Cadmium, Lead, and Mercury and Reproductive Issues in Women
Cadmium, Lead, and Mercury and Reproductive Issues in Women
Background: Metals can interfere with hormonal functioning by binding at the receptor site and through indirect mechanisms; thus, they may be associated with hormonal changes in premenopausal women.
Objectives: We examined the associations between cadmium, lead, and mercury, and anovulation and patterns of reproductive hormones [estradiol, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone] among 252 premenopausal women 18–44 years of age who were enrolled in the BioCycle Study in Buffalo, New York.
Methods: Women were followed for up to two menstrual cycles, with serum samples collected up to eight times per cycle. Metal concentrations were determined at baseline in whole blood by inductively coupled mass spectroscopy. Marginal structural models with stabilized inverse probability weights and nonlinear mixed models with harmonic terms were used to estimate the effects of cadmium, lead, and mercury on reproductive hormone levels during the menstrual cycle and anovulation.
Results: Geometric mean (interquartile range) cadmium, lead, and mercury levels were 0.29 (0.19–0.43) μg/L, 0.93 (0.68–1.20) μg/dL, and 1.03 (0.58–2.10) μg/L, respectively. We observed decreases in mean FSH with increasing cadmium [second vs. first tertile: –10.0%; 95% confidence interval (CI), –17.3% to –2.5%; third vs. first tertile: –8.3%; 95% CI, –16.0% to 0.1%] and increases in mean progesterone with increasing lead level (second vs. first tertile: 7.5%; 95% CI, 0.1–15.4%; third vs. first tertile: 6.8%; 95% CI, –0.8% to 14.9%). Metals were not significantly associated with anovulation.
Conclusions: Our findings support the hypothesis that environmentally relevant levels of metals are associated with modest changes in reproductive hormone levels in healthy, premenopausal women.
Exogenous factors may affect hormonal function, and several epidemiologic studies in peri- and postmenopausal women have suggested that metals alter hormone levels (Gallagher et al. 2010; Krieg 2007; Mendola et al. 2008; Nagata et al. 2005). However, evidence among premenopausal women is sparse (Gerhard et al. 1998; Jackson et al. 2008).
Environmental estrogens act through genomic pathways by binding to the estrogen receptor and initiating transcription of estrogen-activated genes, and through nongenomic pathways that involve signaling initiated in the cellular membrane (Tilghman et al. 2008). Divalent metals, including lead and mercury, can initiate the estrogen receptor by interacting with amino acids at the receptor binding site (Zhang et al. 2008), and both metals exert estrogenic changes in experimental models (Choe et al. 2003). Stoica et al. (2000) reported that cadmium may obstruct the hormone-binding domain of the estrogen receptor-α, thereby affecting subsequent transcriptional processes (Guével et al. 2000), but Silva et al. (2006) reported that cadmium did not have estrogenic properties based on other assays. Cross-sectional data are inadequate to assess hormonal patterns during the menstrual cycle (Howards et al. 2009), especially in association with environmental exposures that may alter hormone levels at certain times of the menstrual cycle but not others. Traditional approaches fail to capture the multiple physiologic parameters during a regular menstrual cycle and do not account for the complex interplay among reproductive hormones, for which traditional methods to control for confounding are inadequate. Further, evaluating hormonal differences from the peak to nadir and shifts in hormonal peaks can provide valuable insight into subclinical changes in hormonal function. Hormonal alterations may increase anovulation, with effects on fertility (Aksel et al. 1976; Lutoslawska et al. 2006), but anovulation has not been assessed among women who have been exposed to metals.
Our objective in the present study was to estimate associations between biomarkers of metal exposures (cadmium, lead, and mercury) and a) patterns of reproductive hormones [estradiol, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH)], including mean change, amplitude, and phase shift across the cycle; b) mean change in reproductive hormones over the menstrual cycle while accounting for dependence between hormones; and c) anovulation among healthy, premenopausal women.
Abstract and Introduction
Abstract
Background: Metals can interfere with hormonal functioning by binding at the receptor site and through indirect mechanisms; thus, they may be associated with hormonal changes in premenopausal women.
Objectives: We examined the associations between cadmium, lead, and mercury, and anovulation and patterns of reproductive hormones [estradiol, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone] among 252 premenopausal women 18–44 years of age who were enrolled in the BioCycle Study in Buffalo, New York.
Methods: Women were followed for up to two menstrual cycles, with serum samples collected up to eight times per cycle. Metal concentrations were determined at baseline in whole blood by inductively coupled mass spectroscopy. Marginal structural models with stabilized inverse probability weights and nonlinear mixed models with harmonic terms were used to estimate the effects of cadmium, lead, and mercury on reproductive hormone levels during the menstrual cycle and anovulation.
Results: Geometric mean (interquartile range) cadmium, lead, and mercury levels were 0.29 (0.19–0.43) μg/L, 0.93 (0.68–1.20) μg/dL, and 1.03 (0.58–2.10) μg/L, respectively. We observed decreases in mean FSH with increasing cadmium [second vs. first tertile: –10.0%; 95% confidence interval (CI), –17.3% to –2.5%; third vs. first tertile: –8.3%; 95% CI, –16.0% to 0.1%] and increases in mean progesterone with increasing lead level (second vs. first tertile: 7.5%; 95% CI, 0.1–15.4%; third vs. first tertile: 6.8%; 95% CI, –0.8% to 14.9%). Metals were not significantly associated with anovulation.
Conclusions: Our findings support the hypothesis that environmentally relevant levels of metals are associated with modest changes in reproductive hormone levels in healthy, premenopausal women.
Introduction
Exogenous factors may affect hormonal function, and several epidemiologic studies in peri- and postmenopausal women have suggested that metals alter hormone levels (Gallagher et al. 2010; Krieg 2007; Mendola et al. 2008; Nagata et al. 2005). However, evidence among premenopausal women is sparse (Gerhard et al. 1998; Jackson et al. 2008).
Environmental estrogens act through genomic pathways by binding to the estrogen receptor and initiating transcription of estrogen-activated genes, and through nongenomic pathways that involve signaling initiated in the cellular membrane (Tilghman et al. 2008). Divalent metals, including lead and mercury, can initiate the estrogen receptor by interacting with amino acids at the receptor binding site (Zhang et al. 2008), and both metals exert estrogenic changes in experimental models (Choe et al. 2003). Stoica et al. (2000) reported that cadmium may obstruct the hormone-binding domain of the estrogen receptor-α, thereby affecting subsequent transcriptional processes (Guével et al. 2000), but Silva et al. (2006) reported that cadmium did not have estrogenic properties based on other assays. Cross-sectional data are inadequate to assess hormonal patterns during the menstrual cycle (Howards et al. 2009), especially in association with environmental exposures that may alter hormone levels at certain times of the menstrual cycle but not others. Traditional approaches fail to capture the multiple physiologic parameters during a regular menstrual cycle and do not account for the complex interplay among reproductive hormones, for which traditional methods to control for confounding are inadequate. Further, evaluating hormonal differences from the peak to nadir and shifts in hormonal peaks can provide valuable insight into subclinical changes in hormonal function. Hormonal alterations may increase anovulation, with effects on fertility (Aksel et al. 1976; Lutoslawska et al. 2006), but anovulation has not been assessed among women who have been exposed to metals.
Our objective in the present study was to estimate associations between biomarkers of metal exposures (cadmium, lead, and mercury) and a) patterns of reproductive hormones [estradiol, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH)], including mean change, amplitude, and phase shift across the cycle; b) mean change in reproductive hormones over the menstrual cycle while accounting for dependence between hormones; and c) anovulation among healthy, premenopausal women.
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