Anterior Pituitary Volume Research Articles

Dehydroepiandrosterone mediates associations between trauma-related symptoms and anterior pituitary volume in children and adolescents.

The anterior pituitary gland (PG) is a potential locus of hypothalamic-pituitary-adrenal (HPA) axis responsivity to early life stress, with documented associations between dehydroepiandrosterone (DHEA) levels and anterior PG volumes. In adults, elevated anxiety/depressive symptoms are related to diminished DHEA levels, and studies have shown a positive relationship between DHEA and anterior pituitary volumes. However, specific links between responses to stress, DHEA levels, and anterior pituitary volume have not been established in developmental samples. High-resolution T1-weighted MRI scans were collected from 137 healthy youth (9-17 years; Mage = 12.99 (SD = 1.87); 49% female; 85% White, 4% Indigenous, 1% Asian, 4% Black, 4% multiracial, 2% not reported). The anterior and posterior PGs were manually traced by trained raters. We examined the mediating effects of salivary DHEA on trauma-related symptoms (i.e., anxiety, depression, and posttraumatic) and PG volumes as well as an alternative model examining mediating effects of PG volume on DHEA and trauma-related symptoms. DHEA mediated the association between anxiety symptoms and anterior PG volume. Specifically, higher anxiety symptoms related to lower DHEA levels, which in turn were related to smaller anterior PG. These results shed light on the neurobiological sequelae of elevated anxiety in youth and are consistent with adult findings showing suppressed levels of DHEA in those with greater comorbid anxiety and depression. Specifically, adolescents with greater subclinical anxiety may exhibit diminished levels of DHEA during the pubertal window, which may be associated with disruptions in anterior PG growth.

Increased pituitary volumes in patients with Sanfilippo syndrome (mucopolysaccharidosis type 3, MPS III).

To evaluate apparent pituitary gland enlargement in patients with Sanfilippo syndrome observed at our institution. Twelve patients with Sanfilippo syndrome with brain MRI were studied. Anterior, posterior, and whole pituitary volumes were estimated using the prolate ellipsoid volume calculation method (π/6 × L × W × H). Convexity along the upper pituitary margin (Elster's grade) was also measured. These values were compared to two age- and sex-matched groups (normal controls and patients with Hurler syndrome) using one-way ANOVA followed by Tukey's post hoc analysis for multiple comparisons. In the Sanfilippo cohort, the mean whole pituitary volume was 529.9 mm, the mean anterior pituitary volume was 333.4 mm, and the mean posterior pituitary volume was 59.1 mm with Elster's grade of 4.2. In the control cohort, the mean whole pituitary volume was 217.4 mm, the mean anterior pituitary volume was 154.8 mm, and the mean posterior pituitary volume was 28.4 mm with Elster's grade of 2.5. In the Hurler syndrome cohort, the mean whole pituitary volume was 310.0 mm, the mean anterior pituitary volume was 178.2 mm, and the mean posterior pituitary volume was 35.4 mm with Elster's grade of 3.5. In our cohort of patients with Sanfilippo syndrome, whole, anterior, and posterior pituitary volumes and degree of convexity along the upper pituitary border were all significantly greater than controls. The cause of these morphological changes is unclear, as is clinical correlation of the findings.

Relationship between Anterior Pituitary Volume and IGF-1 Serum Levels in Soldiers with Mild Traumatic Brain Injury History.

A high mild traumatic brain injury (mTBI) incidence rate exists in military and sport. Hypopituitarism is an mTBI sequela; however, few studies have examined this phenomenon in those with an mTBI history. This cross-sectional study of Special Operations Forces combat soldiers aimed 1) to relate anterior pituitary gland volumes (actual and normalized) to insulin-like growth factor 1 (IGF-1) concentrations, 2) to examine the effect of mTBI history on anterior pituitary gland volumes (actual and normalized) and IGF-1 concentrations, and 3) to measure the odds of demonstrating lower anterior pituitary gland volumes (actual and normalized) or IGF-1 concentrations if self-reporting mTBI history. Anterior pituitary gland volumes were manually segmented from T1-weighted 3D brain MRI sequences; IGF-1 serum concentrations were quantified using commercial enzyme-linked immunosorbent assays. Correlations and linear regression were used to determine the association between IGF-1 serum concentration and anterior pituitary gland volume (n = 74). Independent samples t-tests were used to compare outcomes between mTBI groups and logistic regression models were fit to test the odds of demonstrating IGF-1 concentration or anterior pituitary volume less than sample median based on mTBI group (n = 54). A significant linear relationship between the subjects' anterior pituitary gland volumes and IGF-1 concentrations (r72 = 0.35, P = 0.002) was observed. Soldiers with mTBI history had lower IGF-1 concentrations (P < 0.001) and lower anterior pituitary gland volumes (P = 0.037) and were at greater odds for IGF-1 serum concentrations less than the sample median (odds ratio = 5.73; 95% confidence interval = 1.77-18.55). Anterior pituitary gland volume was associated with IGF-1 serum concentrations. Mild TBI history may be adversely associated with anterior pituitary gland volumes and IGF-1 concentrations. Longitudinal IGF-1 and anterior pituitary gland monitoring may be indicated in those who report one or more mTBI.

Anterior Pituitary Volume in Patients with Transfusion Dependent Anemias: Volumetric Approaches and Relation to Pituitary MRI\u2011R2

PurposeAnterior pituitary iron overload and volume shrinkage is common in patients with transfusion-dependent anemia and associated with growth retardation and hypogonadotropic hypogonadism. We investigated the accuracy of different MRI-based pituitary volumetric approaches and the relationship between pituitary volume and MRI-R2, particularly with respect to growth and hypogonadism.MethodsIn 43 patients with transfusion-dependent anemia (12–38 years) and 32 healthy controls (12–72 years), anterior pituitary volume was measured by a sagittal T1 GRE 3D sequence at 1.5T and analyzed by 3D semi-automated threshold volumetry (3D-volumetry). This reference method was compared with planimetric 2D-volumetry, approximate volume calculations, and pituitary height. Using a multiple SE sequence, pituitary iron as MRI-R2 was assessed by fitting proton signal intensities to echo times. Growth and hypogonadism were obtained from height percentile tables and patients’ medical charts. From body surface area and age adjusted anterior pituitary volumes of controls, Z‑scores were calculated for all subjects. Separation of controls and patients with respect to Z and pituitary R2 was performed by bivariate linear discriminant analysis.ResultsTuned 2D volumes showed highest agreement with reference 3D-volumes (bias −4.8%; 95% CI:−8.8%|−0.7%). A linear discriminant equation of Z = −17.8 + 1.45 · R2 revealed optimum threshold sensitivity and specificity of 65% and 100% for discrimination of patients from controls, respectively. Of correctly classified patients 71% and 75% showed hypogonadism and growth retardation, respectively.ConclusionAccurate assessment of anterior pituitary size requires 3D or precise 2D volumetry, with shorter analysis time for the latter. Anterior pituitary volume Z‑scores and R2 allow for the identification of patients at risk of pituitary dysfunction.

Pituitary Iron: Effect on Pituitary Volume and Function in Transfusion Dependent Thalassemia

The association of iron toxicity with vital organ dysfunction has been extensively investigated in transfusion-dependent-thalassemia (TDT). However, pituitary iron load and its effect on function have been infrequently addressed. Growth delay, hypogonadism and infertility resulting from iron-induced pituitary toxicity are still prevalent, impacting clinical care and patients' quality of life. Early recognition and timely intervention can potentially prevent irreversible damage and restore partial function.AimsWe aimed to determine pituitary iron load and anterior pituitary volume by MRI in various age groups of TDT and examine their association with systemic and organ-specific iron measures. Additionally, we attempted to stratify the occurrence of abnormal anterior pituitary function by these MRI findings. Identifying such risk thresholds could assist in establishing timing and effectiveness of treatment intervention.MRI (1.5T) measurements of anterior pituitary iron (R2) and volume (Vol) were compared to normal controls (Noetzli 2011) with resultant Z-scores. Mean annual ferritin was calculated and cardiac and liver iron concentration (LIC) were determined by MRI-T2* and superconducting quantum interference device (SQUID) biosusceptometry, respectively. Pituitary hormones (LH and FSH) and growth hormone (Z scores for IGF-1 and IGF-BP3) were determined.ResultsFifty-three TDT patients (51% females) age 25±8 years, (range 10-45 years) were enrolled. Thirty-three (62%) had a ZR2 value >2 (mean 5.4) indicating iron accumulation above 97.5th percentile. Thirty-two patients (60%) had a Z-score for anterior-volume (ZVOL) of less than -2 (mean -2.8) indicating gland shrinkage below the 2.5th percent. In 23 patients (43%) both ZR2 and ZVOL exceeded these thresholds. ZR2 inversely correlated with ZVOL; r =-0.32, p<0.02. Pituitary iron increased with age and differed between patients <18 yr (n=14) and those 18-45 yr (n=39) with a mean ZR2 at 0.9±0.6 and 4.3±0.5, respectively (p<0.001). Anterior pituitary volume declined in older patients, lagging after the iron accumulation (Figure).LH/FSH values and ZR2 showed inverse correlation: r = -0.27 (p<0.03) and -0.3 (p< 0.006) respectively. ZVOL and LH/FSH demonstrated a positive correlation: r = 0.40, p<0.05 and 0.37, p<0.003, respectively. Z(IGF-BP3) but not Z(IGF-1) had an inverse correlation with ZR2: r = -0.5 (p<0.001).ZR2 > 4 was found to be a significant predictor for gland shrinkage; Zvol < -2 was present in 17/33 patients with a ZR2>4 compared to 3/20 with a ZR2<4 (p<0.009). Receiver operator (ROC) analysis confirmed it with an AUC of 0.68. ZR2 >4 was also predictive of presence of clinically important cardiac (T2* <20ms, AUC=0.92, p<0.001) and hepatic iron (LIC >10mg/gd.w., AUC= 0.74, p<0.005). Mean ferritin significantly correlated with ZR2 (p<0.001) but not with the gland's volume.ConclusionsAnterior pituitary iron assessed by MRI, increases with age and correlates with total body iron burden in TDT, suggesting cumulative iron toxicity. It results in a decrease in gland size and impaired gonadotropin and growth hormone secretion. Pituitary iron exceeding ZR2 >4, appears to be a significant predictor for change in gland size, that also is associated with cardiac and liver iron-overload. Pituitary MRI and the concomitant liver and cardiac iron quantification can identify patients at high-risk for further pituitary damage, suggesting that early intervention can potentially prevent additional decline in hormonal secretion. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pituitary Volume and Iron Overload Evaluation by 3T MRI in Thalassemia.

To evaluate pituitary volume and iron overload in beta thalassemia major, with the objective of assessing the reliability of this method in predicting hypogonadism. 3T MRI was used to measure pituitary R2 and T2* in 57 beta thalassemia major patients and 30 controls. Anterior pituitary volume was evaluated by MRI planimetry. Cardiac, hepatic, and pancreatic iron overload were also assessed using MRI T2*. Mean serum ferritin was estimated by sandwich immuno-assay. Short stature was defined as height < 3 rd percentile for age, and clinical hypogonadism defined as absence of secondary sexual characteristics at ages ≥13 y for females and ≥ 14 y for males. Short stature was present in 32 patients (56.1%). Of the 47 patients in the pubertal age group, 11(23.4%) had hypogonadism. Serum ferritin correlated positively with pituitary R2 (p = 0.004) and negatively with anterior pituitary volume (p = 0.006), whereas pituitary R2 correlated negatively with cardiac T2* (p = 0.001). Patients with hypogonadism had lower pituitary R2 (p = 0.186), T2* (p = 0.048), and anterior pituitary volumes (p = 0.012) compared to those with normal sexual maturity. Regardless of stature, no significant difference was observed between pituitary R2 (p = 0.267) and T2* (p = 0.451). Mean pituitary R2 in patients (78.99Hz) was higher than in controls (20.8Hz) (p = 0.0001). Anterior pituitary volume was lower in patients (264.83mm3) than in controls (380.87mm3) (p = 0.0001). A threshold value of 22.85Hz for pituitary R2 gave a sensitivity of 84.2% and a specificity of 73.3% in distinguishing pituitary iron content of patients from controls, with an area of 0.864 under the ROC curve. 3T MRI is a reliable method to detect pituitary iron overload and predict risk of hypogonadism in beta Thalassemia.

Pituitary Iron and Volume Are Affecting Hormones and Reproductive Potential

Introduction: Hypogonadism and impaired fertility remain critical problems in transfusion dependent thalassemia (TDT) patients who develop iron overload. Pituitary iron toxicity and resultant gland shrinkage were shown to occur in these patients, starting even during their first decade of life. While MRI screening of iron load in the heart has been linked with cardiac function and has a direct effect on iron chelation practices, little is known on pituitary iron and anterior pituitary volume, as they relate to hormone secretion and reproductive potential. We investigated such an association in order to better understand the development of hypogonadism and infertility and its pathogenesis.Methods: A total of38TDTpatients, age 12-45 y, 20 females and 18 males were enrolled in this study. Relative pituitary iron (R2) and anterior volume was assessed by MRI. These MRI parameters were transformed to Z-scores and compared to published age- and sex-matched normal subjects. Laboratory assessment of gonadal function and predictors of fertility status was performed in patients grouped into adolescents (12-18 y), young adults (19-29 y) and adults (>29 y). LH, FSH were obtained in both genders. In females, Anti Mullerian Hormone (AMH, a predictor of ovarian antral follicle count) was tested, while in males inhibin B (a hormone correlating with sperm count) was obtained; both are a measure of fertility potential.Results: Among the 9 adolescent patients (12-18 y), 3 had delayed puberty. In this cohort, the anterior pituitary iron was moderately increased compared to normal (Z = 2.2 ) and it did not result in a decrease in the gland size (Z = 0.04), while in patients 19-29 years old, a higher R2 with reduced gland size (Z = 5.6 and -2.4, respectively) was noted. These patients had an associated high liver (LIC) and cardiac iron (T2*). Pituitary findings were similar in patients older than 29y (see table). Overall, pituitary iron did not statistically correlate with liver and cardiac iron, though iron has increased with age in all these organs. Pituitary volume, but not iron, correlated with LH level in patients >19 y (r=0.4, P=0.03). AMH levels in women decreased with age in the 3 groups: 5.8±5, 3.1±2.4 and 1.2±0.6 ng/mL, respectively. Inhibin B, in men, decreased as well (124± 60; 115±70; 85±50 pg/mL, respectively) Abstract 1048. Table 1Age (y)nanterior pit. volume (mm3)Z score (pit. vol.)R2 (s-1)Z score(R2)LIC(mg/g dry wt)cardiac T2*(ms)LH(U/L)FSH(U/L)16 ± 19512 ± 1570.0413.1±1.62.210.4 ± 7.030 ± 106.2±8.04.5±1.625 ± 318358 ± 127-2.416.4±2.85.622.8 ± 13.022 ± 104.4±3.04.0±3.034 ± 411392 ± 180-2.216.0±2.84.512.0 ± 5.520 ± 102.6±3.04.0±4.0Normal range: LH (U/L): 2-10 (m), < 30 (f) ; FSH (U/L): 1.4-21 (m), 0.9-15 (f); AMH (ng/mL): 2.1-6 (f); Inhibin B (pg/mL): 25-325 (m).Discussion: These results suggest a significant reduction in pituitary size along with increased iron load in patients in their 20’s affecting reproductive potential, while there is less impact of pituitary iron on hormone secretion in the younger patients. Retrospective analysis of the patients 19-29 years old showed that the majority did not have delayed puberty or primary amenorrhea in their second decade of life, suggesting that their pituitary studies may have been similar to the younger age group in this study. The decline in pituitary size and function as patients’ age could represent decreased or inconsistent adherence to iron chelation, but may also be a result of prolonged and constant oxidative stress damage from labile plasma iron. Efforts to target this age group for closer screening, including monitoring pituitary gland size, along with intensified chelation, could help prevent the gland shrinkage and result in a higher fertility potential. DisclosuresPaley:Novartis Pharma: Employment.

Pituitary Iron and Volume Predicts Hypogonadal Hypogonadism in Transfusional Iron Overload

Abstract 1094 Introduction:Hypogonadotropic Hypogonadism (HH) is one of the most common morbidities in patients with transfusion-dependent anemias such as thalassemia major. Unfortunately, pituitary dysfunction is difficult to detect prior to puberty because of immaturity of the hypothalamic-pituitary-gonadal axis. We used MRI to measure pituitary R2 and volume to determine at what age these patients develop pituitary iron overload and volume loss. Additionally, we aimed to stratify the risk of clinical HH based on pituitary R2 and pituitary volume, and determine predictors of pituitary iron deposition and volume loss. Methods:We recruited 56 patients (52 with thalassemia major and 4 with Blackfan-Diamond syndrome) to have pituitary MRIs to measure pituitary R2 and volume. Diagnosis of HH was determined by either lack of secondary pubertal characteristics by age 13 for females or age 14 for males, by primary or secondary amenorrhea in females ages 16 or older, or by the need for testosterone administration in males. Patients also had pancreas R2*, heart R2*, and liver iron concentration measured by MRI. Normative pituitary R2 and volume trends were determined by a cohort of 100 control patients. Results:Patients were 20.4 ± 12.1 years old and well distributed by sex (31 males, 25 females). All subjects received blood transfusions every 2–4 weeks and were on appropriate chelation therapy as indicated by their physician. Mean pituitary R2 Z-score was 4.5 and mean anterior pituitary volume Z-score was −0.9. Figure 1 shows pituitary R2 values as a function of age, superimposed on normal trends from the control population. Patients with transfusional iron overload began to develop pituitary iron overload in the first decade of life; however, significant iron deposition were observed beginning in the second decade. Heavy pituitary iron deposition (Z-score > 5) and volume loss (Z-score < −2.5) were predictive of HH (Figure 2). Volume loss was highly specific (87%) but identified only half of HH cases. The remaining HH patients had heavy pituitary iron (Z-score > 5), but preserved pituitary volume. Pituitary R2 correlated significantly with serum ferritin as well as liver iron concentration, pancreatic R2*, and cardiac R2* by MRI. [Display omitted] [Display omitted] Discussion:Pituitary iron loading begins as early as the first decade of life in chronically transfused patients, meriting a pituitary MRI in children under 10 years old. Severe pituitary iron loading as well as volume loss throughout the second decade of life, and are predictive of HH, warranting more intensive screening in this age group. However, many patients with moderate-to-severe pituitary iron overload retained normal gland volume and function, representing a potential therapeutic window. This may also be explained by improvements in gland function observed following intensive chelation therapy. Serial tracking of pituitary iron and volume trends on age-appropriate nomograms should improve diagnostic accuracy and toxicity prophylaxis. Disclosures:Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy; Cooleys Anemia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

A Novel Frame Shift Mutation in the GHRH Receptor Gene in Familial Isolated GH Deficiency: Early Occurrence of Anterior Pituitary Hypoplasia

Mutations in the genes encoding for GHRH receptor (GHRHR) and GH (GH1) are the most common cause of familial isolated GH deficiency (IGHD). GHRHR mutations are often associated with anterior pituitary hypoplasia (APH), but this has been reported almost exclusively in children older than 8 yr. We analyzed the GHRHR and measured pituitary size in a consanguineous family with the father and three of the five siblings with IGHD. The aim of the study was to find the mutated gene in a family with severe IGHD. We sequenced the whole GHRHR coding regions and the intron-exon boundaries from peripheral DNA of the index patient. After identifying the novel mutation, we sequenced the region of interest in the other members of the family. We measured the anterior pituitary volume from magnetic resonance imaging (MRI). The father and the three affected children were homozygous for a new frame-shift mutation in the coding sequence of exon 4 (corresponding to the extracellular domain of the receptor) (c.340delG) that places the downstream sequence out of frame [corrected]. The mother and two unaffected siblings were heterozygous for the mutation. Two of the affected children had MRI evidence of APH before reaching 6 yr of age. We describe a new mutation in the GHRHR in a family with IGHD. The presence of frank APH before age 6 yr shows that MRI-evident reduced pituitary size can be present in GHRHR mutations even in children younger than 8 yr of age.

Changes In Pituitary Iron and Volume with Deferasirox In Transfusional Iron Overload

AbstractAbstract 5161 Introduction:The relationship between organ iron overload and clinical toxicity in chronically transfused patients is not completely understood. Given that hypogonadotropic hypogonadism (HH) is the most common endocrine problem in chronically transfused patients, it is important to qualify the effects of pituitary iron overload. MRI can image preclinical pituitary iron deposition, similar to its use in the heart, liver and pancreas. Increased pituitary R2, a surrogate for iron, and decreased pituitary volume predict clinical and biochemical HH in iron overloaded adults 1,2. However, data regarding pituitary iron deposition and its effect on pituitary growth in the pediatric population is lacking. In addition, the effect of chelation therapy on pituitary iron and volume over time is unknown. We present first year results from a two year observational trial of changes in pituitary R2 and volume in response to deferasirox therapy in patients with transfusional siderosis. Methods:We report 16 chronically-transfused patients with Thalassemia Major and one patient with Diamond Blackfan Anemia studied over a one year period. All patients were on deferasirox for at least 6 months prior to start of study; drug dosing was determined by the patient's physician and was independent of the research study. The average age at the final exam was 14.1 ± 5.2 years (range: 5.1–24.6 years). All studies were performed on a 1.5 T Philips Achieva. Anterior pituitary R2 was assessed in the sagittal and coronal planes using multiple spin echoes from 15 to 120 ms. Pituitary volume was assessed using a 3D spoiled gradient echo sequence with 1 mm3 isotropic voxels. Pituitary R2 was calculated by pixelwise monoexponential fit, with median values used to represent the overall gland R2; boundaries were confirmed by a board-certified neuroradiologist. Normative data for pituitary iron and volume was drawn from another study in 100 normal volunteers. Patient height, pituitary R2, and pituitary volume were all expressed as age corrected Z-scores. MRI estimates of hepatic iron concentration (HIC), cardiac iron (T2*), and pancreatic iron (R2*) were obtained as clinical standard of care. All statistics were performed using JMP5.1 (SAS, Cary, NC). Results:Patients were mild to moderately iron overloaded with HIC of 6.7 ± 6.9 mg/g dry weight, cardiac T2* of 31.3 ± 7.8 ms, and pancreas R2* of 117.2 ± 128.7 Hz at the beginning of the study. These results were not yet available for the one year follow up. Ferritin values were available for 16/17 of the patients at both baseline (1346.9 ± 1479.5 ng/mL) and year one visits (1102.2 ± 1074.0 ng/mL, p=0.24). Change in ferritin did not correlate with change in pituitary R2. Median sagittal measurements of pituitary R2 were 13.7 ± 1.9 Hz (baseline) and 13.4 ± 1.7 Hz (year one). An improvement was seen in average Z-score for patient height and in average Z-score for anterior pituitary volume. There was no correlation between the change in Z-score for height and the change in Z-score for pituitary volume. Figure 1 summarizes the average Z-scores for height, pituitary volume, and pituitary R2 at baseline and at year one; p-values reflect paired statistics. Discussion:The present data suggest that deferasirox monotherapy stabilizes pituitary iron levels and facilitates normal pituitary and somatic growth in children and young adults. Although reductions in pituitary R2 Z-score did not reach statistical significance, the favorable glandular and somatic growth responses suggest that deferasirox is successfully detoxifying glandular iron. Although encouraging, these data are limited by small sample size and short follow-up; two-year data will provide more robust estimates of treatment efficacy and predictors of response.

Pituitary Iron and Volume in Transfusional Iron Overload: Normative Data.

Abstract 4073Poster Board III-1008 IntroductionDespite continuing advances in iron chelation therapy, endocrine dysfunction is common in chronically transfused patients with iron overload. In thalassemia major, hypogonadotropic hypogonadism (HH), impaired glucose tolerance, delayed growth, and hypothyroidism are common, but gonadotrophic function is the most vulnerable and least reversible. Unfortunately, clinical effects of gonadotrophe iron toxicity are not detectable until puberty. Provocative GnRH stimulation can be used to detect preclinical HH, but it can be difficult to interpret in adolescents. Thus, surrogates for preclinical pituitary iron deposition and damage are imperative. MRI can be used to measure pituitary iron (R2) and volume, analogous to its use for the heart, liver, and pancreas. Increased pituitary R2 and decreased pituitary volume predict clinical and biochemical HH in adults with thalassemia major 1,2. However, to apply these techniques to prepubertal patients with iron overload, it is imperative to develop age-appropriate normative data for pituitary iron and volumes. The goal of this study was to determine trends/limits of pituitary R2 and volume in normal subjects between the ages of 2 and 25 years. MethodsWe studied 49 normal volunteers between the ages of 2 and 25 years old; informed consent was obtained in all examinations. Patients as young as four years of age were studied without anesthesia by using video goggles and appropriate coaching. Seven patients were studied under general anesthesia by adding the research MRI (< 10” duration) on to a clinically indicated sedated head MRI. All studies were performed on a 1.5 T Philips Achieva. Anterior pituitary R2 was assessed in the sagittal and coronal planes using a multi-echo spin echo sequence using eight echoes from 15 to 120 ms, five mm thick slices, 1 mm2 inplane resolution, and repetition time (TR) of 500 ms. Pituitary volume was assessed using a 3D spoiled gradient echo sequence with 1 mm3 isotropic voxels, TR 7.2 ms, echo time 3.3 ms, and flip angle of eight degrees.Pituitary R2 was calculated by pixelwise fitting to a monoexponential without a background offset. Regions of interest incorporating the anterior pituitary were manually traced, with mean and median values were used to represent the overall gland R2. All contours were confirmed by a board certified neuroradiologist. Piecewise linear regression was used to describe anterior pituitary volume, while R2 values were well described by simple linear regression. All statistics were performed using JMP5.1 (SAS, Cary, NC). ResultsAnterior pituitary volume increased linearly with age (Figure 1, left) and plateaued at 18 years of age. Normalization with respect to age produced lower variability than normalization with respect to height, weight, and body surface area. No gender differences were observed. Posterior pituitary volume also increased with age but appeared larger in mid puberty than in adulthood (not shown). Sagittal and coronary pituitary R2 increased linearly (r2 = 0.10 and 0.38, p = 0.03 and < 0.001) with age throughout the study interval (Figure 1, right). Mean and median R2 values were unbiased and highly correlated (r2 = 0.93) with one another but median values were more robust to outliers. Pituitary R2 estimates in the sagittal and coronal planes were not statistically equivalent. Sagittal R2 values exhibited a bias of -3% that increased with R2 value. Limits of agreement were ± 20%. With respect to age-normalization, coronal R2 values exhibited 31% lower variability than sagittal images. DiscussionPituitary R2 values and pituitary volumes are age-dependent. Coronal R2 estimates were slightly higher and had lower variability than values calculated in the sagittal plane. This likely reflects the larger and more homogeneous sampling area in coronal pituitary views. Nomograms from these data will improve recognition of preclinical pituitary iron loading and volume-loss in iron overloaded patients. Additional subjects will be necessary to resolve peripubertal changes in posterior pituitary volume, trends in early adulthood, and gender or ethnicity differences. [Display omitted] [Display omitted] Disclosures:Coates:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Wood:Novartis: Research Funding.

MRI Assessment of Pituitary Iron and Volume in Thalassemia, and Relation to Hypothalamic-Pituitary-Gonadal Axis Function (HPG): A Feasibility Study.

Improvements in transfusion and chelation treatment have led to increased survival of patients with thalassemia (THAL), however, HPG axis dysfunction continues as the most prevalent complication of iron-overload in THAL. The critical target organ for HPG axis dysfunction in thalassemia is the anterior pituitary gland. In a pilot study on iron-induced endocrinopathies in chronically transfused thalassemia and sickle cell disease (SCD) patients, we developed MRI methods to quantitatively assess pituitary iron by measuring the transversal relaxation rate (R2), the anterior and posterior volume, and anterior pituitary height. We examined the hypothesis that iron will be elevated in the pituitary of heavily transfused thalassemia patients, but gland volume and height will correlate more closely with function. We scanned 13 subjects (controls 8, HbE-thalassemia and thalassemia major 4, iron-overloaded SCD 1) with a total of 17 measurements in a 1.5 Tesla imager of Children's Hospital Oakland (Philips Gyroscan®) using a quadrature head coil. Two of 4 thalassemia patients were on hormone replacement treatment. The relaxation rate R2 of the anterior pituitary gland was determined from 2 or 3 sagittal slices (3 mm slice thickness, 0.3 mm gap, manually traced ROI covering more than 60% of the gland within each slice) by a turbo-spin echo sequence acquiring 8 evenly spaced echoes (TE = 15, 30,..., 120 ms, TR = 2500 ms). Anterior and posterior pituitary volumes were analyzed from sagittal slices by manual tracing (3D FFE, 1 mm3 isotropic voxel, TE = 4.6 ms, TR = 9.8 ms, a = 15°). Anterior pituitary height was obtained from routine T1 weighted sagittal multi-slice spin echo images (slice thickness 3 mm, gap 0.3 mm). Liver iron concentration (LIC) by SQUID biosusceptometry was used for total body iron estimation. A reproducibility of 2.6 % (COV) was determined in a normal subject for a mean R2 = 11.8 s−1. The relaxation rates for the control group R2 = 10.8 ± 0.8 s−1 and the thalassemia group R2 = 14.3 ± 1.4 s−1 were significantly different (p (U-test) < 0.001) with no overlap. A weak Spearman rank correlation was found with LIC (RS = 0.71, p < 0.04), but not with plasma ferritin. Anterior pituitary height H and volume V were related by V [mm3] = 95 · H [mm] - 187 (R2 = 0.80). For the anterior pituitary, a significant correlation was found between R2 and volume (RS = −0.59, p < 0.04). Although volumes and heights did not significantly differentiate between the patients and controls, the two THAL patients with abnormal pituitary function had lower anterior pituitary volume and height compared with the two others with normal function. The one iron-overloaded SCD patient had normal R2 and pituitary function; volume and height were in the same range as controls. In summary, the higher transverse relaxation rates indicate elevated iron concentrations in the anterior pituitary gland in all of our thalassemia patients. Pituitary volumes or heights alone may reflect pituitary function, but abnormal volume/height was only seen in patients with high R2. Additional studies in patients with thalassemia and SCD are required to confirm these preliminary observations.

Selective loss of anterior pituitary volume with severe pituitary-gonadal insufficiency in poorly compliant male thalassemic patients with pubertal arrest.

Selective loss of anterior pituitary volume with severe pituitary-gonadal insufficiency in poorly compliant male thalassemic patients with pubertal arrest.