Research ajog.org

GYNECOLOGY

Preliminary evidence that cinnamon improvesmenstrual cyclicity in women with polycysticovary syndrome: a randomized controlled trialDaniel H. Kort, MD; Roger A. Lobo, MD

OBJECTIVE: To determine the effect of cinnamon on menstrual taking placebo (median, 0.75; interquartile range, 0.5�0.83 vs

cyclicity and metabolic dysfunction in women with polycystic ovarysyndrome (PCOS).

STUDY DESIGN: In a prospective, placebo controlled, double-blindedrandomized trial, 45 women with PCOS were randomized (1:1) toreceive cinnamon supplements (1.5 g/d) or placebo for 6 months.Menstrual cyclicity (average cycles/month) during the 6 months studyperiod was compared between the 2 groups using the Mann-WhitneyU test. Changes in menstrual cyclicity and insulin resistance betweenbaseline and the 6 month study period were compared between the2 groups using Wilcoxon signed rank tests.

RESULTS: The 45 women were randomized, 26 women completed3 months of the study, and 17 women completed the entire 6 monthsof the study. During the 6 month intervention, menstrual cycles weremore frequent in patients taking cinnamon compared with patients

From the Division of ReproductiveEndocrinology and Infertility, Department ofObstetrics and Gynecology, College ofPhysicians and Surgeons, Columbia University,New York, NY.

ReceivedMarch 7, 2014; revised April 11, 2014;accepted May 6, 2014.

The authors report no conflict of interest.

This research was supported by institutionalfunding (R.A.L., D.H.K.); the Endocrine FellowsFoundation (D.H.K., in part), which suppliedendocrine assays; and Integrity NutraceuticalsInternational (Spring Hill, TN), which supplied thestudy drug and placebo.

Reprints not available from the authors.

0002-9378/$36.00ª 2014 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.ajog.2014.05.009

median, 0.25; interquartile range, 0�0.54; P ¼ .0085; MannWhitney U ). In patients taking cinnamon, menstrual cyclicityimproved from baseline (þ 0.23 cycles/month 95% confidenceinterval, 0.099�0.36), yet did not improve for women taking placebo.(P ¼ .0076, Wilcoxon signed rank). Samples (n ¼ 5) of serum fromthe luteal phase in different patients within the cinnamon group werethawed and ovulatory progesterone levels (>3 ng/mL) confirmed.Luteal phase progesterone levels (>3 ng/mL, n ¼ 5) confirmedovulatory menses. Measures of insulin resistance or serum androgenlevels did not change for either group.

CONCLUSION: These preliminary data suggest that cinnamon sup-plementation improves menstrual cyclicity and may be an effectivetreatment option for some women with PCOS.

Key words: cinnamon, PCOS, randomized controlled trial

Cite this article as: Kort DH, Lobo RA. Preliminary evidence that cinnamon improves menstrual cyclicity in women with polycystic ovary syndrome: a randomizedcontrolled trial. Am J Obstet Gynecol 2014;211:487.e1-6.

ounting evidence has implicated

M insulin resistance and compen-satory hyperinsulinemia in the patho-genesis of polycystic ovary syndrome(PCOS).1 Women with PCOS haveincreased rates of insulin resistance

compared with controls, with absoluterates of insulin resistance as high as 65%in normal weight women and 95% inobese women.2,3 Insulin resistance aswell as hyperandrogenism in womenwith PCOS have been implicated inthe dysfunction of the hypothalamic-pituitary-ovary axis, leading to anov-ulation and menstrual irregularity.4

Insulin sensitizing agents, such asmetformin and thiazolidinediones, havebeen used successfully to treat womenwith PCOS.5 Such agents have beenshown to significantly reduce insulinresistance and androgen levels as well assome inflammatory markers, improvemenstrual irregularity, and improveovulatory function in some women withPCOS.6-8 However, thiazolidinedioneshave multiple safety concerns and met-formin, the most widely used drug inPCOS, is often poorly tolerated becauseof gastrointestinal side effects of nausea(61%), vomiting (30%), and diarrhea(65%).9,10

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Cinnamon, a commonly used spiceused since biblical times, has been foundto have insulin sensitizing effects inboth animal and human studies.11-13

Although the mechanism is incom-pletely understood, cinnamon likelyincreases insulin sensitivity throughintermediate metabolites acting at thecellular level.14 In vitro studies andstudies using animal models have shownthat polyphenol polymers isolated fromcinnamon increase insulin dependentglucose metabolism by activating theinsulin receptor and altering glucosetransport.15-17

Several groups have investigated theuse of cinnamon in the treatment ofdiabetes. In a randomized, controlledclinical trial, daily intake of 1, 3, or 6 gof oral cinnamon (cinnamomum cassia)reduced serum glucose, triglycerides,LDL cholesterol, and total cholesterolin type II diabetes patients comparedwith placebo.12 In another randomized,controlled trial, 3 g of oral cinnamon

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reduced fasting glucose in poorly con-trolled type II diabetes patients.18

Given the preliminary success of usingcinnamon to treat insulin resistant dia-betes and the established use of insulinsensitizing agents in the treatment ofPCOS, cinnamon has been proposed as apossible alternative therapy for PCOS. Inour own prospective placebo-controlledpilot study, cinnamon demonstratedsignificant reductions in fasting glucoseand insulin resistance parameters after8 weeks of oral cinnamon extract, 1 gper day.19 However, the effects of cin-namon on symptoms and the metabolicdysfunction of PCOS have yet to be in-vestigated in a large, randomized con-trolled trial. Accordingly, we appliedto the United States Food and DrugAdministration (FDA) to use cinnamonas an InvestigationalNewDrug (IND) andhave carried out a randomized, double-blinded, placebo-controlled trial in-vestigating the effect of cinnamon onmenstrual cyclicity in women with PCOS.

MATERIALS AND METHODS

All study protocols and procedures wereapproved by the institutional reviewboard of Columbia University. Anapplication to use cinnamon supple-ments (Cinnulin PF; Integrity Nutra-ceuticals International, Spring Hill, TN)as an IND was submitted and acceptedby the FDA (IND no. 110123). Regularreporting to the FDA and data safetymonitoring board was performed as wasrequired.

Patients aged 18-38 years meeting theRotterdam criteria for polycystic ovarysyndrome (oligomenorrhea or amenor-rhea and either [1] clinical or biochem-ical evidence of hyperandrogenism or[2] ultrasound findings of polycysticovaries) were recruited by print adver-tisement for participation in an interna-tional review board approved, registered,randomized, controlled clinical trial(NCT-01483118). Exclusion criteriawere current pregnancy or lactation,current treatment of infertility, establisheddiagnosis of diabetes mellitus, insulinsensitizing treatment within 3 monthsof study enrollment, hormonal treat-ment involving estrogen or progesterone

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within 3 months of study enrollment,systemic, or inhaled corticosteroid use,known hypersensitivity to cinnamon,known seizure disorder, cardiovasculardisease, or cerebrovascular disease. Awide range of body mass index (20-50)was included given the anticipatedpatient population and the suspectedmechanism of action of cinnamonthrough metabolic pathways.Patients meeting inclusion and

exclusion criteria were offered studyparticipation and informed consent wasestablished. Patients were compensatedfor their time and effort at each visit,after randomization. Enrolled study pa-tients were evaluated during the earlyfollicular phase (day 3-7) after a spon-taneous or induced menses. Height,weight, and vital signs were measuredand recorded. Subcutaneous fat thick-ness was measured by transabdominalultrasound. Antral follicle count andovarian volume (p/6 *transverse diam-eter *anterior-posterior diameter * lon-gitudinal diameter) were measured bytransvaginal ultrasound. Fasting bloodsamples were obtained and a 2 hour 75 gglucose tolerance test was performedwith phlebotomy 30, 60, and 120 mi-nutes after glucose ingestion.Subjects were randomized in a 1:1

fashion to receive either cinnamon sup-plements (125 mg capsule, 4 capsules3x/day ¼1500 mg/day) or identicallyappearing 1.5 cm and 0.5 cm white pla-cebo capsules (4 capsules, 3x/day) forthe 6 month study period. The 1500 mgdose was chosen based on publishedclinical trials in diabetic patients andour own pilot study in patients withPCOS.11,16,17 Both the study subjectsand the investigators were blinded forthe duration of the study, as drug andplacebo samples were labeled in code bythe manufacturer (Integrity Nutraceut-icals International). All patients wereadvised to adhere to a balanced diet of1800 calories per day and instructed tocomplete a daily menstrual calendar aswell as an activity log. Compliance withdiet and medications and interval prog-ress was monitored with monthly visitswith the investigators. The 2 hour 75 g.glucose tolerance test was repeated at

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the 3 month visit. A final visit at 6months included height and weightmeasurements, vital signs, repeat trans-abdominal and transvaginal ultrasound,and repeat 75 g glucose tolerance test.

Serum levels of insulin, total testos-terone (T), dehydroepiandrosterone sul-fate (DHEA-S), and sex-hormone bindingglobulin (SHBG) were measured withchemiluminescence assays using Immulite(Diagnostic Products Corporation, LosAngeles, CA). Baseline data from the studysubjects (insulin resistance and androgenprofiles) were compared with establishedcontrols from our previously publishedstudies and reference values.20-23

The primary study outcome wasmenstrual cyclicity, approximated in thestudy by menstrual frequency, (numbermenses/number months observed) dur-ing the study period. Secondary out-comes were change in menstrual cyclicityfrom reported baseline cyclicity, changein insulin sensitivity indices (homeostasismodel of insulin resistance [HOMA-IR],Quantitative Insulin Sensitivity CheckIndex [QUICK-I]), change in glucoseresponse (area under the curve, trape-zoidal method), change in serum andro-gen and SHBG levels, change in weight,change in subcutaneous fat measure-ments, and change in ovarian volume.

TheMann-WhitneyU test was used tocompare the number of menstrual cyclesduring the study period between thepatients taking cinnamon and placebo.Wilcoxon signed-rank tests were used tocompare all variables between baselineand at study completion in both thecinnamon and placebo groups. Thetarget sample size was 40, powered todetect a 40% increase in menstrual cyclefrequency with a type II error of 0.20and a type I error of 0.05.

RESULTS

Study enrollment began in Aug. 2011and was terminated in Sept. 2012because of expiration of the study drugand matched placebo in March 2013.Sixty-three women were screened and45 patients were enrolled in the clinicaltrial (Figure 1). Twenty-three womenwere randomized to receive cinnamonand 22 women were randomized to

FIGURE 1Flowchart

Diagram of patient recruitment, enrollment, and completion of the randomized controlled trial.

Kort. Effect of cinnamon in women with PCOS. Am J Obstet Gynecol 2014.

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receive placebo. Race and ethnic groupswere diverse and well matched betweengroups, including nonHispanic black

TABLE 1Baseline characteristicsIndex Cinnam

Age (y), mean (range) 26.95

BMI (kg/m2), mean, SD 33.0 �Waist circumference (cm), mean, SD 97.0 �Hip circumference (cm), mean, SD 112.2 �Average SQ fat (cm), mean, SD 3.7 �HOMA-IR, mean, SD 2.8 �QUICK-I 0.34

Total T (ng/dL), mean 52.2 �DHEA-S (mg/mL), mean 1.81

SHBG (nmol/L), mean 31.3 �BMI, body mass index; DHEA-S, dehydroepiandrosterone sulfatesignificant; PCOS, polycystic ovary syndrome; QUICK-I, Quantibinding globulin; SQ, subcutaneous.

a Increased compared with historical nonPCOS controls - Hhistorical nonPCOS controls - QUICK-I ¼ 0.358 � 0.0221; c ET ¼ 31 � 11 ng/dL20; d Similar to nonPCOS control e DHEin premenopausal women �51 � 16 nmol/L)23

Kort. Effect of cinnamon in women with PCOS. Am J Obst

(total, n ¼ 18), nonHispanic white(n¼ 8), Hispanic (n¼ 16), Asian (n¼ 1),other (n ¼ 2).

on Placebo Difference

(18e34) 27.86 (18e38) NS

5.6 31.4 � 6.0 NS

12.9 93.1 � 19.4 NS

1.1 112.3 � 21.4 NS

0.82 3.9 � 1.0 NS

1.4a 2.5 � 0.93a NS

� 0.029b 0.35 � 0.044b NS

26.2c 62.0 � 46.3c NS

� 0.71d 1.91 � 1.02d NS

18.2e 36.7 � 16.0 e NS

; HOMA-IR, homeostasis model of insulin resistance; NS, nottative Insulin Sensitivity Check Index; SHBG, sex hormone

OMA-IR ¼ 1.6 (1.2-2.1)22; b Eecreased compared withlevated compared with historical nonPCOS controls e TotalA-S 1.8 � 0.5 mg/mL20; e Lower than established values

et Gynecol 2014.

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Of the 45 women enrolled in the trial,26 patients completed 3 months of in-tervention and 17 patients completed6 months of intervention. Reasons forpatient dropout included loss to follow-up, pregnancy, surgery, moving, andstarting insulin sensitizing with medi-cation. The complete enrollment flow-sheet can be found in Figure 1.

Baseline clinical characteristics, insu-lin resistance, subcutaneous fat mea-surement, and serum androgen levelsmay be found in Table 1. Menstrual datawas collected for a total of 51 months forthe cinnamon group and 47 months forthe placebo group. Baseline menstrualcyclicity (average number of cycles/month) was comparable between thecinnamon and placebo groups (mean,standard deviation, 0.42 � 0.16 vs 0.47� 0.21). Measures of insulin resistanceand serum androgen levels were com-parable between groups and elevatedcompared with historical controls.

Adverse events included headache(4 patients), heartburn symptoms (2 pa-tients), menstrual cramps (2 patients),and nausea with diarrhea (1 patient). Alladverse events resolved during the studyperiod and no serious adverse eventswere reported.

During the 6 month intervention,menstrual cyclicity (number of cycles/month) was more frequent in womentaking cinnamon compared with womenassigned to placebo (median, 0.75; in-terquartile range, 0.5e0.83 vs median,0.25; interquartile range, 0e0.54; P ¼.0085; Mann Whitney U; Table 2,Figure 2). Menstrual cyclicity significantlyimproved from baseline (P ¼ .0076, Wil-coxon matched pairs signed rank test) inwomen taking cinnamon, yet did notimprove in women on placebo (P¼ .145,Wilcoxonmatched pairs signed rank test).Samples (n ¼ 5) of serum from differentpatients within the cinnamon groupdetermined to be in the luteal phase(bleeding within 12 days of blood draw)were thawed and ovulatory progesteronelevels (>3 ng/mL) were confirmed.

For patients completing the study andundergoing the 6 month 75 g glucosetolerance test, insulin resistance did notsignificantly change for either patientstaking cinnamon or patients taking

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TABLE 2Menstrual cyclicityMenstrual cyclicity Cinnamon Placebo P value

Baseline (no. ofcycles/month), median (IQR)

0.42 (0.33e0.63) 0.42 (0.29e0.68) .7 (NS)a

Study period (no. ofcycles/month), median (IQR)

0.75 (0.5e0.83) 0.25 (0e0.54) .0085a

Change during study,� cycles/month (95% CI)

þ 0.23 (0.099e0.36) �0.13 (�0.46 to 0.065) .0076b

CI, confidence interval; IQR, interquartile range; NS, not significant.

a Mann-Whitney U test; b Wilcoxon matched pairs signed rank.

Kort. Effect of cinnamon in women with PCOS. Am J Obstet Gynecol 2014.

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placebo. Measures of insulin sensitivity(HOMA-IR, QUICK-I, and glucose areaunder curve) may be found in Table 3.

Serum androgen and SHBG levels didnot significantly change over the studyperiod in either group. Total testosteronelevels remained mildly elevated in boththe cinnamon (study completion value41.0 ng/dL) and placebo groups (49.7ng/dL). Weight, subcutaneous fat thick-ness, and ovarian volume did not sig-nificantly change in either the cinnamon

FIGURE 2Menstrual cyclicity

Bar chart illustrating the change in menstrual cyc

Error bars indicate interquartile range.

Kort. Effect of cinnamon in women with PCOS. Am J Obstet G

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or placebo group that completed the6 month study.

COMMENT

The above study is the first randomized,double-blinded, controlled trial investi-gating the effect of cinnamon on men-strual cyclicity in women with PCOS.During the 6 months study period,women receiving cinnamon treatmentshowed significant improvements inmenstrual cyclicity, whereas patients

licity in both the cinnamon and placebo groups.

ynecol 2014.

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receiving placebo did not. Sampling ofluteal phase serum progesterone, sono-graphic visualization of corpora lutea,and pregnancy all support that reportedbleeding resulted from ovulatory cycles,rather than merely changes in menstrualflow.

Unfortunately, a mechanism for thepositive effect of cinnamon on men-strual cyclicity was not identified in ourstudy group. The suspected mechanism,improvement in insulin sensitivity, wasnot appreciated. This is in contrast toseveral studies that have shown cinnamonto improve insulin sensitivity in a varietyof patient populations. In the first ran-domized, controlled trial, cinnamon atdifferent dosages (1 g, 3 g, 6 g) decreasedmean fasting glucose (18-29%) in pa-tients with type 2 diabetes.12 Improve-ments were seen as early as 20 days aftersupplementation, with a slight doseresponse and a lasting effect after stop-ping supplementation. In another ran-domized, controlled trial involving typeII diabetes patients, 3 g of daily cinna-mon over 4 months improved fastingglucose by a mean of 18 mg/dL, yet hadno effect on hemoglobin A1C levels.18

Serum insulin levels, and thus measure-ments of insulin resistance, were notreported in either trial, thus makingcomparisons to our study difficult. How-ever, in our own previous pilot study,we reported improved insulin sensi-tivity in patients with PCOS taking 1 gof cinnamon daily (QUICK-I, þ7.7%;HOMA-IR, �44.5%).19 Although it wassurprising that we did not find statisticalchanges in insulin/glucose parametersafter cinnamon, the women who wererandomized to cinnamon and complet-ed the trial had higher HOMA andlower QUICK-I (suggesting more in-sulin resistance), compared with thegroup randomized to placebo treatment.Indeed the participants in the placebogroup who completed the trial hadnormal insulin resistance parameters(Table 3), although the group as a wholewas similar to the cinnamon groupat trial initiation (Table 1) This maysuggest that although we could notdemonstrate changes, women receivingcinnamon had a greater chance forimprovement of insulin resistance with

TABLE 3Insulin resistance

Index

Cinnamon (n [ 11) Placebo (n [ 6)

Baseline 6 months Baseline 6 months

HOMA-IR, median (IQR) 2.3 (1.4e2.8) 2.5 (0.97e3.3) 1.8 (0.71e3.3) 1.2 (0.78e2.6)

QUICK-I, median (IQR) 0.34 (0.33e0.36) 0.33 (0.32e0.39) 0.35 (0.32e0.41) 0.37 (0.33e0.40)

AUC, median (IQR, mg/dLa min) 16,485 (13,995e18,964) 16,515 (15,068e20,190) 13,298 (11,993e15,285) 15,420 (14,468e17,798)

AUC, area under the curve; HOMA-IR, homeostasis model of insulin resistance; IQR, interquartile range; QUICK-I, Quantitative Insulin Sensitivity Check Index.

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treatment over time. Along these lines,fasting blood measurements of glucoseand insulin may not be sensitive enoughto detect subtle changes in insulin resis-tance at the tissue or cellular level, andparticularly with small numbers ofparticipants.

Other mechanisms, such as alteredserum androgens or altered size andcontent of fat mass, may also be in-volved, yet differences could not beidentified in the 6 month time periodwith our sample size.

Adverse events in our trial were notcommon and no serious adverse eventswere reported. This is consistent withpublished data, showing minimal adverseevents and no increase when comparedwith placebo in comparative trials.24

The biggest concern with our trial wasthe high drop out rate of patients duringthe 6 month study period. The recruit-ment period lasted over a year and wewere not able to continue because of ex-piration of the study drug and placebo.Although some patients encountered sit-uations excluding them from furtherparticipation (pregnancy, surgery), themajority of patients who dropped outwere either lost to follow-up or declinedfurther participation. Many possible fac-tors may be involved in this drop out rate,including the large geography of ourcatchment area, required monthly follow-up visits, compensation rates, requireddaily menstrual diary, and recommended1800 calorie dietary restriction using adaily intake diary. Nevertheless, this dropout rate is typical of trials in womenwithPCOS not trying to conceive. Our dataare extremely similar to other clinicaltrials, where a drop out rate of close to50% is not unexpected.25,26 However,

given the high drop out rate, this studyshould be considered a pilot study forfuture investigations.In summary, our data suggest that

cinnamon supplementation may be auseful adjunct in the treatment of men-strual dysfunction in women with PCOS.Further work to confirm these resultsand shed light on the mechanism(s) ofaction is still needed. -

ACKNOWLEDGMENTS

We would like to thank Jeff Wang, MD from theSher Institute for Reproductive Medicine for hisassistance in the genesis of the clinical trial.

We would like to thank Jolene Lalas and LuzSanabria from the Department of OBGYN,Columbia University for their assistance in pa-tient recruitment and data collection.

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