INTRODUCTION:

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women with a prevalence of 5% to 10%¹. It was first described in 1935 by Stein and Leventhal who reported the association between polycystic ovaries and amenorrhea². PCOS is characterized by a heterogeneous spectrum of signs and symptoms, with hyperandrogenism, infrequent ovulation and multiple follicular cystic ovaries of increased size and being the most encountered³.

Hormonal disruptions are common in women with PCOS, as the condition is often associated with increased levels of luteinizing hormone (LH), decreased or normal levels of follicle-stimulating hormone (FSH), and excessive secretion of ovarian and/or adrenal androgens, which leads to certain clinical manifestations such as hirsutism and acne⁴. The 2003 modified Rotterdam criteria are currently recommended for the diagnosis of PCOS, in which two of the following criteria must be present: (1) chronic anovulation, (2) clinical/biochemical hyperandrogenism and (3) polycystic ovaries on ultrasound⁵. The exact cause of PCOS is unknown, however, multiple factors including genetic, environmental, inflammatory and psychological factors may be involved⁶. In addition to reproductive and dermatological consequences, PCOS can also be associated with metabolic issues including obesity, insulin resistance, hyperinsulinemia and dyslipidemia. As a result, women with PCOS are at increased risk of developing type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD)⁷. The syndrome may also be associated with hypothyroidism leading to worsening symptoms⁸. The altered metabolic and hormonal status in PCOS patients can lead to serious gynecological abnormalities and complications, such as certain types of cancer including endometrial, ovarian, breast cancers or others. Several studies have indicated that estrogen excess, insulin resistance and obesity are potential mechanisms of endometrial hyperplasia and cancer development in PCOS^9–11. PCOS may increase the risk of ovarian cancer, possibly due to continued exposure to androgens¹¹. Although there is no clear correlation between ovarian cancer, endometriosis and PCOS, they share common risk factors. However, this complication of PCOS remains controversial¹². Clinical settings have highlighted the importance of health education through structured awareness programs on PCOS among adolescent girls, which helps in early diagnosis to prevent its long-term complications¹³. Changing lifestyle is one of the first-line treatments to improve reproductive and/or metabolic function in PCOS patients. The treatment plan could also include medical agents if necessary, such as insulin sensitizers like metformin, hormonal contraceptives, or anti-androgens ¹⁴. Studies have also referred to herbal treatment as an effective option for PCOS due to its limited side effects compared to medications¹⁵. Phytotherapy with a potential effect on PCOS patients include fennel¹⁶, mint tea¹⁷ or a herbal mixture commercialized as Hinguvachadi choornam drug¹⁸. Melatonin and vitamin D are also thought to play a positive role in improving symptoms related to this syndrome^19,20.

Cancer antigen 125 (CA-125) is a high-molecular-weight glycoprotein encoded by mucin 16 (MUC16) gene²¹. It belongs to the mucins family of proteins that are involved in cell adhesion, signaling and protection of epithelial surfaces²². CA-125 is expressed by epithelial cells which line many body cavities such as endometrial, ovarian, corneal and bronchial, as well as those of the digestive tract^23,24. Plasma concentration of CA-125 increases under certain physiological conditions, such as menstruation, and in Non-neoplastic cases like heart failure, liver diseases and endometriosis. CA-125 levels also increase in many cancers, such as lung, pancreatic, breast and ovarian cancers^25–27. CA-125 plays a crucial role in the medical field, particularly in the diagnosis, monitoring, and management of ovarian cancer. It has proven to be a useful tool in prediction, prognosis and assessment of treatment response²⁸. The importance of CA-125 in PCOS has not been precisely studied. However, two separate studies showed conflicting results ranging from no significant difference in CA-125 levels between women with and without PCOS²⁴ , to a highly significant seven-fold increase in serum CA-125 levels in women with PCOS compared to controls²⁹. Due to the controversial findings describing the role of CA-125 in PCOS morbidity, our study aimed to evaluate the levels of CA-125 in women with PCOS and assess its relationship with the hormonal imbalance associated with the syndrome. The results of this current study may shed light on the role of CA-125 in PCOS pathogenesis and its potential subsequent complications.

MATERIALS AND METHOD:

Study design and participants:

A comparative case-control study was carried out at the gynecology department of Tishreen Hospital in Lattakia, Syria from 5 November 2022 to 30 September 2023. A total of 100 participants, divided into 70 women diagnosed with PCOS and 30 healthy controls, were included in the present study. PCOS diagnosis was made by clinicians according to Rotterdam criteria; ovarian ultrasound was performed for all patients to confirm the diagnosis. Exclusion criteria were as follows: pituitary, thyroid or adrenal disorders, previous use of hormonal treatment before the study, patients with chronic liver and heart disease, and presence of any endometrial abnormality or any type of cancer.

Data collection and measurements:

Demographic information including age, weight and height was collected, and Body mass index (BMI) was calculated according to the following equation: BMI= weight (kg)/height. The presence of polycystic ovaries was confirmed by ultrasound detection. Hirsutism was estimated by the modified Ferriman-Gallwey (mFG) scoring system, which visually assesses and quantifies the amount of terminal body and facial hair growth in nine areas of the body (upper lip, chin, chest, arm, upper abdomen, lower abdomen, upper back, lower back and thighs). A score of 0–4 was assigned to each area examined, such that a score of 0 represented the absence of terminal hairs, a score of 1 represented minimally evident terminal hair growth, and a score of 4 was given when extensive terminal hair growth equivalent to a hairy man was observed. A total mFG score of ≥8 signifies hirsutism ³⁰. Blood samples were collected between the 3rd and 5th day of the menstrual cycle. Progesterone treatment has been used to induce bleeding in women with amenorrhea. Blood was collected on dried red tubes to obtain serum samples. CA-125 was tested using the Automated Immunoassay Analyzer 360. Hormones including LH, FSH, and total testosterone (only 30 patients and 30 controls were assessed for total testosterone) were measured using a Fine Care device.

Statistical analysis:

Statistical Package for the Social Sciences (SPSS) version 20 was used for data analysis. Data were examined for normal distribution using the Kolmogorov-Smirnov test before making static comparisons. Values were expressed as mean ± standard deviation or number (percentage). The independent T-student test was used to compare the means of two independent groups. Pearson correlation was used to study the association between quantitative variables. The receiver operation characteristic curve (ROC Curve) was used to analyze the optimal cut-off value of CA-125 for predicting PCOS. Results were considered statistically significant when p-value ˂ 0.05. This study was approved by the scientific research ethics committee at Tishreen University No. 4461 dated 25/8/2022.

RESULTS:

Population characteristics:

The study sample included 70 PCOS patients (mean age 23.97±0.2 years) and 30 controls (mean age 24.40±1.9). No significant difference was found in the mean age of both groups (P=0.2). On the contrary, hirsutism and BMI scores were significantly higher in PCOS patients compared to controls (11.72±2.4 vs 4.50±1.6, P= 0.0001) and (25,72±3.1 vs 20.95±2.04kg/m², P=0.0001), respectively (Table 1). Among PCOS patients, 50% were overweight and 12.9% were obese according to the classification of the World Health Organization (WHO) for BMI (https://www.who.int/data/gho/data/themes/topics/topic-details/GHO/body-mass-index), whereas only 3.3% of controls were overweight and none were obese (Table 2).

Comparison of CA-125 and hormone profile (LH, FSH, LH/FSH and total testosterone) between PCOS patients and controls:

CA-125 and hormone profile (LH, FSH, LH/FSH and total testosterone) were assessed for the two groups, and results are presented in Table 1. statistically significant elevated LH levels (9.26±4.9 vs 3.89±1.3mIU/ml, P=0.0001), LH/FSH ratio (1.88±1.1 vs 0.67±0.2, P=0.0001) and total testosterone levels (88.93±18.4 vs 33.15±8.3ng/dl, P=0.0001) were observed in the PCOS group compared to controls. On the other hand, no significant difference was found between the two groups regarding FSH levels (P=0.06). CA-125 levels were significantly higher in PCOS patients than in controls (17.90±6.4 vs 7.78±2.9 U/L, P=0,0001). It should be noted that CA-125 levels in both groups were both within normal limits (1.9-20.1 U/L).

Table 1: Comparison of demographic information and serum biochemical findings between PCOS patients and controls.

	Control group	PCOS group	P-value	Sig.
	N=30	N=70	P-value	Sig.
AGE years)	24.40 ± 1.9	23.97 ± 0.2	0.2	NS
BMI (kg/m²)	20.95 ± 2.04	25.72 ± 3.1	0.0001	S
Hirsutism	4.50 ± 1.6	11.72 ± 2.4	0.0001	S
LH (2.4-12.6 mIU/ml)	3.89 ± 1.3	9.26 ± 4.9	0.0001	S
FSH (3.5-12.5 mIU/ml)	6.35 ± 2.2	5.32 ± 1.8	0.06	NS
LH/FSH	0.67 ± 0.2	1.88 ± 1.1	0.0001	S
Total Testosterone (22-80 ng/dl)	33.15 ± 8.3	88.93 ± 18.4	0.0001	S
CA-125 (1.9-20.1 U/L)	7.78 ± 2.9	17.90 ± 6.4	0.0001	S

Table 2: Classification of the participants according to their BMI

BMI	Control group	PCOS group
Underweight (>18.5)	3 (10%)	0 (0%)
Normal weight (18.5-24.9)	26 (86.7%)	26 (37.1%)
Overweight (25-29.9)	1 (3.3%)	35 (50%)
Obesity >30	0 (0%)	9 (12.9%)

Correlation and predictive efficacy of CA-125 in PCOS:

The correlation between CA-125 and each of the LH, FSH, LH/FSH, total testosterone, BMI and mFG score was investigated using Pearson correlation analysis. The results of our study showed a statistically significant negative correlation between CA125 and FSH. Similarly, there were statistically significant positive correlations between CA-125 and both LH values and LH/FSH ratio. For the rest of the variables, no correlation was observed (Figures 1, 2, 3).

Figure 1: Pearson correlation between CA-125 and LH

Figure 2: Pearson correlation between CA-125 and FSH

Figure 3: Pearson correlation between CA-125 and LH/FSH

Finally, the ROC curve was performed to determine a diagnostic cut-off value of CA-125 for PCOS. The value that gave a good discrimination capacity between PCOS and controls, with a sensitivity of 96.7%, a specificity of 87.1% and an area under the curve (AUC) of 0.964, was 11.45 U/L (Figure 4).

Figure 4: ROC curve analysis for PCOS prediction using serum CA-125

DISCUSSION:

In the present study, we reported a statistically significant elevated level of CA-125 in PCOS patients compared to non-PCOS. No potential effect was attributed to the age of patients compared to controls since the two groups were of similar ages (23.97 ± 0.2 vs 24.40±1.9 years P= 0.2). The patient's age ranged from 21 to 28 years; PCOS syndrome is most commonly reported in reproductively active women³¹. PCOS patients included in our study showed an increase in mean BMI compared to controls (25.72±3.1 vs. 20.95 ±2.04, P=0.0001). 50% of PCOS patients were overweight and 12.6% suffered from obesity, whereas only 3.3% of controls were overweight and no one was obese. Women with PCOS generally have an increased prevalence of overweight and central obesity³². Studies have shown that obesity is associated with a significantly higher risk of insulin resistance, considered one of the potential mechanisms for the development of PCOS ³³. Furthermore, hyperinsulinemia resulting from insulin resistance could in turn lead to increased adrenal and ovarian androgen production through several mechanisms, which could also participate in the pathogenesis of PCOS³⁴. Our result is consistent with data reported by other researchers, who demonstrated a statistically significant difference in average BMI between women with PCOS and those without PCOS^35–37.

Hirsutism was measured visually according to the mFG scoring system. Our study showed a statistically higher hirsutism score in PCOS patients compared to controls. Hirsutism is defined as excessive and abnormal growth of coarse body or facial hair in androgen-dependent areas, in a pattern similar to that in men³⁸. A high prevalence of hirsutism in women with PCOS has been widely reported in the literature^39,40. It is considered an important diagnostic sign of clinical hyperandrogenism since 80–90% of patients with hirsutism have hyperandrogenism⁷. Consistent with previously reported data, our results showed a statistically significant difference in mean total testosterone between patients and controls (88.93±18.4 vs 33.15±8.3 ng/dl, P=0.0001). According to the Rotterdam criteria, androgen excess represents an important parameter for the diagnosis of the syndrome ⁴¹. Androgen excess is expressed clinically by the presence of hirsutism and acne, as discussed above, and can be measured by laboratory tests. Testosterone (total or free) and sex hormone-binding globulin (SHBG) stand out as the most frequently used measures for hyperandrogenism ⁴². Studies have shown increased free or total testosterone levels in patients with PCOS ^39,40,43,44. This may be partly explained by the fact that a high concentration of insulin commonly found in PCOS patients acts synergistically with luteinizing hormone to enhance theca cell androgen production ^45,46. SHBG is a plasma steroid hormone-binding protein and is negatively correlated with plasma testosterone. Therefore, PCOS patients most often have decreased SHBG levels, as hyperinsulinemia can down-regulate SHBG synthesis in the liver. Vice versa, decreased levels of SHBG may lead to increased concentrations of biologically active free testosterone, which is associated with the hyperandrogenism observed in PCOS ^45,47,48. However, only total testosterone was available for laboratory assessment of androgen excess in patients included in our study.

Disrupted pituitary hormones are a common feature of PCOS morbidity ^35,49,50, PCOS patients included in our study had higher serum LH levels and LH/FSH ratios than controls. Otherwise, no significant difference was found in serum FSH levels between the two groups. The main pathophysiological mechanism of PCOS is attributed to a neuroendocrine disorder of the hypothalamic-pituitary-gonadal axis ⁵¹. Many studies have reported an increase in the frequency and amplitude of Gonadotropin-Releasing Hormone (GnRH) pulses, which results in increased LH pulsatile secretion ⁵². This enhanced GnRH secretion favors transcription of the LH β subunit over the FSH β subunit ⁵³. PCOS patients typically have a high LH concentration and a normal to low FSH concentration resulting in a high LH/FSH ratio (2-3/1), which is commonly used to indicate abnormal gonadotropin release in patients with PCOS ⁵⁴.

Several hypotheses have been suggested to explain the impact of peripheral hormones on brain function, which in turn contributes to the increased GnRH/LH pulse rate ⁵⁵. 1) Hyperinsulinemia could increase the activity of GnRH-releasing neurons or the pituitary response to GnRH ⁵⁵. This has been proven by studies suggesting that metformin use reduces androgen levels in women with PCOS ⁵⁶.

2) Low serum progesterone levels due to anovulation in women with PCOS could ultimately eliminate the influence of negative progesterone feedback on GnRH release⁵⁷. 3) Androgen excess plays an indirect role by interfering with the ability of estrogen and progesterone to exert negative feedback suppression of GnRH/LH secretion⁵⁸.

To date, only a few previous studies have evaluated the diagnostic significance of CA-125 in PCOS patients, and furthermore, these studies have reported conflicting results. In a study of 30 PCOS patients and 30 controls, Mujawar et al. showed a significantly higher level of CA-125 in PCOS compared to non-PCOS patients ²⁹. Conversely, another study of 20 PCOS subjects and 20 controls reported no significant difference in CA-125 levels between the two groups. However, in this latter study, the low number of patients may have affected the results ²⁴.

The present study showed a statistically significant elevated mean CA-125 in PCOS patients compared to controls, with values remaining within normal limits (1.9 - 20.1 U/L). The ROC curve was performed to determine a diagnostic cut-off value of CA-125 for PCOS. We demonstrated that 11.45 U/L constitutes a relevant threshold for the diagnosis of PCOS with high sensitivity and specificity (96.7%, and 87.1%, respectively).

PCOS is associated with several disorders accompanied by hormonal imbalances and increased CA-125 levels, such as ovarian cancer, endometriosis, and other benign conditions ^59,60. Thus, one of the hypotheses explaining the higher CA-125 level in PCOS patients could be attributed to these underlying comorbidities. It should be noted that all previously diagnosed cancer cases were excluded from this study. However, the increased susceptibility of high-CA-125 PCOS patients to ovarian cancer is not excluded and should be closely assessed in future prospective studies. The increased level of CA-125 could be a potential effect or cause of the hormonal disruption observed in PCOS patients. Consistent with this, our results showed a statistically significant negative correlation between CA-125 and FSH levels and a statistically significant positive correlation between CA-125 and both LH level and LH/FSH ratio. However, the causal relationship between CA-125 and hormonal profile in PCOS patients needs to be evaluated in future investigative studies.

CONCLUSION:

CA-125 can be added as an additional diagnostic marker for PCOS after exclusion of cancers, endometriosis, and pituitary, thyroid, or adrenal disorders. The exact mechanisms underlying the development of polycystic ovary syndrome are not yet clearly understood. Thus, an explanation for the elevated CA-125 levels in PCOS patients could be a step toward unraveling this mystery. Nevertheless, characterizing the exact role of CA-125 in the pathophysiology of PCOS still requires further research.

ABBREVIATIONS:

PCOS Polycystic Ovary Syndrome

CA-125 Cancer Antigen

BMI Body Mass Index

mFG modified Ferriman-Gallwey

LH Luteinizing Hormone

FSH Follicle-Stimulating Hormone

T2DM Type2 Diabetes Mellitus

CVD Cardiovascular Diseases

MUC 16 Mucin 16

SPSS Statistical Package for the Social Sciences

ROC Receiver Operation Characteristic

WHO World Health Organization

SHBG Sex Hormone Binding Globulin

GnRH Gonadotropin-Releasing Hormone

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Received on 10.04.2024 Modified on 06.07.2024

Research J. Pharm. and Tech 2024; 17(11):5445-5451.

DOI: 10.52711/0974-360X.2024.00833