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`Pharmacological Management of Cushing’s Syndrome:
`An Update
`
`atualização
`
`CUONG NGUYEN DANG
`PETER TRAINER
`
`Christie Hospital,
`Manchester, UK.
`
`ABSTRACT
`
`The treatment of choice for Cushing’s syndrome remains surgical. The role
`for medical therapy is twofold. Firstly it is used to control hyper-
`cortisolaemia prior to surgery to optimize patient’s preoperative state and
`secondly, it is used where surgery has failed and radiotherapy has not
`taken effect. The main drugs used inhibit steroidogenesis and include
`metyrapone, ketoconazole, and mitotane. Drugs targeting the hypo-
`thalamic-pituitary axis have been investigated but their roles in clinical
`practice remain limited although PPAR-γ agonist and somatostatin ana-
`logue som-230 (pasireotide) need further investigation. The only drug
`acting at the periphery targeting the glucocorticoid receptor remains
`Mifepristone (RU486). The management of Cushing syndrome may well
`involve combination therapy acting at different pathways of hypercor-
`tisolaemia but monitoring of therapy will remain a challenge. (Arq Bras
`Endocrinol Metab 2007;51/8:1339-1348)
`
`Keywords: Cushing’s syndrome; Drug therapy; Steroidogenesis inhibitor;
`Hypothalamic-pituitary modulator
`
`RESUMO
`
`Manejo Farmacológico da Síndrome de Cushing: Uma Atualização.
`O tratamento de escolha para a síndrome de Cushing ainda é a
`cirurgia. O papel da terapia medicamentosa é duplo: ele é usado para
`controlar o hipercortisolismo antes da cirurgia e otimizar o estado
`pré-operatório do paciente e, adicionalmente, quando ocorre falha
`cirúrgica e a radioterapia ainda não se mostrou efetiva. Os principais
`medicamentos são empregados para inibir a esteroidogênese e
`incluem: metirapona, cetoconazol e mitotano. Medicamentos visando
`o eixo hipotálamo-hipofisário têm sido investigados, mas seu papel
`na prática clínica permanece limitado, embora o agonista PPAR-γ e
`análogo de somatostatina, som-230 (pasireotídeo), requeira estudos
`adicionais. A única droga que age perifericamente no receptor glico-
`corticóide é a mifepristona (RU486). O manejo da síndrome de Cu-
`shing deve envolver uma combinação terapêutica atuando em
`diferentes vias da hipercortisolemia, mas o monitoramento dessa te-
`rapia ainda permanece um desafio. (Arq Bras Endocrinol Metab
`2007;51/8:1339-1348)
`
`Descritores: Síndrome de Cushing; Terapia médica; Inibidores da
`esteroidogênese; Moduladores hipotálamo-hipofisários
`
`Recebido em 01/10/07
`Aceito em 08/10/07
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`Pharmacological Management of CS
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`
`CUSHING’S IS ARARE DISEASE and therefore of min-
`
`imal interest to the pharmaceutical industry and
`hence for many years there were few developments.
`However in recent times there has been renewed inter-
`est in whether agents marketed for other conditions
`may have a role to play in the medical management of
`Cushing’s syndrome. This review will endeavour to
`assess the place of the ‘new’ agents alongside the
`longer established agents.
`The definitive management for Cushing’s syn-
`drome is surgical excision of the underlying cause of
`the hypercortisolaemia, with the exception of ACTH-
`independent bilateral macronodular hyperplasia where
`pharmacological treatment directed against the aber-
`rant receptor can be effective (1). However, in many
`patients with Cushing’s syndrome there is a role for
`medical therapy in certain specific circumstances. It is
`common practice to prepare patients for surgery by
`lowering circulating cortisol levels to reverse the meta-
`bolic consequence of cortisol excess and by implica-
`tion reduce the complications of surgery. This clearly
`depends on the interval to surgery and disease severi-
`ty. As any clinician dealing with Cushing’s syndrome is
`aware establishing the precise aetiology is a challenge
`and it is not always possible to make a definitive diag-
`nosis at first investigation, and in such cases medical
`therapy can be used as a stop gap to control signs and
`symptoms and thereby allow time for re-investigation.
`In patients not cured by surgery or in patients with
`metastatic disease medical therapy can be used to con-
`trol manifestations of the disease. Pituitary radiothera-
`py is extremely effective at controlling hypercortiso-
`laemia but can take several years to have its full effect
`and medical therapy is often required in the interim
`(see figure 1).
`Medical therapy can be separated into agents
`that inhibit adrenal steroidgenesis and those that mod-
`ulate pituitary ACTH release. Currently in clinical
`practice, the most effective, reliable and widely use
`agents are those that inhibit steroidgenesis.
`A major challenge of medical therapy is the
`monitoring of its effectiveness. Urinary free cortisol
`(UFC) measurement is widely used but has several
`major limitations and is intrinsically a poor solution to
`the problem of disease monitoring. Only a small pro-
`portion of cortisol is excreted unaltered in urine and
`UFC immunoassays to varying extent detect biologi-
`cally inactive cortisol metabolites, which may be raised
`in patients treated with agents such as metyrapone.
`UFC has the additional disadvantages of relying on
`complete collection and of being unable to detect
`over-treatment induced hypoadrenalism.
`
`Although more labour intensive, measurement
`of serum cortisol is a more appropriate means of
`assessing disease activity. The best validated technique
`is calculation of a mean serum cortisol from multiple
`measurements taken during a single day. Studies com-
`paring isotopically calculated cortisol production rates
`
`Figura 1. Mean plasma ACTH levels (a) and serum cortisol
`levels (b) during short-term metyrapone therapy in 53
`patients with Cushing’s syndrome. The bars represent the
`median values. ACTH ng/L x 0.225 = pmol/l. [Courtesy of Ver-
`helst JA, Trainer PJ, Howlett TA, et al. Short- and long-term
`responses to metyrapone in the medical management of 91
`patients with Cushing’s syndrome. Clin Endocrinology (Oxf)
`1991;35:169-78]
`
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`to serum levels indicate that a mean serum cortisol in
`the range 150–300 nmol/l equates to a normal corti-
`sol production rate, and this should be the target of
`medical therapy (2).
`The cyclical nature of Cushing’s syndrome in
`some patients means that even after disease control has
`been achieved regular treatment monitoring is
`required.
`
`STEROIDOGENESIS INHIBITION
`
`These agents are the most consistently effective means
`of controlling cortisol secretion.
`
`Metyrapone
`In the era before it was possible to measure plasma
`ACTH, the metyrapone test was used to investigate
`suspected Cushing’s syndrome and hypoadrenalism
`but its use now is exclusively therapeutic (3,4). It acts
`primarily on the final step in cortisol synthesis namely
`the conversion of 11-deoxycortisol to cortisol and
`therefore results in a dramatic increase in circulating
`11-deoxycortisol levels, which can cross-react in serum
`and urine cortisol immunoassays. This cross-reactivity
`may result in spuriously elevated cortisol levels and a
`failure to appreciate that a patient is over-treated and
`hypoadrenal.
`Metyrapone is the most potent, short-acting
`inhibitor of cortisol synthesis with a rapid onset of
`action. Serum cortisol levels fall within four hours of
`an initial dose and care is required to avoid over-treat-
`ment. The routine starting dose is 250 mg three times
`per day with reassessment of cortisol levels 72 hours
`later and dose titration as appropriate until a mean
`cortisol level of between 150 and 300 nmol/l is
`achieved. In patients with severe hypercortisolaemia
`up to 8 gm per day in 3–4 divided doses may be nec-
`essary. Most patients tolerate the drug without diffi-
`culty as long as hypoadrenalism is avoided. Nausea,
`anorexia and abdominal pain can occur but usually
`this is a sign of over-treatment. The major limitation
`of metyrapone is in women as the accumulation of
`cortisol precursors results in elevated androgens,
`which frequently is manifest as hirsutism and acne.
`Although mineralocorticoid precursors levels are ele-
`vated, hypokalaemia, hypertension and oedema are
`not problems, presumably because of the benefits of
`lower circulating cortisol levels (5,6). In patients with
`pituitary-dependent Cushing’s disease, ACTH levels
`rise but there is no evidence that this results in tachy-
`phylaxis (5,7).
`
`Pharmacological Management of CS
`Dang & Trainer
`
`Ketoconazole
`Ketoconazole is an imidazole derivative developed as
`an oral antifungal agent that inhibits cholesterol, sex
`steroid and cortisol synthesis by acting on the
`11β-hydroxylase and C17-20 lyase enzymes (8-11). It
`is the most frequently used agent in the treatment of
`Cushing’s syndrome with the starting dose being 200
`mg twice daily increasing as necessary to 1200 mg/day
`in four divided doses (12,13). In contrast to
`metyrapone it can take several weeks to see the full
`benefit of a dose adjustment and there is less risk of
`over-treatment and hypoadrenalism. With time it is
`effective at controlling the symptoms of Cushing’s
`syndrome and in women its antiandrogenic properties
`are a virtue but in men, gynaecomastia and reduced
`libido have been reported. The most common side
`effects are gastrointestinal upset and skin rashes but
`liver enzyme dysfunction can occur in up to 10% of
`cases, which rarely has proceeded to acute liver failure
`and fatality (14-17). Ketoconazole has the added ben-
`efit of reducing the total cholesterol and LDL choles-
`terol (18).
`Metyrapone and ketoconazole can be very suc-
`cessfully co-administered as the former controls corti-
`sol secretion while waiting for the slower onset of
`action of the latter agent, which in turn lowers andro-
`gens and thus negates one of the major limitations of
`the former.
`
`Mitotane
`Mitotane reduces cortisol production by blocking
`cholesterol side-chain cleavage and 11β-hydroxylase
`(19-21). It was introduced in 1960 for the treatment
`of adrenal carcinoma and subsequently used for the
`treatment of benign causes of Cushing’s syndrome.
`The onset of mitotane action is slow with sustained
`action maintained after discontinuation in up to a
`third of patients (22). When used to control serum
`cortisol levels in benign disease, mitotane is initiated
`at a dose of 0.5–1 gm per day which is increased grad-
`ually by 0.5–1 gm every few weeks to minimise side
`effects. Adverse effects such as nausea, anorexia and
`diarrhoea are common with doses of 2 gm per day
`and almost universal at doses greater than 4 gm per
`day (23). Adrenal insufficiency and neurological side
`effects including abnormal gait, dizziness, vertigo,
`confusion and problem of language expression are
`often seen at higher dose (22). Abnormal liver
`enzymes, hypercholesterolaemia, skin rash, hyporuri-
`caemia, gynaecomastia in male and prolonged bleed-
`ing time are also well recognized (24,25). Changes in
`hormone binding globulins may result in total hor-
`
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`
`mone measurement being unreliable during treat-
`ment and thus caution is required when interpreting
`serum cortisol levels (26,27). Mitotane increases the
`metabolic clearance of exogenously administered
`steroid and the replacement dose of steroid is
`increased by about a third (28). In order to minimise
`side effects mitotane dose should be gradually titrated
`up, taken with meals or at bedtime with food. Chang-
`ing the schedule to once daily or alternate day may
`help with gastrointestinal problems. If side effects are
`severe mitotane can be stopped for a week and restart-
`ed at a lower dose. Mitotane may induce spontaneous
`abortion and is a teratogen. Its effect may persist for
`a number of months after discontinuation and so a
`female patient should avoid pregnancy for up to five
`years after stopping the drug (29).
`
`Aminoglutethimide
`Aminoglutethimide, which was introduced in 1959 as
`an anticonvulsant, has also been used in the treatment
`of breast cancer and was noticed to induce adrenal
`insufficiency. It inhibits the side-chain cleavage of cho-
`lesterol to pregnenolone and therefore inhibits corti-
`sol, oestrogen and aldosterone production and addi-
`tionally inhibits 11β-hydroxylase, 18-hydroxylase and
`aromatase activity
`(30,31).
`Initially aminog-
`lutethimide decreases cortisol production in Cushing’s
`syndrome but appears to be less effective in treating
`Cushing’s disease (32). The suggested mechanism
`may be an increase in ACTH overcoming the enzy-
`matic blockade or it may be induction of hepatic
`enzyme accelerating aminoglutethimide metabolism
`(33,34). Adverse effects such as lethargy, dizziness,
`ataxia and rashes are common on initiation and limit
`its use although they do resolve with time (32,35).
`There are better agents for controlling hypercortiso-
`laemia and aminoglutethimide does not have a place in
`the modern treatment of Cushing’s syndrome (36).
`
`Trilostane
`Trilostane is a competitive inhibitor of 3β-hydroxys-
`teroid dehydrogenase, which is an essential enzyme in
`the synthesis of cortisol, aldosterone and androstene-
`dione. It is an effective inhibitor of steroid synthesis in
`vitro but in man the results have been disappointing
`(37). However, it is used in veterinary practice as it is
`very effective in controlling pituitary-dependent Cush-
`ing’s in dogs (38). The maximum daily dose is 1,440
`mg and patients may experience side effects such as
`abdominal discomfort, diarrhoea and paraesthesia.
`Trilostane has largely fallen out of clinical use but the
`very fact that it is so effective in dogs may mean it jus-
`tifies reconsideration in man.
`
`Etomidate
`Etomidate is a parenteral anaesthetic agent which
`when first introduced was associated with excessive
`mortality in patients in intensive care which was ulti-
`mately explained by the recognition it lowered circu-
`lating cortisol levels by inhibiting 11β-hydroxylase,
`17-hydroxylase, c17-20 lyase as well as cholesterol side
`chain at cleavage (39-41). A number of case reports
`have shown etomidate at 2.5 mg/hour to be effective
`at correcting hypercortisolaemia in seriously ill patients
`with ectopic ACTH production (42-44). Etomidate’s
`use is limited by the need to be given intravenously
`but it has a place in acutely sick patients unable to be
`treated orally where rapid correction of hypercortiso-
`laemia may be life saving.
`
`HYPOTHALAMIC-PITUITARY
`NEUROMODULATORY AGENTS
`
`Pituitary ACTH secretion is regulated by a number of
`neurotransmitters including catecholamines, sero-
`tonin, acetylcholine, GABA and peptides. In Cush-
`
`Ketoconazole
`
`Table 1. Agents inhibiting steroidogenesis in clinical use.
`Agent
`Dose
`Properties
`Metyrapone
`750–8000
`Hypoadrenalism
`mg daily
`Side effects: nausea, abdominal pain, hirsutism, acne
`400–1200
`Slow onset of action
`mg daily
`Side effects: gastro-intestinal upset, rashes, abnormal
`LFT, gynaecomastia & reduced libido in men
`Gradual dose titration, taken with meal
`Side effects: gastro-intestinal upset, neurological
`disturbances, abnormal LFT, hypercholesterolaemia
`Avoid pregnancy up to five years after stopping the drug
`
`Mitotane
`
`500–8000
`mg daily
`
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`ing’s disease the pituitary tumour still remains partial-
`ly responsive to hypothalamic stimuli, illustrated by
`responsiveness to exogenous CRH and dexametha-
`sone. Reports exist advocating the virtues of various
`agents but, to-date, none have gained widespread
`acceptance. However recent data have renewed inter-
`est in the possibility of treating Cushing’s disease with
`centrally acting drugs that modulate through
`dopamine, somatostatin and PPAR receptors function.
`
`Dopamine agonists
`Bromocriptine is a dopamine agonist which has been
`widely used in the treatment of hyperprolactinaemia
`and acromegaly. It is unclear if the action in lowering
`ACTH secretion by bromocriptine is via CRH or
`directly on the pituitary (45-47). A single dose of
`bromocriptine will cause a fall in ACTH in half of the
`patients with Cushing’s disease but unfortunately this
`effect is not maintained in the long term (47,48).
`There are reports that suggest with high dose
`bromocriptine (40 mg/day) there may be clinical
`improvement in up to 50% of patients but others have
`found response rate of only 1–2% in the long term
`(49,50). Potential side effects of bromocriptine
`include nasal congestion, nausea, postural hypoten-
`sion, headaches and hallucination.
`The use of cabergoline in the management of
`Cushing’s disease remains anecdotal. In mixed pitu-
`itary tumour secreting prolactin and ACTH with florid
`clinical signs of Cushing’s disease treatment with
`cabergoline resulted not only in the normalisation of
`prolactin but also clinical and biochemical resolution
`of the features of Cushing’s (51). It has also been use
`to control Cushing’s disease in failed pituitary surgery
`(52,53). Recently there has been renewed interest in
`cabergoline with the publication by Pivonello et al. of
`a case of lung carcinoid with Cushing’s syndrome
`treated with a combination of lanreotide and cabergo-
`line successfully normalising plasma ACTH and UFC
`levels (54). In a study of six patients with ACTH-
`secreting neuroendocrine tumours, dopamine D2
`receptors were expressed in five patients on immuno-
`histochemistry and treatment with cabergoline 3.5
`mg/week for six months normalised UFC in two
`patients although one patient later did have treatment
`escape (55). Case reports of cabergoline use in Nel-
`son’s syndrome have been more encouraging. Casulari
`et al. reported a case of Nelson’s syndrome with failed
`treatment on cyproheptadine (12 mg/day) and
`bromocriptine (7.5 mg/day) but cabergoline (0.5 mg
`twice weekly) normalised the ACTH plasma levels and
`induced complete resolution of the pituitary adenoma
`
`Pharmacological Management of CS
`Dang & Trainer
`
`on MRI (56). There has also been a case report of
`cabergoline (1.5 mg/week) treatment of Nelson’s
`syndrome for six years with normalisation of ACTH
`levels and stable residual pituitary tumour (57).
`The role of dopamine agonists in the manage-
`ment of Cushing’s disease remains limited to the occa-
`sional patient and long-term evidence of efficacy is
`very poor but interest in their use remains unabated.
`The available data are case based anecdote, there is a
`need for a controlled study before treatment can be
`recommended.
`
`PPAR-γ receptor agonists
`In 2002, the nuclear hormone receptor, peroxisome
`proliferator-activated receptor-γ (PPAR-γ) was identi-
`fied in ACTH-secreting pituitary tumour (58). In an
`in vivo experiment, innoculating mice with corti-
`cotroph AtT20 tumour cells, treating with extremely
`high dose of rosiglitazone (150 mg/kg/day) prevent-
`ed the development of tumours. In mice with already
`established corticotroph tumours, rosiglitazone treat-
`ment decreased tumour volume in 75% of cases and
`prevented signs of hypercortisolaemia in all cases, with
`75% reduction in ACTH level and 96% reduction in
`cortisol levels (58). These observations caused great
`interest but are yet to impact on clinical practice.
`In a study of two patients with pituitary-depen-
`dent Cushing’s syndrome treated with rosiglitazone 8
`mg daily for 33 and 20 days (the second patient was
`also taking metyrapone 1 gm/day), 24 hours UFC fell
`in both patients although only in the patient co-treat-
`ed with metyrapone did it reach statistical significance
`(59). In a second study of ten patients, four prior to
`surgery, four following relapse after surgery and two
`immediately after failed surgery treated with 4–16 mg
`of rosiglitazone for 1–8 months (median 3 months),
`there was no consistent reduction in urinary free corti-
`sol, plasma ACTH or serum cortisol levels (60). Side
`effects reported included oedema, weight increase,
`somnolence and increased hirsutism. In one of the larg-
`er studies, fourteen patients with active Cushing’s dis-
`ease (seven untreated and seven post unsuccessful
`transsphenoidal pituitary surgery) were treated with
`8–16 mg of rosiglitazone for 1–7 months (61). In six
`patients, plasma ACTH, serum cortisol and 24 hours
`UFC were lowered but only UFC reached significance.
`Two of the six patients also noted clinical improvement
`on follow up at seven months. No clinical side effects
`were noted but one patient developed hypercholes-
`terolaemia. In a study of seven patients with Nelson’s
`syndrome who took 8 mg of rosiglitazone for 12
`weeks, no significant fall in ACTH was seen (62). Sim-
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`
`ilarly in another study of six patients with Nelson’s syn-
`drome given rosiglitazone 12 mg per day for 14 weeks,
`there was no fall in ACTH levels (63).
`Although most studies used rosiglitazone in
`treating Cushing’s disease, pioglitazone has also been
`tried. In a study of five patients with Cushing’s disease
`treated with pioglitazone 45 mg for 30 days, no alter-
`ation in 24 hours UFC, or ACTH and cortisol
`responses to CRH administration was seen (64).
`Currently the success of PPAR agonists in treat-
`ing Cushing’s disease remains disappointing, failing to
`reproduce the success seen in the in vitro and mouse
`model. However with the small number of patients
`and short duration of treatment, further studies are
`still needed. The discrepancy between the in vitro and
`human experience may reflect the differences in the
`order of magnitude in the dose of rosiglitazone.
`
`Somatostatin analogues
`Octreotide, an analogue of somatostatin, has been
`used extensively to treat neuroendocrine tumours and
`acromegaly. In the 1990s five subtypes of somatostatin
`receptors were identified with expression of somato-
`statin receptor subtypes in mammalian corticotrophs
`being variable (65).
`In one study all five subtype somatostatin recep-
`tors were co-localised in rat pituitary cells expressing
`ACTH (66). Yet in another study only 38% of corti-
`cotrophs expressed somatostatin receptor subtype 5
`(sst5) and 3% expresses somatostatin receptor subtype
`2 (sst2) (67). While in contrast Smith et al. found a
`predominance of sst2 rather than sst5 (68). It is gener-
`ally accepted that sst2 and sst5 are involved in the reg-
`ulation of growth hormone, prolactin and TSH (69).
`In vitro studies suggested that normal cortico-
`troph only responds to somatostatin with inhibition of
`ACTH release if the cells have been cultured in gluco-
`corticoid free medium (70-74). In agreement with this is
`the finding that ACTH secretion in normal individuals is
`not affected by infusion of somatostatin or octreotide
`but is affected in patients with Addison’s disease (75,76).
`Initial reports did show that somatostatin infusion
`decreases plasma ACTH level by between 40% to 70% in
`patients with Nelson’s syndrome (77). However, subse-
`quent studies in Nelson’s syndrome have been less
`impressive and most patients with Cushing’s disease have
`failed to respond (78-82). The chronic treatment of rat
`pituitary tumour cells and mouse corticotroph cells with
`glucocorticoid results in decreased binding of somato-
`statin (83). In cultured human corticotroph, adenoma
`cells pre-treated with hydrocortisone resulted in abolition
`of octreotide-induced inhibition of basal and CRH
`
`induced ACTH release (82). The lack of clinical efficacy
`of octreotide may be due to the down regulation of so-
`matostatin receptors by glucocorticoids. In fact in the
`mouse, sst2 gene promoter sequence is the only somato-
`statin receptor shown to be directly transcriptionally reg-
`ulated by glucocorticoids (84,85). There has been specu-
`lation that octreotide may have a role in treating ectopic
`ACTH producing tumours or in Cushing’s disease in
`combination with ketoconazole but the available eviden-
`ce is unconvincing that it has any role in Cushing’s dis-
`ease (86,87).
`There is renewed interest in somatostatin ana-
`logues in Cushing’s disease because of encouraging
`data emerging from early studies with SOM-230
`(pasireotide, Novartis Pharmaceuticals UK Ltd). It is a
`new somatostatin analogue with affinity to all the
`somatostatin receptor subtypes but with 40 fold high-
`er affinity for sst5 than octreotide (88-90).
`Compared to octreotide, SOM-230 is more
`potent at suppressing ACTH release and at inhibiting
`CRH-induced ACTH release in corticotroph tumour
`cells (91-93). Dexamethasone (10 nM) pre-treatment
`of mouse corticotroph cells fails to suppress SOM-230
`inhibition of CRH-induced ACTH release whereas the
`suppressive effect of octreotide is blocked (92).
`The preliminary results of an open label, single
`arm phase 2 study of fourteen patients with persistent or
`recurrent Cushing’s disease treated with pasireotide 600
`µg subcutaneously twice daily for fifteen days, were
`reported as an abstract at ENDO 2006 (94). Pasireotide
`normalised UFC in 3 patients (21%) and in a further 7
`patients there was at least 40% reduction in UFC com-
`pared to baseline. There was significant improvement in
`symptoms including weight loss, facial rubor, abdomi-
`nal obesity, fatigue and proximal weakness in over 40%
`of patients. The drug was well tolerated but common si-
`de effects were mild to moderated gastrointestinal
`upset, injection site reaction and a transient increase in
`fasting blood glucose with one pre-existing diabetes
`mellitus patient stopping treatment early. Although the
`results of this preliminary study are encouraging the
`final results are awaited and further studies will be requi-
`red to confirm these results.
`
`Cyproheptadine
`Cyproheptadine is a non-selective histamine and sero-
`tonin antagonist. In a small series, at a dose of 24 mg/
`day, it was effective at reducing ACTH in three patients
`with Cushing’s disease (95). There is disagreement on
`whether cyproheptadine acts either directly on the pitu-
`itary or through the inhibition of CRH (96-99). It is
`rarely effective and has no place in current practice. Its
`main side effect is sedation.
`
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`Ritanserin
`Ritanserin is a specific 5-HT2 antagonist which has
`been used in a few patients but its effects do not
`appear to be sustained in most patients (100,101).
`
`Sodium valproate
`Sodium valproate is mainly used as an anti-epileptic
`agent. Evidence for its effectiveness in treating Cush-
`ing’s disease remains conflicting. There are reports
`suggesting it is successful at suppressing ACTH at a
`daily dose of 600 mg, but more recent data have failed
`to demonstrate benefit either as primary therapy or
`after failed pituitary surgery (102,103). However, it
`may have a role as add on therapy to metyrapone at a
`daily dose of 1–2 g (104,105).
`
`Retinoic acid
`Since the 1980’s retinoic acid derivatives are widely
`used by dermatologists in the treatment of acne and
`psoriasis as well as in certain malignancy such as acute
`promyelocytic leukaemia (106,107). Retinoic acid is a
`ligand for Nur77/Nurr1 receptor which is involved in
`the physiological stimulation of ACTH by CRH
`(108). Retinoic acid inhibits cell proliferation and
`induces cell death in ACTH secreting tumours but not
`in normal pituitary cells. In the adrenal cortex it
`inhibits corticosterone secretion and cell proliferation,
`while in a mouse model, it blocks tumour growth and
`reduces circulating ACTH and cortisol. The dose was
`10 mg/kg which is within the dose range in human
`cancer therapy (108). Studies in rodents and dogs
`models of Cushing’s disease have been successful but
`there is now a need for studies in human (108,109).
`
`Agents blocking cortisol action
`Mifepristone (RU486) is a potent antagonist of the
`glucocorticoid and progesterone receptors (110). In
`man mifepristone blocks glucocorticoid action result-
`ing in negative feedback at the hypothalamic-pituitary
`level leading to a rise in ACTH, arginine-vasopressin
`and therefore cortisol (111). Mifepristone, at doses of
`
`Pharmacological Management of CS
`Dang & Trainer
`
`up to 20 mg/kg, has been successfully used to treat a
`small number of patients with ectopic ACTH syn-
`drome and there is every reason to believe that it could
`be successfully used in all patients if it were not for the
`problem of monitoring therapy (112). As a receptor
`antagonist it does not lower circulating cortisol levels,
`which in fact rise, and therefore it is very difficult to
`dose titrate and judge effectiveness. The GH receptor
`antagonist pegvisomant has gained widespread accep-
`tance as a treatment for acromegaly because its effec-
`tiveness can be judged by monitoring IGF-1. Unfor-
`tunately, the HPA axis lack a marker analogous to
`IGF-I. Even with short term use, a number of patients
`did develop symptoms of hypoadrenalism, which is
`problematic as there is no effective method of moni-
`toring over treatment (113). There has also been
`report of a case of mifepristone causing severe
`hypokalaemia that is attributed to excess cortisol acti-
`vation of mineralcorticoid receptor which responded
`to spironolactone therapy (114). With caution,
`mifepristone may have a role in the treatment of Cush-
`ing’s syndrome and could be first line treatment if a
`biochemical measure of disease were identified (115).
`
`CONCLUSIONS
`
`A number of drugs have been used in the management
`of Cushing’s syndrome. Regardless of the aetiology,
`steroid biosynthesis remains the most effective and wide-
`ly used agent. The preferred treatments are metyrapone
`or ketoconazole as monotherapy, or in combination.
`Careful monitoring of therapy is important as all agents
`have the potential of causing hypoadrenalism.
`Currently drugs acting on the hypothalamic-
`pituitary pathways have been less successful in clinical
`practice and their role is likely to be limited to add on
`therapy on an individual basis. However, with the
`identification of new receptors and development of
`agent blocking these receptors, there remains the hope
`that they may still prove to be useful in the future.
`
`Table 2. Potential agents for treating Cushing’s syndrome.
`Receptors
`Agents
`Properties
`Dopamine
`Cabergoline
`Poor long term results but renewed interest
`Bromocriptine
`especially in treating Nelson’s syndrome
`Rosiglitazone
`In vitro success not reproduced in clinical practice
`Pioglitazone
`SOM-230
`(pasireotide)
`Retinoic acid
`Nu77/Nurr1
`Glucocorticoid Mifepristone
`
`PPAR-γ
`
`Somatostatin
`
`Phase 2 study show promising results
`
`Evaluated in mouse model
`Successfully utilised in a small number of patients
`Inability to monitor treatment limits usefulness
`
`Arq Bras Endocrinol Metab 2007;51/8
`
`1345
`
`7
`
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