You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic. For video creation, please contact our Academic Video Service.
Version Summary Created by Modification Content Size Created at Operation
1
Alvin Chandra
 -- 1953 2022-09-27 10:25:37 |
2 format correct
Vivi Li
 Meta information modification 1953 2022-09-27 10:31:17 |

Video Upload Options

We provide professional Academic Video Service to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Simek, S.;  Lue, B.;  Rao, A.;  Ravipati, G.;  Vallabhaneni, S.;  Zhang, K.;  Zaha, V.G.;  Chandra, A. Gender Differences in Cardio-Oncology. Encyclopedia. Available online: https://encyclopedia.pub/entry/27655 (accessed on 14 July 2025).
Simek S,  Lue B,  Rao A,  Ravipati G,  Vallabhaneni S,  Zhang K, et al. Gender Differences in Cardio-Oncology. Encyclopedia. Available at: https://encyclopedia.pub/entry/27655. Accessed July 14, 2025.
Simek, Shawn, Brian Lue, Anjali Rao, Goutham Ravipati, Srilakshmi Vallabhaneni, Kathleen Zhang, Vlad G. Zaha, Alvin Chandra. "Gender Differences in Cardio-Oncology" Encyclopedia, https://encyclopedia.pub/entry/27655 (accessed July 14, 2025).
Simek, S.,  Lue, B.,  Rao, A.,  Ravipati, G.,  Vallabhaneni, S.,  Zhang, K.,  Zaha, V.G., & Chandra, A. (2022, September 27). Gender Differences in Cardio-Oncology. In Encyclopedia. https://encyclopedia.pub/entry/27655
Simek, Shawn, et al. "Gender Differences in Cardio-Oncology." Encyclopedia. Web. 27 September, 2022.
Gender Differences in Cardio-Oncology
Edit
This entry is adapted from the peer-reviewed paper 10.3390/jcm11175167

Gender differences exist throughout the medical field and significant progress has been made in understanding the effects of gender in many aspects of healthcare. The field of cardio-oncology is diverse and dynamic with new oncologic and cardiovascular therapies approved each year; however, there is limited knowledge regarding the effects of gender within cardio-oncology, particularly the impact of gender on cardiotoxicities. The relationship between gender and cardio-oncology is unique in that gender likely affects not only the biological underpinnings of cancer susceptibility, but also the response to both oncologic and cardiovascular therapies. Furthermore, gender has significant socioeconomic and psychosocial implications which may impact cancer and cardiovascular risk factor profiles, cancer susceptibility, and the delivery of healthcare.

cardiotoxicity cardio-oncology gender sex cancer cardiovascular disease

1. Introduction

Great strides have been made in the field of medicine in elucidating the impact of gender on epidemiology, pathophysiology, clinical manifestations, disease progression, and treatment response [1]. This is particularly evident in the field of cardiology [2][3] and oncology [4], but there is a paucity of information of the effects of gender in the burgeoning field of cardio-oncology.

2. Gender Differences in Cancer Susceptibility

The lifetime probability of developing cancer is slightly higher in males (40.2%) when compared to females (38.5%) [5]. This discrepancy is even more apparent in childhood, where male children have about a 20% higher overall rate of incident cancer in comparison to female children [6]. The biological determinants of this observation are not well understood, and there are likely many factors involved. The obvious gender-specific hormonal factors as well as genetic and epigenetic differences certainly play a role in determining risk of cancer. Differences in environmental exposures between genders, such as sun exposure, diet, and tobacco use, have been implicated as well [6]. In fact, the current body of evidence suggests that environmental factors may play the predominant role in determining risk of cancer when compared to genetic factors. For example, a review of registry data from 44,788 pairs of twins in Swedish, Danish, and Finnish twin registries demonstrated that heritable genetic factors made only a minor contribution to the susceptibility of most malignancies [7]. These genetic factors have been described as effect modifiers, with the primary drivers of cancer risk being environmental [8]. Recently, differential response to oxidative stressors between males and females has been suggested in both animal models and humans [9]. With these factors in mind, researchers begin to understand the potential significance of differences in environmental exposures between genders.
Evidence also exists suggesting sexual dimorphism in immune surveillance. Furthermore, immune surveillance is now recognized as a major mechanism protecting hosts from cancer and slowing cancer progression [6]. Females are believed to mount more intense innate and adaptive immune responses in comparison to males. While this may contribute to the lower overall incidence of cancer in females, it likely also leads to the higher incidence of autoimmune diseases in women [6][10]. The mechanism of this phenomenon is thought to relate, in part, to the effects of sex hormones on the immune system. Sex hormone receptors are present on B and T lymphocytes, macrophages, and dendritic cells [6][10]. The effects of sex hormones, particularly estrogens, are thought to modulate the immune response, potentially leading to the differences seen between men and women [10]. An example of the interplay of the genetic, environmental, and immunologic factors can be found in human skin. Men are known to be more prone to skin malignancies [6]. Historically, increased sun exposure in males has been implicated; however, more recently, gender-specific differences in human skin have been increasingly recognized [11]. Ultraviolet radiation is known to induce immunosuppression in human skin, and this effect has been shown to be more significant in men [12]. This multifactorial model of cancer susceptibility is directly related to the gender differences observed in cancer risk.

3. Gender Differences in Response to Cancer Therapies

One of the most relevant gender differences to the clinical practice of cardio-oncology is the difference in response to cancer therapies. Understanding the risk of cardiotoxicity related to specific cancer treatment scenarios is critical to the field of cardio-oncology. Therefore, differential rates of cardiotoxicity by gender must be considered when managing patients with malignancies. These gender differences in response to cancer therapies include direct cardiotoxic effects as well as increased risk of subsequent cardiovascular events related to changes in hormone balance and development of known cardiovascular risk factors (hypertension, obesity, metabolic syndrome, etc.) [13][14][15][16][17].
Perhaps the most robustly studied gender difference in response to cancer therapy is the risk of cardiotoxicity after anthracycline use. Women are significantly more likely to develop cardiotoxicity in comparison to men when treated with anthracyclines, and this effect appears to be particularly prominent when the treatment occurs in childhood [13][14][15]. This observation has been documented in both early (<1 year) and late (>1 year) periods after anthracycline exposure. In a study population of 6493 children with cancer who received anthracycline therapy, cardiotoxicity was confirmed in 106 patients (1.6%) [13]. For the purposes of this investigation, cardiotoxicity was defined as congestive heart failure, abnormal measurements of cardiac function prompting discontinuation of therapy, or sudden death presumed to be cardiac in nature. The authors showed that the risk of cardiotoxicity was nearly two-fold higher (RR 1.9) in female patients compared to male patients [13]. Regarding late cardiotoxicity after anthracycline use, 120 children and adults who had received cumulative doses of 244 to 550 mg/m2 of doxorubicin were evaluated via echocardiography [14]. The participants were treated for either acute lymphoblastic leukemia or osteogenic sarcoma in childhood a mean of 8.1 years prior to the study [14]. Female participants were significantly more likely to show signs of decreased myocardial contractility when compared to males [14]. In fact, based on these observations, female sex is listed as an independent risk factor for anthracycline-related cardiotoxicity in the 2016 European Society of Cardiology Cardio-Oncology Practice Guidelines [18].
The mainstays of treatment for certain malignancies, such as breast and prostate cancers, include the use of hormonally active therapies. These, by design and often gender-specific use, lead to differential effects in men and women. Breast cancer is the most common non-cutaneous malignancy in women in the United States, and with modern therapies, survival rates for breast cancer are relatively high with >90% survival rate at 5 years [16]. This high survival rate can be attributed in part to hormonal therapies targeting estrogen receptor-positive breast cancers [16]. Both selective estrogen receptor modulators (SERMs), such as tamoxifen, and aromatase inhibitors, such as anastrozole, target this pathway, albeit in different ways. SERMs inhibit estrogen by interfering with estrogen binding to estrogen receptors [16]. Aromatase inhibitors lead to systemic depletion of estrogen levels by affecting the hypothalamic–pituitary feedback system [16].
Both aromatase inhibitors and SERMS have potential cardiovascular effects. There is evidence suggesting that aromatase inhibitor use increases cardiovascular events, particularly myocardial infarction, in comparison to placebo and tamoxifen [19][20]. A meta-analysis of seven randomized trials including 16,349 patients comparing anastrozole to placebo showed a modest trend toward increased cardiovascular events (OR 1.18, 95% CI = 1.00–1.40) [20]. A separate meta-analysis evaluated 19 randomized controlled trials including 62,345 patients treated with anastrozole versus tamoxifen. The authors demonstrated a statistically significant increase in cardiovascular events in those patients treated with anastrozole compared to those treated with tamoxifen (RR 1.19, 95% CI = 1.07–1.34), largely driven by myocardial infarction (RR 1.30, 95% CI = 1.11–1.53) [19]. In contrast to aromatase inhibitors, there are limited data suggesting SERMs are less likely to increase the risk of cardiovascular events and may even be protective [16]. SERMs have been shown to decrease low density lipoprotein cholesterol (LDL) and lipoprotein (a), while increasing the risk of diabetes and metabolic syndrome [16][21]. Further investigation is needed to better define the net effect of these changes; however, currently it appears the risk of cardiovascular events with SERMs is lower than with aromatase inhibitors [16][22]. Of note, the estrogen modulation effect of SERMs has been shown to increase the risk of venous thromboembolism and stroke [16][22][23]. As with any therapy, the potential risks of initiating a new treatment need to be considered with the benefits.
In women with premature surgical menopause after oophorectomy or those who require oral contraceptives or hormone replacement therapy as a result of cancer treatment, the risks of these interventions should also be considered gender differences within cardio-oncology. The debate continues regarding the risk/benefit ratio of hormone replacement therapy in menopausal women. There is an association from the Women’s Health Initiative suggesting increased risk of cardiovascular events with hormone replacement therapy, as well as other literature demonstrating increased risk of venous thromboembolism [24][25][26][27]. Furthermore, early-onset menopause appears to increase the risk of premature coronary artery disease and non-fatal cardiovascular events [28]. Specifically, regarding women with premature surgical menopause, including women with prior cancer, there is an association between premature surgical menopause and increased risk of incident cardiovascular disease [29]. In a study of 144,260 postmenopausal women in the United Kingdom, 644 (0.4%) had premature surgical menopause [29]. In comparison to women without premature menopause, those with premature surgical menopause had a significantly increased risk of incident cardiovascular disease (3.9 vs. 7.6%), and this association remained significant after adjustment for conventional cardiovascular risk factors and use of hormone replacement therapy (HR 1.87, 95% CI 1.36–2.58) [29].
Analogous to SERMs and aromatase inhibitors in breast cancer, androgen deprivation therapy has been used successfully in prostate cancer treatment and is associated with significant cardiovascular effects. There are four main classes of hormonally active anti-androgen therapies, including: surgical castration (orchiectomy), gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, and androgen receptor antagonists. Surgical castration leads to rapid and sustained loss of testosterone. GnRH agonists initially increase testosterone levels and later lead to sustained reduction in testosterone by a negative feedback loop mechanism. Conversely, GnRH antagonists cause sustained testosterone reduction without the initial testosterone surge. Finally, androgen receptor antagonists are generally used in conjunction with GnRH agonists/antagonists and lead to further reduction in testosterone activity [16].
While there are limited data regarding surgical castration, the literature suggests increased risk of cardiovascular events with both GnRH agonists and antagonists [16]. A meta-analysis of observational data compared GnRH agonist use to no androgen deprivation therapy and showed an overall increased risk of cardiovascular death (HR 1.36, 95% CI 1.10–1.68) as well as increased risk of myocardial infarction (HR 1.20, 95% CI 1.05–1.38) [30]. In comparison to GnRH agonists, GnRH antagonists are a relatively newer therapy and have shown some promising results specifically regarding reduction in the adverse cardiovascular event profile seen with GnRH agonists [16][31]. Relugolix (GnRH antagonist) was compared to leuprolide (GnRH agonist) in a recent phase 3 clinical trial of 930 participants with advanced prostate cancer [31]. The authors demonstrated a 54% lower risk of major adverse cardiovascular events in patients treated with relugolix compared to leuprolide (HR 0.46, 95% CI 0.24–0.88) [31]. Despite this promising reduction in cardiovascular risk, the assessment and management of the risk of cardiovascular events in patients treated with androgen deprivation therapies will continue to be a vital aspect of cardio-oncology. These therapies are felt to increase cardiovascular risk at least partially through increased prevalence of known cardiovascular risk factors. Androgen deprivation therapy has been associated with increased rates of obesity, metabolic syndrome, hypercholesterolemia, and insulin resistance [16]. While further data are needed to understand if this risk is modifiable by aggressive risk factor management, surveillance for dyslipidemia and diabetes with appropriate initiation of indicated medical therapies is prudent.
Interestingly, a differential response to radiation therapy in men and women has also been documented. A recent meta-analysis of 10 observational studies evaluated rates of incident cardiovascular disease and cardiovascular mortality among 13,975 patients treated for Hodgkin’s lymphoma with radiation therapy [32]. The authors showed a significantly increased risk of incident cardiovascular disease and cardiovascular mortality in women compared to men after radiation therapy (OR 3.74, 95% CI 2.44–5.72) [32]. The authors chose this primary endpoint with the goal of evaluating events they thought would be related to the development of radiation-associated coronary artery disease. This finding may suggest a biological difference in the way men and women tolerate and recover from chest radiation. As with other medical therapies, a dose-related phenomenon has been proposed and may suggest that further investigation is needed to define the ideal dosing and delivery strategies for chest radiation in female patients.

References

  1. Mauvais-Jarvis, F.; Bairey Merz, N.; Barnes, P.J.; Brinton, R.D.; Carrero, J.J.; DeMeo, D.L.; De Vries, G.J.; Epperson, C.N.; Govindan, R.; Klein, S.L.; et al. Sex and gender: Modifiers of health, disease, and medicine. Lancet 2020, 396, 565–582.
  2. EUGenMed Cardiovascular Clinical Study Group; Regitz-Zagrosek, V.; Oertelt-Prigione, S.; Prescott, E.; Franconi, F.; Gerdts, E.; Foryst-Ludwig, A.; Maas, A.H.; Kautzky-Willer, A.; Knappe-Wegner, D.; et al. Gender in cardiovascular diseases: Impact on clinical manifestations, management, and outcomes. Eur. Heart J. 2016, 37, 24–34.
  3. Mosca, L.; Barrett-Connor, E.; Wenger, N.K. Sex/gender differences in cardiovascular disease prevention: What a difference a decade makes. Circulation 2011, 124, 2145–2154.
  4. Wagner, A.D.; Oertelt-Prigione, S.; Adjei, A.; Buclin, T.; Cristina, V.; Csajka, C.; Coukos, G.; Dafni, U.; Dotto, G.P.; Ducreux, M.; et al. Gender medicine and oncology: Report and consensus of an ESMO workshop. Ann. Oncol. 2019, 30, 1914–1924.
  5. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin. 2022, 72, 7–33.
  6. Dorak, M.T.; Karpuzoglu, E. Gender differences in cancer susceptibility: An inadequately addressed issue. Front. Genet. 2012, 3, 268.
  7. Lichtenstein, P.; Holm, N.V.; Verkasalo, P.K.; Iliadou, A.; Kaprio, J.; Koskenvuo, M.; Pukkala, E.; Skytthe, A.; Hemminki, K. Environmental and heritable factors in the causation of cancer—Analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J. Med. 2000, 343, 78–85.
  8. Le Marchand, L. The predominance of the environment over genes in cancer causation: Implications for genetic epidemiology. Cancer Epidemiol. Biomark. Prev. 2005, 14, 1037–1039.
  9. Ali, I.; Hogberg, J.; Hsieh, J.H.; Auerbach, S.; Korhonen, A.; Stenius, U.; Silins, I. Gender differences in cancer susceptibility: Role of oxidative stress. Carcinogenesis 2016, 37, 985–992.
  10. Klein, S.L. Immune cells have sex and so should journal articles. Endocrinology 2012, 153, 2544–2550.
  11. Giacomoni, P.U.; Mammone, T.; Teri, M. Gender-linked differences in human skin. J. Dermatol. Sci. 2009, 55, 144–149.
  12. Damian, D.L.; Patterson, C.R.; Stapelberg, M.; Park, J.; Barnetson, R.S.; Halliday, G.M. UV radiation-induced immunosuppression is greater in men and prevented by topical nicotinamide. J. Investig. Dermatol. 2008, 128, 447–454.
  13. Krischer, J.P.; Epstein, S.; Cuthbertson, D.D.; Goorin, A.M.; Epstein, M.L.; Lipshultz, S.E. Clinical cardiotoxicity following anthracycline treatment for childhood cancer: The Pediatric Oncology Group experience. J. Clin. Oncol. 1997, 15, 1544–1552.
  14. Lipshultz, S.E.; Lipsitz, S.R.; Mone, S.M.; Goorin, A.M.; Sallan, S.E.; Sanders, S.P.; Orav, E.J.; Gelber, R.D.; Colan, S.D. Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N. Engl. J. Med. 1995, 332, 1738–1743.
  15. Ohman, R.E.; Yang, E.H.; Abel, M.L. Inequity in Cardio-Oncology: Identifying Disparities in Cardiotoxicity and Links to Cardiac and Cancer Outcomes. J. Am. Heart Assoc. 2021, 10, e023852.
  16. Okwuosa, T.M.; Morgans, A.; Rhee, J.W.; Reding, K.W.; Maliski, S.; Plana, J.C.; Volgman, A.S.; Moseley, K.F.; Porter, C.B.; Ismail-Khan, R.; et al. Impact of Hormonal Therapies for Treatment of Hormone-Dependent Cancers (Breast and Prostate) on the Cardiovascular System: Effects and Modifications: A Scientific Statement From the American Heart Association. Circ. Genom. Precis. Med. 2021, 14, e000082.
  17. Okwuosa, T.M.; Zaha, V.G. Sex Differences in Cardio-Oncology: Considerations for the Practicing Clinician and Researcher. Circulation 2022, 145, 510–512.
  18. Zamorano, J.L.; Lancellotti, P.; Rodriguez Munoz, D.; Aboyans, V.; Asteggiano, R.; Galderisi, M.; Habib, G.; Lenihan, D.J.; Lip, G.Y.H.; Lyon, A.R.; et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur. Heart J. 2016, 37, 2768–2801.
  19. Khosrow-Khavar, F.; Filion, K.B.; Al-Qurashi, S.; Torabi, N.; Bouganim, N.; Suissa, S.; Azoulay, L. Cardiotoxicity of aromatase inhibitors and tamoxifen in postmenopausal women with breast cancer: A systematic review and meta-analysis of randomized controlled trials. Ann. Oncol. 2017, 28, 487–496.
  20. Goldvaser, H.; Barnes, T.A.; Seruga, B.; Cescon, D.W.; Ocana, A.; Ribnikar, D.; Amir, E. Toxicity of Extended Adjuvant Therapy with Aromatase Inhibitors in Early Breast Cancer: A Systematic Review and Meta-analysis. J. Natl. Cancer Inst. 2018, 110, 31–39.
  21. Lipscombe, L.L.; Fischer, H.D.; Yun, L.; Gruneir, A.; Austin, P.; Paszat, L.; Anderson, G.M.; Rochon, P.A. Association between tamoxifen treatment and diabetes: A population-based study. Cancer 2012, 118, 2615–2622.
  22. Braithwaite, R.S.; Chlebowski, R.T.; Lau, J.; George, S.; Hess, R.; Col, N.F. Meta-analysis of vascular and neoplastic events associated with tamoxifen. J. Gen. Intern. Med. 2003, 18, 937–947.
  23. Hernandez, R.K.; Sorensen, H.T.; Pedersen, L.; Jacobsen, J.; Lash, T.L. Tamoxifen treatment and risk of deep venous thrombosis and pulmonary embolism: A Danish population-based cohort study. Cancer 2009, 115, 4442–4449.
  24. Rossouw, J.E.; Anderson, G.L.; Prentice, R.L.; LaCroix, A.Z.; Kooperberg, C.; Stefanick, M.L.; Jackson, R.D.; Beresford, S.A.; Howard, B.V.; Johnson, K.C.; et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002, 288, 321–333.
  25. Chester, R.C.; Kling, J.M.; Manson, J.E. What the Women’s Health Initiative has taught us about menopausal hormone therapy. Clin. Cardiol. 2018, 41, 247–252.
  26. Hulley, S.; Grady, D.; Bush, T.; Furberg, C.; Herrington, D.; Riggs, B.; Vittinghoff, E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998, 280, 605–613.
  27. Luca, F.; Abrignani, M.G.; Parrini, I.; Di Fusco, S.A.; Giubilato, S.; Rao, C.M.; Piccioni, L.; Cipolletta, L.; Passaretti, B.; Giallauria, F.; et al. Update on Management of Cardiovascular Diseases in Women. J. Clin. Med. 2022, 11, 1176.
  28. Zhu, D.; Chung, H.F.; Dobson, A.J.; Pandeya, N.; Giles, G.G.; Bruinsma, F.; Brunner, E.J.; Kuh, D.; Hardy, R.; Avis, N.E.; et al. Age at natural menopause and risk of incident cardiovascular disease: A pooled analysis of individual patient data. Lancet Public Health 2019, 4, e553–e564.
  29. Honigberg, M.C.; Zekavat, S.M.; Aragam, K.; Finneran, P.; Klarin, D.; Bhatt, D.L.; Januzzi, J.L., Jr.; Scott, N.S.; Natarajan, P. Association of Premature Natural and Surgical Menopause With Incident Cardiovascular Disease. JAMA 2019, 322, 2411–2421.
  30. Zhao, J.; Zhu, S.; Sun, L.; Meng, F.; Zhao, L.; Zhao, Y.; Tian, H.; Li, P.; Niu, Y. Androgen deprivation therapy for prostate cancer is associated with cardiovascular morbidity and mortality: A meta-analysis of population-based observational studies. PLoS ONE 2014, 9, e107516.
  31. Shore, N.D.; Saad, F.; Cookson, M.S.; George, D.J.; Saltzstein, D.R.; Tutrone, R.; Akaza, H.; Bossi, A.; van Veenhuyzen, D.F.; Selby, B.; et al. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N. Engl. J. Med. 2020, 382, 2187–2196.
  32. Khalid, Y.; Fradley, M.; Dasu, N.; Dasu, K.; Shah, A.; Levine, A. Gender disparity in cardiovascular mortality following radiation therapy for Hodgkin’s lymphoma: A systematic review. Cardiooncology 2020, 6, 12.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Shawn Simek
,
Brian Lue
,
Anjali Rao
,
Goutham Ravipati
,
Srilakshmi Vallabhaneni
,
Kathleen Zhang
,
Vlad G. Zaha
,
Alvin Chandra
View Times: 493
Revisions: 2 times (View History)
Update Date: 27 Sep 2022
Table of Contents
    1000/1000
    Hot Most Recent
    Academic Video Service
    Feedback