Risk of Hypoglycemia in Diabetes Mellitus in Relation to Testosterone Levels in Men and Estradiol Levels in Women: A Systematic Review

Background: Hypoglycemia is a major limiting complication of diabetes mellitus (DM) therapy, capable of triggering life-threatening cardiovascular and neurological events. Emerging evidence suggests that sex hormones—testosterone in men and estradiol in women—modulate glucose counter-regulation, insulin sensitivity, and sympathoadrenal function. However, the clinical impact of sex hormone status on hypoglycemia risk in diabetic patients remains incompletely defined. Methods: A systematic literature review was conducted in accordance with PRISMA 2020 guidelines. Four databases (SciSpace, SciSpace Full Text, Google Scholar, PubMed) were searched using structured queries addressing: (i) testosterone–hypoglycemia associations in men with DM; (ii) estradiol–hypoglycemia associations in women with DM; (iii) sex hormone–mediated mechanisms of glucose counter-regulation; and (iv) clinical implications for diabetes management. Results: From 457 identified records, 405 underwent abstract screening after deduplication. Seven studies met full inclusion criteria. Evidence was predominantly concentrated on estradiol–hypoglycemia relationships in women with type 1 and type 2 DM. Longer reproductive lifespan and postmenopausal hormone replacement therapy (HRT) were associated with significantly reduced risk of severe hypoglycemia. Estradiol was found to enhance insulin sensitivity, preserve counter-regulatory hormone responses, and protect metabolic sensing neurons in the ventromedial hypothalamus. No studies directly examined testosterone–hypoglycemia relationships in men with DM. Conclusions: Estradiol exerts protective effects against hypoglycemia in diabetic women through insulin-sensitizing, counter-regulatory, and neuroprotective mechanisms. Reproductive lifespan, menopausal status, and menstrual cycle phase should be considered when stratifying hypoglycemia risk in women with DM. Testosterone–hypoglycemia interactions in men remain unstudied, warranting targeted clinical investigation.