Lithuanian University of Health Sciences
Faculty of Medicine
Department of Gynecology and Obstetrics
Final Master Thesis
Infertility and Endometriosis: Review of a clinical case of
infertility linked to endometriosis
1.TITLE PAGE
Author: Rik Deemter
Supervisor: Prof. Rosita Aniulienė
2. TABLE OF CONTENT
1.TITLE PAGE ... 1 2. TABLE OF CONTENT ... 2 3. SUMMARY ... 3 4. ACKNOWLEDGEMENT ... 4 5. CONFLICT OF INTEREST ... 46. PERMISSION ISSUED BY THE ETHICS COMITTEE ... 4
7. ABBREVIATIONS ... 4 8. TERMS ... 5 9. INTRODUCTION ... 5 10. AIM: ... 6 11. OBJECTIVES ... 6 12. RESEARCH METHODOLOGY: ... 6 13. CASE PRESENTATION: ... 6 14. LITERATURE REVIEW: ... 9 14. DISCUSSION ... 25 15. CONCLUSION ... 27 16. REFERENCES:... 29 17. ANNEX ... 33
3. SUMMARY
Author´s name: Rik DeemterResearch title: Infertility and Endometriosis: Analyzing a clinical case of infertility linked to endometriosis
Aim: The aim of this review is to evaluate the clinical approach of an infertile women with endometriosis with regard to the newest guidelines and the guidelines of the highest quality.
Objectives: 1. To present the clinical case and the interventions applied 2. To provide the latest guidelines regarding endometriosis
3. To compare the latest guidelines with the approach applied in the case
Methods: PubMed/ Medline, Cochrane Library, UpToDate, national and international guidelines were searched to find applicable sources on the topics of endometriosis and the latest guidelines. Out of the two guidelines, one national guideline was chosen by the latest date of publication, the second as a result of a systematic review evaluating the guideline as the highest quality. Also, the latest recommendation for approaching infertility, recommended by a national committee, has been included.
Results: The guidelines of ESHRE and NICE for treating infertility associated with endometriosis, as well as the clinical approach towards infertility in general, recommended by the American College of Obstetricians and Gynecologists, were applied in the treatment of this infertile couple.
Conclusion:
Endometriosis is a debilitating disease affecting many women. Existing research and guidelines do not provide enough substantial information for developing high quality guidelines, therefore research must be expanded. The discordance between national and international guidelines has to be addressed and the quality of guidelines has to be raised.
4. ACKNOWLEDGEMENT
I would like to thank Prof. Rosita Aniulienė for her help and advice during the process of writing this final master thesis. Furthermore, I would like to thank my father Frederik Deemter and my friend Sebastian Milster for their support in finalizing this thesis.
5. CONFLICT OF INTEREST
The author reports no conflict of interest during this study.6. PERMISSION ISSUED BY THE ETHICS COMITTEE
Personal data regarding the patient were not disclosed to the author.7. ABBREVIATIONS
LSIL: Low-grade squamous intraepithelial lesionHPV: Human Papillomavirus BMI: Body mass index bpm: beats per minute LH: Luteinizing Hormone
FSH: Follicle-stimulating hormone TSH: Thyroid-stimulating hormone PCR: Polymerase chain reaction FT4: thyroxine
NT: Nuchal translucency
BGS: Group B Streptococci
CRP: C Reactive Protein
WHO: World Health Organization APL: Antiphospholipid
TPO: Thyroid Peroxidase TG: Thyroglobulin
Sin.: Sinister (left) Dex.: Dexter (right) IL: Interleukin
DNA: Deoxyribonucleic acid
17bHSD2: 17β-Hydroxysteroid dehydrogenase 2
VIP: Vasoactive Intestinal Peptide CGRP: Calcitonin Gene-Related Peptide SP: S Protein
NPY: Neuropeptide Y
PGP 9.5: Ubiquitin carboxy-terminal hydrolase L1
CYP19: Cytochrome P19
MRI: Magnetic resonance imaging
NICE: National Institute for Health and Care Excellence GnRH: Gonadotropin-Releasing-Hormone
ESHRE: European Society of Human Reproduction and Embryology
8. TERMS
Endometrium: Mucous membrane lining the inner part of the uterus Chorionamnionitis: Inflammation of the fetal membranes
Ovariolysis: Removal of adhesions around the ovaries
Oligoovulation/ Anovulation: Ovulation occurring infrequent/ not at all
9. INTRODUCTION
Endometriosis is a condition characterized by endometrial growth outside the uterine cavity. Affecting about 10% of women in their reproductive age, the diseases is quite common among the female population. The clinical presentation is rather unspecific and is often undiagnosed for many years. The disease can be complicated by infertility, which will be discussed in detail later on.
10. AIM:
The aim of this review is to evaluate the clinical approach of an infertile women with endometriosis with regard to the newest guidelines and the guidelines of the highest quality. With this approach the latest guidelines and/or the highest possible standard of guideline will be made available for clinical practice.
11. OBJECTIVES
The objectives are to present the clinical case, to provide the latest guidelines for clinicians, to compare if the patient has been treated according to the latest guidelines and if the guidelines need to be updated.
12. RESEARCH METHODOLOGY:
In order to achieve this, scientific databases have been searched to provide information associated with this topic. The databases included are PubMed/Medline, Cochrane Library and UpToDate. The keywords used were “endometriosis” and “infertility” in combination with the subcategories “prevalence”, “epidemiology”, “clinical presentation”, “diagnosis” and “treatment”. The two guidelines “to compare the clinical approach” to were chosen by the date of publication, as well
the guideline recommended by a systematic review rating this guideline as the highest quality. The approach towards infertility has been chosen by the most recent date of publication.
13. CASE PRESENTATION:
First contact on 15th September 2017A thirty-two-year-old women consults a physician. She seeks help with conceiving a child as she has been trying unsuccessfully with her partner for more than two years. The anamnesis reveals that menarche occurred at the age of 13. Her menstrual cycle is regular at 30 days and lasts seven days. Neither miscarriages, nor abortions have been reported. The couple states that they have sexual intercourse twice per week. Her partner is a father of three children of which the youngest is thirteen years old.
Anamnesis vitae: Two years ago, LSIL was established with the PAP smear, the patient was tested negative for HPV, no allergies established.
Physical examination:
Height: 167 cm, weight: 56 kg, BMI 20.08 Blood pressure: 136/68 mmHg,
Heart rate: 81 bpm
Ultrasound: 15th September 2017
Uterus in retroversion, size 67x38x40 mm. Endometrial thickness seven millimeters.
The left ovary is of 36x21mm with a 14mm follicle and a 15mm implant containing viscous fluid implant. The right ovaries size is 28x23mm with follicles and a 9mm viscous fluid containing implant. There were no signs of free fluid in the pelvis.
The preliminary diagnosis established after the ultrasound was: Ovarian endometriosis and primary infertility.
Hormone profile:
Hormone Result Normal range
Progesterone 50.68 nmol/l Follicular phase: £ 6.52 nmol/l;
Luteal phase £ 47.25 nmol/l
LH: 7.5 U/l Follicular phase 1.7-13.3 U/l
Ovulatory phase 4.1-68.7 U/l Luteal phase 0.5-19.8 U/l)
FSH: 11.8 IU/l Follicular phase: 4.5-11 IU/l
Luteal phase: 1.5-10.8 IU/l
TSH: 3.13 mU/l 0.4-3.6 mU/l
Prolactin 736.22 mU/l
429.06 mU/l (4 months later)
105-548 mU/l
FSH, LH, Prolactin measured at the 3rd-5th day of the cycle (Date 10th of October 2017)
TSH, Progesterone measured at the 20th-23rd day of the cycle (Date 2nd of October 2017) HPV PCR: Date 28th July 2017 (provided by personal gynecologist)
tested for DNA types: 16/18/31/33/35/39/45/51/52/56/58/59/68
Sexual transmitted diseases: 4th of October 2017
Tested for C. trachomatis, M. genitalium, N. gonorrhoeae and T. vaginalis, which were all found negative by PCR.
Examination of the thyroid gland:
The thyroid gland was found to be soft during palpation. Sonographic examination of the thyroid gland revealed a normal size with a hypoechogenic nodule of three millimeters in the left lobe. Being infertile with a TSH > 2.5 mUI/l and a normal FT4, indicated the initial treatment with Levothyroxine 50mcg/day, after a consultation with an endocrinologist.
Surgical report of diagnostic laparoscopy: 15th November 2017
The laparoscopy was performed under general anesthesia. Ovariolysis sin., cystectomy dex. and coagulation of an endometrial lesion on the left ovary was accomplished. Tubal patency was tested with methylene blue, showing no pathological finding. There were no complications during the operation which was followed up by prophylactic antibiotic treatment with cefazolin 2.0 g.
The laparoscopic findings include: normal sized uterus in anteversion with a smooth surface. The left ovary (4x3x2cm) fixed to the posterior surface of the uterus and the sacrouterine ligament with deep infiltrating endometrial lesions. The left fallopian tube appears normal with free fimbriae. The right ovary (3x2x2cm) with a 1 cm endometrioma filled with brown viscous liquid. The right fallopian tube appears normal with free fimbriae.
Recommendation after surgery: remove the sutures after 7-10 days, if no conception occurs after half a year, schedule for reconsultation. No hormonal treatment was prescribed after the surgery.
Histological report of the cystic material:
Confirming the endometrial cyst. The wall of the cyst is fibrotic, with little hemosiderophagues infiltration.
Consultation: 12th of February 2018
The patient conceived naturally. The patient takes folic acid. There is no bleeding, no diabetes is diagnosed. According to the last menses the fetal age is 14 weeks and two days. Ultrasound examination: The fetus is alive, the placenta is located at the posterior wall of the uterus, CRL – 67.6mm (13 weeks, 0 days), NT- 1.81mm, venous blood supply and tricuspid valve are normal, changes typical for chromosomal abnormalities have not been noticed. A double test (11-13+6 week of
Patau and Turners syndrome. The test used is called “LifeCycle 4.0” and its result was negative. Based on the ultrasound calculation and the last menses, the conception happened in the week after the laparoscopic treatment.
Consultation: 27th august 2018 41+2 week of gestation
The woman arrived at the hospital and was hospitalized, for her due date had passed. Two days later the woman´s water broke and the process of labor started. Five million units of penicillin i/v were administered due to BGS colonization. At the time of hospitalization, the woman had a fever of 37,8°C and the blood count showed leukocytosis and an increased CRP value. The fetus and the mother both had an elevated heart rate. The situation was interpreted as chorionamnionitis, therefore the treatment was altered to ampicillin, metronidazole and gentamycin. The course of delivery was uneventful and at 23:35 the woman gave birth to a boy of 3895g, 52cm, APGAR score 10 -10, pH at the fontanelle 7.21, time after the water broke 10:05 hours, overall time 14:45 min. An episiotomy was performed and sutured afterwards, the placenta was evaluated and parts of it remained in the at the uterine fundus, which were revised in the operating theater, the blood loss was less than 500ml. The patient stayed in hospital for one more day and was discharged with the newborn and the recommendation to continue the antibiotic therapy for five more days.
14. Literature review:
Infertility:
The WHO defines infertility as “a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse” and affects an estimated number of 48.5 million couples. (1)
Since infertility is considered a disease affecting a couple, influential factors are classified into female, male and both male and female.
Primary infertility is defined as being unable to bear a child, whereas not conceiving another child after already giving birth is considered secondary infertility. Causes for primary infertility in women can be of ovarian, fallopian tube, pelvic adhesion, uterine, cervical, endometriotic or genetic origin. Additionally, certain lifestyle, immune and inherited thrombophilia have been associated with infertility. A decent number of infertile women don´t present themselves with a distinct cause for infertility.This is considered unexplained infertility. Causes for ovulatory dysfunction typically can be ruled out if women are menstruating regularly and experience accompanying symptoms such as breast tenderness, dysmenorrhea, bloating, fatigue, headaches. If the cycle is irregular or absent, causes for oligoovulation or anovulation have to be considered, and so should be pregnancy. Potential causes for anovulation have
been classified by the WHO into three groups: hypothalamic pituitary failure, hypothalamic-pituitary-ovarian axis and finally hypothalamic-pituitary-ovarian failure. Group I ovulation disorders equate to hypogonadotropic hypogonadism which is characterized low levels of gonadotropins and estrogen deficiency. Group II ovulation disorders are represented the most among the population with about 85% where normogonadotropic normoestrogenic anovulation is present. Polycystic ovary syndrome is such a case, which is found in about in about 5-10 % of women of reproductive age. Group III ovulation disorders is hypergonadotropic hypoestrogenic anovulation present in primary ovarian dysgenesis (absence of ovarian follicles) or ovarian resistance (follicular form). Hyperprolactinemic anovulation is described separately in this classification. Hyperprolactinemia is inhibiting GnRH, thus resulting in a diminished secretion of estrogen. Cycles may be regular anovulatory, but most commonly found is oligomenorrhea or amenorrhea. (2) Another important factor is aging, since every woman is born with a limited number of primordial follicles. With every menstrual cycle because of atresia this number declines and fertility finds its natural end in the menopause. Aged oocytes are found to be a reason for reduced fecundity. With age chromosomal abnormalities and dysfunction of organelles is more common. Tubal abnormalities and pelvic adhesions impair the transport of the oocyte from the ovary to the ampulla and about 30% of infertile women having an associated pathology, this cause of infertility is a considerably large entity. The main cause of tubal infertility is pelvic inflammatory disease, while others include, endometriosis, intrauterine contraceptive devices or complications after abdominal surgery. (3)
Uterine causes of infertility can be mechanical or associated with reduced receptivity of the endometrium, both leading to reduced rates of implantation. Uterine anomalies are known to increase the likelihood of adverse pregnancy outcomes.(4) Intrauterine adhesions, also known as Asherman´s syndrome are likely to be found in the infertile population with estimated numbers between 2.8-45.5%, depending on the subpopulation.(5)
Cervical factors can cause infertility. They are best evaluated by the post coital test, which can if tested positive exclude cervical factors. The cervical factors are divided into three groups: anatomical defect, abnormal mucus and abnormal post coital test and normal mucus.(6)
Inherited thrombophilia has been demonstrated to cause recurrent IVF. A case control study found that the presence of thrombophilia, not necessarily due to the same cause, showed a significant association between thrombophilia and infertility. A possible mechanism could be thrombosis of maternal vessels, which leads to lower perfusion of the intervillous space and subsequently to placentation failure. (7) In 2014 a meta-analysis had been conducted in order to evaluate epidemiological associations of celiac disease and infertility. The results of the study showed a significantly higher risk of celiac disease among infertile women and higher rates of adverse pregnancy outcomes among women suffering from celiac disease. The effect of celiac disease has been proven in patients who have not been diagnosed with celiac
activity of celiac disease. (8) The link between autoimmunity and infertility has been further established in a systematic review about serum auto-antibodies and female infertility. Higher levels of antibodies (APL, TPO, TG, ANA, B2-GP1, ASCA) were found in infertile women. (9)
Female genetic causes of infertility have multiple facets. Polycystic ovarian syndrome and the above discussed anovulatory features has been discussed already. Several genes are believed to be associated with this syndrome, but their influence on sex hormone regulation, insulin sensitivity and steroid biosynthesis, as well as the known clinical combination of obesity and PCOS, strongly suggest a genetic
influence on fertility.
The anatomical differentiation of sexes in the human body is a complex process and disturbance may lead to gonadal dysgenesis, with a variety of genotypical variations but common features may include gonadal streaks, primary amenorrhea, uterine hypoplasia, etc.
Premature ovarian failure describes the onset of menopause before the age of 40. There are multiple genes associated with this condition, but the etiology has not been fully understood yet. (10)
Male factors of infertility roughly can be classified into three groups. Firstly, pre-testicular causes which are extra-gonadal endocrine disorders. Also, there are testicular causes that are disorders concerning the testes. The third group of factors are post-testicular causes that are disorders concerning obstructions/impaired transportation of the ductular system that normally transports the otherwise healthy sperm from the testes to the ostium urethrae externus.
Pre-testicular disorders include the following hypothalamic disorders: Kallmann syndrome, isolated LH deficiency, isolated FSH deficiency, congenital hypogonadotropic syndromes, craniopharyngioma or other tumors, trauma, post-infection, radiation. Along the hypothalamic-pituitary-gonadal axis tumors, infarctions, sarcoidosis, surgical trauma can cause infertility. Furthermore, hyperprolactinemia, glucocorticoid excess and disruption of normal thyroid function are known causes of subfertility. Testicular causes of subfertility include chromosomal disorders, which can impair normal development and thus function of the testes, vanishing testes syndrome, Noonan syndrome, varicocele, myotonic dystrophy, orchitis, cryptorchism, chemical damage to testicular tissue, germinal aplasia, idiopathy testicular failure, aging, paraplegia, polyglandular failure, obesity and chronic liver failure.
Post-testicular causes of subfertility can be caused by mechanical obstruction anywhere from the epididymis to the urethra, whether it is congenital or acquired. The obstruction can be functional too, if there is sympathetic denervation or ejaculatory disorders and impotence.(11)
Lifestyle factors associated with infertility which are based on evidence are smoking and obesity. Inconclusive results due to sparse available research content include psychological stress, caffeine and alcohol consumption and environmental pollutants. (12)
If no identifiable cause for infertility has been established by standard investigations, infertility is described as unexplained.
Infertility approach according ACOG (American College of Obstetricians and Gynecologists) outline (2019)(13)
The Basic Infertility Evaluation recommended by the ACOG consists of taking a detailed history of both the woman and the man to identify potential causes for infertility. The anamnesis should evaluate the duration of infertility and previous interventions, a detailed sexual and gynecological anamnesis, as well as medical anamnesis oriented towards infertility. The physical examination of the female partner is focused on vital signs, thyroid, breast and pelvic examination. Additional evaluation for etiology of infertility is applied to women and men. The female partner is tested for ovarian reserve, ovulatory function and structural abnormalities. The investigation may focus on antimüllerian hormone, antral follicle count, FSH and a history of poor response to IVF stimulation, to determine the ovarian reserve. Clinical history of the menstrual character, midluteal progesterone level, positive LH tests, biphasic basal body temperature or cervical mucus changes can be used to evaluate the ovulatory function. Serum thyrotropin and prolactin should be added to the investigation of ovulatory dysfunction.
The tubal factor is examined by hysterosalpingography, though due to a low positive predictive factor, further investigations like sonohysterography and hysterosalpingo-contrast sonography may be required. Sonographic evaluation of the uterus is a valid option to exclude uterine factors for infertility. The most definitive diagnostic tool is a hysteroscopy, but this is not recommended as initial evaluation of infertile women, due to cost and access considerations. Possible müllerian anomalies sometimes require other imaging modalities such as MRI or three-dimensional ultrasonography to accurately differentiate and confirm the diagnosis.
Male factor infertility can be evaluated by a woman´s health specialist but it may be reasonable to refer the male partner to an expert in male reproductive medicine. Any abnormality noted on the male history or semen analysis warrants a referral to a specialist. The anamnesis of the male partner is directed towards the character of infertility, sexual history and a detailed history focusing on aspects of medical aspects which might contribute to infertility such as developmental errors, surgeries, gonadal trauma etc. The cornerstone of additional investigations is the analysis of the partner semen. Two to five days of abstinence are recommended to achieve optimal results. The sample should be collected by masturbation and if obtained at home, examined within one hour and transported at room or body temperature. (The detailed recommendation is added to the annex)
Endometriosis:
Endometriosis is a disease characterized by extrauterine growth of endometrial stromal and glandular cells. This condition affects around ten % of women in reproductive age.
The pathogenesis of endometriosis still remains unclear, however different theories have been postulated. These can be classified into two potential groups: implants originating from the uterine endometrium, and on the other hand implants forming from tissues other than the uterus.
The main theory of what is believed to be the origin of endometriosis is called retrograde menstruation, a process where small amounts of endometrium enter the peritoneal cavity through the fallopian tubes and form endometrial focuses. Although menstrual blood findings on laparoscopic examinations are considered physiological, 90% of patients with endometriosis had bloody fluid accumulations in the perimenstrual time. The fact that women with antegrade outflow anomalies are more likely to develop endometriosis support this theory.(14,15). Still an explanation has to be found why 90% of women show retrograde flow, but only 10% develop the disease. Another theory about endometriosis evolving from intrauterine cell findings outside their natural environment is hematogenous or lymphatic spread which can explain incidents of endometrial cells outside the peritoneal cavity, for instance in the lungs, bones or brain. The other spectrum of assumptions, involving a non-uterine origin of endometrial cells consist of the following: coelomic metaplasia, describing peritoneal tissue which undergoes a transformation to ectopic endometrial tissue. Müllerianosis, a concept including the idea of remnants of the Müllerian duct which under influence of estrogens evolves into endometriotic lesions. Also stem or progenitor cells from the bone marrow are suspected to possibly transform into endometrial cells.(16) The distribution according to the anatomical site was found in a prospective observational study from 1989 to 2009 including 1101 patients. The data showed that most of the lesions occurred on the ovaries (66.94%), the utero-sacral ligaments (45.51%), the ovarian fossa (32.15%), the pouch of Douglas (29.52%) and the bladder (21.25%). Extrapelvic locations include abdominal wall endometriosis, the thoracic cavity, including the pleura, the pericardium and the diaphragm, the gastrointestinal tract, in the liver and gallbladder, although being very rare, the urinary tract and muscular tissue.(17,18)
Risk factors for developing endometriosis:
1994 MOEN described an assumption of a genetic predisposition for developing endometriosis, by comparing monozygotic twins to other types of sisters, showing an increased incidence of the disease among the genetical identical individuals(19). The ENDO study (Endometriosis, Natural history, Diagnosis and Outcome) has set the goal to identify environmental chemicals and risk factors causing endometriosis. Among them benzophenone, phthalates, metals and trace elements like copper and chromium, organochlorine pesticides and perlfuoralkyl and polyfluoroalkyls were pointed out to increase the risk of being diagnosed endometriosis.(20) In January 2019 modifiable risk factors such as
caffeine and alcohol consumption, smoking and physical activity have been scrutinized, but no indicative finding of any significance has been established in association with endometriosis. (21) Characteristics of the menstrual cycle such as onset and length as well as duration of menstruation have been shown to influence the likelihood of being diagnosed with endometriosis. An earlier onset, a short cycle and prolonged days of bleeding highlight the importance of hormonal influences. (22)
Another prognostic factor is gravity and parity. As infertility is known to be complication of endometriosis, it is not surprising to find nulligravity and nulliparity to be a risk factor.(23)
How is endometriosis linked to infertility?
Endometriosis and infertility are closely linked together. Epidemiologically there is evidence that 25-50% of infertile women are diagnosed with endometriosis and on the other hand 30-25-50% of women suffering from endometriosis are unable to conceive a child.
Pathogenetic mechanisms causing infertility associated with endometriosis include: Dysfunctional uterotubal motility, chronic inflammatory processes in the peritoneum, compromised hormonal function, anti-endometrial antibodies and detrimental effects on spermatozoa. Both adenomyosis and endometriosis have a significant effect on the ovum tubal transport mechanisms. A decrease of ciliated cells in the isthmus and the ampullary segment have been found comparing to a control group, furthermore the ciliary beat frequency, as well as decreased smooth muscle functionality concerning diminished contraction frequency and amplitude-to-weight ratio, demonstrating a drop in the capacity to transport the gametes and the embryo to the uterine cavity.(24)
Chronic inflammatory processes in the peritoneum:
Chronic inflammation in any kind of tissue ultimately leads to a changed microenvironment. As this delicate equilibrium is put into disbalance the physiological process is disturbed. This can be roughly described by an increased amount of inflammatory substances, including Il-1, Il-8, Il-10 and TNF alpha, triggering a reduced response of the ovaries. The inflammatory process is further hindering fertilization by immobilization of sperm cells, possible DNA damage in sperm cells and impeding the fusion of gametes.(25) A noteworthy mention is the compromised hormonal function, comprised by luteinized unruptured follicle, luteal phase defects and progesterone resistance. The level of interference is not only locally present, but might also be found to be systemic. Luteinized unruptured follicle is a condition where the follicle is not undergoing stimulation in the presence of LH. Although the exact relation has not been established yet, an amassment of concomitant diagnosis counting endometriosis, as well as infertility has been observed. (26) The hypothalamo-pituitary-ovarian axis might be compromised too. Endometriosis patients present themselves with altered serum hormone levels, namely decreased
or endometrial receptivity. The endometrium is undergoing transformation into the secretory stage under the influence of progesterone, a hormone formed by corpus luteum. The responsiveness of the progesterone receptor has been demonstrated to be decreased in endometriosis patients. The consequence displays as a potentially decreased ability to provide the fertile environment necessary for the implantation of a fertilized egg. Proinflammatory conditions are promoted by metabolization of estradiol to the estrone which is metabolized by 17b-hydroxysteroid dehydrogenase type 2. The expression depends on progesterone, which if the responsiveness is decreased leads indirectly to a more estrogenic environment (as estradiol is more potent) in endometriotic tissues, leading to a proinflammatory state and promoting endometriosis, since the disease is estrogen dependent.
Anti-endometrial antibodies are found in higher frequencies in patients with endometriosis and infertile women. They are believed to be a risk factor for successful implantation.(27)
Clinical presentation of Endometriosis:
As mentioned above, endometriosis affects mainly women in the reproductive age with the highest prevalence around the age of 31-35. There is evidence that a delay of approximately 6.7 years occurs from the onset of symptoms until the surgical diagnosis of endometriosis.
Table 2. Symptoms of endometriosis Symptom(s) Occurrence rate
Dysmenorrhea 60-80%
Chronic pelvic pain 40-50%
Deep dyspareunia 40-50%
Infertility 30-50%
Severe menstrual pain and irregular flow and/or premenstrual spotting
10-20%
Tenesmus, dyschezia, hematochezia, costiveness or diarrhea
Dysuria, pollakiuria, micro- or macroscopic hematuria
1-2%
Systemic symptoms include nausea, hemoptysis, acute abdomen, lethargy, pain at other anatomical sites, for example scapular of thoracic pain. It is important to mention that the severity of the symptoms not necessarily correlates with the severity of the laparoscopic findings. Symptoms of atypical lesions usually involve organ malfunction pain and at the designated site, often described occurring in a periodic manner. Endometriosis might also be asymptomatic and only found incidentally, there are no definite numbers on how large this group of patients is. Studies on asymptomatic women with incidental findings set the prevalence in the ballpark of around 1-7%
Physical examination:
Physical examination of the patient can contribute to the diagnosis of endometriosis. The results depend on the size and localization of the masses. Tenderness on vaginal examination, nodules on the posterior fornix, adnexal masses and immobility or lateral placement of the cervix or uterus. Findings on the physical examination might also be inconclusive, as they can be normal but this should not exclude the diagnosis of endometriosis.
Laboratory investigation:
Laboratory investigation of patients with endometriosis so far show no specific features. Standard investigations “like a complete blood count, urinalysis, urine culture and blood biochemistry” should be included in the diagnostic process of endometriosis to rule out potential differential diagnosis like pelvic or urinary tract inflammatory processes.
In the recent years several biomarkers have been evaluated for a potentially non-invasive method to diagnose endometriosis.
A systematic review on diagnostic biomarkers by Cochrane with the intention to find a marker to meet up with laparoscopy, the gold standard of diagnosing endometriosis, evaluated 77 endometrial biomarkers. The article shows that there are promising biomarkers “but to meet the Cochrane criteria” more studies of higher quality need to be performed.
Out of these 77 biomarkers only two biomarkers have been investigated in a sufficient manner to draw applicable results. These biomarkers are called PGP 9.5 and CYP19. PGP 9.5.
CYP 19, encoding for aromatase catalyzes the transformation of androstenedione to estrone and testosterone to estradiol, is shown to be expressed significantly higher in patients with endometriosis.
Even more promising to replace laparoscopy to diagnose endometriosis is the marker PGP 9.5. This marker of small nerve fibers appears to be diagnostically as potent as a laparoscopic investigation, although the expression seems to be highly dependent on the type of sample collection and on laboratory essays, establishing a viable option which needs further investigation and validation.
Further biomarkers with promising qualities are: 17bHSD2, Il-1R2, caldesmon, VIP, CGRP, SP, NPY. But since these markers have been studied only in individual studies, further research is required.(28)
Imaging:
Investigating in endometriosis, a comparison between ultrasound and MRI has established different outcomes in sensitivity and specificity for these two modalities. Multiple studies have been taken a look at, concluding that ultrasound may help surgeons to determine whether surgery was needed. Also, validating MRI to replace surgery in the diagnosis of endometriosis, although cost of an MRI and the small number of data available for analysis do not put this method at the first line of recommendations for diagnosing endometriosis. Mean sensitivity and specificity of all studies included in the Cochrane review add up to 0.79 (95% CI 0.70 to 0.88) and 0.72 (95% CI 0.51 to 0.90) (29).
Laparoscopy remains the Gold standard of diagnosing endometriosis but confirmation is only achieved by histopathological examination of the lesions extracted. The outcomes of fecundity, pregnancy rates and recurrence rates are similar to those of laparotomy. (30)
Classification of endometriosis:
There a several ways to classify endometriosis. The World Endometriosis Society consensus recommends to include the revised American Society for Reproductive Medicine (r-ASRM) classification and “where appropriate” the ENZIAN and Endometriosis Fertility Index staging systems. (31) The r-ASRM classification combines the anatomical site and the extent of the diseases affecting it. The awarded points are added up and give rise to a score which then classifies the disease from stage I to IV. Furthermore, the r-ASRM suggests to obtain histological samples of endometriotic cysts. Also, endometriosis should be categorized by its color and the percentage of a surface it covers. Figure 1 shows how to classify according to r-ASRM(32)
The endometriosis fertility index was published in 2008 by Adamson and Pasta. Their objective was to provide a clinical tool that could predict successful fertilizations after receiving surgical endometriosis treatment and not attempting IVF conception. They analyzed data from 579 infertile patients to identify factors that influence the likelihood of becoming pregnant after they underwent surgery. A database of 275 variables was established and statistically examined and the result was a scoring system which allowed clinicians to make a prediction for successfully attempting to become pregnant. Three factors or variables, as the authors call them, were used to collect data. The patients history, including
anamnestic data of the women and men, like age, duration of infertility etc. . Secondly data collected from hysteroscopy and thirdly results of the abdominal surgery, provided by the surgeon examining adnexa, fimbriae and ovaries, creating a functional score, which reflects the biological capacity of the organ or structure. The data collected provides a score ranging from 0-10, from which conclusions about the probability of becoming pregnant in the first, second or third year can be drawn. Form and estimation chart can be found in the annex (33)
The ENZIAN Classification is an addition to r-ASRM to further indicate the severity of the disease, since the r-ASRM classification can only be applied to intraperitoneal lesions. ENZIAN additionally focuses more on deep infiltrating lesions. There are three axes in which the small pelvis is divided into a three-dimensional space to describe the location of a lesion more precisely. The A axis ranges from the pouch of Douglas over the rectovaginal septum to the vagina, the B axis from the sacrouterine ligament to pelvic wall, and the C axis from the rectovaginal septum and its dorsally oriented compartment including the adjacent pararectal space and the rectum. This is schematically illustrated in figure 2 (34). While dividing the pelvis in this particular manner allows for labelling the lesion into multiple compartments a classification similar to oncological staging is used and splits up lesions into four separate entities, depending on the extent to which the disease is represented in the three dimensions of the small pelvis. Endometriotic lesions found on the bladder, the ureters, the intestines or the diaphragm are treated as single entities and classified separately.
NICE regulations on diagnosing and treating endometriosis 2017, latest guideline published (35)
NICE recommends to treat Patient suffering from endometriosis in specialized centers. This includes a specialized team consisting of a gynecologist with a main focus on endometriosis including advanced laparoscopic surgical skills, a urologist and colorectal surgeon with interest in endometriosis, an endometriosis specialist nurse, a multidisciplinary pain management team, radiological and histopathological facilities and fertility services.
Signs and symptoms of endometriosis:
“Suspect endometriosis in women (including young women aged 17 and under) presenting with 1 or more of the following symptoms or signs:
- period-related pain (dysmenorrhea) affecting daily activities and quality of life - deep pain during or after sexual intercourse
- period-related or cyclical gastrointestinal symptoms, in particular, painful bowel movements - period-related or cyclical urinary symptoms, in particular, blood in the urine or pain passing urine - infertility in association with 1 or more of the above
Inform women with suspected or confirmed endometriosis that keeping a pain and symptom diary can aid discussions
Offer an abdominal and pelvic examination to women with suspected endometriosis to identify abdominal masses and pelvic signs, such as reduced organ mobility and enlargement, tender nodularity in the posterior vaginal fornix, and visible vaginal endometriotic lesions.
If a pelvic examination is not appropriate, offer an abdominal examination to exclude abdominal masses.”
Diagnosis of endometriosis:
1. Ultrasound:
To strengthen the suspicion of endometriosis, if clinical presentation indicates the pathology. To establish whether there are deep infiltrating lesions in the bowel, bladder or ureter.
In case transvaginal ultrasound may be inappropriate, transabdominal ultrasound can be considered.
2. Serum CA125
Should not be used to diagnose endometriosis. Serum levels of 35IU/l or more may be indicative, but patients may be diagnosed even though the serum levels are lower than 35 IU/l.
3. MRI
Pelvic MRI is not preferred to be the first choice in diagnosing women with endometriosis presenting with clinical features suggesting endometriosis. It may be used to evaluate the extent to which deep endometriosis infiltrates other anatomical structures.
4. Diagnostic laparoscopy
Diagnostic laparoscopy should be considered, even in the case that the ultrasound investigation is normal. If endometriotic lesions are found on the bowel, bladder or ureter, a MRI of the pelvis should be done prior to the operative laparoscopy.
During laparoscopy samples can be taken to on the one hand confirm the diagnosis of endometriosis and on the other hand to exclude malignancy
5. Staging endometriosis: NICE does not specifically name a classification system
Outpatient follow-up of patient with confirmed endometriosis should be considered deep endometriosis infiltrating bladder, bowel or ureter or if one or more endometrioma lager than three cm is present. This particularly accounts for women who elect to not undergo surgery
7. Pharmacological pain management:
Analgesia is achieved by choosing paracetamol or a NSAID. This can be tested for three months and be reevaluated. The proper drug is chosen by assessing the reis profile of the patient and considering any comorbidities and the women´s preferences. In case of neuropathic pain, amitriptyline, duloxetine, gabapentin or pregabalin (according to neuropathic pain treatment guideline) can be offered as initial treatment.
Treatment of neuropathic pain, that should be avoided, see table 5.
8. Hormonal treatment
Types of hormonal treatment suitable for alleviating symptoms of endometriosis are the combined pill, progestogen-only pill, progestogen injection, progestogen IUS or progestogen implant. A patient decision aid is available online. The link will be provided in the references.
9. Surgical management
The patient plays a central role in decision-making and planning the surgical procedure. After establishing consensus with the patient laparoscopy is performed unless there are contraindications. During laparoscopy endometriosis is diagnosed and treatment can be considered if uncomplicated ovarian endometriomas are present and in case that peritoneal endometriosis does not involve the bowel, bladder or ureter. If the latter is present, consider GnRH analogues three months prior to the surgical procedure. As for the surgical procedure, excision is to be preferred over ablation of to treat endometriomas.
Surgery can be combined with hormonal treatment to prolong the benefits of the surgery and manage the symptoms.
9.1 hysterectomy
Perform hysterectomy if indicated. All endometriotic lesions should be excised in the same surgery.
9.2 Surgical management if fertility is a priority
Excision or ablation of endometriotic lesions and adhesiolysis. This accounts for endometriosis not involving bladder, ureter or bowel.
Cystectomy and excision of the cyst wall also improve the chances of spontaneous pregnancies. Following up on cystectomy, it is recommended to remind oneself of the patient´s ovarian reserve including possible testing
Do not offer patients who are trying to conceive hormonal treatment, since it is not improving the odds of a spontaneous pregnancy.
Systematic review of international guidelines regarding endometriosis:
A systematic review published in the international journal of Obstetrics and Gynaecology regarding guidelines about diagnosis and treatment of endometriosis analyzed two international and five national guidelines. They were evaluated according to Appraisal of Guidelines for Research & Evaluation (AGREE-II) and graded with a methodological quality score. The guidelines included were from the American College of Obstetricians and Gynecologists (ACOG), Australasian Certificate of Reproductive Endocrinology and Infertility Consensus Expert Panel on Trial Evidence (ACCEPT), Collége National des Gynécologues et Obstétriciens Français (CNGOF), European Society of Human Reproduction and Embryology (ESHRE) Management of women with endometriosis,
National German Guideline (S2k) Diagnosis and Treatment of Endometriosis (NGG), Society of Obstetricians and Gynecologists of Canada (SOGC) and World Endometriosis Society (WES) Consensus on current management of endometriosis. The best score was achieved by ESRHRE for it being the highest quality according to the AGREE-II. Surprisingly the review found that there is a substantial discrepancy between the guidelines. For example, the authors point out that guidelines (ACOG and NGG) did not agree on hormonal treatment after surgery. In addition, the authors criticized the lack of citing evidence or only citing expert´s opinions in some guidelines and that certain topics like psychological interventions were seldomly discussed in guidelines. (36)
ESHRE Guidelines: (37)
Since the guidelines of the ESHRE are quite extensive, especially concerning the pain management of patients with endometriosis, only an outline tailored to this case will be presented in the text, whilst the entire guideline can be found in the annex. The letters in brackets behind the statement refer to the level of evidence.
A: Meta-analysis, systematic review or multiple RCTs (high quality)
B: Meta-analysis, systematic review or multiple RCTs (moderate quality) Single RCT, large non-randomised trial, case-control or cohort studies (high quality)
C: Single RCT, large non-randomised trial, case-control or cohort studies (moderate quality) D: Non-analytic studies, case reports or case series (high or moderate quality)
“Diagnosis of endometriosis: Signs and symptoms:
1. The GDG recommends that clinicians should consider the diagnosis of endometriosis in the presence of gynecological symptoms such as: dysmenorrhea, non-cyclical pelvic pain, deep dyspareunia, infertility, fatigue in the presence of any of the above. (GPP)
2. The GDG recommends that clinicians should consider the diagnosis of endometriosis in women of reproductive age with non-gynecological cyclical symptoms (dyschezia, dysuria, hematuria, rectal bleeding, shoulder pain). (GPP)
Clinical examination:
1. The GDG recommends that clinicians should perform clinical examination in all women suspected of endometriosis, although vaginal examination may be inappropriate for adolescents and/or women without previous sexual intercourse. In such cases, rectal examination can be helpful for the diagnosis of endometriosis. (GPP)
2. Clinicians may consider the diagnosis of deep endometriosis in women with (painful) induration and/or nodules of the rectovaginal wall found during clinical examination, or visible vaginal nodules in the posterior vaginal fornix (Bazot, et al., 2009) (C)
3. Clinicians may consider the diagnosis of ovarian endometrioma in women with adnexal masses detected during clinical examination (Bazot, et al., 2009, Condous, et al., 2007, Eskenazi, et al., 2001, Koninckx, et al., 1996, Ripps and Martin, 1992). (C)
4. Clinicians may consider the diagnosis of endometriosis in women suspected of the disease even if the clinical examination is normal (Chapron, et al., 2002). (C)
Ultrasound:
1. In women with symptoms and signs of rectal endometriosis, transvaginal sonography is useful for identifying or ruling out rectal endometriosis (Hudelist, et al., 2011). (A)
2. Clinicians are recommended to perform transvaginal sonography to diagnose or to exclude an ovarian endometrioma (Moore, et al., 2002). (A)
3. The GDG recommends that clinicians base the diagnosis of ovarian endometrioma in
premenopausal women on the following ultrasound characteristics: ground glass echogenicity and one to four compartments and no papillary structures with detectable blood flow. (GPP)
4. Clinicians should be aware that the usefulness of 3D sonography to diagnose rectovaginal endometriosis is not well established (Pascual, et al., 2010). (D)
MRI:
1. Clinicians should be aware that the usefulness of magnetic resonance imaging (MRI) to diagnose peritoneal endometriosis is not well established (Stratton, et al., 2003). (D)
Biomarkers:
1. Clinicians are recommended not to use biomarkers in endometrial tissue, menstrual or uterine fluids to diagnose endometriosis (May, et al., 2011). (A)
2. Clinicians are recommended not to use immunological biomarkers, including CA-125, in plasma, urine or serum to diagnose endometriosis (May, et al., 2010, Mol, et al., 1998). (A)
Barium enema, transvaginal sonography, transrectal sonography and MRI to establish the extent of disease in deep endometriosis:
1. The GDG recommends that clinicians should assess ureter, bladder, and bowel involvement by additional imaging if there is a suspicion based on history or physical examination of deep
endometriosis, in preparation for further management. (GPP)
2. Treatment:
Adhesion prevention after endometriosis surgery:
1. Clinicians can use oxidized regenerated cellulose during operative laparoscopy for endometriosis, as it prevents adhesion formation (Ahmad, et al., 2008). (B)
2. It is not reasonable for clinicians to use icodextrin after operative laparoscopy for endometriosis to prevent adhesion formation, as no benefit has been shown (Brown, et al., 2007, Trew, et al., 2011). (B) 3. The GDG recommends that clinicians should be aware that other antiadhesion agents (polytetrafluoroethylene surgical membrane, hyaluronic acid products) have been studied and proven effective for adhesion prevention in the context of pelvic surgery, although not specifically in women with endometriosis. (GPP)
Secondary prevention of endometriosis:
1. In women operated on for an endometrioma (≥ 3 cm), clinicians should perform ovarian cystectomy, instead of drainage and electrocoagulation, for the secondary prevention of endometriosis associated dysmenorrhea, dyspareunia and non-menstrual pelvic pain (Hart, et al., 2008).
2. After cystectomy for ovarian endometrioma in women not immediately seeking conception, clinicians are recommended to prescribe hormonal contraceptives for the secondary prevention of endometrioma (Vercellini, et al., 2010).
Hormonal therapies for treatment of endometriosis-associated infertility:
1.In infertile women with endometriosis, clinicians should not prescribe hormonal treatment for suppression of ovarian function to improve fertility (Hughes, et al., 2007). (A)
Surgery for treatment of endometriosis-associated infertility:
1. Infertile women with AFS/ASRM stage I/II endometriosis, clinicians should perform operative laparoscopy (excision or ablation of the endometriosis lesions) including adhesiolysis, rather than performing diagnostic laparoscopy only, to increase ongoing pregnancy rates (Jacobson, et al., 2010, Nowroozi, et al., 1987). (A)
2. In infertile women with AFS/ASRM stage I/II endometriosis, clinicians may consider CO2 laser vaporization of endometriosis, instead of monopolar electrocoagulation, since laser vaporisation is associated with higher cumulative spontaneous pregnancy rates (Chang, et al., 1997). (C)
3. In infertile women with ovarian endometrioma undergoing surgery, clinicians should perform excision of the endometrioma capsule, instead of drainage and electrocoagulation of the endometrioma wall, to increase spontaneous pregnancy rates (Hart, et al., 2008) (A)
4. The GDG recommends that clinicians counsel women with endometrioma regarding the risks of reduced ovarian function after surgery and the possible loss of the ovary. The decision to proceed with surgery should be considered carefully if the woman has had previous ovarian surgery (GPP)
5. In infertile women with AFS/ASRM stage III/IV endometriosis, clinicians can consider operative laparoscopy, instead of expectant management, to increase spontaneous pregnancy rates (Nezhat, et al., 1989, Vercellini, et al., 2006a). (B)
Hormonal therapies adjunct to surgery for treatment of endometriosis associated infertility:
1.In infertile women with endometriosis, the GDG recommends clinicians not to prescribe adjunctive hormonal treatment before surgery to improve spontaneous pregnancy rates, as suitable evidence is lacking. (GPP)
2. In infertile women with endometriosis, clinicians should not prescribe adjunctive hormonal treatment after surgery to improve spontaneous pregnancy rates (Furness, et al., 2004) (A)
Non-medical management strategies for treatment of endometriosis associated infertility:
1. The GDG does not recommend the use of nutritional supplements, complementary or alternative medicine in the treatment of endometriosis-associated infertility, because the potential benefits and/or harms are unclear. However, the GDG acknowledges that some women who seek complementary and alternative medicine may feel benefit from this. (GPP)”
14. Discussion
Case approach and treatment strategy.
According to the ACOG approach of infertile couples the case has been addressed in a proper manner. A detailed anamnesis of the woman´s sexual, gynecological and medical history has been achieved by an interview and a standardized questionnaire to make sure no point has been overlooked. The anamnesis reveals that the couple is trying to achieve pregnancy and has unprotected sexual intercourse for more than two years, which by definition of the WHO is classified as infertility. The basic tests for evaluating an infertile couple have been carried out, including anamnesis, physical examination and pregnancy evaluation of the women, and history and semen analysis of the male partner. In this case the male factor seems less relevant since he has three children with a previous partner, although the youngest is thirteen years old. As reassuring of the capacity of the semen is advisable. As for the female factors of infertility, a hormone profile, complete blood count, biochemical serum analysis and a transvaginal ultrasound have been performed. The hormone profile revealed hyperprolactinemia in a single measurement, which could not be repeated in subsequent measurements. Also, subclinical hypothyroidism with slightly elevated TSH levels but normal FT4 levels was noticed and treated with levothyroxine. The rest of the hormonal, biochemical and serological evaluation revealed no pathological findings related to infertility. The sonographic evaluation of the uterus and adnexa raised the suspicion of endometriosis, which according to the guidelines presented is confirmed by the Gold standard of laparoscopy. During the diagnostic laparoscopy, the stage II endometriotic lesions were removed by coagulation and excision of the endometrioma including adhesiolysis and the material obtained during surgery has been examined histologically, like recommended by the guidelines. Hormonal treatment after the surgery was not indicated, since the sole purpose of the intervention was to improve fecundity. In the perspective if cost effectiveness it´s reasonable not further investigate potential causes for infertility after a legitimate cause of has been established.
As for the points not in line with the guidelines we have no information on adhesion prevention used during the surgery. We can see that physicians can use oxidized regenerated cellulose for adhesion prevention recommended at the level B in the guidelines.
Recommendations not mentioned by the guidelines, but controversial with the literature are the classification and the thyroid hormone substitution and the classification used.
There is little evidence that untreated subclinical hypothyroidism (elevated TSH, normal FT4) decreases fecundity especially with at TSH ranges from 2.5-4.0 mIU/l and substitution with levothyroxine increases the chances for conceiving. The grade of recommendation for thyroxine substitution at levels of TSH between 2.5 and 4.0 mIU/l is “C” and for levels > 4 mIU/l grade (B). (38)
Another point which might be reconsidered for the future management of endometriosis is the extension of classification systems for endometriosis. As presented in the literature analysis the World
Endometriosis Society consensus recommends to include the revised American Society for Reproductive Medicine (r-ASRM) classification and “where appropriate” the ENZIAN and Endometriosis Fertility Index staging systems to improve the understanding of the entire extent of the disease. Currently only r-ASRM is being used and does not supply enough data, especially on deep infiltrating endometriosis, pregnancy outcome and prognostic features. One more regard is that stage II endometriosis is considered mild and pregnancy can be achieved without surgical intervention. However there is evidence that operative laparoscopy is superior to diagnostic laparoscopy and since the extend of the disease can only be established by laparoscopy, the operative procedure has its merit.(39)
Endometriosis guidelines:
As mentioned there are differences in the quality of the guidelines. The ESHRE guideline is far more advanced in regard of establishing a scientifically sound guideline. The ESHRE guidelines have been published in 2014 and an update has not been released so far. The latest guideline available is the one published by NICE in 2017 but this does not live up to the scientific standard set by the ESHRE. High quality studies are required to improve the understanding of the disease, develop new and safe diagnostic tools and provide an updated guideline. The annex includes a table, where the recommendations by NICE and ESHRE are listed next to each other and demonstrates quite graphically how different these two guidelines are.
National vs international guidelines:
As afore mentioned the guidelines for the clinical approach of endometriosis differ from one country to another. The problem is as the countries develop their own guidelines, that not always a standardized procedure for the development is used to ensure high quality guidelines are being produced. The AGREE-II criteria should be the standard ensuring that no avoidable errors in the developing process occur. Since smaller organizations with smaller financial capacities will always depend on the research of bigger facilities an approach may be to combine research funds and developing processes. This not only increases the financial power, but also introduces more expertise to the pool of scientists developing new guidelines. Introducing different input into the process will decrease the chance of being investigating in one direction too much and potentially bring up different aspects, which if a small group is in charge of, could get out of sight.
Since we already established that countries have different resources, another topic should be addressed. The highest standard of medical practice cannot be achieved all around the world. Cultural, political or economical barriers may interfere with the highest level of medical practice. In this case a solid framework of recommendations which can be altered according to the specific needs of clinical practice
can be implemented into each individual system. This is also true for local laws and ethical standards which can interfere with a global perspective and the subsequent development of guidelines.
Contemporary relevance:
The ESHRE have been published in September 2013. In the time line from 2014 until May 2020 7707 articles have been published on PubMed using the keyword “Endometriosis”, 4292 articles were published for “Endometriosis treatment” and 1669 for “Endometriosis Infertility”. This shows that a lot of material concerning endometriosis has been added. But without any implementation into the guidelines, which have not been updated since 2013.(41)(42)(43)
Implementation for primary health care physicians:
Since Endometriosis is affecting a large quantity of the female population, family physicians can face the challenge of patients suffering from endometriosis in their daily practice. Primary physicians are in a great position to educate patients about endometriosis. Especially when considering, that the
diagnostic delay of endometriosis is about 6-7 years, general practitioners can have a large influence in the early detection of endometriosis and therefore shortening the time of delay. This is achieved by a detailed history including the gynecological aspects and specifically investigating for chronic pelvic pain, dysmenorrhea, dyspareunia, cyclic bladder or bowel dysfunctions and possible infertility. In case of suspected endometriosis or infertility associated with endometriosis early referral to a women´s health specialist has to be achieved. When treating a patient with endometriosis, the primary health care physician should keep in mind that GnRH analogues (nafarelin, leuprolide, buserelin, goserelin or triptorelin) and possible add-back therapy including progestin only or estrogen plus progestin add- back are used to treat endometriosis associated pain and prevent relapse of endometriosis. These medications have extensive profiles of drug-to-drug interactions and possible dose adjustments need to be considered.(44,45)
15. Conclusion
The guidelines were applied in this case, although the literature suggests some slight adjustments concerning the classification. Of course, one case is not suitable to display deficiencies of a guideline and was merely used to guide the discussion. While conducting the research for this paper it became apparent that there is a lack of high-quality studies. Since endometriosis is quite common and the effects
can be as drastic as in this case there is a substantial need to improve the research in this field in order to develop new reliable testing methods and possibly different treatment approaches. Also, the discordance among the guidelines can be improved by unifying resources and following a standardized procedure e.g. AGREE-II. Another problem is that large population studies are difficult to achieve, since endometriosis is exclusively diagnosed by laparoscopy. In the future combined studies, carried out in different countries could be done to increase the number of patients participating in the same study. The newly gained knowledge has to be implemented into existing guidelines, to make the latest research findings available to the public.
16. References:
1. Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA. National, Regional, and Global Trends in Infertility Prevalence Since 1990: A Systematic Analysis of 277 Health
Surveys. Low N, editor. PLoS Med [Internet]. 2012 Dec 18 [cited 2020 Mar 4];9(12):e1001356. Available from: https://dx.plos.org/10.1371/journal.pmed.1001356
2. Ovulation disorders - Fertility - NCBI Bookshelf [Internet]. [cited 2020 Mar 5]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK327781/
3. Briceag I, Costache A, Purcarea VL, Cergan R, Dumitru M, Briceag I, et al. Fallopian tubes--literature review of anatomy and etiology in female infertility. J Med Life. 2015 Apr
1;8(2):129–31.
4. Hassan MAM, Lavery SA, Trew GH. Congenital uterine anomalies and their impact on fertility [Internet]. Vol. 6, Women’s Health. 2010 [cited 2020 Mar 7]. p. 443–61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20426609
5. Dreisler E, Kjer JJ. Asherman’s syndrome: Current perspectives on diagnosis and management. Vol. 11, International Journal of Women’s Health. Dove Medical Press Ltd; 2019. p. 191–8. 6. Scott JZ, Nakamura RM, Mutch J, Davajan V. The cervical factor in infertility: diagnosis and
treatment. Fertil Steril. 1977;28(12):1289–94.
7. Safdarian L, Najmi Z, Aleyasin A, Aghahosseini M, Rashidi M, Asadollah S. Recurrent IVF failure and hereditary thrombophilia. Iran J Reprod Med. 2014 Jul 1;12(7):467–70.
8. Tersigni C, Castellani R, de Waure C, Fattorossi A, De Spirito M, Gasbarrini A, et al. Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms. Hum Reprod Update [Internet]. [cited 2020 Mar 9];20(4):582–93. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24619876
9. Deroux A, Dumestre-Perard C, Dunand-Faure C, Bouillet L, Hoffmann P. Female Infertility and Serum Auto-antibodies: a Systematic Review. Vol. 53, Clinical Reviews in Allergy and
Immunology. Humana Press Inc.; 2017. p. 78–86.
10. Venkatesh T, Suresh PS, Tsutsumi R. New insights into the genetic basis of infertility. Vol. 7, Application of Clinical Genetics. Dove Medical Press Ltd.; 2014. p. 235–43.
11. Chan SL. Male infertility: diagnosis and treatment. Can Fam Physician [Internet]. 1988 Aug [cited 2020 Mar 10];34:1735–8. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/21253072
12. Homan GF, Davies M, Norman R. The impact of lifestyle factors on reproductive performance in the general population and those undergoing infertility treatment: A review. Vol. 13, Human Reproduction Update. 2007. p. 209–23.
Available from: https://www.acog.org/Clinical-Guidance-and-Publications/Committee- Opinions/Committee-on-Gynecologic-Practice/Infertility-Workup-for-the-Womens-Health-Specialist?IsMobileSet=false
14. Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol. 1984;64(2):151–4.
15. Sanfilippo JS, Wakim NG, Schikler KN, Yussman MA. Endometriosis in association with uterine anomaly. Am J Obstet Gynecol. 1986;154(1):39–43.
16. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Vol. 98, Fertility and Sterility. 2012. p. 511–9.
17. Audebert A, Petousis S, Margioula-Siarkou C, Ravanos K, Prapas N, Prapas Y. Anatomic distribution of endometriosis: A reappraisal based on series of 1101 patients. Eur J Obstet Gynecol Reprod Biol. 2018 Nov 1;230:36–40.
18. Machairiotis N, Stylianaki A, Dryllis G, Zarogoulidis P, Kouroutou P, Tsiamis N, et al. Extrapelvic endometriosis: A rare entity or an under diagnosed condition? Vol. 8, Diagnostic Pathology. 2013.
19. Moen MH. Endometriosis in monozygotic twins. Acta Obstet Gynecol Scand. 1994;73(1):59– 62.
20. Environmental Chemicals and Risk of Endometriosis. [cited 2020 Jan 25]; Available from: https://www.ncbi.nlm.nih.gov/pubmed/22992575
21. Hemmert R, Schliep KC, Willis S, Peterson CM, Louis GB, Allen-Brady K, et al. Modifiable life style factors and risk for incident endometriosis. Paediatr Perinat Epidemiol. 2019 Jan 1;33(1):19–25.
22. Barbieri RL. Reproductive history and endometriosis among premenopausal women. Obstet Gynecol. 2004;104(5):965–74.
23. Peterson CM, Johnstone EB, Hammoud AO, Stanford JB, Varner MW, Kennedy A, et al. Risk factors associated with endometriosis: Importance of study population for characterizing disease in the ENDO Study. Am J Obstet Gynecol. 2013;208(6):451.e1-451.e11.
24. Xia W, Zhang D, Ouyang J, Liang Y, Zhang H, Huang Z, et al. Effects of pelvic endometriosis and adenomyosis on ciliary beat frequency and muscular contractions in the human fallopian tube. Reprod Biol Endocrinol. 2018 May 12;16(1).
25. Lin YH, Chen YH, Chang HY, Au HK, Tzeng CR, Huang YH. Chronic niche inflammation in endometriosis-associated infertility: Current understanding and future therapeutic strategies. Vol. 19, International Journal of Molecular Sciences. MDPI AG; 2018.
16];13(6):355–68. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6813156
27. Tanbo T, Fedorcsak P. Endometriosis-associated infertility: aspects of pathophysiological mechanisms and treatment options. Acta Obstet Gynecol Scand [Internet]. 2017 Jun [cited 2020 Jan 28];96(6):659–67. Available from: http://doi.wiley.com/10.1111/aogs.13082
28. Gupta D, Hull ML, Fraser I, Miller L, Bossuyt PM, Johnson N, et al. Endometrial biomarkers for the non-invasive diagnosis of endometriosis. Cochrane Database Syst Rev [Internet]. 2016 Apr 20 [cited 2020 Feb 2]; Available from: http://doi.wiley.com/10.1002/14651858.CD012165 29. Nisenblat V, Bossuyt PM, Farquhar C, Johnson N, Hull ML. Imaging modalities for the
non-invasive diagnosis of endometriosis. Cochrane Database Syst Rev [Internet]. 2016 Feb 26 [cited 2020 Feb 9];2016(2). Available from: http://doi.wiley.com/10.1002/14651858.CD009591.pub2 30. Bateman BG, Kolp LA, Mills S. Endoscopic versus laparotomy management of endometriomas.
Fertil Steril [Internet]. 1994 Oct [cited 2020 Mar 16];62(4):690–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7926074
31. World Endometriosis Society consensus on the classification of endometriosis | Human Reproduction | Oxford Academic [Internet]. [cited 2020 Feb 24]. Available from: https://academic.oup.com/humrep/article/32/2/315/2631390
32. FERTILITY AND STERILITY® Special contribution Revised American Society for Reproductive Medicine classification of endometriosis: 1996 American Society for Reproductive Medicine*t.
33. Adamson GD, Pasta DJ. Endometriosis fertility index: The new, validated endometriosis staging system. Fertil Steril. 2010 Oct 1;94(5):1609–15.
34. Offizielles Organ der Österreichischen IVF-Gesellschaft Offizielles Organ der Österreichischen Menopause-Gesellschaft Homepage: www.kup.at/gynaekologie Online-Datenbank mit Autoren-und Stichwortsuche [Internet]. [cited 2020 Feb 24]. Available from: www.kup.at/gynaekologie 35. Recommendations | Endometriosis: diagnosis and management | Guidance | NICE.
36. Hirsch M, Begum M, Paniz É, Barker C, Davis C, Duffy J. Diagnosis and management of endometriosis: a systematic review of international and national guidelines. BJOG An Int J Obstet Gynaecol. 2018 Apr 1;125(5):556–64.
37. Endometriosis guideline [Internet]. [cited 2020 Mar 1]. Available from:
https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Endometriosis-guideline
38. Committee of the American Society for Reproductive Medicine P. Subclinical hypothyroidism in the infertile female population: a guideline. Fertil Steril [Internet]. 2015 [cited 2020 Mar 14];104:545–53. Available from: http://dx.doi.org/10.1016/j.fertnstert.2015.05.028
39. Duffy JMN, Arambage K, Correa FJS, Olive D, Farquhar C, Garry R, et al. Laparoscopic surgery for endometriosis. Vol. 2014, Cochrane Database of Systematic Reviews. John Wiley
