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Cyclical Cushing's syndrome: an update

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I was unable to get the images that go with this, but it is very interesting reading. Thanks, Ami, for telling me about it!


Current Opinion in Endocrinology, Diabetes and Obesity


© 2007 Lippincott Williams & Wilkins, Inc.


Volume 14(4), August 2007, p 317-322


Cyclical Cushing's syndrome: an update



Mullan, Karen R; Atkinson, A Brew; Sheridan, Brian

Correspondence to A.B. Atkinson, Regional Centre for Endocrinology and Diabetes,

Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BA, Northern Ireland, UK

Tel: +44 28 90 633357; fax: +44 28 90 310111; e-mail:





Purpose of review: This article reviews the features of cyclical hypercortisolism. This syndrome was once considered to be very rare but is now being increasingly recognized.


Recent findings: Either true cycles or the variant of episodic and fluctuating levels of hypercortisolism can lead to considerable clinical dilemmas, which are discussed. The review details possible pathophysiological mechanisms and the effects of centrally acting drugs.


Summary: Cyclical Cushing's syndrome is a pattern of hypercortisolism in which the biochemistry of cortisol production fluctuates rhythmically. This syndrome is often associated with fluctuating symptoms and signs. This type of case was initially thought to be rare. It has, however, recently been recognized as occurring much more frequently. The phenomenon is important because it can, if not recognized, lead to errors in diagnosis and differential diagnosis of the syndrome and in assessment of therapeutic outcomes. All of these can have very serious clinical consequences. Clinical researchers, including ourselves, have developed criteria, protocols and dynamic biochemical tools to detect cycling in patients with hypercortisolism. Unfortunately, the mechanisms causing the abnormal pathophysiology have not been well elucidated but some recent insights have been gained. The review discusses strateges for diagnosing and managing this important subgroup of patients with hypercortisolism.





Significant cortisol fluctuations in Cushing's syndrome were first recognized in 1956 by Birke et al. [1] (Fig. 1). They reported large fluctuations in the excretion of 17-ketosteroids and of 17-ketogenic steroids in a woman described as having all the classic symptoms of Cushing's syndrome. Repeated measurements confirmed large cyclical fluctuations about every 10 days over 40 days. In retrospect this is probably the first such case, although that honour is usually ascribed to Bailey [2]. He presented evidence for periodicity in cortisol production in a patient with a slow-growing carcinoid-type malignant bronchial carcinoid (Fig. 2).



Figure 1 Day-to-day variation in the excretion of 17-ketosteroids (open circles) and 17-ketogenic steroids (filled circles) in a 40-year-old woman with Cushing's syndrome



Figure 2 Graph showing the results of metabolic studies covering twocycles



We now define true cyclicity as needing at least three peaks and two troughs of cortisol production (see below) to establish the diagnosis, and the former (Fig.1) but not the latter case (Fig. 2) fulfills the criteria, the latter being described as intermittent or fluctuating in nature.


The next important case described was one from Vanderbilt University, USA. Brown et al. [3] described a patient with Cushing's disease who appeared to exhibit a paradoxical response to dexamethasone. Having found this response they studied the patient over 100 days and discovered that the overactivity was spontaneously rhythmic, with cycles occurring approximately every 11 days, and that the apparent paradoxical response to dexamethasone had been purely fortuitous (Fig.3).




Figure 3 Summary of a patient's daily morning plasma cortisol levels and daily 24-h urinary excretion of 17-OHCS and 17-KS over a 100-day study period




Many of the earlier cases are reviewed and referenced in an earlier publication of our group, which reported the first series of patients with the condition. Until that series such cases were thought to be both unusual and rare but we reported five, well-established cases of cyclical Cushing's syndrome in a series of 14 patients with hypercortisolism [4]. In 1992 we reported a further three patients whom we studied after trans-sphenoidal microsurgery for Cushing's disease, because their symptoms and signs were slow to settle and/or because they had variable endocrine results [5]. All were established as having cyclical Cushing's syndrome, first diagnosed postoperatively (Fig. 4). We suggested then that this may be a much more common finding than previously recognized and emphasized the need for detailed and ongoing endocrinological investigation after pituitary surgery for hypercortisolism. Our more recent studies have borne this out. In a report of the long-term outcome in 63 patients who had pituitary surgery for the treatment of Cushing's disease between 1979 and 2000 [6] we described our detailed follow-up of the 45 patients who achieved apparent remission after surgery. Of these 45 patients, 10 had late relapses and, of those 10, six demonstrated definite cyclical cortisol production.



Figure 4 Early-morning urinary cortisol (nmol/l) to creatinine ([mu]mol/l)ratios in (a) patient 1, (:spudnikshamus: patient 2 and © patient 3 with cyclical Cushing's syndrome



Tools to detect cyclicity


Cortisol cycling has been defined as occurring when at least three peaks and two troughs of cortisol production are apparent. This definition often requires prolonged study and hence detecting cyclical Cushing's syndrome has been a significant challenge to endocrinologists as 24-h urinary free cortisol sampling is time-consuming and laborious for the patient. When we first began to study the cyclical phenomenon, therefore, we performed a study comparing the 24-h urinary cortisol/creatinine ratio with the early-morning ratio for samples from 46 patients, and a correlation of 0.93 was found. To confirm that sending samples at ambient temperature in the mail led to no loss of cortisol, a fresh urine sample was left at room temperature for 7 days. Each morning an aliquot was removed and frozen. After the 7 days, the samples were analyzed for urinary cortisol concentrations. No differences were found [4]. These validation experiments have allowed us to follow patients for prolonged periods, with the patient posting daily urine samples from home. Salivary samples could also be used in a similar way in centres that have normal standard levels established. Hermus et al. [7] reported a case in which the patient had cyclical Cushing's syndrome and who was followed daily for 2 years with 24-h urinary free cortisol. Daily morning fasting saliva samples were also taken in the second year and they found significant correlations between the saliva sample and the 24-h urinary free cortisol measurements taken before and after the sample. Cortisol peaks in saliva also coincided with urinary cortisol peaks in the series. Although reports on its use for demonstrating cyclicity are sparse, salivary measurement of cortisol may eventually prove to be an easily accessible way to establish patterns of secretion over extended periods.


Types of cycle


In general, most cases described to date are of one type of regular cycle, with cycle lengths of between 12 h and 85 days having been reported. There have been a few patients for whom more complex patterns have been reported. Jordan et al. [8] reported a lady with a predominant cycle of 2-6 days. She also demonstrated an abnormal circadian rhythm with afternoon peaks of cortisol. In addition to these, Fourier analysis showed what appeared to be a separate 35-day cycle. Our first case [9] was a woman with clinical signs of Cushing's syndrome studied continuously for an extended period after demonstration of a paradoxical response to dexamethasone. She proved to have a corticotropin cell adenoma of the pituitary which caused secretion of corticotropin (ACTH) and cortisol in two distinct rhythms that were clearly visible on perusal of the data (Fig. 5). One rhythm consisted of a period of 40 days of excess cortisol production, followed by a period of 60-70 days of normal production. During the period of excess cortisol production there was a second rhythm, consisting of peaks of cortisol production every 3-6 days with intervening troughs of normal cortisol production. The long duration of normal cortisol production phases in this patient demonstrates the difficulty in excluding Cushing's syndrome in patients with suggestive clinical symptoms but normal serum and urinary cortisol levels if these tests are measured for a single, short phase of several days. We could also have falsely attributed responsiveness to centrally active drugs in her case (see below).


Figure 5 Urinary cortisol (nmol/l) to creatinine ([mu]mol/l) ratios during a 557-day period



In general, however, the vast majority of cases will emerge as cyclical if a continuous study of 28 days is performed. This is our standard procedure when we suspect the diagnosis and when the clinical condition permits prolonged study.




In every case where possible Cushing's syndrome is being assessed, a clinical decision has to be made at some point as to how far to take investigation, as no one test is infallible. The decision should be based on the clinical index of suspicion plus enough tests for the experienced endocrinologist to be confident that, in all probability, Cushing's syndrome has been excluded. In some cases this testing may need to include prolonged assessment for cyclicity. That decision should be made by an endocrinologist experienced in management of Cushing's syndrome.


Differential diagnosis


In differential diagnosis it has to be noted that cyclicity has been associated with all of the various causes of the syndrome. It can lead to incorrect interpretation of differential diagnostic tests such as petrosal sinus samplingand the high-dose dexamethasone test with subsequent incorrect management decisions. The investigator has to look carefully at this possibility in all cases.


Possible mechanisms and the effects of therapeutic interventions


As discussed above, cyclical Cushing's has been reported mostly in pituitary-dependent Cushing's disease. It has been described there in both de-novo and, increasingly, in recurrent pituitary disease. It has also been described in primary adrenal disease, in carcinoid tumors and other tumors producing corticotropin ectopically. The high number of reports in pituitary disease may simply reflect that most cases of endogenous hypercortisolism are pituitary in origin. However, it might reflect some central effect causing rhythmic secretion. If this is the case then the rhythms in adrenal cases remain unexplained. Those seen in cases of ectopic corticotropin may occur because of similar types of receptors and control to the central cases.


Cycles of steroid production in normal people have been reported, suggesting that cyclical Cushing's may simply be an exaggeration of the normal cyclical variation in a subgroup of patients [10]. Other proposed mechanisms of central cycling of corticotropin, and thereby cortisol, have included cyclical changes in central neurotransmitter tone. In our report of five cases of cyclical Cushing's, we used the dopamine agonist bromocriptine and the serotonin antagonist cyproheptadine, either alone or in combination, in four patients. Only one patient showed a response to the combination but we could not attempt

to verify this because of side effects [4].


Francia et al. [11] recently described an interesting case of relapsing and remitting hypercortisolism secondary to a lung carcinoid, which was controlled for some time on two separate occasions with bromocriptine before a relapse while the patient was still on this medication. However, definite cycles were not demonstrated. Watanobe et al. [12] characterized well a pituitary case with cycles of 2-3 weeks. Test doses of bromocriptine on two occasions preoperatively were associated with a decrease in cortisol but no prolonged trial was given. Postoperatively, however, a course of bromocriptine did not cause a biochemical remission or interrupt her periodic hormonogenesis.


Beckers et al. [13] described a patient with probable cyclical Cushing's disease who had a sustained response to sodium valproate, a drug known to increase [gamma]-aminobutyric acid (GABA), which in turn inhibits secretion of corticotropin hormone. Initially he appeared to respond to bromocriptine but then relapsed while still receiving this drug. He then had a clear 2-year remission on sodium valproate and relapsed rapidly when this regime was interrupted. Caution is required as this remains an isolated report. We did not confirm a similar response in the single patient in whom we have tried the drug [5].


Another proposed mechanism is of spontaneous haemorrhages or apoptosis within the pituitary adenoma. Alarifi et al. [14] reported a most unusual case that, over a period of 6 years, ran a fluctuating course characterized by periods of hypercortisolism and adrenal insufficiency due to repeated episodes of infarction of a pituitary adenoma, some, but not all, of which were symptomatic. Although the authors describe this patient's case as cyclical evidence for a true rhythm, this is not shown and it might be best described as fluctuating. It is difficult to explain why recurrent apoplexy such as this might occur in a rhythmical cycle.


Corticosteroid-binding globulin deficiency has been cited as a pitfall in interpreting unusual plasma cortisol levels in Cushing's syndrome by Watanobe et al. [15], who reported a patient with cyclical Cushing's disease associated with corticosteroid-binding globulin deficiency and falsely low plasma cortisol levels. This protein deficiency would not appear to explain rhythmical fluctuations, however.


Recently Arnaldi et al. [16] have reported a 56-year-old woman with cyclical Cushing's syndrome due to ectopic corticotropin from a bronchial carcinoid tumor. The patient was not continuously studied to confirm true cycles, but is of great interest as the tumor expressed pro-opiomelanocortin, orticotrophin-releasing hormone receptor and V3-vasopressin receptor. Somatostatin receptors 1, 2, 3 and 5 were also detected, as was ghrelin and both growth-hormone secretagogue receptors. In-vivo studies showed corticotropin hyperresponsiveness to the growth-hormone secretagogue hexarelin. The authors postulated a possible autocrine/paracrine modulatory effect of these factors in ectopic corticotropin cases. It is entirely possible that such abnormalities may also occur in pituitary-dependent disease.


As part of their elegant studies into aberrant receptors as a cause of Cushing's syndrome (for review see [17]), Yared et al. [18] reported a case, in abstract form, of combined hyperaldosteronism with intermittent hypercortisolism in a patient with 5-hydroxytryptamine agonist responsive bilateral adrenal hyperplasia. They noted that the response to metoclopramide (a 5-hydroxytryptamine agonist) was greatest during a period of high urinary free cortisol but the aberrant regulation was maintained during periods of normal urinary free cortisol, which suggests that another mechanism may be at play to cause the cyclicity.




Cyclical Cushing's disease is more common in hypercortisolism than previously thought, but can be somewhat difficult to diagnose. It should be considered in those individuals with features of hypercortisolism, but documented normal cortisol values, or in patients with fluctuating serum cortisol levels and anomalous responses to dexamethasone. It should also be considered after pituitary surgery in those patients with immeasurable serum cortisol values basally or following suppression with dexamethasone, in whom the features of hypercortisolism are slow to resolve or in whom there is evidence of clinical relapse. As regards therapy, Burke's commentary of 1992 [19] still holds true. He stated that fluctuation is a problem in assessing therapy in Cushing's patients. Normal cortisol levels on one or a few occasions after surgery do not allow cure to be assumed. This scenario applies equally well to studies using drugs instead of surgery. Our high index of suspicion for this form of hypercortisolism, and our ability to diagnose it easily using sequential early-morning urinary cortisol/creatinine ratios, has, we believe, enabled us to diagnose relapse at an earlier and more subtle stage, and to assess response to drugs efficiently. Further studies of the effect of sodium valproate and other centrally active drugs would be warranted, including the newer somatostatin analogues.


Endocrinologists must be aware of the possibility of cyclical oversecretion of cortisol in all patients with discordant clinical and biochemical findings. Collection of outpatient sequential early-morning cortisol to creatinine ratios initially over 28 days, refutes or confirms the diagnosis in the vast majority of cases. Sequential late-evening salivary cortisol estimations have great potential significance for future diagnosis, but this remains to be confirmed. The mechanisms remain unclear, but we speculate that abnormal responses to other rhythmical paracrine and endocrine hormones may be responsible.


Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 358).




1 Birke G, Diczfalusky E, Plantin L. Fluctuation in the excretion of adrenocortical

steroids in a case of Cushing's syndrome. J Clin Endocrinol 1956; 16:286-290.


2 Bailey RE. Periodic hormonogenesis - a new phenomenon. Periodicity in function

of a hormone producing tumour in man. J Clin Endocrinol 1971; 32:317-320.


3 Brown RD, Van Loon GR, Orth DN, Liddle GW. Cushing's disease with periodic

hormonogenesis: one explanation for paradoxical response to dexamethasone. J

Clin Endocrinol Metab 1973; 36:445-451. Bibliographic Links


4 Atkinson AB, Kennedy AL, Carson DJ, et al. Five cases of cyclical Cushing's

syndrome. Br Med J (Clin Res Ed) 1985; 291:1453-1457.


5 Atkinson AB, McCance DR, Kennedy L, Sheridan B. Cyclical Cushing's syndrome

first diagnosed after pituitary surgery: a trap for the unwary. Clin Endocrinol

(Oxf) 1992; 36:297-299.


6 Atkinson AB, Kennedy A, Wiggam MI, et al. Long-term remission rates after

pituitary surgery for Cushing's disease: the need for long-term surveillance.

Clin Endocrinol (Oxf) 2005; 63:549-559. Buy Now


7 Hermus AR, Pieters GF, Borm GF, et al. Unpredictable hypersecretion of

cortisol in Cushing's disease: detection by daily salivary cortisol

measurements. Acta Endocrinol (Copenh) 1993; 128:428-432. Bibliographic Links


8 Jordan RM, Ramos-Gabatin A, Kendall JW, Gaudette D, et al. Dynamics of

adrenocrticotrophin (ACTH) secretion in cyclic Cushing's syndrome: evidence for

more than one abnormal ACTH biorhythm. J Clin Endocrinol Metab 1982; 55:531-537.

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Sorry, folks! I can't link to the article because it came from a reference library at the university where my daughters go. The information is there for you to use the same to get it. I'll try to get a better copy with images from another reference library. If you have a subscription to this journal, you will be able to access it through their site online.


Here is what is available online: Click me





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This paragraph made me think of Sandy:


Another proposed mechanism is of spontaneous haemorrhages or apoptosis within the pituitary adenoma. Alarifi et al. [14] reported a most unusual case that, over a period of 6 years, ran a fluctuating course characterized by periods of hypercortisolism and adrenal insufficiency due to repeated episodes of infarction of a pituitary adenoma, some, but not all, of which were symptomatic. Although the authors describe this patient's case as cyclical evidence for a true rhythm, this is not shown and it might be best described as fluctuating. It is difficult to explain why recurrent apoplexy such as this might occur in a rhythmical cycle.


Isn't this interesting!?!?!

Corticosteroid-binding globulin deficiency has been cited as a pitfall in interpreting unusual plasma cortisol levels in Cushing's syndrome by Watanobe et al. [15], who reported a patient with cyclical Cushing's disease associated with corticosteroid-binding globulin deficiency and falsely low plasma cortisol levels. This protein deficiency would not appear to explain rhythmical fluctuations, however.
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That is a brilliant report Robin! Very up to date too - I think there's a few people who will find that useful info to take to thier Dr! :angry:


DAVE!!! CATHY!!!....anyone else for that?!!! :wub:

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Y'all have Ami (Addflower) to thank! She asked me if I could get it. SHe found the abstract. You know, this is the very reason these boards are priceless. You know what they say about 2 minds...well, put hundreds of minds together....see what you get!!?!?!?!!?!?!


In a sidenote, I just talked to my poor, sick dad. He saw part of the TLC programs on the world's tallest people, and especially the one where the poor fellow in Russia had acromegaly. He said, "Robin, he had the same surgery you did! It was just secreting a different kind of hormone. They said this was very rare, and I wanted to tell them it's not as rare as they thought. " ANd he went on about that I told him about this article and he was so interested. I'm telling you, my parents are observant and smart. They'll spread the word and help anyone they can with the knowledge they've gained from my experience. If we keep on sharing information, eventually it will make a difference!




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Thanks Ami and Robin! I'm so glad you posted this. This really makes me feel good about the 3 weeks straight of testing with midnight serums. I had the peaks and troughs! I felt like just going here and there, it was not showing a very good picture for me. I'm so glad I decided to do it the way I did.



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This is a great article!


What every came of this with the UK Cushies?

Did anyone contact them?


Did you ask them what it takes for them to diagnose a cyclical Cushie?

Did you offer to be part of their research study? ... at least you would have an expert to talk to? Or at least an interested doctor!

Did you tell them there were all of us cyclical Cushies out here waiting to be analyzed and listened to and written up in a medical journal?!


Yes, like Robin said, this board is the best for the articles it can share with us.

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Oh thank you, thank you, thank you Robin and Ami!!!! This article supports some theories of mine! It stated that most cyclical cases are on an approximate 11 day cycle, but there are some cases of different cycles. It seems to me that most of the different cycles cited in the article were all ectopic sources. And with one ectopic source, they were never able to even establish a pattern since it was so erratic.


After a ton of serious testing and charting, I've come to learn that I am almost always a little high. About every 2 weeks I get SUPER-DUPER high for a couple of days and then go back to a little high. I've never, ever had a normal mid-night serum. The lowest I've gotten is 6.4, and that was when I felt "normal."


I've long suspected I have an ectopic source, especially since I don't seem to have the extended lows, depression and anxiety that most cushies seem to have. I also don't have the constant headaches or vision changes experienced by most pit. cushies. I've wondered many times why I don't have the HALLMARK depression and anxiety that stems from cushings. I just chalked it up to my "sparkling personality."


But now it seems that ectopic cushies do seem to cycle differently than pit. cushies. Every now and then, I'm talking like every 3 or 4 months, I will crash. But it's only for a few hours at best. During this time I do feel like a black cloud has covered me. It is oppressive. It is depressive. It is horrible. I can completely understand why suicide is the #2 cause of death for cushies. (If Judy's stat. is correct). I could not IMAGINE living like this for any amount of time.


So I'm off to L.A. in a few weeks for an IPSS and imaging of different body parts. I was able to convince the good Dr. F. to humor me with this. So if my theory is correct, the IPSS should show nothing, my second pit. MRI should be clean just like the first, and hopefully, the other imaging will pick up something good.


Way to go ladies!


melly in nv

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sorry if i'm being a bit slowwww - can u explain from the article how cortisol/creatine ratios work??

does that help in the dx? is there a magic number?

how do u calculate this ratio?



Dido! Can anyone explain this better?

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