Abstract

Corticosteroidi
STORIA
1563 Eustachio scopre l’esistenza delle ghiandole surrenali
1849 Addison attribuisce la “pelle bronzea” a
malfunzionamento delle ghiandole surrenali
1856 Brown-Sequard rimuove le ghiandole surrenali di gatti e
cani i quali poi moriranno nell’arco di qualche giorno
dimostrando cosi’ l’importanza vitale di queste ghiandole.
1894 Viene scoperta la suddivisione delle surrenali (corteccia
e midollare). L’adrenalina viene secreta dalla midollare.
1938 Reichstein isola 29 nuove sostanze dalla corteccia
surrenale e tutte sono steroidi.
1948 Kendall isola il cortisone
1950 Kendall, Reichstein ed Hench riceveranno il premio
Nobel per la medicina
“For a long period I had from time to time met with a very remarkable form
of general anaemia, occurring without any discoverable cause whatever.
The disease presented in every instance the same general character,
pursued a similar course, and, with scarcely a single exception, was
followed, after a variable period, by the same fatal result. The appetite is
impaired or entirely lost; the whites of the eyes become pearly; the pulse
small and feeble. The body wastes, slight pain or uneasiness is from time
to time referred to the region of the stomach, and there is occasionally
actual vomiting, which in one instance was both urgent and distressing;
Neither the most diligent inquiry, nor the most careful physical
examination, tends to throw the slightest gleam of light upon the precise
nature of the patient’s malady; But with a more or less manifestation of the
symptoms already enumerated, we discover a most remarkable, and, so
far as I know, characteristic discoloration taking place in the skin.”
Thomas Addison, 1855
Rev Endocr Metab Disord. 2010 Jun;11(2):147-53.
The diagnosis of Cushing's syndrome.
Carroll TB, Findling JW.
Endocrinology Center (TBC, JWF), Medical College of Wisconsin, W129 N7055
Northfield Drive Building A, Suite 203, Menomonee Falls, WI 53051, USA.
[email protected]
Abstract
Spontaneous Cushing's syndrome is well known but unusual clinical disorder. Many of
the clinical features (central weight gain, glucose intolerance, hypertension, muscle
weakness) are seen in other common conditions. Recognition of patients with multiple
features, features unusual for their age (i.e. early onset osteoporosis or hypertension),
patients with features more specific to Cushing's syndrome (i.e. easy bruising, facial
plethora, and violaceous striae), and patients with incidental adrenal mass or
polycystic ovary syndrome should prompt an evaluation for cortisol excess. Late-night
salivary cortisol, 1 mg overnight dexamethasone suppression testing, or 24 h urine
free cortisol determination have excellent diagnostic characteristics and should be
obtain in patients with suspected Cushing' syndrome. If this initial testing is
abnormal, further evaluation should be directed by an endocrinologist experienced in
the diagnosis and differential diagnosis of Cushing' syndrome.
Cushing’s Support & Research Foundation
Symptoms Vary
And may include
any number of these:
Abdominal weight gain
Red, round ‘moon’ face
Thinning extremities
‘Buffalo hump’
High blood pressure
High blood sugar
Muscle weakness
Osteoporosis/Fractures
Infections
Blood clots
Visual field defects
Illustration from Mayo Clinic Family Health Book, 2d. ed, 1996
Easy bruising
Thinning skin
Poor wound healing
Acne
Purple striae
Hirsutism
Female balding
Menstrual irregularity
Sleep disorders
Excessive hunger
Excessive thirst
Frequent urination
Sweating
Anxiety
Confusion
Concentration loss
Memory loss
Depression
Suicidal thoughts
Panic attacks
Courtesy of www.CSRF.com
HPA
Ipotalamo
Ipofisi
Surrenali
I glucocorticoidi sono degli ormoni rilasciati dale ghiandole surrenali sotto lo
stimolo ipofisario dell’ACTH e ancor prima dallo stimolo ipotalamico
rappresentato dal CRH. Il glucocorticoide per eccellenza è il cortisolo. Molti
glucocorticoidi di sintesi sono altamente efficaci nel trattare malattie
infiammatorie, quali asma, reazioni autoimmuni e allergie. I loro effetti
terapeutici sono generalmente ascrivibili alla forte azione inibitoria sulla
produzione di cellule T così come sulla inibizione del rilascio di interleuchina 2 e
del suo recettore. Anche le interleuchine proinfiammatorie 1, 6 e 12, vengono
inibite nel loro rilascio così come per il Tumor necrosis factor alfa presente nei
monociti e macrofagi. Questi effetti sono mediati dai recettori per i
glucocorticoidi presenti nel citoplasma. Una volta legati al suo recettore i
glucocorticoidi traslocano nel nucleo e regolano l’espressione genica legandosi
specificativamente a sequenze di DNA con geni detti elementi dei recettori dei
glucocorticoidi. Il recettore dei glucocorticoidi altera anche l’espressione genica
attraverso l’interazione diretta con proteine non recettoriali legate al promotore
presente sul gene.
A queste azioni antiinfiammatorie però sono legati effetti collaterali quali
aumento di peso corporeo, diabete, ipertensione, osteoporosi, cambiamenti
comportamentali e alterazione del sonno.
Livelli di cortisolo durante la giornata e durante I giorni della settimana
The measurement of late-night salivary cortisol, usually at 2300
to 2400 h, has proven to be a very useful approach to the
diagnosis of Cushing’s syndrome.
L’inspiegabile osservazione che ricercatori negli anni cinquanta vedevano in pazienti a cui
venivano date quantità elevate di cortisone per os ma avevano piccole concentrazioni di
cortisone nel plasma con un alto livello di cortisolo è stato finalmente chiarito in anni recenti.
Paradossalmente il composto E (cortisone) che Kendall usava è una molecola inattiva che
richiede la trasformazione metabolica in cortisolo per svolgere la sua attività
antinfiammatoria. La conversione sistemica del cortisone a cortisolo è principalmente per
via epatica attraverso la 11 beta idrossisteroidedeidrogenasi 1 (11betaHSD1) che riduce il
cortisone a cortisolo. La 11 beta idrossisteroidedeidrogenasi 2 (11betaHSD2) riconverte
il cortisolo in cortisone ed è generalmente espressa nel tessuto e dipende dall’attivazione del
recettore mineralocorticoideo per attivazione dei mineralocorticoidi nel rene. Poichè sia
l’aldosterone che il cortisolo sono entrambi potenti agonisti mineralocoricoidei l’attività della
11betaHSD2 è richiesta in quei siti dove il cortisolo deve essere disattivato e quidi prevenire
l’occupazione dei recettori mineralocorticoidei.
11betaHSD1
11betaHSD2
Cortisone
Cortisolo
Farmaci glucocorticoidei
Beclometasone
BDP is actually a pro-drug with weak glucocorticoid receptor
binding affinity, that is hydrolysed via esterase enzymes to an
active metabolite beclomethasone 17-monopropionate (B-17-MP)
Beclomethasone 17,21-dipropionate (BDP) is a topically active corticosteroid used
in the treatment of asthma and rhinitis. It was first available in 1972 in a
pressurized metered-dose inhaler (MDI) and later in a dry powder inhaler and an
aqueous nasal spray.
Numerazione degli atomi di carbonio nello scheletro degli steroidi
Milestones included the discovery that whereas 9a-fluorination increased antiinflammatory potency, it also caused excessive protein loss, potassium loss,
sodium retention and oedema.
On the other hand, introduction of a 1,2 double bond in the A ring (to create
prednisone from cortisone and prednisolone from cortisol) created derivatives
with improved anti-inflammatory properties and reduced undesirable side
effects.
16a-Hydroxylated compounds retained glucocorticoid activity without
concomitant salt and fluid retention while 16a-methylation further increased
anti-inflammatory activity. Combining 9a-fluorination, 1-dehydrogenation and
16a-methylation yielded dexamethasone, which was the most potent nonsalt
retaining anti-inflammatory of its time
MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI CORTISONICI
Inibizione della PLA2 da parte dei glucocorticoidi
Vie di formazione dei macrofagi
Effetti dei glucocorticoidi sulle cellule immunitarie
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i
glucocorticoidi GR alfa. Una volta che il ligando si lega al Gralfa questo si dissocia dalla
proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero
al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come
monomero con un’altro fattore di trascrizione (TF). (REs response elements, RNPII RNA
polymerase II, GRE glucocorticoid response element).
Gli enzimi 11beta-Idrossisteroide deidrogenasi
Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma
attiva a quella inattiva. I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide.
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per
l’aldosterone cui necessita l’enzima 11beta HSD2. Per questo motivo i glucocorticoidi
circolano a più alte concentrazioni del mineralocorticoide aldosterone ed in condizioni
normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo. In
contrasto, le cellule endoteliali contengono l’enzima 11bHSD2 e di conseguenza I recettori
per I mineralocorticoidi sono normalmente attivati dall’aldosterone.
Attivazione classica e alternativa dei macrofagi. I fenotipi polarizzati di macrofagi sono
largamente definiti come classici e attivati alternativamente. I macrofagi attivati
classicamente rispondono all’interferone gamma e lipopolisaccaridi e giocano un ruolo
importante nel tipo 1 dell’infiammazione, nella distruzione del tessuto, nell’uccisione di
parassiti intracellulari e nella resistenza ai tumori. In contrasto, i macrofagi attivati
alternativamente rispondono a fattori come l’interleuchina 4 o 3 o 10, ai complessi
immunitari, al TGF beta e ai glucocorticoidi e contribuiscono all’infiammazione di tipo 2,
alla rimodellazione del tessuto, all’angiogenesi, alla incapsulazione dei parassiti e alla
progressione del tumore.
Effetti dei Glucocorticoidi sull’osso
Journal of Endocrinology (2009) 201, 309–320
Tipico dosaggio dei cortisonici per prevenire
la soppressione dell’asse ipotalamo-ipofisi-surrene
Medical management of adrenal disease: a narrative review.
Michalakis K, Ilias I.
Department of Endocrinology, E Venizelou Hospital, 2, Athens GR-11521, Greece.
Adrenal diseases comprise for a variety of medical endocrine issues, ranging from partial
or complete gland insufficiency, to several kinds of adrenal hyperfunction, either of
congenital or neoplastic etiology. For hypofunction of the adrenals (partial or complete)
the treatment of choice is medical; the mainstay of treatment is hydrocortisone. Patients
with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with
glucocorticoids to control androgen excess. Most benign neoplastic adrenal diseases that
cause hyperfunction of the gland are surgically treated, however this may not be always
feasible or effective. For Cushing's syndrome ketoconazole controls cortisol's
hypersecretion, whereas in case of bilateral idiopathic hyperaldosteronism spironolactone
controls hypokalemia and hypertension. For neoplastic adrenomedullary disease surgery
is the treatment of choice; medical treatment is used preoperatively (mainly alpha
blockers) and in case of disease persistence and /or recurrence (mainly metyrosine). For
malignant adrenocortical disease, surgical removal remains the indicated treatment, but if
the potential for surgical intervention is limited due to tumor extension, medical
treatment can alleviate symptoms of hormone hypersecretion; mitotane in selected
patients has good results
Endocr Regul. 2009 Jul;43(3):127-35.
Eventi avversi da cortisonici
Effetti dei cortisonici sul sistema nervoso centrale
Psychiatry Clin Neurosci. 2009 Oct;63(5):613-22.
Central nervous system effects of natural and synthetic
glucocorticoids.
Fietta P, Fietta P, Delsante G.
Psychiatry Department, Hospital of Lodi, Lodi, Italy. [email protected]
Abstract
Natural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive
responses to stress, involving almost all organs and tissues, including brain. Since their therapeutic
availability, synthetic GC (SGC) have been successfully prescribed for a variety of diseases. Mounting
evidence, however, demonstrated pleiotropic adverse effects (AE), including central nervous system (CNS)
disturbances, which are often misdiagnosed or underestimated. The aim of the present study was therefore to
review and discuss the CNS effects of both NGC and SGC. A detailed search was carried out of the available
literature using the PubMed (US National Library of Medicine) database. Cortisolemia plays a crucial role
in control of behavior, cognition, mood, and early life programming of stress reactivity.
Hypercortisolemia or SGC treatments may induce behavioral, psychic and cognitive disturbances,
due to functional and, over time, structural alterations in specific brain target areas. These AE are
generally dose and time dependent (infrequent at prednisone-equivalent doses <20 mg/day) and usually
reversible. Pediatric patients are particularly susceptible. Behavioral changes, including feeding and
sleeping modifications, are common. Psychic AE are unpredictable and heterogeneous, usually
mild/moderate, severe in 5-10% of cases. Manic symptoms have been mostly associated with short SGC
courses, and depressive disorder with long-term treatments. Suicidality has been reported. Cognitive
AE peculiarly affect declarative memory performance. Physiologic levels of NGC are essential for efficient
brain functions. Otherwise, hypercortisolemia and SGC treatments may cause dose-/time-dependent
neuropsychic AE and, over time, structural alterations in brain target areas. Clinicians should carefully monitor
patients, especially children and/or when administering high doses SGC.
PMID: 19788629 [PubMed - indexed for MEDLINE]
Cardiovasc J Afr. 2009 Jul-Aug;20(4):233-6.
Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence: a metaanalysis and systematic review of the literature.
Athappan G, Gale S, Ponniah T.
Caritas St Elizabeth Medical Centre, Tufts School of Medicine, Boston, USA.
[email protected]
OBJECTIVE: Corticosteroids are the treatment of choice in most forms of vasculitis. However, their
role in the primary treatment of Kawasaki disease (KD) is controversial. Our aim was to conduct a
meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to
standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD.
METHODS: We included randomised trials comparing the addition of corticosteroids to
conventional primary therapy for Kawasaki disease. RESULTS: A total of four studies were identified,
which included 447 patients. The meta-analysis revealed a significant reduction in re-treatments
with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy
alone [odds ratio (OR) 0.48; 95% confidence interval (CI): 0.24- 0.95]. There was however no
significant reduction in the incidence of coronary artery aneurysms among patients who received
corticosteroid therapy plus standard therapy, compared with standard therapy alone for either up
to a month (OR 0.74; 95% CI: 0.23-2.40) or over one month ([OR 0.74; 95% CI: 0.37-1.51). Similarly
no significant differences between treatment groups were noted in incidence of adverse events (OR
0.81; 95% CI: 0.05-0.88).
CONCLUSION: The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki
disease decreased rates of re-treatment with intravenous immunoglobulin. However the addition
of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or
adverse events.
Duchenne muscular dystrophy (DMD) is a disease linked to the Xchromosome which affects 1 in 3,600-6,000 newborn males. It is
manifested by the absence of the dystrophin protein in muscle fibres,
which causes progressive damage leading to death in the third decade of
life. The only medication so far shown to be
effective in delaying the progression of this illness are corticosteroids,
which have been shown to increase muscle strength in randomised
controlled studies; long-term studies have demonstrated that they prolong
walking time and retard the progression of respiratory dysfunction, dilated
cardiomyopathy and scoliosis.
Several potential drugs are now being investigated. Genetic therapy,
involving the insertion of a dystrophin gene through a vector, has proven
effective in animals but not humans. Currently under clinical study is
Ataluren, a molecule that binds with
ribosomes and may allow the insertion of an aminoacid in the premature
termination codon, and exon-skipping, which binds with RNA and
excludes specific sites of RNA splicing, producing a dystrophin that is
smaller but functional. There are also
Endogenous Cushing’s syndrome results from excessive glucocorticoid
production with a failure of the normal negative feedback effect on the
hypothalamo-pituitary–adrenal axis. It is traditionally divided into ACTHdependent
and ACTH-independent Cushing’s syndrome. In the majority of cases, it is
caused by an adenoma in the pituitary gland secreting ACTH hormone
(Cushing’s disease),
The medical therapy of hypercortisolaemia in Cushing’s syndrome is predominantly
based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites, or
alternatively by antagonism of the glucocorticoid receptor or the suppression of
ACTH.
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic
enzyme inhibitors currently in use.
Kawasaki disease
Vascoliti
Br J Haematol. 2010 Jun;149(5):638-52. Epub 2010 Apr 12.
The optimal use of steroids in paediatric
acute lymphoblastic leukaemia: no easy
answers.
McNeer JL, Nachman JB.
Section of Paediatric Haematology/Oncology, University of Chicago Comer Children's
Hospital, Chicago, IL, USA.
Abstract
Glucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia
(ALL), but usage differs between cooperative group protocols. All groups use glucocorticoids
during induction but vary on whether to use dexamethasone or prednisone. Issues to consider
in the choice of induction steroid include impact on event-free and overall survival, acute
morbidity such as infection risk, diabetes, and behavioural disturbances and long-term
complications such as avascular necrosis. It is generally agreed that dexamethasone is the
steroid of choice for groups using a delayed intensification phase, but dosing schedules
(intermittent versus continuous) vary. There is no consensus on the potential benefit of steroid
administration during maintenance therapy.
Tossicità da corticosteroidi
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia però ad essi sono associati eventi tossici
importanti.
- Le tossicità a breve termine sono mialgia, miopatia,
infezioni, iperglicemia, problemi comportamentali,
soppressione dell’asse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento.
- La necrosi avascolare dell’osso è di particolare gravità
perchè ha un grande impatto nella qualità della vita per il
resto della vita del paziente.
INIBITORI DELLA BIOSINTESI DEI
CORTICOSTREROIDI
•METIRAPONE (inibitore della 11b-idrossilazione)
•TRILOSTANO (inibitore della 3 b-idrossisteroide
deidrogenasi)
•KETOCONAZOLO (Blocca la rottura della catena laterale
del colesterolo)
Il metirapone blocca la sintesi del cortisolo
attraverso l’inibizione della steroid 11βhydroxylase. Questo fatto stimola l’ipofisi a
produrre ACTH la quale aumenta nel
plasma i livelli di 11-deoxycortisol levels.
Quando un eccesso di ACTH è la causa di
ipercortisolismo, il test del metirapone aiuta
a vedere se la causa è l’ACTH ipofisaria o
è di natura ectopica ovvero non-ipofisaria.