|Year : 2019 | Volume
| Issue : 2 | Page : 251-256
Sertoli cell function in young males with metabolic syndrome
Uma Kaimal Saikia, Kunjan Saikia, Dipti Sarma, Sonali Appaiah
Department of Endocrinology, Gauhati Medical College, Guwahati, Assam, India
|Date of Web Publication||21-May-2019|
Uma Kaimal Saikia
Department of Endocrinology, Gauhati Medical College, Guwahati - 781 032, Assam
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Context: The last few decades have witnessed an alarming increase in the prevalence of the metabolic syndrome (MetS) worldwide including India. Apart from the known risks of MetS in terms of cardiovascular risk and mortality, there is increasing evidence that it also leads to alteration in testicular function and fertility. Aims: To assess the presence of hypogonadism and Sertoli cell dysfunction in young adult males with MetS and correlate these parameters with different components of the MetS. Settings and Design: Cross-sectional study conducted in the Department of Endocrinology, Gauhati Medical College, a tertiary care hospital in North East India. Subjects and Methods: Young adult males with MetS aged 20–40 years and age-matched healthy males who served as controls were examined clinically. Laboratory investigations done in the fasting state included blood glucose, lipid profile, serum follicle-stimulating hormone (FSH), inhibin B and total testosterone (Te). Semen was collected after 3 days abstinence and analysis done. Statistical Analysis: Baseline parameters were presented as median and 'Kruskal–Wallis' test was used to compare them. Pearson test and multiple regression analysis were used to assess the correlation and association between variables. Results: Fifty cases with MetS and 30 controls were included in the study. Subjects with MetS had significantly lower levels of total Te, FSH and inhibin B. They also had significantly lower semen volume, sperm count and total as well as progressive motility. There was a significant negative correlation of waist circumference and positive correlation of inhibin B with total sperm count. A significant negative association of serum triglycerides with semen volume was also found. Conclusion: MetS is a state of hypogonadotropic hypogonadism as reflected by low total Te, FSH and inhibin B levels with semen abnormalities reflecting Sertoli cell dysfunction.
Keywords: Hypogonadism, metabolic syndrome, Sertoli cell, sperm abnormalities
|How to cite this article:|
Saikia UK, Saikia K, Sarma D, Appaiah S. Sertoli cell function in young males with metabolic syndrome. Indian J Endocr Metab 2019;23:251-6
|How to cite this URL:|
Saikia UK, Saikia K, Sarma D, Appaiah S. Sertoli cell function in young males with metabolic syndrome. Indian J Endocr Metab [serial online] 2019 [cited 2021 Mar 1];23:251-6. Available from: https://www.ijem.in/text.asp?2019/23/2/251/258686
| Introduction|| |
The last few decades have witnessed an alarming increase in the prevalence of metabolic syndrome (MetS) worldwide including India. A recent study in urban Eastern India of 1178 adults has shown a prevalence of 24.9% in males and 42.3% in females. Another recent study from Dibrugarh town of Assam in North Eastern India found a prevalence of MetS of 47.6% in an urban population of 1700 subjects. Apart from the known risks of MetS in terms of cardiovascular risk and mortality, there is increasing evidence that it also leads to alteration in testicular function and fertility. Various studies have focused on the association of MetS with suppression of Leydig cell function as reflected by low serum testosterone levels. Recent studies have also highlighted the occurrence of Sertoli cell dysfunction in subjects with MetS. The Sertoli cells provide developing germ cells with structural and hormonal support. Inhibin B is a dimeric peptide produced in the testis by the Sertoli cells and is emerging as a marker of Sertoli cell function. Animal studies have shown that the neonatal and pubertal period witness an increase in the number of Sertoli cells along with a rise of circulating inhibin B levels. In the adult testis the Sertoli cells occupy around 25% of the volume of the seminiferous tubules and each Sertoli cell surrounds several germ cells providing structural and biochemical support.
Inhibin B levels have been found to decline with increasing obesity in young adult males possibly indicating that obese men have fewer Sertoli cells than normal weight men. Defects in spermatogenesis have also been described in men with obesity and MetS including low ejaculatory volume, sperm count, sperm concentration and defects in motility. Abnormal spermatozoal mitochondrial membrane potential (MMP) and sperm with high DNA fragmentation have also been reported in men with MetS., Hypogonadism with low testosterone and low sex hormone-binding globulin (SHBG) levels in young adults with MetS have been reported previously from our centre. Data on the defects in spermatogenesis in adult males with the MetS are lacking from North East India. The present study was designed to assess the presence of hypogonadism and Sertoli cell dysfunction in young adult males with MetS.
| Subjects and Methods|| |
This study was conducted in the Department of Endocrinology, Gauhati Medical College which is a tertiary care hospital in North East India. A total of 50 subjects in the age group of 20–40 years who fulfilled the International Diabetes Federation (IDF) 2005 criteria for the diagnosis of MetS were included. Thirty age-matched men without MetS were taken as controls. Subjects having a known genetic disorder causing hypogonadism, a history of pituitary disease or any central nervous system (CNS) lesion, any testicular pathology like testicular tumours, genital tract infection, varicocele or undescended testis, mumps or orchitis, testicular trauma, radiation or reproductive organ surgery, any medication known to affect testicular function, thyroid disease or any major systemic illness were excluded from the study. The study was approved by the institutional ethics committee and informed consent was taken from the participants.
A thorough clinical evaluation of the subjects was done including body mass index (BMI), waist circumference (WC), blood pressure (BP) and genital examination. When measuring the WC the recommendation made by the National Heart, Lung, and Blood Institute (NHBLI) was followed. Blood samples were collected from the subjects in the fasting state for glucose and lipid profile. Pooled samples were collected for follicle-stimulating hormone (FSH), total testosterone (Te) and inhibin B in the fasting state and stored at −20°C. Plasma glucose and lipid profile estimation were done by the auto analyzer Vitros 5600. The assays for FSH and Te were performed by radioimmunoassay. The normal range of Te was taken as 2.5–8.5 ng/ml with an intra- and interassay coefficient of variation (CV) of 6.15% and 5.8%, respectively. Normal range of FSH was 1.3–11.5 IU/L and intra- and interassay CV was 4.2% and 4.6%, respectively. Inhibin B was measured by the enzyme-linked immunosorbant assay (ELISA). The normal range was 25–325 pg/ml and intra- and interassay CV was <10% and <12%, respectively.
Semen was collected for analysis after 3 days of abstinence in a wide mouth sterile container. The analysis was performed according to the World Health Organisation (WHO) 2010 guidelines and appearance, volume, count, morphology and motility noted.
Statistical analysis was performed by the use of the Statistical Analysis Software (SAS) 9.3. Baseline parameters were presented as median and 'Kruskal–Wallis' test was used to compare the median values. Pearson correlation was done to find out the pattern of correlation between the independent variables. Multiple regression analysis was carried out to see the association between different variables. Statistical significance was set at P value of ≤ 0.05.
| Results|| |
The baseline characteristics of the cases and controls are shown in [Table 1]. As expected subjects with MetS had significantly higher WC, BMI, systolic and diastolic blood pressure (SBP and DBP), fasting blood glucose (FBG), triglyceride (TG) and lower high-density lipoprotein (HDL) levels as compared to the controls. The serum levels of total Te, FSH and iInhibin B were significantly lower than the controls in subjects of MetS.
|Table 1: The comparison of clinical, biochemical and hormonal parameters of cases and controls|
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Comparison of semen parameters in subjects of MetS with that of controls showed significantly lower total sperm count, volume and lower total as well as progressive motility in the MetS group [Table 2]. No difference was found regarding sperm morphology between the two groups.
When the correlation of different variables with semen parameters was analysed in the subjects of MetS, it was seen that the WC has a significant negative correlation with the total sperm count. No correlation with the other parameters of semen was observed. Among the hormones a significant positive correlation of inhibin B was found with total count while the correlation of the other hormones and semen parameters were not significant [Table 3].
|Table 3: Correlation of different variables with semen parameters in cases (n=50)|
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Multiple regression analysis in the subjects with MetS showed WC and inhibin B to have a significant negative and positive association with total sperm count, respectively. The other parameters did not have any significant association with the sperm count [Table 4]. No significant association of any of the parameters with total motility, progressive motility or sperm morphology was seen.
|Table 4: Multiple regression analysis of variables in relation to sperm count in cases (n=50)|
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In the control group the correlation analysis did not show any relation of WC to semen parameters [Table 5]. However, there was a significant negative correlation of age with volume and total motility of semen. Multiple regression analysis showed a significant negative association of serum TG with semen volume in cases [Table 6].
|Table 5: Correlation of different variables with semen parameters in controls (n=30)|
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|Table 6: Multiple regression analysis of variables in relation to semen volume in cases (n=50)|
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| Discussion|| |
Hypogonadism is a feature of MetS and is postulated to be multifactorial. One of the principal mechanisms is a state of hyperestrogenic hypogonadotropic hypogonadism induced by excess aromatase activity in MetS patients because of obesity, which results in both lower total and free Te levels. The resulting low Te increases lipoprotein lipase activity and TG uptake leading to increased obesity and insulin resistance and further androgen deficiency. High leptin levels in obese men have also been postulated to play a role in reduced androgen levels in obese men. MetS is considered to be a state of low-grade inflammation. High levels of inflammatory cytokines have been found in seminal fluid of patients with MetS reflecting a local reproductive tract inflammatory state which may have direct detrimental effect on the hypothalamo-pituitary-testicular axis, negatively modulating male reproductive function. In the present study serum total Te, inhibin B and FSH levels were significantly lower in subjects with MetS as compared to controls possibly reflecting a state of impaired Sertoli and Leydig cell function combined with an inadequate gonadotropin response due to obesity. Gonadotropin release from the pituitary could be suppressed due to estrogen and proinflammatory cytokines released due to increased adiposity creating a state of secondary hypogonadism. Our findings are in concordance with the study of Robeva et al. of 20 men with MetS and 20 age-matched non-obese men who also documented significantly lower levels of Te and SHBG and has also been seen in meta-analysis of various studies., An inverse relation between inhibin B levels and BMI has been found in a cross-sectional study of 1558 young men. Declining levels of inhibin B with increasing obesity with 26% lower levels in obese men have also been reported. Which of the two hormones FSH or inhibin B better reflects Sertoli cell dysfunction of MetS? For answering this question linear regression analysis was carried out and it was found that only inhibin B had a significant positive relationship with the total sperm count even after adjusting for age. Neither FSH nor total Te showed any significant relationship with any of the semen parameters. The superiority of inhibin B as a better marker of spermatogenesis than FSH has also been demonstrated in previous studies.,
The pattern of semen abnormalities observed among the cases in the present study, is consistent with several studies done on semen abnormalities of subjects with higher BMI. Jensen et al. in their study of 1558 Danish men observed a lower sperm concentration and total count in men with BMI >25 kg/m2. Stewart et al. examined the semen quality in fertile Australian men and demonstrated that BMI was an independent factor related to total sperm count. There was a significant lower total sperm count in obese men with BMI of >30 kg/m2. A recent Iranian study by Hajshafiha et al. done on 159 male patients who attended an infertility clinic concluded that at higher BMI values the likelihood of oligospermia increased. Obese men were found to be 3.5 times more likely to have oligospermia as compared to normal counterparts.
As regards motility, the findings of decreased total and progressive motility of sperms in the subjects with MetS corroborates with the results of two previously published studies. Kort et al. in their study of 520 men demonstrated that in those with BMI >25 kg/m2 there was decreased total motility of sperms per ejaculate. It was also observed in the study that BMI had a significant negative relationship with sperm motility. La Vignera et al. observed that in overweight and obese men there was a significantly lower progressive motility of sperms along with significantly more sperms with abnormal morphology. An additional finding of our study, which was not seen in several earlier studies, is the lower semen volume in subjects of MetS. However a recent study of 32 men with MetS found significantly reduced levels for ejaculate volume, sperm concentration, total sperm count, sperm vitality and total and progressive motility as compared to the control group. The percentages of sperm with abnormal MMP and DNA fragmentation were also found to be significantly increased.
Correlation analysis of the present study showing a significant negative correlation of WC but not BMI with total sperm count could be explained in two ways. Firstly, the cases were selected based on the WC primarily and not on BMI. Second, the disparity observed with these two closely related parameters could be due to statistical analysis of a small number of cohorts. Nevertheless, this does not alter the conclusion that obesity which is a part of MetS has significant correlation with the decreased total sperm count.
The other parameters of semen analysis – motility, morphology and volume did not show any significant correlation with either BMI or WC and is in accordance with the correlation analysis of the aforementioned studies. We found a significant negative association of serum TG levels with semen volume. A potential link between lipids and sperm parameters has been suggested by previous animal and human studies. In the Longitudinal Investigation of Fertility and Environment (LIFE) study a significant negative association was observed between total cholesterol and semen volume while free cholesterol was negatively associated with percent sperm head with acrosome, sperm head area and sperm head perimeter. Another study has shown that increased TGs correlate with significantly reduced sperm motility in a group of infertile men. The mechanism is not clear but hormone sensitive lipase (HSL) which liberates free fatty acids from TGs may play a key role. Fatty acids are important for spermatogenesis.
The limitation of the study is a small sample size of the study cohort. Another limitation is that it was total Te that was measured without estimation of SHBG or free Te levels and hence this should be kept in mind while interpreting Te levels.
| Conclusion|| |
MetS is a state of hypogonadotropic hypogonadism as reflected by low testosterone, FSH and inhibin B levels. The Sertoli cell dysfunction of MetS is evident in low total sperm count, volume, low total and progressive motility with normal sperm morphology as compared to healthy non-obese controls. There is a negative correlation of WC with total sperm count. TG levels have a significant negative association with semen volume. Among the hormones only inhibin B has a significant positive association with total sperm count, thus demonstrating its superiority over FSH as a marker of Sertoli cell function.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Prasad DS, Kabir Z, Dash AK, Das BC. Prevalence and risk factors for metabolic syndrome in Asian Indians: A community study from urban Eastern India. J Cardiovasc Dis Res 2012;3:204-11. [Full text]
Mahanta TG, Joshi R, Mahanta B, Gogoi P. Determinants of metabolic syndrome amongst persons living in Dibrugarh district of Assam. Clin Epidemiol Glob Health 2017;5:52-61.
Mrukk DD, Cheng CY. Sertoli and Sertoli germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis. Endocr Rev 2004;25:747-806.
Winters SJ, Wang C, Abdelrahaman E, Hadeed V, Dyky MA, Brufsky A. Inhibin B levels in healthy young adult men and pre pubertal boys: Is obesity the cause for the contemporary decline in sperm count because of fewer Sertoli cells? J Androl 2006;27:560-4.
De Krestrer DM, Loveland K, O Bryan M. Spermatogenesis. Endocrinology Adult and Paediatric. Jameson and DeGroot 7th
ed. 2016. p. 2325-53.
Leisegang K, Bovic PJD, Henkel RR. Metabolic syndrome is associated with increased seminal fluid cytokines and reproductive dysfunction in a case controlled male cohort. Am J Reprod Immunol 2016;76:155-63.
Michalakis K, Mintziori G, Kapraro A, Tarlatzis B, Goulis DG. The complex interaction between obesity, MS and reproductive axis: A narrative review. Metab Clin Exp 2013;62:457-78.
Choudhury BK, Choudhury SD, Saikia UK, Sarma D. Gonadal function in young adult males with metabolic syndrome. Diabetes Metab Syndr 2013;7:129-32.
NHBLI Obesity Education Initiative: Practical Guide to the Identification, Evaluation and Treatment of Overweight and Obesity in Adults 2000.
WHO laboratory manual for the Examination and Processing of human semen 2010.
Hammoud AD, Gibson M, Peterson CM, Hamilton BD, Carrell DT. Obesity and male reproductive potential. J Androl 2006;27:619-26.
Mah PH, Wittert GA. Obesity and testicular function. Mol Cell Endocrinol 2010;316:180-6.
Jones TH. Testosterone associations with erectile dysfunction, diabetes and the metabolic syndrome. Eur Urol Suppl 2007;6:847-57.
Robeva R, Tomova A, Kirilov G, Kumanov P. Anti Mullerian hormone and Inhibin B levels reflect altered Sertoli cell function in men with Metabolic Syndrome. Andrologia 2012;44:329-34.
Corona G, Monami M, Rastrelli G, Aversa A, Tishova Y, Saad F, et al.
Testosterone and Metabolic syndrome: A meta analysis study. J Sex Med 2011;8:272-83.
Brand JS, Van der Tweal I, Grebbee DE, Emmelot Vonk MH, Van der Schouw YT. Testosterone, sex hormone binding globulin and the metabolic syndrome: A systematic review and meta-analysis of observational studies. Int J Epidemiol 2011;40:189-207.
Jensen TK, Andersson AM, Jorgensen N, Andersen AG, Carlsen E, Petersen JH, et al.
Body mass index in relation to semen quality and reproductive hormones among 1,558 Danish men. Fertil Steril 2004;82:863-70.
Jensen TK, Andersson AM, Hjollund NH, Scheike T, Kolstad H, Giwercman A, et al.
Inhibin B as a serum marker of spermatogenesis: Correlation to differences in sperm concentration and follicle stimulating hormone levels. A study of 349 Danish men. J Clin Endocrinol Metab 1997;82:4059-63.
Kumanov P, Nandipati K, Tomova A, Agarwal A. Inhibin B is a better marker of spermatogenesis than other hormones in the evaluation of male factor infertility. Fertil Steril 2006;86:332-8.
Stewart TM, Liu DY, Garrett C, Jorgensen N, Brown EH, Baker HWG. Association between andrological measures, hormones and semen quality in fertile Australian men: Inverse relationship between obesity and sperm output. Hum Reprod 2009;24:1561-8.
Hajshafiha M, Ghareaghaji R, Salemi S, Sadegh-Asadi N, Sadeghi-Bazargani H. Association of body mass index with some fertility markers among male partners of infertile couples. Int J General Med 2013;6:447-51.
Kort HI, Massey JB, Elsner CW, Mitchell-Leaf D, Shapiro DB, Witt MA, et al.
Impact of body mass index values on sperm quantity and quality. J Androl 2006;27:450-2.
La Vignera S, Condorelli RA, Vicari E, Calogero AE. Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters. J Androl 2012;33:53-8.
Schisterman EF, Mumford SL, Chen Z, Browne RW, Barr DB, Kim S, et al.
Lipid concentrations and Semen quality: The LIFE Study. Andrology 2014;2:408-15.
Ergun A, Kose SK, Aydos K, Ata A, Avci A. Correlation of seminal parameters with serum lipid profile and sex hormones. Arch Androl 2007;53:21-3.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]