Prolactin-adjusted ACTH Ratio in Predicting Lateralization of ACTH Source During Simultaneous Bilateral Inferior Petrosal Sinus Sampling in Patients with Cushing's Disease.

INTRODUCTION: Prolactin-adjusted adrenocorticotropic hormone (ACTH) ratio is used to improve the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS) for lateralization of pituitary adenoma. OBJECTIVE: To study the use of prolactin for successful catheterization during BIPSS, the role of prolactin-normalized ACTH ratio for confirmation of Cushing's disease (CD) and prolactin-adjusted ACTH ratio in predicting the lateralization. PATIENTS AND METHODS: BIPSS was done in patients with CD; prolactin-adjusted ACTH ratio was compared with intersinus ACTH ratio, magnetic resonance imaging, and intraoperative findings for localization of pituitary adenoma. Histopathology was taken as "gold standard" for the diagnosis of CD. RESULTS: Eight patients underwent BIPSS. All the patients underwent transsphenoidal surgery. All these patients had proper venous sampling during BIPSS as determined by inferior petrosal sinus (IPS):Peripheral prolactin ratio of ≥1.8. Prolactin-normalized ACTH ratio of ≥1.3 was achieved in all the eight patients, which was consistent with the diagnosis of CD. Concordance of intersinus ACTH ratio ≥1.4 with the intraoperative findings was found in five of eight (62.5%) patients depicting correct lateralization. Concordance of prolactin-adjusted ACTH ratio with intraoperative findings was found in four of eight (50%) patients. Seven of eight patients had concordance of intersinus ACTH ratio with prolactin-adjusted ACTH ratio. CONCLUSION: Prolactin is a useful marker for successful catheterization, confirming the diagnosis of CD during BIPSS, and prolactin-adjusted ACTH ratio does not add to the accuracy of lateralization of pituitary adenoma compared with intersinus ACTH ratio.

Diagnostic accuracy and comparison of BIPSS in response to lysine vasopressin and hCRH.

CONTEXT: Bilateral inferior petrosal sinus sampling (BIPSS) using hCRH is currently considered the 'gold standard' test for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS). Vasopressin is more potent than CRH to stimulate ACTH secretion as shown in animal studies; however, no comparative data of its use are available during BIPSS. OBJECTIVE: To study the diagnostic accuracy and comparison of hCRH and lysine vasopressin (LVP) stimulation during BIPSS. PATIENTS AND METHODS: 29 patients (27-Cushing's disease, 2-ectopic CS; confirmed on histopathology) underwent BIPSS and were included for the study. Patients were randomized to receive hCRH, 5 U LVP or 10 U LVP during BIPSS for ACTH stimulation. BIPSS and contrast-enhanced magnetic resonance imaging (CEMRI) were compared with intra-operative findings of trans-sphenoidal surgery (TSS) for localization and lateralization of the ACTH source. RESULTS: BIPSS correctly localized the source of ACTH excess in 29/29 of the patients with accuracy of 26/26 patients, using any of the agent, whereas sensitivity and PPV for lateralization with hCRH, 5 U LVP and 10 U LVP was seen in 10/10, 6/10; 10/10,8/10 and 7/7,6/7 patients respectively. Concordance of BIPSS with TSS was seen in 20/27, CEMRI with BIPSS in 16/24 and CEMRI with TSS in 18/24 of patients for lateralizing the adenoma. Most of the side effects were transient and were comparable in all the three groups. CONCLUSION: BIPSS using either hCRH or LVP (5 U or 10 U) confirmed the source of ACTH excess in all the patients, while 10 U LVP correctly lateralized the pituitary adenoma in three fourth of the patients.

UTILITY OF A SINGLE LATE-NIGHT PLASMA CORTISOL AND ACTH FOR THE DIAGNOSIS OF CUSHING SYNDROME.

OBJECTIVE: To evaluate the diagnostic efficacy of various screening tests for the diagnosis of Cushing syndrome (CS). METHODS: Thirty-five patients with CS and 16 patients of pseudo-CS were enrolled. Assessment of 24-h urinary free cortisol (UFC), late-night salivary cortisol (LNSC), overnight dexamethasone suppression test (ONDST), late-night plasma cortisol (LNPC), and adrenocorticotropic hormone (ACTH) on outpatient basis, and during sleep as well as in awake state after 48 hours of hospital admission. RESULTS: We found that 24-h UFC performed the best among the screening tests with sensitivity, specificity and areas under the curve (AUCs) of 96.0%, 99%, and 0.988, respectively, at a cut-off of 144.6 µg/24 h. A cut-off of 10.5 nmol/L for LNSC had sensitivity 85.7%, specificity 88.2%, and an AUC of 0.897. A cut-off of 412.4 nmol/L for LNPC on outpatient basis had sensitivity 88.2%, specificity 91.2%, and an AUC of 0.957. Cut-offs of 215 and 243.3 nmol/L for LNPC during sleep and awake states after acclimatization had sensitivity, specificity, and an AUC of 94.1%, 88.2%, and 0.958, respectively. An ONDST cut-off of 94.6 nmol/L provided sensitivity, specificity, and an AUC of 96.0%, 99.03% and 0.995, respectively. A cut-off of 30.3 pg/mL for late-night ACTH on outpatient basis had sensitivity 67.6%, specificity 99.9%, and an AUC 0.796.A cut-off of 22.6 pg/mL for ACTH during sleep state after acclimatization had sensitivity, specificity, and an AUC of 73.5%, 99.2%, and 0.827, respectively. CONCLUSION: UFC is the best screening test for CS. Furthermore, single measurements of LNPC and ACTH help to establish the diagnosis and ACTH dependency of CS in the majority of patients with CS. ABBREVIATIONS: ACTH = adrenocorticotropic hormone AUC = area under the curve CRH = corticotropin-releasing hormone CS = Cushing syndrome ECLIA = electrochemiluminescence immuno-assay LDDST = low-dose dexamethasone suppression test LNPC = late-night plasma cortisol LNSC = late-night salivary cortisol ONDST = overnight dexamethasone suppression test RIA = radio-immuno assay UFC = urinary free cortisol.

Diagnostic utility of testosterone priming prior to dynamic tests to differentiate constitutional delay in puberty from isolated hypogonadotropic hypogonadism.

CONTEXT: Differentiation between constitutional delay in puberty (CDP) and isolated hypogonadotropic hypogonadism (IHH) during adolescence is a great clinical challenge, and the available diagnostic tests are of limited value. OBJECTIVE: To study the effect of withdrawal of short-term, low-dose testosterone therapy (testosterone priming) on the discriminatory power of dynamic tests for hypothalamo-pituitary-testicular axis to differentiate CDP from IHH. DESIGN: A prospective study (n = 30) consisting of 20 boys with delayed puberty (group A) and 10 patients with IHH (group B). INTERVENTION: Patients in groups A and B underwent Triptorelin and hCG stimulation tests, prior to and 2 months after withdrawal of 'testosterone priming' (100 mg intramuscularly 4 weekly for 3 months) and were followed up until the onset of puberty or 18 years of age, whichever was earlier. RESULTS: At baseline, Triptorelin-stimulated 4 h LH, with a cut-off of 2·8 IU/l, and hCG-stimulated day 7 testosterone with a cut-off of 3·8 nmol/l had sensitivities of 80% each, and specificities of 93% and 87%, respectively, to diagnose CDP. After withdrawal of testosterone, a 4 h LH cut-off of 14·7 IU/l and day 7 testosterone cut-off of 10·3 nmol/l had sensitivities of 93% and 88% respectively, and specificity and positive predictive value of 100% each. A basal inhibin B > 94·7 ng/l was discriminatory for diagnosing CDP after withdrawal of testosterone priming. CONCLUSIONS: Inhibin B levels or 4 h LH after Triptorelin stimulation are the best discriminatory tests to differentiate CDP from IHH, when performed after withdrawal of 'testosterone priming'.

Fibrogenesis Imperfecta Ossium and Response to Human Growth Hormone: A Potential Therapy.

Context: Fibrogenesis imperfecta ossium (FIO) is a rare bone disease manifested by generalized bone pain, fragility fractures, progressive disability, and extensive mineralization defect seen in bone biopsy specimens. The pathogenesis of the disease is unknown and currently there is no effective treatment. Objective: To report on the effect of recombinant human growth hormone (rhGH) therapy in FIO. Design: An observational study in two patients. Setting: Endocrinology clinic in an academic institution. Patients or Other Participants: Two siblings with FIO. Intervention(s): rhGH was administered subcutaneously at a dose of 1 U daily for 1 year. Main Outcome Measures: Changes in clinical, biochemical, radiological, and bone histological (i.e., light and transmission electron microscopy, and histomorphometry) investigations. Results: Except for an elevated serum alkaline phosphatase level, results of routine biochemical, hematological, and hormonal investigations were normal in both patients. Radiographs showed pseudofractures and bone scans revealed a "beheaded" tracer activity pattern (i.e., superscan without uptake in the skull). Bone biopsy specimens showed severe mineralization defect simulating osteomalacia with disorganized collagen fibril alignment. Treatment with rhGH was followed by clinical, biochemical, and radiological improvement in both the patients, with substantial improvement in the mineralization defect, most likely due to rhGH-induced improvement in collagen fibril arrangement. Conclusion: We report on two brothers with FIO and demonstrate clinical improvement and restoration of normal bone pathology with rhGH therapy. We suggest that rhGH is a potential therapy for FIO for which no effective therapy currently exists.

Congenital hypothyroidism - An usual suspect at an unusual age: A case series.

UNLABELLED: Menorrhagia is the most common menstrual irregularity in hypothyroid women. However, it is an uncommon presentation of congenital hypothyroidism (CH). In the era of newborn screening across the world, when CH is extremely rare, we came across four cases of CH due to delayed diagnosis, presenting in adulthood with severe menorrhagia. AIMS: To signify the atypical presentation of CH in late adulthood due to delayed diagnosis and its sequelae; and to increase the awareness about this treatable condition. SETTINGS AND DESIGN: This is a cross-sectional analysis of consecutive patients with CH presenting after 18 years between 2010 and 2012 from the CH registry of Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), India. SUBJECTS AND METHODS: Four patients of CH presenting late (>18 years) with atypical presentations out of total 16 cases of CH within a period of 3 years were analyzed for clinical, hormonal, and imaging findings. RESULTS: Between the years 2010 and 2012, 16 cases of CH were registered at our center out of which four cases presented in late adolescence and adulthood with menorrhagia. Age range of these patients was 18-30 years. All four patients were females presenting with anemia secondary to menorrhagia and upon evaluation were found to have CH. All of them showed improvement after starting treatment and are currently doing well with regular menstrual cycles. CONCLUSIONS: Our study demonstrates the importance of thyroid evaluation in a patient presenting with menorrhagia along with short stature. There is need for awareness among clinicians regarding the clinical features of CH and nationwide screening for CH in our country.

Acute lymphocytic leukaemia presenting as a metabolic bone disease.

A 7-year-old boy presented with the acute onset of low backache of 2 months duration. An x-ray of thoracolumbar spine revealed multiple vertebral fractures, and biochemical evaluation showed hypercalcaemia with a suppressed parathyroid hormone which raised the possibilities of malignancy, granulomatous conditions or vitamin D toxicity. Despite the absence of blast cells in his blood, the bone marrow biopsy was unequivocally diagnostic of acute lymphoblastic leukaemia.