Philippa Bridge-Cook, PhD

Philippa is a scientist and writer currently working as a medical writing consultant and as the Executive Director of The Endometriosis Network Canada, a non-profit organization whose mission is to provide education, awareness, support, and hope to people affected by endometriosis. Philippa has previously worked in molecular diagnostics at Luminex in Toronto, Canada. Philippa's academic experience includes a Ph.D. in Medical Genetics and Microbiology from the University of Toronto.

Bladder Pain Syndrome – Interstitial Cystitis

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Symptoms of pain related to the bladder, urinary urgency and/or frequency affect up to 12 million Americans and can range from uncomfortable to extremely debilitating. These symptoms can affect both men and women, although they are more common in women. Although these symptoms can be difficult to treat because there is no particular treatment that works for a majority of individuals, a range of treatment options do exist. With patient, physician, and sometimes other healthcare providers working together to explore options, relief from bladder symptoms can be achieved.

Symptoms of bladder pain syndrome – interstitial cystitis include recurring pelvic pain, pressure or discomfort. Pain may worsen with specific food or drinks, and with bladder filling. Pain can be specifically located in the bladder, urethra, or vagina, and/or more generally present in the lower abdomen, pelvis, and lower back. Pain with sexual intercourse is a common symptom. Urinary frequency (the need to urinate frequently) is often present and can be extreme, with some patients needing to urinate up to 60 times per day. Urinary urgency (a strong need to urinate) can also be present. This can also be accompanied by spasms.

Interstitial cystitis, the original name for this disease, had fairly strict diagnostic criteria that did not encompass all patients with this similar set of bladder symptoms, so other names have been proposed including painful bladder syndrome (PBS), bladder pain syndrome (BPS), and hypersensitive bladder syndrome. Some doctors now use the name interstitial cystitis to encompass all patients with bladder pain symptoms not from other causes (such as infection), and some doctors use the newer nomenclature such as bladder pain syndrome. Some doctors use the term interstitial cystitis to refer only to a subset of patients who have ulcerations in the wall of the bladder called Hunner’s ulcers. These differences can be confusing to patients.

Diagnosis of BPS can be challenging, since patients can present with a wide variety of symptoms, and the symptoms often overlap with other pelvic diseases such as endometriosis and adenomyosis. BPS is usually diagnosed through the clinical signs and symptoms of the patient, and by ruling out other conditions such as bladder infection and bladder cancer. In the past, cystoscopy with hydrodistention (slowing filling the bladder with fluid, then looking at the bladder wall using a camera scope), and the potassium sensitivity test, have been used to diagnose BPS, but these tests are no longer recommended because they can trigger additional pain in patients, and they are sometimes negative even in the presence of disease.

There is no cure for BPS, and treatments are directed at symptom control. The American Urological Association (AUA) recommends trying treatments in order from least invasive to most invasive. Treatments required for any individual may vary over the course of time, and sometimes multiple treatments at once may be used. The first line of treatments include education about normal bladder function, and self-care strategies to help manage bladder pain. An important self-care strategy for many BPS patients is to avoid dietary food triggers. There are some foods such as citrus, vinegar, tomatoes and coffee that are common triggers in individuals whose bladder pain is affected by diet; however, it is important to identify your own individualized food triggers, since they may be different for different individuals.

The second line treatments recommended by the AUA include manual physical therapy, and certain medications– both oral medications, and medications delivered via catheter to the bladder. Manual physical therapy should be performed by a pelvic floor physical therapist trained in manual therapy techniques, and Kegel exercises should be avoided. Oral medications include amitriptyline (an antidepressant sometimes used to treat pain), and antihistamines. Intravesical medications (delivered by catheter to the bladder directly) include heparin, lidocaine, and DMSO.

Third line treatments become more invasive, and include cystoscopy with hydrodistention, and surgical treatment of Hunner’s ulcers if found. Fourth line treatments include surgically implanted electrical nerve stimulators. Additional treatment possibilities include cyclosporine (an immunosuppressive drug), Botox injections, and surgery to remove the bladder. These options can have significant side effects and complications, so they are only undertaken when no other treatment strategies have worked. Pain management strategies should be used at all stages of treatment, and include over the counter and prescription painkillers, as well as stress management techniques and physical therapy.

Individuals with BPS may be more likely to have certain other diseases as well. It is highly associated with endometriosis, with some studies suggesting that up to 80 percent of patients with endometriosis also have BPS/IC. Individuals with allergies, migraines, or asthma may have a greater chance of developing BPS/IC. BPS/IC is also strongly associated with irritable bowel syndrome, and is also associated with vulvodynia, fibromyalgia, chronic fatigue syndrome, and lupus.

Recent research indicates that different pain syndromes often occur together in the same patient, often as well as other systemic diseases. As the relationships between various pain syndromes and different diseases become better understood, this may lead to new and better treatment options that are able to treat the whole individual rather than trying to treat each separate syndrome, in patients who have multiple diseases. One common frustration in patients with multiple diseases is that each specialist only looks at and treats their own clinical area, and then patients themselves have to coordinate care between specialists and different approaches, which may sometimes even conflict with each other. Many patients would welcome the change to treat and understand their body as one system, with the help of specialist health care providers who understand the relationships between different diseases and different parts of the body. Unfortunately, this type of integrated care delivery is currently only available to patients with certain life-threatening conditions such as cancer or heart disease, and only in the most advanced hospital systems. For now, patients with BPS/IC have to take charge of managing their own way through their treatment options.

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Why Lupron is a Poor Diagnostic Tool for Endometriosis

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In my work with The Endometriosis Network Canada, I have heard many women say that their doctors told them that if their pain does not go away on Lupron, then the pain must not be from endometriosis. Lupron never has and never will be an effective tool for diagnosing whether pain is due to endometriosis. Not only does Lupron have the potential for significant side effects, which alone should abrogate its use as a diagnostic tool, but it also is not at all effective at diagnosing endometriosis and distinguishing it from other conditions.

Lupron is a synthetic version of a naturally occurring hormone called gonadotropin-releasing hormone, and its action is actually stronger than the naturally occurring GnRH. It is a long-acting medication that initially stimulates hormones in the pituitary gland that control the menstrual cycle, and then suppresses these functions. It is typically given as a 1 month or 3 month injection.

Lupron Side Effects

Lupron therapy is associated with a significant potential for side effects. One of the biggest problems with Lupron is its effect on bone density (it can decrease bone density), and this effect is not always completely reversible after Lupron is discontinued. Lupron can also cause joint pain, which in some cases is permanent. Other potential side effects include hot flashes, vaginal dryness, headaches, mood swings, decreased interest in sex, depression (in some cases severe), cognitive problems, fatigue, acne, headaches, and upset stomach. Personal stories of women’s experiences of the downside of Lupron can be found here, here, here, here, and here.

Given all of these side effects, you might be wondering: why would anyone subject themselves to the potential for at best, a month of these side effects, and at worst, a lifetime of some of them, for the purpose of diagnosis? Even from the side effect perspective, using Lupron to try to diagnose endometriosis seems like a bad idea. But now we come to the more technical part of the discussion, which will address whether Lupron could even work as a diagnostic tool for endometriosis.

How to Evaluate a Diagnostic Tool

To evaluate the effectiveness of a diagnostic tool, the two measures that are used are called sensitivity and specificity. Sensitivity addresses the question of how often the diagnostic tool will pick up the disease, in people who have that disease. Specificity addresses the question of how often the test will be positive in people who actually do not have the disease (but may have conditions other than the one you are testing for). A good diagnostic test will pick up the presence of the condition in most people who have it, while not testing positive in people who may have similar symptoms but have a different disease. In other words, a good diagnostic test will have fairly high sensitivity and specificity.

All devices or tests that are approved by regulatory agencies as diagnostics have to undergo testing to demonstrate sufficient sensitivity and specificity. Lupron has not undergone such testing, because it was not developed as a diagnostic, and is not meant to be used as one. However, given the clinical trials that were done looking at the effectiveness of Lupron as a drug therapy, it is clear that the sensitivity and specificity of it as a diagnostic would not support its use in that way.

Lupron as a Diagnostic?

The clinical trial data published by the manufacturer in its prescribing information can be illuminating when considering its sensitivity and specificity for diagnosing endometriosis. The clinical trials used several measures to assess response to the drug, such as pelvic pain, dyspareunia (pain with intercourse), dysmenorrhea (pain with periods), and pelvic tenderness. The results showed that Lupron was by far the most effective at treating dysmenorrhea, compared to the other symptoms. Almost 90 percent of study participants had dysmenorrhea before taking Lupron, and after 6 months of treatment, fewer than 10 percent still had dysmenorrhea. (Not surprisingly, within 6 months after completing treatment, about 80 percent had dysmenorrhea again.) Looking at endometriosis symptoms other than pelvic pain, about 75 percent of study participants had pelvic pain at the start of the study, and 45 percent still had pelvic pain at the end. Lupron was similarly less effective at treating other symptoms of endometriosis.

From these results, we can get an idea of what the sensitivity of Lupron as a diagnostic would be. Imagine giving Lupron to a group of women with endometriosis, whose symptoms will vary from primarily dysmenorrhea, to all different types of pelvic pain at different times (or in some cases, all times) of the menstrual cycle. Those who have primarily dysmenorrhea will feel that their pain has been treated, whereas, because it is less effective on all other types of pain and symptoms, some women may feel that their pain did not decrease at all (remember, 45 percent of women still had pelvic pain after 6 months of Lupron). This is why it is completely incorrect for any doctor to say that if a woman’s pain did not decrease on Lupron, the pain cannot be from endometriosis. Therefore, the sensitivity of Lupron as a diagnostic for endometriosis is predicted to be poor, because in a significant number of women who actually do have endometriosis, it will not treat their pain substantially.

The specificity of Lupron as a diagnostic would be even worse. Clearly Lupron is effective at treating dysmenorrhea, because by its very mechanism of action it puts a woman into chemically-induced menopause, and you cannot have dysmenorrhea when you are not having periods. However, there are many causes of dysmenorrhea other than endometriosis. So even if Lupron does work to treat a woman’s pain (by preventing periods), this does not ensure that the cause of the pain was endometriosis.

A Call for More Research

There is no doubt that women would benefit greatly from a non-invasive diagnostic test for endometriosis, given that surgery is currently the only way to definitively diagnose it. However, Lupron is not sensitive or specific enough to be useful diagnostically. New diagnostic tests have been developed for many other diseases using recent advances in technology such as imaging methods, blood biomarkers, next generation sequencing, and others. A sensitive and specific diagnostic test for endometriosis is desperately needed. However, with so little funding going to basic and applied research into endometriosis, it is unlikely that this need will be met until this funding situation improves. As Siddhartha Mukherjee said about cancer in his book The Emperor of All Maladies:

“A disease needed to be transformed politically before it could be transformed scientifically.”

This is the situation that cancer research was in, during the 1940s, and sadly this is where we are at now, with endometriosis, a disease that affects one in ten women and has for centuries, in 2016.

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Bleeding Disorders Overlooked in Women with Heavy Periods

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Four years ago, when the heavy period bleeding which I’d had since adolescence suddenly became much worse, I never would have predicted that the cause of the bleeding would not be correctly diagnosed and treated until after I’d had an unnecessary surgery, a preventable major complication of another surgery, months of severe anemia and more. And yet many women may be at risk for similar problems without realizing it.

Heavy period bleeding (medically called menorrhagia) is a very common problem in women of reproductive age, affecting up to 30 percent of women. This type of bleeding can be very debilitating and difficult to deal with, as well as posing a diagnostic challenge for doctors to identify the underlying cause.

There are many possible causes of menorrhagia, including hormonal imbalances and dysfunction of the ovaries, fibroids, uterine polyps, adenomyosis, intrauterine devices (IUDs), and in rare cases, cancers of the reproductive system. One cause that is not often considered is a bleeding disorder. Up to 20 percent of women with menorrhagia may have von Willebrand’s disease, which is the most common of the so-called “mild” bleeding disorders (which include any bleeding disorder not classified as a severe hemophilia). The number of women with menorrhagia who have an undiagnosed bleeding disorder is even higher when platelet function disorders, another type of “mild” bleeding disorder, are included.

Studies have shown that gynecologists are not likely to consider a bleeding disorder as a possible cause when investigating menorrhagia, and are not likely to refer women with heavy period bleeding to a hematologist for further investigation, even when gynecological causes are ruled out. One study found that only four percent of physicians surveyed would consider von Willebrand’s disease as a possible diagnosis in women with menorrhagia, and only 3 percent of physicians would refer patients to a specialist.

Studies have also shown that women with undiagnosed bleeding disorders are more likely to be subjected to unnecessary surgical procedures, including hysterectomy, as a “fix” for the bleeding that doesn’t address the underlying problem. Menorrhagia is the major reason for approximately 300,000 hysterectomies per year in the U.S. Given the prevalence of undiagnosed bleeding disorders in this population, 60,000 or more hysterectomies per year could be performed in women whose menorrhagia could be addressed with treatment for their bleeding disorder instead of a major surgery. Women with von Willebrand’s disease are more likely to undergo a hysterectomy (26 percent of women with von Willebrand’s disease, compared to 9 percent of women in the control group) and to have the hysterectomy at a younger age.

In addition, undiagnosed bleeding disorders have a serious effect on women’s quality of life, and put women at risk for medical complications. Although women who have not experienced it, or men, who of course cannot experience it, may dismiss heavy period bleeding as simply a nuisance, it is far more than that. It can cause serious problems such as anemia, complications from childbirth and surgical procedures, lost work or school time, lifestyle issues, psychological disruptions, and have major effects on quality of life. The health-related quality of life for women with menorrhagia and a bleeding disorder was studied and found to be similar to that of HIV-positive men with severe hemophilia, underscoring the difficult symptoms and lifestyle issues that can result from these problems.

My own medical history reads like a clinical case study designed to educate doctors about the possible pitfalls of undiagnosed bleeding disorders, and judging by the numbers, there are many more women out there going through the same thing. After my son was born, the menorrhagia I’d had since I was a teenager worsened significantly. I had gynecological causes ruled out—no polyps, fibroids, or cancer. I already had been diagnosed with endometriosis, but that was not thought to be the cause of the bleeding. My gynecologist deemed the cause to be “hormonal” and spent two years trying to fix it with birth control pills, which didn’t work. At some point during those two years I asked for a referral to a hematologist, which I was told I didn’t need after a few preliminary blood clotting tests came back normal. I had an endometrial ablation, which also didn’t work, and caused my pelvic pain to worsen so severely that my first period after the ablation landed me in the ER (increased pelvic pain is a known risk with endometrial ablation).

I had enough of a history the first time I asked to warrant a referral. My history at that time included bleeding complications with my first laparoscopy for endometriosis, history of heavy periods with gynecological causes ruled out, easy bruising and bleeding gums. However, it took four more years of suffering with the symptoms of anemia, low ferritin, and heavy periods, one unnecessary surgical procedure (the ablation), and a preventable surgical complication that required a subsequent surgery (I had a major internal hemorrhage after excision surgery for endometriosis and removal of my left ovary and tube) and three more requests for hematology referrals, before I was finally referred to a hematologist and ultimately diagnosed with a bleeding disorder. And some studies show that the diagnostic delay from onset of bleeding symptoms can be up to 16 years! It is time for this to change. Gynecologists need to consider the possibility of bleeding disorders, and work with hematologists when appropriate, when trying to diagnose the underlying causes of menorrhagia.

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This post was published here previously July 2013. 

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An Often Overlooked Cause of Fatigue: Low Ferritin

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Fatigue is a very common complaint, reported to general practice doctors up to 25 percent of office visits. The incidence of fatigue is even higher than this, however, since many people experiencing fatigue do not report it to their doctors. Many people are tired because of busy lives, work and home obligations, and not getting enough rest. Fatigue is also a component of many illnesses and chronic diseases. Often fatigue is dismissed by doctors either as being a normal part of life, or as being a result of emotional disturbances or stress. Women are three times more likely to have fatigue than men.

Iron Deficiency Anemia

One common cause of fatigue in reproductive age, menstruating women is iron deficiency anemia. A lesser known cause but possibly equally prevalent is low ferritin, caused by low iron stores. Iron deficiency anemia occurs when there is not enough iron in the body, and the production of red blood cells is affected. It can affect up to 20 percent of women. Causes of iron deficiency anemia in menstruating women include heavy periods, gynecological diseases such as fibroids or adenomyosis, gastrointestinal bleeding, and gastrointestinal malabsorption.

Iron deficiency anemia is often assessed by taking blood and measuring the hemoglobin level: hemoglobin is a protein in red blood cells that binds to iron, and transports oxygen in the blood. Hemoglobin is measured as part of a complete blood count (CBC). Normal hemoglobin range in the blood is usually 12 to 15 g/dL, but the normal range can vary slightly depending on the lab. In iron deficiency anemia hemoglobin values are lower than 12 g/dL.

Symptoms of iron deficiency anemia include:

  • Fatigue
  • Shortness of breath
  • Dizziness
  • Headaches
  • Cold hands and feet
  • Pale skin
  • Chest pain
  • Weakness
  • Restless legs syndrome

Iron deficiency anemia is usually easily recognized and treated. The CBC is a very commonly performed blood test, and low hemoglobin, plus other results contained within the CBC panel, is a good indicator of iron deficiency anemia. It is treated with oral iron, which can be obtained in drug stores without a prescription. Side effects of oral iron include nausea, vomiting, constipation, diarrhea, dark colored stools, and abdominal pain. Iron supplements should not be taken without having a doctor monitor the blood levels of iron, since too much iron can cause buildup of excess iron and organ damage.

Low Ferritin and Fatigue

Although the importance of treating iron deficiency anemia is well recognized, many health practitioners do not test the body’s iron stores, and low iron stores, indicated by low ferritin levels, can also cause fatigue. Ferritin is a protein that stores iron in the body. It is not measured by the CBC, but can be measured by a separate blood test. Usually the only consequence of low ferritin is thought to be that it might put a person at risk for developing iron deficiency anemia. However, low ferritin on its own, even without anemia, can cause fatigue.

Several studies have shown that in people with fatigue, with normal hemoglobin levels, oral iron supplementation can improve fatigue. This was particularly true when ferritin levels were below 50 µg/L. Intravenous iron supplementation is another option for treatment and may be particularly appropriate if the ferritin levels are below 15 µg/L. Most labs use 12 -150 µg/L as the normal range for women for ferritin, although this may vary from lab to lab. Therefore, many women who could benefit from iron supplementation for fatigue may be classified as having “normal” ferritin levels.

The normal reference ranges are obtained by sampling ferritin concentrations in populations of women, many of whom may have had iron deficiency, and whether the lower limit of the normal range is actually too low has been brought into question. The fact that iron supplementation improves fatigue when ferritin levels are below 50 µg/L would suggest that this is the case. Therefore, all women should be aware that low iron levels can contribute to fatigue even if anemia is not present, that checking ferritin is an important part of an investigation into unexplained fatigue, and that even if their ferritin levels are deemed to be “normal”, that if the levels are below 50 µg/L, iron supplementation may improve their fatigue.

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This post was first published on April 2, 2014. 

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Why is Endometriosis in Fetuses Important?

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Inaccurate theories about how and why endometriosis develops are widely accepted by medical practitioners, despite much evidence against them. Acceptance of these theories leads to the perpetuation of medical therapies that do not work. It is important to understand the origins of endometriosis in order to move forward and develop effective treatments for this devastating disease.

Endometriosis and Sampson’s Theory

Endometriosis is defined as the presence of endometrium-like tissue outside of the uterine cavity. Many medical practitioners and lay press oversimplify this to state that endometriosis occurs when the lining of the uterus is found outside the uterine cavity. However, there are many publications enumerating the differences between endometriosis lesions and the endometrium found inside the uterus. Evidence for this goes back at least to 1981, and possibly earlier, and research into these differences is still ongoing. However, the common perception that endometriosis is merely endometrium outside of the uterus persists.

One prominently cited theory as to how endometriosis develops is known as Sampson’s theory. This theory suggests that retrograde menstruation, menstrual blood flowing backwards (away from the uterus) through the Fallopian tubes towards the pelvic cavity, deposits fragments of endometrium into the pelvis, which can then implant and grow into lesions.

There are numerous problems with this theory. First of all, there is no evidence that endometrial cells in the peritoneal fluid can attach to the lining of the pelvis (the peritoneum), and in addition, endometrial cells are not commonly present in peritoneal fluid. Furthermore, as stated earlier, there are many differences between the endometrium inside the uterus, and endometriosis lesions. In addition, 90 percent of women have retrograde menstruation, but only approximately 10 percent have endometriosis. Sampson’s theory cannot explain the presence of this disease in fetuses, in men, and in girls who have symptoms with the onset of puberty or even prior to puberty. And it cannot explain the presence of endometriosis in areas outside of the pelvis, such as the lungs and skin.

Alternate Theories – A Fetal Component

Alternate theories that fit better with the available evidence have been proposed, including metaplasia (changing of one cell type into another cell type), developmental defects (also known as Mullerianosis), genetic factors and environmental factors. However, no single theory has been proven to be correct, and most likely a combination of various influences contribute to the development of the disease. According to the current evidence, there is most likely some embryological component. The theory of Mullerianosis explains the development of endometriosis as endometrial tissue that was misplaced during fetal development, that later develops into endometriosis lesions. Evidence in support of this comes from the fact that endometriosis has been found in female fetuses with the same incidence as in women, about 10 percent.

The Persistence of Sampson’s Theory – A Safety Net for Inadequate Treatment

Why has Sampson’s theory continued to be so persistent despite all the evidence to the contrary? First, no alternative theory has been sufficiently proven enough to displace it, although certainly enough evidence against it exists that it ought to be displaced. Second, most doctors who treat endometriosis do not specialize in the disease, and the science behind its development is probably not something they have much interest in.

It is damaging to endometriosis patients to have Sampson’s theory continue to be accepted despite evidence to the contrary. It gives gynecologists a reason not to strive for complete removal of the disease from all organs, because there’s no point in trying to remove all of it, if it will just be re-implanted with the next period. Sampson’s theory provides justification for the high recurrence rates observed from surgeons who do not specialize in treating endometriosis.

However, surgeons who specialize in it, who carefully excise all disease, have shown that it is possible to have low recurrence rates following complete excision. This requires not only the knowledge of all the possible visual appearances of endometriosis, but the surgical ability to excise disease from areas most gynecologists cannot, such as bladder, ureters, intestines, or diaphragm.

Sampson’s Theory and Medications that Prevent Menstruation

Acceptance of Sampson’s theory gives pharmaceutical companies an excellent tool to convince doctors to prescribe medications that prevent menstruation. If Sampson’s theory is correct, then any hormonal treatment that stops women’s periods will treat endometriosis. Several drugs that are currently on the market can stop periods—Lupron and similar drugs, by inducing a menopausal state, and birth control pills, used continuously. However, as would be expected, since Sampson’s theory is not correct, these medications have never cured endometriosis. Some patients may experience temporary relief of symptoms, especially when the symptoms are primarily connected to having periods, but hormonal medical therapies do not treat the underlying disease.

The Origins of Disease Matter

Though debating disease origins may seem like an arcane point, not relevant to most endometriosis patients on a daily basis, it is highly relevant because it is so linked to the inadequate and ineffective treatment most patients receive. In order to truly move forward and make progress in how this disease is treated, wider recognition of Sampson’s theory as fatally flawed must occur. If endometriosis is present in the fetus, then it is an entirely different disease than one of retrograde menstruation. Understanding this is critical for better treatments options.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

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This article was published originally on October 2013. 

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Hope for Cyclic Vomiting Syndrome

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Two days ago, I helped my twelve year old daughter pack for two weeks of overnight camp. We followed the suggested packing list that the camp provided, and when we got near the bottom of the list I realized there was one important thing that was not there that she needed—her medication and supplements. My daughter has had cyclic vomiting syndrome (CVS) since she was two years old, a disease that causes her to have frequent episodes of severe nausea, vomiting, and abdominal pain.

She has bravely managed this debilitating disease for 10 years. She has been going to camp for four years already, and every year she has had a vomiting episode at camp—one year while she was out on a canoe trip, and one year starting early in the morning on the day she was supposed to leave. When she was younger she used to have episodes like clockwork every two months, and as she got older, her episodes became less predictable, and more responsive to events in her life such as stress, fatigue, or even excitement. She would sometimes have three episodes within one month, and other times go for as long as three months without an episode. On average she would have one to two episodes per month.

This year, for the first time, she has had only two episodes of vomiting in the last seven months. This dramatic change occurred after she started a new regimen of dietary supplements—L-carnitine and Coenzyme Q10. We decided to try using these supplements after learning about research that suggests that CVS may be caused partly or completely by mitochondrial dysfunction. More information about the connection between CVS and mitochondrial dysfunction can be found here. L-carnitine and Coenzyme Q10 assist the mitochondria with energy production and thus, help compensate for mitochondrial dysfunction and potentially improve symptoms in CVS patients. These supplements may also help improve symptoms in other disorders linked to mitochondrial dysfunction such as migraine, irritable bowel syndrome, fibromyalgia, and medication adverse reactions.

Results from small clinical studies on the use of these supplements for cyclic vomiting syndrome have been very promising. A retrospective chart review study found that using these two supplements, along with a dietary protocol of fasting avoidance (having three meals and three snacks per day), was able to decrease the occurrence of, or completely resolve, the CVS episodes in many patients. The supplements were also shown to be safe and well tolerated, with few side effects.

My daughter noticed an immediate improvement in her symptoms. She had almost daily morning nausea even when not having a vomiting episode, and this disappeared almost right away. She started asking for breakfast, when previously I’d always had to try to convince her to eat at least half a piece of toast. She now will often eat either three eggs and two pieces of toast, or a big plate of dinner leftovers for breakfast. She also has a better appetite throughout the day. I don’t think I ever heard her say the words “I’m hungry” until this past year, when she was 12 years old. Previously quite underweight, in the past 7 months she has literally gained as much weight as she gained in the previous 7 years.

The first 2 months on the supplements she had no vomiting episodes. Then she ran out of her supplements while my husband and I were away, and within 2 days she was having a vomiting episode. Then over the last 5 months she has had one more episode, after a period of extreme stress. This represents a huge decrease in episode frequency for her. When we got to packing her medications and supplements for camp, I packed her supplements with careful instructions for the doctor as to the dosage, and the fact that she has to take them every day to prevent episodes, as we saw earlier this year what happens when she stops them even briefly. I then started looking around the house for her Zofran pills (a strong prescription anti-emetic), which was what we would usually use to try to stop her vomiting when she was having an episode. I have always sent them to camp with the instructions that they are to be used if she starts vomiting. I couldn’t find the Zofran anywhere—it had been so long since we had needed it. I called the pharmacy, but they didn’t have any in stock. I found one emergency pill stashed in my purse and I packed that, but I have a feeling that this could be her first year enjoying camp with no interruptions due to illness.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

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Postscript: This article was published originally in July of 2014. We are happy to report that after years of suffering from CVS, Philippa’s daughter remains largely episode free with relapses only when she misses her supplements or changes her routine. For more on cyclic vomiting syndrome search our archive. 

 

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Thoracic Endometriosis

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Endometriosis is a common disease, affecting up to 10% of women. It is characterized by the presence of tissue similar to the lining of the uterus (the endometrium) forming abnormal growths elsewhere in the body. Usually endometriosis growths/lesions are found in the pelvis, most commonly in the cul-de-sac (between the rectum and the back wall of the uterus), the ligaments of the pelvis, the bladder, the ovaries and tubes, and the sigmoid colon.

Endometriosis lesions can more rarely be found outside of the pelvis, and the most common type of extrapelvic endometriosis is thoracic endometriosis. Although thoracic endometriosis is relatively rare, there has been an increase in diagnosis in recent years, probably because of increased awareness among medical professionals that endometriosis can occur outside of the pelvis. Thoracic endometriosis is often found in conjunction with severe pelvic endometriosis.

The average onset of symptoms of thoracic endometriosis is 35 years old, much later than for pelvic endometriosis, where symptoms often begin in adolescence. It is not clear why this is the case. In addition, the majority of thoracic endometriosis is right-sided, with a smaller number of cases being left-sided or bilateral.

Symptoms and Clinical Presentation

The most common symptom of thoracic endometriosis is catamenial chest pain, which is chest pain occurring right before or during menstruation. In one study, 80% of women with thoracic endometriosis had catamenial chest pain. In another study, 90% of women had chest pain, 30% had shortness of breath, and 7% coughed up blood. These symptoms occurred more often during menstruation, but were not necessarily limited to menstruation. In 40% of women, chest pain was the only symptom of thoracic endometriosis.

The four main clinical entities associated with thoracic endometriosis are catamenial pneumothorax, catamenial hemothorax, catamenial hemoptysis, and lung nodules. Of these, catamenial pneumothorax has been the most researched. This is when the lung collapses during menstruation. It is considered to be catamenial when the collapse occurs during the window of 24 hours prior to the onset of menstruation to 72 hours after onset. The majority of catamenial pneumothorax is caused by thoracic endometriosis; however, not all pneumothorax associated with endometriosis is catamenial. In one study of 150 thoracic endometriosis patients, 37% of the pneumothoraces were catamenial, and 63% were non-catamenial. Pneumothorax typically causes chest pain and shortness of breath.

Catamenial hemothorax is bleeding between the chest wall and the lung that occurs during menstruation. This is a rare cause of pleural effusion (fluid around the lung), and like pneumothorax, usually causes chest pain and shortness of breath. Catamenial hemoptysis is coughing up blood during menstruation, and is usually associated with chest pain and shortness of breath. Catamenial hemothorax and catamenial hemoptysis occur in thoracic endometriosis less frequently than catamenial pneumothorax. Pulmonary nodules are one of the least frequent manifestations of thoracic endometriosis, and are masses in the lung that can be mistaken for malignancy. They can be asymptomatic, or sometimes cause coughing up blood.

In most if not all cases of thoracic endometriosis, lesions are also found on the diaphragm. In the majority of women, diaphragmatic endometriosis penetrates through the diaphragm. However, in a small number of women, the endometriosis lesions are found only on the visceral (abdominal/pelvic) side of the diaphragm, or only on the pleural (thoracic/lung) side. Not all women with diaphragmatic endometriosis will also have thoracic endometriosis. The symptoms of endometriosis on the diaphragm are similar to the symptoms of thoracic endometriosis, with chest pain during menstruation. This pain may radiate to the shoulder, neck or arm.

In rare cases, endometriosis on the pericardium has been reported (here, and here). The pericardium is the membrane that surrounds the heart. These women also had diaphragmatic endometriosis, and one of them had severe pelvic endometriosis, and the other had an endometrioma in her liver.

How Does Thoracic Endometriosis Develop?

A common theory about the development of endometriosis, known as Sampson’s theory, suggests that retrograde menstruation, menstrual blood flowing backwards (away from the uterus) through the Fallopian tubes towards the pelvic cavity, deposits fragments of endometrium into the pelvis, which can then implant and grow into lesions. This theory has many flaws, as discussed here. The existence of endometriosis outside of the pelvis is one of several facts about endometriosis that cannot be explained by Sampson’s theory.

So how does endometriosis outside of the pelvis develop? There are three main theories, and it may be through one or a combination of these that endometriosis develops in the thorax. The fact that thoracic endometriosis develops later than pelvic endometriosis may suggest that there is something fundamentally different about the way it develops. The migration theory suggests that endometriosis moves through the peritoneum (the lining of the pelvis) to the diaphragm, and from there, can move into the thorax through small holes in the diaphragm. The embolization theory suggests that endometriosis can be transplanted to the thorax from the pelvis through the lymph circulation, or the blood. Lastly, the metaplasia theory suggests that certain cell types can be transformed or changed into endometriosis. Clearly, more research is needed to delineate how thoracic endometriosis develops, and even how pelvic endometriosis develops, as this is not fully understood either.

Diagnosis

The definitive diagnosis of thoracic endometriosis, like all endometriosis, is through biopsy of endometriosis lesions/growths that have been removed surgically. Video-assisted thoracoscopic surgery can be used to visualize and remove endometriosis growths in the thorax. This type of surgery is similar to pelvic laparoscopy, where a small video camera scope allows the visualization of the surgical area, and instruments are inserted through small separate incisions. However, without surgery, a tentative diagnosis can be made through the clinical history and sometimes imaging results. In a woman with pelvic endometriosis, thoracic endometriosis may be suspected if catamenial chest pain is present, or any of the other clinical entities described above. Chest x-rays can show pneumothorax, pleural effusions, or lung nodules. CT scans may show certain findings characteristic of thoracic endometriosis, but sometimes CT scans are normal when a woman is not menstruating. MRI can also be helpful.

Treatment

Hormone therapy such as birth control pills, depo-provera, and Lupron are associated with greater than 50% recurrence of symptoms within six months after treatment was stopped. Video-assisted thoracoscopic surgery has been shown to be a safe option for treatment of thoracic endometriosis, and it can be combined with pelvic laparoscopy in the same surgery if pelvic endometriosis also needs to be treated. As with all surgery to excise endometriosis, the goal is to locate all of the lesions and remove them completely, in order to minimize recurrence. Most studies of surgical treatment of thoracic endometriosis have a fairly short followup, typically median followup of 18 months, and the number of patients in the studies is usually a small number, so it is difficult to draw robust conclusions about the long-term effectiveness of surgery. In one study, all patients had improvements in symptoms after surgery, but two out of 25 had recurrence at nine and twelve months respectively. Overall, though, surgical excision of thoracic endometriosis appears to be effective in the majority of cases.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

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This article was published originally on July 16, 2016. 

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Restless Legs Syndrome

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Restless Legs Syndrome (RLS), also called Willis-Ekbom disease, is both a neurological and a sleep disorder that is common, but under-recognized.  It is characterized by an irresistible urge to move the legs that is worse in the evening or at night. The sensation in the legs is often described as a creepy or crawly feeling in the legs, jitteriness in the legs, or itchy bones. Sometimes the sensation can be painful as well, like a deep ache. The hallmark of RLS is that these symptoms worsen at night or when trying to rest, and the symptoms are relieved by movement. In more severe forms of the disease, the abnormal sensations can also be present in other parts of the body.

RLS occurs in about 7 to 11 percent of individuals, and is two times more common in women than in men. For many people with the disorder, the symptoms are relatively mild, but for individuals with moderate to severe symptoms, it can be quite debilitating, mostly because of the sleep disturbance caused by the symptoms. About 3 percent of the population has RLS with symptoms significant enough to require medical management. RLS is a lifelong disorder and while symptoms may wax and wane over time, they rarely go away completely. Overall, the symptoms tend to worsen with age.

Restless legs syndrome can be primary, meaning that it is not associated with any other conditions, or it can be secondary to other conditions such as iron deficiency and end-stage renal disease. Secondary RLS can also occur in the third trimester of pregnancy. Primary RLS is associated with an earlier age of onset, and often with a positive family history of other family members having RLS. Although all of the mechanisms behind the development of RLS are not fully understood, both iron deficiency and abnormalities in the dopamine neurotransmitter system are involved.

Iron Abnormalities in Restless Legs Syndrome

The link between iron status and restless legs syndrome has been known for over 50 years, ever since the disorder was first described. The lower a person’s iron levels are, the more severe the symptoms of RLS. In order to understand how various blood tests measure and define different types of low iron levels/iron deficiency, some understanding of how the body stores and uses iron is required. Iron is stored in the liver as ferritin, and is released to make hemoglobin in new red blood cells, as required. Hemoglobin is a major component of red blood cells, and is required to carry oxygen in the blood. When the hemoglobin is low (measured by a blood test for hemoglobin or hematocrit), iron deficiency anemia occurs, with symptoms of fatigue, weakness, shortness of breath, headaches, and more. However, even when the hemoglobin is normal, iron deficiency can be present in the form of low ferritin, and this can lead to fatigue and other anemia-like symptoms. One limitation of ferritin as a measure of iron deficiency is that it can be elevated despite low iron stores, in the presence of inflammation.

Several studies have shown that giving iron supplementation can improve the symptoms of restless legs syndrome, and in fact, can do so even when individuals have normal hemoglobin and ferritin levels. This is thought to be because RLS is associated with low iron in the central nervous system, rather than low iron in the blood circulation. Although low iron in the blood will result in low iron in the central nervous system, with normal iron levels in the blood (normal ferritin and hemoglobin levels), there can still be low iron in the cerebrospinal fluid, which is a fluid found in the spine and brain. Furthermore, using MRI images, certain areas of the brain have been shown to have low iron in individuals with RLS. Faulty transport of iron across the blood brain barrier has been demonstrated in individuals with RLS, explaining why iron may be normal in the circulating blood, but low in the brain. How this low iron in the brain leads to RLS is not entirely understood, but there is some evidence linking it to the dopamine abnormalities in RLS, which are discussed in more detail below.

Studies of iron therapy for RLS have shown that oral iron therapy can improve symptoms in individuals with low ferritin. However, when ferritin is normal, intravenous iron treatment is required, probably because oral iron is very poorly absorbed. Studies of intravenous iron therapy for RLS (here, here and here) have shown that this treatment is safe and effective, and lasts at least 24 weeks, depending on the type of iron given and the dose.

Dopamine Abnormalities in Restless Legs Syndrome

Levodopa, a drug used to treat Parkinson’s disease, was found to treat symptoms of RLS, at least upon initial use of the drug. Levodopa is converted into dopamine in the body, and therefore it was thought that RLS resulted from a deficiency of dopamine, and thus was treatable with a medication that converts to dopamine. However, brain imaging studies have shown that dopamine is in fact increased in the brains of individuals with RLS. This increase causes the number of receptors for dopamine on neurons in the brain to decrease, something that is predicted given the way neurotransmitters act in the brain, and has been borne out with studies showing fewer dopamine receptors in the brains of individuals with RLS. Levels of dopamine change with the circadian rhythms and are lower in the evening and at night. The increase in dopamine in RLS is compensated for by a decrease in dopamine receptors, leading to an overall balance during the day, but at nighttime when dopamine levels are lower, there is an overall deficit of dopamine activity, leading to the symptoms of RLS.

In addition to levodopa, another type of drug called dopamine agonists are also used to treat RLS. These drugs include ropinirole and pramiprexole; they act by stimulating the dopamine receptors the same way that natural dopamine would. All of these medications have been found to cause something called augmentation, which is when symptoms improve at the beginning of treatment, but over time the symptoms worsen and start happening earlier in the day. This occurs because instead of treating the root cause of the disease, adding additional dopamine to a system that already has an excess of it is actually ends up creating a bigger imbalance over time, decreasing dopamine receptors further.

Treatment Options

In addition to dopamine agonists, other pharmacuetical agents prescribed for RLS include gabapentin, opioids, and benzodiazepines. All of these options have a significant downside, either in the form of side effects (gabapentin), addiction (opioids and benzodiazepines), or augmentation/worsening of RLS (dopamine agonists). Intravenous iron treatment, as discussed above, may be a better option that is safer and also effective. There are also non-pharmacological treatment options that have been shown to ease symptoms in some individuals. These include moderate exercise, leg massage, hot baths or heating pads, and a regular sleep schedule and avoiding naps. Avoidance of lifestyle and diet factors that may worsen symptoms can also help–this includes avoidance of alcohol, nicotine, and caffeine. Finally, some medications can worsen RLS, and these should be avoided if possible: antidepressants, anti-psychotics, diphenhydramine (Dramamine), and dopamine antagonists used to treat nausea and vomiting, such as metoclopramide. In many individual combining non-pharmacological approaches with iron therapy may make symptoms manageable.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter.

This article was published originally on January 11, 2017.

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