Blog #6: What does Endometriosis have to do with the #1 Killer of Women?

It’s all a bad dream.  Kinda like an out-of-body experience, but I’m watching myself living. No matter how loud I scream or move around, my real-self can’t see or hear me.  Its awful. Watching the life I created wither.  The life-long efforts to keep the ‘bad genes’ asleep.  The ones that have plagued my family and ancestors.  Its hard not having 100% control of my health.

Despite diet, exercise, weight control and the usual healthy lifestyle choices, its frustrating that some diseases, like endometriosis, often require assistance from the healthcare community.  What angers me, is the potential many short-sighted treatments which target a specific organ or system TODAY may negatively impact other area(s) of a person’s body, oft not ‘clinically’ apparent, until TOMORROW.

I won’t go on about the plethora of consequences, like elevated risk for hip and vertebrae compression fractures from osteoporosis; memory loss and risk for dementia as a few long-term consequences possibly through TODAY’s offerings of endometriosis care. But.

1. I AM going to WRITE about the impact of endometriosis, as a disease AND treatments that can contribute to the #1 global killer of women: Cardiovascular disease (CVD). (1)  
2. I AM going to WRITE about lack of attention to long-term side-effects with drug trials.
3. I AM going to WRITE about scientific findings which suggest a better approach to treatment that could be a Win-Win against endometriosis AND CVD

Until the 4th or 5th decade, most of us don’t consider how CVD could impact our life.  Even for healthcare providers, its often far removed from Today’s thoughts.  The disjointed healthcare system of specialists, hyper-focused on one body part or system, tend to rely on a single ‘gatekeeper’ to take care of the person as a whole. This is a serious concern.  Although development of specialties has led to greater depth of knowledge in their focus area, they must still maintain responsibility for impact of treatments they initiate, and their impact on other body systems.

“The GOOD physician treats the DISEASE; the GREAT physician treats the PATIENT who has the disease”  –  Sir William Osler

What will happen if I develop clinically apparent CVD?  Will stairs and hills become obstacles I can’t overcome? Will I be prematurely restricted where I can explore on foot, in my community, nearby woods and adventures in the mountains I have always loved?  Will I be able to travel after retirement?  Will I grow old with the person I love?  Will I have to take medications?  Will I be able to afford them?  Will I have to live in a nursing home because I can no longer care for myself?

I WRITE this Open Letter:

To the appointed leaders in researcher, healthcare, pharmaceutical companies and medical organizations:

You hold the fate of over 176 million women, transgender people and rare cis-males who live with endometriosis in your hands.  Their life is not limited to Today. Their life includes Tomorrow’s. The course of treatment Today, does impact life Tomorrow.

Urgency exists Today for greater knowledge of  intrinsic, extrinsic processes, common line’s of pathogenesis and interactions of endometriosis and cardiovascular disease. It’s time to look beyond association.  It’s not only a question of how and why the presence of endometriosis in the body impact’s on cardiovascular disease.  There is concern for the impact of currently accepted treatment intervention for their deleterious impact on cardiovascular health.  A related concern includes a  consistently lack of long-term follow-up of risk factors across all phases of drug trials to include significant extension of the standard 6 mth to 1 year time period. 

It’s with hope, sharing my perspective, supported by scientific evidence and observation of the fore mentioned concerns about endometriosis, its treatment options and development of cardiovascular disease will be factored into consideration of treatment options provided to persons with endometriosis, regardless of their age and current health status.  To reiterate, CVD is the number one killer of women worldwide.  

“In the last few years, several lines of research have focused their attention on the possibility of specific CV (Cardiovascular) involvement in women affected by endometriosis, documenting the presence of markers of sub clinical atherosclerosis in these subjects. (ref7-11 in 2)

As expected, it was determined that hysterectomy with/without oophorectomy contributed to development of cardiovascular events as consequence to the loss of  estrogen induced cardiovascular protection.  The investigators calculated a (46%) contribution to the frequency of cardiovascular incidents.  Most interesting, a history of Birth Control Pills (OCP) was not associated with the incidence of cardiovascular disease among women with endometriosis.  If hysterectomy w/without oophorectomy is responsible for 46% of the association, what factor(s) contribute to the remaining 54% association of endometriosis and cardiovascular disease?

Women still face the unresolved debate that a large portion of gynecology can’t get passed:  treatment of endometriosis by removing a woman’s uterus with or without the ovaries.  These procedures and belief still remain deeply rooted in practice among many parts of the world and based upon concept that endometriosis is due monthly menstrual debri entering the abdominopelvic cavity instead of passing out the body.  Even worse, removing health organs and leaving active endometriosis lesions untreated, or possibly worse, superficially burned, to remain in the body. All of these scenarios creates conditions that accentuate development of cardiovascular disease.  Just thinking about the consequences makes my bones, brain and heart hurt!

Despite decades of investigation and adherence to this practice, evidence of direct attachment of menstrual debri that has developed within a biological human female is still lacking. The accumulation of data that demonstrates endometriosis disease activity after hysterectomy has led more providers to approach treatment of endometriosis without removal of a normal uterus (and ovaries), if they are not diseased.  In fact, recent discoveries suggest these organs aren’t limited to a role in reproduction.  Evidence is accumulating of their impact on long term systemic wellness of biological females.(4)  This brings us back to the decades-old approach to treatment for endometriosis. The provider, intently focused on a single system (reproductive) and concerns that brought the person with the disease to them, Today.  What about the WHOLE person?  What about Tomorrow?

 Another mainstay among gynecology for treatment of endometriosis is hormone manipulation. The decades long debate: is endometriosis a surgical or medical disease? First, and foremost, the question must be asked and the answer acknowledged:  What diseases in the body are ‘diagnosed’ based upon a response to a pharmaceutical agent?  (For example: Diabetes clearly demonstrate abnormal blood values BEFORE intervention with diet modifications and supplemental insulin as needed.)  Every disease I can recall off the top of my head demonstrates clinical and objective test results (imaging, blood values, saliva, urine samples etc, etc) reaches a diagnosis based upon objective findings.  To date, all conservative attempts to diagnose endometriosis aren’t sensitive NOR specific enough. 

The debate and argument applied by some stakeholders in attempt to justify pharmaceutical agents for ‘diagnose’ of endometriosis is frightening.  To determine if a person has or does not have endometriosis based upon reaction to a hormone suppressant agent doesn’t take consideration for human variability.  This is deeply concerning to me. Most particular based upon the personal experiences of myriad women I have interacted with and their shared experiences, some women with disease will be false negative. These women will not receive a diagnosis despite having endometriosis when they fail to have symptom reduction or resolution with hormone suppression.  In contrast, other women will respond positively to hormone suppression yet don’t have endometriosis. These women would be false positive for endometriosis and given a diagnosis.  A grave situation for women dismissed and active disease left untreated.  A grave situation for women placed on hormone suppression with a range of positive relief, consequences with harms outweighing benefits, many not apparent until later in life. 

Oral Contraceptives/Birth Control (OCP’s) are the most common pharmaceutical agents first used to treat endometriosis. OCP’s can cause side effects of identifiable risk factors for CVD.  They include elevated blood levels of Low Density Lipoprotiens (LDL’s) (the Bad cholesterol), reduced levels of High Density Lipoprotiens (HDL’s)  and increased blood pressure.  OCP’s also increase the risk of Deep Vein Thrombosis (DVT’s), blood clot formation, which occurs most commonly in the lower leg. 

Most providers either attempt multiple OCP’s of various hormone combinations to relieve a patients symptoms if the first agent is ineffective, or recommend use of stronger pharmaceutical agents, most designed to induce partial or complete cease of estrogen production by the ovary(ies).  Among these agents, include GnRH agonists (ie. Lupron) and GnRH antagonists (ie. Orilissa). 

Like BCP’s, hormone suppressants also increase CVD risk factors.  In addition, hormone suppressants reduce or cease estrogen produced by the ovaries. The cardiovascular protection provided by estrogen is lost.  Hormone suppressants compound risk for cardiovascular disease development.  Between atherosclerotic build-up, inadequate repair of internal vessel walls and inability of the blood vessels for normal dilation, endometriosis lesions remain in the body.  (More on this later.)  

Risk factors of cardiovascular and other adverse conditions, are collected in most drug trials for treatment of endometriosis.  However, data collection is commonly limited to 6 mths – 1 year following the study completion.  The limited follow-up period of 6 mths – 1 year was a concern highlighted in the Institute of Clincal and Economic Review (ICER) public hearing for GnRH-antagonist Elegolix (Orilissa) held July 2018. (5)   ICER gave recommendation for longer follow-up following drug-trial to clarify benefits vs long-term complications.

In addition to lengthening the post-trial follow-up period, the way data is grouped, analyzed and presented in pharmaceutical trials is at the discretion of the investigators (see example below). 

Example: The most recent Elagolix (Orilissa) drug trial followed LDL, HDL and BP of each subject.(8)  Initial Cholesterol levels among the majority subjects were in the ‘low’ risk group, a lesser number in the ‘normal’ risk group. No subjects were among the top three associated risk-levels for CVD prior to starting the drug trial. The investigators determined that the n# of subjects with cholesterol levels of  ≥140mg/ml/cholesterol ‘high risk’ at the end of 6 mths would be compared to the n# of subjects < 140mg/ml. 

To explain this.  A mean cholesterol level of 100mg/ml among subjects prior to test.  A 40% increase in cholesterol levels over the 6 month test period would be required before the investigators considered the subject to experience significant increase in cholesterol.  Instead of comparatives of each person pre/post values, the number of persons  ≥140mg/ml/cholesterol was counted.  This number would be compared to the group to determine if blood cholesterol levels were a ‘significant’ concern.  Another way to view the data:  The majority of subjects would blood cholesterol levels to increase three to four complete levels in a 6 month duration to be considered ‘significant’.  Analysis of data using N number of persons instead of analysis of each subjects pre/post blood cholesterol changes provides drastically different information. 

The freedom to include/remove and rearrange data and a lack of mandated submission of all raw data in addition to the final drug-trial report (which presents selective material) for FDA approval need reassessment.

To review: use of hysterectomy, with and without oophorectomy, and pharmaceutical agents for the treatment of endometriosis are associated with development of cardiovascular disease risk factors.  Traditional measurements include blood cholesterol levels, blood pressure, presence of diabetes and familial history.  More sensitive methods to detect sub clinical cardiovascular disease have recently been investigated, and validated for the use among women with endometriosis. These methods further the suggestion that the relationship between endometriosis and cardiovascular disease may be more than an  association. (6,7) More to follow.

Moving beyond medical management, laparoscopic surgery is the next treatment consideration.  Most important, Laparoscopy IS the Standard Procedure (with a tissue sample) to Diagnose endometriosis; NOT pharmaceutical agents.  Does laparoscopic surgery impact the development of CVD?  Lets first clarify the two surgical techniques applied directly to endometriosis lesions: ablation and excision.  Ablation is the use of thermal energy to ‘destroy’ endometriosis lesions.  The advantages of ablation is the ease of use by board certified gynecologists, doesn’t require advanced skills to apply and shorter surgical times.  Disadvantages of ablation include: limited depth of penetration to 1-2 mm (unable to ‘destroy’ deeper disease); limited to organs and tissues which energy can be applied to (hence endometriosis lesions on some organs cannot be treated) and residual eschar and debri can generate sustained inflammation after surgery.  Advantages of excision include:  removal of endometriosis lesion by using energy to ‘cut out’ the lesion and remove it from the body (clean margins without residual disease that can regrow/remain active); healthy tissue margins without diseased or injured tissue limits sustained inflammation following surgery.  Disadvantages of excision include: longer operative time; significantly less providers available with excision skills to obtain care; often higher out-of-pocket costs due to lack of insurer coverage.

Back to Laparoscopy and impact on CVD development.  Its plausible to deduce that retained endometriosis lesions,  in addition to eschar and debri from ablation will not resolve the inflammatory process innate to endometriosis.  As a result, the presence of endometriosis (debri and/or remaining active deeper disease of lesions deeper than 1-2 mm depth) will continue its association with development of  CVD.   This brings me to my argument for LAPEX (laparoscopic excision) as Gold Standard. 

Among all of the treatment options for endometriosis, cutting out the disease is the ONLY intervention which is a Win-Win situation against Endometriosis AND CVD development.  What evidence leads me to this position? Data collected from women who underwent gynecological surgery for endometriosis and non-endometriosis were monitored for cardiac risk factors prior to surgery with a 2 year follow-up.(8)  Traditional cardiovascular risk factors were collected. Additional measurements of Force-Mediated Dilation (FMD) was included. The use of FMD is:

“very relevant because endothelial dysfunction, is one of the earliest markers of vessel wall deterioration in atherosclerosis, (and) has a prognostic relevance even in the absence of traditional cardiovascular risk factors.”(8)

Results of their study provide new opportunities to look into the relationship between endometriosis lesions and vascular wall dysfunction.   Prior to surgery, those with endometriosis had a significant reduction for capacity of blood vessels to dilate, compared to women with other gynecological concerns.  Two years following surgery, those who underwent gynecological surgery for other conditions, had no significant change in measurements.  Those with endometriosis who underwent excision surgery had significant improvement of vascular dilation from their preoperative measurements AND their postoperative measurements were similar to the postoperative values of those who underwent non-endometriosis gynecological surgery.  

“This study demonstrates, for the first time, that laparoscopic surgical treatment (excision) of endometriosis leads to improvement of endothelial function, with a consequent reduction of cardiovascular risk of women with endometriosis.”(8)

The investigators have established that the improved vascular ability to dilate are:

“…related to inflammation reduction after surgery, since both inflammation and endothelial activation serological markers reverted to values similar to controls. In particular, we can hypothesize that surgical excision of endometriosis lesions entails removal of the main source of inflammation; with regard to the observation that, in endometriosis, inflammatory processes are also linked to pro-inflammatory cytokine production by ectopic endometrial cells themselves.” (8)

It’s vital for medical providers to understand, despite a lack of traditional cardiovascular risk factors, inflammation associated with endometriosis, secretions from their lesions and now, evidence which suggests a shared genetic origin for both diseases require greater depth of counsel to patient’s.  Full disclosure of ALL benefits and potential harms of each treatment and acknowledge the majority of  interventions for endometriosis may contribute to cardiovascular disease.(9,10)  It should also be recognized that their impact may occur at a sub clinical level for years.  Women with endometriosis with early vascular wall dysfunction prior to development of atherosclerotic disease demonstrate significantly more ‘arterial stiffness’ than women without endometriosis.(7) The validation of FMD and baPMV measurements that reliably detects early vascular wall dysfunction and sub clinical atherosclerosis is a tool for closer monitor for early changes associate with CVD.

The relationship of endometriosis and cardiovascular disease must contribute to the prudence in selection of treatments.  If data is true about the presence of endometriosis in the body and advancement of cardiovascular disease among these persons, it makes economic sense that an option for excision of lesions should be given. The enormity of healthcare burden, worldwide from cardiovascular disease, as the number one morbidity and mortality among females – even a portion of the estimated 10% of women with endometriosis in which CVD can be reduced or prevented with removal of endometriosis from their bodies is staggering to think about.  Not only to remove the disease but also to improve the overall well-being of the individual whom may be able to integrate better exercise tolerance, earn wages and afford a more nutritious diet and lower stresses.

Summary:

What we do and do not know about endometriosis, treatments and CVD:

• We KNOW At Least an association exists between the presence of endometriosis lesions and cardiovascular disease
• We KNOW hormone suppression DOESN’T remove or stop disease. 
• We KNOW hormone suppression reduces/ceases production of estrogen from the primary organ (ovary).
• We KNOW estrogen is protective for heart and vascular injury and repair.  
• We DONT KNOW the likelihood for ovarian production of estrogen to return following various durations and doses of hormone suppressants. 
• We DO KNOW that the lesions are STILL PRESENT in the body during and after hormone suppression. 
• We DO KNOW the use of pharmaceutical agents to Diagnose endometriosis is NOT sensitive NOR selective at acceptable levels.
• We DO KNOW ablation surgery only penetrates 1-2mm depth.  Ablation, cannot be applied to all areas where endometriosis may be present.  The procedure creates inflammatory debri AND the endometriosis lesion remains in the body (and may be active).
• We DO KNOW excision surgery removes endometriosis lesions from the body. Skilled removal there is no residual debri or active tissue left behind.  Excision removes the SOURCE of inflammation and contributing factors of cardiovascular disease.  

Conclussion:

The person sitting in front of you in the office with endometriosis may not be under your care in a year, decade or more. However, the treatments you offer and information you disclose about the pros and cons of each available intervention, can significantly impact this person Today AND Tomorrow.  It’s very hard for all who provide medical care to consider implications of a treatment implemented Today that Can Contribute to life-altering cardiac and vascular concerns Tomorrow. As the relations between endometriosis, cardiovascular disease and treatment options gains more clarity, it’s with hope that prudence in selection of treatment approaches for Today’s concerns of endometriosis AND their potential impact on Tomorrow’s cardiovascular disease are routine. That tomorrow may not be far off for many.  Isn’t it time to join the modern world?  Lets cut to the chase.  Why does the treatment of endometriosis continue around the roundabout (Blog 5)? Off in the horizon, the potential to significantly lower mortality and morbidity awaits.  Not for one, but two disease processes.  The fact that heart disease is the number one killer of women across the globe AND about 10% of the worlds female inhabits have endometriosis.  Do the math.

Suggested Investigation:

A.) Expand on recent studies for the effect of endometriosis excision and risk factor for cardiovascular disease, to include measurement values of early vascular wall dysfunction and subclinical atherosclerotic disease.  

B.)  Investigate the relationship of the secretive properties of endometriosis lesions and endothelial wall disruption and restorative dysfunction.

C.)  Mandate multi-year follow up on all drug trials.  In addition, require data collection of cardiovascular disease risk factors, to include measurements of sub clinical atherosclerotic disease (using FMD and/or baPWV), blood pressure, circulating cholesterol levels (LDL’s & HDL’s).  All pre/post experimental values compared as:

1. ) experimental group vs control group collective 
2. ) between age groups of the experimental group 
3. ) between the same age group of experimental vs control       
4. ) disease stage.

D.) Mandate all drug trials require multi-year follow to determine long-term impact of hormone manipulation and suppression of ovarian estrogen production to establish the probability of full ovarian reserve and variations from 100% pre clinical testing.

Speaking for 176 million +

Trish   (October 25th, 2019)               Tweet Trish’s Blog    

Citations:

1.) World Health Organization

2.) Endometriosis and atherosclerosis: what we already know and what we have yet to discover. Clinical Opinion. Gynecology. AJOG. April 2015. Sanotor L et al. 

3.)  Endometriosis and Risk of Coronary Heart Disease. Circ Cardiovasc Qual Outcomes. 2016;9:257-264. Mu F., Rich-Edwards J, Rimm EB, Spiegelman D, Missmer SA. 

4.) Hysterectomy Associated with Long-Term Health Risks. American Journal of Nursing. 2018;118(4):16. Potera C. .

5.)  Endometriosis: Final Evidence Report- Elagolix for Treating Endometriosis.  Institute of Clinical and Economic Review.  https://icer-review.org/material/endo-final-evidence-report/  Release date: August 3, 2018.

6.) Increased asymmetric dimethylarginine and enhanced inflammation are associated with impaired vascular reactivity in women with endometriosis. Atherosclerosis.2011;219:784-788.

7.) Arterial Stiffness is increased in young women with endometriosis. J Obstet Gynaecol.2015;35(7):711-715. Tani A et al. 

8.) Regression of endothelial dysfunction in patients with endometriosis after surgical treatment: a 2-year follow-up study. Gynaecology Hum Repro.2014;29(6):1205-1210. Santoro L et al. 

9.) Rahmioglu N, Nyholt DR, Morris AP, Missmer SA, Montgomery GW, Zondervan KT. Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide associations and replication datasets. Hum Reprod Update. 2014;20:702-716. doi:10.1093/humupd/dmu015.  As reported in: Endometriosis and atherosclerosis: what we already know and what we have yet to discover. Clinical Opinion. AJOG. April 2015. Sanotor L et al. 

10.) Uno S., Zembutsu H, Hirasawa A, Takahashi A, Kubo M, Akahane T, Aoki D, Kamatani N, Hirata K, Nakamura Y. A genome-wide associatoin study identifies genetic variants in the CDKN2BAS locus associated with endometriosis  in Japanese. Nat Genet. 2010;42:707-710.  As reported in: Endometriosis and atherosclerosis: what we already know and what we have yet to discover. Clinical Opinion. AJOG. April 2015. Sanotor L et al. 

Reader Resources:

Last month (September 2019) the WHO released an updated chart to categorize your risk of CVD based upon a compilation of risk factors and occurrence of MI/CVA resultant in death across 21 global regions.  An Risk Chart is established for each region of the globe.  https://www.who.int/news-room/detail/02-09-2019-who-updates-cardiovascular-risk-charts

Heart Disease in Women – Fact Sheet Womens Health.gov 2017

American Heart Association Statistical Fact Sheet Women and Cardiovascular Disease 2013

WISE Study Protocal

WISE Study follow-up 10 year mortality

Cardiovascular Disease in Women Clinical Perspectives 2016

Women and Coronary Microvascular Disease

Boston Scientific: Close the Gap Health Equity for Life

National Institute of Health Category Spending (Annual)  Estimates of Funding for Various Research, Condition and Disease Categories (RCDC))