Milk thistle, resveratrol, and interpreting studies…

18 10 2012

I’d emailed Dr. Braverman asking about some things I’d heard and repeated (and will be changing here on the FAQ) about milk thistle and resveratrol.  Wanted to share the response from him, and indirectly his colleague Dr. Dana Myatt.

“ok here is an educated and well articulated response from Dr. Myatt with references. I am sure this will help answer many questions.

Jeffrey Braverman MD FACOG

Medical Director
Braverman Reproductive Immunology

From: Dr. Dana Myatt []
Sent: Wednesday, October 17, 2012 4:23 PM
To: jbraverman @
Subject: Milk Thistle Reply

“An IVF Doctor Said Not to Take Milk Thistle”

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 therefore 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.” (icon_cool.gif

And 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?


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.”

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.”

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:

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.


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.



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