Multiple aberrant hormone receptors in Cushing’s Syndrome

Eur J Endocrinol. 2015 May 13. pii: EJE-15-0200. [Epub ahead of print]
Multiple Aberrant Hormone Receptors in Cushing’s Syndrome.

Abstract

The mechanisms regulating cortisol production when ACTH of pituitary origin is suppressed in primary adrenal causes of Cushing’s syndrome include diverse genetic and molecular mechanisms. These can lead either to constitutive activation of the cAMP system and steroidogenesis or to its regulation exerted by the aberrant adrenal expression of several hormone receptors, particularly G-protein coupled hormone receptors (GPCR) and their ligands.

Screening for aberrant expression of GPCR in BMAH and unilateral adrenal tumors of patients with overt or subclinical CS demonstrates the frequent co-expression of several receptors. Aberrant hormone receptors can also exert their activity by regulating the paracrine secretion of ACTH or other ligands for those receptors in BMAH or unilateral tumors.

The aberrant expression of hormone receptors is not limited to adrenal Cushing’s syndrome but can be implicated in other endocrine tumors including primary aldosteronism and Cushing’s disease. Targeted therapies to block the aberrant receptors or their ligands could become useful in the future.

PMID:
25971648
[PubMed – as supplied by publisher]

California Doctors – So far

california

 

The doctors listed here have been recommended to Cushing’s Help by other patients as being helpful to them.  These physicians are familiar with the symptoms and treatment of Cushing’s Disease (pituitary) and Cushing’s Syndrome. Your primary care physician may be able to order very basic screening tests. Some of these doctors may require a referral and/or an abnormal test result prior to scheduling an appointment.

Cushing’s Help does not endorse any particular physician. Choosing a particular physician and substantiating his/her expertise is the responsibility of the individual patient.

To recommend your own doctor for this list, please fill out this form.

This list is a continuing resource as new doctors are added, edited OR removed.  

These doctors are also available on this map.  Please add yourself and/or your doctor

California

Beverly Hills

Cohan, Pejman 

Specialty: Neuroendocrine 

Location: 150 N Robertson Blvd # 210
Beverly Hills, CA

Phone: 310-657-3030

Patient Comment: He’s been my Endo for 15 years. Only sees neuroendocrine patients


Freemont

Kunwar, Sandeep

Specialty: Neurosurgeon

Hospital: Washington Hospital

Location: Freemont, CA

Hospital: UCSF

Location: San Francisco, CA

Website: http://www.ucsfhealth.org/sandeep.kunwar

Patient Comments: And dr kunwar at ucsf was my very skilled surgeon. I didn’t have to see his endo preop

I also had my surgery done with Dr. Kunwar at Washington Hospital in Fremont (East Bay). He does a few days a week in Fremont and the rest in SF. This is my third recurrence and I would definitely recommend him


Srinivasan, Lakshmi

Specialty: Endocrinologist

Hospital: Palo Alto Medical Foundation

Location: Freemont, CA

Patient Comments: My endo is Dr. Lakshmi Srinivasan at Palo Alto Medical Foundation in Fremont. She is fantastic–takes a lot of time during every appt and is very attentive and responsive to email and calls.


Los Angeles

Friedman, Theodore

Specialty: Cushing’s, Growth Hormone Deficient, Hypopituitary, adrenal, thyroid, fatigue

Address: 1125 S. Beverly Drive. Suite 730

Location: Los Angeles, CA

Hospital: Charles Drew

Website: http://goodhormonehealth.com

Patient Comments:  I am a Dr Friedman patient, he is wonderful.


 Orange

Linskey, Mark 

Specialty: Neurosurgeon 

Hospital: UCI

Location: Orange, CA

Website: http://www.ucirvinehealth.org/find-a-doctor/l/mark-linskey/

Patient Comment: The pit surgery was done by both Linskey and Bhendarkar and I am doing well post op, they are very diligent in their care. If I have to have another surgery for Cushing’s I will definitely use this team again.


Bhandarkar, Naveem

Specialty: ENT

Hospital: UCI

Location: Orange/Irving, CA

Website: http://www.ent.uci.edu/faculty/naveen-d-bhandarkar-md

Patient Comment: The pit surgery was done by both Linskey and Bhendarkar and I am doing well post op, they are very diligent in their care. If I have to have another surgery for Cushing’s I will definitely use this team again.


San Francisco

Kunwar, Sandeep

Specialty: Neurosurgeon

Hospital: Washington Hospital

Location: Freemont, CA

Hospital: UCSF

Location: San Francisco, CA

Website: http://www.ucsfhealth.org/sandeep.kunwar

Patient Comments: And dr kunwar at ucsf was my very skilled surgeon. I didn’t have to see his endo preop

I also had my surgery done with Dr. Kunwar at Washington Hospital in Fremont (East Bay). He does a few days a week in Fremont and the rest in SF. This is my third recurrence and I would definitely recommend him


More coming soon!

“My feet are killing me!” An unusual presentation of Cushing’s syndrome

Adverse effects of steroid excess on bone metabolism are well established but presentation of Cushing’s syndrome with metabolic bone disease is reported to be uncommon. We describe a case of Cushing’s syndrome presenting with pathological fractures probably present for 8 years before diagnosis.

A 33 year old nurse first sustained spontaneous stress fractures of her metatarsals in 1994, with repeated fractures occurring up to 2002. In 2001 she developed hypertension, acute lumbar back pain and gained weight.

In 2002 she was admitted to hospital with chest/back pain. Lumbar spine X-ray showed new fracture of L3,old fractures of L4/5,with fractured ribs on CXR. Isotope bone scan revealed multiple hot spots. MRI showed collapse of T8 with features consistent with malignant disease. The primary malignancy was sought and a left-sided 1.5 centimetre thyroid nodule detected.

Suspicious cytology prompted thyroid lobectomy revealing follicular variant of papillary carcinoma. T8 biopsy revealed chronic infection with Propionobacteria rather than metastatic carcinoma. Despite antibiotic therapy further spontaneous vertebral fractures developed. Bone densitometry revealed Z scores of minus 2.4 at L2-4, minus 2.5 and 2.9 at the hips.

Referral to our centre prompted investigations for Cushing’s syndrome. Serum potassium was 4.1 millimols per litre, androgens, calcitonin and urinary catecholamines all normal. TSH was suppressed by T4 therapy. Urinary free cortisol values were raised,(563-959 nanomols per 24hours) with loss of diurnal rhythm in cortisol secretion (9am 429-586,midnight 397-431 nanomols per litre)and no suppression on low or high dose dexamethasone. Abdominal CT showed a 3.5 centimetre adrenal mass. These findings were consistent with adrenal dependent Cushing’s syndrome. Risedronate and metyrapone were commenced before adrenalectomy, completion thyroidectomy and ablative radioiodine.
Comment: Cushing’s syndrome may present with spontaneous fractures in both axial and appendicular skeleton in the absence of marked clinical features. This case demonstrates the importance of thorough investigation of unexplained fractures.

LM Albon, JD Rippin & JA Franklyn

From http://www.endocrine-abstracts.org/ea/0005/ea0005p26.htm

Adrenal insufficiency – how to spot this rare disease and how to treat it

adrenal-glandsAddison’s disease, or adrenal insufficiency, is a rare hormonal disorder of the adrenal glands that affects around 8,400 people in the UK.

The adrenal glands are about the size of a pea and perched on top of the kidneys, and affect the body’s production of the hormones cortisol and sometimes aldosterone.

When someone suffers from adrenal insufficiency, those glands aren’t producing a sufficient amount of these hormones. This can have a detrimental effect on someone’s health and well-being. But because the symptoms are similar to a host of other conditions, Addison’s disease can prove tough to isolate.

What to look out for

According to advice provided by the NHS, the symptoms in the early stages of Addison’s disease, which affects both men and women, are gradual and easy to misread as they’re similar to many other conditions.

People can experience severe fatigue, muscle weakness, low moods, loss of appetite, unintentional weight loss, low blood pressure, nausea, vomiting and salt craving.

“Symptoms are often misread or ignored until a relatively minor infection leads to an abnormally long convalescence, which prompts an investigation,” says Professor Wiebke Arlt from the Centre for Endocrinology, Diabetes & Metabolism at the University of Birmingham.

Life-threatening condition

If Addison’s disease is left untreated, the level of hormones produced by the adrenal gland will gradually decrease in the body. This will cause symptoms to get progressively worse and eventually lead to a potentially life-threatening situation called an adrenal, or Addisonian, crisis. Signs include severe dehydration; pale, cold, clammy skin; rapid, shallow breathing; extreme sleepiness; severe vomiting and diarrhoea. If left untreated, it can prove fatal, so the patient should be admitted to hospital as an emergency.

Back to basics

To understand the disorder, it’s important to get to grips with the basics and that means understanding what the adrenal glands are – and so to the science.

“Adrenal glands have an inner core (known as the medulla) surrounded by an outer shell (known as the cortex) ,” explains Arlt.
The inner medulla produces adrenaline, the ‘fight or flight’ stress hormone. While the absence of this does not cause the disease, the cortex is more critical.

“It produces the steroid hormones that are essential for life: cortisol and aldosterone,” he adds.

“Cortisol mobilises nutrients, enables the body to fight inflammation, stimulates the liver to produce blood sugar and also helps control the amount of water in the body. Aldosterone, meanwhile, regulates the salt and water levels, which can affect blood volume and pressure.”

Why does it happen?

The disorder occurs if the adrenal glands are destroyed, absent or unable to function and failure of the glands themselves is known as primary adrenal insufficiency.

“It’s most often caused by autoimmune disease where the body’s immune system mounts an attack against its own adrenal glands,” explains Arlt.

“However it can also be caused by infection, most importantly by tuberculosis and sometimes by both adrenal glands being surgically removed.”

The pituitary effect

Another important cause is any disease affecting the pituitary gland, which is located behind the nose at the bottom of the brain.
“The pituitary is the master gland that tells the other glands in the body what to do,” continues Arlt.

“The pituitary gland produces a hormone called ACTH (adrenocorticotropic hormone to give it its full name), which travels in the blood stream to the adrenal glands.

“Here it acts as a signal, causing the adrenal glands to produce more cortisol. If the pituitary gland stops making ACTH, [then] cortisol production by the adrenals is no longer controlled properly and a condition called secondary adrenal insufficiency arises.”

But in most cases, aldosterone is still produced, which means that people suffering from secondary adrenal insufficiency have fewer problems than those with primary adrenal insufficiency.

Determining a diagnosis

Due to the ambiguous nature of the symptoms, a Short Synacthen Test (SST) needs to be performed in order to diagnose adrenal insufficiency.

“This measures the ability of the adrenal glands to produce cortisol in response to (the pituitary hormone) ACTH,” says Arlt. “When carrying out this test, a baseline blood sample is drawn before injecting a dose of ACTH, followed by drawing a second blood sample 30 to 60 minutes later. Failing adrenal glands will not be able to produce a certain level of cortisol.”

Getting treatment

If someone has been conclusively diagnosed with adrenal insufficiency, they should receive adrenal hormone replacement therapy as advised by an endocrinologist, a doctor specialising in hormone-related diseases.

“A normal adrenal gland does not need supplements to function properly and there is no recognised medical condition called ‘adrenal fatigue’,” warns Arlt.

“Either the adrenal gland is fine and needs no treatment or there is adrenal insufficiency due to adrenal or pituitary failure.”

So if in doubt, don’t self-diagnose but book an appointment with your GP.

For more information, visit Addison’s Disease Self-Help Group (www.addisons.org.uk) or Pituitary Foundation.

From https://home.bt.com/lifestyle/wellbeing/adrenal-insufficiency-how-to-spot-this-rare-disease-and-how-to-treat-it-11363985141306

Silibinin from milk thistle seeds as novel, non-invasive treatment strategy for Cushing Disease

Silibinin has an outstanding safety profile in humans and is currently used for the treatment of liver disease and poisoning. Scientists at the Max Planck Institute of Psychiatry in Munich discovered in collaboration with scientists from the Helmholtz Zentrum München in cell cultures, animal models and human tumor tissue that silibinin can be applied to treat Cushing Disease, a rare hormone condition caused by a tumor in the pituitary gland in the brain. The researchers have filed a patent and now plan clinical trials using silibinin as a non-invasive treatment strategy. Thus, in future, patients might not have to undergo brain surgery anymore.
Treatment with silibinin, a constituent of milk thistle seeds, alleviated symptoms of Cushing Disease in cell cultures, animal models and human tumor tissue. In future, patients might not have to undergo brain surgery anymore.

Cushing Disease, not to be confused with Cushing’s Syndrome, is caused by a tumor in the pituitary gland in the brain. The tumor secrets increased amounts of the stress hormone adrenocorticotropin (ACTH) followed by cortisol release from the adrenal glands leading to rapid weight gain, elevated blood pressure and muscular weakness. Patients are prone to osteoporosis and infections and may show cognitive dysfunction or even depression. In 80 to 85 % of the patients, the tumor can be removed by uncomfortable brain surgery. For inoperable cases, there is currently only one targeted therapy approved, which unfortunately causes intense side effects such as hyperglycemia in more than 20 % of the patients.

Scientists around Günter Stalla, endocrinologist at the Max Planck Institute of Psychiatry in Munich, have now discovered in cell cultures, animal models and human tumor tissue that a harmless plant extract can be applied to treat Cushing Disease. “Silibinin is the major active constituent of milk thistle seeds. It has an outstanding safety profile in humans and is already used for the treatment of liver disease and poisoning,” explains Marcelo Paez-Pereda, leading scientist of the current study published in the renowned scientific journal Nature Medicine. After silibinin treatment, tumor cells resumed normal ACTH production, tumor growth slowed down and symptoms of Cushing Disease disappeared in mice.

In 2013, the Max Planck scientists filed a patent on a broad family of chemical and natural compounds, including silibinin, to treat pituitary tumors. Compared to humans, where only 5.5 in 100,000 people worldwide develop Cushing Disease, this condition is very common in several pets. For example, 4 % of dogs and even 7 % of horses suffer from Cushing Disease. Thus, the researchers now plan to test special formulations with a very pure substance and slow release of the active component silibinin in clinical trials.

Silibinin: Mode of action

“We knew that Cushing Disease is caused by the release of too much ACTH. So we asked ourselves what causes this over production and how to stop it,” says Paez-Pereda. In their first experiments, the researchers found tremendously high amounts of the heat shock protein 90 (HSP90) in tumor tissue from patients with Cushing Disease. In normal amounts, HSP90 helps to correctly fold another protein, the glucocorticoid receptor, which in turn inhibits the production of ACTH. “As there are too many HSP90 molecules in the tumor tissue, they stick to the glucocorticoid receptor,” explains Paez-Pereda. “We found that silibinin binds to HSP90 thus allowing glucocorticoid receptor molecules to dissolve from HSP90. With silibinin, we might have discovered a non-invasive treatment strategy not only for the rare Cushing Disease but also for other conditions with the involvement of glucocorticoid receptors, such as lung tumors, acute lymphoblastic leukemia or multiple myeloma,” concludes Paez-Pereda.

From http://www.psych.mpg.de/2034377/PM1507