Surgical and Non-Surgical Treatment of Endometriosis

Maciej Barczentewicz, Radosław Maksym, Magdalena Machlarz

IIRRM 11th Annual General Meeting 2014 & Restorative Reproductive Medicine Conference

Stratford-upon-Avon, UK | July 9th, 2014

Male Fertility Support33rd Annual Meeting of the American Academy of

FertilityCare™ ProfessionalsStratford-upon-Avon, UK | July 9-12, 2014

Maciej Barczentewicz, Wojciech Dzierżak

Faculty Disclosure

Doctor Maciej E. Barczentewicz, MD

Dr. Maciej E. Barczentewicz has listed no financial interest/arrangement that would be considered

a conflict of interest.

Surgical and Non-Surgical Treatment of Endometriosis

Presentation Outline

• Update• Critical appraisal• Our Management• Our results• Case presentation

Endometriosis Endometrial tissue is found outside the uterus

• Pelvic pain: dysmenorrhoea, dyspareunia, dyschezia• Subfertility• High Prevalence ( 4-20% )• Incidence rate 1 per mille / year• Limited treatment possibilities• Ovarian cancer risk is 27-80% higher

Clinical types of endometriosis

• Subtle endometriosis : 1-3 mm superficial• Typical endometriosis : 5-40 mm superficial lesions• Cystic ovarian endometriosis• Deep involved endometriosis• Peritoneal Pockets or Allen en Master syndrome

Adenomyosis

Endosalphingiosis

Retrograde menstruation

Sampson JA. Peritoneal endometriosis due to the menstrualdissemination of endometrial tissue into the peritonealcavity. Am J Obstet Gynecol 1927; 14:422-469.

Retrograde menstruation - physiologic

„Endometriosis does not exist. All women

have endometriosis”

J. Evers 1994, ESHRE

Endometriosis Theories• Coelomic metaplasia• Hormones• Apoptosis Suppression and Alteration of

Endometrial Cell Fate• Stem Cells• Genetics• Oxidative Stress and Inflammation• Immune Dysfunction

Immune Dysfunctionwomen with endometriosis

• Presence of Immune complex antigen-antibody IgG & C3 complement in endometrium Weed JC, Arquembourg PC 1980

• Peripheral blood T cells low and B cells high activity , high antibodies syntesis Stratseva 1980

• High level of IgA & IgG anti-endometrial and anti-ovarian antibodies in peripheral blood Mathur 1982

• Presence of Anti- phospholipid antibodies IgG and IgM in peripheral blood Gleicher 1986

• Women with endometriosis are at increased risk for a host of other diseases including chronic fatigue syndrome, multiple sclerosis, lupus, underactive thyroid, and rheumatoid arthritis National Institute of Child Health and Human Development 2002

• CD4⁺ CD25⁺ FOXP3⁺ regulatory T cells in peripheral blood and peritoneal fluid of patients with endometriosis. Olkowska-Truchanowicz J, Maksym RB et al. 2013

• High rate of allergies among women with endometriosis Matalliotakis 2012

Role of allergy and autoimmune infamantory diseases (endometriosis):

Matalliotakis et al., 2012; Bungum et al., 2014

• positive correlation between endometriosis and allergic manifestations, including hay fever, sinus allergic rhinitis, and food allergy type 1 (immediate type hypersensitivity)

• women with endometriosis frequently suffer from autoimmune inflammatory diseases, allergies and asthma

• study indicated a link between endometriosis and increased risk of allergic autoimmune disorders (that should further be explored)

Audit of York Nutritional Laboratory survey, conducted by the Department of Health Studies, University of York, on behalf of the British Allergy Foundation. 2001, January

Food hypersensitivity and IgG-dependent immune reactions:

• No significant correlation between food hypersensitivity and fertility problems

• IgG-dependent allergy affects about 45% of USA and Europe population, and is twice as common in women than in men

• Immunotoxins : immune complexes formed with IgG antibodies and fragments of dietary proteins cause systemic or local chronic inflammation at low intensity

• No specific symptoms, possible changes in the clinical picture in the course of the disease and localization of the lesions

• Delayed reactions : might occur 8-72 hours after the food consumption

Food-specific IgG & immune reactions

•Complement & anafilatoxin generation (C3a, C5a)•Immune cells & release of proinflammatory cytokines (IL-1, IL-6, TNF-a), proteases, ROS-mediated reactions•Basophils and platelets & release of amines vasomotor

Chronic /autoimmune diseases

•Functional bowel disorders (e.g. Irritable bowel syndrome)•Inflammatory bowel disease (e.g. Crohn’s Disease, Ulcerative colitis)•Joint diseases (e.g. Rheumatoid arthritis)•Respiratory disorders (e.g. Asthma, Chronic sinusitis)•Dermatological disorders (e.g. Atopic dermatitis)•Chronic medical conditions (e.g. Obesity, Atherosclerosis, Migraine headaches, Diabetes)

Sampson & McCaskill, 1985; Pelikan, 1988; Crowe & Perdue, 1992; Hazebons & et al., 1996; Aktinson & et al., 2004; Ress & et al., 2005; Harman & Hart, 2007; Zuo & et al., 2007; Wilders & et al., 2008; Bentz & et al., 2010; Aply & et al., 2010;

IgG-dependent food hypersensitivity and chronic/autoimmune diseases:

Vitamin D deficiency – discussion:

• vitamin D role in the pathogenesis and treatment of endometriosis (an immunomodulator and anti-inflammatory agent)

• VDR and vitamin D metabolizing enzymes are found in endometrium (normal cycling, eutopic and ectopic endometrium of women with endometriosis)

• the endometrium is a target of 1, 25 dihydroxyvitamin D actions through regulation of specific genes and via immunomodulation.

• the endometrium in endometriosis expresses dysregulation of some vitamin D enzymes and receptors.

• VDR-agonist was shown to reduce the development of endometriotic lesions and recurrence (mouse model)

Sayegh et al, 2014; Bertone-Johnson et al., 2010; Du et al., 2005, Sayegha et al., 2013

Diagnosis and Treatment of EndometriosisCAROLINE WELLBERY, M.D., Georgetown University School of Medicine, Washington, D.CAm Fam Physician. 1999 Oct 15;60(6):1753-1762.

Aktualne wytyczne

Grades of Recommendations

Supporting evidence

AEvidence from meta-analysis of randomized controlled trials

B Evidence from at least one controlled study without randomization

C Evidence from non-experimental descriptive studies, such as comparative studies, correlation studies, and case-control studies

D Case reports

GPP Evidence from expert committee reports or opinions or clinical experience of respected authorities, or both

Surgical and Non-Surgical Treatment of Endometriosis

Our Management :• Medical treatment : “good” CrMS chart, letrozol , LDN• Diet • Surgery – near contact LPS, LPT – cooperating surgeons in

Poland: Dr Dr: Baryła, Binkiewicz, Gałczyński, Gratkowski, Klimas, Maksym, Ulman,

• Interventional Radiology: prof Małgorzata Szczerbo-Trojanowska, prof Jan Oleszczuk, Dr Waciński

• Psychotherapy ( some cases)

Role of diet and nutrients (endometriosis) – our results, n= 61 (1):

Most frequently consumed foods: •gluten grains: wheat bread, wheat pasta, wheat roll

•dairy products: cheese, sour cream, cottage cheese, cow's milk

•vegetables: potato, tomato

•fruits: apple, banana  

Role of diet and nutrients (endometriosis) – our results, n=61 (2):

 

Conclusions: •too high intake of processing dairy products

•too high intake of processing cereal products

•excessive intake of cereal gluten

•too low intake of gluten-free cereals (including rice, millet, buckwheat, amaranth)

•too low a variety of fruits and vegetables consumed

•too high intake of processed meat

•small intake: fish, legumes, nuts and seeds, unrefined oils

Distribution of food-specific IgG in women with infertility & edometriosis

– our results, n= 124

• In patients with a diagnosis of female subfertility and coexisting endomteriosis are elevated levels of food-specific IgG(1-4)

• The most common “female subfertility” food allergens identified by the diagnostic tests for serum specific IgG(1-4) antibodies are: hen’s eggs (90%), wheat (92%), gluten & other gluten cereals (58%) milk (72%), corn (55%), yeast (51%)

FoodDetective test 46; ELISA IgG(1-4), (Cambridge Nutritional Sciences Ltd/ Genesis Diagnostics Ltd, UK)

Vitamin D deficeincy – our results, n=61

• Vitamin D deficiency: 91,8% (56)

• Vitamin D in the standard: 8,2 % (5)

• The average concentration of vitamin D: 18.7 ng / ml (4.6 ng / ml - 37.3 ng / ml)

11.5 % (7) 0 -10 ng/ml

45.9 % (28) 10 -20 ng/ml

34.4 % (21) 20 - 30 ng/ml

8,2 % (5) 30 - 80 ng/ml

Our Individual Dietetic Program consists of:

•Quantitative and qualitative analysis of individual nutrition habits•Optimization of nutritional program •Recommendations for the preconception nutrition•Recommendations for the anti-inflammatory diet•Recommendations for the elimination and/or rotation diet•Recommendations for the nutrition in the coexisting diseases (on the basis of current scientific data) •Consideration of the possible interactions between nutrition and medicines taken by the patients•Supplementation (in regard to accompanying diseases, and /or elimination diet) •Recommendations for the healthy life style (sport activity, appropriate sleeping time, sun exposition, avoiding the stress, prayer time)

The expected benefits of dietary intervention with our Individual Dietetic

Program:•Mute the allergic response and inflammation in the digestive system 

•Reduction and prevention of mucosal barrier dysfunction to food allergens

•Improved gastrointestinal function and nutrient absorption

•Minimize the likelihood of pseudoallergic reactions

•Recovery of immune tolerance to the actually harmful food 

CASE PRESENTATION

Couple 1 G-0 P-0 Age of wife: 37 Age of husband: 40

• Efforts to conceive: 6 month

• Diagnosis on entry into NPT :

• ENDOMETRIOSIS Grade IV LPS 2011;

• Adhesions - frozen pelvis

• Large Bowel obstruction

• Endometriosis of urinary tract

• Hydronephrosis with left ureteral stricture

• Left fallopian tube occluded

Couple 1 G-0 P-0CrMS from : 30.05.2012

NPT diagnosis: WIFE

• CA 125 178

• Hydrosalpinx

• Latent hyperprolactinemia PRL 490 IU/ml 4265 IU/ml after MTC

• Limited mucus MCS 6.9

• Low progesterone at Peak+7

• FOOD Intolerance

• treatment with bromocryptine, progesterone, vitaminD3 , LDN, Letrozole, ACC, Diet

Couple 1 G-0 P-0

Referal to surgery

Pope Paul VI Institute

Dr Hilgers Omaha , Nebraska USA

Couple 1 G-0 P-0CrMS from : 30.05.2012

NPT diagnosis: HUSBAND

• SPERM ANALISYS 18.09.2012 sperms 32mln/ml motility 34% morph 21% elevated viscosity

• Treatment : suplements; acetylcysteine 600 – fertile period

• SPERM ANALISYS 13.11.2012 sperms 53mln/ml motility 44% morph 29% norm viscosity

Couple 1 G-0 P-0

CrMS from : 30.05.2012

After 12 month of CrMS natural conception Baby Girl 3680 g cesarian section

6.02.2014

CASE PRESENTATION

Couple nr 2 G-0 P-0Woman age 30 Man age 32

Infertility 6 years

Diagnosis on start: 21.10.2009

Male Infertility: sperm sample 2009: sperm count 0,0

Past medical history: Hodgkin's lymphoma CTX 2007

Female infertility: Endometriosis

LPS 2008 endometrioma AFS IV

Couple nr 2 G-0 P-0 CrMS from: 5.06.2010

Diagnosis in NPT: HUSBAND

Hypogonadism, Varicocele 4,5mm, Valsalva maneuver (-)

sperm sample 14.04.2010 : 0.06mln sperm, 15% mobility, 0%morphology, elevated viscosity

sperm sample 6.09.2010: 12mln sperm, 33% mobility, 18%morphology, elevated viscosity

treatment: acetylcysteine

sperm sample 4.04.2011

9mln sperm, 35% mobility, 3%morphology, normal viscosity

Treatment: tamoxifen, Testosterone undecanoate, zinc, alfa lipoic acid, l-carnitine, selenium

Couple nr 2 G-0 P-0

CrMS from: 5.06.2010

sperm sample 10.12.2011 after 4 month tamoxifen, Testosterone undecanoate

21mln sperm, 26% mobility, 18%morphology, elevated viscosity

Libido decrease, Hair loss

treatment: acetylcysteine, zinc, alfa lipoic acid, l-carnitine, selenium

Couple nr 2 G-0 P-0 CrMS from: 5.06.2010

NPT Diagnosis: WIFE

• Abnormal bleeding• Cervical Ectropion

• Latent hyperprolactinemia treatment bromocriptine 1.25 mg

• Low progesterone

• Limited mucus

• Food Intolerance

• Treatment: clomiphene HCG 2500 Peak +3,5,7, Vitamin B6 , guaifenesin

• Electrocoagulation/Hypherfaction

Couple nr 2 G-0 P-0 CrMS from: 5.06.2010

NPT Diagnosis: WIFE

• Abnormal bleeding• Cervical Ectropion

• Treatment: Policresulenum, Hyaluronan

• Near contact LPS 15.04.2011 Frozen pelvis, endometrioma

• Letrozole, Pre Seed

• Psychotherapy

Couple nr 2 G-0 P-0 CrMS from: 5.06.2010

• Natural conception 2-5.12.2011 (follicle tracking)

• Pregnancy test HCG (+) positive

• Ultrasound confirms presence of fetus

Couple 2 G-0 P-0CrMS from: 5.06.2010

Baby girl 3600 g born August 12th 2012 Caesarian Section

Postpartum depression

Lactation 9 month

13.06.2014 charting start

CASE PRESENTATION

Couple nr 3 G-0 P-0Woman age 34 Man age 35

Infertility 12 years

Diagnosis on commencement of treatment:

LPS 2003 ENDOMETRIOSIS, LPS 2005 TUBAL OCCLUSION, LPS 2010 ENDOMETRIOMA, adhesions, myoma, tubes patent

medical treatment: Danazol, GnRH Analoques, Femara 1x1

MALE: sperm count 43 mln motility 50%, 16 % morphology

IUI 2x

In vitro 1x 2005: 5 embryos, transfer 3, kryo 1

Couple nr 3 G-0 P-0

Couple nr 3 G-0 P-0

Creighton Model : 9.05.2011

NaPro Dgn: Wife

Multiple food intolerance including dairy milk, poultry egg, wheat, gluten - low carbohydrates & elimination diet

latent hyperprolactinemia fasting PRL 9,7 ng/ 219 ng after MTC

vitamin D3 12,6 ng

treatment bromocriptin, metformin, vit D3, LDN

Couple nr 3 G-0 P-0 endometriosis IV grade

Couple nr 3 G-0 P-0

3rd cycle - natural conception

pregnancy test HCG (+) positive

Ultrasound confirms presence of fetus

GS 6w6d CRL 6w3d FHR (+)

Progesterone at 6 weeks: 36,1 ng/l estradiol 658 pmol/l

EDD 16.04.2012

27.03.2012 cc Baby girl 2400 g

Couple nr 3 G-0 P-0

Baby girl 2400 g born March 27th 2012 Caesarian Section

Research in course of realisation :

1.Quantitative and qualitative analysis of the nutrition of the patients’ group with the fertility problems and coexisting diseases:

2.Clinical evaluation of elimination diet based of the results of IgG- dependent food hypersensitivity test (in the group of patients with the fertility problems and diagnosed coexisting autoimune disease(s): autoimmune thyroiditis and/or endometriosis)

• autoimmune thyroidis (Hashimoto’s disease)• polycystic ovary syndrome (PCOS)• endometriosis

Research in course of realisation :

3. Analysis of the serum D3 vitamin level (25-OH-D3) (in the group of the women with infertility problems)

4. Establishment of the dietary standards in the diagnostics and therapy of female infertility and coexisting diseases

5.Development of educational standards regarding the dietary habits and life style in the preconception period of women with infertility problems

6.Infertility & Psychology : Stress level and quality of marital bonding

7.Retrospective treatment outcome analisys

8.iNest – center Number 22

Take home messages:

• Immune Dysfunction• “Good” CrMS chart• LDN• Diet• Surgery

Correspondence address:Maciej BarczentewiczLeśna 3720-423 Lublin,POLAND

phone: 0048 667 660 289e-mail: maciej.barczentewicz@infertility.pl