Gender difference in the association between sensitivity to thyroid hormones with incident high remnant cholesterol levels in euthyroid adults

doi:10.21203/rs.3.rs-3083026/v1

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Gender difference in the association between sensitivity to thyroid hormones with incident high remnant cholesterol levels in euthyroid adults

https://doi.org/10.21203/rs.3.rs-3083026/v1

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Background

Whether resistance to thyroid hormones affect the atherogenic remnant cholesterol (RC) levels remains unknown. The aim of this study was to explore the association of sensitivity to thyroid hormones with the incident high RC levels in euthyroid Chinese adults and further explore this association was modified by gender differences.

Methods

We performed a post hoc analysis including eligible participants from the 11223 who underwent at least two health examinations and were with RC < 0.8 at baseline from 2006 to 2010. Central and peripheral sensitivity to thyroid hormones such as thyroid-stimulating hormone index (TSHI) and thyrotrophic thyroxine resistance index (TT4RI), thyroid feedback quantile-based index (TFQI) and free triiodothyronine (FT3)/free thyroxine (FT4) were calculated.

Results

Participants with RC levels had higher levels of TSHI ,TT4RI and TFQI than participants in the normal RC group in females. However, there were no differences of TSHI, TT4RI, TFQI and FT3/FT4 between the normal RC group and the high RC group in males. In the multi-adjusted models, the highest tertiles (tertiles 3) of TSHI was associated with an increased high RC levels risk compared with the lowest tertiles (tertiles 1) (HR = 1.819, 95%CI 1.268–2.607, P = 0.001) in females. The association was also significant using TT4RI and TFQI as indices of central sensitivity to thyroid hormones in females. In stratified analyses, the relationship between thyroid hormone sensitivity and incident high RC levels was statistically significant in women < 48 years old, but not in ≥ 48 years old.

Conclusion

High TSHI ,TT4RI and TFQI increase risk of incident high RC levels in euthyroid Chinese adults in females, suggesting that central resistance of thyroid hormones may participant in the pathophysiological process of high RC levels.

Sensitivity to thyroid hormones

Remnant cholesterol

Gender difference

Triglyceride-rich lipoproteins in an important type of atherogenic dyslipidemia. Remnant cholesterol (RC) is the cholesterol content of triglyceride-rich lipoproteins and can be indirectly calculated by total cholesterol(TC) minus low-density lipoprotein cholesterol (LDL-C) minus high-density lipoprotein cholesterol (HDL-C) (1). Recently, the value of remnant-C in different diseases is drawing attention. More specifically, an increasing body of evidence suggests that remnant-C is associated with cardiovascular disease (CVD) ant its outcomes independent of traditionary lipid profiles including LDL-C (1, 2). Furthermore, several cross-section or prospective longitudinal studies indicated that high remnant-C increased risks of diabetes mellitus, hypertension, and non-alcoholic fatty liver disease (NAFLD) (3–6). Hence, investigation of risk factors of high remnant-C and timely prevention urgently needed.

Dyslipidemia is usually accompanied by thyroid dysfunction. The impact of thyroid-stimulating hormone (TSH) and thyroid hormones on lipid profile has also been extended to individuals with normal thyroid function. Intriguingly, higher normal range TSH and free triiodothyronine (FT3) were both associated with increased TC and LDL-C(7, 8), which seemed to be contradictory. Some scholars speculated that co-occurrence of high TSH and high thyroid hormones might represent central or peripheral resistance of thyroid hormones in the condition of some diseases. Thyroid feedback quantile-based index (TFQI), thyroid-stimulating hormone index (TSHI) and thyrotrophic thyroxine resistance index (TT4RI) represent central sensitivity to thyroid hormones, while FT3/free thyroxine (FT4) represent peripheral sensitivity to thyroid hormones (9). Emerging observational evidence has shown that impaired sensitivity to thyroid hormones increased risks of diabetes mellitus, metabolic syndrome, hypertension and NAFLD (10–12), all of these diseases were significantly correlated to dyslipidemia. Given these findings, it is conceivable that impaired sensitivity to thyroid hormones may impact lipid metabolism. A recent cohort study supported that serum RC levels were positively correlated with TFQI, TSHI, and TT4RI, while negatively correlated with FT3/FT4 ratio levels in Chinese euthyroid adults (13). A subsequent study further study which was conducted in patients with coronary heart disease confirmed the association of sensitivity to thyroid hormones with dyslipidemia (14). However, the above two studies were conducted with a cross-sectional study design. Therefore, we extend previous findings and provide a longitudinal cohort study to explore the association of sensitivity to thyroid hormones with incident high RC levels in euthyroid Chinese adults. Furthermore, we aimed to analyses whether this association was modified by gender.

Study population

A total of 25997 participants who underwent at least two health check-up exams with lipid profile from the Health Promotion Center of the First Affiliated Hospital of Nanjing Medical University were enrolled between January 2017 and January 2021. Normal RC level was defined as fasting RC < 0.8 mmol/l according to the joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical (15). We further included 21032 participants whose baseline RC level < 0.8 mmol/l. Participants had a history of thyroidectomy, thyroid dysfunction, autoimmune thyroiditis were excluded. We also excluded participants who had a history of diabetes, hypertension, cardiovascular diseases, stroke, cancer, taking lipid lowering agents, serious liver or renal disease. Participants who underwent at least two screening exams at no more than 1 year were also excluded. Finally, 11223 participants were included in the final analysis. The study was conducted in accordance with the 1964 Declaration of Helsinki. The study protocol was approved by the Human Research Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (2023-SR-047), that waived the requirement for informed consent because the study was based on existing clinical data routinely collected for health screening purposes.

Data collection and definition

Demographics (age, sex, race/ethnicity), smoking habits, disease and medication history were obtained based on a face-to-face interview by physicians. Weight, height and blood pressure were measured by well-trained nurses in accordance with standard protocols. At baseline, fasting antecubital venous blood samples of all participants were collected for further measuring biochemical parameters and thyroid function. Biochemical indicators such as plasma glucose, lipid profile and serum uric acid were detected by the Chemistry Analyzer AU5800 (Olympus Corporation, Tokyo, Japan). RC levels were estimated as fasting TC minus LDL-C minus HDL-C. We used high-performance liquid chromatography to measure glycosylated hemoglobin A1c (HbA1c) and electrochemiluminescence immunoassay to measure serum FT3, FT4, and TSH levels. The normal ranges of FT3, FT4, and TSH in our hospital were 3.10–6.80 pmol/L, 12.00–22.00 pmol/L, and 0.27–4.20 mU/L, respectively. The calculation formulas of TFQI, TT4RI, and TSHI were referred to previous studies [13–14]. The last visit in this study was the incident high RC levels or the last available visit for participants who did not develop incident high RC levels.

Statistical Analysis

Data were presented as the mean with standard deviation or numbers (n) with proportions (%). Differences between two groups or among three groups were compared with the Student’s t test or one-way ANOVA or Pearson’s chi-squared test. In the current study, we used thyroid hormone sensitivity markers at baseline to predict the subsequent risk of high RC levels. The hazard ratios (HR) and 95% confidence intervals (CI) were calculated by cox regression models and adjusted for baseline confounding factors. Dose-response associations of thyroid hormone sensitivity markers at baseline and incident high RC levels were conducted restricted cubic splines with knots at the tertiles of the sample distribution. All analyses were performed using SPSS 18.0 statistics software and Empower (R) with P < 0.05 (two-sided) representing statistical significance.

Baseline characteristics of individuals according to incident high RC levels

During the follow-up period, a total of 1270 (11.32%) progressed to the status of high RC levels. The baseline clinical and laboratory characteristics of the participants are presented in Table 1 based on whether high RC levels occurred. Compared with participants in the normal RC group, participants in the high RC group tended to be older, were males, smokers and had higher WBCC and neutrophil count at baseline. As for the metabolic parameters at baseline, participants with high RC levels had higher BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose (FPG), HbA1c, TC, triglyceride (TG), LDL-C and uric acid, while lower HDL-C than participants with normal RC levels. Moreover, levels of FT3 and FT4 were significant higher in participants with high RC levels than those with normal RC levels. However, there were no differences of TSH between two groups.

Table 1

Baseline characteristics of individuals according to incident high RC levels
	Normal RC RC(n = 9953)	High RC (n = 1270)	P value
Age(years)	39.93 ± 10.43	43.14 ± 10.84	< 0.01
Sex(male/female)	5007(50.31)	909(71.57)	< 0.01
Smoking(n,%)	1229(12.35)	275(21.65)	< 0.01
BMI (kg/m2)	23.22 ± 3.12	24.66 ± 2.99	< 0.01
SBP (mmHg)	120.33 ± 14.89	125.60 ± 15.14	< 0.01
DBP (mmHg)	74.38 ± 10.45	78.11 ± 10.68	< 0.01
WBCC(×10^9/L)	5.87 ± 1.46	6.25 ± 1.54	< 0.01
Neutrophil count(×10^9/L)	3.42 ± 1.15	3.62 ± 1.21	< 0.01
FBG (mmol/L)	5.15 ± 0.69	5.33 ± 0.79	< 0.01
HbA1c (%)	5.37 ± 0.43	5.49 ± 0.53	< 0.01
TC (mmol/L)	4.83 ± 0.76	5.48 ± 0.81	< 0.01
TG (mmol/L)	1.16 ± 0.55	1.66 ± 0.75	< 0.01
LDL-C(mmol/L)	2.96 ± 0.60	3.62 ± 0.67	< 0.01
HDL-C(mmol/L)	1.40 ± 0.31	1.28 ± 0.27	< 0.01
Uric acid (mmol/l)	319.81 ± 82.12	356.03 ± 83.81	< 0.01
FT3(pmol/L)	4.97 ± 0.61	5.05 ± 0.62	< 0.01
FT4(pmol/L)	17.09 ± 1.90	17.25 ± 1.91	< 0.01
TSH(mIU/L)	2.13 ± 0.82	2.17 ± 0.83	0.11
Values are presented as mean ± standard deviation.
RC : remnant cholesterol ; BMI, body mass index ; SBP, systolic blood pressure ; DBP, diastolic blood pressure ; WBCC : white blood cell count ; FBG, fasting blood glucose ; TC, total cholesterol ; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol ; HDL-C, high-density lipoprotein cholesterol ; FT3: free triiodothyronine; FT4: free thyroxine; TSH: thyroid stimulating hormone

Indices of thyroid hormone sensitivity at baseline based on gender difference

In females, levels of TSHI (3.04 ± 0.41 vs 2.92 ± 0.44, P < 0.001), TT4RI (39.50 ± 13.95 vs 35.79 ± 13.54, P < 0.001) and TFQI (0.056 ± 0.379 vs -0.015 ± 0.390, P = 0.001) were significantly higher in participants in the high RC group than those in participants in the normal RC group (Table 2). The FT3/FT4 levels (0.283 ± 0.041 vs 0.301 ± 0.042, P = 0.091) showed decreased trends in the high RC group, although the difference did not reach statistical significance (Table 2).

Table 2

Comparison of indices of thyroid hormone sensitivity at baseline between participants with and without incident high RC levels based on gender difference
	Males			Females
	Normal RC	High RC	P	Normal RC	High RC	P
n	5007	909		4946	361
TSHI	3.03 ± 0.47	3.01 ± 0.48	0.279	2.92 ± 0.44	3.04 ± 0.41	< 0.001
TT4RI	36.76 ± 14.67	36.38 ± 14.28	0.469	35.79 ± 13.54	39.50 ± 13.95	< 0.001
FT3/FT4	0.303 ± 0.041	0.301 ± 0.042	0.326	0.284 ± 0.037	0.280 ± 0.040	0.091
TFQI	-0.009 ± 0.403	-0.033 ± 0.400	0.110	-0.015 ± 0.390	0.056 ± 0.379	0.001
Values are presented as mean ± standard deviation.
RC : remnant cholesterol ; TSHI: thyroid-stimulating hormone index; TT4RI: thyrotrophic thyroxine resistance index ; FT3: free triiodothyronine; FT4: free thyroxine; TFQI: thyroid feedback quantile-based index.

In males, there were no differences of TSHI (3.03 ± 0.47vs 3.01 ± 0.48, P = 0.28), TT4RI (36.76 ± 14.67 vs 36.38 ± 14.28, P = 0.47), TFQI (-0.09 ± 0.403 vs -0.032 ± 0.400, P = 0.110) and FT3/FT4 (0.303 ± 0.041 vs 0.301 ± 0.042, P = 0.326) between the normal RC group and the high RC group (Table 2).

Associations between thyroid hormones sensitivity and incident high RC levels

The associations between each thyroid hormones sensitivity index and risk of incident high RC levels in females were analyzed by cox regression models. The HRs for high RC levels per 1-SD increase in TSHI, TT4RI, and TFQI at baseline were 1.906 (95%CI 1.362–2.667, P < 0.001), 1.017(95%CI 1.007–1.027, P = 0.001 ), and 1.846 (95% CI 1.284–2.654, P = 0.001), respectively, in females after full adjustment for potential covariates and metabolic variables. Multivariable-adjusted HR for participants in the tertiles3 vs the tertiles1 (reference) was 1.819 (95% CI 1.268–2.607, P = 0.001) for TSHI. For participants in tertiles 2 vs the tertiles1 group, the multivariable-adjusted HR was 1.706 (95% CI 1.181–2.462, P = 0.004) for TSHI (Fig. 1A). Participants with tertiles 3 of TT4RI and TFQI had a 1.659-fold higher risk and 1.473-fold higher risk of incident high RC levels compared with those with tertiles 1 of TT4RI and TFQI, respectively (Fig. 1B, 1C) after adjustment for confounding factors. However, TSHI, TT4RI, FT3/FT4 and TFQI were not associated with incident of high RC levels in males.

In addition, we also observed obviously linear dose-effect associations of incident high RC levels with TSHI(P _non−linear = 0.976), TT4RI (P _non−linear = 0.529)and TFQI (P _non−linear = 0.762) with the restricted cubic spline analysis (Fig. 2A, B, C).

Associations between thyroid hormones sensitivity and incident high RC levels according to different ages

The average menopausal age was set at 48 years in in Chinese city women according to a previous study (16). We therefore selected 48 as the cut-off point for subgroup analysis stratified by age in females. In younger females aged < 48 years old, the risk of incident high RC levels was significantly elevated in participants in the high tertiles of TSHI, TT4RI, and TFQI compared to those in the low tertiles, with adjusted HRs of 2.056 (95%CI 1.225–3.452) for TSHI, 1.906 (95%CI 1.153–3.152) for TT4RI, and 1.778 (95%CI 1.077–2.935) for TFQI in the fully adjusted model (Table 3). However, these associations disappeared after adjustment for confounding factors in older females aged ≥ 48 years old (Table 4).

Table 3

Associations between thyroid hormones sensitivity and incident high RC levels in females aged < 48 years old
	Model 1		Model 2
	HR(95%CI)	P	HR(95%CI)	P
TSHI
Tertiles 1	Reference		Reference
Tertiles 2	1.946(1.328–2.852)	0.001	2.054(1.223–3.449)	0.006
Tertiles 3	1.829(1.242–2.694)	0.002	2.056(1.225–3.452)	0.006
TT4RI
Tertiles 1	Reference		Reference
Tertiles 2	1.264(0.861–1.855)	0.232	1.377(0.817–2.319)	0.230
Tertiles 3	1.721(1.191–2.487)	0.004	1.906(1.153–3.152)	0.012
TFQI
Tertiles 1	Reference		Reference
Tertiles 2	1.652(1.146–2.380)	0.007	1.881(1.152–3.073)	0.012
Tertiles 3	1.474(1.013–2.145)	0.043	1.778(1.077–2.935)	0.024
Modle1: unjust
Modle2: adjustment for age, BMI, WBCC, neutrophil count, SBP, DBP, FBG, HbA1c, TG, and uric acid

Table 4

Associations between thyroid hormones sensitivity and incident high RC levels in females aged ≥ 48 years old
	Model 1		Model 2
	HR(95%CI)	P	HR(95%CI)	P
TSHI
Tertiles 1	Reference		Reference
Tertiles 2	1.452(0.987–2.134)	0.058	1.520(0.894–2.586)	0.122
Tertiles 3	1.608(1.106–2.337)	0.013	1.723(1.037–2.865)	0.036
TT4RI
Tertiles 1	Reference		Reference
Tertiles 2	1.473(0.986–2.201)	0.059	1.477(0.864–2.524)	0.154
Tertiles 3	1.643(1.112–2.428)	0.013	1.481(0.865–2.534)	0.152
TFQI
Tertiles 1	Reference		Reference
Tertiles 2	1.652(0.874–1.289)	0.498	0.699(0.410–1.191)	0.188
Tertiles 3	1.429(1.005–2.033)	0.047	1.273(0.800-2.026)	0.309
Modle1: unjust
Modle2: adjustment for age, BMI, WBCC, neutrophil count, SBP, DBP, FBG, HbA1c, TG, and uric acid

The incidence rate of high RC levels according to tertiles of indices of thyroid hormone sensitivity in females

To further assess the correlations of thyroid hormones sensitivity with incident of high RC levels. female participants were stratified into three groups by the tertiles of TSHI, TT4RI, and TFQI, respectively. The incidences of high RC levels were higher in women in the middle and highest tertiles of TSHI than that in the lowest tertiles (7.95% vs 7.64% vs 4.84%, respectively; P < 0.01). The similar results were also observed in tertiles of TT4RI (8.58% vs 6.73% vs 5.00%, respectively; P < 0.01) and TFQI (7.87% vs 76.82% vs 5.71%, respectively; P = 0.04).

In the current study, we found that central resistance to thyroid hormones increased risk of high RC levels only in women, regardless of possible confounding risk factors, suggesting that gender can affect regulation of sensitivity to thyroid hormones on serum RC levels. As far as we know, this is the first study to explore the association of sensitivity to thyroid hormones with risk of high RC levels in a longitudinal cohort of euthyroid adults.

Recently, RC has attracted attention for its more abundant, larger, carrying more cholesterol than LDL-C particles. Hence, it is more likely that RC is more harmful to people’s health. Several epidemiological studies have shown that high levels of RC may potentially yield important residual risk information for atherosclerotic cardiovascular disease (ASCVD) beyond traditional lipid profiles including LDL-C and apolipoprotein B in patients without known ASCVD(1, 2), suggesting that RC is essential for the primary prevention of CVD. Furthermore, elevated RC levels were independently correlated with an increased risk of coronary artery calcium progression and adverse cardiovascular outcomes (17, 18). Further evidence suggested that elevated RC levels are also associated with metabolic diseases, such as diabetes and its complications and NAFLD (19, 20). Gene mutations, environmental factors, lifestyle, hormone homeostasis and inflammation contributed to high levels RC (21, 22). Previous studies showed that high levels RC were positively correlated with age, BMI, blood pressure and blood glucose(4, 21, 23). Consistent with that, we found that participants with high RC levels had higher age, BMI, SBP, DBP, FBG and HbA1c at baseline. We also found that low-grade inflammation makers such as WBCC and neutrophil count increased in participants with high RC levels.

Both Clinical and experimental studies support a key role of thyroid hormones even within the reference range in the regulation of lipid metabolism(24, 25). Interestingly, FT3, FT4, and TSH has been suggested to be positively associated with dyslipidemia in euthyroid individuals or some disease status(26–28). These contradictory conclusions in previous studies indicate a complex interplay between numerous mechanisms underlies the pathophysiologic links between thyroid hormones and lipid metabolism. Current literature reveals that central resistance to thyroid hormone which characterized by elevated levels of thyroid hormones and TSH can be accompanied in some disease conditions, due to homeostatic compensation. TT4RI, TSHI and TFQI have been considered to be a reliable surrogate of central sensitivity to thyroid hormones, while FT3/FT4 ratio has been proposed as a surrogate marker of peripheral sensitivity to thyroid hormones in many studies. Currently, a large multicenter retrospective study indicated that high levels of TT4RI, TSHI and TFQI increased risk of dyslipidemia, while high levels of FT3/FT4 decreased risk of dyslipidemia in patients with coronary heart disease (14). In addition, high levels of RC could be corrected by T4 replacement therapy (29). In light of this, it is plausible that sensitivity to thyroid hormones affects the risk of high RC levels. To our best knowledge, there was only one study that explored the association of sensitivity to thyroid hormones with high RC levels(13). However, this study was conducted with a cross-sectional study design. No data have been available so far on the longitudinal associations of incident high RC levels with sensitivity to thyroid hormones. In the present study, we found that FT3 levels at baseline were significantly higher in the high RC group, while FT4 and TSH levels at baseline showed increased trends in the high RC group. Together these findings suggest that resistance to thyroid hormones state may exist in the development of high RC levels. To confirm this this hypothesis, we further found that TT4RI, TSHI and TFQI at baseline were significantly higher in females with incident high RC levels, while FT3/FT4 at baseline showed decreased trends. Moreover, high levels of baseline TT4RI, TSHI and TFQI were independent risk factors for the increased risk of incident high RC levels in females, consistent with the cross-sectional study (13). However, we did not find the differences of TT4RI, TSHI ,TFQI and FT3/FT4 at baseline in males between the high RC group and the normal RC group, indicating that gender differences in the relationship between resistance to thyroid hormones and high RC levels. Therefore, the female population with central resistance to thyroid hormones need more attention in the clinical practice. Although the link between central resistance to thyroid hormones and incident high RC levels is more consistent in females, the exact mechanism behind this phenomenon has still remained unclear. One possible explanation is that estrogen modify the central resistance to thyroid hormones related to high RC levels. In the present study, females aged < 48 years old with the highest tertiles of TSHI ,TT4RI, and TFQI were 2- fold, 1.9-fold, and 1.8-fold, respectively, more likely to incident high RC levels, compared to the lowest tertiles adjusted for multiple potential confounders, but these associations did not remain significant in females aged ≥ 48 years old after adjustment for demographic and traditional risk factors. We speculate that sex hormones may be involved in the pathophysiological process of central resistance to thyroid hormones to incident high RC levels. The exact mechanism warrants investigation in future studies.

The strengths of the present study are that we designed a large longitudinal study to explore the association between sensitivity to thyroid hormones with incident high RC levels in Chinese euthyroid adults and examine gender differences in this association. However, this study has several limitations. First, participants were recruited from a single center, so whether these results are generalizable in other populations is uncertain. Second, we did not measure estrogen in females, so we could not explore the role of estrogen in the link between sensitivity to thyroid hormones with incident high RC levels. Finally, RC was indirectly calculated based on levels of TC, LDL-C and HDL-C rather than a direct measurement in our study. However, estimated RC which is well correlated with direct measurement is an affordable and inexpensive method in clinical practice.

In summary, here we reported for the first time that central resistance to thyroid hormones increased risk of incident high RC levels in females, supporting the important role of the hypothalamic-pituitary-thyroid hormonal axis in lipid metabolism. We have provided evidence for explaining the current contradictions about the association between thyroid hormones and dyslipidemia, while future research are warranted to confirm our studies and to explore the underlying mechanisms.

Acknowledgements

We appreciate the help and support of all participants who took part in the study.

Author contributions

Wen Guo, Jing Lu , Jue Jia and Qun Zhang participated in the study design. Wen Guo, Jing Lu, Xiaona Li, Wenfang Zhu and Nainzhen Xu were involved in the conduct of the study, data collection and data analysis. Wen Guo , Jue Jia and Qun Zhang wrote and modified the manuscript. All authors read and approved the final manuscript.

Funding

This study was supported by Jiangsu Province Capability Improvement Project through Science，Technology and Education（ZDXK202248）and Young Scholars Fostering Fund of the First Affiliated Hospital of Nanjing Medical University (No. PY2021008).

Data availability

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding authors.

Ethics approval and consent to participate

The study was conducted in accordance with the 1964 Declaration of Helsinki. The study protocol was approved by the Human Research Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (2023-SR-047), that waived the requirement for informed consent because the study was based on existing clinical data routinely collected for health screening purposes.

Consent for publication

All authors agree to publish this work.

Competing interests

The authors declare that they have no conflicts of interest.

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No competing interests reported.

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Gender difference in the association between sensitivity to thyroid hormones with incident high remnant cholesterol levels in euthyroid adults

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Abstract

Background

Methods

Results

Conclusion

Figures

Introduction

Materials and Methods

Study population

Data collection and definition

Statistical Analysis

Results

Baseline characteristics of individuals according to incident high RC levels

Indices of thyroid hormone sensitivity at baseline based on gender difference

Associations between thyroid hormones sensitivity and incident high RC levels

Associations between thyroid hormones sensitivity and incident high RC levels according to different ages

Discussion

Conclusions

Declarations

References

Additional Declarations

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