Thursday, April 3, 2014

Progesterone and Nerve Pain

Progesterone is not only involved in reproductive organs, but it also is important in nerves. Progesterone is a neurosteroid, which means it is also produced in the brain. In studies it has shown to be actively involved in the protection and healing of nerves. So much so, it is being investigated as treatment for multiple sclerosis and stroke!! (see below)

How does this affect endometriosis?

We have talked before about endometriosis and nerve pain. I think this explains it simply:

"Endometriosis acts a pain generator through multiple mechanisms. Endometriosis can cause a significant amount of inflammation. This inflammation can result in scarring and nerve damage. It is this scarring and nerve damage that leads to stimulation of the spinal cord and ultimately the brain to detect continuous pain signals. When this becomes long term and severe phenomena such spinal wind up and neuroplasticity occur leading to difficult to treat chronic pain."

"Some of the most painful endometriosis lesions are those that invade the pelvic nerves.
For example, endometriosis of the pudendal nerve (PN) can cause severe neuralgia (nerve pain) in those places that are innervated by this nerve, such as the anus, labia, perineum, rectum, vaginal area, and urethra, just to name a few. However, the pain may radiate beyond these areas.  Reported symptoms include stabbing pain, numbness, bowel symptoms, and painful intercourse. Endometriosis of the PN is often mistaken for other conditions, such as pelvic floor disorders, interstitial cystitis, and musculoskeletal disorders. Endometriosis that affects the obturator nerve, which crosses through the pelvic region and innervates the inner thighs, can cause pain that radiates down the leg or toward the groin area or hips. Another way that endometriosis can cause leg pain is when it affects the pudendal nerve, which innervates the lower vagina and external female genitalia. As with the obturator nerve, any areas connected to the pudendal nerve can become painful due to the endometriotic lesions. Endometriosis has also been found traveling along the obturator nerve to the adductor compartment of the thigh (P Waer, et al, Japan Journal of Radiology, 2012), which can cause pain in the hips and thighs."

"Deeply infiltrating endometriosis (DIE) is endometriosis that has penetrated deeper than 5
mm under the peritoneum ( a layer of tissue lining the abdominal cavity). Tissue that penetrates deeper than 10mm is linked with severe menstrual or pelvic pain( Cornillie F, 1990)....Samples/biopsies of this deep tissue contain nerve fibres and inflammatory cells in and around the implants.These findings may explain why deep implants cause pain (Wang G, 2009)."

So we see that endometriosis can cause nerve damage and excite nerves that can lead to long term nerve pain. Progesterone has been shown to help repair nerve damage, so can progesterone help decrease nerve related pain due to endometriosis?

"The steroid hormones produced in the brain include progesterone, and in particular various compounds closely related to progesterone. The manner in which they take effect is basically different from that of progesterone itself, classically affecting the progesterone receptor on the DNA inside the cell core. The Neurosteroids influence neurohormonal transmission from certain nerve cells to their subordinate nerve cells....Numerous different neurotransmitters are present in the central nervous system. One of these is gamma amino butyric acid (GABA). This molecule bonds with receptors serving as a sluice for chloride ions. Bonding with GABA opens the »sluice gates«, so that the chloride ions can stream into the plasma of the nerve cell. This induces a rise in the excitement threshold of the nerve cell. It is also explains the known calming and anxiety-reducing effect of progesterone (Fig. 10). Progesterone calms anxiety at nerve cell contacts (synapses): Neurosteroids, such as progesterone bond with certain GABA receptors, thereby enhancing the effect of GABA. This consists in channelling chloride ions into the subordinate nerve cell, thereby raising its excitement threshold. The result is a calming effect."

"Progesterone is emerging as an important protective agent against various injuries to the nervous system. Neuroprotective and remyelinating effects have been documented for this neurosteroid, which is synthesized by, and acts on, the central and peripheral nervous systems. Neuropathic pain is a severe, persistent condition that is generally resistant to treatment, and poses major personal, social, and economic burdens. The purpose of this study was to determine if single-dose or repeated progesterone administration would alleviate tactile hypersensitivity in a rat model of neuropathic pain, and to determine if early versus late initiation of treatment has an effect on the outcome.
...These results indicate that progesterone, when administered immediately after nerve injury, and for a sufficient period of time, can prevent the development of neuropathic pain, and may offer new strategies for the treatment of this highly debilitating condition."

" In a small pilot study of patients with central intractable pain reported at the 2012 American Academy of Pain Medicine Annual Meeting, progesterone was shown to have regenerative or ameliorative effects.

"Forest S. Tennant, MD, DrPH, of Veract Intractable Pain Clinic, West Covina, CA, studied 34 patients (23 women, 13 men) between the ages of 29–69 years with high levels of pain. These subjects were noted to have low serum levels of allopregnanolone, the metabolite of progesterone. Animal studies have shown that progesterone has a regenerative effect on neural tissue.1,2 To determine if progesterone has a similar effect in humans, Dr. Tennant evaluated the efficacy of administration of oral or topical medroxyprogesterone to patients with presumed central, intractable pain who had been maintained on opioids ranging from three to twenty-five years.
Prior to the study, patients had constant pain for at least three years, a history of periodic allodynia and hyperalgesia, had failed multiple peripheral-pain treatments, demonstrated excess sympathetic discharge signs (e.g., tachycardia, hypertension, diaphoresis, mydriasis, vasoconstriction, hyperreflexia), and insomnia. All patients also were on ≥1 concomitant medications: bedtime sedative, neuropathic agent, stimulant, anti-inflammatory agent, antidepressant, or anxiolytic.
The patients were given medroxyprogesterone 10mg orally twice a day or 20mg/1mL topically ≥1 time a day. Patients receiving oral medroxyprogesterone could be titrated to 40mg/day if needed. If there was no response to medroxyprogesterone after 60 days, the therapy was discontinued.
After two months, 65% of patients reported that they felt better and wished to continue medroxyprogesterone. Patients reported feeling less pain and suffering or more happiness (71%); increased energy and more involvement in social activities (64%); improved memory, concentration, or reading ability (50%); less depression (43%), reduced need for polypharmacy (33%), and improved sleep or libido (21%).

"Given the results of this small study suggesting that progesterone may have a regenerative or ameliorative effect on central, intractable pain, Dr. Tennant feels that further clinical trials are warranted. He states that “medroxyprogesterone was selected as a convenient, commercial preparation, but there may be more optimal progesterone agents or administration systems than those employed here."

"These results suggest that progesterone produces antinociceptive effects through neuroprotective action in animals with LPA-induced trigeminal neuropathic pain. Moreover, progesterone has potential utility as a novel therapy for trigeminal neuropathic pain relief at an appropriate managed dose and is therefore a possible future treatment strategy for improving the recovery from injury....It is well known that the progesterone synthesized by neurons and glial cells plays an important role in neuroprotection and myelination as a neurosteroid. A particularly noteworthy property of progesterone is that it not only provides strong neuroprotection but also promotes myelin formation, either during development or during the remyelination of axons in adults....The neuroprotective effects of progesterone have been extensively studied in the rat spinal cord injury model or in the Wobbler mouse, a model of spontaneous motor neuron degeneration [33]. Progesterone also exerts protective effects on axonal pathology in experimental autoimmune encephalomyelitis, a multiple sclerosis animal model that manifests spinal cord demyelination [34]. The marked protective effects of progesterone on spinal motor neurons involve the up-regulation of brain-derived neurotrophic factor (BDNF), a key regulator of neuronal and glial functions [35]. Exogenous progesterone also enhances the concentrations of P0 and PMP22 proteins in co-cultures of dorsal root ganglion (DRG) neurons and Schwann cells [36] and stimulates the expression of their gene promoters in cultured rat Schwann cells [37]. These previous results suggest that progesterone plays an important role either in signaling the initiation of myelination or in enhancing the rate of myelin synthesis after lesion formation [38-41]....Progesterone is an excellent candidate molecule for neuroprotection and myelin repair, because it easily crosses the blood-brain barrier and exerts concerted beneficial influences on multiple processes [42]. The roles of the classical progesterone and non-classical GABA (A) receptors have been reported previously via observations in sciatic nerve and/or Schwann cells in the presence of these receptors [43]....Our present data demonstrate that a daily administration of progesterone produces a significant anti-allodynic effect. Interestingly, delayed and prolonged significant anti-allodynic effects were observed after the final administration of progesterone in our rat model. These results suggest that treatment with progesterone produces not only early anti-nociception but also delayed and prolonged anti-nociception....Our present findings also demonstrate that daily treatments with progesterone produce significant anti-allodynic effects in the rats with LPA-induced demyelination without any motor impairment. Moreover, our current analyses further demonstrate that progesterone treatment significantly recovers the demyelination produced by LPA injection. Although our data do not indicate a direct interrelationship between a blockade of demyelination and antinociception, progesterone treatment seems to produce antinociception either by preventing demyelination or by promoting remyelination in our LPA-induced trigeminal neuropathic pain model. Hence, new strategies for developing treatments against trigeminal neuralgia like nociception, which simultaneously potentiate axonal regeneration, promote remyelination, or the recovery of nerve functions, are needed."

"...neuroendocrine research over the past decades has established that progesterone has multiple functions beyond reproduction....There are also major advantages to use natural progesterone in neuroprotective and myelin repair strategies, because progesterone is converted to biologically active metabolites in nervous tissues and interacts with multiple target proteins.... Progesterone in the brain is derived from the steroidogenic endocrine glands or from local synthesis by neural cells. Stimulating the formation of endogenous progesterone is currently explored as an alternative strategy for neuroprotection, axonal regeneration, and myelin repair.... progesterone is also a neurosteroid, which means that it is also synthesized within the nervous system. Thus, in addition to its endocrine mode of signaling, it acts on neural target cells via autocrine/paracrine mechanisms....Over the past few years, evidence has accumulated that progesterone and its metabolites are also synthesized in the human nervous system...That estradiol can potentiate the promyelinating effect of progesterone has recently been shown in an experimental model of cuprizone-induced demyelination....These observations strongly suggest that progestagens may protect oligodendrocytes and promote myelin repair by acting in concert with estrogens, and.... In a they point to an increased efficacy of combined progestagen and estrogen administration for treating demyelinating conditions... in addition, the cooperation between progesterone and estradiol may indirectly exert beneficial influences on myelin repair by regulating energy supply and neuroinflammatory responses via astrocytes.... A strong indirect argument in favor of hormonal influences on multiple sclerosis is provided by the observed sex differences in the incidence and course of the disease, and by the pregnancy-associated changes in the relapse rate. Thus, according to a cross-sectional study conducted in France, the women–men ratio of multiple sclerosis is 2.6 (Fromont et al., ). Intriguingly, the gap between sexes in the incidence of the disease has increased over the last decades (Noonan et al., ; Bentzen et al., ). The course of multiple sclerosis is noticeably influenced by pregnancy. Thus, the rate of relapses is reduced during the last 3 months of pregnancy, when circulating levels of progesterone and estrogens are highest, but it is markedly increased during the first 3 months post-partum, after a drop in sex steroid levels...Treatment with a progestin is obviously an option for women with multiple sclerosis, as in the ongoing Popart’mus trial...Natural progesterone, tested in most experimental preclinical studies, may also offer a wider range of benefits than the more selective progestins. Indeed, progesterone exerts multiple beneficial effects on the nervous system, which may not be mimicked all by synthetic compounds. First, some of the effects of progesterone in the nervous system, including its neuroprotective and psychopharmacological actions, are mediated by its neuroactive metabolites, and in particular by allopregnanolone...Progesterone present in the brain is either derived from the steroidogenic endocrine glands or form local synthesis. From this concept derives another therapeutic option for treating degenerative diseases and lesions of the nervous system: stimulating the synthesis of endogenous progesterone and its metabolites in the brain....In conclusion, multiple therapeutic approaches remain to be further explored for promoting myelin repair with progestagens in demyelinating diseases or after injury. The administration of synthetic progestins and natural progesterone are both interesting options. An important question is their mode of administration. Nasal application, easy to implement for efficient delivery of progesterone into the brain, deserves particular attention. Because natural progesterone is converted in the brain to neuroactive metabolites, and because the hormone targets multiple signaling mechanisms, its future use for the treatment of demyelinating diseases, and other neurological disorders should be considered. Stimulating the production of endogenous neuroprogesterone in the nervous system with TSPO ligands offers new perspectives for remyelinating and neuroprotective interventions."

"Neuroscientist Dr. Donald G. Stein and his colleagues have been investigating this question and have discovered something remarkable -- that the hormone progesterone confers profound neuroprotective effects that improve outcomes and reduce mortality following brain injuries.
Progesterone provides powerful neuroprotection to the fetus, particularly in late pregnancy, when it helps suppress neuronal excitation that can damage delicate new brain tissue. Dr. Stein and his colleagues have found that in addition to protecting the fetal brain, progesterone also protects and heals injured brain tissue....In a clinical trial known as ProTECT II, one hundred patients with moderate to severe traumatic brain injury were randomly assigned to receive standard treatment for head injury, or identical standard treatment plus three days of intravenous progesterone. The levels of progesterone administered equated to about triple the natural levels seen at the end of pregnancy.  Normally, the average mortality rate for the types of severe brain injury seen in participants of this study is about 30-33 percent, with conventional treatment.  However, the group treated with progesterone had a mortality rate of only 13 percent – a more than 50 percent reduction in mortality rate compared to those receiving standard treatment!"

"In females, progesterone levels naturally start to decline around age 30 [Source: Hargrove]. The progesterone that the body makes is slightly different than the “progestins” found in standard medical hormone replacement regimens. This slight change is considered by many to be enough to demonstrate the problems discovered by the Women’s Health Initiative, such as increased heart disease and cancer [Source: Rossouw]. Perhaps the most successful progesterone treatment comes from using bioidentical hormones, progesterone that is a better match to the body’s own hormone.
For relief from PMS or menopause-related headaches, a cream form of progesterone can be applied at the start of the pain. Progesterone has clinically been used 7-14 days prior to the onset of menses to lessen PMS symptoms of bloating, cramping and irritability. Progesterone used in capsule form, clinically, helped those patients who experienced difficulty sleeping. Progesterone has been effective in alleviating hot flashes for many women as well [Source: Leonettie]....Other data has shown bioidentical progesterone has a protective effect against cell proliferation, or overgrowth..."

"During pregnancy, ovulation stops. The endometriosis generally become less active, and may get smaller and less tender. This seems to be the result of the hormonal changes pregnancy brings. These include high levels of progesterone, the presence of HCG (human chorionic gonadatropin) and prolactin, among others."

So we see that progesterone is showing promise as a treatment for neurological disorders but I have not found any specific studies on using it to help nerve pain associated with endometriosis. Hormones to lower estrogen are used to treat endometriosis but we must keep in mind that they work temporarily and come with many side effects and sometimes permanent damage to our systems. Also as is noted in one of the studies above, the combination of estrogen and progesterone have a higher beneficial effect for nerves. And also noted above, there is far more benefits seen with bioidentical progesterone as compared to synthetic progestins. Complete removal of endometriosis lesions, especially as early as possible before more damage is done, is optimal treatment for endometriosis itself. However if you have nerve pain from having endometriosis or multiple surgeries, progesterone may show promise as a treatment.

"Drugs can be used to affect the amount of estrogen stimulation the endometriosis receives. Theoretically, the less stimulation the tissue receives, the less cell activity occurs in the lesions. This, in turn, slows the rate of progression and the amount of local injury. The price you pay is in side effects from the medicine, the cost of the drugs, and the fact that the endometriosis is still there...."

"Progesterone is usually given in a long-acting depot form via injection (depo-provera). Progesterone can also prevent ovulation and reduce circulating estrogen levels. Side effects include irregular bleeding, bloating, weight gain, and more. Expense is reasonable. In Dr. Albee’s and the CEC’s opinion, depo-provera is not a good choice for women who have not completed their childbearing. A small percentage of women who take depo-provera never ovulate again.GNRH analogs (Synarel, Lupron, Zoladex and Danocrine) are drugs that stop virtually all ovarian activity (hormone production and ovulation). The results are very similar to menopause, with some differences in the FSH and LH levels. This class of drugs is very effective in reducing activity of the endometriosis, but they are extremely expensive. They also cause significant side effects, including hot flashes, palpitations, headache, sleep disturbances, vaginal dryness, depression, decreased libido, bone demineralization, weight gain, mood swings, and much more.  These drugs do not cure endometriosis, and we do not prescribe them, only in a few specific circumstances. Aromatase Inhibitors, anti-estrogens, and SERMS (selective estrogen receptor modulators) are other forms of suppressive therapy which use different means to reduce the estrogenic (hormonal) stimulation of endometriosis. None are commonly used for a variety of different reasons which include unproven effectiveness, significant side effects, and/or significant cost...."

Bonus note:

"Neurosteroidogenic agents that lack benzodiazepine-like side effects show promise in the treatment of anxiety and depression."

"Nerve damage can lead to intractable nerve pain, such as vulvodynia (vulvar pain), coccygodynia (tailbone pain), pudendal nerve pain (pain in the pubic area), and sciatica (pain in the buttocks, back and legs). In neuropelveology, not only gynecological and urological factors but also neurological factors that may cause pelvic nerve disorders are considered in the diagnosis....There is a dichotomy of knowledge, with gynecologists on the one side, who are not trained in neurology and do not have a good knowledge of the anatomy of the pelvic nerves, and neurosurgeons and neurotramatologists, who are not trained in pelvic surgery – particularly laparoscopic pelvic surgery – and are not very knowledgeable about gynecological diseases on the other. Neuropathic pelvic pain is mainly treated with medication, especially if secondary to surgery. This situation definitely needs to change because laparoscopy offers safe and reproducible access to all of the pelvic nerves in a form not achievable in conventional open surgery. Through advances in video endoscopy, improvements in laparoscopic and microsurgical instruments, and the introduction of laparoscopic electrostimulation of the pelvic nerves (also known as Laparoscopic Neuro-Navigation, LANN), laparoscopy has become an indispensable tool for diagnosing and treating the causes of chronic neuropathic pelvic pain, for example, by laparoscopically performing classical neurosurgical procedures such as nerve decompression surgery. Nerve stimulation through the laparoscopic implantation of neuroprostheses (electrodes) is also possible; this is referred to as the “LION procedure”....Diseases of the nerves are rarely cited as causes of pain although the nerves are the target of all pharmacotherapeutic approaches to pain management. Traditionally, a doctor learns to seek the cause of disease at the site where the pain occurs. In the case of neuropathic pain (nerve pain), the cause of pain is not generally the nerve but something else located further along the path from the nerves to the brain....The site of origin of pain, pain radiation, factors that worsen or improve the pain, and accompanying symptoms are also important criteria. Autonomic pain is described as dull pain arising from deep within the pelvis. It frequently radiates to the lower back and buttocks and is accompanied by autonomic symptoms such as headache, nausea and general malaise. Pain caused by pelvic nerve damage, on the other hand, is perceived as localized burning pain that is transmitted from a precisely identifiable location to the corresponding nerve dermatome (area of skin supplied by a nerve). If accessible by vaginal or rectal examination, the doctor can test the pelvic nerves by palpation (tapping on them). In the affected patients, palpation induces acute pain that radiates over the distribution of the nerve (Tinel’s sign). The sciatic nerve cannot be accessed by vaginal examination, whereas sacral nerve roots S2–S4 and the pudendal nerve are easy to locate via the vaginal route.
Pelvic nerve injuries may occur due to compression, irritation or entrapment, resulting in neuropathic pain disorders and pelvic organ dysfunction (bladder, bowel and sexual dysfunctions). The most common neuropathic pain disorders are:
  • Sciatica
  • Lower back pain and lower abdominal pain
  • Pudendal neuralgia (pudendal nerve pain, pain in the pubic area)
  • Pain in the buttocks
  • Pain in the coccygeal region (coccygodynia, tailbone pain)
  • Pain in the genital area (vulvar and vaginal pain in women / prostate pain, chronic prostatitis, testicular pain and penile pain in men)
...Phantom pain may ultimately develop. Phantom limb pain after amputation is a well known phenomenon. For example, leg amputees may experience pain in the absent foot because the nerves that normally relay information from the foot to the brain are still intact even though the leg is amputated.
The main causes of nerve damage are as follows:
      Surgical nerve damage (especially after cancer, endometriosis or uterine prolapse surgery in the pelvis)
  • Endometriosis of the pelvic nerves, especially the sciatic nerve
  • Compression or entrapment of pelvic nerves by enlarged pelvic blood vessels
  • Rare tumors of the pelvis, including schwannoma, chondrosarcoma of the sacral bone and sacral teratoma
  • Other causes – including diabetes, autoimmune disorders and idiopathic neuropathy (nerve pain with no apparent cause) – are much less common. Inflammatory diseases, autoimmune diseases, diabetic neuropathy, herpes-related neuralgia and multiple sclerosis are some of the possible causes of chronic neuropathic pelvic pain.

    "A nervous system disorder must be suspected in any woman presenting with vulvar or vaginal pain in combination with headache, irritable bowel syndrome, interstitial cystitis, fibromyalgia, chronic fatigue syndrome, back pain and/or jaw problems. Various studies have shown an increased incidence of anxiety, stress and depression in women suffering from vulvodynia. These accompanying symptoms are especially helpful for diagnosing a neurological cause of pain....Visceral pain occurring secondary to (radical) hysterectomy or surgical removal of the parametrium (pelvic connective tissue) is caused by damage to a network of nerves called the inferior hypogastric plexus. The affected individuals experience “phantom pelvic pain”, which is caused by neuroma formation (new tissue growth on the damaged nerves) and produces symptoms similar to those of phantom limb or stump pain after limb amputation."