Polycystic Ovary Syndrome

Introduction Polycystic ovary syndrome (PCOS) is a common endingocrinology disorder affecting 1520% of women in reproductive age worldwide (1). PCOS characterized by hyperandrogenism and high aim of insulin safeguard which leads to the dysfunction of the hypothalamic-pituitary-ovary axis, resulting in anovulation and menstrual deadening (2-6).PCOS is considered the most common cause of anovulatory infertility. Around 90%95% of an-ovulatory women visiting infertility clinics have PCOS (7). The sure first-line infertility treatment in women with polycystic ovary syndrome is Clomiphene Cit enjoin. However, it has drawbacks, including its over either poor efficacy (only a 22% rate of live birth with up to six cycles of clomiphene (8)), ovulation rate of only 46% (9) and an undesirable side- subject profile, including fancy changes and hot flushes.Failure either to ovulate (clomiphene resistance), or to conceive with ovulation (clomiphene failure) of ecstasy leads to the use of mor e pricey treatment options for infertility that associated with higher multiple maternal quality rates and an appendd risk of the ovarian hyperstimulation syndrome (10). Insulin-sensitizing agents, such(prenominal) as metformin, have been used successfully to treat women with PCOS (11).However, metformin also has multiple undesirable GI side marrows such as nausea (61%), vomiting (30%), and diarrhea (65%). (12,13) Furthermore, many women who have PCOS ar not satisfied with pharmaceutical treatment. In a survey done on women with PCOS, 99% show their desire for effective treatment alternatives to fertility drugs, (14) and as many as 70% of women with PCOS use completing medicines (15-16).Herbal Medicine is still widely used from world population for approximately 75-80% this is because that herbal medicine is considered more culturally acceptable, less dangerous and more natural form of treatment (17). In Saudi-Arabian Arabia, approximately 80% of the population use herbal me dicine, and one of the main reasons is the ease of use of herbs that could be taken vivaly without painful procedure or invasive methods (18).Cinnamon, a commonly used spice, has perish a natural product of interest because it has been considered to have health benefits, such as lessen crinkle glucose, total cholesterol, LDL cholesterol and decreasing insulin resistance (19). Cinnamon increases insulin sensitivity likely because of its effect on intermediate metabolites acting at the cellular level (20). Several studies stated that polyphenol polymers isolated from cinnamon bark bark could increase insulin-dependent glucose metabolism. (21-23)Cinnamon usually causes no serious side effects. The reported unseemly events of cinnamon include headache, pyrosis and menstrual cramps (24). In general, herbal medicines are better tolerated than pharmaceutical medications as shown in a organized review for critical evaluation of clinical efficacy and adverse events of herbal remedies (2 5). Cinnamon extract may offer a low cost, readily available and relatively easily implemented style of reducing insulin resistance and thereby improving ovulation in women with PCOS.2.Literature Review A disarrange, two-fold-blinded, controlled trial investigating the effect of cinnamon on menstrual cyclicity in women with PCOS, women receiving daily 1.5 g of cinnamon treatment showed probatory improvements in menstrual cyclicity, whereas patients receiving placebo did not. Sampling from different patients in the theatre of operations showed the luteal phase serum progesterone (progesterone level 3 ng/mL), sonographic visualization of corpora lutea, and maternalism which all support that the bleeding has resulted from ovulatory cycles, rather than merely changes in menstrual flow (24).That suggests that cinnamon supplement may have an effect on ovulation induction in women with PCOS. Regarding the effect of cinnamon on insulin resistance, a depicted object conducted in 2017 involving 66 women with PCOS in a randomized, double?blind placebo?controlled clinical trial. The women in the first group treated by cinnamon capsules 1.5 g/ mean solar day for tercet months and the second group by placebo capsules. The homeostatic model assessment for insulin resistance (p = .014) reduced after(prenominal) the collar months in the cinnamon group compared with the placebo (26).Another randomized control study concluded that oral administration of 1g of cinnamon extract daily for eight weeks was well tolerated and improved insulin sensitivity in nondiabetic women with PCOS (27). A double-blind randomized control study, comparing the effect of cinnamon and metformin on insulin resistance in 112 women with PCOS fetching 1g of cinnamon versus 1g of metformin daily, shows that both significantly decreasing the insulin resistance (28).A study in non-PCOS patients with gilded serum glucose, 173 patients were enrolled and given 500mg of cinnamon daily for two months, showed a significant reduction on moderation insulin, glucose, total cholesterol, and LDL cholesterol and enhanced insulin sensitivity (29). There are many studies conducted on metformin as insulin-sensitizing agent on ovulation in PCOS women. In a systematic review, forty-four trials (3992 women) were included for analysis, 38 of them using metformin and involving 3495 women, clinical pregnancy rates were improved for metformin versus placebo (pooled OR 2.31, 95% CI 1.52 to 3.51, 8 trials, 707 women) and for metformin and clomiphene versus clomiphene alone (pooled OR 1.51, 95% CI 1.17 to 1.96, 11 trials, 1208 women) (30).Since the cinnamon have been suggested to improve the insulin resistance in previous studies and taking into account the side effects of metformin, a cinnamon supplement may offer a good and natural alternative to metformin as an insulin-sensitizing agent and thereby improve the ovulation in women with PCOS.3. RationalThe rarely and non-serious reported side effe cts of cinnamon on with the cost-effectiveness and availability lead to the need of exploring the effectiveness of cinnamon supplement as a antonymous medicine for ovulation induction in women with PCOS.4.1 AimTo determine the effectiveness of cinnamon supplement and clomiphene change state (CC) combine on ovulation in women with PCOS.4.2ObjectivesPrimary ObjectiveTo compare the effectiveness of cinnamon supplement in combination with clomiphene change state versus clomiphene citrate alone on ovulation in women with PCOS, in queer Abdulaziz University Hospital in Jeddah 2018.Secondary ObjectivesTo measure the difference in insulin resistance after three months of cinnamon add-on in women with PCOS in King Abdulaziz University Hospital in Jeddah 2018.To determine the effect of cinnamon and CC combination on menstrual cyclicity, approximated by menstrual frequency, during the study period, in women with PCOS in King Abdulaziz University Hospital in Jeddah 2018.To measure the pre gnancy rate in women with PCOS in King Abdulaziz University Hospital in Jeddah 2018.To evaluate the note of sustenance in women with PCOS in King Abdulaziz University Hospital in Jeddah 2018.Materials and MethodsPlace of studyThe study impart be carried out in King Abdulaziz University Hospital, Obstetrics and gynecology clinics, in Jeddah 2018.Exclusion criteriaCurrent pregnancy or lactation.Current use of treatment of infertility.Established diagnosis of diabetes mellitus.Use of Insulin-sensitizing treatment in spite of appearance the past three monthsHormonal treatment involving estrogen or progesterone within the past three months.Known hypersensitivity to cinnamon.Use of statin medication.Any other supplements that contain cinnamon within the past month.BMI 35.Sample SizeTo detect a clinically significant difference of 30% between the antecedently reported systematic review of ovulation rate (46%) (9) with a one-sided 5% significance level and power of 80%, a sample size o f 82 participants (41 per arm) is required. (Fleiss, Statistical Methods for Rates and Proportions, formulas 3.18 &3.19).RandomizationThe participants allow for be randomized in 11 fashion using a computer class by trained assistance.Allocation concealment pass on be ensured using similar bottles labeled by letters A and B to receive either the combination of cinnamon supplement and clomiphene citrate or clomiphene citrate with placebo. The intervention allocation impart be blind for both investigators and participants.5.6 hitchThe Cinnamomum cassia(C. aromaticum) capsules pass on be purchase from Spring Valley company (distributed by Wal-Mart Stores, Inc. USA) by the investigator.Placebo capsules result be prepared by Batterjee Pharma Company and will contain 450 mg of starch and 50 mg of cinnamon powder (to improve blindness regarding taste and odor). Shape, size, and color of placebo capsules will be completely similar to the cinnamon capsules.Cinnamon and placebo capsules will be provided to both groups monthly for 12 weeks. Participants will be required to consume two capsules twice per day after meals (2g/day).The last packages of capsules will be look into at the end of the month, and the summate of remaining capsules will be counted after that, new packages will be delivered to patients. All capsules will be given simultaneously with the clomiphene citrate medication. Participants will be asked to stay on their normal lifestyle including daily food and physical activity level.The 2g dose of cinnamon is chosen base on published clinical trials in patients with PCOS (8,15,16,17).All participants in both groups will be followed for three months or until pregnancy confirmed. The three month-period has chosen found on a systematic review that showed the effect of cinnamon could be as early as 4 weeks and up to 18 weeks (31).5.7 Adherence compliancy with diet and medications and interval progress will be monitored with monthly visits with the inv estigator or his trained assistances along with SMS reminder or WhatsApp messages.Also, participants will be asked to return all study packs (including empty bottles) at either monthly visit.5.8 Patient safetyPatients will be monitored monthly during the study period, and any occurrence of adverse events will be recorded.5.9 Study OutcomesPrimary outcome Progesterone level 3ng/mL (ovulation confirmation) or pregnancy confirmed.Secondary outcomes Changes in insulin resistance, menstrual cyclicity, pregnancy rate and fertility quality of life at the end of the study in comparison with the baseline set.ProcedureThe study will be initiated after obtaining approval from the building block of Biomedical Ethics in King Abdulaziz University and approval from Saudi Food and Drug Authority. All patients will be explained the procedure and risks involved in common, understandable languages and a written informed consent will be obtained.First visit Patients meeting inclusion and exclusion criteria will be evaluated during the early follicular phase (day 3-7) after a spontaneous or bring on menses (medroxyprogesterone acetate 10 mg twice?daily for 5 days) forBaseline blood worko (Hormone profile FSH, LH and testosterone levels).o In day 21 (luteal phase) patients will be tested for progesterone level.o Insulin resistance using homeostasis model of insulin resistance HOMA-IR and Quantitative Insulin aesthesia Check Index QUICK-I.? QUICK= 1 / (log(fasting insulin U/mL) + log(fasting glucose mg/dl))? HOMA-IR= (FPI(mU/l) FPG (mmol/l))/22.5Height and system of weights will be measured and recorded for body mass index (BMI). Diagnosis of oligo-/anovulation will be based on a menstrual pattern of oligo/amenorrhoea (cycle 35 days) and/or a low mid-luteal serum progesterone concentration. Hyperandrogenaemia will be diagnosed either clinically (acne/hirsutism) or biochemically (testosterone ?2.5 nmol/l).Last Visit At the end of three months, all subjects will be re-evaluat ed during the early follicular phase (day 3-7) after a spontaneous or induced menses forBaseline blood work(Hormone profile FSH, LH, testosterone levels).o In day 21 patients will be tested for progesterone level.Insulin resistance using homeostasis model of insulin resistance HOMA-IR and Quantitative Insulin Sensitivity Check Index QUICK-I.Height and weight for body mass index (BMI).Menstrual cyclicity, approximated by menstrual frequency, (number menses/number months observed).Pregnancy rate using positive urinary hCG and ultrasound detection of the gestational sac.Assessment of dietary recess To assess participants dietary intake, a 24-h food recall will be collected three quantify during the study (at baseline, middle and end of study). Patients will complete food descriptions including food and drinks (brand names), food preparation (ingredients) in detail as much as possible in the last day.Pictures of food commonly consumed in Saudi Arabia, together with a set of common hou sehold measurement tools (glass, cup, soup bowls, plates, teaspoon and tablespoon) will be provided to assist subjects in estimating the portion sizes of the food. Assessment of physical activity levels IPAQ will be employ to assess the physical activity level of participants. The IPAQ form comprises walking, moderate- intensity and vigorous-intensity activity and will be verbalised as metabolic equivalents per minute (MET-min) per week. The levels of physical activity will be categorized into low, moderate and high, based on the IPAQ criteria.Statistical AnalysisStatistical analysis will be performed using SPSS 25. Data will be expressed as mean SD for continuous variables and percentage for non-continuous variables. Normality tests will be assessed by means of Shapiro-Wilk tests carried out on each parameter before analysis. Intention-to-treat (ITT) analysis will include all randomized subjects, regardless of whether or not they received the study treatments.Per protocol (PP) analysis will include all randomized subjects who received the study drug and were not lost to follow-up. Participants who lost to follow-up will be assumed neither to be pregnant nor to have ovulation in the ITT analysis.Relative risk, relative risk reduction, Number necessary to Treat and Number Needed to Harm will be calculated at 95% trustfulness interval.Study variablesVariableOperational definitioni.e., indicatorScale of measurementOvulationProgesterone level in capillary bloodContinuousProgesterone level 3ng/mLInsulin resistanceHOMA-IR and QUICK-IOrdinalHOMA-IR Healthy Range 1.0 (0.51.4)?Less than 1.0 means insulin-sensitive which is optimal.?Above 1.9 indicates early insulin resistance.?Above 2.9 indicates significant insulin resistance.QUICK-I range between 0.45 in healthy individuals and 0.30 in diabetics.Lower values reflect greater resistance with values below 0.339 indicating insulin resistance.Menstrual cyclicityMenstrual frequencyContinuous(No. of menses/ No. of mon th)Pregnancy rateNo. of pregnancies including live births, induced abortions, and fetal deaths per 1,000Continuous(Number of pregnancies including live births, induced abortions, and fetal deaths / Number of women aged 15 44 years) 1,000Quality of lifeInfertility quality of life questionnaire OrdinalEthical considerationsApproval from the Unit of Biomedical Ethics in King Abdulaziz University will be obtained before the start of the study.Informed consent of the participants will be considered an essential prerequisite for enrollment in the study.This study will be registered in Saudi Food and Drug Administration (SFDA) and at Clinicaltrial.gov website.Confidentiality of the response of the participants will be ensured by keeping the collected data secured and used only for the study purpose.Study durationThe enlisting period will be three months each arm group will be followed for three months, the total study duration with data analysis and writing the thesis will be ten months. Table1 study time frame