Gene mutation discovery sparks hope for effective endometriosis screening
By Karen N. Peart February 6, 2012

Researchers at Yale School of Medicine have, for the first time, described the genetic basis of endometriosis, a condition affecting millions of women that is marked by chronic pelvic pain and infertility. The researchers’ discovery of a new gene mutation provides hope for new screening methods.

Published in the Feb. 3 early online issue of EMBO Molecular Medicine, the study explored an inherited mutation located in part of the KRAS gene, which leads to abnormal endometrial growth and endometrial risk. In endometriosis, uterine tissue grows in other parts of the body, such as the abdominal cavity, ovaries, vagina, and cervix. The condition is often hereditary and is found in 5%-15% of women of reproductive age, affecting over 70 million women worldwide.

Although the disorder has been studied for many years, its exact cause and how it develops remained unclear. It was previously shown that activating the KRAS gene caused mice to develop endometriosis. However, no mutations in this gene have been identified in women with endometriosis.

Led by senior author Dr. Hugh S. Taylor, professor and chief of the Division of Reproductive Endocrinology and Infertility in the Department of Obstetrics, Gynecology & Reproductive Sciences, the authors studied 132 women with endometriosis and evaluated them for a newly identified mutation in the region of the KRAS gene responsible for regulation. This mutation was previously linked to an increased risk of lung and ovarian cancer by study co-author Joanne Weidhaas, M.D., assistant professor of therapeutic radiology.

“We found that 31% of the women with endometriosis in the study carried this mutation, compared to only 5.8% of the general population,” said Taylor. “The presence of this mutation was also linked to higher KRAS protein levels and associated with an increased capacity for these cells to spread. It also may explain the higher risk of ovarian cancer in women who have had endometriosis.”

The Yale team is the first to identify a cause of this common and previously little understood disease. “This mutation potentially represents a new therapeutic target for endometriosis as well as a basis of potential screening methods to determine who is at risk for developing endometriosis,” said Taylor.

Other authors on the study include Olga Grechukhina, Rafaella Petracco, Shota Popkhadze, Trupti Paranjape, Elcie Chan, Idhaliz Flores, and Joanne Weidhaas.

The National Institutes of Health supported the study.

Citation: EMBO Molecular Medicine DOI: 10.1002/emmm.201100200

 
See related: Genetic variants on chromosome 1 and 7 more likely to induce endometriosis.

For further education, please see the Genetics Home Reference guide.

While use of prescription opioids for cancer and other end-of-life pain is increasingly accepted, if you are going to suffer in agony for years, rather than months, mercy is harder to find. Indeed, it seems a given by the media that because addicts sometimes fake pain to get drugs, doctors should treat allpatients as likely liars—and if a physician is conned by an addict, the doctor has only herself to blame.

But do we really want our doctors to treat us as if we were guilty until proven innocent? Do we really want the routine use of invasive procedures—ranging from nerve conduction tests to repeated scans and surgeries—to “prove” we’re really hurting? And do we actually want physicians to be held responsible for the actions of a patient who dissembles and does not take drugs as prescribed?

The answers to these questions are at the heart of the bizarre way we view synthetic opioid medications and the suffering of the 116 million Americans who have moderate to severe chronic pain, according to Institute of Medicine estimates.

In recent weeks, for example, New York Sen. Charles Schumer, anti-drug abuse advocates and reporters have inveighed against the potential FDA approval of an experimental opioid painkiller called Zohydro—professing to be horrified by the introduction of a new class of “100% pure” hydrocodone “superdrugs” that they have already dubbed “the next OxyContins.” And many states are weighing laws like one now in place in Washington state, which limits the doses of opioids that can be used by chronic pain patients.

When people consider the use of these medications in chronic pain, addiction fears are typically the first thing that comes up. Moreover, media coverage rarely includes the perspective of pain patients— or does so only to knock those who advocate for access to opioids as pawns of the pharmaceutical industry.

If the press—often quoting leading public health officials like Dr. Thomas Frieden, the director of the CDC—is to be believed, the US is in the throes of an “epidemic” of prescription painkiller abuse. Frieden even claimed at a recent press conference on opioid-related deaths that doctors are now more responsible than drug dealers for America’s addiction problems. “The burden of dangerous drugs is being created more by a few irresponsible doctors than drug pushers on street corners,” Friedman said.

However, the opioid issue looks very different when you examine the numbers closely. For one, the rates of Americans addicted to OxyContin, Vicodin, percocet, fentanyl and other products in our synthetic narcotic medicine cabinet are not rising. In fact, they have been steady at 0.8% since 2002, according to the government’s own statistics.

Moreover, fewer than 1% of people over 30 (without a prior history of serious drug problems) become an addict while taking opioids; for chronic pain patients who are not screened for a history of previous drug problems, the addiction rate is 3.27%. That means, of course, that more than 96% do not become addicted.

Yet these statistics usually go unmentioned in media accounts because they do not confirm the preferred panic narrative. Also left out is the fact that around 80% of Oxy addicts (a) did not obtain the drug via legitimate prescription for pain and/or (b) had a prior experience of rehab. Their contact with the medical system—if any—was not what caused their addictions.

So, the first thing the public really needs to know about what doctors call “iatrogenic addiction” is that it is extremely rare. If you’ve made it out of your 20s without becoming an addict, the chances that you will get hooked on pain treatment are miniscule—and even young people are not at high risk in most medical settings.

Nonetheless, the media continue to love them some “innocent victims”—and the real story of not-so-blameless drug users who move from heavy drinking, cocaine use and marijuana smoking to prescription drug abuse is just not as compelling. This, sadly, only contributes to the delusion that anyone who is treated for chronic pain with opioids is at risk for drowning in the—gasp!—ubiquitous riptide of addiction.

The panic leads to policies that require pain patients to be urine-tested, to be called in to their doctors’ offices for random “pill counts” and to make frequent visits—all of which is not only humiliating but expensive and time-consuming. There’s little evidence that such policing prevents addiction or does anything else beyond inconveniencing and stigmatizing pain patients.

And indeed, the stigma of addiction is what’s behind the curtain here. Imagine suffering from incurable daily pain so severe that it feels like your legs are being dipped in molten iron or your spine is being scraped out by sharp talons. Even if you did, in a worst-case scenario, join the tiny percentage of patients who develop a new addiction and became obsessed with using opioids, would this really be worse, especially if you had safe and legal access to them?

Most of the physical and psychological horrors of addiction come with loss of control and with being unable to be present for family, work and friends. But pain can produce even greater dysfunction and emotional distance, and its ability to destroy relationships is at least as monstrous. Moreover, maintenance on opioids can typically stabilize people with addictions, without numbing or incapacitating them. So why do we panic?

In the absence of true pharmaceutical innovation (Zohydro and other “superdrugs” are mere purer versions of VIcodin without the acetaminophen ), opioids remain the only medications that can even begin to touch severe pain, though they are far from perfect. But since they rarely lead to addiction—and since addiction (or opioid maintenance treatment) may actually sometimes be the lesser of evils—does it really make sense to restrict and even deny their benefits to pain patients?

When the situation is considered rationally, our outsized fear of addiction has little to do with the reality of chronic pain. Instead, it’s about the way we see addicts: gun-toting robbers of Oxy from pharmacies and other scummy, lying, sociopathic criminals—people we don’t want to be around or become.

Even though readers of this site know that drugs don’t somehow “make” ordinary people into such demonic figures—and that addicts can also be as kind, compassionate and hard-working as anyone else— the stigma runs deep.

Much of it, I think, comes from the same evasion of responsibility that allows us to blame doctors for addictions. After all, it’s not doctors who tell their patients to inject or snort their oral painkillers, to drink while taking opioids, to take more than prescribed or to lie, cheat and steal to obtain them.

These actions are deliberately taken by drug seekers. Doctors don’t “make” anyone make the ongoing choices that lead to impaired self-control. While trauma histories, psychiatric disorders like depression and/or genetics do make some of us more vulnerable to taking this path, no one can force us to do it. And if we see doctors—or, for that matter, dealers—as having “caused” our addictions, we open ourselves up to be dehumanized and stigmatized.

That is because if we are seen as incapable of making good choices, how can we expect respect for our desires and preferences? If we can’t control ourselves, why shouldn’t we be incarcerated to protect others from our actions? After all, when the public sees us as mindless zombies, their response is not sympathy for our supposed powerlessness but fear and disgust at our imagined violence.

Even the overdose issue is mismanaged due to our hatred of addicts. Overdoses have now overtaken car accidents as a leading cause of accidental death, but it’s unclear how much of this increase is due to the actual rise in the use of opioids and how much to medical examiners simply attributing more deaths to these drugs since they are now found in more dead people. What is clear is that most of these deaths occur in the context of drug abuse—95%, according to one study of one of the hardest-hit states. A large number of these deaths could be prevented by providing the antidote to opioid poisoning, naloxone, with prescriptions for the drugs. But because we want the wages of sin to be death, however, drug warriors have largely prevented funding for programs to broadly distribute that lifesaving medication.

The opioid problem is really the stigma of addiction writ large. Consequently, if we want to stop getting in the way of access to painkillers for people who genuinely need them, we need to take responsibility for our own actions and help fight this stigma. No one but you can make yourself into an addict. But chronic pain can happen to anyone.

A new test has been developed by surgeons and scientists based at Southampton’s teaching hospitals, that could transform they way early-stage endometriosis is diagnosed.

In an investigation funded by the Infertility Research Trust, Miss Ying Cheong, a consultant gynecologist and co-funder of the Complete Fertility Center in Southampton, together with Dr. Tracey Newman, an academic at the University of Southampton’s faculty of medicine, used small particles marked with fluorescent markers to bring to light areas of affected tissue.

Endometriosis, a female health disorder that occurs when small pieces of the uterus grow on to different organs such as the ovaries and fallopian tubes, that can cause heavy bleeding, stomach and back pain as well as infertility, can take up to seven to surface. In the UK, approximately 2 million women are affected by this condition, several of whom are diagnosed between 25 and 40 years of age.

Even though drugs can be used to relieve pain, the most likely treatment is to have the affected areas surgically removed, however, because there are no visual signs of early endometriosis, tissue can only be removed in large sections based on the judgement of the surgeon.

A clear division between normal and diseased cells to give complete accuracy was demonstrated in the initial results from samples that were tested by the investigation team.

Miss Cheong, who is also a senior lecturer in obstetrics and gynecology at the University of Southampton, explained:

“Although we have only completed the pilot stage of our work, early results show this method enables us to uncover early endometriosis which the naked eye cannot even see during surgery and would only normally be treated by a surgeon removing whole sections of tissue based on judgement rather than specifics.

“In early stages of our ongoing research we aim to advance the visualization of the disease during surgery based on our results, but we hope to go on to develop treatment strategies to complement surgical treatment by directly delivering medication attached to nanoparticles.”

Today, Miss Cheong presents her discoveries in London at the beginning of the three-day European Society of Gynecological Endoscopy conference, which also, via satellite on Friday, will show live surgery from Southampton University Hospitals NHS Trust’s Princess Anne Hospital. Two advanced hysterectomy procedures – laparoscopic subtotal and single port – will be performed by Miss Cheong, fellow consultant gynecologists Mr Adam Moors and Dr Sameer Umranikar and three other visiting surgeons to hundreds of international colleagues attending the event at the ExCeL.

Mr Moors, a specialist in gynecological endoscopic surgery explains:

“It is a reflection on the quality of service here in Southampton that we have been invited to showcase some of the advanced minimally invasive surgery we perform here on a daily basis to an audience of leading experts from across the world.”

A study has linked vitamin D deficiency with an increased risk for cancer and autoimmune diseases like MS, lupus and rheumatoid arthritis (RA).

Vitamin D deficiency is connected with conditions such as rickets, which causes softness or weakening of the bones. However, this recent study by lead author Dr. Sreeram Ramagopalan from the Wellcome Trust Centre for Human Genetics at Oxford University and his colleagues further implicates vitamin D in other serious illnesses.

Vitamin D interacts with our genes through the vitamin D receptor. This receptor binds to the human genome at specific locations and in this way influences how a gene is expressed. In the study, the researchers used DNA sequencing technology to map vitamin D receptor binding throughout the human genome and found more than 2000 places where this binding happened. They discovered that the vitamin D receptor binding is enhanced at specific areas of the human genome that is associated with autoimmune diseases like type I diabetes, MS, RA and Crohn’s disease, as well as certain cancers, including leukemia and colorectal cancer. These illnesses are caused by a combination of genetic and environmental factors and vitamin D deficiency appears to be a major environmental factor in increasing the risk of developing such disorders. The study also found sites for vitamin D receptor binding in areas of the genome that contain genetic changes more common in people from Europe and Asia. This offered support for the theory that lighter skin and hair color evolved as populations moved to more northern and less sunny areas in order to maximize vitamin D absorption from the sun.

What does this mean in a practical sense? Dr. Ramagopalan is quoted as saying ‘There is now evidence supporting a role for vitamin D in susceptibility to a host of diseases. Vitamin D supplements during pregnancy and the early years could have a beneficial effect on a child’s health in later life.” Some countries (e.g., France) have started public health measures to help protect pregnant women and small children against vitamin D deficiency.

How to Assess Your Vitamin D Level and Increase Your Levels

It is estimated that 1 billion people worldwide do not get enough vitamin D. In the US, as many as 70% of children and adults are D deficient. The cause of this is a combination of not enough sun exposure and a diet low in vitamin D. Certain medications may also impact vitamin D absorption and kidney and liver disease can also lead to vitamin D deficiency.

Finding out whether your vitamin D levels are low is a matter of a simple blood test called the 25-hydroxy vitamin D test. Access to getting the test may become an issue, though. Due to vitamin D deficiency increasingly being implicated in many health conditions and the subsequent popularity of the test, Medicare has proposed vitamin D testing restrictions. In the Canadian province of Ontario, the provincial public health insurance OHIPdecided in late 2010 to only cover the cost (about $50) for a small number of medical disorders.

To increase your level of vitamin D, include more oily fish, such as salmon, mackerel and tuna in your diet. Egg yolks and mushrooms also contain vitamin D and you can choose cereal and milk fortified with vitamin D.

Vitamin D is also sometimes called the “sunshine vitamin” because your skin absorbs it through the rays of the sun. In fact, in the summer 15 minutes of sun exposure (without sunblock) can give you about 20,000 IU of vitamin D. On the other hand, it is generally not recommended that you expose yourself to sun without sunblock for longer periods of time, due to the risk of skin damage and skin cancer.

It’s a good idea to use vitamin D supplements. The Institute of Health has set the recommended dietary allowance to be 600 units a day, but this is generally accepted to be much too low. As well, with vitamin D there is no “one-size-fits-all” solution – how much you need depends on factors like how D deficient you are, which medical conditions you have, etc. It usually recommended that you should supplement by adding 1-2,000 IU of vitamin D per day, although people who are severely deficient or have certain medical conditions may take up to 5-10,000 IU per day. Vitamin D in liquid form, usually available in a health food store, has better absorption rates and are therefore recommended above vitamin D tablets.

The Many Benefits of Vitamin D

In the past several years, Vitamin D has been connected to benefits in a number of medical conditions. It has been known for a long time that it plays a crucial role in the absorption of calcium, which helps protect your bones from osteoporosis, but did you know Seasonal Affective Disorder is connected to vitamin D deficiency? As well, older adults who have low levels of vitamin D are more likely to become depressed.

Vitamin D also plays a role in the management of chronic pain, particularly musculoskeletal pain in conditions like fibromyalgia, RA and diabetic neuropathy. It’s quite common for people who live with chronic pain to have a vitamin D deficiency. Some doctors routinely test their patient’s vitamin D levels and include vitamin D supplements as part of the treatment plan.

The knowledge that vitamin D can not just make you feel better, but may also help lower the risk of cancer and autoimmune disorders is amazing news. Perhaps the future will bring even more incredible findings about the importance of vitamin D.

Imagine a pain in your abdomen so excruciating that you are unable to get out of bed for several days every month. That is horrible enough, but when it continues 12 times a year for more than 27 years, majority of people would agree it is cruel.

Most women with endometriosis will recognise this shocking scenario as not imaginary, but very real. They know the misery of pelvic pain and have poignant stories of how endometriosis has devastated their lives with terrible suffering. Many women feel angry or despondent about being robbed off a normal life during teenage, adulthood and even sometime a ruined motherhood.

Endometriosis is a gynaecological condition, which occurs when, cells like the ones (endometrial cells) lining inside of the uterus (womb) grow outside, usually on the surfaces of organs in pelvic and abdominal areas. It can be found within the peritoneal cavity, on the ovaries and the bowels or bladder. In extremely rare cases, endometriosis can be found in lungs or other parts of the body. Endometriosis can affect any menstruating woman, from time of her first period to menopause, regardless of race, ethnicity or socio-economic status. Endometriosis rarely persists after menopause. The disorder, for which there is no absolute cure, affects over 70 million women and girls worldwide. Often stigmatized as simply “painful periods,” Endometriosis is a puzzling and widely misunderstood illness.

It is not known exactly what causes endometriosis. But over the years several theories have been advanced to explain the probable cause of the disease although none can fully explain the various clinical manifestations of the disease. A theory proposed by John Sampson in the 1920s, suggests that endometriosis may result from something called “retrograde menstrual flow”, in which some of the tissue that a woman sheds during her period flows back through the tubes and grows in the pelvic cavity. While studies show that retrograde menstrual flow is a universal phenomenon among women of reproductive age, the theory fall short of explaining why the tissues survive in some women, but fail in others. Another theory proposed by Iwanoff in 1898, claims that, the transformation of what we call coelomic epithelium into endometrial-like tissue may be a cause of endometriosis. This theory has been supported by experimental data. The induction theory, proposes that an endogenous factor can induce peritoneal cells to develop into endometrial tissue. This theory has been supported by experiments in rabbits.

Lymphatic or vascular hypothesis suggests that endometrial fragments may be transported through blood vessels or the lymphatic system to other parts of the body. This theory speculates how endometriosis ends up in distant sites, such as the lung, brain, or the skin. A genetic linkage has been adduced which claims that, this disease could be inherited, or result from genetic errors, making some women more prone to develop the condition than others.

Studies show that the risk of endometriosis is seven times greater if the disease has affected a first-degree relative. This theory has been supported by experiments in mouse model but has not been verified either in women. Immunological etiology (cause) has also been conjured since studies report that many women with endometriosis exhibit immunological abnormalities. It is speculated that the immune system may fail to clear the menstrual debris in the pelvic cavity, allowing the endometrial cells to implant and develop into endometriosis.

Also most scientists agree that endometriosis is exacerbated by oestrogen; a hormone involved in the thickening of the endometrium and appears to promote the growth of disease implants. Some studies have pointed out environmental factors like toxins may contribute to the development of endometriosis, though this theory has not been confirmed and remains controversial.

The most common symptoms of endometriosis are abdominal pain and infertility. Some studies have reported that endometriosis may occur in 30%-40% of women with infertility and the incidence of endometriosis in women with pelvic pain may be higher than 50%.

Endometriosis associated pain may include but not limited to extremely painful (disabling) menstrual cramps, chronic pelvic pain (which includes lower back pain and pelvic pain), pain during or after sex, painful bowel movements or painful urination during menstrual periods, heavy menstrual periods and bleeding between periods. The amount of pain a women feels is sometimes not linked to degree of endometriosis. Some women have no pain even though their disease is extensive, while others have severe chronic pelvic pain even though they have only few affected areas.

The relation between endometriosis and pain is still shrouded in the mist of intricate puzzle and ignorance. Many women with endometriosis feel pain during their periods. Normally, a woman’s menstrual cycle involves her endometrial tissue to build up, breaks down into blood and tissue debris, and is shed as her menstrual flow or period. This cycle of growth and shedding happens every month under normal condition. Endometriosis grows outside the uterus and also goes through a similar cycle, build-up, breakdown and bleed every month. The problem is the tissue is in the wrong place and can’t leave the body the way a woman’s period normally does. Studies show that as part of this process, endometriosis may spur the production of substances that may irritate the nearby tissue, as well as provoke the release of chemicals that cause or mediate pain. Over time, endometriosis areas can grow and become nodules or bumps on the surface of pelvic organs, or become cysts (fluid-filled sacs) in the ovaries and may cause the organs in the pelvic area to adhere together.

Endometriosis is more than just simple “killer” cramps. Women and girls around the world continue to suffer in silence with a disease that can be potentially devastating to every aspect of their lives. It can be so painful as to render a woman or teenager unable to care for herself or her family, attend work, school, or social functions, or go about her normal routine. Endometriosis has a negative impact on the individual quality of life, affecting both physical and emotional well-being. A study by the American Endometriosis Association, demonstrated that 81% of the endometriosis patients in USA were unable to work, including household chores, because of pelvic pain. Approximately 27% were incapacitated for 3 or more days and 87% complained of fatigue or low energy. These figures are indicators of enormous suffering, in addition to the healthcare costs incurred. The need to develop intervention strategies is eminent, a published poll reveals women have to wait an average of 11.7 years in US and 8 years in UK to get a correct diagnosis after the initial onset of symptoms and a patient will seek the counsel of five or more physicians before her pain is adequately addressed and diagnosed. Once diagnosed, it is not unusual for a patient to undergo repeat surgeries and embark on many different medical therapies in an attempt to treat her symptoms. Endometriosis is a bit puzzling. We do not know why it causes such extreme symptoms in some women, while less in others. The treatment options can sometimes be unsuccessful. Sadly, endometriosis is associated with menstruation, sex, infertility, and pain (taboos in many societies), thus it is a disease that is not well known, understood, or accepted in the general public. This is frustrating for those who suffer from endometriosis, and for those who care for someone with the disease.

There is no non-invasive test to diagnose endometriosis. In fact, the only gold standard diagnosis of endometriosis is a surgical procedure known as laparoscopy and confirm histologically by taking a biopsy of the suspicious tissue.

However, this is an expensive, minimally invasive procedure. Furthermore, a specialised surgeon is needed for adequate assessment of the pelvis, for recognition of the various types and appearances of the disease. If the patients decline surgery, this makes diagnosis a challenge, and therefore an experienced gynaecologist should be able to recognise symptoms suggestive of endometriosis. The fact that there is no non-invasive diagnostic test for endometriosis is frustrating for clinicians as well as for women with the disease and underscores the need for search of better diagnostic tools.

Since the cause of endometriosis remains unknown, a treatment that fully cures the disease is yet to be developed. Choosing a holistic, treatment option comes down to the individual woman’s needs, depending on symptoms, age, and reproductive desires.

Pain is the most common symptom in many women with endometriosis, mainly managed by painkillers, which may vary from simple analgesics to non-steroidal anti-inflammatory drugs. Most researchers agree that endometriosis is exacerbated by oestrogen. Subsequently, hormonal treatments for endometriosis attempt to reverse oestrogen production in a woman’s body and thereby alleviate symptoms. However, hormonal therapies have varying degrees of side effects, and unfortunately, whatever pain relief is achieved tends to be only temporary for many women. Most gynaecologists agree that laparoscopic surgery is the only way to diagnose and treat endometriosis. Laparoscopy involves a small cut or incision in the abdomen, inflating the abdomen with harmless gas, and then inserts a viewing instrument with help of light (Laparoscope) into the abdomen. The success of surgery depends largely on the skills of the surgeon and the thoroughness of the surgery. The aim is to remove all endometriosis lesions, cysts, and adhesions. Today, most endometriosis surgery is being done through the laparoscopy, although a full abdominal incision called a laparotomy may still be required in rare cases for extensive disease or bowel resections.

Although the prevalence of endometriosis is well documented in women living in the developed world, studies among African women are still limited. The current myth is that endometriosis rarely affects women of African origin. However, among African-American women in the USA, studies have shown endometriosis is one of the common indications for major gynaecological surgery and hysterectomy, and is associated with a high hospital costs. Although genetically, African-American and African women from the African continent are not necessarily identical given the known genetic admixture among the African-American population. Lack of awareness of endometriosis as a potentially disabling disease and poor access to state-of art diagnostic and therapeutic facilities has contributed to the meagre data on prevalence of the disease in the African population. There is need to initiate awareness campaign of endometriosis to reach all women in Africa. Also to highlight the general lack of information, facilitate endometriosis research efforts and draw attention to the impact and implications of the disease to healthcare systems in our country and the continent in general.

The writer is a Senior Scientist with special interest in endometriosis and ovarian cancer research