Whole-exome sequencing reveals candidate high-risk susceptibility genes for endometriosis.

BACKGROUND: Endometriosis is a common, chronic disease among fertile-aged women. Disease course may be highly invasive, requiring extensive surgery. The etiology of endometriosis remains elusive, though a high level of heritability is well established. Several low-penetrance predisposing loci have been identified, but high-risk susceptibility remains undetermined. Endometriosis is known to increase the risk of epithelial ovarian cancers, especially of endometrioid and clear cell types. Here, we have analyzed a Finnish family where four women have been diagnosed with surgically verified, severely symptomatic endometriosis and two of the patients also with high-grade serous carcinoma. RESULTS: Whole-exome sequencing revealed three rare candidate predisposing variants segregating with endometriosis. The variants were c.1238C>T, p.(Pro413Leu) in FGFR4, c.5065C>T, p.(Arg1689Trp) in NALCN, and c.2086G>A, p.(Val696Met) in NAV2. The only variant predicted deleterious by in silico tools was the one in FGFR4. Further screening of the variants in 92 Finnish endometriosis and in 19 endometriosis-ovarian cancer patients did not reveal additional carriers. Histopathology, positive p53 immunostaining, and genetic analysis supported the high-grade serous subtype of the two tumors in the family. CONCLUSIONS: Here, we provide FGFR4, NALCN, and NAV2 as novel high-risk candidate genes for familial endometriosis. Our results also support the association of endometriosis with high-grade serous carcinoma. Further studies are required to validate the findings and to reveal the exact pathogenesis mechanisms of endometriosis. Elucidating the genetic background of endometriosis defines the etiology of the disease and provides opportunities for expedited diagnostics and personalized treatments.

Non-obstetric surgery during pregnancy and the effects on maternal and fetal outcomes: A systematic review.

BACKGROUND AND OBJECTIVE: Non-obstetric surgery is fairly common in pregnant women. We performed a systematic review to update data on non-obstetric surgery in pregnant women. The aim of this review was to evaluate the effects of non-obstetric surgery during pregnancy on pregnancy, fetal and maternal outcomes. METHODS: A systematic literature search of MEDLINE and Scopus was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search span was from January 2000 to November 2022. Thirty-six studies matched the inclusion criteria, and 24 publications were identified through reference mining; 60 studies were included in this review. Outcome measures were miscarriage, stillbirth, preterm birth, low birth weight, low Apgar score, and infant and maternal morbidity and mortality rates. RESULTS: We obtained data for 80,205 women who underwent non-obstetric surgery and data for 16,655,486 women who did not undergo surgery during pregnancy. Prevalence of non-obstetric surgery was between 0.23% and 0.74% (median 0.37%). Appendectomy was the most common procedure with median prevalence of 0.10%. Near half (43%) of the procedures were performed during the second trimester, 32% during the first trimester, and 25% during the third trimester. Half of surgeries were scheduled, and half were emergent. Laparoscopic and open techniques were used equally for abdominal cavity. Women who underwent non-obstetric surgery during pregnancy had increased rate of stillbirth (odds ratio (OR) 2.0) and preterm birth (OR 2.1) compared to women without surgery. Surgery during pregnancy did not increase rate of miscarriage (OR 1.1), low 5 min Apgar scores (OR 1.1), the fetus being small for gestational age (OR 1.1) or congenital anomalies (OR 1.0). CONCLUSIONS: The prevalence of non-obstetric surgery has decreased during last decades, but still two out of 1000 pregnant women have scheduled surgery during pregnancy. Surgery during pregnancy increases the risk of stillbirth, and preterm birth. For abdominal cavity surgery, both laparoscopic and open approaches are feasible.

Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata.

Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1 A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.

Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding.

Uterine Fibroids, or leiomyomata, affect millions of women world-wide, with a high incidence of 75% within women of reproductive age. In ~30% of patients, uterine fibroids cause menorrhagia, or heavy menstrual bleeding, and more than half of the patients experience symptoms such as heavy menstrual bleeding, pelvic pain, or infertility. Treatment is symptomatic with limited options including hysterectomy as the most radical solution. The genetic foundations of uterine fibroid growth have been traced to somatic driver mutations (MED12, HMGA2, FH -/-, and COL4A5-A6). These also lead to downstream expression of angiogenic factors including IGF-1 and IGF-2, as opposed to the VEGF-driven mechanism found in the angiogenesis of hypoxic tumors. The resulting vasculature supplying the fibroid with nutrients and oxygen is highly irregular. Of particular interest is the formation of a pseudocapsule around intramural fibroids, a unique structure within tumor angiogenesis. These aberrations in vascular architecture and network could explain the heavy menstrual bleeding observed. However, other theories have been proposed such as venous trunks, or venous lakes caused by the blocking of normal blood flow by uterine fibroids, or the increased local action of vasoactive growth factors. Here, we review and discuss the evidence for the various hypotheses proposed.

Robotic versus laparoscopic surgery for severe deep endometriosis: protocol for a randomised controlled trial (ROBEndo trial).

INTRODUCTION: Endometriosis is a common gynaecological disease affecting around 10% of fertile-aged women, causing severe pain symptoms. Deep endometriosis is defined as endometriotic implants that infiltrate the underlying organs more than 5 mm in depth. Surgery for deep endometriosis requires advanced multidisciplinary surgical technique, often in very difficult surgical conditions, with increased risks of complications. Robotic surgery offers a high-definition three-dimensional view and articulating instruments that may allow more precise dissection than conventional laparoscopy in the pelvic area. The superiority of robotic surgery has not, however, been provedin randomised controlled studies, and there is a lack of long-term outcome data. Advanced endometriosis surgery offers an excellent platform to study the feasibility and long-term outcomes of robotic surgery compared with conventional laparoscopy. METHODS AND ANALYSIS: ROBEndo is a prospective, randomised, controlled clinical trial in a single-centre setting. Patients with deep endometriosis verified by MRI needing surgery at Oulu University Hospital (Oulu, Finland) will be considered eligible. 70 patients will be allocated 1:1 to receive either robotic-assisted or conventional laparoscopic surgery in two strata: radical surgery (with the removal of the uterus and adnexae) and gynaecological organ-sparing surgery. The primary outcome will be the surgical outcome as regards to pain symptoms measured on numeric rating scale (NRS) questionnaires at 24 hours and 6, 12 and 24 months postoperatively. As secondary outcomes, intraoperative measures, enhanced recovery after surgery factors, complications, cost and long-term quality of life measured with Endometriosis Health Profile-30 (EHP-30), Female Sexual Function Index (FSFI) and 15-dimensional (15D) questionnaires will be compared. ETHICS AND DISSEMINATION: This study has been approved by the Northern Ostrobothnian Hospital District Ethical Committee at Oulu University Hospital (212/2021). Informed consent will be obtained during the preoperative check-up by the operating gynaecologist. The results will be published in peer-reviewed international journals. TRIAL REGISTRATION NUMBER: NCT05179109.

Laparoscopically guided transversus abdominis plane block versus local wound analgesia in laparoscopic surgery for peritoneal endometriosis: study protocol for a prospective randomized controlled double-blinded LTAP-trial.

BACKGROUND: Ultrasound-guided transversus abdominis plane block (TAP) performed by anesthesiologist has been shown to be an effective and safe analgesia method in abdominal surgery, reducing postoperative opioid consumption. Recently, there has been growing interest to insert TAP under laparoscopic vision (LTAP) by surgeon. LTAP has been used in laparoscopic gastrointestinal surgery, but studies on LTAP in gynecologic laparoscopic surgery are sparse and inconsistent. The purpose of this study is to compare the efficacy of LTAP and local wound analgesia in laparoscopic surgery due to suspected or diagnosed superficial peritoneal endometriosis. METHODS: The LTAP-trial is a prospective randomized controlled double-blinded study comparing the efficacy and safety of LTAP with local wound analgesia in laparoscopic endometriosis surgery. Patients are randomized to receive LTAP with levobupivacaine and wound infiltration with placebo or wound infiltration with levobupivacaine and LTAP with placebo. The primary outcome is postoperative opioid consumption measured by patient-controlled analgesia (PCA) pump. Secondly, subjective postoperative pain up to 24 h postoperatively will be measured by Numeric Rating Scale (NRS). Additional outcome measures are factors related to recovery and length of stay in the hospital as well as a 6-month follow-up survey regarding pain (NRS) and endometriosis-related wellbeing (endometriosis-related health profile, EHP-30) after surgery. A total of 46 patients will be randomized in a proportion of 1:1. DISCUSSION: Patients with peritoneal endometriosis are often prone to severe postoperative pain that may prohibit their enhanced recovery after laparoscopy. Thus, there is a need for effective postoperative pain management with minimal side-effects. This study focusing on laparoscopically inserted transversus abdominis plane block may provide new insight in dealing with postoperative pain after laparoscopic endometriosis surgery as well as after other gynecologic surgery. TRIAL REGISTRATION: The LTAP-trial -protocol has been prospectively registered to ClinicalTrials.gov , ID: NCT04735770 . Registered on February 2021.

Comparison of 2SC, AKR1B10, and FH Antibodies as Potential Biomarkers for FH-deficient Uterine Leiomyomas.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome caused by germline fumarate hydratase (FH) mutations and characterized by uterine and cutaneous leiomyomas and renal cell cancer. Currently, there is no generally approved method to differentiate FH-deficient uterine leiomyomas from other leiomyomas. Here, we analyzed 3 antibodies (S-(2-succino)-cysteine [2SC], aldo-keto reductase family 1, member B10 [AKR1B10], and FH) as potential biomarkers. The study consisted of 2 sample series. The first series included 155 formalin-fixed paraffin-embedded uterine leiomyomas, of which 90 were from HLRCC patients and 65 were sporadic. The second series included 1590 unselected fresh frozen leiomyomas. Twenty-seven tumors were from known HLRCC patients, while the FH status for the remaining 1563 tumors has been determined by copy number analysis and Sanger sequencing revealing 45 tumors with monoallelic (n=33) or biallelic (n=12) FH loss. Altogether 197 samples were included in immunohistochemical analyses: all 155 samples from series 1 and 42 available corresponding formalin-fixed paraffin-embedded samples from series 2 (15 tumors with monoallelic and 7 with biallelic FH loss, 20 with no FH deletion). Results show that 2SC performed best with 100% sensitivity and specificity. Scoring was straightforward with unambiguously positive or negative results. AKR1B10 identified most tumors accurately with 100% sensitivity and 99% specificity. FH was 100% specific but showed slightly reduced 91% sensitivity. Both FH and AKR1B10 displayed also intermediate staining intensities. We suggest that when patient's medical history and/or histopathologic tumor characteristics indicate potential FH-deficiency, the tumor's FH status is determined by 2SC staining. When aberrant staining is observed, the patient can be directed to genetic counseling and mutation screening.

Uterine leiomyomas in hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome can be identified through distinct clinical characteristics and typical morphology.

INTRODUCTION: Hereditary leiomyomatosis and renal cell cancer (HLRCC) constitute a tumor susceptibility syndrome caused by germline mutations in the fumarate hydratase (FH) gene. The most common features are leiomyomas of the uterus and the skin. The syndrome includes a predisposition to early-onset, aggressive renal cell cancer. It is important to identify women with HLRCC among other uterine leiomyoma patients in order to direct them to genetic counseling and to identify other affected family members. MATERIAL AND METHODS: We conducted a nationwide historical study to identify typical clinical characteristics, uterine leiomyoma morphology, and immunohistochemistry for diagnosing HLRCC. The study included 20 women with a known FH germline mutation and 77 women with sporadic uterine leiomyomas. The patient records of all women were reviewed to obtain clinical details regarding their leiomyomas. Uterine leiomyoma tissue specimens from 43 HLRCC-related leiomyomas and 42 sporadic leiomyomas were collected and prepared for histology analysis. A morphologic description was performed on hematoxylin & eosin-stained tissue slides, and immunohistochemical analysis was carried out for CD34, Bcl-2, and p53 stainings. RESULTS: The women with HLRCC were diagnosed with uterine leiomyomas at a young age compared with the sporadic leiomyoma group (mean 33.8 years vs. 45.4 years, P < 0.0001), and their leiomyomas occurred as multiples compared with the sporadic leiomyoma group (more than four tumors 88.9% vs. 30.8%, P < 0.0001). Congruently, these women underwent surgical treatment at younger age compared with the sporadic leiomyoma group (mean 37.3 years vs. 48.3 years, P < 0.0001). HLRCC leiomyomas had denser microvasculature highlighted by CD34 immunostaining when compared with the sporadic leiomyoma group (112.6 mean count/high-power field, SD 20.8 vs. 37.4 mean count/high-power field, SD 21.0 P < 0.0001) and stronger anti-apoptotic protein Bcl-2 immunostaining when compared with the sporadic leiomyoma group (weak 4.7%, moderate 44.2%, strong 51.2% vs. 26.2%, 52.4%, 21.4%, respectively, P = 0.003). No differences were observed in p53 staining. CONCLUSIONS: Women with HLRCC may be identified through the distinct clinical characteristics: symptomatic and numerous leioymyomas at young age, and morphologic features of FH-mutant leiomyomas, aided by Bcl-2 and CD34 immunohistochemistry. Further, distinguishing individuals with a germline FH mutation enables proper genetic counseling and regular renal monitoring.

Endometriosis and Uterine Fibroids (Leiomyomata): Comorbidity, Risks and Implications.

Uterine Fibroids (leiomyomata) and endometriosis affect millions of women world-wide. Although aetiology and natural history of the conditions are markedly different, symptoms can overlap and make differential diagnoses necessary, often using invasive methods such as laparoscopy. Considerable comorbidity exists between the two conditions and needs to be taken into account when treating fibroids and/or endometriosis. The genetic foundations of both uterine fibroids and endometriosis remain to be fully understood but recent evidence suggest common underpinnings. Here, we discuss the comorbidity of uterine fibroids and endometriosis and the implications for diagnosis, treatment and risks.

Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability.

Uterine leiomyomas (ULs) are benign tumors that are a major burden to women's health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by TERT, TERC, OBFC1 - highlighting the role of telomere maintenance - TP53 and ATM. Genes involved in genitourinary development, WNT4, WT1, SALL1, MED12, ESR1, GREB1, FOXO1, DMRT1 and uterine stem cell marker antigen CD44, formed another strong subgroup. The combined risk contributed by the 22 loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis, and in part explain the more frequent occurrence of UL in women of African origin.

Uterine fibroids and cardiovascular risk.

STUDY QUESTION: Are uterine fibroids associated with increased cardiovascular risk? SUMMARY ANSWER: This study reports an association between increased serum lipids and metabolic syndrome with an increased risk of uterine fibroids. WHAT IS KNOWN ALREADY: Recent studies suggest similarities in biological disease mechanisms and risk factors for fibroids and atherosclerosis: obesity, hypertension and abnormal serum lipids. These findings are awaiting confirmation that a population-based follow-up study could offer with extensive health examination data collection linked with a national hospital discharge register. STUDY DESIGN, SIZE, DURATION: The Northern Finland Birth Cohort (NFBC1966) is a population-based long-term follow-up study including all children with estimated date of delivery in 1966 in the Northern Finland area. The data were collected from national registries, postal questionnaires and clinical health examinations. The study population for this study comprised all females included in the NFBC1966 that underwent an extensive clinical health examination at age 46 years (n = 3635). PARTICIPANTS/MATERIALS, SETTING, METHODS: All females included in the NFBC1966 who were alive and traceable (n = 5118) were invited for the 46-year follow-up study; 3268 (63.9%) responded, returned the postal questionnaire and attended the clinical examination. Uterine fibroid cases were identified through the national hospital discharge register that has data on disease diagnoses based on WHO ICD-codes. Uterine fibroid codes, ICD-9: 218 and ICD-10: D25 were used for case identification. Self-reported fibroid cases were identified through the postal questionnaire. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 729 fibroid cases were identified, including 293 based on hospital discharge registries. With adjustment for BMI, parity, education and current use of exogenous hormones the risk of prevalent fibroids rose significantly for every 1 mmol/l increase in LDL (OR = 1.13, 95% CI: 1.02-1.26 for all cases) and triglycerides (OR = 1.27, 95% CI: 1.09-1.49 for all cases). Metabolic syndrome associated with hospital discharge-based fibroid diagnosis (OR = 1.48, 95% CI: 1.09-2.01). Additionally every 1 unit increase in waist-hip ratio associated with fibroids (OR = 1.32, 95% CI: 1.10-1.57). LIMITATIONS, REASONS FOR CAUTION: The case ascertainment may present some limitations. There was likely an under-identification of cases and misclassification of some cases as controls; this would have diluted the effects of reported associations. The data analysed were cross-sectional and therefore cause and effect for the associations observed cannot be distinguished. WIDER IMPLICATIONS OF THE FINDINGS: Increased serum lipids and metabolic syndrome are associated with increased risk of uterine fibroids. Along with central obesity these findings add to an increased risk for cardiovascular disease among women with fibroids. These observations may suggest that there are shared predisposing factors underlying both uterine fibroids and adverse metabolic and cardiac disease risk, or that metabolic factors have a role in biological mechanisms underlying fibroid development. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Academy of Finland, University Hospital Oulu, University of Oulu, Finland, Northern Finland Health Care Foundation, Duodecim Foundation, ERDF European Regional Development Fund-Well-being and health: Research in the Northern Finland Birth Cohort 1966. The authors declare no conflict of interest.

MED12 mutations and FH inactivation are mutually exclusive in uterine leiomyomas.

BACKGROUND: Uterine leiomyomas from hereditary leiomyomatosis and renal cell cancer (HLRCC) patients are driven by fumarate hydratase (FH) inactivation or occasionally by mediator complex subunit 12 (MED12) mutations. The aim of this study was to analyse whether MED12 mutations and FH inactivation are mutually exclusive and to determine the contribution of MED12 mutations on HLRCC patients' myomagenesis. METHODS: MED12 exons 1 and 2 mutation screening and 2SC immunohistochemistry indicative for FH deficiency was performed on a comprehensive series of HLRCC patients' (122 specimens) and sporadic (66 specimens) tumours. Gene expression analysis was performed using Affymetrix GeneChip Human Exon Arrays (Affymetrix, Santa Clara, CA, USA). RESULTS: Nine tumours from HLRCC patients harboured a somatic MED12 mutation and were negative for 2SC immunohistochemistry. All remaining successfully analysed lesions (107/116) were deficient for FH. Of sporadic tumours, 35/64 were MED12 mutation positive and none displayed a FH defect. In global gene expression analysis FH-deficient tumours clustered together, whereas HLRCC patients' MED12 mutation-positive tumours clustered together with sporadic MED12 mutation-positive tumours. CONCLUSIONS: Somatic MED12 mutations and biallelic FH inactivation are mutually exclusive in both HLRCC syndrome-associated and sporadic uterine leiomyomas. The great majority of HLRCC patients' uterine leiomyomas are caused by FH inactivation, but incidental tumours driven by somatic MED12 mutations also occur. These MED12 mutation-positive tumours display similar expressional profiles with their sporadic counterparts and are clearly separate from FH-deficient tumours.

Controlled ovarian hyperstimulation leads to high progesterone and estradiol levels during early pregnancy.

STUDY QUESTION: Are there differences in estrogen and progesterone secretion in singleton pregnancies, up to Week 11, between spontaneous pregnancies, after controlled ovarian hyperstimulation and fresh embryo transfer (COH + ET) and after frozen embryo transfer in a spontaneous cycle (FET)? SUMMARY ANSWER: Serum progesterone and estradiol (E2) concentrations after COH + ET were higher in early pregnancy, lasting up to Week 7-8, than FET and spontaneous pregnancies, while hormone levels after FET did not differ from spontaneous pregnancies. WHAT IS ALREADY KNOWN: The risk of adverse perinatal outcomes after COH + ET seems to be increased when compared with spontaneous pregnancies. One of the reasons suggested for this is related to ovarian hyperstimulation. STUDY DESIGN, SIZE, DURATION: This was a prospective cohort study consisting of three different groups of pregnant women which were followed-up weekly until Week 11 of their pregnancies. The spontaneous pregnancy group consisted of 41 women, the COH + ET group consisted of 39 and the FET group consisted of 30 women. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women in the control group with spontaneous conception were recruited from local prenatal clinics. Women in the COH + ET and FET groups were recruited from the Reproductive Unit of Oulu University Hospital. At each visit, a three-dimensional ultrasonography was performed to examine the ovarian volumes and vascularization. A blood sample was drawn to analyse progesterone and E2 levels. The pregnancy outcome was included in the analysis. MAIN RESULTS AND THE ROLE OF CHANCE: At pregnancy Week 5, the serum progesterone levels were higher after the COH + ET (median 312, inter-quartile range 183-480 nmol/l), when compared with the spontaneous (63, 52-80 nmol/l; P < 0.001) and FET (74, 48-96 nmol/l; P < 0.001) pregnancies. At Week 11, the P (189, 124-260 nmol/l) was still higher in the COH + ET group (FET 101, 78-120 nmol/l, P < 0.001; spontaneous 115, 80-139 nmol/l, P < 0.01) than the other two groups. The E2 levels at Week 5 were also significantly higher after COH + ET (4.1, 2.2-6.6 nmol/l) than in the spontaneous pregnancies (1.1, 0.7-1.6 nmol/l, P < 0.001) or after FET (0.7, 0.6-0.9 nmol/l, P < 0.001). The volume of the ovaries and the intraovarian vasculature in the COH + ET group were significantly higher when compared with the other two groups (P < 0.001). The birthweight was negatively correlated with the serum P (R -0.340, P < 0.01) and E2 (R= -0.275, P < 0.05) in pregnancy Weeks 5-8. In the multivariate analysis evaluating the factors affecting birthweight of the newborn, the significant factors were the length of gestation, maternal height and progesterone or E2 secretion during Weeks 5-8. LIMITATIONS, REASONS FOR CAUTION: Because of the low number of patients in this study, larger cohort studies are required to confirm the findings. WIDER IMPLICATIONS OF THE FINDINGS: The findings here indicate that COH-induced increased luteal activity should be evaluated by measuring steroid levels or the ovarian size or vascularity, rather than number of oocytes retrieved. If unphysiologically high steroid activity during pregnancy after COH contributes to the risk of adverse perinatal outcomes after fresh embryo transfer, milder stimulation protocols or even freezing of all of the embryos should be considered. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a research grant from the Academy of Finland. The authors declare no conflicts of interest.

Strong family history of uterine leiomyomatosis warrants fumarate hydratase mutation screening.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome characterized by cutaneous and uterine leiomyomas and renal cell cancer. HLRCC is caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. A Finnish family with nine closely related women with uterine leiomyomas was detected by an alert gynecologist. No cutaneous or renal cell tumors were reported in the family when it was referred to genetic analyses. Samples were available from seven patients, and a novel germline FH mutation was detected in five of them. Mutation carriers were symptomatic, had multiple tumors and were diagnosed at an early age. This study emphasizes the importance of considering FH mutation screening when gynecologists encounter families with multiple severe uterine leiomyoma cases. Due to possibility of phenocopies more than one patient should be tested. Early mutation detection allows regular screening of the mutation carriers and enables early detection of possible highly aggressive renal tumors. It may also affect family planning as multiple myomas at early age may significantly reduce fertility.

Do symptomatic endometriosis and uterine fibroids appear together?

OBJECTIVES: Endometriosis and uterine fibroids are common gynecological disorders in fertile women. It has been suggested that these two disorders may be associated with each other. In this study, we tested whether this connection exists. In addition, we wanted to evaluate whether they both affect fertility independently of each other. MATERIALS AND METHODS: THE PREVALENCE OF ENDOMETRIOSIS AND UTERINE FIBROIDS WAS INVESTIGATED IN THREE GROUPS OF PATIENTS: Symptomatic patients requiring surgery either for endometriosis (n=182), or for uterine fibroids (n=240) and asymptomatic patients undergoing laparoscopic sterilization (n=183). The prevalences were examined in three age groups: 35-39 yrs, 40-44 yrs and ≥ 45 yrs. The significance of both diagnoses on fertility was assessed using logistic regression analysis. RESULTS: Uterine fibroids were detected in 25.8% (47/182) of patients with endometriosis. Endometriosis was detected in 19.6% (47/240) of patients with uterine fibroids. 5.5% (10/183) women undergoing sterilization had endometriosis and 19.3% (17/183) had uterine fibroids. Both uterine fibroids and endometriosis were, independently of each other, related to subfertility (OR, 95% CI: 3.8, 2.3-6.5; 6.8, 4.0-11.6, respectively). CONCLUSIONS: The results suggest that symptomatic endometriosis appears together with symptomatic uterine fibroids. Both diseases seem to decrease female fertility independently of each other.

Natural history of familial myomas.

OBJECTIVE: To study the natural history of myomas in familial cases and to compare the tendencies of myomas between familial and non-familial cases. STUDY DESIGN: Subjects with familial and non-familial myomas were identified from the hospital records and the reliable details of the myomas were collected. RESULTS: In the familial cases there are several myomas, four or more. In the non-familial cases, there is usually only one single myoma, which is bigger than in familial cases. In the familial group, the diagnosis and surgery was made earlier. In the familial group, there were more pregnancies and less infertility problems. CONCLUSION: There is a significant difference in the natural history of the familial and non-familial cases. In familial cases, subjects have four or more myomas while in non-familial cases the fibroid is single and large.