Coenzyme Q₁₀ (CoQ₁₀) is the predominant form of ubiquinone in man. The name ubiquinone (or ubidecarenone) refers to its ubiquitous diffusion in organisms and tissues. It is a key component of the ATP-producing oxidative phosphorylation chain, placed in the inner mitochondrial membrane, and linking flavoproteins and cytochroms. However, it is also a powerful lipophilic antioxidant, in particular in its reduced form, ubiquinol (Figure 1), which represents more than 80% of the total CoQ₁₀ in human plasma and protects biological membranes and lipoproteins. Furthermore, new roles in different cellular functions have been discovered recently, regarding other cell organelles like lysosomes, Golgi apparatus and plasmatic membranes [1]. Finally, CoQ₁₀ can participate in many aspects of the oxido-reductive control of the cellular signaling pathways, at least via the auto-oxidation of semi-quinon which can be a primary source of H₂O₂ generation [2]. Also CoQ₁₀ involvement in cell proliferation was investigated [1], but most data at present concerns its energetic and antioxidant roles [3]. CoQ₁₀ levels in biological fluids can be accurately measured by HPLC, with a method standardized by the International CoQ₁₀ Association. Furthermore, electrochemical detection (HPLC-EC) allows measuring both the reduced (ubiquinol) and oxidized (ubiquinone) forms of CoQ₁₀ [4]. The CoQ₁₀ normal value range in human plasma is 0.8–1.2 mg/L. Since CoQ₁₀ in the blood stream is prevalently transported in lipoproteins and above all low-density lipoproteins (LDL), CoQ₁₀ values are commonly normalized for those of cholesterol (nmol/mmol), in order to minimize the confounding effect of cholesterol. Systemic hormones are variously involved in the regulation of metabolism, and act as a certain modulation on body antioxidant systems, both in physiological and pathological conditions, with hormone excess or deficiency [5]. The aim of this paper is to summarize the main findings of the literature about the link between hormonal systems and circulating CoQ₁₀ levels.

The clinical value of CoQ₁₀ is clear with respect to the antioxidant protection of lipoproteins. In fact, circulating LDLs are particularly prone to oxidative damage with generation of cytotoxic products, associated with atherosclerosis [13]. In LDLs, CoQ₁₀ is oxidized before vitamin E, and the appearance of fat acids hydroperoxides occurs only after ubiquinol depletion [14], indicating CoQ₁₀ as a first-line barrier against oxidative stress. Moreover, the treatment per os with exogenous CoQ₁₀ in normal subjects induces an increase of ubiquinol levels in plasma and lipoproteins and an augmented resistance to LDL peroxidation [15]. Oxidative stress, obesity, metabolic syndrome and insulin resistance are crucial elements in the pathogenesis of atherosclerosis and cardiovascular disease, because of the association with lipoproteins rich in triglycerides (small and dense LDLs), oxidized LDLs, antibodies anti-oxidized LDLs and other oxidized and glycated particles, F2-isoprostans, soluble adhesion molecules, augmented levels of fibrinogen and PAI-1 e low levels of t-PA, an increase in CRP, IL-6, AA, omocistein, advanced glycation products [16–18]. Dealing with diabetes, blood plasma and cellular antioxidant defense is often reduced [19], and also CoQ₁₀ plasma levels were found to be decreased in diabetic patients [20]. So we understand why lipoproteins isolated by diabetic subjects are more susceptible to the oxidation process.

The significance of oxidative stress in coronary cardiopathy has been investigated in a case-control study [21] and in two important cohort studies, the “Nurses’ Health Study” [22] and the “Physicians’ Health Study” [23]. The positive effect of the treatment with CoQ10 on angina pectoris, total arrhythmias, and left ventricular function after myocardial infarction was shown in the short term [24], as well as the long-term prognosis [25]. In conclusion, there is a relationship between low concentrations of plasma CoQ₁₀ and coronary disease, even if this correlation is not so strong as even to be considered a casual relation [26]. However, ubiquinol/ubiquinone ratio is considered an oxidative stress marker in coronary disease and LDL/CoQ₁₀ ratio was proposed as an index of coronary risk factor [20].

There are a lot of medical investigations concerning the potential therapeutic usefulness of CoQ₁₀ in the treatment of various diseases, including endocrine ones: cardiovascular, neurological, muscular, immunologic, dental, diabetes, male infertility [3,27].

Both hyperthyroidism and hypothyroidism are associated with enhanced oxidative stress involving enzymatic and non-enzymatic antioxidants [28]. In particular, hyperthyroidism is associated with reduced circulating levels of α-tocopherol [29,30] and CoQ₁₀ [31,32], and some complications of hyperthyroidism are due to oxidative stress in target tissues [33]. Increasing CoQ₁₀ values were found when going from hyper- to hypo-thyroidism, with euthyroism in the middle [34], and in a previous study we showed a significant inverse correlation between thyroid hormones and plasma CoQ₁₀ [35]. This correlation was further confirmed in other studies and in a larger group of patients [32], and could cover diagnostic usefulness in those clinical conditions characterized by uncoupling of thyroid hormone levels and metabolic status, like amiodarone-induced thyroid dysfunction [35] and inappropriate thyroid stimulating hormone secretion.

Values of CoQ₁₀ in hyperthyroid patients are among the lowest reported in different human diseases (Table 1). The reasons for this phenomenon include: decreased synthesis related to competition for tyrosine, which is a common substrate for CoQ₁₀ and thyroxin synthesis (but this hypothesis was disconfirmed by experimental data in animals; increased CoQ₁₀ utilization, due to the increased metabolic demand; increased degradation; decreased levels of carriers in serum, since it is demonstrated that release of very-low-density lipoproteins from liver is decreased in hyperthyroidism. Symmetrical mechanisms can be invoked to explain high CoQ₁₀ levels in hypothyroid patients.

In patients who underwent total thyroidectomy for papillary carcinoma or multinodular goiter, we found that patients with non toxic multinodular goiter exhibited low CoQ₁₀ values in pathological areas, probably related to colloid accumulation; on the contrary, in active proliferating tissues (toxic goiter or neoplasm) CoQ₁₀ concentrations were greater than in unaffected areas [32]. These data pointed toward increased CoQ₁₀ uptake related to increased metabolic demand. Pharmacological treatment with metimazole, restoring normal values of thyroid hormones, also normalizes CoQ₁₀ values (Figure 3), as seen in hyperthyroidal children too, even after CoQ₁₀ was adjusted to cholesterol concentration, confirming a lipid-independent effect (apart from a decreased carrier capacity in serum) of the hyperthyroid state on the CoQ₁₀ levels [5,36].

More recently, we tested a group of patients with low-T₃ syndrome due to chronic obstructive pulmonary disease: again CoQ₁₀ was higher than patients with the same disease and normal T₃ levels, suggesting that real hypothyroidism could be present in such situation [37].

Antioxidant systems represent a key defense mechanism in our body and an unbalance of these systems can underly a wide spectrum of human disease. The reported experimental data show that systemic hormones can affect their levels, both in physiological and pathological conditions. However CoQ10 can be affected by different mechanisms; its low levels in plasma, in fact, can be due to accelerated metabolism and/or consumption, such as in hyperthyroidism and acromegaly, or a reduced synthesis, such as in hypoadrenalism and hypogonadism (Figure 2).

All pituitary hormones and the dependent glands (thyroid, adrenal, gonads) are involved, even if an unequivocal picture is far from being designed. However, it seems clear that in all the considered conditions, the effect of thyroid hormones is predominant on other hormones in influencing CoQ₁₀ plasma levels. Even though more controlled studies are needed, the clinical usefulness of CoQ₁₀ determination for a diagnosis refinement, or CoQ₁₀ oral supplementation as a support to the specific endocrine therapy, has already been demonstrated in many cases.