The Sex Series – Part Six: Male pelvic dysfunction and mast cells

Chronic pelvic pain syndrome (CPPS) affects about 15% of male patients and 90% of patients with chronic prostatitis. Patients with these conditions experience pain in the pelvis, abdomen and genitalia, as well as urinary tract symptoms without evidence of infection. Pain can be intermittent or constant, and can interfere with daily activities including sitting, standing, urination and defecation.

CPPS also causes sexual symptoms. Painful ejaculation, erectile dysfunction, and other types of ejaculation dysfunction are all common in this patient group.  In one study, 40% of patients with CPPS were found to have erectile dysfunction.  In another, 72% of patients reported either erectile dysfunction or difficulty with ejaculation.

Pelvic floor dysfunction is a component of CPPS. Many of these patients have abnormally tense pelvic floor muscles, which can cause muscle spasm and obstruct bloodflow. CPPS patients are more likely than healthy controls to have vascular dysfunction associated with nitric oxide level. In a group of 146 patients with CPPS and verified pelvic floor spasm, 56% experienced painful ejaculation.  Visceral and myofascial pain and spasm of the muscles in the pelvic floor contribute to CPPS.  While pelvic floor dysfunction has been well researched for female patients, there are far fewer studies on pelvic floor dysfunction in men.  Biofeedback and pelvic floor physical therapy can resolve issues with erectile dysfunction and other sexual issues.

IL-17, expressed by special T cells called Th17 cells, is required to develop CPPS-like conditions in animal models. IL-17 triggers mast cell degranulation and secretion of many inflammatory molecules.  A number of mast cell mediators are elevated in patients with CPPS. IL-1b, TNF, IL-6 and IL-8 are higher in seminal fluid of these patients.  CCL2 and CCL3 expression is also increased. In the prostate of animals with a CPPS model, TNF, IL-17a, IFN-γ and IL-1b are all increased.

Tryptase has been found to induce pelvic pain. Levels of tryptase and carboxypeptidase A3 are higher in CPPS patients than in healthy controls.  Tryptase binds to a receptor called PAR2.  When tryptase binds to this PAR2 receptor, it is thought that it makes nerves oversensitive. If the PAR2 receptor is blocked, pelvic pain is mitigated.  In animal models where they cannot make tryptase-like products, pelvic pain does not develop in CPPS.

Nerve growth factor (NGF) is a mast cell mediator that has been implicated in CPPS. It is elevated in seminal plasma of CPPS patients and directly correlates with pain level. It is thought that NGF makes the peripheral nerves oversensitive and causes more nerve cells than usual to be present. NGF and tryptase were elevated in prostate secretions of most CPPS patients in a small patient group. Of note, NGF release occurs and increases weeks after initial symptoms.

In animal models, injecting cetirizine (H1 antihistamine) into the peritoneal cavity decreased pain by about 13.8%; ranitidine (H2 antihistamine), 6.1%; cromolyn, 31.4%. A combination of all three decreased pain by 69.3%. When cromolyn and cetirizine were used together, larger pain relief was achieved than when used individually, but this was not seen when using ranitidine and cromolyn together.  These data suggest that H2 signaling is not a major contributor in chronic pelvic pain in male patients.

Pelvic floor dysfunction is also common in heritable connective tissue diseases and is often present in hypermobile patients.

References:

Done JD, et al. Role of mast cells in male chronic pelvic pain. Journal of Urology 2012: 187, 1473-1482.

Roman K, et al. Tryptase-PAR2 axis in experimental autoimmune prostatitis, a model for chronic pelvic pain syndrome. Pain 2014: 155 (7), 1328-1338.

Cohen D, et al. The role of pelvic floor muscles in male sexual dysfunction and pelvic pain. Sex Med Rev 2016; 4, 53-62.

Murphy SF, et al. IL17 mediates pelvic pain in experimental autoimmune prostatitis (EAP). PLoS ONE 2015, 10(5) : e0125623.

 

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part One)

Ehlers Danlos Syndrome (EDS) is a heritable connective tissue disease with six major subtypes. EDS occurs in approximately 1/5000 births.  Classical EDS (cEDS) and hypermobility type EDS (HEDS or ht-EDS) are the most common forms, with approximately 90% of patients having one of these types.  Vascular EDS (vEDS) affects about 5% of EDS patients.  The remaining types are rare. Generally, EDS patients demonstrate hypermobility of joints, excessive stretchiness of the skin (hyperextensibility) and fragility of soft tissues.

Ehlers Danlos is diagnosed by clinical evaluation and diagnostic testing.  Mutations affecting structure of collagen, a key component of connective tissue, have been identified for cEDS and vEDS.  For hypermobility type EDS, no consistent genetic anomality has been found.  As a result, diagnosis of this subtype relies upon patient history and clinical examination.

The Beighton scale is a nine point scale for evaluating hypermobility.  One point is granted for each: elbow hyperextended more than 10°, knee hyperextended more than 10°, thumb that can be touched to the forearm, and fifth finger that can be passively bent back more than 90°.  One further point is granted for being able to place the palms flat on the floor with knees fully extended.  A score of 5 points or more is suggestive of joint hypermobility, a major criterion for diagnosis of HEDS.

In addition to an appropriate Beighton score, soft skin with normal or slight hyperextensibility and absence of significant soft tissue abnormalities are also important for HEDS diagnosis.  Excessive skin hyperextensibility and serious fragility of connective tissue could be indicative of other forms of EDS.

Hypermobility type EDS was regarded for many years as a benign laxity of the joints.  In recent years, this position has been debunked, though this belief still persists for many medical providers. Hypermobility and musculoskeletal pain were previously recognized as the dominant manifestations, but we now know that HEDS can cause cardiovascular, gastrointestinal, genitourinary and neurologic symptoms, among others.  In fact, the aspects of this disease that aren’t musculoskeletal are the most disabling and are correlated with lower quality of life

Symptoms arising from dysfunction of the autonomic nervous system have serious impact on quality of life as demonstrated in a number of conditions, including chronic fatigue syndrome and fibromyalgia.  Autonomic dysfunction can be assessed with an Autonomic Symptom Profile (ASP), a questionnaire of 169 questions that evaluates symptoms in eight broad categories: orthostatic (upright posture), secretomotor (secretion of substances by glands), urinary, GI, pupillomotor (movement of the pupil), vasomotor (changing diameter of blood vessels), reflex syncope (dysfunction of blood pressure and heart rate) and sleep function. These functions are all controlled by the autonomic nervous system.

References:

de Wandele I, et al. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Seminars in Arthritis and Rheumatism 2014, 44: 93-100.

de Wandele I, et al. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls. Seminars in Arthritis and Rheumatism 2014, 44: 353-361.

Wallman D, et al. Ehlers-Danlos Syndrome and Postural Tachycardia Syndrome: A relationship study. Journal of Neurological Sciences 2014, 340: 99-102.

Mast cells in nerve pain

Mast cells are heavily involved in the generation and sensation of pain. The role of mast cells in neurogenic pain (also called nerve pain or neuropathy) is well established and is responsible for a number of painful conditions.

Pain is transmitted like this:

  1. You first feel the pain in nerve endings called nociceptors.
  2. These nerve endings and capillaries in the nearby tissue form a “pain unit” that sends pain signals.
  3. Mast cells are often found close to these nerve endings and capillaries. They release mediators like prostaglandins, histamine and bradykinin.
  4. Nociceptors release mediators like substance P, VIP and CRH, which activate mast cells.
  5. Mast cells then release mediators that increase permeability of the vessels and sensitize the nociceptors. This cycle, in which the nerve endings activate mast cells and the mast cells activate the nerve endings, is called a positive feed back loop. The end result is neurogenic inflammation, or inflammation caused by nerves.

Mast cells can communicate with nerve endings in a number of ways. The first way is by releasing mediators, which may bind to receptors on the nerve cells. A second way is by mast cells sticking to nerve cells through molecules like CADM-1 and N-cadherin; they are able to send signals when their membranes are touching. A third way is by the nerve cells ingesting mediators released by mast cells. These mediators are then transported to other nerve cells, where it can affect which genes are turned on and used.

Mast cells also draw other immune cells to the site of inflammation, like neutrophils and T cells. These cells also release mediators that increase pain, forming another positive feedback loop. The result is that inflammation can spread beyond the initial site of pain, causing a secondary, larger pain response. Hyperalgesia is an exaggerated pain response that is more severe than expected based upon the injury. Mast cells are thought to be directly involved in hyperalgesia and histamine is thought to cause this heightened pain sensation.

Chronic pain has been associated with mast cell degranulation. Degranulation close to colonic nerves is correlated with abdominal pain in IBS patients. Tryptase and histamine can also activate enteric nerves, causing the nerves to be oversensitive. Esophageal pain is also a function of mast cell degranulation.

The specific mechanism of bladder pain due to interstitial cystitis is not clear. However, mast cells are often elevated in IC patients, and contribute to inflammation. It is thought that activation of bladder nerves causes release of substance P by local nerve endings, which activates mast cells.

Overly sensitive and painful skin is sometimes a function of mast cells as well. A significant increase in mast cells has been found in the dermis of fibromyalgia patients. Chronic granulomatous inflammation of the skin causing pain has also been found to be from degranulation of mast cells.

 

References:

Heron, Anne, Dubayle, David. 2013. A focus on mast cells and pain. Journal of Neuroimmunology 264 (2013) 1–7.

Parada, C.A., Tambeli, C.H., Cunha, F.Q., Ferreira, S.H., 2001. The major role of peripheral release of histamine and 5-hydroxytryptamine in formalin-induced nociception. Neuroscience 102, 937–944.

Theoharides, T.C., Kempuraj, D., Sant, G.R., 2001. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology 57, 47–55.

Theoharides, T.C., Donelan, J., Kandere-Grzybowska, K., Konstantinidou, A., 2005. The role of mast cells in migraine pathophysiology. Brain Res. Brain Res. Rev. 49, 65–76.

Gao, G., Ouyang, A., Kaufman, M.P., Yu, S., 2011. ERK1/2 signaling pathway in mast cell activation-induced sensitization of esophageal nodose C-fiber neurons. Dis. Esophagus 24, 194–203.

MCAS: Neurologic and psychiatric symptoms

The neuropsychiatric symptoms associated with MCAS are numerous and are results of the chemicals released by mast cells.

Headaches are a very common complaint. They can sometimes be managed with typical remedies (Excedrin, Tylenol) and antihistamine treatment often helps with this symptom quickly. However, in some patients, headaches can be disabling. Diagnosis of migraine is not unusual, with mast cell degranulation having been tied previously to migraines.

Dizziness, lightheadedness, weakness, vertigo, and the feeling of being about to faint are all typical in MCAS, though true fainting spells are less common than in mastocytosis. These symptoms often cause many MCAS patients to be diagnosed with dysautonomia or POTS.

MCAS patients often experience increased activation of sensory and motor nerves. This manifests as generic neurologic symptoms, sometimes several at once, like tingling, numbness, paresthesia and tics. Tics generally do not spread from the place they initially present. Paresthesias seem to progress for a period of time, then wane and disappear. Extremities are most commonly affected.

EMG and nerve conduction studies are typically normal or abnormal in a way that is not diagnostic. These tests sometimes reflect a possibility of chronic inflammatory demyelinating polyneuropathy (CIDP.) These patients also sometimes are positive for monoclonal gammopathy of unknown significance (MGUS), a blood marker that has been tied to multiple myeloma. However, in these patients, the MGUS is believed to be an effect of the MCAS.

Another subset of patients are diagnosed with subacute combined degeneration (SCD), a deterioration of the spinal cord associated with B12 deficiency. They are sometimes treated for pernicious anemia despite lack of hematologic support for this diagnosis.

Prostaglandin D2 is a known effector of nerve damage and has been blamed for many of the neurologic symptoms seen in MCAS. Astrogliosis, abnormal proliferation of astrocytes (nerve cells in the brain), and demyelination (loss of the insulating cover for nerves that allows the body to send signals) are markers of neurodegeneration. These factors cause scarring and inhibit nerve repair mechanisms. PGD2 is made by an enzyme called hematopoietic PGD synthase. In mice that don’t make this enzyme, these kinds of neuroinflammation are suppressed. Treatment of normal mice with an inhibitor of this enzyme (HQL-72) also decreases these actions. This indicates that PGD2 is critical in causing neuroinflammation including demyelination. PGD2 also activates pain receptors strongly, causing sometimes profound neurologic pain.

PGD2 is also the most potent somnagen known, meaning that it induces sleep more strongly than any other molecule. MCAS patients report inordinately deep sleep, “mast cell coma.” This is likely due to excessive PGD2. Conversely, some MCAS patients also have insomnia, from excessive histamine.

I have written at length before about cognitive and psychiatric manifestations of mastocytosis, which are the same as in MCAS. Cognitive and mood disturbances are all kinds are reported. Brain fog, including short term memory troubles and word finding problems, is the most common symptom. Irritability, anger, depression, bipolar affective disorder, ADD, anxiety, panic disorders and even sometimes frank psychosis can present. Such symptoms in mastocytosis patients were referred to as mixed organic brain syndrome, a term coined in 1986. The important aspect of these symptoms in MCAS is that they are caused by mast cell activation. As such, they are most effectively treated by managing mast cell release symptoms. Some patients do find relief in some psychiatric medications, but the psychiatrist should be aware that these symptoms are part of mast cell pathology.

Additionally, PTSD is not rare in MCAS patients. This is most often due to the trauma from negative interactions with the medical industry.

Autism is significantly increased in patients with mastocytosis. Similar findings are beginning to surface with MCAS patients. Interesting, most autism spectrum disorder patients have food intolerance and general allergic symptoms. A future post will discuss this in more detail.

References:

Afrin, Lawrence B. Presentation, diagnosis and management of mast cell activation syndrome. 2013. Mast cells.

Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J. Hematol. Oncol.2011;4:10-17.

Ikuko Mohri, Masako Taniike, Hidetoshi Taniguchi, Takahisa Kanekiyo, Kosuke Aritake, Takashi Inui, Noriko Fukumoto, Naomi Eguchi, Atsuko Kushi, Hitoshi. Prostaglandin D2-Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination in twitcher. The Journal of Neuroscience, April 19, 2006 • 26(16):4383– 4393.

Rogers MP, et al. Mixed organic brain syndrome as a manifestation of systemic mastocytosis. Psychosom Med. 1986 Jul-Aug;48(6):437-47.

 

Neurologic symptoms of mast cell disease

Mast cells are known to closely associate with nerve endings and to be important in neurotransmission.  This can translate into a variety of neurologic symptoms.
In 2011, a retrospective study on the neurologic symptoms of mast cell patients (171 SM patients, 52 CM patients, all adult) was published.  The following is a summary of the results.
Syncope (fainting) is a well-defined complication of mastocytosis, reported here in 14.3% of patients .  In these patients, evaluation revealed that the likelihood of epileptic involvement was likely low.  About 2/3 of patients who had fainting episodes also had loose stool, cramping, nausea, sweating and flushing accompanying the episode.  Prostaglandin D2 and histamine are known to cause low blood pressure and fainting in addition to GI symptoms.  Aspirin is thought to protect against acute vascular collapse and fainting, and sees use in tolerant patients for these purposes.   
16.6% of mastocytosis patients complained of back pain.  In all but one patient, the cause was determined to be multifocal compression fractures throughout the spine, including thoracic region.  Vertebroplasty, a procedure in which special bone cement is applied to the fractured vertebrae, has been suggested for symptom relief of these patients.  One patient was found to have back pain due to dense mast cell infiltration of the vertebrae.  In this patient, radiation therapy provided symptom relief.
35% of patients reported headaches.  Several of these patients met the criteria for migraines.  Mast cells have been implicated repeatedly in migraine pathology, and mastocytosis patients are more likely to suffer from them than the general population.  In response to mast cell degranulation, reactive changes have been noted in trigeminal nerve, the structure responsible for sensation in the face and activities like chewing.  Trigeminal neuralgia has been noted in some patients with mast cell disease.
This paper was also the first to find a link between mastocytosis and multiple sclerosis.  Two adults with ISM developed relapsing remitting MS, and a patient with isolated UP developed primary progressive MS.  Mast cells are known to associate with MS lesions, and mast cell activation can be detected in cerebrospinal fluid of MS patients.  This study found an MS frequency of 1.3% among mastocytosis patients, compared to 0.1% in the general population.
Lastly, an association has been found between overall mast cell burden and susceptibility to experimental autoimmune encephalitis (EAE.)
Reference:
Smith, Jonathan H, Butterfield, Joseph H, Pardanini, Animesh, DeLuca, Gabriele, Cutrer, F Michael.  Neurologic symptoms and diagnosis in adults with mast cell disease.  Clinical Neurology and Neurosurgery 113 (2011) 570-574.

Histamine effects on neurotransmitters (serotonin, dopamine and norepinephrine)

Some of the most important actions of histamine involve regulation of neurotransmitters.  Release of acetylcholine, norepinephrine and serotonin are all controlled in part by histamine levels.  Injection of histamine into the hypothalamus increased metabolism of norepinephrine and serotonin, while dopamine metabolism increased in some places and not in others.  Medications that block the H1 receptor increase dopamine release.  Histamine stimulates prolactin release via the H2 receptor, which in turn inhibits dopamine production.  Histamine can locally increase the concentration of norepinephrine.

Serotonin is a neurotransmitter.  This means that cells nerve cells use this to communicate.  Most of the serotonin in the body is found in the GI tract, where it controls the way the intestine moves food through it.  However, one study indicated that as much as 40% of serotonin in the human body could originate in mast cells.  Serotonin is metabolized to 5-HIAA, which can be tested for as a sign of mast cell activation.
Serotonin released in the GI tract eventually enters the blood stream. On its way to the blood stream, it is taken up by platelets and later used in clotting.   Serotonin is released when eating, which decreases dopamine release and decreases appetite.  If the food consumed is irritating to the GI tract, more serotonin is secreted to move it through the gut faster.  In these situations, the serotonin cannot be fully taken up by platelets and enters the blood stream as free serotonin.  When this happens, it stimulates vomiting.  Some foods contain serotonin, but it does not cross the blood brain barrier and thus does not affect brain chemistry. 
Mast cells contain dopamine, a hormone and neurotransmitter.  This chemical is most often associated with reward seeking behavior, including addiction behaviors.  It also has other important roles, including motor functions.  Mast cell activation causes depletion of dopamine as frequent degranulation causes a decrease in dopamine production by these cells.   Dopamine can be converted to norepinephrine.
In blood vessels, dopamine inhibits norepinephrine release and acts as vasodilator.  Dopamine also increases sodium excretion and urine output, reduces insulin production, reduces GI motility, protects intestinal mucosa and reduces activity of lymphocytes.  It is responsible for cognitive alertness.  If you consider that high histamine levels can decrease dopamine levels, this means that in a mast cell patient, low dopamine levels might cause decreased urine output, increased GI motility and overactivation of white blood cells.  Additionally, low dopamine can translate into higher than normal norepinephrine levels, which could be the link between mast cell disease and POTS.  Brain fog and decreased alertness are effects of low dopamine.
Defective transmission of dopamine is also found in painful conditions like fibromyalgia and restless legs syndrome, associated with mast cell disease.  Activation of D2 dopamine receptors causes nausea and vomiting.  Metoclopramide is a D2 inhibitor and achieves its anti-nausea effects through this mechanism. (Note: metoclopramide can inhibit histamine metabolism and for this reason is not recommended for mast cell patients.)  Some dopaminergic drugs like clozapine, bromocriptine and haloperidol inhibit mast cell degranulation.
Norepinephrine is responsible for concentration and vigilance.  It also increases vascular tone by action on alpha adrenergic receptors.  Norepinephrine is important in the fight or flight response, directly increasing heart rate, triggering release of glucose, increasing blood flow to skeletal muscle and increasing brain oxygen supply.  Interestingly, fasting increases norepinephrine for days.  Glucose intake, but not carbohydrate or protein intake, also increases norepinephrine.  Increased histamine can cause increases in norepinephrine production and secretion.