Diagnosing and treating the elderly individual with hypopituitarism.

Hypopituitarism in the elderly is an underestimated condition mainly due to the non-specific presentation that can be attributed to the effects of aging and the presence of comorbidities. Diagnosis and treatment of hypopituitarism often represent a challenging task and this is even more significant in the elderly. Diagnosis can be insidious due to the physiological changes occurring with aging that complicate the interpretation of hormonal investigations, and the need to avoid some provocative tests that carry higher risks of side effects in this population. Treatment of hypopituitarism has generally the goal to replace the hormonal deficiencies to restore a physiological balance as close as possible to that of healthy individuals but in the elderly this must be balanced with the risks of over-replacement and worsening of comorbidities. Moreover, the benefit of some hormonal replacement therapies in the elderly, including sex hormones and growth hormone, remains controversial.

Adrenal cysts less than 10 cm can be safely observed.

BACKGROUND: Adrenal cysts are rare and appropriate management is unclear due to a lack of data on their natural history. Understanding adrenal cyst growth patterns would assist in clinical management. METHODS: This single-institution study included all adult patients diagnosed with simple adrenal cysts between 2004 and 2021. Baseline characteristics and outcomes of those who underwent resection (ADX) or observation (OBS) were compared using the chi-squared test, student's t-test, and Wilcoxon rank-sum test. Growth curves and sensitivity analysis were plotted for all patients who had follow-up imaging. RESULTS: We identified 77 patients with imaging-confirmed adrenal cysts. The majority were female (75.3%) and more than half were white (55.8%). One-third of patients underwent ADX, and the remaining were observed. ADX patients were younger (median age [IQR]: 55.5 y [45.0-68.2 y] vs. 44.2 y [38.7-55.0 y], p = 0.01) and more likely to be Hispanic (12% vs. 0%, p = 0.05). ADX patients presented with larger cysts (5.6 vs. 2.6 cm, p = 0.002). The median time from diagnosis to last follow-up was 1.1 y for ADX and 4.1 y for OBS. Average growth for OBS was 0.3 cm/y, while average growth for ADX was 3.9 cm/y. In ADX patients, cysts >10 cm grew significantly faster than cysts <10 cm (median growth rate 13.2 cm/y vs. 0.3 cm/y, p < 0.05). There was no adrenal malignancy diagnosis, hyperfunctionality, or observation-related complications (e.g., rupture). CONCLUSION: While size >4-6 cm has guided surgical referral for solid adrenal masses, this study demonstrates a size threshold of 10 cm, below which asymptomatic, simple adrenal cysts can safely be observed.

Brain morphometry and estimation of aging brain in subjects with congenital untreated isolated GH deficiency.

PURPOSE: Individuals with isolated GH deficiency (IGHD) due to a mutation in the GHRH receptor gene have a normal life expectancy and above 50 years of age, similar total cognitive performance, with better attention and executive function than controls. Our objectives were to evaluate their brain morphometry and brain aging using MRI. METHODS: Thirteen IGHD and 14 controls matched by age, sex, and education, were enrolled. Quantitative volumetric data and cortical thickness were obtained by automatic segmentation using Freesurfer software. The volume of each brain region was normalized by the intracranial volume. The difference between the predicted brain age estimated by MRI using a trained neuronal network, and the chronological age, was obtained. p < 0.005 was considered significant and 0.005 < p < 0.05 as a suggestive evidence of difference. RESULTS: In IGHD, most absolute values of cortical thickness and regional brain volumes were similar to controls, but normalized volumes were greater in the white matter in the frontal pole and in the insula bilaterally, and in the gray matter, in the right insula and in left Caudate (p < 0.005 for all comparisons) We also noticed suggestive evidence of a larger volume in IGHD in left thalamus (p = 0.006), right thalamus (p = 0.025), right caudate (p = 0.046) and right putamen (p = 0.013). Predicted brain ages were similar between groups. CONCLUSION: IGHD is primarily associated with similar absolute brain measurements, and a set of larger normalized volumes, and does not appear to alter the process of brain aging.

Patient-reported outcomes in patients with acromegaly treated with pegvisomant in the ACROSTUDY extension: A real-world experience.

PURPOSE: To report the effects of pegvisomant (PEGV) treatment on patient-reported outcomes in acromegaly patients. METHODS: We conducted an extension study of an open-label, multinational, non-interventional study (ACROSTUDY) evaluating the long-term safety and efficacy of PEGV for acromegaly in routine clinical practice. Enrolled patients were rollover patients from ACROSTUDY, or treatment naïve/semi-naïve (NSN; no PEGV within 6 months of enrollment). Exploratory efficacy endpoints were changes in symptoms with the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) and quality of life with the Acromegaly Quality of Life questionnaire (AcroQoL) analyzed by controlled or uncontrolled IGF-I levels. Results were analyzed in all patients, in NSN patient subgroup, and by diabetes status. RESULTS: A total of 544 patients with acromegaly were enrolled, including 434 rollover subjects from ACROSTUDY and 110 NSN patients. Mean PEGV treatment duration was 7.8 years (range, 0-19.6 years). Overall, the majority of PASQ scores improved over time, but there was no significant difference between IGF-I controlled or uncontrolled groups. In the NSN subgroup, most PASQ and AcroQoL scores remained similar to baseline up to 1 year, regardless of IGF-I control. Patients with diabetes reported better PASQ scores over time with PEGV treatment, regardless of IGF-I control. IGF-I normalization increased from 10% of patients at baseline to more than 78% at year 10, with a mean daily PEGV dose of 18.7 mg. CONCLUSIONS: Overall, patients treated with PEGV had small improvements in PASQ. While IGF-I normalization increased with PEGV treatment, IGF-I control had no effects on PASQ and AcroQoL scores.

Disruption of the GHRH receptor and its impact on children and adults: The Itabaianinha syndrome.

Since 1994, we have been studying an extended kindred with 105 subjects (over 8 generations) residing in Itabaianinha County, in the Brazilian state of Sergipe, who have severe isolated GH deficiency (IGHD) due to a homozygous inactivating mutation (c.57 + 1G > A) in the GH releasing hormone (GHRH) receptor (GHRHR) gene. Most of these individuals have never received GH replacement therapy. They have low GH, and very low and often undetectable levels of serum IGF-I. Their principal physical findings are proportionate short stature, doll facies, high-pitched-voice, central obesity, wrinkled skin, and youthful hair with delayed pigmentation, and virtual absence of graying. The newborns from this cohort are of normal size, indicating that GH is not needed for intra-uterine growth. However, these IGHD individuals exhibit a myriad of phenotypic changes throughout the body, with a greater number of beneficial than harmful consequences. This GHRH signal disruption syndrome has been a valuable model to study the GH roles in body size and function. This reviews summarized the findings we have reported on this cohort.

Levoketoconazole improves clinical signs and symptoms and patient-reported outcomes in patients with Cushing's syndrome.

PURPOSE: The efficacy of levoketoconazole in treating hypercortisolism was demonstrated in an open-label phase 3 study (SONICS) of adults with endogenous Cushing's syndrome (CS) and baseline mean urinary free cortisol (mUFC) ≥ 1.5× ULN. Clinical signs and symptoms and patient-reported outcomes from the SONICS trial were evaluated in the current manuscript. METHODS: Patients titrated to an individualized therapeutic dose entered a 6-month maintenance phase. Secondary endpoints included investigator-graded clinical signs and symptoms of CS during the maintenance phase, and patient-reported quality of life (CushingQoL questionnaire) and depression symptoms (Beck Depression Inventory II [BDI-II]). RESULTS: Of 94 enrolled patients, 77 entered the maintenance phase following individualized dose titration. Significant mean improvements from baseline were noted at end of maintenance (Month 6) for acne, hirsutism (females only), and peripheral edema. These improvements were observed as early as Day 1 of maintenance for hirsutism (mean baseline score, 7.8; ∆ - 1.9; P < 0.0001), end of Month 1 for acne (mean baseline score, 2.8; ∆ - 1.2; P = 0.0481), and Month 4 for peripheral edema (mean baseline score, 1.0; ∆ - 0.5; P = 0.0052). Significant mean improvements from baseline were observed by Month 3 of maintenance for CushingQoL (mean baseline score, 44.3; ∆ + 6.9; P = 0.0018) and at Month 6 for BDI-II (mean baseline score, 17.1; ∆ - 4.3; P = 0.0043) scores. No significant mean improvement was identified in a composite score of 7 other clinical signs and symptoms. CONCLUSIONS: Treatment with levoketoconazole was associated with sustained, meaningful improvements in QoL, depression, and certain clinical signs and symptoms characteristic of CS. ClinialTrials.gov identifier: NCT01838551.

Multidisciplinary management of acromegaly: A consensus.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.

Growth hormone-releasing hormone (GHRH) deficiency promotes inflammation-associated carcinogenesis.

The somatotropic axis, in addition to its well-known metabolic and endocrine effects, plays a pivotal role in modulation of inflammation. Moreover, growth hormone (GH)-releasing hormone (GHRH) has been involved in the development of various human tumors. In this work we aimed to investigate the consequences of GHRH deficiency on the development of inflammation-associated colon carcinogenesis in a mouse model of isolated GH deficiency due to generalized ablation of the GHRH gene [GHRH knock out (GHRHKO)]. Homozygous GHRHKO (-/-) male mice and wild type (C57/BL6, +/+) male mice as control group, were used. After azoxymetane (AOM)/dextran sodium sulfate (DSS) treatment -/- mice displayed higher Disease Activity Index (DAI) score, and more marked weight loss compared to +/+ animals. Additionally, -/- mice showed a significant increase in total tumors, in particular of large size predominantly localized in distal colon. In colonic tissue of AOM/DSS-treated -/- mice we found the presence of invasive adenocarcinomas, dysplasia and colitis with mucosal ulceration. Conversely, AOM/DSS-treated +/+ mice showed only presence of adenomas, without invasion of sub-mucosa. Treatment with AOM/DSS significantly increased prostaglandin (PG)E2 and 8-iso-PGF2α levels along with cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF)-α, nuclear factor kappa B (NF-kB) and inducible nitric oxide synthase (iNOS) gene expression, in colon specimens. The degree of increase of all these parameters was more markedly in -/- than +/+ mice. In conclusion, generalized GHRH ablation increases colon carcinogenesis responsiveness in male mice. Whether this results from lack of GH or GHRH remains to be established.

The 5-factor modified frailty index predicts health burden following surgery for pituitary adenomas.

PURPOSE: Frailty is known to influence cost-related surgical outcomes in neurosurgery, but quantifying frailty is often challenging. Therefore, we investigated the predictive value of the 5-factor modified frailty index (mFI-5) on total hospital charges, LOS, and 90-day readmission for patients undergoing pituitary surgery. METHODS: The medical records of all patients undergoing endoscopic endonasal resection of pituitary adenomas at an academic medical center between January 2017 and December 2018 were retrospectively reviewed. Bivariate statistical analyses were conducted using Fisher's exact test, chi-square test, and independent samples t-test. Linear and logistic regression models were used for multivariate analysis. RESULTS: Our cohort (n = 234) had a mean age of 53.8 years (standard deviation 14.6 years). Sex distributions were equal, and most patients were Caucasian (59%). On multivariate linear regression, with each one-point increase in mFI-5, total LOS increased by 0.64 days in the overall cohort (p < 0.001), 1.08 days in the Cushing disease cohort (p = 0.045), and 0.59 days in non-functioning tumors cohort (p = 0.004). Total charges increased by $3954 in the whole cohort (p < 0.001), $10,652 in the Cushing disease cohort (p = 0.033), and $2902 in the non-functioning tumors cohort (p = 0.007) with each one-point increase in mFI-5. Greater mFI-5 scores were associated with greater odds of 90-day readmission in both overall and Cushing disease cohorts, but these associations did not reach statistical significance. CONCLUSION: A patient's mFI-5 score is significantly associated with increased length of stay and hospital charges for patients undergoing pituitary surgery. The mFI-5 may hold peri-operative value in patient counseling for pituitary adenoma surgery.

Increased pain and inflammatory sensitivity in growth hormone-releasing hormone (GHRH) knockout mice.

Growth hormone (GH) and GH-releasing hormone (GHRH), in addition to metabolic and endocrine effects, play a role in the modulation of pain and inflammation. We aimed to elucidate the consequences of GHRH deficiency on acute nociceptive stimulation and on both acute and chronic inflammatory stimuli in a mouse model of GH deficiency. Mice with generalized ablation of the GHRH gene (GHRH knock out, GHRHKO, -/-) were compared to wild type (GHRH +/+) mice. Responsiveness to acute nociceptive stimulation and to acute inflammatory stimulation was evaluated by conventional hot plate apparatus and formalin test, respectively. We also evaluated responsiveness to colonic inflammation induced both in vivo, after dextran sodium sulfate (DSS) treatment, or ex vivo, by incubating colon segments with bacterial lipopolysaccaride (LPS). Macroscopical and histological examinations were performed, prostaglandin (PG) E2 and 8-iso-PGF2α levels and cyclooxigenase (COX)-2 and tumor necrosis factor (TNF)-α gene expression were measured. Compared to controls, -/- mice showed decreased response latency during the hot plate test, and increased licking/biting time in formalin test, particularly in the second phase of inflammation. DSS treated -/- mice showed a significant increase of colonic inflammation compared to controls. Moreover DSS treatment increased PGE2 and 8-iso-PGF2α levels, along with COX-2 and TNF-α gene expression more markedly in colon specimens of -/- mice compared to controls. LPS-induced PGE2 and 8-iso-PGF2α production from colonic segments incubated ex vivo was also increased in -/- mice. Generalized GHRH gene ablation increases sensitivity to thermal pain and both acute and persistent inflammatory stimuli in male mice.

Somatostatin receptor ligands in acromegaly: clinical response and factors predicting resistance.

INTRODUCTION: Somatostatin (SST) receptor ligands (SRL), in particular those of first generation (Octreotide and Lanreotide), are widely used in medical treatment of acromegaly, but they assure biochemical control of disease (and the possibility of an improvement of clinical symptoms and tumor shrinkage), only in a subset of patients. DISCUSSION: The mechanisms underlying the so called "SRL resistance" are various and involve in particular SST receptor expression and molecular pathways of signal transduction. Different predictors of SRL response have been reported, including clinical and biochemical features (gender, age, growth hormone and insulin-like growth factor-I levels at diagnosis), and tumor characteristic (both at preoperative magnetic resonance imaging study and histopathology) as well as expression of SST receptors. In some cases, only a "partial resistance" to SST can be detected, probably due to the presence of other impaired molecular mechanisms involved in signal transduction, which compromise specific pathways and not others. This may explain some cases of dissociated response between biochemical control and tumor shrinkage.

Walter E. Dandy: his contributions to pituitary surgery in the context of the overall Johns Hopkins Hospital experience.

BACKGROUND: Walter E. Dandy (1886-1946) was an outstanding neurosurgeon who spent his entire career at the Johns Hopkins Hospital. After graduating from medical school in 1910, he completed a research fellowship in the Hunterian laboratory with Harvey Cushing and then joined the Department of Surgery as resident, rising to the rank professor in 1931. Dandy made several contributions that helped building the neurosurgical specialty, most famously the introduction of pneumo-ventriculography to image brain lesions for which he received a Nobel prize nomination. He also performed many pituitary surgeries, although his role in this area is less known and overshadowed by that of Cushing's. PURPOSE: This retrospective cohort study was designed to unveil Dandy's pituitary work and place it in the context of the overall pituitary surgeries performed at the Johns Hopkins Hospital. METHODS: Pituitary surgery data were obtained by screening the paper and electronic surgical pathology records of the Department of Pathology, as well as the general operating room log books of the Johns Hopkins Hospital housed in the Chesney Medical Archives. RESULTS: A total of 3211 pituitary surgeries associated with a pathological specimen were performed between February 1902 and July 2017 in 2847 patients. Most of the surgeries (2875 of 3211 89%) were done by 21 neurosurgeons. Dandy ranks 4th as number of surgeries, with 287 pituitary operations in 35 years of activity. He averaged 8 pituitary surgeries per year, a rate that positions him 6th among all Hopkins neurosurgeons. With the exception of his first operation done in July 1912 while Cushing was still at Hopkins, Dandy approached the pituitary gland transcranially, rather than transphenoidally. The majority of Dandy's pituitary patients had a pathological diagnosis of pituitary adenomas, followed by craniopharyngiomas and sellar cysts. In the decades Dandy operated, pituitary surgeries represented 0.56% of the total Johns Hopkins surgeries, a percentage significantly greater (p < 0.001) than the 0.1% observed in modern days. Dandy's pituitary clinical work was matched by important experimental studies done in the early stages of his career. CONCLUSIONS: This study highlights the role of Dandy as an important contributor to advance our understanding of pathophysiology and treatment of pituitary diseases.

A multicenter, observational study of lanreotide depot/autogel (LAN) in patients with acromegaly in the United States: 2-year experience from the SODA registry.

PURPOSE: This analysis evaluates the 2-year effectiveness and safety of lanreotide depot/autogel (LAN), as well as treatment convenience and acromegaly symptom relief, from the Somatuline® Depot for Acromegaly (SODA) registry, a post-marketing, open-label, observational, multicenter, United States registry study. METHODS: Patients with acromegaly treated with LAN were eligible for enrollment. Demographics, LAN dose, extended dosing interval (EDI) (interval of injections ≥42 days), insulin-like growth factor 1 (IGF-1), growth hormone (GH), glycated hemoglobin, adverse events (AEs), injection convenience, and symptom data were collected. RESULTS: As of September 29, 2014, 241 patients were enrolled in SODA. IGF-1 levels below age- and gender-adjusted upper normal limit (ULN) were achieved in 71.2% at month (M) 12 and 74.4% at M24; GH ≤2.5 µg/L in 83.3% at M12 and 80.0% at M24; GH <1.0 µg/L in 61.7% at M12 and 61.4% at M24. Both IGF-1 < ULN and GH ≤2.5 µg/L were achieved in 65.0% at M12 and 54.8% at M24; both IGF-1 < ULN and GH < 1.0 µg/L were achieved in 51.7 and 42.9% at M12 and M24, respectively. EDI regimen was 5.0% at baseline and 12.0% at M24. At M24, acromegaly symptoms appeared stable or improved. The most common AE was arthralgia (25.7%). Among 106 serious AEs reported by 42 patients, 10 were deemed related to therapy in 9 patients. At M24, 73.1% of patients rated LAN as convenient. CONCLUSIONS: SODA indicates 2-year biochemical control with majority of patients achieving both IGF-1 < ULN and GH ≤2.5 µg/L. LAN was generally well tolerated with no new or unexpected safety signals reported during the observation period. clinicaltrials.gov Clinical Trial Identifier: NCT00686348.

Endocrinological side-effects of immune checkpoint inhibitors.

PURPOSE OF REVIEW: Three mAbs targeting immune checkpoint proteins are available for the treatment of patients with melanoma, lung, and kidney cancer, and their use will likely expand in the future to additional tumor types. We here update the literature on the incidence and pathophysiology of endocrine toxicities induced by these agents, and discuss management guidance. RECENT FINDINGS: Immune checkpoint inhibition may trigger autoimmune syndromes involving different organs, including several endocrine glands (pituitary, thyroid, adrenals, and endocrine pancreas). Hypophysitis is more frequently associated with ipilimumab, whereas the incidence of thyroid dysfunction is higher with nivolumab/pembrolizumab. Primary adrenal insufficiency can rarely occur with either treatment. Autoimmune diabetes is very rare. As hypophysitis and adrenalitis may be life-threatening, endocrinological evaluation is essential particularly in patients developing fatigue and other symptoms consistent with adrenal insufficiency. Corticosteroids should be promptly used when hypophysitis-induced adrenal insufficiency or adrenalitis are diagnosed, but not in thyroiditis or diabetes. No impact of corticosteroids on the efficacy/activity of immune checkpoint-inhibiting drugs is reported. Hormonal deficiencies are often permanent. SUMMARY: In absence of predicting factors, accurate information to patients provided by the oncology care team is essential for early diagnosis and to limit the consequences of checkpoint inhibition-related endocrine toxicity.

CT Appearance of Adrenal Cystic Lymphangioma: Radiologic-Pathologic Correlation.

OBJECTIVE: Cystic lymphangioma is an uncommon lesion in the adrenal gland. Because of the lesion's rarity, few descriptions of it can be found in the radiology literature. We therefore describe a series of these lesions with a focus on CT characteristics with correlation to gross and microscopic pathology features. MATERIALS AND METHODS: Retrospective review identified seven patients with definitive pathologic findings of cystic lymphangioma of the adrenal gland and available diagnostic CT examinations. CT examinations were reviewed for key imaging features and correlated to gross and microscopic pathology. Lesions were generally described in corresponding reports as likely representing adenomas or hematomas based on CT findings. RESULTS: All cystic lymphangiomas included in this series were well-circumscribed lesions with low-attenuation internal contents and thin walls, without evidence of solid components or nodularity. No measurable contrast enhancement was seen in these lesions. Six of the seven lesions contained calcifications with one of two patterns: either thick, curvilinear, and dystrophic-appearing or thin and scattered. On gross and microscopic pathology, the lesions were composed of dilated cystic spaces containing serous fluid and lined by bland endothelial cells. CONCLUSION: Though rare, an adrenal cystic lymphangioma should be suspected on CT when a unilocular or multilocular, low-attenuation, nonenhancing lesion is present in the region of the adrenal gland, particularly if the lesion contains either of the above-noted calcification patterns. Recognition of these findings may allow more conservative treatment of selected patients harboring these lesions.

Computed Tomography Appearance of Surgically Resected Adrenal Hematomas.

OBJECTIVE: Adrenal hemorrhages arise as a result of a number of conditions and may exhibit a variety of appearances on computed tomography (CT). On occasion, patients will undergo adrenalectomy for treatment of a presumptive adrenal neoplasm that on surgical pathology is identified as an adrenal hemorrhage. We evaluated the CT appearance of surgically resected adrenal masses from our institution over a period of 15 years that ultimately proved to be adrenal hematomas. METHODS: A surgical pathology archive was queried for all cases of adrenal hemorrhage. Only cases with a corresponding diagnostic CT were included. Cases were excluded if an underlying adrenal mass was present. For the remaining cases, the CT appearances were evaluated by 2 radiologists quantitatively and qualitatively. RESULTS: Our search yielded 18 cases of adrenal hemorrhage, of which 5 cases had corresponding CT and no underlying secondary process within the adrenal. All of the adrenal hematomas in this series demonstrated an ovoid morphology and were well defined, with an average maximum diameter of 8.9 cm and highly variable attenuation on noncontrast CT (average attenuation range, 13.1-44.0 Hounsfield units [HU]). Four of the 5 lesions had degrees of peripheral enhancement that was either thin and somewhat uniform or heterogeneous and irregular. None of the lesions demonstrated invasion of the periadrenal fat or adjacent organs. CONCLUSIONS: Adrenal hematomas with a mass-like configuration offer a potential diagnostic dilemma for radiologists and surgeons. Although it is rare that an adrenal hemorrhage is surgically resected, awareness of the potential appearances of these lesions is important to spare patients from unnecessarily aggressive surgery.

MANAGEMENT OF CATECHOLAMINE-SECRETING TUMORS IN PREGNANCY: A REVIEW.

OBJECTIVE: Catecholamine-secreting tumors (pheochromocytomas and paragangliomas) presenting during pregnancy are extremely rare, but they can be fatal to both mother and fetus. Recent discoveries in the genetic background of these tumors are expected to address an increasing number of at-risk women to prenatal diagnosis. METHODS: The literature was reviewed in order to provide clinicians with a practical and updated guide on how to manage this life-threatening condition. RESULTS: The clinical presentation of catecholamine-secreting tumors can be deceptive and mimic common disorders of pregnancy. Silent catecholamine-secreting tumors can become evident during pregnancy, and hypertension cannot be considered a hallmark for this condition: some women may be normotensive or develop orthostatic hypotension. Biochemical screening includes measurement of plasma free metanephrines or urinary fractioned metanephrines. Measurement of catecholamines, dopamine, and methoxytyramine can provide further information on tumor biology, location, and prognosis. Diagnostic imaging is limited, and medical treatment requires a cautious balance between hemodynamic control and effects on the fetoplacental unit. Several genes have been associated with syndromes including catecholamine-secreting tumors, and positive genetic testing can correlate with tumor behavior. Timing and modalities for tumor removal and delivery, including anesthetic management, depend on gestational age, maternal and fetal wellbeing, control of catecholamine excess, suspicion of multiple or malignant disease, and surgical accessibility to the tumor. CONCLUSION: A timely diagnosis and a multidisciplinary approach are the keys to improve pregnancy outcomes in patients with a catecholamine-secreting tumor; each case should be managed in a tertiary referral center.

VENOUS SAMPLING FOR CUSHING DISEASE: COMPARISON OF INTERNAL JUGULAR VEIN AND INFERIOR PETROSAL SINUS SAMPLING.

OBJECTIVE: Because magnetic resonance imaging (MRI) fails to detect many adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, inferior petrosal sinus sampling (IPSS) is considered the gold standard to differentiate Cushing disease (CD) from ectopic ACTH secretion syndrome (EAS). Some authors have suggested internal jugular vein sampling (IJVS) as an alternative to IPSS. METHODS: We simultaneously compared IJVS to IPSS in 30 consecutive patients referred for ACTH-dependent Cushing syndrome and equivocal MRI exams. Five sites were simultaneously sampled in each patient (right and left IPS, right and left IJV, and femoral vein) before and after the administration of corticotrophin-releasing hormone or desmopressin. The test was considered consistent with CD when the IPS to peripheral ratio was >2 at baseline or >3 after stimulus and the IJV to peripheral ratio was >1.7 at baseline or >2 after stimulus. RESULTS: In 27 of 30 patients, IPSS results were consistent with a central source of ACTH. Two of the other 3 patients had EAS (one lung carcinoid and one occult), and 1 patient had pathology-proven CD. The sensitivity of IPSS was 96.4%. Only 64.2% of these patients had results meeting criteria for a central source of ACTH by IJVS criteria. Twenty patients with centralizing IPPS have undergone pituitary surgery. Of these, the central origin of excessive ACTH was confirmed with certainty in 16 patients. Among these 16 patients, the IPSS sensitivity was 93.8%, whereas 5 patients had false-negative IJVS (68.7% sensitivity). CONCLUSION: These results do not support the routine use of IJVS in establishing if the pituitary is the source of excessive ACTH. ABBREVIATIONS: ACTH = adrenocorticotropic hormone CD = Cushing disease CRH = corticotrophin-releasing hormone CS = Cushing syndrome DDAVP = desmopressin EAS = ectopic ACTH secretion IJVS = internal jugular vein sampling IPSS = inferior petrosal sinus sampling JVS = jugular venous sampling MRI = magnetic resonance imaging.

Older individuals heterozygous for a growth hormone-releasing hormone receptor gene mutation are shorter than normal subjects.

Growth hormone (GH)-releasing hormone (GHRH) is the most important stimulus for GH secretion by the pituitary gland. Subjects homozygous for GHRH receptor (GHRHR) gene (GHRHR) inactivating mutations have severe GH deficiency, resulting in severe short stature if not treated. We previously reported that young adults heterozygous for the c.57+1G>A null GHRHR mutation (MUT/N) have reduced weight and body mass index (BMI) but normal stature. Here we have studied whether older MUT/N have an additional phenotype. In a cross-sectional study, we measured height, weight and blood pressure, and calculated BMI in two groups (young, 20-40 years of age) and old (60-80 years) of individuals heterozygous for the same GHRHR mutation, and compared with a large number of individuals of normal genotype residing in the same geographical area. Standard deviation score (SDS) of weight was lower, and BMI had a trend toward reduction in young heterozygous compared with young normals, without significant difference in stature. Conversely, SDS of height was lower in older heterozygous individuals than in controls, corresponding to a reduction of 4.2 cm. These data show a reduced stature in older subjects heterozygous for the c.57+1G>A GHRHR mutation, indicating different effects of heterozygosis through lifespan.