Cushing’s Syndrome (CS) is the result of a prolonged and inappropriate high exposition to free serum glucocorticoids. It comprises a series of signs and symptoms proper of the prolonged effect of the glucocorticoids. The clinical presentation may vary depending on the cause of the CS [1] because sudden signs may be secondary to ectopic adrenocorticotropic hormone (ACTH) producing tumours, not in the pituitary gland; while insidious presentations are more common in the Cushing’s Disease (CD).

The incidence of CS, depending on pituitary, is estimated in 5 to 10 cases per million/year, predominantly in women [2]. Patients with CS have a five-fold higher mortality, compared with the general population [3]. The screening (performed in diabetic patients whose disease is difficult to control and who are hypertensive and obese) suggests that the prevalence may reach up to 2-5% [4].

In spite of the advances in the CS treatment, the rate of relapse after transsphenoidal surgery (TSS) in CD goes up to 3 to 17% [5]; and in more recent series the reported average percentage is 12% at 4 years, after surgery [6].

The remission rates in CD are inconsistent and depend on several factors like the tumour extension, expertise of the neurosurgeon, and on the application of biochemical criteria for their definition [7]. The biochemical remission criteria followed in different centres sometimes are heterogeneous [6,8-11], and due to the fact that there is not any cortisol limit value that completely excludes the possibility of recurrence, a long-term biochemical follow-up is required [7].

The success rate in a second TSS oscillates between 38-67% [12] with an increase in the complications risk [13,14].

The main CS treatment, depending on ectopic ACTH production, is the tumour resection, with remission rates between 30-47% [15]. The probability of success depends on the possibility of tumour resection and expertise of the surgeon.

When surgery is not possible or fails, other palliative therapies to reduce the cortisol level are considered. The bilateral adrenalectomy is used in up to 56% of the cases which cannot be treated in another way [16]. Although the surgery is the first-line treatment, the pharmacological therapy is an attractive alternative as adjuvant therapy because its objective is to increase the disease remission. The use of drugs for CS is also relevant in the preoperative setting because it attempts to improve the medical conditions of the patient, before surgery.

This review explains the pharmacological options for the CS. They have been subdivided according to their pharmacodynamic properties.

Ketoconazole

Drug derived from imidazole; mainly indicated as antifungal. Since 1983, Engerlhardt and Weber [17] reported the effectiveness of this drug for adrenocortical adenoma CS. Later on, they recorded the inhibitory effect of ketoconazole in the following adrenal enzymes: 17, 20 desmolase (where it has its most potent effect), an in a less degree in 17 a-Hydroxylase, 11 b-Hydrosylaxe, 16a and 18-Hydroxylase. Both in vivo and in vitro, the androgens inhibition is higher than the one with cortisol (30-50% vs. 19%, respectively) [17].

Feelders et al. [18] have documented that ketoconazole inhibits the production of ACTH in AtT20 mouse cells and in human corticotropic tumour cells. Besides, ketoconazole inhibits cell growth in part for apoptosis induction.

A dose between 400 and 1200 mg/day of ketoconazole may reduce the production of cortisol in patients with CS derived from different aetiologies; thus, it may be administered 2 or 3 times a day. The initial intake may be 200 mg BID, then a progressive titration until a maximum dose of 1200 mg/day, based on serum cortisol and free urinary cortisol in 24 hours [18-20]. The blood pressure control is more effective in patients with CS who receive antihypertensive and ketoconazole than only with antihypertensive [21]. The main adverse effect of ketoconazole is hepatotoxicity: an increase in the serum concentration of hepatic enzymes is reported in 5-15% of the

patients and hepatic impairment in 1 from 15000 cases [17,22]. It may also provoke rash (2%), oedema (6%), gastrointestinal disorders (8%), male hypogonadism, and gynecomasty (13%) [18,23]. It is important to regard that when ketoconazole interacts with p450 cytochrome enzymes, it may modify serum concentrations from different drugs [20]. There are reports of paraneoplastic CS, where up to 28% present complete hormonal response and symptomatic hypoadrenalism in 12% out of the total of the treated cases; although most of the patients die because of progressive malign disease, related to escape phenomenon from the ketoconazole inhibition [19]. Prospective trials with monotherapy (based on ketoconazole) have not been performed yet. Data about effectiveness have been taken from retrospective studies, most of them with a small number of patients.

Castinetti et al. [24] reported that ketoconazole induced biochemical remission in 50% of the patients with CD. Regarding all the trials, the results show that ketoconazole has an effectiveness of 70% [24], because the CD remission rates vary from 25 to 93% [17,23,25,26]. The trials are different because of the characteristics of the patients, treatment time, and adjuvant therapies, among others.

Ketoconazole has been administered in some cases of CS during pregnancy; and the adverse effects have been delay in the intrauterine growth, besides potential antiandrogenic effects produced by the inhibition of the aromatase enzyme [27]. Teratogenic and embryotoxic potential have been reported in mice with a very high dose [28]. It has also been reported that a patient with CD did not accept surgical treatment, but a normal baby born (by vaginal delivery) with a gestation of 37 weeks was documented [29], nevertheless, there is scarce experience about the use of drugs during pregnancy in humans thus, we do not recommend it.

Metyrapone

Metyrapone was examined in humans nearly immediately after discovering the blockade effects on the steroidogenesis in animals [30]. Nowadays, it is considered an alternative treatment in patients with CS. This is a selective inhibitor of the CYP11B1 (11b-Hydrosylaxe) which diminishes the aldosterone synthesis; nevertheless, the accumulation of 11-desoxicortisol concentrations maintain (at least partially) the functions depending on mineralocorticoids. In some studies, the inhibitory capacity of metyrapone in the 17a, 18- and 19 hydroxylase is mentioned, effects which minor clinical relevance [31].

• The initial recommended dose is 250 mg four times a day, with a maximum dose of 6 g/day [32]; however, the maximum steroidogenesis suppression demands the usage of about 4 g/day [33]. In patients with CD, the cortisol decrease is observed within the 2 hours after the first dose, which reaches a biochemical control in 75% of them with an average dose of 2.5 g/day [34]; in some studies, an excellent control up to 66 months has been reported [35]. Obviously, the administration has been monitored to recognize the potential development of hypocortisolism [18].

Treatment with metyrapone effectively inhibits the aldosterone biosynthesis and accumulates its precursors with a weak mineralocorticoid activity; thus, the electrolytic balance and the blood pressure vary according to every patient condition, depending on the degree of aldosterone inhibition and stimulation of 11-desoxicorticosterone [32], in some cases, synthetic mineralocorticoids are required.

The mainstay metyrapone clinical indications are severe hypercotisolism secondary to unresectable ectopic cortical adrenocarcinoma or ectopic production of ACTH [36], as well as adjuvant in case of surgical failure by CD. In this condition the dosage is 500-750 mg three of four times a day [33].

A potential disadvantage in the CD treatment is the compensatory increase in ACTH production and the probability of developing Nelson Syndrome (NS), which in turn, may increase the adrenal production of cortisol, as well as androgens and mineralocorticoid precursors [18]. Based on these grounds, the prolonged administration results in various degrees of hirsutism and acne (19% to 70%) and high blood pressure [34]. Other adverse effects include nausea, headache, sedateness, rash [33]. Hypertension and hypocalcemia are less likely to develop in cases of independent ACTH [36].

Etomidate

This is an anaesthetic-hypnotic agent, imidazolic derivative which inhibits the steroidogenesis by inhibiting the cleavege of the side-chain of cholesterol and the enzymes 17-hydroxilase, 11 b-Hydroxylase, and C17-20 lyase. Some a-adrenergic agonist properties have also been attributed to it [37].

Etomidate induces apnea and hypnosis within 10-15 minutes after its IV administration. Due to this “fast” action, etomidate is really effective in patients with CS who present acute complications which are life-threatening, for instance, psychosis and severe hypertension. Most of the times, these episodes are secondary to ectopic ACTH production [38]. Etomidate is exclusively administered intravenously in doses of 0.03 to 0.3 mg/kg/hr in a continuous infusión [18], which reaches cortisol reductions in periods of 11-24 hours [36]. It has shown so significant effects that some authors have used it in combination with hydrocortisone infusions in order to keep the stable cortisol levels, mainly in children [39]. Other reports have stated its indication in patients with long-term evolution of CD (more than 14 years) and with unsuccessful TSS, which presented an acute psychotic break. In these cases, etomidate was administered in doses of 3.0-3.5 mg/hr along with hydrocortisone infusion, which results in remission of the acute clinical manifestation [40].

The etomidate adverse effects include sedation, hypotension, hypertension, and bradicardia [20]. Etomidate is associated with mortality increase in patients severely ill because it enables acute adrenal failure; thus, it is only indicated in selective, complicated, intrahospital cases, which require short-term clinical improvement or temporal treatment before a definite therapy, but it is necessary to have in mind the possibility of requiring a concomitant infusion of hydrocortisone [36,41].

Mitotane

This is an adrenolitic agent mainly indicated in the treatment of adrenal carcinoma. It is effective to prolong survival or as adjuvant in metastatic disease. Besides these effects in the suppression of the cell growth, mitotane inhibits the specific enzymatic actions, particularly in the cleavage of the side-chain of cholesterol and 11b-Hydroxylase, which implies a diminished production of cortisol [18]. It has also been reported that mitotane normalises the urinary free cortisol (UFC) levels in 84% of patients [42]. The drug is better absorbed when taken with fat food, since absorption and transportation are coupled to lipoproteins [36].

Once the mitotane administration is stopped, it is possible to observe mitotane concentrations in serum up to 6 to 9 weeks, due to it is stored in fat tissue. It is mainly excreted in stools (60%). Oral doses oscillate between 2-16 g/day; the treatment should continue for at least 3 months. It is not recommended its administration in combination with spironolactone, because it interferes with suprarenal suppression [43].

At doses more than 4 g/day increases the likelihood of suppression of aldosterone [36], as well as the requirement of fludrocortisone therapy as mineralocorticoid replacement. The long-term remission rates at more 4 g/day doses (adrenolitic doses) reach up to 30% [20] nevertheless, it has been reported that the combination of mitotane and pituitary cobalt radiation causes clinical and biochemical remission in 80% of the patients with CD [44], but near 60% of the patients presents relapse when stopping to receive the medication [45].

The mitotane adverse effects are dose-dependent and usually unbearable with doses of 6 g/day. In the follow-up, the measure of UFC is crucial because the serum cortisol may be high, even when the free circulating is not. This condition is attributable to the fact that mitotane increases the fixation of cortisol to the corticosteroids binding globuline [36].

The predominant adverse effects of high-dose mitotane are anorexia, drowsiness, lack of coordination, which may be reversible when stopping the administration of the drug. Hepatotoxicity may develop, as well as teratogenic potential; thus, the patients must be informed about it, and precautions must be observed. The adrenalitic effect involves oxidative damage by free radicals [36], and may induce adrenal failure and hypercholesterolemia [18].

Maintenance therapy with mitotane may be a reasonable option in cases of persistent and non-treatable CD [46]. But, it is the last option (because of its adrenolitic and cytotoxic effects) in case of failure or intolerance to other drugs with a better security profile.

Aminoglutemide

This drug blocks the steroid production because it inhibits enzymes CYP11A1, CYP11B1, and aromatase [47]. It has been indicated for children and adults with CS at a dose of 500 to 2000 mg/ day. Aminoglutemide has not shown to be effective as monotherapy. Nowadays, it is not available in the market; hence, it is excluded as a current therapeutic option.

Dopaminergic agonists

Dopamine is a catecholaminergic neurotransmitter predominant in the central nervous system. It acts by means of its receptors (D₁-D₅). The D₂ receptor expresses heterogeneously and variably at the anterior and intermediate lobules in the hypophysis up to 89% of all types of pituitary tumours. At present, the dopaminergic agonists play a central role in the treatment of prolactinomas, but the D₂ expression have also been recognized in a variable way in 23% to 80% of the ACTH secretory pituitary adenomas. The expression of D₂ receptor has been related to the inhibitory effect of the dopaminergic agonists in the ACTH secretion in vitro [48,49].

Bromocriptine is a D₂ agonist and a D₁ antagonist, pharmacokinetically with scarce detectable remnants in the circulation in 11-14 hours [50]. In cell cultures of human pituitary tumours, bromocriptine inhibits the ACTH secretion and induces apoptosis in AtT-20 cells [48]. In a study of 23 patients with CD, treatment with bromocriptine at a dose of 1.25-30 mg/day during 3-180 weeks, 42% reach normal urinary and plasma concentrations of glucocorticoids; the ACTH concentrations went down >50% in 18% of the patients. Better results have been reported at a dose of 17.5-40 mg/day [51,52]. In different studies, the effectiveness of bromocriptine is 0 to 50%, with urinary and/or plasma cortisol normalization in ≤ 10% of the nonselected patients [48,53], along with scarce results in a long-term period [8].

Cabergoline is an ergot derivative, dopaminergic agonist with a higher selectivity and affinity than bromocriptine by the D₂ receptor. It is indicated in the treatment of prolactinomas; it is fully excreted within 240 hours in an enterohepatic way [51].

Godbout et al. [54] carried out a retrospective analysis on monotherapy with cabergoline in 30 patients with CD at an initial dose of 0.5-1.0 mg/week with progressive adjustments until a maximum dose of 6 mg/week, taking the UFC as a criterion. A complete response was reached in 3-6 months in 36.6% of the patients and a partial response of 13.3%. At a long-term period (median of 37 months), 30% maintain complete response at a dose of 2.1 mg/week, the partial responders did not maintain the long-term improvement shown initially.

Pivonello et al. [55] carried out a prospective study with 20 patients who had undergone previous surgery without disease remission at an initial dose of 1 mg/week with monthly adjustments until achieve response or a maximum dose of 7 mg/week (median 3.5 mg/week). It was reported a response to cabergoline in a 3-month period in 15 patients (75%), just ten of them maintain it. The continued control within 24 months could be achievable in 8 (40%) of the patients (two patients were excluded because of symptomatic hypotension); besides, a tumour reduction was recorded in 20% of the patients and an improvement in hypertension and glucose intolerance in most of the patients, irrespective of UFC changes.

Lila et al. [56] carried out another prospective study, but they included 20 patients without surgical remission, with or without adjuvant radiotherapy at an initial dose of 1 mg/week and a maximum dose of 5 mg/week (median 3.6 mg/week) with a maximum followup to a year. Serum markers were assessed Midnight Serum Cortisol (MNSC), Low-dose Dexamethasone Suppression Serum Cortisol (LDSC) and were recorded a pharmacological response of 28%, 25%, and 17% in terms of LDSC or MNSC (or both), isolated LDSC and isolated MNSC, respectively; they did not assess UFC. They observed that the patients with low basal cortisol concentrations; MNSC, and LDSC, before the beginning of the treatment, had a higher probability to respond to the drug.

With respect to the combined therapies, Vilar et al. [57] carried out a study to assess cabergoline effectiveness (3 mg/week) alone or in combination with relatively low ketoconazole doses (≤ 400 mg/day) in 12 patients with CD, treated unsuccessfully with TSS. After 6-months treatment the UFC was normalized in 25% of the patients with only one cabergoline dose 2-3 mg/week. It recorded UFC reductions from 15-48.8%. Adding ketoconazole to 9 patients (without promising response to cabergoline) achieved the UFC normalization in 6 patients at a dose of 200 to 400 mg/day.

A weighty fact to be considered is that there is no homology among the laboratory tools and the biochemical criteria used to prove complete or partial response [54,55] until MNSC and LDSC [56]. Likewise, the maximum administered doses and the follow-up time differs; then, the results are not the same. More prospective studies with homogeneous criteria, dose, and follow-up time are necessary to establish a firm posture about the usefulness of the dopaminergic agonists. At present, cabergoline may be considered as a first option in this pharmacological group because of its higher selectivity upon D₂, tolerability, and evidence in the long-term follow-up; nevertheless, there is not enough information. Apart from differences attributable to methodological matters, the variability in expression of dopaminergic receptors in these pituitary adenomas may be added [53].

With respect to cabergoline, there are reports about tumour reduction in 2 cases of pituitary ACTH-secreting adenomas associated to NS at a dose of 2 mg/week during a year [58,59]. With respect to security profile, valvular damage has not been recorded in patients treated with low doses; however, an increase in the prevalence of tricuspid regurgitation has been reported in cases of cumulated doses >180 mg [60].

Somatostatin analogues

Somatostatin, a cyclopeptide present in two active forms (aminoacids 14 and 28), widely disseminates at brain level and in peripheral tissues. Its biological actions are mediated by the binding of 5 receptors to G protein, named somatostatin receptor (sst_1-5), dependent on the receptor isoform. It conditions inhibition of the hormone secretion or inhibition of cell proliferation and apoptosis; it also regulates the releasing of several hormones like growing hormone, glucagon, insulin, gastrin, and ghrelin. Likewise, it inhibits exocrine secretions, as well as the intestinal motility [61].

SST_1-5 inhibit cell proliferation by a dependent pathway of fosfotirosine-fosfatase, and interacts with the MAPK pathway. More recent studies suggest an additional interaction with a serine-threoninephosphatase. SST₃ is cytotoxic and causes cell death or apoptosis by means of a mechanism depending on fosfotirosine-phosphatase and activation of proteins p53 and Bax [48]. Natural somatostatin binds with great affinity to the 5 receptors. Nevertheless, somatostatin effectiveness is limited because of its accelerated catabolism at serum level. Some time ago, several stable somatostatin analogues were synthesized metabolically; among them, ocreoctide and lanreotide bind only to sst₂ with high subnanomolar affinity. They have a moderate affinity with sst₃ and sst₅, besides, they show a low or no binding with sst₁ and sst₄. In patients with CD, somatostatin and octrotide have not proven significant inhibition of the ACTH secretion [62,63].

Somatostatin and its analogues may suppress ectopic ACTHsecreting from neuroendocrine tumours. Tumours positive to octreoscan would indicate the presence of somatostatin receptors; then it is more likely that they respond to this ACTH and cortisol suppression therapy. Nevertheless, the expression or record of such receptors is variable [36,64]. Thanks to previous reports, the limited effectiveness has been proven (specifically octreotide) probably due to the presence of high cortisol concentrations which induce a low regulation of SST₂ [65]. A noteworthy future tool to optimise the medical treatment would be the target search for somatostatin tumour receptors by rabbit monoclonal antibodies UMB-4 and UMB-1 during routine hystopathological examination in order to choose the best drug according to the predominant receptor [66].

Pasireotide is a recent somatostatin analogue, with multireceptor activity. It is a cyclohexapeptide which binds with great affinity to all the sst receptors, except sst₄. Conversely with octreotide, pasireotide shows a high subnanomolar affinity to sst₅ and better metabolic stability. Lesche et al. [62] showed that it is less effective than octreotide in inducing internalization and signalling of the sst₂ receptors. In contrast, pasireotide is more effective in inducing internalization and signalling of sst₃ and sst₅ receptors. This latter is really important since it predominates in the ACTH-secreting adenomas and it is diminished in adenomas with aggressive behaviour [49]. The functional activity of pasireotide upon sst₁, sst₃, and sst₅ is >30, 11, and 158 times higher, respectively, and 7 times lower upon sst₂ [23].

Ben-Shlomo et al. [67] documented that in mouse corticotropic tumour cells, the pasireotide action is determined by the SST₅ expression and that the action upon SST₂ is minimum. In a similar trial, pasireotide showed inhibition of the basal and stimulated release of ACTH, but neither did it inhibit the cell proliferation or induce apoptosis, or the synthesis inhibition of propiomelanocortine. That suggests that the potential mechanism of action is a blockade in the ACTH release or an increase in its degradation [48]. In a phase II study, which includes patients with CD recently diagnosed or with postsurgical relapse at a dose of 600 mg pasireotide during 15 days, a reduction in UFC was achieved in 76% of the patients. 17% of them reach normal UFC concentrations; likewise, direct effect upon ACTH release was observed, the stable serum concentration of the drug was reached within 5 days after beginning the treatment [68]. Recently, a phase III study with pasireotide assessed 162 patients with newly diagnosed CD or with persistence/relapse: 82 patients at a dose of 600 mg/BID and 80 patients at a dose of 900 mg/BID. An increase in dose was considered at a dose of 300 mg/BID in case of absence of response posterior to the first 3 months of treatment (until a maximum dose of 1,200 mg/BID), which establishes a normal UFC level after 6 months of treatment as the main objective. That study found a response in 12 patients with 600 mg, and in 21 in the group of 900 mg. Besides, the clinical stigmas, the salivary cortisol level, and in ACTH decreased. Additionally, a decrease in the tumour volume of 9% was documented in the group of 600 mg/ BID and 46.3% in the group of 900 mg/BID. The investigators concluded that pasireotide is a potential drug for the treatment of patients with CD [69].

Pasireotide has also demonstrated benefits when it is administered in combination with other drugs in pituitary or adrenal action, in patients with therapeutic failure to it. A recent trial examined 17 patients with CD to assess the effectiveness of the medical therapy with pasireotide as the base treatment. Such therapy was extended sequentially with cabergoline and ketoconazole. The sequence begins with pasireotide 100 mg sc three times a day. If the UFC did not normalise on day 15, pasireotide dose increase to 250 mg sc three times a day. On day 28, cabergoline was added to pasireotide, if the level of UFC was high. If the level of UFC was not normal on day 60, ketoconazole was added at a dose of 200 mg three times a day. Pasireotide induced normalization of UFC in 4 out of 17 patients on day 60. A total of 8 out of 17 patients still presented high UFC in spite of the combined therapy. The addition of ketoconazole induced complete response in 88% of the patients (6 out of remaining 8), plus a clinical improvement of blood pressure, weight, and waist circumference. The adverse effects included deterioration of the glucose metabolism and IGF-1 decrease [70].

On the other hand, since somatostatin receptors have been found in the normal adrenal cortex and in adrenocortical tumours, it is postulated that pasireotide may have an effect upon this level; however, more evidence is required [61].

Pasireotide security profile has been assessed in healthy volunteers and in cases of acromegaly, CD, and carcinoid syndrome carriers. After single or multiple doses, the most common adverse effects were gastrointestinal. Transitory fasting and/or postprandial glucose increase has been recorded [61]. In the study carried out by Colao et al. [69] 72.8% of the patients developed hyperglycemia; 45.6% of them needed antihyperglycemic treatment; the patients with concomitant diabetes were more likely to develop uncontrolled serum glucose; no cases of ketoacidosis or hyperosmolar state were reported; 8% of the patients presented data of hypocortisolism which required decrease or temporal withdrawal of the dose.

Alternative therapies for pituitary

A wide variety of drugs has been examined with the purpose of supporting the management of patients with persistent or relapsing disease; among them we can mention glitazones (PPAR-g agonists) and valproate magnesium. Some studies in patients only demonstrated contradictory results. The advances in the research have enabled a better comprehension of the pathogenesis of the pituitary tumour processes. CD is not the exception because the research of more targeted therapies, these latter drugs offer little concern for the development of clinical trials.

Mifepristone

The progesterone receptor regulates its effects by specific transcription of depending-ligand genes [71]. The first report about RU486, a glucocorticoid and progesterone receptor antagonist was published in 1981 by Spitz [72] Mifepristone is a synthetic steroid (synthetic norethindrone progestin derivative) which primarily acts as a potent progesterone and cortisol antagonist. It has mainly indicated as a drug for interrupting pregnancy; although it is effective in additional clinical settings [71]. In high doses, it is a powerful specific antagonist of the type II glucocorticoid receptor and preventing actions of hypercortisolism on target organs [20,72].

It is absorbed in the gastrointestinal tract and has an absolute bioavailability of 69% after the administration at a dose of 20 mg. Within 1 to 2 hours after intake, the maximum serum concentration is reached. Mifepristone’s half life in humans is 0-40 hrs and binds to serum proteins in 98%. Mifepristone and its metabolites have a higher affinity for the glucocorticoid receptor (mifepristone 100%, metabolites 45-61%) than dexamethasone (23%) and cortisol (9%). It inhibits the CYP3A4 enzymatic activity in vitro [36,71]. The different metabolites bind to the proteins and disseminate to various organs, including the central nervous system [36].

A crucial fact is that in the follow-up serum ACTH and cortisol do not give data about the efficacy, which must be exclusively assessed according to a clinical ground [20]. A potential adverse effect in patients with CD under mifepristone treatment is the ACTH and cortisol rise by feedback. As the mineralocorticoids are not blocked, the cortisol increase may enable hypokalemia; hence, a blockade with a mineralocorticid antagonist as spironolactone or eplerrenone may be necessary. Hypercortisolism symptoms like anorexia, nausea, arthralgia, and headache may also appear, and need for dose adjustment [36].

Johanssen and Allolio [73] carried out a retrospective analysis of the hypercortisolism treatment with mifepristone in a total of 18 patients. Daily doses administered varied from 5-30 mg/kg/day. The results suggested a significant improvement in patients who had undergone surgery and inhibitors of adrenal steroidogenesis could not control hypercortisolism. A favourable fact is its fast onset of action; thus, it is particularly effective in acute crisis like cortisol-induced psychosis.

Fleseriu et al. [74] performed a multicenter study in patients with CS and surgical treatment failure. Mifepristone was administered at doses of 300-1200 mg/day. Thirty four patients out of 50 who participated in the study-finished the 24-week follow-up and a significant improvement was reported in the glucose metabolism, without changes in the median blood pressure. There was a meaningful decrease in the waist circumference, body fat and an increase in the insulin sensitivity. The most common adverse effects were gastrointestinal and fatigue (48%). this latter was the leading cause of treatment discontinuation. Adrenal failure was reported in two patients, 34% of the total presented hypokalemia.

Recently, it was reported that two cases under mifepristone treatment enabled “positivization” in two bronchial carcinoid tumours which at the beginning did not respond to ¹¹¹in-pentetreotide (octreoscan). The dosage began in 400 mg/day and was adjusted until 600 and 800 mg/day. The findings reinforce the theory of the inhibition of SST2 expression in neuroendocrine tumour cells by hypercortisolism. This clears the path about mifepristone new indications with a “therapeutic diagnose” which may increase the diagnostic sensitivity previously reported with octreoscan (50% in most of the series) after the receptor antagonism [64].

Food and Drug Administration (FDA) authorized the mifepristone administration in February 2012 for hyperglycemia control in adults with endogenous hypercortisolism and diabetes mellitus, glucose intolerance or for patients who were not candidate for surgery or did not respond to surgery [75]. Along with the FDA authorization, we suggest its administration in cases of partial efficacy and/or non-availability and/or intolerance to other drugs because (in the case of mifepristone) there are not current objective tools for a long-term follow-up (based on biochemical criteria). Likewise, its administration may be considered in case of psychotic crisis secondary to hypercortisolism and/or in cases where a fast response is needed because of the severity of the case [76].

Dopastatin

It is a chimeric molecule which may take advantage of the assumed potential of the interaction of the somatostatin and dopamine receptors. It has a high activity on the D₂ and SST₂ receptors, and a moderate one upon SST₅. Its role on the non-functional pituitary adenomas executes a cytostatic and cytotoxic effect mediated by D₂ and involving activation of ERK1/2 and p38 pathways [77]. Regarding its efficacy in ACTH secretors, the preliminary results, obtained in vitro, were promising since they demonstrated inhibitory capacity of the dose-dependent cell replication in 60% of the patients [78]. Later on, it has been reported that the dopastatin acute subcutaneous administration showed prolonged half life and duration of the biological effect; nevertheless, the chronic administration resulted in a metabolite with dopaminergic activity of gradual accumulation which interferes with the activity of the original drug [79].

When this article was finished, the only therapy authorized by FDA for the management of CS in humans is mifepritsone because it has very accurate indications. We do not consider that it discredits or call into question the efficacy of the medical therapy, as long as the differences of the mechanisms of action, efficacy of each drug, and adverse effects are clear.

It is important to take into account that most the pharmacological agents, previously described, may induce adrenal failure. Therefore, patients and their caregivers must be informed and trained about these risks in order to be able to recognize the alarm signs and symptoms and ask for a timely medical attention.

It is evident that there are a lot to be researched and excelled in the treatment of CS.

We thank the Endocrinology and Metabolism Department staff at the Hospital General de México and Hospital Regional de Alta Especialidad del Bajío.