Indication to dynamic and invasive testing in Cushing's disease according to different neuroradiological findings.

PURPOSE: Dynamic testing represents the mainstay in the differential diagnosis of ACTH-dependent Cushing's syndrome. However, in case of undetectable or detectable lesion < 6 mm on MRI, bilateral inferior petrosal sinus sampling (BIPSS) is suggested by current guidelines. Aim of this study was to analyze the performance of CRH, desmopressin and high-dose dexamethasone suppression test (HDDST) in the differential diagnosis of ACTH-dependent Cushing's syndrome as well as the impact of invasive and noninvasive tests on surgical outcome in patients affected by Cushing's disease (CD). METHODS: Retrospective analysis on 148 patients with CD and 26 patients with ectopic ACTH syndrome. RESULTS: Among CD patients, negative MRI/lesion < 6 mm was detected in 97 patients (Group A); 29 had a 6-10 mm lesion (Group B) and 22 a macroadenoma (Group C). A positive response to CRH test, HDSST and desmopressin test was recorded in 89.4%, 91·4% and 70.1% of cases, respectively. Concordant positive response to both CRH/HDDST and CRH/desmopressin tests showed a positive predictive value of 100% for the diagnosis of CD. Among Group A patients with concordant CRH test and HDDST, no difference in surgical outcome was found between patients who performed BIPSS and those who did not (66.6% vs 70.4%, p = 0.78). CONCLUSIONS: CRH, desmopressin test and HDDST have high accuracy in the differential diagnosis of ACTH-dependent CS. In patients with microadenoma < 6 mm or non-visible lesion, a concordant positive response to noninvasive tests seems sufficient to diagnose CD, irrespective of MRI finding. In these patients, BIPSS should be reserved to discordant tests.

"Non-Classical" Indication for Provocative Testing of Growth Hormone: A Retrospective Cohort Study in Adult Patients Under Replacement Therapy.

BACKGROUND: Adult growth hormone deficiency (GHD) is considered a rare condition. Current guidelines state that GH provocative test is indicated in patients affected by organic hypothalamic/ pituitary disease or with a history of head injury, irradiation, hemorrhage or hypothalamic disease with multiple pituitary deficiencies. Nevertheless, the clinical picture related to GHD may be subtle. OBJECTIVE: We have retrospectively evaluated the indication to GHRH+arginine test in our monocentric cohort of patients treated with hrGH in order to assess whether other conditions had been considered as a rationale for provocative testing. METHODS: Ninety-six patients (51 females and 45 males), aged 19-67 years were included. The GHRH+arginine test had been performed in 29 patients with organic hypothalamic/pituitary disease and in 4 patients for Childhood onset-GHD (CoGHD). In other patients, the diagnosis was suspected for "non classical" reasons in the clinical picture suspected for GHD. RESULTS: Classical indications included previously known primary empty sella (n=15), pituitary surgery (n=14), pituitary cyst (n=1), non-secreting pituitary tumors (n=3) but more than half of the patients (57.3%) had been studied for "non classical" indications: metabolic syndrome (n=25), asthenia (n=13), heart failure (n=4), osteoporosis (n=6), unexplained hypoglycaemia (n=1) and infertility (n=6). The latter represented a significant percentage in the male subgroup under 45 ys. IGF-1 levels were lower than 50th percentile in 63% of patients. Finally, among non-classical reasons, organic pituitary disease was discovered in 22 patients. CONCLUSION: Idiopathic GHD may be unrecognized due to its subtle manifestations and that an extended use of dynamic GH tests may reveal such conditions. A potential field of investigation could be to identify subsets of patients with clinical conditions caused or worsened by underlying unrecognized GHD.

Non-invasive Diagnostic Strategy in ACTH-dependent Cushing's Syndrome.

CONTEXT: Inferior petrosal sinus sampling (IPSS) is used to diagnose Cushing's disease (CD) when dexamethasone-suppression and CRH tests, and pituitary magnetic resonance imaging (MRI), are negative or give discordant results. However, IPSS is an invasive procedure and its availability is limited. OBJECTIVE: To test a noninvasive diagnostic strategy associated with 100% positive predictive value (PPV) for CD. DESIGN: Retrospective study. SETTING: Two university hospitals. PATIENTS: A total of 167 patients with CD and 27 patients with ectopic ACTH-syndrome investigated between 2001 and 2016. MAIN OUTCOME MEASURE(S): Performance of a strategy involving the CRH and desmopressin tests with pituitary MRI followed by thin-slice whole-body computed tomography (CT) scan in patients with inconclusive results. RESULTS: Using thresholds of a cortisol increase > 17% with an ACTH increase > 37% during the CRH test and a cortisol increase > 18% with an ACTH increase > 33% during the desmopressin test, the combination of both tests gave 73% sensitivity and 98% PPV of CD. The sensitivity and PPV for pituitary MRI were 71% and 99%, respectively. CT scan identified 67% EAS at presentation with no false-positives. The PPV for CD was 100% in patients with positive responses to both tests, with negative pituitary MRI and CT scan. The Negative Predictive Value was 100% in patients with negative responses to both tests, with negative pituitary MRI and positive CT scan. Using this strategy, IPPS could have been avoided in 47% of patients in whom it is currently recommended. CONCLUSIONS: In conjunction with expert radiologic interpretation, the non-invasive algorithm studied significantly reduces the need for IPSS in the investigation of ACTH-dependent Cushing's syndrome.

Intraoperative unfolding and postoperative pruning of the pituitary gland after transsphenoidal surgery for pituitary adenoma: A volumetric and endocrinological evaluation.

PURPOSE: To describe the volumetric changes that the pituitary gland (PG) undergoes during and after transsphenoidal surgery (TSS), and to evaluate if unfolding and/or pruning are related to endocrinological outcome measures. METHODS: Retrospective evaluation of data prospectively collected of a cohort of patients undergoing TSS for a pituitary adenoma with the adjunctive use of high field 3 Tesla intraoperative MRI. All patients underwent a full endocrinological workup preoperatively, as well as at 6 weeks and 1 year postoperatively. A decrease in PG volume ≥15% between the intraoperative and 3-month, or between the 3-month and 12-month measurements, was considered early and late pruning, respectively. RESULTS: The PG unfolds significantly during TSS, and subsequently undergoes pruning up until 1 year postoperatively, in most cases returning to the preoperatively measured PG volume. A smaller baseline PG volume predicts intraoperative unfolding. Early pruning of the PG after surgery was associated with new functional deficits. Baseline pituitary compression also correlated to newly occurring deficits after surgery. A larger 1-year pituitary volume was associated with biochemical remission in secreting adenomas. CONCLUSIONS: The PG shows dynamic change during and after TSS for pituitary adenoma. Small baseline and 3-month PG volumes, as well as early pruning were independently associated with new deficits. Our findings warrant prospective validation in a larger cohort with higher statistical power.

Macimorelin as a Diagnostic Test for Adult GH Deficiency.

Purpose: The diagnosis of adult GH deficiency (AGHD) is challenging and often requires confirmation with a GH stimulation test (GHST). The insulin tolerance test (ITT) is considered the reference standard GHST but is labor intensive, can cause severe hypoglycemia, and is contraindicated for certain patients. Macimorelin, an orally active GH secretagogue, could be used to diagnose AGHD by measuring stimulated GH levels after an oral dose. Materials and Methods: The present multicenter, open-label, randomized, two-way crossover trial was designed to validate the efficacy and safety of single-dose oral macimorelin for AGHD diagnosis compared with the ITT. Subjects with high (n = 38), intermediate (n = 37), and low (n = 39) likelihood for AGHD and healthy, matched controls (n = 25) were included in the efficacy analysis. Results: After the first test, 99% of macimorelin tests and 82% of ITTs were evaluable. Using GH cutoff levels of 2.8 ng/mL for macimorelin and 5.1 ng/mL for ITTs, the negative agreement was 95.38% (95% CI, 87% to 99%), the positive agreement was 74.32% (95% CI, 63% to 84%), sensitivity was 87%, and specificity was 96%. On retesting, the reproducibility was 97% for macimorelin (n = 33). In post hoc analyses, a GH cutoff of 5.1 ng/mL for both tests resulted in 94% (95% CI, 85% to 98%) negative agreement, 82% (95% CI, 72% to 90%) positive agreement, 92% sensitivity, and 96% specificity. No serious adverse events were reported for macimorelin. Conclusions: Oral macimorelin is a simple, well-tolerated, reproducible, and safe diagnostic test for AGHD with accuracy comparable to that of the ITT. A GH cutoff of 5.1 ng/mL for the macimorelin test provides an excellent balance between sensitivity and specificity.

Dynamic GnRH and hCG testing: establishment of new diagnostic reference levels.

OBJECTIVE: Gonadotropin-releasing hormone (GnRH) and human chorionic gonadotropin (hCG) stimulation tests may be used to evaluate the pituitary and testicular capacity. Our aim was to evaluate changes in follicular-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone after GnRH and hCG stimulation in healthy men and assess the impact of six single nucleotide polymorphisms on the responses. DESIGN: GnRH and hCG stimulation tests were performed on 77 healthy men, 18-40 years (reference group) at a specialized andrology referral center at a university hospital. The potential influence of the tests was illustrated by results from 45 patients suspected of disordered hypothalamic-pituitary-gonadal axis. METHODS: Baseline, stimulated, relative and absolute changes in serum FSH and LH were determined by ultrasensitive TRIFMA, and testosterone was determined by LC-MS/MS. RESULTS: For the reference group, LH and FSH increased almost 400% and 40% during GnRH testing, stimulated levels varied from 4.4 to 58.8 U/L and 0.2 to 11.8 U/L and FSH decreased in nine men. Testosterone increased approximately 110% (range: 18.7-67.6 nmol/L) during hCG testing. None of the polymorphisms had any major impact on the test results. Results from GnRH and hCG tests in patients compared with the reference group showed that the stimulated level and absolute increase in LH showed superior identification of patients compared with the relative increase, and the absolute change in testosterone was superior in identifying men with Leydig cell insufficiency, compared with the relative increase. CONCLUSIONS: We provide novel reference ranges for GnRH and hCG test in healthy men, which allows future diagnostic evaluation of hypothalamic-pituitary-gonadal disorders in men.

TRENDS IN GROWTH HORMONE STIMULATION TESTING AND GROWTH HORMONE DOSING IN ADULT GROWTH HORMONE DEFICIENCY PATIENTS: RESULTS FROM THE ANSWER PROGRAM.

OBJECTIVE: Adult growth hormone deficiency (AGHD) results in physiologic impairments that may reduce quality of life and negatively impact body composition. AGHD can be treated with recombinant human growth hormone (GH). This study analyzes AGHD patients enrolled in the American Norditropin(®) STUDIES: Web-Enabled-Research (ANSWER) Program/NovoNet, a U.S. observational noninterventional study of patients treated with Norditropin(®) (somatropin [recombinant DNA origin] injection) at the discretion of their physicians. METHODS: Data were evaluated for GH stimulation test (GHST) usage and Norditropin(®) doses over 4 years. RESULTS: Adults (N = 468) with isolated GHD (IGHD) or multiple pituitary hormone deficiency (MPHD) were evaluated. The most commonly used GHSTs were arginine + L-dopa (27%; mostly a single center) and glucagon (25%; most frequent test after 2009). The percent of patients meeting recommended test-specific cut points varied from 32 to 100%, depending on the GHST used. Mean baseline GH doses were higher for MPHD patients and for younger patients in both IGHD and MPHD groups. CONCLUSION: MPHD was more common than IGHD. Mean GH doses were higher in younger patients, consistent with a transition from higher pediatric to lower adult dosing. Over time, glucagon became the most popular GHST. The use, in some patients, of other GHSTs with cut points, as well as starting doses not consistent with current recommendations, highlights the need for continued education regarding treatment guidelines for AGHD.

High prevalence of pituitary dysfunction after aneurysmal subarachnoid hemorrhage: a long-term prospective study using dynamic endocrine testing.

OBJECTIVE: Impaired systemic hormonal activity caused by hypothalamic and pituitary injury may contribute to neuropsychologic disturbances and poor quality of life after aneurysmal subarachnoid hemorrhage (SAH). This prospective study was designed to longitudinally evaluate long-term clinical outcome and pituitary function after SAH using dynamic tests for adrencorticotropic and somatotropic secretory capacity. METHODS: Endocrine function was assessed by basal hormonal concentrations at 6-12 months and 12-24 months after SAH. At the 12-24 months follow-up, dynamic provocative evaluation of adrenocorticotropic hormone (ACTH) and growth hormone (GH) was performed using the insulin tolerance test (ITT). In patients where ITT was contraindicated, an ACTH stimulation test was used to assess ACTH capacity, and a growth hormone releasing hormone (GHRH)-arginine stimulation test was used to assess GH capacity. RESULTS: Of 60 patients with SAH screened, 51 were included in the study, and 44 remained to be tested at the two follow-up visits. As assessed by basal hormone concentrations alone, the prevalence of pituitary dysfunction was 34% at 6-12 months and 41% at 12-24 months. When using dynamic tests (12-24 months), impaired pituitary function was detected in 43%. The ITT detected more cases of central hypoadrenalism and GH deficiency compared with the ACTH- and GHRH-arginine-stimulation tests, respectively. CONCLUSIONS: Application of dynamic endocrine tests revealed a high frequency of long-term hypothalamic-pituitary dysfunction after aneurysmal SAH. The role of pituitary dysfunction in the recovery after SAH merits further evaluation.

Comparison of two growth hormone stimulation tests and their cut-off limits in healthy adults at an outpatient clinic.

OBJECTIVE: A peak GH less than 3 µg/L to insulin tolerance test (ITT) is commonly used as a threshold indicating severe adult GH deficiency (GHD). This cut-off is based on results obtained by polyclonal radioimmunoassays preferably under standard conditions at hospital. Our aim was to evaluate the validity of this cut-off limit using two currently used immunometric GH assays and to compare GH responses in the ITT and the GH releasing hormone + arginine (GHRH + ARG) test in healthy adults at our outpatient endocrine unit. DESIGN: ITT was performed on 73 subjects and the GHRH + ARG test on those 28 who showed insufficient response to the ITT. METHODS: GH was measured by an immunofluorometric and immunochemiluminometric assay. RESULTS: GH peak above 3 µg/L was observed in 56% of the healthy volunteers with adequate hypoglycemia in the ITT. Among the 28 subjects with a peak GH below 3 µg/L, only two overweight men had a GH peak response below the commonly used cut-off limit of 9.1 µg/L in the GHRH + ARG test. CONCLUSIONS: Lean healthy adults could erroneously be classified as GH deficient by the ITT while their results in the GHRH + ARG test were normal. The GH results are highly dependent on the immunoassay used, but false positive results in the ITT are often obtained even if lower cutoff limits determined on the basis on the calibration of the GH assay are used. Confounding factors seemed to blunt the GH response to the ITT more than to the GHRH + ARG test at our outpatient clinic.

Burns, hypertrophic scar and galactorrhea.

An 18-year-old woman was admitted to Motahari Burn Center suffering from 30% burns. Treatment modalities were carried out for the patient and she was discharged after 20 days. Three to four months later she developed hypertrophic scar on her chest and upper limbs. At the same time she developed galactorrhea in both breasts and had a disturbed menstrual cycle four months post-burn. On investigation, we found hyperprolactinemia and no other reasons for the high level of prolactin were detected.She received treatment for both the hypertrophic scar and the severe itching she was experiencing. After seven months, her prolactin level had decreased but had not returned to the normal level. It seems that refractory hypertrophic scar is related to the high level of prolactin in burns patients.

Selective use of the insulin tolerance test to diagnose hypopituitarism.

The insulin tolerance test is considered the gold standard for assessing the hypothalamic-pituitary-adrenal and growth hormone (GH) axes, but its use varies considerably among different endocrine units. We recommend using the insulin tolerance test to assess the hypothalamic-pituitary-adrenal axis within 3 months of pituitary surgery, where adrenocorticotropic hormone 1-24 testing is equivocal, and to assess for GH deficiency where the patient is being considered for GH replacement therapy. We also discuss safety issues, how to ensure adequate hypoglycaemia and possible alternative tests, such as the overnight metyrapone test and glucagon test.

Enhanced cortisol suppression following administration of low-dose dexamethasone in first-episode psychosis patients.

OBJECTIVE: Impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis and hyper-activity of this system have been described in patients with psychosis. Conversely, some psychiatric disorders such as post-traumatic stress disorder (PTSD) are characterised by HPA hypo-activity, which could be related to prior exposure to trauma. This study examined the cortisol response to the administration of low-dose dexamethasone in first-episode psychosis (FEP) patients and its relationship to childhood trauma. METHOD: The low-dose (0.25 mg) Dexamethasone Suppression Test (DST) was performed in 21 neuroleptic-naïve or minimally treated FEP patients and 20 healthy control participants. Childhood traumatic events were assessed in all participants using the Childhood Trauma Questionnaire (CTQ) and psychiatric symptoms were assessed in patients using standard rating scales. RESULTS: FEP patients reported significantly higher rates of childhood trauma compared to controls (p = 0.001) and exhibited lower basal (a.m.) cortisol (p = 0.04) and an increased rate of cortisol hyper-suppression following dexamethasone administration compared to controls (33% (7/21) vs 5% (1/20), respectively; p = 0.04). There were no significant group differences in mean cortisol decline or percent cortisol suppression following the 0.25 mg DST. This study shows for the first time that a subset of patients experiencing their first episode of psychosis display enhanced cortisol suppression. CONCLUSIONS: These findings suggest there may be distinct profiles of HPA axis dysfunction in psychosis which should be further explored.

Extended endoscopic transplanum-transtuberculum approach for pituitary adenomas.

Few pituitary adenomas require removal through a transcranial route. This may be associated with more significant morbidity and mortality, compared to the transsphenoidal approach. An endoscopic, extended, transplanum-transtuberculum approach (ETTA) in selected pituitary adenomas may offer an alternative to the transcranial route. We describe our technique and experience of ETTA in pituitary adenomas over 10 years. Between 2000 and 2010, we performed 700 endoscopic endonasal procedures for pituitary adenomas. Nineteen patients (13 men; mean age, 48 years; range, 22-76 years) underwent 22 ETTAs. Thirteen patients had non-functioning adenomas. Three tumor groups were identified: (1) tumors developing in or around the pituitary stalk; (2) tumours with sub- frontal extension and (3) tumours with a major extrasellar component. Mean follow-up was 37 months (range 6-72 months). Gross total resection was achieved in 11 procedures (no recurrences), with partial tumour resection in 11 procedures. Of the 12 patients with visual symptoms, ten improved. Of eight patients with hormonal hypersecretion four were cured. Complications included CSF leak (14%), haemorrhage (9%), hemiplegia (5%). There were no mortalities. Experience using the ETTA for pituitary adenomas is limited because it is indicated in highly selected cases (3.1% of our series). An absolute indication is represented by ectopic secreting pituitary stalk/peri-stalk adenomas. ETTA is a useful option in midline frontal adenomas and adenomas with a major extrasellar component, but has a higher morbidity than that seen in the standard transsphenoidal approach. A study comparing ETTA versus transcranial resection is highly desirable.

Serotonergic function and treatment of behavioral and psychological symptoms of frontotemporal dementia.

OBJECTIVES: The purposes of this study were first, to evaluate the effectiveness of citalopram in treating behavioral disturbances in frontotemporal dementia (FTD) subjects and second, to determine whether an association exists between serotonergic function, as determined by a neuroendocrine challenge, and treatment response. DESIGN: Single-dose citalopram (30 mg per os) challenge followed by a 6-week open-label study. SETTING: Outpatients referred to memory clinics. PARTICIPANTS: Fifteen patients suffering from FTD with severe behavioral and psychological symptoms of dementia. INTERVENTION: Following citalopram challenge, all patients were treated with citalopram titrated to a target dose of 40 mg once daily. MEASUREMENTS: Behavioral disturbances, using the Neuropsychiatric Inventory (NPI) (primary outcome) and Frontal Behavioural Inventory (secondary outcome), were assessed. Change in prolactin concentration following citalopram challenge was used as an index of central serotonergic response. RESULTS: Citalopram treatment was effective in treating behavioral symptoms, with significant decreases in NPI total score (F[2, 28] = 6.644, p = 0.004), disinhibition (F[2, 28] = 4.030, p = 0.029), irritability (F[2, 28] = 7.497, p = 0.003) and depression (F[2, 28] = 3.467, p = 0.045) scores over the 6 weeks. Significant improvement in Frontal Behavioural Inventory scores suggested that citalopram was also effective in the treatment ofbehaviors specific to FTD. A lower change score in concentration of prolactin was significantly positively correlated with greater improvement in the total NPI score from baseline to endpoint (r = 0.687, p = 0.005). A blunted response to a citalopram challenge, implying a dysfunctional serotonergic system, predicted a more positive treatment outcome. CONCLUSIONS: The results suggest that despite the endogenous serotonin deficiency of FTD, citalopram treatment may be effective in targeting the behavioral disturbances characteristic of FTD.

Allopregnanolone levels decrease after gonadotropin-releasing hormone analog stimulation test in girls with central precocious puberty.

BACKGROUND: Allopregnanolone, a neuroactive steroid mainly secreted by adrenals and gonads, is a hormone that seems to play a role in precocious puberty, as demonstrated by its high baseline levels found in girls with central precocious puberty (CPP). Allopregnanolone concentrations significantly increase after GnRH and ACTH stimulation test suggesting both its ovarian and adrenal production. AIM: Aim of this study was to evaluate allopregnanolone concentrations after GnRH and GnRH agonist analog stimulation test in girls with CPP to better establish its secretion source. SUBJECTS AND METHODS: Gonadotropins and steroid hormones were evaluated in different days after GnRH and triptorelin stimulation test in 15 CPP girls. RESULTS: After GnRH stimulation, LH, FSH, and allopregnanolone concentrations significantly increased (p<0.05). After triptorelin administration LH, FSH, estradiol and DHEAS levels significantly increased (p<0.05), while allopregnanolone concentrations significantly decreased (1.08±0.24 vs 0.87±0.28 nmol/l; p=0.003). CONCLUSIONS: The different response of allopregnanolone to GnRH and GnRH agonist analog might reflect the agonist and antagonist action exerted by these secretagogues. Our data suggest the prevalent gonadal allopregnanolone production in CPP subjects and the usefulness of its measurement in the diagnosis of CPP.

The rational use of pituitary stimulation tests.

BACKGROUND: Diseases of the pituitary gland can lead to the dysfunction of individual hormonal axes and to the corresponding clinical manifestations. The diagnostic assessment of pituitary function has not yet been standardized. METHODS: The members of the Neuroendocrinology Section and the Pituitary Study Group of the German Society for Endocrinology (Deutsche Gesellschaft für Endokrinologie) prepared outlines of diagnostic methods for the evaluation of each of the pituitary hormonal axes. These outlines were discussed in open session in recent annual meetings of the Section and the Study Group. RESULTS: For the evaluation of the thyrotropic axis, basal TSH and free T4 usually suffice. For the evaluation of the gonadotropic axis in men, the testosterone level should be measured; if the overall testosterone level is near normal, then calculating the free testosterone level may be additionally useful. In women, an intact menstrual cycle is sufficient proof of normal function. In the absence of regular menstruation, measurement of the basal estradiol and gonadotropin levels aids in the diagnosis of the disturbance. For the evaluation of the adrenocorticotropic axis, the basal cortisol level may be helpful; provocative testing is in many cases necessary for precise characterization. The evaluation of the somato-tropic axis requires provocative testing. Aside from the insulin tolerance test, the GHRH-arginine test has become well established. Reference ranges normed to the body mass index (BMI) are available. CONCLUSION: The diagnostic evaluation of pituitary insufficiency should proceed in stepwise fashion, depending on the patient's clinical manifestations and underlying disease. For some pituitary axes, measurement of basal hormone levels suffices; for others, stimulation tests are required. In general, the performance of combined pituitary tests should be viewed with caution.