Date Published: April 15, 2019
Publisher: Public Library of Science
Author(s): Tadeusz Osadnik, Natalia Pawlas, Kamila Osadnik, Kamil Bujak, Marta Góral, Mateusz Lejawa, Martyna Fronczek, Rafał Reguła, Hanna Czarnecka, Marcin Gawlita, Joanna Katarzyna Strzelczyk, Małgorzata Gonera, Marek Gierlotka, Lech Poloński, Mariusz Gąsior, Alok Deoraj.
The offspring of patients with premature coronary artery disease (P-CAD) are at higher risk for cardiovascular disease, compared with subjects without a family history (FH) of P-CAD. The increased risk for cardiovascular disease in subjects with FH of early-onset CAD results from unfavorable genetic variants as well as social, behavioral and environmental factors, which are more prevalent in this group. Previous studies have shown that specific sex hormone levels may be associated with the risk of cardiovascular disease. The aim of this study was to compare wide range of biochemical marker levels including i.e. the levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone, estradiol, testosterone and sex-hormone binding globulin (SHBG) between young healthy male adults with and without FH of P-CAD.
The study group consisted of young healthy Polish male adults enrolled in a MAGNETIC case-control study, who were recruited between July 2015 and October 2017. The inclusion criteria were as follows: male sex, age ≥18 and ≤35 years old, FH of P-CAD (cases) or no P-CAD in first-degree relatives (controls). The comparison of continuous and categorical variables was performed using the Student’s t-test or the U-Mann–Whitney test, and Fisher’s exact test, respectively. The correlations between FSH, LH, testosterone, progesterone, SHBG and other laboratory parameters were assessed using the Spearman rank correlation test. Both univariable and multivariable logistic regression analyses were performed to assess the association between analyzed variables and FH of P-CAD.
A total of 411 subjects (223 cases and 188 controls) were included in the study. There was a higher prevalence of major cardiovascular risk factors in subjects with FH of P-CAD (smoking, higher total and LDL cholesterol levels, higher body mass index and lower HDL cholesterol level). Moreover, the offspring of patients with P-CAD had lower SHBG level, and higher LH and progesterone levels in the crude comparison, compared with individuals without FH of P-CAD. After adjustment for confounding variables, progesterone and LH were determined to be independently associated with FH of P-CAD.
Progesterone and LH levels are significantly associated with FH of P-CAD, independent of traditional risk factors for CAD.
The frequency of cardiovascular disease before the age of 55 is lower in women. At the age of 55, the lifetime risk of cardiovascular disease for males and females is similar. Females are, however, more likely to suffer from cerebrovascular disease or develop heart failure, whereas males are more likely to suffer from coronary artery disease as an initial event . These observed differences in the manifestation of atherosclerotic cardiovascular disease led to research focusing on the role of sex hormones in the pathophysiology of atherosclerosis. It has been postulated that the lower frequency of premature coronary artery disease (P-CAD) in premenopausal women compared to men is primarily due to the protective effect of female sex hormones [2,3]. Lower estrogen levels in females are associated with a higher risk of cardiovascular disease [2,3]. In contrast, other studies have shown that progestogens added to standard hormonal replacement therapy consisting of estrogens increased the risk of cardiovascular events in postmenopausal women [4,5]. It has also been shown that in men, lower levels of testosterone and estradiol were associated with a higher coronary artery calcium score in the Offspring and Third Generation Cohorts of the Framingham Heart Study .
The following analysis is a part of the MAGNETIC (Metabolic and Genetic Profiling of Young Adults with and without a Family History of Premature Coronary Heart Disease) project. The MAGNETIC project is a case-control study that aims to analyze the classical and genetic risk factors of CAD in healthy young adults with and without FH of P-CAD. The study design of the MAGNETIC project has been described previously .
Progesterone in men is synthesized in the testicles and adrenal glands, and its serum level, in contrast to that of women, does not alternate periodically or with age [14–17]. Higher levels of progesterone in the offspring of patients with P-CAD detected in the crude comparison, as well as the results of the multivariable analysis, indicate a potential association between progesterone levels and FH of P-CAD. To the best of our knowledge, no previous studies have analyzed the association between endogenous progesterone and cardiovascular disease in humans. The relationship between progesterone and the pathophysiology of CAD was the subject of a few experimental studies on animal models. In 1996, Hanke et al. demonstrated that in the rabbit model of atherosclerosis, progesterone therapy inhibited the beneficial effect of estrogen therapy on plaque size, likely by affecting arterial sex hormone receptors. Moreover, in the same study, therapy with progesterone alone was associated with considerably increased intimal thickening, compared with the castrated control rabbits . Recently, Yang et al. demonstrated that progesterone induces the expression of macrophage CD36, a receptor for oxidized LDL that enhances foam cell formation. This effect was shown to be mediated by the transcription factor peroxisome proliferator-activated receptor γ . Additionally, Wassmann et al. demonstrated that progesterone antagonizes the vasoprotective effect of estrogen by reducing the expression of extracellular superoxide dismutase and activating NADPH oxidase. Therefore, progesterone increases the production of reactive oxygen species in vascular smooth muscle cells .
Progesterone is significantly corelated with markers for insulin resistance in young healthy male adults. Both progesterone and LH levels are significantly associated with FH of P-CAD, independent of traditional risk factors for CAD.