Hi nanna1,
I want to chime in on this discussion on the relation among quercetin, curcumin, mast cell activation, progesterone and estrogen, because I personally take quercetin and curcumin often, and I invest a lot of time to minimize drug/supplement interaction.
You raised several interesting points and I enjoyed reading your references.
My main points are
1. The biggest reason to use Quercetin and Curcumin is their TDO/IDO inhibitor properties. Mast cell stabilizer is a nice BUT secondary effect.
2. Dietary supplement of Quercetin are associated with serum level far below the concentration needed to be highly estrogenic.
3. The main factors in fertility are sperm count and sperm motility. I have yet to see research papers that show significant effects from quercetin or curcumin at concentrations similar to dietary supplement levels.
Flavonoids (i.e. curcumin, luteolin, quercetin, etc?) bind to and act on the estrogen (ER) and progesterone receptors (PR) [1, 2].
I am not sure about how strong an estrogenic effect curcumin and quercetin actually have. In Fig.3 of Ref.1, you can see that estrogen induction effects becomes significant only when quercetin concentration exceeds 4uM. If you use Quantum's dosage (500mg), the peak serum concentration is only about 1uM (interpolating from the data found
here). Also considering the half-life of quercetin is
11hrs, the active concentration is even smaller than 1uM, since the paper measured the effect by incubating the cell line in a constant-concentration quercetin solution for 20hrs. Eyeballing Fig.3, you can roughly estimate the effect is less than 2% of 1nM of estradiol for 20hrs. Assuming the effect of estradiol scales linearly with its concentration, quercetin will induce an effect less than 20pM of estradiol, in comparison to the reference range for average male adult (
50-200pM).
To set the right context, skin contact with thermal paper (receipts etc) for 4mins gives you a
dose of BPA (via skin absoprtion) approximately 2x more potent than a 500mg quercetin dose.
I will be interested in reading other paper you may have on curcumin.
The positive effects of these flavonoids on the brain are due mostly to their estrogenic [1] and progestogenic signaling [3, 4].
No, the main effects of quercetin and curcumin for POIS treatment is their TDO/IDO inhibition. please see quantum's original post on his prepack for details.
Progesterone stabilizes mast cells, while estrogen causes mast cell activation [5, 6]. Flavonoids stabilize mast cells by enhancing progesterone signaling (see Figure 3) [2]. Diosgenin, from Fenugreek and Wild Yam extracts, is a prodrug for progesterone [7] and Quercetin can increase the secretion of progesterone [8]. Additionally, flavonoids reduce inflammation through progesterone signaling where progesterone inactivates the Phospholipase A2 enzyme required for the arachidonic acid (AA) cascade [9, 10].
The anti-inflammatory effects of flavonoids cannot be explained by their antioxidant properties, since the universal antioxidant N-acetylcysteine does not display such anti-inflammatory effects [11]. Nonetheless, progesterone/estrogen signaling can influence the antioxidant status of the body by regulating the zinc/copper ratio [12] with estrogen favoring copper accumulation [13]. An important hormonal difference to note is that while flavonoids can stimulate the estrogen receptor directly in the absence of estrogen, flavonoids require the addition of progesterone in order to enhance PR signaling.
So flavonoid supplementation is primarily a type of hormone therapy [14]. This is why I cautioned against taking flavonoid extracts in the original post. At high concentrations, (achieved through extracts) some become estrogenic.
No. Some flavonoid, such as soy-derived isoflavonoid and Diosgenin, have strong hormonal effects. But that does not mean quercetin and curcumin are equally estrogenic.
The effect of quercetin on progesterone is controversial. There are also
papers showing quercetin inhibits progesterone production.
I suspect that the deleterious effect that curcumin has on sperm[15] at high concentrations might be attributable to its estrogen receptor binding, but as far as I know, this idea has not been explored scientifically.
The paper by Naz is not about oral intake of curcumin, but rather directly applying curcumin solution to a vagina!! The concentration he used is really high, from 31.25uM to 500uM. According to
another study, 31uM of curcumin starts to be toxic to red blood cells (forming spiky protrusions on red blood cells). One would need to worry about anemia before sperm motility! Also, there is no evidence that semen has particularly high concentration of curcumin than blood either.
If curcumin is a significant issue, Indians would have trouble producing babies, because their diets are very high in turmeric. But it looks like they will be the most populated country before 2030!
However, other flavonoids like licorice are less estrogenic and have positive effects on sperm at high (extract) concentrations[16, 17].
Flavonoid (non-competitive) binding to the progesterone receptor appears to sensitize the receptor to progesterone stimulation. From this standpoint, it would seem like one would want to take the progesterone prodrug, pregnenolone, to enhance the curcumin/quercetin/luteolin mast stabilizing, anti-inflammatory and neuroprotection effect. Both Fenugreek extract and Wild Yam extract contain some of the progesterone prodrug, diosgenin, in addition to their own set of flavonoids. I suspect that prodrugs will synergistically boost the effects of flavonoids on POIS symptoms. Also, from the list of herbs studied the 2nd reference, it appears that mistletoe and damiana had the largest progesterone/estrogen stimulation ratios (even higher than turmeric and ginger). I do make it a point to get flavonoids through foods (capers, onions, apples, spicy foods, vegetable currys).
1. Flavonoids Induce the Synthesis and Secretion of Neurotrophic Factors in Cultured Rat Astrocytes: A Signaling Response Mediated by Estrogen Receptor (2013)
It is far more tricky to supplement progesterone and pregnenolone than quercetin/curcumin. One should always get carefully tested on their hormone levels, and consult an endocrinologist. Without knowing the status of Hypothalamic?pituitary?gonadal axis and Hypothalamic?pituitary?adrenal axis, it is very hard to predict the result of supplementing progesterone, unless you know how different pathways in your body is upregulated or downregulated. I know two people from the gym who developed hypogonadism from taking progesterone, including fertility issues, enlarged breasts, etc, the very problem you want to avoid.
