Endometriosis may double the risk for ovarian cancer

Endometriosis may double the risk for ovarian cancer

By I. Soussis MD

Women with endometriosis are 1.9 times more likely to develop ovarian cancer, but are at no higher risk for endometrial and cervical cancers, a meta-analysis suggests.

The study, “Impact of endometriosis on risk of ovarian, endometrial and cervical cancers: a meta-analysis,” was published in the journal Archives of Gynecology and Obstetrics.

While endometriosis is considered a benign gynecologic disease, it displays features similar to those seen in malignant tumors, including:

  • the ability to invade other tissues

  • a high rate of new blood vessel formation

  • development of local and distant sites of lesions

These characteristics of endometriosis rendered its classification as behaving similar to tumor-like lesions by the World Health Organization, and growing evidence suggests that the condition may represent an initial stage of tumor progression.

While some studies have associated endometriosis with an increased risk for developing different gynecologic tumors, namely ovarian and endometrial cancers, the results are conflicting.

Therefore, a team of researchers in China performed a meta-analysis to investigate the link between endometriosis and the risk for three gynecological cancers: ovarian, endometrial, and cervical.

Out of 8538 studies retrieved from several databases, they analyzed 25 studies, which included 15 cohort and 10 case-control studies. These studies had been conducted in different countries, including Taiwan, the U.S., Australia, Sweden, Denmark, the Netherlands, Japan, Canada, and Spain, with one study involving joint participation of multiple countries.

The researchers evaluated the risk factor between endometriosis and ovarian cancer in 23 studies, between endometriosis and endometrial cancer in 9 studies, and between endometriosis and cervical cancer in 3 studies.

They found that endometriosis was associated with an increased risk (1.9 times) for developing ovarian cancer. In fact, the ovary is one of the major target organs for the malignant transformation of endometriosis. An integrated analysis of different studies revealed a great overlap between the genetic alterations of both endometriosis and ovarian cancer.

Of note, researchers found that endometriosis increased the risk for developing some subtypes of ovarian cancer: endometrioid and clear-cell type.

No clear evidence supports a link between endometriosis and the risk for endometrial cancer, and endometriosis was not associated with an increased risk for cervical cancer.

Despite the authors’ efforts in making a robust comparison of the different studies using rigorous selection criteria, they were limited to the number of available articles about each cancer type. There were more ovarian cancer studies available, which could have influenced the observations to some extent, the study noted.

There is insufficient evidence to support the theory of endometriotic lesions as a precancerous lesion,” the researchers wrote.

Their meta-analysis suggests that endometriosis is a potential risk factor for developing ovarian cancer, but additional studies are required to understand further if endometriotic lesions are precancerous.

If endometriosis is considered a precancerous lesion, the current treatment management needs to be modified,” the researchers concluded, noting that patients with endometriosis need to be closely observed and rechecked regularly to prevent malignant changes.

My opinion

The association between endometriosis and clear-cell cancer of the ovary and endometrioid ovarian cancer is well established. This meta-analysis confirms it and also clarifies that there is no increased risk between endometriosis and endometrial and cervical cancer.

Women with endometriosis should have life-long regular follow up by their doctors.



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Scientists identify the reason endometriosis causes infertility

Scientists identify the reason endometriosis causes infertility

By I Soussis MD

Deficiency of a protein in the womb has been identified as the reason why endometriosis causes infertility, according to a new study published in Science Translational Medicine.

American and South Korean researchers investigated the link between endometriosis and infertility. In endometriosis, womb-lining tissue grows outside of the uterus, often on the ovaries and fallopian tubes. This can lead to chronic pain and is associated with infertility, but the mechanism has been unclear.

Around ten percent of women have endometriosis and up to 50 percent of endometriosis patients have infertility”, said lead author Dr Jae-Wook.

The scientists compared endometrial tissue from 21 women with endometriosis and infertility with samples from healthy women.

They observed that levels of a protein called histone deacetylase 3 (HDAC3) in the lining of the uterus of women with endometriosis were lower compared to healthy women. Previously developed animal models of endometriosis in mice and baboons supported this finding.

The team then developed mice unable to produce HDAC3 in uterine cells, all of which were infertile. Dr Jeong and his colleagues were able to show that HDAC3 is necessary for embryo to implant in the womb. Follow-up experiments with human endometrial cells cultured in vitro showed that HDAC3 is a crucial part of the changes that occur in the uterus, in preparation for and during pregnancy.

This study could help endometriosis patients and their doctors select more effective treatments and enable a better understanding of female infertility.

My opinion

Finally, the enigma of endometriosis starts to unravel. This is a significant study that shows for the first time that the levels of HDAC3 are crucial for the development of fertile endometrium. This line of research may lead to new treatments for endometriosis caused infertility.

It may also help in cases of recurrent implantation failure in IVF patients without endometriosis.

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Early life sexual and physical abuse dramatically increases risk of endometriosis

Early life sexual and physical abuse dramatically increases risk of endometriosis

By I.Soussis MD

A prospective cohort study found that women reporting severe and/or chronic abuse of multiple types during childhood and adolescence had a 79% higher risk of laparoscopically confirmed endometriosis.

Severe abuse was defined as being kicked, bitten, punched or physically attacked more than once, or choked or burned ever, whereas severe sexual abuse was considered forced sexual activity during both childhood and adolescence.

“We saw stronger associations among women whose endometriosis was most likely diagnosed as a result of pelvic pain symptoms,” said lead author Holly Harris, ScD, an assistant professor of epidemiology at the Fred Hutchinson Cancer Research Center in Seattle, Washington.

Previous studies led by members of Dr. Harris’ research team had shown a connection between early life abuse and both uterine fibroids and hypertension. “Given recent links found between endometriosis and hypertension, one of the next logical steps was to examine the association between abuse and risk of endometriosis,” Dr. Harris told Contemporary OB/GYN.

For the study, which appeared in the journal Human Reproduction, data were collected from 60,595 premenopausal women from 1989 to 2013 as part of the Nurses’ Health Survey II cohort.

Participants completed a questionnaire on exposure to violence.

A total of 3,394 cases of endometriosis were diagnosed during 24 years of follow-up.

Overall, 34% of study participants reported moderate or severe physical abuse during early life and 11% of study participants reported forced sex, while 14% of women diagnosed with endometriosis had severe sexual abuse history.

“It is extremely important for readers, clinicians and women with or those who care about women with endometriosis to understand that these results absolutely do not imply that all women who have endometriosis have been abused,” Dr. Harris said. “Abuse in early childhood and adolescence is common among both women with and without endometriosis.”

The associations between abuse and endometriosis were stronger in women presenting without infertility. This group was also more likely to report pelvic pain.

“Sadly, childhood abuse is real, is a major public health issue, and can have long-lasting impacts on health,” Dr. Harris said. “In addition, for women with pelvic pain with or without endometriosis, it is important that they know that these symptoms are not normal.”

When these women raise concerns about their pain with clinicians, they should not be dismissed, no matter their age or history, according to Dr. Harris. “There is a growing body of evidence that pain sensitization can result from a physiologic response to the stress and trauma of abuse,” she said. “This occurs not only among women with endometriosis but also among women with other pain conditions.”


Read more: https://academic.oup.com/humrep/article-abstract/33/9/1657/5055017?redirectedFrom=fulltext


Source: http://www.contemporaryobgyn.net/endometriosis/does-abuse-affect-risk-endometriosis?rememberme=1&elq_mid=4894&elq_cid=607376&GUID=69980457-AFA5-43B0-B217-28D67525EA6C

Is there a link between caffeine and endometriosis?

Is there a link between caffeine and endometriosis?

By I.Soussis MD


Research on the link between caffeine and endometriosis does not give a definite answer.

A 1993 study released by the Harvard School of Public Health found that women who drank two or more cups of caffeinated coffee per day, or four cans of soda, were twice as likely to develop endometriosis.

A meta-analysis of eight studies (including a total of 1,407 women with endometriosis) conducted in order to establish whether caffeine influences the risk of endometriosis, provided no evidence of an association between coffee/caffeine consumption and the risk of endometriosis.

Many believe that caffeine intake increases estrogen levels, which may increase the chance of developing endometriosis or worsening the symptoms of the condition.

Caffeine inhibits the liver’s ability to reduce our estrogen levels. Εstrogen levels, which are increased by the caffeine intake cannot be reduced by the body’s natural functions.

Studies have shown that women who drink one cup of coffee per day have higher estrogen levels than women who drink none and that women who drink 4-5 cups of coffee per day have 70% higher estrogen levels than other women. Coffee consumption and total caffeine use may increase the levels of oestradiol in the first part of the cycle, independently of related habits of alcohol or tobacco use.

My opinion

High intake of caffeine (from various sources) may be linked to the development of endometriosis. Coffee/caffeine consumption, as currently used in diet, does not carry a health risk. Women need to establish whether their own consumption of caffeine is related to the severity of the symptoms of endometriosis.





Depression in women with endometriosis linked to chronic pain

Depression in women with endometriosis linked to chronic pain

By I.Soussis MD
The complex relationship between endometriosis and depression in women is largely determined by chronic pelvic pain, a systematic review has found.

According to the researchers, raising awareness among physicians on the nature of this relationship, which “is arguably more complex than a direct cause-effect relationship,” is essential to finding the best course of treatment and improving the quality of life of women with endometriosis.

The review study, “Depressive symptoms among women with endometriosis: a systematic review and meta-analysis,” was published in the American Journal of Obstetrics & Gynecology.

Endometriosis, a chronic disease caused by the abnormal growth of endometrium outside the uterus, is estimated to affect approximately 10 percent of women of reproductive age.

The disorder is mainly associated with infertility and chronic pelvic pain, but patients may also experience painful sexual intercourse (dyspareunia), painful or irregular menstrual cycles (dysmenorrhea), painful bowel movements (dyschezia), psychological issues, and overall low quality of life.

Symptoms of depression are significantly more common among individuals with chronic pain. Therefore, “an association between endometriosis and depression may be reasonably expected,” the researchers say. However, so far, no study explored this potential relationship thoroughly.

In this review study, the authors established two goals: first, to determine if there is a link between endometriosis and depression; and second, to assess whether depression is more common in women with chronic pelvic pain associated with endometriosis than in women with endometriosis but without pelvic pain and women with pelvic pain but without endometriosis.

The review included studies published over the past 30 years focused on comparing the clinical outcomes of women with and without endometriosis, or, among those with endometriosis, women with and without chronic pelvic pain.

A meta-analysis from 24 studies involving a total of 99,614 women revealed that those with endometriosis had significantly higher levels of depression than those not affected by the disease. This effect was even stronger when the researchers performed the same type of analysis on 11 studies (1,070 women) comparing between healthy women and those with endometriosis.

Further analysis showed that women with endometriosis who also experienced chronic pelvic pain had higher levels of depression than those who did not report pain.

However, no significant differences were found between women with endometriosis and chronic pain and those with chronic pain not affected by the disease.

“The findings of our multiple meta-analyses provide converging evidence that chronic pain, rather than endometriosis itself, is the main determinant of depressive symptoms,” the researchers wrote. “Screening for psychiatric symptoms among women with endometriosis has therefore been advocated, and our findings would suggest to particularly direct it to those with chronic pain.”

“Future studies into possible modulators of the association will hopefully provide further insights about how to improve the quality of life of women with endometriosis and/or pelvic pain,” they concluded.


My opinion

In our effort to provide personalized care in patients with endometriosis, the impact of chronic pelvic pain on the quality of life should be taken into consideration. Such patients might benefit from psychological assessment and possibly treatment for depression.

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image credit https://www.medicalnewstoday.com/articles/301822.php

Endometriosis and endometrial cancer have common genetic causes

Endometriosis and endometrial cancer have common genetic causes

By I. Soussis MD

Both endometriosis and endometrial cancer have a genetic component. Genome-wide association studies (GWAS) identifying single nucleotide polymorphisms (SNPs) -differences in a single DNA building block, called a nucleotide-  associated with either disease.

Endometriosis and endometrial cancer may be linked, as suggested by the fact that higher levels of estrogen increase the risk for both diseases, which, in turn, is lessened with treatments such as contraceptive pills and hormonal therapies.

Moreover, both disorders correlate with greater risk for uterine fibroids and ovarian cancer. Further suggesting the link, cancer-related genetic changes, including dysregulation of genes, have been reported in endometriosis.

The new study, “Genetic overlap between endometriosis and endometrial cancer: evidence from cross‐disease genetic correlation and GWAS meta‐analyses,” appeared in the journal Cancer Medicine.

Epidemiological studies have led to conflicting data regarding this potential association, which may have been due to small sample sizes, underdiagnosis and misdiagnosis of endometriosis, and inability to adjust for variables such as oral contraceptives, the scientists said.

As such, they conducted a GWAS, using separate datasets for endometriosis and endometrial cancer to study the extent of a common genetic cause for both diseases. 

The team subsequently combined the datasets in a meta‐analysis – a statistical study that combines the results of various studies — to find genetic loci, or specific spots in chromosomes, potentially associated with risk for both disorders.

In total, the datasets for endometriosis included 3,194 cases and 5,330 controls, while those for endometrial cancer had 2,057 cases and 3,866 controls. Results of the meta‐analysis were compared with those from a dataset including 4,402 endometrial cancer cases and 28,758 controls.

The results revealed the presence of weak to moderate, but significant, genetic overlap between the  diseases, as well as significant SNP pleiotropy, which refers to disease-associated SNPs correlating with variation in gene expression and/or DNA methylation -the addition of a methyl chemical group to DNA, regulating gene expression- in both disorders.

Thirteen distinct loci were associated with the diseases, with one locus -SNP rs2475335- located within the PTPRD gene, associated at a significant level. PTPRD is a commonly inactivated gene across different types of cancer. Deletions and mutations in this gene have been detected in numerous tumor types, including endometrial cancer. The PTPRD protein regulates the activation of STAT3, a transcription factor -proteins that control gene expression- previously implicated in both endometriosis and endometrial cancer.

The other identified risk loci contain candidate genes such as SKAP1, associated with ovarian cancer, potentially relevant as causes and/or treatment targets of endometriosis and endometrial cancer, the investigators said.

“Our genetic study indicates that endometriosis and endometrial cancer have a moderate, but significant, shared genetic etiology,” the researchers said. Studies are now needed to better understand how the identified risk loci affect both diseases, the team stated.

“Our genetic correlation analysis supports recent large epidemiological studies indicating an increased risk of endometrial cancer in women previously diagnosed with endometriosis,” according to the researchers.

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Endometriosis can also affect adolescents

Endometriosis can also affect adolescents

By I.Soussis MD

Although endometriosis is commonly characterized as a disease affecting adult women of reproductive age, a review article compiled by an international panel of experts and published in Best Practice & Research Clinical Obstetrics and Gynaecology highlighted that it can also affect adolescents and younger women.

In addition, the authors reported that many women may experience their first symptoms in their teen years, but that they may not be recognized as indicative of endometriosis until later in their lives.

Risk factors for endometriosis in adolescents and young women include:

  • congenital abnormalities of the Müllerian duct  (due to increased incidents of retrograde menstruation),
  • first-degree relative with endometriosis, which accounts for approximately 50% of the risk for developing the disease,
  • early onset of menses,
  • prolonged menstruation (> 5 days),
  • short menstrual cycle interval (< 28 days), and
  • early-onset dysmenorrhea.

Studies have also reported associations between endometriosis and exposure to passive smoke during childhood and elevated levels of 2,4-dihydroxybenzophenone (found in sunscreens).

Other risk factors include premature birth, low body mass index, high caffeine or alcohol intake, and acne.

Consumption of soy formula as an infant has been observed to double the risk of endometriosis compared to that in women who were not exposed to dietary soy isoflavones as infants, reported the authors.

Potential protective factors identified:

  • use of oral contraceptives (OCs)
  • regular exercise
  • onset of menses after age 14
  • increased intake of omega-3 fatty acids

Black and Hispanic race compared to white or Asian race may also offer some degree of protection.

Symptoms and signs in adolescents:

Endometriosis lesions often have a different appearance in adolescents than in adults when visualized on laparoscopy: ovarian endometriomas and deep endometrial lesions are more the norm compared to powder-burn lesions seen in adult women.

Ovarian endometriomas are typically filled with “syrup-like chocolate material” and are surrounded by duplicated ovarian parenchyma. They have fibrotic walls and adhesions on the surface, according to the authors and are lined by endometrial epithelium, stroma, and glands. They are typically visualized in the rectovaginal septum, rectum, rectosigmoid colon, bladder, ureter, uterine ligaments, and vagina.

As in adults, the lesions should be staged from minimal disease (Stage 1) to severe disease (Stage 4), based on their size, location, and the types seen, and the extent of adhesions.

Distinguishing primary dysmenorrhea from endometriosis:

Many teens present with dysmenorrhea, which in light of the new information about the development of endometriosis in adolescents and young women should be evaluated to rule out endometriosis.

In adolescents with endometriosis, dysmenorrhea tends to be the first symptom of the disease and increases in severity over time. The pain is both cyclic and acyclic and interferes with school attendance, social activities, and exercise. Teens who are sexually active often report dyspareunia and gastrointestinal distress.

The clinical diagnosis can be verified with pelvic ultrasound and magnetic resonance imaging (MRI), but laparoscopy is the only way to obtain a definitive diagnosis.

The disease is unlikely to resolve spontaneously and is typically treated with nonsteroidal anti-inflammatory drugs, oral contraceptives, and progestin-only contraceptives. Laparoscopy and surgery may be an option for adolescents who fail to respond to medical therapy.

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Is medical cannabis effective as a treatment for endometriosis?

Is medical cannabis effective as a treatment for endometriosis?

By. I.Soussis MD

Studies show that medical cannabis has a positive effect on symptoms of endometriosis and may even stop its proliferation, according to Moshe Hod, a Tel Aviv University medical school professor of obstetrics and gynecology and president of the European Association of Perinatal Medicine. Moshe Hod is also head of Gynica, an Israeli startup specializing in cannabis-based solutions in the field of women’s health.

According to Gynica, the female reproductive system contains the most endocannabinoid receptors in the human body, after the brain.

Gynica is the first company that will carry out research and development at the newly licensed Lumir Lab.

Israel is extending its reputation as a world leader in medical cannabis research with the establishment of Lumir Lab (a cannabinoid research lab) at the campus of the Hebrew University of Jerusalem. Cannabinoids is one of the active ingredients unique to the cannabis plant.

The lab is headed by Czech analytic chemist Lumír Ondřej Hanuš, one of the world’s leading cannabinoids researchers.

Gynica and the Lumir Lab will collaborate on a treatment for endometriosis, a disease common in women that is defined by abnormal extrauteral growths of uterine endometrial tissue and associated with severe pain. Partly because how the abnormal growths become associated with pain is poorly understood, the pain is difficult to alleviate without resorting to hormones or surgery.

Recent studies showed that sensory and sympathetic nerve fibers sprout branches to innervate the abnormal growths. This situation, together with the knowledge that the endocannabinoid system is involved in uterine function and dysfunction and that exogenous cannabinoids were once used to alleviate endometriosis-associated pain, suggests that the endocannabinoid system is involved in both endometriosis and its associated pain.

Approximately 180 million women suffer from endometriosis worldwide.

“More research is needed in order to understand the mechanisms of action and identify which active cannabinoids most effectively eliminate endometriotic lesions, prevent recurrence and reduce pain with no negative impact on the ovulation cycle” professor Moshe Hod said.

“Currently, the vast majority of the cannabis products available in various markets have no scientific basis, which prevents the medical community from supporting the legitimacy of treatments based on cannabis,” said Hod. “We aim to provide tools and solutions that are not currently available.”

Israel has one of the world’s most progressive regulatory frameworks for medical cannabis.




Image credit: https://www.health.harvard.edu/diseases-and-conditions/endometriosis2


Surgery improves pregnancy odds for women with colorectal endometriosis

Surgery improves pregnancy odds for women with colorectal endometriosis

By I Soussis MD

Secondary analysis of results from a French trial investigating the effects of surgical management of colorectal endometriosis found that the intervention effectively improved postoperative fertility rates, including the ability to conceive naturally. 

The study is one of the first to evaluate the impact of first-line surgery on pregnancy rates in this population.

First-line assisted reproductive technology (ART) is the recommended strategy for improving pregnancy rates in women with endometriosis, but is a subject of controversy in the gynecological community due to a lack of high-quality data comparing it to surgical management. 

In addition, the European Society of Human Reproduction and Embryology (ESHRE) has reported that there was no evidence that surgical management of deep endometriosis would improve pregnancy rates prior to ART.

The study population consisted of 55 women from the ENDORE (Functional Outcomes of Surgical Management of Deep Endometriosis Infiltrating the Rectum) randomized trial conducted between March 2011 and August 2013 who wished to conceive. 

ENDORE was an unblinded, parallel-arms, controlled trial designed to determine if conservative rectal surgery was superior to segmental resection in women with colorectal endometriosis.

All of the women had deep endometriosis reaching into the rectum up to 15 cm from the anus with lesions measuring more than 20 mm in length. The endometrial lesions at minimum involved the muscular layer in depth and up to half of the rectal circumference. Twenty-five subjects underwent a conservative surgical procedure (shaving or disc excision) and 30 had radical rectal surgery (segmental resection). The surgeries were all performed by the same gynecologist. Subjects were followed for 50 to 79 months.

Of 36 patients who wanted to become pregnant after surgery, 23 (63%) had tried unsuccessfully prior to surgery for more than a year (the infertile group). After surgery, 29 patients became pregnant (81%), and some had more than one pregnancy, for a total of 37 pregnancies. Odds of postoperative conception improved over time.


Probability of Pregnancy After Surgery

At 12 months At 24 months At 36 months At 48 months
33.4% (95% CI: 20.6-51.3%) 60.6% (95% CI: 44.8-76.8%) 77% (95% CI: 61.5-89.6%) 86.8% (95% CI: 72.8-95.8%)

Overall, 17 women became pregnant naturally and 12 used ART (in vitro fertilization, intrauterine insemination, or oocyte donation). Looking specifically at the 23 infertile women, three-quarters (17) were able to conceive, and half of the pregnancies occurred naturally.

In total, 24 of the 37 pregnancies occurred as a result of natural conception, and subjects who were advised by their physicians to try to conceive naturally got pregnant significantly earlier than subjects who were referred for ART (P= 0.008).

Although the study had a small sample size, was subject to possible ascertainment bias  and preoperative and postoperative fertility assessments were not performed for all women, the trial was prospective with long-term follow up. 

It showed that fertility and the ability to conceive naturally can be restored by first-line surgery in women who are infertile due to colorectal endometriosis, perhaps in part due to the ability of women with endometriosis-related severe dyspareunia to engage in regular sexual intercourse postoperatively.

The authors stopped short of recommending that surgery for infertility be recommended over ART until more studies are performed. They suggested that in the interim “Physicians should ultimately offer patients a balanced perspective of the potential benefits and potential harms of alternative options.”

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Source: http://www.contemporaryobgyn.net/endometriosis/does-surgery-improve-pregnancy-odds-women-colorectal-endometriosis?rememberme=1&elq_mid=3948&elq_cid=550575&GUID=337689F9-99FE-489C-A600-B32594ED6E4B


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