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- Johansson, Therese
(författare)
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Leveraging genetic and population-level data to improve women’s health
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hormonal contraception (HC) and menopausal hormone therapy (MHT) are commonly used medicines, but their safety profiles are uncertain due to conflicting research. This thesis aims to examine the potential risks associated with HC and MHT by utilizing large-scale population-based cohorts.In Paper I, we prospectively examined the link between oral contraceptives (OCs) and MHT use with the risk of stroke in the UK Biobank (UKB). Cox regression with time-varying exposures was used to investigate if treatment effects vary with time and to avoid immortal time bias. We included time-varying covariates to account for potential confounding factors that change over time and might affect the exposure level. Our research showed higher stroke risk during the initial period after initiating both treatments and increased stroke risk with MHT use regardless of menopause timing.In Paper II, we calculated the hazard rate of the first incidence of depression following OC use. To avoid the influence of healthy-user bias, we estimated the risk in first-time users and excluded previous users in the reference group. A unique aspect of our study was the sibling analysis, which explored the causal relationship between OC use and depression by examining female sibling pairs in the UKB. Our findings showed that initiating OC was associated with a higher risk of depression, especially among adolescents and during the initial phase of treatment.Paper III explored the genetic predisposition to venous thromboembolism (VTE) among OC users in the UKB. Using polygenic risk scores, we demonstrated that women with a high genetic liability for VTE have a significantly increased risk when initiating OC. This suggests that genetic screening may be beneficial in personalising contraceptive advice and mitigating the risk of thrombotic events.In Paper IV, we investigated the association between different types of contemporary MHT and the risk of cardiovascular disease, building upon our findings from Paper I. We emulated a target trial using the Swedish nationwide registers to estimate the intention-to-treat and per-protocol effect. We showed that specific MHT treatments, particularly those that combine estrogen and progestin, are linked to an increased risk of ischemic heart disease (IHD) and venous thromboembolism (VTE). Tibolone was positively associated with IHD and cerebral infarction but not VTE. In Paper V, we examined the risk of depression following HC initiation using the Swedish nationwide registers. Our research expanded upon the findings of Paper II by including various types of modern HCs and employing an emulated target trial study design. We observed an increased risk of depression among various HCs and found that the risk of depression is influenced by different dosages and types of progestins rather than the route of administration.Using advanced analytical methods, we identified critical risk periods, variations in risk between different treatments and the interplay between treatment and genetics. While HC and MHT offer significant benefits, their potential side effects warrant careful consideration. Therefore, prescribing HCs and MHT should be approached with nuance, emphasising individual risk assessments and ongoing monitoring to optimise safety.
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