Relationship between decreased testosterone levels and lipid metabolism disorders in men with coronary heart disease

The dissertation is devoted to the study of the relationship between decreased testosterone levels and lipid metabolism disorders in men with coronary heart disease (CHD). The research determines the prevalence of androgen deficiency in men with CHD, analyzes the influence of hormone replacement therapy with chorionic gonadotropin preparations on lipid and carbohydrate metabolism and anthropometric parameters, and also assesses the association between testosterone levels and the effectiveness of statin treatment in patients with dyslipidemia. The author evaluates the hormonal profile in men with CHD and age-related androgen deficiency, comparing the data obtained with parameters of the lipid spectrum and cardiovascular risk factors. The practical significance of the work is related to the substantiation of the expediency of normalizing testosterone levels in men with CHD in order to increase the effectiveness of hypolipidemic therapy.

Relevance of the Problem

It is known that prior to menopause, cardiovascular diseases occur considerably less frequently in women than in men under 50 years of age [British Heart Foundation Statistics Database, 1996]. According to Dick P. et al. [2005], sex is an important prognostic factor in patients with atherosclerosis. According to Japanese researchers, 82.3% of fatal infarctions occur in men and only 17.7% in women [Hirobe K., 2005]. To date, a group of "classical" risk factors for the development of atherosclerosis has been identified: male sex, age, arterial hypertension, diabetes mellitus, hyperlipidemia, as well as a number of other factors, such as elevated levels of insulin, fibrinogen, blood coagulation factor VII, plasminogen activator inhibitor-1, and others. At the same time, an active search continues for new factors contributing to the development of atherosclerosis, among which considerable attention is being paid to age-related hormonal changes that may influence sex differences in the structure and severity of cardiovascular diseases.

Androgen replacement therapy has a history of 60 years, thanks to Thomas H.B. and Hill R.T., who in 1940 were the first to successfully apply testosterone propionate for the treatment of androgen insufficiency in men, while the classical indications for its use have long remained congenital hypogonadism; however, recently HRT has been gaining increasing popularity for the treatment of PADAM syndrome (partial androgen deficiency of the aging male). Recently, the term age-related hypogonadism has been used to describe PADAM syndrome, according to data from the Massachusetts Male Aging Study (MMAS), for men of all ages.

It has been noted that after 30-40 years of age the testosterone level decreases by approximately 1-2% per year [Stelator, 2000]. In men aged 80 years, the testosterone level averages approximately 40% of the hormone level at age 25. In men with chronic concomitant diseases (diabetes mellitus, arterial hypertension, coronary heart disease), the testosterone level is 10-15% lower than in healthy individuals of the same age.

Hormone replacement therapy with testosterone preparations not only improves sexual function in men but also has a positive effect on the course of many somatic conditions, in particular cardiovascular diseases, which occupy a leading place among the causes of male mortality in the Russian Federation and worldwide. Russia currently holds first place among European countries in mortality from CVD. The statistics of cardiovascular mortality in Russia are as follows: out of every 100,000 people, 330 men and 154 women die annually from myocardial infarction alone, and 204 men and 151 women from strokes.

The long-standing and entrenched belief that androgens, in particular testosterone, impair the state of the cardiovascular system, based on the epidemiological association between male sex and the earlier and more frequent occurrence of CVD, and on evidence that the life expectancy of men is on average 8 years shorter than that of women [Lerner & Kannel, 1986; Assmann G., Cullen P., Jossa F., Lewis B., Mancini M., 1999], has until practically the present time restrained not only the prescription of HRT to men with CHD and hypogonadism but also the conduct of research in this area.

Notions of the adverse effect of androgens on the CVS were also based on data indicating that boys during puberty show a decrease in the level of antiatherogenic HDL with a simultaneous increase in the level of TG and LDL, and on analogous changes in the lipid spectrum during treatment of adolescents with delayed puberty with testosterone esters [Caron P., 1989; Santner S.J., 1998; Kirkland R.T., 1987]. In women with hirsutism and hyperandrogenemia, a predominance of atherogenic lipoprotein fractions in blood serum has also been revealed [Vermeulen A., 2001].

On the other hand, as early as the first half of the last century, reports appeared concerning the ability of testosterone to increase tolerance to physical exertion and to reduce the severity of clinical manifestations of CHD in men [Walker T.C., 1942; Lesser M., 1946; Agaletskaya A.M., Vartapetov B.A., 1946]. Russian scientists at the beginning of the last century demonstrated that AH develops more frequently in men with decreased sexual function [S.I. Karchikyan, 1930], and the administration of testosterone exerts a pronounced hypotensive effect [T.T. Glukhenky, 1946]. Improvement of coronary blood flow and decreased myocardial ischemia following the administration of testosterone were noted by Webb C.M. (1999), Rosano G.M. (1999), and English K. (2000). Moreover, an association has been established between decreased serum levels of testosterone, estrone, free insulin-like growth factor-1 (IGF-1), and the thickness of the intima-media complex [Van den Beld A.W., Bots M.L., 2003]. Similar results were obtained in the study by Hak A.E. et al. (2002), who found a negative association between endogenous testosterone levels and the degree of involvement and progression of aortic atherosclerosis in men.

In studies designed to examine the influence of exogenous testosterone on blood lipid composition, highly contradictory results were obtained - from the absence of changes or a decrease in antiatherogenic and atherogenic lipoproteins to their increase [Meriggiola M.C., 1995; Zgliczynski S., 1996; Ozata M., 1996; Sih R., 1997; Snyder P., 2001]. It is quite probable that the level of plasma testosterone achieved during treatment is of essential significance. Thus, in studies on the use of androgens in eugonadal patients with the achievement of supraphysiological concentrations (as occurs in athletes using anabolic steroids and in men on contraception with high doses of testosterone), a decrease in HDL levels was obtained [Marcovina S.M., 1996; Zmuda J.M., 1996]. In men with drug-induced hypogonadism caused by the administration of gonadotropin-releasing hormone (GnRH) agonists, a simultaneous increase in HDL and LDL(a) was observed, that is, a pro- and antiatherogenic effect at the same time. Administration of testosterone preparations against this background led to restoration of LDL levels [Bagatel C.J., 1992; Von Eckardstein A., 1997].

Thus, the attitude toward the effects of androgens on the cardiovascular system remains in many respects dualistic and not fully understood, which attests to the relevance of studying the influence of sex hormones on the state of the cardiovascular system in men.

Furthermore, there is no doubt that at present the central place in the prevention and treatment of cardiovascular diseases is occupied by modern lipid-lowering therapy, which is based on the prescription of statins. However, until now, no assessment of changes in the hormonal profile during statin treatment has been performed, nor has the relationship between changes in sex hormone levels and changes in the lipid spectrum in patients with CHD been studied.

AIM OF THE RESEARCH

The aim of the research is to determine the prevalence of androgen deficiency in men and the influence of lipid-lowering and hormone replacement therapy on the lipid profile, as well as on indicators of carbohydrate and fat metabolism in men with CHD.

In accordance with the stated aim, the following OBJECTIVES OF THE RESEARCH were formulated:

1. To study the secretion of sex hormones in men with CHD.

2. To determine the influence of hormone replacement therapy on androgen levels, parameters of the lipid profile, and other risk factors for coronary heart disease (CHD) in men.

3. To evaluate the effect of statins on parameters of the lipid profile and androgen status in men with CHD.

MAIN STATEMENTS TO BE DEFENDED:

1. In men with CHD, a decrease in testosterone levels is observed in 61.17% of cases.

2. In men with age-related androgen deficiency, disturbances of lipid metabolism are observed in 82.92% of cases.

3. Therapy with chorionic gonadotropin, which increases testosterone secretion, exerts a positive effect on lipid metabolism in patients with dyslipidemia and CHD, and in patients with age-related androgen deficiency without CHD.

4. A low testosterone level reduces the effectiveness of statins in the treatment of dyslipidemia in men.

SCIENTIFIC NOVELTY OF THE WORK

A study of the hormonal status in men with CHD was conducted, demonstrating a high prevalence of testosterone deficiency. The influence of HRT on the lipid profile, anthropometric parameters, and carbohydrate metabolism in men with CHD was studied. An association was revealed between low testosterone levels and risk factors for CHD (dyslipidemia, abdominal obesity, impaired carbohydrate metabolism). The role of androgen deficiency in reducing the effectiveness of statins in the treatment of dyslipidemia in patients with CHD was demonstrated.

PRACTICAL SIGNIFICANCE

The effectiveness of therapy aimed at normalizing testosterone in men with CHD and androgen deficiency was demonstrated with respect to improvement of lipid and carbohydrate metabolism parameters, as well as its positive influence on abdominal obesity, which will allow a broader use of this method of therapy in the treatment of men with cardiovascular diseases. The necessity of normalizing testosterone levels in patients with CHD and dyslipidemia was demonstrated in order to increase the effectiveness of hypolipidemic therapy with statins.

IMPLEMENTATION

The main statements and results of the research have been implemented in the practice of examination and management of patients at the Endocrinology Research Centre, City Clinical Hospital No. 51 of Moscow, and are used in the scientific and pedagogical work at the Department of Clinical Pharmacology of MGMSU.

APPROVAL OF THE DISSERTATION

The materials of the dissertation were discussed at the III Conference of Young Scientists of Russia with international participation (Moscow, January 2004), the 4th World Congress on Aging Male Issues (Prague, February 2004), the 12th International Congress of Endocrinology (Lisbon, September 2004), the 2nd All-Russian Conference "Men's Health" (Moscow, October 2005), and at a joint meeting of the staff of the Department of Clinical Pharmacology of MGMSU, the Department of Andrology and Urology of the State Institution of the Endocrinology Research Centre of the Russian Academy of Medical Sciences, and physicians of City Clinical Hospitals No. 50, No. 51, and No. 81 of the Moscow Department of Health on 17 June 2005.

PUBLICATIONS

On the topic of the dissertation, 6 scientific works have been published.

1. Relationship between lipid metabolism disorders and decreased testosterone levels in men. Vorslov L.O., Koroleva O.S., Kalinchenko S.Yu., Gomula A. "Fundamental Sciences and Progress of Clinical Medicine," Collection of Abstracts of the III Conference of Young Scientists of Russia with international participation. 20-24 January 2003. p. 124.

2. Age-related androgen deficiency (PADAM syndrome) in men: diagnosis and treatment. S. Kalinchenko, V. Vadov, L. Vorslov. Journal "Vrach" 2003 (6) pp. 21-24.

3. Erectile dysfunction as a manifestation of endothelial dysfunction. S. Kalinchenko, L. Vorslov, A. Koval "Vrach" 2004 (7) pp. 45-49.

4. Association between testosterone and metabolic syndrome. Kalinchenko S., Vorslov L. Aging Male 2004 Vol. 7 No. 1 P. 82.

5. Case-effect relation between testosterone deficiency and metabolic syndrome in men. Kalinchenko S., Vorslov L. Abstracts of the 12th International Congress of Endocrinology. Lisbon, August 31 - September 4, 2004. P. 320.

6. Prevalence of androgen deficiency in patients with CHD. Vorslov L.O., Mskhalaya G.Zh., Kalinchenko S.Yu. Materials of the Conference "Men's Health." Moscow. 19-21 November 2005. P. 17.