The Effect Of Polycystic Ovarian Syndrome Treatment On Ocular Surface
Conditions: Poly Cystic Ovary Syndrome
Sponsor: Cairo University

                                                                                                           
 
Research Template 
1 
 
Final Version: April 2019 
 
Faculty of Medicine, Cairo University Postgraduate 
Research Protocol Template 
(Please read carefully provided guidance documents for a comprehensive understanding and proper formulation of 
your thesis protocol and required forms) 
 
1. Study 
 
a- Proposed Study Title: The effect of  polycystic ovarian syndrome treatment on ocular 
surface. 
b- Degree :   MD. 
c- Date of Registration of MSc or MD: March 2021. 
 
     2. Candidate  
 
a. Name:   Mohamed Saad Emam Ahmed.  
b. Occupation: Ophthalmology resident.  
c. Affiliation: Memorial institute of ophthalmic research.  
d. Email addresses: Mohamedsaad2032@gmail.com 
e. Full mailing address: 59L, Pyramids Gardens, Haram, Giza. 
f. 
Phone number: 01007654385 
3. Supervisors Contact Information 
  
a.   Principal supervisor:    Name: Prof. Dr. Ahmed Mohamed Ali Sherif.  
                                          Department: Ophthalmology department, Cairo university.  
 Phone number: 01221088299 
 E-mail addresses: AhmedSherif@kasralainy.edu.eg  
b.   Other supervisors: 
 
1- Name: Prof. Dr. Malak Ismail El Shazly. 
    Department: Ophthalmology department, Cairo university. 
    Phone: 0122224483 
    Email: Melshazly75@hotmail.com  
2- Name : Dr. Ayah Abd Elfatah Marrie.  
    Department: Ophthalmology department, Cairo university. 
    Phone:  01006771238                        
    Email: ayahmarrie@hotmail.com  
 
 

                                                                                                           
 
Research Template 
2 
 
Final Version: April 2019 
3- Name: Dr. Mohamed Reda Hassan Khedr 
Department:  Obstetrics and gynecology department, Cairo university. 
Phone: 01000769345 
Email: Mo.Reda2011@yahoo.com    
4. Scientific committee approval  
(Was it scientifically approved by the department?) Yes. 
            Date of approval: 1-11-2022 
 
5. Background and Rationale: (Describe the research question and justification for 
undertaking the study explaining the aspects of novelty in the study) 
           Polycystic ovary syndrome (PCOS) is one of the most common 
endocrinopathies, affecting approximately 9% to 18% of women in reproductive 
age.(1) Although the exact pathogenesis of PCOS remains unclear, the characteristic 
symptoms include oligoanovulation, polycystic ovarian morphology could be 
explained by hyperandrogenism and hyperestrogenemic not balanced by 
progesterone.(2) The endocrine, inflammatory, and metabolic changes associated with 
PCOS have consequences for vision, including neurovascular, metabolic changes in 
the retina, macular and optic nerve thickness changes.(3) 
          In recent years it has been discovered that female sex steroids have both 
systemic and ocular effects, Estrogen, progesterone and androgen receptors have 
been found in the cornea, lens, iris, ciliary body, retina, lacrimal glands, meibomian 
glands and conjunctiva,(4) The influence of hormone replacement therapy in 
menopausal women remains unclear, as some authors support the idea that it 
improves the quality and the volume of the tear film, whereas others have shown that 
it increases the risk of dry eye, It's possible that HRT may alleviate postmenopausal 
dry-eye symptoms by increasing goblet cell density.(5) However, other studies 
suggest that HRT worsens dry-eye symptoms in some cases, and estrogen-only HRT 
seems to be worse than a combined estrogen and progesterone therapy.(6)  
       Reports are stressing on the effect of PCOS on tear film stability rather than 
amount of the tears denoting the possible effect on meibomian glands (MGs) 
functions, Loss and morphological deterioration of the MGs are observed in PCOS 
patients(7),Yonca Asfuroglu et al. reported that Dry eye was well established in 
patients with PCOS. They proposed that hyperandrogenism, insulin resistance and 
subclinical inflammation may be possible contributing factors to the Dry eye 
spectrum in these patients, They correlated the severity of the Dry eye with the level 
of inflammation and hyperandrogenism.(8)  
 
           For Treatment of Non-fertility outcomes, combined oral contraceptive pills 
(COCPs), metformin and anti-androgen drugs are used. COCPs  are recommended as 
first-line medical treatment for the management of hyperandrogenism and regulation 
of menstrual cycles,(9) A study by Chen et al. reported that COCPs have no direct 

                                                                                                           
 
Research Template 
3 
 
Final Version: April 2019 
impact on Dry eye, They found no significant differences in Dry eye, as measured by 
tear osmolarity and ocular surface disease index (OSDI) or Symptom Assessment in 
Dry Eye (SANDE) questionnaires, between patients taking OCPs and those not 
taking OCPs. However, results were not conclusive.(10) 
           Because of the metabolic features of PCOS such as insulin resistance and 
hyperinsulinemia; insulin-sensitizing agents, especially metformin, have been used 
as a treatment option for PCOS with OCPS as the second line of treatment. (11) 
Metformin has a protective effect in diabetic retinopathy, glaucoma, and age related 
macular degenerations,(12) It can also improves objective measures of Dry Eyes and 
focus score in Sjögren′s Disease.(13)  
           The role of antiandrogens in the treatment of hirsutism in PCOS is 
controversial; however, there is some weak evidence that flutamide and 
spironolactone reduce hirsutism.(14) Ilaria Macche et al. found that ocular surface 
findings are improved by systemic anti-androgen treatment in PCOS and correlate 
with the severity of the androgen excess-related skin signs.(15)  
             
          For Treatment of Fertility Indications, Pharmacological options include 
ovulation induction with clomiphene citrate (CC), letrozole (aromatase inhibitor), 
metformin, and gonadotrophins(16); The effect of clomiphene citrate (ovarian 
stimulant)  on vision is minimal; reduction in foveal flicker sensitivity was the only 
observed visual disturbance.(17) 
             Although visual disturbance is a possible side effect of aromatase inhibitors 
use, its incidence is quite variable.(18) Studies found increased tear osmolarity and 
meibomian gland drop out in women on letrazole with symptomatic dry eye.(19) 
 
6. Objectives: (describe specific objectives or hypotheses behind the study) 
The purpose of this study is to prospectively evaluate the ocular surface effects of 
polycystic ovarian syndrome  and different drugs used in its management.   
 

                                                                                                           
 
Research Template 
4 
 
Final Version: April 2019 
7. Study Design: (Please fill in the appropriate study design, see attached PDF guide) 
  
- Descriptive: - Survey (cross sectional)   
                   - Qualitative 
 
- Analytic: - Observational: - Case-control study 
                                        - Cross sectional analytic study 
                                        - Cohort (Longitudinal) study 
 
              - Experimental: - Randomized Clinical Trial                     Phase: 
                                       - Non-randomized clinical trial 
                                       - Animal study 
                                       - Cellular study 
 
- Others:   Please describe:        
             
8. Study Methods 
- 
Population of study: (Please provide all details regarding participants including gender, age 
range and disease conditions. Also indicate if this protocol involves children, prisoners, 
pregnant women or cognitively impaired or mentally disabled subjects) 
 
            Two groups with confirmed laboratory and ultrasonography diagnosis of PCOS  , First group 
will include 30 eyes of 30 females in childbearing period (18-40 years old) scheduled for 
treatment for non- fertility indications with oral contraceptive pills (as a first line of 
treatment), and the second group will  include 30 eyes of 30  females in childbearing period 
(18-40 years old) scheduled for treatment with Clomiphene citrate (as a first line of 
treatment), for fertility indications.   
 
- 
Study location: (Please provide where the study will be conducted and from where study 
participants will be recruited) 
Patients will be recruited from gynecology and dermatology Kasr Al-Ainy clinics and will 
undergo their ophthalmic examination and investigations at the department of ophthalmology, 
Kasr Al-Ainy school of medicine.  

                                                                                                           
 
Research Template 
5 
 
Final Version: April 2019 
- 
Inclusion criteria: 
1. Females at child bearing period (18-40 years old). 
2. Patients recently diagnosed with polycystic ovarian syndrome.   
 
- 
Exclusion criteria: 
- 
1.Patients who were diagnosed with Dry eye disease.   
2.Patients who were treated with hormonal replacement therapy, Metformin, Aromatase 
inhibitors, clomiphene citrate or androgen antagonists. 
3. Patients who underwent ocular surgeries. 
4. patients with history of diabetes mellitus or hypertension.    
 
- 
Methodology in details: 
Two groups with confirmed laboratory and ultrasonography diagnosis of PCOS, First group 
will include 30 eyes of 30  females in childbearing period (18-40 years old) scheduled for 
treatment for non- fertility indications with Estradiol valerate / Norgestre tablets for six 
months, The second group will  include 30 eyes of 30  females in childbearing period (18-40 
years old) scheduled for treatment with Clomiphene citrate  for fertility indications for 6 
months.  
. 
- Follicle stimulating hormone (FSH), luteinizing hormone (LH) , androgen, estrogen, 
progesterone , fasting insulin and neutrophil to lymphocyte ratio (NLR)  will be obtained.  
-The two groups will undergo complete ophthalmic examination including :  
 
             *Full history.  
*Standard Patient Evaluation of Eye Dryness Questionnaire (SPEED) in order to quickly   
track the progression of dry eye symptoms over time.  
  *Manifest refraction. 
* Corrected distance visual acuity. 
* Anterior segment examination using slit lamp, Schirmer's test and tear film breakup time 
test. 
* Fundus examination. 
* Measuring central corneal thickness (CCT) using Corneal pachymetry. 
•Beside Schirmer's test, tear film breakup time test and fluorescein break-up patterns, Dry 
eye assessment will be performed using Dry Eye Diagnostic System device (D130, Medi-
Works Precision Instruments; Shanghai, China). Device to have a Dry eye diagnosis brings 
out an automatic result of non-invasive break up test (NIBUT) and tear meniscus height 
after taking one video. It is a fully automatic analysis system to provide efficient quantified 
evaluation for the overall stability of the tear film. Also it uses identification system that 
depicts the tear meniscus area and measures the tear height automatically.  
The device also automatically analyses the meibomian glands, lipid layer thickness, and 
eyelid margin. The built-in infrared lighting system helps to obtain the enormous image 
scope of the meibomian glands. Finally the device  identifies and calculates percentages of 

                                                                                                           
 
Research Template 
6 
 
Final Version: April 2019 
conjunctival congestion and ciliary congestion, Thus evaluating the severity of eye 
congestion. If the degree of severity of eye congestion is more than two, it is abnormal. 
*Examination and laboratory tests will be done before, 3 months after starting treatment   
and after finishing the treatment course. 
 
- 
Intervention: 
 
- 
Diagnostic intervention (please describe): 
 
Imaging ocular surface  using dry eye diagnostic system. 
- 
Therapeutic intervention (please describe):         
 
- 
No intervention  
 
- 
Does the research involve? 
          Human participants 
          Biological samples/Tissues 
          Identifiable private data/Information     
 
- 
Type of consent of study participants: 
 
          Written consent 
          Oral consent 
          No consent needed (Please justify) 
- 
Potential risks:  
(Please mention all risks involved even mild ones as pain, discomfort, chance of 
infection or psychological effects) 
 
1- No possible risks 
 
 
 

                                                                                                           
 
Research Template 
7 
 
Final Version: April 2019 
- 
Confidentiality of data: (Please explain how privacy and confidentiality of data and 
records will be maintained)  
- 
Names and private data of patients will not be published, only the results of the study 
will be analyzed and published. 
 
      9- Study outcomes: 
- 
Primary outcomes (Most important measurable outcomes) 
1- Measuring changes in meibomian glands function, break up time, tear 
meniscus height, and  lipid layer thickness in polycystic ovarian syndrome  and 
with different drugs used in managing it.  
- Secondary outcome parameters (other outcomes to be assessed) 
1- Measuring eye lid margin, conjunctival hyperemia, and ocular surface staining 
in polycystic ovarian syndrome  and with different drugs used in managing it. 
 
2-  Measuring the central corneal thickness (CCT) changes in polycystic ovarian 
syndrome  and with different drugs used in managing it. 
 
         10- Sample size (number of study subjects included and justification including the clinical and 
statistical assumptions supporting sample size calculation) 
 
                                                                                                (Takazawa & Morita, 2020) 
n = sample size 
Z a/2 (The critical value that divides the central 95% of the Z distribution) 
ZB (The critical value that divides the central 20% of the Z distribution) 
p1 = prevalence in case group 
p2 = prevalence in control group. 
q = 1-p 
 
 
 

                                                                                                           
 
Research Template 
8 
 
Final Version: April 2019 
Epi Info STATCALC was used to calculate the sample size by considering the following 
assumptions:- 95% two-sided confidence level, with a power of 80%. & α error of 10% (20). The final 
maximum sample size taken from the Epi- Info output was 26. Thus, the sample size was increased to 
30 subjects with total 30 eyes in each group to assume any drop out cases during follow up. 
 
         11- Statistical analysis (Please describe your data analysis plan) 
Data management and analysis will performed using Statistical Package for Social Sciences (SPSS). 
Median and range for non-parametric measures and ordinal (scores) data. Numerical data will be 
presented as means ± standard deviations (SD). Categorical data will be presented as number and 
percentages %. Pairwise comparisons between the two groups for normally distributed variables will 
be done using the Student’s t-test; the Mann–Whitney test, a nonparametric test equivalent to the t-
test, will be used in non-normally distributed variables. The Repeated measures ANOVA test will be 
used to compare the effect change within and between the study groups at different visits. The chi-
square test or the Fisher’s exact test will be used to compare between the groups with respect to 
categorical data. All p-values will be two-sided. P-values < 0.05 will be considered significant 
 
         12- Source of funding: (Please include source of funding even if self funding) 
 
- Faculty of Medicine, Cairo University  
- Other sources: 
Please specify: Self-funding 

                                                                                                           
 
Research Template 
9 
 
Final Version: April 2019 
      13- Time plan:  
              
             - When to start? Immediately after acceptance. 
 
              - When expected to finish? After 18 months  
 
              - When to publish? After 18 months 
  
      14- References: 
1. March WA, Moore VM, Willson KJ, Phillips DIW, Norman RJ, Davies MJ. The prevalence of polycystic 
ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Human Reproduction. 
2009 Nov 12;25(2):544–51. 
2. FRANKS S, MCCARTHY MI, HARDY K. Development of polycystic ovary syndrome: involvement of 
genetic and environmental factors. International Journal of Andrology. 2006 Feb;29(1):278–285. 
3. Souza-Júnior JE de, Garcia CA de A, Soares EMM, Maranhão TMO, Lemos TMAM, 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. Journal of 
Ophthalmology . 2015;2015:1–8. 
4. Gupta PD, Johar K, Nagpal K, Vasavada AR. Sex Hormone Receptors in the Human Eye. Survey of 
Ophthalmology. 2005 May;50(3):274–284. 
5. Pelit A, Bağiş T, Kayaselçuk F, Dursun D, Akova Y, Aydin P. Tear Function Tests and Conjunctival 
Impression Cytology before and after Hormone Replacement Therapy in Postmenopausal Women. European 
Journal of Ophthalmology. 2003 May;13(4):337–342. 
6. Schaumberg DA. Hormone Replacement Therapy and Dry Eye Syndrome. JAMA. 2001 Nov 
7;286(17):2114.  
7. Balıkçı A, Ulutaş H, Özgen G. Evaluation of meibomian gland morphology and anterior segment parameters 
by Sirius topography systems in polycystic ovary syndrome. Indian Journal of Ophthalmology. 
2022;70(8):2922.. 
8. Asfuroğlu Y, Kan Ö, Asfuroğlu M, Baser E. Association Between Dry Eye and Polycystic Ovary Syndrome: 
Subclinical Inflammation May Be Part of the Process. Eye &amp; Contact Lens: Science &amp; Clinical 
Practice. 2020 Jun 1;47(1):27–31. 
9. Helvaci N, Yildiz BO. Oral contraceptives in polycystic ovary syndrome. Minerva Endocrinol 2014; 39 (03) 
175-187. 
10. Chen SP, Massaro-Giordano G, Pistilli M, Schreiber CA, Bunya VY. Tear Osmolarity and Dry Eye 
Symptoms in Women Using Oral Contraception and Contact Lenses. Cornea. 2013 Apr;32(4):423–328. 
11. Lashen H. Review: Role of metformin in the management of polycystic ovary syndrome. 
Therapeutic Advances in Endocrinology and Metabolism. 2010 Aug;1(3):117–128. 
12. Kusturica J, Kulo A, Rakanović-Todić M, Burnazović-Ristić L, Maleškić S. Potential Protective Effects of 
Metformin on Ocular Complications in Patients with Type 2 Diabetes. Metformin [Working Title] [Internet]. 
2020 Feb 25.. 
13. Sharma R, Chaudhari KS, Kurien BT, Grundahl K, Radfar L, Lewis DM, et al. Sjögren Syndrome without 
Focal Lymphocytic Infiltration of the Salivary Glands. The Journal of Rheumatology. 2019 May 15;47(3):394–
399. 
14. Rittmaster RS. ANTIANDROGEN TREATMENT OF POLYCYSTIC OVARY SYNDROME. 
Endocrinology and Metabolism Clinics of North America. 1999 Jun;28(2):409–421.. 

                                                                                                           
 
Research Template 
10 
 
Final Version: April 2019 
15. Ilaria Macchi, Laura Guccione, Flavio Mantelli, Alessandra Micera, Costanzo Moretti, Stefano Bonini; 
Ocular surface findings associated to clinical signs of hyperandrogenism assessed by an innovative 
videodermoscopic method. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5428. 
16. Franik S, Eltrop SM, Kremer JA, Kiesel L, Farquhar C. Aromatase inhibitors (letrozole) for subfertile 
women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews . 2018 May 24;2018(5). 
17. Racette L, Casson PR, Claman P, Zackon DH, Casson EJ. An investigation of the visual disturbances 
experienced by patients on clomiphene citrate. Fertility and Sterility. 2010 Mar;93(4):1169–1172. 
18. Almafreji I, Smith C, Peck F. Review of the Literature on Ocular Complications Associated With 
Aromatase Inhibitor Use. Cureus. 2021 Aug 30;13(8):e17565. 
19. Khoo P, Groeneveld T, Boyle F, O’Neill S, Forster B, Watson SL. Dry eye signs and symptoms in patients 
on aromatase inhibitor therapy. Eye.  2021 Apr 19;36(4):766–772. 
20. Takazawa A, Morita S. Optimal Decision Criteria for the Study Design and Sample Size of a Biomarker-
Driven Phase III Trial. Therapeutic Innovation &amp; Regulatory Science. 2020 Jan 27;54(5):1018–1034. 
 
    
1- Please fill in all the included sections and don’t delete any part of the template 
2- For choice brackets, please just use the fill in function in word