Polycystic Ovary Syndrome

Introduction Polycystic ovary syndrome (PCOS) is a popular endocrinology disorder affecting 1520% of women in reproductive age worldwide (1). PCOS characterized by hyperandrogenism and high take of insulin opposite which leads to the dysfunction of the hypothalamic-pituitary-ovary axis, resulting in anovulation and catamenial irregularity (2-6).PCOS is considered the most common ca spend of anovulatory infertility. Around 90%95% of an-ovulatory women visiting infertility clinics cede PCOS (7). The current first-line infertility manipulation in women with polycystic ovary syndrome is Clomiphene Cit evaluate. However, it has drawbacks, including its over either woeful efficacy (only a 22% straddle of live birth with up to six cycles of clomiphene (8)), ovulation rate of only 46% (9) and an undesirable side- incumbrance visibility, including humor changes and hot flushes.Failure either to ovulate (clomiphene resistance), or to conceive with ovulation (clomiphene failure) frequ ently leads to the use of more expensive treatment options for infertility that associated with higher triune pregnancy rates and an increased adventure of the ovarian hyperstimulation syndrome (10). Insulin-sensitizing agents, such as met carcassin, save been used successfully to treat women with PCOS (11).However, metformin also has ternary undesirable gastrointestinal side establishs such as illness (61%), vomiting (30%), and diarrhea (65%). (12,13) Furthermore, numerous another(prenominal) women who have PCOS are not quelled with ph tree branchaceutical treatment. In a survey done on women with PCOS, 99% expressed their desire for arrangeive treatment alternatives to fertility medicates, (14) and as many as 70% of women with PCOS use complementary euphonys (15-16).Herbal Medicine is simmer down 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 for m of treatment (17). In Saudi Arabia, approximately 80% of the population use herbal medicine, and one of the main reasons is the ease of use of herbs that could be interpreted orally with prohibited painful mental process or invasive methods (18).Cinnamon, a commonly used spice, has become a natural product of interest because it has been considered to have health benefits, such as reducing blood glucose, kernel cholesterol, beta-lipoprotein cholesterol and decreasing insulin resistance (19). Cinnamon increases insulin sensitivity likely because of its effect on intermediate metabolites acting at the cellular train (20). several(prenominal) studies stated that polyphenol polymers isolated from cinnamon bark could increase insulin-dependent glucose metabolism. (21-23)Cinnamon usually causes no serious side effects. The reported inauspicious events of cinnamon include headache, heartburn and menstrual cramps (24). In general, herbal medicines are better tolerated than pharmace utical medications as shown in a imperious review for critical evaluation of clinical efficacy and adverse events of herbal remedies (25). Cinnamon extract may twisting a execrable cost, readily available and relatively easily utilise means of reducing insulin resistance and thereby improving ovulation in women with PCOS.2.lit Review A randomized, double- silver screened, controlled trial investigating the effect of cinnamon on menstrual cyclicity in women with PCOS, women receiving periodic 1.5 g of cinnamon treatment showed significant improvements in menstrual cyclicity, whereas patients receiving placebo did not. Sampling from different patients in the take up showed the luteal phase serum progesterone (progesterone train 3 ng/mL), sonographic visual image of corpora lutea, and pregnancy which all support that the bleeding has resulted from ovulatory cycles, rather than merely changes in menstrual flow (24).That suggests that cinnamon appendage may have an effect on ovu lation induction in women with PCOS. Regarding the effect of cinnamon on insulin resistance, a study 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/day for tether months and the second group by placebo capsules. The homeostatic model mensuratement for insulin resistance (p = .014) reduced later the three months in the cinnamon group compared with the placebo (26).Another randomized control study cogitate that oral administration of 1g of cinnamon extract daily for eight weeks was intimately tolerated and improved insulin sensitivity in nondiabetic women with PCOS (27). A double-blind randomized control study, canvass the effect of cinnamon and metformin on insulin resistance in 112 women with PCOS taking 1g of cinnamon versus 1g of metformin daily, shows that both significantly decreasing the insulin resistance (28).A study in non-PCOS patients with elevated serum glucose, 173 patients were enrolled and given 500mg of cinnamon daily for two months, showed a significant reduction on fasting 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 digest, 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 only when (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 ther eby improve the ovulation in women with PCOS.3. RationalThe rarely and non-serious reported side effects of cinnamon along with the cost-effectiveness and availability lead to the need of exploring the effectiveness of cinnamon supplement as a complementary medicine for ovulation induction in women with PCOS.4.1 AimTo dress the effectiveness of cinnamon supplement and clomiphene change state (CC) conspiracy on ovulation in women with PCOS.4.2ObjectivesPrimary ObjectiveTo compare the effectiveness of cinnamon supplement in combination with clomiphene citrate versus clomiphene citrate alone on ovulation in women with PCOS, in King Abdulaziz University hospital in Jeddah 2018.Secondary ObjectivesTo rhythm the exit in insulin resistance after three months of cinnamon postscript 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 stones throw the pregnancy rate in women with PCOS in King Abdulaziz University Hospital in Jeddah 2018.To evaluate the quality of life in women with PCOS in King Abdulaziz University Hospital in Jeddah 2018.Materials and MethodsPlace of studyThe study give be carried out in King Abdulaziz University Hospital, Obstetrics and gynecology clinics, in Jeddah 2018.Exclusion criteria authorized pregnancy or lactation.Current use of treatment of infertility.Established diagnosis of diabetes mellitus.Use of Insulin-sensitizing treatment at bottom the past three monthsHormonal treatment involving estrogen or progesterone in spite of appearance the past three months.Known hypersensitivity to cinnamon.Use of statin medication.Any other supplements that contain cinnamon deep down the past month.BMI 35.Sample SizeTo detect a clinically significant difference of 30% mingled with the previously reported system atic review of ovulation rate (46%) (9) with a one-sided 5% significance level and magnate of 80%, a sample size of 82 participants (41 per arm) is required. (Fleiss, statistical Methods for pass judgment and Pro fortunes, formulas 3.18 &3.19).RandomizationThe participants leave alone be randomized in 11 fashion using a computer program by dexterous assistance.Allocation concealment lead be ensured using similar bottles designate by letters A and B to receive either the combination of cinnamon supplement and clomiphene citrate or clomiphene citrate with placebo. The intervention allocation will be blind for both investigators and participants.5.6 interpositionThe Cinnamomum cassia(C. aromaticum) capsules will be purchase from Spring valley company (distributed by Wal-Mart Stores, Inc. USA) by the investigator.Placebo capsules will 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 od or). Shape, size, and comment 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 down two capsules twice per day after meals (2g/day).The last packages of capsules will be checked at the end of the month, and the number 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 forbear their normal lifestyle including daily nutrient and physical activity level.The 2g window glass of cinnamon is chosen based 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 based on a systematic review that showed the effect of cinnamon could be as early as 4 weeks and up t o 18 weeks (31).5.7 AdherenceCompliance with diet and medications and time interval progress will be monitored with monthly visits with the investigator or his train assistances along with SMS reminder or WhatsApp messages.Also, participants will be asked to return all study packs (including empty bottles) at every monthly visit.5.8 Patient galoshPatients 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 values.ProcedureThe study will be initiated after obtaining commendation from the unit of Biomedical Ethics in King Abdulaziz University and approval from Saudi feed and Drug Authority. All patients will be explained the procedure and risks involv ed in common, understandable languages and a writ decennary informed admit will be obtained.First visit Patients meeting inclusion and expulsion criteria will be evaluated during the early follicular phase (day 3-7) after a oral or induce 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 Sensitivity mark off 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 weight will be measured and recorded for frame 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-evaluated 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 human chorionic gonadotrophin and ultrasound detection of the gestational sac.Assessment of dietetical intake To assess participants dietary intake, a 24-h food recall will be collected three times 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 ofttimes as possible in the last day.Pictures of food commonly consumed in Saudi Arabia, together with a set of common household standard 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 applied to assess the physical activity level of participants. The IPAQ form comprises walking, moderate- intensity and vigorous-intensity activity and will be expressed 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. information will be expressed as mean SD for continuous variables and parcel for non-continuous variables. Normality tests will be assessed through Shapiro-Wilk tests carried out on distributively parameter i n front 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 false neither to be pregnant nor to have ovulation in the ITT analysis.Relative risk, relative risk reduction, Number Needed to Treat and Number Needed to Harm will be calculated at 95% confidence 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(prenominal) 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 di abetics.Lower values reflect greater resistance with values below 0.339 indicating insulin resistance.Menstrual cyclicityMenstrual frequencyContinuous(No. of menses/ No. of month)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 enrolment 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 timeThe r ecruitment period will be three months each arm group will be followed for three months, the total study term with data analysis and writing the thesis will be ten months.Table1 study time frame