The Influence of Sex Hormones on Cardiovascular Health: Current Perspectives and Future Directions

Kirolos Eskandar

doi:10.37711/rpcs.2024.6.2.449

Authors

Kirolos Eskandar Johannes Diakonie Klinik, Mosbach, Germany. https://orcid.org/0000-0003-0085-3284

DOI:

https://doi.org/10.37711/rpcs.2024.6.2.449

Keywords:

hormonas sexuales, salud cardiovascular, estrógeno, testosterona, terapia de reemplazo hormonal, medicina personalizada, equidad en la atención médica

Abstract

The intricate relationship between sex hormones and cardiovascular health has garnered increasing attention, revealing significant implications for both disease prevention and therapeutic strategies. This literature review aims to elucidate the multifaceted roles of estrogen, progesterone, and testosterone in cardiovascular physiology and pathology. Estrogen is widely recognized for its protective effects on vascular function, lipid metabolism, and atherosclerosis prevention, while testosterone presents a more complex picture with both beneficial and detrimental impacts on cardiovascular risk. Progesterone, often overlooked, also plays a critical role in modulating these effects. Additionally, this review explores how sex hormones influence endothelial function, inflammatory responses, and contribute to gender differences in cardiovascular disease prevalence. The impact of menopause and hormone replacement therapy (HRT) on cardiovascular health is critically examined, highlighting ongoing debates and current guidelines. Furthermore, the cardiovascular implications of gender-affirming hormone therapy in transgender individuals are discussed. By synthesizing current perspectives and identifying future research directions, this review underscores the potential for personalized medicine approaches that consider hormonal status to optimize cardiovascular health outcomes.

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References

Roth GA, Johnson C, Abajobir A, et al. Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015. J Am Coll Cardiol. 2017;70(1):1-25. doi:10.1016/j.jacc.2017.04.052.

Maas AHEM, Rosano G, Cifkova R, et al. Cardiovascular health after menopause transition, in the context of the ESHRE 2020 guidelines on endometriosis and reproductive health. Eur Heart J. 2021;42(27):2725-2733. doi:10.1093/eurheartj/ehab273.

Toth PP, Banach M. Statin therapy in postmenopausal women: A comprehensive review. Curr Atheroscler Rep. 2021;23(1):3. doi:10.1007/s11883-020-00908-1.

Filardo G, Hasselblad V, Dickersin K, et al. Progesterone for preventing preterm birth. Cochrane Database Syst Rev. 2020;1(1). doi:10.1002/14651858.CD004947.pub4.

Rosano GMC, Sheiban I, Massaro R, et al. Low testosterone levels in men with coronary artery disease: athophysiological mechanisms and potential therapeutic implications. J Clin Endocrinol Metab. 2020;105(4). doi:10.1210/clinem/dgaa132.

Wang Y, Dean JL, Millar MR, et al. Functional analysis of novel androgen-responsive genes in prostate cancer cells identifed by cDNA microarray profling. J Biol Chem. 2004;279(38):31879-31887. doi:10.1074/jbc.M402878200.

Boardman HM, Hartley L, Eisinga A, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev. 2020;(3). doi:10.1002/14651858.CD002229.pub5.

Virani SS, Alonso A, Aparicio HJ, et al. Heart disease and stroke statistics—2021 update. Circulation. 2021. 10.1161/CIR.0000000000000950 [PubMed]

Kopp W. How Western diet and lifestyle drive the pandemic of obesity and civilization diseases. Diabetes, Metab Syndr Obes Targets Ther. 2019;12:2221–2236. doi: 10.2147/DMSO.S216791.

Oneglia A, Nelson MD, Merz CNB. Sex differences in cardiovascular aging and heart failure. Curr Heart Fail Rep. 2020;17:409–423. doi: 10.1007/s11897-020-00487-7.

Lam CSP, Arnott C, Beale AL, Chandramouli C, Hilfker-Kleiner D, Kaye DM, Ky B, Santema BT, Sliwa K, Voors AA. Sex differences in heart failure. Eur Heart J. 2019;40:3859–3868c. Comprehensive overview of how heart failure progression and symptoms differ between men and women.

Dewan P, Rørth R, Jhund PS, et al. Differential impact of heart failure with reduced ejection fraction on men and women. J Am Coll Cardiol. 2019;73:29–40. doi: 10.1016/j.jacc.2018.09.081.

Savji N, Meijers WC, Bartz TM, et al. The association of obesity and cardiometabolic traits with incident HFpEF and HFrEF. JACC Hear Fail. 2018;6:701–709. doi: 10.1016/j.jchf.2018.05.018.

Chen X, Savarese G, Dahlström U, Lund LH, Fu M. Age-dependent differences in clinical phenotype and prognosis in heart failure with mid-range ejection compared with heart failure with reduced or preserved ejection fraction. Clin Res Cardiol. 2019;108:1394–1405. doi: 10.1007/s00392-019-01477-z.

Santema BT, Ouwerkerk W, Tromp J, et al. Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study. Lancet. 2019;394:1254–1263. doi: 10.1016/S0140-6736(19)31792-1.

Shi W, Sheng X, Dorr KM, et al. Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation. Dev Cell. 2021;56:3019–3034.e7. doi: 10.1016/j.devcel.2021.09.022.

El Khoudary SR, Aggarwal B, Beckie TM, Hodis HN, Johnson AE, Langer RD, Limacher MC, Manson JE, Stefanick ML, Allison MA. Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association. Circulation. 2020. 10.1161/CIR.0000000000000912. Current advice and statement by the American Heart Association on Cardiovascular risk related to menopause.

Fuentes N, Silveyra P. Estrogen receptor signaling mechanisms. Adv Protein Chem Struct Biol. 2019;116:135–170. doi: 10.1016/bs.apcsb.2019.01.001.

Chistiakov DA, Myasoedova VA, Melnichenko AA, Grechko AV, Orekhov AN. Role of androgens in cardiovascular pathology. Vasc Heal Risk Manag. 2018;14:283–290. doi: 10.2147/VHRM.S173259.

Barrientos G, Llanos P, Basualto-Alarcon C, Estrada M. Androgen-regulated cardiac metabolism in aging men. Front Endocrinol. 2020;11:316. doi: 10.3389/fendo.2020.00316.

Vanh K, Liu J. Differential effects of progestogens used for menopausal hormone therapy. Clin Obs Gynecol. 2018;61:454–462. doi: 10.1097/GRF.0000000000000364.

Ferreira C, Trindade F, Ferreira R, Neves JS, Leite-Moreira A, Amado F, Santos M, Nogueira-Ferreira R (2021) Sexual dimorphism in cardiac remodeling: the molecular mechanisms ruled by sex hormones in the heart. J Mol Med. 2021. 10.1007/s00109-021-02169-w. Recently published roadmap towards the development of sex-specifc therapeutic approaches.

Pedroza DA, Subramani R, Lakshmanaswamy R. Classical and non-classical progesterone signaling in breast cancers. Cancers (Basel). 2020. 10.3390/cancers12092440.

Sickinghe AA, Korporaal SJA, den Ruijter HM, Kessler EL (2019) Estrogen contributions to microvascular dysfunction evolving to heart failure with preserved ejection fraction. Front Endocrinol. 2019;10:442. Relevant overview pertaining to estrogen-related effects in patients with heart failure with preserved ejection fraction.

Cruz-Topete D, Dominic P, Stokes KY. Uncovering sex-specific mechanisms of action of testosterone and redox balance. Redox Biol. 2020;31:101490. doi: 10.1016/j.redox.2020.101490.

Dai Q, Likes CE, 3rd, Luz AL, Mao L, Yeh JS, Wei Z, Kuchibhatla M, Ilkayeva OR, Koves TR, Price TM. A mitochondrial progesterone receptor increases cardiac beta-oxidation and remodeling. J Endocr Soc. 2019;3:446–467. doi: 10.1210/js.2018-00219.

Lan C, Cao N, Chen C, et al. Progesterone, via yes-associated protein, promotes cardiomyocyte proliferation and cardiac repair. Cell Prolif. 2020;53:e12910.

You Y, Tan W, Guo Y, Luo M, Shang FF, Xia Y, Luo S. Progesterone promotes endothelial nitric oxide synthase expression through enhancing nuclear progesterone receptor-SP-1 formation. Am J Physiol Hear Circ Physiol. 2020;319:H341– H348. doi: 10.1152/ajpheart.00206.2020.

Pang Y, Thomas P. Involvement of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) in mPRalpha (PAQR7)-mediated progesterone induction of vascular smooth muscle relaxation. Am J Physiol Endocrinol Metab. 2021;320:E453–E466. doi: 10.1152/ajpendo.00359.2020.

Spaziani M, Radicioni AF Metabolic and cardiovascular risk factors in Klinefelter syndrome. Am J Med Genet C Semin Med Genet. 2020;184:334–343. Overview of cardiovascular effects of androgen defciencies relevant to the current article.

Pizzocaro A, Vena W, Condorelli R, et al. Testosterone treatment in male patients with Klinefelter syndrome: a systematic review and meta-analysis. J Endocrinol Invest. 2020;43:1675–1687. doi: 10.1007/s40618-020-01299-1.

Martinez C, Rikhi R, Haque T, Fazal A, Kolber M, Hurwitz BE, Schneiderman N, Brown TT. Gender identity, hormone therapy, and cardiovascular disease risk. Curr Probl Cardiol. 2020;45:100396. doi: 10.1016/j.cpcardiol.2018.09.003.

Gagliano-Jucá T, Basaria S. Testosterone replacement therapy and cardiovascular risk. Nat Rev Cardiol. 2019;16:555– 574. Extensive overview testosterone-based therapies and cardiovascular effects.

Zhao D, Guallar E, Ballantyne CM, et al. Sex hormones and incident heart failure in men and postmenopausal women: the atherosclerosis risk in communities study. J Clin Endocrinol Metab. 2020. 10.1210/clinem/dgaa500.

Verdonschot JAJ, Hazebroek MR, Krapels IPC, et al. Implications of genetic testing in dilated cardiomyopathy. Circ Genom Precis Med. 2020. 10.1161/CIRCGEN.120.003031. Demonstration of how genetic predisposition is not always reflected in heart failure–related symptoms and the importance of genetic screening to improve personalized medicine.

Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, et al. Genetic variants associated with cancer therapy-induced cardiomyopathy. Circulation. 2019;140:31–41. doi: 10.1161/CIRCULATIONAHA.118.037934.

De Blok CJ, Wiepjes CM, van Velzen DM, Staphorsius AS, Nota NM, Gooren LJ, Kreukels BP, den Heijer M. Mortality trends over fve decades in adult transgender people receiving hormone treatment: a report from the Amsterdam cohort of gender dysphoria.Lancet Diabetes Endocrinol. 2021; 9:663–670. doi: 10.1016/S2213-8587(21)00185-6.

Streed CG, Beach LB, Caceres BA, Dowshen NL, Moreau KL, Mukherjee M, Poteat T, Radix A, Reisner SL, Singh V; American Heart Association Council on Peripheral Vascular Disease; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Radiology and Intervention; Council on Hypertension; and Stroke Council. Assessing and addressing cardiovascular health in people who are transgender and gender diverse: a scientific statement from the American Heart Association.Circulation. 2021; 144:e136– e148. doi: 10.1161/CIR.0000000000001003.

Obstetricians AC, Gynecologists, Practice CG, Obstetricians AC, Gynecologists, Women CHCU. Health care for transgender and gender diverse individuals: ACOG committee opinion, number 823.Obstet Gynecol. 2021; 137:e75–e88.

Moreira Allgayer RMC, Borba GDS, Moraes RS, Ramos RB, Spritzer PM. The effect of gender-afirming hormone therapy on the risk of subclinical atherosclerosis in the transgender population: a systematic review.Endocr Pract. 2023; 29:498–507. doi: 10.1016/j.eprac.2022.12.017.

Banks K, Kyinn M, Leemaqz SY, Sarkodie E, Goldstein D, Irwig MS. Blood pressure effects of gender-afrming hormone therapy in transgender and gender-diverse adults.Hypertension. 2021; 77:2066–2074. doi: 10.1161/HYPERTENSIONAHA.120.16839.

Reckelhoff JF, Shawky NM, Romero DG, Yanes Cardozo LL. Polycystic ovary syndrome: insights from pre-clinical research.Kidney360. 2022; 3:1449–1457. doi: 10.34067/KID.0002052022.

Shawky NM, Patil CN, Dalmasso C, Maranon RO, Romero DG, Drummond H, Reckelhoff JF. Pregnancy protects hyperandrogenemic female rats from postmenopausal hypertension.Hypertension. 2020; 76:943–952. doi: 10.1161/HYPERTENSIONAHA.120.15504

Chen J, Yu J, Yuan R, Li N, Li C, Zhang X. mTOR inhibitor improves testosterone-induced myocardial hypertrophy in hypertensive rats.J Endocrinol. 2022; 252:179–193. doi: 10.1530/JOE-21-0284

Lichtenecker DCK, Argeri R, Castro CHM, Dias-da-Silva MR, Gomes GN. Cross-sex testosterone therapy modifes the renal morphology and function in female rats and might underlie increased systolic pressure.Clin Exp Pharmacol Physiol. 2021; 48:978–986. doi: 10.1111/1440-1681.13495

Santos JD, Oliveira-Neto JT, Barros PR, Damasceno LEA, Lautherbach N, Assis AP, Silva CAA, Sorgi CA, Faccioli LH, Kettelhut IC, et al. Th17 cell-linked mechanisms mediate vascular dysfunction induced by testosterone in a mouse model of gender-afirming hormone therapy.Am J Physiol Heart Circ Physiol. 2022; 323:H322–H335. doi: 10.1152/ajpheart.00182.2022

Bartels CB, Uliasz TF, Lestz L, Mehlmann LM. Short-term testosterone use in female mice does not impair fertilizability of eggs: implications for the fertility care of transgender males. Hum Reprod. 2021; 36:189–198. doi: 10.1093/humrep/deaa282

Kinnear HM, Hashim PH, Dela Cruz C, Chang FL, Rubenstein G, Nimmagadda L, Elangovan VR, Jones A, Brunette MA, Hannum DF, et al. Presence of ovarian stromal aberrations after cessation of testosterone therapy in a transgender mouse model.Biol Reprod. 2023; 108:802–813. doi: 10.1093/biolre/ioad019

Burinkul S, Panyakhamlerd K, Suwan A, Tuntiviriyapun P, Wainipitapong S. Anti-androgenic effects comparison between cyproterone acetate and spironolactone in transgender women: a randomized controlled trial.J Sex Med. 2021; 18:1299–1307. doi: 10.1016/j.jsxm.2021.05.003

Lee KS, Zhang JJY, Kirollos R, Santarius T, Nga VDW, Yeo TT. A systematic review and meta-analysis of the association between cyproterone acetate and intracranial meningiomas.Sci Rep. 2022; 12:1942. doi: 10.1038/s41598-022-05773-z

Forster RB, Engeland A, Kvale R, Hjellvik V, Bjørge T. Association between medical androgen deprivation therapy and long-term cardiovascular disease and all-cause mortality in nonmetastatic prostate cancer.Int J Cancer. 2022; 151:1109-1119. doi: 10.1002/ijc.34058

Kokorovic A, So AI, Serag H, French C, Hamilton RJ, Izard JP, Nayak JG, Pouliot F, Saad F, Shayegan B, et al. UPDATE - Canadian Urological Association guideline on androgen deprivation therapy: adverse events and management strategies. Can Urol Assoc J. 2022; 16:E416–E431. doi: 10.5489/cuaj.8054

Malhotra A, Kort S, Lauther T, Mann N, Skopicki HA, Parikh PB. Prevalence and predictors of cardiovascular disease and risk factors in transgender persons in the united states.Crit Pathw Cardiol. 2022; 21:42–46. doi: 10.1097/HPC.0000000000000271

Totaro M, Palazzi S, Castellini C, Parisi A, DAmato F, Tienforti D, Baroni MG, Francavilla S, Barbonetti A. Risk of venous thromboembolism in transgender people undergoing hormone feminizing therapy: a prevalence meta-analysis and meta-regression study.Front Endocrinol (Lausanne). 2021; 12:741866. doi: 10.3389/fendo.2021.741866

Martinez-Martin FJ, Kuzior A, Hernandez-Lazaro A, de Leon-Durango RJ, Rios-Gomez C, Santana-Ojeda B, Perez-Rivero JM, Fernandez-Trujillo-Comenge PM, Gonzalez-Diaz P, Arnas-Leon C, et al. Incidence of hypertension in young transgender people after a 5-year follow-up: association with gender-afirming hormonal therapy.Hypertens Res. 2023; 46:219–225. doi: 10.1038/s41440-022-01067-z

Klaver M, van Velzen D, de Blok C, Nota N, Wiepjes C, Defreyne J, Schreiner T, Fisher A, Twisk J, Seidell J, et al. Change in visceral fat and total body fat and the effect on cardiometabolic risk factors during transgender hormone therapy.J Clin Endocrinol Metab. 2022; 107:e153–e164. doi:10.1210/clinem/dgab616

Yun Y, Kim D, Lee ES. Effect of cross-sex hormones on body composition, bone mineral density, and muscle strength in trans women.J Bone Metab. 2021; 28:59–66. doi: 10.11005/jbm.2021.28.1.59

Blackmore K, Young CN. Central feminization of obese male mice reduces metabolic syndrome.Brain Sci. 2022; 12:1324. doi: 10.3390/brainsci12101324

Connelly PJ, Clark A, Touyz RM, Delles C. Transgender adults, gender-afirming hormone therapy and blood pressure: a systematic review.J Hypertens. 2021; 39:223–230. doi:10.1097/HJH.0000000000002632

Njoroge JN, Tressel W, Biggs ML, Matsumoto AM, Smith NL, Rosenberg E, Hirsch CH, Gottdiener JS, Mukamal KJ, Kizer JR. Circulating androgen concentrations and risk of incident heart failure in older men: the Cardiovascular Health Study.J Am Heart Assoc. 2022; 11:e026953. doi: 10.1161/JAHA.122.026953

Banga S, Heinze-Milne SD, Godin J, Howlett SE. Signs of diastolic dysfunction are graded by serum testosterone levels in aging C57BL/6 male mice.Mech Ageing Dev. 2021; 198:111523. doi: 10.1016/j.mad.2021.111523

Yeap BB, Marriott RJ, Antonio L, Raj S, Dwivedi G, Reid CM, Anawalt BD, Bhasin S, Dobs AS, Handelsman DJ, et al. Associations of serum testosterone and sex hormone-binding globulin with incident cardiovascular events in middle-aged to older men.Ann Intern Med. 2022; 175:159–170. doi: 10.7326/M21-0551

Khoudary SRE, Aggarwal B, Beckie TM, Hodis HN, Johnson AE, Langer RD, Limacher MC, Manson JE, Stefanick ML, Allison MA. Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientifc statement from the American Heart Association.Circulation. 2020; 142:e506–e532. doi: 10.1161/CIR.0000000000000912

Kim C, Saran R, Hood M, Karvonen-Gutierrez C, Peng MQ, Randolph JFJ, Harlow SD. Changes in kidney function during the menopausal transition: the Study of Women’s Health Across the Nation (SWAN) – Michigan site.Menopause. 2020; 27:1066–1069. doi: 10.1097/GME.0000000000001579

Zhu X, Tang Z, Cong B. Selective estrogen receptor modulators: an updated review of clinical applications and side effects. Cancer Manag Res. 2020;12:5857-5871. doi:10.2147/CMAR.S278868

Patel SM, Mavinkurve M, Menon DV. Cardiovascular risk prediction: The old, the new, and the future. Methodist Debakey Cardiovasc J. 2020;16(3):e1-e7. doi:10.14797/mdcj-16-3-270