Comparison of hormonal replacement therapy delivery routes in terms of safety profiles and clinical considerations
Delivery route
Safety profile
Clinical considerations
Oral estrogen
Increases venous thromboembolism risk due to first-pass hepatic metabolism, leading to procoagulant effects [3, 29]
More effective in improving lipid profiles but may worsen triglyceride levels [13]
Transdermal estrogen
Bypasses hepatic metabolism, reducing thromboembolic and stroke risks [12, 29]
Preferred option for women with metabolic syndrome or cardiovascular risk factors [12, 29]; has neutral effects on triglycerides and may offer safer cardiovascular outcomes in women with type 2 diabetes [3, 12, 29]
Vaginal estrogen
Minimal systemic absorption, primarily used for urogenital symptoms [3, 13]
Safer alternative for localized symptoms in women with high systemic risks [3, 13]
This comparative evaluation highlights that transdermal estrogen is generally the safest option for postmenopausal women with T2DM, while oral formulations should be used selectively
Declarations
Acknowledgments
The authors thank Fatima M.A. Odhaib for her artistic contribution of Figure 1.
Author contributions
BAAS and SAO: Conceptualization, Investigation, Validation, Writing—original draft, and Writing—review & editing. Both authors read and approved the submitted version.
Conflicts of interest
The authors declare that there are no conflicts of interest.
Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.
References
North American Menopause Society. The 2012 hormone therapy position statement of The North American Menopause Society.Menopause. 2012;19:257–71. [DOI] [PubMed] [PMC]
Kapoor E, Kling JM, Lobo AS, Faubion SS. Menopausal hormone therapy in women with medical conditions.Best Pract Res Clin Endocrinol Metab. 2021;35:101578. [DOI] [PubMed] [PMC]
Carrasquilla GD, Frumento P, Berglund A, Borgfeldt C, Bottai M, Chiavenna C, et al. Postmenopausal hormone therapy and risk of stroke: A pooled analysis of data from population-based cohort studies.PLoS Med. 2017;14:e1002445. [DOI] [PubMed] [PMC]
Appiah D, Winters SJ, Hornung CA. Bilateral oophorectomy and the risk of incident diabetes in postmenopausal women.Diabetes Care. 2014;37:725–33. [DOI] [PubMed]
de Lauzon-Guillain B, Fournier A, Fabre A, Simon N, Mesrine S, Boutron-Ruault M, et al. Menopausal hormone therapy and new-onset diabetes in the French Etude Epidemiologique de Femmes de la Mutuelle Générale de l’Education Nationale (E3N) cohort.Diabetologia. 2009;52:2092–100. [DOI] [PubMed] [PMC]
Oliver-Williams C, Glisic M, Shahzad S, Brown E, Baena CP, Chadni M, et al. The route of administration, timing, duration and dose of postmenopausal hormone therapy and cardiovascular outcomes in women: a systematic review.Hum Reprod Update. 2019;25:257–71. [DOI] [PubMed]
Cagnacci A, Venier M. The Controversial History of Hormone Replacement Therapy.Medicina (Kaunas). 2019;55:602. [DOI] [PubMed] [PMC]
Salpeter SR, Walsh JME, Ormiston TM, Greyber E, Buckley NS, Salpeter EE. Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women.Diabetes Obes Metab. 2006;8:538–54. [DOI] [PubMed]
Speksnijder EM, Ten Noever de Brauw GV, Malekzadeh A, Bisschop PH, Stenvers DJ, Siegelaar SE. Effect of Postmenopausal Hormone Therapy on Glucose Regulation in Women With Type 1 or Type 2 Diabetes: A Systematic Review and Meta-analysis.Diabetes Care. 2023;46:1866–75. [DOI] [PubMed]
Anagnostis P, Christou K, Artzouchaltzi A, Gkekas NK, Kosmidou N, Siolos P, et al. Early menopause and premature ovarian insufficiency are associated with increased risk of type 2 diabetes: a systematic review and meta-analysis.Eur J Endocrinol. 2019;180:41–50. [DOI] [PubMed]
Paschou SA, Athanasiadou KI, Papanas N. Menopausal Hormone Therapy in Women with Type 2 Diabetes Mellitus: An Updated Review.Diabetes Ther. 2024;15:741–8. [DOI] [PubMed] [PMC]
Araújo DAC, Farias MLF, Andrade ATL. Effects of transdermal and oral estrogen replacement on lipids and glucose metabolism in postmenopausal women with type 2 diabetes mellitus.Climacteric. 2002;5:286–92. [PubMed]
Honigberg MC, Zekavat SM, Aragam K, Finneran P, Klarin D, Bhatt DL, et al. Association of Premature Natural and Surgical Menopause With Incident Cardiovascular Disease.JAMA. 2019;322:2411–21. [DOI] [PubMed] [PMC]
Matthews KA, Crawford SL, Chae CU, Everson-Rose SA, Sowers MF, Sternfeld B, et al. Are changes in cardiovascular disease risk factors in midlife women due to chronological aging or to the menopausal transition?J Am Coll Cardiol. 2009;54:2366–73. [DOI] [PubMed] [PMC]
Paschou SA, Anagnostis P, Goulis DG, Lambrinoudaki I. Diet and lifestyle for post-reproductive health: Focus on diabetes.Case Rep Womens Health. 2018;18:e00056. [DOI] [PubMed] [PMC]
Espeland MA, Brinton RD, Hugenschmidt C, Manson JE, Craft S, Yaffe K, et al.; WHIMS Study Group. Impact of Type 2 Diabetes and Postmenopausal Hormone Therapy on Incidence of Cognitive Impairment in Older Women.Diabetes Care. 2015;38:2316–24. [DOI] [PubMed] [PMC]
Moran C, Phan TG, Chen J, Blizzard L, Beare R, Venn A, et al. Brain atrophy in type 2 diabetes: regional distribution and influence on cognition.Diabetes Care. 2013;36:4036–42. [DOI] [PubMed] [PMC]
Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study.JAMA. 2004;291:2947–58. [DOI] [PubMed]
Espeland MA, Brinton RD, Manson JE, Yaffe K, Hugenschmidt C, Vaughan L, et al.; WHIMS-MRI2 Study Group. Postmenopausal hormone therapy, type 2 diabetes mellitus, and brain volumes.Neurology. 2015;85:1131–8. [DOI] [PubMed] [PMC]
Espeland MA, Miller ME, Goveas JS, Hogan PE, Coker LH, Williamson J, et al.; Whisca Study Group. Cognitive function and fine motor speed in older women with diabetes mellitus: results from the women’s health initiative study of cognitive aging.J Womens Health (Larchmt). 2011;20:1435–43. [DOI] [PubMed] [PMC]
Manschot SM, Biessels GJ, Valk Hd, Algra A, Rutten GEHM, Grond Jvd, et al.; Utrecht Diabetic Encephalopathy Study Group. Metabolic and vascular determinants of impaired cognitive performance and abnormalities on brain magnetic resonance imaging in patients with type 2 diabetes.Diabetologia. 2007;50:2388–97. [DOI] [PubMed] [PMC]
Rettberg JR, Yao J, Brinton RD. Estrogen: a master regulator of bioenergetic systems in the brain and body.Front Neuroendocrinol. 2014;35:8–30. [DOI] [PubMed] [PMC]
Brinton RD. Estrogen regulation of glucose metabolism and mitochondrial function: therapeutic implications for prevention of Alzheimer’s disease.Adv Drug Deliv Rev. 2008;60:1504–11. [DOI] [PubMed] [PMC]
Hugenschmidt CE, Duran T, Espeland MA. Interactions between estradiol, diabetes, and brain aging and the risk for cognitive impairment.Climacteric. 2021;24:359–65. [DOI] [PubMed] [PMC]
Henderson VW, John JAS, Hodis HN, McCleary CA, Stanczyk FZ, Shoupe D, et al. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis.Neurology. 2016;87:699–708. [DOI] [PubMed] [PMC]
Slopien R, Wender-Ozegowska E, Rogowicz-Frontczak A, Meczekalski B, Zozulinska-Ziolkiewicz D, Jaremek JD, et al. Menopause and diabetes: EMAS clinical guide.Maturitas. 2018;117:6–10. [DOI] [PubMed]
Chen Y, Hsieh T, Lee C, Wu M, Fu Y. Estrogen Therapy and Ischemic Stroke in Women with Diabetes Aged Over 55 Years: A Nation-Wide Prospective Population-Based Study in Taiwan.PLoS One. 2015;10:e0144910. [DOI] [PubMed] [PMC]
Crook D, Godsland IF, Hull J, Stevenson JC. Hormone replacement therapy with dydrogesterone and 17β-oestradiol: effects on serum lipoproteins and glucose tolerance during 24 month follow up.Br J Obstet Gynaecol. 1997;104:298–304. [DOI] [PubMed]
Paschou SA, Marina LV, Spartalis E, Anagnostis P, Alexandrou A, Goulis DG, et al. Therapeutic strategies for type 2 diabetes mellitus in women after menopause.Maturitas. 2019;126:69–72. [DOI] [PubMed]
Cho S, Kim M, Jung S, Cho JM, Kim SG, Park S, et al. Potential benefits of hormone replacement therapy on cardiovascular and kidney outcomes in postmenopausal women with chronic kidney disease.J Nephrol. 2025;38:491–501. [DOI] [PubMed]
Szekacs B, Vajo Z, Varbiro S, Kakucs R, Vaslaki L, Acs N, et al. Postmenopausal hormone replacement improves proteinuria and impaired creatinine clearance in type 2 diabetes mellitus and hypertension.BJOG. 2000;107:1017–21. [DOI] [PubMed]
Manwaring P, Morfis L, Diamond T, Howes LG. The effects of hormone replacement therapy on plasma lipids in type II diabetes.Maturitas. 2000;34:239–47. [DOI] [PubMed]
Hodis HN, Mack WJ. Menopausal Hormone Replacement Therapy and Reduction of All-Cause Mortality and Cardiovascular Disease: It Is About Time and Timing.Cancer J. 2022;28:208–23. [DOI] [PubMed] [PMC]
Czyzyk A, Szczepanik Z. Diabetes mellitus and cancer.Eur J Intern Med. 2000;11:245–52. [DOI] [PubMed]
Abudawood M. Diabetes and cancer: A comprehensive review.J Res Med Sci. 2019;24:94. [DOI] [PubMed] [PMC]
Bolton JL. Menopausal Hormone Therapy, Age, and Chronic Diseases: Perspectives on Statistical Trends.Chem Res Toxicol. 2016;29:1583–90. [DOI] [PubMed] [PMC]
Clendenen TV, Koenig KL, Shore RE, Levitz M, Arslan AA, Zeleniuch-Jacquotte A. Postmenopausal levels of endogenous sex hormones and risk of colorectal cancer.Cancer Epidemiol Biomarkers Prev. 2009;18:275–81. [DOI] [PubMed] [PMC]
Aktas G, Tel BMA, Tel R, Balci B. Treatment of type 2 diabetes patients with heart conditions.Expert Rev Endocrinol Metab. 2023;18:255–65. [DOI] [PubMed]
Bilgin S, Kurtkulagi O, Duman TT, Tel BMA, Kahveci G, Kiran M, et al. Sodium glucose co-transporter-2 inhibitor, Empagliflozin, is associated with significant reduction in weight, body mass index, fasting glucose, and A1c levels in Type 2 diabetic patients with established coronary heart disease: the SUPER GATE study.Ir J Med Sci. 2022;191:1647–52. [DOI] [PubMed] [PMC]
Thurston RC, Karvonen-Gutierrez CA, Derby CA, Khoudary SRE, Kravitz HM, Manson JE. Menopause versus chronologic aging: their roles in women’s health.Menopause. 2018;25:849–54. [DOI] [PubMed]
Shufelt CL, Brown V, Carpenter JS, Chism LA, Faubion SS, Joffe H, et al. The 2023 nonhormone therapy position statement of The North American Menopause Society.Menopause. 2023;30:573–90. [DOI] [PubMed]
Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, Woodruff GN. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the α2δ subunit of a calcium channel.J Biol Chem. 1996;271:5768–76. [DOI] [PubMed]
Miller VM, Naftolin F, Asthana S, Black DM, Brinton EA, Budoff MJ, et al. The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned?Menopause. 2019;26:1071–84. [DOI] [PubMed] [PMC]
