Polycystic Ovary Syndrome

Introduction

Polycystic ovary syndrome (PCOS) is a common endocrinology disorder affecting 15–20% of women in reproductive age worldwide.  PCOS characterized by hyperandrogenism and high level of insulin resistance which leads to the dysfunction of the hypothalamic-pituitary-ovary axis, resulting in anovulation and menstrual irregularity.

PCOS is considered the most common cause of anovulatory infertility. Around 90%–95% of an-ovulatory women visiting infertility clinics have PCOS . The current first-line infertility treatment in women with polycystic ovary syndrome is Clomiphene Citrate. However, it has drawbacks, including its overall poor efficacy (only a 22% rate of live birth with up to six cycles of clomiphene , ovulation rate of only 46%  and an undesirable side-effect profile, including mood changes and hot flushes.

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Failure either to ovulate (clomiphene resistance), or to conceive with ovulation (clomiphene failure) often leads to the use of more expensive treatment options for infertility that associated with higher multiple pregnancy rates and an increased risk of the ovarian hyperstimulation syndrome . Insulin-sensitizing agents, such as metformin, have been used successfully to treat women with PCOS .

However, metformin also has multiple undesirable gastrointestinal side effects such as nausea (61%), vomiting (30%), and diarrhea (65%).  Furthermore, many women who have PCOS are not satisfied with pharmaceutical treatment. In a survey done on women with PCOS, 99% expressed their desire for effective treatment alternatives to fertility drugs, and as many as 70% of women with PCOS use complementary medicines .

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 . 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 taken orally without painful procedure or invasive methods .

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, total cholesterol, LDL cholesterol and decreasing insulin resistance . Cinnamon increases insulin sensitivity likely because of its effect on intermediate metabolites acting at the cellular level . Several studies stated that polyphenol polymers isolated from cinnamon could increase insulin-dependent glucose metabolism.

Cinnamon usually causes no serious side effects. The reported adverse events of cinnamon include headache, heartburn and menstrual cramps. In general, herbal medicines are better tolerated than pharmaceutical medications as shown in a systematic review for critical evaluation of clinical efficacy and adverse events of herbal remedies . Cinnamon extract may offer a low cost, readily available and relatively easily implemented means of reducing insulin resistance and thereby improving ovulation in women with PCOS.

Literature Review

A randomized, double-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 significant improvements in menstrual cyclicity, whereas patients receiving placebo did not. Sampling from different patients in the study showed the luteal phase serum progesterone (progesterone level >3 ng/mL), sonographic visualization of corpora lutea, and pregnancy which all support that the bleeding has resulted from ovulatory cycles, rather than merely changes in menstrual flow.

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 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 three months and the second group by placebo capsules. The homeostatic model assessment for insulin resistance (p = .014) reduced after the three months in the cinnamon group compared with the placebo .

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 . A double-blind randomized control study, comparing 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.

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. 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).

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.

• Rational: The 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.
• Aim: To determine the effectiveness of cinnamon supplement and clomiphene citrate (CC) combination on ovulation in women with PCOS.

Objectives

Primary Objective

• To 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 Objectives

• To measure the difference in insulin resistance after three months of cinnamon supplementation 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 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 methods

Place of study

The study will be carried out in King Abdulaziz University Hospital, Obstetrics and gynecology clinics, in Jeddah 2018.

Exclusion criteria

• Current pregnancy or lactation.
• Current use of treatment of infertility.
• Established diagnosis of diabetes mellitus.
• Use of Insulin-sensitizing treatment within the past three months
• Hormonal 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.

Sample Size

To detect a clinically significant difference of 30% between the previously reported systematic review of ovulation rate (~46%) (9) with a one-sided 5% significance level and power of 80%, a sample size of 82 participants (41 per arm) is required. (Fleiss, Statistical Methods for Rates and Proportions, formulas 3.18 &3.19).

Randomization

The participants will be randomized in 1:1 fashion using a computer program by trained assistance.

Allocation concealment will 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 will be blind for both investigators and participants.

Intervention

The 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 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 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 keep their normal lifestyle including daily food and physical activity level.The 2g dose 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 to 18 weeks (31).

Adherence

Compliance with diet and medications and interval progress will be monitored with monthly visits with the investigator 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 every monthly visit.

Patient safety

Patients will be monitored monthly during the study period, and any occurrence of adverse events will be recorded.

Study Outcomes

• Primary 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.
• Procedure: The study will be initiated after obtaining approval from the Unit 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 induced menses (medroxyprogesterone acetate 10 mg twice?daily for 5 days) for:
• Baseline blood work: o (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 Check Index [QUICK-I].? QUICK= 1 / (log(fasting insulin µU/mL) + log(fasting glucose mg/dl))? HOMA-IR= (FPI(mU/l) × FPG (mmol/l))/22.5

Height and weight 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-evaluated during the early follicular phase (day 3-7) after a spontaneous or induced menses for:

Baseline 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 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 much as possible in the last day.

Pictures of food commonly consumed in Saudi Arabia, together with a set of common household 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 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 Analysis

Statistical 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 through 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 Needed to Treat and Number Needed to Harm will be calculated at 95% confidence interval.

• 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.

Ethical considerations

• Approval 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 duration

• The recruitment 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

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