Exploring the role of irisin as a potential biomarker in adolescents and young adults with polycystic ovarian syndrome

Abstract

Background:

Irisin is a myokine potentially linked to insulin sensitivity. Polycystic ovarian syndrome (PCOS) is a prevalent hormonal condition defined by insulin resistance. Previous studies have reported elevated circulating irisin levels in adult females with PCOS.

Objective:

To examine the differences in serum irisin levels between lean and obese adolescents and young adults with PCOS and their respective lean and obese controls and to explore the relationship between irisin levels and the metabolic and reproductive characteristics of the participants.

Design:

Cross-sectional study design.

Methods:

The study included 60 cases of PCOS and 60 controls. These participants were categorized based on their body mass index (BMI) into lean and obese. Fasting serum irisin levels, physical, metabolic, hormonal, and reproductive characteristics of the participants were measured.

Results:

Lean cases of PCOS had significantly elevated levels of fasting serum irisin (PCOS = 17.07 ± 5.61 ng/ml vs lean controls = 11.04 ± 7.51 ng/ml; p = 0.002), glucose, insulin, homeostasis model of assessment-insulin resistance index (HOMA-IR), luteinizing hormone (LH), estradiol, and testosterone and significantly lower levels of quantitative insulin sensitivity check index (QUICKI) compared to the lean controls. Obese cases of PCOS had significantly higher levels of fasting serum irisin (PCOS = 22.06 ± 3.83 ng/ml vs obese controls = 16.86 ± 6.74 ng/ml; p = 0.011), glucose, insulin, HOMA-IR, LH, estradiol, and testosterone and significantly lower levels of follicle-stimulating hormone (FSH) and QUICKI compared to obese controls. The findings revealed a significant positive correlation of serum irisin levels with BMI, glucose, insulin, HOMA-IR, LH, estradiol, and testosterone(all p-values < 0.001). There was also a significant positive correlation with triglycerides (TAGs) (p = 0.001), total cholesterol (p = 0.005), and low-density lipoprotein cholesterol (p = 0.024). Additionally, there was a significant negative correlation with high-density lipoprotein cholesterol (p = 0.001) and QUICKI (p < 0.001) in the entire study cohort. Fasting serum glucose (β = 0.337, p = 0.029), TAGs (β = 0.249, p = 0.006), and LH (β = 0.382, p = 0.004) were positive predictors of serum irisin concentrations in the overall sample.

Conclusion:

Lean and obese adolescent and young adult cases of PCOS had significantly higher fasting serum irisin levels than their respective controls. Metabolic and reproductive traits of the participants also correlated with irisin.

Introduction

Polycystic ovarian syndrome (PCOS) is a significant medical condition due to its extensive and potentially severe complications. It is one of the most prevalent endocrine disorders that affects women of reproductive age worldwide. The global prevalence of PCOS is 15% based on the broader Rotterdam criteria. ¹ This syndrome is characterized by polycystic ovaries, ovulatory malfunction, increased androgen levels, and/or clinical signs of hyperandrogenism. ² Moreover, a substantial percentage of women diagnosed with PCOS suffer from obesity and/or insulin resistance, resulting in hyperinsulinemia. ³ The seriousness of PCOS is underscored by the heightened risk it poses for women, making them significantly more susceptible to developing severe health issues such as infertility, impaired glucose tolerance, type-2 diabetes mellitus, gestational diabetes, dyslipidemia, cardiovascular disease, and endometrial carcinoma. The impact of these potential complications highlights the importance of PCOS as a condition requiring vigilant medical attention and management.^{4 –6}

Insulin resistance is one of the most significant metabolic aberrations recognized in patients with PCOS. The insulin resistance observed in PCOS principally involves the reduced ability of this hormone to facilitate glucose transport and inhibit lipolysis in adipocytes, even while insulin binding remains normal. ⁷ As a result, the excessive release of insulin due to compensatory hyperinsulinemia has a heightened impact on other tissues that are typically less responsive to insulin, such as the pituitary gonadotrophs, causing increased secretion of luteinizing hormone, ⁸ and the ovarian theca cells, leading to stimulated secretion of androgens.^7,9 Insulin resistance is experienced by almost 70% of women with PCOS.^7,10 However, the exact prevalence of insulin resistance in PCOS is still unknown due to constraints in assessment methodologies. Furthermore, there are no definitive criteria for the diagnosis of PCOS, and it continues to be a subject of debate. Therefore, it is crucial to explore biomarkers associated with insulin resistance for early detection of PCOS and to monitor the condition across various treatment approaches. ¹¹

Irisin is a myokine that was identified by Boström et al. ¹² in 2012. It is produced and secreted when the Fibronectin type III domain-containing protein 5 (FNDC5) is cleaved. The peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) upregulates the expression of the FNDC5 gene in skeletal muscle as a reaction to physical exercise. ¹² Irisin is believed to play a role in the process of converting white adipocytes into brown adipocytes and increasing thermogenesis through the activation of p38 MAPK and ERK MAPK signaling pathways.^{12 –14} In addition, irisin has been reported to enhance glucose uptake in skeletal muscle cells by increasing the insertion of GLUT4 in the outer surface of the cell membrane. ¹⁵ Available literature has demonstrated a positive correlation between circulating irisin levels and utilization of energy, loss of weight, and a negative correlation with insulin resistance in rodents. ¹² Additional experimental evidence demonstrates that the subcutaneous perfusion of irisin decreases the levels of triglycerides (TAGs), total cholesterol, and free fatty acids (FFAs) in the bloodstream. It also reduces hyperglycemia and improves insulin sensitivity in obese mice. ¹⁶ Nonetheless, human research has shown inconsistent results, and there remains a lack of clear evidence on whether circulating irisin levels are linked to improved glucose homeostasis and insulin sensitivity.^13,17,18 For instance, reported evidence suggests that the serum level of irisin is higher in individuals with metabolic syndrome and has a positive correlation with body mass index (BMI), fasting serum glucose, TAGs, and homeostasis model of assessment-insulin resistance index (HOMA-IR). ¹⁷ Similarly, another study demonstrated elevated serum irisin levels in patients with type 2 diabetes. ¹⁹ Conversely, circulating levels of irisin have been reported to be reduced in overweight/obese individuals, ¹³ type-2 diabetics, ¹⁸ and gestational diabetics. ²⁰

Given the prevalence of insulin resistance among most patients with PCOS and the possible association of irisin with insulin sensitivity, it is plausible that irisin’s involvement in the pathogenesis of PCOS is likely, and it has the potential to serve as a new biomarker for the disorder.

Only a few studies^{21 –28} have investigated circulating levels of irisin in adult females with PCOS yielding inconsistent findings. Some of these studies have reported significantly higher levels of irisin in PCOS patients in comparison to controls,^21,22,24,28 while others have found lower ²³ or nonsignificant ²⁵ differences in mean serum irisin concentrations. The variability in these findings may be attributed to BMI acting as a confounding factor. Studies have reported that irisin, which is generally indicative of body fat, ²⁹ is positively correlated with BMI in adult females, across a broad range of BMI values and regardless of PCOS status.^24,28,30,31

Moreover, there is a scarcity of studies regarding irisin levels in young girls. Diagnosing PCOS during adolescence and early adulthood is a topic of debate and requires careful consideration due to the potential confusion of symptoms with normal pubertal changes. ³² Discovering biomarkers that can enhance diagnostic precision may reduce unnecessary treatment for otherwise healthy adolescents and young adults during this crucial stage of their lives. Early diagnosis of PCOS allows for timely intervention to address both the physical and psychological symptoms associated with this lifelong condition, whether through counseling or medication, thereby reducing the risk of complications such as fertility issues, hirsutism, and type-2 diabetes. So far, only one study has examined the levels of serum irisin in adolescent females with PCOS, focusing exclusively on lean adolescents and reporting significantly elevated irisin levels in this subgroup of adolescent PCOS patients. ³³

The present study aimed to determine whether serum irisin levels, which have been positively associated with BMI in humans, can serve as a reliable biomarker for PCOS in adolescent and young adult females, particularly by accounting for the influence of BMI as a potential confounding factor. To achieve this, the study was designed to investigate and compare serum irisin levels in lean and obese adolescents and young adults with PCOS against corresponding groups of lean and obese controls. Furthermore, the study also analyzed the relationship between serum irisin levels and the hormonal, metabolic, and lipid profiles of the participants.

Objectives

1. To analyze and compare the fasting serum levels of irisin between lean and obese adolescents and young adults diagnosed with PCOS and their respective lean and obese control groups.

2. To investigate the correlation between serum irisin levels and various metabolic and hormonal parameters, including BMI, fasting serum TAGs, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), glucose, insulin, HOMA-IR, quantitative insulin sensitivity check index (QUICKI), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone.

3. To assess which variables are independently associated with serum irisin.

Methods

Figure 1 represents a diagrammatic illustration of the methods used in the study.

Figure 1.

Methods used in the study.

PCOS: polycystic ovarian syndrome; BMI: body mass index; HOMA-IR: homeostasis model assessment-insulin resistance index; QUICKI: quantitative insulin sensitivity check index; CAH: congenital adrenal hyperplasia; CVS: cardiovascular.

Study design and participants: It was a cross-sectional study conducted on adolescent and young adult females aged 13–21 years. The cases of PCOS were selected from females attending the Department of Obstetrics and Gynecology at Shifa International Hospitals between August 2020 and January 2022. Participants in the control groups consisted of medical and pharmacy students enrolled at Shifa Tameer-e-Millat University.

Sampling: The sampling technique used was consecutive sampling. The sample size was calculated using the WHO sample size calculator, with a 95% confidence interval and 90% power. The test values of the population means were 8.3 for the PCOS group and 11.1 for the control group, with a pooled standard deviation of 3.9. This resulted in a sample size of 60 PCOS cases and 60 controls, which were further divided into four groups: 30 obese PCOS cases, 30 lean PCOS cases, 30 obese controls, and 30 lean controls.

Inclusion criteria (patients): PCOS was diagnosed in both lean and obese individuals, who were at least 2 years post-menarche based on the revised Rotterdam criteria. The diagnosis, done by the gynecologist, required the presence of at least two of the following three manifestations: (1) oligo and/or anovulation, (2) clinical and/or biochemical hyperandrogenism, and (3) polycystic ovaries visible on ultrasound. ³⁴

Inclusion criteria (controls): Participants in the control groups were lean and obese females having regular menstrual cycles without clinical and/or biochemical hyperandrogenism.

Exclusion criteria (patients and controls): Exclusion criteria for all participants included known causes of hyperandrogenism and ovulatory dysfunction other than PCOS, such as late-onset congenital adrenal hyperplasia, 21-hydroxylase deficiency, Cushing syndrome, hyperprolactinemia, thyroid diseases, and androgen-secreting adrenal or ovarian tumors. Individuals with prediabetes, diabetes, neoplasms, history of smoking, cardiovascular disorders, hypertension, renal impairment, pregnancy, or contraceptive use were also excluded. Additionally, none of the PCOS cases or controls had been on any medication for at least the past 3 months.

Informed consent: Informed consent was received from all participants aged 18 years or above and from the parents of younger participants.

BMI measurement: BMI was calculated by dividing weight (kg) by height (m²). According to WHO criteria, obesity was defined as a BMI ⩾ 30 kg/m² and normal weight (lean) was defined as a BMI < 25 kg/m². ³⁵

Sample/data collection: In the PCOS groups, blood samples were collected in the morning after an overnight fast, either between the 2nd and 5th days of a spontaneous bleeding episode or independently of the cycle in cases of amenorrhea. In the control groups, blood samples were collected during the early follicular phase (days 2–5 of the menstrual cycle). Serum was separated by centrifugation and stored at −70°C in the research lab of Shifa Tameer-e-Millat University until further analysis.

Biochemical and hormonal measurements: Serum levels of glucose, total cholesterol, TAGs, and HDL-C were measured using enzyme-colorimetric assays (Advanced Medical Products, Austria). LDL-C levels were calculated using the Friedewald equation ³⁶ :

$$\begin{array}{l}\mathrm{LDL}(\mathrm{mg}/\mathrm{dl})=\mathrm{total}\mathrm{cholesterol}\\ -[\mathrm{HDL}+(\mathrm{triglycerides}/5)]\end{array}$$

Serum levels of insulin, LH, FSH, testosterone, and estradiol were determined using enzyme-linked immunosorbent assay (ELISA, Perkin Elmer, USA).

The serum concentration of irisin was measured using an ELISA kit from Elab Sciences USA, with the catalog number E-EL-H2254.

All assays were conducted in strict accordance with the manufacturer’s instructions.

HOMA-IR and QUICKI calculation: HOMA-IR index for the assessment of insulin resistance was calculated by using Matthews et al., ³⁷ equation.

$$\begin{array}{l}\mathrm{HOMA}-\mathrm{IR}=[\mathrm{Fasting}\mathrm{glucose}(\mathrm{mg}/\mathrm{dl})\\ x\mathrm{fasting}\mathrm{insulin}(\mathrm{\mu }\mathrm{IU}/\mathrm{ml})]/405.\end{array}$$

Insulin resistance was accepted as HOMA-IR > 2.5. ³⁷

Insulin sensitivity was calculated by QUICKI;

$$\begin{array}{l}\mathrm{QUICKI}=1/[\log (\mathrm{fasting}\mathrm{insulin}\mathrm{in}\mathrm{\mu }\mathrm{IU}/\mathrm{ml})\\ +\log (\mathrm{fasting}\mathrm{glucose}\mathrm{in}\mathrm{mg}/\mathrm{dl})].\end{array}$$

The STROBE reporting guidelines were employed for this cross-sectional study. ³⁹

Statistical analysis: The data were analyzed using IBM’s Statistical Package for Social Sciences (SPSS) version 22. All variables were expressed as mean ± standard deviation (SD). Comparisons among the groups were determined by one-way analysis of variance (ANOVA) followed by post hoc Tukey’s t-test. Confidence intervals were set at 95%. Correlation between the variables was studied using Pearson’s correlation coefficient. Multiple regression models were used to study which variables were independently associated with irisin. Multiple regression was conducted with the backward method after checking all assumptions. All p-values were two-sided and p-value of <0.05 was considered statistically significant.

Results

Table 1 presents the descriptive statistics for each study group and the p-values from the ANOVA. Table 2 shows the differences between the study groups as determined by the post hoc Tukey test, presented in the form of p-values.

Table 1.

Clinical and biochemical characteristics of the study groups.

Parameter	Groups				p-Value*
	Lean PCOS (n = 30) (mean ± SD)	Obese PCOS (n = 30) (mean ± SD)	Lean control (n = 30) (mean ± SD)	Obese control (n = 30) (mean ± SD)
Age (years)	17.32 ± 1.89	17.22 ± 2.20	18.12 ± 1.03	17.98 ± 0.80	0.065
BMI (kg/m2)	20.87 ± 1.87	31.94 ± 4.43	21.42 ± 2.43	31.04 ± 1.73	<0.001
Irisin (ng/ml)	17.07 ± 5.61	22.06 ± 3.83	11.04 ± 7.51	16.86 ± 6.74	<0.001
TAGs (mg/dl)	80.94 ± 29.66	137.00 ± 46.47	84.64 ± 25.56	151.15 ± 47.85	<0.001
Total cholesterol (mg/dl)	131.39 ± 15.17	194.86 ± 10.66	138.81 ± 9.2	199.35 ± 13.59	<0.001
LDL-C (mg/dl)	80.63 ± 21.55	150.11 ± 26.98	92.65 ± 27.15	158.92 ± 33.01	<0.001
HDL-C (mg/dl)	65.03 ± 16.47	40.49 ± 5.82	68.65 ± 12.01	38.43 ± 3.76	<0.001
Glucose (mg/dl)	102.26 ± 11.33	108.84 ± 10.66	77.43 ± 13.02	97.43 ± 9.61	<0.001
Insulin (µIU/ml)	12.95 ± 2.44	20.92 ± 3.31	8.59 ± 2.96	11.63 ± 2.62	<0.001
HOMA-IR	3.34 ± 0.65	5.61 ± 0.99	1.65 ± 0.66	2.79 ± 0.68	<0.001
QUICKI	0.44 ± 0.03	0.37 ± 0.02	0.61 ± 0.13	0.48 ± 0.06	<0.001
LH (mIU/ml)	7.98 ± 1.67	9.31 ± 2.03	4.26 ± 1.04	6.40 ± 0.91	<0.001
FSH (mIU/ml)	5.51 ± 0.74	5.62 ± 0.52	5.93 ± 0.60	6.25 ± 1.36	0.006
Estradiol (pg/ml)	26.02 ± 5.9	28.24 ± 7.81	16.01 ± 3.51	22.41 ± 6.32	<0.001
Testosterone (ng/ml)	0.80 ± 0.65	1.24 ± 0.59	0.23 ± 0.08	0.32 ± 0.07	<0.001

Values in bold indicate statistically significant differences among groups.

^*Values are presented as p-values of ANOVA (p < 0.05 is significant).

BMI: body mass index; TAGs: triglycerides; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; HOMA-IR: homeostasis model assessment-insulin resistance index; QUICKI: quantitative insulin sensitivity check index; LH: luteinizing hormone; FSH: follicle-stimulating hormone.

Table 2.

Comparison of variables among different study groups.

Parameter	Lean PCOS vs obese PCOS	Lean PCOS vs lean control	Lean PCOS vs obese control	Obese PCOS vs lean control	Obese PCOS vs obese control	Lean control vs obese control
BMI (kg/m2)	<0.001	0.876	<0.001	<0.001	0.609	<0.001
Irisin (ng/ml)	0.015	0.002	0.999	<0.001	0.011	0.003
TAGs (mg/dl)	<0.001	0.982	<0.001	<0.001	0.491	<0.001
Total Cholesterol (mg/dl)	<0.001	0.099	<0.001	<0.001	0.498	<0.001
LDL-C (mg/dl)	<0.001	0.336	<0.001	<0.001	0.612	<0.001
HDL-C (mg/dl)	<0.001	0.565	<0.001	<0.001	0.883	<0.001
Glucose (mg/dl)	0.115	<0.001	0.353	<0.001	0.001	<0.001
Insulin (µIU/ml)	<0.001	<0.001	0.313	<0.001	<0.001	0.001
HOMA-IR	<0.001	<0.001	0.052	<0.001	<0.001	<0.001
QUICKI	0.001	<0.001	0.308	<0.001	<0.001	<0.001
LH (mIU/ml)	0.005	<0.001	0.001	<0.001	<0.001	<0.001
FSH (mIU/ml)	0.963	0.254	0.008	0.521	0.031	0.493
Estradiol (pg/ml)	0.493	<0.001	0.109	<0.001	0.002	0.001
Testosterone (ng/ml)	0.001	<0.001	0.001	0.001	<0.001	0.878

Values in bold indicate statistically significant differences among groups.

Values are presented as p-values of post hoc Tukey t-test (p < 0.05 is significant).

BMI: body mass index; TAGs: triglycerides; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; HOMA-IR: homeostasis model assessment-insulin resistance index; QUICKI: quantitative insulin sensitivity check index; LH: luteinizing hormone; FSH: follicle-stimulating hormone.

Irisin

The lean PCOS group had significantly higher serum levels of irisin compared to the lean control group (p = 0.002). The obese PCOS group had significantly elevated serum levels of irisin compared to the obese control group (p = 0.011), lean PCOS group (p = 0.015), and lean control group (p = 0.001). Moreover, the obese control group revealed a significant elevation in serum levels of irisin (p = 0.003) than the lean control group.

Glycemic indices

The lean PCOS group had significantly higher levels of glucose (p < 0.001), insulin (p < 0.001), HOMA-IR (p < 0.001) along with lower levels of QUICKI (p < 0.001) compared to the lean control group. The obese PCOS group had significantly elevated serum levels of glucose (p = 0.001), insulin (p < 0.001), HOMA-IR (p < 0.001), and lower QUICKI (p < 0.001) levels compared to the obese control group. Compared to the lean PCOS group, the obese PCOS group had significantly higher insulin (p < 0.001), HOMA-IR (p < 0.001), and lower QUICKI (p = 0.001). When compared to the lean control group, the obese PCOS group had significantly higher glucose (p < 0.001), insulin (p < 0.001), HOMA-IR (p < 0.001), as well as lower QUICKI (p < 0.001). Additionally, the obese control group had significantly higher glucose (p < 0.001), insulin (p = 0.001), HOMA-IR (p < 0.001), and lower QUICKI (p < 0.001) compared to the lean control group.

Hormonal profile

The lean PCOS group had significantly higher levels of LH (p < 0.001), estradiol (p < 0.001), and testosterone (p < 0.001) compared to the lean control group, and significantly increased levels of LH (p = 0.001) and testosterone (p = 0.001), along with lower FSH (p = 0.008) levels compared to the obese control group. The obese PCOS group had significantly elevated serum levels of LH (p < 0.001), estradiol (p = 0.002), testosterone (p < 0.001), and lower FSH (p = 0.031) levels compared to the obese control group. Compared to the lean PCOS group, the obese PCOS group had significantly higher levels of LH (p = 0.005), and testosterone (p = 0.001). When compared to the lean control group, the obese PCOS group had significantly higher LH (p < 0.001), estradiol (p < 0.001), and testosterone (p = 0.001). Moreover, the obese control group had significantly higher LH (p < 0.001) and estradiol (p = 0.001) compared to the lean control group.

BMI and lipid profile

Compared to the lean PCOS group, the obese PCOS group had significantly higher BMI (p < 0.001) and serum levels of TAGs (p < 0.001), total cholesterol (p < 0.001), LDL-C (p < 0.001), and lower HDL-C (p < 0.001). When compared to the lean control group, the obese PCOS group had significantly higher BMI (p < 0.001) and serum levels of TAGs (p < 0.001), total cholesterol (p < 0.001), LDL-C (p < 0.001) as well as lower HDL-C (p < 0.001). Additionally, the lean PCOS group had significantly increased levels of HDL-C (p < 0.001) along with lower BMI (p < 0.001), TAGs (p < 0.001), total cholesterol (p < 0.001) and LDL-C (p < 0.001) compared to the obese control group. The obese control group had significantly higher BMI (p < 0.001) and serum levels of TAGs (p < 0.001), total cholesterol (p < 0.001), LDL-C (p < 0.001), and lower HDL-C (p < 0.001) compared to the lean control group. There were no statistically significant differences between the lipid profile of the lean PCOS and lean control groups nor between obese PCOS and obese control groups.

Table 3 presents the correlation of serum irisin with other variables in the total sample. For the total sample, serum irisin levels showed positive correlation with BMI (p < 0.001) and serum levels of TAGs (p = 0.001), total cholesterol (p = 0.005), LDL-C (p = 0.024), glucose (p < 0.001), insulin (p < 0.001), HOMA-IR (p < 0.001), LH (p < 0.001), estradiol (p < 0.001), and testosterone (p = 0.001) and negative correlation with serum HDL-C (p < 0.001) and QUICKI (p < 0.001).

Table 3.

Correlation of serum irisin with other variables in total sample.

Parameter	Total (n = 120)
	Coeff*	p-Value**
BMI (kg/m2)	0.348	<0.001
TAGs (mg/dl)	0.299	0.001
Total cholesterol (mg/dl)	0.265	0.005
LDL-C (mg/dl)	0.215	0.024
HDL-C (mg/dl)	−0.335	<0.001
Glucose (mg/dl)	0.397	<0.001
Insulin (µIU/ml)	0.429	<0.001
HOMA-IR	0.462	<0.001
QUICKI	−0.359	<0.001
LH (mIU/ml)	0.432	<0.001
FSH (mIU/ml)	−0.156	0.100
Estradiol (pg/ml)	0.346	<0.001
Testosterone (ng/ml)	0.307	0.001

Values in bold indicate statistically significant differences among groups.

BMI: body mass index; TAGs: triglycerides; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; HOMA-IR: homeostasis model assessment-insulin resistance index; QUICKI: quantitative insulin sensitivity check index; LH: luteinizing hormone; FSH: follicle-stimulating hormone.

^*Values are presented as Pearson’s correlation coefficient.

^**Values are presented as p-values of Pearson’s correlation (p < 0.05 is significant).

Table 4 shows the results of multiple regression analysis in the overall sample. This model was finalized after three stages (F statistic of ANOVA was 272.378 with p < 0.001, R² = 0.898, and adjusted R² = 0.895). The findings demonstrate glucose (B = 0.064, β = 0.337, p = 0.029), TAGs (B = 0.038, β = 0.249, p = 0.006), and LH (B = 0.950, β = 0.382, p = 0.004) as positive predictors of serum irisin concentrations.

Table 4.

Multiple regression analysis of variables associated with serum irisin in total sample (n = 120).

Variables	Unstandardized regression coefficients		Standardized coefficient	t-statistic	p-Value
	B	SE	β
Glucose (mg/dl)	0.064	0.029	0.337	2.218	0.029
TAGs (mg/dl)	0.038	0.013	0.249	2.810	0.006
LH (mIU/ml)	0.950	0.324	0.382	2.928	0.004

Values in bold indicate statistically significant results.

This model is the final after 3 stages. F statistic of ANOVA was 272.378 with p < 0.001. R² = 0.898 and adjusted R² = 0.895.

LH: luteinizing hormone; TAGs: triglycerides).

Multiple regression conducted with the backward method.

Discussion

Irisin is a myokine that stimulates the conversion of white adipose tissue into brown adipose tissue, enhancing its metabolic characteristics and increasing overall energy expenditure in the body. Therefore, irisin is currently being examined as a potentially effective focus for the diagnosis and treatment of metabolic diseases. ⁴⁰ The present study is among the pioneering efforts to explore the role of circulating irisin as a potential biomarker for PCOS in adolescents and young adults. This objective was achieved by comparing fasting serum irisin levels between lean and obese adolescents and young adults with PCOS and their respective lean and obese controls.

The present study’s results revealed that both lean and obese adolescent and young adult cases of PCOS exhibited higher fasting serum irisin levels compared to their respective lean and obese controls. Additionally, the obese controls and obese PCOS cases showed higher fasting serum irisin levels compared to their lean counterparts. Multiple studies have demonstrated a significant correlation between the levels of irisin in the bloodstream of humans and indices of adiposity, such as BMI, with the greatest levels found in obese.^{30,41 –43} Moreover, Foda et al. ⁴⁴ reported a significant positive correlation of fasting serum irisin and TAGs levels. The findings of the present study are consistent with this trend, showing that the obese participants had increased circulating levels of irisin than their lean counterparts (in the PCOS and control groups). Serum TAGs levels were also found to be independently associated with circulating irisin in the total sample. However, significant elevation of serum irisin levels in lean PCOS patients as compared to lean controls in the present study cannot be ascribed to variances in BMI. A few previous studies also documented significantly higher fasting irisin levels in adult lean PCOS women compared to the lean controls.^21,44,45 Similarly, Bacopoulou et al. ³³ documented significantly higher fasting irisin levels in adolescent lean PCOS women than controls. Given that most patients with PCOS have tendency to become insulin resistant, the rise in fasting serum irisin levels among PCOS patients, regardless of their BMI, may be explained by irisin’s potential role as a regulator of insulin sensitivity and glucose homeostasis.^33,40

In the present study, the marked increase in fasting serum glucose, insulin, and HOMA-IR observed in both lean and obese PCOS groups, relative to their respective lean and obese controls, supports the notion that insulin resistance in PCOS is independent of BMI. These findings align with those reported in adults by Foda et al. ⁴⁴ Additionally, the present study revealed that fasting serum irisin demonstrated a positive correlation with fasting glucose, insulin, and HOMA-IR, and a negative correlation with QUICKI, across the entire study cohort. Serum glucose was also found to be independently associated with circulating irisin in the total sample. Similar trends have been observed in non-PCOS populations, where irisin levels have been positively correlated with parameters of glucose homeostasis such as fasting blood glucose^17,46 insulin levels,^43,48 and HOMA-IR ¹⁷ in adults. Likewise, in line with the results of the present study, previous studies have reported a positive correlation of fasting serum irisin with fasting insulin ²⁴ and HOMA-IR ²⁸ in the entire study population (controls and PCOS) and with HOMA-IR ⁴⁴ in the PCOS groups (lean and obese) among adult women. Serum irisin has also been found to have a positive correlation with serum glucose, insulin, and HOMA-IR and a negative correlation with QUICKI across the entire sample (lean PCOS and lean controls) of adolescent women. ³³

Considering, (1) PCOS as an insulin-resistant state and (2) significant positive correlations between insulin resistance indices (fasting insulin and HOMA-IR) and serum irisin, Li et al. ²⁸ proposed that irisin could serve as an insulin resistance marker in adult females with PCOS. Building on findings from adult studies and the research by Bacopoulou et al., ³³ the present study further supports the idea that irisin dysregulation is linked to metabolic dysfunction in adolescent and young adult cases of PCOS, potentially leading to the progression of PCOS and its associated complications in adulthood. However, studies conducted on rodents have demonstrated that irisin has the ability to enhance metabolic status.^12,47 This seemingly contradictory finding might indicate an adaptive response in which circulating irisin levels increase to compensate for the decreasing insulin sensitivity and metabolic disruptions observed in PCOS as suggested by earlier research. ³⁰ Moreover, the elevated levels of irisin in PCOS patients have been described as a state of “irisin resistance,” ⁴⁸ similar to “insulin resistance,” ²¹ where circulating hormone levels rise in an attempt to produce the desired physiological effect.

In the present study, serum LH and testosterone levels were notably higher in both lean and obese PCOS groups compared to their respective control groups (lean and obese). Additionally, circulating levels of irisin were positively correlated with serum LH and testosterone with serum LH being independently associated with circulating irisin in the overall sample. Similar findings have also been reported in an animal study, where chronic irisin exposure significantly increased serum LH and testosterone levels in Sprague Dawley rats. ⁴⁹ Hyperandrogenism affects 60%–80% of women with PCOS. ⁴³ This hyperandrogenemia, alongside insulin resistance has a reciprocal relationship with PCOS. ⁵⁰ Elevated LH levels promote ovarian hyperandrogenism in PCOS, ⁵¹ while androgens can directly induce insulin resistance in skeletal muscle. Conversely, insulin resistance leads to hyperinsulinemia, which contributes to hyperandrogenism in the theca cells of polycystic ovaries. ⁵² Given the significant positive correlation between circulating irisin levels and insulin resistance, it follows that irisin levels also exhibit a positive correlation with LH and androgens.

The strength of our study lies in its consideration of BMI as a confounding factor that might affect insulin resistance and serum irisin concentrations in adolescent and young adult females. However, the study has some limitations, including a relatively small sample size and a cross-sectional design, which does not allow for the establishment of causality between increased serum irisin levels and PCOS. To strengthen our conclusions, larger, longitudinal studies are recommended.

Conclusion

Lean and obese adolescent and young adult cases of PCOS had significantly higher fasting serum irisin levels than their respective controls. Metabolic and reproductive traits of the participants also correlated with irisin.