1.
`
`Background
`
`2. Medical need
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`Existing treatment
`
`Scientific rationale for
`potential new drugs
`
`Current research goals
`
`Competitive environment
`
`Potential development issues
`
`Expert opinion
`
`Review
`
`Drugs in the medical treatment of
`Cushing’s syndrome
`
`David E Schteingart
`University of Michigan, Division of Metabolism, Endocrinology and Diabetes, Department of
`Internal Medicine, 1150 West Medical Center Dr, Rm 5570; Medical Center Research Building 2,
`Ann Arbor, MI, 48109, USA
`
`Cushing’s syndrome is a complex endocrine condition with potential serious
`complications if untreated or inadequately treated. Transsphenoidal surgery
`with resection of a pituitary adenoma is successful in 75 – 80% of patients, but
`approximately 20 – 25% show persistence of Cushing’s, and a similar propor-
`tion may experience recurrence within 2 – 4 years post-op. When surgery fails,
`medical treatment can temporarily suppress excessive cortisol production and
`ameliorate its clinical manifestations while more definitive therapy becomes
`effective. We describe pharmacological approaches to the treatment of
`Cushing’s syndrome. Drugs used to suppress cortisol secretion are mostly
`inhibitors of steroidogenesis. Ketoconazole, fluconazole aminoglutethimide,
`metyrapone, mitotane and etomidate are in that category. Ketoconazole is in
`current use while other drugs, although mostly available in the past, continue
`to have a potential role either alone or in combination. Drugs that suppress
`adrenocorticotropic hormone (ACTH) secretion are less popular as standard
`treatment and include cyproheptadine, valproic acid, cabergoline, somato-
`statin analogs, PPAR-g agonists, vasopressin antagonists. Some of these drugs
`have been tested in limited clinical trials but there is potential therapeutic
`benefit in analogs with better specificity for the class of receptors present in
`ACTH-secreting tumors. A third category of drugs is glucocorticoid receptor
`antagonists. Mifepristone is currently being tested in clinical trials in patients
`with persistent or recurrent Cushing’s disease and in patients with metastatic
`adrenal cortical carcinoma or ectopic ACTH syndrome not amenable to
`surgery. We also review replacement
`therapy after
`surgery
`and
`non-specific drugs to treat complications in patients with severe hypercortisol.
`The review provides a complete survey of the drugs used in the medical
`treatment of Cushing’s, and new advances in the development of pituitary-
`active drugs as well as receptor blockers of glucocorticoid action. It also
`provides avenues for exploration of new drugs active on somatostatin, dopa-
`mine and vasopressin receptors. There are effective pharmacological agents
`capable of chronically reversing biochemical and clinical manifestations of
`hypercortisolemia in Cushing’s syndrome but new drugs are needed with
`action at the pituitary level.
`
`Keywords: ACTH, glucocorticoids, hypercortisolemia, pituitary tumors
`
`Expert Opin. Emerging Drugs (2009) 14(4):661-671
`
`1. Background
`
`Cushing’s syndrome is the clinical manifestation of glucocorticoid steroid hormone
`excess. It consists of weight gain with trunkal adiposity, impaired glucose tolerance
`or diabetes, hypertension,
`irritability,
`insomnia, cognitive impairment, mood
`changes
`ranging from anxiety and depression to psychosis and foremost,
`
`10.1517/14728210903413522 © 2009 Informa UK Ltd ISSN 1472-8214
`All rights reserved: reproduction in whole or in part not permitted
`
`661
`
`1
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`Drugs in the medical treatment of Cushing’s syndrome
`
`Article highlights.
`
`. If inadequately treated, Cushing’s syndrome is associated
`with serious complications.
`. When surgical treatment fails, medical treatment offers
`temporary relief.
`. Drugs suppress Cortisol secretion by inhibiting
`steroidogenesis.
`. Glucocorticoid receptor antagonists are useful when
`inhibition of steroidogenesis is inadequate.
`. New drugs are needed with primary action at the
`pituitary level.
`
`This box summarises key points contained in the article.
`
`Table 1. Etiologic types of Cushing’s syndrome.
`
`ACTH dependent
`Pituitary
`
`Microadenomas
`
`Macroadenomas
`
`Hyperplasia
`Ectopic
`
`CRH and ACTH
`ACTH independent
`Adrenal cortical tumors
`
`Adenomas
`
`Carcinomas
`
`Adrenocortical
`
`Hyperplasia
`
`Macronodular
`
`and associated hypokalemia but frequently resemble the clinical
`picture of pituitary ACTH-dependent disease. Neoplasms
`secreting ACTH may be located in the head (paranasal sinus
`neuroendocrine tumors), neck (medullary thyroid cancer),
`chest (oat-cell lung cancer, malignant thymomas, bronchial
`carcinoids) or abdomen (islet cell tumors, paragangliomas) [1].
`They are distinguished from pituitary tumors by lack of central
`to peripheral gradients of ACTH during IPS sampling.
`A primary adrenal etiology is identified by the finding of
`elevated cortisol with suppressed ACTH levels, and the
`discovery on adrenal imaging of a unilateral adrenal mass
`or bilateral micro or macronodular hyperplasia. The benign or
`malignant nature of unilateral adrenal masses can be suspected
`on the basis of size and lipid content. Masses larger than 5 cm
`have a greater probability of being malignant, and lipid-rich
`masses have higher probability of being benign [2]. Bilateral
`primary pigmented micronodular adrenal disease (PPNAD)
`can be associated with extra-adrenal neoplasmas and lentigi-
`nosis syndrome (Carney complex). Carney is due to mutations
`in the PRKAR1A gene which may act as a tumor suppressor
`gene by regulating PKA activity. This in turn can suppress or
`stimulate cell growth and differentiation. Bilateral macronod-
`ular hyperplasia may be associated with adrenal cortical
`expression of aberrant receptors [1].
`Treatment of Cushing’s syndrome depends on its etiologic
`sub-type. The primary treatment for pituitary ACTH-depen-
`dent disease is transsphenoidal resection of a pituitary ade-
`noma and occasionally hypophysectomy [1]. Resection of the
`primary tumor is the treatment for ectopic ACTH syndrome,
`and resection of the adrenal tumor or unilateral or bilateral
`adrenalectomy, the treatment for ACTH-independent disease.
`
`Primary pigmented micronodular – Carney complex
`
`Secondary to expression of illicit receptors
`
`2. Medical need
`
`manifestations of protein catabolism, with skin and muscle
`atrophy,
`loss of bone mineral density and osteoporosis.
`Cushing’s syndrome can result from the administration of
`glucocorticoids or spontaneous cortisol hypersecretion. There
`are several etiologies of endogenous hypercortisolism, includ-
`ing excessive adrenocorticotropic hormone (ACTH) secretion
`or a primary increase in cortisol production [1]. Rarely, over-
`expression of glucocorticoid receptors can lead to Cushing’s
`syndrome. These various sub-types are listed in Table 1.
`Pituitary ACTH-dependent hypercortisolism, also known as
`Cushing’s disease (CD), account for 70% of all cases, the
`majority of them being caused by a microadenoma measuring
`less than 10 mm. These adenomas can be detected by MRI or in
`case of questionable MRI imaging, by inferior petrosal sinus
`(IPS) sampling. Macroadenomas may extend into the supra or
`parasellar areas and invade the cavernous sinus. Syndromes of
`ectopic ACTH and/or corticotropin releasing hormone (CRH)
`secretion can be characterized by high ACTH and cortisol levels
`
`Transsphenoidal surgery with resection of a pituitary adenoma
`is successful in 75 – 80% of patients, depending on the skill
`and experience of
`the surgeon performing the surgery.
`Approximately 20 – 25% have persistence of Cushing’s,
`and a similar proportion may experience recurrence within
`2 – 4 years post-op. Invasive ectopic ACTH-secreting tumors
`can present with local invasion or distant metastases and be
`unresectable, and patients with Stage IV, metastatic adrenal
`cortical carcinoma may not be amenable to surgical control or
`suppression with chemotherapy. Patients with adrenal cortical
`hyperplasia may not wish to have a bilateral adrenalectomy
`that will render them adrenal insufficient for life.
`When surgery fails to reverse the hypercortisolemia, med-
`ical treatment is available to temporarily suppress excessive
`cortisol production and ameliorate its clinical manifestations
`while more definitive therapy becomes effective. Untreated
`or inadequately treated Cushing’s syndrome can lead to
`cardiovascular mortality, skeletal fractures, limiting proximal
`muscle weakness,
`insulin resistant hyperglycemia
`and
`persistent cognitive deficits.
`
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`Expert Opin. Emerging Drugs (2009) 14(4)
`
`2
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`

`

`Table 2. Drugs used for treatment of Cushing’s
`syndrome.
`
`Category
`
`Drugs
`
`Adrenal inhibitors
`
`Suppressors of ACTH
`
`Antagonists of aberrant
`adrenal receptors
`
`Reverse cortisol effect
`
`Substitution therapy
`
`Ketoconazole, fluconazole
`aminoglutethimide, metyrapone,
`mitotane, etomidate, trilostane
`
`Cyproheptadine, valproic acid,
`cabergoline, somatostatin analogs,
`PPAR-gı¨ agonists, VP antagonists
`b-blockers, V1a receptor antagonists,
`GnRH antagonist, somatostatin
`analogs
`
`Glucocorticoid receptor antagonists,
`mifepristone
`
`Hydrocortisone, prednisone,
`fludrocortisone, DHEA
`
`Drugs to treat
`symptoms
`
`CNS active: antidepressants,
`anxiolytic, antipsychotic, hypnotics
`
`Antihypertensive,
`diuretics
`
`Glucose lowering
`
`Lipid lowering
`
`Antiresorptive
`
`ACTH: Adrenocorticotropic hormone; DHEA: Dehydroepiandrosterone;
`GnRH: Gonadotropin-releasing hormone; VP: Vasopressin.
`
`3. Existing treatment
`
`Various pharmacological agents are available to suppress
`cortisol production and ameliorate the clinical manifestations
`of Cushing’s syndrome. The majority of the available drugs
`are old but still in use. The efficacy of newer drugs still needs
`to be validated by well-designed and powered clinical trials.
`Given the infrequent occurrence of Cushing’s syndrome and
`the heterogeneity of its etiology, this is not likely to be
`accomplished any time soon.
`Drugs used in the treatment of Cushing’s syndrome fall
`into several categories:
`
`1) Adrenal inhibitors/adrenalytic drugs
`2) Suppressors of ACTH secretion
`3) Drugs to block aberrant adrenal receptors
`4) Drugs to reverse the effect of excessive cortisol; secretion.
`5) Substitution therapy following pituitary or adrenal surgery
`6) Drugs
`to treat
`symptoms associated with Cushing’s
`syndrome
`
`Table 2 summarizes the major drugs involved and Table 3
`their mechanism of action.
`
`3.1 Description of drugs
`3.1.1 Adrenal inhibitors
`3.1.1.1 Ketoconazole
`An imidazole derivative, it inhibits the synthesis of ergosterol
`in fungi and cholesterol in mammalian cells by blocking
`
`Schteingart
`
`demethylation of lanosterol. In addition to the effect on
`cholesterol
`synthesis, ketoconazole inhibits mitochondrial
`cytochrome P-450-dependent enzymes such as 17a-hydrox-
`ylase, 11b-hydroxylase and cholesterol side chain cleavage
`enzyme in rat and mouse adrenal preparations. Used in
`clinical practice as an antifungal medication, ketoconazole
`has become an important inhibitor of gonadal and adrenal
`steroidogenesis in doses as low as 200 – 600 mg/day. Several
`reports have been published on long-term treatment with
`ketoconazole in patients with Cushing’s syndrome which
`resulted in sustained decrease of urinary free cortisol and
`reversal of the clinical manifestations of hypercortisolism [3,4].
`The drug can be used as initial treatment in cases of severe
`hypercortisolism and in preparation for more definitive ther-
`apy such as transsphenoidal surgery. Early reports suggested
`that not all types of Cushing’s respond to a similar degree and
`that patients with ACTH-independent disease have a more
`sustained suppression [5]. Overall, the response to ketocona-
`zole has been quite consistent, regardless of the etiology of
`hypercortisolism. Patients with very high cortisol levels such as
`seen in metastatic adrenal cancer or ectopic ACTH syndrome
`may require doses as high as 1200 mg/day. When patients are
`treated with ketoconazole, adrenal insufficiency is avoided by
`adjusting the dose to allow normal cortisol levels. Toxic side-
`effects are rare with the lower doses but significant with the
`higher doses. The most frequent adverse effects of ketocona-
`zole are nausea, vomiting, abdominal pain and pruritus.
`Hepatotoxicity, primarily of the hepatocellular type, can
`occur. Early markers for these side-effects are serum alkaline
`phosphatase, ALT, AST, and bilirubin. These should be
`monitored at frequent intervals during treatment and keto-
`conazole should be discontinued if there is elevation of
`enzymes > 3 times above the ULN.
`
`3.1.1.2 Fluconazole
`Like ketoconazole, fluconazole is an antifungal azole derivative
`which has been shown to suppress cortisol secretion in isolated
`case reports of patients with adrenal cortical carcinoma at a
`dose of 200 mg/day [6]. However, fluconazole may not be as
`effective as ketoconazole in suppressing steroid production [7].
`
`3.1.1.3 Aminoglutethimide
`We were the first to report that aminoglutethimide can inhibit
`cortisol secretion and reverse the clinical manifestations of
`cortisol excess in a patient with functioning adrenal cancer, an
`effect that could be sustained for 6 months [8]. Aminoglu-
`tethimide blocks steroid production by inhibiting cholesterol
`side chain cleavage and blocking the conversion of cholesterol
`to pregnenolone. As a consequence, the synthesis of cortisol,
`aldosterone and androgens is suppressed. The drug had been
`used in adults and children in doses of 500 – 2000 mg/day.
`Cortisol levels would fall gradually but eventually patients
`might have needed glucocorticoid replacement. In patients
`with ACTH-dependent Cushing’s, aminoglutethimide had
`
`Expert Opin. Emerging Drugs (2009) 14(4)
`
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`

`Drugs in the medical treatment of Cushing’s syndrome
`
`Table 3. Drug treatment of Cushing’s syndrome:
`mechanism of drug action.
`
`Drug
`
`Ketoconazole
`
`Aminoglutethimide
`
`Metyrapone
`
`Mitotane
`
`Etomidate
`
`Trilostane
`
`Cyproheptadine
`
`Cabergoline
`
`Somatostatin analogs
`
`Valproic acid
`
`Glitazones
`
`Mifepristone
`
`Main mechanism of action
`# 17-hydroxylase, 11b-hydroxylase,
`cholesterol scc
`# Cholesterol scc
`# 11b-hydroxylase
`Formation of ccyl chloride, binding
`to bionucleophiles
`# 11b-hydroxylase
`# 3b-hydroxysteroid dehydrogenase
`Serotonin receptor antagonist
`
`Dopamine agonist
`
`Somatostatin receptor agonists
`# GABA reuptake; " GABA
`PPAR-g agonists
`Type II glucocorticoid receptor
`antagonist
`
`temporary suppressive effects on cortisol secretion but this
`effect could be reversed under the stimulating effect of
`ACTH [9]. The effect of aminoglutethimide was promptly
`reversed if therapy was interrupted. A subsequent report [10]
`showed palliation of the clinical manifestations of hypercor-
`tisolism in a much larger series of patients with Cushing’s
`syndrome. Aminoglutethimide could cause gastrointestinal
`(anorexia, nausea, vomiting) and neurologic (lethargy, seda-
`tion, blurred vision) side-effects and hypothyroidism in 5% of
`patients. Skin rash was frequent in the first 10 days of
`treatment but it subsided with continued administration.
`Headaches could occur with larger doses. Because of its ability
`to block early steps in steroidogenesis, aminoglutethimide was
`a useful drug for treating patients with adrenal cancer whose
`tumors produced combination of cortisol, aldosterone and
`androgens. Unfortunately, the manufacturer stopped producing
`the drug in 2007 and it is no longer available.
`
`3.1.1.4 Metyrapone
`An 11b-hydroxylase inhibitor, metyrapone was used initially
`in the differential diagnosis of Cushing’s syndrome but was
`later applied to the management of hypercortisolism. Depend-
`ing on the dose, cortisol suppression occurs within hours of a
`daily dose of 4.5 gm but the suppression can be maintained
`chronically with doses of 500 – 2000 mg/day. An early
`report [11] showed the possibility of prolonged amelioration
`of the clinical manifestations of CD with metyrapone.
`Other case reports confirmed this result when the drug is
`administered alone [12] or combined with aminoglutethi-
`mide [13] but it was suggested the drug is useful only as
`adjunctive treatment of CD [14]. Metyrapone is no longer
`commercially available but it can be obtained for use on a
`
`compassionate basis in patients with severe hypercortisolism
`secondary to metastatic ACC or inoperable ectopic ACTH
`syndrome. Nausea, vomiting and dizziness are potential side-
`effects and they may be related to sudden cortisol withdrawal
`and adrenal insufficiency. Another side-effect, when given
`to patients with CD, is acne and hirsutism, because block-
`ing steroidogenesis causes an increase in ACTH and stimu-
`lation of androgen synthesis by shunting steroidogenic
`precursors into the androgen pathway. The increase in andro-
`gens may be beneficial in patients with marked catabolic
`effects from the hypercortisolemia. Androgen increase is
`less likely to occur in ACTH-independent forms of Cushing’s.
`inhibition of 11-b hydroxylase by
`As a consequence of
`metyrapone, desoxycorticosterone levels may increase and
`cause hypertension and hypokalemia in patients with pituitary
`ACTH-dependent disease. This effect is not likely in those
`with ACTH-independent types of Cushing’s syndrome.
`
`3.1.1.5 Mitotane
`Of the various cytotoxic drugs used, mitotane is the oldest,
`with selective activity on the adrenal cortex. It has been used
`mainly in the treatment of patients with ACC but it is also
`effective in lower doses as an adrenalytic drug for the treat-
`ment of CD. Mitotane has well-proven adrenalytic effects in
`animals and humans. We reported that low doses of mitotane
`in combination with pituitary cobalt irradiation caused clin-
`ical and biochemical remission in 80% of patients with
`CD [15]. The adverse effects of mitotane are dose dependent
`and usually intolerable at doses above 6 g daily. Some patients
`with adrenal cancer may tolerate larger doses for limited time.
`The drug is best administered with fat-containing foods since
`its absorption and transport appears coupled to lipoproteins.
`The cortisol response to mitotane therapy should be followed
`by measuring urinary free cortisol. Serum cortisol levels can be
`elevated even when circulating free cortisol is not elevated,
`since mitotane increases binding of cortisol to corticosteroid
`binding globulin. In low doses (2 – 4 g daily), mitotane has
`less adrenalytic effects on the zona glomerulosa and is less
`likely to suppress aldosterone production. With larger doses,
`replacement with 9a-fluorocortisol may be necessary. Prom-
`inent early side effects of large doses of mitotane are anorexia,
`nausea, somnolence and incoordination. Side effects can be
`reversed by interrupting therapy for several days and restarting
`the drug at a lower dose. A maculopapular exanthem
`and exfoliative dermatitis can occur; but both are rare. Hep-
`atotoxicity requiring interruption in therapy can occur.
`Because of potential teratogenicity, patients should be advised
`against pregnancy.
`We have studied the mechanism of adrenalytic effect of
`mitotane. It involves transformation to and acyl chloride via
`P450-mediated hydroxylation and covalent binding to specific
`bionucleophiles [16]. It also involves oxidative damage with
`formation of free radicals such as superoxide that generates
`hydroxylated radicals and induces lipid peroxidation. We have
`postulated that the ability of mitotane to be metabolically
`
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`

`transformed and covalently bound to target proteins within
`the cell determines its pharmacological activity [17]. We have
`confirmed this by blocking the metabolic transformation by
`substituting the hydrogen on the beta carbon by a methyl
`group. Methylated mitotane does not have adrenalytic activ-
`ity [18]. The metabolic activity of mitotane varies among
`species, the drug being most effective in dogs and modestly
`effective in humans.
`
`3.1.1.6 Etomidate
`Used as a hypnotic anesthetic agent, etomidate is associated
`with increased mortality in critically ill patients by causing
`acute adrenal insufficiency. Etomidate reduces serum cortisol
`and aldosterone but increases plasma ACTH, 11-deoxycorti-
`sol and deoxycorticosterone, suggesting inhibition of the
`P450c11b. In healthy men and women, etomidate causes a
`dose-dependent blunting of the cortisol response to exogenous
`corticotrophin [19]. Several studies report short-term, contin-
`uous infusions of etomidate reduce serum cortisol concentra-
`tions in 11 – 24 h. A case report of a patient with severe
`hypercortisolism secondary to ectopic ACTH syndrome
`showed intravenous infusion of etomidate was effective in
`suppressing cortisol levels for 8 weeks [20]. In a severe hyper-
`cortisolemic child, an etomidate infusion (3.0 mg/h i.v.)
`decreased serum cortisol from 1,250 to 250 nmol/l within
`24 h and a combination of etomidate and hydrocortisone
`therapy maintained stable serum cortisol levels for 12 days [21].
`In general, etomidate is only used in cases of severe and
`complicated hypercortisolemia as temporary treatment prior
`to more definitive therapy.
`
`3.1.1.7 Trilostane
`Trilostane is a competitive inhibitor of the steroidogenic
`enzyme 3-beta hydroxysteroid dehydrogenase. It blocks the
`conversion of pregnenolone to progesterone and eventually
`the synthesis of cortisol, aldosterone and androstenedione. It
`has been used in patients with CD with biochemical and
`clinical improvement in one series [22] but another series found
`no consistent fall in cortisol levels [23]. Currently, trilostane has
`been approved in veterinary practice for
`treatment of
`Cushing’s syndrome in dogs and horses.
`
`3.1.2 Corticotropin inhibitors
`3.1.2.1 Cyproheptadine
`A serotonin receptor antagonist, cyproheptadine, given in doses
`of 24 mg/day, was reported as being effective in suppressing
`ACTH and cortisol secretion in patients with CD [24]. This
`effect was sustained for several months and was reversed upon
`discontinuing the drug. Subsequent trials failed to show efficacy
`of cyproheptadine in the treatment of patients with CD.
`
`3.1.2.2 Cabergoline
`ACTH-secreting pituitary tumors associated with CD may
`express dopamine D2 receptors and respond to dopamine
`
`Schteingart
`
`agonists. Several cases have been described of suppression of
`ACTH levels and amelioration of symptoms of Cushing’s
`syndrome with cabergoline, 7 mg/week, a much higher dose
`than the 1 – 2 mg/week used in patients with prolactino-
`mas [25,26]. Cabergoline has also been used for the treatment of
`Nelson syndrome [27].
`
`3.1.2.3 Somatostatin analogs
`The majority of pituitary adenomas causing CD express
`somatostatin (ssr5) and/or dopamine (D2) receptors [28].
`A somatostatin receptor agonist, pasireotide, binds to sst 1,
`2, 3 and 5 and inhibits CRH-stimulated ACTH secretion
`in vitro acting mainly through the sts5 receptor [29]. This
`somatostatin analog has been tested in a Phase II, open label,
`single arm multicenter clinical trial in patients with persistent
`or recurrent CD but the results were insufficient and only a
`small percentage of patients normalized their cortisol level [30].
`Somatostatin and somatostatin analogs can suppress ACTH
`secretion from ectopic ACTH-secreting neuroendocrine
`tumors. Tumors with positive octreoscan scintigraphy, indi-
`cating the presence of somatostatin receptors, are the most
`likely to respond to this therapy with suppression of ACTH
`and cortisol levels [31].
`
`3.1.2.4 Valproic acid
`This is a GABA reuptake inhibitor and by increasing GABA it
`can potentially suppress CRH. However, it has no proven
`efficacy in CD. Patients with Nelson syndrome and pituitary
`macroadenomas have been reported to have responded to
`valproic acid with decrease in ACTH secretion and reduction
`in tumor size but it is unlikely this would have occurred
`because of suppression of CRH, since CRH is usually low in
`patients with pituitary ACTH-dependent CD. It is possible
`that in those patients valproic acid may have had a direct effect
`on the tumor [33].
`
`3.1.2.5 PPAR-g agonists
`The response of patients with Cushing’s syndrome to PPAR-g
`agonists is controversial. Some reports show suppression of
`ACTH and cortisol levels with rosiglitazone [34,35], while other
`studies failed to show a response to pioglitazone [36]. Another
`study failed to lower plasma ACTH levels in patients with
`Nelson’s syndrome [37].
`
`3.1.3 Antagonists of adrenal aberrant receptors
`Several cases of Cushing’s syndrome associated with ACTH-
`independent macronodular
`adrenal
`cortical hyperplasia
`(AIMAH) have been reported, in whom the hypersecretion
`of cortisol was regulated not by ACTH but by non-physio-
`logical mechanisms through aberrant receptors [38]. The aber-
`rant adrenal expression and function of one or several
`G-protein-coupled receptors can lead to cell proliferation
`and abnormal regulation of
`steroidogenesis. In cases of
`
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`

`Drugs in the medical treatment of Cushing’s syndrome
`
`food-dependent hypercortisolism, cortisol secretion was medi-
`ated through the release of gastric inhibitory polypeptide
`(GIP) and the expression of aberrant GIP receptors in the
`adrenal glands [39]. Treatment for these patients was bilateral
`adrenalectomy although one report suggests somatostatin-
`inhibited cortisol secretion. Isolated cases have been described
`in whom cortisol secretion was regulated by b-adrenergic
`mechanisms [40], vasopressin [41] and luteinizing hormone
`(LH) [42]. Cortisol secretion can be blocked in vitro by various
`antagonists and this opens the way for pharmacological
`treatment in these cases. Patients with aberrant b-adrenergic
`receptors could be treated with b blockade with propanolol;
`those with aberrant vasopressin receptors with V1a receptor
`antagonists and patients with aberrant LH receptors with
`gonadotropin-releasing hormone antagonists such as luprolide
`acetate. A case of aldosteronoma with aberrant receptors has
`been described [43] but it is not clear if these receptors
`regulated aldosterone secretion by the adenoma.
`
`3.1.4 Glucocorticoid receptor antagonists
`3.1.4.1 Mifepristone
`A progesterone receptor and type II glucocorticoid receptor
`antagonist, mifepristone is being investigated as an antiglu-
`cocorticoid drug
`in the
`treatment of persistent or
`recurrent CD. It has also been used on a compassionate
`use basis in patients with inoperable ectopic ACTH syndrome
`and metastatic cortisol-secreting adrenal cortical carcinoma.
`Retrospective studies in Europe show that mifepristone is
`effective
`in ameliorating the clinical manifestations of
`Cushing’s syndrome in patients with adrenal cortical carci-
`noma, ectopic ACTH syndrome and pituitary ACTH-
`dependent disease [44]. Prospective clinical trials are currently
`underway in patients with Cushing’s syndrome.
`
`3.1.5 Substitution therapy
`Following transsphenoidal surgery and suppression of normal
`pituitary corticotropes, patients develop secondary adrenal
`insufficiency and require glucocorticoid substitution with
`either hydrocortisone or prednisone. Initially, patients may
`require relatively higher than physiological replacement doses
`because they are at risk for developing symptoms of steroid
`withdrawal. These symptoms include increased tiredness,
`arthalgiae, myalgiae, anorexia, headaches. Hydrocortisone
`doses initially required to treat these symptoms are between
`30 and 40 mg/daily and prednisone 7.5 – 10 mg/daily. The
`dose is
`slowly tapered to maintenance (hydrocortisone
`20 – 25 mg and prednisone 5 mg). We prefer hydrocortisone,
`because we can monitor the adequacy of replacement by
`measuring either serum cortisol or urinary free cortisol levels,
`and adjust the dose in order to obtain levels in the normal range.
`Monitoring glucocorticoid replacement by clinical indicators
`such as bone mineral density, glucose tolerance or fat distri-
`bution is not always accurate and we do not have a biomarker of
`optimal replacement like TSH for thyroxine. Serum cortisol
`day curves are of
`limited value to assess adequacy of
`
`replacement but weight or surface area-calculated doses of
`cortisol may provide a better means of determining replace-
`ment. In our experience with many patients with post-surgical
`adrenal insufficiency, urine free cortisol provides a simple and
`accurate means for calculating the optimal replacement dose.
`Patients with secondary adrenal insufficiency usually do not
`require mineralocorticoid replacement. In contrast, patients
`who have been treated by total adrenalectomy will require
`mineralocorticoid replacement in addition to hydrocortisone.
`The usual dose is fludrocortisone 0.05 – 0.2 mg daily and the
`optimal dose can be determined by measuring plasma renin.
`The dose of hydrocortisone needs to be adjusted upward under
`conditions of acute stress and the dose of fludrocortisone needs
`to be increased at times of high temperatures and excessive
`sweating. In spite of adequate replacement with glucocorticoids
`and mineralocorticoids, patients may continue to complain of
`fatigue. Serum dehydroepiandrosterone (DHEA) levels are
`often low and replacement with DHEA should be considered
`but the case for this replacement is not completely supported by
`available clinical trials.
`
`3.1.6 Drugs to treat symptoms
`The most effective approach to reversing the clinical mani-
`festations of Cushing’s syndrome is reversal of the hypercor-
`tisolemia and restoration of normal cortisol levels. Frequently,
`however, there is a need to treat the specific manifestations of
`cortisol excess.
`Patients with hypertension are treated with antihyper-
`tensive drugs and those with diabetes with insulin or oral
`glucose lowering drugs. Hypertension can be drug resistant
`and patients may require combination of three or four
`drugs. The diabetes is insulin-resistance and patients require
`high doses of
`insulin or oral agents,
`including insulin
`sensitizers. Lipid-lowering drugs such as statins may be
`needed to control hyperlipidemia and antiresorptive drugs,
`Vitamin D and calcium to treat osteoporosis. Patients with
`Cushing’s syndrome present with moderate-to-severe psy-
`chiatric symptoms. These symptoms include insomnia, rest-
`lessness, depression, cognitive impairment and occasional
`psychosis, requiring treatment with psychotropic drugs.
`These can be mild anxiolytic drugs or antidepressants, but
`in selected cases with psychotic behavior, antipsychotic drugs
`may be needed.
`
`4. Scientific rationale for potential new drugs
`
`Drugs that can suppress ACTH secretion should be a major
`objective of treatment in patients with pituitary disease. The
`drugs listed with corticotrope-suppressive ability have not
`been effective enough because either not all tumors have
`the appropriate receptors that will allow them to respond
`or the drug is not specific enough for the putative target.
`There are five different subtypes of somatostatin receptors
`(ssts 1 – 5) expressed in pituitary corticotropes in vitro,
`especially if cortisol
`levels are low. Somatostatin receptor
`
`666
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`Expert Opin. Emerging Drugs (2009) 14(4)
`
`6
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`subtype 5 (sst5) is expressed in pituitary corticotrope adeno-
`mas but sst2 receptors are expressed at lower levels. Activation
`of these receptors can decrease ACTH release in cultured
`corticotrope adenomas. While pituitary adenomas do not take
`up 111I-pentreotide in vivo and do not respond to somato-
`statin, octapeptide somatostatin analogs are potent inhibitors
`of ACTH in patients with Nelson syndrome who are on
`cortisol replacement after bilateral adrenalectomy. Develop-
`ment of somatostatin analogs with specific binding to sst5
`receptors could make somatostatin an effective drug for
`treatment of pituitary ACTH-dependent CD [29,30].
`Another potential class of drugs for suppressing ACTH
`secretion is vasopressin antagonists. Arginine and lysine vaso-
`pressin have been used in the diagnosis of CD. Desmopres-
`sin, a long-acting analog can stimulate ACTH secretion from
`pituitary adenomas, but normal corticotropes usually do not
`respond. This is felt to be due to the expression of V2 and V3
`receptors in the neoplastic corticotropes. Development of
`receptor-specific vasopressin antagonists could lead to agents
`that suppress ACTH-secreting adenomas and reverse hyper-
`cortisolemia. Several such antagonists are now available.
`Lixivaptan has been recently approved by the FDA and
`Physuline has been produced in Japan. These antagonists
`bind preferentially to V2 and V1a receptors and their effect is
`mainly on water reabsorption by the renal tubule. It is not
`certain they will be able to suppress ACTH secretion.
`Antagonists specific for V3 receptors are more likely to be
`effective in CD.
`PPAR-g receptors are abundantly expressed in ACTH-
`secreting pituitary tumors. In vitro, PPAR-g agonists inhibit
`ACTH-secreting pituitary tumor growth, proliferation and
`ACTH secretion in human and murine models and in vivo,
`in murine corticotroph tumors. The results of treatment
`of patients with CD with rosiglitazone have been inconsis-
`tent. Here again the response may be determine