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 Table of Contents  
RESEARCH PROTOCOL
Year : 2014  |  Volume : 8  |  Issue : 1  |  Page : 3-8

Homoeopathy in polycystic ovarian syndrome: A randomized placebo-controlled pilot study


, India

Date of Submission18-Feb-2014
Date of Acceptance19-Feb-2014
Date of Web Publication29-Mar-2014

Correspondence Address:
Central Council for Research in Homoeopathy
New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0974-7168.129671

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  Abstract 

Background: Polycystic ovarian syndrome (PCOS) is an emerging health problem in young females characterized by ovarian dysfunction and hyperandrogenism. Existing information indicates a positive role of homoeopathy but more rigorous studies are desirable. This protocol has been developed to undertake a pilot study to evaluate the efficacy of homoeopathic intervention using established diagnostic criteria.
Methods/Design:
It will be a multi-centric, randomized, placebo controlled pilot study with a 6-month intervention and follow up period. Minimum 60 cases fulfilling the eligibility criteria will be enrolled and randomized to receive either the homoeopathic intervention or the identical placebo. Both the arms follow lifestyle modification for weight reduction. Primary endpoint will be the establishment of regular menstrual cycle along with improvement in either ultrasonology or hirsutism/acne. Secondary endpoints will be to compare the changes in total and individual domain scores of PCOS questionnaire at monthly interval and the changes in ultrasound of polycystic ovaries. For the primary outcome and each of the secondary outcomes, both per protocol and modified intention to treat analysis will be done.
Discussion:
This pilot study has been planned considering the varied presentation of PCOS as per international diagnostic criteria and accordingly the composite endpoints have been kept for evaluation. The outcome of this pilot study will help in planning a definite study.
Trial registration: CTRI/2013/09/003983 [Registered on: 16/09/2013].

Keywords: Anovulation, Homoeopathy, Hyperandrogenism, Insulin resistance, Oligomenorrhoea, Polycystic ovarian syndrome, Polycystic ovary syndrome questionnaire


How to cite this article:
Central Council for Research in Homoeopathy. Homoeopathy in polycystic ovarian syndrome: A randomized placebo-controlled pilot study. Indian J Res Homoeopathy 2014;8:3-8

How to cite this URL:
Central Council for Research in Homoeopathy. Homoeopathy in polycystic ovarian syndrome: A randomized placebo-controlled pilot study. Indian J Res Homoeopathy [serial online] 2014 [cited 2019 Jun 17];8:3-8. Available from: http://www.ijrh.org/text.asp?2014/8/1/3/129671


  Background Top


Polycystic ovarian syndrome (PCOS) is a complex metabolic, endocrine and reproductive disorder affecting approximately 5-10% of the female population in developed countries. The developing countries like China and India, undergoing rapid nutritional transitions due to westernised diets and lifestyle also indicate similar prevalence (9.13%). [1],[2] Its clinical characteristics include hyperandrogenism, chronic anovulation, insulin resistance and infertility. While reproductive features are prominent, it has potential for major metabolic consequences including obesity, type 2 diabetes and cardiovascular disease. [3] It remains a syndrome and, as such, no single diagnostic criterion (such as hyperandrogenism or PCO) is sufficient for diagnosis. It also remains a diagnosis of exclusion. Known disorders such as late-onset congenital adrenal hyperplasia that mimic the PCOS phenotype should be excluded. [4]

Although there are more than 5,000 scientific publications, majority relates to pathophysiology and treatment of PCOS but assessment of psychological impact has largely been ignored. Only recently has the complexity of the symptomatology of PCOS begun to be investigated in a comprehensive manner to address the psychosocial implications. It has been concluded that depression and anxiety are common in patients with PCOS as compared with healthy women. Depression in PCOS is often associated with obesity and metabolic abnormalities. [5],[6] The depression and anxiety did not show a significant change in PCOS after treatment with oral contraceptive pills. [7] Homoeopathic prescription being holistic might help in these aspects, hence, polycystic ovary syndrome questionnaire (PCOSQ), which evaluates emotional aspects along with body hair, weight, infertility and menstrual problems for the assessment of quality of life is being used in the study. [8]

Lifestyle modification is the first line of treatment and it is known that even 5-10% weight loss has led to significant clinical benefits improving psychological outcomes, reproductive and metabolic features. [9],[10] In conventional medical system, metformin, oral contraceptives, anti-androgens, clomiphene citrate and thiazolidinediones are used for the management of different presentations of PCOS. Metformin is commonly used either alone or in combination with other medicines for the treatment of most of the clinical manifestations of PCOS. [11] In a study, metformin reduced hyperinsulinaemia and hyperandrogenaemia, independently of changes in body weight. In a large number of subjects these changes were associated with striking, sustained improvements in menstrual abnormalities and resumption of ovulation [12] but it causes gastrointestinal intolerance (nausea, abdominal pain and/or diarrhoea) in 30% of patients. It is contraindicated in liver disease and certain other clinical conditions. Other medicines also have their side effects. [11]

There are few reports indicating the usefulness of homoeopathic treatment. Sanchez et al., [13] and Gupta et al., [14] reported symptomatic as well as ultrasonological improvement but more studies are required with proper rigor. Council has developed this protocol for a pilot study. The primary objective of the study shall be to determine the feasibility of the study to evaluate the efficacy of homoeopathic intervention in PCOS in establishing the menstrual regularity with either ultrasonological improvement of PCO or improvement in hirsutism/acne and the secondary objective shall be to assess the changes in ultrasound reports of polycystic ovaries and to assess the changes in the total and individual domain scores of PCOSQ.


  Methods/Design Top


Study Design

The study shall be multi-centric, randomized, placebo controlled with 6-month intervention and follow up period.

Eligibility Criteria

The inclusion criteria for the study are: (1) female aged 18-36 years (2) oligomenorrhoea (intermenstrual period of more than 35 days for 3 consecutive cycles)/ amenorrhoea for more than 3 months (2 years after menarche) (3) ultrasound findings of polycystic ovaries [The PCO should have at least one of the following: either 12 or more follicles measuring 2 ± 9 mm in diameter or increased ovarian volume (>10 cm 3 ). If there is evidence of a dominant follicle (>10 mm) or a corpus luteum, the scan should be repeated during the next cycle. Only one ovary fitting this definition or a single occurrence of one of the above criteria is sufficient to define the PCO. [15] (4) clinical evidence of hirsuitism (Ferriman score 8 and above) [16] and/or acne (acne global severity scale score 1 and above) [17] ; (5) Body Mass Index (BMI) 23 and above (6) participants willing to adopt healthy diet and to take regular exercise (at least 30 minutes of exercise for at least 5 days a week) (7) written informed consent from the patient.

The exclusion criteria includes: (1) diabetes mellitus, Cushing's disease, hyper-prolactinemia; (2) untreated hypo or hyperthyroidism (3) adrenal hyperplasia and adrenal tumour (4) ovarian tumour (5) hyperthecosis (6) significant renal impairment (7) history of intake of drugs aldactone/metformin or history of oral contraceptive pills (OCP) use or intake of drugs known to interfere with carbohydrate metabolism 4 weeks prior to enrolment (8) pregnancy, breast feeding (9) cases with any systemic disease.

The patients presenting with PCOS will be screened for eligibility and will undergo pelvic ultrasound, complete blood count with erythrocyte sedimentation rate, fasting glucose, thyroid function test, serum prolactin, basal morning 17α-hydroxyprogesterone (17OHP), complete urine examination and urine pregnancy test in case of married women with amenorrhoea prior to enrolment.

Types of Intervention

Patients fulfilling the eligibility criteria will be enrolled and randomized as per computer generated randomization chart [18] to receive either the homoeopathic intervention or the identical placebo as illustrated in [Figure 1]. Medicine shall be given in Q, 6C, 30C, 200C or 1M potency as per the prescribing totality. Mother tincture shall only be prescribed in persistent amenorrhoea. The medicine will be repeated depending on the potency and complaints of the patient in accordance with the principles of homoeopathy. [19] All the participants will be asked to follow healthy diet and to take up regular exercise (at least 30 minutes of exercise at least 5 days a week).
Figure 1: Flow chart of the study groups

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Criteria for Baseline Assessment and Follow Up

All the enrolled subjects will undergo complete case taking along with clinical examination, baseline investigations for sex hormone binding globin, Luteinizing Hormone/Follicle Stimulating Hormone (LH/FSH) ratio, total Testosterone, Dehydroepiandrosterone sulphate (DHEAS), serum insulin, glucose insulin ratio, triglycerides and High-Density Lipoprotein (HDL)-cholesterol at baseline and shall fill PCOSQ.

Patient will be assessed at monthly intervals (or earlier as per the need) for 6 months. Symptomatic assessment and clinical examination will be done every month and PCOSQ will be filled. Any inter-current complaint arising during the treatment period is to be managed as per the acute totality in both the groups. Prescription will be changed and selection of the medicine will be based on the characteristic symptoms including exciting cause, mental and physical generals and qualified particular symptoms modified as a consequence of acute disease. Previously prescribed medicine/placebo is to be discontinued as per the need of the case till acute phase is over. Record of any such event is to be maintained in follow up sheet for acute phase. If the case does not respond to the homoeopathic intervention, patient shall be referred accordingly for the conventional treatment. The patient will be encouraged to revert back after the acute phase gets over. Such cases will be followed up as per the protocol subsequently.

At completion of the study, symptomatic assessment, clinical examination and pelvic ultrasound will be done. All patients will fill PCOSQ. Only those investigations will be repeated at 6 months, which were out of range at baseline.

Study Endpoints

Primary study endpoint is the establishment of regular menstrual cycle along with either ultra sonological improvement of PCO or improvement in hirsutism/acne. Secondary study endpoints are to compare the changes in total and individual domain scores of PCOSQ (consists of five domains, each relating to a common symptom of PCOS; emotions, body hair, weight, infertility and menstrual problems. Each question on the PCOSQ is associated with a 7-point scale in which 7 represents optimal function and 1 the poorest function) in verum and placebo groups at monthly interval for 6 months and to compare the changes in ultrasound reports of polycystic ovaries at entry and 6 months in verum and placebo groups.

Randomization

Separate sets of random numbers have been generated for the two study sites (each site is strata) using stratified randomization method.

Allocation

The patients fulfilling the eligibility criteria shall be enrolled and randomized as per computer generated randomization chart to receive either the homoeopathic intervention or the identical placebo.

Blinding

The patients will remain blinded to the identity of the treatment group.

Sample Size Calculation

In the initial stage of the study, 30 cases of PCOS in verum and 30 cases in placebo group shall be enrolled. After the analysis of the data, the sample size shall be revisited and according to the outcome of this study, further study shall be continued or discontinued.

Study Duration

The duration of the study will be 2 years (1 year for enrolment, 6 months for follow up and 6 months for data compilation).

Data Collection

Each case will be followed up for 6 months to assess the outcome results of the treatment. Study data will be collected at baseline, every follow up (monthly or early if required) and at final/termination visit. The patients will be evaluated for symptomatic, clinical assessment, laboratory parameters and adverse events, if any, as per the study protocol.

Statistical Analysis

Data obtained during the study would be verified and analyzed using Statistical Package for Social Sciences (SPSS) version 20. Chi square test shall be applied for checking the improvement in menstrual cycle and acne. Pre and post analysis (paired t test) shall be applied for checking the changes in hirsutism, ultrasound assessment of ovaries and laboratory investigations. Repeated measure analysis of variance (ANOVA) and pre and post analysis (paired t test) shall be applied for checking the difference in the total score and individual domain score of PCOSQ. Hereditary factor, socio-economic status, stress, etc., would be considered as potential confounders in PCOS.

For the primary outcome and each of the secondary outcomes, both per protocol and modified intention to treat (mITT) analysis will be done. mITT analysis will be done on the patients completing a minimum of three scheduled follow up visits.

Regulatory and Ethical Approval

The study protocol is in accordance with the latest revision of the Helsinki declaration [20] on human experimentation and Good Clinical Practices India. [21] Although, medicines proposed to be used during the study are known homoeopathic pharmacopoeal preparations, yet necessary clearance of the Ethical Committee and Scientific Advisory Committee has been obtained before undertaking the study.


  Discussion Top


As the PCOS is a multi-faceted problem with reproductive, endocrine and metabolic dysfunction; therefore, the study has been planned keeping in view the multi-factorial evaluation of the intervention. Accordingly, to establish the diagnosis of PCOS, the criteria laid down by 2003 Consensus Statement on PCOS [4] and 2006 Androgen Excess Society have been followed. [22] It is reported that Lifestyle modification should be the first line of treatment and is effective in reducing the signs and symptoms of PCOS, [13] therefore, the study has been designed as placebo controlled trial with both the arms following Lifestyle modification so that the effect of Lifestyle modification and homoeopathy can be evaluated.

As the investigations are only suggestive and not fully confirmatory, therefore, the outcome will be assessed on composite endpoints, namely, menstrual regularity, ultrasonological improvement of PCO [15] and hyperandrogenism (hirsutism and/or acne as per Ferriman-Gallwey scoring system [16] and/or acne global severity scale [17] ). PCOSQ, a validated questionnaire, will be used for evaluation of quality of life in cases of PCOS. [8]

Conventional treatment varies as per the symptoms and also has some side effects. Studies in homoeopathy [14],[15] have indicated a positive role but these studies primarily evaluated menstrual irregularity and PCO through ultrasonography. Hyperandrogenism and effect of Lifestyle modification was not evaluated and statistical rigor was also lacking. Due consideration has been given to all these aspects while drafting this protocol.

High quality protocols facilitate proper conduct, reporting and external review of clinical trials. This study protocol is in accordance with the SPIRIT 2013 [23] and covers all the domains of model validity of homoeopathic trials (MVHT). [24] The protocol shall generate data that can be reported as per CONSORT guidelines for reporting randomised trials with parallel groups [25] and the Reporting data on Homoeopathic Treatments (RedHot) supplement to CONSORT. [26] The overall risk of bias appears to be minimal as only one domain (allocation concealment) out of six has high risk of bias. [27] The study is not double-blind due to nature of disease, which may require multiple prescriptions in different potencies depending on the presentation, and moreover the outcome measures are not likely to be influenced by lack of blinding. The outcome of this pilot study will help in planning a definite study subsequently.

Trial Status

Participant recruitment has been initiated in February 2014.


  Contributions Top


Study concept and design: Raj K. Manchanda, 1 Chetna Deep Lamba

Expertise: 2 Madhu Aggarwal, 3 Neelam Aggarwal, 4 Ajay Ajmani, 5 Ravindra Mohan Pandey

Coordination: Raj K. Manchanda, 1 Chetna Deep Lamba, 6 Vikram Singh, 7 Anil Khurana, 8 Jaya Gupta, 8 Praveen Oberai

Statistical planning: 9 Maya Padmanabhan, 1 Chetna Deep Lamba

Drafting of protocol with ethical and technical approval: 1 Chetna Deep Lamba

Drafting and revision of manuscript: 1 Chetna Deep Lamba

Critical review of manuscript: Raj K. Manchanda

Funding/ Support:
Central Council for Research in Homoeopathy.

Contributor's information

Director General, Central Council for Research in Homoeopathy

1 Scientist-1, Central Council for Research in Homoeopathy

2 Professor and Head, Dept. of Obstetrics and Gynaecology,

Dr. B. R. Sur Homoeopathic Medical College and Hospital, New Delhi

3 Senior Consultant, Dept. of Obstetrics and Gynaecology, Post Graduate Institute of Medical Education and Research, Chandigarh

4 Senior Consultant, Dept. of Endocrinology, BLK Super Specialty Hospital, New Delhi

5 Professor and Head, Dept. of Biostatistics, All India Institute of Medical Sciences, New Delhi

6 Former Deputy Director (H), Central Council for Research in Homoeopathy

7 Assistant Director (H)/ Scientist-4, Central Council for Research in Homoeopathy

8 Scientist-4, Central Council for Research in Homoeopathy

9 Statistical Assistant, Central Council for Research in Homoeopathy.

 
  References Top

1.Heidi A. Polycystic ovary syndrome (PCOS) in urban India. Manlove University of Nevada, Las Vegas. Available from: http://digitalscholarship.unlv.edu/cgi/viewcontent.cgi?article=1937&context=thesesdissertations [Last accessed on 2011 Jan 05].  Back to cited text no. 1
    
2.Nidhi R, Padmalatha V, Nagarathna R, Amritanshu R. Prevalence of polycystic ovarian syndrome in Indian adolescents. J Pediatr Adolesc Gynecol 2011;24:223-7.  Back to cited text no. 2
    
3.Evidence-based guideline for the assessment and management of polycystic ovary syndrome. Jean Halles for Women′s health. Available from http://www.med.monash.edu.au/epidemiology/news/sept2nded/evidence-based-guideline-polycystic-ovary-syndrome.pdf [Last accessed on 2011 Jan 05].  Back to cited text no. 3
    
4.Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19:41-7.  Back to cited text no. 4
    
5.McCook, Reame NE, Thatcher SS. Health-related quality of life issues in women with polycystic ovary syndrome. J Obstet Gynecol Neonatal Nurs 2005;34:12-20.  Back to cited text no. 5
    
6.Cinar N, Kizilarslanoglu MC, Harmanci A, Aksoy DY, Bozdag G, Demir B, et al. Depression, anxiety and cardio metabolic risk in polycystic ovary syndrome. Hum Reprod 2011;26:3339-45.  Back to cited text no. 6
    
7.Cinar N, Harmanci A, Demir B, Yildiz BO. Effect of an oral contraceptive on emotional distress, anxiety and depression of women with polycystic ovary syndrome: A prospective study. Hum Reprod 2012;27:1840-5.  Back to cited text no. 7
    
8.Cronin L, Guyatt G, Griffith L, Wong E, Azziz R, Futterweit W, et al. Development of a health-related quality-of-life questionnaire (PCOSQ) for women with polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab 1998;83:1976-87.  Back to cited text no. 8
    
9.Bates GW Jr, Propst AM. Polycystic ovarian syndrome management options. Obstet Gynecol Clin North Am 2012;39:495-506.  Back to cited text no. 9
    
10.Ganie MA, Kalra S. Polycystic ovary syndrome-A metabolic malady, the mother of all lifestyle disorders in women-Can Indian health budget tackle it in future? Indian J Endocrinol Metab 2011;15:239-41.  Back to cited text no. 10
    
11.Sheehan MT. Polycystic ovarian syndrome: Diagnosis and management. Clin Med Res 2004;2:13-27.  Back to cited text no. 11
    
12.Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: A randomized, double-blind, placebo controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 2000;85:139-46.  Back to cited text no. 12
    
13.Sanchez-Resendiz J, Guzman-Gomez F. Polycystic ovary syndrome. Boletin Mexicano de Homeopatica 1997;30:11-5.  Back to cited text no. 13
    
14.Gupta. Polycystic Ovarian Disease (PCOD). The Homoeopathic Heritage; May 2009;11-7  Back to cited text no. 14
    
15.Balen AH, Laven JS, Tan SL, Dewailly D. Ultrasound assessment of the polycystic ovary: International consensus definitions. Hum Reprod Update 2003;9:505-14.  Back to cited text no. 15
    
16.Available from: http://www.ae-society.org/tools [Last accessed on 2012 Jul 04].  Back to cited text no. 16
    
17.Available from: http://www.fda.gov/ohrms/dockets/ac/02/briefing/3904B1_03_%20Acne%20Global%20Severity%20Scale.pdf [Last accessed on 2012 Jul 04].  Back to cited text no. 17
    
18.Randomization chart. IBM SPSS ver 20.0.  Back to cited text no. 18
    
19.Hahnemann S. Organon of Medicine. Reprint, 5 th ed. New Delhi: B Jain Publishers; 1982.  Back to cited text no. 19
    
20.Declaration of Helsinki. Available from: http://www.wma.net/en/20activities/10ethics/10helsinki/draft_historical_contemporary_perspectives.pdf [Last accessed on 2012 Jul 04].  Back to cited text no. 20
    
21.Good Clinical Practices for Clinical Research in India. Available from: http://cdsco.nic.in/html/GCP.htm [Last accessed on 2012 Jul 04].  Back to cited text no. 21
    
22.Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, et al. Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: The complete task force report. Fertil Steril 2009;91:456-88.  Back to cited text no. 22
    
23.Chan AW, Tetzlaff JM, Gôtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: Guidance for protocols of clinical trials. BMJ 2013;346:e7586.  Back to cited text no. 23
    
24.Mathie RT, Roniger H, Van Wassenhoven M, Frye J, Jacobs J, Oberbaum M, et al. Method for appraising model validity of randomised controlled trials of homoeopathic treatment: Multi-rater concordance study. BMC Med Res Methodol 2012;12:49.  Back to cited text no. 24
    
25.Schulz KF, Altman DG, Moher D. CONSORT Group. CONSORT 2010 statement: Updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c332  Back to cited text no. 25
    
26.Dean ME, Coulter MK, Fisher P, Jobst KA, Walach H. Reporting data on homoeopathic treatments (RedHot): A supplement to CONSORT. J Altern Complement Med 2007;13:19-23.  Back to cited text no. 26
    
27.Available from: http://ohg.cochrane.org/sites/ohg.cochrane.org/files/uploads/Risk%20of%20bias%20assessment%20tool.pdf [Last accessed date on 2012 Dec 09].  Back to cited text no. 27
    


    Figures

  [Figure 1]


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TANG [HUMANITAS MEDICINE]. 2016; 6(1): 7.1
[Pubmed] | [DOI]



 

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