American Journal of Obstetrics & Gynecology
Volume 198, Issue 1 , Pages 28.e1-28.e5, January 2008

How should we manage atherogenic dyslipidemia in women with polycystic ovary syndrome?

  • Manfredi Rizzo, MD, PhD

      Affiliations

    • Department of Clinical Medicine and Emerging Diseases, University of Palermo, Palermo, Italy
    • Corresponding Author InformationReprints: Manfredi Rizzo, MD, PhD, Dipartimento di Medicina Clinica e delle Patologie Emergenti, Universita’ di Palermo, Via del Vespro, 141, 90127 Palermo, Italy.
    • ,
  • Kaspar Berneis, MD

      Affiliations

    • Division of Endocrinology and Diabetology, University Hospital, Zurich, Switzerland.
    • ,
  • Enrico Carmina, MD

      Affiliations

    • Department of Clinical Medicine and Emerging Diseases, University of Palermo, Palermo, Italy
    • ,
  • Giovam Battista Rini, MD

      Affiliations

    • Department of Clinical Medicine and Emerging Diseases, University of Palermo, Palermo, Italy

Received 7 May 2007; received in revised form 3 September 2007; accepted 8 September 2007.

Article Outline

Despite their young age, women with polycystic ovary syndrome (PCOS) have increased cardiovascular risk. Besides normal concentrations of low-density lipoprotein (LDL) cholesterol, dyslipidemia is very common and includes elevated triglyceride levels and low high-density lipoprotein cholesterol concentrations. Recent findings also showed that women with PCOS have qualitative LDL alterations, with increased levels of atherogenic small, dense LDL particles. Such lipid abnormalities constitute a common form of dyslipidemia, the so-called atherogenic lipoprotein phenotype (ALP), associated with a greater cardiovascular risk. Weight reduction and increased physical activity may constitute first-line therapy for ALP in PCOS, and lipid lowering drugs, particularly nicotinic acid and fibrates, should be used in patients with severe dyslipidemia. Statins have usually a lower impact on ALP, and their beneficial effect is often moderate. Insulin-sensitizing medications favorably alter each component of ALP and combined therapy with these agents remains an option; in particular, the combination pioglitazone plus metformin seems to be particularly beneficial.

Key words: atherosclerosis, high-density lipoprotein cholesterol, polycystic ovary syndrome, small and dense low-density lipoprotein, triglycerides

 

Cardiovascular diseases represent the major cause of death in both sexes, but women have hormonal protection before menopause, and the onset of cardiovascular diseases is usually delayed by 10-15 years in comparison with men.1 However, young women may show increased cardiovascular risk if affected by a common endocrine disease called polycystic ovary syndrome (PCOS).2 PCOS represents the most frequently encountered endocrinopathy in women, affecting up to 10% of those in reproductive age, and despite their young age, women with PCOS show increased cardiovascular risk and this finding has been consistently reported across several geographic areas and ethnic groups.1, 2

See related editorial, page 4

Women with PCOS are more likely than normally cycling women to have insulin resistance, central adiposity, hypertension, and the metabolic syndrome3; in addition, several markers of clinical and subclinical atherosclerosis, including serum markers (such as C-reactive protein and homocysteine), carotid intima-media thickness, coronary artery calcium, and echocardiographic patterns have also been found to be altered.3, 4, 5 Besides normal concentrations of low-density lipoprotein (LDL) cholesterol, dyslipidemia is very common and includes elevated triglyceride levels and low high-density lipoprotein (HDL) cholesterol concentrations.6

Recent findings also showed that women with PCOS have significant qualitative LDL alterations, with increased levels of atherogenic small, dense LDL particles.7 Increased plasma triglyceride levels (>150 mg/dL) and decreased HDL cholesterol concentrations (<50 mg/dL) are usually accompanied by the presence of atherogenic small, dense LDL particles in the so-called atherogenic lipoprotein phenotype (ALP) or lipid triad,8, 9 which is therefore a form of dyslipidemia constituted by the concomitant presence of 3 lipid abnormalities (Figure 1).

  • View full-size image.
  • FIGURE 1. 

    Atherogenic lipoprotein phenotype (ALP), LDL heterogeneity, and plasma triglyceride and HDL-cholesterol concentrations

  • The atherogenic lipoprotein phenotype (ALP), LDL heterogeneity and plasma triglyceride and HDL-cholesterol concentrations.

  • Modified from Griffin BA, Caslake MJ, Yip B, et al. Atherosclerosis 1990;83:59-67.

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Small dense LDL particles and atherogenic dyslipidemia in PCOS 

LDL comprises multiple distinct subclasses that differ in size, density, physicochemical composition, metabolic behavior, and atherogenicity, with at least 4 major subspecies: large LDL-I, medium LDL-II, small LDL-III, and very small LDL-IV.7 Different studies have shown that LDL size may be decreased in women with PCOS because of increased smaller, more dense particles.7, 10, 11, 12, 13, 14, 15 This point is crucial because a number of evidences suggest that the quality rather than the quantity of LDL exerts a direct influence on the cardiovascular risk7; for this reason, the predominance of small dense LDL particles has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III.8

We searched for and reviewed all the available evidence in a systematic way. A literature search (by Medline and Scopus) was performed using the following headings: “small dense LDL,” “LDL size,” “LDL subfractions,” “LDL subclasses,” “LDL distribution,” and “PCOS” and “polycystic ovary syndrome” up to May 7, 2007. The authors also manually reviewed the references of selected articles for any pertinent material. Preliminarily, some reports have suggested that women with PCOS may have increased levels of small, dense LDL particles by indirect analysis of triglyceride and HDL cholesterol levels. However, the technique used for assessing LDL size is crucial; 4 studies were directly investigated by gradient gel electrophoresis LDL peak particle size in American-Hispanic, Canadian, and European (Italian and French) women (Table).7, 10, 11, 12 The 2 European studies included more patients and led to similar results: LDL mean size was large but significantly smaller than the controls.7, 10 The other 2 studies indicated that in different ethnic populations, LDL size in women with PCOS may be even much smaller,11, 12 probably because of their increased triglyceride plasma levels.

TABLE. LDL size as assessed by gradient gel electrophoresis (in angstroms, as mean ± SD) in women with PCOS and controls in 4 different published studies
StudyPopulationPCOS, nControls, nLDL size in PCOSLDL size in controlsP value
Berneis et al7Italian3024273±2282±2.0069
Dejager et al10French3127275±1282±2.0060
Legro et al11Hispanic1621254±5254±12NS
Lemieux et al12Canadian17—242±1——

LDL, low-density lipoprotein; PCOS, polycystic ovary syndrome.

Rizzo. Managing atherogenic dyslipidemia in women with polycystic ovary syndrome. Am J Obstet Gynecol 2008.

Recently,7 we found in our PCOS Mediterranean population that the reduction in LDL size was related to peculiar changes in the LDL subclass distribution: a strong reduction in the largest fraction (LDL-I) with a concomitant increase in both medium-sized (LDL-IIB) and smallest, most dense particles (LDL-III and -IV). This finding is consistent with an earlier report by Pirwany et al.13 These authors also showed that higher concentrations of LDL-III may occur only when plasma triglyceride concentrations increases, and this finding was also confirmed in our study, in which we showed significant correlations between LDL size and HDL cholesterol (positive) and triglyceride (inverse) levels.

With regard to the impact of ALP in PCOS, we found in our group of Mediterranean patients that individual features of ALP (eg, high triglycerides, low HDL cholesterol, elevated small, dense LDL particles) are common (up to 53%), but because of relatively low triglyceride levels, complete ALP is uncommon (7%; Figure 2).7 Yet we cannot exclude that ALP may be more common in US PCOS populations in whom circulating triglycerides are much higher, but, to date, no data on such prevalence have been reported.

  • View full-size image.
  • FIGURE 2. 

    Prevalence of complete and incomplete forms of atherogenic lipoprotein phenotype (ALP) in patients with PCOS

  • Modified from Griffin BA, Caslake MJ, Yip B, et al. Atherosclerosis 1990;83:59-67.

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Management of atherogenic dyslipidemia and treatment options 

Weight reduction and increased physical activity constitute first-line therapy for atherogenic dyslipidemia and lipid-lowering drugs, in particular nicotinic acid and fibrates, remain an option; statins have generally a lower impact on ALP, but combined therapy with nicotinic acid and fibrates is more beneficial.8, 9 As suggested by treatment plans,8, 9 atherogenic dyslipidemia can become a target for therapy after the goal for LDL cholesterol has been achieved, which means that LDL cholesterol remains the primary target of therapy. However, this point is still in debate, because this approach may leave substantial excess risk for cardiovascular disease in patients with this type of dyslipidemia.

In patients with PCOS, weight reduction has a greater relevance. Obesity is the most well-known factor that may modify the androgenic phenotype; in fact, obesity is a classic characteristic of PCOS that worsens insulin resistance and hyperandrogenism.2 Although some patients with mild hyperandrogenic syndromes are obese, only patients with classic PCOS have a significant increase of prevalence of obesity when compared with the normal population.1 However, sometimes patients with PCOS are not overweight and may need a different therapeutical approach.

Use of statins represent a recent therapeutical option in the management of PCOS, for their pleiotropic effects on cardiovascular risk and potentially, as recently described, for lowering testosterone levels. Statins potentially lower all LDL subclasses with a moderate net effect on atherogenic small, dense LDL particles.14 However, a strong variation has been noticed among the different agents on their effects on plasma lipids and LDL size and subclasses: rosuvastatin and atorvastatin seem to be more effective in reducing triglycerides, rosuvastatin, and simvastatin in raising HDL cholesterol, fluvastatin, atorvastatin, and rosuvastatin in reducing atherogenic small, dense LDL particles.14 These evidences should be considered when choosing the type (and dosage) of statin for women with PCOS.

One of the features of PCOS is insulin resistance, and it has been reported that by the age of 40 years, up to 40% will have type 2 diabetes or impaired glucose tolerance. The therapy with metformin (500 mg 3 times/day for 3-6 months or 850 mg twice a day for 14 weeks) in women with PCOS led to a decrease in total and LDL cholesterol as well as in plasma triglycerides but with a very large variability among groups and individuals.15, 16, 17 A recent metaanalysis of such studies revealed that total cholesterol, triglycerides, and HDL cholesterol did not change with metformin, whereas LDL cholesterol was significantly reduced.18 However, we cannot exclude that therapy with metformin in women with PCOS may have a significant impact on ALP, which is considered as a whole risk factor (as already shown in patients with type 2 diabetes), but this needs to be specifically tested in future studies.

Finally, promising data are available from thiazolidindiones, which are beneficial in reducing triglyceride concentrations (particularly pioglitazone). In women with PCOS, a therapy with rosiglitazone (4 mg/day for 3-12 months) led to reduced total cholesterol, LDL cholesterol, and triglyceride concentrations, with increased HDL cholesterol levels.19, 20, 21 Also, the addition of pioglitazone (45 mg/day for 10 months) to metformin (850 mg 3 times per day) plus diet led to a significant increase in HDL cholesterol levels.22 Yet it has been recently shown that rosiglitazone may be associated with a significant increase in the risk of myocardial infarction and cardiovascular death.23

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Comment 

One of the key points that still need to be fully addressed is the role of androgens on cardiovascular risk. Hyperandrogenism, as isolated androgen excess, has not been clearly recognized so far as a risk factor for cardiovascular disease, even if many authors have tried to correlate it with the earlier onset of atherosclerosis in men than women.24 In a recent study, we found that women with classic PCOS (eg, with hyperandrogenism and chronic anovulation) had a significantly higher prevalence of obesity, insulin resistance, and dyslipidemia in relation to those with ovulatory PCOS (with hyperandrogenism, polycystic ovaries, and normal ovulatory cycles) or idiopathic hyperandrogenism.25 Prospective studies performed on pre- and postmenopausal women failed to show a clear association between hyperandrogenism and future cardiovascular events, suggesting a limited role of androgens on cardiovascular risk, although other metabolic conditions, including obesity, insulin resistance, and dyslipidemia seem to play a major role on cardiovascular risk in women with PCOS.6

With regard to dyslipidemia, women with PCOS show different proatherogenic lipid alterations, including increased plasma triglyceride levels, low HDL cholesterol concentrations, and the presence of small, dense LDL particles. Such lipid abnormalities constitute the so-called ALP.8, 9 We recently reported in our Mediterranean population that individual features of ALP may be common but complete ALP is relatively uncommon.7 Yet ALP may be probably more common in the US PCOS populations in whom circulating triglycerides are much higher. We cannot also exclude that the presence of such atherogenic dyslipidemia may significantly increase the cardiovascular risk in women with PCOS, but to date no direct data is available.

Ideally patients should always be managed according to international guidelines made by scientific societies. Although we mentioned international guidelines for managing dyslipidemia,8, 9 to date no guidelines on management of atherogenic dyslipidemia in patients with PCOS are available. We suggest that weight reduction and increased physical activity may constitute first-line therapy for atherogenic dyslipidemia in women with PCOS, although lipid-lowering drugs, in particular nicotinic acid and fibrates, should remain an option only for patients with severe dyslipidemia, keeping in mind that these molecules are not indicated for pregnancy and that niacin can aggravate insulin resistance so that diabetes may be provoked. Statins usually have a lower impact on ALP, and their beneficial effect is often moderate. Also, because most outcome studies are performed in populations over the age of 40 years, it may be debatable whether it is cost effective to commit women with PCOS to lifetime lipid-lowering therapy; side effects and cost should always be taken into account before prescribing lipid-lowering agents to women with this syndrome.

Beyond traditional treatments with oral contraceptive pills, cyclic progestins, ovulation induction, and antiandrogenic medications, women with PCOS are currently managed with insulin-sensitizing medications, which are able to favorably alter each component of ALP. Combined therapy with these agents remains an option; in particular, the combination pioglitazone plus metformin seems to be particularly beneficial. It remains to be tested by future prospective studies whether insulin-sensitizing agents may be able to reduce cardiovascular risk in women with PCOS by reducing atherogenic dyslipidemia and carotid intima-media thickness (short-term endpoint) or cardiovascular morbidity and mortality (long-term endpoint).

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References 

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 Cite this article as: Rizzo M, Berneis K, Carmina E, et al. How should we manage atherogenic dyslipidemia in women with polycystic ovary syndrome? Am J Obstet Gynecol 2008;198:28.e1-28.e5.

PII: S0002-9378(07)01113-1

doi:10.1016/j.ajog.2007.09.014

Refers to article:

  • Pioglitazone and metformin for increased small low-density lipoprotein in polycystic ovary syndrome: Counterpoint

    Robert A. Wild
    American Journal of Obstetrics & Gynecology January 2008 (Vol. 198, Issue 1, Pages 4-6)

American Journal of Obstetrics & Gynecology
Volume 198, Issue 1 , Pages 28.e1-28.e5, January 2008

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