On Oct 6, 4:26 pm, neil0...@yahoo.com wrote:

neil,
thanks for the update.  i wish it were different.  to be sick & to be
working so hard to find answers & relief even as new things emerge to
further complicate life - it's all so difficult.  i'm glad that you
have the ability to advocate on your own behalf & to have the help of
some competent people.  & i am glad for your sense of humor (here is a
link to eddie izzard & computers - less offensive than his religious
stuff.  if you like it, imo, 'dressed to kill' is his best performance
available.  http://www.youtube.com/watch?v=k6C_HjWr3Nk)

i am very sorry to hear about the serious health news regarding one of
our friends on this forum.  my best thoughts & wishes are sent - may
better news be forthcoming.

best,
ellen

re: fall in michigan.  quite a dry summer, to my delight but harsh on
the trees.  now the temps have been swinging & we're in a mid to high
80s run, which further messes with everything.  did head north a few
weeks ago - too early for much color but right on time for the
republican convention...  (ellen+spontaneity often doesn't work
well).  but there were patches of lovely beauty - all good for the
soul.  my favorite time of year here.

I'm really sorry to hear that.
You'll be in my thoughts.

Actually, I may have some things to report along those lines too in a
few days.  (I just had my prostate biopsy and I'm waiting with bated
breath for the results.)

Ya THINK?  :-)

Neither of those can reliably dx DM.  The HbA1c isn't to be used as a dx
screen, it fails to discern whether you're spiking high after meals,
then having a reactive low, the pattern in the earlier years of type 2
DM.  It's just an average.

I eat zero starch.  Tons of leafy, colorful, fibrous stuff.  And dark
chocolate and red wine and good cheeses.

Uh, erm... www.PHLAUNT.com/diabetes

It turns out that at least 10% of all type 2 DM is caused by undiagnosed
Cushing's syndrome, and among hospitalized patients, this group has the
most DM complications.  I'm DM without IR (I reversed it with diet), I
have a fasting insulin half the low end of normal.

Too much effing illness.  Too many useless, uninformed, uncurious doctors.

  I married a

You can do it yourself!

Good luck.  The whole endocrine story is just mind boggling.  The more I
learn, the less I know, it's just so complex and intertwined.  I'm
reduced to referring to it as the "whole enchilada."  Another cheap
metaphor.

Susan

Yabbut, he's blown it, too.  He's completely focused on insulin as the
issue, ignoring the totality of the obesity picture involving cortisol,
HGH, thyroid, etc.

The only form of Vit D recommended is D3, or cholecalciferol,
specifically.  I take about 5000 iu a few times per week. It helps
prevent a lot of cancers, balance, issues, immune function.

Keep that endo on tap!  And if he fails to find the cortisol elevations
on the first try, refer to this:

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
[Neuroendocrinology]

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:
ab.atkinson@royalhospitals.n-i.nhs.uk

Abstract

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.
----------------------------------------------

Introduction

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, (cool.gif 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.

Diagnosis

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.

Conclusion

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).

References

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.

Me, too, I'm just getting caught up with this group after being away.

I didn't realize it was another member with the surgery, so please send
my best wishes to the unnamed, and Steven, best of luck with your
outcome, too.

Susan

Re "Inoculation"

Came across the following this evening by accident. While not an
"inoculation" seems to be  similar in principle.  Myself not competent
to make any observations but would be interested in the opinions of
others:-

Respivax polybacterial immunostimulator
Active substance - each tablet contains 25 mg freeze-dried active
substance for children and 50 mg freeze - dried active substance for
adults, comprising freeze-dried killed bacterial cultures of the
following microbial species: Streptococcus pneumoniae, Branhamella
catarrhalis, Streptococcus pyogenes of group A, Haemophilus influenzae
type b, Sraphylococcus aureus, Klebsiella pneumoniae in quantities
corresponding to 0.625x109 cells of each microorganism for children
and 1.25x109 cells of each microorganism for adults. It contains from
0.001 to 0.1 mg formaldehyde.

http://www.biogenicstimulants.com/bulbio/respivax.phtml?PHPSESSID=529aea2cc04365
ab143c270df33ddaba

PS As a lurker for the past few months have learned much and
appreciate all -- the group has made my own chronic condition more
bearable and helped me to feel much less alone.  Thanks.

Michael