The Role of 11-Oxygenated Androgens and Endocrine Disruptors in Androgen Excess Disorders in Women
Abstract
:1. Introduction
- (1)
- metabolic parameters (parameters of insulin resistance, liver enzymes, lipids and glucose concentrations)
- (2)
- unconjugated and conjugated levels of 25 steroid hormones, with emphasis on classic androgens, 11-oxygenated androgens, and 7-oxygenated metabolites of DHEA
- (3)
- unconjugated levels of 18 EDs including bisphenols (bisphenol A-BPA, BPS, BPF, BPAF, BPAP, BPZ, BPP), parabens (methyl-, ethyl-, propyl-, butyl-, benzyl- paraben), benzophenones (benzophenon-3 = oxybenzone, benzophenone-1), phytoestrogens (daidzein, genistein, S-equol), and nonylphenol (NP)
- (4)
- concentrations of 27 cytokines
- (1)
- Do levels of 11-oxygenated androgens differ between age- and BMI-matched women with PCOS (n = 10), women with IH (n = 12), and the control group (n = 20)? Do they contribute to the circulating androgen pool in these women?
- (2)
- Do levels of EDs differ between women with PCOS, women with IH, and the control group? Can EDs be involved in the pathogenesis of these disorders?
- (3)
- Is IH also a low-grade inflammation state similar to PCOS?
- (4)
- Are there differences in the levels of 11-oxygenated androgens, EDs, cytokines, and immunomodulatory 7-oxygenated metabolites of DHEA between normal-weight (n = 10) and obese (n = 9) women with PCOS? Is there an effect of obesity?
- (5)
- What are the relationships among 11-oxygenated androgens, EDs, metabolic parameters, and cytokine levels?
2. Results
2.1. Basic and Metabolic Characteristics
2.2. Cytokine Profiles in Women with PCOS, Women with IH, and Correlation Analysis
2.3. Hormonal Profiles of Women with IH and Women with PCOS
2.4. Correlations of Classic and 11-Oxygenated Androgens with Metabolic Parameters
2.5. ED Levels in Women with Idiopathic Hirsutism and PCOS and Their Correlations with Androgens, 11-Oxygenated Androgens, Metabolic Parameters and Immune Parameters
- Ethylparaben (EP) was detected in 15% of controls, 33% of women with IH, and 10% of women with PCOS.
- Propylparaben (PP) was detected in 10% of controls, 33% of women with IH, and 10% of women with PCOS.
- Benzophenone-1 was detected in 5% of controls, 17% of women with IH, and 10% of women with PCOS.
- Daidzein was detected in 40% of controls, 42% of women with IH, and 20% of women with PCOS.
- Genistein occurred in 15% of controls, 8% of women with IH, and 20% of women with PCOS.
- S-equol was detected in one sample of a woman with PCOS.
- Butylparaben (BP) was detected in one sample of a woman with IH.
2.6. Differences in Steroid, ED and Cytokine Levels between Normal-Weight and Obese Women with PCOS
3. Discussion
4. Materials and Methods
4.1. Study Population
4.2. Materials and Chemicals
4.3. Sample Collection
4.4. Analysis of Biochemical Markers, Hormone and Cytokine Levels
4.5. Analysis of Steroid Hormones and Endocrine Disruptors (EDs)
4.5.1. Sample Preparation
4.5.2. LC-MS/MS Parameters
4.6. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Controls (n = 20) | Women with IH (n = 12) | Women with PCOS (n = 10) | p-Value | Multiple Comparison | |
---|---|---|---|---|---|
Age [y] | 29 (26–38) | 33 (27–37) | 28 (24–32) | 0.434 | |
BMI [kg/m2] | 20.4 (19.9–23.2) | 23.7 (20.3–25.3) | 21.6 (18.5–24.5) | 0.328 | |
HOMA-IR | 1.3 (0.9–1.8) | 1.7 (1.2–2.2) | 1.7 (1.3–2.7) | 0.125 | |
Insulin [mIU/L] | 5.9 (3.9–7.7) | 6.9 (5.2–10.0) | 8.1 (6–11.6) | 0.15 | |
Glucose [mmol/L] | 5.0 (4.9–5.3) | 5.2 (5.0–5.4) | 5.2 (4.9–5.3) | 0.539 | |
Hemoglobin A1c [mmol/mol] | 32.0 (31.0–33.0) | 35.5 (32.0–38.0) | 34 (34–35) | <0.001 | C<H, P |
Albumin [g/L] | 47 (45–50) | 48 (46–50) | 50 (47–52) | 0.226 | |
ALP [µkat/L] | 0.88 (0.82–1.00) | 0.94 (0.82–1.14) | 1.22 (0.94–1.48) | 0.129 | |
AST [µkat/L] | 0.32 (0.30–0.37) | 0.34 (0.31–0.36) | 0.33 (0.30–0.46) | 0.724 | |
GGT [µkat/L] | 0.22 (0.18–0.27) | 0.22 (0.20–0.26) | 0.27 (0.21–0.36) | 0.239 | |
ALT [µkat/L] | 0.22 (0.20–0.24) | 0.29 (0.26–0.30) | 0.25 (0.24–0.31) | 0.008 | C<H, P |
Cholesterol [mmol/L] | 4.32 (4.07–5.36) | 4.37 (4.27–5.50) | 4.61 (4.32–4.97) | 0.699 | |
HDL cholesterol [mmol/L] | 1.82 (1.74–2.09) | 1.93 (1.65–2.10) | 1.82 (1.52–2.07) | 0.739 | |
LDL cholesterol [mmol/L] | 2.39 (1.98–3.35) | 2.55 (2.31–3.39) | 2.74 (2.29–3.26) | 0.643 | |
Triglycerides [mmol/L] | 0.74 (0.67–0.81) | 0.85 (0.61–1.30) | 0.77 (0.70–0.97) | 0.454 |
7αOH-DHEA | 7βOH-DHEA | 7-ketoDHEA | ||||
---|---|---|---|---|---|---|
r | p-Value | r | p-Value | r | p-Value | |
IL-1ra | 0.313 | 0.028 | 0.311 | 0.030 | 0.311 | 0.029 |
IL-1β | 0.397 | 0.006 | 0.604 | <0.0001 | 0.467 | 0.001 |
IL-2 | 0.204 | 0.159 | 0.261 | 0.070 | 0.298 | 0.037 |
IL-4 | 0.214 | 0.139 | 0.239 | 0.099 | 0.224 | 0.122 |
IL-5 | −0.012 | 0.938 | 0.179 | 0.258 | 0.144 | 0.364 |
IL-6 | 0.195 | 0.180 | 0.232 | 0.109 | 0.222 | 0.125 |
IL-7 | 0.142 | 0.330 | 0.214 | 0.140 | 0.244 | 0.091 |
IL-8 | 0.076 | 0.605 | 0.100 | 0.494 | 0.137 | 0.349 |
IL-9 | 0.176 | 0.227 | 0.229 | 0.114 | 0.216 | 0.136 |
IL-10 | 0.130 | 0.546 | 0.327 | 0.119 | 0.126 | 0.556 |
IL-12(p70) | 0.248 | 0.104 | 0.322 | 0.033 | 0.346 | 0.021 |
IL-13 | 0.298 | 0.038 | 0.378 | 0.007 | 0.366 | 0.010 |
IL-15 | 0.101 | 0.509 | 0.261 | 0.083 | 0.232 | 0.125 |
IL-17 | 0.239 | 0.110 | 0.367 | 0.012 | 0.294 | 0.047 |
Eotaxin | −0.096 | 0.513 | −0.030 | 0.840 | −0.103 | 0.480 |
FGF basic | 0.031 | 0.835 | 0.076 | 0.602 | 0.080 | 0.584 |
GM-CSF | 0.179 | 0.219 | 0.221 | 0.128 | 0.233 | 0.107 |
G-CSF | 0.203 | 0.162 | 0.250 | 0.083 | 0.202 | 0.165 |
IFN-γ | 0.228 | 0.115 | 0.222 | 0.125 | 0.275 | 0.056 |
IP-10 | 0.095 | 0.518 | 0.192 | 0.185 | 0.102 | 0.484 |
MCP-1(MCAF) | 0.250 | 0.083 | 0.236 | 0.103 | 0.241 | 0.095 |
MIP-1α | 0.292 | 0.042 | 0.275 | 0.056 | 0.305 | 0.033 |
MIP-1β | 0.111 | 0.446 | 0.402 | 0.004 | 0.176 | 0.226 |
PDGF-BB | −0.046 | 0.754 | 0.026 | 0.858 | −0.013 | 0.932 |
RANTES | −0.135 | 0.356 | 0.075 | 0.611 | −0.095 | 0.517 |
TNF-α | 0.159 | 0.276 | 0.181 | 0.214 | 0.215 | 0.138 |
VEGF | 0.040 | 0.786 | 0.106 | 0.474 | 0.103 | 0.485 |
Controls (n = 20) | Women with IH (n = 12) | Women with PCOS (n = 10) | p-Value | Multiple Comparison | |
---|---|---|---|---|---|
AMH [ng/mL] | 2.52 (2.11–3.53) | 2.14 (0.83–3.62) | 8.53 (6.14–10.95) | 0.000 | C, H<P |
SHBG [nmol/L] | 68.9 (51.8–91.3) | 57.3 (48.8–64.7) | 44.3 (27.4–75.3) | 0.131 | |
LH [IU/L] | 6.6 (5.5–8.0) | 7.1 (4.9–9.5) | 9.3 (7.0–11.6) | 0.082 | |
FSH [IU/L] | 7.1 (5.5–9.0) | 5.9 (5.1–7.5) | 6.1 (3.3–7.3) | 0.509 | |
LH/FSH | 0.83 (0.69–1.13) | 1.21 (0.85–1.55) | 1.71 (1.53–2.21) | <0.001 | C, H<P |
Pregnenolone [ng/mL] | 0.995 (0.577–1.274) | 1.441 (0.901–2.670) | 1.182 (0.856–2.295) | 0.170 | |
17OHPreg [ng/mL] | 5.495 (3.669–11.617) | 5.565 (2.550–6.748) | 9.105 (3.226–13.095) | 0.282 | |
Progesterone [ng/mL] | 0.123 (0.098–0.185) | 0.098 (0.098–0.098) | 0.098 (0.098–0.295) | 0.400 | |
17OHProg [ng/mL] | 0.433 (0.367–0.517) | 0.503 (0.340- 0.695) | 0.839 (0.560–0.882) | 0.011 | C, H<P |
11DOF [ng/mL] | 0.282 (0185–0.611) | 0.310 (0.185–0.540) | 0.630 (0.211–0.884) | 0.451 | |
11DOC [ng/mL] | 0.022 (0.014–0.042) | 0.014 (0.014–0.031) | 0.030 (0.014–0.075) | 0.547 | |
Cortisol [ng/mL] | 188 (138–231) | 197 (165–225) | 177 (132–286) | 0.727 | |
Cortisone [ng/mL] | 42.74 (40.05–47.16) | 44.58 (37.56–51.81) | 46.52 (39.50–49.73) | 0.989 | |
Corticosterone [ng/mL] | 2.099 (1.237–4.38) | 2.452 (1.544–3.029) | 3.289 (1.237–6.82) | 0.574 | |
Aldosterone [ng/mL] | 0.134 (0.068–0.179) | 0.092 (0.055–0.148) | 0.126 (0.108–0.255) | 0.758 | |
DHEA [ng/mL] | 7.64 (4.63–11.53) | 6.28 (5.05–8.33) | 12.62 (7.85–16.12) | 0.041 | H<P |
T [ng/mL] | 0.235 (0.202–0.269) | 0.229 (0.096–0.301) | 0.362 (0.264–0.460) | 0.015 | C, H<P |
Free T [pmol/L] | 25.2 (21.4–35.9) | 32.3 (26.1–46.7) | 46.8 (36.8–59.4) | 0.003 | C<P |
Epitestosterone [ng/mL] | 0.005 (0.004–0.010) | 0.007 (0.003–0.010) | 0.014 (0.009–0.018) | 0.003 | C, H<P |
A4 [ng/mL] | 1.195 (0.945–1.431) | 1.135 (0.643–1.638) | 2.119 (1.706–2.625) | 0.001 | C, H<P |
DHT [ng/mL] | 0.098 (0.066–0.118) | 0.066 (0.066–0.076) | 0.102 (0.086–0.133) | 0.045 | H<C, P |
11βOHA4 [ng/mL] | 0.701 (0.414–0.908) | 0.458 (0.325–0.631) | 1.029 (0.527–1.404) | 0.036 | H<P |
11KT [ng/mL] | 0.407 (0.329–0.503) | 0.303 (0.191–0.396) | 0.483 (0.325–0.647) | 0.022 | H<C, P |
11OHT [ng/mL] | 0.138 (0.100–0.148) | 0.085 (0.060–0.113) | 0.145 (0.088–0.226) | 0.027 | H<C, P |
7αOHDHEA [ng/mL] | 0.358 (0.228–0.596) | 0.285 (0.223–0.326) | 0.565 (0.328–0.632) | 0.017 | H<C, P |
7βOHDHEA [ng/mL] | 0.148 (0.066–0.200) | 0.098 (0.081–0.136) | 0.201 (0.158–0.257) | 0.031 | H<P |
7KDHEA [ng/mL] | 0.083 (0.065–0.110) | 0.062 (0.045–0.078) | 0.102 (0.079–0.116) | 0.005 | H<C, P |
Estrone [ng/mL] | 0.033 (0.026–0.037) | 0.028 (0.022–0.052) | 0.047 (0.035–0.057) | 0.031 | C, H<P |
17β-Estradiol [ng/mL] | 0.021 (0.016–0.030) | 0.027 (0.015–0.037) | 0.023 (0.021–0.030) | 0.818 |
11βOHA4 | 11KT | 11OHT | DHEA | A4 | T | DHT | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
r | p-Value | r | p-Value | r | p-Value | r | p-Value | r | p-Value | r | p-Value | r | p-Value | |
Age | −0.100 | 0.485 | −0.145 | 0.309 | 0.127 | 0.374 | −0.137 | 0.338 | −0.329 | 0.018 | −0.101 | 0.481 | −0.087 | 0.542 |
BMI | −0.100 | 0.504 | −0.002 | 0.990 | 0.052 | 0.727 | 0.083 | 0.580 | 0.132 | 0.377 | 0.277 | 0.059 | −0.226 | 0.128 |
HOMA-IR | 0.244 | 0.098 | 0.366 | 0.011 | 0.233 | 0.115 | 0.257 | 0.081 | 0.471 | 0.001 | 0.357 | 0.014 | −0.094 | 0.530 |
Insulin | 0.242 | 0.091 | 0.375 | 0.007 | 0.236 | 0.100 | 0.196 | 0.173 | 0.436 | 0.002 | 0.347 | 0.014 | −0.094 | 0.517 |
Cholesterol | −0.165 | 0.253 | −0.225 | 0.117 | −0.056 | 0.700 | −0.203 | 0.158 | −0.150 | 0.299 | −0.078 | 0.589 | −0.320 | 0.024 |
Triglycerides | 0.034 | 0.817 | 0.137 | 0.345 | 0.061 | 0.676 | 0.093 | 0.521 | 0.220 | 0.125 | 0.246 | 0.085 | −0.149 | 0.303 |
LDL cholesterol | −0.136 | 0.345 | −0.110 | 0.449 | −0.001 | 0.997 | −0.128 | 0.377 | −0.105 | 0.466 | −0.083 | 0.568 | −0.286 | 0.044 |
HDL Cholesterol | −0.077 | 0.596 | −0.171 | 0.234 | −0.222 | 0.121 | −0.249 | 0.081 | −0.128 | 0.374 | −0.048 | 0.743 | −0.077 | 0.595 |
Hemoglobin A1c | 0.072 | 0.621 | 0.066 | 0.654 | 0.128 | 0.382 | 0.099 | 0.498 | 0.258 | 0.073 | 0.187 | 0.198 | −0.228 | 0.115 |
Glucose | 0.104 | 0.474 | 0.068 | 0.637 | 0.119 | 0.410 | 0.271 | 0.057 | 0.329 | 0.020 | 0.334 | 0.018 | 0.037 | 0.798 |
ALP | 0.135 | 0.351 | 0.276 | 0.052 | 0.177 | 0.218 | 0.032 | 0.826 | 0.226 | 0.114 | 0.126 | 0.382 | −0.132 | 0.362 |
ALT | 0.040 | 0.784 | −0.030 | 0.838 | 0.038 | 0.791 | 0.136 | 0.346 | 0.358 | 0.011 | 0.437 | 0.002 | −0.170 | 0.237 |
AST | 0.007 | 0.964 | 0.026 | 0.859 | 0.054 | 0.708 | 0.015 | 0.915 | 0.270 | 0.058 | 0.353 | 0.012 | −0.133 | 0.356 |
GGT | 0.143 | 0.323 | 0.263 | 0.066 | 0.241 | 0.092 | 0.252 | 0.077 | 0.369 | 0.008 | 0.373 | 0.008 | −0.030 | 0.834 |
Controls (n = 20) | Women with IH (n = 12) | Women with PCOS (n = 10) | p-Value | |
---|---|---|---|---|
∑parabens | 0.013 (0.013–0.081) | 0.0395 (0.013–0.753) | 0.013 (0.013–0.087) | 0.448 |
MP [ng/mL] | 0.013 (0.013–0.070) | 0.0395 (0.013–0.583) | 0.013 (0.013–0.072) | 0.405 |
MP occurrence (%) | 35 | 58 | 40 | |
BPA [ng/mL] | 0.123 (0.041–0.289) | 0.107 (0.092–0.162) | 0.053 (0.014–0.113) | 0.234 |
BPA occurrence (%) | 85 | 92 | 60 | |
BPS [ng/mL] | 0.028 (0.011–0.039) | 0.011 (0.011–0.039) | 0.035 (0.028–0.051) | 0.465 |
BPS occurrence (%) | 65 | 50 | 90 | |
oxybenzone [ng/mL] | 0.014 (0.014–0.053) | 0.014 (0.014–0.054) | 0.014 (0.014–0.039) | 0.938 |
oxybenzone occurrence (%) | 35 | 33 | 30 |
Normal Weight Women with PCOS (n = 10) | Obese Women with PCOS (n = 9) | p-Value | |
---|---|---|---|
BMI [kg/m2] | 21.6 (18.4–24.5) | 34.6 (32.9–35.7) | <0.0001 |
AMH [ng/mL] | 8.525 (6.140–10.950) | 5.500 (4.535–6.555) | 0.025 |
BPA [ng/mL] | 0.053 (0.014–0.113) | 0.193 (0.138–0.302) | 0.014 |
BPS [ng/mL] | 0.035 (0.027–0.055) | 0.029 (0.011–0.041) | 0.206 |
MP [ng/mL] | 0.013 (0.013–0.072) | 0.013 (0.013–0.070) | 1.000 |
oxybenzone [ng/mL] | 0.014 (0.014–0.039) | 0.014 (0.014–0.078) | 0.767 |
11βOHA4 [ng/mL] | 1.029 (0.527–1.404) | 0.618 (0.377–0.958) | 0.149 |
11KT [ng/mL] | 0.483 (0.325–0.647) | 0.436 (0.267–0.637) | 0.545 |
11OHT [ng/mL] | 0.145 (0.088–0.226) | 0.114 (0.095–0.170) | 0.589 |
A4 [ng/mL] | 2.119 (1.706–2.625) | 1.547 (1.130–2.310) | 0.128 |
T [ng/mL] | 0.362 (0.264–0.460) | 0.315 (0.215–0.462) | 0.441 |
DHEA [ng/mL] | 12.625 (7.850–16.119) | 7.095 (6.133–12.213) | 0.330 |
DHT [ng/mL] | 0.102 (0.086–0.133) | 0.064 (0.059–0.103) | 0.084 |
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Vitku, J.; Varausova, A.; Skodova, T.; Kolatorova, L.; Vosatkova, M.; Vcelak, J.; Vrbikova, J.; Simkova, M.; Svojtkova, M. The Role of 11-Oxygenated Androgens and Endocrine Disruptors in Androgen Excess Disorders in Women. Int. J. Mol. Sci. 2024, 25, 9691. https://doi.org/10.3390/ijms25179691
Vitku J, Varausova A, Skodova T, Kolatorova L, Vosatkova M, Vcelak J, Vrbikova J, Simkova M, Svojtkova M. The Role of 11-Oxygenated Androgens and Endocrine Disruptors in Androgen Excess Disorders in Women. International Journal of Molecular Sciences. 2024; 25(17):9691. https://doi.org/10.3390/ijms25179691
Chicago/Turabian StyleVitku, Jana, Anezka Varausova, Tereza Skodova, Lucie Kolatorova, Michala Vosatkova, Josef Vcelak, Jana Vrbikova, Marketa Simkova, and Michaela Svojtkova. 2024. "The Role of 11-Oxygenated Androgens and Endocrine Disruptors in Androgen Excess Disorders in Women" International Journal of Molecular Sciences 25, no. 17: 9691. https://doi.org/10.3390/ijms25179691