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Open access

I Azzam, S Gilad, R Limor, N Stern and Y Greenman

Reichenbach A Geenen B Kozicz T Andrews ZB. Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress . Biological Psychiatry 2012 72 457 – 465 . ( doi:10.1016/j.biopsych.2012.03.010 ) 22521145 10

Open access

Carolina Inda, Natalia G Armando, Paula A dos Santos Claro and Susana Silberstein

are essential to the stress response driving both basal and stress-induced hypothalamic–pituitary–adrenal axis (HPA) activation. Besides the hypothalamus, CRH is widely distributed in extrahypothalamic circuits of the brain where it functions as a

Open access

Trevor Lewis, Eva Zeisig and Jamie E Gaida

Background

While metabolic health is acknowledged to affect connective tissue structure and function, the mechanisms are unclear. Glucocorticoids are present in almost every cell type throughout the body and control key physiological processes such as energy homeostasis, stress response, inflammatory and immune processes, and cardiovascular function. Glucocorticoid excess manifests as visceral adiposity, dyslipidemia, insulin resistance, and type 2 diabetes. As these metabolic states are also associated with tendinopathy and tendon rupture, it may be that glucocorticoids excess is the link between metabolic health and tendinopathy.

Objective

To synthesise current knowledge linking glucocorticoid exposure to tendon structure and function.

Methods

Narrative literature review.

Results

We provide an overview of endogenous glucocorticoid production, regulation, and signalling. Next we review the impact that oral glucocorticoid has on risk of tendon rupture and the effect that injected glucocorticoid has on resolution of symptoms. Then we highlight the clinical and mechanistic overlap between tendinopathy and glucocorticoid excess in the areas of visceral adiposity, dyslipidemia, insulin resistance and type 2 diabetes. In these areas, we highlight the role of glucocorticoids and how these hormones might underpin the connection between metabolic health and tendon dysfunction.

Conclusions

There are several plausible pathways through which glucocorticoids might mediate the connection between metabolic health and tendinopathy.

Open access

Tatiana V Novoselova, Peter J King, Leonardo Guasti, Louise A Metherell, Adrian J L Clark and Li F Chan

The melanocortin-2-receptor (MC2R), also known as the ACTH receptor, is a critical component of the hypothalamic–pituitary–adrenal axis. The importance of MC2R in adrenal physiology is exemplified by the condition familial glucocorticoid deficiency (FGD), a potentially fatal disease characterised by isolated cortisol deficiency. MC2R mutations cause ~25% of cases. The discovery of a MC2R accessory protein MRAP, mutations of which account for ~20% of FGD, has provided insight into MC2R trafficking and signalling. MRAP is a single transmembrane domain accessory protein highly expressed in the adrenal gland and essential for MC2R expression and function. Mouse models helped elucidate the action of ACTH. The Mc2r-knockout (Mc2r / ) mice was the first mouse model developed to have adrenal insufficiency with deficiencies in glucocorticoid, mineralocorticoid and catecholamines. We recently reported the generation of the Mrap / mice which better mimics the human FGD phenotype with isolated glucocorticoid deficiency alone. The adrenal glands of adult Mrap / mice were grossly dysmorphic with a thickened capsule, deranged zonation and deranged WNT4/beta-catenin and sonic hedgehog (SHH) pathway signalling. Collectively, these mouse models of FGD highlight the importance of ACTH and MRAP in adrenal progenitor cell regulation, cortex maintenance and zonation.

Open access

Paal Methlie, Steinar Hustad, Ralf Kellman, Bjørg Almås, Martina M Erichsen, Eystein S Husebye and Kristian Løvås

Objective

Liquid chromatography–tandem mass spectrometry (LC–MS/MS) offers superior analytical specificity compared with immunoassays, but it is not available in many regions and hospitals due to expensive instrumentation and tedious sample preparation. Thus, we developed an automated, high-throughput LC–MS/MS assay for simultaneous quantification of ten endogenous and synthetic steroids targeting diseases of the hypothalamic–pituitary–adrenal axis and gonads.

Methods

Deuterated internal standards were added to 85 μl serum and processed by liquid–liquid extraction. Cortisol, cortisone, prednisolone, prednisone, 11-deoxycortisol, dexamethasone, testosterone, androstenedione and progesterone were resolved by ultra-high-pressure chromatography on a reversed-phase column in 6.1 min and detected by triple-quadrupole mass spectrometry. The method was used to assess steroid profiles in women with Addison's disease (AD, n=156) and blood donors (BDs, n=102).

Results

Precisions ranged from 4.5 to 10.1% relative standard deviations (RSD), accuracies from 95 to 108% and extraction recoveries from 60 to 84%. The method was practically free of matrix effects and robust to individual differences in serum composition. Most postmenopausal AD women had extremely low androstenedione concentrations, below 0.14 nmol/l, and median testosterone concentrations of 0.15 nmol/l (interquartile range 0.00–0.41), considerably lower than those of postmenopausal BDs (1.28 nmol/l (0.96–1.64) and 0.65 nmol/l (0.56–1.10) respectively). AD women in fertile years had androstenedione concentrations of 1.18 nmol/l (0.71–1.76) and testosterone concentrations of 0.44 nmol/l (0.22–0.63), approximately half of those found in BDs of corresponding age.

Conclusion

This LC–MS/MS assay provides highly sensitive and specific assessments of glucocorticoids and androgens with low sample volumes and is suitable for endocrine laboratories and research. Its utility has been demonstrated in a large cohort of women with AD, and the data suggest that women with AD are particularly androgen deficient after menopause.

Open access

Britt J van Keulen, Conor V Dolan, Bibian van der Voorn, Ruth Andrew, Brian R Walker, Hilleke Hulshoff Poll, Dorret I. Boomsma, Joost Rotteveel and Martijn J.j. Finken

Objective: Sex differences in disease susceptibility might be explained by sexual dimorphism in hypothalamic-pituitary-adrenal axis activity, which has been postulated to emerge during puberty. However, studies conducted thus far lacked an assessment of Tanner pubertal stage. This study aimed to assess the contribution of pubertal development to sexual dimorphism in cortisol production and metabolism.

Methods: Participants (n=218), were enrolled from a population-based Netherlands Twin Register. At the ages of 9, 12 and 17 years Tanner pubertal stage was assessed, and early-morning urine samples were collected. Cortisol metabolites were measured with GC-MS/MS, and ratios were calculated, representing cortisol metabolism enzyme activities, such as A-ring reductases, 11β-HSDs and CYP3A4. Cortisol production and metabolism parameters were compared between sexes for pre-pubertal (Tanner stage 1), early-pubertal (Tanner stage 2-3) and late-pubertal (Tanner stage 4-5) stages.

Results: Cortisol metabolite excretion rate decreased with pubertal maturation in both sexes, but did not significantly differ between sexes at any pubertal stage, although in girls a considerable decrease was observed between early- and late-pubertal stage (P<0.001). A-ring reductase activity was similar between sexes at pre- and early-pubertal stages, and was lower in girls than in boys at late-pubertal stage. Activities of 11β-HSDs were similar between sexes at pre-pubertal stage, and favored cortisone in girls at early- and late-pubertal stages. Cytochrome P450 3A4 activity did not differ between sexes.

Conclusions: Prepubertally, sexes were similar in cortisol parameters. During puberty, as compared to boys, in girls the activities of A-ring reductases declined and the balance between 11β-HSDs progressively favored cortisone. Our findings suggest that the sexual dimorphism in cortisol may either be explained by rising concentrations of sex steroids or by puberty-induced changes in body composition.

Open access

Lisa Arnetz, Neda Rajamand Ekberg, Kerstin Brismar and Michael Alvarsson

regulation of adipose tissue distribution in humans . International Journal of Obesity 1996 20 291 – 302 . 5 Roy M Collier B Roy A . Hypothalamic–pituitary–adrenal axis dysregulation among diabetic outpatients . Psychiatry Research 1990 31

Open access

Ferdinand Roelfsema, Diana van Heemst, Ali Iranmanesh, Paul Takahashi, Rebecca Yang and Johannes D Veldhuis

D. Characterization of the hypothalamic-pituitary-adrenal-axis in familial longevity under resting conditions . PLoS ONE 2015 10 e0133119 . ( doi:10.1371/journal.pone.0133119 ) 10.1371/journal.pone.0133119 26193655 4 Roelfsema F Pijl

Open access

Janko Sattler, Jinwen Tu, Shihani Stoner, Jingbao Li, Frank Buttgereit, Markus J Seibel, Hong Zhou and Mark S Cooper

. Circadian relationships between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis . Journal of Clinical Endocrinology and Metabolism

Open access

Eva Novoa, Marcel Gärtner and Christoph Henzen

assess the function of the hypothalamic–pituitary–adrenal axis . Clinical Endocrinology 1996 2 151 – 156 . ( doi:10.1046/j.1365-2265.1996.600482.x ). 13 Giordano R Picu A Bonelli L Balbo M Berardelli R Marinazzo E Corneli G Ghigo E