Approach to androgen excess in women: Clinical and biochemical insights.

Androgen excess in women typically presents clinically with hirsutism, acne or androgenic alopecia. In the vast majority of cases, the underlying aetiology is polycystic ovary syndrome (PCOS), a common chronic condition that affects up to 10% of all women. Identification of women with non-PCOS pathology within large cohorts of patients presenting with androgen excess represents a diagnostic challenge for the endocrinologist, and rare pathology including nonclassic congenital adrenal hyperplasia, severe insulin resistance syndromes, Cushing's disease or androgen-secreting tumours of the ovary or adrenal gland may be missed in the absence of a pragmatic screening approach. Detailed clinical history, physical examination and biochemical phenotyping are critical in risk-stratifying women who are at the highest risk of non-PCOS disorders. Red flag features such as rapid onset symptoms, overt virilization, postmenopausal onset or severe biochemical disturbances should prompt investigations for underlying neoplastic pathology, including dynamic testing and imaging where appropriate. This review will outline a proposed diagnostic approach to androgen excess in women, including an introduction to androgen metabolism and provision of a suggested algorithmic strategy to identify non-PCOS pathology according to clinical and biochemical phenotype.

Ultrahigh-Resolution Mass Spectrometry-Based Platform for Plasma Metabolomics Applied to Type 2 Diabetes Research.

Metabolomics-the endpoint of the omics cascade-is increasingly recognized as a preferred method for understanding the ultimate responses of biological systems to stress. Flow injection electrospray (FIE) mass spectrometry (MS) has advantages for untargeted metabolic fingerprinting due to its simplicity and capability for high-throughput screening but requires a high-resolution mass spectrometer to resolve metabolite features. In this study, we developed and validated a high-throughput and highly reproducible metabolomics platform integrating FIE with ultrahigh-resolution Fourier transform ion cyclotron resonance (FTICR) MS for analysis of both polar and nonpolar metabolite features from plasma samples. FIE-FTICR MS enables high-throughput detection of hundreds of metabolite features in a single mass spectrum without a front-end separation step. Using plasma samples from genetically identical obese mice with or without type 2 diabetes (T2D), we validated the intra and intersample reproducibility of our method and its robustness for simultaneously detecting alterations in both polar and nonpolar metabolite features. Only 5 min is needed to acquire an ultra-high resolution mass spectrum in either a positive or negative ionization mode. Approximately 1000 metabolic features were reproducibly detected and annotated in each mouse plasma group. For significantly altered and highly abundant metabolite features, targeted tandem MS (MS/MS) analyses can be applied to confirm their identity. With this integrated platform, we successfully detected over 300 statistically significant metabolic features in T2D mouse plasma as compared to controls and identified new T2D biomarker candidates. This FIE-FTICR MS-based method is of high throughput and highly reproducible with great promise for metabolomics studies toward a better understanding and diagnosis of human diseases.

The effects of acute hyponatraemia on bone turnover in patients with subarachnoid haemorrhage: A preliminary report.

CONTEXT: Animal data and cross-sectional human studies have established that chronic hyponatraemia predisposes to osteoporosis; the effects of acute hyponatraemia on bone turnover have not been determined. Our objective was to test the hypothesis that acute hyponatraemia leads to dynamic effects on bone turnover. DESIGN: A prospective observational pilot study. METHODS: Bone turnover markers [C-terminal crosslinking telopeptide of type 1 collagen (CTX-1), N-propeptide of type 1 collagen (P1NP) and osteocalcin] were measured prospectively over one week in 22 eunatraemic patients with subarachnoid haemorrhage. Patients treated with glucocorticoids were excluded. RESULTS: Eight patients developed acute hyponatraemia, median nadir plasma sodium concentration 131 mmol/L (IQR 128-132), and 14 remained eunatraemic, nadir plasma sodium concentration 136 mmol/L (IQR 133-137). Significant main effects of hyponatraemia were found for P1NP (p = .02) and P1NP:CTX-1 ratio (p = .02), both fell in patients with acute hyponatraemia, with significant interaction between hyponatraemia and time from baseline for P1NP (p = .02). Significant main effects of time from baseline (p < .001) but not hyponatraemia (p = .07) were found for osteocalcin. For CTX-1, significant main effects of time from baseline (p = .001) but not hyponatraemia (p = .65) were found. There was a positive correlation between change in P1NP:CTX-1 ratio and nadir plasma sodium concentration, r = +.43, p = .04. Median serum cortisol (measured on days 1, 3 and 7) was higher in the hyponatraemia group than in those who remained eunatraemic, 545 nmol/L (IQR 373-778) versus 444 nmol/L (IQR 379-542) p = .03. CONCLUSION: These data suggest that acute mild hyponatraemia is associated with a reduction in bone formation activity.

Structural analysis of petroporphyrins from asphaltene by trapped ion mobility coupled with Fourier transform ion cyclotron resonance mass spectrometry.

Molecular characterization of compounds present in highly complex mixtures such as petroleum is proving to be one of the main analytical challenges. Heavy fractions, such as asphaltenes, exhibit immense molecular and isomeric complexity. Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) with its unequalled resolving power, mass accuracy and dynamic range can address the isobaric complexity. Nevertheless, isomers remain largely inaccessible. Therefore, another dimension of separation is required. Recently, ion mobility mass spectrometry has revealed great potential for isomer description. In this study, the combination of trapped ion mobility and Fourier transform ion cyclotron resonance mass spectrometry (TIMS-FTICR) is used to obtain information on the structural features and isomeric diversity of vanadium petroporphyrins present in heavy petroleum fractions. The ion mobility spectra provided information on the isomeric diversity of the different classes of porphyrins. The determination of the collision cross section (CCS) from the peak apex allows us to hypothesize about the structural aspects of the petroleum molecules. In addition, the ion mobility signal full width at half maximum (FWHM) was used as a measure for isomeric diversity. Finally, theoretical CCS determinations were conducted first on core structures and then on alkylated petroporphyrins taking advantage of the linear correlation between the CCS and the alkylation level. This allowed the proposal of putative structures in agreement with the experimental results. The authors believe that the presented workflow will be useful for the structural prediction of real unknowns in highly complex mixtures.

Thin Water Films Enable Low-Temperature Magnesite Growth Under Conditions Relevant to Geologic Carbon Sequestration.

Injecting supercritical CO2 (scCO2) into basalt formations for long-term storage is a promising strategy for mitigating CO2 emissions. Mineral carbonation can result in permanent entrapment of CO2; however, carbonation kinetics in thin H2O films in humidified scCO2 is not well understood. We investigated forsterite (Mg2SiO4) carbonation to magnesite (MgCO3) via amorphous magnesium carbonate (AMC; MgCO3·xH2O, 0.5 < x < 1), with the goal to establish the fundamental controls on magnesite growth rates at low H2O activity and temperature. Experiments were conducted at 25, 40, and 50 °C in 90 bar CO2 with a H2O film thickness on forsterite that averaged 1.78 ± 0.05 monolayers. In situ infrared spectroscopy was used to monitor forsterite dissolution and the growth of AMC, magnesite, and amorphous SiO2 as a function of time. Geochemical kinetic modeling showed that magnesite was supersaturated by 2 to 3 orders of magnitude and grew according to a zero-order rate law. The results indicate that the main drivers for magnesite growth are sustained high supersaturation coupled with low H2O activity, a combination of thermodynamic conditions not attainable in bulk aqueous solution. This improved understanding of reaction kinetics can inform subsurface reactive transport models for better predictions of CO2 fate and transport.

Synergistic Coupling of CO2 and H2O during Expansion of Clays in Supercritical CO2-CH4 Fluid Mixtures.

We used IR and XRD, with supporting theoretical calculations, to investigate the swelling behavior of Na+-, NH4+-, and Cs+-montmorillonites (SWy-2) in supercritical fluid mixtures of H2O, CO2, and CH4. Building on our prior work with Na-clay that demonstrated that H2O facilitated CO2 intercalation at relatively low RH, here we show that increasing CO2/CH4 ratios promote H2O intercalation and swelling of the Na-clay at progressively lower RH. In contrast to the Na-clay, CO2 intercalated and expanded the Cs-clay even in the absence of H2O, while increasing fluid CO2/CH4 ratios inhibited H2O intercalation. The NH4-clay displayed intermediate behavior. By comparing changes in the HOH bending vibration of H2O intercalated in the Cs-, NH4-, and Na-clays, we posit that CO2 facilitated expansion of the Na-clay by participating in outer-sphere solvation of Na+ and by disrupting the H-bond network of intercalated H2O. In no case did the pure CH4 fluid induce expansion. Our experimental data can benchmark modeling studies aimed at predicting clay expansion in humidified fluids with varying ratios of CO2 and CH4 in real reservoir systems with implications for enhanced hydrocarbon recovery and CO2 storage in subsurface environments.

Outcomes of endoscopic transsphenoidal surgery for Cushing's disease.

BACKGROUND: Transsphenoidal surgery (TSS) to resect an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is the first-line treatment for Cushing's disease (CD), with increasing usage of endoscopic transsphenoidal (ETSS) technique. The aim of this study was to assess remission rates and postoperative complications following ETSS for CD. METHODS: A retrospective analysis of a prospective single-surgeon database of consecutive patients with CD who underwent ETSS between January 2012-February 2020. Post-operative remission was defined, according to Endocrine Society Guidelines, as a morning serum cortisol < 138 nmol/L within 7 days of surgery, with improvement in clinical features of hypercortisolism. A strict cut-off of < 50 nmol/L at day 3 post-op was also applied, to allow early identification of remission. RESULTS: A single surgeon (MJ) performed 43 ETSS in 39 patients. Pre-operative MRI localised an adenoma in 22 (56%) patients; 18 microadenoma and 4 macroadenoma (2 with cavernous sinus invasion). IPSS was carried out in 33 (85%) patients. The remission rates for initial surgery were 87% using standard criteria, 58% using the strict criteria (day 3 cortisol < 50 nmol/L). Three patients had an early repeat ETSS for persistent disease (day 3 cortisol 306-555 nmol/L). When the outcome of repeat early ETSS was included, the remission rate was 92% (36/39) overall. Remission rate was 94% (33/35) when patients with macroadenomas were excluded. There were no cases of CSF leakage, meningitis, vascular injury or visual deterioration. Transient and permanent diabetes insipidus occurred in 33 and 23% following first ETSS, respectively. There was one case of recurrence of CD during the follow-up period of 24 (4-79) months. CONCLUSION: Endoscopic transsphenoidal surgery produces satisfactory remission rates for the primary treatment of CD, with higher remission rates for microadenomas. A longer follow-up period is required to assess recurrence rates. Patients should be counselled regarding risk of postoperative diabetes insipidus.

Critical Water Coverage during Forsterite Carbonation in Thin Water Films: Activating Dissolution and Mass Transport.

In geologic carbon sequestration, CO2 is injected into geologic reservoirs as a supercritical fluid (scCO2). The carbonation of divalent silicates exposed to humidified scCO2 occurs in angstroms to nanometers thick adsorbed H2O films. A threshold H2O film thickness is required for carbonate precipitation, but a mechanistic understanding is lacking. In this study, we investigated carbonation of forsterite (Mg2SiO4) in humidified scCO2 (50 °C and 90 bar), which serves as a model system for understanding subsurface divalent silicate carbonation reactivity. Attenuated total reflection infrared spectroscopy pinpointed that magnesium carbonate precipitation begins at 1.5 monolayers of adsorbed H2O. At about this same H2O coverage, transmission infrared spectroscopy showed that forsterite dissolution begins and electrical impedance spectroscopy demonstrated that diffusive transport accelerates. Molecular dynamics simulations indicated that the onset of diffusion is due to an abrupt decrease in the free-energy barriers for lateral mobility of outer-spherically adsorbed Mg2+. The dissolution and mass transport controls on divalent silicate reactivity in wet scCO2 could be advantageous for maximizing permeability near the wellbore and minimize leakage through the caprock.

The contribution of serum cortisone and glucocorticoid metabolites to detrimental bone health in patients receiving hydrocortisone therapy.

BACKGROUND: Glucocorticoid therapy is the most common cause of iatrogenic osteoporosis. Less is known regarding the effect of glucocorticoids when used as replacement therapy on bone remodelling in patients with adrenal insufficiency. Enhanced intracellular conversion of inactive cortisone to active cortisol, by 11 beta-hydroxysteroid dehydrogenase type 1(11ß-HSD1) and other enzymes leading to alterations in glucocorticoid metabolism, may contribute to a deleterious effect on bone health in this patient group. METHODS: Study design: An open crossover prospective study randomizing ten hypopituitary men, with severe ACTH deficiency, to three commonly used hydrocortisone dose regimens. MEASUREMENTS: Following 6 weeks of each regimen, patients underwent 24-h serum cortisol/cortisone sampling, measurement of bone turnover markers, and a 24-h urine collection for measurement of urinary steroid metabolites by gas chromatography-mass spectrometry (GC-MS). Serum cortisone and cortisol were analysed by liquid chromatography-mass spectrometry (LC-MS). RESULTS: Dose-related and circadian variations in serum cortisone were seen to parallel those for cortisol, indicating conversion of ingested hydrocortisone to cortisone. The median area under the curve (AUC) of serum cortisone was significantly higher in patients on dose A (20 mg/10 mg) [670.5 (IQR 621-809.2)] compared to those on dose C (10 mg/5 mg) [562.8 (IQR 520.1-619.6), p = 0.01]. A negative correlation was observed between serum cortisone and bone formation markers, OC [1-49] (r = - 0.42, p = 0.03), and PINP (r = - 0.49, p = 0.01). There was a negative correlation between the AUC of night-time serum cortisone levels with the bone formation marker, OC [1-49] (r = - 0.41, p = 0.03) but there were no significant correlations between day-time serum cortisone or cortisol with bone turnover markers. There was a negative correlation between total urinary cortisol metabolites and the bone formation markers, PINP (r = - 0.39, p = 0.04), and OC [1-49] (r = - 0.35, p = 0.06). CONCLUSION: Serum cortisol and cortisone and total urinary corticosteroid metabolites are negatively associated with bone turnover markers in patients receiving replacement doses of hydrocortisone, with nocturnal glucocorticoid exposure having a potentially greater influence on bone turnover. TRIAL REGISTRATION: Irish Medicines Board Clinical Trial Number - CT900/459/1 and EudraCT Number - 2007-005018-37 . Registration date: 07-09-2007.

Diagnosis and management of central diabetes insipidus in adults.

Central diabetes insipidus (CDI) is characterized by hypotonic polyuria due to impairment of AVP secretion from the posterior pituitary. In clinical practice, it needs to be distinguished from renal resistance to the antidiuretic effects of AVP (nephrogenic DI), and abnormalities of thirst appreciation (primary polydipsia). As nephrogenic diabetes insipidus is rare in adults, unless they are treated with lithium salts, the practical challenge is how to differentiate between CDI and clinical disorders of excess thirst. The differential diagnosis is usually straight forward, but the recommended gold standard test, the water deprivation test, is not without interpretative pitfalls. The addition of the measurement of plasma AVP concentrations improves diagnostic accuracy, but the radioimmunoassay for AVP is technically difficult, and is only available in a few specialized centres. More recently, the measurement of plasma copeptin concentrations has been claimed to provide a reliable alternative to measurement of plasma AVP, without the sampling handling challenges. In addition, the measurement of thirst ratings can help the differentiation between CDI and primary polydipsia. Once the diagnosis of CDI is biochemically certain, investigations to determine the cause of AVP deficiency are needed. In this review, we will outline the diagnostic approach to polyuria, revisit the caveats of the water deprivation test and review recent data on value of adding AVP/copeptin measurement. We will also discuss treatment strategies for CDI, with analysis of potential complications of treatment.

Management of hypothalamic disease in patients with craniopharyngioma.

Patients with craniopharyngioma experience excess morbidity and mortality when compared with the background population and with other hypopituitary patients. Large, suprasellar tumours which form micropapillae into surrounding structures can cause hypothalamic damage before any therapeutic intervention; attempted gross total resection can lead to hypothalamic obesity, sleep disorders, thirst disorders and dysregulation of temperature as well as panhypopituitarism. The management of tumour bulk and the pathophysiology of hypothalamic complications have been reviewed extensively. We present a practical, clinical approach to management of hypothalamic disease in a patient with craniopharyngioma and highlight potential targets for future pharmacological or surgical intervention.

Hyponatraemia in patients with community-acquired pneumonia; prevalence and aetiology, and natural history of SIAD.

OBJECTIVE: Hyponatraemia is common in community-acquired pneumonia (CAP) and is associated with increased mortality. The mechanism of hyponatraemia in CAP is not completely understood and treatment is therefore ill-defined. We aimed to define the causation of hyponatraemia in CAP. DESIGN: Prospective, single-centre, observational study of all patients with CAP and hyponatraemia (≤ 130 mmol/L) during a 9-month period. PATIENTS: The prevalence of each subtype of hyponatraemia, and the associated mortality, was determined in 143 admissions with CAP (Study 1). A sub-cohort of patients with SIAD (n = 10) was prospectively followed, to document the natural history of SIAD associated with CAP (Study 2). MEASUREMENTS: In Study 2, blood and urine were collected on day 1, 3, 5 and 7 following admission for measurement of plasma vasopressin, sodium, osmolality and urine osmolality. RESULTS: In study 1, 143/1723(8.3%) of CAP patients had hyponatraemia (≤130 mmol/L). About 66 had SIAD (46%), 60(42%) had hypovolaemic hyponatraemia (HON), 13(9%) had hypervolaemic hyponatraemia (HEN) and 4(3%) patients had hyponatraemia due to glucocorticoid hormone deficiency. Mortality was higher in the HEN than in the HON, SIAD or normonatraemic groups (P < 0.01). In Study 2, plasma sodium concentration normalized in 8/10 (80%) by day 7. Two patients with persistent hyponatraemia were discovered to have underlying bronchiectasis. CONCLUSIONS: Hyponatraemia in CAP is most commonly secondary to SIAD or hypovolaemia. HEN is less common, but has worse prognosis. Prospective observation demonstrates that in SIAD, plasma AVP and sodium concentrations normalize with antimicrobials; failure of reversal of suggests underlying lung disease, such as bronchiectasis.

Posterior pituitary dysfunction following traumatic brain injury: review.

Neurohypophysial dysfunction is common in the first days following traumatic brain injury (TBI), manifesting as dysnatremia in approximately 1 in 4 patients. Both hyponatremia and hypernatremia can impair recovery from TBI and in the case of hypernatremia, there is a significant association with excess mortality. Hyponatremia secondary to syndrome of inappropriate antidiuretic hormone secretion (SIAD) is the commonest electrolyte disturbance following TBI. Acute adrenocorticotropic hormone (ACTH)/cortisol deficiency occurs in 10-15% of TBI patients and can present with a biochemical picture identical to SIAD. For this reason, exclusion of glucocorticoid deficiency is of particular importance in post-TBI SIAD. Cerebral salt wasting is a rare cause of hyponatremia following TBI. Hyponatremia predisposes to seizures, reduced consciousness, and prolonged hospital stay. Diabetes insipidus (DI) occurs in 20% of cases following TBI; where diminished consciousness is present, appropriate fluid replacement of renal water losses is occasionally inadequate, leading to hypernatremia. Hypernatremia is strongly predictive of mortality following TBI. Most cases of DI are transient, but persistent DI is also predictive of mortality, irrespective of plasma sodium concentration. Persistent DI may herald rising intracranial pressure due to coning. True adipsic DI is rare following TBI, but patients are vulnerable to severe hypernatremic dehydration, exacerbation of neurologic deficits and hypothalamic complications, therefore clinicians should be aware of this possible variant of DI.

Clinical features and autoimmune associations in patients presenting with Idiopathic Isolated ACTH deficiency.

OBJECTIVE: Idiopathic Isolated ATCH deficiency (IIAD) is a rare cause of secondary adrenal insufficiency. As the condition is rare, and the diagnostic criteria ill-defined, there are few good clinical descriptions in the literature. We have described presenting features, autoimmune associations, natural history and responses to CRF, in a large case series of patients presenting with IIAD. DESIGN: This is a retrospective case note analysis with data derived from the recently commenced National Pituitary Database of Ireland. PATIENTS: Twenty-three patients with isolated ACTH deficiency were identified. A thorough chart and biochemistry review was performed. RESULTS: Twenty-three patients were examined (18 women and 5 men). Age at presentation ranged from 17 to 88 years, (median 48 years). Most patients complained of fatigue; 9 patients presented with hyponatraemia, 13 had autoimmune illnesses (primary hypothyroidism, n = 9). CRF stimulation testing was available in 12 of the 23 patients, 5 of whom demonstrated a rise in plasma ACTH concentrations, indicating hypothalamic, rather than pituitary aetiology. Two patients recovered ACTH secretion, and 2 patients progressed to have other pituitary hormone deficiencies. CONCLUSIONS: IIAD typically presents with insidious symptoms. Euvolaemic hyponatraemia is common at diagnosis. It is associated with autoimmune diseases, particularly primary hypothyroidism. As two patients recovered ACTH secretion, and two progressed to other pituitary hormone deficits, repeat pituitary testing should be considered, to identify recovery of function, or progression to other hormone deficits.

ALTERATIONS IN THYROID HORMONE LEVELS FOLLOWING GROWTH HORMONE REPLACEMENT EXERT COMPLEX BIOLOGICAL EFFECTS.

OBJECTIVE: Alterations in the thyroid axis are frequently observed following growth hormone (GH) replacement, but uncertainty exists regarding their clinical significance. We aimed to compare fluctuations in circulating thyroid hormone levels, induced by GH, to changes in sensitive biological markers of thyroid hormone action. METHODS: This was a prospective observational clinical study. Twenty hypopituitary men were studied before and after GH replacement. Serum thyroid-stimulating hormone (TSH), thyroid hormones, and insulin-like growth factor 1 were measured. Changes in thyroid hormone concentrations were compared to alterations in resting metabolic rate and cardiac time intervals. Health-related quality of life (QOL) was assessed by disease-sensitive and generic questionnaires. RESULTS: Following GH replacement, free thyroxine concentration declined and free triiodothyronine level increased. Resting energy expenditure increased, particularly in subjects with profound hypopituitarism, including TSH deficiency (16.73 ± 1.75 kcal/kg/min vs. 17.96 ± 2.26 kcal/kg/min; P = .01). Alterations in the thyroid axis were more pronounced in subjects with a low/normal baseline respiratory quotient (RQ) who experienced a paradoxical rise in RQ (0.81 vs. 0.86; P = .01). Subjects with a high baseline RQ experienced a slight but nonsignificant fall in RQ without alteration in thyroid axis. The isovolumetric contraction time was shortened during the study; however, this did not reach statistical significance. Improvements in QOL were observed despite alterations in thyroid axis. CONCLUSION: Changes in the thyroid axis following GH replacement are associated with complex tissue-specific effects. These fluctuations may induce a hypothyroid phenotype in some tissues while appearing to improve the biological action of thyroid hormone in other organs. ABBREVIATIONS: AGHDA = Assessment of Growth Hormone Deficiency in Adulthood; CHOox = carbohydrate oxidation; ET = ejection time; fT3 = free triiodothyronine; fT4 = free thyroxine; GH = growth hormone; GHD = growth hormone deficiency; HB-RQ = high baseline respiratory quotient; HPT = hypothalamic-pituitary-thyroid; ICT = isovolumetric contraction time; IGF-1 = insulin-like growth factor 1; IRT = isovolumetric relaxation time; LB-RQ = low baseline respiratory quotient; LV = left ventricular; NHP = Nottingham Health Profile; QOL = quality of life; REE = resting energy expenditure; RQ = respiratory quotient; rT3 = reverse triiodothyronine; SF-36 = Short Form 36; TSH = thyroid-stimulating hormone; T3 = triiodothyronine; T4 = thyroxine; TT3 = total triiodothyronine; TT4 = total thyroxine.

DIFFERENTIAL REGULATION OF 11ß-HYDROXYSTEROID DEHYDROGENASE TYPE 1 ACTIVITY IN PATIENTS WITH DIFFERING ETIOLOGIES OF HYPOPITUITARISM.

OBJECTIVE: Pituitary patients with different etiologies of hypopituitarism exhibit differing phenotypes, despite similar replacement therapy strategies. We hypothesized that differential regulation of the isoenzyme 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1), which mediates the net autocrine conversion of cortisone to cortisol in adipose tissues and liver, may play a role. METHODS: We studied 11ß-HSD1 activity (using urine cortisol/cortisone metabolites ratio) in 36 hypopituitary patients with treated craniopharyngiomas, treated remitted Cushing disease, and treated nonfunctioning pituitary adenomas + prolactinomas on and off growth hormone (GH) replacement. RESULTS: 11ß-HSD1 activity was higher in subjects with craniopharyngioma both on and off GH, as evidenced by increased tetrahydrocortisol to tetrahydrocortisone metabolite ratios compared to other diagnostic groups, but there was no difference in body mass index, insulin levels, serum hormone measurements, or hydrocortisone dose between groups. CONCLUSION: Craniopharyngiomas are associated with enhanced 11ß-HSD1 activity compared to other diagnostic hypopituitary groups, and this may contribute to the adverse phenotypic and metabolic features seen in this condition. ABBREVIATIONS: BMI = body mass index; Em = cortisone metabolites; Fm = cortisol metabolites; GH = growth hormone; 11ß-HSD1 = 11ß-hydroxysteroid dehydrogenase type 1; IGF-1 = insulin-like growth factor 1; NFPA = nonfunctioning pituitary adenoma; THE = tetrahydrocortisone; THF = tetrahydrocortisol.

Mortality rates are lower in SIAD, than in hypervolaemic or hypovolaemic hyponatraemia: Results of a prospective observational study.

OBJECTIVE: Hyponatraemia is associated with increased mortality, but the mortality associated specifically with SIAD is not known. We hypothesized that mortality in SIAD was elevated, but that it was less than in hypervolaemic (HEN) or hypovolaemic (HON) hyponatraemia. DESIGN: Mortality rates are presented as risk ratios (RR),with 95% confidence intervals (CI), and compared to normonatraemic controls (NN). METHODS: Prospective, single centre, noninterventional study of all patients with hyponatraemia (≤130 mmol/L) admitted to hospital. RESULTS: A total of 1323 admissions with hyponatraemia were prospectively evaluated and 1136 contemporaneous NN controls. 431(32.6%) hyponatraemic patients had HON, 573(43.3%) had SIAD and 275(20.8%) patients had HEN. In patient mortality was higher in hyponatraemia than NN (9.1% vs 3.3%, P<.0001). The RRs for in-hospital mortality compared to NN were: SIAD, 1.76 (95% CI 1.08-2.8, P=.02), HON 2.77 (95% CI 1.8-4.3, P<.0001) and HEN, 4.9 (95% CI 3.2-7.4, P<.0001). The mortality rate was higher in HEN (RR 2.85; 95% CI 1.86-4.37, P<.0001) and in HON, (RR 1.6; 95% CI 1.04-2.52; P=.03), when compared to SIAD. The Charlson Comorbidity Index was lower in SIAD than in eunatraemic patients (P<.0001). 9/121(7.4%) patients died with plasma sodium <125 mmol/L and 4(3.3%) with plasma sodium <120 mmol/L. However, 69/121(57%) patients died with a plasma sodium above 133 mmol/L. CONCLUSIONS: We confirmed higher all-cause mortality in hyponatraemia than in NN. Mortality was higher in SIAD than in normonatraemia and was not explained on the basis of co-morbidities. Mortality was higher in HON and HEN than in SIAD. Mortality rates reported for all-cause hyponatraemia in the medical literature are not applicable to SIAD.

The effect of growth hormone replacement on the thyroid axis in patients with hypopituitarism: in vivo and ex vivo studies.

OBJECTIVE: Alterations in the hypothalamic-pituitary-thyroid axis have been reported following growth hormone (GH) replacement. The aim was to examine the relationship between changes in serum concentration of thyroid hormones and deiodinase activity in subcutaneous adipose tissue, before and after GH replacement. DESIGN: A prospective, observational study of patients receiving GH replacement as part of routine clinical care. PATIENTS: Twenty adult hypopituitary men. MEASUREMENTS: Serum TSH, thyroid hormones - free and total thyroxine (T4) and triiodothyronine (T3) and reverse T3, thyroglobulin and thyroid-binding globulin (TBG) levels were measured before and after GH substitution. Changes in serum hormone levels were compared to the activity of deiodinase isoenzymes (DIO1, DIO2 and DIO3) in subcutaneous adipose tissue. RESULTS: The mean daily dose of growth hormone (GH) was 0·34 ± 0·11 mg (range 0·15-0·5 mg). Following GH replacement, mean free T4 levels declined (-1·09 ± 1·99 pmol/l, P = 0·02). Reverse T3 levels also fell (-3·44 ± 1·42 ng/dl, P = 0·03) and free T3 levels increased significantly (+0·34 ± 0·15 pmol/l, P = 0·03). In subcutaneous fat, DIO2 enzyme activity declined; DIO1 and DIO3 activities remained unchanged following GH substitution. Serum TSH, thyroglobulin and TBG levels were unaltered by GH therapy. CONCLUSIONS: In vitro analysis of subcutaneous adipose tissue from hypopituitary human subjects demonstrates that GH replacement is associated with significant changes in deiodinase isoenzyme activity. However, the observed variation in enzyme activity does not explain the changes in the circulating concentration of thyroid hormones induced by GH replacement. It is possible that deiodinase isoenzymes are differentially regulated by GH in other tissues including liver and muscle.

Analysis of Photoirradiated Water Accommodated Fractions of Crude Oils Using Tandem TIMS and FT-ICR MS.

For the first time, trapped ion mobility spectrometry (TIMS) in tandem with Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) is applied to the analysis of the low energy water accommodated fraction (WAF) of a crude oil as a function of the exposure to light. The TIMS-FT-ICR MS analysis provided, in addition to the heteroatom series identification, new insights into the WAF isomeric complexity (e.g., [m/z; chemical formula; collision cross section] data sets) for a better evaluation of the degree of chemical and structural photoinduced transformations. Inspection of the [m/z; chemical formula; collision cross section] data sets shows that the WAF composition changes as a function of the exposure to light in the first 115 h by initial photosolubilization of HC components and their photo-oxidation up to O4-5 of mainly high double bond equivalence species (DBE > 9). The addition of high resolution TIMS (resolving power of 90-220) to ultrahigh resolution FT-ICR MS (resolving power over 400k) permitted the identification of a larger number of molecular components in a single analysis (e.g., over 47k using TIMS-MS compared to 12k by MS alone), with instances of over 6-fold increase in the number of molecular features per nominal mass due to the WAF isomeric complexity. This work represents a stepping stone toward a better understanding of the WAF components and highlights the need for better experimental and theoretical approaches to characterize the WAF structural diversity.

Adipsic diabetes insipidus in adult patients.

INTRODUCTION: Adipsic diabetes insipidus (ADI) is a very rare disorder, characterized by hypotonic polyuria due to arginine vasopressin (AVP) deficiency and failure to generate the sensation of thirst in response to hypernatraemia. As the sensation of thirst is the key homeostatic mechanism that prevents hypernatraemic dehydration in patients with untreated diabetes insipidus (DI), adipsia leads to failure to respond to aquaresis with appropriate fluid intake. This predisposes to the development of significant hypernatraemia, which is the typical biochemical manifestation of adipsic DI. METHODS: A literature search was performed to review the background, etiology, management and associated complications of this rare condition. RESULTS: ADI has been reported to occur in association with clipping of an anterior communicating artery aneurysm following subarachnoid haemorrhage, major hypothalamic surgery, traumatic brain injury and toluene exposure among other conditions. Management is very difficult and patients are prone to marked changes in plasma sodium concentration, in particular to the development of severe hypernatraemia. Associated hypothalamic disorders, such as severe obesity, sleep apnoea and thermoregulatory disorders are often observed in patients with ADI. CONCLUSION: The management of ADI is challenging and is associated with significant morbidity and mortality. Prognosis is variable; hypothalamic complications lead to early death in some patients, but recent reports highlight the possibility of recovery of thirst.