Interview with Stephanie (Steph), PCOS/Possible Cushing's Patient

The next interview on BlogTalk Radio will be Wednesday, April 22 at 6:00 PM eastern.  The Call-In number for questions or comments is (657) 383-0416.

Steph has a bio posted here: http://cushingsbios.com/2015/04/16/stephanie-steph-undiagnosed-bio/

The archived interview will be available after 7:00 PM Eastern through iTunes Podcasts (Cushie Chats) or BlogTalkRadio.  While you're waiting, there are currently 82 other past interviews to listen to!

In her bio, Steph writes:

Hi. My name Steph, and this has been a long journey for me so far, and I see a long road ahead. Hopefully their will be a rainbow once all these clouds have melted away.

I just turned 33 years old (this month) and have been dealing with symptoms of Cushing’s since I was a pre-teen without even knowing it. I was diagnosed (or possibly mis-diagnosed) with PCOS when I was about 11. That’s when the irregular (to almost non-existent) menstrual cycles, hirutism (chin, upper lip, upper and lower thighs, fingers, toes, basically everywhere) and weight problems began. I was immediately put on birth control to regulate my periods, which only made my life a living nightmare. They forced on a fake (non-ovulating) period and made my moods a disaster. I went on to be on birth control until from the age of 11 until about 3 years ago when I just couldn’t take it anymore, and took myself off. I’ve been using herbal supplements for menstrual regulalation since then, and feel MUCH better.

Over the years I’ve always felt like there was something “more than PCOS” wrong with me. From the extreme inability to lose weight normally, and the ease to gain it, to the weak legs, vitamen d insuffeciency, high cholesterol, high blood pressure, extreme irritability, now non-existent cycle, shortness of breath (just from walking up 1 flight of stairs), slow healing, hoarse voice, high testosterone, male pattern baldness, blurry vision, EXTREME brain fog etc….. It has been very, very, very tough and emotional over the years. It has taken a toll on my personality, emotions, and those around me….

The way that I found out about cushing’s is rather unique. I was on a popular PCOS message board site called “soul cysters”, and I have always been EXTREMELY self conscience of my round puffy face, and was wondering if it could be a side effect of PCOS. So I searched Puffy face on the message board to see if others on the board had experienced it, and sure enough Cushing’s came up, and a suprising number of women either had both (cushing’s and PCOS) or had been mis-diagnosed, which apparently is very common with cushing’s. it was like a gigantic light bulb went off in my head when I started googling cushings symptoms. All these things that I have been experiencing almost my entire life started coming together. I’m really not crazy!! Everything is possibly related. Im almost 100% sure that this is it!!! I don’t know if this is a good or bad thing, as I see that cushing’s is curable in most cases, but it is also scary, and diagnosing it seems like hell!!

I have began my -already slow- journey to diagnosis. And, the the Dr.’s don’t seem to be all that well informed. However, I am DETERMINED. I am excited at the thought of possibly being able to get my life back through surgery or meds. I went to a well respected Endo in my area, and she is gonna test all of my hormones, including my cortisol level. Though she didn’t seem to be too informed on Cushing’s when I brought it up, along with my “dead ringer” symptoms. I’m going to a pulmonologist on the 29th as suggested by my GP (who also thinks I have cushings, but admits he’s not well informed enough or equipped to diagnose). I’m also going to an OBGYN soon (tried going to one today, and had to walk out because it was such a bad experience). But I am determined to get 2nd, 3rd, and however many opinions are needed until I am satisfied.

Also, on a side note, possibly having cushing’s, along with having PCOS, has made me look at the doctors and the medical profession as a whole in a different light. I feel like if you find a genuinely good doctor who listens, cares, takes you seriously, and is willing to test you without question, and work with you, your levels, and your symptoms, you are blessed!! I have had so many doctors try to push meds down my throat (for their own pockets/greed obviously) when it wasn’t needed or necessary without hesitation or question. And, then when I tell them that the medicine is affecting me adversely, they just tell me to keep taking it! It’s sad and ridiculous. I’ve had to learn to do my own research, know my own body well, and trust my own judgement…..

I will be praying for myself and everyone on this message board who has had to deal with this horrific symptoms over the years.

Updates coming…..

HOME | Sitemap | Adrenal Crisis! | Abbreviations | Glossary | Forums |Donate | Bios | Add Your Bio

Research Study: An Open Label Study to Assess the Safety and Efficacy of COR-003 (2S, 4R-ketoconazole) in the Treatment of Endogenous Cushing’s Syndrome

Objectives:         

The purpose of this study is to test the effects of different doses of COR-003 on people with Cushing’s syndrome (CS) primarily by measuring the cortisol levels in urine and secondarily by measuring other health parameters such as blood pressure, weight, and liver function. This study is also being conducted to see if there is any harm caused when using COR-003.

This study is an open label study. That means both the health providers and the participants in the study are aware of the drug or treatment being given.

Eligibility:

Adult Subjects (18 years or older) with elevated levels of cortisol due to endogenous CS.

Confirmed diagnosis of persistent or recurrent CS (with or without therapy) or newly diagnosed disease, if subjects are not candidates for surgery. CS will be defined according to the criteria in the guidelines for diagnosis of CS (Nieman 2008).

Women who are pregnant or lactating are not eligible for this study.

Individuals with other health conditions or diagnoses may not be eligible for this study.

These and other eligibility criteria are best reviewed with a doctor who is participating in the study. You can also get more detailed eligibility information about the study by clicking here to visithttp://www.clinicaltrials.gov.

Study Design:

• The study will begin with a screening period to make sure subjects are eligible to participate in the study.
• After the screening period, subjects who are eligible for participation will each be given several different doses of COR-003, to be taken orally in tablet form.
• After an individualized dose has been selected, participants will take COR-003 for six months.
• Finally, participants will continue in the study for an additional six months at doses to be determined by the study doctor.

Throughout the study, participants will meet regularly with a study doctor and will take part in a variety of medical tests to make sure they are doing well and to see if COR-003 is working.

Participants in the study should be sure they have the time to participate. Participants will generally be followed for over a year:

Study Locations

The study is currently taking place in several places around the world (United States, Belgium, France, Israel, Netherlands, Spain, and Sweden).
Additional information on the study can be found at clinicaltrials.gov throughthis link.

Study sponsor: Cortendo AB

For more information, please contact:

Jim Ellis at Cortendo AB tel: +1 (610) 254-9245 or jellis@cortendo.com

Cushing’s Awareness Patient Day

Saturday, February 1st, 2014

San Francisco, California

Hosted by Kate Tully, R.N. and Katherine Waidner, R.N.
Cushing’s Patient Advocates – Corcept Therapeutics

Agenda and details to follow

The day will focus on endogenous Cushing’s, a condition caused by high cortisol in your body.

The day will not cover exogenous Cushing’s caused by steroids taken for various health conditions including asthma, arthritis or lupus.

Enzyme linked to obesity

Researchers find that increased levels of an enzyme in fat cells lead to dangerous levels of abdominal obesity.

Previous studies have shown that the stress hormone cortisol can lead to an accumulation of fat round the abdomen. For instance, people with Cushing’s disease – where there’s excess cortisol in the blood – have too much abdominal fat. It’s bad for health to have fat in this area – it’s linked to diabetes and heart disease. That’s why it’s healthier to be a ‘pear shape’ rather than an ‘apple shape’. The distribution of fat in your body really does matter.

Researchers in Scotland and the US have now focussed upon an enzyme that produces cortisol to see what effect it has on abdominal fat. Working on mice genetically-modified to produce the enzyme – and therefore cortisol – in fat cells, they find that even a small increase in levels produces dramatic effects. The mice, compared with normal animals, gained fat in the abdominal area even on a low fat diet. They developed diabetes, high blood pressure, and also tended to eat more. It opens up the possibility of further studies on human obesity, and also perhaps could lead to therapies that block this enzyme and so reduce fat accumulation.

From http://www.tele-management.ca/2013/09/enzyme-linked-to-obesity/

Cyclic Cushing’s syndrome: a clinical challenge

1. J R Meinardi1,2, 
2. B H R Wolffenbuttel2 and 
3. R P F Dullaart2

+Author Affiliations

1. 1Department of Internal Medicine, Canisius Wilhelmina Ziekenhuis, PO Box 9015, 6500 GS Nijmegen, The Netherlands and 2Department of Endocrinology, University Medical Centre Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands

1. (Correspondence should be addressed to: R P F Dullaart; Email:r.p.f.dullaart@int.umcg.nl)

Next Section

Abstract

Cyclic Cushing’s syndrome (CS) is a rare disorder, characterized by repeated episodes of cortisol excess interspersed by periods of normal cortisol secretion. The so-called cycles of hypercortisolism can occur regularly or irregularly with intercyclic phases ranging from days to years.

To formally diagnose cyclic CS, three peaks and two troughs of cortisol production should be demonstrated. Our review of 65 reported cases demonstrates that cyclic CS originates in 54% of cases from a pituitary corticotroph adenoma, in 26% from an ectopic ACTH-producing tumour and in about 11% from an adrenal tumour, the remainder being unclassified. The pathophysiology of cyclic CS is largely unknown.

The majority of patients with cyclic CS have clinical signs of CS, which can be either fluctuating or permanent. In a minority of patients, clinical signs of CS are absent. The fluctuating clinical picture and discrepant biochemical findings make cyclic CS extremely hard to diagnose. Clinicians should therefore be aware of this clinical entity and actively search for it in all patients with suspected CS but normal biochemistry or vice versa.

Frequent measurements of urinary cortisol or salivary cortisol levels are a reliable and convenient screening tool for suspected cyclic CS. Cortisol stimulation or suppression tests may give spurious results owing to spontaneous falls or rises in serum cortisol at the time of testing. When cyclic CS is biochemically confirmed, further imaging and laboratory studies are guided by the presence or absence of ACTH dependency. In cases of suspected ectopic ACTH production, specific biochemical testing for carcinoids or neuroendocrine tumours is required, including measurements of serotonin in platelets and/or urine, chromogranin A and calcitonin.

Read the entire article here:  http://www.scribd.com/doc/159503297/Cyclic-Cushing%E2%80%99s-syndrome-a-clinical-challenge

Cushing’s Syndrome is Hazardous to Your Health

People with Cushing’s syndrome, even when treated, have higher morbidity and mortality rates that comparable controls. That is the conclusion of a new study published in the June issue of the Journal of Clinical Endocrinology Metabolism. The study by Olaf Dekkers et al, examined data records from the Danish National Registry of Patients and the Danish Civil Registration System of 343 patients with benign Cushing’s syndrome of adrenal or pituitary origin (i.e., Cushing’s disease) and a matched population comparison cohort (n=34,300).  Due to the lengthy delay of many patients being diagnosed with Cushing’s syndrome, morbidity was investigated in the 3 years before diagnosis while  morbidity and mortality were assessed during complete follow-up after diagnosis and treatment.

The study found that mortality was twice as high in Cushing’s syndrome patients (HR 2.3, 95% CI 1.8-2.9) compared with controls over a mean follow-up period of 12.1 years. Furthermore, patients with Cushing’s syndrome were at increased risk for:

• venous thromboembolism (HR 2.6, 95% CI 1.5-4.7)
• myocardial infarction (HR 3.7, 95% CI 2.4-5.5)
• stroke (HR 2.0, 95% CI 1.3-3.2)
• peptic ulcers (HR 2.0, 95% CI 1.1-3.6)
• fractures (HR 1.4, 95% CI 1.0-1.9)
• infections (HR 4.9, 95% CI 3.7-6.4).

The study also found that this increased multimorbidity risk was present before diagnosis indicating that it was due to cortisol overproduction rather than treatment.

Many of the Cushing’s syndrome patients underwent surgery to remove the benign tumor. For this group, the investigators performed a sensitivity analysis of the  long-term mortality and cardiovascular risk in this  subgroup (n=186)  considered to be cured after operation (adrenal surgery and patients with pituitary surgery in combination with a diagnosis of hypopituitarism in the first 6 months after operation).  The risk estimates for mortality (HR 2.31, 95% CI 1.62-3.28), venous thromboembolism (HR 2.03, 95% CI 0.75-5.48), stroke (HR 1.91, 95% CI 0.90-4.05), and acute myocardial infarction (HR 4.38, 95% CI 2.31-8.28) were also increased in this subgroup one year after the operation.

The standard treatment for endogenous Cushing’s syndrome is surgery. This past year, Signifor (pasireotide) was approved for treatment of adults patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.  Cushing’s disease, which accounts for the majority of Cushing’s syndrome patients, is defined as the presence of an ACTH producing tumor on the pituitary grand. In the study by Dekker’s et al, the percentage of patients with Cushing’s disease is not known. We look forward to reexamination of this dataset in a few years following the introduction of more treatment options for Cushing’s disease as well as an analysis that explores the differences in mortality/morbidity rates in the different subsets of patients that make of Cushing’s syndrome (Cushing’s disease, ectopic Cushing’s syndrome, Exogenous Cyshing’s syndrome).

References

Dekkers OM, Horvath-Pujo, Jorgensen JOL, et al, Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J Clin Endocrinol Metab 2013 98(6): 2277–2284. doi: 10.1210/jc.2012-3582

- See more at: http://www.raredr.com/medicine/articles/cushing%E2%80%99s-syndrome-hazardous-your-health-0

Research and Markets: Pituitary ACTH Hypersecretion (Cushing's Disease) - Pipeline Review Report, H1 2013 Edition

Research and Markets (http://www.researchandmarkets.com/
research/rdf6gm/pituitary_acth) has announced the addition of the "Pituitary ACTH Hypersecretion (Cushing's Disease) - Pipeline Review, H1 2013" report to their offering.

'Pituitary ACTH Hypersecretion (Cushing's Disease) - Pipeline Review, H2 2013', provides an overview of the indication's therapeutic pipeline. This report provides information on the therapeutic development for Pituitary ACTH Hypersecretion (Cushing's Disease), complete with latest updates, and special features on late-stage and discontinued projects. It also reviews key players involved in the therapeutic development for Pituitary ACTH Hypersecretion (Cushing's Disease).

Scope

- A snapshot of the global therapeutic scenario for Pituitary ACTH Hypersecretion (Cushing's Disease).

- A review of the Pituitary ACTH Hypersecretion (Cushing's Disease) products under development by companies and universities/research institutes based on information derived from company and industry-specific sources.

- Coverage of products based on various stages of development ranging from discovery till registration stages.

- A feature on pipeline projects on the basis of monotherapy and combined therapeutics.

- Coverage of the Pituitary ACTH Hypersecretion (Cushing's Disease) pipeline on the basis of route of administration and molecule type.

- Key discontinued pipeline projects.

- Latest news and deals relating to the products.

Companies Involved in Pituitary ACTH Hypersecretion (Cushing's Disease) Therapeutics Development

• Isis Pharmaceuticals, Inc.
• Ipsen S.A.
• Novartis AG
• HRA Pharma, SA
• Cortendo Invest AB

Drug Profiles: Product Description, Mechanism of Action and R&D Progress

• LCI-699
• mifepristone
• ISIS-GCCRRx
• Inhibitors of ACTH receptor
• ketoconazole
• Next Generation Cortisol Inhibitor
• pasireotide Long Acting Release

For more information visit http://www.researchandmarkets.com/research/rdf6gm/pituitary_acth

Read more here: http://www.heraldonline.com/2013/06/17/4952623/research-and-markets-pituitary.html#storylink=cpy

Read more here: http://www.heraldonline.com/2013/06/17/4952623/research-and-markets-pituitary.html#storylink=cpy

Salk scientists find potential therapeutic target for Cushing's disease

LA JOLLA, CA---Scientists at the Salk Institute for Biological Studies have identified a protein that drives the formation of pituitary tumors in Cushing's disease, a development that may give clinicians a therapeutic target to treat this potentially life-threatening disorder.

The protein, called TR4 (testicular orphan nuclear receptor 4), is one of the human body's 48 nuclear receptors, a class of proteins found in cells that are responsible for sensing hormones and, in response, regulating the expression of specific genes. Using a genome scan, the Salk team discovered that TR4 regulates a gene that produces adrenocorticotropic hormone (ACTH), which is overproduced by pituitary tumors in Cushing's disease (CD). The findings were published in the May 6 early online edition of Proceedings of the National Academy of Sciences.

"We were surprised by the scan, as TR4 and ACTH were not known to be functionally linked," says senior author Ronald M. Evans, a professor in Salk's Gene Expression Laboratory and a lead researcher in the Institute's Helmsley Center for Genomic Medicine. "TR4 is driving the growth and overexpression of ACTH. Targeting this pathway could therapeutically benefit treatment of CD."

In their study, Evans and his colleagues discovered that forced overexpression of TR4 in both human and mouse cells increased production of ACTH, cellular proliferation and tumor invasion rates. All of these events were reversed when TR4 expression was reduced.

First described more than 80 years ago, Cushing's disease is a rare disorder that is caused by pituitary tumors or excess growth of the pituitary gland located at the base of the brain. People with CD have too much ACTH, which stimulates the production and release of cortisol, a hormone that is normally produced during stressful situations.

While these pituitary tumors are almost always benign, they result in excess ACTH and cortisol secretion, which can result in various disabling symptoms, including diabetes, hypertension, osteoporosis, obesity and psychological disturbances. Surgical removal of the tumors is the first-line therapy, with remission rates of approximately 80 percent; however, the disease recurs in up to 25 percent of cases.

Drugs such as cabergoline, which is used to treat certain pituitary tumors, alone or in combination with ketoconazole, a drug normally used to treat fungal infections, have been shown to be effective in some patients with Cushing's disease. More recently, mefipristone-best known as the abortion pill RU-486-was approved by the FDA to treat CD. Despite these advances in medical therapy, the Salk scientists say additional therapeutic approaches are needed for CD.

"Pituitary tumors are extremely difficult to control," says Michael Downes, a senior staff scientist in the Gene Expression Laboratory and a co-author of the study. "To control them, you have to kill cells in the pituitary gland that are proliferating, which could prevent the production of a vital hormone."

Previous studies have found that, by itself, TR4 is a natural target for other signaling molecules in the pituitary. Small-molecule inhibitors that have been developed for other cancers could be potentially applied to disrupt this signaling cascade. "Our discovery," says Evans, a Howard Hughes Medical Institute investigator and holder of the March of Dimes Chair in Molecular and Developmental Biology, "might lead clinicians to an existing drug that could be used to treat Cushing's disease."

Source: Salk Institute

Diagnostic performance of salivary cortisol in the diagnosis of Cushing's syndrome, adrenal incidentaloma and adrenal insufficiency

Ceccato F, Barbot M, Zilio M, Ferasin S, Occhi G, Daniele A, Mazzocut S, Iacobone M, Betterle C, Mantero F, Scaroni C.

Source

F Ceccato, Department of Medicine - DIMED, University of Padova, Endocrinology Unit, Padova, Italy.

Abstract

OBJECTIVE:

Salivary cortisol has been recently suggested for studies on the hypothalamic-pituitary-adrenal (HPA) axis: lack of circadian rhythm is a marker of Cushing's syndrome (CS), and some authors report that low salivary cortisol levels may be a marker of adrenal insufficiency. The aim of our study was to define the role of salivary cortisol in specific diagnostic setting of HPA axis disease.

SUBJECTS AND METHODS:

We analyzed morning salivary cortisol (MSC) and late night salivary cortisol (LNSC) in 406 subjects: 52 Cushing's disease (CD), 13 ectopic-CS, 17 adrenal-CS, 27 CD in remission (mean follow-up of 66 ± 39 months), 45 adrenal incidentalomas, 73 patients assessed of CS and then ruled out for endogenous hypercortisolism, 75 patients with adrenal insufficiency and 104 healthy subjects.

RESULTS:

A LNSC value above 5.24 ng/mL differentiated CS from controls with high sensitivity (96.3%) and specificity (97.1%), we found higher LNSC in ectopic-CS than in CD. We found no difference in MSC and LNSC levels between CD in remission and healthy subjects. Both MSC and LNSC were higher in adrenal incidentaloma than in healthy controls. MSC below 2.65 ng/mL distinguished patients with adrenal insufficiency from controls with high sensitivity (97.1%) and specificity (93.3%).

CONCLUSIONS:

salivary cortisol is a useful tool to assess endogenous cortisol excess or adrenal insufficiency and to evaluate stable CD in remission.

PMID:

 

23610124

 

[PubMed - as supplied by publisher]

From PubMed

Know Your Number

English: "Dr. Harvey Cushing," oil on canvas, by the American artist Edmund Tarbell. Courtesy of the Dittrick Medical History Center. (Photo credit: Wikipedia)

From my email:

As an advocate for patients with Cushing’s disease and their supporters, you certainly understand the importance of continually monitoring cortisol.
April 8th marks Cushing’s Awareness Day and the birthday of Dr. Harvey Cushing, who first described the disease in 1912. We want to use the month of April to bring attention to this disease. In honor of this day, Novartis Pharmaceuticals Corporation is kicking off “Know Your Number,” an important new program emphasizing the importance of cortisol regulation.

Being an advocate for those with Cushing’s disease and for those who care for them, you know that even after a successful pituitary surgery, where cortisol levels return to normal, there is still up to a 35% risk the pituitary tumor could begin to grow again, thus causing hypercortisolism. This potential rise in cortisol is also true for patients who are currently taking medication to control their Cushing’s disease. Over time, this control may begin to diminish. These important facts make it essential that your members are aware of the need to monitor their cortisol level.

Novartis Pharmaceuticals Corporation is initiating an important new program, and we would like to partner with Cushing’s Help and Support to bring this information to your membership and to all patients with Cushing’s disease. “Know Your Number” reminds both endocrinologists and patients that hypercortisolism can have devastating consequences on a patient’s body and emotions. “Know Your Number” promotes follow-up cortisol testing to help identify those patients whose cortisol levels have increased.

Please reach out to your membership with this message during the month of April as we celebrate Dr. Harvey Cushing’s birthday.

To learn more about this program and Cushing’s disease, and to download a discussion guide, please visit www.CushingsDisease.com

Know Your Number.

Depressed Mood and Other Psychiatric Manifestations of Cushing's Syndrome: Relationship to Hormone Levels

Thirty-five consecutive patients with Cushing's syndrome were studied prospectively prior to treatment.

A consistent constellation of psychiatric disturbances was found, including impairments in affect (depressed mood and crying), cognitive functions (decreased concentration and memory), and vegetative functions (decreased libido and insomnia).

A statistically significant relationship was found between the overall psychiatric disability rating and cortisol and ACTH level. The relationship of depressed mood and hormone levels was examined. Low ACTH levels were significantly associated with milder rather than pronounced depressed mood.

The implications of the similarities in psychiatric manifestations between Cushing's syndrome and the primary affective disorders are discussed.


MONICA N. STARKMAN, MD, DAVID E. SCHTEINGART, MD, AND
M. ANTHONY SCHORK, PHD

Read the PDF here.

Exophthalmos: A Forgotten Clinical Sign of Cushing's Syndrome

Case Reports in Endocrinology

Volume 2013 (2013), Article ID 205208, 3 pages

http://dx.doi.org/10.1155/2013/205208

Aldo Schenone Giugni,1 Shylaja Mani,1 Subramanian Kannan,2 and Betul Hatipoglu2

1Department of Internal Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue Desk NA10, Cleveland, OH 44195, USA
2Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic Foundation, 9500 Euclid Avenue Desk F20, Cleveland, OH 44195, USA

Received 3 February 2013; Accepted 22 February 2013

Academic Editors: C. Capella, T. Cheetham, M. Demura, and K. Iida


Copyright © 2013 Aldo Schenone Giugni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.



Abstract

Exophthalmos is typically associated with Graves' ophthalmopathy. Although originally described by Harvey Cushing, exophthalmos is an underappreciated sign of Cushing's syndrome. We present a case of a 38-year-old female who presented with severe bilateral proptosis and was subsequently diagnosed with Cushings disease. We discuss the possible mechanisms causing exophthalmos in patients with either endogenous or exogenous hypercortisolemia.





1. Case Presentation

A 38-year-old female noticed progressively worsening bilateral proptosis for a period of two years, to the point causing episodes of ocular dislocation from her sockets. She also noted irregular menstrual cycles during this time and was amenorrheic for 6 months prior to referral. She underwent extensive workup by her primary care physician including thyroid tests which were normal. She then underwent orbital decompression surgery in June 2011 with transient improvement of symptoms. However in the next 12 months she gained 60 lbs and developed proximal muscle weakness, purplish abdominal striae, facial hirsutism, and easy bruisability. She was also diagnosed with new onset diabetes and hypertension during this time and was treated with Metformin and Lisinopril, respectively. Physical examination revealed an obese female with a BMI of 43 and BP . She had frank stigmata of Cushings syndrome (CS). She had bilateral proptosis with Hertel’s exophthalmometry readings of 26 mm (right) and 27 mm (left) (Figure 1). Visual acuity was  bilaterally. There was no corneal/conjunctival congestion or lid retraction/lag. Fundus exam was normal. Extraocular movements were intact and visual fields were normal on confrontation. Tonometry was not performed. Labs done prior to referral indicated midnight salivary cortisol of 654 ng/dL (normal 112 ng/dL) and post 1 mg dexamethasone cortisol of 16.9 mcg/dL. Random ACTH level was 50 (8–42 pg/mL). MRI of pituitary gland revealed 1.6 cm macroadenoma with deviation of the stalk to the right (Figure 2). MRI also indicated bilateral exophthalmos with increased retrorbital fat (Figure 2). Prolactin was 40 (2–17.4 ng/mL) consistent with stalk effect, gonadotropins were low, and IGF-1, free T4 were normal. Patient underwent trans-sphenoidal removal of the tumor which stained diffusely with ACTH (Figure 3). Patient is being treated with hydrocortisone and followed closely by her ophthalmologist. Although the exophthalmos persisted after the pituitary surgery, episodes of ocular dislocation had not occurred at 3 months followup.




Figure 1: Bilateral exophthalmos as seen on MRI.





Figure 2: MRI of pituitary (coronal view) (arrows showing the macroadenoma and stalk deviation).





Figure 3: Histology: (a) H&E stain showing basophilic cells at magnification 200. (b) Positive ACTH staining.


2. Discussion

Exophthalmos or proptosis refers to forward displacement of the eyeball. It has to be differentiated from retraction of the eyelids, which can cause an illusion of exophthalmos. Conventionally, exophthalmos refers to ocular proptosis secondary to endocrinopathies. Graves’ disease is the most common endocrine cause of exophthalmos. Although described in 1932 by Harvey Cushing in 4 of his 12 patients with Cushings disease, this is an often forgotten clinical sign [1] in patients with CS. We have presented a case highlighting the importance of exophthalmos and its association with hypercortisolemia.

Exophthalmos is seen in about 30–45% of patients with Cushings syndrome (CS) [1–3]. Kelly reported that exophthalmos (exceeding 16 mm) occurred in 45% of active CS, 21% of iatrogenic CS, and 20% of treated CS in comparison to 2% in controls [3]. Cases of severe exophthalmos preceding the evolution of CS have been reported in the literature [4, 5].

The cause of exophthalmos in CS is still unknown. Multiple theories have been proposed including fat redistribution and increased retro-orbital fat, associated thyroid disease, and an exophthalmos causative factor. It has been proposed that retro-orbital fat deposition is also part of the fat re-distribution seen in CS, resulting in increase in volume of the retro-orbital tissues and a consequent rise in intra-orbital pressure [3, 6]. Orbital fat volume was increased in patients with CS and orbital muscles are relatively spared [7, 8]. In contrast to patients with Graves’ disease the retrorbital fat in CS is devoid of inflammatory cell infiltration. Whether differential fat deposition in the orbits is due to increased glucocorticoid receptor density, defective lipolysis or increased lipoprotein lipase activity is not known.

Conflict of Interests

The authors report no conflict of interests.




References

H. Cushing, “The basophil adenomas of the pituitary body and their clinical manifestation,”Bulletin Johns Hopkins Hospital, vol. 50, pp. 173–195, 1932.
T. A. Howlett, L. H. Rees, and G. M. Besser, “Cushing's syndrome,” Clinics in Endocrinology and Metabolism, vol. 14, no. 4, pp. 911–945, 1985. View at Scopus
W. Kelly, “Exophthalmos in cushing's syndrome,” Clinical Endocrinology, vol. 45, no. 2, pp. 167–170, 1996.
M. Nezu, I. Miwa, K. Minai, and T. Kagami, “A case of Cushing's syndrome associated with severe exophthalmos,” Nihon Naika Gakkai, vol. 76, no. 8, pp. 1290–1293, 1987. View at Scopus
A. Boschi, M. Detry, T. Duprez et al., “Malignant bilateral exophthalmos and secondary glaucoma in iatrogenic Cushing's syndrome,” Ophthalmic Surgery and Lasers, vol. 28, no. 4, pp. 318–320, 1997. View at Scopus
S. W. Panzer, J. R. Patrinely, and H. K. Wilson, “Exophthalmos and iatrogenic Cushing's syndrome,” Ophthalmic Plastic and Reconstructive Surgery, vol. 10, no. 4, pp. 278–282, 1994.View at Scopus
R. G. Peyster, F. Ginsberg, J. H. Silber, and L. P. Adler, “Exophthalmos caused by excessive fat: CT volumetric analysis and differential diagnosis,” American Journal of Roentgenology, vol. 146, no. 3, pp. 459–464, 1986. View at Scopus
G. Forbes, D. G. Gehring, C. A. Gorman, M. D. Brennan, and I. T. Jackson, “Volume measurements of normal orbital structures by computed tomographic analysis,” American Journal of Roentgenology, vol. 145, no. 1, pp. 149–154, 1985. View at Scopus

Cushing’s Syndrome, Prostate Cancer and Adrenocortical Carcinoma

Orphagen has identified and characterized small molecule antagonists to steroidogenic factor-1 (SF-1). SF-1 binds to and regulates DNA promoter elements in the major transporters and enzymes required for adrenal steroid synthesis. It is also required for development of the adrenal gland. SF-1 antagonists inhibit cortisol secretion in adrenal cells and have potential application in two orphan indications, Cushing’s syndrome and adrenocortical carcinoma. In addition, SF-1 appears to have an important role in the progression of advanced prostate cancer.

 

  Cushing’s syndrome: An estimated 20,000 people in the US have Cushing’s, with more than 3,000 new cases diagnosed each year. The incidence is similar in Europe. Cushing’s syndrome disproportionately affects females, who make up about 75% of the diagnosed cases. Symptoms of Cushing’s syndrome can include obesity, diabetes, psychiatric disorders, osteoporosis and immune suppression. Cushing’s syndrome is caused by elevated secretion of cortisol from the adrenal gland, in association with pituitary, adrenal or other cancers. Orphagen has identified small molecule antagonists to SF-1 that have the potential to suppress cortisol levels in all Cushing’s patients without serious side effects.

  Adrenocortical carcinoma (ACC): ACC is a rare malignancy with an extremely poor prognosis (5-year overall survival: 37-47%). Complete surgical resection offers hope for long-term survival but surgery is not an option in up to two-thirds of patients because metastasis has usually occurred by the time of diagnosis. SF-1 is recognized as a potential mechanism-based therapeutic target for control of ACC and an SF-1 antagonist could be used in the treatment of ACC.

  Pediatric ACC: Pediatric ACC is a very rare but aggressive cancer with a long-term survival rate of about 50%. Approximately 60% of children with adrenocortical tumors are diagnosed before the age of four. The SF-1 gene is amplified and SF-1 protein is overexpressed in the vast majority of childhood adrenocortical tumors strongly implicating SF-1 in pediatric adrenocortical tumorigenesis.

  Castration resistant prostate cancer (CRPC): CRPC is the most common cancer in males. Surgery is not an option if the cancer has spread beyond the prostate gland, at which point patients typically receive hormonal therapy, essentially chemical castration. This course of therapy usually fails within two years, resulting in castration resistant prostate cancer (CRPC). Most patients eventually succumb to CRPC, which is the second leading cause of cancer deaths in men. SF-1 antagonists may: (1) block the adrenal androgens that circumvent chemical castration, and are a primary cause of CRPC; and (2) inhibit synthesis of androgens within the prostate tumor itself, where SF-1 may control induction of enzymes for de novo androgen synthesis in treatment-resistant cancers. From http://www.orphagen.com/research_cushings.html

Early Detection, Treatment Needed To Reduce Risk Of Death, Cardiovascular Disease In Cushing's Disease Patients

Even after successful treatment, patients with Cushing's disease who were older when diagnosed or had prolonged exposure to excess cortisol face a greater risk of dying or developing cardiovascular disease, according to a recent study accepted for publication in The Endocrine Society's Journal of Clinical Endocrinology & Metabolism (JCEM). 

Cushing's disease is a rare condition where the body is exposed to excess cortisol - a stress hormone produced in the adrenal gland - for long periods of time. 

Researchers have long known that patients who have Cushing's disease are at greater risk of developing and dying from cardiovascular disease than the average person. This study examined whether the risk could be eliminated or reduced when the disease is controlled. Researchers found that these risk factors remained long after patients were exposed to excess cortisol. 

"The longer patients with Cushing's disease are exposed to excess cortisol and the older they are when diagnosed, the more likely they are to experience these challenges," said Eliza B. Geer, MD, of Mount Sinai Medical Center and lead author of the study. "The findings demonstrate just how critical it is for Cushing's disease to be diagnosed and treated quickly. Patients also need long-term follow-up care to help them achieve good outcomes." 

The study found cured Cushing's disease patients who had depression when they started to experience symptoms of the disease had an elevated risk of mortality and cardiovascular disease. Men were more at risk than women, a trend that may be explained by a lack of follow-up care, according to the study. In addition, patients who had both Cushing's syndrome and diabetes were more likely to develop cardiovascular disease. 

The study examined one of the largest cohorts of Cushing's disease patients operated on by a single surgeon. The researchers retrospectively reviewed charts for 346 Cushing's disease patients who were treated between 1980 and 2011. Researchers estimated the duration of exposure to excess cortisol by calculating how long symptoms lasted before the patient went into remission. The patients who were studied had an average exposure period of 40 months. 

The findings may have implications for people who take steroid medications, Geer said. People treated with high doses of steroid medications such as prednisone, hydrocortisone or dexamethasone are exposed to high levels of cortisol and may experience similar conditions as Cushing's disease patients. 

"While steroid medications are useful for treating patients with a variety of conditions, the data suggests health care providers need to be aware that older patients or those who take steroid medications for long periods could be facing higher risk," Geer said. "These patients should be monitored carefully while more study is done in this area." 

From http://www.medicalnewstoday.com/releases/256284.php