Trans, gender-diverse people with endometriosis fight ‘double battle’ against pain and lack of recognition
Menstrual-related condition affects 1 in 10 people with a uterus — but is usually seen as affecting women only
Julie Landry * CBC News
Posted: Mar 31, 2021

The day Sally Zori went to the hospital in Vancouver for their hysterectomy, the journey from the registration desk to the operating table was punctuated by astonished questions about their name, their ID, their gender and their appearance.

Zori, a transgender person who was assigned female at birth, was suffering from the excruciating pain of endometriosis and opted to have a hysterectomy to relieve the symptoms. But their interaction with hospital staff before the operation elicited a different kind of pain.

“[The nurse] hands me a pink hospital gown and leads me to the women’s locker-room to change. I look at her and say, ‘Don’t you think it would be a better idea to take me to the men’s locker-room?'” recalls Zori, 35.

Zori has not had lower surgery, but they have a beard and no breasts. “I am very clearly 100 per cent a man,” they say.

“For me, the biggest challenge was the constant having to prove who I was, a legitimate human. And I notice this across the board in the medical field.”

1 in 10

For those people with a uterus who don’t identify as a woman, such dehumanizing experiences make it even more difficult to live with endometriosis, a menstrual-related condition causing agonizing pain that has been little researched and is often misdiagnosed.

Zori, who lives in Vancouver, had experienced painful periods their whole life, but didn’t know they had endometriosis until they ended up in the emergency room due to the pain. They were quickly referred to a specialist who confirmed the diagnosis.

Endometriosis affects one in 10 people with a uterus. It occurs when tissue similar to the lining of the uterus implants in the pelvic cavity to form lesions, cysts and other growths, according to Endometriosis Network Canada. This can cause pain, internal scarring, infertility and other medical complications.

Relatively little research has been done on the causes, treatment and a potential cure for the condition, which has left many women who suffer from it short of physical, mental and emotional support.

But the struggle for recognition is even greater for transgender and gender-diverse people with the condition, who feel forgotten because endometriosis is often seen as a problem only for women.

Many are now demanding greater inclusivity in the fight to get endometriosis better recognized by health-care workers and researchers.

Surprise diagnosis

Some people think their gender was likely the reason they lived with endometriosis longer than they should have.

Like Zori, Eli — CBC has agreed not to use their last name because they don’t want to be identified in their workplace — only found out they had the condition when they ended up in a Vancouver hospital. In Eli’s case, it was after emergency surgery.

“It was a total surprise,” says Eli, 33, who identifies as non-binary.

Eli, who lives in Vancouver, says endometriosis was never considered in their case, even though they had endured common symptoms of the condition for years, including chronic pain in the neck and lower back and intense pelvic pain during their period.

“I do often wonder if I was more stereotypical cis female presenting, if that would have been linked, because it just wasn’t in my case,” says Eli, who continues to suffer chronic pain, affecting the amount of work they can do every day.

‘Super-gendered disease’

For Terri, another endometriosis sufferer, the pain of menstruation seemed to evoke the pain felt living in the body they were assigned at birth — a form of distress known as gender dysphoria.

“I would even say that maybe it was because of the endometriosis that I realized I was non-binary because it gave me so much trouble. Maybe if I had had a normal period it would have had a completely different outcome,” says Terri, whose last name CBC has agreed to withhold because their family doesn’t yet know Terri is non-binary.

Terri ended up in the emergency room several times due to the pain of endometriosis and eventually had to stop working. The suffering and stress caused by the condition led to suicidal thoughts, they say.

Terri, who lives in Toronto, has been given a respite from the physical pain thanks to a combination of medication and an intrauterine device. But the mental and emotional toll of constantly having to explain their gender and condition remains.

“Sometimes it’s exhausting having to explain to everyone and having to educate everyone … Not only on gender, but also on endometriosis, especially since it’s a super-gendered disease. It’s like a double battle,” Terri says.

They would like to be able to navigate a more inclusive health-care system and support groups, including information and awareness sessions with medical staff.

“The language needs to change a bit to include other people,” Terri says.

Available support

That’s one of the tasks being undertaken by Trans Care B.C., the first provincial body responsible for supporting a network of gender-affirming care.

Nurse educator Lauren Goldman is one of the organization’s staff developing training materials, also available online, for medical providers to feel more confident treating transgender and gender-diverse patients.

She says Trans Care B.C. can help patients connect with a health provider who is comfortable and has experience working with such patients.

But Goldman agrees there is much to improve.

“We know that gender-diverse people experience health inequities that are related to sexual and reproductive health care,” she says.

“Many patients share that they have experiences of significant body dysphoria and a lot of physical and emotional discomfort during physical exams, inadequate screening and also low service expectations.”

‘Endo warriors’

Endometriosis advocacy groups have already taken steps to address the added challenges faced by gender-diverse people living with the condition.

The website for Endometriosis Network Canada, for example, makes it clear that it’s not exclusively a “women’s condition.”

The organization’s blog co-ordinator, Maia Leggott, wrote a widely shared article for the website titled, It’s Time for the Endometriosis Community to Drop Gendered Language, which proposes, among other things, using the term “endo warriors” as a term of solidarity instead of “endo sisters.”

Leggott, a cisgender woman, admits she had to learn to use more inclusive language. She follows support groups and sometimes sees tough interactions between cisgender women and trans and non-binary people.

“It’s not always easy and it takes a lot of emotional labour for trans and non-binary folks to constantly be defending their identity,” Leggott says.

Human first

Zori’s hysterectomy was ultimately successful in stopping the symptoms of endometriosis.

But they still dream of a world where everyone is seen as human first. They would like medical forms to contain more than “male” and “female” checkboxes, but many boxes or one where each situation can be explained.

And they want an open endometriosis community in which no one feels sidelined because of their identity. After all, Sally says, women themselves have been marginalized for centuries.

“Now it’s time for us to include all the rest of the marginalized people,” Sally says.

Transgender People with Endometriosis Often Suffer in Silence
By Laken Brooks
October 14, 2021

Before reading this article, you may consider referring to these vocabulary terms:

• Cisgender: The state of identifying your gender with the sex you were assigned at birth
• Transgender: The state of not identifying your gender with the sex you were assigned at birth. For example, a person who is born with a uterus may not identify as being a woman.
• Nonbinary: The state of not identifying your gender as being exclusively male or female, or identifying your gender outside of the gender binary altogether

Because health researchers tend to label menstrual illnesses as “women’s diseases,” some trans people may not recognize their symptoms as warning signs for endometriosis.

Being diagnosed with endometriosis can make you feel like you’re invisible. Historically, doctors have underestimated menstrual pain. But transgender and nonbinary patients often face an additional layer of frustration as they fight for equitable healthcare.

We need better reproductive education
One major obstacle for all menstruating people is the dearth of reproductive education. In middle school, I and my female-identifying friends were shuffled off to a basement classroom where a kind nurse showed us pads, told us how to tie a jacket around our waists to hide leaks, and warned us against having sex. Many sex ed courses, like the one I experienced, do not describe important anatomical details of a period: how the texture and color of your blood can change, how to differentiate between normal cramps or something more serious, and how much bleeding is normal.

Challenges for transgender students
Many children are left to discover these important reproductive realities on their own. I had never heard the word “endometriosis” until I was in my twenties. But transgender students carry an especially heavy burden. Because sex ed courses often divide up male and female students, transgender adolescents fall through the gaps. If a transgender student attends the sex ed course that corresponds with their genitalia, that student may risk outing themselves. They may feel unwelcome in a “girl’s class” when they do not identify as a girl. Therefore, some trans students miss out on important lessons about their periods.

Recognizing endometriosis warning signs
Because health researchers tend to label menstrual illnesses as “women’s diseases”, some trans people may not recognize their symptoms as warning signs for endometriosis. It’s difficult to know just how many trans patients suffer in silence with endometriosis. In fact, only a handful of scientific studies have analyzed the topic. But in a 2020 article in Journal of Pediatric and Adolescent Gynecology, researchers found that the majority of trans people with endometriosis are diagnosed after they’ve transitioned their gender.¹ Even after a transgender male patient begins testosterone therapy, he can still have painful symptoms and complications in his uterus.

Delayed diagnosis
Although transgender people can also experience endometriosis, they are less likely than cisgender women to seek diagnosis. Why? Many patients rely on their OB/GYN to perform tests and assess their risk for endometriosis. But most transgender people do not feel safe when visiting a gynecologist. Some reasons why these patients may feel uncomfortable include the following: gendered intake forms, medical discrimination, judgmental doctors, and harassment.

Researchers in Ontario interviewed transgender men in their community to ask about their experiences with gynecological care.² Of this group, 92% of patients were anxious about visiting a gynecologist. More seriously, 54% had actively avoided getting screenings, pap smears, or other important treatments. Without visiting a gynecologist, transgender people face an uphill battle in getting diagnosed for endometriosis.

How medical professionals can meet the needs of trans patients
Fortunately, medical professionals and health advocates can be better allies. Here are some suggestions for how you can be more inclusive to transgender endometriosis patients:

• Use phrases like “people with endometriosis” or “menstruating people”
• Encourage your local healthcare providers to relabel their “women’s services” as “menstrual services”
• Encourage your OB/GYN to include more gender and sex options on their intake paperwork
• Support your local LGBTQ+ health organizations
• Support and follow groups like ThemsHealth, which is a social media platform that highlights trans-friendly health professionals who talk about wellness issues.

Endometriosis isn’t just a woman’s issue — it’s a human issue. And together, we can push to make menstrual care and education more accessible to every person of every gender.

Hey all, just wanted to let you know that I have discovered an issue with font rendering on this website. I’m correcting blog entries as I discover them. I’m going to have to go back to pasting articles into a different word processor and cleaning them up there before pasting into Word Press here.

As always, I use this blog as a sort of archive for everything endometriosis, and sometimes I do not have a lot of time to spend on this site, so I do a hasty copy-paste. I apologise. I do always make sure you have the source link to the actual news article, magazine article, biography or research report, though.

Much love to my endo siblings, stay strong!

France formally recognises endometriosis as ‘long-term condition’
The bill was passed unanimously through parliament. It means that all costs of care and treatment for the painful condition will now be covered by the state
14 January 2022
By Hannah Thompson

Endometriosis, a painful and debilitating condition that affects 1 in 10 women in France, has been formally recognised as a ‘long-term condition’ by the French parliament.

A “long-term condition” (affection longue durée (ALD)) in France means that care and treatment for the illness is completely covered by l’Assurance maladie.

The bill was put forward by political party (far-left) La France Insoumise, and l’Assemblée Nationale voted it through unanimously yesterday (January 13), with 111 votes for, and zero against.

MP for Seine-Saint-Denis Clémentine Autain, who presented the bill and wanted to have the definition “set in stone”, said the vote was “a giant step forward for millions of women”.

She said: “We can create a raft of rights for women who suffer. [This will especially help] poorly-paid women, those in precarious conditions, and the poorest [for whom the illness] is even more difficult to live with.”

Endometriosis is a disorder where tissue that usually lines the inside of the uterus grows outside the uterus, usually in the ovaries, fallopian tubes and pelvis. It can cause pain, bleeding, irritation, scar tissue, and even fibrous adhesions that can cause organs to stick together.

It can cause painful periods, pain during sex, painful bowel movements, excessive bleeding, fatigue, digestive issues, nausea, and infertility.

It can be difficult to diagnose and it still takes an average of seven years before women are diagnosed correctly.

The ALD decision comes two days after President Emmanuel Macron announced the launching of a national strategy to combat the illness.

He stated: “It’s not only a ‘women’s problem’. It’s society’s problem.”

The national plan will aim to boost understanding and awareness of the issue, as well as improve diagnosis rates and treatment plans.

The Worldwide Endometriosis March is LIVE now at:

10 Research-Backed Truths About Endometriosis
What Endometriosis Patients Want Healthcare Professionals to Know
Kristina Kasparian, PhD
March 13, 2022

If you read that title again, it may seem strange to you. Patients wanting physicians to know more about a medical condition? Isn’t that a little backward?

Although this debilitating health condition afflicts nearly 200 million individuals globally,^1,2 endometriosis (en-doe-me-tree-O-sis, “endo” for short) remains misdiagnosed³ and ineffectively treated⁴ due to the scarcity of research funding⁵ and specialized medical training,⁶ as well as due to stigmas⁷ and biases^8,10 that impede patients’ timely access to healthcare.

Studies have shown that it can take six to twelve years¹¹ and consultations with five or more doctors¹² to diagnose endometriosis. Once a person is finally diagnosed, management remains challenging given the systemic¹³ nature of the disorder and its impact on the patient’s whole body, mental health, and quality of life.

Endometriosis patients have the added burden of having to be tireless advocates for their condition to catalyze change in how endo is perceived, discussed, diagnosed, and treated worldwide.

Here are 10 research-backed truths that endometriosis advocates would like medical staff (and the general public) to know about endo.

1. The definition of “endometriosis” needs updating in clinical practice

Endometriosis is a condition where tissue similar (but not identical) to the lining of the uterus grows elsewhere in the body.^14,15 This tissue creates inflammation, internal bleeding and fibrous scar tissue formation, restricts normal organ functioning, and causes chronic pain, interfering with fertility.¹⁶

Traditional definitions describe endometriosis as a condition where the endometrium (the lining of the uterus) grows outside the uterus as an ectopic or rogue form of the “normal” endometrial tissue. However, research analyzing immune cell dysfunctions and genetic pathways for endometriosis has demonstrated that endometriosis lesions have qualitatively different, pro-inflammatory and fibrotic properties than the “normal” endometrium that lines the uterus.¹⁷ Endometriosis lesions also have the capacity to produce their own estrogen¹⁸ from the local production of aromatase, which is not typically found in the uterine lining.^19,20

Despite these findings, many prominent clinical centers and high-ranking websites continue to inaccurately define endometriosis as a condition where the endometrium grows outside of the uterus. Why is this such an important distinction to make? Besides ensuring that clinical practice reflect actual scientific data, it’s important to get this distinction right because it informs medical treatment.

Treatments recommended for endometriosis typically include hormonal suppression, pregnancy or even hysterectomy, all with the same underlying goal of suppressing estrogen production by the ovaries and blocking menstruation. Unfortunately, these “treatments” do not necessarily stop the progression of endometriosis. A hysterectomy that leaves behind endometriosis outside the uterus is obviously ineffective. Hormonal therapies cause considerable side-effects and are not a one-size-fits-all solution for all patients. Though pregnancy is often encouraged by physicians as a method of rendering any endometriosis dormant, scientific findings have shown that pregnancy is not reliably associated with the regression of endometriosis lesions nor with improved symptoms, and that endometriosis may continue to advance²¹ during pregnancy.

(Side note: Patients find it psychologically triggering when offered pregnancy as a cure for their illness, when not all patients wish to become parents and over 50% of endometriosis patients struggle with infertility.)

2. A painful period is not the only symptom of endometriosis

Traditionally, endo is described as a (horrendously, debilitatingly, life-interruptingly) painful period. Very often, this (horrendous, debilitating, life-interrupting) pain is normalized and trivialized.²² Though painful menstruation is one of its hallmark symptoms, it is not necessarily the first symptom to appear, nor is pain limited to the time surrounding one’s period or ovulation.

Endometriosis is a complex, whole-body disease that impacts every bodily system.²³ Though not all individuals with endometriosis will have the same range or severity of symptoms, the condition can afflict the digestive, respiratory, urinary, reproductive, immune, lymphatic, musculoskeletal and nervous systems. As a result, the condition can cause a wide range of symptoms,²⁴ often clustering together, such as: extremely painful periods, painful sex, painful or difficult bowel movements, difficulty getting pregnant, bloating, abdominal/pelvic pain any time during the month, back pain, nausea and vomiting, constipation, diarrhea, food intolerances, allergies, brain fog, leg pain or numbness, urinary pain or dysfunction, chest pain, difficulty breathing, lung collapse, heavy or irregular bleeding, chronic anemia, fatigue, mood disturbances, vulvodynia, pain with tampons, migraines…Phew, that’s a long list!

Patients who complain about urinary or digestive issues are often misdiagnosed with urinary infections or irritable bowel syndrome,²⁵ though endo should be suspected and discussed early on. General practitioners, gynecologists and gastrointestinal specialists — who are often the first physicians seen by patients seeking to get to the bottom of their symptoms — must attentively listen for clues and ask the right questions to evaluate the patient’s full range of symptoms and how they may cluster together.

“It could be endometriosis” should be a sentence that patients hear during their first appointment(s) and not after a decade since their consultation with that very first physician who sent them home with Tylenol.

3. Endometriosis is not “just” a gynecological or reproductive condition

Endometriosis is not limited to the ovaries, nor to the pelvic region. It is not as rare as previously thought for endometriosis to involve extra-pelvic regions²⁶ like the urinary system (eg, bladder, ureters, kidneys), the digestive system (eg, intestines), and the thoracic region (eg, diaphragm, lungs, liver). Endo disrupts the functioning of the nervous system causing central sensitization,²⁷ a heightened response²? or hyperexcitability of the nervous system as a result of persistent pain. Given its whole-body nature, the treatment of endometriosis should not solely rely on a gynecologist but requires the involvement of a multidisciplinary team^29,30 with targeted pain management strategies.³¹

Research has also increasingly shown that endometriosis may not have one single disease pathway³² and has not yet been reliably associated with specific biomarkers.³³ Alterations and abnormalities in the endocrine and immune systems have been documented,^34,35 suggesting once again that the condition deserves more attention as a complex systemic disorder.

Endometriosis needs to be defined and treated as a systemic, multi-specialty condition and not “simply” a gynecological or reproductive disorder.

4. Imaging and colonoscopy are not enough to rule out endometriosis

One of the reasons for long diagnostic delays is the way that scans such as ultrasounds, CTs or MRIs are ordered and interpreted by radiologists and physicians. Extra-pelvic regions are not always thoroughly investigated when a physician orders a scan focusing on the pelvis. In addition, “normal” findings are typically interpreted as a lack of disease, and the patient is left without an explanation for their debilitating symptoms.

Experts argue that endometriosis cannot currently be ruled out by imaging. Endometriosis lesions are highly variable and take on many different appearances. Even on MRI, certain types of lesions and locations are more difficult to visualize.³⁶ Researchers focusing on the diagnostic accuracy of ultrasound methods have shown that sonographers should be trained on a systematic approach³⁷ to detect endometriosis. The sensitivity of imaging methods for diagnosing endometriosis is experience-dependent; results depend on the expertise of the person interpreting the scan.³⁸ Additional training and research are required before imaging methods can be considered a reliable tool for early diagnosis.

Patients complaining of digestive disturbances and intestinal issues are sometimes sent for a colonoscopy, but given that endometriosis rarely goes through the full thickness of the bowel’s layers, it would not be seen during a colonoscopy. A normal colonoscopy, however, cannot rule out endometriosis on the bowel or involvement of nearby structures irritating the bowel due to inflammation or fibrous adhesions. A study comparing pre-operative colonoscopy results with surgical findings showed that colonoscopy failed to detect 92% of cases of bowel involvement in endometriosis patients.⁴⁰

Though imaging protocols and interpretations should definitely be improved and standardized for earlier diagnosis and better surgical planning, the only definitive way to diagnose endometriosis remains laparoscopic surgery and histopathology of the excised tissue.⁴⁰

5. Early teens can have endometriosis before their first period

Patients are sometimes told they are “too young” to have endo, which continues to be erroneously defined as a menstrual problem. Clinical reports and research have shown that endometriosis lesions are found in young patients even before their first period^41,42 and that 70% of teens complaining of chronic pelvic pain were later diagnosed with endometriosis.⁴³ Diagnostic delays of up to twelve years can be reduced if young patients’ first complaints of abdominal or pelvic pain are taken more seriously.⁴⁴

6. Excision surgery is the gold standard to treat endometriosis

Surgery is typically considered a last resort and medical management of endometriosis is commonly suggested as the first-line treatment for endometriosis. Although hormonal therapy may effectively mask endometriosis symptoms in some — but not all — patients, the gold standard to remove the disease is to cut out (excise) the aberrant tissue from its root⁴⁵ rather than to burn it off the surface (ablate). Ablation or coagulation is a superficial approach that leaves the disease behind and results in poor outcomes, higher reoperation rates, and increased pain.⁴⁶ Despite these results, ablation (rather than excision or resection) remains the most widespread surgical approach for endometriosis.

Though minimally invasive, this surgery is not to be downplayed, unlike the way it was recently portrayed on Grey’s Anatomy (S18e10), where the patient was almost immediately diagnosed with endometriosis at the hospital, recommended surgery and told, “Let’s see if we can get it done today!” Endometriosis surgery is one of the most complex and specialized types a surgeon can perform.⁴⁷ According to surgical specialist Dr. Aileen Caceres, a patient’s anatomy is often so distorted by endometriosis that it can take two or more hours to establish normal anatomy before any endometriosis excision can even begin. Excision surgery is not a simple surgery any gynecologist can perform. The multidisciplinary input of colorectal or urologic surgeons is also often necessary.

Additional funding and medical training are imperative to increase the number of specialists worldwide for a condition afflicting 200 million people. Surgery is neither promptly nor financially accessible to patients, many of which have to travel and pay out of pocket for expert care.

7. Chronic pain must be treated in parallel

Access to pain management is a human right^48,49 and endometriosis pain should never be underestimated or dismissed as attention-seeking, drug-seeking, or depressive behavior.

In spite of being the only method of removing endometriosis, excision surgery is not a magical fix that alleviates the patients’ symptoms overnight. There are a number of possible pain generators besides the lesions themselves. After years of persistent inflammation, pain and physical/emotional trauma, the central nervous system has adapted to endometriosis and must be retrained. It has been well documented that persistent pain leads to poor posture and impacts the musculoskeletal system. Endometriosis patients frequently also suffer from pelvic floor dysfunction, vulvodynia, interstitial cystitis, and other pain syndromes due to higher muscle tension and a decreased ability to coordinate or relax muscles.³¹ The central nervous system has learned to live under repeated threat, in fight-or-flight mode, which heightens the brain’s perception of pain.⁵⁰ Shorter diagnostic delays would reduce the damage caused to the nervous system.

Complementary measures help decrease inflammation and tone down the heightened response of the nervous system, such as physiotherapy and pelvic floor rehabilitation, osteopathy, dietary changes, mindfulness, pain medication, muscle relaxants, cognitive behavioral therapy, or transcutaneous electrical nerve stimulation (TENS). A multidisciplinary approach is most effective in managing endometriosis, in parallel with surgical approaches.^29,30

8. A diagnosis is not optional, even if the condition is “benign”

Many healthcare providers prefer managing endometriosis medically, with an official (surgical) diagnosis considered optional and unnecessary. In their view, if symptoms can be attenuated through medical management, with hormonal therapy or pain medication, it’s a win for everyone. A risky surgery is avoided, wait times are reduced, and surgery resources are reserved only for those patients for whom all other treatments fail.

The problem is that medical management is not a viable solution for a huge proportion of endometriosis sufferers, including patients who wish to become pregnant. The side-effects are often debilitating, sending patients spiraling further into despair as they don’t feel like themselves and can’t get a handle on their daily routine. This trial-and-error wait-and-see strategy may seem like the less invasive option, but it allows endometriosis to invade every facet of the patient’s existence and costs them years of their life.

The relief reported by millions of patients worldwide when they recall waking up from surgery and being told they had advanced endometriosis is proof that a diagnosis is a crucial first-step (not a last resort) to healing.

Endometriosis is categorized as a benign condition though research has documented its association with a number of severe comorbidities, including certain forms of malignancy — endometriosis has been linked to several other chronic⁵¹ and autoimmune⁵² diseases, a higher risk of ovarian⁵³ and breast cancer,⁵⁴ thyroid cancer,⁵⁵ melanoma,⁵⁶ and cardiovascular⁵⁷ disease. Patients with endometriosis are often also diagnosed with adenomyosis (endometriosis found in the muscle wall of the uterus), fibromyalgia, interstitial cystitis, fibroids or hernias, leading them to experience more pain. It is important for providers to consider the possibility of comorbidities.

Dr. Leonardi, endometriosis surgeon and sonographer, argues that “endometriosis is ignored because it is benign; it is time to treat endometriosis as if it were cancer.”⁵⁸

As a benign condition, endometriosis should not be fatal, but it has been. Patients have died from complications of their undiagnosed and untreated endometriosis, and 50% of endo sufferers report having contemplated suicide.⁵⁹

9. Endometriosis care is negatively affected by unconscious bias

The word hysteria originates from the Greek word for uterus. Historically, women’s complaints about pain have been taken less seriously. A study investigating gender bias in the treatment of pain revealed that women who went to the ER with acute abdominal pain had to wait longer to receive medical treatment for their pain than men presenting with the same symptoms.⁶⁰ Another study showed that men were more likely to be recommended analgesics for pain, while women were more likely to be recommended psychological treatment.⁶¹

Endo symptoms are taken even less seriously in people of color. African American women, for example, have reported being faced with myths that lead to their dismissal, such as beliefs that Black women are more likely to have painful periods or that they are drug seekers.⁶² Studies have shown that African American women are perceived as being less sensitive to pain due to thicker skin and less sensitive nerve endings than white patients⁶³ — biases that influence how likely they are to receive the care they deserve.

LGBTQA2S+ patients also run into serious barriers when trying to access healthcare. Not all individuals with a uterus identify as “woman”, but language in healthcare is not inclusive, with endo described as affecting “girls” and “women”. Gendered medical spaces like fertility clinics or gynecologist offices also leave patients feeling underrepresented and isolated. Trans or non-binary patients report hiding their gender identity from their physicians out of fear of not being able to access appropriate care.^64,65

10. Endo impacts quality of life and costs our economy billions

Endometriosis is a global health crisis that drastically reduces people’s productivity,⁶⁶ autonomy, social engagement, and overall quality of life.⁶⁷ Living with debilitating symptoms has a tremendously detrimental impact on patients’ mental health⁶⁸ and relationships.⁶⁹ Endometriosis incurs a cost of billions of dollars a year on the economy^70,71 and constitutes a serious global health crisis.

Endometriosis is a complex and severely debilitating condition that warrants multi-specialty care. Much can be done to increase research funding, specialized training opportunities, and public awareness of endo.

Above all, patients would like to remind practitioners that empathy can drive change. Empathy is what allows us to remain open-minded as humans, to listen attentively, to keep our biases in check, to recognize when something is beyond our realm of expertise, and to be curious to learn more to make lives better.

Empathy makes the invisible visible.

Follow Kristina Kasparian on Instagram for more endometriosis resources!

References

(1) Zondervan, K., Becker, C., & Missmer, S.A. (2020). Endometriosis. New England Journal of Medicine, 382, 1244–1256.

(2) Bontempo, A. C., & Mikesell, L. (2020). Patient perceptions of misdiagnosis of endometriosis: results from an online national survey. Diagnosis, 7(2), 97–106.

(3) Greene, R., Stratton, P., Cleary, S. D., Ballweg, M. L., & Sinaii, N. (2009). Diagnostic experience among 4,334 women reporting surgically diagnosed endometriosis. Fertility and sterility, 91(1), 32–39.

(4) Rolla E. (2019). Endometriosis: advances and controversies in classification, pathogenesis, diagnosis, and treatment. F1000Research, 8, F1000 Faculty Rev-529.

(5) As-Sanie, S., Black, R., Giudice, L. C., Valbrun, T. G., Gupta, J., Jones, B., … & Nebel, R. A. (2019). Assessing research gaps and unmet needs in endometriosis. American journal of obstetrics and gynecology, 221(2), 86–94.

(6) Leonardi, M., Lam, A., Abrão, M. S., Johnson, N. P., & Condous, G. (2020). Ignored because it is benign–it is time to treat endometriosis as if it were cancer. Journal of Obstetrics and Gynaecology Canada, 42(4), 507–509.

(7) Sims, O. T., Gupta, J., Missmer, S. A., & Aninye, I. O. (2021). Stigma and Endometriosis: A Brief Overview and Recommendations to Improve Psychosocial Well-Being and Diagnostic Delay. International Journal of Environmental Research and Public Health, 18(15), 8210.

(8) As-Sanie, S., Black, R., Giudice, L. C., Valbrun, T. G., Gupta, J., Jones, B., … & Nebel, R. A. (2019). Assessing research gaps and unmet needs in endometriosis. American journal of obstetrics and gynecology, 221(2), 86–94.

(9) Hoffman, K. M., Trawalter, S., Axt, J. R., & Oliver, M. N. (2016). Racial bias in pain assessment and treatment recommendations, and false beliefs about biological differences between blacks and whites. Proceedings of the National Academy of Sciences, 113(16), 4296–4301.

(10) Lowik, A. J. (2020). “Just because I don’t bleed, doesn’t mean I don’t go through it”: Expanding knowledge on trans and non-binary menstruators. International Journal of Transgender Health, 22(1–2), 113–125.

(11) Ballard, K., Lowton, K., & Wright, J. (2006). What’s the delay? A qualitative study of women’s experiences of reaching a diagnosis of endometriosis. Fertility and sterility, 86(5), 1296–1301.

(12) Ballweg, M. L. (2004). Impact of endometriosis on women’s health: comparative historical data show that the earlier the onset, the more severe the disease. Best practice & research Clinical obstetrics & gynaecology, 18(2), 201–218.

(13) Taylor, H. S., Kotlyar, A. M., & Flores, V. A. (2021). Endometriosis is a chronic systemic disease: Clinical challenges and novel innovations. The Lancet, 397(10276), 839–852.

(14) World Health Organization (WHO). International Classification of Diseases, 11th Revision (ICD-11) Geneva: WHO 2018.

(15) International Working Group of AAGL, ESGE, ESHRE and WES, Carla Tomassetti, Neil P Johnson, John Petrozza, Mauricio S Abrao, Jon I Einarsson, Andrew W Horne, Ted T M Lee, Stacey Missmer, Nathalie Vermeulen, Krina T Zondervan, Grigoris Grimbizis, Rudy Leon De Wilde, An international terminology for endometriosis, 2021,, Human Reproduction Open, Volume 2021, Issue 4, 2021.

(16) Bulletti, C., Coccia, M. E., Battistoni, S., & Borini, A. (2010). Endometriosis and infertility. Journal of assisted reproduction and genetics, 27(8), 441–447.

(17) Giacomini, E., Minetto, S., Li Piani, L., Pagliardini, L., Somigliana, E., & Viganò, P. (2021). Genetics and inflammation in endometriosis: Improving knowledge for development of new pharmacological strategies. International Journal of Molecular Sciences, 22(16), 9033.

(18) Mori, T., Ito, F., Koshiba, A., Kataoka, H., Takaoka, O., Okimura, H., … & Kitawaki, J. (2019). Local estrogen formation and its regulation in endometriosis. Reproductive Medicine and Biology, 18(4), 305–311.

(19) Bulun, S. E., Fang, Z., Imir, G., Gurates, B., Tamura, M., Yilmaz, B., … & Deb, S. (2004, January). Aromatase and endometriosis. In Seminars in reproductive medicine (Vol. 22, ?01, pp. 45–50).

(20) Mikhaleva, L. M., Radzinsky, V. E., Orazov, M. R., Khovanskaya, T. N., Sorokina, A. V., Mikhalev, S. A., … & Sinelnikov, M. Y. (2021). Current knowledge on endometriosis etiology: a systematic review of literature. International Journal of Women’s Health, 13, 525.

(21) Leeners, B., Damaso, F., Ochsenbein-Kölble, N., & Farquhar, C. (2018). The effect of pregnancy on endometriosis — facts or fiction?. Human reproduction update, 24(3), 290–299.

(22) Rubinsky, V., Gunning, J. N., & Cooke-Jackson, A. (2020). “I thought I was dying:”(Un) supportive communication surrounding early menstruation experiences. Health Communication, 35(2), 242–252.

(23) Taylor, H. S. (2019). Endometriosis: a complex systemic disease with multiple manifestations. Fertility and Sterility, 112(2), 235–236.

(24) Nezhat, C., Vang, N., Tanaka, P. P., & Nezhat, C. H. (2020). Optimal management of endometriosis and pain. Endometriosis in Adolescents, 195–204.

(25) Chiaffarino, F., Cipriani, S., Ricci, E., Mauri, P. A., Esposito, G., Barretta, M., … & Parazzini, F. (2021). Endometriosis and irritable bowel syndrome: a systematic review and meta-analysis. Archives of Gynecology and Obstetrics, 303(1), 17–25.

(26) Andres, M. P., Arcoverde, F. V., Souza, C. C., Fernandes, L. F. C., Abrão, M. S., & Kho, R. M. (2020). Extrapelvic endometriosis: a systematic review. Journal of Minimally Invasive Gynecology, 27(2), 373–389.

(27) Zheng, P., Zhang, W., Leng, J., & Lang, J. (2019). Research on central sensitization of endometriosis-associated pain: a systematic review of the literature. Journal of Pain Research, 12, 1447.

(28) As-Sanie, S., Harris, R. E., Harte, S. E., Tu, F. F., Neshewat, G., & Clauw, D. J. (2013). Increased pressure pain sensitivity in women with chronic pelvic pain. Obstetrics and gynecology, 122(5), 1047.

(29) Agarwal, S. K., Foster, W. G., & Groessl, E. J. (2019). Rethinking endometriosis care: applying the chronic care model via a multidisciplinary program for the care of women with endometriosis. International Journal of Women’s Health, 11, 405.

(30) Opoku-Anane, J., Orlando, M. S., Lager, J., Lester, F., Cuneo, J., Pasch, L., … & Giudice, L. C. (2020). The development of a comprehensive multidisciplinary endometriosis and chronic pelvic pain center. Journal of Endometriosis and Pelvic Pain Disorders, 12(1), 3–9.

(31) Mechsner, S. (2022). Endometriosis, an Ongoing Pain — Step-by-Step Treatment. Journal of Clinical Medicine, 11(2), 467.

(32) Tosti, C., Pinzauti, S., Santulli, P., Chapron, C., & Petraglia, F. (2015). Pathogenetic mechanisms of deep infiltrating endometriosis. Reproductive Sciences, 22(9), 1053–1059.

(33) Hudson, Q. J., Perricos, A., Wenzl, R., & Yotova, I. (2020). Challenges in uncovering non-invasive biomarkers of endometriosis. Experimental Biology and Medicine, 245(5), 437–447.

(34) Herington, J. L., Bruner-Tran, K. L., Lucas, J. A., & Osteen, K. G. (2011). Immune interactions in endometriosis. Expert review of clinical immunology, 7(5), 611–626.

(35) Kyama, C. M., Overbergh, L., Mihalyi, A., Meuleman, C., Mwenda, J. M., Mathieu, C., & D’Hooghe, T. M. (2008). Endometrial and peritoneal expression of aromatase, cytokines, and adhesion factors in women with endometriosis. Fertility and sterility, 89(2), 301–310.

(36) Foti, P. V., Farina, R., Palmucci, S., Vizzini, I. A. A., Libertini, N., Coronella, M., … & Ettorre, G. C. (2018). Endometriosis: clinical features, MR imaging findings and pathologic correlation. Insights into imaging, 9(2), 149–172.

(37) Leonardi, M., & Condous, G. (2018). How to perform an ultrasound to diagnose endometriosis. Australasian journal of ultrasound in medicine, 21(2), 61–69.

(38) Alborzi, S., Rasekhi, A., Shomali, Z., Madadi, G., Alborzi, M., Kazemi, M., & Nohandani, A. H. (2018). Diagnostic accuracy of magnetic resonance imaging, transvaginal, and transrectal ultrasonography in deep infiltrating endometriosis. Medicine, 97(8).

(39) Milone, M., Mollo, A., Musella, M., Maietta, P., Fernandez, L. M. S., Shatalova, O., … & Milone, F. (2015). Role of colonoscopy in the diagnostic work-up of bowel endometriosis. World Journal of Gastroenterology, 21(16), 4997.

(40) Rafique, S., & Decherney, A. H. (2017). Medical management of endometriosis. Clinical obstetrics and gynecology, 60(3), 485.

(41) Marsh, E. E., & Laufer, M. R. (2005). Endometriosis in premenarcheal girls who do not have an associated obstructive anomaly. Fertility and sterility, 83(3), 758–760.

(42) Troìa L., Biscione A., Colombi I., Luisi S. (2021) Management of Endometriosis in Teenagers. In: Genazzani A.R., Nisolle M., Petraglia F., Taylor R.N. (eds) Endometriosis Pathogenesis, Clinical Impact and Management. ISGE Series. Springer, Cham.

(43) Yeung Jr, P., Sinervo, K., Winer, W., & Albee Jr, R. B. (2011). Complete laparoscopic excision of endometriosis in teenagers: is postoperative hormonal suppression necessary?. Fertility and sterility, 95(6), 1909–1912.

(44) Youngster, M., Laufer, M. R., & Divasta, A. D. (2013). Endometriosis for the primary care physician. Current opinion in pediatrics, 25(4), 454–462.

(45) Abbott, J. A., Hawe, J., Clayton, R. D., & Garry, R. (2003). The effects and effectiveness of laparoscopic excision of endometriosis: a prospective study with 2–5 year follow?up. Human Reproduction, 18(9), 1922–1927.

(46) Pundir, J., Omanwa, K., Kovoor, E., Pundir, V., Lancaster, G., & Barton-Smith, P. (2017). Laparoscopic excision versus ablation for endometriosis-associated pain: an updated systematic review and meta-analysis. Journal of minimally invasive gynecology, 24(5), 747–756.

(47) Redwine, D. (2013). Why is laser vaporization best avoided in the surgical treatment of endometriosis? Retrieved from http://endopaedia.info/treatment2.html

(48) Lohman D, Schleifer R, Amon JJ. Access to pain treatment as human right. BMC Medicine. 2010;8:8.

(49) Brennan F, Carr DB, Cousins M. Pain management: a fundamental human right. Anesth Analg. 2007;105(1):205–221.

(50) Nijs, J., George, S. Z., Clauw, D. J., Fernández-de-las-Peñas, C., Kosek, E., Ickmans, K., … & Curatolo, M. (2021). Central sensitisation in chronic pain conditions: latest discoveries and their potential for precision medicine. The Lancet Rheumatology, 3(5), e383-e392.

(51) Kvaskoff, M., Mu, F., Terry, K. L., Harris, H. R., Poole, E. M., Farland, L., & Missmer, S. A. (2015). Endometriosis: a high-risk population for major chronic diseases?. Human reproduction update, 21(4), 500–516.

(52) Shigesi, N., Kvaskoff, M., Kirtley, S., Feng, Q., Fang, H., Knight, J. C., … & Becker, C. M. (2019). The association between endometriosis and autoimmune diseases: a systematic review and meta-analysis. Human reproduction update, 25(4), 486–503.

(53) Gaia?Oltean, A. I., Braicu, C., Gulei, D., Ciortea, R., Mihu, D., Roman, H., … & Berindan?Neagoe, I. (2021). Ovarian endometriosis, a precursor of ovarian cancer: Histological aspects, gene expression and microRNA alterations. Experimental and Therapeutic Medicine, 21(3), 1–1.

(54) Kvaskoff, M., Mahamat-Saleh, Y., Farland, L. V., Shigesi, N., Terry, K. L., Harris, H. R., … & Missmer, S. A. (2021). Endometriosis and cancer: A systematic review and meta-analysis. Human reproduction update, 27(2), 393–420.

(55) Gandini, S., Lazzeroni, M., Peccatori, F. A., Bendinelli, B., Saieva, C., Palli, D., … & Caini, S. (2019). The risk of extra-ovarian malignancies among women with endometriosis: a systematic literature review and meta-analysis. Critical reviews in oncology/hematology, 134, 72–81.

(56) Kvaskoff, M., Han, J., Qureshi, A. A., & Missmer, S. A. (2014). Pigmentary traits, family history of melanoma and the risk of endometriosis: a cohort study of US women. International journal of epidemiology, 43(1), 255–263.

(57) Mu, F., Rich-Edwards, J., Rimm, E. B., Spiegelman, D., & Missmer, S. A. (2016). Endometriosis and risk of coronary heart disease. Circulation: Cardiovascular Quality and Outcomes, 9(3), 257–264.

(58) Leonardi, M., Lam, A., Abrão, M. S., Johnson, N. P., & Condous, G. (2020). Ignored because it is benign–it is time to treat endometriosis as if it were cancer. Journal of Obstetrics and Gynaecology Canada, 42(4), 507–509.

(59) Bevan, G. (2019, October 6). Endometriosis: Thousands share devastating impact of condition. BBC News. Retrieved March 12, 2022, from https://www.bbc.com/news/health-49897873

(60) Schäfer, G., Prkachin, K. M., Kaseweter, K. A., & de C Williams, A. C. (2016). Health care providers’ judgments in chronic pain: the influence of gender and trustworthiness. Pain, 157(8), 1618–1625.

(61) Chen, E. H., Shofer, F. S., Dean, A. J., Hollander, J. E., Baxt, W. G., Robey, J. L., … & Mills, A. M. (2008). Gender disparity in analgesic treatment of emergency department patients with acute abdominal pain. Academic Emergency Medicine, 15(5), 414–418.

(62) The Endometriosis Summit. (2020). Race and Endometriosis: Exploring Myths and Misconceptions. https://www.theendometriosissummit.com/blog/myths-and-misconceptions-perpetuating-racism-in-endometriosis-infertility-and-pelvic-pain.

(63) Hoffman, K. M., Trawalter, S., Axt, J. R., & Oliver, M. N. (2016). Racial bias in pain assessment and treatment recommendations, and false beliefs about biological differences between blacks and whites. Proceedings of the National Academy of Sciences of the United States of America, 113(16), 4296–4301.

(64) Cheng, P. J., Pastuszak, A. W., Myers, J. B., Goodwin, I. A., & Hotaling, J. M. (2019). Fertility concerns of the transgender patient. Translational Andrology and Urology, 8(3), 209.

(65) Dutton, L., Koenig, K., & Fennie, K. (2008). Gynecologic care of the female-to-male transgender man. Journal of Midwifery & Women’s Health, 53(4), 331–337.

(66) Culley, L., Law, C., Hudson, N., Denny, E., Mitchell, H., Baumgarten, M., & Raine-Fenning, N. (2013). The social and psychological impact of endometriosis on women’s lives: a critical narrative review. Human reproduction update, 19(6), 625–639.

(67) Della Corte, L., Di Filippo, C., Gabrielli, O., Reppuccia, S., La Rosa, V. L., Ragusa, R., … & Giampaolino, P. (2020). The burden of endometriosis on women’s lifespan: a narrative overview on quality of life and psychosocial wellbeing. International Journal of Environmental Research and Public Health, 17(13), 4683.

(68) Gambadauro, P., Carli, V., & Hadlaczky, G. (2019). Depressive symptoms among women with endometriosis: a systematic review and meta-analysis. American Journal of Obstetrics and Gynecology, 220(3), 230–241.

(69) Facchin, F., Buggio, L., Vercellini, P., Frassineti, A., Beltrami, S., & Saita, E. (2021). Quality of intimate relationships, dyadic coping, and psychological health in women with endometriosis: Results from an online survey. Journal of psychosomatic research, 146, 110502.

(70) Nnoaham, K. E., Hummelshoj, L., Webster, P., d’Hooghe, T., de Cicco Nardone, F., de Cicco Nardone, C., … & Study, W. E. R. F. G. (2011). Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertility and sterility, 96(2), 366–373.

(71) Soliman, A. M., Surrey, E., Bonafede, M., Nelson, J. K., & Castelli-Haley, J. (2018). Real-world evaluation of direct and indirect economic burden among endometriosis patients in the United States. Advances in therapy, 35(3), 408–423.

Summary:

• “It’s a condition that the main symptom is pain and pain, as we know, it can often get dismissed in women and gender diverse people”
• “Despite its prevalence, experts say it can take anywhere from five to 10 years to get a diagnosis and receive treatment — which can range from hormone treatment to surgical interventions.”
• “I’m in pain all the time. The bad pain is almost getting to a point where you’re not thinking properly. You have brain fog and you feel like you’re going to pass out from the pain, the pain so bad you can’t get out of bed. You can’t walk. You can’t even go to the bathroom. We’ve been told periods are supposed to be painful. They’re not. You’re not supposed to be missing work. You’re not supposed to be missing things with your friends, activities outside of your everyday life. You’re not supposed to be missing those things because of period pain or pain outside of your period.” -Keana Casault

Women with endometriosis enduring extreme pain due to pandemic surgery delays, lack of expertise
Eva Uguen-Csenge · CBC News · Posted: Mar 09, 2022 5:00 AM PT

Every morning, Keana Casault wakes up and assesses herself on a personal pain scale.
“If I say I’m at a five out of 10 of pain, that’s probably the average person’s 10 out of 10,” said the 25-year-old university student.

Where she sits on that pain scale impacts every single decision for the rest of the day. Whether she can take a shower, do groceries, go to university classes or even take her dog for a walk.
“I’m in pain all the time,” she said. “The bad pain is almost getting to a point where you’re not thinking properly. You have brain fog and you feel like you’re going to pass out from the pain, the pain so bad you can’t get out of bed. You can’t walk. You can’t even go to the bathroom.”

Casault, 25, is one of over a million Canadian women living with endometriosis — a gynecological disease that causes debilitating chronic pain and can in severe cases lead to organ damage. There is no known cure for the illness.

Despite its prevalence, experts say it can take anywhere from five to 10 years for women to get a diagnosis and receive treatment — which can range from hormone treatment to surgical interventions.
The pandemic has extended wait-times for those surgeries — considered elective procedures — and is forcing women with endometriosis to put their lives on hold while they await a surgery that they deem essential.

“There is indeed a major backlog of patients with endometriosis,” said Dr. Mathew Leonardi, a gynecological surgeon at McMaster University Medical Centre in Ontario. He says there were several months during the pandemic where he could only perform surgeries for gynecological cancers.
“There are months where I might operate on one or two endo patients, which is a really unfortunate state because the volume of patients is again astronomical and we need to be operating at a higher frequency.”

Pandemic delays surgeries 
Endometriosis occurs when tissue similar to the lining of the uterus implants in the pelvic cavity outside the uterus to form lesions, cysts and other growths, according to Endometriosis Network Canada. This can cause pain, internal scarring, infertility and other medical complications.
The Society of Obstetricians and Gynaecologists of Canada recommends that hormone and pain medication treatments be explored for patients before considering surgery. But some patient advocates argue that a specific surgical intervention known as an excision laparoscopy — in which a surgeon removes as much of the endometriosis tissue as possible — is the gold standard of treatment. 

Dr. Catherine Allaire, who heads UBC’s division of gynaecologic specialities, says surgical delays are having a major impact on patients living with the disease.
“The suffering is what I’m concerned about and the extra months of suffering that the patients are going through,” she said.
“The problem is not only the delay from our booking surgery to them getting surgery, but the delay in getting to us, for example, seeing their family doctors was difficult, getting imaging was difficult.” 

Casault, who lives in Burnaby and is studying tourism management at Capilano University, has been experiencing those delays first hand. She first started experiencing extreme pain a decade ago when she was only 15.
She underwent an initial surgery in Nelson, B.C., when she was 17 which was deemed inconclusive. Since then, she’s gone through years of unsuccessful hormone treatments.
“I’ve tried pretty much everything and none of it’s worked,” she said. “A lot of it’s made a huge negative impact on my life, so I decided that I am done waiting for that and I really, really need to have the surgery.”
Because she received a surgery eight years ago, Casault hasn’t been considered a priority case for a surgical treatment in B.C. She decided to go to a specialist out-of-province and has had an initial consult with Leonardi in Ontario.
“I need to get this done. I want to feel better. I’m only 25.”

The pandemic has accentuated wait times for all elective surgeries, but those working in the field of gynecology say resources have always been limited.
“It’s reflected in research funding. It’s reflected in remuneration for gynecological surgery,” said Leonardi.

Both he and Allaire say there are societal factors at play that delay diagnosis.
“It’s a condition that the main symptom is pain and pain, as we know, it can often get dismissed in women and gender diverse people,” said Allaire.

Leonardi also says that true specialists in diagnosing and treating endometriosis through excision surgery are few and far between across Canada. He says while it’s estimated that 10 per cent of women have the disease, he estimates only one per cent of doctors are specialized in endometriosis.

Calls for national action plan
Advocacy group EndoAct Canada has been pushing the federal government to develop a national action plan on endometriosis like the one that exists in Australia and was recently announced in France — a three-pillar strategy that focuses on increased education, improved clinical management and care, and research. 
In response to questions from CBC News about a national action plan, the office of federal Health Minister Jean-Yves Duclos emailed a statement underlining its commitment to improving access to sexual and reproductive health. The statement did not mention endometriosis or any of the relevant treatments for the disease.

Leonardi believes that while there is no cure for endometriosis, early intervention is key to improving patient outcomes.
“If we treat that disease properly at the beginning when kind of in its menstrual cyclical pain state, I really do believe that we can prevent people from developing chronic pelvic pain where they are in pain all the time,” he said.
Leonardi says that requires more funding for gynecological research. 

For Casault, proper care starts with ending the normalization of menstrual pain.
“We’ve been told periods are supposed to be painful. They’re not,” she said.
“You’re not supposed to be missing work. You’re not supposed to be missing things with your friends, activities outside of your everyday life. You’re not supposed to be missing those things because of period pain or pain outside of your period.”

Endometriosis pain and epithelial neutrophil activating peptide-78 levels

Published: 25 February 2022
Barbara Gardella, Mattia Dominoni, Andrea Gritti, Anna Arrigo, Silvia Antonucci, Giulia Vittoria Carletti, Valentina Musacchi & Giampiero Pietrocola

Abstract

Endometriosis is a chronic gynecological disorder involved in the pathogenesis of chronic pelvic pain, based on a probable up regulation of the inflammatory system. The objective of the study is to investigate the peritoneal and serum levels of ENA-78 with the severity of endometriosis symptoms (dysmenorrhea, chronic pelvic pain and dyspareunia) using the visual analogue scale (VAS). This is a prospective case–control study that included 53 symptomatic women with evidence of endometriosis and 53 age-matched controls who underwent elective laparoscopic surgery for benign diseases. The concentration of ENA-78 was assessed in blood and peritoneal fluid samples in the follicular phase. In peritoneal fluid and plasma, the concentration of ENA-78 was significantly higher in cases than in controls (p?<?0.001). A significant correlation was observed between peritoneal fluid ENA-78 levels and the severity of dysmenorrhea (Spearman Rho?=?0.237; p?=?0.014), and chronic pelvic pain (Spearman Rho?=?0.220; p?=?0.022) in endometriosis patients. Plasma levels ENA-78 showed a significant correlation with the severity (VAS score) of chronic pelvic pain (Spearman Rho?=?0.270, p?=?0.005 for cases), though a weak correlation was evident between plasma levels of ENA-78 and severity of dysmenorrhea (Spearman Rho?=?0.083, p = 0.399 for cases). In conclusion, chronic pelvic pain in endometriosis is caused by changes of local and systemic activated chemokine patterns. These modifications involve the relationship between pro-inflammatory, angiogenic and angiostatic chemokines that modulate the severity of endometriosis associated symptoms.

Introduction

Endometriosis is a chronic gynecological disorder, affecting at least 10% of reproductive-aged women and is characterized by the growth of endometrium?like tissue outside the uterus. Ectopic endometrial cells in the peritoneal cavity are thought to cause pelvic pain and infertility. The presence of endometriotic lesion affects at least the immune and the reproductive systems.

Several theories supported that a different immunological response facilitates the implants of endometrial cells in peritoneal cavity. Cytokines, chemokines, angiogenic factors, and growth factors are engaged in the proliferation and development of endometriotic lesions, as laboratory evidence has demonstrated.

Although endometriosis may be asymptomatic, it can often cause debilitating pelvic pain, dyspareunia and dysmenorrhea or other symptoms including chronic fatigue. The cause of the neuropathic endometriosis-related pain is unclear. The anatomical aspect of the lesions shows increased germination of Nerve Growth Factor (NGF)-mediated nerve fibers and an alteration of pro-inflammatory pattern, but the lack of correlation between severity of lesions and symptoms suggests the presence of other triggering factors. The correlation between high levels of chemokines (chemotactic cytokines) and endometriosis was found for the first time in 1993.

During the past 30 years, many researchers have evaluated different types of chemokines in patients with endometriosis in order to establish a potential role of chemokines in the pathogenesis of the disease. Although the exact role of chemokines in the pathogenesis of endometriosis remains unsolved, it is clear that cytokines, chemokines, and angiogenic factors cause the development, progression and growth of ectopic endometrial tissue. Furthermore, the chemokines could mediate and modulate the inflammatory response concerning endometriotic implants. In particular, previous papers reported the association between Epithelial neutrophil-activating peptide-78 (ENA-78) expression and endometriosis neoangiogenesis. The chemokine ENA-78 is a neutrophil chemotactic factor, which activates neutrophils and promotes cytosolic- free calcium changes, and it induces neoangiogenesis. ENA-78 is a C-X-C (cysteine separated by another amino-acid) of 8.3 KDa protein. This chemokine is composed by 78 amino-acids and it contains four cysteines and it seems to be a homologue of IL-8. The ENA-78 expression is induced by several inflammatory mediators and its production is stimulated by IL-1 and tumour necrosis factor-alpha (TNF-alpha) properly in stromal endometrial cells. While the presence of cytokines, as IL-8 and IL-6, were predominantly expressed in glandular endometrial tissue, ENA-78 was expressed in the stromal component. The high concentration of ENA-78, IL-6, and IL-8 were demonstrated in the peritoneal fluid of women with endometriosis, demonstrating their role in the pathogenesis of disease. In addition, a recent study demonstrated that monocyte chemoattractant protein-1 (MCP-1), hepatocyte growth factor (HGF), and insulin-like growth factor-1 (IGF-1) in peritoneal fluid and serum contributed to the development of endometriosis. Additionally the expression of vascular endothelial growth factor A, C-X-C-motif chemokine ligand 8, IL-6, and intercellular adhesion molecule-1 genes demonstrated an up-regulation in endometrial mesenchymal stem cells in cases of endometriois. The peritoneal level of ENA-78 expression may be a reflection of the progression of endometriosis causing growth and maintenance of ectopic endometrial lesions, and stimulating leucocytes to produce growth factors and cytokines, and endometrial stromal proliferation with direct effects on these tissues. The correlation between ectopic endometrial tissue and inflammatory status results in dysmenorrhea and chronic pain. For this reason in clinical practice, a visual analogue scale (VAS) may be used as a sensitive measure instrument of intensity and frequency of pelvic pain, which allows the determination of the characteristics of the symptoms from a patient’s perspective.

The objective of the study is to investigate the peritoneal and serum levels of ENA-78 with severity of endometriosis symptoms (dysmenorrhea, chronic pelvic pain and dyspareunia) using the VAS scale.

Materials and methods

This is a prospective case–control study carried-out at the Department of Obstetrics and Gynecology, IRCCS Policlinico S. Matteo Hospital, University of Pavia, Italy, between July 2014 to December 2018. The study included 53 symptomatic women with laparoscopic and histopathological evidence of endometriosis and 53 age-matched controls who underwent elective laparoscopic surgery for benign diseases or tubal sterilization. The inclusion criteria to be assigned as control were the following: (a) superimposable age (±?2 years) to index case; (b) no evidence of endometriosis during a careful abdominal and pelvic laparoscopic exploration performed immediately after each index case; (c) no history or evidence of pelvic inflammatory disease or malignancies: (d) no evidence of rheumatological or autoimmune disease. The study protocol was approved by the Hospital Ethical Committee (Comitato Etico of IRCCS Policlinico S. Matteo Hospital, protocol number 722-rcr2012-bis-23). The informed written consent was obtained from the patients. All methods and procedures were performed in accordance with the relevant guidelines and regulations.

All patients (control and study group) were recruited without hormonal intake and they underwent to surgical procedure in the follicular phase.

Both cases and controls received a preoperative routine assessment including pelvic examination and transvaginal ultrasonography. Carbohydrate Antigen 125 (CA-125) was measured in blood samples. The measure of CA-125 performed during the follicular phase at pre-operative assessment. Pelvic magnetic resonance imaging was performed only in three patients in which deep infiltrating endometriosis was suspected in order to assess the infiltration of the intestinal wall.

All cases had histological diagnosis of endometriosis on surgical biopsy. The patients with endometriosis were recruited for infertility, severe pelvic pain and suspected symptomatic deep endometriosis confirmed during the ultrasound exam. Both score and grade of endometriosis were evaluated during laparoscopy according to the revised criteria of the American Fertility Society (rAFS) (American Society for Reproductive Medicine, 1996).

Socio-demographic and clinical data were collected by an interview. Presence and severity of pain symptoms potentially related to the diagnosis were evaluated by administering a symptom-oriented questionnaire to each patient. Severity of symptoms (dysmenorrhea, chronic pelvic pain, dyspareunia, catamenial dyschezia/hematochezia, dysuria) was graded according to 10 items of the VAS scale (from 0?=?no pain to 10?=?unbearable pain). The impact of symptoms on sexual activity was scored according to the interference with sexual intercourse as follows: dyspareunia score 0?=?absence of pain during intercourse; score 1?=?mild dyspareunia, that does not interfere with the frequency of intercourse; score 2?=?moderate dyspareunia, which reduces the frequency of intercourse; score 3?=?severe dyspareunia, which disables intercourse. Blood sample and peritoneal fluids were collected from each patient on the day of surgery. All patients underwent surgery during the follicular phase of the menstrual cycle.

Collection of plasma and peritoneal fluid

Blood samples were collected from an antecubital vein into EDTA tubes and then centrifuged at 1600?×?g for 15 min to remove the cellular fraction. Plasma was immediately frozen at ?80 °C in order to minimize protein degradation. Peritoneal fluid was collected at the beginning of each laparoscopy by using a cannula inserted in the pouch of Douglas, injecting 20 ml and subsequently drawing 10 ml of saline solution. The liquid withdrawn was centrifuged at 1600?×?g for 15 min to separate the cellular fraction. The obtained supernatant was also immediately frozen at a ?80 °C.

Measurement of ENA-78 concentrations in plasma and peritoneal fluid

ENA-78 concentration was measured both in plasma and peritoneal fluid. Procarta Cytokine® Assay Kit (Affymetrix, Inc., Santa Clara, CA, USA) was used according to the manufacturer’s instructions. Briefly, after standard preparation, filter plate was wet with 150 µl/well of reading buffer and incubated for 5 min at room temperature. A mixture containing 5000 microspheres of ENA-78 was incubated with standards or samples in a final volume of 100 µl, for 30 min under continuous shaking. After three washes by vacuum filtration with washing buffer, diluted biotinylated antibodies against ENA-78 were added. After 30 min of incubation, Streptavidin-PE (Affymetrix, Inc. Santa Clara, CA, USA) diluted in assay buffer was added. At the end of 30 min of incubation, under continuous shaking and after washing, the fluorescence intensity of the beads was measured using the Luminex instrument, LabScan 100 (Luminex Corporation. Austin, USA) in a final volume of 120 µl of the assay buffer. Data analysis was performed with a Bio-Plex Manager software using a five-parametric logistic curve. The detection limit of the assay system for all antigens was 1 pg/ml.

Statistical analysis

Statistical analysis was carried out with the Chi-square and Mann–Whitney U test to compare categorical and continuous variables, respectively. Correlations between severity of endometriosis-related symptoms as evaluated by VAS scales and concentrations of ENA-78 were evaluated by the Spearman rank correlation coefficient.

Results

The case group had the following rAFS surgical evaluation: 16 women stage 1 (30.2%); 19 women stage 2 (35.9%); 7 women stage 3 (13.2%) and 11 women stage 4 (20.8%), respectively. In the control group, surgery confirmed benign conditions, including mature teratomas in 16 women (30.2%), cystoadenomas in 6 women (11.3%) and myomas in 18 women (34%). The remaining 13 control women (24.5%) were candidates for tubal sterilization.

Table 1 shows demographic and clinical data before the surgery. Plasma CA-125 concentration and rate of infertility were significantly higher in cases than in controls (p?=?0.001 and p?=?0.04, respectively). On the other hand, controls had higher BMI than cases (p?=?0.03). Categorical analysis showed a high rate of dysmenorrhea and chronic pelvic pain among women with endometriosis as compared to controls (p?<?0.001 and p?=?0.001, respectively). Mean VAS scores for dysmenorrhea were significantly higher (p?<?0.001) in cases (6.45?±?2.85) than in controls (2.87?±?3.47).

Mild chronic pelvic pain from at least 6 months was reported by 67.7% (11/17) of patients with stage I endometriosis; 73.7% (14/19) of patients with stage II suffered moderate chronic pelvic pain with VAS?>?5, whereas 89% (16/18) of patients with stage III and IV reported severe pain (VAS?>?8). As expected, 86.8% (46/53) of controls did not report chronic pelvic pain with an average VAS score of 0.94?±?2.30, significantly lower compared with cases (5.60?±?3.26; p?<?0.001).

Mean VAS scores for dyspareunia (2.23?±?2.91 in cases versus 1.68?±?3.1 in controls, p?=?0.16) and dyschezia (1.15?±?2.53 in cases versus 0.36?±?1.15 in controls; p?=?0.085) did not differ between the two groups, likely due to the low percentage of nodules of the rectum-vaginal septum (3/53).

Peritoneal fluid expression of ENA-78 in cases and controls

In peritoneal fluid, the concentration of ENA-78 was significantly higher in cases than in controls (12.4?±?26.6 pg/ml for cases vs 2.2?±?6.6 pg/ml; p?<?0.001). In addition, a significant correlation was observed between peritoneal fluid ENA-78 levels and the severity of dysmenorrhea (Spearman Rho?=?0.237; p?=?0.014), and chronic pelvic pain (Spearman Rho?=?0.220; p?=?0.022).

Additionally, the ENA-78 level was higher in the peritoneal fluid in patients with endometriosis at stage IV than in the first stage of disease and its level increased in relation with different stages.

Plasma expression of ENA-78 in cases and controls

Plasma levels of ENA-78 was significantly higher in women with endometriosis than in controls (p?<?0.001, 1260.4?±?1391.8 pg/ml for cases vs 508.5?±?1066.1 pg/ml for controls). Interestingly, ENA-78 showed a significant correlation with the severity (VAS score) of chronic pelvic pain (Spearman Rho?=?0.270, p?=?0.005 for cases) (Fig. 1). However, a weak correlation was evident between plasma levels of ENA-78 and the severity of dysmenorrhea (Spearman Rho?=?0.083, p 0.399 for cases), as it is represented in Fig. 1. The plasma level of ENA-78 was higher in stage IV endometriosis than in the first stage of disease, and its level increased in relation with different stages and the severity of endometriosis.

Discussion

ENA-78 has an important role in the pathogenesis of rheumatoid arthritis, gastric and inflammatory bowel diseases, ovarian carcinoma, psychiatric syndromes (infant autism, depression), chronic prostatitis, and gastric and lung cancer. In fact, ENA-78 contains ERL element (Glu-Leu-Arg) that can cause neutrophil chemotaxis, cytosolic-free calcium changes, and angiogenesis in inflammatory tissue, but it is less active in the release of neutrophil granulocytes, macrophages, fibroblasts, endothelial cells, monocytes, epithelial tissue, platelets, alveolar and intestinal epithelial cells producing ENA-78: this process is involved in the recruitment of neutrophils and mononuclear cells in the sites of inflammatory processes and in the production of molecules involved in leukocyte adhesion. This mechanism is able to increase the production of inflammatory cytokines. Literature data has previously reported that the expression of ENA-78 by endometrial stromal cells were significantly stimulated by lipopolysaccharide (LPS), Il-1beta and TNF-alpha in peritoneal fluid of women with endometriosis.

It is probable that the ectopic endometrial tissue can induce an inflammatory pattern in the site of its implantation with a rise in levels of cytokines which lead to an increase in the secretion of ENA-78. In addition, the macrophage activation induced by ENA-78 can increase the recruitment of peritoneal lymphocytes responsible for chronic local inflammation and amplify the expression of multiple pro-inflammatory mediators of pain. For example, in ectopic endometriotic lesions there is a direct relationship between the number of macrophages and the density of nerve fibers, suggesting a direct relationship between immune activation and generation of pain. In a recent study also the adipose tissue, in the retroperitoneal cavity adjacent to pelvic endometriosis, was more fibrotic and showed signs of neo-angiogenesis with a significantly higher level of infiltration of macrophages in the endometriosis group.

In addition, endometriosis pain is probably not only caused by the local immune response since it is well known that not in all cases, the removal of lesions improves pain relief (20–28% of patients do not have pain relief after surgery).

Probably the proinflammatory systemic response could explain the sensory nerve activation and altered nociceptive pathways.

Moreover we found that also the plasma concentration of ENA-78 is higher in the patients with endometriosis than in controls and is directly correlated to the severity of pain, especially to chronic pelvic pain and dysmenorrhea as a possible expression of systemic immune activation.

This inflammatory response is probably able to sustain the continuous proliferation of cytokines and chemokines and the consequent abnormal response to pain stimulus. The finding of increased plasma concentrations of ENA-78 in patients with endometriosis compared to controls and the direct correlation between plasma ENA-78 and the severity of chronic pelvic pain suggest that additional pathways other than local mechanisms, can regulate endometriosis-related pain.

Peripheral sensitization causes the drop of threshold for neuronal activation, inducing pain from a stimulus that does not normally provoke pain (allodynia) or heightens existing pain (hyperalgesia). If inflammation persists, nociceptors can become chronically hypersensitive even after inflammation resolution. This peripheral hypersensitivity of nociceptive fibers could explain allodynia and hyperalgesia of endometriosis.

This theory is supported by animal models in which an up-regulation of CXCR2 and CXCR3 receptors and their chemokine ligands exist in populations of neurons in chronic pain models16.

Furthermore, we can speculate that the altered pattern of chemokine activity causes hyper-excitability at when regarding the level of down-regulation of neurons that causes a central sensitization that maintains chronic pelvic pain even in the absence of lesions.

In conclusion, our study suggests that chronic pelvic pain in endometriosis is associated with changes of local and systemic chemokine patterns. These modifications involve the relationships between pro-inflammatory, angiogenic and angiostatic chemokines that modulate the severity of associated symptoms.

Since the up-regulation of chemokines and their receptors could be one of the mechanisms that contributes to the severity of chronic pelvic pain, these molecules may represent a specific therapeutic target. In fact, the efficacy of currently used anti-inflammatory drugs and hormonal therapy is limited. New therapeutic approaches to block the effects of the cytokine cascade could be a promising way for the treatment of patients with symptomatic endometriotic lesions non-responsive to conventional therapy and could have a benefit from the development of new immunomodulatory drugs.

You can download the PDf here.

I first heard about Henrietta Lacks through a friend three years ago when she shared a news article about Johns Hopkins naming a new research building after her. In that article, I learned that “Henrietta Lacks was a young mother of five from eastern Baltimore County who, despite radiation treatment at the Johns Hopkins Hospital, died in 1951 of an aggressive cancer. Lacks was the source of the HeLa cell line that has been critical to numerous advances in medicine.”

When I first read the article, I thought that was pretty cool that Johns Hopkins was trying to right the wrong they had done decades prior; they took Henrietta’s cells for scientific study without her permission and immediately reaped the benefits of science because of her. But she died from the aggressive cancer. I understood when I read the article that naming a building in her honour is nice and all, but I feel there is still so much more that needs to be done to do right by her family specifically.

You might be asking, “how does the story of Henrietta Lacks relate directly to Endometriosis?”

Over the past 19 years, I have subscribed to several medical journals in an effort to try to learn more about endometriosis. Whenever I felt I had a decent understanding of the research, I would regurgitate what I learned by posting to this blog. Occasionally I would run across the term “HeLa” in some of those research papers, but the science and language of the papers was over my head, so they never got posted here, though I kept them in a folder^{1, 2, 3}. So while I had seen the term “HeLa” in endometriosis-related research papers and medical studies, I didn’t know the Very Important History behind the HeLa cells.

Even at the time of seeing the Johns Hopkins article my friend had posted three years ago, I still hadn’t quite put the history and significance together. It was one of those “I think I’ve seen that term somewhere before but can’t recall where…” and in fact, it had been almost a decade since I’d seen that term, as indicated by the linked references above. This also sadly corresponds to me having abandoned blogging about endometriosis for many years in the wake of a devastating divorce, whereupon I was made to feel that I was ‘obsessed’ with being sick by constantly talking about endometriosis with friends, family, in my blog and in my video series. The ex spouse used this as justification for their affair, and even went so far as to say that he couldn’t take care of me anymore, despite the fact I was employed full time as a preschool teacher and was also engaged in hobbies outside of the home at his request. But I digress…

As I was saying, I still hadn’t quite put the history and significance together.

Until May 2021.

That’s when another friend shared an MLive article about Henrietta Lacks – this time in regards to the COVID-19 vaccine. I was moved by the article in many regards:

• I didn’t know the Pfizer vaccine for COVID-19 was developed in Michigan until I read that article, and it just so happens that the Pfizer vaccine is what I received in April, 2021, and I’m also originally from Michigan.
• The vaccine was developed using the HeLa cell line, and the article went into much more detail about Henrietta Lacks and her family legacy than the Johns Hopkins article had.
• And her great nephew Jermaine lives in Michigan, and has been honouring his Great Aunt Henrietta by teaching others about her and how her immortal cells are contributing to major scientific breakthroughs to this very day.
• Jermaine started out with an art exhibit in a Kalamazoo Michigan library, then developed a virtual presentation to continue educating people during the pandemic, and now he’s taken it on the road as The Immortal Life of Henrietta Lacks Traveling Museum.

Additionally, there is also a book, published in 2010 titled The Immortal Life of Henrietta Lacks, which I finally purchased last year. Rebecca Skloot, the author of that book, also created The Henrietta Lacks Foundation, which I donated to. The Foundation’s statement reads:

Established in 2010 by Rebecca Skloot, author of The Immortal Life of Henrietta Lacks, the Foundation is inspired by the life of Henrietta Lacks, whose cancer cells—code named HeLa—were taken without her knowledge in 1951. They became one of the most important tools in medicine—with damaging consequences for her family, many of whom often struggled to get access to the very health care advances their mother’s cells helped make possible. Unfortunately, there are numerous examples of historic research studies conducted on individuals—particularly within minority communities—without their knowledge or consent. These include the Tuskegee Syphilis Studies, the Human Radiation Experiments, and others. The Henrietta Lacks Foundation seeks to provide assistance to individuals and their families who have been directly impacted by such research. The Foundation also seeks to promote public discourse concerning the role that contributions of biological materials play in scientific research and disease prevention, as well as issues related to consent, and disparities in access to health care and research benefits, particularly for minorities and underserved communities.

The Henrietta Lacks Foundation

In May 2021 after reading the MLive article, I was so overcome with gratitude for the immortal cells of Henrietta Lacks that I declared, “I need a Henrietta Lacks saint candle, okay?”

Saint Candles are pretty pop-culture, but I couldn’t find one anywhere for Henrietta Lacks. In December 2021, I searched again to no avail, so I looked up some companies creating Saint Candles and picked one I felt might be a good fit. I emailed a store in New Orleans called Mose, Mary and Me. I told them a bit about Henrietta Lacks and why I felt she should have a Saint Candle. Initially it was a custom order for me and my friend who had told me about Mrs. Lacks a few years ago, but both me and my friend hoped the candle would also be added to Mose Mary and Me’s existing line of candles. Great news! It has! You can buy a Saint Henrietta Lacks candle, too! Mose Mary and Me chose the image based upon a painting of her at the Smithsonian National Portrait Gallery (read about the portrait here).

If you purchase a Saint candle, please also pop over to the Henrietta Lacks Foundation and make a donation so that we may also continue to honour her family and the Black community while we thank Henrietta Lacks for the medical breakthroughs that have allowed us to better understand endometriosis.

January 7, 2022 Followup! The results of the survey above were published in October 2021:

Characterizing menstrual bleeding changes occurring after SARS-CoV-2 vaccination
Menstrual bleeding after SARS-CoV-2 vaccination
Authors: Katharine MN Lee, Eleanor J Junkins, Urooba A Fatima, Maria L Cox, Kathryn BH Clancy
October 12, 2021

Abstract:
Many people began sharing that they experienced unexpected menstrual bleeding after SARS-CoV-2 inoculation. This emerging phenomenon was undeniable yet understudied. We investigated menstrual bleeding patterns among currently and formerly menstruating people, with a research design based off our expectations that these bleeding changes related to changes in clotting or inflammation, affecting normal menstrual repair. In this sample, 42% of people with regular menstrual cycles bled more heavily than usual, while 44% reported no change, after being
vaccinated. Among people who typically do not menstruate, 71% of people on long-acting reversible contraceptives, 39% of people on gender-affirming hormones, and 66% of post menopausal people reported breakthrough bleeding. We found increased/breakthrough bleeding was significantly associated with age, other vaccine side effects (fever, fatigue), history of pregnancy or birth, and ethnicity. Changes to menstrual bleeding are not uncommon nor dangerous, yet attention to these experiences is necessary to build trust in medicine.

Results:
After data cleaning and aggregation of the first three months of data collection, participants in our sample (N=39,129) were between 18 to 80 years old (median=33 years; median age=34.22 years, SD=9.18). All participants were fully vaccinated (at least fourteen days after all required doses) and had not contracted COVID-19 (diagnosed or suspected). This sample was (90.9%) woman-only identifying and 3,557 (9.1%) gender diverse; 32,983 (84.3%) white only identifying and 6,146 (15.7%) racially diverse; and 31,134 (79.6%) non-Hispanic or Latinx and 7,995 (20.4%) Hispanic, Latinx, or other.
Respondents in this sample were vaccinated with Pfizer (N=21,620), Moderna, (N=13,001), AstraZeneca (N=751), Johnson & Johnson (N=3,469), Novavax (N=61), or other (N=204) vaccines, with 23 not reporting vaccine type. Self-report of localized vaccine side effects (soreness at injection site) after the first dose and second dose were 87.6% and 77.4%, respectively, across all vaccine types. Systemic vaccine side effects (headache, nausea, fever,
and/or fatigue) were experienced by 54.3% and 74.6% of participants after the first and second dose, respectively. Of those that reported systemic vaccine side effects, 40.6% experienced systemic effects after both doses.
Vaccine symptoms, period changes (flow and length), period symptoms, and timing of period symptoms reported by study respondents are presented by age categories. The Johnson & Johnson vaccine, being the only single
dose vaccine at the time of survey, was excluded from later analyses.

Of Note:
“In spontaneously cycling subgroups, a higher proportion of respondents with endometriosis (52.4%), menorrhagia (44.6%), and/or fibroids (46.3%) reported experiencing a heavier menstrual flow post-vaccine than the non-diagnosed respondents (40.8%)” and “premenopausal, spontaneously cycling respondents who were diagnosed with endometriosis, menorrhagia, and/or fibroids were more likely to report experiencing heavier bleeding post-vaccine compared to those without any diagnosed reproductive condition. We also find that many respondents who had post-vaccine changes did not have them until fourteen days or longer post-inoculation, which extends beyond the typical seven days of adverse symptom reporting in vaccine trials.”

You can read the full article as a PDF here.

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There have been concurrent studies on this topic, and so far I have found two more:

Effect of COVID-19 vaccination on menstrual periods in a retrospectively recruited cohort
Victoria Male
Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
November 15, 2021

Introduction:
As the UK COVID-19 vaccination programme is rolled out to younger participants, the MHRA’s surveillance scheme, Yellow Card, is increasingly receiving reports from people who have noticed a change in their menstrual cycle following vaccination: at 10 November 2021, 37571 such reports had been made. It is important to note that most people who report such a change following vaccination find that their period returns to normal the following cycle and that there is no evidence that COVID-19 vaccination adversely affects female fertility. Nonetheless, people are concerned by these reports. Investigating the potential link between COVID-19 vaccination and menstrual changes is important for maintaining public trust in the vaccination programme and, if a link is found, to allow people to plan for potential changes to their cycles.

Results:

• Brand of vaccine is not associated with differences in timing or flow of next period.
• People on hormonal contraception were more likely to report a change to menstrual flow.
• Timing of vaccination does not have a clear effect on timing or flow of next period.
• Menstrual changes following dose 2 are closely associated with those following dose 1.
• People who have a diagnosis of endometriosis or PCOS may be more likely to experience a change in the timing of their cycle following vaccination.

Of Note:
“We found that respondents who had a diagnosis of a menstrual or gynaecological condition were not more likely to report a change in flow than those who did not have such a diagnosis, and that those with a diagnosis of heavy or abnormal menstrual bleeding or uterine fibroids were not more likely to report a change in timing. We hope that our findings will be reassuring to people with these conditions. However, we did find a slight increase in the frequency of people with endometriosis who reported an earlier than usual period, and in people with polycystic ovaries who reported a later than usual period. It will be important to follow up this finding to determine whether these groups really are more likely to experience a change to the timing of their cycle. In the interim, we emphasise that these findings should not be used to counsel people who have these diagnoses against vaccination. Indeed, it is important for those who are particularly concerned about changes to their menstrual cycles to be reminded that COVID infection itself may cause this.”

You can read the full article as a PDF here.

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Association Between Menstrual Cycle Length and Coronavirus Disease 2019
(COVID-19) Vaccination
A U.S. Cohort
Alison Edelman, MD, MPH, Emily R. Boniface, MPH, Eleonora Benhar, PhD, Leo Han, MD, MPH, Kristen A. Matteson, MD, MPH, Carlotta Favaro, PhD, Jack T. Pearson, PhD, and Blair G. Darney, PhD, MPH
January 5, 2022

OBJECTIVE:
To assess whether coronavirus disease 2019 (COVID-19) vaccination is associated with changes in cycle or menses length in those receiving vaccination as compared with an unvaccinated cohort.

METHODS:
We analyzed prospectively tracked menstrual cycle data using the application “Natural Cycles.” We included U.S. residents aged 18–45 years with normal cycle lengths (24–38 days) for three consecutive cycles before the first vaccine dose followed by vaccine-dose cycles (cycles 4–6) or, if unvaccinated, six cycles over a similar time period. We calculated the mean within-individual change in cycle and menses length (three prevaccine cycles vs first- and seconddose cycles in the vaccinated cohort, and the first three cycles vs cycles four and five in the unvaccinated cohort). We used mixed-effects models to estimate the adjusted difference in change in cycle and menses length between the vaccinated and unvaccinated cohorts.

RESULTS:
We included 3,959 individuals (vaccinated 2,403; unvaccinated 1,556). Most of the vaccinated cohort received the Pfizer-BioNTech vaccine (55%) (Moderna 35%, Johnson & Johnson/Janssen 7%). Overall, COVID-19 vaccine was associated with a less than 1-day change in cycle length for both vaccine-dose cycles compared with prevaccine cycles (first dose 0.71 dayincrease, 98.75% CI 0.47–0.94; second dose 0.91, 98.75% CI 0.63–1.19); unvaccinated individuals saw no significant change compared with three baseline cycles (cycle four 0.07, 98.75% CI 20.22 to 0.35; cycle five 0.12, 98.75% CI 20.15 to 0.39). In adjusted models, the difference in change in cycle length between the vaccinated and unvaccinated cohorts was less than 1 day for both doses (difference in change: first dose 0.64 days, 98.75% CI 0.27–1.01; second dose 0.79 days, 98.75% CI 0.40–1.18). Change in menses length was not associated with vaccination.

CONCLUSION:
Coronavirus disease 2019 (COVID-19) vaccination is associated with a small change in cycle length but not menses length.

Of note:
We conducted multiple sensitivity analyses to confirm the robustness of our results.

• First, we compared changes in cycle and menses length by vaccine brand.
• Second, we excluded individuals with any prevaccination cycle whose absolute cycle length was outside of the 24–38-day range (579 individuals).
• Third, we excluded any individuals who reported polycystic ovarian syndrome, thyroid disorder, or endometriosis (226 individuals).
• Fourth, we excluded any individuals who reported use of emergency contraception during at least one study cycle (157 individuals).
• Finally, although the data did not meet the missing at random assumption required for imputation techniques, we used imputation followed by weighting with covariate balancing propensity scores and bootstrapped SEs to confirm that our results were not biased by missing data.

You can read the rest as PDF here.