Estrogen and the Vascular Endothelium: The Unanswered Questions.

Premenopausal women have a lower incidence of cardiovascular disease compared with age-matched male counterparts, but this discrepancy is abolished following the transition to menopause or during low estrogen states.

• The sex-based difference in CVD incidence disappears at menopause, suggesting estrogen plays a protective role.
• Low estrogen states in general, not just menopause, are associated with the loss of this cardiovascular protection.
• This observation forms a foundational premise for investigating estrogen as a cardiovascular protective agent.

Increased risk for CVD correlates with long-term oral contraceptive use, hormone replacement therapy in older postmenopausal cisgender females, and gender affirmation treatment for transgender females.

• These clinical observations challenge the paradigm that estrogen is universally cardioprotective.
• Three distinct patient populations show increased CVD risk with estrogen exposure: oral contraceptive users, older postmenopausal women on HRT, and transgender females on gender-affirming hormone therapy.
• Clinical outcomes in individuals undergoing estrogen treatment have been described as 'highly variable.'

Vascular endothelial dysfunction serves as a nidus for the development of many cardiovascular diseases and is highly predictive of future CVD risk.

• Endothelial dysfunction is identified as a key mechanistic link between estrogen exposure and cardiovascular outcomes.
• Despite preclinical studies indicating that estrogen promotes a quiescent, functional endothelium, this does not consistently translate to improved CVD outcomes clinically.
• The review focuses specifically on endothelial health as the central mechanism under investigation.

Basic and preclinical data indicate that estrogen is vasculoprotective, supporting the concept that hormone therapy could improve cardiovascular health.

• A 'large amount of basic and preclinical data' supports estrogen's vasculoprotective role.
• Preclinical studies indicate that estrogen promotes a quiescent, functional endothelium.
• Despite this body of evidence, translation to clinical cardiovascular benefit remains undemonstrated in key populations.

The review identifies critical knowledge gaps regarding estrogen's effects on large and small artery function and presents novel mechanisms that may explain the lack of cardiovascular benefit in unique patient populations.

• The review covers estrogen's influence on both large and small artery function separately.
• Novel mechanisms and hypotheses are presented to explain discordance between preclinical and clinical findings.
• Unique patient populations examined include postmenopausal cisgender women, oral contraceptive users, and transgender females.
• The paper frames these as 'unanswered questions' requiring further investigation.