Explanation of localised provoked vulvodynia

Early outlined interdisciplinary theoretical explanation of localised provoked vulvodynia: cortisol/ glucocorticoid receptor distortion and demyelination are the missing links

By:  Journalist Klaus Cort, klauscort@gmail.com

Abstract

Localised provoked vulvodynia (LPV) is unexplained chronic pain in the vulvar vestibule. 10- 16 percent of U.S. women have experienced vulvodynia. Mechanical allodynia and increased intraepithelial innervation in the posterior part of the vulvar vestibule are the signs of LPV. Among vulvodynia-researchers, there is consensus on a multi-factorial aetiology of LPV. Factors statistically associated with and therefore suspected causes of LPV are genes affecting interleukin-1 and mannose-binding lectin, stress, anxiety, depression, use of OCs, repeated vulvovaginal infections, and thereby repeated use of antifungals and antibiotics. However, if these multiple factors produce the same signs, they must affect the same biological mechanisms.

Method and main findings: the approach has been an inter- and multidisciplinary iterative search for and combining of research results, with the aim to explain LPV. Two questions have guided the search and selection:

1) Which biological mechanisms are affected by all the statistically suspected causes of LPV?

2) What can cause the signs of LPV?

The answers found are:

1) The glucocorticoid receptor (GR)-cortisol.

2) Demyelination (accompanied by mast cell degranulation and other inflammatory signs).

Finally, medical literature states that GR-cortisol has a key role in SC myelination/demyelination, mast cell degranulation and in the inflammatory immune response. Thus, GR-cortisol distortion and demyelination links from the statistically suspected causes to the signs of LPV.

Conclusion: LPV is caused by distortion of cortisol metabolism primarily in SCs, which causes demyelination and increased immune response. Demyelination cause innervation of the epithelium and, via neurotransmitters and ionchannels, chronic pain. Interactions between the HPA-axis and the nerve- and immune systems make LPV a systemic condition also affecting the brain.

Consequence: LPV was unexplained. Hormone disturbance by medicine should be minimised.

Introduction

By The International Society for the Study of Vulvovaginal Disease (ISSVD) vulvodynia is defined as “vulvar discomfort, most often described as burning pain, occurring in the absence of relevant visible findings or a specific, clinically identifiable, neurologic disorder.” Vulvodynia is subdivided according to whether the pain is generalised or localised and whether the pain is provoked, unprovoked or mixed (1). Localised provoked vulvodynia (earlier called vestibulodynia or vulvar vestibulitis) and generalised unprovoked vulvodynia (earlier called dysaesthetic vulvodynia, essential vulvodynia or vulvar dysesthesia) seems to be two major subforms. Another subdivision is in primary and secondary, meaning onset of vulvodynia before (or at) and after sexual debut respectively.

Most LPV patients are aged 18 – 35 years, but onset or discovery of primary localised provoked vulvodynia can occur already with the first use of tampon. Two cases where the patient was only 4 years old have been described (2)(3). Generalised unprovoked vulvodynia is most common in menopause or later (4). Mixed forms of vulvodynia do often occur (5). A continuum of signs and symptoms developing or appearing different with age could be an alternative understanding of vulvodynia (6) (and partly (7)). - Advancing age is associated with a higher level of diurnal cortisol secretion, an increased cortisol response to challenge and deterioration of myelin sheaths (8)(9).

The lifetime prevalence of vulvodynia in the USA is 10- 16 percent, 4-7 percent of women have the symptoms at any one time (4)(10). Prevalence is stable among sexually active women of any age. Vulvodynia is rarely diagnosed, but can resolve after a mean duration of 12.5 years (11).

LPV is statistically associated with several other chronic medical conditions: irritable bowel syndrome, chronic fatigue, fibromyalgia, interstitial cystis, stress, anxiety and depression, but the strongest associations are with yeast infections, urinary tract infections and bacterial vaginosis (4)(10)(12)(13)(14)(15). Most results point to a connection between vulvodynia and use of OCs (17)(18)(19)(20)(21)(22).

Increased innervation of the epithelium in the vulvar vestibule is found in nearly all LPV-patients (23)(24)(25). It has been suggested as a diagnostic criterion for localised provoked vulvodynia (25)(26). The vulvar vestibule of LPV patients has no active inflammation (27)(28), but there are presence of inflammatory markers/ immune activity: increased number of mast cells, macrophages and inflammatory cytokines (26)(28)(29)(30)(31).

Women with LPV have an increased superficial blood flow and often an erythema in the posterior parts of the vestibular mucosa, and enhanced systemic pain perception (32)(33). Central sensitization is pronounced in LPV patients with a long history of LPV (34)

Method

The approach has been an inter- and multidisciplinary focus on the problem of the aetiology of LPV, an iterative search for and combining of research results from inside and outside the specific field of vulvodynia research, with the aim to explain LPV. Two simple, and obvious to ask, work-questions has guided the search for and selection of research results:

1) What can cause the signs (mechanical allodynia and neural hyperplasia) of LPV?

2) Which biological mechanisms are affected by all the statistically suspected causes of LPV?

The answers found are mapped and literally outlined in figure 1.

Figure 1 and the text below

When discussing the aetiology of vulvodynia, vulvodynia-researchers most often use the term multi-factorial (31)(35)(36). This is not disagreed upon here. However, if multiple factors produce the same disease, they must act at the same specific biological mechanism in the human body.

Figure 1 depicts many of the factors of LPV, and how they can be related through known biological mechanisms. An arrow, -->,  means “affects” or “cause an effect on”, i.e. OCs affect CBG-level in the blood (in the upper right corner of the figure). Paragraph-headings with arrows refer to the same relations in figure1. Figure 1 is thus a detailed “table of contents”, and depicts the interrelations of the paragraphs below. Paragraphs with no arrow in the heading are background information, selected for better understanding of the explanation presented here and possible relevance for research in and explanation of LPV that goes beyond. A covering review of all the relations depicted as arrows is not the goal with this text, and it should not be expected, as it would require several hundred pages.

 The general table of contents is:

Part I. explains the signs of LPV, chronic pain and neural hyperplasia, as a result of demyelination (arrows in the bottom-right and bottom-mid sections of figure 1).

Part II. Explains demyelination as a result of GR-cortisol distortion (arrow pathways between GR-cortisol and demyelination inside the Schwann cell (SC) in figure 1).

Part III. Explains GR-cortisol distortion as a result of factors statistically associated with LPV (arrow pathways from “Primary causes of LPV” to “GR-cortisol” in figure1).

Part IV. LPV, cortisol and the brain (arrows in the lower left of figure 1, light-blue background)

Part V. Conclusion, significance and consequences.

Please study figure 1 at this point and keep an eye at it while reading the text.

Abbreviations

11β-HSD1: 11β-hydroxysteroid dehydrogenase type 1

11β-HSD2: 11β-hydroxysteroid dehydrogenase type 2

ACTH Adrenocorticotrophic hormone

cAMP. Cyclic adenosine monophosphate

CAR: Constitutive androstane receptor

CBG: Corticoid binding globulin (also called transcortin) 

CORT: Cortisol in humans/corticosterone in mice and rats.

CREB: cAMP response element-binding protein

DHEA: Dehydroepiandrosterone (DHEAS: DHEA-sulphate)

EAAT: Excitatory amino acid transporters

ENaC: Epithelial sodium channel

ERK: Extracellular signal-regulated kinase (ERK1, ERK2)

ER: Estradiol/estrogen receptor

GABA: γ-Aminobutyric acid

GC: Glucocorticoid

GILZ: Glucocorticoid-induced leucine zipper

GITR: Glucocorticoid-induced TNF-receptor-related protein

GR: Glucocorticoid receptor (GRα, GRβ)

GRE’s Glucocorticoid response elements

hGR: Human Glucocorticoid receptor (hGRα, hGRβ)

IL: Interleukin (IL-1α, IL-1β, IL-6)

IL-1RA: Interleukin-1 receptor antagonist

JNK: c-Jun N-terminal kinase

LPV: Localised provoked vulvodynia

LRP-1: Low Density Lipoprotein Receptor-Related Protein 1

MAPKs: Mitogen-activated protein kinases (ERK, JNK, p38 MAPK etc.)

MBL: Mannose binding lectin

MR: Mineralocorticoid receptor

NCX: Na(+)/Ca(2+) exchanger, sodium-calcium exchanger

NF-κB: Nuclear factor-kappaB

NGF: Nerve growth factor

NMDA: N-methyl-D-aspartate

NMDAR: N-methyl-D-aspartate receptor

P0: Protein zero

PI3K: Phosphatidylinositol 3-kinase

PKC: Protein kinase C (PKC-α, -β , -δ and –ζ)  

PMP22: Peripheral myelin protein-22

PNS: Peripheral nervous system

PXR: Pregnane X receptor

RAR: Retinoic acid receptor

RVVIs: Recurrent vulvovaginal infections

RXR:  Retinoid X receptor

SGK: Serum- and glucocorticoid-inducible kinase (SGK1, SGK2, SGK3)

SC: Schwann cell

SHBG: Sex hormone binding globulin

TNF: Tumor necrosis factor (TNF-α)

TRP: Transient receptor potential (TRPV1, TRPA1, TRPM8)

TRPA1: Transient receptor potential ankyrin 1

TRPV1: Transient receptor potential vanilloid 1

I. Demyelination causes the signs and symptoms of LPV

This part describes how demyelination changes sensory-nerves into unmyelinated (of course) and pain transmitting nerves with a propensity to grow - in the case of LPV into the epithelium of the vulvar vestibule.

Demyelination ­­-->  neural hyperplasia

Myelin contains several proteins, which inhibit or restrict neural growth (i.e. myelin-associated glycoprotein (MAG) and neurite outgrowth inhibitor (Nogo)), and demyelination cause neuronal growth (37)(38)(39). Loss of myelin may thus explain the innervation of the epithelium observed in LPV.

Neural hyperplasia associated with pain and an increased number of mast cells is also found in non-inflamed appendices from patients with acute appendicular pain (40)(41). (Several factors causing both demyelination and neural hyperplasia are described in part II, and demyelination in the brain of LPV patients is shortly described in part IV.).

Demyelination --> Ion-channels

Demyelination causes altered axon-SC interactions: axonal components of nodes fragment and disappear, glial and axonal paranodal and juxtaparanodal proteins no longer cluster, and axonal Kv1.1/Kv1.2 K+ channels move from the juxtaparanodal region to appose the remaining heminodes (42). Demyelination trigger membrane remodelling in injured afferents and perhaps in uninjured neighbours, which causes increased cellular excitability: enhanced membrane resonance, rhythmogenesis, and ectopic spiking, which are the characteristics of a primary neuropathic pain signal. This is due in large part to subtype-selective abnormalities in the expression and trafficking of Na+ channels (43). Na+ channel isoforms are differentially targeted to distinct domains of the same axon in a process associated with formation of compact myelin. During development, Na(v)1.2 is expressed first and becomes clustered at immature nodes of Ranvier, but as myelination proceeds, Na(v)1.6 replaces Na(v)1.2 at nodes (44). Demyelination causes a significant switch from Nav1.6 to Nav1.2 expression (45). SC remyelination restores the normal pattern of Nav1.6 and Kv1.2 at nodes of Ranvier (46).

These results might in addition suggest that myelin has a key role in keeping homeostatic concentrations of Na(+) and K(+) at nodes of Ranvier.

Demyelination --> TRPV1, NMDA --> chronic pain

Focal peripheral nerve axon demyelination is accompanied by nociceptive pain behaviour in mice. The demyelination leads to delayed functional expression of neuronal chemokine receptors. Chemokine signalling by both injured and adjacent, uninjured sensory neurons are correlated with the maintenance phase of a persistent pain state. Chemokines can directly excite subsets of sensory neurons. This excitation is likely to be due to transactivation of ion channels, such as the transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 (TRPV1 and TRPA1), expressed by sensory nerves (47). Cortisol has been found to regulate some chemokine receptors (48)(49). TRPV1 and TRPA1 channels are members of the TRP superfamily of structurally related, non-selective cation channels. The functions of TRPV1 and TRPA1 interlink with each other to a considerable extent, especially in relation to pain and neurogenic inflammation where TRPV1 is co expressed on the vast majority of TRPA1-expressing sensory nerves (50). Increased TRPV1 innervation in vulvodynia tissues compared

TRPV1 activation induces Ca(2+) entry, a prolonged elevation of presynaptic mitochondrial and cytosolic Ca(2+) and a concomitant enhancement of glutamate release at sensory synapses and action potential firing by postsynaptic neurons (52).

Activation of N-methyl-D-aspartate (NMDA) receptors (NMDAR) sensitizes TRPV1 by enhancing serine phosphorylation through protein kinase C (PKC). Thus it seems that the NMDAR and TRPV1 forms a signalling complex that underlies the sensitization of nociceptors (53)

Models of neuropathic pain are created by inflicting injuries to peripheral sensory nerves i.e.  chronic constriction, axotomy and demyelination. Demyelination can be caused by increased Ca(2+) in SCs and is accompanied by increased neuronal Ca(2+) (47)(54).

Axotomy, on the other hand, causes loss of neuronal inward Ca(2+) flux through voltage-gated Ca(2+) channels and decreased neuronal cytosolic Ca(2+) (55).

Apart from urging caution in the interpretation of these models, this might also be relevant in the understanding of the effectiveness of vestibulectomy as a treatment of LPV. Testosterone and progesterone are other treatments of LPV, and dehydroepiandrosterone (DHEA) might have a potential for the same purpose, as all three hormones block Ca(2+) channels of varying types (22)(56)(57)(58)(59).

Capsaicin, the pungent ingredient in hot chilli peppers activates TRPV1, which leads to a burning sensation (60).

In the USA, Hispanic women are 80% more likely to experience chronic vulvar pain than are White and African American women (61).

Is it because of differences in chilli intake, differences in genes or more stress in Hispanic women (maybe caused by minority/immigrant-situation and/or Hispanic sex-roles)?

Whereas low capsaicin concentrations results in sensitization and activation of TRPV1 receptors, higher concentrations of topical capsaicin can result in desensitization of TRPV1-positive afferents and eventually withdrawal of epidermal nerve fibres (62)(63). Capsaicin could thus be both a cause and a treatment possibility in LPV.

Ion-channels --> chronic pain

TRPV1 is of course not the only ion-channel involved in pain sensation. Other TRP-channels, Voltage-gated Ca(2+) channels and Voltage-gated K(+) channels also play major roles in the development and maintenance of neuropathic pain  (64)(65)(66)(67). The importance of the Na(+)/Ca(2+) exchanger (NCX) for both neuronal and glial cells is described in part II., because NCX’s are regulated by some of the same factors as, and interacts with, myelination.

GR-cortisol --> ion-channels

Corticosterone, injected or induced by water avoidance stress, leads to increased TRPV1 receptor expression and function in rats (68).

GR-cortisol regulates the cross membrane exchangers of Na(+) for Ca(2+), K(+) and H(+) respectively(69)(70)(71)(72). In addition, the Na(+) transport by the epithelial sodium channel (ENaC) is regulated by glucocorticoids (GCs) via  GC-induced leucine zipper (GILZ) and serum- and GC-inducible protein kinase 1 (SGK1). An ENaC-like channel has recently been found in rat PC12 cells (a neuronal cell model) and in a human colonic cell line. Thus, ENaC channels are most likely to be present in mucosal tissue and in the nerves herein. GILZ expression is also rapidly stimulated by aldosterone, which strongly stimulates ENaC-mediated Na(+) transport by inhibiting extracellular signal-regulated kinase (ERK) signalling. However, the GR is indispensable for physiological responses to aldosterone in ENaC induction via the mineralocorticoid receptor (MR), and SGK1 and ERK interact. (73)(74)(75)(76)(77).

GC-induced hypertension is in part caused by a dysregulation of Na(+) homeostasis (78).

Women with LPV have an increased superficial blood flow in the posterior parts of the vestibular mucosa most probably caused by a neurogenic vasodilatation (32) - being a result of oppositely  dysregulated Na(+) homeostasis (hypotension), it is implied here.

In a randomized, double blinded, placebo-controlled study (of  botulinum toxin A) 0.5 mL saline, with and without botulinum toxin A, injected in the musculus bulbospongiosus produced equal and significant pain reductions (P < 0.001) in LPV patients (79).

Increased activity or even re-reversing of the Na(+)/Ca(2+) exchanger (NCX) could be the underlying effect of this unintended treatment.

If there is strong (local?) lack of Na(+) even the placebo-concentration has an alleviating effect.

Na(+) regulates different glutamate receptors outside and inside the neuronal cell membrane. The enhancement of NMDARs by intracellular Na(+) interacts with Ca2(+)-dependent inactivation (80).  –   NaCl (or another Na(+) source) as a conservative treatment of LPV should be considered further. A less conservative treatment of LPV could be a mineralocorticoid aimed at increasing GILZ.

GR-Cortisol  --> Neurotransmitters

Glutamate is one of the major excitatory neurotransmitters in the central nervous system, but has also a role in the transduction of sensory input in the peripheral nervous system (PNS), and in particular in the nociceptive pathway. There is strong support for the presence of GRs on presynaptic nerve terminals acting to facilitate the release of neuronal glutamate (81).

Serotonin is regulated by MR and GR responsive promoter elements (82)(83)(84).

A PNS interconnection between GR-cortisol and dopamine, which involves both SCs and neurons, is described  in “GR-cortisol à arylsulphatase A à demyelination” in part II.

II. GR-cortisol distortions cause demyelination

All the molecular instruments playing the symphony of myelination/demyelination are conducted by GR-cortisol. If the conductor is disturbed, you are sure of a bad concert. However, if some of the instruments play out of tune, it can also result in a bad performance – demyelination.

Of course, the way the molecular instruments play affects the GR-conductor and the other molecular instruments. Only for limitation-reasons, these relations are not, or only briefly described here.

The GR and myelin genes

The regenerative (demyelinating) response of SCs is directly related to the pathophysiology of a number of neurodegenerative diseases, and is dependent on an intricate gene regulatory program coordinated by a number of transcription factors and microRNAs, which are correlated with myelination and proliferation gene clusters (85)

Of key importance is the mutually antagonistic relationship between Early growth response protein 2 (Egr2 / Krox20) and the transcription factor c-jun that regulates the transitions between nonmyelinating and myelinating SCs. This antagonistic relationship is regulated by GILZ (86)(87).

The promotors of peripheral myelin protein-22 (PMP22) and protein zero (P0) genes are only activated in SCs, and only by ligand activated GR. Strangely, the GR antagonist RU486 does not abolish the effect of glucocorticosteroids, instead it stimulates promoter activities by itself (88). In SCs, the GR also makes use of unusual coactivators for its binding to the GC response elements (GRE’s). Expected coactivators inhibits GR transcriptional activity, which in stead is mediated by β-catenin (89)(90).

Neuregulin-1

Neuregulin-1 (Nrg1) provides a key axonal signal that regulates SC proliferation, migration and myelination through binding to SC receptors (called ErbB2/3). Both the membrane-bound type III and the soluble isoform II of Nrg1 elicit a promyelinating effect at low concentrations, and they both inhibit myelination at higher concentrations, by activation of mitogen-activated protein kinases (MAPKs) and induction of increased expression of the transcription factor c-Jun (91)(92). However, Nrg1 type I expression in SCs themselves plays a pivotal role in remyelination (93).

GR-cortisol --> demyelination

Cortisol and progesterone are decisive in the production of myelin. The two steroids both initiate and control the rate of myelin formation (94). A single SC produces myelin equivalent to many thousands of its own weight. The number of GC receptors (GR’s) is therefore extremely high in schwann-cells, and schwann-cells are extremely sensitive to variations in cortisol level in a u-shaped manner. A small increase relative to the normal physiological level can be beneficial, while both decreases and lager increases in cortisol level can cause endoplasmic reticulum stress, wrongly folded proteins, myelin-failure and eventually schwann-cell death (95)(96)(97).

GR-cortisol --> PXR/… --> demyelination

When bound to GR, cortisol regulates the activity of retinoic acid (RA) bound to its receptors RAR and RXR (98). RA-RAR regulates the production of proteins essential for myelin. RA up-regulates myelin basic protein (Mbp) and myelin P0, when connecting to RXR, and it down-regulates the production of MAG when connecting to RAR. Changes in GR-cortisol level can therefore lead to myelin failure (99). RA, acting through the RAR-β, inhibits the neuronal membrane-bound receptor of myelin-activated Nogo, through the transcriptional repression of Nogo receptor interacting protein (Lingo-1), which results in lacking inhibition of neurite outgrowth (100).

Lingo-1 is a potent inhibitor of oligodendrocyte differentiation and myelination, both when expressed by oligodendrocytes and when expressed by neuronal cells (101).

At least 70 percent of myelin is lipids. The lipid metabolism is vulnerable in part due to the particular lipid composition of myelin and the transport of lipid-associated myelin proteins (102).

The production of lipids is regulated by the pre-hormone pregnenolone, when this connects to its receptor PXR (pregnane X receptor). PXR-pregnenolone is regulated by GR-cortisol. Changes in GR-cortisol level can therefore lead to failures in lipid metabolism (98).

A GC-controlled gene network is involved in the regulation of triglyceride homeostasis (103). This was found in adipocytes, but might apply for other cells with high production/maintenance of triglycerids like SCs.

GR-cortisol --> kinases --> neural hyperplasia, demyelination --> pain

Kinases are enzymes that can rapidly and reversibly phosphorylate specific residues of cellular proteins and as such affect their structure, function, location or metabolism (78).

It is well documented that MAPK pathways can increase peripheral pain sensitivity (104).

Activation of both ERK and p38 MAPK signalling pathways are involved in neurite outgrowth and differentiation of PC12 cells toward a neuronal phenotype (105). Normally, after nerve injury, SCs dedifferentiate into a progenitor-like state, proliferate, and repopulate the damaged nerve. Once axons have regenerated SCs then redifferentiate and remyelinate. Elevated MAPK (/ERK) signalling in SCs is a crucial trigger for SC dedifferentiation in vivo (106)(107). Both inhibition and activation of p38 MAPK cause demyelination (108)(109)(110)(111), which suggests a U-shaped relation, when demyelination is depicted as a function of p38 MAPK activity. GR-Cortisol activates MAPK (/ERK) through genomic mechanisms, but also interacts with MAPKs in a non-genomic way (112).

PKC-mediated phosphorylation of  the myelin protein P0 is necessary for P0-mediated homophilic adhesion, and alteration of this process can cause demyelinating neuropathy in humans (113).

PKC phosphorylates the transcription factor Sp1 that can activate the myelin basic protein (MBP) promoter (114)

PKC is a key component in the signalling pathways that mediate the inhibitory activities of myelin on neuronal growth. MAG, Nogo and oligodendrocyte myelin glycoprotein (OMgp) all interact with the same receptor complex to effect inhibition via PKC (115)(116).

GR activation increase mRNA and protein level of PKC. However, this effect is isoform specific. The PKC isoforms -α, -β and -ε are strongly increased, while the -δ and -ζ  isoforms are not affected.  In mesenteric arteries from hypertensive rats Dexamethasone decrease PKC activation (117)(118(119), which suggests an inverted U relationship between GR activation (x-axis) and PKC activity (in the hypertensive rats GR-activity and PKC-activity is all ready near or beyond the turning point in the inverted U before the dexamethasone treatment, as hypertension is regulated by GR).

NMDA receptors and PKCγ are regulated by GR through a cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)-dependent pathway (shown in spinal cord by chronic morphine exposure)(120).

Glutamate, Ca(2+) --> demyelination, pain

Activation of myelinic NMDA glutamate receptors mediates Ca2+ accumulation in central myelin in response to chemical ischemia in vitro. Given that axons are known to release glutamate, this suggests a mechanism of axo-myelinic signalling of importance for disorders in which demyelination is a prominent feature (121).

Neurotransmitters (i.e. γ-Aminobutyric acid (GABA), acetylcholine, adenosine, glutamate) are active on SCs. Prevention of glutamate induced excitatory, toxic and demyelinating effects is desirable to preserve the integrity of PNS. Removal of glutamate from the extracellular space is accomplished by the high affinity glutamate transporters called excitatory amino acid transporters (EAATs), which are present in SCs, in the myelin layer and at neuronal synapses (122)(123(124).

The glutamate released by neurons into the synaptic cleft is inactivated by EAATs that catalyzes the co-transport of 3 Na(+) ions, one H(+) ion, and one glutamate molecule into the cell, in exchange for one K(+) ion. Five EAATs has been identified:EAAT1 (also called GLAST), EAAT2 (GLT-1), EAAT3 (EAAC1 or excitatory amino acid carrier 1), EAAT4 and EAAT5. EAATs are affected by several effectors, including free radicals, arachidonic acid, protein kinases A, B and C, phosphatidylinositol 3-kinase (PI3K)  and SGK1, SGK2, and SGK3. All three SGK isoforms and PKB increase EAAT2 activity and plasma membrane expression. PKC activation on the other hand leads to the internalization of both EAAT2 and the dopamine transporter, and thereby a reduction in neurotransmitter clearance capacity (125)(126)(127)(128)(129).

NCX and EAAT

The sodium-calcium exchanger NCX, of which there three isoforms are known, is a bidirectional transporter that catalyzes the electrogenic exchange of 3 Na(+) for 1 Ca(2+), depending on the electrochemical gradient of the substrate ions (130). During oligodendrocyte precursor cells (OPC) differentiation into oligodendrocyte phenotype NCX1 is downregulated and  NCX3 is strongly upregulated. NCX3-knockout mice show reduced size of spinal cord and marked hypo-myelination, as revealed by decrease in myelin basic protein (MBP) expression and increase in OPC number (131)

NCX1 and NCX3 basal expression decreases when c-Jun N-terminal kinase (JNK) or ERK 1/2 are blocked. Whole-cell Na(+) /Ca(2+) exchange decreases when JNK and ERK 1/2 are blocked and increases when MAPKs are activated by nerve growth factor (NGF) (132).

NCX1 and NCX3 up-regulation contribute to the survival action of the PI3K pathway (during chemical hypoxia) (133).

Both PKC and PKA activation enhance NCX reverse mode, which in neurons results in Ca(2+) influx and NMDA excitotoxicity (134)(135).

EAAC1 (also called EAAT3), is expressed in neuronal and glial mitochondria where it participates in glutamate-stimulated ATP production. There is  colocalization, mutual activity dependency, physical interaction between EAAC1 and NCX1 both in neuronal and glial mitochondria, and NCX1 is the key player in the glutamate-induced energy production (136).

During ischemia the mitochondrial Na(+)/Ca(2)+ exchanger, driven in the Na(+) import/Ca(2+) export mode, contributes to Ca(2+) increase in the cytosol (in rat optic nerve) (137).

Thus, assuming the presence of the NCX-EAAT-complex in the cell membrane, the normal NCX mode (Na(+) import, Ca(2+) export) competes with EAAT for the 3 Na(+), which regulates glutamate homeostasis. Excessive glutamate release and /or lack of extracellular Na(+) makes EAAT win this competition, NCX is forced into reverse mode, the NA (+) is recycled, and the cost of removing excessive glutamate is increased intracellular Ca (2+). In SCs and myelin, the increased intracellular Ca(2+) leads to demyelination. In neuronal cells, it leads to excitotoxicity.

However, NCX is not the only source of intracellular Ca(2+). TRPV1 has been mentioned earlier.

Another example: Increased intracellular calcium causes functional derangement in SCs from rats with Charcot-Marie-Tooth neuropathy (PMP22 gene overexpression). A PMP22-related overexpression of the P2X7 purinoceptor/channel (members of the family of ionotropic ATP-gated receptors) leads to the influx of extracellular Ca(2+) and demyelination (138).

GR-cortisol --> LRP-1 --> NMDA

Low Density Lipoprotein Receptor-Related Protein 1 (LRP-1) modulates NMDA receptor-dependent intracellular signalling and NMDA-induced regulation of postsynaptic protein complexes (139).

Deletion of  the LRP1 gene in SCs (scLRP1(-/-)) induces abnormalities in axon myelination and in ensheathment of axons by nonmyelinating SCs in Remak bundles. These anatomical changes in the PNS are associated with mechanical allodynia, even in the absence of nerve injury, and central sensitization in pain processing including increased p38MAPK activation and activation of microglia in the spinal cord (140).

LRP1 is regulated by ligand activated GR (141)(142).

LRP1 functions as a potent activator of PI3K in SCs and, by this mechanism, increase the SC unfolded protein response, which limits apoptosis (143).

GR-cortisol --> arylsulphatase A, dopamine --> demyelination

In humans, most Dopamine circulates as dopamine sulfate, which can be de-conjugated to bioactive dopamine by arylsulfatase A. Human adipocytes express functional dopamine-receptors and arylsulfatase A, suggesting a regulatory role for peripheral dopamine (144).

Dopamine receptors D1 and D5 (D1-like receptors), are linked to a stimulatory G protein, that stimulate adenylyl cyclase and increases cAMP production. D2R, D3R, and D4R (D2-like receptors) are linked to an inhibitory G protein, that inhibit adenylyl cyclase and calcium channels, and modulate potassium channels (145).

Metachromatic leukodystrophy is a lysosomal storage disorder caused by deficiency in the sulfolipid degrading enzyme arylsulfatase A. In the absence of a functional arylsulfatase A, gene sulpholipids accumulate. The storage is associated with progressive demyelination and various finally lethal neurological symptoms. Lipid storage, however, is not restricted to myelin-producing cells but also occurs in neurons. Accumulation in neurons contributes to disease phenotype, hyperexcitability and axonal degeneration (146).

Cortisol in physiological concentrations (0.03 microM) causes an increased accumulation of myelination-associated sulpholipids in SCs. It is caused by a cortisol-concentration-dependent inhibition in arylsulphatase A activity (147)(148).

High cortisol levels may thus cause a “metachromatic leukodystrophy-light”: dys-/demyelination, low arylsulphatase A  leading to missing stimulation of peripheral neuronal dopamine receptors and hyperexcitability.

GR-cortisol --> microRNA --> neural hyperplasia, demyelination

MicroRNAs are small non-coding RNA molecules, which functions in transcriptional and post-transcriptional regulation of gene expression. A cohort of microRNAs coordinate SC dedifferentiation through a combinatorial modulation of their positive and negative gene regulators during the acute phase of PNS injury (149)(150).

MicroRNA-221 and -222 promote SC proliferation and migration after sciatic nerve injury (151). MicroRNA-222 promotes neurite outgrowth from adult dorsal root ganglion neurons following sciatic nerve transaction (152).

RNA polymerase II  is an enzyme that catalyzes the transcription of DNA to synthesize precursors of mRNA and most microRNA (153)(154) The GR functions at multiple steps during transcription initiation by RNA polymerase II (155).

Other steroids --> demyelination

Progesterone and its derivatives also control the production of proteins that are unique and essential for myelin. The gene expression of Glycoprotein Po is stimulated via the progesterone receptor. In addition, tetrahydroprogesterone increases PMP22 gene expression via the GABA-A receptor. Also over expression of PMP22 can cause dysmyelination. Both lack and surplus of progesterone can therefore cause dys- and demyelination. SCs can produce progesterone (156)(157)(158).

Testosterone is vital for the production of P0 and PMP22. When connecting to the androgen receptor, testosterone controls P0, while the control over PMP22 is most likely via the GABA-A receptor (159).

Other steroids --> GR-cortisol

Key regulators of cortisol activity are the enzymes 11β-hydroxysteroid dehydrogenases, 11β-HSD1 and 11β-HSD2. 11β-HSD1 reduces cortisone to active cortisol. 11β-HSD2 oxidizes cortisol to the inactive cortisone. 11β-HSD2 is strongly expressed and active in quiescent (myelinating) SCs. In proliferating SC, 11β-HSD2 exhibits a strong decrease in activity and mRNA concentration. Metabolites of progesterone affects cortisol metabolism by inhibiting 11β-HSD1 and 11β-HSD2. A metabolite of DHEA, competitively inhibits 11β-HSD1(160)(161)(162)(163).

III. The statistical suspects of LPV cause GR-cortisol distortion

The GR has been shown by microarray analysis to regulate up to 10–20% of the human genome in different cell types (164). The effect of human GR (hGR) antagonists is worrying and is likely to result in adverse effects (98). Moreover, logically the same goes for agonists of hGR. The GC function is the most important regulatory system of homeostasis (165).

Oral contraceptives --> CBG, SHBG --> GR-Cortisol

Endogenous pain modulation of experimentally induced (acute) pain is less effective in users of oral contraceptives (OCs) than in normally menstruating women (166).

OCs induce significant lower mechanical pain thresholds in the vestibular mucosa in healthy women. The most sensitive area is the posterior vestibule, the by far most common localisation of LPV. OCs might thus be one contributing factor in the development of LPV (20).

OCs increases plasma concentrations of corticoid binding globulin (CBG also called transcortin) and  sex hormone binding globulin (SHBG) in a magnitude of 50-300 percent. The CBG increase results in increased total cortisol, but unchanged free serum cortisol. However, women on oestrogens may have altered free serum cortisol kinetics and they thus may be potentially overexposed to GCs. The SHBG increase results in decrease of free testosterone and other androgens (167)(168)(169)(170)(171)(172).

CBG may regulate access of GCs to the brain and other tissues of the body. CBG is expressed in the human hypothalamus and cerebrospinal fluid. CBG functions as a protein thermocouple that is exquisitely sensitive to temperature change, releasing cortisol in response to increasing temperatures within the human physiological range (173).

Genes and CBG

Some CBG-null mice have an 10-fold increase in free corticosterone levels other have markedly reduced total circulating corticosterone at rest and in response to stress (174)(175).

In humans, a mutation in the CGB-gene is associated with hypotension and fatigue. The CBG null patients have normal free serum cortisol levels but lack a CBG-bound pool of readily releasable cortisol (168)(176). Two other genetic variants of CBG, the Leuven and Lyon mutations, reduce CBG cortisol binding affinity 3- and 4-fold, respectively (177). Chronic fatigue is co-morbid with LPV. This raises the question: are mutations in the CBG-gene a cause of LPV?

Oral contraceptives --> SHBG --> LPV

SHBG may also play a role in generating the LPV-like reduced pain thresholds found in the posterior vulvar vestibule of (otherwise) healthy OC-users. Among LPV patients using different combined contraception, those using low dose estradiol and second generation progestin have significantly lower increase in SHBG levels, that is associated with less reduced free total testosterone ratios and less sexual pain (178).

Oral contraceptives --> other steroids --> GR-cortisol

However, the main effect of OCs is to increase free estradiol and progestin (although  some will bind to the increased SHBG and CBG, respectively).

The ER-estradiol interacts with the DNA-binding transcription factor c-Jun, which promotes the nonmyelinating state of SCs. Estrogen can trigger rapid ‘‘non-genomic signalling’’ associated with the activation of second messengers as the MAPK, PKC and PI3K which can cause increased intracellular Ca(2+) and demyelination (179).

Estradiol is an antagonist of GC-induced GILZ gene expression in human uterine epithelial cells and murine uterus. GILZ gene expression is associated with several of the immune-related functions of GCs (180) - and myelination and Na(+)-homeostasis, as mentioned earlier.

17-β estradiol produces significant decreases in GR concentrations and GR mRNA levels. Chronic E(2) treatment reduce GR to very low levels. The estrogen mediated suppression is long lasting (more than 10 days after withdrawal) and can not be easily reversed. (in MCF-7 breast cancer cell line) (181).

Estrogen agonists down regulate GR through an ER-dependent increase in Mdm2 protein, an E3 ubiquitin ligase that targets the GR to the proteasome (in MCF-7 breast cancer cell line) (182).

Estrogen reduce ligand-induced GR phosphorylation, which is associated with the active form of GR, by increasing expression of protein phosphatase 5, which mediates the dephosphorylation of GR at Ser-211 (in MCF-7 breast cancer cell line) (183).

Estradiol causes a dysregulation of HPA axis negative feedback as evidenced by the inability of dexamethasone to suppress diurnal and stress-induced CORT (Cortisol in humans/corticosterone in mice and rats) and ACTH secretion. The ability of estradiol to inhibit GC negative feedback occurs specifically via ER-α acting at the level of the paraventricular nucleus of the hypothalamus (184). (The respectively referenced authors’ choice of word for the female sex hormone(s) has been used).

Antifungals ­­--> GR-cortisol --> CAR, PXR

Imidazole antimycotic drugs possess GC antagonist activity by virtue of occupancy of GC receptor sites. Dose-dependent, competitive displacement of [3H]dexamethasone binding is in the potency sequence: clotrimazole > ketoconazole > RS 49910 (185).

Ketoconazole and miconazole are antagonists of hGR and inhibits the expression of GR-responsive genes: tyrosine aminotransferase and both PXR and CAR, and further CAR and PXR target genes including cytochromes P450: CYP2B6, CYP2C9, and CYP3A4. Fluconazole has no such effects (98). CYP3A4 is involved in the hydroxylation and termination in activity of steroid hormones, especially testosterone, estrogen and cortisol (186).

Ketoconazole and erythromycin causes dramatic conformational changes upon binding to CYP3A4, a differential but substantial (>80%) increase in the active site volume, providing a structural basis for ligand promiscuity of CYP3A4 (169). Clotrimazole induces overexpression of PXR (187)(188).

Antifungals ­­--> CAR, PXR --> lipid metabolism

Three triazoles used in agriculture myclobutanil, propiconazole and triadimefon all significantly perturb the fatty acid, steroid, and xenobiotic metabolism pathways in the male rat liver. In addition, triadimefon modulate expression of genes in the liver from the sterol biosynthesis pathway. The three triazoles perturb fatty acid and steroid metabolism predominantly through the CAR and PXR signalling (189).

Antifungals --> Other steroids

Imidazoles (econazole, ketoconazole, miconazole, prochloraz) and triazoles (epoxiconazole, propiconazole, tebuconazole) all show endocrine disrupting effects. The mechanism seems to be disturbance of steroid biosynthesis. The conazoles decrease the formation of estradiol and testosterone, and increase the concentration of progesterone, indicating inhibition of enzymes involved in the conversion of progesterone to testosterone (190).

Clotrimazole --> GR-cortisol --> pain

Clotrimazole is a widely used drug for the topical treatment of vaginal yeast infections. Common side effects of topical clotrimazole application include irritation and burning pain of the skin and mucous membranes. Transient receptor potential (TRP) channels in primary sensory neurons underlie these unwanted effects of clotrimazole. The transient receptor potential (TRP) superfamily is a large group of cation channels that play a general role as cellular sensors of thermal, mechanical and chemical stimuli, and in the initiation of irritation and pain caused by such stimuli. Clotrimazole in clinically relevant concentrations is an agonist of TRPV1 and TRPA1 and a potent antagonist of TRPM8. A covalent binding of clotrimazole to the channels is unlikely (191).

Clotrimazole’s strong competitively displacement of cortisol from the GR and overactivation of both PXR and TRPV1, suggests that clotrimazole overactivates the GR, which is unlike other

–azoles that block the GR and are antagonists of TRPV1 (98)(185)(192)(193).

Undue use of medicine --> antibiotics, antifungals

When women present to physicians, yeast vaginitis is often diagnosed solely based on self-diagnosis or the patient’s history - even though an accurate diagnosis requires clinical assessment, a positive fungal culture result, and a vaginal pH assessment. Among women who use over-the-counter antifungal medications, 50% do not have yeast infections (194).

Chronic pain --> Painkillers --> GR-cortisol

Painkillers are not normally included on the list of “statistical suspects” of LPV. However, chronic pain and Hypersensibility may lead to more than normal consumption of painkillers, especially when LPV is not diagnosed. As painkillers also interfere with cortisol metabolism, they are here added to the list.

Acute adrenocorticotrophic hormone (ACTH)-mediated cortisol production in trout interrenal cells in vitro is significantly depressed (20-40%) by salicylate, ibuprofen and acetaminophen. Salicylate is the major metabolite and active component of aspirin (acetylsalicylic acid). Salicylate is a corticosteroid disruptor in trout and the targets include the key rate-limiting step in interrenal steroidogenesis and brain GC signalling (195). 

Sodium salicylate significantly enhances neuronal excitation in the hippocampal CA1 area of rats. Aspirin might impair hippocampal synaptic and neural network functions through its actions on GABAergic neurotransmission. Given the capability of aspirin to penetrate the blood-brain barrier, this implies that aspirin intake may cause network hyperactivity and be potentially harmful in susceptible subpopulations (196).

The function of Type II GC receptors is inhibited by sodium salicylate in a non- competitive way. Sodium salicylate enhances the density of Type III GC receptors. Depending on the dosage, sodium salicylate increase the number of sites of binding 3H-corticosterone to type III GCal receptors (197)(198).

(In this older nomenclature of GC receptors: type I= MR, type II= GR and Type III= CBG-like, likely to be the 11β-HSD enzymes (199)(200)).

Painkillers --> other steroids

Mild analgesic drugs have been associated with anti-androgenic effects in animal experiments. Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders. There is an association between the timing and the duration of mild analgesic use during pregnancy and the risk of cryptorchidism. These findings are supported by anti-androgenic effects in rat models leading to impaired masculinization, a reduction in the anogenital distance (201). 

Antibiotics --> GR-Cortisol

Penicillins and cephalosporins have a strong action on the most important regulatory system of homeostasis, the GC function. Penicillin G and cefazolin induce a dose-dependent increase in the density of the type III GC receptors and a decrease in the affinity of 3H-corticosterone with the type III GC receptors. The activation of the function of the type III GC receptor by penicillin G and cefazolin is not competitive. Cefazolin also increase the density of the type II GC receptors (165). A combination of trimethoprim and sulfamethoxazole induce a rapid physiological stress response, an increase in plasma cortisol and glucose, and sensitivity, which requires more than 48-h period for regaining homeostasis, in two species of fish (202). Trimethoprim and the combination with sulfamethoxazole are often used in treatment of urinary tract infections, a condition that is co-morbid with LPV (12)(203).

Antibiotics --> GR-cortisol --> NMDA --> pain

LPV and use of antibiotics against vulvovaginal infections are statistically associated (13). Neurotoxicity is common among many groups of antibiotics in at-risk patients and can range from ototoxicity, neuropathy and neuromuscular blockade to confusion, non-specific encephalopathy, seizures and status epilepticus. The underlying mechanism of neurotoxicity is in many patient-cases activation of NMDA receptors and/or inhibition of GABA-A receptors (204).

MAPKs contribute to central sensitization and neuropathic pain. A particular chain of events resulting in NMDA activation (shown in the superficial spinal cord) is:

p38 MAPK --> chemokine CCL2 --> TNF-α -->  NMDA  --> pain.

The proinflammatory cytokines, that at low concentrations (1–10 ng/ml) induce central sensitization, are tumor necrosis factor (TNF)-α , interleukin (IL)-1β and IL-6. TNF-α enhances excitatory synaptic transmission by increasing the frequency of spontaneous excitatory postsynaptic currents and the amplitude of AMPA- or NMDA-induced currents. IL-6 inhibits inhibitory synaptic transmission by reducing the frequency of spontaneous inhibitory postsynaptic currents and the amplitude of GABA- and glycine-induced currents. IL-1β can both enhance excitatory synaptic transmission and reduce inhibitory synaptic transmission (205)(206)(207).

Cortisol activates MAPK through genomic mechanisms, but also interacts with MAPK in a non-genomic way. Cortisol is known to regulate some chemokine receptors. GC-induced TNF- receptor-related protein (GITR) is - not surprisingly - induced by cortisol. Cortisol affects NMDA and GABA signalling (48)(49)(111)(112)(208).

Metronidazole, chromatin, cancer and demyelination

Metronidazole (nitroimidazole) is an antibiotic often used against vulvar infections and Crohn’s disease. Metronidazole is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in ex­perimental animals (209). Although options are limited, alternative therapies to the nitroimidazole antibiotics are available (210).

In women, there is an association between bacterial vaginosis and cervical intraepithelial neoplasia (211). Crohn’s disease is a recognized risk factor for cancer of the small intestine, with relative risks reported as high as 60. A meta-analysis showed a relative risk of 33.2 (95% CI: 15.9-60.9) (212). Patients with Crohn's disease also have an increased risk of colorectal cancer (213).  Whether the increased risk of cancer in the two patient-populations is caused by metronidazole or the two different inflammation-related diseases cannot be decided because of the “experimental setup” in this in vivo big scale test in humans.

Nitroimidazole derivatives exhibit genotoxic effects, large numbers of sister chromatid exchanges and chromosomal aberrations in cultured human lymphocytes and in the non-human primate, Cebus libidinosus. These effects are not randomly distributed, but concentrated at chromosomes rich in heterochromatin (214)(215)(216)(217).

The GR regulate the activity of many genes by binding to target sites within promoter regions of genes assembled as chromatin. Transcriptional activation is mediated by the GR remodelling of chromatin complexes (218)(219)(220). All major human cancers, in addition to having a large number of genetic alterations, exhibit prominent epigenetic abnormalities that can be used as biomarkers for the molecular diagnosis of cancer (221).

Metronidazole is associated with numerous neurologic complications, most commonly peripheral neuropathy. Case reports have been published describing motor, sensory and autonomic neuropathy. Nerve conduction studies demonstrate a peripheral neuropathy manifested by reduced sensory nerve and compound muscle action potentials. Neuropathy is typically detected in patients on chronic therapy, although it has been documented in those taking large doses for acute infections.

There are few reports on metronidazole-induced encephalopathy (222)(223).

Testosterone serum level is decreased by both high and therapeutic doses of metronidazole (224)(225)(226). In users of OCs less reduction of testosterone (by low dose estradiol OCs) is associated with less LPV-like signs and symptoms (178).

PKC, TRPV1 and the interaction between the chromatin remodeler BRG1, neuregulin-1, nuclear factor-kappaB (NF-κB) and the GR are common factors for cancer and demyelination. Recently it was found that a physical interaction in the cytosol is part of the GR- NF-κB cross-talk. (51)(78)(227)(228)(229)(230)(231)(232)(233)(234).

In conclusion/discussion: the hormone distortion, neurological complication, genotoxic, epigenetic and likely carcinogenic effects of metronidazole makes metronidazole a very likely cause of demyelination/LPV. In number of cases and rate of diagnosis, LPV is best described as the bulk of the iceberg. The underlying mechanism is likely to be malfunctions of GR-metronidazole replacing GR-cortisol functions.

Genes --> Stress, anxiety, depression

Genes associated with major depression and posttraumatic stress disorder have recently been identified (235)(236)(237)(238). A subtype of the corticotropin-releasing hormone receptor, CRHR1, has a key role in anxiety, depressive disorders and stress-associated pathologies (239).

Genes -->  Interleukin-1 --> RVVI’s

There is a genetic profile of women suffering of vulvodynia, especially genetic polymorphisms from genes coding for cytokines, IL-1 receptor antagonist (IL-1RA) and IL-1 β, and a gene coding for mannose-binding lectin (31).

The IL-1RA antagonist is a naturally occurring down-regulator of proinflammatory immune responses. In the gene coding for it, allele 2 was found homozygous in 52.9% of women with LPV, and only in 8.5 % of control women (240).

The gene coding for the IL-1RA is located on chromosome 2 in close proximity to the genes coding for IL-1 α  and IL-1β. IL-1α and IL-1β are major inducers of proinflammatory immune responses. IL-1RA is normally present in the circulation of healthy persons, whereas IL-1α and IL-1 β are not typically detectable in the absence of disease or autoimmunity. In some studies where persons homozygous for allele 2 of IL-1RA had higher circulating IL-1RA levels than did persons with other genotypes, IL-1β levels were also elevated. This resulted in the lowest IL-1RA/ IL-1β ratio and was associated with a heightened and prolonged proinflammatory immune response (241).

LPV patients with these genetic polymorphisms have a chronic unspecific inflammation and an inadequate inflammatory response, both in normal state and under infection (31).

This results in a greater frequency of candida and human papillomavirus infections and a higher frequency of allergy (242).  As mentioned in the introduction, LPV is also associated with a greater frequency of other infections. Whether these associations in part can be ascribed to genetic polymorphisms remains to be found out.

Interleukin 1 --> GR-cortisol --> kinases --> neural hyperplasia

IL-1β increases central melanocortin signalling by activating a subpopulation of proopiomelanocortin neurons in the arcuate nucleus of the hypothalamus and stimulating their release of melanocyte-stimulating hormone (243). Both IL-1α and IL-1β increase cortisol, androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate production in a human adrenocortical cell line (244). Genetic variations in the IL-1β gene contribute to the HPA axis alteration assessed by dexamethasone-suppression- test-cortisol in healthy subjects (245).

IL-1α induces activation of p38 mitogen-activated protein kinase and inhibits GR function. (246).

Corticosteroids can also be locally synthesized in various other tissues via locally expressed mediators of the hypothalamic-pituitary-adrenal (HPA) axis or renin-angiotensin system (RAS). . Local synthesis creates high corticosteroid concentrations in extra-adrenal organs, sometimes much higher than circulating concentrations. Locally synthesized GCs regulate activation of immune cells, while locally synthesized mineralocorticoids regulate blood volume and pressure (247). Both IL-1 and ACTH (adrenocorticotropic hormone) induce local cortisol synthesis in epidermis (248).

In melanocytes CRH (corticotropin-releasing hormone) stimulation of corticosteroids production is mediated by ACTH. The melanocyte response to CRH is highly organized along the same functional hierarchy as the HPA axis. This pattern demonstrates the fractal nature of the response to stress with similar activation sequence at the single-cell and whole body levels (249).

Melanocytes and SCs are derived from the multipotent population of neural crest cells,

and they are intimately interconnected far beyond previously postulated limits in that they share a common post-neural crest progenitor, i.e. the SC precursor (250). (Remember that SCs shifts to a progenitor-like state under demyelination and neural hyperplasia).

Long before any of the above was known, in 1995, Dyer et al. found: Binding of the stable melanocortin analogue Org2766 to cultured rat sciatic nerve SCs increased NGF receptors on SCs and evoked the release of neurotrophic factor(s) that synergized with NGF in stimulating neurite outgrowth. Thus SCs are a primary target for the action of melanocortins and melanocortins might stimulate neurite sprouting (251).

In a novel animal model of pruritus, induced by successive topical application of GC to mouse skin, NGF mRNA was slightly increased and remained high even after GC discontinuation. (252). GITR activation is required for the phosphorylation of ERK1 and ERK2 by NGF that is necessary for neurite growth (253).

Genes --> MBL --> GR-cortisol --> kinases --> demyelination --> pain

A single nucleotide polymorphism at codon 54 in the Mannose binding lectin (MBL) gene is associated with the development of primary LPV and a reduced capacity for TNF-α  production in response to microbial components. The MBL gene results in formation of an unstable MBL that is rapidly degraded. Thus, individuals carrying this MBL polymorphism have lowered circulating and vaginal MBL levels and they are more susceptible to a variety of infections (254).

MBL is an early complement factor that tag for innate immune recognition, which is needed for the inhibition of the primary MAPKs (ERK1/2, JNK, and particularly p38 MAPK) by naturally arising IgM antibodies. Such naturally arising IgM antibodies can suppress proinflammatory responses to purified agonists for Toll-like receptors (TLRs). The suppression of TLR-mediated MAPK signalling, correlates with, and has an absolute requirement for, the induction and nuclear localization of MAPK phosphatase-1, a prototypic counter-regulatory factor for the primary MAPKs known to mediate GC suppression of immune responses (255)

Lack of MBL thus results in insufficient stimulation of this particular GR-cortisol-controlled inhibitory pathway that can dampen pathogenic inflammatory responses. The lacking suppression of the primary MAPKs results in demyelination and mechanical allodynia (47)(108).

Recurrent vulvovaginal infections (RVVI’s) --> GR-cortisol

Bodily insults, including inflammation, pain, infection or even mental stress, lead to activation of the hypothalamic-pituitary-adrenal (HPA) axis, which stimulates the adrenal cortex to release GCs such as cortisol (256).

Farmer et al. showed that recurrent yeast infection in the mouse replicates important features of human provoked vulvodynia: mechanical allodynia and hyperinnervation localized to the vulva. Mechanical hypersensitivity persisted long after the resolution of the active infection. Long-lasting behavioural allodynia in a subset of mice was also observed after a single, extended Candida infection, as well as after repeated vulvar inflammation induced with zymosan, a mixture of fungal antigens. Only a subset of the infected mice exhibited LPV-like signs, which may indicate the importance of genetic background for the development of LPV. The other results indicate that LPV may be connected to increased immune response. The infected mice were in between infections treated with fluconazole, as were the placebo mice (28). As fluconazole does not interfere with the GR, fluconazole was an excellent choice.

Transient pre-treatment of healthy humans with cortisol induces a delayed systemic inflammatory response. This inflammatory response is maximal at an intermediate concentration, which approximates that observed in vivo following a major systemic inflammatory stimulus (257).

Both synthetic and endogenous GCs down-regulate GR mRNA level (258).

Increased expression of GRβ, which has a dominant negative effect on GRα-induced transactivation of GRE-driven promoters, could also be a possible underlying effect. However, GRβ has also intrinsic gene-specific transcriptional activity distinct from that of GRα (259)  Higher ratios of the expression level of hGRα/ hGRβ correlate with GC sensitivity, while lower ratios correlate with GC resistance (260).

SCs and the immune response

SCs express a plethora of pattern recognition receptors that allows them to recognize exogenous as well as endogenous danger signals. SCs initiate and regulate local immune responses by presenting antigens and by secreting pro- and anti-inflammatory cytokines, chemokines and neurotrophic factors, which will further attract immune cells. SCs express high levels of TLRs. By interacting with immune cells SCs contribute in shaping immune responses that can lead to inflammatory neuropathies (261)(262)(263)(264)(265).

Mast cells and SCs

The number of mast cells is increased in tender sites of the vulvar vestibule in LPV-patients compared with nontender sites and sites in control-women (29). Mast cell degranulation is accompanied by hyperalgesia, tissue edema, and neutrophils influx in the hindpaws of mice (266).

The SGK1 participates in the stimulation of Ca(2+) entry into and degranulation of mast cells (267).  Degranulation of mast cells is accompanied by release of heparanase, heparin, histamine and serotonin. SCs express both histamine and serotonin receptors (268)(269)(270)(271). Heparin is strongly alkaline. Alkaline pH causes pain sensation through activation of TRPA1 (272)(273). Mast cell-derived proteases can degrade myelin proteins, and myelin proteins or their breakdown products can potentiate further mast cell degranulation (274). Myelin debris is an important variable in the inflammatory response during demyelinating events (275)(276). The interactions of SC demyelination and mast cell degranulation may thus be highly relevant in the understanding of LPV. Further research is needed.

IV. LPV, GR-cortisol and the brain

Demyelination

Young women with relatively short-standing LPV (1 to 9 yrs) have, compared to controls, significantly higher grey (unmyelinated) matter densities in pain modulatory and stress-related areas of hippocampus and basal ganglia, which is related to lowered pain thresholds and increased pain catastrophizing scores (277).

Glutamate is released by stress and GC’s. (278)(279)(280). By a nongenomic action, GC enhances NMDA neurotoxicity through facilitating intracellular free calcium increment and attenuating the ERK1/2-mediated neuroprotective signalling (in a hippocampal neuron culture) (281).

Overactivation of ionotropic glutamate receptors in oligodendrocytes induces cytosolic Ca(2+) overload and excitotoxic death and demyelination. Intracellular Ca2+ release through ryanodine receptors contributes to this. In the white (myelinated) matter Ca(2+) influx into myelin induces myelin degradation in tissues and in vivo. Glutamate application results in paranodal myelin splitting and retraction. The break of axo-glial junctions exposes juxtaparanodal K+ channels, resulting in axonal conduction deficit (282)(283)(284).

GR-cortisol --> Neurotransmitters --> Sensitization, Hypersensibility

The GR-cortisol induced increased ERK and NMDA receptor activation is involved in stress-enhanced allodynia and enhanced central sensitization. The adult hippocampus remains sensitive to even brief exposures to cortisol (285)(286).

The central nucleus of the amygdala, CeA, has been identified as a site of nociceptive processing that is important for sensitization induced by peripheral injury. The metabotropic glutamate receptor 5 (mGluR5) is an integral component of nociceptive processing in the CeA. Pharmacological activation of mGluRs in the CeA of mice is sufficient to induce peripheral hypersensitivity in the absence of injury (287).

GR-cortisol --> Ionchannels

GR activation affects various properties of voltage-dependent Na+ and Ca2+ conductances in hippocampal CA1 neurons and in the basolateral amygdala, and thereby neuronal excitability in the cells of these areas of the brain (288)(289).

LPV (chronic pain) --> stress, anxiety, depression

More women with LPV show blunted morning awakening cortisol and report more signs of burnout, and emotional and bodily symptoms of stress compared with healthy control women of the same age (14). Vulvodynia increases the risk of both new and recurrent onset of depression and anxiety (15). Among treatment-seeking women with vulvodynia and with lifetime major depressive disorder, the majority (62.5%) reported that their first depressive episode occurred before the onset of vulvodynia (16).

GR-cortisol --> stress, anxiety, Depression

The balance between corticosteroid actions induced via activation of the MR and the GR determines the brain's response to stress. In addition to the delayed genomic role, membrane-associated nongenomic signalling of MRs and GRs play a major role for the coordination of a rapid adaptive response to stress (290)

Corticosteroids can exert maladaptive rather than adaptive effects when their actions via MRs and GRs are chronically unbalanced due to chronic stress (291).

GCs exert opposing rapid actions on glutamate and GABA release by activating divergent G protein signalling. The simultaneous rapid stimulation of nitric oxide and endocannabinoid synthesis by GCs has important implications for the impact of stress on the brain as well as on neural-immune interactions in the hypothalamus (292).

GRs are critical to the negative feedback process that inhibits additional GC release. Compared to males, female rats have fewer GRs and impaired GR translocation following chronic adolescent stress. Under conditions of chronic stress, attenuated negative feedback in females would result in hypercortisolemia, an endocrine state thought to cause depression. Sex differences in stress-related receptors thus shift females more easily into the development of mood and anxiety disorders (293).

GR function is impaired in major depression, resulting in reduced GR-mediated negative feedback (GC resistance) on the HPA axis. A lack of the 'positive' effects of cortisol on the brain, because of GC resistance, is likely to be involved in the pathogenesis of depression. (294)(295).

Chronic elevated levels of GCs down regulates the expression of mGluR5, and may thus contribute to impairments in glutamate neurotransmission in MDD (296).

Ineffective action of GC hormones on target tissues could lead to immune activation,  and GC resistance could be responsible for the enhanced vulnerability of depressed patients to develop neurodegenerative changes later in life (297).

Psychosocial environment --> Stress, anxiety, depression --> GR-cortisol

Young women exposed to an episodic stressor in the midst of chronic stress show increased cortisol output and reduced expression of GR mRNA. By contrast, when women has low levels of chronic stress, episodic events were associated with decreased cortisol output and increased GR mRNA Simultaneous exposure to episodic and chronic stress may create wear and tear on the body, whereas exposure to episodic stress in the context of a supportive environment may toughen the body, protecting it against subsequent stressors (298).

Strictly healthy caregivers of Alzheimer’s disease patients are significantly more stressed, anxious and depressed, but have similar cortisol levels, reduced DHEAS levels, increased cortisol/ DHEAS ratio, impaired HPA axis response to DEX intake, higher T cell proliferation and increased sensitivity to GCs compared to age-matched controls (299).

V. Conclusion and consequences

Conclusion: Although the evidence presented here might be considered circumstantial, the conviction must be:

Conclusion: LPV is caused by distortion of cortisol metabolism primarily in SCs, which causes demyelination and  increased immune response. Demyelination cause innervation of the epithelium and, via neurotransmitters and ionchannels, chronic pain. Interactions between the HPA-axis and the nerve- and immune systems make LPV a systemic condition also affecting the brain.

LPV is a mechanical allodynia. There is evidence, that demyelination cause mechanical allodynia. There is evidence of neural hyperplasia in LPV. There is evidence, that demyelination causes neural hyperplasia. There is evidence, that several GR-cortisol controlled factors cause both neural hyperplasia and demyelination. There is evidence, that LPV patients have experienced GR-cortisol distortions through the factors statistically associated with LPV.

LPV is caused by increased cortisol and/or decreased GR-function, simultaneously or consecutively. All the statistically suspected causes of LPV leads to increase of cortisol and decreased GR function. OCs increase cortisol through increase in CBG, and decrease GR function through ER-estradiol antagonism towards the GR. Repeated or major infections increase cortisol, which by it self leads to decreased GR expression. GCs, and some antifungals and antibiotics increase cortisol (/GC) level and reduce or inhibit GR function. While clotrimazole likely overactivates the GR, metronidazole likely malfunctions as a ligand for GR resulting in gentoxity and possibly cancer, and therefore both are likely causes of LPV.

The IL genetic polymorphism increase IL, which is associated with chronic elevated immune response, increased cortisol and decreased GR function. The MBL genetic polymorphism interrupts a specific immune response controlled by GR-cortisol, which via MAPKs cause in demyelination. Stress, anxiety and depression are also connected to high cortisol and/or impaired GR-function and demyelination.

LPV is caused by demyelination. Increased cortisol leads to increased expression of TRPV1, NMDA and increased intracellular calcium in glial cells, neuronal cells and in myelin itself, which leads to demyelination in the PNS and in stress related parts of the brain. Impaired GR function leads to lower GILZ, which affects the immune system, Na (+)-homeostasis and myelination. Demyelination and increased intracellular calcium makes sensory neuronal cells transmit pain signals instead of sensory signals.

Significance and consequences

Many million women now know why they suffer – provided the message is spread. This text is of course far from the full and final explanation of LPV, but it may be a beginning to that. Prevention, treatment of, and research in LPV can now take a direction and may advance in giant leaps for womankind.

The use of the different existing antifungals and antibiotics should be reconsidered in accordance with their hormone-disturbing effects. These effects should be fully clarified, and absence of such effects should be targeted in development and approval of new antifungals and antibiotics.

OCs, that do not have hormone-disturbing effects, are on the other hand at present hard to imagine. Nevertheless, these effects should be minimised, and these effects should be better known by research, doctors and users. Finally, the use of GCs should be reconsidered.

The research results presented here, and their combination, are not specific to LPV or vulvodynia, but may be relevant to many other illnesses: of course, those found co-morbid with LPV, but also other allodynias or even neuropathic pains in general, other diseases of mucous membranes, HPA-axis and myelin. – All the more reason to minimise the distortion of GR-cortisol (and other steroids and their receptors) caused by medicine. Use of alternatives to metronidazole and clotrimazole in the treatment of vulvovaginal infections would be a logical first step in this many-mile walk. 

Comments can be made and read below the references.

References

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