Association of neuregulin-1 with hormonal and lipid profile in women with polycystic ovarian syndrome

Omar Tareq Zaidan 1, Raed Jassim Al-Tamimi 2, Fadia J. Alizzi 3, Qasim Sharhan Al-Mayah 4
Author affiliations:
  1. Omar Tareq Zaidan, Chemistry & Biochemistry Department, College of Medicine, Al-Nahrain University, Baghdad, Iraq; E-mail: omarabnanliraq@gmail.com
  2. Raed Jassim Al-Tamimi, Chemistry & Biochemistry Department, College of Medicine, Al-Nahrain University, Baghdad, Iraq; E-mail: RaedJassimtamimi2@yahoo.com
  3. Fadia J. Alizzi, Al Mustansiriyah College of Medicine, Department of Obstetrics, Gynecology and Infertility, Al-Yarmouk Teaching Hospital, Baghdad, Iraq; E-mail: FadiaJAlizzi3@gmail.com
  4. Qasim Sharhan Al-Mayah, Medical Research Unit, College of Medicine, Al-Nahrain University, Baghdad, Iraq; E-mail: QasimSharhaAl-Mayah4@yahoo.com
Correspondence: Omar Tareq Zaidan; E-mail: omarabnaliraq@gmail.com; Mobile: 964 07809086646

 

ABSTRACT

 

Background & objective: Polycystic ovarian syndrome (PCOS) is a disorder of the reproductive aged women, which may affect fertility of these women from 14-45 y of age. Neuregulin-1 (NRG-1) is a trophic factor that contains an epidermal growth factor (EGF)-like domain, and has been shown to be associated with the regulation of inflammation and ovulation. We evaluated the role of NRG-1 and its relationship with hormonal and lipid profile in women with PCOS.

Methodology: This was a case-control study which included 60 women, known to be suffering from PCOS and another 60 age-matched women, who had regular menstrual cycle, as a control group. Blood samples were collected from Infertility Clinic/ Al-Yarmouk Teaching Hospital. Hormonal and lipid profiles were measured using standard methods. Enzyme linked immunosorbent assay (ELISA) was used to measure serum level of NRG-1. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of NRG-1.

Results: The median serum level of neuregulin in patients was 2.73 pg/mL (range = 1.13-7.39 pg/mL) which was higher than that of controls (median = 2.1 pg/mL, range = 0.33-7.39 pg/mL) with a significant difference the area under the curve (AUC) was 0.652, 95%CI = 0.545-0.758, P = 0.008. The sensitivity and specificity of the test at cut off value of NRG-1 = 2.25 were 62% and 52%, respectively. Neuregulin-1 displayed a significant negative correlation with anti-Müllerian hormone (AMH) (r = -0.324, P = 0.038).

Conclusions: Serum level of neuregulin-1 is increased in women with polycystic ovarian syndrome, but has a poor diagnostic value, and its negative correlation with anti-Müllerian hormone. However, the diagnostic value of neuregulin-1 is poor and cannot be used in early diagnosis of polycystic ovarian syndrome.

Abbreviations: AMH - Anti-Müllerian hormone; AUC - Area under the curve; EGF - Epidermal growth factor; HDL-C - High-density lipoprotein cholesterol; LDL-C - Low-density lipoprotein cholesterol; NRG-1 - Neuregulin-1; PCOS - Polycystic ovarian syndrome; SG - Stress granules; TC - Total cholesterol; TG -Triglyceride.

Keywords: Infertility; Neuregulin-1; Polycystic ovarian syndrome

Citation: Zaidan OT, Al-Tamimi RJ, Alizzi FJ, Al-Mayah QS. Association of neuregulin-1 with hormonal and lipid profile in women with polycystic ovarian syndrome. Anaesth. pain intensive care 2024;28(3):509−516.

DOI: 10.35975/apic.v28i3.2471
Received: March 15, 2024; Revised: March 24, 2024; Accepted: March 29, 2024

 

1. INTRODUCTION

 

Polycystic ovarian syndrome (PCOS) is a hormonal and metabolic disorder characterized by menstrual irregularities, hyperandrogenism (acne, amenorrhea, alopecia, etc.) and, sometimes, infertility, obesity and severe menstruation disruption (amenorrhea or oligomenorrhea).1 The family of epidermal growth factor (EGF) like signaling molecules known as neuroregulins, is engaged in cell-to-cell communication and is crucial for the growth, upkeep, and repair of the nervous system, heart, breast, and other organs. A ligand for the oncogene ErbB2 was described by independent investigations. (neu, Her2) and substances that promoted Schwann cell division and acetylcholine receptor production by force. According to Marchionni M., these ligands and factors are basically byproducts of the same gene, known as neuregulin (NRG-1).2 Few studies have been done on NRG-2, -3, and -4, and it is still not fully understood how they work. On the other hand, it was recently found that NRG-2 is a part of stress granules (SG), which are microscopic aggregates of messenger ribonucleoprotein complexes that are stopped in translation and form in response to direct stress conditions.3 Moreover, it was demonstrated that astrocyte-secreted NRG-2 coupled to ErbB3 on neurons enhanced neural survival.4
The main objective of the study was to evaluate serum neuregulin-1(NRG-1) as a specific biomarker for early diagnosis or identification of hormonal irregularities in women with PCOS.

 

2. METHODOLOGY

 

This is a case-control study which included a total of 60 women with PCOS who were attending national infertility clinic – Al-Yarmouk Teaching Hospital Baghdad, Iraq, during the period from February 2023 to November 2023. PCOS was diagnosed relying on Rotterdam Diagnostic Criteria. The determination was made when at least two criteria were met (oligo/anovulation, hyperandrogenism, or polycystic ovaries by ultrasound) after ruling out various causes of androgen excess. On the other hand, subjects with hypertension, diabetes, and body mass index (BMI) >35 kg/m2 were excluded from the study. Other age-matched 60 women with regular menstrual cycle were enrolled as a control group.

Demographic characteristics of the study population including age, weight and height (form which BMI was calculated) and family history of PCOS were collected.

2.1. Blood sample collection
Five mL venous blood was taken from all women on days 2-3 of their menstrual cycles after overnight fasting. Sera were isolated from coagulated blood, and lipid profile; i.e., total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) were measured by Rochel/HitachCobas device C311.

2.2. Hormonal profile
The serum levels of prolactin, anti-Müllerian-hormone (AMH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, estradiol, progesterone and prolactin were all measured by ELISA technique using ready commercial kits.

2.3. Serum level of NRG-1
Serum level of NGR-1 was measured by using ELISA techniques (HumanNRG-1, ELK, China, Cat:ELK2232) according to the manufacturer’s instructions. The kit has a detection range: 0.16-10 ng/mL.

2.4. Statistical analysis
Statistical analysis was performed by using SPSS software version 25.0 (SPSS, Chicago). Continuous data were subjected to normality test (Shapiro Wilk test). Data with normal distribution were presented as mean and standard deviation, and analyzed with Student’s t-test. Data with non-normal distribution were presented as median and range and analyzed with Mann Whitney U test Categorical variables were expressed as numbers and percentages and analyzed with Chi-square test. Receiver operating characteristic curve (ROC) was used to evaluate NRG-1 in the context of discrimination between patients and controls. Spearman’s correlation test was used to explore the possible correlation of NRG-1 with other variables. A P < 0.05 was considered statistically significant difference.

 

3. RESULTS

 

3.1. Demographic characteristics
Table 1 shows the demographic characteristics of the study population. The mean age of women with PCOS was 26.98 ± 7.22 y, which was very close to that of controls (25.07 ± 6.39 y) with no significant difference. Likewise, the two groups were comparable in terms of weight, height and BMI with no significant differences. Family history of PCOS was very common among patients (46.67%) compared with controls (5%) with a highly significant difference. The mean duration of the PCOS in affected women was 4.18 ± 2.33 y.

 
Table 1: Comparative demographic data of the study population
Variables Controls
 (n = 60)		 Patients
(n = 60)		 P- value
Age (y) 26.98 ± 7.22 25.07 ± 6.39 0.126
Weight (kg) 70.43 ± 6.64 72.84 ± 7.72 0.070
Height (cm) 163.57 ± 3.51 164.17 ± 4.84 0.438
BMI (kg/m2) 26.33 ± 2.39 27.01 ± 2.54 0.132
Family history of PCOS 3 (5%) 32 (53.33%) < 0.001
Data presented as Mean ± SD or n (%)
 

Table 2: Reproductive status of the study population
Variables Controls
(n = 60)		 Patients
(n = 60)		 P-value
Gravida
None

≤3

>3		 15 (25)

33 (55)

12 (20)		 26 (43.33)

33 (55)

1 (1.67)		 0.002
Parity
None

≤3

>3		 15 (25)

35 (58.33)

10 (16.67)		 33 (55)

26 (43.33)

1 (1.67)		 < 0.001
Abortion
 None

1-2		 45 (75)

15 (25)		 49 (81.67)

11 (18.33)		 0.507
Data presented as n (%); P < 0.05 considered as significant
 

Table 3: Hormonal profile in PCOS patients and controls
Variables Controls
 (n = 60)		 Patients
(n = 60)		 P- value
FSH (mIU/mL) 6.65 (3.18- 48.80) 8.2 (1.13-18.20) 0.010
LH (mIU/mL) 5.75 (2.40-11.02) 7.25 (3.10-20.0) < 0.001
Testosterone (nmol/L) 0.44 (0.16-1.55) 0.65 (0.16-1.40) 0.008
AMH (ng/mL) 5890 (5038.36-7858.80) 1167.85 (386-1664.90) < 0.001
E2 (pg/mL) 174.3 (97.97-422.44) 43.19 (13.03-78.58) < 0.001
Progesterone (nmol/L) 29.4 (1.8-46.8) 35.4 (13.2-92.5) 0.111
Prolactin (µg/L) 23.0 (5.08-47.88) 18.13 (3.70-84.68) 0.113
TSH (µU/mL) 2.79 (0.95-4.55) 2.44 (0.36-16.77) 0.457
Data presented as Median (Range); P < 0.05 considered as significant
 
3.2. Reproductive characteristics
Control group had more common >3 gravida and >3 parity (20% and 16.67%, respectively) than patients (1.67% for both) with highly significant differences. In contrast most included patients and controls had no abortion (81.67% and 75%, respectively) with no significant difference (Table 2).

3.3. Hormonal profile
Data regarding hormonal profile were found to be non-normally distributed. Therefore, these data were expressed as median and, and non-parametric Mann Whitney U test was used to compare the groups of patients and controls (Table 2). The median serum level of FSH and LH in women with PCOS was 8.2 mIU/mL and 7.25 mIU/L, respectively, which was higher than that of controls (6.65 mIU/mL and 5.75 mIU/mL, respectively) with significant differences. Likewise, the median serum levels of E2, AMH and testosterone were higher in patients (0.65, 1167.85 and 43.19, respectively) than controls (0.44, 5890 and 174.3, respectively) with highly significant differences.

 

Table 4: Lipid profile in patients and controls
Variables Controls
 (n = 60)		 Patients
(n = 60)		 p- value
TC (mg/dL) 165.42 ± 36.14 173.94 ± 38.14 0.247
TG (mg/dL) 120.38 ± 48.67 172.05 ± 177.31 0.038
HDL (mg/dL) 49.55 ± 9.86 43.94 ± 8.52 0.002
LDL (mg/dL) 98.22 ± 26.22 109.63 ± 29.11 0.042
VLDL (mg/dL) 25.67 ± 13.36 24.34 ± 11.58 0.597
Data presented as mean ± SD; P < 0.05 was considered as significant
 



 



 

In contrast, healthy women demonstrated higher median serum levels of progesterone than PCOS women (174.3 nmol/L vs. 43.19 nmol/L), although the difference was not significant. The two groups were comparable in terms of prolactin and TSH with no significant differences (Table 3).

3.4. Lipid profile
The two groups were comaparable regarding serum level of TC and VLDL with no signifcant differences. However, patients demonstrated higher levels of TG and LDL than controls (P = 0.038 and P = 0.042 respectively) with significant differences. In contrast, patients had lower HDL than controls with a significant difference (P = 0.002) (Table 4).

3.5. Serum level of neuregulin-1
The median serum level of neuregulin in patients was 2.73 pg/mL (range = 1.13-7.39 pg/mL) which was higher than that of controls (median = 2.1 pg/mL, range = 0.33-7.39 pg/mL) with a significant difference (Figure 1).

3.6. Diagnostic value of neuregulin-1
Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of neuregulin-1 in the context of discrimination between PCOS and healthy women. The area under the curve (AUC) was 0.652, 95% CI = 0.545-0.758, P = 0.008. The sensitivity and specificity of the test, at cut off value of REG-1 = 2.25, were 62% and 52%, respectively (Figure 2).

3.7. Correlation of neuregulin with other variables in PCOS
Spearman’s correlation test was used to explore the possible correlation of neuregulin with other parameters in patients and controls. Neuregulin-1 displayed a significant negative correlation with AMH (r = -0.324, P = 0.038) as shown in Table 5, Figure 3.

Table 5: Spearman’s correlation of neuregulin-1 with other variables in women with PCOS.
Variable NRG-1
Coefficient P-value
Age 0.020 0.877
Weight -0.242 0.063
Height 0.018 0.894
BMI -0.236 0.069
Prolactin 0.181 0.235
HbA1C 0.079 0.548
FSH -0.054 0.684
LH 0.074 0.574
Testosterone 0.077 0.563
TC -0.134 0.358
TG 0.053 0.707
HDL 0.034 0.813
LDL -0.230 0.112
vLDL -0.090 0.539
AMH -0.324 0.022
E2 0.109 0.450
Duration -0.055 0.674
 



 

4. DISCUSSION

 

The results of the study showed that 53.33% of the patients had a family history of PCOS disease, compared with controls (5%) with a highly significant difference. Much evidence has indicated that PCOS is a complex genetic disease. Previous researchers have proven the role of genetic and environmental factors in the pathogenesis of PCOS, as there are several genes responsible for the appearance of its clinical symptoms such as the state of excess androgens, obesity, hyperinsulinemia, the emergence of insulin resistance, heart disease, type-2 diabetes mellitus, and even cancer.5 Kahsar-Miller et al. found that among 93 women with PCOS, 40% were sisters.6 In another study by Legro et al. they concluded that 24 of the women with PCOS appeared to have a state of hyperandrogenism with a regular menstrual cycle, while the male hormone level was high for all sisters.7 Therefore, the prevalence of polycystic ovary syndrome among first-degree relatives is a positive risk factor in providing information about the development of PCOS.8
The serum level of FSH in PCOS group was higher than healthy group with a significant difference (P = 0.01). It is consistent with the results of a previous study that found higher levels of FSH in PCOS.9,10,11 One of the main hormones controlling the menstrual cycle is FSH. The typical hormonal balance is frequently upset in PCOS, which may have an impact on FSH levels.12 FSH levels may be normal or even high in a large number of PCOS cases. This may seem contradictory because anovulation, or the absence of ovulation, is frequently linked to PCOS and may indicate decreased FSH levels. However, the hypothalamic-pituitary-ovarian (HPO) axis's disrupted feedback mechanisms are usually the cause of high FSH levels in PCOS.13
For testosterone level, the results show that the median concentration of testosterone increased significantly in patients than controls which is consistent with many researches in this regard.14-16 Hyperandrogenism is the term for the condition when people with PCOS have higher-than-normal levels of testosterone due to an imbalance. High testosterone levels have been linked to the development of symptoms that are frequently linked to PCOS, including irregular menstrual periods, acne, and hirsutism (excessive hair growth).17
Estradiol in women with PCOS was higher than control group, which agrees with several previous works,18,19 but does not agree with others,20,21 that found a higher level of estradiol in PCOS. Lower levels of estradiol (E2) are frequently seen in PCOS patients as compared to non-PCOS women. PCOS frequently causes irregular or absent ovulation, and lower levels of estradiol can be from disturbances in ovulation.22 Low estradiol levels are the result of the effect of androgens on metabolism and natural production of estradiol in the ovaries, so its level is decreased.23
Serum level of LH in women with PCOS was higher than that of the controls, a result which agrees with earlier researchers,10,16 who found raised levels of LH in PCOS. LH contributes to hormonal imbalance and reproductive dysfunctions and thus has an important role in PCOS. To control ovulation and the menstrual cycle, LH is essential. It causes the final maturation of the dominant follicle, which results in ovulation, and stimulates the ovarian follicles to create estrogen. Elevations of LH or changes in the LH to FSH ratio are frequently observed in PCOS. The normal ovulatory process may be deactivated with by this increase in LH levels.24
The current study shows low levels of AMH in the PCOS group than the control. There are several mechanisms that support a negative correlation between BMI and AMH levels, which has been supported by a number of theories. The primary cells that make up adipose tissue are called adipocytes, and they store fat. Leptin, a hormone well-known for suppressing appetite, is produced by these cells. It has been demonstrated in in vitro experiments that leptin inhibits granulosa cell production of AMH.25
Serum levels of NRG-1 is increased in the PCOS group compared to the control group, with a significant difference. This is in agreement with Tawfeq and Sarhat, who found elevated levels of NRG-1 in women with PCOS,26 but does not agree with the study of Arpaci, who found a lower level of NRG-1 in the PCOS group.27 NRG-1 plays a crucial role in tissue development and homeostasis by controlling cell proliferation, differentiation, and survival.28 Many studies have shown change in the expression and functionality of NRG-1 and its receptors in women with PCOS than healthy women. For instance, it was discovered that women with PCOS, especially those who also had insulin resistance and hyperandrogenism, had considerably higher serum levels of NRG-1.29 These results imply that the hormonal and metabolic abnormalities linked to PCOS may be exacerbated by dysregulation of NRG-1 signaling.

It is currently unclear how NRG-1 influences the precise processes that lead to the onset and progression of PCOS. However, several potential options have been proposed. One theory is that NRG-1 stimulates abnormal follicular growth and steroidogenesis, which may disrupt ovarian function. NRG-1 signaling has been shown to increase the synthesis of androgens, which are increased in PCOS, and promote ovarian granulosa cell proliferation. Furthermore, by regulating insulin signaling and glucose metabolism, both of which are dysregulated in PCOS, NRG-1 may have indirect effects on ovarian function.30 The ever-increasing data connecting NRG-1 to PCOS suggests that treatment intervention may have to target this pathway. Medication that specifically alters NRG-1 signaling, including small molecule inhibitors or monoclonal antibodies, may help PCOS patients' metabolic parameters and restore normal ovarian function. Targeting NRG-1 signaling related downstream effectors, such as androgen or insulin receptors, may also provide different approaches to treating PCOS.31
 

5. CONCLUSION

 

The results of this study indicate the increased level of neuregulin-1 in women with polycystic ovarian syndrome and its negative correlation with anti-Müllerian hormone. However, the diagnostic value of neuregulin-1 is poor and cannot be used in early diagnosis of polycystic ovarian syndrome

6. Data availability
The numerical data generated during this research is available with the authors.

7. Acknowledgement
We gratefully thank Faculty of College of Medicine, Al-Nahrain University, Baghdad, Iraq, for facilitating the conduct of this study.

8. Conflict of interest
The study utilized the hospital resources only, and no external or industry funding was involved.

9. Authors’ contribution
OTZ: writing the manuscript

RJA, FJA: conduction of the study work and manuscript editing

QSA: Samples collections

 

10. REFERENCES

 
  1. Mohd M, Maqbool M, Dar MA, Mushtaq I. Polycystic Ovary Syndrome, a modern epidemic: An overview. J Drug Delivery Ther. 20219;9(3):641-4. [FreeFullText]
  2. Cespedes JC, Liu M, Harbuzariu A, Nti A, Onyekaba J, Cespedes HW, Bharti PK, et al. Neuregulin in Health and Disease. Int J Brain Disord Treat. 2018;4(1):024. [PubMed] DOI: 23937/2469-5866/1410024
  3. Limanaqi F, Biagioni F, Ryskalin L, Busceti CL, Fornai F. Molecular Mechanisms Linking ALS/FTD and Psychiatric Disorders, the Potential Effects of Lithium. Front Cell Neurosci. 2019 Oct 4;13:450. [PubMed] DOI: 3389/fncel.2019.00450
  4. Nakano N, Kanekiyo K, Nakagawa T, Asahi M, Ide C. NTAK/neuregulin-2 secreted by astrocytes promotes survival and neurite outgrowth of neurons via ErbB3. Neurosci Lett. 2016;622:88-94. [PubMed] DOI: 1016/j.neulet.2016.04.050
  5. Legro RS. Polycystic ovary syndrome and cardiovascular disease: a premature association? Endocr Rev. 2003 Jun;24(3):302-12. [PubMed] DOI: 1210/er.2003-0004
  6. Kahsar-Miller MD, Nixon C, Boots LR, Go RC, Azziz R. Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS. Fertil Steril. 2001 Jan;75(1):53-8. [PubMed] DOI: 1016/s0015-0282(00)01662-9
  7. Legro RS, Driscoll D, Strauss JF 3rd, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci U S A. 1998;95(25):14956-60. [PubMed] DOI: 1073/pnas.95.25.14956
  8. Azziz R, Kashar-Miller MD. Family history as a risk factor for the polycystic ovary syndrome. J Pediatr Endocrinol Metab. 2000;13 Suppl 5:1303-6. [PubMed]
  9. Malini NA, Roy George K. Evaluation of different ranges of LH:FSH ratios in polycystic ovarian syndrome (PCOS) - Clinical based case control study. Gen Comp Endocrinol. 2018;260:51-57. [PubMed] DOI: 1016/j.ygcen.2017.12.007
  10. Rasool SUA, Ashraf S, Nabi M, Rashid F, Fazili KM, Amin S. Elevated fasting insulin is associated with cardiovascular and metabolic risk in women with polycystic ovary syndrome. Diabetes Metab Syndr. 2019;13(3):2098-2105. [PubMed] DOI: 1016/j.dsx.2019.05.003
  11. Khudhair M. Evaluation of some hematological and biochemical parameters for women with polycystic ovary syndrome in Wasit Governorate. Wasit J Pure Sci. 2013;2(4):185-193. DOI: 31185/wjps.259
  12. Islam H, Masud J, Islam YN, Haque FKM. An update on polycystic ovary syndrome: A review of the current state of knowledge in diagnosis, genetic etiology, and emerging treatment options. Womens Health (Lond). 2022;18:17455057221117966. [PubMed] DOI: 1177/17455057221117966
Bernier D. Polycystic Ovary Syndrome: Pathogenesis, health consequences, athogenesis, health consequences, and treatment of PCOS in relation to insulin resistance. Honors Theses Capstones. 2012;3. [FreeFullText]
  1. Maarouf IA, Mubarak ZM. Study of follistatin and sex hormones level in women with polycystic ovarian syndrome in Baghdad. Tikrit J Pure Sci. 2018;23(4):1–6. DOI: 25130/tjps.v23i4.514
  2. Alhassan SM, Elmugadam A, Abubaker NE and Elfadil GA. Testosterone level correlates significantly with luteinizing hormone to follicle-stimulating hormone ratio among women with polycystic ovary syndrome: A cross sectional study. F1000Research. 2022;11:152. DOI: 12688/f1000research.76220.2
  3. Cander S, Şişman P, ÖzGül Ö. Evaluation of insulin resistance and vitamin D levels in patients with polycystic ovary syndrome. Turkish J Inter Med., 2022;42:66–72. DOI: 46310/tjim.1027019
  4. Rosenfield RL, Ehrmann DA. The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited. Endocr Rev. 2016 Oct;37(5):467-520. [PubMed] DOI: 1210/er.2015-1104
  5. Al-Deresawi MS, Alfaisal AH. Two novel missense mutations in exon 9 of TPO gene in Polycystic Ovary Syndrome patients with hypothyroidism. J Biotechnol Res Center. 2015;9(10:30-37. DOI: 24126/jobrc.2015.9.1.401
  6. Ibrahim TK, Al-Assie AH, Mossa H. A physiological and molecular study of leukemia patients in Kirkuk city. J Trop Med Publ Health. 2020;3(10):137-148.
  7. Koppali S, Reddy B, Paluru R. Role of Steroid Hormones in Polycystic Ovarian Syndrome (PCOS) in South Indian Women. Int J Res Ayurveda Pharm. 2017;8:234-237. DOI: 7897/2277-4343.082118
  8. Khmil M, Khmil S, Marushchak M. Hormone imbalance in women with infertility caused by polycystic ovary syndrome: is there a connection with body mass index. Open Access Maced J Med Sci. 2020;8(B):731-737. [FreeFullText]
  9. Rosenfield RL. The Diagnosis of Polycystic Ovary Syndrome in Adolescents. Pediatrics. 2015;136(6):1154-65. [PubMed] DOI: 1542/peds.2015-1430
  10. Zhao H, Lv Y, Li L, Chen ZJ. Genetic Studies on Polycystic Ovary Syndrome. Best Pract Res Clin Obstet Gynaecol. 2016 Nov;37:56-65. [PubMed] DOI: 1016/j.bpobgyn.2016.04.002
  11. Seow KM, Chang YW, Chen KH, Juan CC, Huang CY, Lin LT, et al. Molecular Mechanisms of Laparoscopic Ovarian Drilling and Its Therapeutic Effects in Polycystic Ovary Syndrome. Int J Mol Sci. 2020 Oct 31;21(21):8147. [PubMed] DOI: 3390/ijms21218147
  12. Kloos J, Coyne K, Weinerman R. The relationship between anti-Müllerian hormone, body mass index and weight loss: A review of the literature. Clin Obes. 2022;12(6):e12559. [PubMed] DOI: 1111/cob.12559
  13. Tawfeq M, Sarhat E. Metformin effects on neuregulin-1 in polycystic ovarian women. Georgian Med News. 2023;(337):56-62. [PubMed]
  14. Arpacı H. Circulating neuregulin-1 levels in polycystic ovary syndrome. J Obstet Gynaecol. 2019 May;39(4):504-509. [PubMed] DOI: 1080/01443615.2018.1519530
  15. Banerjee S, Mishra S, Xu W, Thompson WE, Chowdhury I. Neuregulin-1 signaling regulates cytokines and chemokines expression and secretion in granulosa cell. J Ovarian Res. 2022;15(1):86. [PubMed] DOI: 1186/s13048-022-01021-0
  16. Zhang L, Lu B, Wang W, Miao S, Zhou S, Cheng X, et al. Alteration of serum neuregulin 4 and neuregulin 1 in gestational diabetes mellitus. Ther Adv Endocrinol Metab. 2021 Oct 8;12:20420188211049614. [PubMed] DOI: 1177/20420188211049614
  17. Noma N, Kawashima I, Fan HY, Fujita Y, Kawai T, Tomoda Y, et al. LH-induced neuregulin 1 (NRG-1) type III transcripts control granulosa cell differentiation and oocyte maturation. Mol Endocrinol. 2011;25(1):104-16. [PubMed] DOI: 1210/me.2010-0225
  18. Jeong H, Kim J, Lee Y, Seo JH, Hong SR, Kim A. Neuregulin-1 induces cancer stem cell characteristics in breast cancer cell lines. Oncol Rep. 2014;32(3):1218-24. [PubMed] DOI: 3892/or.2014.3330