Familial hypercholesterolemia (FH) is an autosomal dominant disorder arising from genetic variants that impair the clearance of low-density (LDL) lipoproteins [1, 2]. FH is characterized by markedly elevated LDL cholesterol (LDL-C) from birth and is associated with a 10-fold increased risk of coronary artery disease (CAD) in untreated individuals [3]. The more common form, heterozygous FH (HeFH), results from a single pathogenic allele and affects approximately 1 in 300 individuals worldwide [1, 2]. Homozygous FH (HoFH), the more severe form caused by biallelic pathogenic variants, occurs in 1 in 160,000 to 1 in 300,000 births [4]. Up to 90% of FH cases result from LDL receptor (LDLR) variants, although apolipoprotein B-100 (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9), and rarely, recessive LDLR adaptor protein 1 (LDLRAP1) variants, also disrupt LDLR function, leading to elevated LDL-C [4, 5].

Despite the availability of effective lipid-lowering therapies (LLT), FH remains underdiagnosed and undertreated globally [1, 2]. Evidence from the largest registry of FH globally, the FH Studies Collaboration (FHSC), demonstrated that most patients worldwide are not identified until their fifth decade of life, with less than 2% of adult cases diagnosed during childhood [1]. This delay is clinically consequential, as approximately one in six adults already has established atherosclerotic cardiovascular disease (ASCVD) at the time of diagnosis [1]. In women, the burden of FH is further influenced by hormonal and reproductive factors that complicate disease recognition and long-term management [6, 7]. Compared to men, women are diagnosed 3–7 years later, treated less intensively, and are 37% less likely to achieve guideline-recommended lipid targets [1, 6]. Moreover, interruption of LLT during preconception, pregnancy, and breastfeeding leads to an estimated loss of 2.3 median years of statin therapy per woman [7]. Consequently, women may accumulate substantial untreated LDL-C exposure during early and middle adulthood [7,8,9].

ASCVD risk may accelerate further after menopause, a period characterized by rising LDL-C levels and worsening cardiovascular risk profiles [10, 11], compounding the overall ASCVD burden in women with FH [12, 13]. Despite growing recognition of these concerns, important gaps remain in optimizing FH care across the female lifespan [14]. This review summarizes current evidence on the clinical course of FH in women, emphasizing diagnostic disparities, reproductive and menopausal transitions, and opportunities for targeted strategies to improve long-term cardiovascular outcomes.

LDL-C Burden and Diagnostic Considerations Across the Lifespan of Women with FH

The physiological disadvantage for women with familial hypercholesterolemia (FH) begins long before clinical recognition. While FH is present from birth, untreated girls with FH have higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) than their male counterparts from birth up to 19 years [8, 15]. This observation may appear counterintuitive, given that premenopausal women in the general population tend to have a more favorable lipid profile than men, partly because endogenous estrogen increases hepatic LDLR expression, thereby enhancing LDL-C clearance [16]. In FH, however, this effect appears insufficient to offset the magnitude of genetically impaired LDL-C metabolism. Indeed, Johansen et al., using repeated LDL-C measurements over a 12-year follow-up of 438 individuals with FH before age 19, demonstrated that the sex difference in the combined pre- and post-treatment LDL-C burden widened over time [9]. By age 19, women with FH were more than twice as likely as men to have exceeded the LDL-C burden threshold of 125 millimolar-years, a level associated with high ASCVD risk [9]. Strikingly, all women had reached this threshold by age 30, whereas it took until the age of 40 for all men to reach the same threshold [9]. Age and sex-related changes in LDL-C and estimated LDL-C burden from this study are shown in Fig. 1. Similarly, cross-sectional data from the FHSC registry [17] for 11,848 children and adolescents with FH suggested that untreated LDL-C concentrations are similar in boys and girls from age 4–10 years but diverge around puberty (from age 11 years onwards), becoming approximately 0.7 mmol/L higher in girls by age 17 years (Fig. 2). In line with our observations in the FHSC [17], a recent study from Slovenia’s Universal FH Screening Program showed no significant differences in LDL-C levels between prepubertal girls and boys with FH aged approximately 5–6 years [18].

Fig. 1The alternative text for this image may have been generated using AI.

Age and sex-related changes in LDL-C and estimated LDL-C burden. Obtained from Johansen et al. 2023 [9], under the CC BY-NC-ND license. The figure shows measurements of LDL-C (Panel A) and estimated LDL-C burden (Panel B). Individual data points in grey are connected with lines to highlight the subject-specific trends. The figure also shows the sex-specific means and 95% CIs within age strata (< 10 years [n = 275], 10–19 years [n = 1528], 20–29 years [n = 843], and ≥ 30 years [n = 258])

Fig. 2The alternative text for this image may have been generated using AI.

Smoothed percentile curves for LDL-C concentration at entry into the registry among children and adolescents not taking LLT. Blue lines: Untreated male individuals. Red lines: Untreated female individuals. Data are cross-sectional, stratified by age and sex. Adapted from Dharmayat et al. 2024 [17], with permission.

After accumulating a substantial LDL-C burden from early in life, women with FH then face additional challenges during their reproductive years. Pregnancy is characterized by marked physiological hyperlipidemia, with a 30–50% increase in LDL-C [19]. In women with FH, who begin pregnancy from a much higher LDL-C baseline, absolute LDL-C concentrations in late gestation may reach levels of 8-9 mmol/L or higher [20]. This period is especially vulnerable because the physiological rise in circulating lipids often coincides with the interruption of therapy, leaving women exposed to prolonged periods of uncontrolled LDL-C concentrations [7, 20]. Furthermore, the physiological stress of pregnancy may contribute to raised blood pressure and dysglycaemia, which may be harbingers of future risk of hypertension and diabetes, and thus may additionally contribute towards atherosclerosis [21, 22].

Beyond the reproductive years, menopause is another critical period in the life course of women with FH [11]. In a Canadian cohort, LDL-C levels increased by 12% overall during menopausal transition, with a greater increase among women with an FH-causing variant (1.23 mmol/L) than in those without (0.39 mmol/L) [11]. Similarly, among adult participants from the FHSC registry, women aged 50 or 55 years or older had LDL-C levels that were, on average, about 0.6 mmol/L higher than those of men (p value < 0.0001) [1]. These findings suggest that menopause may further exacerbate cumulative LDL-C exposure and accelerate ASCVD risk in women with FH [10, 11]. Taken together, these observations highlight how hormonal transitions across the female life course shape lipid biology, and longitudinal data capturing LDL-C trajectories and associated ASCVD outcomes in women with FH remain a key area for future research.

Despite the early and progressive accumulation of LDL-C burden, women with FH are consistently diagnosed later than men [1, 23,24,25,26]. This diagnostic delay is about 3–7 years in women [1, 23,24,25], although one Vietnamese study reported a delay of up to 11 years among female index cases [26]. This pattern is particularly concerning, given that diagnosis of FH already tends to occur late in life for both sexes, frequently only after ASCVD events have occurred [1, 24]. Current diagnostic criteria, such as the Dutch Lipid Clinic Network (DLCN), the Simon Broome Register, and the Make Early Diagnosis to Prevent Early Deaths (MEDPED), do not incorporate sex-or age-specific adjustments, and their performance remains an important area for research [27]. Where genetic testing is available, it provides a definitive diagnosis independent of clinical criteria; however, access remains highly variable globally, with cost and availability representing significant barriers in many healthcare systems [28]. Cascade screening of first-degree relatives is the most cost-effective strategy for identifying new cases [29]. However, the delayed diagnosis in women compared to men inherently delays the screening of their children and siblings. Overall, given the consequences of delayed diagnosis, including greater cumulative LDL-C burden, delayed cascade screening, and hence increased ASCVD risk for both the woman with FH and her undiagnosed relatives, heightened awareness among healthcare professionals is needed to ensure women with FH are identified and treated as early as possible to avoid the cascade of harm resulting from “the law of unintended consequences”.

Treatment Strategies Across the Life Span of Women with FH

The goal of FH management is to reduce the future risk of ASCVD, primarily through early diagnosis, effective LDL-C lowering, and management of traditional ASCVD risk factors. For high-risk patients, such as those with FH, current guidelines set by the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) recommend LDL-C targets of < 1.4 mmol/L for adults with ASCVD or FH and one additional risk factor and < 1.8 mmol/L for those without ASCVD, alongside a minimum 50% LDL-C reduction from untreated levels [30]. Although trial data demonstrate that men and women with FH appear to derive similar responses to lipid-lowering therapy (LLT) [6], a previous analysis from our group of 42,167 patients with FH across the 6 WHO regions showed that women were 37% less likely to achieve guideline-recommended LDL-C goals [1]. This likely reflects differences in prescribing patterns for LLT rather than therapeutic responses between men and women.

Statins remain the cornerstone of treatment for both children and adults with FH and provide LDL-C reductions of 30–50% at high doses using more potent regimens [31, 32]. In children, European guidelines recommend starting statin therapy around 8–9 years of age, with ezetimibe added from age 10 if targets are not met [33]. In adults as well as children, ezetimibe is the second-line agent of choice, providing an additional 24% reduction in LDL-C [34]. For patients requiring greater LDL-C lowering, PCSK9 inhibitors reduce LDL-C by 57–67% in HeFH [35, 36], although responses in HoFH may vary depending on residual LDLR activity [37, 38]. Treatment options for HoFH have been expanded by evinacumab, which lowers LDL-C by 47% independent of the LDLR pathway [39, 40]. Bempedoic acid may be a useful option in cases of statin intolerance [41], especially for women, who are more likely than men to report statin-muscle-related symptoms (31% vs. 26%, p < 0.01) [42].

Despite advances in LLT availability for FH (Table 1), a meta-analysis of 36 observational studies (129,441 subjects) indeed showed that women with FH are 26% less likely than men to be receiving any LLT, and 30–34% less likely to receive high-intensity statins, ezetimibe, PCSK9 inhibitors, or combination therapy. Additionally, women were 22% less likely than men to attain a 50% LDL-C reduction, and 46% less likely to reach LDL-C values < 1.8 mmol/L [6]. Management for women with FH becomes even more challenging during preconception, pregnancy, and breastfeeding, when most LLTs are contraindicated or not recommended [47]. Oral LLTs such as statins, ezetimibe, and bempedoic acid are generally discontinued approximately one month before actively trying to conceive, while PCSK9 monoclonal antibodies require discontinuation at least three months beforehand, and Inclisiran potentially 9–12 months in advance [45]. Statins have been classified by the United States Food and Drug Administration (FDA) as contraindicated (X) during pregnancy for decades. In 2021, the FDA requested the removal of the longstanding warning, acknowledging that the benefits may outweigh the risks in a small group of very high-risk patients, but still advised that most pregnant patients should stop statins [44, 60]. By contrast, the European Medicines Agency has not made a comparable regulatory change and continues to list statins as contraindicated during pregnancy [60]. As such, the only available therapy options for women with FH are lipoprotein apheresis or bile acid sequestrants such as cholestyramine or colesevelam [47]. Lipoprotein apheresis is highly effective with 60–70% LDL-C reduction; however, it is expensive, requires multiple invasive sessions, and is only available at specialized centers, creating a significant barrier to care for women [47]. Bile acid sequestrants have the advantage of oral intake but have modest LDL-C-lowering efficacy (15–20%) and are often poorly tolerated due to gastrointestinal side effects [47, 61].

Table 1 Available and emerging lipid-lowering therapies for patients with FH and their considerations in pregnancy

The consequences of the time lost in therapy are substantial. A study of 102 women from Norway and the Netherlands found that although the median pregnancy-related off statin period was 2.3 years, some women experienced off-treatment periods of up to 14 years, corresponding to a loss of 20% of lifetime statin treatment years [7]. When untreated years in childhood and prior to diagnosis are also factored in, women with FH spent a median of 66.3% (41.9–100%) of their lifetime without LLT [62]. Notably, 22% of women with FH who breastfed reported stopping earlier than desired in order to restart statin therapy, and 86% of them reported needing more information about pregnancy and breastfeeding in the context of FH [7]. A recent review addressing these gaps presents an updated meta-analysis confirming that statin exposure in pregnancy is not associated with increased congenital malformations (OR 1.03, 95% CI 0.89–1.18). As such, the authors recommend individualized consideration of statin continuation after the first trimester in high-risk women, such as those with established ASCVD or HoFH, following shared decision making [45]. The same review highlights that women with FH face an increased risk of pre-eclampsia during pregnancy, which itself is associated with increased long-term CVD risk, further underscoring the need for enhanced monitoring during pregnancy. Regarding breastfeeding, reintroducing LLT at 6–12 months postpartum represents a pragmatic approach to minimizing cumulative LDL-C exposure without unduly compromising breastfeeding benefits [45]. Even so, high-quality prospective data on LLT therapy during pregnancy and breastfeeding remain limited and represent a pressing research need.

Although elevated LDL-C is the key driver of ASCVD in FH, this risk is further amplified by traditional risk factors, including obesity, type 2 diabetes, hypertension, and smoking. In a recent US multicenter study of 782 FH patients, hypertension was a stronger predictor of premature ASCVD than smoking or diabetes in both sexes, with slightly higher odds in women (4.25) than men (3.83) [63]. Our FHSC analysis of 29,265 adults with HeFH demonstrated that globally, overweight was more common in men (42%) than in women (30%), whereas obesity was slightly more prevalent in women (17.2% vs. 15.4%). Importantly, the association between obesity and CAD was similar in men and women, underscoring the need for equally aggressive weight management in both sexes [64]. Obesity was also associated with fivefold higher odds of type 2 diabetes in the pooled cohort, but women remained 19% less likely than men to have diabetes, after adjusting for age, BMI, and LLT [65], as reported in a smaller cohort [66]. Overall, these findings highlight that sex may need to be considered in the personalized management of traditional cardiometabolic risk factors in FH to reduce ASCVD risk.