Endometriosis and irritable bowel syndrome: similarities and differences in the spectrum of comorbidities.

STUDY QUESTION: Do the spectrum and prevalence of comorbidities of endometriosis and irritable bowel syndrome (IBS) overlap? SUMMARY ANSWER: Despite several overlapping symptoms, the most significantly associated comorbidities of endometriosis and IBS are different and are rather related to the organ systems primarily involved in the index diagnosis. WHAT IS KNOWN ALREADY: Endometriosis and IBS both have several similar unspecific symptoms, such as recurrent abdominal pain, cramping and anxiety, and both diseases affect young women and are associated with a number of comorbidities causing a poor quality of life. However, a detailed study, revealing the full spectrum of endometriosis and IBS comorbidities in the same study population, is lacking. STUDY DESIGN, SIZE, DURATION: This article presents a retrospective in silico analysis of the data from a large nationwide biobank-based cohort consisting of 121 773 women. After excluding all first- and second-degree relatives, the data of up to 65 421 women were analyzed. PARTICIPANTS/MATERIALS, SETTING, METHODS: International Classification of Disease-10 diagnosis main codes associated with endometriosis (N80) and IBS (K58) diagnoses were identified from the Estonian Biobank dataset by linking with the Estonian Health Insurance Fund and other relevant registries. The associations between N80 and K58 and other diagnosis codes were tested using logistic regression, adjusting for age at recruitment and 10 genetic principal components to account for potential population stratification. Bonferroni correction was applied to account for multiple testing. MAIN RESULTS AND THE ROLE OF CHANCE: Both women with endometriosis and IBS suffered from more conditions compared to the control group, with 226 and 428 diagnosis codes statistically significantly more frequent in women with respective diagnosis compared to controls. Women suffering from both conditions had 275 significantly associated comorbidities. A remarkable proportion of women with IBS or endometriosis suffered also from endometriosis (9.0%) or IBS (13.6%), respectively. In endometriosis, the most prevalent diagnoses were related to diseases of the genitourinary system (33 N-category codes) and in women with IBS, the most associated diagnoses were related to digestive disorders and gastrointestinal tract (52 codes from K-category). Among the most significant diagnoses in endometriosis were uterine leiomyomas (D25), menstrual disorders (N92) and infertility (N97) (P < 1 × 10-315 for all), and in IBS, lactose intolerance (E73), gastritis and duodenitis (K29) and functional dyspepsia (K30) were in the top list of most significant comorbidities (P < 1 × 10-315 for all). LIMITATIONS, REASONS FOR CAUTION: The information about the severity stages of endometriosis and subtypes of IBS was not available for analysis. The findings may not be fully extrapolated to all female populations, because all participants were from one geographic area and had good access to health services. WIDER IMPLICATIONS OF THE FINDINGS: These findings support previous studies that have found a high prevalence of pre-selected comorbidities in women with endometriosis and IBS. However, taking into account the differences in the full spectrum of comorbidities of endometriosis and IBS may aid in diagnosing these disorders. Women and healthcare providers need to be aware that women with endometriosis are at high risks of complications during pregnancy and should be carefully monitored. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Estonian Research Council (grant PRG1076), Horizon 2020 innovation grant (ERIN, grant no. EU952516), Enterprise Estonia (grant no. EU48695), MSCA-RISE-2020 project TRENDO (grant no. 101008193) and by the European Union through the European Regional Development Fund (Projects no. 2014-2020.4.01.15-0012 and no. 2014-2020.4.01.16-0125). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

No evidence of somatic DNA copy number alterations in eutopic and ectopic endometrial tissue in endometriosis.

BACKGROUND: De novo somatic copy number aberrations (SCNAs) in eutopic and ectopic endometria are thought to be involved in the pathogenesis of endometriosis. In this study we used, for the first time, high-density single nucleotide polymorphism-array technology for accurate detection of SCNAs, inherited DNA copy number variations (CNVs) and copy-neutral loss of heterozygosity (cn-LOH) patterns in patients with endometriosis. METHODS: The Illumina HumanOmniExpress array was used to detect de novo somatic genomic alterations in eutopic and ectopic endometria from 11 women (eight with Stage I-II endometriosis and three with Stage III-IV endometriosis) by comparatively analysing DNA from peripheral blood, eutopic endometrium and a pure population of endometriotic cells harvested from endometriotic lesions by laser capture microdissection (LCM). The frequency of the CNV in 3p14.1 from blood DNA of 187 endometriosis patients (94 with Stage I-II endometriosis and 93 with Stage III-IV endometriosis) and 171 healthy women from the Estonian general population was evaluated. RESULTS: Analysis of array data showed that LCM DNA can be used successfully for detection of genetic changes as all inherited CNVs were identified in all tissues studied. No unique SCNAs or cases of cn-LOH were found in either eutopic or ectopic endometrium when compared with blood DNA. The frequency of the deletion allele in 3p14.1 did not differ between studied groups. CONCLUSIONS: In the present study no endometriosis-specific SCNAs or regions of cn-LOH in eutopic or ectopic endometrium were found. Nevertheless, as we studied only 17 endometriotic tissues derived from 11 patients we cannot entirely exclude the occurrence of rare SCNAs. Based on our results we suggest that molecular mechanisms other than chromosomal rearrangements most likely underlie the onset and progression of endometriosis.

Terminations of pregnancy in the European Union.

OBJECTIVE: To study the current legislation and trends in terminations of pregnancy in the European Union (EU). DESIGN: Data were collected on legislation and statistics for terminations of pregnancy. SETTING: Population-based statistics from the EU member states. POPULATION: Women in reproductive age in the 27 EU member states. METHODS: Information on legislation was collected for all 27 EU member states. Statistical information until 2008 was compiled from international (n = 24) and national sources (n = 17). Statistical data were not available for Austria, Cyprus and Luxembourg. MAIN OUTCOMES MEASURES: Terminations of pregnancy per 1000 women aged 15-49 years. RESULTS: Ireland, Malta and Poland have restrictive legislation. Luxembourg permits termination of pregnancy on physical and mental health indications; Cyprus, Finland, and the UK further include socio-economic indications. In all other EU member states termination of pregnancy can be performed in early pregnancy on a women's request. In general, the rates of termination of pregnancy have declined in recent years. In total, 10.3 terminations were reported per 1000 women aged 15-49 years in the EU in 2008. The rate was 12.3/1000 for countries requiring a legal indication for termination, and 11.0/1000 for countries allowing termination on request. Northern Europe (10.9/1000) and Central and Eastern Europe (10.8/1000) had higher rates than Southern Europe (8.9/1000). Northern Europe, however, had substantially higher rates of termination of pregnancy among teenagers. CONCLUSION: A more consistent and coherent reporting of terminations of pregnancy is needed in the EU. The large variation of termination rates between countries suggests that termination of pregnancy rates may be reduced in some countries without restricting women's access to termination. Sexual education and provision of access to reliable and affordable contraception are essential to achieve low rates of termination of pregnancy.

Androgen receptor gene haplotype is associated with male infertility.

The purpose of the current study was to evaluate the importance of androgen receptor (AR) gene haplotypes and polymorphic CAG/GGN microsatellites in the aetiology of male infertility. We genotyped six haplotype-tagging single nucleotide polymorphisms and CAG/GGN microsatellites of the AR gene in 112 infertile and 212 control Estonian men. A total of 13 AR haplotypes (HAP1-13) were identified, among which HAP4 was found to confer increased risk for male infertility (OR = 5.15, 95% CI = 1.75-15.15, p = 0.003). However, infertile patients and controls had similar lengths and distributions of both AR CAG (mean +/- SD number of repeats 21.1 +/- 2.5 vs. 21.2 +/- 2.3, respectively) and GGN (mean +/- SD number of repeats 22.5 +/- 1.5 vs. 22.4 +/- 1.9, respectively) repeats. In addition, HAP2 was associated with more CAG repeats (r = 1.17, p = 0.033) and HAP3 with fewer CAG repeats (r = -2.93, p < 0.001) than the major haplotype HAP1. HAP3 and HAP4 were associated with more GGN repeats (r = 1.35, p = 0.001 and r = 1.36, p = 0.002, respectively) than HAP1. In conclusion, our results implicated the AR-HAP4 gene haplotype in increased risk for male infertility, while no association was found between AR CAG/GGN microsatellites and impaired spermatogenesis.

Does hormone replacement therapy affect the use of prescription medicines in postmenopausal women: experience from the Estonian Postmenopausal Hormone Therapy Trial [ISRCTN35338757].

OBJECTIVE: To determine how postmenopausal hormone therapy (HRT) is related to the use of other prescription medication. DESIGN: Follow up of a randomised controlled trial with a blind subtrial of hormone therapy versus placebo and a nonblind subtrial of open label hormone therapy versus nontreatment. POPULATION: A total of 1823 postmenopausal women aged 50-64 at the time of sampling participated in the trial from 1999 to 2004. METHODS: Use of prescription medication was identified by records in the central computerised database of the Estonian Health Insurance Fund. MAIN OUTCOME MEASURES: The use of 21 classes of prescription medication was compared in the hormone therapy arms and placebo or nontreatment trial arms. The influence of women's socio-economic characteristics on the intensity of concomitant medication use was also examined. RESULTS: The proportion of women using any prescription medication besides hormone therapy did not differ between the arms. However, the type of prescribed drugs varied between the arms. After combining data from both hormone therapy arms, for women using HRT the combined hazard ratio was 1.26 (95% CI: 1.05-1.53) for the use of calcium channel blockers, 1.48 (95% CI: 1.10-1.99) for local vaginal treatment, 0.70 (95% CI: 0.50-0.99) for hypnotics and sedatives and 0.77 (95% CI: 0.60-0.99) for selective serotonin reuptake inhibitors (SSRIs). Women who were older, who had a higher body mass index, who were unemployed and who lived outside the capital used more prescription drugs in comparison with others. CONCLUSIONS: Hormone therapy did not increase the overall use of prescription medication other than hormone therapy, but the types of drugs used in hormone therapy and nontherapy arms varied, with increased use of calcium channel blockers for hypertension and local vaginal treatments for vaginal candidiasis and decreased use of hypnotics, sedatives and SSRIs in the HRT arms.

Social determinants of birthweight and length of gestation in Estonia during the transition to democracy.

BACKGROUND: To investigate social variation in birthweight and length of gestation in Estonia in the period of transition to a democracy and market economy. METHODS: All live births resulting from singleton pregnancies reported to the Estonian Medical Birth Registry in 1992-1997 (n = 84, 629) were studied with respect to social variation in birthweight and preterm delivery (<37 weeks gestation). The results were adjusted for maternal age, parity, education, nationality, marital status, smoking in pregnancy, sex of the infant (and gestational age). RESULTS: Between 1992 and 1997, mean birthweight increased from 3,465g to 3,497g (P < 0.001) and the preterm rate fell from 5.8% to 5.1% (P = 0.001). Maternal education, marital status and nationality were all independently related to the mean birthweight and the risk of preterm birth. The mean difference in birthweight between children of mothers with basic and university education was 87 g (95% CI : 74-100). Children born to mothers of non-Estonian compared to Estonian nationality were on average 77 g lighter (95% CI: 70-84). While the effect of nationality and marital status on birthweight was relatively stable during the study period, differences in birth outcome by maternal education became stronger. CONCLUSIONS: The mean birthweight increased and the preterm rate decreased in Estonia as a whole during the transition. However, the improvements were not shared equally by all social groups. An increase in variation in birthweight by maternal education was particularly notable.

Estonian medical birth registry 1992-1994: association of risk factors with perinatal mortality.

OBJECTIVE: To investigate the association of different maternal sociodemographic characteristics and infant sex with perinatal mortality among primiparas and multiparas. STUDY DESIGN: Analysis of routine data from the Estonian Medical Birth Registry covering the whole of Estonia. A total of 47 358 infants (including stillborns) with a birth weight 1000 g or more from 1992 through 1994 were studied. Perinatal mortality rate, crude odds ratio (OR) and adjusted OR (calculated by a logistic regression model) were used to evaluate the association. OR values were adjusted for maternal age at delivery, maternal ethnicity, educational level, residence, marital status, smoking status, history of previous abortion and infant sex. RESULTS: The perinatal mortality rate was 12.2 per 1000 total births among primiparous and 14.3 among multiparous women. The highest adjusted ORs of perinatal deaths were found in older (35 years and over) primiparas (1.78; 95% confidence interval (CI 0.88-3.57)) and multiparas (1.81; 95% CI 1.29-2.55), in unmarried (single) primiparas (1.59; 95% CI 1.14-2.20) and multiparas (1.98; 95% CI 1.29-3.05), in smoking primiparas (1.69; 95% CI 1.09-2.63) and multiparas (1.51; 95% CI 1.02-2.25), and in multiparas with unknown smoking status (1.98; 95% CI 1.18-3.33). CONCLUSION: The study provides further evidence that perinatal mortality is positively associated with increased maternal age, unmarried (single) status and smoking.

PIP: This study was conducted to investigate the association of different maternal sociodemographic characteristics and infant sex with perinatal mortality among primiparas and multiparas. The data were based on the Estonian Medical Birth Registry (EMBR) which maintains a database of all infants born in hospitals and of the few home deliveries. From 1992 to 1994, 47,022 live births and 336 stillbirths were recorded in the EMBR. Of mothers younger than 20 years old, 26.5% were primiparous and 2.8% were multiparous; among mothers aged 35 years and older, 1.8% were primiparous and 12.0% were multiparous. Results showed that the perinatal mortality rate was 12.2%/1000 total births among primiparous and 14.3% among multiparous women. The highest adjusted odds ratios of perinatal deaths were found in older (35 years and up) primiparas (79%) and multiparas (1.8%); in unmarried primiparas (1.5%) and multiparas (2.0%); in smoking primiparas (1.7%) and multiparas (1.5%); and in multiparas with unknown smoking status (2.0)%. Therefore, perinatal mortality in Estonia was positively associated with increased maternal age, unmarried (single) status, and smoking.

Abortion in the framework of family planning in Estonia.

OBJECTIVE: To analyze the legal status of abortion and trends in childbirth, abortions and contraceptive use in Estonia. DESIGN: National statistical data on induced abortions, spontaneous abortions, births and contraceptive use in Estonia. RESULTS: Even though induced abortion is legal in Estonia, the abortion rate has been declining but is still high and in 1994 was 53.8 per 1000 women of fertile age. Among young women under 20 years of age, abortions decreased slightly in the period 1992-94 (from 55.5 to 41.5 per 1000). The birth rate has been declining rapidly in recent years, resulting in a net population reduction. The use of modern contraceptives is increasing but is still low. CONCLUSION: Survey on abortion and on contraceptive sales and use are needed. To improve family planning and prevent unwanted pregnancies it is important to increase awareness among the entire population--and especially among young people--by information, education and communication. A high standard of counseling, including pre- and postabortion counseling and in the youth services, is essential.

PIP: A post-independence (1992-93) decree issued by the Estonian Ministry of Social Affairs permits abortion on request up to 12 weeks of gestation and, on medical grounds, up to 20 weeks. According to reports received by the Estonian Medical Statistical Bureau, the 1994 abortion rate was 53.8/1000 women of reproductive age. Among women under 20 years of age, the abortion rate declined from 55.5/1000 in 1992 to 41.5/1000 in 1994. Only mini-abortions and abortions performed for medical reasons are free of charge; women with health insurance pay 50% of the cost of most procedures. Funds from abortion fees are used to subsidize contraception for full-time students, women in the first postpartum year, and women who had an induced abortion in the past three months. All other women must pay the full price of contraception. In 1994, only 234 out of every 1000 fertile women were using effective forms of contraception (IUDs and hormonal methods). However, the birth rate has been declining rapidly since 1990 and the rate of natural increase became negative in 1993 (-4.0). The fact that abortion but not contraception is subsidized has facilitated reliance on abortion as a family planning method. Recommended, to reduce the abortion rate and improve the family planning situation in Estonia, are improved contraceptive counseling, including pre- and post-abortion services, and school-based sex education.

Births in Finland and Estonia from 1992 to 1996: convergent differences?

OBJECTIVE: To describe the differences in childbearing, in prenatal and obstetrical practices, and in perinatal health outcome in Finland and Estonia. DESIGN: Registry study using the data from the Finnish and Estonian medical birth registries for years 1992 to 1996 (in total 324,021 and 74,297 newborns, respectively). RESULTS: In 1992 the birth rates were 51 per 1,000 women aged 15 to 49 in Finland and 48 per 1,000 in Estonia. The birth rate declined in the study period in both countries, but the decline was more rapid in Estonia (-26%) than in Finland (-6%). In the same period the rates of induced abortion declined in both countries (-34% and -6%, respectively), but the rate in 1996 was still much higher in Estonia (46/1,000) than in Finland (8/1,000). Compared with Finnish mothers, Estonian mothers were younger, had fewer multiple births, less prenatal care and fewer interventions during pregnancy and delivery. The intervention rates increased in both countries during the study period, but this increase was more rapid in Estonia. The infant outcomes were poorer in Estonia, but the differences between Estonia and Finland decreased during the 1990's. CONCLUSIONS: The differences in prenatal and maternal care and in induced abortion rates have decreased between Estonia and Finland. Changes in maternal backgrounds, improved referral system for complicated pregnancies, improvements in prenatal care and in availability of appropriate equipment and technology may have caused improved maternal and infant health in Estonia, but this should be further investigated.

Hereditary triosephosphate isomerase (TPI) deficiency: two severely affected brothers one with and one without neurological symptoms.

A 13-year-old Hungarian boy (B.J.Jr.) with congenital haemolytic anaemia (CHA) and hyperkinetic torsion dyskinesia was found to have severe triose-phosphate isomerase (TPI) deficiency. One of his two brothers (A.J.), a 23-year-old amateur wrestler, has CHA as well, but no neurological symptoms. Both have less than 10% TPI activity and a highly increased dihydroxyacetone phosphate (DHAP) level in their red blood cells. Their TPI had a slow electrophoretic mobility and was heat unstable. Both parents and a third brother are healthy heterozygous carriers of the defect. A.J. represents a unique phenotype from the point of view that all published "homozygotes" had severe neurological alterations from infancy or early childhood except one infant who died at 11 months, probably too young for neurological symptoms to be noted. In contrast to the two affected Hungarian brothers all but one "homozygote" has died before the age of 6 years. The striking difference in the clinical course of the defect between the two brothers with the same severe red blood cell enzyme deficiency may originate from unusual differences between two double heterozygous brothers resulting inter alia in different levels of TPI expression in various tissues. Significantly lower TPI activities were found in both the T- and B-cells of the propositus as compared to the respective cells of the neurologically symptom-free brother.