Metabolic effects of aromatase inhibition

Aromatase, a member of the cytochrome P450 superfamily, catalyses the conversion of androgens to estrogens; specifically, testosterone to estradiol and androstenedione to estrone. Aromatase is widely expressed across a range of tissues and deleterious metabolic effects are observed in both murine aromatase knock-out models and in rare human cases of aromatase deficiency. The effects of pharmacological inhibition of aromatase, as employed in the treatment of breast cancer, are not well characterised. This thesis addresses the hypothesis that aromatase inhibition, and consequent changes in sex steroid hormone action (higher androgen:estrogen ratio), results in disadvantageous changes in body composition and reduced insulin sensitivity. In a cohort study of 197 community-dwelling men, lower testosterone and SHBG concentrations were observed in those fulfilling criteria for metabolic syndrome, although no relationship with estrogens was observed. The strongest determinant of circulating estrogens was substrate androgen concentration. A case-control study of aromatase inhibitor treated breast cancer patients and age-matched controls (n=40) demonstrated decreased insulin sensitivity and increased body fat in those treated with aromatase inhibitors; serum leptin concentration and leptin mRNA transcript levels (in subcutaneous adipose tissue) were elevated in this group. In healthy male volunteers (n=17), 6 weeks of aromatase inhibition (1 mg anastrozole daily) resulted in reduced glucose disposal during a hyperinsulinaemic euglycaemic clamp study, with d2-glucose and d5-glycerol tracers. No effects upon hepatic insulin sensitivity, lipolysis or body composition were noted, although serum leptin concentration was reduced following aromatase inhibitor administration. In conclusion, aromatase inhibition is associated with increased insulin resistance and, in women, increased body fat. This may be relevant for patients receiving aromatase inhibitor therapy, where more careful monitoring of glucose tolerance may be warranted

Presentation, diagnostic assessment and surgical outcomes in primary hyperparathyroidism:a single centre's experience

Objective: Primary hyperparathyroidism (PHPT) is a common reason for referral to endocrinology but the evidence base guiding assessment is limited. We evaluated the clinical presentation, assessment and subsequent management in PHPT. Design: Retrospective cohort study. Patients: PHPT assessed between 2006 and 2014 (n = 611) in a university hospital. Measurements: Symptoms, clinical features, biochemistry, neck radiology and surgical outcomes. Results: Fatigue (23.8%), polyuria (15.6%) and polydipsia (14.9%) were associated with PHPT biochemistry. Bone fracture was present in 16.4% but was not associated with biochemistry. A history of nephrolithiasis (10.0%) was associated only with younger age (P = 0.006) and male gender (P = 0.037). Thiazide diuretic discontinuation was not associated with any subsequent change in calcium (P = 0.514). Urine calcium creatinine clearance ratio (CCCR) was <0.01 in 18.2% of patients with confirmed PHPT. Older age (P < 0.001) and lower PTH (P = 0.043) were associated with failure to locate an adenoma on ultrasound (44.0% of scans). When an adenoma was identified on ultrasound the lateralisation was correct in 94.5%. Non-curative surgery occurred in 8.2% and was greater in those requiring more than one neck imaging modality (OR 2.42, P = 0.035). Conclusions: Clinical features associated with PHPT are not strongly related to biochemistry. Thiazide cessation does not appear to attenuate hypercalcaemia. PHPT remains the likeliest diagnosis in the presence of low CCCR. Ultrasound is highly discriminant when an adenoma is identified but surgical failure is more likely when more than one imaging modality is required

Subarcsecond resolution observations of warm water towards three deeply embedded low-mass protostars

Water is present during all stages of star formation: as ice in the cold outer parts of protostellar envelopes and dense inner regions of circumstellar disks, and as gas in the envelopes close to the protostars, in the upper layers of circumstellar disks and in regions of powerful outflows and shocks. In this paper we probe the mechanism regulating the warm gas-phase water abundance in the innermost hundred AU of deeply embedded (Class~0) low-mass protostars, and investigate its chemical relationship to other molecular species during these stages. Millimeter wavelength thermal emission from the para-H2-18O 3(1,3)-2(2,0) (Eu=203.7 K) line is imaged at high angular resolution (0.75"; 190 AU) with the IRAM Plateau de Bure Interferometer towards the deeply embedded low-mass protostars NGC 1333-IRAS2A and NGC 1333-IRAS4A. Compact H2-18O emission is detected towards IRAS2A and one of the components in the IRAS4A binary; in addition CH3OCH3, C2H5CN, and SO2 are detected. Extended water emission is seen towards IRAS2A, possibly associated with the outflow. The detections in all systems suggests that the presence of water on <100 AU scales is a common phenomenon in embedded protostars. We present a scenario in which the origin of the emission from warm water is in a flattened disk-like structure dominated by inward motions rather than rotation. The gas-phase water abundance varies between the sources, but is generally much lower than a canonical abundance of 10^-4, suggesting that most water (>96 %) is frozen out on dust grains at these scales. The derived abundances of CH3OCH3 and SO2 relative to H2-18O are comparable for all sources pointing towards similar chemical processes at work. In contrast, the C2H5CN abundance relative to H2-18O is significantly lower in IRAS2A, which could be due to different chemistry in the sources.Comment: 12 pages, 9 figure

Astrochemistry of Sub-Millimeter Sources in Orion: Studying the Variations of Molecular Tracers with Changing Physical Conditions

Cornerstone molecules (CO, H_2CO, CH_3OH, HCN, HNC, CN, CS, SO) were observed toward seven sub-millimeter bright sources in the Orion molecular cloud in order to quantify the range of conditions for which individual molecular line tracers provide physical and chemical information. Five of the sources observed were protostellar, ranging in energetics from 1 - 500L_sun, while the other two sources were located at a shock front and within a photodissociation region (PDR). Statistical equilibrium calculations were used to deduce from the measured line strengths the physical conditions within each source and the abundance of each molecule. In all cases except the shock and the PDR, the abundance of CO with respect to H_2 appears significantly below (factor of ten) the general molecular cloud value of 10^-4. {Formaldehyde measurements were used to estimate a mean temperature and density for the gas in each source. Evidence was found for trends between the derived abundance of CO, H_2CO, CH_3OH, and CS and the energetics of the source, with hotter sources having higher abundances.} Determining whether this is due to a linear progression of abundance with temperature or sharp jumps at particular temperatures will require more detailed modeling. The observed methanol transitions require high temperatures (T>50 K), and thus energetic sources, within all but one of the observed protostellar sources. The same conclusion is obtained from observations of the CS 7-6 transition. Analysis of the HCN and HNC 4-3 transitions provides further support for high densities n> 10^7 cm^-3 in all the protostellar sources.Comment: 36 pages, 8 figures, Astronomy and Astrophysics in pres

European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders.

This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders (PARAT) in 2019, were discussed during two virtual workshops in 2021, and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosing to familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represent areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT, need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborns children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed for a broader clinical audience, and were developed with focus on endocrinologists in training