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Fowkes R.C.,Endocrine Signalling Group | Moradi-Bidhendi N.,Queen Mary, University of London | Branceleone V.,University of Basilicata | Zariwala M.G.,University of Westminster | And 4 more authors.

Salivary cortisol is commonly used as a clinical biomarker of endocrine status and also as a marker of psychosocial stress. Annexin-A1 (AnxA1) is an anti-inflammatory protein whose expression is modulated by glucocorticoids. Our principal objectives were to (i) detect the presence of and (ii) measure AnxA1 protein in whole human saliva and to (iii) investigate whether salivary cortisol and AnxA1 are correlated in healthy humans. A total of 37 healthy participants (male and female) were used in the study. Saliva was collected using salivette tubes. Salivary cortisol and AnxA1 protein were sampled at between 3 and 6 time points over 24. h and measured for cortisol and AnxA1 protein using specific ELISA's. The presence of salivary AnxA1 protein was confirmed by Western blotting.AnxA1 protein is detectable in whole human saliva, as detected by Western blot analysis and ELISA. A diurnal rhythm was evident in both salivary cortisol (. P<. 0.01) and AnxA1 (. P<. 0.01) and was defined as a significant difference in time 0 (waking) samples compared to 'bed' (2300. h) samples. AnxA1 protein did not exhibit an awakening response (. P>. 0.05), whereas salivary cortisol was significantly elevated between time 0 and 30. min post waking (. P<. 0.001).AnxA1 protein correlates positively with salivary cortisol, indicating that cortisol is most likely a regulator of AnxA1 in human saliva. © 2012 Elsevier Ltd. Source

Walker A.P.,University College London | Fowkes R.C.,Endocrine Signalling Group | Saleh F.,University College London | Kim S.-H.,University of London | And 7 more authors.
Sexual Development

There have been few testicular histology reports of adult patients with congenital adrenal hypoplasia/hypogonadal hypogonadism (AHC/HH), but Leydig cell hyperplasia has been observed, an indicator of the possibility of malignant transformation. We aimed to define the basis of AHC/HH in 4 pedigrees of different ethnic backgrounds. One patient was elected to have testicular biopsy which was examined for evidence of carcinoma in situ (CIS). NR0B1 mutation analysis was performed by sequence analysis. NR0B1 expression was investigated by RT-PCR. Testicular biopsy sections were stained with HE or immunostained for OCT3/4, an established marker of CIS. We identified NR0B1 variants in the 4 AHC pedigrees: pedigree 1 (United Arab Emirates), c.1130A>G predicting p.(Glu377Gly); pedigree 2 (English Caucasian), c.327C>A predicting p.(Cys109*); pedigree 3 (Oman), a 6-bp deletion of a direct repeat, c.857-862delTGGTGC predicting p.(Leu286-Val287del); pedigree 4 (English Caucasian), c.1168+1G>A, a regulatory variant within the NR0B1 splice donor site. This last male patient, aged 30 years, presented with evidence of HH but incomplete gonadotrophin deficiency, following an earlier diagnosis of Addison's disease at 3 years. Hormonal therapy induced virilisation. Testicular biopsy was performed. The c.1168+1G>A variant abrogated normal splicing of testicular mRNA. Histological examination showed poorly organised testicular architecture and absence of spermatozoa. Morphological analyses and the absence of immunohistochemical staining for OCT3/4 excluded the presence of malignant germ cell cancer and its precursor lesion, CIS. These studies add to the knowledge of the types and ethnic diversity of NR0B1 mutations and their associated phenotypes, and provide insight into the assessment and interpretation of testicular histology in AHC and HH. © 2012 S. Karger AG, Basel. Source

Cabrera-Sharp V.,Endocrine Signalling Group | Mirczuk S.M.,Endocrine Signalling Group | Shervill E.,Endocrine Signalling Group | Michael A.E.,St Georges, University of London | Fowkes R.C.,Endocrine Signalling Group
Cell and Tissue Research

In target tissues, cortisol is metabolised by two 11β-hydroxysteroid dehydrogenase (11βHSD) isoenzymes, namely 11βHSD1 and 11βHSD2, both of which are co-expressed in the boar testis and reproductive tract. The present study has assessed whether cortisol-cortisone metabolism in boar testis and caput epididymidis can be regulated via the gonadotrophin-cAMP signalling pathway. 11βHSD activities were measured by using a radiometric conversion assay in static tissue culture. In both testis and caput epididymidis, the net reduction of cortisone but not the net oxidation of cortisol, was significantly decreased by luteinising hormone (by 53 ± 20% and 45 ± 9%, respectively, P < 0.05), forskolin (by 60 ± 7% and 57 ± 9%, respectively, P < 0.01) and 8-bromo-cAMP (by 54 ± 4% and 64 ± 1%, respectively, P < 0.01). This suppression of 11-ketosteroid reductase activity in the boar testis by forskolin could be attenuated by the protein kinase A (PKA) inhibitor, H89. Hence, within the boar testis and the caput epididymidis, the local actions of glucocorticoids are modulated by gonadotrophin-cAMP-PKA signalling via their selective effects on the reductase activity of 11βHSD. © 2013 Springer-Verlag Berlin Heidelberg. Source

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