Abstract
Purpose:
To compare the optical coherence tomography (OCT)-based retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness at the posterior pole, and total macular thickness of women with the polycystic ovarian syndrome (PCOS) versus healthy reproductive age group females.
Methods:
The study included 110 eyes of 55 diagnosed cases of PCOS (study group) and 110 eyes of 55 healthy reproductive age group (15–49 years) females (control group). All patients underwent a detailed ophthalmological evaluation followed by an OCT to measure their retinal thicknesses. The body mass index (BMI) of patients was noted and compared with the retinal thickness. Also, the lipid profile and serum testosterone levels of PCOS patients were recorded.
Results:
The retinal thicknesses in the two study were similar and there was no statistically significant difference. However, on stratification with BMI, it was seen that in patients with BMI>30 kg/m2, the superior Retinal Nerve Fibre Layer (RNFL) was significantly thicker in the PCOS group as compared with the control group (P = 0.0006). The mean serum testosterone level in patients with PCOS was 141.3 ± 23.2. Also, 65.45% of patients had a serum testosterone level of more than 70 ng/dL. The mean HDL cholesterol in patients with PCOS was 38.1 ± 15.6. The mean LDL cholesterol in PCOS patients was 98.4 ± 21.7, and the mean total cholesterol in PCOS patients was 153.6 ± 27.3.
Conclusion:
Androgens have a trophic action on nerves, which could explain the increased RNFL thickness in these patients.
Keywords: Optical coherence tomography, polycystic ovarian syndrome, retinal nerve fiber layer
Polycystic ovary syndrome (PCOS) is one of the most frequent endocrine disorders in women of the reproductive age group.[1,2] The prevalence of the disease is 4–26% worldwide.[3,4] It presents with a variety of symptoms caused due to hyperandrogenism and ovulatory dysfunction.[4,5] It may be associated with metabolic syndrome, insulin resistance, glucose intolerance, type 2 diabetes, cardiovascular disease, obesity, and dyslipidemia.[6,7,8]
The relationship between eye changes in PCOS is unexplored, especially in the Indian population. Because PCOS is known to be associated with metabolic syndrome and changes in glucose metabolism, it is interesting to study retinal changes in these patients as compared to healthy females of the reproductive age group. Target organs in these patients experience an unopposed hyperestrogenemic effect that cannot be counteracted by progesterone. They respond to estrogen by producing certain proteins (e.g., cathepsin D, alpha- 2-macroglobulin, and aromatase cytochrome P45), which are involved in vital cellular functions such as differentiation, proliferation, and maturation. As expected, ocular tissues such as the ciliary body and retinal pigment epithelium show the presence of most of these proteins. Androgens have also been studied to affect gene expression and lipid synthesis in meibomian glands, making them a target organ for these hormones.[9,10]
Initial studies in patients with PCOS have demonstrated increased retinal nerve fiber layer (RNFL) thickness around the optic nerve compared with healthy women and its association with the presence of hyperandrogenism. The hormonal effects have also been said to cause aqueous layer deficiency and evaporative dry eye disease.[11,12,13,14,15]
The aim of this study was to compare optical coherence tomography OCT-based RNFL and ganglion cell layer (GCL) thickness at the posterior pole, and total macular thickness in women with PCOS versus healthy reproductive age group females.
Methods
The study was a cross-sectional comparative study and included 55 patients who were diagnosed cases with PCOS according to Rotterdam’s criteria, 2013, and 55 healthy reproductive age group females to serve as the control group. The study was conducted in the Department of Ophthalmology in collaboration with the Department of Obstetrics and Gynecology. The patients diagnosed with PCOS were advised to visit the Department of Ophthalmology.
The Rotterdam criteria require the presence of two of the following:[16,17]
Hyperandrogenism (clinical or biochemical)
Ovulatory dysfunction (oligo or anovulation)
Polycystic ovaries on Ultrasound (USG) (At least one ovary with i) 12 follicles of 2–9 mm ii) volume >10 mL.
Patients giving written informed consent to inclusion and participation in the trial were included in the study.
Exclusion criteria were women with other endocrine disorders, renal or liver failure; chronic users of drugs that might interfere with the metabolism of carbohydrates, lipids, and with renal function (such as diuretics, antihypertensives, antilipemic agents, and corticosteroids); smoking; alcohol consumption; or illicit drug use, women who had undergone any ocular surgery, women not giving written informed consent and uncooperative patients in whom the parameters could not be measured.
A detailed history regarding the onset of symptoms, if any, duration, progression, and any associated complaints were assessed. The presence of symptoms resulting from hyperandrogenism and ovulatory dysfunction were excluded from the control group. Hirsutism is the most reliable marker of clinical hyperandrogenism. Ovulatory dysfunction presents clearly in the form of oligomenorrhea or amenorrhea.[2] Because Rotterdam’s criteria require any two of the three above parameters for a diagnosis of PCOS, excluding the first two by history would be sufficient to exclude the presence of PCOS in the control population. History regarding any major medical illness or addiction was also recorded. The demographic details of the patient were recorded. These patients included treatment-naïve patients, patients solely on lifestyle modification, and also those on oral contraceptive pills. The treatment duration was variable. The baseline parameters including visual acuity (both unaided and best corrected) using Snellen’s charts, intraocular pressure (IOP) with applanation tonometer, central corneal thickness with the help of an autorefractometer, and Schirmer’s test with Schirmer’s strip were performed. The patients then underwent a thorough slit-lamp examination to evaluate the anterior segment; Ocular Surface Staining Score (OSSS) and tear film break-up time were measured. Patients were looked for any evidence of meibomian gland dysfunction (MGD). This was followed by a dilated fundus examination with a + 90D lens. Indirect ophthalmoscopy with a +20 D lens was also performed. After recording all these findings, a three-dimensional 3D OCT using Topcon Spectral Domain OCT Machine was performed.
Images of the OCT-based retinal nerve fiber layer thickness at the disc and macula were taken. For the disc, the values from the quadrant-wise map were noted and for the macula, the superior and inferior RNFL thickness were noted. OCT-based evaluation of the ganglion cell layer thickness at the macula was done and the superior and inferior GCL+ (ganglion cell layer + inner plexiform layer) thickness values were noted. OCT-based central macular thickness was measured using a 3D macular scan.
In addition to these parameters, the height and weight of patients were recorded and the body mass index (BMI) was calculated. For PCOS patients, the serum testosterone levels and the lipid profile of the patients were also noted.
Results
A total of 110 patients were enrolled in the study. 55 patients were diagnosed with PCOS according to Rotterdam’s Criteria that formed the study group and 55 patients were healthy reproductive age group females satisfying the inclusion and exclusion criteria.
In all, 81.8% of patients in the PCOS group and 89.09% of patients in the control group resided in urban areas. Three PCOS patients and five controls had a history of hypothyroidism. A family history of systemic diseases ( Diabetes Mellitus [DM], Hypertension [HTN], Coronary Artery Disease [CAD], Chronic Kidney Disease [CKD], etc.) was found in 18 PCOS patients and 17 controls. The difference between the two groups was not statistically significant [Table 1].
Table 1.
Demographic details of the study population
| Case | Control | P | |
|---|---|---|---|
| Age | |||
| Mean+SD | 26.32±5.84 | 32.09±7.83 | 0.236 |
| Residence | |||
| Urban | 45 (81.81%) | 49 (89.09%) | 0.279 |
| Rural | 10 (18.18%) | 6 (10.90%) | |
| Systemic History | |||
| Hypothyroidism | 3 (5.45%) | 5 (9.09%) | 0.304 |
| Others | 4 (7.27%) | 3 (5.45%) | |
| Family History | |||
| DM | 8 (14.5%) | 9 (16.3%) | 0.806 |
| HTN | 4 (7.27%) | 4 (7.27%) | |
| Others | 6 (10.9%) | 4 (7.27%) |
Clinical evidence of hyperandrogenism was found in 35 (63.63%) PCOS patients (history of hirsutism). Oligo/anovulation was found in 39 (79.90%) patients (irregular menstrual cycles, dysmenorrhea). Thirty-four patients (61.81%) had evidence of polycystic ovaries on ultrasound.
The mean age of patients was significantly lower in the PCOS group as compared to that in the control group.
In all, 63.64% of PCOS patients had an unaided distance visual acuity of 0.00 on the logMAR scale, whereas 49.09% of controls had the same. The BCVA was 0.00 on the logMAR scale in all our patients. Among the PCOS patients, 21% had no refractive error, 46% had a refractive error of <2D, and 33% had a refractive error between >2–4D. Among the controls, 17% had no refractive error, 36% had a refractive error of <2D, and 47% had a refractive error between >2 and 4D.
The Intraocular Pressure (IOP), Central Corneal Thickness (CCT), Schirmer’s test, Tear Film Break-Up Time (TBUT), and Ocular Surface Staining Score (OSSS) were comparable between the two groups in our study.
Table 2 shows the SD-OCT parameters that were analyzed. We analyzed the peripapillary RNFL thickness, the RNFL thickness at the macula, the total macular thickness, and the GCL + thickness.
Table 2.
Retinal thicknesses among our study groups
| Variables | Case (Mean±SD) | Control (Mean±SD) | t | P |
|---|---|---|---|---|
| Peripapillary RNFL thickness | ||||
| I | 243.54±10.64 | 243.01±9.29 | 0.276 | 0.782 |
| S | 226.23±14.16 | 223.72±12.86 | 0.972 | 0.333 |
| N | 148.30±6.96 | 147.45±6.93 | 0.645 | 0.52 |
| T | 163.01±10.73 | 162.29±10.78 | 0.354 | 0.723 |
| Macular RNFL thickness | ||||
| I | 72.85±4.87 | 72.89±5.03 | 0.038 | 0.969 |
| S | 66.61±4.57 | 66.85±4.73 | 0.266 | 0.79 |
| Central macular thickness (CMT) | 366.18±10.67 | 364.54±9.89 | 0.833 | 0.406 |
| GCL+ | ||||
| I | 141.09±11.51 | 139.98±11.12 | 0.513 | 0.608 |
| S | 139.18±11.44 | 137.98±13.07 | 0.512 | 0.609 |
The RNFL thickness was uniformly distributed among the two study groups both at the disc and the macula as there was no significant difference between the two.
We then stratified the patients according to BMI dividing them into two groups. Group 1 included patients with BMI < 30 kg/m2, Group 2 included patients with BMI > 30 kg/m2.
The RNFL thickness was then compared. Interestingly, in patients with BMI >30 kg/m2, the superior RNFL was significantly thicker in the PCOS group as compared with the control group (P = 0.0005) [Table 3].
Table 3.
Superior RNFL Thickness Among the Two Groups After Stratification According to BMI
| BMI (kg/m2) | SUP RNFL thickness | t | P | |
|---|---|---|---|---|
|
| ||||
| Case (Mean±SD) | Control (Mean±SD) | |||
| <30 | 96.57±12.68 | 105.62±3.56 | 3.062 | 0.128 |
| >30 | 119.27±12.76 | 103.47±15.25 | 4.564 | 0.0005 |
Multiple linear regression was also carried out using age, BMI, and the presence or absence of a diagnosis of PCOS as independent variables and retinal thicknesses as the dependent variables. However, we did not obtain any statistically significant results.
We also studied the serum testosterone and lipid profile of our PCOS patients.
The mean serum testosterone level in patients with PCOS was 141.3 ± 23.2. Braunstein et al.[18] gave the reference ranges for testosterone in premenopausal women. The serum testosterone levels in clinics were divided into normal or raised depending on lab values for our lab. In all, 65.45% of patients had a serum testosterone level of more than 70 ng/dL [Table 4]. The PCOS group was then subdivided into those with serum testosterone levels <70 ng/dL and >70 ng/dL and the retinal thicknesses were compared. However, we did not find any significant results in doing so.
Table 4.
Serum testosterone values among the PCOS patients
| Case (Mean±SD) | Range (mg/dL) | No of patients | |
|---|---|---|---|
| Testosterone (ng/dL) | 138.3±23.2 | <70 | 19 (34.54%) |
| >70 | 36 (65.45%) |
The mean HDL cholesterol in patients with PCOS was 38.1 ± 15.6. The mean LDL cholesterol in PCOS patients was 98.4 ± 21.7 and the mean total cholesterol in PCOS patients was 153.6 ± 27.3 [Tables 5 and 6].
Table 5.
Lipid profile of the PCOS patients
| Case (Mean±SD) | Range (mg/dL) | No. of patients | |
|---|---|---|---|
| HDL (mg/dL) | 43.4±15.6 | >50 | 24 (46.63%) |
| <50 | 31 (56.36%) | ||
| LDL (mg/dL) | 99.5±21.7 | <100 | 26 (47.27%) |
| >100 | 29 (52.72%) | ||
| Total Cholesterol (mg/dL) | 198.7±27.3 | <200 | 27 (49.09%) |
| >200 | 28 (50.90%) |
Table 6.
Abbreviations with full forms
| Abbreviation | Full Form |
|---|---|
| GCL | Ganglion Cell Layer |
| RNFL | Retinal Nerve Fiber layer |
| AVG | Average |
| CMT | Central Macular Thickness |
| BMI | Body Mass Index |
| HDL | High Density Lipoprotein |
| LDL | Low Density Lipoprotein |
However, because these parameters were studied retrospectively, similar data for the control group were not available to us.
Discussion
The aim of this study was to compare OCT-based RNFL and GCL thickness at the posterior pole, and total macular thickness in women with PCOS and healthy reproductive age group females.
The study recorded the RNFL thickness at the disc and the macula, the total macular thickness, and the GCL + thickness. The GCL + included the GCL + inner plexiform layer thickness.
The patients were then stratified into two groups according to BMI.
There was no significant difference in the total macular thickness between the two groups. Edvan et al. did a significant study where they found that in the absence of insulin resistance, there were no statistically significant differences among the means of the measurements of the total macular thickness between the studied groups.[11]
Our study found no significant difference in the RNFL thickness at the disc and the macula. This could be due to the fact that patients in our study were relatively younger, which means that they were diagnosed earlier.
However, on stratification according to BMI, we found that the superior RNFL thickness in the PCOS group was significantly thicker than that in the control group. Stratified analysis of the remaining retinal thicknesses did not reveal any significant results.
The RNFL in patients with PCOS was significantly thicker in the superior quadrant and those with BMI >30 kg/m2. This was in concurrence with studies conducted earlier by Edvan et al.,[11] Demir et al.[13] and Acmaz et al.[12] who also found a similar result. This could be due to the fact that androgens have a trophic effect on the nerves and this could suggest that PCOS has a protective effect on the RNFL. The hyperestrogenemic effect in PCOS cannot be balanced by progesterone and induces changes in the target organs. Ogueta et al.[9] described estrogen-induced proteins (e.g., cathepsin D, alpha-2-macroglobulin, and aromatase cytochrome P45), which play an important role in vital cellular functions such as differentiation, proliferation, and maturation. Most of these proteins are found in ocular tissues such as the ciliary body and the retinal pigment epithelium.
Our study found no significant difference between the RNFL thickness at the macula. This was in contrast to the study conducted by Edvan et al.[11] where they found significant thickening in the temporal inner macula (TIM), the inferior inner macula (IIM), the nasal inner macula (NIM), and the nasal outer macula (NOM). In another study conducted by Acmaz et al., nasal outer macula (NOM) and temporal outer macula (TOM) were statistically thicker in the PCOS group than in the control group. Fovea center thickness and temporal inner macula were, however, significantly thinner in the PCOS group than in the healthy control group. Therefore, it seems that the effect of PCOS on the macula is not clear and needs further studies.
Acmaz et al.[12] measured the choroidal thickness in patients with PCOS using an Enhanced Depth Optical Coherence Tomography(EDOCT) and found a significantly thicker choroid in patients with PCOS. Our study was, however, limited by the use an SD OCT, which does not measure the choroidal thickness.[13]
PCOS is characterized by an irregular menstrual cycle, ovulatory dysfunction, and hyperandrogenism. Metabolic alterations, insulin resistance, and obesity are often seen in patients with PCOS. Insulin resistance can cause diabetic eye changes in women with PCOS. However, we did not find any diabetic eye changes in our PCOS patients.
In addition to the above, we assessed the IOP, CCT, Schirmer’s test, and TBUT in these patients.
There was no significant difference in the IOP and CCT among the two groups. Meibomian glands are a target organ of androgen hormones, which have been shown to regulate gene expression and lipid synthesis in these tissues.[14] Androgen deficiency may lead to MGD and evaporative dry eye syndrome. Estrogen is an antagonist of meibomian gland function and may promote the development of evaporative dry eyes.[14] This was consistent with the studies done by Adıyeke et al.[14] and Demir et al.[13] who did not find any significant difference between the IOP of the groups. However, in the study done by Karaca et al., a significant difference was found between the Central Corneal Thickness (CCT) among the two groups where the CCT in patients was found to be significantly thicker in PCOS patients.
Previous studies conducted by Bonini et al.[19] and Yavas et al.[20] found no significant difference between the values of Schirmer’s test between the two study groups. Our study also failed to find a significant difference. However, in the study conducted by Karaca et al., a significantly lower Schirmer’s test value was found in PCOS patients. Interestingly, TBUT was found to be significantly lower in PCOS patients in all three studies, unlike our study. This could be explained by the fact that factors such as high temperature and windy climate that are present in our study region, would cause patients with dry eyes to be equally distributed in our study and control groups. In all, the higher prevalence of dry eyes in our study region could be a confounding factor.
We also assessed the OSSS and found no significant difference between the two groups. This was consistent with the above findings. However, no other studies have evaluated the same.
Conclusion
Our results suggest that hyperandrogenemia can modify the RNFL in patients with PCOS. A limitation of our study would be that PCOS was not ruled out biochemically in the control group. Treatment of PCOS can probably ameliorate symptoms of dry eyes in these patients. However, further studies need to be done with a larger sample size to confirm the posterior segment changes in these patients and compare the effect of treatment on the parameters that we assessed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
- 1.Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005;352:1223–36. doi: 10.1056/NEJMra041536. [DOI] [PubMed] [Google Scholar]
- 2.Escobar-Morreale HF. Polycystic ovary syndrome: Definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol. 2018;14:270–84. doi: 10.1038/nrendo.2018.24. [DOI] [PubMed] [Google Scholar]
- 3.Deswal R, Narwal V, Dang A, Pundir CS. The prevalence of polycystic ovary syndrome: A brief systematic review. J Hum Reprod Sci. 2020;13:261–71. doi: 10.4103/jhrs.JHRS_95_18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet. 2007;370:685–97. doi: 10.1016/S0140-6736(07)61345-2. [DOI] [PubMed] [Google Scholar]
- 5.Georgopoulos NA, Saltamavros AD, Vervita V, Karkoulias K, Adonakis G, Decavalas G, et al. Basal metabolic rate is decreased in women with polycystic ovary syndrome and biochemical hyperandrogenemia and is associated with insulin resistance. Fertil Steril. 2009;92:250–5. doi: 10.1016/j.fertnstert.2008.04.067. [DOI] [PubMed] [Google Scholar]
- 6.Acién P, Quereda F, Matallin P, Villarroya E, López-Fernández JA, Acién M, et al. Insulin, androgens, and obesity in women with and without polycystic ovary syndrome: A heterogeneous group of disorders. Fertil Steril. 1999;72:32–40. doi: 10.1016/s0015-0282(99)00184-3. [DOI] [PubMed] [Google Scholar]
- 7.Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev. 2012;33:981–1030. doi: 10.1210/er.2011-1034. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Pasquali R. Metabolic syndrome in polycystic ovary syndrome. Metab Syndr Consequent Endocr Disord. 2018;49:114–30. doi: 10.1159/000485995. [DOI] [PubMed] [Google Scholar]
- 9.Ogueta SB, Schwartz SD, Yamashita CK, Farber DB. Estrogen receptor in the human eye: influence of gender and age on gene expression. Invest Ophthalmol Vis Sci. 1999;40:1906–11. [PubMed] [Google Scholar]
- 10.Wild RA, Carmina E, Diamanti-Kandarakis E, Dokras A, Escobar-Morreale HF, Futterweit W, et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: A consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab. 2010;95:2038–49. doi: 10.1210/jc.2009-2724. [DOI] [PubMed] [Google Scholar]
- 11.de Souza-Júnior JE, Garcia CA, Soares EM, Maranhão TM, Lemos TM, Azevedo GD. Polycystic ovary syndrome: Aggressive or protective factor for the retina? Evaluation of macular thickness and retinal nerve fiber layers using high- definition optical coherence tomography. J Ophthalmol. 2015;2015:193078. doi: 10.1155/2015/193078. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Acmaz G, Ataş M, Gülhan A, Acmaz B, Ataş F, Aksoy H. Evaluation of the macula, retinal nerve fiber layer, and choroid thickness in women with polycystic ovary syndrome using spectral-domain optical coherence tomography. Reprod Sci. 2014;21:1044–9. doi: 10.1177/1933719114522523. [DOI] [PubMed] [Google Scholar]
- 13.Demir M, Guven D, Koc A, Ozdemir S, Can E. Retinal nerve fiber layer thickness in women with polycystic ovary syndrome. J Ophthalmol. 2013;2013:1–3. doi: 10.1155/2013/752186. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Karaca Adıyeke S, Karaca İ, Yıldırım S, Adıyeke M, Uyar İ, Türe G. Anterior segment findings in women with polycystic ovary syndrome. Türk Oftalmol Derg. 2017;47:24–7. doi: 10.4274/tjo.73659. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Gonen T, Celik C, Oznur M, Abali R, Gonen KA, Horozoglu F, et al. Tear osmolarity and ocular surface changes in patient with polycystic ovary syndrome. Curr Eye Res. 2013;38:621–5. doi: 10.3109/02713683.2012.749917. [DOI] [PubMed] [Google Scholar]
- 16.Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. The androgen excess and PCOS society criteria for the polycystic ovary syndrome: The complete task force report. Fertil Steril. 2009;91:456–88. doi: 10.1016/j.fertnstert.2008.06.035. [DOI] [PubMed] [Google Scholar]
- 17.Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81:19–25. doi: 10.1016/j.fertnstert.2003.10.004. [DOI] [PubMed] [Google Scholar]
- 18.Braunstein GD, Reitz RE, Buch A, Schnell D, Caulfield MP. Testosterone reference ranges in normally cycling healthy premenopausal women. J Sex Med. 2011;8:2924–34. doi: 10.1111/j.1743-6109.2011.02380.x. [DOI] [PubMed] [Google Scholar]
- 19.Bonini S, Mantelli F, Moretti C, Lambiase A, Bonini S, Micera A. Itchy-dry eye associated with polycystic ovary syndrome. Am J Ophthalmol. 2007;143:763–71.e2. doi: 10.1016/j.ajo.2007.01.030. [DOI] [PubMed] [Google Scholar]
- 20.Yavas GF, Ozturk F, Kusbecı T, Ermıs SS, Yılmazer M, Cevrıoglu S, et al. Meibomian gland alterations in polycystic ovary syndrome. Curr Eye Res. 2008;33:133–8. doi: 10.1080/02713680701858410. [DOI] [PubMed] [Google Scholar]