Psychiatric disorders and mortality due to external causes following diagnosis of endometriosis at a young age: a longitudinal register-based cohort study in Finland.

BACKGROUND: Endometriosis diagnosed in adults is associated with increased risk of various psychiatric disorders. However, little is known concerning psychiatric comorbidity and mortality due to external causes associated with endometriosis diagnosed at a young age. OBJECTIVE: This longitudinal cohort study aimed to investigate the link between surgical diagnosis of endometriosis at a young age and subsequent psychiatric disorders and mortality due to external causes. In addition, we compared the occurrence of the most common psychiatric disorders between different sites of surgically confirmed endometriosis (ovarian vs other) because of possible differences in pain manifestations. STUDY DESIGN: We conducted a retrospective register-based cohort study. Altogether 4532 women with surgically confirmed diagnosis of endometriosis before the age of 25 years from 1987 to 2012 were identified from the Finnish Hospital Discharge Register. They were matched with women without surgically diagnosed endometriosis for age and municipality on the index day (n=9014). Women were followed up from the index day until the end of 2019 for the outcomes of interest, which included 9 groups of psychiatric disorders (inpatient episodes since 1987, outpatient episodes since 1998) and death due to external causes, including deaths due to accidents, suicides, and violence (Finnish Register of Causes of Death). Cox proportional hazard models were applied to assess the crude and parity-adjusted hazard ratios and 95% confidence intervals. RESULTS: The cohort's median age was 22.9 years (interquartile range, 21.3-24.1) at the beginning and 42.5 years (36.7-48.3) after a median follow-up time of 20.0 years (14.5-25.7). We observed a higher hazard of depressive, anxiety, and bipolar disorders in women with endometriosis compared with the reference cohort, with depressive and anxiety disorders being the two most common psychiatric disorders. These differences appeared early and remained the same during the entire follow-up, irrespective of whether assessed from the data on inpatient episodes only or the data on both in- and outpatient episodes. The corresponding adjusted hazard ratios were 2.57 (95% confidence interval, 2.11-3.14) and 1.87 (1.65-2.12) for depressive disorders, 2.40 (1.81-3.17) and 2.09 (1.84-2.37) for anxiety disorders, and 1.71 (1.30-2.26) and 1.66 (1.28-2.15) for bipolar disorders, respectively. A higher hazard was observed for nonorganic sleeping disorders for the first 10 years only (3.83; 2.01-7.30) when assessed using the data on both in- and outpatient episodes. When based on inpatient records, a higher hazard for alcohol/drug dependence after 15 years of follow-up (2.07; 1.21-3.54) was observed. The difference in hazard for personality disorders tended to increase during follow-up (<10 years, 2.12 [1.28-3.52]; ≥10 years, 3.08 [1.44-6.57]). Depressive and anxiety disorders occurred more frequently in women with types of endometriosis other than ovarian endometriosis. No difference in deaths due to external causes was observed between the endometriosis and reference cohorts. CONCLUSION: Surgical diagnosis of endometriosis at a young age was associated with increased incidence of several psychiatric disorders. Moreover, within the endometriosis population, psychiatric comorbidity was more common in women with types of endometriosis other than ovarian endometriosis. We speculate that chronic pain is essential in the development of these psychiatric disorders, and that early and effective pain management is important in reducing the risk of psychiatric morbidity in young women. More research concerning the associations and management of endometriosis and associated psychiatric disorders is warranted.

Clinical and molecular risk factors for repeat interventions due to symptomatic uterine leiomyomas.

BACKGROUND: Repeat leiomyoma occurrence or even reintervention is common after myomectomy. Little is known about the factors related to repeat interventions. OBJECTIVES: This study aimed to determine the frequency of leiomyoma-related reintervention after an initial laparoscopic or abdominal myomectomy and to analyze both clinical and molecular risk factors for reinterventions. Another objective was to define the frequency of clonally related tumors from repeat operations. STUDY DESIGN: This retrospective cohort study included 234 women who had undergone laparoscopic or abdominal myomectomy in 2009-2014. Information on repeat leiomyoma-related interventions as well as on other clinical factors was collected from medical records after a median follow-up time of 11,4 years (range 7,9-13,8 years) after the index procedure. The effect of clinical risk factors on the risk of reintervention was analyzed by the Kaplan-Meier estimator and the Cox proportional hazards model. For molecular analyses, we examined the mutation profiles of 133 formalin-fixed paraffin-embedded leiomyoma samples from 33 patients with repeat operations. We screened the tumors for the three primary leiomyoma driver alterations-MED12 mutations, HMGA2 overexpression, and FH-deficiency-utilizing Sanger sequencing and immunohistochemistry. To further assess the clonal relationship of the tumors, we executed whole-exome sequencing for 52 leiomyomas from 21 patients who exhibited the same driver alteration in tumors obtained from multiple procedures. RESULTS: Reintervention rate at 11,4 years after myomectomy was 20% (46/234). Number of leiomyomas removed at the index myomectomy was a risk factor (hazard ratio 1.21; 95% confidence interval 1.09-1.34). Age at index myomectomy (hazard ratio 0.94; 95% confidence interval 0.89-0.99) and postoperative parity (hazard ratio 0.23; 95% confidence interval 0.09-0.60) were protective factors. Molecular characterization of tumors from index and non-index operations confirmed a clonal relationship of the tumors in 3/33 (9%) patients. None of the leiomyomas harboring a MED12 mutation -the most common leiomyoma driver- were confirmed clonally related. FH-deficiency was detected in repeat leiomyomas from 3/33 (9%) patients. All these patients harbored a germline FH mutation, which is distinctive for the hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Finally, we identified three (3/33; 9%) patients with two tumors each displaying somatic mutations in a recently identified novel leiomyoma driver gene, YEATS4. All YEATS4 mutations were different and thus the tumors were not clonally related. CONCLUSION: Our study shows that reintervention is common after surgical myomectomy. Uterine leiomyomas typically develop independently, but some share a clonal origin. Repeat leiomyoma occurrence may be due to genetic predisposition, such as a germline FH mutation. Distinct somatic YEATS4 mutations identified in multiple leiomyomas from the same patient indicate a possible role for YEATS4 in repeat leiomyomas.

Recurrent pelvic organ prolapse after hysterectomy; a 10-year national follow-up study.

PURPOSE: Hysterectomy may be a risk factor for pelvic organ prolapse (POP). We assessed the risk of recurrent POP (operations and visits) after hysterectomy among women with previous POP. We also studied patient and operation related risk factors for POP recurrence. METHODS: This retrospective cohort study included 1697 women having previous POP diagnosis or POP at the time of hysterectomy (FINHYST 2006 cohort). Follow-up was until the end of 2016. The data was derived from the Finnish National Care register linked to the cohort. Hysterectomy approaches and other demographics were compared to the risk of a prolapse diagnosis and/or surgery. Cox regression model was used to identify hazard ratios. RESULTS: Following hysterectomy, a total of 280 women (16.5%) had a POP reoperation and 359 (21.2%) had an outpatient visit due to POP. Vaginal vault prolapse repair was the most common POP reoperation (n = 181, 10.7%), followed by anterior wall repair (n = 120, 7.1%). Median time to POP reoperation was 3.7 years. Hysterectomy approach did not affect reoperations or visits. Previous cesarean section and anterior repair during hysterectomy were associated with decreased risk, whereas concomitant sacrospinous fixation and uterus prolapse as the main indication led to increased risk of anterior/vault prolapse reoperations. Concomitant posterior repair decreased posterior reoperations and visits, but uterus weight over 500 g caused a fivefold increased risk of posterior prolapse visit. Residential status was associated with elevated risk of any POP reoperations and visits. CONCLUSIONS: Approximately one out of five women suffering from POP ensue POP reoperation or visit after hysterectomy. These high rates are independent on hysterectomy approach, but probably indicate that hysterectomy may worsen previous pelvic floor dysfunction.

Quality of life after myomectomy according to the surgical approach and MED12 mutation status.

OBJECTIVE: Molecular status of uterine leiomyomas has been shown to affect both tumor characteristics and treatment response. Mutations in mediator complex subunit 12 (MED12), the most prevalent alterations in leiomyomas, are associated with tumor size and number of leiomyomas. Myomectomy can be performed by laparoscopy or by open abdominal surgery, depending on the size and number of leiomyomas removed. The aim of this study was to examine the association between MED12 mutation status and surgical approach of myomectomy. We also evaluated myomectomy patients' quality of life after laparoscopic or abdominal surgery and according to the MED12 mutation status. STUDY DESIGN: The prospective cohort study included 104 women who underwent laparoscopic or abdominal myomectomy at the Helsinki University Hospital during 2015-2019. Patients filled in the validated Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire before the operation and 6 and 12 months after the operation. Medical records were reviewed to collect clinical data. Leiomyoma tissue samples were collected and screened for MED12 mutations. RESULTS: Patients undergoing abdominal myomectomy had larger and more numerous leiomyomas compared to patients with laparoscopic myomectomy (10 cm vs 7.4 cm, p < 0.001 and 3 vs 1 leiomyomas, p < 0.001, respectively). A mean change of over 20 points was seen in UFS-QOL scores at 6 months after both laparoscopic and abdominal myomectomy (p < 0.001). MED12 mutations were detected in 178/242 (74 %) of leiomyomas. Of the patients, 45/97 (46 %) had only MED12 positive leiomyomas, while 39/97 (40 %) had only MED12 wild type leiomyomas. The number of leiomyomas removed was higher among patients with MED12 positive leiomyomas than in patients with MED12 wild type tumors (p < 0.001). Laparoscopic approach was equally common in both groups (62 % and 64 %), and there was no statistically significant difference in the UFS-QOL scores. CONCLUSION: Both laparoscopic and abdominal myomectomy significantly improved the quality of life. While MED12 mutations were related with multiple leiomyomas and therefore potentially generated a greater leiomyoma burden, they were not associated with the surgical approach. Pre- and postoperative quality of life was comparable between patients regardless of MED12 status.