Coexistence of Endometriosis and Uterine Dysfunction in Infertile Women Ludwig Kiesel University of Münster Department of Gynecology and Obstetrics Münster, Germany
Symptoms: Risk of Endometriosis Compared with controls, women with endometriosis had ORs (95%CI) for the following symptoms: infertility 8.2 (6.9-9.9) dysmenorrhea 8.1 (7.2-9.3) dyspareunia 6.8 (5.7-8.2) abdominopelvic pain 5.2 (4.7-5.7) menorrhagia 4.0 (3.5-4.5) urinary tract symptoms 1.2 (1.0-1.3) 2
Coexistence of Endometriosis and Uterine Dysfunction in Infertile Women Literature: Leiomyoma Adenomyosis Müllerian anomalies
Coexistence Questions: Prevalence? Common cause? Relevance?
Coexistence of Endometriosis and Uterine Dysfunction in Infertile Women
Coexistence of Endometriosis and Uterine Fibroids (Leiomyoma) 6
Leiomyoma: Challenges to investigate coexistence with endometriosis While diagnosis of leiomyoma is an ultrasonographic one, the dignosis of endometriosis is based on the gold standard (laparoscopy). Both can be operated by laparoscopy Coexistence of endometriosis adversely affects conception rate Leiomyoma and endometriosis share common symptoms; pelvic pain +/- infertility Both are estrogen-dependent diseases Bergeron et al., 2006 7
Leiomyoma: Studies Of the 131 patients, 113 were diagnosed with endometriosis and fibroids, while 18 were diagnosed with fibroids alone. (Huang et al., 2010). Coexistence in 21.2% of patients. Endometriosis was more common in those with subfertility (44% vs 25.7%; p =.02). (Maclaran et al., 2014). 150 case reports of leiomyomatosis peritonealis dissemenata, all in reproductive-age women. 7 of them (4.6%) were associated with endometriosis components in the smooth muscle nodules affecting the mesentry, ovaries, colon and omentum. (Toriyama et al., 2013). 8
Study: Coexistence of Endometriosis and Uterine Fibroids: Prevalence Do symptomatic endometriosis and uterine fibroids appear together? Uimari O, Järvelä I, Ryynänen M. Do symptomatic endometriosis and uterine fibroids appear together?. Journal of Human Reproductive Sciences. 2011;4(1):34 Study design: Retrospective study evaluating patients who require surgery for endometriosis (n=182), patients who require surgery for uterine fibroids (n=240) and a control group who undergo sterilization (n=183) 9
Coexistence of Endometriosis and Fibroids Prevalence (Uimari et al 2011) Results: 25.8% of patients with endometriosis had also uterine fibroids. 19.3% of patients with uterine fibroids had also endometriosis. prevalence of endometriosis was increased among fibroid patients compared to the control group (37.0% vs. 6.8%) until the age of 44 years. 10
Coexistence of Endometriosis and Fibroids Prevalence Prevalence of endometriosis Prevalence of uterine fibroids Uimari, et al., 2011 11
Coexistence of Endometriosis and Uterine Fibroids-Prevalence Strong Association Between Endometriosis and Symptomatic Leiomyomas Nezhat C, Li A, Abed S, Balassiano E, Soliemannjad R, Nezhat A et al. Strong Association Between Endometriosis and Symptomatic Leiomyomas. JSLS : Journal of the Society of Laparoendoscopic Surgeons. 2016;20(3):e2016.00053. Study design: Retrospective study evaluating patients (n=208) who underwent laparoscopic myomectomy or hysterectomy Results: 87.1 % of patients with leiomyoma were also diagnosed with endometriosis + 4.3% with adenomyosis 51.3% of the patients with both fibroids and endometriosis suffered from stage 3 or 4 endometriosis 12
Coexistence of Endometriosis and Fibroids Infertility Mechanisms*: Size and location Alteration of uterine contractions Induction of chronic inflammation of the myometrium by fibroids Excess of cytokines, growth factors, neurotensin, neuropeptides, enkephalin and oxytocin modulators in the fibroid capsule Purohit &Vigneswaran K.. 2016. 13
Coexistence of Endometriosis and Fibroids Infertility Genetic Reduction of abence of HOXA10 Cakmak & Taylor 2010 Alterations in the endo-myometrial junctional zone Reduction of macrophages and unk cells Kitaya &Yasuo 2010 Possible alteration of steroid hormone receptors 14
Coexistence of Endometriosis and Fibroids Aromatase Adrenal Ovary Androstendion Aromatase + PGE 2 Peripheral tissues E1 E2 + COX-2 Arachidonic acid Bulun et al 2008 15
Dysregulated expression of micrornas in endometriosis suggest a mechanistic contribution Ohlsson-Teague et al. 2010 16
Leiomyoma and endometriosis: Coincidence Dysregulated expression of micrornas 17
Coexistence of Endometriosis and Fibroids Summary Leiomyomas and endometriosis are both hormon-dependent conditions, that can be a source of pelvic pain and menstrual abnormalities Both with symptom severity that is poorly correlated to preoperative and operative findings Size of the dominant fibroid showed inverse association with severity of endometriosis Significant overlap of symptomsà difficult to discern which pathology leads to which symptoms >> Adequate inspection, especially of young patients with subfertility or nulliparity and those who present with pain disproportionate to the size of their fibroids 18
Adenomyosis Coexistence with Endometriosis 19
Coexistence of Adenomyosis and Endometriosis: Studies 1.
Adenomyosis with Endometriosis Laparoscopy Endometriosis group (n= 160) Control group (no endometriosis) (n= 67) MRI (JZ) The prevalence of adenomyosis in endometriosis was 79% Kunz et al., 2005 21
Coexistence of Adenomyosis and Endometriosis Leyendecker et al., 2015 22
Coexistence Adenomyosis and Endometriosis Leyendecker et al., 2015 23
Adenomyosis: Pathogenetic link? Leyendecker et al., 2009 24
Adenomyosis and Endometriosis: Common pathogenesis?
Coexistence of Adenomyosis and Endometriosis: Summary Diagnosis: TVS and MRT are highly sensitive to detect adenomyosis, diagnosis of endometriosis demands laparoscopy While endometriosis can be operated by laparoscopy, adenomyosis (diffuse form) ususally demands a conservative management Coexistence of endometriosis adversely affects the conception rate Adenomyosis and endometriosis share common symptoms; pain +/- infertility Both are estrogen-dependent disease 26
Müllerian anomalies Ugur et al., 1995 27
Uterine anomalies and endometriosis Septate uterus A retrospective study 120 patients were evaluated (29.4 +/- 4.7 years; mean +/- SD) with a septate uterus. The control group consisted of 486 consecutive infertile patients (30.8 +/- 6.3 years) with a normal hysteroscopy and laparoscopy The incidence of dysmenorrhoea was comparable in both groups. Nawroth et al., 2006 28
Müllerian anomalies and Endometriosis Non-obstructive uterine anomalies (septate uterus) Septate uterus (HSK) (n= 120) Control (n= 486) Associated endometriosis (25.8%) p-value = 0.006 Associated endometriosis (15.2%) Nawroth et al., 2006 29
Müllerian anomalies and Endometriosis Obstructive uterine anomalies Müllerian Anomalies (n= 186) No Müllerian Anomalies (n= 3240) Associated endometriosis (n= 37, 19.8%) p-value > 0.05 Associated endometriosis (n= 619, 19.1%) These results show that endometriosis is not more frequent in patients with müllerian anomalies as a whole, but outflow obstruction is an important contributing factor, as Obstructive anomalies were associated more with endometriosis as compared with nonobstructive anomalies (p < 0.001). Evaluating patients with müllerian anomalies contributes proof in favor of the theories of retrograde menstruation and celomic metaplasia, but against a possible relation of a developmental defect of differentiation or migration of the müllerian duct system during embryogenesis. Grimbizis et al, 2013 30
Summary: Coexistence with endometriosis Leiomyoma: Adenomyosis: Müllerian anomalies (with obstruction) increased increased increased Anovulation: PCO: unclear unclear Breast cancer Ovarian cancer: Endometrial cancer: Cervical cancer: increased (moderate) increased same decreased
Coexistence with Endometriosis Prevalence: > controls are difficult to define Causal relationships: > are difficult to demonstrate, no RCTs
Coexistence with Endometriosis Prevalence: > controls are difficult to define Causal relationships: > are difficult to demonstrate, no RCTs > diseases may appear to have similar but have different pathogenesis
Coexistence of Endometriosis and Uterine Dysfunction in Infertile Women Coexistence: relevance?
or is it coincidence?