BEYOND VASOMOTOR SYMPTOMS: A RATIONALE AND PROTOCOL FOR A RANDOMIZED CONTROLLED TRIAL OF TESTOSTERONE AND DHEA ON COGNITIVE AND CARDIOVASCULAR HEALTH IN PREMATURE OVARIAN INSUFFICIENCY

Abstract

Background: Premature Ovarian Insufficiency (POI) results in a premature and profound deficiency of not only oestrogen but also androgens. While oestrogen replacement is standard, the role of androgen replacement remains underexplored. Existing research focuses predominantly on sexual function, overlooking the potential long-term impacts on cognitive function and cardiovascular health. This paper presents the rationale and a detailed protocol for a rigorous randomized controlled trial (RCT) designed to address this gap.

Materials and methods: This proposed 24-month, double-blind, placebo-controlled RCT will enroll 150 women diagnosed with POI, stratified by aetiology (spontaneous vs. iatrogenic). Participants will be randomized into three parallel arms: (1) Standard hormone replacement therapy (HRT) + placebo; (2) Standard HRT + transdermal testosterone (300 mcg/day); (3) Standard HRT + oral DHEA (50 mg/day). The primary outcomes are cognitive function (assessed by the CNS Vital Signs battery and self-reported Cognitive Failures Questionnaire) and cardiovascular health (assessed using carotid intima-media thickness, flow-mediated dilation, and 24-hour ambulatory blood pressure monitoring). Secondary outcomes include mus- cle mass (DXA scan) and quality of life.

Results: This paper does not present results but rather the scientific rationale and a detailed methodological framework for a definitive trial. We hypothesize that androgen supplementation, in addition to standard HRT, will significantly better preserve cognitive function and yield more favorable cardiovascular parameters, with potentially differential effects.

Conclusion: There is a critical need for high-quality evidence on the long-term, non-sexual health benefits of androgen therapy in POI. This proposed trial provides a rigorous, feasible, and ethically sound model to answer this important clinical question, potentially shifting the paradigm of POI management from symptom control to comprehensive, long-term preven- tative health.