The long-term association between bilateral oophorectomy and depression: a prospective cohort study.

OBJECTIVE: Depression is a leading cause of disability globally and affects more women than men. Ovarian sex steroids are thought to modify depression risk in women and interventions such as bilateral oophorectomy that permanently change the sex steroid milieu may increase the risk of depression. This study aimed to investigate the associations between unilateral and bilateral oophorectomy and depression over a 25-year period (1993-2018) and whether this varied by age at oophorectomy or use of menopausal hormone therapy. METHODS: Twenty-five thousand one hundred eighty-eight nurses aged ≥45 years from the Danish Nurse Cohort were included. Nurses with depression prior to baseline were excluded. Poisson regression models, with log-transformed person-years as offset, were used to assess the associations between oophorectomy and incident depression. Nurses who retained their ovaries were the reference group. RESULTS: Compared with nurses with retained ovaries, bilateral oophorectomy was associated with a slightly higher rate of depression (rate ratio [RR], 1.08; 95% confidence interval [CI], 0.95-1.23), but without statistical significance. However, when stratified by age at oophorectomy, compared with nurses with retained ovaries, bilateral oophorectomy at age ≥51 years was associated with higher rates of depression (RR 1.16; 95% CI, 1.00-1.34), but not bilateral oophorectomy at age <51 years (RR 0.86; 95% CI, 0.69-1.07); P value for difference in estimates = 0.02. No association between unilateral oophorectomy and depression was observed. CONCLUSIONS: In this cohort of Danish female nurses, bilateral oophorectomy at age ≥51 years, but not at younger ages, was associated with a slightly higher rate of depression compared with those who retained their ovaries.

Oophorectomy and rate of dementia: a prospective cohort study.

OBJECTIVE: Globally, dementia disproportionally affects women, which is not fully explained by higher female longevity. Oophorectomy at any age leads to the permanent loss of ovarian sex steroids, potentially increasing the risk of dementia. We aimed to investigate the association between oophorectomy and dementia and whether this was conditional on age at oophorectomy, hysterectomy or use of hormone therapy (HT). METHODS: A prospective study of 24,851 female nurses from the Danish Nurse Cohort. Nurses were followed from age 60 years or entry into the cohort, whichever came last, until date of dementia, death, emigration or end of follow-up (December 31, 2018), whichever came first. Poisson regression models with log-transformed person-years as offset were used to estimate the associations. RESULTS: During 334,420 person-years of follow-up, 1,238 (5.0%) nurses developed dementia and 1,969 (7.9%)/ 1,016 (4.1%) contributed person-time after bilateral-/unilateral oophorectomy. In adjusted analyses, an 18% higher rate of dementia was observed following bilateral oophorectomy (aRR 1.18: 95% CI, 0.89-1.56) and 13% lower rate (aRR 0.87: 95% CI, 0.59-1.23) following unilateral oophorectomy compared to nurses who retained their ovaries. Similar effects were detected after stratification according to age at oophorectomy. No statistically significant modifying effects of hysterectomy or HT were detected (Pinteraction≥0.60). CONCLUSIONS: Bilateral, but not unilateral, oophorectomy was associated with an increased rate of incident dementia. We were unable to establish whether this association was conditional on hysterectomy or HT use. Although an increase in dementia after bilateral oophorectomy is biologically plausible, limited statistical power hampers the precision of the estimates.

Bilateral oophorectomy and rate of colorectal cancer: A prospective cohort study.

Worldwide, colorectal cancer is the second most common cancer and third cause of cancer death in women. Estrogen exposure has been inversely associated with colorectal cancer. Oophorectomy reduces circulating estrogen, but the effect on colorectal cancer remains uncertain. The aim of this study was to examine the association between unilateral and bilateral oophorectomy and subsequent risk of colorectal cancer, and whether this association varied by menopausal status at time of oophorectomy, use of hormone replacement therapy (HRT) at baseline, hysterectomy and baseline body mass index (BMI). The study included 25 698 female nurses (aged ≥45 years) participating in the Danish Nurse Cohort. Nurses were followed from baseline until date of colorectal cancer, death, emigration or end of follow-up at December 31, 2018, whichever came first. We examined the association between oophorectomy and colorectal cancer (all ages and stratified by menopausal status). The potential modifying effects of hysterectomy, HRT use at baseline and BMI were investigated. During 542 140 person-years of follow-up, 863 (3.4%) nurses were diagnosed with colorectal cancer. Bilateral oophorectomy was associated with a 79% increased colorectal cancer rate, adjusted rate ratio (aRR) (95% confidence interval [CI]): 1.79 (1.33-2.42). Effect estimates following unilateral oophorectomy also showed higher rate of colorectal cancer, although less pronounced and nonstatistically significant (aRR) (95% CI): 1.25 (0.86-1.82). Similar results were seen when stratifying by menopausal status. The association was not modified by baseline HRT use, hysterectomy or BMI. Oophorectomy was associated with increased rate of colorectal cancer, with highest rates among women with bilateral oophorectomy.

Cardiovascular mortality after bilateral oophorectomy: a prospective cohort study.

OBJECTIVES: Bilateral oophorectomy permanently reduces endogenous estrogen exposure and may increase cardiovascular mortality in women. This study aimed to investigate the association between bilateral oophorectomy and cardiovascular mortality and whether this association was conditional on hysterectomy or on the use of hormone therapy at the time of study entry. METHODS: A prospective cohort study of 25,338 female nurses aged ≥ 45 years within the Danish Nurse Cohort. Nurses were enrolled in 1993 or 1999 and followed until death, emigration, or end of follow-up on December 31, 2018, whichever came first. Exposure was bilateral oophorectomy. Outcome was cardiovascular mortality. Associations were estimated using Poisson regression models with log person-years as the offset. RESULTS: A total of 2,040 (8.1%) participants underwent bilateral oophorectomy. During a mean follow-up of 21.2 (SD: 5.6) years, 772 (3.0%) nurses died from cardiovascular disease. In adjusted analyses, a 31% higher rate of cardiovascular mortality was observed after bilateral oophorectomy (aMRR 1.31; 95% CI, 0.88-1.96) compared with women who retained their ovaries. No evidence of effect modification by use of hormone therapy at baseline or by hysterectomy on the association between bilateral oophorectomy and cardiovascular mortality was observed. CONCLUSION: Bilateral oophorectomy may be associated with cardiovascular mortality in women, but the estimate was not statistically significant. Additionally, we were unable to make firm conclusions regarding the possible modifying role of hormone therapy and hysterectomy on this potential association. Additional studies are needed to replicate this work.

Endocrine Disrupting Chemicals and Risk of Testicular Cancer: A Systematic Review and Meta-analysis.

The incidence of many hormone-dependent diseases, including testicular cancer, has sharply increased in all high-income countries during the 20th century. This is not fully explained by established risk factors. Concurrent, increasing exposure to antiandrogenic environmental endocrine disrupting chemicals (EDCs) in fetal life may partially explain this trend. This systematic review assessed available evidence regarding the association between environmental EDC exposure and risk of testicular cancer (seminomas and nonseminomas). Following PRISMA guidelines, a search of English peer-reviewed literature published prior to December 14, 2020 in the databases PubMed and Embase® was performed. Among the 279 identified records, 19 were eligible for quality assessment and 10 for further meta-analysis. The completeness of reporting was high across papers, but over 50% were considered subject to potential risk of bias. Mean age at diagnosis was 31.9 years. None considered effects of EDC multipollutant mixtures. The meta-analyses showed that maternal exposure to combined EDCs was associated with a higher risk of testicular cancer in male offspring [summary risk ratios: 2.16, (95% CI:1.78-2.62), 1.93 (95% CI:1.49-2.48), and 2.78 (95% CI:2.27-3.41) for all, seminoma, and nonseminoma, respectively]. Similarly, high maternal exposures to grouped organochlorines and organohalogens were associated with higher risk of seminoma and nonseminoma in the offspring. Summary estimates related to postnatal adult male EDC exposures were inconsistent. Maternal, but not postnatal adult male, EDC exposures were consistently associated with a higher risk of testicular cancer, particularly risk of nonseminomas. However, the quality of studies was mixed, and considering the fields complexity, more prospective studies of prenatal EDC multipollutant mixture exposures and testicular cancer are needed.

Breast cancer rate after oophorectomy: A Prospective Danish Cohort Study.

The association between oophorectomy and risk of breast cancer in the general population is uncertain. The aim of our study was to determine the breast cancer rate in women from the general population after oophorectomy (performed before/after menopause), and whether this varies by use of hormone replacement therapy (HRT), hysterectomy, body mass index (BMI) and shift work. The study included 24 409 female nurses (aged ≥45 years) participating in the Danish Nurse Cohort. Nurses were followed from cohort entry until date of breast cancer, death, emigration or end of follow-up at 31 December 2018, whichever came first. Poisson regression with log-transformed person-years as the offset examined the association between oophorectomy and breast cancer (all ages and stratified by menopausal status at time of oophorectomy). The potential modifying effect of HRT use, hysterectomy, BMI and shift work on the associations was estimated. During 502 463 person-years of follow-up, 1975 (8.1%) nurses were diagnosed with breast cancer. Bilateral oophorectomy was associated with a reduced breast cancer rate compared to nurses with preserved ovaries, adjusted rate ratio (95% confidence interval): 0.79 (0.64; 0.99). Similar associations (magnitude and direction) were detected for unilateral oophorectomy and when stratifying according to menopausal status at time of oophorectomy, but without statistical significance. Unilateral and bilateral oophorectomy is associated with a reduced breast cancer rate in women from the general population. This association is not modified by use of HRT, hysterectomy, BMI or shift work.

Sex-dependent associations between maternal prenatal stressful life events, BMI trajectories and obesity risk in offspring: The Raine Study.

Background: There is a high and growing prevalence of childhood obesity which increases the risk of adult obesity and adverse physical and mental health outcomes in adulthood. Experimental and clinical data suggest that the early life environment, particularly prenatal stress, may program development of obesity in the offspring. But few studies have assessed the associations between prenatal maternal stress and rapid (ascending) weight gain, which is the strongest predictor of adult obesity and metabolic disease. Experimental data indicate that the associations may be sex dependent, but the sex-dependent association between prenatal stress and growth in the human offspring during childhood and adolescence is largely unexplored. The aim of this study is to investigate the association between prenatal exposure to stressful life events and childhood obesity in the offspring and whether maternal smoking during pregnancy and breastfeeding mediate this. Method: Participants from a large prospective population-based Australian pregnancy cohort study (The Raine Study, n=2868) were closely and frequently followed from prenatal life (18 weeks gestation) through to adolescence. Maternal stressful life events were prospectively recorded at 18 and 34 weeks and childhood BMI (categorized into six z-score trajectories) was measured from 3 to age 14 years. We studied the prospective association between maternal exposure to stressful life events and BMI z-score trajectories in 2056 offspring (1082 boys). Mothers prospectively reported stressful life events at 18- and 34-weeks' gestation using a standardized and validated 10-point questionnaire. Age- and gender-specific z-scores for BMI were obtained from height and weight at age 3, 5, 8, 10 and 14 years using standardized methods. Latent class group analysis identified six distinct trajectory classes of BMI z-score. Multinomial logistic regression was used to examine the associations between maternal stressful life events and gender-specific BMI z-score trajectories as well as risk of overweight/obesity at each age point. Mediation analyses were also conducted to model the indirect associations through maternal smoking during pregnancy and breastfeeding. Results: Of the 2056-included offspring, 1322 (64.3%) were exposed to at least one maternal stressful life event during early gestation and 1203 (58.5%) were exposed in late gestation. In boys, exposure to stressful life events in early but not late gestation was significantly associated with ascending (accelerated) weight-gain (ages 3-14 years) (adjusted odds ratio (aOR): 1.25, 95% CI: 1.02, 1.52) and increased risk of overweight (aOR: 1.18, 95% CI: 1.00, 1.39) aged 10 years. No similar associations were observed in girls. We observed that 29.2% of the association between more maternal stressful life events and obesity in male offspring was mediated by breastfeeding for less than 6 months. Likewise, up to 35% of the association between more maternal stressful life events and obesity in male offspring was mediated by maternal smoking during the index pregnancy. Conclusion: Prenatal stress in early gestation is directly associated with accelerated childhood weight gain (assessed by childhood BMI z-score trajectories) and risk of obesity in adolescent boys, but not girls and breastfeeding and maternal smoking significantly mediates this association.

Trends in the Incidence of Central Precocious Puberty and Normal Variant Puberty Among Children in Denmark, 1998 to 2017.

Importance: There has been a worldwide secular trend toward earlier onset of puberty in the general population. However, it remains uncertain if these changes are paralleled with increased incidence of central precocious puberty (CPP) and normal variant puberty (ie, premature thelarche [PT] and premature adrenarche [PA]) because epidemiological evidence on the time trends in the incidence of these puberty disorders is scarce. Objective: To provide valid epidemiological data on the 20-year secular trend in the incidence rates of CPP and normal variant puberty. Design, Setting, and Participants: This population-based, 20-year cohort study used national registry data for all youth in Denmark registered with an incident diagnosis of CPP, PT, or PA in the Danish National Patient Registry from 1998 to 2017 (N = 8596) using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). We applied the maximum diagnostic age limit for precocious puberty (ie, onset of puberty before age 8 years for girls and age 9 years for boys) with and without a 12-month lag to address time from first contact to final registration in the Danish National Patient Registry. Data analysis was conducted in 2019. Exposures: Diagnosis of CPP, PT, or PA. Main Outcomes and Measures: The age-specific and sex-specific incidence rates of first-time diagnosis of CPP, PT, and PA were estimated using data from the Danish National Patient Registry from 1998 to 2017, and information about the total number of children at risk within the same age groups and sex from Statistics Denmark. Incidences were stratified according to immigration group (Danish origin, first-generation immigrant, second-generation immigrant). Results: Overall a total 8596 children (7770 [90.4%] girls; median [interquartile] age at diagnosis for boys, 8.0 [7.1-9.0] years; for girls, 8.0 [7.6-8.5] years) were registered with an incident diagnosis of CPP, PT, or PA, of whom 7391 (86.0%) had Danish origin (6671 [90.3%] girls), corresponding to 370 new cases in children with Danish origin per year. The 20-year mean annual incidence rates of CPP, PT, PA, and all 3 conditions per 10 000 girls with Danish origin were 9.2 (95% CI, 8.0 to 10.3), 1.1 (95% CI, 0.7 to 1.5), 1.3 (95% CI, 0.9 to 1.7), and 11.5 (95% CI, 10.3 to 12.8), respectively. For boys with Danish origin, the 20-year mean annual incidence rates per 10 000 boys were lower: 0.9 (95% CI, 0.6 to 1.2), 0.2 (95% CI, 0.1 to 0.4), and 1.1 (95% CI, 0.7 to 1.4) for CPP, PA, and the sum, respectively. There was a 6-fold increase in incidence for girls with Danish origin (from 2.6 per 10 000 to 14.6 per 10 000) and a 15-fold increase for boys with Danish origin (from 0.1 per 10 000 to 2.1 per 10 000). The 20-year mean incidence of CPP and PA among girls in the first-generation and second-generation immigrant groups were greater than that of girls with Danish origin. The incidence rate for CPP per 10 000 girls in the first-generation and second-generation groups were 13.7 (95% CI, 9.3 to 18.2) and 14.2 (95% CI, 4.6 to 23.9), respectively; the incidence rate for PA per 10 000 girls in the first-generation and second-generation groups were 2.0 (95% CI, 0.3 to 3.6) and 1.5 (95% CI, -1.6 to 4.7), respectively. No differences associated with immigration status were observed among boys. Conclusions and Relevance: Our findings suggest that the annual incidence of CPP and normal variant puberty has substantially increased in Denmark during the last 20 years. These findings have implications for short-term and long-term health and potentially for the international classification of the reference age of puberty.

Marked Increase in Incident Gynecomastia: A 20-Year National Registry Study, 1998 to 2017.

CONTEXT: Gynecomastia, the proliferation of mammary glandular tissue in the male, is a frequent but little-studied condition. Available prevalence data are based on selected patient populations or autopsy cases with their inherent bias. OBJECTIVE: The objective of this work is to evaluate the age-related incidence and secular trends in gynecomastia in the general population. DESIGN: An observational, 20-year national registry study was conducted. SETTING: This population-based study used nationwide registry data. PARTICIPANTS: Participants included all Danish males (age 0-80 years) with a first-time diagnosis of gynecomastia. MAIN OUTCOME MEASURES: All Danish males (age 0-80 years) were followed up for incident diagnosis of gynecomastia in the Danish National Patient Registry from 1998 to 2017 using the International Codes of Diseases, 10th revision, and the Danish Health Care Classification System. Age-specific incidence rates were estimated. The hypothesis tested in this study was formulated prior to data collection. RESULTS: Overall, a total 17 601 males (age 0-80 years) were registered with an incident diagnosis of gynecomastia within the 20-year study period, corresponding to 880 new cases per year and an average 20-year incidence of 3.4 per 10 000 men (age 0-80 years). The average annual incidence was 6.5/10 000 in postpubertal males age 16 to 20 years and 4.6/10 000 in males age 61 to 80 years, with a respective 5- and 11-fold overall increase in these 2 age groups over the 20-year period. CONCLUSIONS: The incidence of gynecomastia has dramatically increased over the last 20 years, implying that the endogenous or exogenous sex-steroid environment has changed, which is associated with other adverse health consequences in men such as an increased risk of prostate cancer, metabolic syndrome, type 2 diabetes, or cardiovascular disorders.

A history of cryptorchidism is associated with impaired testicular function in early adulthood: a cross-sectional study of 6376 men from the general population.

STUDY QUESTION: Is there a difference in testicular function in early adulthood between men born with cryptorchidism and men born with normally descended testes? SUMMARY ANSWER: In men from the general population, a history of cryptorchidism was associated with lower total testis volume and impaired semen quality as well as altered serum levels of reproductive hormones. WHAT IS KNOWN ALREADY: The association between cryptorchidism and testicular function is well documented in studies based on sub-fertile or infertile men recruited from a clinical setting. However, the association has not previously been investigated in men from the general population, who were unselected regarding fertility status. STUDY DESIGN, SIZE, DURATION: This is a cross-sectional population-based study of 6376 young Danish men examined from 1996 to 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study is based on young men from the greater Copenhagen area, Denmark (median age of 19 years) who were unselected regarding fertility status and semen quality. The young men delivered a semen sample, had a blood sample drawn and underwent a physical examination including assessment of testis volume. Participants completed a questionnaire regarding cryptorchidism at birth, current lifestyle and their mother's pregnancy, after consulting their mother. The differences in markers of testicular function, including testis volume, semen parameters and reproductive hormones between men with and without a history of cryptorchidism were investigated with multiple linear regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE: The participation rate was 24% for the entire study period. Overall, a history of cryptorchidism was associated with reduced testicular function. In the adjusted models, a history of cryptorchidism was associated with a 3.5 ml lower total testis volume, determined by orchidometer (P < 0.001), 28% lower sperm concentration (95% CI: -37 to -20) and 26% lower inhibin B/FSH ratio (95% CI: -50 to -22) compared to men without a history of cryptorchidism, suggesting a reduced spermatogenetic capacity. Men with a history of cryptorchidism also had a slightly reduced Leydig cell function expressed as a 6% lower testosterone/LH ratio (95% CI: -12 to -0.7). The significant effect sizes and different markers of testicular function pointing in the same direction across the different models based on a large sample size support that the results are not chance findings. LIMITATIONS, REASONS FOR CAUTION: Information on cryptorchidism at birth and treatment modus was obtained by retrospective self-report, and each participant only delivered one semen sample. WIDER IMPLICATIONS OF THE FINDINGS: The results suggest that men with a history of cryptorchidism could be at increased risk of experiencing fertility problems. However, among these men there is a wide variation in semen quality and further research is needed in order to identify the subgroup of boys born with cryptorchidism who are at the greatest risk of impaired semen quality when reaching adulthood. STUDY FUNDING/COMPETING INTEREST(S): The study received financial support from the Research fund of Rigshospitalet, Copenhagen University Hospital; the European Union (Contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT-2002-00603. FP7/2007-2013, DEER Grant agreement no. 212844); the Danish Ministry of Health; the Danish Environmental Protection Agency; A.P. Møller and wife Chastine McKinney Møllers Foundation; and Svend Andersens Foundation. None of the founders had any role in the study design, collection, analysis or interpretation of data, writing of the paper or publication decisions. The authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.

Strains of the heterotrophic flagellate Bodo designis from different environments vary considerably with respect to salinity preference and SSU rRNA gene composition.

The morpho species Bodo designis is widespread and abundant globally in highly contrasting terrestrial and aquatic ecosystems. Whether the forms of Bodo designis from contrasting environments are conspecific, i.e. largely genetically identical, or whether they merely share the external morphology is presently not known. We examined the ability of different strains of Bodo designis isolated from different environments at different geographical sites to survive and grow at a salinity range of 0.5-45%. The Bodo designis strains from marine, freshwater, and terrestrial environments showed a different ability to cope with altered physiological conditions. Most of the tested strains were only able to tolerate a small salinity range, whereas others were able to withstand all tested salinity levels. We further examined the phylogenetic relationship between the different strains by sequencing the small subunit (SSU) rRNA gene. The resulting phylogenetic analyses suggest a huge genetic variation within Bodo designis, and also imply that Dimastigella and Rhyncomonas are developed inside Bodo designis. If the biological species concept is used, the genetic differences as well as the physiological barriers between the different strains of Bodo designis, would suggest that they should be assigned to different species.