Early life stress in women with autoimmune thyroid disorders.

Autoimmune thyroid disorders (AITD) represent the most frequent of all autoimmune disorders. Their aetiopathogenesis is incompletely understood, but most likely multifactorial. Early life stress can have long-lasting effects on the immune system. The aim of the present study was to investigate, for the first time, whether patients with AITD are more frequently affected by early life stress. A total of N = 208 women were recruited into a case-control study. Of these, n = 78 (median age: 53, interquartile range: 15) were patients recruited from a thyroid outpatient clinic with confirmed Hashimoto's thyroiditis, Graves' disease, or AITD not otherwise specified. The remaining n = 130 age- and BMI-matched women (median age: 53, interquartile range: 12) were recruited from the general population. Early life stress was measured with the Childhood Trauma Questionnaire. Patients with AITD did not differ from controls regarding sexual abuse, physical abuse, and physical neglect. However, a greater number of patients reported emotional neglect (29.7% vs. 19.5%) and emotional abuse (41.3% vs. 32%). This study provides initial evidence for emotional neglect and abuse as potential risk factors for the development of AITD. Prospective confirmation of these findings could pave the way for the development of interventions to prevent AITD in predisposed individuals.

Endogenous oestradiol and progesterone as predictors of oncogenic human papillomavirus (HPV) persistence.

BACKGROUND: High-risk human papillomavirus (HR-HPV) is the main aetiological factor for the development of cervical cancer. While nearly 70% of HR-HPV infections are cleared within 12 months, in the remainder of women they persist and can progress into cervical cancer. Oestradiol and progesterone have been shown to be involved in the development and progression of cervical cancer. The objective of this study was to investigate, for the first time, whether diurnal oestradiol and progesterone are also involved in HR-HPV persistence - before cervical cancer develops. METHODS: A total of N = 39 women between 18 and 31 years of age were investigated. All were nulliparous and regular users of combined oral contraceptives. Presence of HR-HPV was determined by cervical swabs. Salivary oestradiol and progesterone were measured upon awakening and at 11 am, 2 pm, and 5 pm. All HR-HPV positive women were re-tested in terms of HR-HPV status 12 months later. RESULTS: HR-HPV positive women had significantly higher morning (p = .007, partial eta2 = .221) and daily oestradiol levels (p < .001, partial eta2 = .442) when compared to HR-HPV negative women. In addition, those with persistent HR-HPV 12 months later had significantly elevated morning (p = .005, partial eta2 = .534) and daily (p = .027, partial eta2 = .346) oestradiol. Progesterone was found to be unrelated to HR-HPV. CONCLUSIONS: Oestradiol was positively linked to HR-HPV presence and persistence. Provided that these findings are replicated, regular monitoring of oestradiol levels may prove useful in identifying women who are at risk of developing cervical cancer.

Is stress related to the presence and persistence of oncogenic human papillomavirus infection in young women?

BACKGROUND: Persistent infection with high-risk human papillomavirus (HR-HPV) is the most important risk factor for the development of cervical cancer, but factors contributing to HR-HPV persistence are incompletely understood. The objective of this study was to test for associations of chronic stress and two aspects of diurnal cortisol secretion (i.e., the cortisol awakening response [CAR] and total cortisol output over the day [AUCgday]) with HR-HPV status at baseline and 12 months later (follow-up). METHODS: We evaluated 188 women (25 ± 3 years) at baseline. Follow-up investigation was restricted to HR-HPV infected women at baseline. Of the initial 48 HR-HPV positive participants, 42 completed the follow-up (16 HR-HPV positive and 26 HR-HPV negative). At baseline and follow-up, we determined HR-HPV status in cervical smears, assessed chronic stress, and repeatedly measured salivary cortisol over the day. At baseline, we analyzed salivary cortisol only in a subgroup of 90 participants (45 HR-HPV negative and 45 HR-HPV positive). RESULTS: At baseline, higher chronic stress (excessive demands at work: p = .022, chronic worrying: p = .032), and a higher CAR (p = .014) were related to baseline HR-HPV positivity. At follow-up, there was a statistical trend for a positive association between the CAR and HR-HPV positivity (p = .062). Neither the CAR nor the AUCgday mediated the associations between chronic stress and HR-HPV status. CONCLUSIONS: Our findings suggest that both chronic stress and diurnal cortisol are related to the presence of HR-HPV infection and may thus play a role in HPV-associated cervical carcinogenesis.

Sleep and Methylation of Estrogen Receptor Genes, ESR1 and GPER, in Healthy Middle-Aged and Older Women: Findings from the Women 40+ Healthy Aging Study.

PURPOSE: Sleep problems in middle-aged and older women are very common and have been associated with menopause-related changes in estrogen levels. However, not all women experience sleep problems as they enter perimenopause, and epigenetic mechanisms might contribute to the differences in sleep quality within this population. In this study, we hypothesized that increased methylation of two estrogen receptor (ER) genes (ESR1 and GPER) would be associated with increased sleep problems in healthy pre-, peri-, and postmenopausal women, either directly or indirectly through the experience of vasomotor symptoms (VMS). MATERIALS AND METHODS: In 130 healthy women aged 40-73 years, we assessed DNA methylation from dried blood spots (DBS). Women rated their sleep quality using the Pittsburgh Sleep Quality Index (PSQI), and VMS using the Menopause Rating Scale (MRS). RESULTS: Higher percentage methylation of ESR1 was associated with increased sleep problems, mediated by VMS, even after controlling for age, menopausal status, body mass index, estradiol levels, depressive symptoms, and caffeine consumption. There was no significant association between GPER methylation and either sleep problems or VMS. CONCLUSION: The study findings support an association between increased ESR1 methylation and sleep problems through increased VMS among healthy women aged 40-73 years.

Differential ESR1 Promoter Methylation in the Peripheral Blood-Findings from the Women 40+ Healthy Aging Study.

Background Estrogen receptor α (ERα) contributes to maintaining biological processes preserving health during aging. DNA methylation changes of ERα gene (ESR1) were established as playing a direct role in the regulation of ERα levels. In this study, we hypothesized decreased DNA methylation of ESR1 associated with postmenopause, lower estradiol (E2) levels, and increased age among healthy middle-aged and older women. Methods We assessed DNA methylation of ESR1 promoter region from dried blood spots (DBSs) and E2 from saliva samples in 130 healthy women aged 40-73 years. Results We found that postmenopause and lower E2 levels were associated with lower DNA methylation of a distal regulatory region, but not with DNA methylation of proximal promoters. Conclusion Our results indicate that decreased methylation of ESR1 cytosine-phosphate-guanine island (CpGI) shore may be associated with conditions of lower E2 in older healthy women.

DNA Methylation in Healthy Older Adults With a History of Childhood Adversity-Findings From the Women 40+ Healthy Aging Study.

Background: Adversity in early development seems to increase the risk of stress-related somatic disorders later in life. Physiologically, functioning of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes is often discussed as long-term mediators of risk. In particular, DNA methylation in the glucocorticoid receptor gene promoter (NR3C1) has been associated with type and strength of early life adversity and subsequent effects on HPA axis signaling in humans. Animal studies, moreover, suggest changes in DNA methylation in the estrogen receptor gene (ERα) upon early life adversity. We investigated the association of type and severity of childhood adversity with methylation in NR3C1 and ERα and additionally considered associations between methylation and steroid hormone secretion. Methods: The percentage of methylation within the NR3C1 promoter and the ERα shore was investigated using dried blood spot samples of 103 healthy women aged 40-73 years. Childhood adversity was examined with the Childhood Trauma Questionnaire. Linear regression analyses were performed with methylation as dependent variable and the experience of emotional abuse and neglect, physical abuse and neglect, and sexual abuse (compared to non-experience) as independent variables. All analyses were controlled for age, BMI, annual household income, and smoking status and were adjusted for multiple testing. Results: Overall, over 70% of the sample reported having experienced any kind of abuse or neglect of at least low intensity. There were no significant associations between childhood adversity and methylation in the NR3C1 promoter (all p > .10). Participants reporting emotional abuse showed significantly higher methylation in the ERα shore than those who did not (p = .001). Additionally, higher levels of adversity were associated with higher levels of ERα shore methylation (p = .001). Conclusion: In healthy women, early life adversity does not seem to result in NR3C1 promoter hypermethylation in midlife and older age. This is the first study in humans to suggest that childhood adversity might, however, epigenetically modify the ERα shore. Further studies are needed to gain a better understanding of why some individuals remain healthy and others develop psychopathologies in the face of childhood adversity.