Somatostatin and dopamine receptors as targets for medical treatment of Cushing?s Syndrome

[~MaryO~]

From Reviews in Endocrine & Metabolic Disorders

 

Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome

 

C. de Bruin, R. A. Feelders, S. W. J. Lamberts and L. J. Hofland(1) Department of Internal Medicine, Erasmus Medical Center, room Ee569 's Gravendijkwal 230, 3015, CE Rotterdam, The Netherlands

 

Received: 11 February 2008 Accepted: 12 June 2008 Published online: 19 July 2008

 

Abstract Somatostatin (SS) and dopamine (DA) receptors are widely expressed in neuroendocrine tumours that cause Cushing's Syndrome (CS). Increasing knowledge of specific subtype expression within these tumours and the ability to target these receptor subtypes with high-affinity compounds, has driven the search for new SS- or DA-based medical therapies for the various forms of CS. In Cushing's disease, corticotroph adenomas mainly express dopamine receptor subtype 2 (D2) and somatostatin receptor subtype 5 (sst5), whereas sst2 is expressed at lower levels. Activation of these receptors can inhibit ACTH-release in primary cultured corticotroph adenomas and compounds that target either sst5 (pasireotide, or SOM230) or D2 (cabergoline) have shown significant efficacy in subsets of patients in recent clinical studies. Combination therapy, either by administration of both types of compounds separately or by treatment with novel somatostatin?dopamine chimeric molecules (e.g. BIM-23A760), appears to be a promising approach in this respect. In selected cases of Ectopic ACTH-producing Syndrome (EAS), the sst2-preferring compound octreotide is able to reduce cortisol levels effectively. A recent study showed that D2 receptors are also significantly expressed in the majority of EAS and that cabergoline may decrease cortisol levels in subsets of these patients. In both normal adrenal tissue as well as in adrenal adenomas and carcinomas that cause CS, sst and DA receptor expression has been demonstrated. Although selected cases of adrenal CS may benefit from sst or DA-targeted treatment, its total contribution to the treatment of these patients is likely to be low as surgery is effective in most cases.

 

Keywords Corticotroph adenoma - Cushing's disease - ACTH - Cortisol - Pituitary - Adrenal

 

Disclosure statement: The authors of this manuscript have nothing to disclose.

 

C. de Bruin (Corresponding author)Email: c.debruin@erasmusmc.nl

 

R. A. FeeldersEmail: r.feelders@erasmusmc.nl

 

S. W. J. LambertsEmail: s.w.j.lamberts@erasmusmc.nl

 

L. J. HoflandEmail: l.hofland@erasmusmc.nl

[fallerb]

Can anyone explain what this says a little more plainly, please?

[ADDflower]

I will try.

 

Abstract Somatostatin (SS) and dopamine (DA) receptors are widely expressed in neuroendocrine tumours that cause Cushing's Syndrome (CS).

 

Tumors that cause Cushing's Syndrome tend to be covered with receptors of these two types. Think of receptors like a puzzle or a block sorter, some things fit, some things don't and other things fit mostly (but aren't the right part). They name the receptors based on what sticks best in them or activates them.

 

 

Increasing knowledge of specific subtype expression within these tumours and the ability to target these receptor subtypes with high-affinity compounds, has driven the search for new SS- or DA-based medical therapies for the various forms of CS.

I think this is pretty straight forward, because they've learned about the presence of these receptors they're studying them to see if they can trick them.

 

In Cushing's disease, corticotroph adenomas mainly express dopamine receptor subtype 2 (D2) and somatostatin receptor subtype 5 (sst5), whereas sst2 is expressed at lower levels.

this is a description of the type of receptors.

 

Activation of these receptors can inhibit ACTH-release in primary cultured corticotroph adenomas and compounds that target either sst5 (pasireotide, or SOM230) or D2 (cabergoline) have shown significant efficacy in subsets of patients in recent clinical studies.

 

sticking something into the receptors seems to make the tumors stop releasing ACTH, at least in a petri dish, when using cells that have been harvested directly from the tumor.

 

Combination therapy, either by administration of both types of compounds separately or by treatment with novel somatostatin?dopamine chimeric molecules (e.g. BIM-23A760), appears to be a promising approach in this respect.

 

Using both chemicals at the same time seems to work best in people tested.

 

In selected cases of Ectopic ACTH-producing Syndrome (EAS), the sst2-preferring compound octreotide is able to reduce cortisol levels effectively.

 

Mentioning another thing that worked... the sst2-preferring compound refers to the type of receptor that the chemical binds to.

 

A recent study showed that D2 receptors are also significantly expressed in the majority of EAS and that cabergoline may decrease cortisol levels in subsets of these patients. In both normal adrenal tissue as well as in adrenal adenomas and carcinomas that cause CS, sst and DA receptor expression has been demonstrated. Although selected cases of adrenal CS may benefit from sst or DA-targeted treatment, its total contribution to the treatment of these patients is likely to be low as surgery is effective in most cases.

 

This says that despite the fact that these things seem to work they think that the usefulness of the treatment will be limited since most people get better from surgery alone.

 

****

 

I hope that helps... (and that I didn't mess it up)

[fallerb]

OK - I may not have understood all that correctly but...

Could perhaps then your body try to plug up the receptors by using your own dopamine thereby causing you to be low in it? Or is that totally off the mark of what they are saying?

[Jo MacRaild]

The receptors are like the switch on for the abnormal tissue or tumor, & the meds chemically block it switching on..so reducing tumor output.

 

The self leveling trying to control or interrupt production on other hormone levels is interesting. It would make sense in the body trying to stay alive & balance wouldn't it ? Do you have low dopamine ? Same here.. Well..I've been told it's low, as prolactin is high..& you produce more dopamine to cut or balance abnormal prolactin production..dont know if they've actually tested D ? or if it's just another presumption of what normal folks should do..

 

I've oft wonderred on the GH too..If so many endo tumors fire off to Gh, is that why , so many folks have low GH.. makes the HPA axis look very smart if it does !! suppose we'll have to wait for medical science to advance & see whats the actual tumor & whats not..