Immune-inflammation markers are related to hormone levels in polycystic ovary syndrome: a case-control study

Abstract

Background

We aimed to evaluate the relationships between the pan immune-inflammation value (PIV), the systemic immune-inflammation index (SII), and hormonal levels in patients with polycystic ovary syndrome (PCOS).

Methods

160 patients with PCOS and 142 healthy participants took part in the study. Demographic characteristics, lymphocytes, monocytes, neutrophils, white blood cells (WBC), platelets, fasting glucose levels, hormonal parameters as insulin, dehydroepiandrosterone sulfate (DHEASO₄), prolactin, free and total testosterone, estradiol, luteinizing hormone (LH), 17-OH-progesterone, follicle-stimulating hormone (FSH), and 11-deoxycorticosterone were examined. Hematological indices, SII and PIV, were calculated. Receiver operating characteristic (ROC) analysis showed the diagnostic potential of the research parameters.

Results

The median WBC, SII and PIV values (7.63, 605.5, 312.69, respectively) were significantly higher in patients (p = 0.023; p < 0.001; p = 0.002; respectively). The median free testosterone, 17-OH progesterone, and LH values were also significantly higher in PCOS group (p = 0.009, p = 0.017, p = 0.012, respectively). Statistically significant and positive correlations were found between SII and insulin, SII and DHEA-SO₄, PIV and insulin, and PIV and DHEA-SO₄ levels (p = 0.006, p = 0.003, p = 0.037, p = 0.042, respectively). A statistically significant and positive correlation was also observed between PIV and free testosterone levels (p = 0.008). We found that a baseline serum SII > 520.0 and PIV > 262.4 were associated with PCOS with 65% specificity and 61% sensitivity for the SII (area under the curve [AUC], 0.669; 95% CI 0.584–0.755; p < 0.001) and 58% specificity and 60% sensitivity for the PIV ([AUC], 0.642; 95% CI 0.555–0.729; p = 0.002).

Conclusions

Monitoring SII and PIV may assist clinicians in evaluating inflammation and treatment needs in patients with PCOS.

Clinical trial number

Not applicable.

Introduction

Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects women of reproductive age. This syndrome leads to metabolic and cardiovascular disorders associated with infertility, obesity and insulin resistance. PCOS is a systemic, polygenic also an autoimmune and inflammatory disease. The genes controlling the steroidogenesis and androgenesis pathways go by the name of contributing the pathophysiology of PCOS [1, 2]. Anovulation and/or oligoovulation causes cysts in the ovarian antral follicles, and some of these cysts produce androgens. Therefore, PCOS causes a number of hyperandrogenism findings to occur. At the Rotterdam consensus workshop (2003), hyperandrogenism, menstrual cycle irregularities and insulin resistance were defined as the main characteristics of PCOS [3].

Lipid profiles, blood pressure and cycle duration (as anthromorphometric parameters), mean ovarian volume and follicle count (as ultrasonographic parameters), thyroid function tests, prolactin, AMH, FSH, testosterone, SHBG and free androgen index (as endocrine parameters) all may indicate PCOS [4]. Excess abdominal fat mass increases inflammation; thus, androgen levels increase, ovulation is inhibited, and metabolic functions become irregular [5].

The systemic immune inflammation index (SII) is an integrated inflammatory biomarker [6] and can reflect the local immune response and systemic inflammation [7, 8]. Studies have focused on the clinical consequences of immune-inflammatory mechanisms in various diseases recently. The pan immune-inflammation value (PIV), a new inflammatory marker, can reflect the systemic inflammatory response more comprehensively by combining and evaluating neutrophil, monocyte, platelet and lymphocyte counts [9, 10]. Both indices are non-invasive, easily obtained, and can correlate with inflammation activity and severity for PCOS to demonstrate the peripheral effects of hormone levels in the disease.

Studies investigating the relationship between PCOS and inflammation are available in the literature [11–13], but to the best of our knowledge, our study is the first to evaluate the relationship between two new inflammation markers (SII and PIV) and the hormonal levels of patients with PCOS.

Methodology

Our study was conducted in accordance with the standards of the Declaration of Helsinki. Our study protocol was approved by Erciyes University Faculty of Medicine Ethics Committee (year: 2019, no: 841).

Our study included newly diagnosed 160 patients with PCOS presented to our hospital’s endocrinology outpatient clinic in 2017 and were diagnosed according to the Rotterdam criteria. The control group consisted of 142 healthy participants without signs of hirsutism and PCOS. The biochemical test results of the patients were accessed through the hospital laboratory information system, and our study was planned to retrospectively evaluate the results approved by a biochemistry specialist. It’s a standard practice to draw blood in the early follicular phase (typically cycle days 2–5, and often specifically day 3 of the menstrual cycle) and in the early morning in our endocrinology clinics. The fasting glucose and insulin hormone levels of the patients were measured with an Olympus AU2700 (Beckman Coulter), and the other hormone levels were measured (DHEA-SO₄, prolactin, total testosterone, free testosterone, FSH, LH, estradiol, 17-OH-progesterone, and 11-deoxycorticosterone) with an Immulite 2000 hormone autoanalyzer (Siemens Healthcare Diagnostics).

Other inflammation markers were calculated according to the following formulas: SII = platelet (PLT) count (10³/mm³) × neutrophil count / lymphocyte count, PIV = neutrophil count (10³/mm³) × PLT count (10³/mm³) × monocyte count (10³/mm³) / lymphocyte count (10³/mm³).

High body mass index (BMI > 25) is one of the main factors that aggravate inflammation and PCOS. So, BMI values were calculated for each participant in the two groups.

Hormone replacement therapy, previous anti-inflammatory medication, pregnancy, malignancy, acute or chronic kidney and/or liver disease, the presence of active infection and recent surgery were among the exclusion criteria for the study.

Statistical analysis

The Kolmogorov-Smirnov and Shapiro-Wilk tests were used to analyse the normal distribution of the variables. We used Student’s t test to replace variables with a normal distribution, and the Mann-Whitney U test to determine variables that were not normally distributed. Continuous variables with a nonnormal distribution were presented as the median and interquartile range (25–75%) and normally distributed continuous variables were presented as the mean ± standard deviation (SD). Spearman’s maintenance coefficients were recorded for consistency values between parameters. Receiver operating characteristic (ROC) curve analyses were performed for WBC, SII and PIV for screening patients with PCOS to controls. Values of p < 0.05 were considered significant. All of the statistical analyses were done by version 23.0 SPSS software for Windows (SPSS Inc., USA).

Results

The age information and biochemical test results of the patients are summarized in Table 1. The mean ages in the PCOS and control groups were 22.9 ± 4.7 and 23.3 ± 5.1 years, respectively (p > 0.05). BMI values were not statistically different in the two groups (p > 0.05).

Table 1.

Comparison of the baseline characteristics and biochemical parameters of the study groups

	PCOS group	Control group	p value
Number of participants	160	142	-
Age (years)	22.97 ± 4.71	23.33 ± 5.14	> 0.05
BMI (kg/m2)	< 24.9 (10%)	< 24.9 (10%)	> 0.05
	25-29.9 (50%)	25-29.9 (60%)
	30-34.9 (40%)	30-34.9 (30%)
	35-39.9 (0%)	35-39.9 (0%)
WBC (x103/mm3)	7.63 (6.44–9.27)	7.1 (6.22–8.61)	0.023*
PLT (x103/mm3)	332.46 ± 11.96	315.65 ± 14.19	0.439
Neutrophil (x103/mm3)	4.37 ± 0.21	4.28 ± 0.12	0.069
Lymphocyte (x103/mm3)	2.48 ± 0.09	2.49 ± 0.006	0.997
Monocyte (x103/mm3)	0.53 ± 0.02	0.51 ± 0.01	0.446
Fasting glucose (mg/dL)	93 (88–101)	89.5 (85–95)	0.603
Insulin (µIU/mL)	9.71 (7.10-13.42)	8.29 (5.70-11.16)	0.799
DHEA-SO4 (µg/dL)	282.32 ± 24.16	248.19 ± 20.52	0.620
Prolactin (ng/mL)	14.68 (9.25–23.70)	14.17 (10.29–19.42)	0.234
17-OH progesterone (ng/mL)	0.408 (0.28–0.679)	0.377 (0.268–0.502)	0.017*
Total testosterone (ng/mL)	0.624 ± 0.24	0.564 ± 0.22	0.112
Free testosterone (pg/mL)	2.13 (1.53–2.93)	1.66 (1.26–2.04)	0.009*
FSH (mIU/mL)	6.67 (5.23–8.20)	7.17 (6.01–8.84)	0.23
LH (mIU/mL)	13.12 (10.86–16.62)	5.03 (3.88–8.77)	0.002*
Estradiol (pg/mL)	46.5 (36.5–58.5)	49 (31.25–69.5)	0.537
11-deoxycortisol (ng/mL)	2.94 (1.75–3.87)	2.95 (2.12–3.82)	0.598
SII	605.5 (457.53-928.19)	469.27 (374.09-486.99)	0.000**
PIV	312.69 (214.36-492.58)	244.32 (171.15–349.2)	0.002*

WBC, white blood cell; PLT, platelet; DHEA-SO₄, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; LH, luteinizing hormone; SII, systemic immune inflammation index; PIV, pan immune-inflammation value. Student’s t-test was used for group comparisons; the data are presented as the means ± SDs. The Mann-Whitney U test was used; the data are presented as the median and interquartile range (25–75%). *p < 0.05, p < 0.001** statistically significant

The median WBC, SII and PIV values (7.63, 605.5, and 312.69, respectively) were significantly higher in the PCOS group (p = 0.023, p < 0.001, and p = 0.002, respectively). The median 17-OH progesterone, free testosterone and luteinizing hormone (LH) values were also significantly higher in the PCOS group (p = 0.017, p = 0.009, and p = 0.012, respectively). The mean PLT, neutrophil and monocyte values were numerically higher; the median fasting glucose, insulin, prolactin, DHEA-SO₄ and total testosterone values were numerically higher; and the median follicle-stimulating hormone (FSH), 11-deoxycorticosteron and estradiol values and mean lymphocyte values were numerically lower in the PCOS group, but the differences were not statistically significant (p > 0.05) (Table 1).

In the Spearman correlation analysis, the correlations between the SII and PIV values of patients with PCOS and their hormonal levels (insulin, DHEA-SO₄, total and free testosterone) were examined. Statistically significant and positive correlations were found between the SII and insulin, the SII and DHEA-SO₄, PIV and insulin, and PIV and DHEA-SO₄ levels (p = 0.006, p = 0.003, p = 0.037, and p = 0.042, respectively). A statistically significant and positive correlation was also observed between SII and free testosterone levels (p = 0.008) (Table 2).

Table 2.

Spearman’s correlations between hormone levels (insulin, DHEA-SO₄, total testosterone, free testosterone) and inflammatory markers (SII and PIV) in PCOS patients

	Correlation Coefficient / P value
	SII	PIV
Insulin (µIU/mL)	0.225 / 0.006*	0.252 / 0.003*
DHEA-SO4 (µg/dL)	0.162 / 0.037*	0.158 / 0.042*
Total testosterone (ng/mL)	0.036 / 0.643	0.045 / 0.563
Free testosterone (pg/mL)	0.207 / 0.008*	0.134 / 0.088

*p < 0.05, statistically significant

We performed ROC curve analysis of the SII, PIV and WBC count and determined the optimal cut-off points for the SII and PIV using the maximum value of Youden’s index (sensitivity + specificity − 1). We found that a baseline serum SII > 520.0 and PIV > 262.4 associated with PCOS with 65% specificity and 61% sensitivity for the SII (area under the curve [AUC], 0.669; 95% CI 0.584–0.755; p < 0.001) and 58% specificity and 60% sensitivity for PIV ([AUC], 0.642; 95% CI 0.555–0.729; p = 0.002) (Fig. 1).

Fig. 1.

Receiver operating characteristic (ROC) analysis of SII, PIV and WBC levels of study groups

Discussion

PCOS is a common endocrine disorder that affects reproductive age women. It is characterized by polycystic ovaries, hormonal abnormalities, and a variety of clinical properties. The diagnosis of the disease necessitates the positivity of at least two of the following three characteristics: 1- amenorrhea or oligomenorrhea, 2- polycystic ovaries on ultrasound and 3- biochemical or clinical signs of hyperandrogenism [13].

Follicular fluid contains proinflammatory cytokines in PCOS that is associated with inflammation [11]. Another condition that is also associated with increased levels of proinflammatory cytokines is abdominal obesity [11]. Platelets, lymphocytes, monocytes, and neutrophils each play important roles in the immune system and exhibit unique properties that significantly influence inflammatory response as the key components of peripheral blood [14]. Under inflammatory conditions, neutrophils rapidly migrate from the blood to inflamed tissues. They also secrete cytokines and proinflammatory chemokines to attract other inflammatory parameters. However, the presence of excessive neutrophils can lead to tissue damage and inflammatory disorders. Studies have indicated that for neutrophil migration in various chronic or acute inflammatory diseases platelets are required [15, 16].

SII and PIV represent easily calculable biomarkers derived from a formula containing the ratios of various immune and inflammatory cells obtained through routine blood tests. In our study, we compared the SII and PIV values of two groups, namely, patients with PCOS and controls. We found that both the SII and PIV values were significantly higher in the PCOS group (p < 0.001 and p = 0.002, respectively). We also evaluated the correlation of the SII and PIV values with the hormone parameters of patients with PCOS. The PIV values were significantly positively correlated with the DHEA-SO₄ and insulin levels (p = 0.042and p = 0.003, respectively), whereas the SII values were significantly positively correlated with the DHEA-SO₄, insulin and free testosterone levels (p = 0.037, p = 0.006 and p = 0.008, respectively). These hormones and their serum levels are all related directly with the clinical outcomes of patients with PCOS and their relation with inflammation markers are also meaningful. There are studies in the literature evaluating inflammation in patients with PCOS. However, to the best of our knowledge, our study is the first in the literature to evaluate the SII and PIV together in patients with PCOS. Shruthi and colleagues evaluated the levels of IL-6, IL-10, IL-27, IL-38, IL-1Ra, FGF-21, TNF-α and adiponectin in patients with PCOS and reported that the levels of these inflammatory markers were higher in patients [17]. However, these biomarkers are research parameters that cannot be obtained or used routinely in all healthcare centers and hospitals and have high costs. In recent years, easy-to-use, practical and inexpensive biomarkers have become preferable for routine patient evaluation. Recently, Zhou et al. compared the SII with lipid parameters in patients with PCOS and reported that the SII was higher in patients with PCOS with abnormal lipid metabolism [18]. In our study, we showed that the SII and PIV values were higher in patients with PCOS and were correlated with the DHEA-SO₄, insulin and free testosterone values.

Recent studies about PCOS also show that inflammation aggravates other clinical signs and symptoms as mental and psychological stress and migraine attacks in patients with PCOS [19–21]. All these clinical conditions cause a decrease in the quality of life of the patients.

Our aim in this study was to once again emphasize the role of inflammation in the pathophysiology of PCOS and, while doing so, to use inexpensive inflammatory markers that we can easily obtain from the parameters routinely requested in the biochemical evaluations of these patients, for the first time in the literature.

This study had two limitations: 1- the sample size was relatively small and 2- it was designed retrospectively. So we were not able to obtain patient serum samples, or evaluate other inflammatory biomarkers and compare with the SII and PIV together. Therefore, further prospective studies on this subject are needed.

Conclusion

SII and PIV, inflammation markers formulated from routine complete blood count parameters, are easy to use and inexpensive parameters. In our study, we suggest that the SII and PIV values can help clinicians evaluate inflammation or clinical aggravation in patients with PCOS. SII and PIV values may also be helpful in evaluating patients’ anti-inflammatory treatment needs, depending on the degree and aggravation of inflammation. Therefore, monitoring inflammation in patients with PCOS, especially with low-cost biomarkers, may lead to an increase in the quality of life of these patients.

Abbreviations

SII

Systemic immune-inflammation index

PIV

Pan immune-inflammation value

PCOS

Polycystic Ovary Syndrome

WBC

White blood cells

DHEASO₄

Dehydroepiandrosterone sulfate

FSH

Follicle-stimulating hormone

LH

Luteinizing hormone

SHBG

Sex hormone binding globuline

ROC

Receiver operating characteristic

Author contributions

NC, IC: Conceptualization, Formal Analysis, Supervision, Writing -original draft, Writing - review & editing.

Funding

The authors declare that this study has received no financial support.

Data availability

All the research data were presented in the manuscript.

Declarations

Ethics approval and consent to participate

The retrospective study was approved by the Erciyes University Clinical Research Ethics Committee (year:2019, no:841). There was no need to obtain signed informed consent to participate prior to the examination because this study designed retrospectively.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.