Study on the relationship between hormone and Lp(a) in Chinese overweight/obese patients
BMC Endocrine Disorders volume 22, Article number: 131 (2022)
Obesity is a risk factor for metabolic diseases and often influences hormone change. Lipoprotein (a) (Lp(a)) is associated with various metabolic diseases, but there are few studies on the relationship between Lp(a) and hormones in obese patients. This study investigated the the relationship between Lp(a) and hormones in Chinese overweight/obese people.
A total of 410 overweight/obese patients (Body mass index (BMI) ≥ 25 kg/m2) were included and underwent sociodemographic data investigations and relevant clinical examinations. Lp(a) was analyzed by colorimetric enzymatic assays and hormone was measured with chemiluminescence immunoassay method. According to Lp(a) levels, they were categorized into 3 groups: the lower Lp(a) group (Lp(a) levels < 30 mg/dl), the moderate Lp(a) group (Lp(a) levels between 30 mg/dl and 120 mg/dl) and the higher Lp(a) group (Lp(a) levels > 120 mg/dl). The differences of hormone levels among the three groups were compared and the relationship between Lp(a) and hormones was analyzed by Spearman’s rank correlation.
The higher Lp(a) group had significantly lower testosterone (TES) levels compared with the lower and moderate Lp(a) groups in the case of gender, age and BMI matching. Lp(a) concentration was negatively correlated with TES levels in all participants and the negative association between Lp(a) and TES levels was also observed when the analysis was stratified by gender. Additionally, the TES was statistically related with Lp(a) levels in the multiple linear regression model (95% confidence interval: − 0.451 to − 0.079).
TES levels was negatively associated with Lp(a) levels in Chinese overweight/obese patients.
Lipoprotein (a) (Lp(a)) is a complex of an low-density lipoprotein-like (LDL-like) particle that contains an apolipoprotein B100 (apoB100) molecule and a glycoprotein apolipoprotein(a) (apo (a)), which linked by a disulfide bridge . Plasma concentrations of Lp(a) range from 1 mg /dl to 300 mg /dl in human  and are rarely affected by gender, age, lifestyle and food intake . At present, abundant studies have demonstrated that increased Lp(a) is a risk factor for cardiovascular disease especially coronary artery disease and atherosclerosis [4,5,6,7,8]. The relationship between Lp(a) and diabetes remains controversial. Some studies suggested that high Lp(a) levels could increase diabetes risk , some investigations indicated that Lp(a) had no association with diabetes [10, 11], but in recent years, increasing studies demonstrated that T2DM patients had lower Lp(a) levels [6, 12,13,14]. What’s more, Lp(a) is also associated with other metabolic diseases, such as non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (Mets) [15, 16].
Obese patients are often accompanied by glucose and lipid metabolism disorders. Lp(a), as an indicator of lipid metabolism, often changes in obese people. What is more, metabolism disorders can further affect hormone levels. However, there are few studies on Lp(a) and the relationship between Lp(a) and hormones in obese patients. By exploring the association between variation of Lp(a) and various hormone levels in overweight/obese people, we found serum testosterone levels is negatively associated with Lp(a) levels, which maybe provide a new idea for discovering the mechanism between Lp(a) and other diseases.
Materials and methods
Study design and subjects
A total of 410 overweight/obese participants were included in this cross-sectional study from January 2017 to November 2020 at the Medical Nutrition and Weight Loss Center of Beijing Chao-Yang Hospital, Capital Medical University. All of them were asked about their histories of diseases and drugs and received laboratory tests. The inclusion criteria were as follows: age between 15 and 65 years and BMI ≥ 25 kg/m2. The patients with cardiovascular disease, infectious disease, severe hepatic or renal insufficiency, systemic inflammatory disease, cancer, use of hypoglycemic or lipid-lowering drugs were excluded. All subjects were divided into three groups based on the Lp(a) levels: the lower Lp(a) group (Lp(a) levels < 30 mg/dl), the moderate Lp(a) group (Lp(a) levels between 30 mg/dl and 120 mg/dl) and the higher Lp(a) group (Lp(a) levels > 120 mg/dl) .
All participants provided written informed consent. The protocol of this study was approved by the Ethics Committee of Beijing Chao-Yang Hospital, Capital Medical University.
Clinical and biochemical measurements
For each patient, the following demographic data were collected: gender, age, body height and weight. After an overnight fasting, venous blood samples of every subject were obtained for further measurement at the central chemistry laboratory of the Beijing Chao-Yang Hospital, Capital Medical University. Total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and Lp(a) were analyzed by colorimetric enzymatic assays using a Dade Behring Dimension RXL autoanalyzer (Dade Behring Diagnostics, Marburg, Germany). Fasting blood glucose (FBG) was estimated with glucose oxidase method using Hitachi 747 and fasting insulin (FINS) was estimated by chemiluminescence immunoassay using a Centaur XP immunoassay system (Siemens Healthcare Diagnostics, Germany). Growth hormone (GH), testosterone (TES), follicle-stimulating hormone (HFSH), prolactin (PRL), luteinizing hormone (LH) and estradiol (E2) were measured with chemiluminescence immunoassay method using Access 2 immunoassay system (Beckman Coulter, Inc., Brea, CA, USA). Body mass index (BMI) was calculated using following formula: body weight (kg)/[height(m)]2. Homoeostasis model assessment of insulin resistance (HOMA-IR) was used to estimate insulin resistance, which calculated using the following formula: HOMA-IR = FBG (mmol/L) × FINS (mU/L) / 22.5.
All statistical analyses were performed using software SPSS (version 26.0, SPSS Inc., Chicago, IL, USA). For the analysis of differences among groups, the variables of normal distribution, represented by mean ± standard deviation, were assessed with one-way ANOVA and Bonferroni was selected for post-hoc comparison, while non-normally distributed data, expressed by medians with interquartile range, were evaluated with Kruskal-Wallis analysis and Bonferroni analysis was used for correction. The proportions were analyzed by chi-square tests. Spearman’s rank correlation was used to assess the relationship between Lp(a) and other indices. Multiple linear regression analysis (enter method) was used to analyze whether the variables were associated with Lp(a) after adjusting for potential confounding factors. All tests were two-tailed, and P < 0.05 were considered statistically significant.
Characteristics of overweight/obese patients with different levels of Lp(a)
Clinical data pertaining to the metabolism of the overweight/obese patients were presented in Table 1. All subjects were divided into three groups based on the Lp(a) levels: the lower Lp(a) group contained 137 participants, the moderate Lp(a) group contained 137 participants and the higher Lp(a) group contained 136 participants. The levels of LDL-C, TC, GH and TES were increased in the higher Lp(a) group in contrast with the lower Lp(a) group. Moreover, significant differences in LDL-C and TES levels were observed between the higher Lp(a) group and the moderate Lp(a) group. Additionally, other hormones such as HFSH, LH, PRL and E2 did not show difference statistically.
Clinical metabolic characteristics of the gender subgroups were presented in Supplemental Table 1 and Supplemental Table 2. In male subgroup, the higher Lp(a) group showed significantly higher GH and LDL-C concentration and significantly decreased TES concentration relative to the lower Lp(a) group, as well as statistical difference in GH levels between the moderate group and the higher group were observed. In female subgroup, the levels of LDL-C were higher and the levels of TES were lower in the higher Lp(a) group compared with the lower Lp(a) group. Interestingly, the higher Lp(a) group had decreased TES concentration compared with the moderate Lp(a) group. Other parameters did not show difference among three groups in gender subgroups.
Correlation analysis between Lp(a) and other parameters
Table 2 showed that Lp(a) was positively correlated with GH (r = 0.139, P < 0.05) and negatively correlated with TG (r = − 0.142, P < 0.05) and TES (r = − 0.190, P < 0.001) in all participants. Additionally, the negative association between Lp(a) and TES was also observed in the male and female groups respectively (Table 2). Furthermore, there was a significant positive correlation between HDL-C, LDL-C, GH, E2 and Lp(a) while negative correlation between Lp(a) and TG in the male group. We also found Lp(a) was positively correlated with TC and LDL-C in the female group.
Multiple linear regression analysis between Lp(a) and other indices
To further assess the relationship between Lp(a) and other parameters, we conducted a multiple linear regression analysis on the significant variables found by Spearman’s rank correlation analysis or considered clinically relevant, including gender, age, BMI, TC, TG, HDL-C, LDL-C, TES and GH (Table 3). We found that TES levels were independently related with Lp(a) levels (β = − 0.266, P < 0.05, 95% CI = − 0.451 to − 0.079) after adjustment for gender, age, BMI, TC, TG, HDL-C and LDL-C. This significant result was also observed in male and female participants, respectively (Supplemental Table 3 and Supplemental Table 4).
The purpose of this study was to investigated the the relationship between Lp(a) and hormones in Chinese overweight/obese people. Our results showed that serum TC, LDL-C and GH levels were significantly increased in the higher Lp(a) group compared with the lower Lp(a) group, as well as the higher Lp(a) group had higher LDL-C levels compared with moderate groups. Despite comparable clinical parameters, the patients with an increased Lp(a) had lower levels of TES compared with the patients with a moderate and lower Lp(a). We also observed serum TES levels were significantly decreased with the increase of Lp(a) levels whether stratified by gender or not. Multiple regression analyses showed that the TES was independently related with Lp(a) levels after adjusting for confounding factors.
We found Lp(a) always had a significant association with lipid metabolism indices, such as LDL-C. These results reiterated the close relationship between Lp(a), an indicator of lipid metabolism, and other lipid metabolism parameters. As we all know, ApoB100 and apo(a) exist in a molar ratio of 1:1 in Lp(a) and apo(a) can be isolated from the LDL-like portion only by reductive cleavage . What’s more, the main locus controlling Lp(a) concentration is the LPA gene . Lp(a) biosynthesis includes the following processes: (i) transcription of LPA gene; (2) protein translation; (iii) motion through the secretory pathway; (iv) assembly of Lp(a) composition . All of these are likely to be regulated to contribute to concentration of plasma Lp(a). The evidence for extracellular synthesis of apo(a) was found in several human studies, in part from circulating LDL, while evidence for cycling and recombination of apo(a) into Lp(a) has also been represented [19, 20].
In our study, we also found that TES and GH were associated with Lp(a) levels, particularly TES, which indicated hormones were responsible for the concentration of Lp(a). This finding was consistent with previous research, which serum Lp(a) concentration increased after 6 weeks in GH-deficient adults treated with recombinant GH . Moreover, there was a study investigated the effect of TES on Lp(a). The finding reported inhibition of TES lead to increased Lp(a) levels . It also has been reported that Lp(a) is related to bile acid content, body weight change and insulin change [23,24,25,26], but their mechanism has not been clarified. Our research further proofed that TES was negatively correlated with Lp(a) levels whatever in male or female people.
A previous study has reported that serum levels of Lp(a) are related to waist circumference in NAFLD patients with low prevalence of co-morbidities, which proved larger waists, where the thickness of subcutaneous fat exceeds visceral fat, are predictors of levels of serum Lp(a) . Interestingly, waist circumference is inversely associated with total and free TES has been reported by previous investigators in community dwelling men . These conclusions are consistent with our findings. A explanation for the link between Lp(a) and TES maybe come from inflammatory cytokines. It has been reported by earlier studies that IL-17 related chemokine (Eotaxin) is central to the amount of visceral fat and obesity was associated with increased IL-17A production in humans [29, 30]. What is more, testosterone suppresses proinflammatory and up regulates anti inflammatory cytokines [31, 32]. Also there was negative association between IL-17 and TES, indicating inflammation suppresses testosterone levels .
There are several controversial reports on the relationship between Lp(a) concentrations and metabolic diseases. It is well known that Lp(a) has an independent causal association with cardiovascular disease, which has been extensively demonstrated from various aspects. The results of the studies showed that Lp(a) concentration was associated dose-dependently with coronary heart disease risk, peripheral artery disease, heart failure, and lifespan , suggesting that Lp(a) is a potent harbinger of clinical cardiovascular disease . Mendelian randomization analysis further confirmed the above conclusion . However, the effects of Lp(a) on diabetes were not consistent, and it was currently more likely to think that low Lp(a) concentration was associated with diabetes [6, 12,13,14]. Nevertheless, the consensus that diabetes was a risk factor for cardiovascular disease contradicted the above research conclusion. So, we need to further explore the reasons behind it. Additionally, our study provides a basis for the changes of metabolic indicators in clinical patients. For the patients treated with TES, Lp(a) levels may change, leading to other metabolic disorders.
There are several limitations in our study. Firstly, this study is cross-sectional research which resulting to no causal relationship can be drawn. Therefore, prospective studies are needed to confirm the conclusion. Secondly, compared with prior research, our study had a relatively small sample size. Finally, sex hormone secretion including TES, HFSH, LH, PRL and E2 might be affected by the menstrual cycle in female. However, the present study was not standardized for the menstrual cycle.
TES levels was negatively associated with Lp(a) levels in Chinese overweight/obese patients.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Body mass index
High-density lipoprotein cholesterol
Low-density lipoprotein cholesterol
Fasting blood glucose
Homeostasis model assessment of insulin resistance
Borrelli MJ, Youssef A, Boffa MB, Koschinsky ML. New Frontiers in Lp(a)-targeted therapies. Trends Pharmacol Sci. 2019;40(3):212–25. https://doi.org/10.1016/j.tips.2019.01.004.
Kostner KM, Kostner GM, Wierzbicki AS. Is Lp(a) ready for prime time use in the clinic? A pros-and-cons debate. Atherosclerosis. 2018;274:16–22. https://doi.org/10.1016/j.atherosclerosis.2018.04.032.
Littmann K, Wodaje T, Alvarsson M, Bottai M, Eriksson M, Parini P, et al. The Association of Lipoprotein(a) plasma levels with prevalence of cardiovascular disease and metabolic control status in patients with type 1 diabetes. Diabetes Care. 2020;43(8):1851–8. https://doi.org/10.2337/dc19-1398.
Vasquez N, Joshi PH. Lp(a): addressing a target for cardiovascular disease prevention. Curr Cardiol Rep. 2019;21(9):102. https://doi.org/10.1007/s11886-019-1182-0.
Mehta A, Virani SS, Ayers CR, Sun W, Hoogeveen RC, Rohatgi A, et al. Lipoprotein(a) and family history predict cardiovascular disease risk. J Am Coll Cardiol. 2020;76(7):781–93. https://doi.org/10.1016/j.jacc.2020.06.040.
Gudbjartsson DF, Thorgeirsson G, Sulem P, Helgadottir A, Gylfason A, Saemundsdottir J, et al. Lipoprotein(a) concentration and risks of cardiovascular disease and diabetes. J Am Coll Cardiol. 2019;74(24):2982–94. https://doi.org/10.1016/j.jacc.2019.10.019.
Shah NP, Wang Q, Wolski KE, Cho L, McErlean E, Ruotolo G, et al. The role of lipoprotein (a) as a marker of residual risk in patients with diabetes and established cardiovascular disease on optimal medical therapy: post hoc analysis of ACCELERATE. Diabetes Care. 2020;43(2):e22–4. https://doi.org/10.2337/dc19-1117.
Saleheen D, Haycock PC, Zhao W, Rasheed A, Taleb A, Imran A, et al. Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis. Lancet Diabetes Endocrinol. 2017 Jul;5(7):524–33. https://doi.org/10.1016/S2213-8587(17)30088-8.
Jenkins AJ, Steele JS, Janus ED, Santamaria JD, Best JD. Plasma apolipoprotein (a) is increased in type 2 (non-insulin-dependent) diabetic patients with microalbuminuria. Diabetologia. 1992;35(11):1055–9. https://doi.org/10.1007/bf02221681.
Császár A, Dieplinger H, Sandholzer C, Karádi I, Juhász E, Drexel H, et al. Plasma lipoprotein (a) concentration and phenotypes in diabetes mellitus. Diabetologia. 1993;36(1):47–51. https://doi.org/10.1007/bf00399092.
Levitsky LL, Scanu AM, Gould SH. Lipoprotein(a) levels in black and white children and adolescents with IDDM. Diabetes Care. 1991;14(4):283–7. https://doi.org/10.2337/diacare.14.4.283.
Paige E, Masconi KL, Tsimikas S, Kronenberg F, Santer P, Weger S, et al. Lipoprotein(a) and incident type-2 diabetes: results from the prospective Bruneck study and a meta-analysis of published literature. Cardiovasc Diabetol. 2017;16(1):38. https://doi.org/10.1186/s12933-017-0520-z.
Ding L, Song A, Dai M, Xu M, Sun W, Xu B, et al. Serum lipoprotein (a) concentrations are inversely associated with T2D, prediabetes, and insulin resistance in a middle-aged and elderly Chinese population. J Lipid Res. 2015;56(4):920–6. https://doi.org/10.1194/jlr.P049015.
Ye Z, Haycock PC, Gurdasani D, Pomilla C, Boekholdt SM, Tsimikas S, et al. The association between circulating lipoprotein(a) and type 2 diabetes: is it causal? Diabetes. 2014;63(1):332–42. https://doi.org/10.2337/db13-1144.
Nam JS, Jo S, Kang S, Ahn CW, Kim KR, Park JS. Association between lipoprotein(a) and nonalcoholic fatty liver disease among Korean adults. Clin Chim Acta. 2016;1(461):14–8. https://doi.org/10.1016/j.cca.2016.07.003.
Sung KC, Wild SH, Byrne CD. Lipoprotein (a), metabolic syndrome and coronary calcium score in a large occupational cohort. Nutr Metab Cardiovasc Dis. 2013;23(12):1239–46. https://doi.org/10.1016/j.numecd.2013.02.009.
Schmidt K, Noureen A, Kronenberg F, Utermann G. Structure, function, and genetics of lipoprotein (a). J Lipid Res. 2016;57(8):1339–59. https://doi.org/10.1194/jlr.R067314.
Kronenberg F, Tsimikas S. The challenges of measuring Lp(a): a fight against Hydra? Atherosclerosis. 2019;289:181–3. https://doi.org/10.1016/j.atherosclerosis.2019.08.019.
Demant T, Seeberg K, Bedynek A, Seidel D. The metabolism of lipoprotein(a) and other apolipoprotein B-containing lipoproteins: a kinetic study in humans. Atherosclerosis. 2001;157(2):325–39. https://doi.org/10.1016/s0021-9150(00)00732-2.
Jenner JL, Seman LJ, Millar JS, Lamon-Fava S, Welty FK, Dolnikowski GG, et al. The metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein (a) in human beings. Metabolism. 2005;54(3):361–9. https://doi.org/10.1016/j.metabol.2004.10.001.
Edén S, Wiklund O, Oscarsson J, Rosén T, Bengtsson BA. Growth hormone treatment of growth hormone-deficient adults results in a marked increase in Lp(a) and HDL cholesterol concentrations. Arterioscler Thromb. 1993;13(2):296–301. https://doi.org/10.1161/01.atv.13.2.296.
von Eckardstein A, Kliesch S, Nieschlag E, Chirazi A, Assmann G, Behre HM. Suppression of endogenous testosterone in young men increases serum levels of high density lipoprotein subclass lipoprotein A-I and lipoprotein(a). J Clin Endocrinol Metab. 1997;82(10):3367–72. https://doi.org/10.1210/jcem.82.10.4267.
Chennamsetty I, Claudel T, Kostner KM, Baghdasaryan A, Kratky D, Levak-Frank S, et al. Farnesoid X receptor represses hepatic human APOA gene expression. J Clin Invest. 2011;121(9):3724–34. https://doi.org/10.1172/JCI45277.
Berk KA, Yahya R, Verhoeven AJM, Touw J, Leijten FP, van Rossum EF, et al. Effect of diet-induced weight loss on lipoprotein(a) levels in obese individuals with and without type 2 diabetes. Diabetologia. 2017;60(6):989–97. https://doi.org/10.1007/s00125-017-4246-y.
Williams DB, Hagedorn JC, Lawson EH, Galanko JA, Safadi BY, Curet MJ, et al. Gastric bypass reduces biochemical cardiac risk factors. Surg Obes Relat Dis. 2007;3(1):8–13. https://doi.org/10.1016/j.soard.2006.10.003.
Neele DM, de Wit EC, Princen HM. Insulin suppresses apolipoprotein(a) synthesis by primary cultures of cynomolgus monkey hepatocytes. Diabetologia. 1999;42(1):41–4. https://doi.org/10.1007/s001250051110.
Tarantino G, Finelli C, Gioa S, Citro V, La Sala N, Gentile M. Serum levels of Lp(a) are related to waist circumference in NAFLD patients with low prevalence of co-morbidities. Scand J Clin Lab Invest. 2016;76(7):544–52. https://doi.org/10.1080/00365513.2016.1207249.
Svartberg J, von Mühlen D, Sundsfjord J, Jorde R. Waist circumference and testosterone levels in community dwelling men. Tromsø study Eur J Epidemiol. 2004;19(7):657–63. https://doi.org/10.1023/b:ejep.0000036809.30558.8f.
Tarantino G, Costantini S, Finelli C, Capone F, Guerriero E, La Sala N, et al. Is serum Interleukin-17 associated with early atherosclerosis in obese patients? J Transl Med. 2014;6(12):214. https://doi.org/10.1186/s12967-014-0214-1.
Sumarac-Dumanovic M, Stevanovic D, Ljubic A, Jorga J, Simic M, Stamenkovic-Pejkovic D, et al. Increased activity of interleukin-23/interleukin-17 proinflammatory axis in obese women. Int J Obes. 2009;33(1):151–6. https://doi.org/10.1038/ijo.2008.216.
D'agostino P, Milano S, Barbera C, Di Bella G, La Rosa M, Ferlazzo V, et al. Sex hormones modulate inflammatory mediators produced by macrophages. In: Cutolo M, Masi AT, Bijlsma JWJ, Chikanza IC, Bradlow HL, Castagnetta L, editors. Neuroendocrine Immune Basis of the Rheumatic Diseases. Volume 876, edn. New York: New York Acad Sciences; 1999. p. 426–9. https://doi.org/10.1111/j.1749-6632.1999.tb07667.x.
Liva SM, Voskuhl RR. Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production. J Immunol. 2001;167(4):2060–7. https://doi.org/10.4049/jimmunol.167.4.2060.
Keshri N, Nandeesha H, Kattimani S. Elevated interleukin-17 and reduced testosterone in bipolar disorder. Relation with suicidal behaviour. Asian J Psychiatr. 2018;36:66–8. https://doi.org/10.1016/j.ajp.2018.06.011.
This work was supported by grants from the Beijing Talents foundation (2018–12) to J.L.; and the Chinese National Natural Science Foundation (No. 81770792) to G.W.
Ethics approval and consent to participate
All participants provided written informed consent. The protocol of this study was approved by the Ethics Committee of Beijing Chao-Yang Hospital, Capital Medical University. All methods were carried out in accordance with relevant guidelines and regulations.
Consent for publication
The authors declare that they have no competing interests
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Characteristics of male participants with various levels of Lp(a). Supplemental Table 2. Characteristics of female participants with various levels of Lp(a). Supplemental Table 3. Multiple linear regression between Lp(a) levels and other parameters in male participants. Supplemental Table 4. Multiple linear regression between Lp(a) levels and other parameters in female participants.
About this article
Cite this article
Chang, X., Bian, N., Ding, X. et al. Study on the relationship between hormone and Lp(a) in Chinese overweight/obese patients. BMC Endocr Disord 22, 131 (2022). https://doi.org/10.1186/s12902-022-01021-7
- Regression analysis