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Fertility Supplements Questions and Answers

There is a lot of misinformation out there and it can cause a lot of distress and worry to women trying to conceive.

On this page Dr. Myatt will address some of these concerns regarding natural supplementation, vitamins, herbs, and more.

Using Flavones to Lower IL-6: Which is better - Luteolin / Diosmin or Maxi Flavone?

Milk Thistle - is it safe?

Green Tea - Causes Inflammation?

Myo-inositol in the Treatment of PCOS and Non-PCOS Infertility

What's So Special About Maxi Greens?


Using Flavones to Lower IL-6: Which is better - Luteolin / Diosmin or Maxi Flavone?

Interleukin 6 (IL-6) is both a pro-inflammatory and anti-inflammatory cytokine. (1-3)

As a class, flavones lower inflammation and inflammatory cytokines including IL-1, IL-6,
IL-18 and TNF-a. (4) Flavone-containing herbs have a synergistic effect when used in combination.(5-6)

The flavones contained in Maxi Flavone all have IL-6 lowering properties.

These IL-6 lowering herbs include Pycnogenol (pine bark) (7-8), red grape seed extract (resveretrol) (9-17), bilberry (Vaccinum myrtillus) (18-19), green tea (Camellia sinensis) polyphenols (20-23), ginkgo (24-26), milk thistle (27) and citrus bioflavonoids (4,28)

Further, the IL-6 lowering properties of the herbs in Maxi Flavone have been studied in humans. (8,12-14,16-19,25,27)

Luteolin and its semi-synthetic structural analog diosmin have been studied only in rodents for their IL-6-lowering properties. (29)

Maxi Flavone Or Luteolin/Diosmin for IL-6?

Maxi Flavone contains a combination of flavonoid herbs. Benefits of Maxi Flavone include:

  • Each herb in this formula has demonstrated IL-6 lowering properties (4,7-28)
  • The IL-6 lowering properties of these flavones have been studied in humans (8,12-14,16-19, 25, 27)
  • Safety of these flavones has been documented in humans (8,12-14,16-19, 25, 27)
  • Flavones work synergistically so that a combination of flavones may be more effective than an isolated flavone. (5,6)

Luteolin / Diosmin:

  • Has been studied only in rodents for IL-6 lowering properties and in only one study (29)
  • Has strong estrogenic properties that may not be desirable for many infertile women (30)
  • Isolated flavones may not be as effective as an array of flavones for lowering inflammatory cytokines.(5,6)

Until more research is available on luteolin/diosmin, Maxi Flavone multi-flavone formula would appear a superior choice for addressing elevated IL-6 than any single flavonoid including luteolin or its semi-synthetic analogue diosmin.

References

1.) Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S.
The pro- and anti-inflammatory properties of the cytokine interleukin-6.
Biochim Biophys Acta. 2011 May;1813(5):878-88.
2.) Z Xing, J Gauldie, G Cox, H Baumann, M Jordana, X F Lei, and M K Achong
IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute
inflammatory responses. J Clin Invest. 1998 January 15; 101(2): 311320.
3.) Rose-John S, Scheller J, Elson G, Jones SA. Interleukin-6 biology is coordinated by membrane-bound
and soluble receptors: role in inflammation and cancer. J Leukoc Biol. 2006 Aug;80(2):227-36. Epub 2006 May 17.
4.) Landberg R, Sun Q, Rimm EB, Cassidy A, Scalbert A, Mantzoros CS, Hu FB, van Dam RM. Selected dietary
flavonoids are associated with markers of inflammation and endothelial dysfunction in U.S. women. J Nutr. 2011 Apr 1;141(4):618-25.
5.) Rahman MM, Ichiyanagi T, Komiyama T, Hatano Y, Konishi T. Superoxide radical- and peroxynitrite-scavenging activity of anthocyanins; structure-activity relationship and their synergism. Free Radic Res. 2006 Sep;40(9):993-1002.
6.) Sagar SM, Yance D, Wong RK. Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer-Part 1. Curr Oncol. 2006 Feb;13(1):14-26.
7.) Ozer Sehirli A, Sener G, Ercan F. Protective effects of pycnogenol against ischemia reperfusion-induced oxidative renal injury in rats.Ren Fail. 2009;31(8):690-7.
8.) Scheff SW, Ansari MA, Roberts KN.Neuroprotective effect of Pycnogenol® following traumatic brain injury. Exp Neurol. 2013 Jan;239:183-91.
9.) Cullberg KB, Olholm J, Paulsen SK, Foldager CB, Lind M, Richelsen B, Pedersen SB. Resveratrol has inhibitory effects on the hypoxia-induced inflammation and angiogenesis in human adipose tissue in vitro.
Eur J Pharm Sci. 2013 May 13;49(2):251-7.
10.) Gatson JW, Liu MM, Abdelfattah K, Wigginton JG, Smith S, Wolf S, Minei JP. Resveratrol decreases inflammation in the brain of mice with mild traumatic brain injury. J Trauma Acute Care Surg. 2013 Feb;74(2):470-4; discussion 474-5.
11.) Marier JF, Chen K, Prince P, Scott G, del Castillo JR, Vachon P.
Production of ex vivo lipopolysaccharide-induced tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 is suppressed by trans-resveratrol in a concentration-dependent manner. Can J Vet Res. 2005 Apr;69(2):151-4.
12.) Rizzo A, Bevilacqua N, Guida L, Annunziata M, Romano Carratelli C, Paolillo R. Effect of resveratrol and modulation of cytokine production on human periodontal ligament cells. Cytokine. 2012 Oct;60(1):197-204.
13.) Su YC, Li SC, Wu YC, Wang LM, Chao KS, Liao HF.
Resveratrol downregulates interleukin-6-stimulated sonic hedgehog signaling in human acute myeloid leukemia. Evid Based Complement Alternat Med. 2013;2013:547430.
14.) Tomé-Carneiro J, Gonzálvez M, Larrosa M, Yáñez-Gascón MJ, García-Almagro FJ, Ruiz-Ros JA, García-Conesa MT, Tomás-Barberán FA, Espín JC. One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. Am J Cardiol. 2012 Aug 1;110(3):356-63.
15.) Wight RD, Tull CA, Deel MW, Stroope BL, Eubanks AG, Chavis JA, Drew PD, Hensley LL.Resveratrol effects on astrocyte function: relevance to neurodegenerative diseases. Biochem Biophys Res Commun. 2012 Sep 14;426(1):112-5.
16.) Wuertz K, Quero L, Sekiguchi M, Klawitter M, Nerlich A, Konno S, Kikuchi S, Boos N. The red wine polyphenol resveratrol shows promising potential for the treatment of nucleus pulposus-mediated pain in vitro and in vivo.
Spine (Phila Pa 1976). 2011 Oct 1;36(21):E1373-84.
17.) Xie XH, Zang N, Li SM, Wang LJ, Deng Y, He Y, Yang XQ, Liu EM.
Resveratrol Inhibits respiratory syncytial virus-induced IL-6 production, decreases viral replication, and downregulates TRIF expression in airway epithelial cells. Inflammation. 2012 Aug;35(4):1392-401.
18.) Karlsen A, Paur I, Bøhn SK, Sakhi AK, Borge GI, Serafini M, Erlund I, Laake P, Tonstad S, Blomhoff R. Bilberry juice modulates plasma concentration of NF-kappaB related inflammatory markers in subjects at increased risk of CVD. Eur J Nutr. 2010 Sep;49(6):345-55.
19.) Kolehmainen M, Mykkänen O, Kirjavainen PV, Leppänen T, Moilanen E, Adriaens M, Laaksonen DE, Hallikainen M, Puupponen-Pimiä R, Pulkkinen L, Mykkänen H, Gylling H, Poutanen K, Törrönen R. Bilberries reduce low-grade inflammation in individuals with features of metabolic syndrome. Mol Nutr Food Res. 2012 Oct;56(10):1501-10.
20.) Ahmed S, Marotte H, Kwan K, Ruth JH, Campbell PL, Rabquer BJ, Pakozdi A, Koch AE. Epigallocatechin-3-gallate inhibits IL-6 synthesis and suppresses transsignaling by enhancing soluble gp130 production. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14692-7.
21.) Cavet ME, Harrington KL, Vollmer TR, Ward KW, Zhang JZ. Anti-inflammatory and anti-oxidative effects of the green tea polyphenol epigallocatechin gallate in human corneal epithelial cells. Mol Vis. 2011 Feb 18;17:533-42.
22.) Hosokawa Y, Hosokawa I, Ozaki K, Nakanishi T, Nakae H, Matsuo T.
Tea polyphenols inhibit IL-6 production in tumor necrosis factor superfamily 14-stimulated human gingival fibroblasts. Mol Nutr Food Res. Mol Nutr Food Res. 2010 Jul;54 Suppl 2:S151-8.
23.) Katiyar SK, Raman C. Green tea: a new option for the prevention or control of osteoarthritis. Arthritis Res Ther. 2011 Aug 10;13(4):121.
24.) Chen JS, Chen YH, Huang PH, Tsai HY, Chen YL, Lin SJ, Chen JW.
Ginkgo biloba extract reduces high-glucose-induced endothelial adhesion by inhibiting the redox-dependent interleukin-6 pathways. Cardiovasc Diabetol. 2012 May 3;11:49.
25.) Ching-Hsiang L, Chiao-Wen H, Nan-Fu C, Wen-Sheng L, Ya-Fen H, Wen-Tung W. In vivo effects of Ginkgo biloba extract on interleukin-6 cytokine levels in patients with neurological disorders. Indian J Pharmacol. 2012 Jan;44(1):118-21.
26.) Zhou YH, Yu JP, Liu YF, Teng XJ, Ming M, Lv P, An P, Liu SQ, Yu HG.
Effects of Ginkgo biloba extract on inflammatory mediators (SOD, MDA, TNF-alpha, NF-kappaBp65, IL-6) in TNBS-induced colitis in rats. Mediators Inflamm. 2006;2006(5):92642.
27.) Täger M, Dietzmann J, Thiel U, Hinrich Neumann K, Ansorge S.
Restoration of the cellular thiol status of peritoneal macrophages from CAPD patients by the flavonoids silibinin and silymarin.
Free Radic Res. 2001 Feb;34(2):137-51.
28.) Kim JA, Park HS, Kang SR, Park KI, Lee DH, Nagappan A, Shin SC, Lee WS, Kim EH, Kim GS. Suppressive effect of flavonoids from Korean Citrus aurantium L. on the expression of inflammatory mediators in L6 skeletal muscle cells. Phytother Res. 2012 Dec;26(12):1904-12.
29.) Parker-Athill E, Luo D, Bailey A, Giunta B, Tian J, Shytle RD, Murphy T, Legradi G, Tan J. Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism. J Neuroimmunol. 2009 Dec 10;217(1-2):20-7.
30.) Zand RS, Jenkins DJ, Diamandis EP. Steroid hormone activity of flavonoids and related compounds.Breast Cancer Res Treat. 2000 Jul;62(1):35-49.


 

“An IVF Doctor Said Not to Take MilkThistle" and Other Uninformed Medical Advice

From an infertility forum website, where the patient quoted an IVF doc as saying not to take milk thistle because "It makes the liver work better / metabolize things faster so it can metabolize your drugs too and hence shouldn't be taken during an IVF cycle."  There are no studies cited.

Unsubstantiated comments like this occur when a doctor steps outside of his/her area of expertise. That's unfortunate, because it can cause a lot of needless alarm AND potentially drive patients away from helpful treatments. So, let's set the record straight about this unsupported statement and about the usefulness of milk thistle in infertility.

The dose of milk thistle required to upregulate liver enzymes and therefor increase drug metabolism is of a 10 to 30-fold magnitude higher than anything Dr. Braverman or I use for infertility. A woman would have to take 24 doses of Maxi Flavone daily to achieve this increased drug metabolism effect, if even that would do it.

In the one lab rat study cited, an equivalent human female dose would be 2400mg+ per day.(1) Maxi Flavone contains 100mg per dose, maximum 200mg per day at the highest recommended intake. At this dose, there is not one study which shows that liver enzymes are upregulated enough to alter blood levels of any drug.(2-5)

Dr. Braverman and I are going for antioxidant, anti-inflammatory, and TNFa inhibitory effect of milk thistle but we are well below any liver-enzyme upregulating (and therefor IVF drug-changing) effect. (16-20)

600mg of milk thistle per day in HUMANS (not just lab rats) did not show any significant effect on drug-metabolizing liver enzymes. (6) Other studies have shown a minimal effect on liver enzymes (P450, CYP's, etc) even at concentrations much higher than doses found in Maxi Flavone.(7)

Only at very high concentrations has milk thistle been shown to affect liver enzymes. According the the FDA, "In view of the clinically relevant plasma concentration of approx. 0.2 microM measured as silibinin, it is evident that there is no drug-drug interaction problem with silymarin." (8)

Any by the way, many foods and drugs affect this same liver enzyme system far more than milk thistle. Did you know that many “health foods” such as kale, cabbage, Brussels sprouts, broccoli, arugula, watercress, grapefruit, pomegranate, and others can all have a profound effect on this important enzyme system?

http://dmd.aspetjournals.org/content/early/2006/01/13/dmd.105.007930.full.pdf
http://en.wikipedia.org/wiki/Cruciferous_vegetables

HOLD THE MAYO

Milk Thistle according to Mayo Clinic's website:

"Theoretically, because milk thistle plant extract might have estrogenic effects, women with hormone sensitive conditions should avoid milk thistle above ground parts. Some of these conditions include breast, uterine, and ovarian cancer, endometriosis, and uterine fibroids." http://www.mayoclinic.com/health/silymarin/NS_patient-milkthistle/DSECTION=safety

Mayo clinic has some incredibly poorly referenced, contradictory articles on their site. I would not rely on them for authoritative herbal information. It is outside their area of expertise. (Don't expect your brain surgeon to be an expert in acupuncture and don't expect your acupuncturist to be an expert in brain surgery.)

For example, the cited Mayo clinic article on milk thistle actually contradicts itself. In one place it says "silymarin and silibinin in milk thistle reduce the growth of human breast, cervical and prostate cancer cells” and in another place it says "...should avoid milk thistle in... breast, uterine, and ovarian cancer..."  Which is it, Mayo?

Contrary to Mayo's "theoretical" (read that: "unreferenced") concerns, milk thistle has actually proven to be beneficial for the hormone-related conditions cited above in numerous studies. (9-15)

Next, someone thought they were revealing a smoking gun by quoting, "Silybin, an extract from seeds of milk thistle (Silybum marianum), is known to have hepato-protective, anticarcinogenic, and estrogenic effects." http://www.ncbi.nlm.nih.gov/pubmed/20183284

Be sure to look at the doses when reading abstracts or medical journal articles. Dose makes a big difference. (I addressed this issue in a recent previous email)

This rat study used 18mg/kg given twice per day. That would equate to 2,454 mg per day for a 150-pound female. Maxi Flavone has 100mg total to be taken once per day. This is less than 1/24th the dose that has demonstrated estrogenic effects. (1)

Let's Dump In Some Totally Unrelated Studies for Good Measure...

What was said: Reservatol increases Nk cell activity: http://www.ncbi.nlm.nih.gov/pubmed/20082299

Dr. Myatt’s Comment: Resveretrol has potent antioxidant and anti-inflammatory effects. Resveretrol also suppresses TNF-alpha. Please see the extensive reference list here: Grape Seed Extract. Repeat after me, “preponderance of evidence” and “dose” (see below).

What was said: Grape seed extract and pycnogenol are aromatase inhibitors. Aromatase is an enzyme present in fat tissue and in ovaries that converts testosterone to estrogen. When it is inhibited, there will be more testosterone. Sometimes in short doses this is ok, as femara is works by being an aromatase inhibitor. "But it is not good to take this for longer times as it can inhibit ovulation and lead to high testosterone levels which are toxic to our eggs."

Dr. Myatt's comment
: Here we have a medical opinion from a layperson. Would this really be the best source of information about improving fertility? Again, dose. The amount of aromatase effect from the doses of grape seed and pycnogenol in Maxi Flavone are insufficient to cause a hormone shift. Besides, your infertility specialist can easily measure hormone levels and would know if such a shift were occurring.

Dr. Myatt's Caution About "References" and "Experts"

For any question you type into Pub Med (the medical journal article abstract website), you will find references that support both sides of the question. There's almost never "black and white." Instead, there are "ten thousand shades of gray." Here's what you need to know:

One reference does not make "proof" and an isolated lab rat study does not "prove" anything. The "preponderance of evidence," including number of studies, how well-conducted the studies were, whether the studies were test-tube or lab rat studies versus human studies, who funded the studies, all must be taken into account.

I see a lot of women quoting single lab-rat or test-tube studies without any knowledge or consideration of the above-mentioned factors. So, when you are reading such "proofs" posted by non-physicians, please keep these factors in mind and "consider the source."
 
Also, I believe any statement that has absolutely NO references should be dismissed on its face. References might not constitute "proof," but at least they need to be there. Otherwise, any one of us can sit in our easy chair and "theorize."

Theorizing won't get you pregnant; it will simply waste your time.

Fertility is not individual brush strokes; it is the whole picture taken together. Dr. Braverman takes the "whole picture" view.

He is an expert in IVF, one of the most renown in the world. But when he is out of his area of expertise, he turns to me or another expert for their evaluation. He doesn't just "make stuff up" like some so-called "experts." THAT is the mark of a true professional.


References

1.) El-Shitany NA, Hegazy S, El-Desoky K. Evidences for antiosteoporotic and selective estrogen receptor modulator activity of silymarin compared with ethinylestradiol in ovariectomized rats. Phytomedicine. 2010 Feb;17(2):116-25. Epub 2009 Jul 3.
2.) Breinholt V, Lauridsen ST, Dragsted LO. Differential effects of dietary flavonoids on drug metabolizing and antioxidant enzymes in female rat. Xenobiotica. 1999 Dec;29(12):1227-40.
3.) Doehmer J, Weiss G, McGregor GP, Appel K. Assessment of a dry extract from milk thistle (Silybum marianum) for interference with human liver cytochrome-P450 activities. Toxicol In Vitro. 2011 Feb;25(1):21-7. Epub 2010 Sep 7.
4.) Gurley B, Hubbard MA, Williams DK, Thaden J, Tong Y, Gentry WB, Breen P, Carrier DJ, Cheboyina S. Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity: comparison of a milk thistle and black cohosh product to rifampin and clarithromycin. J Clin Pharmacol. 2006 Feb;46(2):201-13.
5.) Gurley BJ, Barone GW, Williams DK, Carrier J, Breen P, Yates CR, Song PF, Hubbard MA, Tong Y, Cheboyina S. Effect of milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans. Drug Metab Dispos. 2006 Jan;34(1):69-74. Epub 2005 Oct 12.
6.) van Erp NP, Baker SD, Zhao M, Rudek MA, Guchelaar HJ, Nortier JW, Sparreboom A, Gelderblom H. Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan. Clin Cancer Res. 2005 Nov 1;11(21):7800-6.
7.) Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Carrier J, Khan IA, Edwards DJ, Shah A. In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto. Clin Pharmacol Ther. 2004 Nov;76(5):428-40.
8.) Doehmer J, Tewes B, Klein KU, Gritzko K, Muschick H, Mengs U.
Assessment of drug-drug interaction for silymarin. Toxicol In Vitro. 2008 Apr;22(3):610-7. Epub 2007 Dec 8.
9.) Agarwal R, Agarwal C, Ichikawa H, Singh RP, Aggarwal BB. Anticancer potential of silymarin: from bench to bed side. Anticancer Res. 2006 Nov-Dec;26(6B):4457-98.
10.) Kim S, Han J, Kim JS, Kim JH, Choe JH, Yang JH, Nam SJ, Lee JE.
Silibinin suppresses EGFR ligand-induced CD44 expression through inhibition of EGFR activity in breast cancer cells. Anticancer Res. 2011 Nov;31(11):3767-73.
11.) Lu W, Lin C, King TD, Chen H, Reynolds RC, Li Y.
Silibinin inhibits Wnt/ -catenin signaling by suppressing Wnt co-receptor LRP6 expression in human prostate and breast cancer cells. Cell Signal. 2012 Dec;24(12):2291-6. doi: 10.1016/j.cellsig.2012.07.009. Epub 2012 Jul 20.
12.) Nejati-Koshki K, Zarghami N, Pourhassan-Moghaddam M, Rahmati-Yamchi M, Mollazade M, Nasiri M, Esfahlan RJ, Barkhordari A, Tayefi-Nasrabadi H. Inhibition of leptin gene expression and secretion by silibinin: possible role of estrogen receptors. Cytotechnology. 2012 Apr 17. [Epub ahead of print]
13.) Noh EM, Yi MS, Youn HJ, Lee BK, Lee YR, Han JH, Yu HN, Kim JS, Jung SH.
Silibinin enhances ultraviolet B-induced apoptosis in mcf-7 human breast cancer cells. J Breast Cancer. 2011 Mar;14(1):8-13. Epub 2011 Mar 31.
14.) Scambia G, De Vincenzo R, Ranelletti FO, Panici PB, Ferrandina G, D'Agostino G, Fattorossi A, Bombardelli E, Mancuso S.Antiproliferative effect of silybin on gynaecological malignancies: synergism with cisplatin and doxorubicin. Eur J Cancer. 1996 May;32A(5):877-82.
15.) Yu HC, Chen LJ, Cheng KC, Li YX, Yeh CH, Cheng JT. Silymarin inhibits cervical cancer cell through an increase of phosphatase and tensin homolog. Phytother Res. 2012 May;26(5):709-15. doi: 10.1002/ptr.3618. Epub 2011 Oct 20.
16.) Manna SK, Mukhopadhyay A, Van NT, Aggarwal BB. Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis.J Immunol. 1999 Dec 15;163(12):6800-9.
17.) Johnson VJ, He Q, Osuchowski MF, Sharma RP. Physiological responses of a natural antioxidant flavonoid mixture, silymarin, in BALB/c mice: III. Silymarin inhibits T-lymphocyte function at low doses but stimulates inflammatory processes at high doses. Planta Med. 2003 Jan;69(1):44-9.
18.) Polyak SJ, Morishima C, Shuhart MC, Wang CC, Liu Y, Lee DY. Inhibition of T-cell inflammatory cytokines, hepatocyte NF-kappaB signaling, and HCV infection by standardized Silymarin. Gastroenterology. 2007 May;132(5):1925-36. Epub 2007 Feb 21.
19.) Feher J, Lang I, Deak G, et al. Free radicals in tissue damage in liver diseases and therapeutic approach. Tokai J Exp Clin Med 1986;11:121–34.
20.) Toklu HZ, Tunali Akbay T, Velioglu-Ogunc A, Ercan F, Gedik N, Keyer-Uysal M, Sener G. Silymarin, the antioxidant component of Silybum marianum, prevents sepsis-induced acute lung and brain injury. J Surg Res. 2008 Apr;145(2):214-22. Epub 2007 Oct 22.


Green Tea - Causes Inflammation?

Green Tea (Camillia sinesis) is an antioxidant that suppresses TNF- .(44-48 )
Full references for this can be found on this page

There is one recent lab rat study which says HUGE DOSE of epigallocatechin-3-gallate, an isolate from green tea, promotes inflammation.  This dose was 1% of total food intake. A person would have to be eating GRAMS of pure epigallocatechin-3-gallate per day to achieve this dose. Maxi Flavone contains 180 milligrams of a 50% catechin mix. This is miniscule compared to doses used in this rodent study.

In the same study, as in numerous other studies, smaller doses were anti-inflammatory. (1)

Contrast this to NUMEROUS studies which show that green tea is anti-inflammatory. (2-14)

Bottom line: HUGE doses of isolated epigallocatechin-3-gallate from green tea may be inflammatory, at least in one lab-rat study.

Smaller doses are well-proven to be anti-inflammatory in numerous studies including human studies.

Dr. Myatt's Additional Note: People have died from drinking too much water (electrolyte disturbance). Does this "prove" that water-drinking is dangerous? Hardly. All substances and their effects are dose-related.  "The dose makes the poison." --- Paracelsus

References
1.) Pae M, Ren Z, Meydani M, Shang F, Smith D, Meydani SN, Wu D. Dietary supplementation with high dose of epigallocatechin-3-gallate  promotes inflammatory response in mice. J Nutr Biochem. 2012 Jun;23(6):526-31. Epub 2011 Jun 17.
2.) Akhtar N, Haqqi TM. Epigallocatechin-3-gallate suppresses the global interleukin-1beta-induced inflammatory response in human chondrocytes.Arthritis Res Ther. 2011 Jun 17;13(3):R93.
3.) Babu PV, Si H, Liu D.Epigallocatechin gallate reduces vascular inflammation in db/db mice possibly through an NF-?B-mediated mechanism.Mol Nutr Food Res. 2012 Sep;56(9):1424-32. doi: 10.1002/mnfr.201200040. Epub 2012 Jul 2.
4.) Bogdanski P, Suliburska J, Szulinska M, Stepien M, Pupek-Musialik D, Jablecka A.Green tea extract reduces blood pressure, inflammatory biomarkers, and oxidative stress and improves parameters associated with insulin resistance in obese, hypertensive patients. Nutr Res. 2012 Jun;32(6):421-7. Epub 2012 Jun 20.
5.) Bornhoeft J, Castaneda D, Nemoseck T, Wang P, Henning SM, Hong MY.
The protective effects of green tea polyphenols: lipid profile, inflammation, and antioxidant capacity in rats fed an atherogenic diet and dextran sodium sulfate.J Med Food. 2012 Aug;15(8):726-32. Epub 2012 Jun 25.
6.) Cavet ME, Harrington KL, Vollmer TR, Ward KW, Zhang JZ. Anti-inflammatory and anti-oxidative effects of the green tea polyphenol epigallocatechin gallate in human corneal epithelial cells. Mol Vis. 2011 Feb 18;17:533-42.
7.) Chatterjee A, Saluja M, Agarwal G, Alam M. Green tea: A boon for periodontal and general health. J Indian Soc Periodontol. 2012 Apr;16(2):161-7. doi: 10.4103/0972-124X.99256.
8.) Chen J, Qin S, Xiao J, Tanigawa S, Uto T, Hashimoto F, Fujii M, Hou DX.
A genome-wide microarray highlights the antiinflammatory genes targeted by oolong tea theasinensin A in macrophages. Nutr Cancer. 2011;63(7):1064-73. Epub 2011 Aug 24.
9.) El-Mowafy AM, Al-Gayyar MM, Salem HA, El-Mesery ME, Darweish MM. Novel chemotherapeutic and renal protective effects for the green tea (EGCG): role of oxidative stress and inflammatory-cytokine signaling. Phytomedicine. 2010 Dec 1;17(14):1067-75. Epub 2010 Sep 18.
10.) Li J, Ye L, Wang X, Liu J, Wang Y, Zhou Y, Ho W. Epigallocatechin gallate inhibits endotoxin-induced expression of inflammatory cytokines in human cerebral microvascular endothelial cells. J Neuroinflammation. 2012 Jul 6;9:161.
11.) Lee YJ, Choi DY, Yun YP, Han SB, Oh KW, Hong JT. Epigallocatechin-3-gallate prevents systemic inflammation-induced memory deficiency and amyloidogenesis via its anti-neuroinflammatory properties. J Nutr Biochem. 2012 Sep 5. [Epub ahead of print]
12.) Park HJ, Lee JY, Chung MY, Park YK, Bower AM, Koo SI, Giardina C, Bruno RS. Green tea extract suppresses NF?B activation and inflammatory responses in diet-induced obese rats with nonalcoholic steatohepatitis. J Nutr. 2012 Jan;142(1):57-63. Epub 2011 Dec 7.
13.) Ramesh E, Geraldine P, Thomas PA.Regulatory effect of epigallocatechin gallate on the expression of C-reactive protein and other inflammatory markers in an experimental model of atherosclerosis. Chem Biol Interact. 2010 Jan 5;183(1):125-32.
14.) Syed DN, Afaq F, Kweon MH, Hadi N, Bhatia N, Spiegelman VS, Mukhtar H.
Green tea polyphenol EGCG suppresses cigarette smoke condensate-induced NF-kappaB activation in normal human bronchial epithelial cells. Oncogene. 2007 Feb 1;26(5):673-82. Epub 2006 Jul 24.


Myo-inositol in the Treatment of PCOS and Non-PCOS Infertility

Inositol is part of the vitamin B complex. It occurs as 9 different isomers, but only two of these are of interest in fertility: myo-inositol (MYO) and d-chiro-inositol (DCI)

Both MYO and DCI have been studied and found useful in the treatment of PCOS (PolyCystic Ovary Syndrome). (1-14)

However, only MI has been show to be present in follicular fluid and only MI was able to improve oocyte and embryo quality(1,2,9,12,15), ovulation induction (6-8,10-11) and hormone balance. (3-5,13)

DCI does not have even remotely as much research behind it as MYO. (16)

Therefor, for fertility issues with or without PCOS, I recommend the myo-inositol form.

Please note that some of these studies used melatonin in combination with myo-inositol (2,11-12). Melatonin alone has also been studied and found useful for improving egg quality. (17-18)

Myo-inositol may also improve other associated risks of PCOS (such as high triglycerides and blood sugars) with or without an effect on egg quality. (3,5,7)

Most forms of inositol available in health food stores are probably the myo-inositol form. However, many products do not specify this on the label. I would always want to verify the actual form with the manufacturer before using.

A product called "Pregnitude" is available, containing myo-inositol plus folic acid. Several studies used myo-inositol with folic acid and found improved egg quality in PCOS. (9,11)  All pre-pregnant women should already be getting folic acid from their multiple because of it's importance in preventing spina bifida. This makes the "magic" in Pregnitude the myo-inositol. Pregnitude is individually packaged by 2 gram serving, which is convenient, but the price is double what what most myo-inositol powders are.

Daily dose of myo-inositol for improving egg quality is 2-4 grams per day. This can be taken as 2 grams, once or twice daily.

Myo-inositol product has a mild sweet taste and can be taken in water, smoothie, Super Shake --- whatever makes it easiest.

Egg Quality Protocol, Especially for PCOS Patients (Dr. Myatt's recommendation based on the studies)

  1. myo-inositol: 2-4 grams per day
  2. melatonin: 3mg per day (take this at bedtime)
  3. folic acid: 400mcg (this amount or more should already be in a good multi-vitamin)

 [Nurse Mark comment: Any woman seeking to improve or enhance fertility should be using a good quality Optimal Dose multivitamin - we recommend Maxi Multi of course - but for those who want to shop around for something else, please use the ingredient list on the Maxi Multi page as a reference for what an Optimal Dose multivitamin should contain.]

References
1.) Ciotta L, Stracquadanio M, Pagano I, Carbonaro A, Palumbo M, Gulino F. Effects of myo-inositol supplementation on oocyte's quality in PCOS patients: a double blind trial. Eur Rev Med Pharmacol Sci. 2011 May;15(5):509-14. [##myo for PCOS##]
2.) Carlomagno G, Nordio M, Chiu TT, Unfer V. Eur J Obstet Gynecol Reprod Biol. 2011 Dec;159(2):267-72. Epub 2011 Aug 10.
Contribution of myo-inositol and melatonin to human reproduction. http://www.ncbi.nlm.nih.gov/pubmed/21835536 [###myo and melatonin; egg quality##]
3.) Costantino D, Minozzi G, Minozzi E, Guaraldi C. Metabolic and hormonal effects of myo-inositol in women with polycystic ovary syndrome: a double-blind trial. Eur Rev Med Pharmacol Sci. 2009 Mar-Apr;13(2):105-10.  {## myo for PCOS; hormones and metabolic factors##]
4.) Donà G, Sabbadin C, Fiore C, Bragadin M, Giorgino FL, Ragazzi E, Clari G, Bordin L, Armanini D. Inositol administration reduces oxidative stress in erythrocytes of patients with polycystic ovary syndrome.Eur J Endocrinol. 2012 Apr;166(4):703-10. Epub 2012 Jan 5. [##MYO improves oxidative stress (decreases oxidative species), improves hormones in PCOS##]
5.) Genazzani AD, Lanzoni C, Ricchieri F, Jasonni VM. Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome.Gynecol Endocrinol. 2008 Mar;24(3):139-44.[##MYO; menstrual cycle improvements; better non-fertility numbers; 2 grams per day##]
6.) Gerli S, Mignosa M, Di Renzo GC. Effects of inositol on ovarian function and metabolic factors in women with PCOS: a randomized double blind placebo-controlled trial. Eur Rev Med Pharmacol Sci. 2003 Nov-Dec;7(6):151-9. [##myo, PCOS, ovulation induction##]
7.) Gerli S, Papaleo E, Ferrari A, Di Renzo GC. Randomized, double blind placebo-controlled trial: effects of myo-inositol on ovarian function and metabolic factors in women with PCOS. Eur Rev Med Pharmacol Sci. 2007 Sep-Oct;11(5):347-54. [## MYO, PCOS, improved ovulation, improved non-fertility peramiters (including weight loss)}
8.) Morgante G, Orvieto R, Di Sabatino A, Musacchio MC, De Leo V. The role of inositol supplementation in patients with polycystic ovary syndrome, with insulin resistance, undergoing the low-dose gonadotropin ovulation induction regimen.Fertil Steril. 2011 Jun 30;95(8):2642-4. Epub 2011 Feb 5. [myo, PCOS, ovulation induction##]
9.) Papaleo E, Unfer V, Baillargeon JP, Fusi F, Occhi F, De Santis L. Fertil Steril. 2009 May;91(5):1750-4. Epub 2008 May 7. Myo-inositol may improve oocyte quality in intracytoplasmic sperm injection cycles. A prospective, controlled, randomized trial. [##myo+ folic acid for egg quality in PCOS##]
10.) Papaleo E, Unfer V, Baillargeon JP, De Santis L, Fusi F, Brigante C, Marelli G, Cino I, Redaelli A, Ferrari A. Myo-inositol in patients with polycystic ovary syndrome: a novel method for ovulation induction.Gynecol Endocrinol. 2007 Dec;23(12):700-3. Epub 2007 Oct 10. [##myo for ovulation in PCOS##]
11.) Rizzo P, Raffone E, Benedetto V. Effect of the treatment with myo-inositol plus folic acid plus melatonin in comparison with a treatment with myo-inositol plus folic acid on oocyte quality and pregnancy outcome in IVF cycles. A prospective, clinical trial. Eur Rev Med Pharmacol Sci. 2010 Jun;14(6):555-61. [##myo+folic acid+melatonin##]
12.) Unfer V, Raffone E, Rizzo P, Buffo S. Gynecol Endocrinol. 2011 Nov;27(11):857-61. Epub 2011 Apr 5. Effect of a supplementation with myo-inositol plus melatonin on oocyte quality in women who failed to conceive in previous in vitro fertilization cycles for poor oocyte quality: a prospective, longitudinal, cohort study. http://www.ncbi.nlm.nih.gov/pubmed/21463230  [##myo and melatonin##]
13.) Unfer V, Carlomagno G, Dante G, Facchinetti F. Effects of myo-inositol in women with PCOS: a systematic review of randomized controlled trials. Gynecol Endocrinol. 2012 Jul;28(7):509-15. doi: 10.3109/09513590.2011.650660. Epub 2012 Feb 1. {##myo and improved ovarian function##]
14.) Nestler JE, Jakubowicz DJ, Reamer P, Gunn RD, Allan G. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. N Engl J Med. 1999 Apr 29;340(17):1314-20.[##DCI for PCO##]
15.) Galletta M, Grasso S, Vaiarelli A, Roseff SJ. Bye-bye chiro-inositol - myo-inositol: true progress in the treatment of polycystic ovary syndrome and ovulation induction. Eur Rev Med Pharmacol Sci. 2011 Oct;15(10):1212-4. {####myo for egg quality, not dci)
16.) Galazis N, Galazi M, Atiomo W. D-Chiro-inositol and its significance in polycystic ovary syndrome: a systematic review.Gynecol Endocrinol. 2011 Apr;27(4):256-62. Epub 2010 Dec 10.[##DCI not much research##]
17.) Batioglu AS, Sahin U, Gürlek B, Oztürk N, Unsal E. The efficacy of melatonin administration on oocyte quality. Gynecol Endocrinol. 2012 Feb;28(2):91-3. Epub 2011 Jul 20. [##melatonin##]
18.) Tamura H, Takasaki A, Miwa I, Taniguchi K, Maekawa R, Asada H, Taketani T, Matsuoka A, Yamagata Y, Shimamura K, Morioka H, Ishikawa H, Reiter RJ, Sugino N. Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. J Pineal Res. 2008 Apr;44(3):280-7.
[##melatonin##]


What's So Special About Maxi Greens?

As with Maxi Flavone, Maxi Greens is designed to be a broad-spectrum anti-inflammatory and nutritional herbal formula. Maxi Greens contains:

1.) Anti-inflammatory herbs (the same ones as in Maxi Flavone): ginkgo biloba, bilberry,green tea, milk thistle, grape seed and pine bark (pycnogenols). See the full references for these herbs in the Maxi Flavone article.

2.) Nutrient-dense "super green foods."

Maxi Greens includes wheat grass and several additional "green super foods" including: alfalfa, wheat grass, barley grass and wheat sprouts. Here is what the scientific literature says about these green food herbs.

I.) Alfalfa: a nutrient-rich herb high in chlorophyll, vitamins and micronutrients. Alfalfa is rich in vitamins A, B1, B6, C, E and K as well as calcium, potassium, iron and zinc.
Alfalfa has anti-inflammatory (1) and antioxidant properties.(2) Alfalfa reduced cytokine levels and ameliorated severity of auto-immune disease in animal models.(3,4)

II.) Wheat grass: contains vitamins A, B12, C and E, as well as amino acids lysine, tryptophan and phenylalanine. Wheat grass is 70% chlorophyll. Because of its high A,C, and E content, wheat grass is considered anti-inflammatory.(5)

III.) Barley grass: Has a high antioxidant activity. (6,7)

IV.) Wheat sprouts: contain meaningful amounts of A, B1, B2, B3, B5, B6, B12, B17, C, D, E, F, H, K, P, choline, folic acid, inositol, PABA, boron, calcium, chlorine, chromium, cobalt, copper, iodine, iron, magnesium, manganese, molybdenum, nickel, phosphorus, potassium, selenium, silicon, sodium, sulphur, zinc.(8) Wheat sprouts were shown to have antioxidant activity in bisphenol-induced ROS in young women.(9)

V.) Blue Green Algae contains dietary fiber, fatty acids, essential amino acids, and vitamins A, B, C, and E. (10) Blue green algae and other algal species exhibit immunomodulatory, antitumor, antithrombotic, anticoagulant, anti-mutagenic, anti-inflammatory, antimicrobial, and antiviral activities including anti-HIV infection, herpes, and hepatitis viruses. (11-13)
It is likely because of its immunomodulatory and antioxidant properties that algal species are anti-allergenic.(14)

VI.) Spirulina is high in proteins, acid, vitamins and minerals. It is anti-inflammatory.(15)

VII.) Chlorella contains 60 percent protein by weight. It is high in chlorophyll, vitamins, minerals and phytonutrients. It is rich in polysaccharides, nucleic acids, peptides, essential fatty acids and B vitamins. Chlorella is rich in vitamins A, C, E, niacin and folate. Chlorella has the complete vitamin B-complex with more B-12 than beef liver by weight. Chlorella contains more beta carotene than carrots and other green leafy green vegetables. Additional nutritional content of chlorella includes zinc, iron, calcium, magnesium, potassium, trace minerals and polysaccharides. (16)

Chlorella has anti-inflammatory properties. (17) It is also a biological response modifier. (18)

Because of its unique ability to bind with mercury, lead, and cadmium, chlorella can be used as a heavy metal chelator. Studies have shown that it has a superior ability to safely draw toxic metals that accumulate in the gut and intestinal tract. (19-22)

One study suggests that chlorella can stimulate cytokine production in human peripheral blood mononuclear cells. However, this study was performed ex vivo and at blood levels significantly higher (10 to 100mcg/ml) than would be expected from the dose contained in Maxi Greens. (23)

In addition to the "green" super-foods, we included flavonoid-rich super foods as well. Flavonoids, as a class of antioxidants, are anti-inflammatory.

Acerola Juice Powder
Acerola is high in vitaminc C, A, B1, B2 and B3, calcium, iron, carotenoids and bioflavonoids. (24)
Aceroal exerts potent antioxidant and anti-inflammatory properties. (24-27)

Beet Juice Powder:
Beet juice (also known as beetroot juice) is one of the richest sources of dietary antioxidants, with high total antioxidant capacity (TAC) and total polyphenol (TP) content. (28)

Beet root juice has been shown to protect against xenobiotic-induced oxidative stress in animal studies. (29,30)

Spinach Powder:
Spinach contains significant amounts if vitamin A, E, K, B2, B3, B6, folate and minerals calcium, magesiun, phosphorus, potassium, selenium, manganese and zinc. Spinach also has significant omega-3 fatty acids as linolenic acid. (24)

Because of its high polyphenol, flavonoid and carotene content, spinach has potent anti-inflammatory and antioxidant properties. (31-34)

Papaya (leaf) Papaya contains significant amounts of vitamins A, C, E, K and folate and minerals calcium, magnesium and potassium. (24) Papaya leaf suppresses inflammatory cytokines and exerts anti-inflammatory responses in both human and animal models. (35-37)

Dunaliella salina algae is a green algae that is a rich source of beta carotenoids including lycopene and zeaxanthin. (38-41) In studies, the synthetic beta carotene has had adverse effects in smokers while the natural form of beta carotene, as found in Dunaliella salina, has protective effects.(42,43)

Preliminary evidence suggests that natural beta-carotene supplementation results in better antioxidant activity and anticancer activity in humans than does supplementation with synthetic beta-carotene. (44,45)

Broccoli and Cauliflower are vegetables in the "Cruciferous" family. They are high in diindolylmethane (DIM), a metabolite of Indole-3-carbinol (I3C), a compound found in cruciferous vegetables including broccoli, cabbage, kale, bruseel sprouts and cauliflower. Diindolemethanes (DIM) is one of the major anticancer substances in the class of sulfur-containing chemicals called glucosinolates.(46)

DIMs help decrease estrogen metabolism by upregulating the P450 enzyme system. The net result of this effect is to decrease circulating estrogen levels and correct estrogen dominance. Because many causes of infertility including endometriosis, PCOS, ovarian cysts, and anovulation are all characterized by estrogen dominance, the addition of DIM by way of cruciferous vegetables can help balance hormones in favor of fertility.(47-49)

DIM inhibits the inflammatory response.(50-54) and possess antioxidant activity and decrease radical oxygen species (ROS) by acting as an ROS scavenger. (55-59)

Probiotic Cultures (dairy-free) Probiotics exert anti-inflammatory effects (60-61) and down-regulate inflammatory cytokines (62-63) including NF-êB, TNF-á, IL-6, and p-Akt (64-66)

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4.) Apelgren LD, Bailey DL, Fouts RL, Short L, Bryan N, Evans GF, Sandusky GE, Zuckerman SH, Glasebrook A, Bumol TF. The effect of a selective estrogen receptor modulator on the progression of spontaneous autoimmune disease in MRL lpr/lpr mice. Cell Immunol. 1996 Oct 10;173(1):55-63.
5.) Seymour K. Wheat Grass. Illinois State University. http://horticulturecenter.illinoisstate.edu/gardens/documents/grain.pdf
6.) Kamiyama M, Shibamoto T. Flavonoids with potent antioxidant activity found in young green barley leaves. J Agric Food Chem. 2012 Jun 27;60(25):6260-7. doi: 10.1021/jf301700j. Epub 2012 Jun 18.
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