`
` Neuroendocrinology 2010;92(suppl 1):125–130
` DOI: 10.1159/000314224
`
` Published online: September 10, 2010
`
` Medical Treatment of Cushing’s
`Syndrome: Glucocorticoid Receptor
`Antagonists and Mifepristone
`
` Frederic Castinetti Bernard Conte-Devolx Thierry Brue 
`
` Service d’endocrinologie, diabète et maladies métaboliques, et Centre de référence des maladies rares d’origine
`hypophysaire DEFHY, Hôpital de la Timone, Marseille , France
`
` Key Words
` Cushing’s disease ⴢ Anticortisolic drug ⴢ Ectopic ACTH
`secretion ⴢ Adrenal carcinoma ⴢ Bilateral adrenal
`hyperplasia ⴢ Glucocorticoid receptor antagonist
`
` Abstract
` Mifepristone is the first and only available glucocorticoid re-
`ceptor antagonist. It was initially mainly considered as a so-
`called ‘contragestive’ pill due to its antiprogestin activity. In
`this review, we summarize the results of mifepristone report-
`ed in the literature as a treatment of Cushing’s syndrome.
`Most of the patients were treated due to unsuccessful sur-
`gery and/or partially effective anticortisolic drugs. The ma-
`jority of them presented a rapid decrease of clinical signs of
`hypercortisolism during the first month of treatment; about
`half experienced a reduction in their elevated blood pres-
`sure, and half of the diabetic patients presented improved
`blood glucose levels. Mifepristone treatment has 2 main
`drawbacks: (1) the blockade of glucocorticoid receptors
`leads to increased ACTH and cortisol levels, making it diffi-
`cult to adapt the treatment and diagnose adrenal deficien-
`cy, and (2) increased cortisol levels can also lead to severe
`hy pokalemia. Follow-up of efficacy should only be clinical
`(weight, blood pressure, skin lesions) and biological (regular
`blood potassium sampling). Dose adjustment will be per-
`formed based on these parameters. The lack of a large avail-
`
`able prospective cohort of patients on mifepristone, and the
`scarcity of data on its long-term effects, does not allow rec-
`ommending it as a first-line drug in the treatment of hyper-
`cortisolism. However, as mifepristone is a rapidly effective
`drug, it can play a role in the management of hypercorti-
`solism. The main indication is the partial efficacy or bad tol-
`erance of other well-known anticortisolic drugs, either by re-
`placement (bad tolerance, lack of effectiveness) or addition
`(multimodal approach) of mifepristone.
` Copyright © 2010 S. Karger AG, Basel
`
` Introduction
`
` Cushing’s syndrome can be caused by adrenal, pitu-
`itary or ectopic tumors. Surgery remains the first-line
`treatment, and can be followed by pituitary irradiation or
`bilateral adrenalectomy if necessary. Medical manage-
`ment remains, however, of major interest when surgery is
`impossible, in preparation for surgery, or when surgery is
`partially effective. The efficacy of usual anticortisolic
`drugs (ketoconazole, metyrapone, mitotane, etc.) is not
`constant and may be limited by their poor tolerance [1, 2] .
`Mifepristone, a glucocorticoid receptor antagonist ini-
`tially considered as a so-called ‘contragestive’ pill, may
`represent an alternative [3] . Our recent European collab-
`orative retrospective study [3] allowed to discuss the po-
`
`Fax +41 61 306 12 34
`E-Mail karger@karger.ch
`www.karger.com
`
` © 2010 S. Karger AG, Basel
`0028–3835/10/0925–0125$26.00/0
`
` Accessible online at:
`www.karger.com/nen
`
` Thierry Brue
` Department of Endocrinology, Diabetes and Metabolic Diseases
` Timone Hospital, 204, rue Saint-Pierre
` FR–13385 Marseille Cedex 05 (France)
` Tel. +33 4 91 38 55 05, Fax +33 4 91 38 45 42, E-Mail thierry.brue   @   ap-hm.fr
`
`1
`
`TEVA1011
`
`

`

` Fig. 1. Clinical picture of a patient before
`(left) and 6 months after (right) treatment
`with mifepristone for an ectopic ACTH
`syndrome. Note the decrease in upper
`body obesity and facial erythrosis after
`treatment.
`
`tential future role of this drug in the management of
`Cushing’s syndrome. In the present review, we will main-
`ly talk about mifepristone, as data about other potential
`glucocorticoid receptor antagonists are only experimen-
`tal.
`
` Pharmaceutical Properties
`
` Mifepristone is a substituted 19-nor steroid compound
`chemically designated as 11 ␤ -[ p -(dimethylamino)phe-
`nyl]-17 ␤ -hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.
`It is the first and currently only available glucocorticoid
`receptor antagonist treatment [4] . Other glucocorticoid
`receptors are currently evaluated, but no clinical trial
`has been published to date [5] . Mifepristone has also a
`strong anti-progestin activity, and a weak anti-androgen
`activity: its relative binding affinity at the glucocorti-
`coid receptor is more than three times that of dexameth-
`asone and more than ten times that of cortisol; affinity
`at the progesterone receptor is more than twice that of
`progesterone, and affinity at the androgen receptor is
`less than one third that of testosterone. It does not bind
`to the estrogen receptor or the mineralocorticoid recep-
`tor. Following oral administration of a single dose of
`400–600 mg, mifepristone is rapidly absorbed, with a
`peak plasma concentration occurring approximately 90
`min after ingestion. Of note, in the absence of progester-
`one or cortisol, mifepristone can also act as a weak ago-
`nist [5, 6] .
`
` Efficacy
`
` Mifepristone appears as a rapidly effective drug in
`controlling signs of hypercortisolism. To date, 37 pa-
`tients, mainly adults, have been reported in the literature
`
`as having received mifepristone for various etiologies of
`Cushing’s syndrome ( table 1 ) [7–16] . Most of them were
`treated due to unsuccessful surgery and partially effec-
`tive or badly tolerated medical treatment. Up to 85% pre-
`sented a decrease of their clinical signs of hypercorti-
`solism (weight loss, improvement of skin signs) during
`the first month of mifepristone ( fig. 1 ). About half expe-
`rienced a reduction in their elevated blood pressure and
`half of the diabetic patients also presented improved
`blood glucose levels, sometimes leading to withdrawal
`of antidiabetic drugs. The majority of the patients have
`been treated for an advanced adrenal carcinoma, ectopic
`ACTH secretion or Cushing’s disease.
`
` Adrenal Carcinoma
` Seventeen patients have been reported to date. In the
`majority of cases, mifepristone was given in advanced ad-
`renal carcinomas after failed surgery, and lack of efficacy
`of classical anticortisolic drugs (including mitotane). Me-
`dian duration of treatment was 3 months (range 0.25–9).
`Clinical signs of hypercortisolism improved in 76% of
`the cases during the first month of treatment. In our se-
`ries, 60% of the patients presented improved blood pres-
`sure levels. Interestingly, one patient with severe psycho-
`sis had a drastic improvement of psychiatric signs in the
`first few days of mifepristone treatment.
`
` Ectopic ACTH Secretion
` Twelve patients have been treated with mifepristone
`after unsuccessful surgery or lack of identified tumor.
`Median duration of treatment was 5.5 months (range
`0.3–18). All patients presented an improvement of their
`clinical signs. About half of them experienced decreased
`blood pressure levels. Severe psychosis signs improved
`in the first few days of mifepristone treatment in 1 pa-
`tient.
`
`126
`
`Neuroendocrinology 2010;92(suppl 1):125–130
`
` Castinetti/Conte-Devolx/Brue
`
`
`
`2
`
`

`

`Table 1. Individual data of patients treated with mifepristone for adrenal carcinoma (patients 1–17), ectopic ACTH secretion (18–29),
`Cushing’s disease (30–34) or other causes (35–37)
`
`Patient
`No.
`
`Sex/
`age
`
`Dose
`mg/day
`
`Previous
`treatments
`
`Duration
`months
`
`High
`BP
`
`Hypoka-
`lemia
`
`Adrenal
`insufficiency
`
`Diabetes
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`
`F/45
`F/32
`F/NA
`M/62
`M/43
`M/63
`F/39
`F/52
`F/52
`F/45
`F/63
`M/20
`F/47
`F/38
`F/44
`M/64
`M/52
`M/36
`M/42
`F/63
`F/55
`F/46
`M/25
`F/2
`F/46
`F/37
`M/55
`F/43
`F/38
`M/45
`M/56
`F/50
`F/45
`M/51
`F/38
`F/52
`F/14
`
`5–22 mg/kg
`400
`20–30 mg/kg
`400
`400–800 mg
`1,000
`400
`400–600
`400–600
`400–2,000
`600
`600–1,200
`400–1,200
`400–600
`200–600
`200–400
`600
`5–22 mg/kg
`5–22 mg/kg
`5–22 mg/kg
`5–22 mg/kg
`800–1,600
`5–20 mg/kg
`75–300
`600
`800
`400–600
`600
`400–800
`400–800
`600–1,200
`600
`600
`400–2,000
`5–22 mg/kg
`600
`400
`
`2
`2
`4
`9
`0.5
`6
`2.5
`3
`3
`1
`2
`1
`2
`3
`2
`1.5
`0.25
`10
`12
`4
`2.5
`0.3
`2.5
`2
`2
`10
`1
`2
`18
`12
`24
`0.5
`3
`18
`1.5
`6
`8
`
`M
`M
`M
`M
`M+K
`M+K
`M+K
`M+K
`M+m
`M+m
`M+m
`M+E
`
`m+chemotherapy
`none
`chemotherapy
`chemotherapy
`E+m
`K
`K
`K
`K
`–
`–
`K
`–
`K
`–
`
`d
`
`d
`d
`
`d
`
`d
`
`d
`
`d
`
`f
`}
`f
`f
`–
`}
`f
`}
`–
`–
`–
`–
`
`f
`f
`d
`d
`f
`d
`d
`
`–
`–
`–
`d
`}
`
`–
`–
`
`}
`d
`d
`d
`d
`–
`d
`d
`–
`–
`–
`d
`
`f
`–
`d
`d
`d
`d
`d
`
`–
`–
`}
`d
`d
`
`}
`–
`
`f
`–
`–
`}
`–
`–
`}
`–
`–
`–
`–
`}
`
`f
`f
`f
`–
`f
`f
`–
`–
`–
`–
`–
`–
`
`f
`–
`
`Previous treatments are treatments administered before the start of mifepristone therapy: M = mitotane; K = ketoconazole; m =
`metyrapone; E = etomidate. High blood pressure (BP), hypokalemia, adrenal insufficiency and diabetes: f = alleviation or improve-
`ment on mifepristone; d = worsening or onset on mifepristone; } = unchanged on mifepristone; – = absent before treatment, unchanged
`on mifepristone; blank space for patients 1–5 = not available.
`
` Cushing’s Disease
` Five patients have been treated to date because of the
`lack of pituitary adenoma visualized on MRI, failed sur-
`gery, bad tolerance to other anticortisolic drugs or partial
`efficacy of a radiosurgical procedure. Mean duration of
`
`treatment was 11 months (range 0.5–24). All but one pa-
`tient presented improved clinical signs. Again, 1 patient
`with severe psychosis had a drastic improvement of psy-
`chiatric signs in the first few days of mifepristone treat-
`ment.
`
` Mifepristone in Cushing’s Syndrome
`
`Neuroendocrinology 2010;92(suppl 1):125–130
`
`127
`
`3
`
`

`

` Of note, 1 patient has been treated for bilateral adrenal
`hyperplasia, and 2 for a likely benign adrenal adenoma
`(but the precise etiology is unclear). All of them experi-
`enced a rapid improvement of clinical signs of hyper-
`cortisolism during the first month of mifepristone treat-
`ment [10] .
`
` Tolerance
`
` In Cushing’s syndrome, hypokalemia is directly relat-
`ed to glucocorticoid excess as massive hypercortisole-
`mia leads to incomplete renal inactivation of cortisol by
`11 ␤ -dehydrogenase, and hence mineralocorticoid excess.
`Mifepristone requires careful medical attention and a
`close follow-up of this specific point. As mifepristone
`blocks only glucocorticoid action, the mineralocorticoid
`activity of cortisol excess is not affected by mifepristone
`treatment, thus leading to hypokalemia. On the contrary,
`mifepristone may lead to an increase of plasma ACTH
`and consecutively of cortisol levels in some patients with
`Cushing’s syndrome, particularly with Cushing’s disease
`due to alterations in negative feedback (a mechanism of
`hypokalemia similar to the one observed in Cushing’s
`syndrome without treatment) [5] . Mifepristone-induced
`hypokalemia was observed in one third of the 37 Cush-
`ing’s patients reported to date. In a few cases, hypokale-
`mia was very severe, requiring high doses of oral and
`intravenous potassium, and intensive anti-aldosterone
`treatment. Severe hypokalemia should thus represent a
`contraindication for this treatment and potassium levels
`need to be carefully monitored. The same mechanism
`can induce increased blood pressure levels, which was ob-
`served in 5 patients, despite an improvement of clinical
`signs of hypercortisolism. The ideal treatment remains
`high dose anti-aldosterone treatment: there is no need
`for a systematic prescription at the onset of mifepristone,
`except in case of low-normal hypokalemia.
` Moreover, the lack of available biological parameters
`of follow-up on treatment obviously represents a limita-
`tion for the use of mifepristone. Signs suggestive of adre-
`nal insufficiency have been reported in 16% of the 37 pa-
`tients reported to date. The blockade of glucocorticoid
`receptors does not allow determining the efficacy of the
`drug by measuring ACTH and cortisol levels that are in-
`creased by mifepristone treatment. However, this low rate
`of adrenal deficiency is puzzling taking into account the
`mechanism of action of mifepristone: it is probably due
`to a partial blockade of glucocorticoid receptor antago-
`nists, or a weak agonist effect of the drug [5] . Manage-
`
`ment of adrenal deficiency is also difficult: hydrocorti-
`sone is not effective; dexamethasone (1 mg for 400 mg of
`mifepristone) should be given during 48 h in parallel with
`mifepristone withdrawal. Mifepristone can be re-initiat-
`ed at a lower dose after the treatment of adrenal deficien-
`cy [17] .
` Antiprogestin effects are also important to notice as
`they can induce an endometrial hyperplasia (relative hy-
`perestrogenia). Three patients have been reported in the
`literature with this adverse effect [14] . Pelvic ultrasonog-
`raphy should be performed yearly in every woman before
`menopause.
`
` Dose and Follow-Up
`
` Mifepristone should be initiated at a low dose (200–
`400 mg/day), and increased every 2–4 weeks based on
`clinical efficacy and tolerance. The maximal dose given
`should be around 400–800 mg/day. Increasing the dose
`up to 1,000 mg/day is usually not necessary, and increas-
`es the risk of adverse effects. However, increase in the
`dose of mifepristone could be performed more rapidly in
`case of severe signs of psychosis [10] .
` Follow-up of efficacy, and dose adjustments should
`mainly rely on clinical and necessarily imperfect param-
`eters like weight, blood pressure or skin lesions. ACTH
`and cortisol levels will be increased, and do not represent
`a good marker of the efficacy of the drug. Adrenal defi-
`ciency should be suspected in case of weakness, fatigue,
`nausea, vomiting, and hypoglycemic episodes [10] .
` As mentioned previously, only a limited number of pa-
`tients have been treated long-term with mifepristone,
`probably because more than a third of patients reported
`to date presented an advanced adrenal carcinoma. If
`long-term treatment is considered, pelvic ultrasonogra-
`phy should be performed at least yearly in nonmenopaus-
`al women. No specific adverse effects other than the ones
`seen at short-term have been reported.
`
` Pros and Cons in Comparison with Other
`Anticortisolic Drugs
`
` The potential risks and benefits of mifepristone have
`to be weighed against alternative treatment options. The
`majority of other anticortisolic drugs have the major ad-
`vantage to induce decreased cortisol levels: they are thus
`easier to follow (regular measures of plasma cortisol lev-
`els), whereas during mifepristone, cortisol concentration
`
`128
`
`Neuroendocrinology 2010;92(suppl 1):125–130
`
` Castinetti/Conte-Devolx/Brue
`
`
`
`4
`
`

`

`provides no guidance for treatment. However, the other
`anticortisolic drugs classically expose patients to fre-
`quent and/or severe side effects without superior efficacy.
`Ketoconazole has been reported to induce serious and
`life-threatening hepatotoxicity, although this side effect
`is rare (1/15,000 cases). Moreover, ketoconazole is no lon-
`ger available in some European countries (e.g. Germany)
` [2] . Metyrapone, an inhibitor of 11 ␤ -hydroxylase, is not
`easily available in several European countries and may
`also be associated with significant side effects [18] . Etomi-
`date can only be used intravenously and, therefore, should
`be reserved for severe cases [19] . The use of mitotane can
`be difficult due to a narrow therapeutic window, and
`overall bad tolerance (gastrointestinal and neurotoxic ef-
`fects). Moreover, most of these treatments are not as rap-
`idly effective as mifepristone. This is particularly true for
`mitotane, which requires several weeks before being ful-
`ly effective [20, 21] .
` Thus, treatment with mifepristone may be of signifi-
`cant value in the medical treatment of Cushing’s syn-
`drome in a high percentage of cases. Its place must be
`defined in regards of the severity of the disease. Due to
`the low number of patients reported, mifepristone cannot
`be recommended as a first-line treatment, even in com-
`parison with more classical anticortisolic drugs. Mife-
`pristone should be reserved to patients with lack of/par-
`tial efficacy and/or bad tolerance of well-known thera-
`peutic procedures, i.e. surgery, radiotherapy and other
`anticortisolic drugs. Of note, mifepristone can be added
`to other anticortisolic drugs, as they have different mech-
`
`anisms of actions. In this case, follow-up (mainly in terms
`of signs of adrenal deficiency and potassium levels)
`should be very strict.
`
` Conclusion
`
` Mifepristone represents a rapidly effective treatment
`to control signs of hypercortisolism with the main draw-
`back of the impossibility to follow blood cortisol levels.
`The risk of severe hypokalemia needs to be closely moni-
`tored and further limits its widespread use. Despite these
`promising results, the lack of a large available prospective
`cohort of patients on mifepristone, and the scarcity of
`data on its long-term effects, does not allow recommend-
`ing it as a first-line drug in the treatment of hypercorti-
`solism. However, as mifepristone is a rapidly effective
`drug, its main indication is the partial efficacy or bad tol-
`erance of other well-known anticortisolic drugs especial-
`ly in patients with psychiatric signs of hypercortisolism.
`Only a limited number of patients have been treated long-
`term with mifepristone and if long-term treatment is con-
`sidered, one should keep in mind the anti-progestin ac-
`tivity of mifepristone, as this can lead to endometrial hy-
`perplasia.
`
` Disclosure Statement
`
` The authors have nothing to disclose.
`
`
`
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`Neuroendocrinology 2010;92(suppl 1):125–130
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` Castinetti/Conte-Devolx/Brue
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`6
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`

`

`Mauro
`endocrinology
`
`Guidelines for Authors
`
`
`
`The Editorial Board of Neuroendocrinology welcomes
`articles for review that report new observations on interac
`tions between the brain and the endocrine system. Papers
`that are published deal with both basic and clinical subjects.
`liditorials, summaries of meetings, and reviews of timely
`topics in basic and clinical neuroendocrinology are also
`published, but these items are accepted only at the invita~
`tion of the liditor-iniChief.
`Submission
`Manuscripts written in linglish should be submitted using
`the online submission website at:
`www.karger.com/nen
`or as e-mail attachment (the preferred word-processing
`package is MS-Word) to the liditorial Office:
`N.Oswald@hrsu.mrc.ac.uk
`liditorial Office ‘Neuroendocrinology'
`Prof. Dr. Robert Millar
`lluman Reproductive Sciences Unit
`’lhe Queen's Medical Research Center
`~l7 Little lirance Crescent
`Edinburgh lilllo 4T] (UK)
`'lel. +44 l3l 208 3107
`
`liditorial Manager
`Nicholas ()swald, Phl)
`N.0swald@hrsu.mrc.ac.uk
`
`Manuscripts should contain unpublished results of re-
`search work, and should be as concise as possible. ’lhe fol-
`lowing presentation is recommended: Abstract, Introduc-
`tory statement on the purpose of the studies. Materials and
`methods, Results, Discussion, and References. Current ab-
`breviations should be used throughout the text and tables
`(for pituitary hormones: ACl'l l, 'lb—lZNI). PSH, GH, Lil,
`'l'SH; for neuropeptides: CR] 1, not CRI‘; GAL: (il lRl l, not
`6th (ianl, not 1.1 lRll; NPY;N'I'; SR” 1, notSRlP;Vll’...),
`and a definition should be provided the first time each ab-
`breviation appears. Please limit abbreviations to those in
`common use, and avoid other abbreviations and acronyms.
`Manuscripts should contain novel, original data. Asa rule,
`the liditorial ollice commits itselfto achieve initial review
`of manuscripts within less than 60 days; average interval
`between submission and publication is 7-9 months. AuA
`thors of articles reporting mostly confirmatory, fragmen—
`tary or preliminary findings may be notified within 2 weeks
`that their manuscript will not be submitted to formal re-
`
`vie
`Such a proposal will be made by the associate Editors
`assisted by one member ofthe liditorial Board. 'lhis pro
`cedure is intended to provide rapid feedback to authors of
`manuscripts which have a poor chance of being accepted
`Authors have the opportunity to appeal against the deci7
`
`sion. Iontributors should know that one ofthe criteria con»
`sidered in reviewing manuscripts is the humane and proper
`treatment of animals. 'lhe editors realize that the use of
`anesthetics, analgesics, and tranqtulizers wotild defeat the
`purpose ofsome experiments. However, the use of painful
`or otherwise noxious stimuli must be carefully and thor-
`oughlyjustified in the paper. Papers that do not meet these
`criteria will not be accepted for publication,
`Conditions
`All manttscriptsare subject to editorial review. Manuscripts
`are received with the explicit understanding that they are
`not under simultaneous consideration by any other piibli
`cation. Submission of an article for pnbhtation implies the
`transfer of the copyright from the author to the publisher
`upon acceplantt'. Accepted papers become the permanent
`property of ‘Nenrocndotrinolog' and may not be it-pio
`duced by any means. in whole or in part. Without the writ
`ten consent of the publisher. it is the author's responsibility
`to obtain permission to reprodutc illustrations. tables, etc.
`from other publications.
`Rapid Communications
`Manuscripts intended for rapid tommnnication must pres
`ent new findings oi siitlicicnt importance to iustilv their
`
`accelerated appearance. Double-spaced manuscripts can-
`not exceed 7 pages, including figures, tables and references;
`longer manuscripts will be returned. Rapid communicav
`tions are reviewed by two members ofthe liditorial Board.
`As '\ rtile, they are either accepted or rejected; only minor
`revision is allowed. Once accepted, they are published with—
`in 2—3 months ofacceptance. Proofs are sent to the liditor-
`in-(Ihief and to the authors.
`Arrangement
`Title page: The first page of each paper should carry the
`title, the authors' full first and last names, and the name of
`the institute or department where the authors conducted
`their research work. In addition, the following should be
`put on the title page: 1. A short title for use as a running
`head. 2. A list of 3—9 key words for indexing purposes. 3.
`’lhe name and complete mailing address as well as phone
`and fax numbers and email address of the individual to
`whom correspondence, proofs, and requests for reprints
`should be addressed.
`
`Abstract: liach paper must have a short abstract describing
`procedures, observations and conclusions, which will ap-
`pear at the beginning of the article. Abstracts should not
`exceed 250 words.
`
`13001110105: Avoid footnotes ifat all possible. When essential.
`they should be numbered consecutively and typed at the
`foot ofthe appropriate page.
`Acknowledgments: Including, where relevant, credit to the
`sources of grant support.
`'litlrles and illustrations: 'l‘ables (numbered in arabic nth
`merals) should be prepared on separate sheets, and each
`should have a suitable heading. Illustrations should be
`numbered in Arabic numerals and legends for the figures
`should be submitted on a separate page. For the reproduc-
`tion of illustrations, only good drawings and original pho-
`tographs can be accepted; negatives or photocopies cannot
`be used. Due to technical reasons, figures with a screen
`background should not be submitted When possible,
`group several illustrations on one block for reproduction
`(max. size 180 X 223 mm) or provide crop marks. Plec-
`tronically submitted b/w half-tone and color illustrations
`must have a final resolution of 300 dpi after scaling, line
`drawings one of 800—1200 dpi.
`Rtferences: In the text identify references by Arabic numer-
`als [in square brackets]. Material submitted for publication
`bUt not yet accepted should be noted as ‘unpublished data‘
`and not be included in the reference list. 'l he list ofreferenc-
`es should include only those publications which are cited in
`the text. Do not alpliabeti‘re; number references in the order
`in which they are first mentioned in the text. 'lhe surnames
`ofall the authors followed by initials should be given. 'lhere
`Should be no punctuation other than a comma to sepa-
`rate the authors. Preferably, please cite all authors. Abbre-
`viate journal names according to the index Medicus sys<
`lem. (Also see International Committee ofMedical lournal
`liditois: Uniform requirements for manuscripts submitted
`to biomedical journals. N lingl I Med 1997;33 .309—3l5.)
`lixnmplt‘s:
`(it) I’M/W's published in perimiiculs: Sun ], Koto ll, Chung
`Kl: Interaction of mom: and allergen challenges on bron-
`tllldl responsiveness and inflammation in sensitised guinea
`pigs. Int Arch Allergy Immunol l9‘)7;l l2zl9l—195.
`(ll) I'll/ms published only with [)0] numbers:
`'lheoharnles '| (I,
`liouther W, Spear K: Serum inter-
`leukin o
`It'ilccis
`disease
`severity
`and
`osteoporosis
`in ill.l\lttt)'lll\l\ patients.
`Int Arch Allergy lmmunol
`l )( )l: ltl.l l ri‘HUfifiilo lli'ili.
`l'th'CWt‘ll V'l': Using and
`(i) Almiogm/vlli: Matthews |)l-'.,
`Understanding Medical Statistics, ed 3,
`revised.
`liasel,
`Kaiger. I‘J‘Io,
`(ii) Iz'illtt'tl books: l’arrcn l’Wlll. liurton |)l{: Antibodies
`dilainst lllV-l from phage display libraries: Mapping ofan
`immune response and progress towards antiviral imnntno
`
`therapy; in Capra ll) (ed): Antibody Engineering, Chem
`lmmunol. Basel, Karger, 1997, vol 65, pp 18:56.
`Papers that have been submitted to a journal but are not
`yet accepted should not be listed in the bibliography, but
`the data in them can be referred to in the text as unpub—
`lished observations. Ifdetails ofmethods are only available
`in papers that are ‘in press', copies ofthe papers should be
`included with the manuscript submitted to ‘Neuroendo-
`crinology’, so that the editorial referees can have adequate
`information to judge the manuscript.
`Reference Management Software: Use of lindNote is rec-
`ommended for easy management and formatting ofcita-
`tions and reference lists.
`
`Digital Object Identifier (DOI)
`S. Karger Publishers supports DOIs as unique identifiers
`for articles. A [>01 number will be printed on the title page
`ofeach article. l)Ols can be useful in the future for identi«
`fying and citing articles published online without volume
`or issue information. More information can be found at
`www.doi.org.
`Author's ChoiceTM
`Karger's Author's Choice service broadens the reach ofyour
`article and gives all users worldwide free and full access
`for reading, downloading and printing at www.karger.coni.
`'lhe option is available for a one-time fee of Clll’ 3()00.—,
`which is a permissible cost in grant allocation. More infor-
`mation can be found at www.karger.com/authors_cboice.
`NIH-Funded Research
`'lhe US. National institutes of Health (NIH) mandates
`under the Nlli Public Access Policy that final, peer-re-
`viewed manuscripts appear in its digital database within
`12 months of the oflicial publication date. As a service to
`authors, Karger submits the final version ofyour article on
`your behalf to PubMed Central. For those selecting our
`premium Author's Choice service, we will send your article
`immediately upon publishing, accelerating the accessibility
`of your work without the usual embargo. More details on
`Nlll's Public Access Policy is available at http://publicac-
`cessniligov/FAthmfia1
`Self—Archiving
`Karger permits authors to archive their prevprints (i.e. pre-
`rcfereeing) or post-prints (Le. final draft post~refereeing)
`on their personal or institution‘s servers, provided the fol-
`lowing conditions are met: Articles may not be used for
`commercial purposes, must be linked to the publisher's ver-
`sion, and must acknowledge the publisher‘s copyright. Atl-
`thors selecting Kargcr’s Author's Choice feature, however.
`are also permitth to archive the final, published version
`oftheir article, which includes copyediting and design im-
`provetnents as well as citation links.
`Proofs
`Unless indicated otherwise, proofs are sent to the first-
`named author and should be returned with the least pos-
`sible delay. Alterations made in proofs, other than the cor-
`rection of printer's errors, are charged to the author. No
`page proofs are supplied.
`E-pub First
`All articles are published electronically ahead ofprint with
`a D01 number and are supplemented later with the definite
`reference ofthe printed version. 'lhe articles become avail-
`able imm