Questions about supplements


3 Posts
Reply RE: Questions about supplements Posted on: Feb 19, 2012 at 8:00am
I am considering taking a highly-recommended supplement that, in part, contains milk thistle, resveratrol, pycnogenol, and gingko. However, I have read that the MT and resveratrol have estrogenic effects, and this might cause issues with premature luteinization. I've also read that gingko may cause problems with implantation. Also the pycnogenol is an aromatase inhibitor so it will stop testosterone being converted to estrogen in fat tissue. So it increases testosterone levels. I have no idea how potent aromatase inhibitor it is though. Can you comment please? Thank you!

Dr. Braverman

2016 Posts
RE: Questions about supplements Posted on: Feb 20, 2012 at 2:56pm
Please forward me the references that discuss these supplements. I will review them and get back to you. Thank you
Dr. Jeffrey Braverman MD FACOG
Medical Director
Braverman Reproductive Immunology P.C.

Dr. Braverman

2016 Posts
RE: Questions about supplements Posted on: Feb 27, 2012 at 11:06am
1.) Is Maxi Flavone appropriate treatment for endometriosis?
Answer: "definitely yes"! (see comments below)

2.) Is Maxi Flavone appropriate during pregnancy?
Answer: that depends on the individual circumstance and if the cause of the original infertility was related to high inflammatory cytokines, and if those same inflammatory substances could endanger the pregnancy, then Maxi Flavone and Omega-3 fatty acids are appropriate. If the original infertility was unrelated to inflammation, then Maxi Flavone is perhaps unnecessary during pregnancy. It will be different for each individual and I encourage consulting your infertility specialist about which nutritional formulas to continue during pregnancy.

Now on to individual comments about the list of references.

For an extensive list of references related to each of the herbs in question, please see this page:


Milk thistle:

"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. "

The above quote was taken from a Mayo clinic article.

The preponderance of research concerning silymarin (milk thistle) shows that it has
profound, positive effects on liver function. Because the liver is responsible for conjugating
estrogen (making it water soluble so it can be excreted by the kidneys), SIL has effects
on estrogen-modulating effects. Specifically, it tends to lower excess estrogen levels.

Further, recent research in people, not rats, shows that SIL is highly useful in hormone-related
cancers as well as endometriosis since both conditions are charceterized by estrogen dominance.

Endometriosis and many cases of infertility are related to increased inflammatory cytokines.
Milk thistle is well-proven to have positive effects on both estrogen balance AND inflammation.

There is also a significant body of evidence showing its safety during pregnancy.


1.) 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.
2.) Deep G, Singh RP, Agarwal C, Kroll DJ, Agarwal R. Silymarin and silibinin cause G1 and G2-M
cell cycle arrest via distinct circuitries in human prostate cancer PC3 cells: a comparison of
flavanone silibinin with flavanolignan mixture silymarin. Oncogene. 2006 Feb 16;25(7):1053-69.
3.) Greenlee H, Atkinson C, Stanczyk FZ, Lampe JW. A pilot and feasibility study on the effects of
naturopathic botanical and dietary interventions on sex steroid hormone metabolism in
premenopausal women. Cancer Epidemiol Biomarkers Prev. 2007 Aug;16(8):1601-9.
4.) Kren V, Walterová D. Silybin and silymarin--new effects and applications.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2005 Jun;149(1):29-41.
[Moon YJ, Wang X, Morris ME. Dietary flavonoids: effects on xenobiotic and carcinogen
metabolism. Toxicol In Vitro. 2006 Mar;20(2):187-210. Epub 2005 Nov 11.
[## Flavones (chrysin, baicalein, and galangin), flavanones (naringenin) and isoflavones
(genistein, biochanin A) inhibit the activity of aromatase (CYP19), thus decreasing estrogen
biosynthesis and producing antiestrogenic effects, important in breast and prostate cancers.
Activation of phase II detoxifying enzymes, such as UDP-glucuronyl transferase, glutathione
S-transferase, and quinone reductase by flavonoids results in the detoxification of carcinogens
and represents one mechanism of their anticarcinogenic effects##]
5.) Reyes H. The spectrum of liver and gastrointestinal disease seen in cholestasis of pregnancy.
Gastroert Clin N Am 1992;21:905–21.[## Milk thistle extract is virtually devoid of any side
effects and may be used by most people, including pregnant and breast-feeding women. In fact,
it has been recommended as a treatment for itching due to poor gallbladder function during
6.) Wayne SJ, Neuhouser ML, Koprowski C, Ulrich CM, Wiggins C, Gilliland F, Baumgartner KB,
Baumgartner RN, McTiernan A, Bernstein L, Ballard-Barbash R. Breast cancer survivors who
use estrogenic botanical supplements have lower serum estrogen levels than non users. Breast
Cancer Res Treat. 2009 Sep;117(1):111-9. Epub 2008 Oct 18.


Yaghmaei P, Parivar K, Masoudi A, Darab M, Amini E. The effect of silybin on passive
avoidance learning and pathological changes in hippocampal CA1 and DG regions in male Wistar
rats offspring. J Asian Nat Prod Res. 2009 Jun;11(6):514-22.

Here's the statement quoted: "Silybin, an extract from seeds of milk thistle (Silybum marianum),
is known to have hepato-protective, anticarcinogenic, and estrogenic effects."

Another rat study. However, there is nothing in the study itself, nor in the articles referenced in
the study, that support the claim of estrogenic effects. The study also notes that, "Silybin
administration during pregnancy resulted in histological changes in hippocampus and better
memory function." In other words, silymarin was safe during pregnancy (in rats) and resulted in
memory improvement. The study had nothing to do with testing estrogen effects of milk thistle.


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.

Here's what the study showed (in rats): that silymarin (SIL) compared to ethinylestradiol (EE)
did NOT cause the changes in hormone levels that EE caused.To quote the study, "EE not SIL
decreased serum cholesterol, total lipids, LH and FSH and increased serum E2."

Bottom line: this study does not support the conclusion that silymarin (milk thistle) has any significant
estrogenic effect. Further, in many of the human and more recent studies cited above, milk thistle has
an estrogen-modulating effect. If estrogen is high, milk thistle helps bring it down because of it's stimulation
of liver conjugation.

Grape seed extract

Grape Seed Extract Is an Aromatase Inhibitor and a Suppressor of Aromatase Expression

Grape seed extract (GSE) contains high levels of procyanidin dimers that have been shown in
our laboratory to be potent inhibitors of aromatase. ttp://

There is evidence that grape seed extract may have aromatase inhibiting properties.

Aromatase inhibitors are accepted medical treatment for ovulation induction and for treatment of
gynecological conditions which can impair fertility, including polycystic ovary syndrome (PCOS)
and endometriosis. Aromatase inhibitors are also used to treat male infertility.


1.) Abushahin F, Goldman KN, Barbieri E, Milad M, Rademaker A, Bulun SE.
Aromatase inhibition for refractory endometriosis-related chronic pelvic pain.
Fertil Steril. 2011 Oct;96(4):939-42. Epub 2011 Aug 24.
2.) Attar E, Bulun SE. Aromatase inhibitors: the next generation of therapeutics for endometriosis?
Fertil Steril. 2006 May;85(5):1307-18.
3.) Begum MR, Ferdous J, Begum A, Quadir E. Comparison of efficacy of aromatase inhibitor and
clomiphene citrate in induction of ovulation in polycystic ovarian syndrome. Fertil Steril. 2009
Sep;92(3):853-7. Epub 2008 Jan 4.
4.) Casper RF. Aromatase inhibitors in ovarian stimulation. J Steroid Biochem Mol Biol. 2007
Aug-Sep;106(1-5):71-5. Epub 2007 May 24.
5.) Casper RF, Mitwally MF. Use of the aromatase inhibitor letrozole for ovulation induction in
women with polycystic ovarian syndrome. Clin Obstet Gynecol. 2011 Dec;54(4):685-95.
6.) de Ziegler D, Mattenberger C, Luyet C, Romoscanu I, Irion NF, Bianchi-Demicheli F.
Clinical use of aromatase inhibitors (AI) in premenopausal women. J Steroid Biochem Mol Biol.
2005 May;95(1-5):121-7.
7.) Heidari Z, Hosseinpanah F, Shirazian N. Achievement of fertility in an infertile man with
resistant macroprolactinoma using high-dose bromocriptine and a combination of human
chorionic gonadotropin and an aromatase inhibitor. Endocr Pract. 2010 Jul-Aug;16(4):669-72.
8.) Lee VC, Ledger W. Aromatase inhibitors for ovulation induction and ovarian stimulation.
Clin Endocrinol (Oxf). 2011 May;74(5):537-46. doi: 10.1111/j.1365-2265.2011.04006.x.
9.) Mitwally MF, Casper RF. Aromatase inhibition reduces gonadotrophin dose required for
controlled ovarian stimulation in women with unexplained infertility. Hum Reprod. 2003
10.) Mitwally MF, Casper RF. Aromatase inhibition reduces the dose of gonadotropin required for
controlled ovarian hyperstimulation. J Soc Gynecol Investig. 2004 Sep;11(6):406-15.
11.) Patry G, Jarvi K, Grober ED, Lo KC. Use of the aromatase inhibitor letrozole to treat male
infertility. Fertil Steril. 2009 Aug;92(2):829.e1-2. Epub 2009 Jun 12.
12.) Pollacco J, Sacco K, Portelli M, Schembri-Wismayer P, Calleja-Agius J. Molecular links
between endometriosis and cancer. Gynecol Endocrinol. 2012 Feb 6. [Epub ahead of print]
13.) Polyzos NP, Tzioras S, Badawy AM, Valachis A, Dritsas C, Mauri D.
Aromatase inhibitors for female infertility: a systematic review of the literature. Reprod Biomed
Online. 2009 Oct;19(4):456-71.
14.) Saylam B, Efesoy O, Cayan S. The effect of aromatase inhibitor letrozole on body mass index,
serum hormones, and sperm parameters in infertile men. Fertil Steril. 2011 Feb;95(2):809-11.
Epub 2010 Oct 8.
15.) Stahl PJ, Stember DS, Goldstein M. Contemporary management of male infertility.
Annu Rev Med. 2012 Feb 18;63:525-40. Epub 2011 Oct 24.
16.) Stauffer F, Furet P, Floersheimer A, Lang M.New aromatase inhibitors from the 3-pyridyl
arylether and 1-aryl pyrrolo[2,3-c]pyridine series. Bioorg Med Chem Lett. 2012 Mar
1;22(5):1860-3. Epub 2012 Jan 28.
17.) Vassiliadis S, Athanassakis I. Recent knowledge and new pharmaceutical products in potential
alleviation of endometriosis. Recent Pat Inflamm Allergy Drug Discov. 2008 Jun;2(2):128-38.



"Endogenous estrogens are steroid hormones synthesized by humans and other mammals; these
hormones bind to estrogen receptors within cells. The estrogen-receptor complex interacts with
unique sequences in DNA (estrogen response elements; EREs) to modulate the expression of
estrogen-responsive genes (17). A compound that binds to estrogen receptors and elicits similar
responses to endogenous estrogens is considered an estrogen agonist, while a compound that
binds estrogen receptors but prevents or inhibits the response elicited by endogenous estrogens is
considered an estrogen antagonist. The chemical structure of resveratrol is very similar to that of
the synthetic estrogen agonist, diethylstilbestrol (see figure 2), suggesting that resveratrol might
also function as an estrogen agonist. However, in cell culture experiments resveratrol acts as an
estrogen agonist under some conditions and an estrogen antagonist under other conditions (18,
19). In estrogen receptor-positive breast cancer cells, resveratrol acted as an estrogen agonist in
the absence of the endogenous estrogen, 17beta-estradiol, but acted as an estrogen antagonist in
the presence of 17beta-estradiol (20, 21). At present, it appears that resveratrol has the potential
to act as an estrogen agonist or antagonist depending on such factors as cell type, estrogen
receptor isoform (ER alpha or ER beta), and the presence of endogenous estrogens (17).

Resveratrol, trans-3,5,4'-trihydroxystilbene, is a phytoestrogen in grapes that is present in red

However, resveretrol suppresses TNF-a, an inflammatory factor related to many cases of infertility.
It is also a potent anti-inflammatory agent and antioxidant.


Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol. 2000 Jun 15;164(12):6509-19.73.)

For a full list of references relating to resveretrol and grape seed, go here:

"For fertility, there is not much evidence to support the use of gingko. It actually may, because of
its anticoagulant properties, prevent embryo implantation in the uterus. While it may be true that
it increases blood flow to reproductive organs, the possibility that it would impair implantation
makes it questionable to use when trying to conceive."

The above statement is an opinion piece, not a quote from any medical research.
I cannot find a single reference in the medical literature which supports the belief that
ginkgo impairs implantation.

Ginkgo has potent anti-inflammatory and antioxidant effects in addition to reducing platelet aggregation.
When inflammatory mechanisms are part of the infertility picture, ginkgo has a wide variety of mechanisms by which it acts.
(see this page for an extensive list of ginkgo references:

The author of the above-quoted opinion suggests that pelvic circulation can be increased by
massage. This misses the point that ginkgo's activity on circulation is by decreased platelet aggregation,
a factor of blood flow effected by high inflammatory cytokines and not known to be improved by mechanically
increasing circulation via massage.

Lastly, I was told that "Also the pycnogenol is an aromatase inhibitor so it will stop testosterone
being converted to estrogen in fat tissue. So it increases testosterone levels. I have no idea how
potent aromatase inhibitor it is though." but I haven't found a source for this yet-- sorry, I'm at
work and "cheating" to be here for a moment.

Please see all of the comments and references for aromatase inhibitors listed above.
"You say 'aromatase inhibitor' like it's a bad thing"!


Some additional thoughts about trying to interpret medical literature
First, reading only the title of a journal article, or taking a single sentence out of context, can be extremely misleading.
Sometimes, the title says "Negative effects of substance X" and the actual article concludes "There were no negative effects
from substance X." Read the entire abstract, at least, when doing research.

Second, an "in vivo" (real people) studies trump test-tube or lab rat studies. You can use the
"Advanced" feature in PubMed to narrow focus on human studies.

Finally, remember that for any topic, you will probably find articles and scientific references on both sides of the question.
THEN the consideration becomes "preponderance of evidence." For human studies saying one thing versus one lab rat study
showing the opposite? I'd go with the four human studies. There is rarely, if ever, a "black and white" in medicine.
Dr. Jeffrey Braverman MD FACOG
Medical Director
Braverman Reproductive Immunology P.C.

Dr. Braverman

2016 Posts
RE: Questions about supplements Posted on: Feb 27, 2012 at 11:23am
also be aware that there are new studies that have shown the aromatase activity of resveratrol has actually been shown to increase successful implantation in patients with endometriois confirming another study that showed letrazole's similar activity also improved implantation.
Dr. Jeffrey Braverman MD FACOG
Medical Director
Braverman Reproductive Immunology P.C.


2 Posts
RE: Questions about supplements Posted on: Jun 22, 2015 at 4:01pm
Is it safe to take pycnogenol and resveratrol during pregnancy?
Vivian zou

Dr. Braverman

2016 Posts
RE: Questions about supplements Posted on: Jun 22, 2015 at 4:42pm
no evidence showing any harm, but I usually have my patients stop once they are pregnant.
Dr. Jeffrey Braverman MD FACOG
Medical Director
Braverman Reproductive Immunology P.C.