Associations of endogenous and exogenous hormonal exposures and cardiovascular disease in women - A FinnGen study

In a study of over 180,000 Finnish women, genetic predisposition to a later natural menopause and longer reproductive span was not found to be protective against cardiovascular disease, whereas the use of exogenous hormones (menopausal hormone therapy and systemic contraceptives) was associated with a reduced long-term risk of stroke and coronary heart disease.

The Gist

Imagine your body as a complex, high-performance car. For decades, scientists have believed that the "fuel" running this car—specifically, the natural estrogen produced by a woman's body—acts as a protective shield against engine trouble (heart disease). The old theory was simple: the longer the engine runs on this natural fuel (a longer reproductive life from first period to menopause), the better the car runs. Conversely, running out of fuel early (early menopause) was thought to leave the engine vulnerable.

This study, conducted by researchers in Finland using data from over 184,000 women, decided to test this theory with a very specific tool: genetic blueprints.

Here is the breakdown of what they found, using some everyday analogies:

1. The Genetic Blueprint vs. The Real-Life Car

The researchers looked at women's DNA to create a "genetic score" that predicts when a woman should naturally start her periods and when she should naturally stop (menopause). They treated these scores like a manufacturer's manual for the car.

• The Expectation: If the manual says the car is built to run on fuel for 40 years, it should be more durable than a car built to run for only 30 years.
• The Surprise: The study found the opposite. Women whose genetic blueprints suggested they would have a longer reproductive life actually had a slightly higher risk of stroke.
• The Analogy: Think of it like a car manufacturer's manual that says, "This model is built to last 200,000 miles." But in reality, the people who bought this specific model drove in the harshest, most stressful conditions (perhaps due to other genetic factors or lifestyle choices) and ended up breaking down sooner. The "blueprint" for a long life didn't actually translate to a longer, healthier life for the heart. The genetic factors that make you stay fertile longer might be linked to other biological processes that aren't actually good for your blood vessels.

2. The "Factory Add-Ons" (Exogenous Hormones)

While the natural genetic blueprint showed some unexpected results, the researchers also looked at "factory add-ons"—medications women take, specifically Menopausal Hormone Therapy (MHT) and birth control pills.

• The Old Fear: For years, doctors warned that adding these external hormones was like pouring the wrong kind of oil into the engine, potentially causing clogs (clots) or overheating (stroke).
• The New Finding: The study found that women who used these medications over their lifetimes actually had lower risks of heart attacks, strokes, and high blood pressure compared to those who never used them.
• The Analogy: It's like discovering that while the car's original manual had some quirks, adding a specific, high-quality aftermarket turbocharger (hormone therapy) actually made the engine run smoother and last longer in the long run.
  • Important Note: The researchers suggest that while taking these hormones right now might carry a small, temporary risk (like a turbocharger spooling up), the long-term history of having used them seems to leave the engine in better shape than if you had never touched them at all.

3. Why the Confusion?

You might wonder, "If early menopause is bad for the heart, why didn't the genetic study show that?"

The authors explain that genetics are only part of the story.

• The "Real World" Factor: In real life, women who hit menopause early often do so because of bad luck with their environment—like heavy smoking, high stress, or poor nutrition. These bad habits damage the heart and stop periods early. So, in real life, "early menopause" and "heart trouble" go hand-in-hand.
• The "Genetic" Factor: The genetic score only looks at the DNA, ignoring the smoking and stress. It turns out that the specific genes that make you fertile longer don't necessarily protect your heart; they might just be doing something else entirely.

The Bottom Line for Everyday Life

This study is a bit of a plot twist for medical science:

1. Don't panic about your genetics: Just because your DNA suggests you might have a long reproductive life doesn't mean you are automatically protected from heart disease, nor does a shorter genetic timeline mean you are doomed.
2. Medication isn't the villain: For many women, using hormone therapy or birth control pills over a lifetime might actually be protective against heart disease and stroke, contrary to old fears.
3. Context matters: The way our bodies work is a mix of our DNA (the blueprint) and our life choices (the driving conditions). The study shows that while the blueprint is interesting, the actual history of how a woman treated her body (including the use of helpful medications) tells a more powerful story about her heart health.

In short: The "natural" path isn't always the safest, and the "artificial" help (medication) might be exactly what keeps the engine running smoothly for the long haul.

Technical Summary

1. Problem Statement

Cardiovascular disease (CVD) exhibits significant sex differences, with women experiencing distinct risk profiles and outcomes compared to men. A prevailing hypothesis suggests that the duration of endogenous estrogen exposure (from menarche to menopause) is cardioprotective. Consequently, shorter reproductive spans and earlier menopause are observationally linked to increased risks of hypertension, stroke, and coronary heart disease (CHD).

However, the biological mechanisms driving these associations remain unclear. It is difficult to distinguish whether the increased risk is caused by the lack of estrogen itself or by the underlying genetic and environmental factors that cause early menopause (e.g., smoking, poor nutrition, socioeconomic status). Furthermore, the long-term cardiovascular effects of exogenous hormone use (Menopausal Hormone Therapy [MHT] and systemic hormonal contraceptives) are complex, with some studies suggesting increased short-term risks (e.g., stroke) while others indicate long-term benefits.

Objective: This study aimed to disentangle the effects of endogenous (genetic) versus exogenous (pharmacological) estrogen exposure on CVD risk in women by utilizing genetic proxies and large-scale register data.

2. Methodology

Study Design and Population:

• Data Source: The study utilized the FinnGen R12 database, a large-scale genomics initiative linking genomic data with high-quality Finnish health registries.
• Cohort: The analysis focused on 184,132 women of European ancestry, aged 40 or older at baseline.
• Exclusions: Women with bilateral oophorectomy (to ensure natural menopause timing) and those with CVD events before age 40 were excluded.
• Follow-up: Median follow-up was 25.8 years (total >4.7 million person-years).

Exposure Variables:

1. Endogenous Exposure (Genetic Proxies):
   • Since phenotypic data on menarche and menopause was unavailable for the entire cohort, the authors constructed Polygenic Scores (PGS) for:
     • Age at menarche.
     • Age at menopause.
     • Length of reproductive span (Age at menopause minus age at menarche).
   • PGS Construction: GWAS summary statistics were derived from UK Biobank (European ancestry, N=109,758). PGS were trained using LDAK (v6.1) MegaPRS under a BayesR prior and applied to FinnGen participants.
2. Exogenous Exposure (Phenotypic):
   • Data was extracted from the Social Insurance Institution of Finland (Kela) drug purchase and reimbursement registers.
   • Systemic Hormonal Contraceptives: Defined as use of ATC code G03A for ≥6 months.
   • Menopausal Hormone Therapy (MHT): Defined as use of ATC codes G03C (Estrogens) or G03F (Combination) for ≥6 months.

Outcomes:

• Hypertension (I9_HYPTENS)
• Stroke (C_STROKE)
• Major Coronary Heart Disease (CHD) events (I9_CHD)

Statistical Analysis:

• Model: Cox proportional hazards models using age as the time scale.
• Adjustments:
  • Primary models adjusted for the first 10 genetic principal components (PCs).
  • Secondary models adjusted for BMI and smoking status.
  • Stratification: Due to detected time-dependence in covariates (BMI, smoking, and hormone use), stratified analyses were performed (BMI divided into quantiles).
• Metrics: Hazard Ratios (HR) with 95% Confidence Intervals (CI) per one standard deviation (SD) increase in PGS.

3. Key Contributions

• Novel Approach: This is one of the first studies to simultaneously compare the effects of genetically predicted endogenous estrogen timing against observed exogenous hormone use on CVD outcomes in a single, large population.
• Resolution of Discrepancy: It addresses the conflict between observational epidemiology (which links longer reproductive spans to lower CVD risk) and genetic epidemiology, revealing that genetic predisposition to later menopause does not necessarily confer the same protective benefits as the phenotypic trait.
• Long-term vs. Short-term Risk: By utilizing registry data covering decades, the study distinguishes between the acute risks of hormone initiation and the long-term cumulative effects of past exposure.

4. Key Results

A. Endogenous Hormonal Exposure (PGS):

• Stroke Risk: Contrary to observational expectations, a higher genetic liability for later menopause and longer reproductive span was associated with a higher risk of stroke.
  • Adjusted HR (per 1 SD increase in PGS): 1.03 [1.01–1.05] for both age at menopause and reproductive span.
• CHD and Hypertension:
  • No significant association was found between reproductive span/menopause PGS and CHD or hypertension.
  • Higher age at menarche PGS was initially associated with lower CHD and hypertension risk, but these associations disappeared after adjusting for BMI, suggesting BMI mediates this relationship.

B. Exogenous Hormonal Exposure (Phenotypic):

• Menopausal Hormone Therapy (MHT):
  • Stroke: Associated with a lower risk (HR 0.85 [0.82–0.89] in adjusted models).
  • CHD: Associated with a lower risk (HR 0.80 [0.76–0.84]).
  • Hypertension: The initial protective association became non-significant after BMI adjustment, suggesting MHT users had lower baseline BMI, which was the primary driver of the reduced hypertension risk.
• Systemic Hormonal Contraceptives:
  • Associated with lower long-term risks for all three outcomes:
    • Hypertension: HR 0.96 [0.93–0.99]
    • Stroke: HR 0.84 [0.80–0.99]
    • CHD: HR 0.83 [0.78–0.89]

5. Significance and Discussion

The "Genetic vs. Phenotypic" Paradox:
The study highlights a critical divergence: while observational studies show that women with shorter reproductive spans have higher CVD risk, the genetic predisposition to a longer span is weakly associated with higher stroke risk.

• Explanation: The authors posit that PGS captures specific genetic pathways (e.g., DNA damage response, neuroendocrine axes) that influence vascular risk independently of estrogen levels. Conversely, observational associations likely reflect environmental confounders (e.g., smoking, stress, low socioeconomic status) that cause both early menopause and poor cardiovascular health. These environmental factors are not captured by the genetic score.

Clinical Implications:

• Genetic Risk Stratification: Genetic predisposition to later menopause should not be assumed to be cardioprotective.
• Exogenous Hormones: The findings suggest that while current use of exogenous estrogen may carry acute risks (as seen in other literature), the long-term cumulative exposure (historical use of MHT or contraceptives) is associated with reduced risks of stroke and CHD. This implies that the "window of opportunity" or long-term adaptation to exogenous hormones may differ from short-term acute effects.
• Confounding by BMI: The study underscores the importance of BMI as a major confounder in hormonal studies, particularly regarding hypertension.

Limitations:

• Retrospective Design: Susceptible to selection bias.
• Missing Data: Significant missingness in smoking (43%) and BMI (30%) data, though stratified analyses were used to mitigate this.
• Lack of Granularity: The study classified users as "ever used" without accounting for specific formulation, dose, route of delivery, or duration of use, which are known to influence CVD risk.

Conclusion:
This study demonstrates that genetic liability to reproductive timing and actual exogenous hormone exposure represent distinct biological dimensions. While genetic factors predicting a longer reproductive span do not appear to protect against stroke, the long-term use of exogenous hormones (MHT and contraceptives) is associated with a reduced risk of major cardiovascular events in this Finnish population.