THE EFFECTIVENESS OF
INOSITOL SUPPLEMENTATION IN
WOMEN WITH POLYCYSTIC
OVARY SYNDROME
Wendy Thompson
Graduate Seminar
ANNU...
Outline
• Background
• PCOS
• Insulin Resistance
• Inositol
• Objective
• Results
• Relationship between PCOS and inositol...
The Significance of the PCOS
3National Institutes of Health Office of Disease Prevention, 2012
• Complex, Multifactorial
•...
PathophysiologyofPCOS
4
Rotstein, A., Srinivasan, R., Wong, E.
McMaster Pathophysiology Review (MPR), 2013
How is PCOS Diagnosed?
NIH 1990 Rotterdam 2003 AE-PCOS Society 2006
• Hyperandrogenism
• Chronic Anovulation
---Both crite...
Insulin Resistance and PCOS
6Tony T. Lee; Mary E. Rausch, 2012
Thecal
Cells
Inositol Structures
7Croze M, 2013
Where do we get MYO?
• Intake
• ~900mg per 2500kcal
• Range: 300mg to 2,000mg
• Absorption
• Bioavailability
• Free Form ~...
Inositol Pathways
• Phosphorylated compounds
• Component of cell membranes
• Signal transduction/cellular signaling
• Epim...
Objective
To determine the effectiveness of inositol
supplements on improving insulin sensitivity and
metabolic parameters...
WHAT IS THE CONNECTION
BETWEEN PCOS AND
INOSITOL?
11
Heimark D, McAllister J, Larner, J. (2014) Decreased myo-
inositol to...
Methods
Ovarian Theca Cells
From size-matched follicles
from age-matched subjects
Age: 28-40
PCOS:
Oligoovulation
Hyperand...
MYO to CI Epimerase Values
130.006 ± 0.002 (n=10) vs. 0.017 ± 0.003 (n=11)
MYO to CI Ratio
14
18 ± 3 (n=6) vs. 5 ± 2 (n=7)
Conclusions/Limitations
• Conclusions:
• CI is overproduced and there is an implied deficiency of MYO in
PCOS theca cells
...
PathophysiologyofPCOS
16
Alex Rotstein, Raginin Srinivasan, Erin Wong
McMaster Pathophysiology Review (MPR), 2013
MECHANISM
Relationship of the
insulin pathway to
phosphatidylinositols
Phosphatidylinositol
Synthase
Myo-Inositol
CMP
Phos...
18Coustan D.,2013
 myo-inositol may
increase insulin
sensitivity by making
more
phosphatidylinositol
available
 glucose ...
DOES MYO SUPPLEMENTATION
IMPROVE INSULIN SENSITIVITY
IN WOMEN WITH PCOS?
19
Gerli S, Mignosa M, DI Renzo GC. (2003) Effect...
Methods
Women with
PCOS
Age: ≤35 years
MYO:
100mg 2x/day
(n=136)
Control:
placebo
(n=147)
20
• Not taking any medications ...
Effects of Myo-Inositol
21
No significant change recorded for fasting insulin, insulin AUC in response
to the glucose chal...
Subgroup Analysis
22
Morbidly Obese
BMI ≥ 37
BMI
• No significant Δ
• Pre: 42.5
• Post: 42.3
HDL
• No significant Δ
• Pre:...
Conclusion
• Not effective in improving glucose or insulin parameters
• May have a beneficial side effect of weight loss w...
Limitations
• Inconsistent timing of measurements
• 12-16 weeks
• High drop out rate
• 30% of treatment group
• Compliance...
WOULD WE SEE AN
IMPROVEMENT IN INSULIN
SENSITIVITY WITH AN
INCREASED DOSE?
25
Costantino D, Minozzi G, Minozzi F, Guaraldi...
Methods
Women with PCOS
Age: 18 - 40 years
Treatment:
4g MYO + 400mcg FA
(n=23)
Control:
400mcg FA
(n=19)
26
• Instructed ...
Changes in Metabolic Parameters
27
Plasma triglycerides decreased by 52%
Glucose and Insulin Measurements
28
Plasma insulin AUC decreased by 36%
ISIcomp increased by 84%
Conclusions
• Improved glucose tolerance and glucose handling
• Reduced the amount of insulin secreted in response to a
me...
Limitations
• Small sample size (N=42)
• Inconsistent timing of measurements
• 6-8 weeks: OGTT
• Compliance was not measur...
WHICH IS MORE EFFECTIVE –
MYO OR DCI IN WOMEN WITH
PCOS?
31
Pizzo A, Laganà AS, Barbaro L. (2014) Comparison
between effec...
Methods
Women with
PCOS
4g MYO +
400mcg FA
(n=25)
1g DCI +
400mcg FA
(n=25)
32
• No medication during the previous 6 month...
Effects of MYO and DCI
MYO
pre
MYO
post Δ%
DCI
pre
DCI
post Δ%
BMI 25.1 ± 5.2 24.7 ± 4.6 - 24.37 ± 5.3 23.87 ± 4.5 -
Glic/...
Comparative Analysis of MYO and DCI
Δ% with MYO
post-treatment
Δ% with DCI
post-treatment
Δ% between
MYO and DCI P-
value
...
Conclusion/Limitations
• Conclusions:
• Both effective in improving insulin sensitivity and SBP
• MYO had a greater decrea...
Summary of Effectiveness
100mg MYO 4g MYO + 400mcg FA 4g MYO +
400mcg FA
1g DCI +
400mc FA
Length 3-4 months <2 months 6 m...
Safety of Inositol
• Very well tolerated
• Dosage of 4g/day
• Minimal to no side effects
• Doses or 12-30g/day
• Mild GI D...
Conclusion/Implications
• Conclusion:
• 4g of MYO/400mcg FA may be beneficial to women with
PCOS in improving some metabol...
Limitations
• Short study length
• Varied diagnostic criteria
• Varied baseline measures
• Many different phenotypes
• No ...
References
• ACOG Practice Bulletin No. 108: Polycystic Ovary Syndrome. Obstet Gynecol.
2009;114(4):936–949.
• Rotstein, A...
41
EXTRA CONTENT
Summary of Baseline Data
100mg MYO 4g MYO +
400mcg FA
4g MYO +
400mcg FA
1g DCI +
400mc FA
Length 3-4 months <2 months 6 m...
100mg MYO 4g MYO +
400mcg FA
4g MYO +
400mcg FA
1g DCI +
400mc FA
BMI  0.9% NS NS NS
Triglycerides NS  52% - -
HDL  5.6...
45M.L. Croze, C.O. Soulage/ Ciochimie 95 (2013) 1811 - 1827
Phosphatidylinositol
Synthase
Calculation for Whole-Food Consumption
• ---Remember this 4g supplement is on top of normal daily
consumption, which is es...
Sample 5g Myo-Inositol Diet
• Breakfast:
• ½ cantaloupe (710mg)
• 1 C milk (10mg)
• 1 C bran flakes (110mg)
• 3 Walnuts (1...
Inositol Food Sources
48
Clements RS Jr, Darnell B. Myo-inositol content of common foods: development of a high-myo-inosit...
49Croze M. & Soulage C. (2013) Potential role and therapeutic interests of myo-inositol in metabolic diseases.
Biochemie. ...
Diagnostic Values
Diagnosis/Test Criteria
Insulin Resistance in Women 3 or more of the following:
• Waist Circumference > ...
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Inositol and PCOS - Seminar Presentation

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This seminar explores the potential connection between two inositol stereoisomers supplements and improvements in insulin sensitivity and various metabolic parameters.

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  • National Institutes of Health Office of Disease Prevention as cited inAmerican Congress of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 108: Polycystic Ovary Syndrome. Obstet Gynecol. 2009;114(4):936–949. [PubMed]5 million in the US
  • http://www.pathophys.org/pcos/
  • Ovarian Dysfunction refers to oligo-anovulation and/or polycystic ovarian morphologyClinical and/or biochemical signs of hyperandrogenismRelated disorders include congenital adrenal hyperplasia, Cushing’s syndrome, hyperprolactinemiahttp://prevention.nih.gov/workshops/2012/pcos/docs/PCOS_Final_Statement.pdfIn women, symptoms of hyperandrogenism frequently include acne, scalp hair loss (androgenic alopecia), excessive facial and body hair (hirsutism), high libido, and others. Collectively, these symptoms are known as virilization.Hyperadrogenemia – a condition of the blood where there is excess androgens that cause male featuresHyperandrogenism – is the collection of symptoms that result from hyperandrogenemia
  • Drawing illustrates the role of insulin resistance in PCOS. Insulin increases the action of LH at the ovary, favoring the production of androgens. In addition, insulin-mediated inhibition of sex hormone–binding globulin (SHBG) synthesis in the liver increases the fraction of free androgens in the serum. Increased adiposity worsens insulin resistance and thus exacerbates the metabolic and endocrine derangements of PCOS.http://pubs.rsna.org/doi/full/10.1148/rg.326125503
  • Sugar alcoholPseudovitaminMYO is the main stereoisomer in:Cells - 90% of cellular inositol FoodSupplements9 Stereoisomers 2 have insulin sensitizing propertiesSmall molecule Structurally similar to glucose – carbohydrate-like moleculeInositol is a polyol by the name of cyclohexanehexol, and is a cyclohexane group (hexagon) with six hydroxyl groups surrounding the structure. Myo-inositol is particularly defined by having a lone axial hydroxyl group (on C2) whereas the other eight possible isomers of inositol are equatorial.[6]Of the nine different types of inositol, two have insulin-sensitizing capabilities: myo-inositol and d-chiro-inositol If D-chiro-inositol is methylated at the 3-carbon, then the molecule that results is known as D-pinitolhttp://www.pcosdiva.com/2012/07/de-mystifying-myo-inositol/http://www.ajcn.org/content/33/9/1954.full.pdf Essential for several types of fish and female gerbils – potential to lead to anorexia, fin degeration, edema, anemia, decreased gastric emptying, reduced growthPsuedovitamin - Produced by the human body from glucoseNot an essential nutrientMYO deficiency in mice resulted in alopecia, inadequate growth, deathMYO has a greater affinity than DCIhttp://examine.com/supplements/Inositol/#ref11Wikipedia!
  • Clements, R.S . Jr., Diethelm, A.G. 1979. The metabolism of myo-inositol by the human kidney. J. Lab. Clin. Med. 93:210-19Clement R. &amp; Darnell, B. (1980) Myo-inositol content of common foods: development of a high-myo-inositol diet. Am J. Clin. Nutr. 33: 1954067Croze M. &amp; Soulage C. (2013) Potential role and therapeutic interests of myo-inositol in metabolic diseases. Biochemie. 95(10);1811-1827Na+ dependent inositol co-transporter 22 minute half-lifeBeef heart and liverPrimarily found in fruit, beans, and seedsPhytate = bound to phosphateTransporter also mediates glucose uptake (can competitively inhibit inositol uptake)Range from 225 to1500 mg/day per 1800 kcal depending on the composition of the dietThis study found that the predicted and measured MYO content was similar until they reached 1,500mgWhen subjects consumed 2x the normal intake of MYO – their plasma concentrations of subjects by 21%Grapefruit juice from concentrate (prepared 3:1) ½ cup (120g) = 456gCanteloupe ¼ melon (100g) = 355g Great Northern Beans ½ cup (100g) = 440mgOrange (100g) = 307g The normal circulating fasting plasma of myo-inositol concentration is ~ 0.03 mMFood products tend to contain myo-inositol more often than not, and the most prevalent food products for this nutrient are whole grain products and citrus fruits whereas dairy and meat products are relatively poor sourcesMyo-Inositol is produced in many human tissues and it is also found in many food sources. The best sources of Myo-Inositol are fruits, beans, grains, and nuts. Fresh vegetables and fruits contain more Myo-Inositol than frozen, canned, or salt-free products. Cantaloupe and citrus fruits other than lemons are very rich in Myo-Inositol and oats and bran contain more than other grains. There is very little Myo-Inositol in milk and yogurt. http://www.allinahealth.org/CCS/doc/Alternative_Medicine/48/10290.htm
  • Myo-inositol Signaling:Initially does not possess any phosphate groupsThe addition of varying phosphate groups to different positions can result in over 70 different signaling molecules within cells. secondary messengers including:Diacylglycerol (DAG)Inositol triphosphate (IP3)Metabolism of MYO is similar to D-chiro-inositol, although myo-inositol has 10-fold greater affinity for this transporter than does D-chiro-inositol. 31, 32, 36, 37DCI is converted from myo-inositol via an epimerase, which is decreased in states of insulin resistanceThe epimerization of myo-inositol to DCI by the oxido-reductive inversion of hydroxyl 3 of myo-inositol MYO is a precursor to DCI in endogenous inositol metabolism3 fates:Oxidation to Co2Used in gluconeogensisUsed in the synthesis of phospholipidshttp://books.google.com/books?id=UR9MnQ806LsC&amp;pg=PA659&amp;lpg=PA659&amp;dq=myo+inositol+is+essential+for+gerbil+fish&amp;source=bl&amp;ots=at1bU_fzdw&amp;sig=Y-NoZaqEbr6lPY6quvPn9PCDQJY&amp;hl=en&amp;sa=X&amp;ei=TXwwU9CYMsnl0gHF8IGABg&amp;ved=0CDAQ6AEwBA#v=onepage&amp;q=myo%20inositol%20is%20essential%20for%20gerbil%20fish&amp;f=falseD-Chiro-Inositol Glycans in Insulin Signaling and Insulin ResistanceMol Med. 2010 Nov-Dec;16(11-12):543-552.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2972396/
  • My First Question is…..http://care.diabetesjournals.org/content/29/2/300
  • in vitro studyTheca cells were obtained from the follicles of women undergoing a hysterectomy – no hormonal medications were taken at the time of surgeryReasons for hysterectomy procedures included: dysfunctional uterine bleeding, endometrial cancer, and/or pelvic painfor MYO content, CI content and a MYO to CI epimerase assay was performedAssay = put the samples and nucleotides and then they added MYO and vortexed and incubated and dried then they calculated the CI contentPCOS: Diagnosed as – hyperandrogenimia and oligoovulation (less than 6 menses/year) = all had elevated serum testosterone levelsExperiments comparing PCOS and normal theca were performed utilizing the 4th passage (31-38 population doublings)Allowed us to perform multiple experiments from the same patient population and were propagated from frozen stocks of second passage cells
  • Two-tailed unpaired t-testShows the epimerase values in a scatergram with mean ± SE (standard error) as shown by horizontal linesThe MYO to CI epimerase specific activity mean value for PCOS is 3X as high as that of normal [0.017 ± 0.003 (n=11) vs. 0.006 ± 0.002 (n=10)]There is also more scatter for the PCOS ovarian theca cells values than for the normal cells (0.002  0.034 vs. 0.0005 0.019)
  • Two-tailed unpaired t-testShows the M/C ratio in a scattergram with mean ± SE as shown by horizontal lines.The mean value for the M/C ratio of normal theca cells is ~4X as high as that for PCOS [18 ± 3 (n=6) vs. 5 ± 2 (n=7)Range for normal cells was 7  24 and PCOS was 2  15
  • Compared to healthy controls, PCOS theca cells have:Difference between normal vs. PCOS theca cells for epimerase activity: p &lt; 0.01Difference between normal vs. PCOS theca cells for M/C ratios: p &lt; 0.002Implied deficiency in the ovaries of women with PCOSUsed cultured cells performed utilizing 4th passage (31-38 population doublings) – allowed them to perform multiple experiments from the same patient populationM/C ratios and epimerase activity are associated with insulin resistance and sensitivity?
  • http://www.pathophys.org/pcos/
  • The synthesis of phosphatidylinositol in the laboratory is catalyzed by phosphatidylinositol synthase and involves CDP-diacylglycerol and L-myo-inositol.[1]CDP and MYO are substrates to produce phophatidylinositol and CMPEnzyme: CDP-diacylglycerol-inositol 3-phosphatidyltransferase
  • Coustan D R Dia Care 2013;36:777-779Relation of the insulin pathway to phosphatidylinositols. The insulin receptor resides in the cell membrane. When its β subunit is phosphorylated by the presence of insulin, insulin receptor substrates (IRSs) are activated. P13K docks to the IRSs, which then leads to phosphorylation of phosphatidylinositol, eventuating in inulin action.It is postulated that myo-inositol may increase insulin sensitivity by making more phosphatidylinositol available. PI3K, phosphatidyl inositol 3-kinase; PDK1, phosphoinositide-dependent kinase 1; PKB, protein kinase B. (Adapted with permission from Agarwal AK, Garg A. Congenital generalized lipodystrophy: significance of triglyceride biosynthetic pathways. Trends EndocrinolMetab 2003;14:214–221.)‏http://care.diabetesjournals.org/content/36/4/777.fullActivation of the insulin receptor causes glucose uptake by mobilizing GLUT4 vesicles, and this occurs after a sequence of events involving intermediates such as PI3K and Akt; between the PI3K and Akt stages, and inositol signaling molecule known as PIP3 is required and its levels seem to help determine overall activity of insulin signalingOnce phosphorylated, these docking proteins recruit the heterodimeric p85/p110-PI3K at the plasma membrane: the regulatory subunit p85 binds to IRS1/2 and this event allows the activation of the catalytic subunit p110, which produces the lipid second messenger PIP3 from PIP2. PIP3 activates a serine/threonine phosphorylation cascade of PH-domain containing proteins: PDK1, the serine/threonine protein kinase B (PKB)/Akt and the atypical protein kinases C ζ and λ isoforms (aPKCζ - λ). Specifically, PKB phosphorylation causes:activation of the mammalian target of rapamycin (mTOR), an intracellular protein as well as a critical component of the PI3K/AKT pathway, that acts as a central regulator of multiple signaling pathways that mediate growth, proliferation and cell differentiation;glycogen synthase kinase-3 (GSK3) inactivation. This event relieves the inhibitory phosphorylation of glycogen synthase (GS), which becomes activated and promotes glycogen synthesis;insulin-stimulated translocation of the glucose transporter GLUT4 at the plasma membrane, resulting in increased glucose uptake. This pathway involves the protein AS160/TBC1D4. AS160 normally inhibits translocation of GLUT4 through its interaction with RabGTPase protein. The inhibitory phosphorylation of AS160 favors the GTP-loaded state of Rab and relieves the inhibitory effect on GLUT4, stimulating its translocation to the plasma membrane. In this way, insulin can promote the docking and fusion of GLUT4-containing vesicles to the plasma membrane and finally stimulate glucose uptake.http://www.intechopen.com/books/type-2-diabetes/mitochondrial-metabolism-and-insulin-actionhttp://www.youtube.com/watch?v=KatbNCEBSDU ---this pathwayhttps://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb1/part2/signals.htm
  • Now that know that PCOS women have a purposed deficiency of inositol is likely contribution to the insulin resistance then will a MYO supplement help?http://care.diabetesjournals.org/content/29/2/300
  • Patients were recruited from gynecology, endocrine, and infertility outpatient clinics.Patients with significant hyperprolactinemia, abnormal thyroid function tests, and congenital adrenal hyperplasia were excluded.PCOS: Diagnosed as – Oligomenorrhea (≤8 periods/year) OR Amenorrhea AND PCOInositol (Gestosan, Lo.Li.Pharma, Rome, Italy)Anthropometric, endocrine, and ovarian ultrasound assessmentsTaken before and after treatment periodAfter: 14 week assessment point (12-16 weeks)Varied b/c measurements needed to be taken outside of the luteal phase
  • Changes in metabolic parameters during placebo or inositol treatment (p-value comparing pre to post)Why only 39/26 pairs????HDL could be attributed to weight loss but an ANOVA was done and was not significant (r=0.34; P &gt;0.07)BMI change in both groups was significant but it increased in placebo and decreased in the inositol groupLeptin decreased significantly in the inositol group (leptin – is a hormone that suppresses appetite (anorexigenic hormone)
  • Morbidly Obese (BMI ≥ 37; n = 11) An increase of 0.26mmol/l reduced the incidence ofevents by 2% in men and 3% in women.
  • Not consistent at the 14-week to ensure measurements were taking outside of the luteal phase because this study also look at reproductive hormones
  • Not consistent at the 14-week to ensure measurements were taking outside of the luteal phase because this study also look at reproductive hormonesMean BMI of 35 which is not representative of PCOS patients (closer to 29)
  • In the previous study we say that 200mg/day of MYO was not effective in improving insulin sensitivity but it improve metabolic parameters – would we see a greater impact if we increased the dose?http://care.diabetesjournals.org/content/29/2/300
  • Form: Inofolic (MYO+FA) &amp; Fertifol (FA)Aim: to investigate the effects of treatment with myo-inositol on circulating insulin, glucose tolerance, ovulation and serum androgens concentrations in women with PCOS.Defined PCOS as: oligomenorrhea, high serum free testosterone level and/or hirsutism
  • Tested for normality using Wilks-Shapiro test and then the distribution was compared with each other using a students two-tailed unpaired or the Wilcoxon rank sum testSlight decrease in systolic and diastolic blood pressurePlasma triglycerides decreased by 52%
  • Insulin sensitivity was determined by the the OGTT and the index of composite whole-body insulin sensitivity (ISIcomp)ISI-comp = Insulin Sensitivity Index = 10,000/square root of ([fasting glucose X fasting insulin] X [mean glucose X mean during OGTT])Tested for normality using Wilks-Shapiro test and then the distribution was compared with each other using a students two-tailed unpaired or the Wilcoxon rank sum test6-8 weeks due to make sure they were in the follicular phase
  • 6-8 weeks due to make sure they were in the follicular phase
  • (oral contraceptives, insulin-sensitizing agents, and others) 6-8 weeks due to make sure they were in the follicular phaseWhen the study was started, patients were in the follicular phase of menstrual cycle (serum progesterone concentration lower than 2.5 ng/ml)
  • In the previous study we saw that 4g/day of MYO was effective in improving insulin sensitivity and improving metabolic parameters – but since MYO is a precursor for DCI would see a different effect if we provided a supplement of DCI inositol instead?doi: 10.3109/09513590.2013.860120.
  • Recruited from Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences of AOU – Gaetano Martino – University of Messina ITALYPCOS diagnosis (Rotterdam criteria = 2/3 of the following: hyperandrogenism, oligo/an-ovulation, PCO)Menstrual irregularitiesHomogenous biophysical features
  • Matched t-testMean +/- Standard Error or Standard Deviation???Glic/IRI ratio = glucose/immunoreactive insulin ratio (similar to glucose to insulin ratio? The higher the better) = measures insulin sensitivityimmunoractive insulin cross-reacts with proinsulin,a marker of islet cell distress or compromised insulin secretion There was a significant correlation between intact proinsulin values and insulin resistance (MMA P &lt; 0.05 and HOMA P &lt; 0.01). Elevation of intact proinsulin values above the reference range (&gt;10 pmmol/l) showed a very high specificity (MMA 100% and HOMA 92.9%) and a moderate sensitivity (MMA 48.6% and HOMA 47.1%) as marker for insulin resistance. Change Percent: Y1-Y2/Y2The Homeostasis Model Assessment (HOMA) estimates can estimate insulin resistance and beta cell functionFasting plasma glucose X Fasting plasma insulin (mg/dl) / 405
  • Student’s t-testComparative analysis of the parameters that showed statistically significant post-treatment reduction or increase with MYO AND DCIFor the factors where MYO and DCI had significant differences between pre- and post- the percent changes were calculated and significant was determined based on p&lt;0.05Glic/IRI ratio = glucose/immunoreactive insulin ratio (similar to glucose to insulin ratio? The higher the better)Change Percent: Y1-Y2/Y2The Homeostasis Model Assessment (HOMA) estimates can estimate insulin resistance and beta cell functionFasting plasma glucose X Fasting plasma insulin (mg/dl) / 405
  • = did not testNS = not significant= number in the treatment group – after drop outs!Study #1 Theca Cells = OO and HAInsert table comparing the studies:AgeBMIOutcomesHow they measured glucose/IR/IS
  • http://www.ncbi.nlm.nih.gov/pubmed/21845803
  • Different phenotypesNo study longer than 6 monthsMetformin vs. MYO: looked only at reproductive outcomes and reported baseline insulin/metabolic parameters but did not look at them after the treatment
  • OvaBoost – Melatonin, MYO, FA, Vitamin E, CoenzymeQInoFolic and Pregnitude = 2g MYO, 200mcg FA – comes in sachetes (powder packets that you mix into water)$25-40 per monthWhy folic acid?n women with polycystic ovary syndrome low folate levels are related to high levels of homocysteine​​. Knowing that women with PCOS have higher cardiovascular risk than other women, it is important to ensure adequate folic acid supplementation to reduce the levels of homocysteine ​​and thus reducing cardiovascular risk (Maria de la Calle, 2007)
  • Hyperinsulinemia: 5 mIU/L (34.73 pmol/LL)= did not testNS = not significant= number in the treatment group – after drop outs!Study #1 Theca Cells = OO and HAInsert table comparing the studies:AgeBMIOutcomesHow they measured glucose/IR/IS
  • = did not testNS = not significant* = number in the treatment group – after drop outs!Insert table comparing the studies:AgeBMIOutcomesHow they measured glucose/IR/IS
  • Croze 2013Most inositol is synthesized in the kidneys = 4g/dayMyo-Inositol is synthesized from glucose in three steps: Glucose is phosphorylated by hexokinase to make D-Glucose-6-PhosphateGlucose-6-P is converted to myoinositol-1-P by the myoinositol-1-phosphate synthase (MIPS)*Myo-inositol-1-phosphate is dephosphorylated by inositol monophosphatase (IMPase 1) to produce myoinositolPentose Phosphate Pathway – releases NADPH (energy)
  • Total: 3,582
  • Based on 100% absorption Dinner = Bean artichoke saladCHO: 61%FAT: 20%PRO: 19%
  • Benefits to other conditions:CancerType II DiabetesGestational DiabetesErectile Dysfunction (in men with T2DM)Psychiatric DisordersObsessive Compulsive DisorderAnxietyDepressionBulimiaMetabolic Syndrome
  • 88cm = 35inhttp://diabetes.niddk.nih.gov/dm/pubs/insulinresistance/#understanding
  • Inositol and PCOS - Seminar Presentation

    1. 1. THE EFFECTIVENESS OF INOSITOL SUPPLEMENTATION IN WOMEN WITH POLYCYSTIC OVARY SYNDROME Wendy Thompson Graduate Seminar ANNU 696 March 27th, 2014
    2. 2. Outline • Background • PCOS • Insulin Resistance • Inositol • Objective • Results • Relationship between PCOS and inositol • Possible mechanism of action • Effectiveness of myo-inositol • Compare the effectiveness of inositol isoforms • Conclusions/Implications • Limitations • Questions 2
    3. 3. The Significance of the PCOS 3National Institutes of Health Office of Disease Prevention, 2012 • Complex, Multifactorial • Heterogeneity • Under-diagnosed 4 Billion Dollars!
    4. 4. PathophysiologyofPCOS 4 Rotstein, A., Srinivasan, R., Wong, E. McMaster Pathophysiology Review (MPR), 2013
    5. 5. How is PCOS Diagnosed? NIH 1990 Rotterdam 2003 AE-PCOS Society 2006 • Hyperandrogenism • Chronic Anovulation ---Both criteria needed • Hyperandrogenism • Oligo-and/or anovulation • Polycystic ovaries ---2 of 3 criteria needed • Hyperandrogenism • Ovarian dysfunction ---Both criteria needed First developed and most commonly used criteria today Formulated to expand on NIH diagnostic definition Formulated to provide an evidence-based definition 5 *All possible related disorders must be ruled out NIH Evidenced Based Methodology Workshop on PCOS, 2012
    6. 6. Insulin Resistance and PCOS 6Tony T. Lee; Mary E. Rausch, 2012 Thecal Cells
    7. 7. Inositol Structures 7Croze M, 2013
    8. 8. Where do we get MYO? • Intake • ~900mg per 2500kcal • Range: 300mg to 2,000mg • Absorption • Bioavailability • Free Form ~ 99% • Phytate form ~ 50% • Synthesis • From glucose in kidneys ~4g/day 8Clement R, 1980; Croze M, 2013; Clements R, 1979
    9. 9. Inositol Pathways • Phosphorylated compounds • Component of cell membranes • Signal transduction/cellular signaling • Epimerase activity 9Croze M, 2013
    10. 10. Objective To determine the effectiveness of inositol supplements on improving insulin sensitivity and metabolic parameters in women with PCOS 10
    11. 11. WHAT IS THE CONNECTION BETWEEN PCOS AND INOSITOL? 11 Heimark D, McAllister J, Larner, J. (2014) Decreased myo- inositol to chiro-inositol (M/C) ratios and increased M/C epimerase activity in PCOS theca cells demonstrate increased insulin sensitivity compared to controls. Endocrine Journal. 61(2);111-117.
    12. 12. Methods Ovarian Theca Cells From size-matched follicles from age-matched subjects Age: 28-40 PCOS: Oligoovulation Hyperandrogenism (n=5+) Control: Normal Ovulation/Fertile Normal Insulin Sensitivity (n=5+) 12 Cells were cultured, scraped, processed and analyzed
    13. 13. MYO to CI Epimerase Values 130.006 ± 0.002 (n=10) vs. 0.017 ± 0.003 (n=11)
    14. 14. MYO to CI Ratio 14 18 ± 3 (n=6) vs. 5 ± 2 (n=7)
    15. 15. Conclusions/Limitations • Conclusions: • CI is overproduced and there is an implied deficiency of MYO in PCOS theca cells • MYO/CI ratios and epimerase activity are likely associated with insulin resistance • Limitations: • Small sample size • Used cultured cells • Reasons for hysterectomy • dysfunctional uterine bleeding, endometrial cancer, pelvic pain 15
    16. 16. PathophysiologyofPCOS 16 Alex Rotstein, Raginin Srinivasan, Erin Wong McMaster Pathophysiology Review (MPR), 2013
    17. 17. MECHANISM Relationship of the insulin pathway to phosphatidylinositols Phosphatidylinositol Synthase Myo-Inositol CMP Phosphatidylinositol CDP-DAG cytidine- diphosphate diacylglycerol M.L. Croze, C.O. Soulage (2013)
    18. 18. 18Coustan D.,2013  myo-inositol may increase insulin sensitivity by making more phosphatidylinositol available  glucose transport (GLUT4),  glycogen synthesis  glycogen synthesis,  gluconeogenesis  glucose transport (GLUT4) IRSs - insulin receptor substrates P13K - phosphatidyl inositol 3-kinase PDK1 - phosphoinositide-dependent kinase 1 PKB - protein kinase B p85 - regulatory subunit p110 - catalytic subunit
    19. 19. DOES MYO SUPPLEMENTATION IMPROVE INSULIN SENSITIVITY IN WOMEN WITH PCOS? 19 Gerli S, Mignosa M, DI Renzo GC. (2003) Effects of inositol on ovarian function and metabolic factors in women with PCOS: a randomized double blind placebo-controlled trial. Euro Rev Med Pharmacol Sci. 7; 151-159.
    20. 20. Methods Women with PCOS Age: ≤35 years MYO: 100mg 2x/day (n=136) Control: placebo (n=147) 20 • Not taking any medications that could influence hormonal profiles • No significant differences between groups at baseline Study Design: Randomized Double-blind Placebo-controlled Length: 16-weeks
    21. 21. Effects of Myo-Inositol 21 No significant change recorded for fasting insulin, insulin AUC in response to the glucose challenge, or fasting glucose
    22. 22. Subgroup Analysis 22 Morbidly Obese BMI ≥ 37 BMI • No significant Δ • Pre: 42.5 • Post: 42.3 HDL • No significant Δ • Pre: 0.95 mmol/L • Post: 0.95 mmol/L Leaner BMI < 37 BMI • P = 0.01 • Pre: 29.4 • Post 28.5 HDL • P = 0.02 • Pre: 1.21 mmol/L • Post: 1.32 mmol/L
    23. 23. Conclusion • Not effective in improving glucose or insulin parameters • May have a beneficial side effect of weight loss with an associated increase in HDL • Had no effect on BMI or HDL in morbidly obese women 23 200mg MYO 12-16 weeks
    24. 24. Limitations • Inconsistent timing of measurements • 12-16 weeks • High drop out rate • 30% of treatment group • Compliance • Lifestyle changes • Did not report CI for post-treatment • Mean BMI = 35 24
    25. 25. WOULD WE SEE AN IMPROVEMENT IN INSULIN SENSITIVITY WITH AN INCREASED DOSE? 25 Costantino D, Minozzi G, Minozzi F, Guaraldi C. (2009) Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double blind trial. Euro Rev Med Pharmacol Sci. 13; 105-110.
    26. 26. Methods Women with PCOS Age: 18 - 40 years Treatment: 4g MYO + 400mcg FA (n=23) Control: 400mcg FA (n=19) 26 • Instructed to not change usual habits of food, sport, and lifestyle • No significant differences between groups at baseline Study Design: Randomized Double-blind Placebo-controlled Length: 12-16 weeks
    27. 27. Changes in Metabolic Parameters 27 Plasma triglycerides decreased by 52%
    28. 28. Glucose and Insulin Measurements 28 Plasma insulin AUC decreased by 36% ISIcomp increased by 84%
    29. 29. Conclusions • Improved glucose tolerance and glucose handling • Reduced the amount of insulin secreted in response to a meal • Provided minor benefits to cardiovascular health independent from weight loss • BP, Triglycerides, Cholesterol 29 4g MYO 12-16 weeks
    30. 30. Limitations • Small sample size (N=42) • Inconsistent timing of measurements • 6-8 weeks: OGTT • Compliance was not measured or reported • ~30% taking medications during the 2 months before the study • High variation in the glucose AUC 30
    31. 31. WHICH IS MORE EFFECTIVE – MYO OR DCI IN WOMEN WITH PCOS? 31 Pizzo A, Laganà AS, Barbaro L. (2014) Comparison between effects of myo-inositol and d-chiro-inositol on ovarian function and metabolic factors in women with PCOS. Gynecol Endocrinol. 30(3); 205-208
    32. 32. Methods Women with PCOS 4g MYO + 400mcg FA (n=25) 1g DCI + 400mcg FA (n=25) 32 • No medication during the previous 6 months or during the study • No significant differences between groups at baseline Study Design: Randomized Double-blind Length: 6 months
    33. 33. Effects of MYO and DCI MYO pre MYO post Δ% DCI pre DCI post Δ% BMI 25.1 ± 5.2 24.7 ± 4.6 - 24.37 ± 5.3 23.87 ± 4.5 - Glic/IRI Ratio 5.52 ± 1.7 9.72 ± 3.8 +43.2% 5.83 ± 1.5 10.56 ± 3.7 +44.8% HOMA 3.51 ± 1.7 1.75 ± 0.8 -100.6% 3.14 ± 1.1 1.61 ± 0.7 -95.0% SBP (mmHg) 104.5 ± 14.0 96 ± 6.6 -8.9% 103.75 ± 14.3 96.25 ± 6.9 -7.8% DBP (mmHg) 68.5 ± 8.2 64.5 ± 6.0 -6.2% 68.12 ± 9.3 64.37 ± 6.2 - 33 Glucose/Immunoreactive Insulin Ratio (Glic/IRI ratio) Homeostasis Model Assessment (HOMA)
    34. 34. Comparative Analysis of MYO and DCI Δ% with MYO post-treatment Δ% with DCI post-treatment Δ% between MYO and DCI P- value Glic/IRI Ratio +43.21 +44.79% 1.58% 0.174 HOMA -100.57% -95.03% 5.54% 0.032 Systolic BP (mmHg) -8.85% -7.79% 1.06% 0.204 34 Glucose/Immunoreactive Insulin Ratio (Glic/IRI ratio) Homeostasis Model Assessment (HOMA)
    35. 35. Conclusion/Limitations • Conclusions: • Both effective in improving insulin sensitivity and SBP • MYO had a greater decrease on DBP and insulin resistance • Limitations: • 4g of MYO vs. 1g of DCI • Physiological ratio 40:1 • Small sample size (N=50) • Did not control for lifestyle changes • Compliance was not measured or reported 35 4g MYO vs 1g DCI 6 months
    36. 36. Summary of Effectiveness 100mg MYO 4g MYO + 400mcg FA 4g MYO + 400mcg FA 1g DCI + 400mc FA Length 3-4 months <2 months 6 months N* 238 42 50 Age at Baseline 28.6 ± 1.7 28.8 ± 1.5 20.25 ± 4.47 19.25 ± 3.47 BMI (kg/m2) at Baseline 34.2 ± 2.5 22.8 ± 0.3 25.1 ± 5.2 24.37 ± 5.31 Metabolic Parameters Measured BMI, WHR, Triglycerides, VLDL, LDL, HDL BMI, WHR, Triglycerides, Cholesterol, BP BMI, BP Insulin/Glucos e Measured Fasting glu/ins, AUC glu/ins Fasting glu/ins, AUC glu/ins, ISIcomp Glic/IRI ratio, HOMA Significant Results BMI, Leptin, HDL SBP/DBP Triglycerides Cholest. Glu AUC Ins AUC SBP/DBP Glic/IRI ratio  HOMA SBP Glic/IRI ratio  HOMA Conclusions Not Effective/Effective Effective Effective Effective 36
    37. 37. Safety of Inositol • Very well tolerated • Dosage of 4g/day • Minimal to no side effects • Doses or 12-30g/day • Mild GI Distributions: • Nausea • Flatus • Diarrhea • Considered safe • 18g/day for 3 months • 2g/day for 1 year 37Carlomagno G, Unfer V. Inositol Safety: Clinical Evidences. (2011) Euro Rev Med Pharmacol Sci. 15; 931-936.
    38. 38. Conclusion/Implications • Conclusion: • 4g of MYO/400mcg FA may be beneficial to women with PCOS in improving some metabolic parameters and insulin sensitivity • Implications: • Lifestyle intervention should be the first-line of treatment • Could be beneficial to women who cannot tolerate metformin due to side-effects • More research is needed 38
    39. 39. Limitations • Short study length • Varied diagnostic criteria • Varied baseline measures • Many different phenotypes • No comparison insulin-sensitizing medications • What happens if they stop taking inositol? • Long-term safety • Limited information on effectiveness of morbidly obese women 39
    40. 40. References • ACOG Practice Bulletin No. 108: Polycystic Ovary Syndrome. Obstet Gynecol. 2009;114(4):936–949. • Rotstein, A., Srinivasan, R., Wong, E. (2013) McMaster Pathophysiology Review (MPR) • Clements, R.S . Jr., Diethelm, A.G. (1979). The metabolism of myo-inositol by the human kidney. J. Lab. Clin. Med. 93:210-19 • Clement R. & Darnell, B. (1980) Myo-inositol content of common foods: development of a high-myo-inositol diet. Am J. Clin. Nutr. 33: 1954067 • Croze M. & Soulage C. (2013) Potential role and therapeutic interests of • myo-inositol in metabolic diseases. Biochemie. 95(10);1811-1827 • Coustan D R Dia Care 2013;36:777-779 • Heimark D, McAllister J, Larner, J. (2014) Decreased myo-inositol to chiro-inositol (M/C) ratios and increased M/C epimerase activity in PCOS theca cells demonstrate increased insulin sensitivity compared to controls. Endocrine Journal. 61(2);111-117. • Gerli S, Mignosa M, DI Renzo GC. (2003) Effects of inositol on ovarian function and metabolic factors in women with PCOS: a randomized double blind placebo-controlled trial. Euro Rev Med Pharmacol Sci. 7; 151-159. • Costantino D, Minozzi G, Minozzi F, Guaraldi C. (2009) Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double blind trial. Euro Rev Med Pharmacol Sci. 13; 105-110. • Pizzo A, Laganà AS, Barbaro L. (2014) Comparison between effects of myo-inositol and d- chiro-inositol on ovarian function and metabolic factors in women with PCOS. Gynecol Endocrinol. 30(3); 205-208 • Carlomagno G, Unfer V. Inositol Safety: Clinical Evidences. (2011) Euro Rev Med Pharmacol Sci. 15; 931-936. 40
    41. 41. 41
    42. 42. EXTRA CONTENT
    43. 43. Summary of Baseline Data 100mg MYO 4g MYO + 400mcg FA 4g MYO + 400mcg FA 1g DCI + 400mc FA Length 3-4 months <2 months 6 months 6 months N* 91 23 25 25 Age at Baseline 28.6 ± 1.7 28.8 ± 1.5 20.25 ± 4.47 19.25 ± 3.47 BMI (kg/m2) at Baseline 34.2 ± 2.5 22.8 ± 0.3 25.1 ± 5.2 24.37 ± 5.31 WHR at Baseline 0.88 ± 0.2 0.88 ± 0.2 - - Fasting Insulin mIU/L 16.7 ± 3.7 32.5 ± 4.1 - - PCOS Diagnostic Criteria OO/OA & PCO OO & high serum free T AND/OR hirsutism Rotterdam = 2/3 of the following: HA, OO/OA, PCO Rotterdam = 2/3 of the following: HA, OO/OA, PCO 43OO = oligoovulation; AO = anovulation; HA = hyperandrogenism; PCO = polycystic ovaries
    44. 44. 100mg MYO 4g MYO + 400mcg FA 4g MYO + 400mcg FA 1g DCI + 400mc FA BMI  0.9% NS NS NS Triglycerides NS  52% - - HDL  5.6% - - - Total Cholesterol NS  18.6% - - Systolic Blood Pressure -  3.1%  8.1%  7.1% Diastolic Blood Pressure -  6.8%  5.8% NS Fasting Insulin NS NS - - Fasting glucose NS NS - - GTT insulin AUC NS  36% - - GTT Glucose AUC -  15.8% - - ISIcomp -  84% - - Glic/IRI Ratio - -  76.1%  81.1% HOMA - -  50.1%  48.7% 44
    45. 45. 45M.L. Croze, C.O. Soulage/ Ciochimie 95 (2013) 1811 - 1827 Phosphatidylinositol Synthase
    46. 46. Calculation for Whole-Food Consumption • ---Remember this 4g supplement is on top of normal daily consumption, which is estimated to be 900mg in 2,500kcal • ---In theory, you would need to consume 5g to have similar effects: 46
    47. 47. Sample 5g Myo-Inositol Diet • Breakfast: • ½ cantaloupe (710mg) • 1 C milk (10mg) • 1 C bran flakes (110mg) • 3 Walnuts (13g) • ½ C grapefruit juice (456mg) • Snack: • 2 dried prunes (94mg) • 16 almonds (84mg) • 1 Kiwi (136mg) • Lunch: • 1 orange (307mg) • 2 slices of stone ground wheat bread (576mg) • 2 T of Peanut Butter (122mg) • ½ C Kidney Beans (250mg) • Snack: • 1 C Lima beans (300mg) • 1 Mango (99mg) • 1 slice stone ground wheat bread (288 mg) • Dinner: • 1C Great Northern Beans (880mg) • 1/2 C artichoke hearts, canned (116mg) • 1 C tomatoes (54mg) • ¼ C onion, yellow (22mg) • 6 oz. chicken (14mg) • Dessert: • 1 Grapefruit (400mg) Totals: MYO: 5,068mg* kcal: 2,342 47
    48. 48. Inositol Food Sources 48 Clements RS Jr, Darnell B. Myo-inositol content of common foods: development of a high-myo-inositol diet. Am J Clin Nutr. (1980)
    49. 49. 49Croze M. & Soulage C. (2013) Potential role and therapeutic interests of myo-inositol in metabolic diseases. Biochemie. 95(10);1811-1827
    50. 50. Diagnostic Values Diagnosis/Test Criteria Insulin Resistance in Women 3 or more of the following: • Waist Circumference > 88cm • Triglycerides ≥ 150 mg/dL • HDL Cholesterol <50 mg/dL • Blood Pressure ≥ 130/85 mm/Hg • Fasting Glucose ≥ 100 mg/dL Fasting Glucose/Insulin Ratio Insulin Resistance: • <4.5 in obese, euglycemic, non-Hispanic white adult PCOS patients • <7.0 in adolescents 75g Oral Glucose Tolerance Test (at 2- hours) Normal: <140mg/dL Impaired GT: 140-199 mg/dL Diabetes: ≥200 mg/dL Fasting Insulin Hyperinsulinemia: 5 mIU/L (34.73 pmol/LL) Waist to Hip Ratio (WHR) Females: • 0.80 or below = Low Risk • 0.81 to 0.85 = Moderate Risk • 0.85 or above = High Risk 50National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH)
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