Is lipid lowering treatment aiming for very low LDL levels safe in terms of the synthesis of steroid hormones?

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Summary

Today atherosclerotic diseases are among the most important causes of death in the world. Epidemiological, clinical, genetic, experimental and pathological studies have clearly shown the role of lipoproteins in atherosclerosis. LDL is the major atherogenic lipoprotein and has been defined as the primary target of lipid lowering treatment by NCEP. Although the level of LDL, the primary target in the treatment of dyslipidemia, has been set as below 100 mg/dl in coronary heart diseases (CHD) and CHD risk equivalents, this level has been pulled down to below 70 mg/dl for the group defined as very high risk group by the ATP (Adult Treatment Panel) guide that has been updated following the new clinical studies. As we already know, cholesterol is the precursor of glucocorticoids, mineralocorticoids and sex steroids, besides being a structural component of the cell membrane. Both adrenal and non-adrenal (ovarian + testicular) all steroid hormones are primarily synthesized using the LDL–cholesterol in the circulation. In addition to this, there is ‘de novo’ cholesterol synthesis in both the adrenals and gonads controlled by the HMG-CoA reductase enzyme. A third pathway, which under normal circumstances has little contribution as compared to the first two, is the use of circulatory HDL–cholesterol by the adrenal and gonadal tissues for the synthesis of steroids. Our knowledge on extremely lowered LDL levels is quite limited. However, since statins both decrease circulatory LDL and inhibit de novo cholesterol synthesis, they are likely to affect the synthesis of steroid hormones.

Introduction

Today atherosclerotic diseases are among the most important causes of death in the world. While only the cardiovascular diseases are responsible for the 38% of the deaths in North America, it is the most common cause of death in Europe in men younger than 65 and the second most common one in women [1].

Pathogenesis of atherosclerosis includes, endothelial dysfunction, migration of smooth muscle cells from the media to the intima and accumulation of the lipid-laden macrophages beneath the endothelium [2], [3]. Epidemiological, clinical, genetic, experimental and pathological studies have clearly shown the role of lipoproteins in atherosclerosis [4], [5], [6], [7], [8], [9].

LDL, constituting 60–70% of total cholesterol, is the major atherogenic lipoprotein and has been defined as the primary target of lipid lowering treatment by NCEP (National Cholesterol Education Program) [5]. A significant number of randomized, controlled clinical studies with large study samples have demonstrated that statins decrease the risk of death due to atherosclerosis [10], [11], [12], [13], [14], [15]. Statins are structurally similar to the cholesterol precursor HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A), and they competitively inhibit the HMG-CoA reductase enzyme that catalyzes the transformation of HMG-CoA to mevalonate, which is the rate-limiting step in the hepatic and extrahepatic biosynthesis of cholesterol [16]. Ezetimib administered concomitantly with statins is a new treatment option in the treatment of dyslipidemia. Ezetimib effectively inhibits the absorption of cholesterol from the intestinal lumen that has both been obtained through diet and entered the extrahepatic circulation via the biliary pathway [17].

Although the level of LDL, the primary target in the treatment of dyslipidemia, has been set as below 100 mg/dl in coronary heart diseases (CHD)1 and CHD risk equivalents2 [5], this level has been pulled down to below 70 mg/dl for the group defined as very high risk group3 by the ATP (Adult Treatment Panel) guide [18] that has been updated following the new clinical studies [11], [12], [13], [14].

Our knowledge on extremely lowered LDL levels is quite limited. Although it has been suggested that LDL levels around 25–60 mg/dl meet physiological needs [19], and this level is around 30 mg/dl in newborn infants emphasizing that low LDL levels are safe [5], and even that the life span in individuals with familial hypobetalipoproteinemia characterized with very low LDL have increased [20], some epidemiological studies suggest that very low LDL levels might lead to an increase in mortality rates due to cerebral hemorrhage [21], [22], [23].

As we already know, cholesterol is the precursor of glucocorticoids (cortisol, corticosterone), mineralocorticoids (aldosterone, deoxycorticosterone) and sex steroids (mainly androgen precursors, dehydroepiandrosterone and androstenedione) synthesized by adrenal cortex, besides being a structural component of the cell membrane [24]. Circulatory LDL is the main source of cholesterol used in this synthesis [25]. LDL–cholesterol enters the cell via receptor-mediated endocytosis through the specific LDL receptors found on the adrenal tissue and is used in the synthesis of steroids [26], [27]. In addition, the adrenal cortex has the capacity to synthesize cholesterol from acetyl coenzyme A via the ‘de novo’ pathway [28]. Basal adrenal steroid synthesis has been maintained probably due to the achievement of this increased compensatory ‘de novo’ synthesis in abetalipoproteinemia subjects characterized by very low LDL levels in the circulation [29] and familial hypercholesterolemia subjects with defective LDL receptors [30]. Although less significant, another source of cholesterol used in the synthesis of steroids is the HDL–cholesterol in the circulation [24], [31], [32].

The contribution of steroid synthesis of adrenal origin to the pool of sex steroids in the circulation is limited. This pool is determined by the androgen and estrogen levels synthesized first by the testicular Leydig cells in men, and granulosa cells derived from the ovaries in women [24], [33]. Like in the synthesis of adrenal steroids, the primary precursor for both testicular [34] and ovarian [35] sex steroids is the LDL in circulation. It is also known that these tissues have the capacity to synthesize cholesterol via the ‘de novo’ pathway [34], [35]. Recent studies have shown that ovarian granulosa cells are capable of using HDL through steroidogenesis [36]. It is possible that a similar mechanism is valid for the synthesis of testicular steroids.

We may state the following in the light of these data:

  • 1.

    Both adrenal and non-adrenal (ovarian + testicular) all steroid hormones are primarily synthesized using the LDL–cholesterol in the circulation.

  • 2.

    In addition to this, there is ‘de novo’ synthesis in both the adrenals and gonads controlled by the HMG-CoA reductase enzyme.

  • 3.

    A third pathway, which under normal circumstances has little contribution as compared to the first two, is the use of circulatory HDL–cholesterol by the adrenal and gonadal tissues for the synthesis of steroids.

It might be stated that the activation of compensatory ‘de novo’ synthesis pathway and synthesis through the HDL–cholesterol pathway are pronounced when the necessary LDL–cholesterol cannot be obtained [24], [25], [26], [27], [28], [29], [30], [31], [32], [34], [35], [36]. At least the basal steroid levels have been maintained in abetalipoproteinemia subjects via the activation of the compensatory ‘de novo’ synthesis [29], [30].

Normally a 5–10% increase is expected in HDL–cholesterol levels due to the use of statins. The HDL–cholesterol-increasing effects of the statins decrease unexpectedly as the dose increases [37], [38], [39], [40], [41]. This suggests that because of the partial inhibition of both the first pathway and the second pathway, steroid synthesis might shift to the HDL pathway leading to a possible attenuation of the increase in HDL levels.

Section snippets

Proofs for and against

There are very few studies investigating the effect of statine therapy on steroid hormones synthesized from cholesterol, and none of these takes the <70 mg/dl target optionally suggested by ATP III for the very high risk group into consideration, since all of these studies have been performed before 2004 the publication date of the updated report of ATP III that suggested very low LDL levels.

Studies aimed at determining the effects of lipid lowering therapy on steroid hormones synthesized from

Summary

Cholesterol is the precursor of glucocorticoids, mineralocorticoids and sex steroids. Both adrenal and non-adrenal (ovarian + testicular) all steroid hormones are primarily synthesized using the LDL–cholesterol in the circulation. Additionally there is ‘de novo’ cholesterol synthesis in both the adrenals and gonads controlled by the HMG-CoA reductase enzyme. A third pathway is the use of circulatory HDL–cholesterol by the adrenal and gonadal tissues for the synthesis of steroids. Since statins

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