Infertility in patients with uterine fibroids: a debate about the hypothetical mechanisms.

Fibroids are benign tumours of the myometrium and are the most common gynaecologic abnormality. Although most fibroids are asymptomatic, they can cause symptoms like heavy menstrual bleeding, pelvic pain, sexual dysfunction, pressure complaints, and infertility. The association between fibroids and infertility has been debated for decades. It is generally acknowledged that the closer the fibroid is to the uterine cavity and the endometrium lining, the more unfavourable effect it might have on fertility, reducing the odds for successful implantation and gestation. Based on the limited available literature, we propose and discuss seven hypotheses on the underlying mechanism by which fibroids may reduce fertility. (i) Fibroids can cause sexual dysfunction, as fibroids can cause dyspareunia, pelvic pain, and prolonged and heavy menstrual bleeding, which could interfere with sexual arousal and as a consequence the frequency of intercourse, resulting in a reduced probability of conception. (ii) Mechanical compression by fibroids on theinterstitial part of the fallopian tubes or deformation of uterine cavity could disturb oocyte and sperm transport. (iii) Fibroids can disturb peristalsis of the junctional zone in the myometrium, which could negatively influence oocyte and sperm transport as well as implantation. In addition, fibroids could induce a detrimental environment for implantation in other ways, by: (iv) changing the vagino-uterine microbiome; (v) disturbing the levels of inflammation and autophagy; (vi) inducing molecular changes in the endometrium; and (vii) inducing aberrant angiogenesis and altering the endometrial blood supply. After the discussion of these hypotheses, the implication of the influence of fibroids on early pregnancy loss is discussed. Surgical fibroid treatment is not tailored nor focussed on the pathophysiology of the fibroid; consequently it may be accompanied by recurrence of fibroids and risks of complications. Unravelling the pathogenic mechanisms about how fibroids influence fertility is essential to evolve classic surgical fibroid treatment. Instead of treatment of fibroid-related symptoms, the research should supports development of fibroid-targeted (pharmaceutical) treatment that is compatible with an active wish to become pregnant.

The Effect of a Myomectomy on Myoma-related Symptoms and Quality of Life: A Retrospective Cohort Study.

STUDY OBJECTIVE: Although it is assumed that myomectomy improves uterine myoma-related symptoms such as pelvic pain and heavy menstrual bleeding (HMB), validated measures are rarely reported. This study aimed to verify the effect of myomectomy on myoma-related symptoms. DESIGN: A retrospective cohort study. SETTING: A university-affiliated hospital. PATIENTS: Our study included 241 patients with a myoma diagnosis and received a myomectomy between 2004 and 2018. Data were collected from the patient medical file and patients responded in 1 questionnaire. INTERVENTIONS: Transcervical resection of myoma (TCRM) and laparoscopic or abdominal myomectomy (LAM). MEASUREMENTS AND MAIN RESULTS: One year after TCRM, a significant number of women experienced symptom improvement for pelvic pain (79% [19/24, p = .01]) and HMB (89% [46/52, p <.001]). For other myoma-related symptoms, abdominal pressure (43%, 10/23), sexual complaints (67%, 2/3), infertility (56%, 10/18), and other complaints (83%, 5/6), improvements were not statistically significant. One year after LAM, a significant number of women experienced symptom improvement for pelvic pain (80%, 74/93), HMB (83%, 94/113), abdominal pressure (85%, 79/93), sexual complaints (77%, 36/47), and other complaints (91%, 40/44). One year after myomectomy, 47% (30/64) (TCRM) and 44% of women (78/177) (LAM) described no myoma-related symptoms. Most women (82% [172/217]) were satisfied with the postoperative result after 1 year and 53% (114/217) would have liked to receive the myomectomy earlier in life. Average quality of life (measured on a 10-point Likert scale) increased from 6.3 at baseline to 8.0 at 1 year after TCRM and from 6.2 to 8.0 1 year after LAM, resulting in a difference of 1.7 points (p <.001; 95% confidence interval, 1.1-2.3) and 1.9 points (p <.001; 95% confidence interval, 1.4-2.3), respectively. CONCLUSION: One year after myomectomy, most women have benefited from myomectomy, concluded by a significant number of women who experienced myoma-related symptom improvement, positive patient satisfaction, and a significant improvement in reported quality of life. Validation of results after conventional treatment such as myomectomy is essential in counseling patients for surgical treatment in today's evidence based practice. In addition, it is necessary to make an adequate comparison with new treatment options for myomas. To provide this, further research should preferably be conducted prospectively or by randomization.

Endometrial Angiogenesis of Abnormal Uterine Bleeding and Infertility in Patients with Uterine Fibroids-A Systematic Review.

Uterine fibroids are the most common benign tumors in women, with abnormal uterine bleeding (AUB) as the main reported symptom. Additionally, an association between fibroids and infertility has been established, especially if the fibroid protrudes in the uterine cavity. Hormonal therapy is associated with side-effects and as well as hysterectomy, which is incompatible with a desire to conceive. To improve treatment, it is essential to unravel the etiology of fibroid-related symptoms. We aim to evaluate endometrial angiogenesis in women with fibroids, with and without AUB, and the influence of pharmaceutical therapies in these patients. Furthermore, we explore the possible role of altered angiogenesis in patients with fibroids and infertility. We performed a systematic review according to PRISMA-guidelines (PROSPERO: CRD42020169061), and included 15 eligible studies. Endometrial expression of vascular endothelial growth factor (VEGF) and adrenomedullin was increased in patients with fibroids. This suggests aberrant angiogenesis, potentially involving disturbed vessel maturation, resulting in immature and fragile vessels. Treatment with gonadotropin-releasing hormone agonist, ulipristal acetate, and continuous oral contraception pills reduced several angiogenic parameters, including VEGF. If infertile and fertile patients with fibroids were compared, a significant decreased expression of the bone morphogenetic protein/Smad-protein pathway was found, possibly caused by the increased expression of transforming growth factor-beta. For future therapeutic development, these different angiogenic pathways could be of interest as possible targets to treat fibroid-related symptoms.

The effect of myomectomy on reproductive outcomes in patients with uterine fibroids: A retrospective cohort study.

RESEARCH QUESTION: What is the effect of myomectomy in women with uterine fibroids on time to live birth and other reproductive outcomes? DESIGN: This was a monocentric retrospective cohort study of 311 women with fibroids, of whom 165 eventually received myomectomy and 146 remained on expectant management. To assess the primary outcome time to live birth, a Cox proportional hazards model with a time-varying covariate for myomectomy was used. In the sensitivity analyses, this was combined with an approach to account for confounders via a cloning/censoring/weighting that aimed to emulate a randomized controlled trial. RESULTS: Notable differences in baseline characteristics between the myomectomy and expectant management group were fibroid size (fibroid >7 cm: myomectomy 48%; expectant management 15%) and whether the patient had fibroid-related complaints (myomectomy 85%, expectant management 67%). The adjusted hazard ratio for the effect of myomectomy compared with expectant management on live birth was 1.26 (95% CI 0.87-1.81). Sensitivity analyses yielded similar results, but secondary outcomes showed that women remaining on expectant management had more often received assisted reproductive technology (63%) compared with those who eventually received myomectomy (38%). CONCLUSIONS: The study did not find a significant difference in time to live birth after myomectomy compared with expectant management in women with fibroids and a wish to conceive, despite more, larger and more symptomatic fibroids in the myomectomy group. The results after myomectomy encourage the execution of a randomized controlled trial in women with large (symptomatic) fibroids not or minimally distorting the intrauterine cavity, and infertility or a desire to conceive.

Uterine Fibroids Causing Preterm Birth: A New Pathophysiological Hypothesis on the Role of Fibroid Necrosis and Inflammation.

According to recent studies and observations in clinical practice, uterine fibroids increase the risk of preterm birth. There are several theories on the pathogenesis of preterm birth in the presence of fibroids. One theory proclaims that fibroid necrosis leads to preterm birth, though pathophysiological mechanisms have not been described. Necrotic tissue secretes specific cytokines and proteins and we suggest these to be comparable to the inflammatory response leading to spontaneous preterm birth. We hypothesize that fibroid necrosis could induce preterm parturition through a similar inflammatory response. This new hypothesis generates novel perspectives for future research and the development of preventative strategies for preterm birth. Moreover, we emphasize the importance of the recognition of fibroids and especially fibroid necrosis by clinicians during pregnancy.

Preterm birth and uterine fibroid necrosis: The clinical presentation illustrated in a case series.

OBJECTIVE: Uterine fibroids increase the risk of preterm birth. The current study highlights uterine fibroid necrosis as a possible cause of (extreme) preterm birth. STUDY DESIGN: Retrospective cohort study in one Dutch academic hospital. Cases were selected from the 526 participants of the MyoFert study (Netherlands Trial Register, NL7990), which included patients who presented between 2004 and 2018 and were between the age of 18 and 45 years at the time of diagnosis of uterine fibroids. Of these participants, 414 women became pregnant. A retrospective chart review of the first pregnancies was performed. The main outcomes were (imminent) preterm birth and signs of fibroid necrosis on ultrasound. In women with signs of fibroid necrosis, the following data were collected systematically: fibroid characteristics, clinical presentation, pregnancy outcome, and postpartum period. RESULTS: In total, 66 women had a preterm birth (16 %, 66/414), of which 25 pregnancies ended between 16 and <24 weeks (38 %, 25/66) and 41 pregnancies ended between 24 and <37 weeks of gestation (62 %, 41/66). Of all women with preterm birth and available ultrasound images, 15 % (7/48) had fibroid necrosis at the time of labour. These seven patients, supplemented with three patients with fibroid necrosis during their first pregnancy and at least one episode of imminent preterm birth, are described in more detail. In these ten patients, the fibroids increased substantially in size during the first and second trimester, leading to severe abdominal pain in all patients and hospital admission in seven patients. Ultrasound examination of the fibroids showed heterogenic changes and focal transonic areas in the fibroid, which are characteristics that indicate fibroid necrosis. In four patients, myomectomy was performed and necrosis was confirmed histologically. CONCLUSION: Fibroid necrosis during pregnancy is likely associated with (imminent) preterm birth. Clinicians are advised to structurally evaluate the myometrium in pregnancy, specifically in women presenting with abdominal pain in the second trimester.

Angiogenesis in abnormal uterine bleeding: a narrative review.

BACKGROUND: Abnormal uterine bleeding (AUB) has a significant socioeconomic impact since it considerably impacts quality of life. Therapeutic options are frequently based on trial and error and do not target disease aetiology. Pathophysiological insight in this disease is required for the development of novel treatment options. If no underlying cause is found for the AUB (e.g. fibroids, adenomyosis, polyps), endometrial-AUB (AUB-E) is usually caused by a primary endometrium disorder. When AUB is induced by prescribed (exogenous) hormones, it is classified as iatrogenic-AUB (AUB-I). Considering vascular modulation and function, AUB-E and AUB-I both could potentially result from abnormal vascularization in the endometrium due to alterations in the process of angiogenesis and vascular maturation. OBJECTIVE AND RATIONALE: We aim to investigate the fundamental role of angiogenesis and vascular maturation in patients with AUB and hypothesize that aberrant endometrial angiogenesis has an important role in the aetiology of both AUB-E and AUB-I, possibly through different mechanisms. SEARCH METHODS: A systematic literature search was performed until September 2021 in the Cochrane Library Databases, Embase, PubMed, and Web of Science, with search terms such as angiogenesis and abnormal uterine bleeding. Included studies reported on angiogenesis in the endometrium of premenopausal women with AUB-E or AUB-I. Case reports, letters, reviews, editorial articles, and studies on AUB with causes classified by the International Federation of Gynecology and Obstetrics as myometrial, oncological, or infectious, were excluded. Study quality was assessed by risk of bias, using the Cochrane tool and the Newcastle-Ottawa Scale. OUTCOMES: Thirty-five out of 2158 articles were included. In patients with AUB-E, vascular endothelial growth factor A and its receptors (1 and 2), as well as the angiopoietin-1:angiopoietin-2 ratio and Tie-1, were significantly increased. Several studies reported on the differential expression of other pro- and antiangiogenic factors in patients with AUB-E, suggesting aberrant vascular maturation and impaired vessel integrity. Overall, endometrial microvessel density (MVD) was comparable in patients with AUB-E and controls. Interestingly, patients with AUB-I showed a higher MVD and higher expression of proangiogenic factors when compared to controls, in particular after short-term hormone exposure. This effect was gradually lost after longer-term exposure, while alterations in vessel maturation were observed after both short- and long-term exposures. WIDER IMPLICATIONS: AUB-E and AUB-I are most likely associated with aberrant endometrial angiogenesis and impaired vessel maturation. This review supports existing evidence that increased proangiogenic and decreased antiangiogenic factors cause impaired vessel maturation, resulting in more fragile and permeable vessels. This matches our hypothesis and these mechanisms appear to play an important role in the pathophysiology of AUB-E and AUB-I. Exploring the alterations in angiogenesis in these patients could provide treatment targets for AUB.

The risk of preterm birth in women with uterine fibroids: A systematic review and meta-analysis.

BACKGROUND: Fibroids have been identified as a possible risk factor for preterm birth, however, the magnitude of this risk is unclear. Our objective was to determine the risk of total, spontaneous, and medically indicated preterm birth in women with fibroids. METHODS: A literature search was performed on 9 June 2021. We selected studies reporting on preterm birth in women with and without fibroids. Fibroids had to be diagnosed by routine ultrasound before or during pregnancy. Main outcomes were total preterm birth <37, <34, <32, and <28 weeks of gestation, and spontaneous and medically indicated preterm birth. Two authors independently performed study selection, data extraction and quality assessment. We performed quality assessment with the Newcastle-Ottawa scale. Meta-analyses were presented as Odds Ratios (ORs) with 95% Confidence Intervals (95%CIs). MAIN RESULTS: The search yielded 2078 unique articles of which 11 were included. Meta-analysis for preterm birth <37 weeks of gestation included 256,650 singleton deliveries: 12,309 with fibroids and 244,341 without fibroids. Women with fibroids had a higher rate of preterm birth (11.6% versus 9.0%; OR 1.66, 95%CI 1.29-2.14). Fibroids were also associated with preterm birth <34 (OR 1.88, 95%CI 1.34-2.65), <32 (OR 2.03, 95%CI 1.40-2.95) and <28 (OR 2.24, 95%CI 1.45-3.47) weeks of gestation. Data on type of preterm birth was limited: one study showed a significant association of fibroids with spontaneous preterm birth and another with indicated preterm birth. The main limitations of the included studies were the lack of correction for confounders, the risk of ascertainment bias due to possible underreporting of fibroids, and the substantial heterogeneity between studies. CONCLUSIONS: Our results suggest fibroids are associated with an increased risk of preterm birth, with a stronger risk at earlier gestational ages. We encourage further research to clarify the association between fibroids and preterm birth by systematic myometrial assessment in pregnancy. REGISTRATION: Prospero database [CRD42020186976].