Adrenocortical Hormone Abnormalities in Men with CP/CPPS

[webslave]

Top docs involved here: Buffington, Nickel, Dimitrakov.

Urology. 2008 Feb;71(2):261-266.

Adrenocortical Hormone Abnormalities in Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome.
Dimitrakov J, Joffe HV, Soldin SJ, Bolus R, Buffington CA, Nickel JC.
Harvard Urological Diseases Research Center, Children’s Hospital Boston, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.

OBJECTIVES: To identify adrenocortical hormone abnormalities as indicators of endocrine dysfunction in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

METHODS: We simultaneously measured the serum concentrations of 12 steroids in patients with CP/CPPS and controls, using isotope dilution liquid chromatography, followed by atmospheric pressure photospray ionization and tandem mass spectrometry.

RESULTS: We evaluated 27 patients with CP/CPPS and 29 age-matched asymptomatic healthy controls. In the mineralocorticoid pathway, progesterone was significantly greater, and the corticosterone and aldosterone concentrations were significantly lower, in the patients with CP/CPPS than in the controls. In the glucocorticoid pathway, 11-deoxycortisol was significantly lower and the cortisol concentrations were not different between the patients and controls. In the sex steroid pathway, the androstenedione and testosterone concentrations were significantly greater in those with CP/CPPS than in the controls. The estradiol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate concentrations were not different between the patients and controls. The National Institutes of Health-Chronic Prostatitis Symptom Index total and pain domain scores correlated positively with the 17-hydroxyprogesterone and aldosterone (P <0.001) and negatively with the cortisol (P <0.001) concentrations.

CONCLUSIONS: Our results suggest reduced activity of CYP21A2 (P450c21), the enzyme that converts progesterone to corticosterone and 17-hydroxyprogesterone to 11-deoxycortisol. Furthermore, these results provide insights into the biologic basis of CP/CPPS. Follow-up studies should explore the possibility that patients with CP/CPPS meet the diagnostic criteria for nonclassic congenital adrenal hyperplasia and whether the hormonal findings improve or worsen in parallel with symptom severity.

PMID: 18308097 [PubMed - as supplied by publisher]

UPDATE IN 2009:

FULL TEXT OF STUDY

[Paso]

And this means in English?

[webslave]

More confirmation that the HPA axis is not working properly, and we have a form of cortisol deficiency. But they go further here and talk about a possible link to Congenital adrenal hyperplasia, which is a long shot in my opinion.

[garyholc]

Does this mean that in the future some drug or treatment could be provided to restore the balance in the body and prevent CPPS?

[J Dimitrakov]

Glad to see our study has generated some interest in the community!

I just wanted to take this opportunity to clarify some aspects of the study. I believe the full-text PDF should be available for free shortly and should be deposited in PubMed Central and it will be very easy to explain the study using Figure 1 in the PDF.

The study took a little more than 2 years to publish since the high-profile journals were unsure of the importance of the topic for the general medical community.

For a start, this is the only triple-blinded paper in the CPPS and PBS/IC literature that I am aware of. Basically, what this means is that the people who recruited and diagnosed CPPS patients were unaware of the results generated by the basic scientists and the statistical analysis which was done by an independent statistician who was blinded to both the patient status (CPPS or controls) and the results of the analysis.

The punchline of the paper really is that there appears to be a lack of a specific substance (an enzyme) in two adrenal pathways which lead to the production of aldosterone and cortisole, and this could explain the systemic symptoms that CPPS patients experience. The substance that appears to be missing is called CYP21A2.

In my humble opinion, the value of the paper lies in the following:

- Provides direct objective evidence that men with CPPS have an abnormality that is the basis for their systemic symptoms;

- Uses a cutting-edge proteomics technology which detects simultaneously 12 metabolites using a very small amount of blood (normally, you need 12 tubes drawn for each of those metabolites to be measured);

- Most importantly, not EVERYONE with CPPS will have that specific defect but the technology allows evaluation of each patient's specific profile and potentially, down the line, allows this test to be used for defining patient subtypes which can be targeted by specific agents for specific treatments.

I was happy to hear through informal discussions that at least two independent groups will be applying our technology in their upcoming MAPP centers (if/when funded).

Best,
Jordan Dimitrakov, MD, PhD

[webslave]

This is very interesting information from Dr Dimitrakov. Here is a genetic description of CYP21A2.

I guess the question I have is about cause and effect. If this enzyme had been missing congenitally, this population would have signs of the deficiency (as per 21-hydroxylase deficiency). But we don't, or at least not all of the signs.

I wonder if the stressing of the HPA axis may lead to an exhaustion of this enzyme's pathway, so that it looks like a gene-mediated deficiency but is actually an environmentally-mediated response, and so a cessation of the provoking environmental stressors and consequent HPA axis dysfunction would lead to normal 21-hydroxylase levels?

[garyholc]

So is this condition a muscular one or not? I'm confused by all of this.... if it is a gene and an enzyme deficiency, why do people find relief when doing PT? I'm struggling to understand how it all fits together - prostate, frequency, pain, muscles, pt etc....

[graeme]

Maybe it could be the cause of the trigger points

There are many who have family members with this condition. My sis has IC and Lightningtree has a twin with CPPS !

Next time you see Bill ask him about this. He has treated twins as well

[J Dimitrakov]

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

[J Dimitrakov]

Gary,

These pathways and cortisol in particular are involved in muscle tension, muscle contraction and relaxation. Some of the substances produced by the adrenal also determine your individual pain perception threshold and can sensitize nerve endings causing the perception of pain induced by stimuli which are normally non-painful (a phenomenon, known as allodynia). Sensitized and damaged nerve endings in the pelvis are also implicated in frequency and urgency. Hope this helps with understanding the whole picture.

Best,
JD

So is this condition a muscular one or not? I'm confused by all of this.... if it is a gene and an enzyme deficiency, why do people find relief when doing PT? I'm struggling to understand how it all fits together - prostate, frequency, pain, muscles, pt etc....

[webslave]

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.

J Clin Endocrinol Metab. 2006 Nov;91(11):4205-14. Epub 2006 Aug 15.

Extensive clinical experience: nonclassical 21-hydroxylase deficiency.
New MI.
Adrenal Steroid Disorders Program, Department of Pediatrics, Mount Sinai School of Medicine, New York, New York 10029, USA. [email protected]

CONTEXT: Nonclassical congenital adrenal hyperplasia (CAH) owing to steroid 21-hydroxylase deficiency (NC21OHD) is the most frequent of all autosomal recessive genetic diseases, occurring in one in 100 persons in the heterogeneous New York City population. NC21OHD occurs with increased frequency in certain ethnic groups, such as Ashkenazi Jews, in whom one in 27 express the disease. NC21OHD is underdiagnosed in both male and female patients with hyperandrogenic symptoms because hormonal abnormalities in NC21OHD are only mild to moderate, not severe as in the classical form of CAH. Unlike classical CAH, NC21OHD is not associated with ambiguous genitalia of the newborn female. MAIN OUTCOME MEASURES: The hyperandrogenic symptoms include advanced bone age, early pubic hair, precocious puberty, tall stature, and early arrest of growth in children; infertility, cystic acne, and short stature in both adult males and females; hirsutism, frontal balding, polycystic ovaries, and irregular menstrual periods in females; and testicular adrenal rest tissue in males. CONCLUSIONS: The signs and symptoms of hyperandrogenism are reversed with dexamethasone treatment.

PMID: 16912124 [PubMed - indexed for MEDLINE]

Thank you, Dr Dimitrakov. I quote the study by Dr Maria New above. I am keen to poll our members to see if they recognise some of the symptoms described above. Members should take the poll here.

[J Dimitrakov]

Some more snippets from Dr. New's article:

"The nonclassical form of 21OHD was discovered during studies of the family members of classically affected patients; some completely asymptomatic family members were discovered to have human lymphocyte antigen (HLA) genetic linkage markers, indicating the presence of mutations at the 21-hydroxylase locus. On hormonal evaluation, diminished 21OH activity was confirmed. All of these individuals later became symptomatic (7). Subsequently, the molecular genetic basis of NC21OHD was described (5)....

Patients with NC21OHD have extremely variable presentations with one or more hyperandrogenic signs. There have been few large-scale studies of the disorder, partly because it was only recently described but also because there are few clinics with large patient populations, ours in New York City being the largest. The papers published to date that include patients diagnosed by DNA report on small groups of patients (3, 4, 5, 8, 9, 10, 11, 12, 13)...

Little has been published about males with NC21OHD. Typically, males with NC21OHD do not suffer from impaired gonadal function and tend to have normal sperm counts (23, 30). However, manifestations of adrenal androgen excess may include short stature or oligospermia and diminished fertility (23, 31, 32). Importantly, reversal of infertility and oligospermia upon treatment with glucocorticoids has been observed (23, 33, 34, 35)...

Through studies of kindreds including a proband with classical or NC21OHD (82) and molecular screening of the 21-hydroxylase alleles of the heterogeneous population of New York City (83), the frequency of NC21OHD has been estimated to be 1:100, making it the most common of all autosomal recessive diseases, even more common than sickle cell anemia, Tay-Sachs, cystic fibrosis, and phenylketonuria (a disease for which newborn screening is mandated in every state in the United States) (Fig. 8). Screening for classical CAH is conducted in 48 states in the United States. The nonclassical form of CAH is not detected by hormonal screening. This would require DNA screening, which is not yet available.

Because the gene for this disorder is autosomal, it occurs equally in men and women. It appears that males are significantly underdiagnosed. Of our 440 nonclassical patients, 344 are females and only 96 are males (unpublished data), indicating that males are infrequently diagnosed.

A higher frequency of NC21OHD was reported in certain ethnic groups (82). The results of this study were supported by a subsequent study of a random population of 100 people (83), which confirmed the highest ethnic-specific frequency to occur in the Ashkenazi Jews at 1:27 (82). Interestingly, whereas the prevalence of NC21OHD in Ashkenazi Jews is high, there is no increased prevalence of the severe classical form of 21OHD in this population (82). Other ethnic groups with high disease frequency included Hispanics (1:40), Slavs (1:50), and Italo-Americans (1:300) (Table 3) (82, 83, 84, 85, 86). These data were based on small groups that have recently been studied in larger groups (Wilson, R., S. Nimkarn, M. Dumic, J. Obeid, M. Azar, H. Najmabadi, F. Saffari, M. New, unpublished data)...."

Best,
JD

[J Dimitrakov]

Some more numbers and facts:

From: New MI. An update of congenital adrenal hyperplasia. Ann N Y Acad Sci. 2004 Dec;1038:14-43.

In boys, early beard growth, acne, and growth spurt may be detected. A highly reliable constellation of physical signs of adrenal (as opposed to testicular) androgen excess in boys is the presence of pubic hair, enlarged phallus, and relatively small testes. In men, signs of androgen excess are difficult to appreciate and may theoretically be manifest only by short stature and/or adrenal sex steroid-induced suppression of the hypothalamic-pituitary-gonadal axis, resulting in diminished fertility.

The presence of 21-hydroxylase deficiency can be discovered during the evaluation of incidental adrenal masses.64 An increased incidence of adrenal incidentalomas has in fact been found in male and female patients with homozygous congenital adrenal hyperplasia (82%) and also in the heterozygote subjects (45%), probably arising from hyperplastic tissue areas and not requiring surgical intervention.65

A subset of nonclassic 21-alpha hydroxylase deficiency (NC-21OHD) individuals are overtly asymptomatic when detected (usually as part of a family study), but it is thought, based on longitudinal follow-up of such patients, that symptoms of hyperandrogenism may wax and wane with time. The gene defect in these so-called cryptic 21-hydroxylase deficient subjects is the same as that found in symptomatic nonclassic patients.

Frequency of nonclassic 21-hydroxylase deficiency (from Speiser, P.W., B. Dupont, P. Rubinstein, et al. 1985. High frequency of nonclassical steroid 21-hydroxylase deficiency. Am. J. Hum. Genet. 37: 650–667.)

Ethic group/Frequency

Ashkenazi Jewish: 1:27
Hispanic: 1:53
Slavic: 1:63
Italian: 1:333
General Caucasian population: 1:100

Best,
JD

[webslave]

Well, the upshot of this deficiency seems to be hypocortisolism (in its severe form called Addison's disease). Symptoms of the severe form (Addison's) are:

Signs and symptoms

Signs and symptoms of Addison's disease usually develop slowly, often over several months, and may include:

* Muscle weakness and fatigue
* Weight loss and decreased appetite
* Darkening of your skin (hyperpigmentation)
* Low blood pressure, even fainting
* Salt craving
* Low blood sugar (hypoglycemia)
* Nausea, diarrhea or vomiting
* Irritability
* Depression

Sometimes, however, the signs and symptoms of Addison's disease may appear suddenly. In acute adrenal failure (addisonian crisis), the signs and symptoms may also include:

* Pain in your lower back, abdomen or legs
* Severe vomiting and diarrhea, leading to dehydration
* Low blood pressure
* Loss of consciousness

Also know as hypoadrenia (by alternative medicine), the symptoms of which are described by wikipedia as:

Tendency to gain weight and unable to lose it, especially around the waist. High frequency of getting the flu and other respiratory diseases and these symptoms tend to last longer than usual. Tendency to tremble when under pressure. Reduced sex drive. Lightheaded when rising from a lying down position. Unable to remember things. Lack of energy in the mornings and also in the afternoon between 3 to 5 pm. Feel better suddenly for a brief period after a meal. Often feel tired between 9 - 10 pm, but resist going to bed. Need coffee or stimulants to get going in the morning. Crave for salty, fatty, and high protein food such as meat and cheese. Pain in the upper back or neck with no apparent reasons . Feels better when stress is relieved, such as on a vacation. Difficulties in getting up in the morning. Lightheaded

Other signs and symptoms include:

Mild depression, Food and or inhalant allergies, Lethargy and lack of energy, Increased effort to perform daily tasks, Decreased ability to handle stress, Dry and thin skin, Hypoglycemia, Low Body Temperature, Nervousness, Palpitation, Unexplained hair loss, Alternating constipation and diarrhea, Dyspepsia

Now I do have a lot of those symptoms!

[webslave]

Veeeerrry interesting. If this is confirmed, it's a breakthrough. I remain neutral at this point....