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)     

A Single-Center Open-Label Study To Investigate The Efficacy And Safety Of Repeated Subcutaneous Injections Of Lanreotide Autogel In Patients With Acromegaly Previously Treated With Octreotide

ObjectiveTo evaluate the efficacy of lanreotide Autogel, a depot preparation of a long-acting somatostatin analogue, in patients with acromegaly who were previously treated with octreotide.MethodsIn a prospective single-center, open-label, comparative study, 13 patients were switched from octreotide treatment (baseline) to lanreotide Autogel therapy at a fixed dosage of 90 mg/4 wk. After 6 injections, the dosage was titrated to 60, 90, or 120 mg/4 wk, on the basis of growth hormone (GH) levels, for a further 6 injections. Mean GH and insulinlike growth factor-I (IGF-I) levels were determined at baseline, during treatment (to 48 weeks), and up to 8 weeks after the last injection.ResultsThere was no significant change in the proportion of patients with GH and IGF-I control from baseline to week 48 (GH, 85% to 89%; IGF-I, 46% to 62%). Mean GH levels changed little from baseline, but mean IGF-I levels were significantly lower after 32 weeks (P < .05) and 48 weeks (P < .02). Data collected at 6 and 8 weeks after the last injection suggested that the efficacy of lanreotide Autogel can persist for longer than 4 weeks.ConclusionThis small study suggests that lanreotide Autogel is at least as effective as octreotide in the control of acromegaly and may last for longer than the recommended 4 weeks. It appears to be a useful alternative to long-acting octreotide in the treatment of acromegaly. (Endocr Pract. 2010;16:191-197)     

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     

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)     

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)     

Medical Treatment Landscape for Active Acromegaly in A Pituitary Center in Israel

Objective: To evaluate current real-life experience with medical treatment for active acromegaly in a large cohort.Methods: Data on demographic parameters, blood tests, imaging studies, and treatments were extracted from the medical records.Results: The cohort included 87 patients (43 male) with active acromegaly. The mean age at diagnosis was 40.2 ± 11.4 years, and the mean duration of follow-up was 7.9 ± 5.8 years. Seventy patients presented with a macroadenoma. Mean baseline insulin growth factor 1 (IGF-1) (n = 67) was 3.2 ± 1.9 × upper limit of normal (ULN). Surgery and radiotherapy were performed in 75 and 10 patients, respectively. Currently, 38 subjects receive somatostatin analogues, pegvisomant as a monotherapy is given to 8 patients, pasireotide is given to 17 patients, cabegoline to 4 patients, estrogen to 2 females, and SSAs combined with pegvisomant to 10 patients. Eight patients are not being actively treated, including 4 following radiotherapy. Good biochemical control (IGF-1 <1.3 × ULN) was achieved in 76 patients (87%), and 11 patients (13%) are currently uncontrolled (IGF-1 >1.3 × ULN). Seventy-eight percent of controlled patients are being given 1 medication; 11% are on combination therapy; 4 patients are well controlled after radiotherapy and 2 are partially controlled without any treatment. The main adverse effects of treatment were diabetes mellitus in 7 patients (on pasireotide) and symptomatic cholelithiasis in 5 patients.Conclusion: Active acromegaly can be controlled medically in most patients, with a low rate of adverse effects. This study displays the characteristic variety of treatment options available for active acromegaly.     

No Benefit of Dedicated Thyroid Nodule Screening in Patients with Acromegaly

Objective: Acromegaly results from the excessive production of growth hormone and insulin-like growth factor-1. While there is up to a 2-fold increased prevalence of thyroid nodules in patients with acromegaly, the incidence of thyroid cancer in this population varies from 1.6 to 10.6% in several European studies. The goal of our study was to determine the prevalence of thyroid nodules and thyroid cancer among patients with acromegaly at a large urban academic medical center in the United States (U.S.).Methods: A retrospective chart review was performed of all patients with acromegaly between 2006–2015 within the University of California, Los Angeles health system. Data were collected regarding patient demographics, thyroid ultrasounds, thyroid nodule fine needle aspiration (FNA) biopsy cytology, and thyroid surgical pathology.Results: In this cohort (n = 221, 49.3% women, mean age 53.8 ± 15.2 &lsqb;SD] years, 55.2% Caucasian), 102 patients (46.2%) underwent a thyroid ultrasound, from which 71 patients (52.1% women, mean age 52.9 ± 15.2 &lsqb;SD] years, 56.3% Caucasian) were found to have a thyroid nodule. Seventeen patients underwent a thyroid nodule FNA biopsy and the results revealed 12 benign biopsies, 1 follicular neoplasm, 3 suspicious for malignancy, and 1 papillary thyroid cancer (PTC), from which 6 underwent thyroidectomy; PTC was confirmed by surgical pathology for all cases (8.5% of all nodules observed).Conclusion: In this sample, the prevalence of thyroid cancer in patients with acromegaly and coexisting thyroid nodules is similar to that reported in the general U.S. population with thyroid nodules (7 to 15%). These findings suggest that there is no benefit of dedicated thyroid nodule screening in patients newly diagnosed with acromegaly.Abbreviations: AACE = American Association of Clinical Endocrinologists; ATA = American Thyroid Association; DTC = differentiated thyroid cancer; FNA = fine needle aspiration; GH = growth hormone; IGF-1 = insulin-like growth factor-1; PTC = papillary thyroid cancer; U.S. = United States     

Consensus of the Polish Society of Endocrinology. Presurgical somatostatin analogs therapy in acromegaly

Consensus statement of the Polish Society of Endocrinology, regarding presurgical somatostatin analogs in acromegaly has been presented. It is suggested to administer depot somatostatin analog (Octreotide LAR at the dose 20 mg and then 30 mg or equivalent doses of Lanreotide Autogel 90/120 mg every 4 weeks) in order to normalize or suppress to a maximal extent GH and IGF-1 concentrations. The period of therapy in case of microadenoma would be at least 3 months (targets: biochemical improvement, reduced risk of disease's complications, perioperative risk reduction, inhibition of tumor growth). The period of therapy in case of macroadenoma would be at least 6 months, until maximal possible reduction of GH and IGF-1 concentrations (targets: tumor shrinkage, biochemical improvement, reduced risk of disease's complications, perioperative risk reduction). Using an uniform approach in a group, as numerous as possible, of treated patients would allow objective evaluation of long-term efficacy of the treatment.     

Consensus statement of the Polish Society for Endocrinology: presurgical somatostatin analogs therapy in acromegaly

Consensus statement of the Polish Society for Endocrinology, regarding presurgical somatostatin analogs in acromegaly has been presented. It is suggested to administer depot somatostatin analog (Octreotide LAR at the dose 20 mg and then 30 mg or equivalent doses of Lanreotide Autogel 90/120 mg every 4 weeks) in order to normalize or suppress to a maximal extent GH and IGF-1 concentrations. The period of therapy in case of microadenoma would be at least 3 months (targets: biochemical improvement, reduced risk of disease's complications, perioperative risk reduction, inhibition of tumor growth). The period of therapy in case of macroadenoma would be at least 6 months, until maximal possible reduction of GH and IGF-1 concentrations (targets: tumor shrinkage, biochemical improvement, reduced risk of disease's complications, perioperative risk reduction). Using an uniform approach in a group, as numerous as possible, of treated patients would allow objective evaluation of long-term efficacy of the treatment.     

Higher Growth Hormone Levels are Associated with Erectile Dysfunction in Male Patients With Acromegaly

Objective: To investigate in vivo correlates of erectile dysfunction (ED) in male patients with acromegaly.Methods: Fifty-one male patients with acromegaly were assessed by the International Index of Erectile Function-5 and Acromegaly Quality of Life (Acro-QoL) questionnaires. The measurement of serum nitric oxide (NO) were performed in patients and age-matched nonacromegalic controls.Results: Among 51 patients analyzed, 32 (62.7%) had ED. Patients with ED showed lower Acro-QoL scores regarding global (69.8 ± 17.7 versus 79.4 ± 11.2; P = .035) and personal relationship dimensions (59.6 ± 22.1 versus 76.8 ± 17.6; P = .012) than non-ED patients. ED patients were older (44.5 ± 11.2 years versus 33.2 ± 8.5 years; P = .04) and showed higher growth hormone (GH) levels (15.5 μg/L &lsqb;interquartile range of 9.5 to 34.5 μg/L] versus 5.9 μg/L &lsqb;interquartile range of 3.4 to 13.9 μg/L]; P = .001) compared to non-ED patients. The cutoff values for identifying ED were 7.9 μg/L for random GH and 5.3 μg/L for GH nadir after oral administration of 75 g of glucose. There was no significant difference in total testosterone levels between the two groups (6.36 ± 4.24 nmol/L versus 9.54 ± 5.50 nmol/L; P = .299). The NO levels in patients with acromegaly were significantly lower than those in nonacromegalic controls (8.77 ± 1.78 μmol/L versus 19.19 ± 5.02 μmol/L, respectively; P = .049). Furthermore, the NO levels were even lower in ED patients than those in non-ED patients (5.14 ± 0.98 μmol/L versus 12.09 ± 3.44 μmol/L; P = .027).Conclusion: Our study showed that ED is prevalent in male acromegalic patients and may be associated with systemic endothelial dysfunction induced by excessive GH. Further studies investigating the mechanism of GH and ED are required.Abbreviations: Acro-QoL = Acromegaly Quality of Life; ED = erectile dysfunction; FSH = follicle-stimulating hormone; GH = growth hormone; IGF-1 = insulin-like growth factor 1; IIEF-5 = international index of erection function-5; LH = luteinizing hormone; MRI = magnetic resonance imaging; NO = nitric oxide; OGTT = oral glucose tolerance test; QoL = quality of life; ROC = receiver operating characteristic     

Cytoplasmic expression of SSTR2 and 5 by immunohistochemistry and by RT/PCR is not associated with the pharmacological response to octreotide

ObjectiveTo evaluate expression of somatostatin receptor subtypes 2 and 5 (SSTR 2 and 5) by RT/PCR and immunohistochemistry (IHC) in GH-secreting adenomas, seeking correlations with response to octreotide.MethodsSSTR2 and 5 expression was tested by IHC (n = 37), RT/PCR (n = 36) or both (n = 13) in GH-secreting adenomas from 60 patients with acromegaly who had undergone pituitary surgery; 36 had been treated preoperatively with octreotide LAR for 3–6 months, and were categorized as responders (achievement of GH <2.5 ng/mL and a normal age-adjusted IGF-1), partial responders (GH and IGF-1 reduction >50% and >30%, respectively) or non-responders. IHC was performed on a tissue microarray using specific antibodies directed to the carboxyl terminus of SSTR2 and 5.ResultsSSTR5 was the predominantly expressed receptor subtype by both IHC and RT/PCR in all tumors tested, regardless of whether they came from octreotide-naïve, octreotide-responsive, or octreotide-resistant patients. Immunostaining was concentrated in the cytoplasm. Neither SSTR2 nor SSTR5 expression correlated with baseline or post-octreotide GH or IGF-1 levels or tumor volume by either method. The agreement rate between RT/PCR and IHC was 77% in all 13 adenomas in which both methods were used.ConclusionExpression of these receptors does not guarantee an adequate response to somatostatin analogs; other functional aspects of this interaction, such as receptor homo- and heterodimerization, and the resulting signaling cascade, probably play a role in determining whether a patient will respond or not to these agents.     

Tumorigenesis of Papillary Thyroid Cancer Is Not BRAF-Dependent in Patients with Acromegaly

Introduction

Several studies have reported a high frequency of papillary thyroid cancer (PTC) in patients with acromegaly. The aim of this study was to determine the prevalence and predictors of thyroid cancer in patients with acromegaly and to investigate the frequency of the BRAF ^V600E mutation in PTC patients with and without acromegaly.

Materials and Methods

We conducted a retrospective study of 60 patients with acromegaly. Thyroid ultrasonography (US) and US-guided fine needle aspiration were performed on nodules with sonographic features of malignancy. We selected 16 patients with non-acromegalic PTC as a control group. The BRAF ^V600E mutation was analyzed in paraffin-embedded surgical specimens of PTC by real-time polymerase chain reaction, and tumor specimens from patients with PTC were stained immunohistochemically with an antibody against insulin-like growth factor-1 receptor β (IGF-1Rβ).

Results

Thyroid cancer was found in 15 (25.0%) patients. No differences in age, sex, initial growth hormone (GH) and IGF-1 percentage of the upper limit of normal values or treatment modalities were observed between patients with and without PTC. Acromegaly was active in 12 of 15 patients at the time of PTC diagnosis; uncontrolled acromegaly had a significantly higher frequency in the PTC group (60%) than in the non-PTC group (28.9%) (p = 0.030). The BRAF ^V600E mutation was present in only 9.1% (1/11) of PTC patients with acromegaly, although 62.5% (10/16) of control patients with PTC had the mutation (p = 0.007). IGF-1Rβ immunostaining showed moderate-to-strong staining in all malignant PTC cells in patients with and without acromegaly. Significantly less staining for IGF-1Rβ was observed in normal adjacent thyroid tissues of PTC patients with acromegaly compared with those without (p = 0.014).

Conclusion

The prevalence of PTC in acromegalic patients was high (25%). An uncontrolled hyperactive GH-IGF-1 axis may play a dominant role in the development of PTC rather than the BRAF ^V600E mutation in patients with acromegaly.     

Impact of adjuvant chemotherapy on survival of women with T1N0M0, hormone receptor negative breast cancer

BackgroundThe benefit of adjuvant chemotherapy in women with T1N0M0 breast cancers is unclear. While gene expression-based prognostic assays may aid management of women with early estrogen receptor (ER) positive tumors, therapeutic decision-making in women with early stage ER negative tumors remains fraught with difficulties. We investigated the association between adjuvant chemotherapy and overall survival in women with T1N0M0, hormone receptor negative breast cancers.MethodAll newly diagnosed breast cancer patients with node-negative and hormone receptor negative tumors measuring ≤ 2 cm at the University Malaya Medical Centre (Malaysia) from 1993 to 2013 were included. Mortality of patients with and without adjuvant chemotherapy were compared and adjusted for possible confounders using propensity score.ResultsOf 6732 breast cancer patients, 341 (5.1%) had small (≤2 cm), node-negative and hormone receptor negative tumors at diagnosis. Among them, only 214 (62.8%) received adjuvant chemotherapy. Five-year overall survival was 88.1% (95% confidence interval (CI): 82.0%–94.2%) for patients receiving chemotherapy and 89.6% (95% CI: 85.1%–94.1%) for patients without chemotherapy. Chemotherapy was not associated with survival following adjustment for age, ethnicity, tumor size, tumor grade, HER2 status, lympho-vascular invasion, type of surgery and radiotherapy administration. However, chemotherapy was associated with a significant survival advantage (adjusted hazard ratio: 0.35, 95%CI: 0.14–0.91) in a subgroup of women with high-grade tumors.ConclusionAdjuvant chemotherapy does not appear to be associated with a survival benefit in women with T1N0M0, hormone receptor negative breast cancer except in those with high-grade tumors.     

The effect of interleukins 27 and 35 and their role on mediating the action of insulin Like Growth Factor -1 on the inflammation and blood flow of chronically inflamed rat knee joint

IntroductionPrevious studies have shown that some cytokines mediate the effect of IGF-1 on inflammation and also association between IGF-1 and vascular endothelial dysfunction. Due to the discrepancies in the inflammatory and anti-inflammatory roles of IL-27 and IL-35, the effects of these cytokines and their IGF-1-mediating role were investigated regarding chronic joint inflammation and synovial blood flow.MethodMale rats were divided into two main groups of histopathology (n = 80) and blood flow (n = 72). These were further divided into ten subgroups of control, vehicle, IGF-1, IL-27, IL-35, their antagonists, IGF-1 + IL-27 antagonist, and IGF-1 + IL-35 antagonist. Inflammation was induced by intra-articular injection of complete Freund adjuvant. Two weeks later (in order to induce chronic inflammation), vehicle or drugs were injected into the joint space every other day until day 28, on which inflammatory indices were assessed histopathologically. In the second subgroups, vehicle or drugs were administered by super-fusion on day 28 and their effects on the joint blood flow (JBF, laser Doppler perfusion method) and the systemic blood pressure were assessed.ResultsEndogenous IL-27 and IL-35 had inflammatory roles and IGF-1 had no effect. IL-27 and IL-35 antagonists had the highest anti-inflammatory and anti-angiogenesis effects and these effects were inhibited by IGF-1. Total inflammation score was 4.5 ± 0.42, 3.50 ± 0.5, 2.25 ± 0.45 and 1.50 ± 0.42 for vehicle, IGF-1 antagonist, IL-27 antagonist and IL-35 antagonist respectively. A significant increase was induced in JBF by IGF-1 antagonist and combination of IGF-1 + IL-35 antagonist.ConclusionIL-27 and IL-35 antagonists may be suitable goals for the treatment of chronic joint inflammation while their anti-inflammatory effects are not exerted via the changes in JBF.     

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)     

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)     

Substantial Shrinkage of Adenomas Cosecreting Growth Hormone and Prolactin with use of Cabergoline Therapy

ObjectiveTo present 2 cases of patients with acromegaly and severe hyperprolactinemia whose primary therapy with cabergoline resulted in hormonal normalization and a considerable reduction in the size of their somatotroph macroadenomas.MethodsWe summarize the clinical presentation and the pertinent laboratory findings in 2 patients with acromegaly, as well as their clinical response to the therapy with cabergoline. A review of the literature regarding the use of cabergoline in acromegaly is also presented.ResultsA 48-year-old man (case 1) and a 26-year-old woman (case 2) were found to have acromegaly associated with very high levels of serum prolactin (2,700 and 5,250 ng/mL, respectively). These patients received first-line therapy with cabergoline that resulted not only in clinical improvement and normalization of growth hormone, prolactin, and insulin-like growth factor-I levels but also in a substantial reduction in the size of their somatotroph macroadenomas. By 6 months after the patients began to take cabergoline, tumor shrinkage of 94% (in case 1) and of 70% (in case 2) was demonstrated by magnetic resonance imaging.ConclusionOur findings demonstrate that cabergoline should be considered for medical treatment of adenomas cosecreting growth hormone and prolactin, even in the presence of large tumors with appreciable suprasellar extension, because substantial tumor shrinkage is possible with this therapy. (Endocr Pract. 2007;13:396-402)     

Estado actual de la histoplasmosis diseminada progresiva en pacientes con infección por el VIH en un hospital de tercer nivel en Perú

BackgroundProgressive disseminated histoplasmosis (PDH) is an endemic disease in most of Latin America, especially among patients with HIV. There are few reports about this disease in Peru.AimsTo describe the clinical, epidemiological and mycological features of patients with PDH and HIV evaluated in a tertiary hospital.MethodsA retrospective study to find out the data of patients diagnosed with PDH and HIV in the period 2000–2019 was carried out. For the statistical analysis of quantitative variables, measures of central tendency and dispersion were used; for the qualitative variables, absolute and relative frequencies were used.ResultsForty-three male patients with PDH were diagnosed in the study period, with a median age of 33 years (IQR: 29–38 years) and a median CD₄ lymphocytes count of 39 cells/mm³ (IQR: 20–83 cells/mm³). Eighty six percent of the patients were born or had travelled to the jungle, 58.1% were alcohol users and 16.1% had a history of pulmonary tuberculosis. When compared to histopathology, the culture had a better sensitivity to achieve a diagnosis (p < 0.05).ConclusionsPeruvian patients with PDH and HIV infection were mainly young male adults that were born or had travelled to the jungle, with a CD₄ count below 100 cells/mm³. In patients with the described characteristics it would be advisable to check for PDH. Implementing rapid diagnostic tests is also necessary.     

The effects of EGF and IGF-1 on FSH-mediated in vitro maturation of domestic cat oocytes derived from follicular and luteal stages

The objective of this study was to evaluate the influence of epidermal growth factor (EGF) and insulin like growth factor-I (IGF-1) on the in vitro maturation of cat oocytes recovered from follicular and luteal stage ovaries. Oocytes from follicular (n = 580) and luteal (n = 209) stages were harvested and divided into four groups, which were cultured in FSH-mediated maturation medium supplemented with: (1) EGF alone (25 ng/mL); (2) IGF-1 alone (100 ng/mL); (3) EGF + IGF-1 (25 ng/mL EGF + 100 ng/mL IGF-I); or (4) no growth factor (control). The proportion of follicular stage oocytes reaching the metaphase II stage was significantly higher than that of oocytes obtained at the luteal stage in both control and study groups (p < 0.001). The percentages of oocytes reaching the metaphase II stage during the follicular period were 62.6% in control; 70.9% in EGF; 72.8% in IGF-1, and 78.1% in EGF + IGF-1 groups, whereas the respective values for gametes collected from luteal stage ovaries were 12.5%, 17.5%, 12.5%, and 16.9%. Additionally, the differences between the study and control groups were significant in the case of follicular stage oocytes. Finally, supplementing the maturation medium with EGF and/or IGF-1 significantly enhanced the meiotic maturation of oocytes recovered from follicular stage ovaries. The present study also demonstrated that the combination of EGF and IGF-I provides an additional or synergic effect on meiotic maturation of oocytes recovered from the follicular stage.