S. Hunkov1, S. Reheda2
1 State Enterprise “L. I. Medved’s Research Center of Preventive Toxicology, Food and Chemical Safety”, Ministry of Health of Ukraine, Kyiv
2 State Institution “Institute of Paediatrics, Obstetrics and Gynaecology, NAMS of Ukraine”, Kyiv, Ukraine
ABSTRACT. Objective. To study the prevalence of smoking among women with polycystic ovary syndrome (PCOS), as well as to establish the relationship between intensity, duration of smoking and serum levels of manganese and nickel.
Materials and methods. A questionnaire survey was performed in two groups of women: the control group (I) included 38 healthy women, and the second group included 52 women with PCOS. In both groups, serum levels of manganese and were determined using inductively coupled plasma mass spectrometry. Statistical processing of the results of the survey was conducted using Statistika 8 software program. The U-Mann-Whitney test was used to assess the statistical significance of the obtained results. Comparison of the prevalence of smoking in both groups was performed using the parameter of statistical significance of differences for two relative values. Spearman coefficient was used for correlation analysis.
Results. In women with PCOS, significantly higher manganese (p = 0.0012) and nickel (p = 0.0000) serum levels were found. In group I, 3 women reported smoking, in group II — 13 women. Among women with PCOS, the prevalence of smoking was significantly higher (p = 0.0000). Both groups differ neither in duration (p = 0.9463) nor in intensity of smoking (p = 0.7366). Duration and intensity of smoking were not associated with serum manganese. The intensity of smoking also did not affect serum levels of nickel. A positive correlation was found between serum nickel and the duration of smoking. Authors believe that during smoking manganese directly penetrates cerebral structures via olfactory rout. Only its small portion penetrates the bloodstream. This explains the high toxicity of manganese.
Conclusion. Among women with PCOS smoking is much more common, however, the intensity and duration of smoking do not differ from the control group. Serum manganese levels are associated neither with duration nor with the intensity of smoking. Serum nickel levels are affected by the duration of smoking, rather than by the intensity of smoking.
Keywords: polycystic ovary syndrome, intensity of smoking, duration of smoking, manganese, nickel.
Polycystic ovary syndrome (PCOS) belongs to multifactorial diseases. In addition to well established risks (glucose level, body weight, different endocrine disorders, etc.), risks include such factors as lifestyle, physical exertion, mental condition, use of drugs, food supplements, and, of course, smoking [1]. During smoking, a huge amount of different toxic substances, including those belonging to endocrine disruptors penetrate human body.
In our previous studies, we have found increased manganese and nickel exposure in women with PCOS [2]. Exposure to these trace elements may predominantly occur alimentary or via respiration. It was proved that smoking may be one of the reasons of exposure to manganese and nickel [3,4].
The objective of this work was to study the prevalence of smoking among women with PCOS, as well as to verify the relationship between intensity, duration of smoking and serum levels of manganese and nickel.
Materials and methods. The study included 2 groups of women: control group — healthy women without conditions of reproductive system (38 women) and women with polycystic ovary syndrome (52 women). Inclusion to the second group was performed as per Rotterdam Convention. The study was performed at the study sites of State Institution “Institute of Pediatrics, Obstetrics and Gynecology, NAMS of Ukraine”, Kyiv, and State Enterprise “L. I. Medved’s Research Center of Preventive Toxicology, Food and Chemical Safety” of the Ministry of Health of Ukraine, Kyiv. Manganese and nickel in blood serum were measured by inductively coupled plasma mass spectrometry Bruker MS 820 (Australia) using special software program ICPMS Expert.
Women underwent questionnaire survey. The questionnaire contained questions about duration of smoking and a daily number of cigarettes. Depending on the duration of smoking, each group was evaluated by a 3-point system: 1–5 years (1 point); 5–10 years (2 points), over 10 years (3 points). A daily number of cigarettes was also evaluated by a 3-point system: up to 10 cigarettes (1 point), 10–20 cigarettes (2 points), over 20 cigarettes (3 points). Further, points were calculated during statistical processing of the results.
Statistical processing of the obtained results was performed using software program Statistika 8. For trace elements, median, 95th percentile (95%) and mean (M) were calculated. U-Mann-Whitney test was used to evaluate statistically significant data. Spearman coefficient (S) was used for correlation analysis. Comparison of the number of smoking women in both groups was performed via determination of the level of statistical significance of differences for two relative values.
Results and discussion. Conducted studies have shown that women with PCOS had increased levels of manganese and nickel (see Table 1).
Table 1
Serum content of macronutrients and trace elements in control women and women with PCOS (mg/L)
As evidenced from literature, smoking results in accumulation of metals in reproductive organs [5]. Manganese and nickel are toxic substances. Effects of manganese are primarily due to impaired function of the dopaminergic cerebral system. Manganese was classified by WHO as endocrine disruptor [6], and nickel — as metalloestrogen. Binding to oestrogen receptors, it stimulates the action of these hormones, thus, it can affect the mechanism of hormonal regulation. It was shown in experiments that accumulation of nickel in ovaries causes degenerative changes in ovarian granulosa cells resulting in impaired steroidogenesis. Nickel nanoparticles impair blood circulation in ovaries that is accompanied by leukocytic infiltration and inflammation in ovaries [7]. These two trace elements are released in large amounts during smoking.
The next stage of work involved the determination of the ratio of smokers among healthy women and women with PCOS (see Table 2).
Table 2
Ration of smoking women in control group and group with PCOS
As it can be seen from Table 2, smokers are more common in women with PCOS. These results confirm common beliefs that smoking can be included to the risk factors of PCOS.
The next stage of the study was a comparison of duration and intensity of smoking in both groups of women. The evaluation was performed by points depending on smoking duration and a daily number of cigarettes (see Table 3).
Table 3
Comparison of the duration and intensity of smoking
As it can be seen from Table 3, duration of smoking in women of both groups was similar. Women with PCOS smoked by 21.80% cigarettes more compared to the control group, however, differences were not statistically significant.
To date, there is no consensus on the mechanisms by which smoking affects the reproductive system. This is partially associated with impaired insulin resistance [8]. It was shown that in smoking women with PCOS there is an increased sensitivity to ACTH that induces hypersecretion of 17-hydroxyprogesterone [9]. Data are available that smoking reduces sensitivity to gonadotropins since increased need in gonadotropins was registered in the cycles of ovarian stimulation in smoking women. Furthermore, lower peak oestradiol levels and basal blood FSH levels were reported [10].
To find out how smoking affects trace elements in women with PCOS, we conducted a correlation analysis of manganese and nickel with smoking intensity and duration.
Table 4
Parameters of correlation analysis of intensity and duration of smoking and serum manganese and nickel levels in women with PCOS (n = 13)
S – Spearman coefficient, р – significance
The obtained results show that the number of cigarettes smoked per day and duration of this addictive habit do not affect serum manganese levels. The number of cigarettes also did not affect the serum nickel levels. However, a positive correlation was found between serum nickel level and smoking duration.
Humans consume the major amount of manganese with food. It is absorbed in the intestine and passes into the bloodstream. Its major portion is excreted with bile. Relatively low amount of manganese penetrates human body via inhalation. However, manganese toxicity after its inhalation has been known since the 19th century, when mineworkers were presented with signs of damage to the central nervous system [3]. The danger of the inhalation route of exposure is due to the fact that when it penetrates the respiratory tract, it accumulates in the olfactory epithelium and indirectly through the axons of the olfactory pathway reaches the cerebral structures. Its greatest accumulation is found in the pituitary gland. When it is absorbed through the olfactory pathway, manganese does not penetrate blood. Therefore, after inhalation exposure, blood manganese levels do not reflect its accumulation by cerebral structures [11]. The experimental studies on monkeys have shown that after inhalation exposure levels of manganese in the pituitary gland are ten times higher than in the blood. This explains why safe inhalation dose is much lower than oral penetration of manganese [12].
In our studies, we did not find the correlation between serum manganese levels and intensity or duration of smoking. However, we have reason to argue that manganese penetrates cerebral structures, bypassing the circulatory system, through the olfactory pathway. For this reason, we are unable to establish a clear correlation between the studied parameters. However, given the high blood levels of manganese in women with PCOS, it can be assumed that along with inhalation exposure, manganese penetrates the body alimentary.
The results regarding nickel were quite unexpected. When smoking one pack of cigarettes a day, 2–12 μg (up to 23 μg) of nickel penetrates the human body. In the inhalation route, about 50% of nickel is adsorbed. According to WHO, a much higher amount of nickel up to 320 μg penetrates the body alimentary. After adsorption, the values are reduced to 45 μg with food and up to 3 μg with water. Thus, it becomes clear that the number of smoked cigarettes can only partially affect the serum nickel levels [4, 12].
Blood nickel levels are affected by the rate of its elimination from the body, which depends on many factors, including the form of the compound that penetrates the body. The elimination half-life of soluble forms of nickel with urine is 20–60 hours, but these data do not take into account the accumulation of poorly soluble forms [12]. For example, it has been experimentally shown that 60% of nickel oxide is excreted from the body in 90 days and 90% of nickel sulphide — in 35 days [4]. Nickel excretion rate from the body depends on the degree of overloading of the detoxification system, chronic diseases, etc. All this suggests that smoking women with PCOS have elevated serum nickel levels, most likely due to prolonged overloading of the body’s detoxification system. Due to this precise reason, we have found a correlation between serum nickel levels and duration of smoking.
Thus, studies have shown the following: women with PCOS have increased levels of exposure to manganese and nickel. Women with PCOS smoke cigarettes much commonly. The intensity and duration of cigarette smoking in women with PCOS virtually did not differ from the control group. The lack of correlation between the daily number of cigarettes, the duration of smoking and serum manganese was proved. When interpreting these results, one should remember that in the inhalation route of exposure to manganese, only a small part of it is absorbed into the blood. A positive correlation was found between serum nickel level and smoking duration. However, the number of cigarettes did not affect the serum nickel levels.
Conclusion
1. Among women with PCOS smoking is much more common, however, the intensity and duration of smoking does not differ from the control group.
2. Serum manganese levels are associated neither with duration, nor with the intensity of smoking. Serum nickel levels are affected by duration of smoking, rather than by the intensity of smoking.
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Надійшла до редакції 24.06.2019 р.