Adrenocortical Hormone Abnormalities in Men with CP/CPPS

[popburner]

Ok - this is terribly interesting!! My question is how does a steroid work to fend off an enzyme deficiency? Maybe that was answered in the past few posts but was beyond my level of understanding -- I'm going to print this topic out and send it to my mother who's a biochemist to explain I think....:)

[J Dimitrakov]

Ok - this is terribly interesting!! My question is how does a steroid work to fend off an enzyme deficiency? Maybe that was answered in the past few posts but was beyond my level of understanding -- I'm going to print this topic out and send it to my mother who's a biochemist to explain I think....:)

See my post from March 10 (reposted below FYI).

Best,
JD

Adrenocortical Hormone Abnormalities in Men with CP/CPPS
by J Dimitrakov on Mon Mar 10, 2008 10:40 pm

Webslave,

You raise the most important question regarding the implications of the study: the cause and effect relationship. Our study was not designed to look at this question, since, for a start, we basically looked at the three pathways involved and tried to discern a pattern. Our approach was totally agnostic of the disease mechanisms or pathways.

It’s difficult to explain the study before a picture but if you find a scheme of the pathways online, it would be easy to understand. Basically, cholesterol from diet is used in the adrenal gland to produce aldosterone, cortisol and sex steroids (testosterone and dehydrotestosterone). These are three separate pathways that are related by virtue of common enzymes (e.g., CYP21A2).

Now on to your question. The way the body works is that CORTISOL levels feed onto the hypothalamus and the pituitary. When cortisol is low (as has been documented in several IC and CPPS studies), the low cortisol signals to the hypothalamus and the pituitary. The hypothalamus releases CRH (corticotrophin releasing hormone) which causes the release of ACTH from the pituitary. That ACTH signal drives the adrenal crazy (in an attempt to make more cortisol) which is impossible due to a block at the level of CYP21A2. Therefore, all substances before the block increase and those after the block decrease.

Is it inborn or acquired? As we state in the article, "CYP21A2 defects traditionally have been described in patients with congenital adrenal hyperplasia (CAH). The hormonal defects in our CP/CPPS population suggest that some might have an inherited or acquired form of nonclassic CAH due to CYP21A2 deficiency. Classic CAH presents with salt wasting or genital ambiguity in infants. In contrast, nonclassic (also known as mild or late-onset) CAH is characterized by partial CYP21A2 deficiency and varying signs of hyperandrogenism—abnormalities that are generally thought to be asymptomatic in men. (Ref 15, 16) In our study, the patients with CP/CPPS also had hormonal evidence of hyperandrogenism, elevated androstenedione and elevated testosterone levels, compared with the controls, a finding that further supports the presence of reduced CYP21A2 activity."

As it turns out, Dr. New in NYC has published on a series of men with nonclassic CYP21A2 (New MI: Extensive clinical experience: nonclassical 21-hydroxylase deficiency. J Clin Endocrinol Metab 91: 4205–4214, 2006, reference #16 in our paper) The symptoms of this non-classic CYP21A2 are quite non-specific and have not been studied in men with CPPS.

Anyway, the bottom-line is that men with CPPS, based on our findings, have either a variable degree of inborn or acquired CYP21A2 deficit. This finding deserves to be studied further in larger patient populations. Good news is that the ones that are found to have the CYP21A2 mutation can benefit from targeted treatments and the test we describe can be used to guide such treatments.

Best,
JD

[webslave]

Some schema

[webslave]

Anyway, the bottom-line is that men with CPPS, based on our findings, have either a variable degree of inborn or acquired CYP21A2 deficit. This finding deserves to be studied further in larger patient populations.

Absolutely! If confirmed, this changes the whole CP/CPPS scene forever.

Good news is that the ones that are found to have the CYP21A2 mutation can benefit from targeted treatments and the test we describe can be used to guide such treatments.

• Could you expand on this (tests, actual treatments, any results you have had, even anecdotally, from these treatments)?
• If possible, please send me a pdf of your paper. I can host it here, when copyright permits.

[J Dimitrakov]

Some schema

Looking at the last scheme, here's a very simple explanation. There are three basic pathways (all start from cholesterol):

#1: end-product - aldosterone
#2: end-product - cortisol
#3: end-product - sex-steroids

Important point: Cortisol levels are the regulators of the system. As a result of either inborn or acquired events (mutations) cortisol becomes LOW.

LOW cortisol signals to the brain at the level of the hypothalamus which signals to the pituitary. Since cortisol is LOW, logically the body tries to..... (think about the answer)

So, the body tries to INCREASE cortisol. Therefore, the low cortisol levels signal to the hypothalamus which signals to the pituitary which releases ACTH (adrenocorticotropic hormone). ACTH normally boosts cortisol back to normal and the normal cortisol shuts off the system (signals to hypothalamus that levels are back to normal and the release of ACTH stops).

OK, what's the situation with our findings?

What we found is that men with CPPS have a block at the level of 21-hydroxylase (the older name for CYP21A2). Look at the figure again and draw an imaginary vertical line at the level of 21-hydroxylase in pathway #1 and #2. What happens if cortisol is low? The system gets activated, the hypothalamus signals to the pituitary and ACTH is released. However, since you have a BLOCK in the pathway that leads to cortisol, you don't get it back to normal and instead there is more progesterone (pathway #1) and 17-OH progesterone (pathway #2) both proximal (above the level of the block). The higher 17-OH is re-directed to the third pathway and results in more androsterone and sex steroids.

Hope this is helpful,

Best,
JD

[webslave]

Good news is that the ones that are found to have the CYP21A2 mutation can benefit from targeted treatments and the test we describe can be used to guide such treatments.

• Could you expand on this (tests, actual treatments, any results you have had, even anecdotally, from these treatments)?
• If possible, please send me a pdf of your paper. I can host it here, when copyright permits.

[carld]

Dr. D and Mark,

Since anxiety is such a major part of symptoms for CP/CPPS....My thoughts are that perhaps this "dysfunction" of the hypothalamus is two fold here. Effecting cortisol thus the brain trying to produce more and causing anxiety and then you have the cascade of events that take place. Is this something that makes scientific sense

So what ever therapy that is there that balances this function of the hypothalamus could possibly help level out anxiety and muscle tension etc...

[J Dimitrakov]

Good news is that the ones that are found to have the CYP21A2 mutation can benefit from targeted treatments and the test we describe can be used to guide such treatments.

Could you expand on this (tests, actual treatments, any results you have had, even anecdotally, from these treatments)?

This is an important point and an interesting question.

As I mentioned in my original post, the approach we used is proteomics-based.
Tests: In terms of research to answer the question about the underlying basis of our finding, the ideal next step would be testing CYP21A2 gene polymorphisms. Using genomic and proteomic techniques, it should be possible to dissect the inherited from the acquired cases on an individual basis.

We are currently recruiting participants for the genomic studies. Those interested in participating would be required to sign an informed consent form, provide a saliva and urine sample and should directly contact me with any questions. Further details of this study are available at http://www.clinicaltrials.gov

Study title “Genetic Study of Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS)”, ClinicalTrials.gov Identifier: NCT00499317

Unfortunately, this is a RESEARCH-ONLY testing at this time and we are not able to report individual test results back participants. However, there is a similar commercially-available FDA-approved platform for diagnostic purposes and we are developing this platform for future diagnostic testing.

In terms of diagnosis, as we note in the discussion section of the paper “future prospective cohort studies should measure both morning ACTH and diurnal cortisol concentrations and perform cosyntropin stimulation testing in patients with CP/CPPS.” While these tests require specialized labs performing the test, I suggest patients discuss these issues with their physicians in a face-to-face meeting.

Actual treatments and results: I am not at liberty to discuss these at this time since there is a manuscript under review. I hope I will be able to discuss this further in the near future.

If possible, please send me a pdf of your paper. I can host it here, when copyright permits.

We have deposited the manuscript in PubMed Central and access should be available for free shortly depending on the terms of the copyright agreement with Elsevier (publisher of Urology). I will make an announcement when this happens.

Best,
JD

[J Dimitrakov]

Dr. D and Mark,

Since anxiety is such a major part of symptoms for CP/CPPS....My thoughts are that perhaps this "dysfunction" of the hypothalamus is two fold here. Effecting cortisol thus the brain trying to produce more and causing anxiety and then you have the cascade of events that take place. Is this something that makes scientific sense

So what ever therapy that is there that balances this function of the hypothalamus could possibly help level out anxiety and muscle tension etc...

Yes, Carl this makes perfect sense. There is a large body of literature suggesting perturbations in several important hypothalamus-related systems which have been well-studied in PTSD (post-traumatic stress disorder). Things, however, are quite complicated and yet fascinating.

Here’s just one example: CRH (corticotropin releasing hormone, sometimes called CRF, corticotropin releasing factor) acts on at least two types of receptors, CRH-1 and CRH-2. Release of CRH from the hypothalamus into the hypothalamic-pituitary portal circulation occurs in response to stress, resulting in activation of the hypothalamic-pituitary-adrenal (HPA) axis and the increased release of cortisol and DHEA. CRH also inhibits a variety of other functions, such as food intake, sexual activity, and endocrine programs for growth and reproduction. Several lines of evidence suggest that early-life stress can produce long-term elevation of brain CRH activity and that individual response to heightened CRH function may depend upon the social environment, past trauma history, and behavioral dominance.

CRH-1-deficient mice display decreased anxiety-like behavior and an impaired stress response. In contrast, CRH-2-deficient mice display increased anxiety-like behavior and are hypersensitive to stress. Thus, evidence exists in favor of opposite functional roles for the two known CRH receptors; activation of CRH-1 receptors may be responsible for increased anxiety-like responses, and stimulation of CRH-2 may produce anxiolytic-like (meaning anxiety-alleviating) responses. Regulation of the relative contribution of the two CRH receptor subtypes to brain CSF pathways may be essential to coordinating psychological and physiological responses to stressors. These receptors might be upregulated in response to different stressors and might have different functional roles.

Hope this is helpful,

Best,
JD

[ramana]

However, there is a similar commercially-available FDA-approved platform for diagnostic purposes and we are developing this platform for future diagnostic testing.

Dear Dr Dimitrakov
Can you provide the name of these tests. These findings are very exciting. THANK YOU!!!

[Spasman]

I will add this in case it would help:

Painful Pelvic Disorder Linked to Small Adrenal Glands:

Painful Pelvic Disorder Linked to Small Adrenal Glands

Friday November 10, 2006 (0103 PST)

In experiments with cats, researchers found the animals who suffered from interstitial cystitis had smaller adrenal glands than those without the condition.

The finding could lead to new treatments for the chronic, painful pelvic disorder that affects more than 700,000 people in the United States, 90 percent of them women.

Interstitial cystitis is a chronic inflammatory condition of the bladder wall. Symptoms include urinary urgency and frequency, difficulty urinating, minimal urine output and pain in the bladder and/or the urethra that is temporarily relieved by voiding. In some patients, pain may radiate to the genitals, rectal area and thighs.

"In cats that have interstitial cystitis, which appears to be the same in cats as in humans, two of the four zones of their adrenal glands are unusually small," says lead researcher Dr. Tony Buffington, a professor of veterinary clinical sciences at Ohio State University.

In their study, Buffington and his colleagues compared the adrenal glands of 13 cats that had interstitial cystitis with eight cats that did not have the disorder.

The adrenal glands of the cats with interstitial cystitis were about half the size of the adrenals in the normal cats, according to the report in the December issue of the Journal of Urology. The adrenal glands sit next to the kidneys and produce hormones that, among other things, help regulate heart rate and blood pressure.

The researchers found that when cats were injected with the stress-inducing compound adrenocorticotropic hormone, those with interstitial cystitis produced lower levels of the stress hormone cortisol, which is produced in the adrenals.

Under normal conditions, the functioning of the adrenal glands in cats with interstitial cystitis appears normal, Buffington says. "It is only under stress that it is abnormal," he adds.

Buffington believes this finding indicates that while there may not be adrenal insufficiency under normal circumstances, there may well be an insufficiency in adrenal reserve during periods of stress.

Interstitial cystitis worsens with stress, Buffington notes. The combination of increased stress and decreased adrenal response may be the reason why, he adds.

These findings may offer a new direction to studying interstitial cystitis in humans that can eventually lead to new treatments, Buffington says.

"Preliminary findings in humans suggest that the same abnormalities in adrenal function may be present in women when the disease is flaring up, but not when the disease is in a quiet state," he notes.

Small adrenal glands may be an underlying risk factor for interstitial cystitis, Buffington speculates.

Interstitial cystitis is a complex disorder and the abnormalities that underlie it are very subtle, Buffington says. These new findings may shed light on the causes of the condition and lead the way to new treatments, he adds.

Dr. Richard Bercik, associate director of urogynecology at Yale University, says that "physicians and lay people need to realize the connection between stress and interstitial cystitis."

"It is not just that stress exacerbates symptoms but also that other diseases associated with stress disorders, for example chronic fatigue syndrome, irritable bowel disease, fibromyalgia, endometriosis, chronic pelvic pain, anxiety, obsessive compulsive disorder, depression, neuralgia, temporomandibular joint (jaw joint) disease, phobias, all can possibly interface with interstitial cystitis," he adds.

Bercik advises that patients with these disorders are at higher risk for interstitial cystitis and should be screened for it.

This study will lead to similar testing in human interstitial cystitis patients, Bercik says. "We know that interstitial cystitis patients have higher norepinephrine levels in the urine, and interstitial cystitis patients with low cortisol in urine tend to have more symptoms."

"These may be two different subgroups, but both point to an altered immune/inflammatory response, which is regulated by the hypothalamic-pituitary-adrenal system," he notes.

More http://researchnews.osu.edu/archive/catfic.htm

[kevin]

Thanks for the link, Spasman. Dr. Buffington is one of the big experts on the HPA axis in CPPS/IC, along with Dr. Dimitrakov.

[jj77]

Great news indeed, even if a lot of work must be done. Congratulations to the docs involved!

[webslave]

Please note that Tony Buffington is involved here. He is Mr Big on the IC and cortisol front, as the article above shows.

[J Dimitrakov]

However, there is a similar commercially-available FDA-approved platform for diagnostic purposes and we are developing this platform for future diagnostic testing.

Dear Dr Dimitrakov
Can you provide the name of these tests. These findings are very exciting. THANK YOU!!!

Hi, Ramana,

I am unable to provide the name of the company since that might be interpreted as endorsement of a specific brand on my part. I will be happy to provide the details once we have completed our studies and have validated the test as a diagnostic (rather than a research) assay

Best,
JD