Peripheral artery disease (PAD) is a progressive and debilitating vascular condition characterized by the narrowing and blockage of lower extremity blood vessels [1, 2]. The spectrum of PAD is broad, with patients being asymptomatic to presenting with intractable rest pain or gangrene, but all are at increased risk of morbidity and mortality [3, 4]. Those with the latter presentation, known as chronic limb-threatening ischemia (CLTI), are at the highest risk, with one year mortality estimated to be 25% [5]. Global estimates indicate that more than 230 million individuals are currently affected with PAD [6, 7]. Prevalence of the disease is predicted to increase by 50% by 2045, primarily due to an ageing population, increase in obesity and diabetes mellitus, and a significant proportion of the population continuing to smoke [7]. Despite its substantial clinical burden, PAD remains relatively under-diagnosed and poorly treated, especially in female patients [2, 8].

While PAD has historically been considered a male-dominant disease, emerging evidence suggests a more equal, if not greater, distribution of disease prevalence in females compared to males [3, 8, 9]. Female PAD patients appear to experience unique pathophysiology, clinical presentations, and treatment outcomes, indicating a need for more personalized treatment approaches. Females with PAD are more likely to be asymptomatic or report atypical symptoms, which can result in delayed diagnosis [3]. Studies also show that female patients face severe functional impairment, poorer quality of life, and worse post-procedural complications following surgical intervention compared to males [4, 6, 9, 10]

Despite these disparities, current research on PAD remains limited in its focus on sex-based differences, with clinical guidelines still reflecting data obtained from male-majority cohorts [8, 9, 11]. This review aims to explore the sex-based differences in PAD, comparing variations in epidemiology, pathophysiology, risk factors, clinical presentation, treatment approaches, and patient outcomes to better understand disease progression in male and female patients and inform treatment decisions (Fig. 1).

Overview of sex-based differences in PAD patients. Created in BioRender. Kansul [28] https://BioRender.com/2jlf5ou

PAD, which affects 7–12 million adults in the USA, has historically been associated as a disease that predominantly affects the male population [3]. Describing the true epidemiology of PAD is challenging given the different diagnostic approaches that can be used; however, it is likely that the disease prevalence in female patients is underreported [12]. The easiest screening test for PAD is an ankle-brachial index (ABI) given its non-invasive nature and when used as a diagnostic tool, the prevalence of PAD is similar in both males and females [12,13,14]. However, ABI is unreliable in many diabetic patients, who represent the most rapidly growing population with PAD, as they often have incompressible vessels that falsely elevate ABI readings, potentially leading to underdiagnosis [15]. Studies have suggested that there are both ethnic and sex differences in ABIs, and there are suggestions that sex-specific ABI guidelines could be beneficial in the diagnostics of PAD in female patients [16, 17].

Further challenges in estimates occur due to the atypical presentation of females with PAD. Symptomatology of cardiovascular diseases have been based on the classical presentation of males, which includes chest pain, midback pain, nausea, dyspnea, and fatigue [18]. However, it is known that female patients often do not present in the same way which can lead to delayed diagnosis [19]. In PAD, many females are asymptomatic, have atypical exercise induced symptoms or have overlapping symptoms due to musculoskeletal diseases which can shroud the true diagnosis of PAD [20]. This ultimately results in the underdiagnosis of PAD, which is significant, as even in patients who are completely asymptomatic, there remains a significant risk of cardiovascular morbidity and mortality.

At the most severe end of the spectrum of PAD is CLTI, in which patients present with intractable rest pain, non-healing ulceration in the presence of PAD or gangrene which again is traditionally expected to affect significantly more males than females [21]. However, an analysis of patients presenting with CLTI to hospitals suggested that the gap is much less, with a study representing almost 200,000 admissions showing that 43% of patients were female [22]. Despite this, however, female patients are frequently under-represented in trials. In the BASIL-2, BASIL-3 and BEST CLI trials which are the largest CLTI randomized clinical treatment trials in the last decade, female inclusion rates were between 19–35% [21, 23, 24]. The implications of this underrepresentation could be significant, as sex-based outcomes following different treatment strategies are well evidenced in the literature and are discussed further in this article.

The pathophysiology of PAD is comprised of various hormonal and biological factors, including endothelial dysfunction, oxidative stress, thrombosis, platelet activation, sex hormone levels, and vascular remodeling. Biological sex plays an important role in determining the extent and presentation of these factors in PAD patients.

Research suggests that male sex hormones, particularly testosterone, have a protective effect against PAD in males, a benefit not widely observed in female patients [2]. A cross-sectional study of 2703 older male subjects revealed that signs of intermittent claudication, a common symptom of PAD in males, was linked to lower testosterone or dihydrotestosterone levels [25]. An inverse relationship between serum androgen levels and PAD symptoms in older males was also demonstrated, with male PAD patients demonstrating lower testosterone and sex hormone binding globulin concentrations [2]. Testosterone deficiency has also been linked to increased oxidative stress, endothelial dysfunction, and inflammation, all of which contribute to increased atherosclerosis [26]. Literature suggests that testosterone may play an independent role in atherosclerosis development and PAD pathogenesis for elderly female patients as well [26]. The findings of existing studies imply that reduced androgen exposure may cause the onset and development of symptomatic PAD [2].

Estrogen, on the other hand, has been shown to protect against PAD in female patients through its regulation of vascular functions and proangiogenic qualities [2, 3, 26]. While clinical and epidemiological studies do not demonstrate strong associations between serum estrogen levels and PAD development, animal studies reveal that estrogen signaling may promote neovascularization and assist in recovery from ischemic PAD. The proangiogenic effects of estrogen are also seen in male animal models, where treatment with estrogen showed improved blood flow [2, 3]. Further research is needed to identify the mechanisms through which estrogens and androgens protect individuals from PAD.

Sex-based differences in endothelial dysfunction play a significant role in PAD pathophysiology as well. Endothelial dysfunction in PAD is linked to oxidative stress, arterial stenosis, and inflammatory activation in skeletal muscle cells [27]. Female PAD patients display greater inflammation, reduced angiogenesis, and altered vasodilation responses compared to males [6]. A study evaluating sex-based differences in vessel wall morphology in 34 end-stage patients (16 females) demonstrated that, while plaque morphology appears to converge between sexes, there is an increased prevalence of luminal thrombus in post-menopausal female patients [28]. Females also demonstrate increased platelet reactivity and greater platelet aggregation, which can affect the development and progression of PAD [28, 29]. Majumdar et al. has also shown differences in platelet function between male and female patients with PAD. Despite having lower rates of significant cardiovascular diseases and risk factors, females were found to have significantly higher platelets reactivity and aggregation and lower levels of platelet inhibition [30]. These differences highlight the sex-based disparities in PAD at the biological and physiological levels and demonstrate a need for more tailored treatment approaches.

PAD is typically evaluated by the presence of traditional cardiovascular risk factors, including smoking, diabetes, hypertension, and chronic kidney disease [4, 31]. While these risks are seen in male and female patients alike, sex-based differences are observed in the prevalence and impact of certain factors on disease presentation and patient quality of life.

Smoking is a significant yet preventable risk factor that contributes to PAD. Although the burden of smoking has decreased in the past few decades due to public awareness efforts, approximately one quarter of all PAD-related deaths remain linked to tobacco use [32, 33]. Studies demonstrate that females with a history of smoking are at greater risk of PAD compared to males, with the risk of cardiovascular disease being 25% greater in female smokers than in male smokers when relatively compared with non-smokers of the same sex [33, 34]. Diabetes is the second most significant risk factor for PAD following smoking, with female patients displaying a greater sex-specific risk for atherosclerotic disease compared to males [35]. Meta-analyses suggest that this increased risk could be attributed to biological variances between males and females, such as in adipose tissue distribution, hormone influences, or genetic factors [36].

Hypertension, a leading risk factor for PAD, is typically considered more predominant in males [5]. However, emerging studies showcase varying incidences of hypertension between sexes, suggesting that blood pressure is a sexually dimorphic trait that varies in females and males throughout their lifetimes [37, 38]. Females also demonstrate a significant increase in blood pressure during menopause, indicating that age and hormonal fluctuations may contribute to their risks of PAD [31]. Chronic kidney disease (CKD) is another high-risk factor for PAD. Newer studies of sex-based disparities in vascular disease development in CKD cohorts indicate that females with CKD have a higher PAD risk compared with males at younger ages, with the risks equalizing between sexes at ages > 70 years [39]. As CKD involves other cardiovascular risk factors such as hypertension and diabetes, it is possible that the overlap of risk factors is what increases PAD risk in younger female patients.

Hypercholesterolemia is also a significant risk factor for PAD [40]. Over 40% of female patients had a total cholesterol of > 200 mg/dL in the NHANES data and the proportion of females with high total cholesterol levels is higher in females > 50 years old compared to males in the same age range [41]. Small increases in low density lipoprotein levels in females are also significantly associated with heightened risks of morbidity and mortality, highlighting the need for tight control of cholesterol [42]. Female patients are also at increased risk of autoimmune diseases and anxiety and depression, both of which are associated with an increased risk of PAD [43, 44]. Overall, sex-based differences in PAD risk factors indicate that females with multiple risk factors are at higher risk of developing PAD [4].

The clinical presentation of PAD is typically defined by symptoms such as intermittent claudication, rest pain, and non-healing wounds/gangrene. However, the majority of PAD patients are asymptomatic or present with atypical symptoms [9, 45]. This is especially pronounced in female patients, leading to delayed diagnosis and treatment for PAD compared to male patients. A systematic review of multiple studies involving a total of 1,929,966 PAD patients confirmed that females were less likely than males to present with intermittent claudication [46]. Instead, female patients with PAD are more prone to develop critical limb ischemia, with some studies suggesting a 2-fold prevalence compared to male PAD patients [7, 47].

Existing risk factors and comorbidities, such as chronic kidney disease and diabetes, may also uniquely impact the presentation of PAD patients based on their sex. A multi-center study of 3,174 participants with CKD revealed that females demonstrated a 1.53-fold higher risk of PAD compared to males, with significant variation by age [39]. Younger females showed an abnormally increased risk of developing PAD, which normalized after the age of 70, while older males had significantly higher PAD risks compared to younger males[39]. While this data conflicts with multiple existing studies reporting PAD as more prevalent in elderly females, this study suggests that comorbidities, such as chronic kidney disease, can affect the clinical presentation of PAD disproportionately by sex [8, 39].

It also appears that PAD when symptomatic affects females more significantly. Studies show that female PAD patients have less muscle strength, are slower when walking, and can only walk shorter distances than male patients, suggesting that differing supportive treatment needs for supervised exercise therapy are required between the sexes [20, 48]. Earlier and more specific screening strategies for PAD in female patients with significant comorbidities are warranted given the worse outcomes, early onset, and rapid functional decline [7].

Treatment methods for PAD primarily aim to limit progression of the disease while improving quality of life for patients. These treatments include exercise therapy, pharmaceutical therapy, and surgical or endovascular interventions. While the common goal of these approaches is to minimize risk factors and lower the incidence of adverse cardiovascular and limb complications, significant sex-based disparities in applied PAD treatments and outcomes remain.

Exercise is considered a first line of therapy for PAD, as regular and supervised exercise therapy (SET) can improve muscle performance, reduce pain, and counter intermittent claudication in PAD patients [27]. Additionally, exercise induces anti-oxidative effects, modulating antioxidant enzymes and regulating endothelial genes associated with improving vascular health. Despite the proven benefits of SET, utilization of this treatment method remains low for PAD patients – even so, males are more likely to be referred for such therapy compared to female patients [49]. A study evaluating SET in individuals with intermittent claudication revealed that both male and female patients saw improvements in absolute claudication distance and functional walking distance after therapy [50]. However, female patients demonstrated a significantly lower increase in absolute claudication distance during the first three months and shorter absolute walking distances after 1 year compared to male patients in the same cohort, yet adherence to SET programs are similar between males and females [50, 51]. While SET remains independently effective for both sexes, female patients may require a more intensive or tailored exercise protocol to achieve recovery rates similar to male patients.

Pharmaceutical therapy is paramount in the initial treatment for PAD patients and includes prescription of statins and antiplatelets. Risk factor management with antihypertensives, antihyperglycemics, and supportive measures in smoking cessation are also crucial. While these guideline-directed medical therapies are shown to reduce risk in PAD patients, prior evaluations have shown differences in treatment outcomes on the basis of sex [52]. An analysis of 9810 PAD patients at the University of Colorado revealed that females were less likely than males to receive guideline-directed medical therapies, regardless of concurrent diseases, symptomatic PAD, or prior lower extremity vascularization treatment [52]. The benefits of statins are well evidenced in both males and females for reducing cardiovascular disease, yet female patients are less likely to be prescribed statins, are more likely to discontinue them, and are less likely to be on a high intensity dosage [53]. Overall, adherence to medication is also notably lower in female patients, which further accelerates PAD progression and functional decline [11, 54]. Cilostazol, a key antiplatelet treatment used to improve intermittent claudication, has shown benefits for both males and females with PAD, contributing to improved initial and absolute walking distances [55,56,57]. A pooled analysis of nine randomized control trials assessing the use of cilostazol for intermittent claudication reported no key differences in treatment outcomes between male and female patients. Another study assessing the effects of rivaroxaban, an anticoagulant, in PAD patients showed that both male and female patients benefited from the treatment, with reduced risk of cardiovascular and limb events. However, females displayed a higher discontinuation rate, impacting the observed benefits [54]. The low usage and adherence of guideline-directed medical therapy in females with PAD could potentially contribute to the worse clinical outcomes they face, such as high risk of cardiovascular events, limb amputations, and unplanned readmissions despite similar disease severity to males [