in IGF-I index only in patients with noninvasive macroadenomas.ConclusionPituitary surgical reintervention in patients with acromegaly results in a low percentage of biochemical cure. If a remnant of a noninvasive macroadenoma is visible and accessible, however, such a procedure may significantly reduce GH and IGF-I levels. (Endocr Pract. 2009;15:431-437)     

Serum IGF-1 In the Diagnosis of Acromegaly and the Profile of Patients with Elevated IGF-1 but Normal Glucose-Suppressed Growth Hormone

ObjectiveTo report the utility of insulin-like growth factor-1 (IGF-1) as a single biomarker for establishing the diagnosis of acromegaly and to examine the clinical and biochemical profile of patients with an elevated IGF-1 in whom a diagnosis of acromegaly could not be confirmed by means of the oral glucose tolerance test (OGTT).MethodsBetween the years 1999 and 2010, we identified 101 patients who underwent pituitary surgery and had histologically proven somatotroph adenomas (Group 1, Gr 1). We selected 149 patients with non- growth hormone (GH) secreting pituitary macroadenomas (Gr 2, n = 97) and microadenomas (Gr 3, n = 52) to serve as control subjects. In addition, we identified 34 patients with elevated IGF-1values in whom acromegaly could not subsequently be proven by the OGTT (Gr 4).ResultsIGF-1 was elevated in all patients with acromegaly prior to therapy with a median (range) standard deviation score (SDS) of + 9.52 (+ 2.34 to + 9.2), compared to SDS − 1.46 (− 2.91 to + 2.17) and − 1.22 (− 2.8 to + 1.58) in Gr 2 and 3, respectively (P < 0.001). IGF- 1 SDS values were + 3.28 (+ 2.05 to + 6.1), and IGF-1 was less than twice the upper limit of normal in all patients in Gr 4. OGTT was performed in 51 of the 101 acromegalic patients. The nadir GH in these patients was 4.01 (0.2 to 46.7) in comparison with 0.2 (< 0.05 to 0.6) in Gr 4 (P < 0.001).ConclusionElevated IGF-1 levels, alone, are sufficient to establish a diagnosis of acromegaly in the majority of clinically suspected cases. The OGTT may be useful to obtain corroborative evidence when there is modest elevation of IGF-1 with absent or equivocal clinical features. (Endocr Pract. 2012;18:817-825)