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Chronic Cigarette Smoking Alters Circulating Sex Hormones and Neuroactive Steroids in Premenopausal Women

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Chronic Cigarette Smoking Alters Circulating Sex Hormones and Neuroactive Steroids in Premenopausal Women Physiol. Res. 61: 97-111, 2012 https://doi.org/10.33549/physiolres.932164 Chronic Cigarette Smoking Alters Circulating Sex Hormones and Neuroactive Steroids in Premenopausal Women M. DUŠKOVÁ1, K. ŠIMŮNKOVÁ1, M. HILL1,4, M. VELÍKOVÁ1, J. KUBÁTOVÁ1, L. KANCHEVA1, H. KAZIHNITKOVÁ1, H. HRUŠKOVIČOVÁ1, H. POSPÍŠILOVÁ1, B. RÁCZ1, M. SALÁTOVÁ1, V. CIRMANOVÁ1, E. KRÁLÍKOVÁ2,3, L. STÁRKA1, A. PAŘÍZEK4 1Institute of Endocrinology, Prague, Czech Republic, 2Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University, Prague, Czech Republic, 3Tobacco Dependence Treatment Centre, Third Medical Department – Department of Metabolism and Endocrinology, First Faculty of Medicine, Charles University, Prague, Czech Republic, 4Department of Obstetrics and Gynecology of the First Faculty of Medicine, Charles University, Prague, Czech Republic Received February 18, 2011 Accepted October 27, 2011 On-line December 20, 2011 Summary lutropin/follitropin ratio. In conclusion, chronic cigarette smoking Chronic smoking alters the circulating levels of sex hormones and augments serum androgens and their 5α/β-reduced metabolites possibly also the neuroactive steroids. However, the data (including GABAergic substances) but suppresses the levels of available is limited. Therefore, a broad spectrum of free and estradiol in the LP and SHBG and may induce hyperandrogenism conjugated steroids and related substances was quantified by in female smokers. The female smokers had pronouncedly GC-MS and RIA in premenopausal smokers and in age-matched increased serum progestogens but paradoxically suppressed (38.9±7.3 years of age) non-smokers in the follicular (FP) and levels of their GABA-ergic metabolites. Further investigation is luteal phases (LP) of menstrual cycle (10 non-smokers and needed concerning these effects. 10 smokers, in the FP, and 10 non-smokers and 8 smokers in the LP). Smokers in both phases of the menstrual cycle showed Key words higher levels of conjugated 17-hydroxypregnenolone, Smoking • Menstrual cycle • Luteal phase • Follicular phase • Sex 5α-dihydroprogesterone, conjugated isopregnanolone, hormones • Neuroactive steroids conjugated 5α-pregnane-3β,20α-diol, conjugated androstenediol, androstenedione, testosterone, free testosterone, conjugated Corresponding author 5α-androstane-3α/β,17β-diols, and higher free testosterone Antonín Pařízek, Department of Obstetrics and Gynecology of the index. In the FP, the smokers exhibited higher levels of First Faculty of Medicine and General Teaching Hospital, conjugated pregnenolone, progesterone, conjugated Apolinářská 18, 128 51 Prague 2, CZ 116 94, Czech Republic. pregnanolone, lutropin, and a higher lutropin/follitropin ratio, but Fax: +420 224 922 545. E-mail: [email protected] lower levels of cortisol, allopregnanolone, and pregnanolone. In the LP, the smokers exhibited higher levels of free and Introduction conjugated 20α-dihydropregnenolone, free and conjugated dehydroepiandrosterone, free androstenediol, 5α-dihydro- Cigarette smoking is one of the most serious testosterone, free and conjugated androsterone, free and substance abuse problems. A variety of human and conjugated epiandrosterone, free and conjugated animal studies have shown that nicotine can induce etiocholanolone, 7α/β-hydroxy-dehydroepiandrosterone isomers, changes in female hormonal balance (Kapoor and Jones and follitropin but lower levels of estradiol and sex hormone 2005, Tutka 2001, Tziomalos and Charsoulis 2004, binding globulin (SHBG) and lower values of the Windham et al. 2005). Besides for the common PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online) © 2012 Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic Fax +420 241 062 164, e-mail: [email protected], www.biomed.cas.cz/physiolres 98 Dušková et al. Vol. 61 reproductive functions in women (Kapoor and Jones (Figures 1 and 2), differs between premenopausal 2005, Windham et al. 2005), such as the menstrual cycle, smokers and age-matched non-smokers in the follicular fertility, gravidity and the health of the fetus, chronic (FP) and luteal phases (LP) of the menstrual cycle. smoking may also influence the activities of the pituitary- adrenal axis and central nervous system (Rohleder and Patients and Methods Kirschbaum 2006). The effects of chronic smoking on cognition (Durazzo and Meyerhoff 2007, Hill et al. 2003, A broad spectrum of C19 and C21-steroid Richards et al. 2003, Sabia et al. 2008), mood (Bertone- metabolites and related substances was determined by Johnson et al. 2008), and severity of drug addiction GC-MS and RIA in four groups of smokers and in age- (Sofuoglu et al. 2009, Sofuoglu et al. 2007) have been matched non-smokers in the follicular (FP) and luteal reported. It is generally accepted that the chemicals in phases (LP) of the menstrual cycle. The first group tobacco smoke alter endocrine function in women, consisted of premenopausal chronic smokers in the FP perhaps at the level of the ovaries, which in turn (n=10), while the second group involved the age- and influences the release of pituitary hormones. More than phase of the menstrual cycle-matched non-smokers 30 carcinogenic chemicals, including nicotine, cotinine (n=10). The third group contained premenopausal chronic cadmium, and polyaromatic hydrocarbons, are present in smokers in the LP (n=8) and the fourth group included tobacco smoke; many of them are fat-soluble and the age and phase of the menstrual cycle-matched non- resistant to metabolism (Mlynarcikova et al. 2005, smokers (n=10). The patients were smokers who were Mukherjee et al. 2006, Shiverick and Salafia 1999). This interested in cessation and visited The Center for endocrine disruption likely contributes to reported Tobacco Dependence, First Faculty of Medicine and associations of smoking with adverse reproductive General University Hospital, Prague. The controls had no outcomes, including menstrual dysfunction (Windham et history of smoking. al. 1999), infertility, and earlier menopause. Studies on The study included women with regular the effects of smoking on female sex hormones have menstrual cycles lasting 28 days. This inclusion criterion concentrated mainly on estrogens and progesterone in the was fulfilled in both controls and patients. The blood in follicular phase of the menstrual cycle (Lucero et al. both groups was collected the 3rd-5th day of the menstrual 2001, Zumoff et al. 1990). cycle in the FP and the 22nd-24th day in the LP. The Mood and well-being are strongly affected by women, in whom the hormonal parameters did not accord neurotransmitters and corresponding receptors in brain with the phase of the menstrual cycle, were additionally structures. The effect of smoking on the concentration of excluded from the study. For the correct determination of gamma-aminobutyric acid (GABA) in the brain has been the phase of the menstrual cycle, we have used the reported (Epperson et al. 2005). Short-term abstinence patient’s self report and we also checked their serum had no significant effect on cortical GABA hormonal levels. The ranges within the 3rd and the 5th day concentrations in either men or women. There was, and within the 22nd and 24th day of the menstrual cycle however, a significant effect of sex, diagnosis were selected due to organizational reasons. In both (smoker/non-smoker), and the menstrual cycle phase on patients and controls, we strived to complete the blood cortical GABA levels. The female smokers experienced a withdrawal as closest to the 3rd and 22nd days of the significant reduction in cortical GABA levels during the menstrual cycle as possible. follicular phase but no cyclicity in GABA levels across For ethical reasons, the design of the study does the menstrual cycle. Alternatively, cortical GABA levels not allow sampling the same women in both cycles, even were similar in smoking and nonsmoking men. The if the multiple cycles sampling in the same two groups aforementioned data indicate possible alterations in the (smokers vs. non-smokers) would be optimal and would biosynthesis and/or catabolism of neuroactive steroids in increase the validity of our findings. Unfortunately, it was premenopausal smokers. However, only little attention impossible to harmonize the patient’s preference of the was paid to neurosteroids (known as potent modulators of day, when the woman decided to cease smoking, with her type A GABA receptors (GABAA-r) and NMDA menstrual cycle. Therefore, only those smokers who were receptors (NMDA-r)) in these subjects. Therefore, we within the aforementioned ranges for FP or LP on the attempted to establish whether the pattern of circulating beginning of the smoking cessation were included in the neuroactive steroids, their precursors and metabolites study. 2012 Smoking, Sex Hormones and Neuroactive Steroids in Premenopausal Women 99 17β-Hy droxy steroid O α O dehy drogenases (HSD17Bs), 17 -Hy droxy lase, 17α-Hydroxylase, OH O aldoketoreductases (AKR1Cs) Cholesterol desmolase C17,20-ly ase OH C17,20-ly ase (CYP11A1) (CYP17A1) (CYP17A1) CHOLESTEROL SULFATE O O O O O S O O S O O S O O S O 5-Androstene-3β,17β-diol O O β O O Pregnenolone sulf ate 17-Hy droxy pregnenolone-3 -sulf ate DHEA sulf ate -3β-sulf ate Sulf atases/sulf otransf erases (SULT2A1, SULT1E1, STS, ARSK) O O O OH Cholesterol desmolase OH (CYP11A1) CHOLESTEROL HO HO HO HO Pregnenolone 17-Hy droxy pregnenolone DHEA 5-Androstene-3β,17β-diol 3β-Hy droxy steroid dehy drogenases (HSD3B1, HSD3B2) O O O OH OH O O O O Progesterone
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