In 1967, Kathrine Switzer became the first female athlete to officially run the Boston Marathon. Although race officials attempted to physically stop her from completing the race, she crossed the finish line and inspired millions of women to follow in her footsteps. Half a century later, sports participation by female athletes has exponentially increased. In 2018, 50% of runners around the globe were female with a female predominance seen in Iceland (59%), the United States (58%), Canada (57%), Ireland (53%), and Australia (52%).¹

The approach to female athletes is markedly different from their male counterparts, due to considerable hormonal changes occurring at multiple stages of life that can significantly impact athletic performance and cardiovascular health. Consequently, competitive female athletes require a multifaceted approach when being evaluated by sports cardiologists.

Sex-Specific Differences in Exercise-Induced Cardiac Remodeling and Risk of Sudden Cardiac Death

Although female athletes have been underrepresented in athlete-based studies, there is a growing emphasis to understand sex-based differences in cardiac adaptation to exercise and the impact on sudden cardiac death (SCD) risk. Studies in multi-sport female athletes dating from as early as 1996 showed larger left ventricular (LV) end-diastolic dimension (LVEDD) and greater LV maximal wall thickness (LVWT) than controls, though LVEDD >54 mm was infrequent and LVWT >12 mm was not observed. Compared to male athletes, females were found to have smaller LV chamber size, wall thickness, and LV mass.² These parameters appear to fragment, however, when LV size is normalized to body surface area (BSA) or lean body mass (LBM), thus posing difficulty in establishing normative LV measurements in female athletes. As with males, the magnitude of cardiac remodeling is dependent on training intensity. A recent study of 75 female collegiate athletes demonstrated an increase in LV mass in female athletes participating in high-intensity sports compared to lower intensity sports, even after adjustment for LBM. Ventricular remodeling in these female athletes appeared balanced, with a proportional increase in LV mass and volume independent of sport type. Therefore, these data question the validity of Morganroth's claim that athletic remodeling varies according to relative levels of static and dynamic exercise, at least among female athletes.^3,4

SCD risk is lower in females than males and interestingly, remains low even when accounting for variance in phenotypic expression of familial cardiomyopathies. In a study of 548,092 marathon finishers over 18 years, during which there was a substantial increase in female participants from 10% to 40%, there were 14 sudden cardiac arrests with only one in a female.⁵

Age-Related Cardiovascular Considerations

1. Pre-Menopause
   
   In addition to biological differences in physiologic and pathologic cardiac remodeling, age-related cardiovascular considerations are present in female athletes. Relative energy deficiency in sport (RED-S), prevalent in females, is a consequence of insufficient caloric consumption and/or excessive energy expenditure, leading to metabolic derangements, osteoporosis, alterations in menstruation, and cardiovascular compromise.⁶ Hypothalamic amenorrhea and oligomenorrhea occur in a state of negative energy balance, which halts the pulsatile secretion of gonadotropin-releasing hormone. Consequently, pulsatile release of luteinizing hormone and follicle-stimulating hormone declines, leading to a deficiency in endogenous estrogen. Estrogen deficiency may contribute to endothelial dysfunction and dyslipidemia and consequently increases cardiovascular risk.⁷ Increased production of inflammatory mediators (interleukin-1, interleukin-6 [IL-6], tumor necrosis factor-α[TNF-α]) can lead to increased synthesis of acute-phase reactants from the liver, including C-reactive protein, fibrinogen, and serum amyloid, all associated with increased risk of cardiovascular disease (CVD).⁷
   
   It is important for sports cardiologists to have heightened suspicion for RED-S and screen for amenorrhea, particularly since treatment may lead to reversibility in cardiac risk. Several studies have shown that return of menstruation over a 2-year period is associated with sustained improvement in vascular function.⁸ Oral contraception and folate supplementation have both been shown to improve endothelial function in athletes.^9,10 In addition, inflammation may also be reversible after athletes improve energy balance. One study showed that serum IL-6 concentration markedly rose with starvation but normalized after weight gain.¹¹ Another showed that in individuals with anorexia, the production of IL-6 and TNF-α decreased with refeeding and weight gain.¹²
2. Pregnancy and Sports Participation
   
   Many elite female athletes are interested in pregnancy. Pregnant and postpartum elite athletes successfully compete in national and international events. One study comparing 34 postpartum Norwegian elite athletes (average age 33.1 years, achieving 292 medals in international competitions, 36 Olympic medals) to 34 active controls (average age 31.5 years) showed no differences in fertility issues, miscarriage rates, low birth weight, or preterm birth.¹³ There were no significant differences in complication rates during pregnancy and delivery. More athletes returned to exercise/sport 0-6 weeks postpartum. Of note, elite athletes had greater rates of body dissatisfaction and drive for thinness as well as stress fractures. Fracture rate may have been elevated due to sudden increase in training load postpartum, inadequate strength training during pregnancy and immediately postpartum, prior history of RED-S, lactation, and/or inadequate replacement of calcium and vitamin D. Importantly, athletes were not satisfied with the advice they received regarding strength training and nutrition during exercise. While the International Olympic Committee (IOC) has summarized current evidence within this field, there are no exercise guidelines for pregnant elite athletes to date, thus emphasizing the importance of additional investigation and provider collaboration when guiding female athletes through an active, healthy pregnancy.^13,14
3. Peri- and Post-Menopause
   
   Estrogen deficiency in younger athletes mirrors that seen in menopausal athletes and contributes to a variety of symptoms that can mimic those commonly seen with cardiac abnormalities. However, many female athletes may not undergo routine cardiac risk stratification, particularly when progressing through menopause and/or shortly thereafter, due to a common assumption that their high level of activity is entirely cardioprotective. Thus, sports cardiologists should include routine screening tests when performing a comprehensive cardiovascular evaluation of female athletes. Furthermore, the risks and benefits of hormone replacement therapy – as well as timing to initiation within 10 years of menopause transition to minimize risks of CVD, venous thromboembolism and stroke – should be discussed.¹⁵

Key Takeaways

As the number of competitive female athletes continues to grow, more data are required to better understand sex-specific differences and inform guidelines related to the management of cardiac issues among female athletes. These are imperative to ensure optimal athletic performance with minimal cardiovascular risk.

References

1. Andersen JJ. The State of Running 2019 (RunRepeat website). 2021. Available at: https://runrepeat.com/state-of-running. Accessed 07/01/2021.
2. Pelliccia A, Maron BJ, Culasso F, Spataro A, Caselli G. Athlete's heart in women: echocardiographic characterization of highly trained elite female athletes. JAMA 1996;276:211-15.
3. Morganroth J, Maron BJ, Henry WL, Epstein SE. Comparative left ventricular dimensions in trained athletes. Ann Intern Med 1975;82:521-24.
4. Kooreman Z, Giraldeau G, Finocchiaro G, et al. Athletic remodeling in female college athletes: the "Morganroth Hypothesis" revisited. Clin J Sport Med 2019;29:224-31.
5. Roberts WO, Roberts DM, Lunos S. Marathon related cardiac arrest risk differences in men and women. Br J Sports Med 2013;47:168-71.
6. Statuta SM, Asif IM, Drezner JA. Relative energy deficiency in sport (RED-S). Br J Sports Med 2017;51:1570-71.
7. Grosman-Rimon L, Wright E, Freedman D, et al. Can improvement in hormonal and energy balance reverse cardiovascular risk factors in athletes with amenorrhea? Am J Physiol Heart Circ Physiol 2019;317:H487-H495.
8. Hoch AZ, Jurva JW, Staton MA, et al. Athletic amenorrhea and endothelial dysfunction. WMJ 2007;106:301-06.
9. Rickenlund A, Eriksson MJ, Schenck-Gustafsson K, Hirschberg AL. Oral contraceptives improve endothelial function in amenorrheic athletes. J Clin Endocrinol Metab 2005;90:3162-67.
10. Hoch AZ, Papanek P, Szabo A, Widlansky ME, Gutterman DD. Folic acid supplementation improves vascular function in professional dancers with endothelial dysfunction. PM R 2011;3:1005-12.
11. Pomeroy C, Eckert E, Hu S, et al. Role of interleukin-6 and transforming growth factor-beta in anorexia nervosa. Biol Psychiatry 1994;36:836-39.
12. Nova E, Gómez-Martínez S, Morandé G, Marcos A. Cytokine production by blood mononuclear cells from in-patients with anorexia nervosa. Br J Nutr 2002;88:183-88.
13. Sundgot-Borgen J, Sundgot-Borgen C, Myklebust G, Sølvberg N, Torstveit MK. Elite athletes get pregnant, have healthy babies and return to sport early postpartum. BMJ Open Sport Exerc Med 2019;5:e000652.
14. Bø K, Artal R, Barakat R, et al. Exercise and pregnancy in recreational and elite athletes: 2016/17 evidence summary from the IOC Expert Group Meeting, Lausanne. Part 3-exercise in the postpartum period. Br J Sports Med 2017;51:1516-25.
15. Oliver-Williams C, Glisic M, Shahzad S, 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.

Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Congenital Heart Disease and Pediatric Cardiology, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Sports and Exercise Cardiology, Vascular Medicine, SCD/Ventricular Arrhythmias, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Nonstatins, Heart Failure and Cardiac Biomarkers, Diet, Exercise, Sports and Exercise and Congenital Heart Disease and Pediatric Cardiology

Keywords: Pregnancy, Ventricular Remodeling, Interleukin-6, C-Reactive Protein, Cardiovascular Diseases, Resistance Training, Oligomenorrhea, Menstruation, Amenorrhea, Abortion, Spontaneous, Follicle Stimulating Hormone, Fibrinogen, Premenopause, Postmenopause, Vitamin D, Fractures, Stress, Acute-Phase Proteins, Body Surface Area, Anorexia, Gonadotropin-Releasing Hormone, Interleukin-1, Premature Birth, Venous Thromboembolism, Body Dissatisfaction, Marathon Running, Risk Factors, Athletes, Death, Sudden, Cardiac, Athletic Performance, Hormone Replacement Therapy, Luteinizing Hormone, Osteoporosis, Energy Metabolism, Cardiomyopathies, Stroke, Infant, Low Birth Weight, Contraception, Postpartum Period, Dyslipidemias, Weight Gain, Inflammation, Tumor Necrosis Factors, Bodily Secretions, Inflammation Mediators, Heart Disease Risk Factors, Risk Assessment, Dietary Supplements, Estrogens, Fertility, Folic Acid, Female

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