Treatment with Synthetic Glucocorticoids and the Hypothalamus-Pituitary-Adrenal Axis

Paragliola, Rosa Maria; Papi, Giampaolo; Pontecorvi, Alfredo; Corsello, Salvatore Maria

doi:10.3390/ijms18102201

Cited by 130 publications

(111 citation statements)

References 92 publications

(123 reference statements)

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“…In Figure , boxplots representing the statistical distribution of cortisone and cortisol urinary levels before (two days before the administration), during (0–24 h after administration) and after (24–72 h after administration) drug administration by different routes were reported. The results obtained show that both cortisol and cortisone decrease significantly ( p < 0.005) in the first 24 h from the systemic administration; whereas after topical administration moderate alteration were registered, confirming the results reported in literature …”

Section: Resultssupporting

confidence: 91%

“…The results obtained show that both cortisol and cortisone decrease significantly (p < 0.005) in the first 24 h from the systemic administration; whereas after topical administration moderate alteration were registered, confirming the results reported in literature. [27][28][29] These observations indicate that cortisol and cortisone might be useful parameters to discriminate permitted and forbidden administrations.…”

Section: Intranasal Administrationmentioning

confidence: 86%

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Urinary excretion profile of prednisone and prednisolone after different administration routes

Mazzarino

Piantadosi

Comunità

et al. 2019

Drug Testing and Analysis

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The urinary excretion profile of prednisolone and prednisone after both systemic (i.e., oral) and topical (i.e., ocular and intranasal) administration was studied by liquid chromatography coupled to mass spectrometry, also to select the most appropriate marker(s) of intake for doping control purposes. Urines were collected from ten subjects every 3 h before and after the administration of therapeutic doses of pharmaceutical formulations containing either prednisone or prednisolone. Samples were subjected to enzymatic hydrolysis (performed for the investigation on the glucuronide profile) followed by liquid/liquid extraction with tert‐butylmethylether in alkaline conditions. The chromatographic separation was carried out on C18 column, employing as mobile phases ultrapurified water and acetonitrile, both containing 0.1% of formic acid. Detection was achieved using as mass spectrometric analyzer a triple quadrupole, with positive ion electrospray ionization and multiple reaction monitoring as acquisition mode. After both systemic and topical use, the compounds excreted in urine in higher concentration were prednisone, prednisolone and 20β‐dihydro‐prednisolone followed by 20α‐dihydro‐prednisolone and 20α/β‐dihydro‐prednisone. All were excreted mainly as unconjugated compounds, with a maximum of excretion in the first 3–9 h after the administration. After systemic use, prednisone and prednisolone were both detectable for at least 24 h in concentrations ranging from 5 to 500 ng/mL and from 5 to 900 ng/mL respectively. Whereas, after topical administration, prednisone and prednisolone were detectable for at least 18 h in concentrations ranging from 5 to 140 ng/mL and from 5 to 50 ng/mL respectively.

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Section: Resultssupporting

confidence: 91%

Section: Intranasal Administrationmentioning

confidence: 86%

Urinary excretion profile of prednisone and prednisolone after different administration routes

Mazzarino

Piantadosi

Comunità

et al. 2019

Drug Testing and Analysis

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“…Children treated with chronic, high‐dose steroids have an equally observed incidence/prevalence of osteoporosis relative to adults, plus impairment of linear growth . Physiologic cortisol in humans, including children is 5 to 7 mg/m 2 /day . During times of illness, cortisol levels increase 10‐fold to 20‐fold (50–100 mg/m 2 /day).…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoids Disrupt Skeletal Angiogenesis Through Transrepression of NF-κB–Mediated Preosteoclast Pdgfb Transcription in Young Mice

Peng

et al. 2020

Journal of Bone and Mineral Research

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In the growing skeleton, angiogenesis is intimately coupled with osteogenesis. Chronic, high doses of glucocorticoids (GCs) are associated with decreased bone vasculature and induce osteoporosis and growth failure. The mechanism of GC‐suppression of angiogenesis and relationship to osteoporosis and growth retardation remains largely unknown. Type H vessels, which are regulated by preosteoclast (POC) platelet‐derived growth factor–BB (PDGF‐BB), are specifically coupled with bone formation and development. We determined the effect of GCs on POC synthesis of PDGF‐BB in relation to type H vessel formation, bone mass, and bone growth in the distal femur of 2‐week‐old young mice receiving prednisolone or vehicle for 2, 4, or 6 weeks. After 2 weeks of prednisolone, the number of POCs were unchanged while POC synthesis of PDGF‐BB was reduced. Longer treatment with prednisolone reduced POCs numbers and PDGF‐BB. These changes were associated with a reduction in type H vessels, bone formation rate, bone mass, and bone length at each time point. In vitro, excessive concentrations of prednisolone (10−6M) resulted in decreased PDGF‐BB concentration and POC numbers. Conditioned medium from POC cultures treated with control concentration of prednisolone (10−7M) or recombinant PDGF‐BB stimulated endothelial tube formation, whereas conditioned medium from control concentration of prednisolone‐treated POC cultures neutralized by PDGF‐BB antibody or excessive prednisolone inhibited endothelial tube formation. Administration of excessive prednisolone attenuated the P65 subunit of nuclear factor kappa B (NF‐κB) binding to the Pdgfb promoter, resulting in lower Pdgfb transcription. Co‐treatment with excessive prednisolone and the glucocorticoid receptor (GR) antagonist (RU486), GR siRNA, or TNFα rescued NF‐κB binding to the Pdgfb promoter and endothelial tube formation. These results indicate that PDGF‐BB synthesis in POCs is suppressed by GCs through transrepression of GR/NF‐κB, thus inhibiting type H vessel formation and associated osteoporosis and growth failure. © 2020 American Society for Bone and Mineral Research.

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“…Exposure to stressors stimulates the secretion of corticotrophin-releasing hormone (CRH), and this hormone eventually stimulates the pituitary gland to secrete adrenocorticotropic hormone (ACTH). ACTH in turn binds to its receptors on the adrenal gland and induces cortisol secretion (20,21), which inhibits ACTH and CRH production (negative feedback mechanism), in a manner similar to that in children with excess exogenous glucocorticoids (22). Children with NS receive supraphysiologic doses of steroids that may potentially inhibit cortisol production.…”

Section: Discussionmentioning

confidence: 99%

“…Although the effect may be transient, it can result in significant morbidity during periods of physiologic stress (23). In children receiving high-dose steroids, adrenal suppression is not apparent and clinicians need to be aware that abrupt withdrawal may trigger adrenal crises (4,22).…”

Section: Discussionmentioning

confidence: 99%

Adrenal Insufficiency in Children With Nephrotic Syndrome on Corticosteroid Treatment

et al. 2020

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Background: Adrenal insufficiency can result from impaired functions at all levels of hypothalamic-pituitary-adrenal (HPA) axis. We here studied risk factors associated with adrenal insufficiency in children receiving prolonged exogenous steroid treatment for nephrotic syndrome. Method:We performed low-dose Synacthen tests (LDSTs, 0.5 µg/m 2 ) in children with steroid-sensitive nephrotic syndrome 4-6 weeks after discontinuation of the corticosteroid therapy. We measured early morning serum cortisol levels at baseline and at intervals of 10, 20, 30, and 60 min following the stimulation test. We defined normal HPA axis stimulation responses as those with peak cortisol cut-off values >550 nmol/L. Result:We enrolled 37 children for this study research. All children enrolled had normal early morning cortisol levels. However, 13 (35.1%) demonstrated HPA axis suppression (by LDST) 4-+6 weeks after discontinuation of oral prednisolone. Nephrotic syndrome diagnosed before 5 years of age (OR, 0.75; 95% CI, 0.57-0.99; p = 0.043), and steroid-dependence [OR, 5.58; 95% confidence interval (CI), 1.06-29.34; p = 0.042] were associated with increased risk of developing adrenal suppression after steroid discontinuation.Conclusion: HPA axis suppression, may go unnoticed without proper screening. A normal early morning cortisol level (275-555 nmol/L) does not exclude adrenal insufficiency in children with steroid-sensitive nephrotic syndrome. Further screening with LDSTs, particularly in children younger than 5 years at diagnosis, may be warranted.

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Treatment with Synthetic Glucocorticoids and the Hypothalamus-Pituitary-Adrenal Axis

Cited by 130 publications

References 92 publications

Urinary excretion profile of prednisone and prednisolone after different administration routes

Urinary excretion profile of prednisone and prednisolone after different administration routes

Glucocorticoids Disrupt Skeletal Angiogenesis Through Transrepression of NF-κB–Mediated Preosteoclast Pdgfb Transcription in Young Mice

Adrenal Insufficiency in Children With Nephrotic Syndrome on Corticosteroid Treatment

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