Understanding Dyslipidemia in Women across their Lifespan: Sex Differences in Lipoprotein Metabolism and Hormonal Influence

Changes in lipids during the menstrual cycle

Lipid levels undergo changes throughout the menstrual cycle. In the follicular phase, TC and LDL levels decrease due to relatively low estrogen levels. During the luteal phase, there is a reduction in TC and LDL levels due to rising estrogen and progesterone. HDL levels reach a peak during ovulation, corresponding to peak estrogen levels. TG levels do not vary significantly with the phases of menstrual cycle. It should be noted that a small variation in lipids of <10% can occur depending on the timing of the test relative to menstruation.

The use of estrogen oral OC pills has been linked to higher levels of HDL and TG and lower LDL. Women with high baseline levels of TG can have significant elevations of TG when taking OC.^[13]

Sex differences in TG

The free fatty acids delivered to the liver from adipose tissue are converted to TG-rich VLDL. Visceral obesity, more common in men is associated with greater hepatic VLDL secretion.^[19] In obese women, increased lipoprotein lipase activity leads to TG clearance, so women have lower TG levels than men despite obesity. These effects are predominantly mediated through ERα. The role of estrogen in controlling hepatic VLDL is illustrated by tamoxifen (used in hormone-sensitive breast cancer), whose anti-estrogenic action causes excess hepatic VLDL production and metabolic dysfunction-associated steatotic liver dysfunction (MASLD).^[20] HRT in postmenopausal women, when given as oral estrogen, results to a raise in VLDL and TG levels due to increased production, whereas transdermal estrogen has a smaller impact on TG as compared to oral estrogens.^[21] TG levels do not vary significantly with the menstrual cycle.^[22]

Sex differences in LDL metabolism

LDL cholesterol is the major atherogenic lipoprotein. Estrogen decreases LDL levels by downregulating PCSK9 expression.^[23,24] These effects are mediated through ERα and GPER. Estrogens also affect LDL particle size and composition. PCSK9 levels are lower in premenopausal women than in men, resulting in fewer small, dense LDL levels, which contribute to CV protection in premenopausal women.

Sex differences in HDL metabolism

HDL cholesterol is the key mediator of reverse cholesterol transport, and higher levels are cardioprotective. Premenopausal women have higher HDL levels than men.^[25] Estrogens increase cholesterol efflux from vascular smooth muscle and peripheral cells by upregulating the ATP-Binding Cassette Transporter A1 (ABCA1) increasing HDL-mediated cholesterol clearance. Estrogens also increase ApoA1 synthesis (the major protein of HDL particles) and promote a shift toward the larger buoyant HDL2 subclass.^[26] In postmenopausal state, hypoestrogenism results in reduced HDL levels and a shift to smaller HDL3 particles, which are less effective in mediating cholesterol efflux and therefore offer less CV protection.

Role of genetics

Genetic differences in sex chromosomes and sex hormones also impact lipoprotein metabolism. The expression of genes related to CV risk differs between males (XY) and females (XX). The higher expression of genes (such as Apoprotein A5 [APO A5], LDL Receptor [LDLR]) in females with two X chromosomes is associated with better lipid parameters and reduced CV risk.^[27] Women with only one X chromosome (e.g. Turner syndrome) have higher LDL and TGL, increased small dense LDL and smaller HDL particles than women with two X chromosomes.^[28]

Pathophysiology of dyslipidemia in PCOS

The key determinants of dyslipidemia in PCOS are probably IR and hyperandrogenism.^[39,40] IR leads to increased hepatic synthesis of VLDL, impaired clearance of TG -rich lipoproteins, and increased free fatty acid flux, resulting in elevated TG and reduced HDL.^[41,42] Hyperandrogenism affects lipid metabolism by increasing hepatic lipase activity and an increased the production of small dense LDL particles and genes causing catabolism of HDL is upregulated.^[43] A state of chronic low-grade inflammation occurs in PCOS which alters lipoprotein metabolism, while genetic factors contribute to elevated LDL and apolipoprotein levels.^[44,45] A combination of multiple mechanisms produce a characteristic atherogenic lipid profile.

Lipid profile alterations in PCOS

The most prominent lipid abnormalities in PCOS are elevated TG and reduced HDL levels. A meta-analysis reported that TG levels were approximately 26 mg/dL higher and HDL levels 6 mg/dL lower in women with PCOS compared to controls.^[46] These alterations were not merely caused by a high BMI and indicate intrinsic abnormalities as they were persistent even after adjusting for the BMI.^[47] Furthermore, PCOS is associated with a reduction in the HDL2 subclass, which possesses the strongest cardioprotective effects.^[48,49] In contrast to typical insulin-resistant states, PCOS is often associated with elevated LDL levels. Meta-analyses have shown LDL levels to be 9–12 mg/dL higher in women with PCOS than in controls with the same BMI.^[50] Moreover, LDL particles in PCOS are often smaller and denser, which is strongly associated with increased atherogenicity and CAD.^[51,52] PCOS is frequently associated with alterations in apolipoproteins A-I, a major HDL component with anti-atherogenic properties, which is significantly reduced in women with PCOS across all BMI ranges.^[53] Apolipoprotein C-I, which inhibits hepatic uptake of TG-rich lipoproteins, is elevated even in the absence of overt dyslipidemia and also in lean women and may be an early marker of lipid disturbance.^[54]

The genetic component of PCOS can be deciphered by the fact that LP(a), an independent risk factor for CV disease which is genetically determined is also frequently elevated in PCOS. Studies have shown that nearly a third of women with PCOS have LP(a) concentrations ≥30 mg/dL, even in the absence of traditional dyslipidemia.^[55,56] Elevated LP(a) is particularly challenging as it is resistant to lifestyle modification and pharmacologic interventions, underscoring the need for comprehensive CV risk assessment in PCOS.

The management includes life style intervention, weight loss, and increased physical activity. Even a small weight loss of 5% can result in substantial improvement in metabolic parameters. The lowering of LDL is the primary target and non-HDL the secondary target in PCOS as recommended by the androgen excess and PCOS society.^[57] Statins are the first-line agents and offer additional benefits such as reductions in testosterone, C-reactive protein, and IR in addition to LDL lowering.^[58] Additional agents such as fibrates and omega-3 fatty acids may be used for TG lowering.

Physiology of lipids during pregnancy

Lipids play an essential role in meeting the metabolic requirements of pregnancy and ensuring appropriate fetal growth and development.^[59] The requirement of lipids in early pregnancy is high to support placental and neurodevelopment and somatic growth of fetus. In the first 6 weeks of gestation, lipid levels gradually decrease, followed by a progressive increase in all lipid parameters – including LP(a) – as pregnancy progresses. Nearly, all lipid fractions increase and peak by the third trimester, resulting in a more atherogenic profile than in non-pregnant individuals. Postpartum, these lipid levels decrease gradually over several months.

TG levels may rise by 250–300%, while LDL, HDL, and TC increase by 36%, 25%, and 43%, respectively. LP(a) levels also elevate, with genetic factors potentially accounting for increases up to 190%.

In the first and second trimesters, the body prepares for the anabolic phase of late pregnancy, with increased insulin secretion and increased production of cortisol, progesterone, leptin, and prolactin. In the third trimester, a net catabolic phase occurs, marked by greater IR and increased production of human placental lactogen and estrogen, further affecting lipid metabolism. It is recommended to assess lipid levels in both the first and third trimesters for all pregnant women, with additional investigations if abnormalities are detected.

Pregnant women with abnormal lipid profiles should be carefully monitored for gestational diabetes mellitus (GDM ), preeclampsia, and fetal wellbeing.^[60,61] It is important to differentiate the typical hyperlipidemic response during pregnancy from abnormal lipid changes. A TC level above 250 mg/dL is, however, considered abnormal during pregnancy. Although the LDL/HDL ratio typically remains stable, there is an increase in small dense LDL and LP(a) particles, contributing to atherogenic risk.

During the first trimester, high TC and TG and low HDL predict adverse outcomes such as GDM, pulmonary embolism, and preterm birth. High TG and low HDL levels in the third trimester have been linked to large-for-gestational age babies and macrosomia.^[13] Parveen et al. (Aligarh, India) reported that the TC, TGL, VLDL, and LDL levels are higher in pregnant women with GDM preeclampsia, preterm labor, or small-for date–babies.^[61] In Bhuvaneswar, India, Das et al. found that GDM was associated with higher TC, VLDL, and TGL levels.^[62] In a study by Singh et al. (270 pregnant women), lipid abnormalities (elevated Serum TC, TGL, and LDL levels and lower HDL) detected in early pregnancy predicted later development of preeclampsia.^[63]

The treatment of dyslipidemia in pregnancy is mainly lifestyle changes in diet and exercise and medications are preferentially avoided. In severe cases such as familial FH bile acid, sequestrants can be used. Statins can be used in patients with FH or established ASCVD patients. Pregnant patients with markedly elevated TG, omega 3 fatty acids may be used to decrease risk of pancreatitis. Statins, ezetimibe, and bile acid sequestrants are safe to use with breast feeding.

METS

METS refers to a cluster of factors, including abdominal obesity, hypertension, IR, dyslipidemia, and glucose intolerance. Gerald Raven originally termed it as syndrome X.^[64] The prevalence of METS is high among women, particularly those with diabetes. An analysis of newly diagnosed diabetes patients showed that 82.9% had METS, with a significantly higher prevalence in women (89.9%) than in men (78.2%, P < 0.001).^[65] Women with METS face an elevated risk of CV morbidity and mortality; this highlights the need for gender-specific approaches in the CV risk assessment and management.^[66] METS is more common in postmenopausal women.^[67] In premenopausal women, several factors such as genetics, IR, obesity, lifestyle choices, disrupted circadian rhythms, sleep disturbances, inflammation, hormonal imbalances, ovarian conditions, GDMs, and pre-eclampsia may play a role in the development of METS.

The components of METS differ in men and women. Men exhibit a higher prevalence of hypertension, hyperglycemia, and hypertriglyceridemia, whereas women have a greater prevalence of abdominal obesity and low HDL.^[68] These differences are linked to variations in fat distribution, hormonal influences, and menopause onset. In women aging and increased in waist circumference are associated with high visceral adipose tissue which is more closely linked to metabolic risk than subcutaneous fat. Among women, the prevalence of abdominal obesity, hypertension, hyperglycemia, and hypertriglyceridemia increase with age, whereas in men, only hypertension and hyperglycemia tend to increase with age. In younger women, the most common METS pattern is high TG, low HDL, and increased waist circumference, while older women often meet all the criteria for METS.^[69]

In a study of 280 adults of Dakshina Kannada, India, the prevalence of METS was 33.9%, 52.9% were obese and 18–49 years were 2.3 times more likely to have METS than over 50 years. Women had higher odds of METS than men (odds ratio 1.49), and those with low socio-economic status were at higher risk.^[70] However, a study from the National family Health survey India (2015–2016) found a much lower METS prevalence: 1.1% in men versus 1.5% in women. Yet, component prevalence was high (hypertension: 43.6% in men, 30% in women; impaired fasting glucose: 53.2% in men, 49.6% in women; and obesity: 2.2% in men, 3.8% in women).^[71] The longitudinal aging study in India (66,606 individuals; 2017–2018) reported an overall METS prevalence of 4.83%, higher in females, urban residents, and physically inactive individuals. These data highlights an increasing trend of METS and its components in India, with females at higher risk underscoring the urgent need for concerted public health action.^[72]

Lipid changes in elderly women

In elderly women, TC and LDL tend to decline with age (but less so than in men), TG increases in women in advanced age) in contrast to men, in whom TG declines with. HDL levels do not differ significantly between older women and men.^[81-83] Women’s longevity has increased in the recent years which translates into a large section of women spending their lives in the post-menopausal phase.Women who are more than 6 years post-menopause tend to have higher LDL and lower HDL levels compared to women who are early post- menopause.^[84]