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Stress and CP/CPPS

Many correlate the onset of CP/CPPS to severe stress

The three basic concepts here are that stress:

  1. increases pelvic muscle tension and nervous activity in the pelvis, causing the nerves to excrete neurotransmitters that activate mast cells, causing inflammation
  2. can cause neuroendocrine imbalances, leading to chronic pain and fatigue syndromes
  3. raises prolactin levels
  4. damages the immune system

All of these actions could cause or exacerbate chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and IC.

 

Diagram Showing How Stress activates Mast Cells




Increased excretion of neurotransmitters

It should be understood that this aspect of stress overlaps with the "Neurogenic" theories, because stress fires up nervous activity which leads to symptoms, to simplify matters. There are several studies showing how stress may cause Interstitial Cystitis, a possibly related disease. Here are two further supporting studies which show that nerves in the lower urinary tract sit alongside mast cells, and can cause them to degranulate, leading to inflammation, under psychological stress:

Here's a recent study:

Increased Plasma Norepinephrine Concentration In Cats With Interstitial Cystitis.
CA Tony Buffington, Karel Pacak.

From the Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Ohio State University, Columbus, Ohio, and Pediatric and Reproductive Endocrinology Branch, National Institutes of Child Health and Human Development, Bethesda, Maryland THE JOURNAL OF UROLOGY 2001;165:2051-2054

ABSTRACT

Purpose: Interstitial cystitis is a chronic urological syndrome affecting humans and domestic animals, including cats (feline interstitial cystitis). The symptoms of interstitial cystitis seem to be exacerbated by stress, suggesting involvement of the sympathetic nervous system and/or hypothalamic-pituitary-adrenal axis. Others have described sympathetic nervous system abnormalities in patients with interstitial cystitis but to our knowledge no data on plasma catecholamine concentrations or hypothalamic-pituitary-adrenal axis function in such patients have been reported. To evaluate the role of these systems in cats with feline interstitial cystitis we simultaneously measured baseline plasma concentrations of catecholamines and their metabolites to assess sympathetic activity, and the response of plasma adenocorticotropic hormone and cortisol concentrations to the infusion of corticotropin-releasing factor.

Materials and Methods: Eight healthy cats and 8 with feline interstitial cystitis were anesthetized and a catheter was placed in the external jugular vein. Four hours after recovery samples were obtained for high performance liquid chromatography analysis of plasma norepinephrine, dihydroxyphenylglycol, epinephrine, dihydroxyphenylalanine, dopamine and dihydroxyphenylacetic acid. In 4 cats per group 1 g. ovine corticotropin-releasing factor per kg. body weight was infused and blood samples were collected at intervals for 120 minutes for determining adenocorticotropic hormone and cortisol.

Results: Significant increases in plasma norepinephrine and dihydroxyphenylglycol as well as a trend toward increased epinephrine were found, whereas no effect on dihydroxyphenylalanine, dopamine, dihydroxyphenylacetic acid, adenocorticotropic hormone or cortisol was identified in cats with feline interstitial cystitis.

Conclusions: These results support and extend previous studies identifying an increase in sympathetic activity in cats with feline interstitial cystitis.

Similar study: J Urol 1998 Mar;159(3):1045-8 Increased tyrosine hydroxylase immunoreactivity in the locus coeruleus of cats with interstitial cystitis. Reche Junior A, Buffington CA

Neuroendocrine Imbalance

Here is a quote from a landmark study:

The chronic pain and fatigue syndromes

Several chronic pain and fatigue syndromes (such as fibromyalgia and chronic fatigue syndrome) have been associated with chronic sickness syndrome manifestations (such as fatigue and hyperalgesia) and with hypoactivity of the stress system (Table III).[2] [19] Interestingly, these clinical manifestations and the hypocortisolism of these patients are quite reminiscent of mild glucocorticoid deficiency (Addison's disease). Patients with glucocorticoid deficiency have elevated levels of proinflammatory cytokines such as IL-6, which may explain their typical sickness syndrome manifestations.[11] [20] When we administered human recombinant IL-6 to these patients, we induced an explosive sickness syndrome that was markedly more severe than that observed in healthy control subjects. In contrast, patients with endogenous hypercortisolism showed very little or no response to IL-6 (unpublished observation).[5] It is tempting to speculate that patients with chronic pain and fatigue syndrome have an imbalance between the immune and inflammatory reactions and the stress response, which results in excessive sickness syndrome manifestations of the former versus the antithetical effects of the latter (Table II).

Journal of Allergy and Clinical Immunology Volume 106 o Number 5 o November 2000 Mosby, Inc. Stress, chronic inflammation, and emotional and physical well-being: Concurrent effects and chronic sequelae. George P. Chrousos MD

Stress and Prolactin

This was a theory touted by Dr Nyberg at one stage, but not much has been heard of it since. Here's the article which started it:

Stress: The effect on the Prostate:

Scientists study effects of stress on prostates.
Painful inflammation can strike in 30s, 40s

Lauran Neergaard - Associated Press

WASHINGTON -- Prostate trouble is an almost inevitable rite of passage for aging men. The walnut-sized gland can enlarge or become cancerous, but it's not something most men think they have to worry about until at least their 50s.

Less known is that prostates also can become inflamed, known as prostatitis -- an extremely painful, chronic disease that often hits younger men, in their 30s and 40s. Prostatitis accounts for 2 million visits to doctors a year, but they're largely in vain.

``We don't know what causes it, and we don't know how to effectively treat it,'' said Dr. Leroy Nyberg of the National Institutes of Health, which is seeking sufferers for a $5.5 million study to bring better understanding of prostatitis. ``A lot of men are disabled by it.''

Enter the rat. It seems that rats get inflamed prostates, too, especially when they're subjected to stress.

Why? Stress can spur excess production of a hormone called prolactin that seems to be involved in the inflammation, says new research by North Carolina State University's Dr. C. Lee Robinette.

To Robinette, a veterinarian who has spent years studying rats and prostate disease, that's a red flag signaling that stress also may be behind much of the human misery.

Humans produce prolactin. And while no one has yet researched a stress connection, some men report that their prostatitis waxes and wanes with stress - - becoming worse with increased pressure at work or illness in the family, for example.

``It does appear that men in high-stress jobs, Type A personalities, are the ones that physicians see a lot of,'' agreed Nyberg.

Stress is one characteristic the NIH's study will watch for this year as researchers try to pinpoint those at risk for prostatitis, and then next year begin looking for treatments.

Prostatitis symptoms include pain in the genital area and lower back accompanied by frequent and urgent urination. It can cause burning or pain during urination or ejaculation, and is one cause of sexual impotence. Severe cases can be disabling.

No one knows just how many men have prostatitis, although experts estimate that half may experience it at some point. It can strike anytime, although of the first 100 men enrolled in the NIH's study, the average age is 41, and many sufferers are in their 30s, Nyberg said.

``Acute bacterial prostatitis'' is caused by an infection that quickly clears up, but it is rare. The vast majority of cases are ``chronic nonbacterial prostatitis,'' where symptoms go away and return without warning. No infection can be found.

It's the mystery that drove Robinette's rat research.

He discovered that the prostates of aging rats frequently become inflamed, and that injecting younger rats with certain compounds could induce similar prostatitis -- creating an animal model to test what causes the disease.

When rats' prostates are inflamed, they have extra-high levels of prolactin. Stress causes bodies -- rats' and people's -- to produce more prolactin. So Robinette subjected prostatitis-suffering rats to stress to see if they got worse than prostatitis-suffering rats left alone.

How do you stress a lab rat? Put it in a small cone for 15 minutes, just small enough that it can't move. Restraint worries rats immensely, Robinette said.

He did this twice a day for four weeks. The stressed rats produced more prolactin and their prostatitis grew worse. The unstressed rats largely healed.

The study suggests that ``maybe stress does exacerbate chronic prostatitis,'' something the NIH's study will examine, Nyberg said.

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But Dr Shoskes has cautioned regarding prolactin:

"I have checked Prolactin levels in about 50 men with CP because of its potential effects on libido and the whole prolactin receptor/BPH issue. Never found a single patient with an abnormal value. Doesn't mean that something isn't happening at the receptor level, but systemically there seems to be no difference. "


Damages the Immune System

Stress can Damage the Immune System

Journal of the National Cancer Institute Editorial. Psychologic Stress, Immunity, and Cancer

Sheldon Cohen, Bruce S. Rabin*

Why publish an article in a major cancer journal that demonstrates an association between psychologic stress and cellular immune function in cancer patients? The potential interest in articles such as Andersen et al. (1), published in this issue of the Journal, is based on the premise that stress may alter the function of the immune system in a manner that influences the development or growth of malignant tissue. This premise is quite controversial and we use this editorial to discuss its underlying assumptions.

1) Psychologic stress can alter immune function.

There is evidence for a number of mechanisms through which psychologic stress might alter immune function (2). These include direct innervation of lymphatic tissue by the central nervous system and stress-elicited release of hormones from the brain that bind to and alter the functions of immunologically active cells. The mechanisms also include behavioral changes that often occur in response to stress: an increase in smoking, an increase in drinking alcohol, a loss of sleep, a reduction in exercise, a degradation of the diet, and a decrease in adherence to medical regimens.

In fact, healthy humans exposed to stressful tasks that last only a few minutes, including difficult cognitive tasks and tasks that induce social anxiety, show suppression of T-cell mitogenesis, and increased numbers of circulating CD8 and natural killer cells (3). Studies of real-life stressors show similar alterations. Living near the Three Mile Island nuclear power plant at the time of the accident, caretaking for a relative with Alzheimer's disease, taking medical school examinations, and clinical depression have all been associated with alterations in both the numbers and functions of various subpopulations of lymphocytes (4). These alterations include a reduced proliferative response to mitogen stimulation, reduced natural killer cell cytotoxicity, as well as changes in the production of cytokines. Although the range of stress' effects on immune function is wide, the magnitude of the effects is small, with stress-suppressed patients usually functioning within the normal range.

2) The immune system plays a role in regulating tumor growth.

Burnet (5) promoted the ``immune surveillance'' theory which postulated that the immune system was capable of eliminating neoplastic cells that developed in the normal individuals. It is likely that the mechanisms of cellular immunity are important to the functioning of immune surveillance. Indeed, subjects who undergo suppression of immune function by pharmacologic means, or who have immunodeficiency diseases, have an increased risk of cancer. This has led to the experimental use of treatment strategies designed to increase the function of the immune system and to focus immune reactants at the site of malignant tissue. The use of immune-enhancing therapies, primarily in patients with malignant melanoma and renal cell carcinoma, has produced limited antitumor responses (6).

3) Immune changes under stress are of the type that would influence tumor growth and metastasis.

There are a variety of stress-induced changes in lymphocyte surface molecules, the potential for cell division, and cytokine production that may play a role in immune regulation of cancer growth. Although there is no direct evidence associating these changes in immunity with disease progression in patients with cancer, animal models suggest that the antitumor cytotoxicity of CD8 and NK lymphocytes and the localized inflammatory response mediated by CD4 lymphocytes may influence tumor growth and metastasis (7). These data are suggestive, but specific immune mechanisms that may suppress cancer in humans are not yet known. Therefore, it is speculative at best to assume that psychologic stress modifies immune components involved in the regulation of tumor growth in cancer patients.

4) Immune changes under stress are of the magnitude that would influence tumor growth and metastasis.

The evidence for an association between suppressed immune function and the onset of cancer derives from cases of profound immunosuppression. These cases include tissue transplant recipients receiving immunosuppressive drugs and individuals with immunodeficiency diseases. However, the associations between stress and immune system function is quite mild in other individuals, with immune function still remaining within normal parameters (4). Such changes seem unlikely to have a clinically significant effect on tumor growth. Even so, stress has been found to be an important predictor of other diseases that occur when there is a failure in immune regulation, including greater susceptibility to and severity of respiratory infections and the onset and severity of autoimmune diseases (4). That stress is a risk factor for these diseases raises the possibility that even small stress-induced changes in immune function might be important clinically. It also suggests that, even if stress does not influence the course of cancer, it might alter the risk of infection and for other immune-related diseases, especially among patients receiving chemotherapy.

5) Stress-reduction interventions will influence the progression of disease.

There is evidence that the reduction of stress by the provision of social support may be associated with an amelioration in the course of some malignant diseases. For example, a study of women with metastatic breast cancer showed an 18-month increase in survival (8), and a study of men and women with melanoma showed increased survival and reduced recurrence after 5-6 years (9). Although the latter study found that the intervention was also effective in increasing natural killer cell cytotoxicity, no associations were observed between this change in immune function and disease recurrence or mortality.

It can be argued that attempts to increase immune function by stress reduction strategies may have only limited effects on immunity and consequently on disease progression. Moreover, the effectiveness of these interventions may be further reduced by the influence of chemotherapeutic agents on immune function. Nevertheless, the provocative findings that social support interventions reduce mortality are hard to ignore. However, it is not clear that the effects of these interventions on mortality are mediated through immune mechanisms. It is possible that the interventions might work through other pathways, such as by increasing adherence to medication or nutritional regimens or by ameliorating the direct effects of stress-induced endocrine response on tumor growth.

In sum, Andersen et al. (1) have linked psychologic experience to immunity in patients whose immune systems are already compromised by disease. The question remains whether the immune changes associated with stress have implications for cancer progression and metastasis. If they do, it also remains to be seen whether stress-reduction interventions can ameliorate cancer progression through immune enhancement. The article by Andersen et al. provides an important piece of this fascinating puzzle, but the solution is still a ways off.

References

(1) Andersen BL, Farrar WB, Golden-Kreutz D, Kutz LA, MacCallum R, Courtney ME, et al. Stress and immune responses after surgical treatment for regional breast cancer.J Natl Cancer Inst 1998; 90: 30-6. Medline Abstract

(2) Rabin BS, Cohen S, Ganguli R, Lysle DT, Cunnick JE. Bidirectional interaction between the central nervous system and immune system.Crit Rev Immunol 1989; 9: 279-312. Medline Abstract

(3) Kiecolt-Glaser JK, Cacioppo JT, Malarkey WB, Glaser R. Acute psychologic stressors and short-term immune changes: what, why, for whom, and to what extent? [editorial].Psychosom Med 1992; 54: 680-5. Medline Abstract

(4) Cohen S, Herbert TB. Health psychology: psychologic factors and physical disease from the perspective of human psychoneuroimmunology.Annu Rev Psychol 1996; 47: 113-42. Medline Abstract

(5) Burnet FM. Immunological surveillance in neoplasia.Transplant Rev 1971; 7: 3-25. Medline Abstract

(6) Rosenberg SA. Karnofsky Memorial Lecture: the immunotherapy and gene therapy of cancer.J Clin Oncol 1992; 10: 180-99. Medline Abstract

(7) Lynch SA, Houghton AN. Cancer immunology.Curr Opin Oncol 1993; 5: 145-50. Medline Abstract

(8) Spiegel D, Bloom JR, Kraemer HC, Gottheil E. Effect of psychosocial treatment on survival of patients with metastatic breast cancer.Lancet 1989; 2: 888-91. Medline Abstract

(9) Fawzy FI, Fawzy NW, Hyun CS, Elashoff R, Guthrie D, Fahey JL, et al. Malignant melanoma. Effects of an early structured psychiatric intervention, coping, and affective state on recurrence and survival 6 year later.Arch Gen Psychiatry 1993; 50: 681-9. Medline Abstract

*Affiliations of authors: S. Cohen, Department of Psychology, Carnegie Mellon University, Pittsburgh, PA; B. S. Rabin, Department of Pathology, University of Pittsburgh School of Medicine.

Correspondence to: Sheldon Cohen, Ph.D., Department of Psychology, Carnegie Mellon University, Pittsburgh, PA 15213.