Natural Aromatase Inhibition

I've been after some natural solutions for lowering aromatase after some negative experiences with DIM. I know Ori Hoffmekler is all about Chrysin for this purpose. But I would love to hear other's knowledge and opinions about the matter. I find it interesting that insulin-lowering medications tend to lower aromatase...hmmm.

But here is an article, or part of an article, showing that a majority of 28 tested flavanoid compounds significantly lowered aromatase:

http://www.springerlink.com/content/080043p354p02488/

I would like to see more concrete numbers. If anybody is keen on the subject, its much appreciated.

Another study showing that chrysin was as potent of an aromatase inhibitor as aminoglutethimide, a pharma aromatase inhibitor:

http://www.sciencedirect.com/science/article/pii/096007609390228O

Chrysin might not be such a good idea, at least according to this article:
http://www.t-nation.com/free_online_article/sports_body_training_performance_bodybuilding_supplements/naturally_occurring_aromatase_inhibitors

I took at a look at the article. It didn't seem like there were too many negative sides listed in the article, but I'm not denying that there could be. There isn't enough research I suppose. From the article they said that it was able to lower aromatase while not lowering 17 B-HSD, which is good. I think the biggest negative is the lack of oral bioavailability. There are other studies showing that absorption is much higher with bioperine taken simultaneously. I wonder if we couldn't do a liposomal mix of chrysin and bioperine to help boost absorption. Thanks for that article though. Great read.

More detail on this subject is deserved, because we haven't talked about this in a few years.

http://edrv.endojournals.org/content/27/6/677.long

I will highlight the important parts.

V. Estrogens in Pilosebaceous Unit Biology

A. Estrogen synthesis and metabolism in the pilosebaceous unit
Estrogens and androgens are closely related sex steroids with interconnected metabolism. Their role in skin physiology was perceived early, whereas the finding that isolated human hair follicles have their own repertoire of sex steroid-metabolizing and synthesizing enzymes (122, 244) represents a much younger insight. For example, isolated human hair follicles harbor the enzymes 5α-reductase, aromatase, and 17β-hydroxysteroid dehydrogenase to control estrogen synthesis in the pilosebaceous unit. Aromatase converts the substrates androstenedione to estrone and testosterone to estradiol (Fig. 2⇑). Interestingly, both dermal papilla cells and outer root sheath keratinocytes reportedly synthesize cytochrome-P450-aromatase (25). Estrone can be converted back and forth to estradiol by 17β-hydroxysteroid dehydrogenase (for review, see Refs. 23 , 25 , 59 , and 245).

This has initiated a shift of paradigm—from the pilosebaceous unit as a mere target organ of steroid hormone activities to the concept that the pilosebaceous unit is an important site of steroid hormone synthesis and metabolism (5). Today, the skin is understood to have established its own para- and autocrine hormonal regulation networks, with the pilosebaceous unit located at center stage; it is now recognized to be highly sensitive to an ever-expanding list of hormonal regulators that are generated and/or metabolized within or in close vicinity to the pilosebaceous unit (8, 9, 52, 53).

B. Estrogen receptor expression in the hair follicle
Until the cloning of a novel gene coding for a second ER, named ERβ, from rat prostate (246) and, thereafter, from human tissue (247), the consensus was that only one ER existed: ERα, cloned in 1986 from MCF-7 cells (178, 248). Both receptors bind E2 with high affinity (228) and bind to classic EREs in a similar manner (249). Both receptors are detectable in the skin of humans and rodents with distinct expression patterns (14, 15, 16, 17, 18, 19, 25, 26, 28, 250, 251, 252, 253) (Table 2⇑).

Recently, Thornton et al. (20, 24) showed that, in human scalp skin, ERβ is the predominant ER. In human hair follicles dissected from male and female nonbalding scalp skin, ERβ expression was found to be localized to nuclei of outer root sheath and epithelial matrix keratinocytes as well as of dermal papilla fibroblasts. In contrast, ERα and the androgen receptor were only expressed in dermal papilla cells. Serial sections also showed strong nuclear expression of ERβ in the cells of the bulge, whereas neither ERα nor androgen receptor was detectable. In the sebaceous gland, ERβ was expressed in both basal and partially differentiated sebocytes. ERα exhibited a similar pattern of expression, whereas the androgen receptor was expressed in the basal and very early differentiated sebocytes (19, 24). In this study, there were no obvious differences in the expression of either ER in male or female skin. The same group found that in cultured human, nonbalding scalp dermal papilla cells, the two ERs exhibited different expression patterns, ERβ showing strong nuclear expression, and ERα granular cytoplasmic expres​sion(24). This different distribution may contribute to a variable E2 responsiveness (254).

The different expression patterns of ER and androgen receptor in the hair follicle and their potential biological relevance deserve special attention, because follicular dermal papilla cells are thought to be the primary target cells within the hair follicle that mediate the growth stimulating signal of androgens by releasing growth factors that act in a paracrine fashion on other cells of hair follicle (255, 256). The exact pattern of androgen receptor expression in the mesenchyme and epithelium of human hair follicle remains a matter of contention, with published results heavily influenced by the respective methodology employed. However, Thornton et al. and other authors have reported that no androgen receptor immunoreactivity is detected in the keratinocytes of the outer root sheath (including its bulge region) and of the inner root sheath, whereas the majority of dermal papilla cells express androgen receptor (257). In contrast, ERs are more widely expressed, and importantly, ERβ is strongly expressed in the bulge region of the outer root sheath. This region contains stem cells for hair follicle keratinocytes that regenerate the follicle during the anagen phase. This suggests that these epithelial stem cells are targets for estrogen action.

The wide distribution of ERβ in human pilosebaceous unit suggests that estrogens play an important role in the maintenance and the regulation of the hair follicle and provides further evidence for estrogen action in nonclassic target tissues. Recently, it was reported that in cultured dermal papilla cells from nonbalding male donors, both ERα and ERβ showed a consistently higher expression, both at the RNA and protein levels, in occiput dermal papilla cells compared with vertex dermal papilla cells (258). With respect to ERβ immunoreactivity, we found that, in anagen VI follicles microdissected from frontotemporal skin, there was a remarkable distribution difference between male and female hair follicles from frontotemporal scalp skin: ERβ immunoreactivity was found in male scalp hair follicles predominantly in the matrix keratinocytes, whereas in female hair follicles, ERβ immunoreactivity was predominantly found in the dermal papilla fibroblasts (10). These data not only highlight substantial, previously underappreciated sex-dependent differences in ERβ expression of an important peripheral E2 target organ, but also underscore the importance of investigating whether E2 effects on the human hair follicle are location-dependent, as is well-recognized for the paradoxical hair growth effects of androgens (64, 259, 260).

Conflicting data have been presented concerning ER expression patterns in murine hair follicles. It has been reported that ERα was expressed only in the dermal papilla and outer root sheath of telogen and early anagen mouse hair follicles and that ERβ was undetectable (26, 250). Recently, however, we could show that both ERα and ERβ as well as the splice variant ERβ ins are expressed throughout the entire, depilation-induced murine hair cycle at both the protein and RNA levels (28). In addition, hair follicles in late anagen (anagen VI) were highly sensitive to regulation by topically applied E2, which rapidly induced premature catagen entry. Therefore, anagen VI mouse pelage hair follicles must express fully functional ERs (28).

ERα immunoreactivity peaks in murine telogen follicles within the dermal papilla and the sebaceous gland, whereas the inner root sheath and outer root sheath show weaker immunoreactivity. In anagen VI, ERα immunoreactivity (IR) is detectable in the outer root sheath and the dermal papilla, whereas in early catagen it is restricted to the dermal papilla and the secondary hair germ. In anagen VI follicles, ERβ is weakly positive in hair matrix and outer root sheath, whereas in catagen and telogen follicles, ERβ is expressed in the dermal papilla, inner root sheath, outer root sheath, and the sebaceous gland. By RT-PCR, ERα and ERβ transcripts can be detected in telogen, anagen V and VI, and late catagen skin mRNA extracts. Investigation of ERβ knockout mice showed an accelerated catagen development along with an increase in the number of apoptotic hair follicle keratinocytes (28). Taken together, this suggests that the catagen-promoting properties of E2 in murine skin are mediated by ERα and that ERβ mainly functions as a silencer of ERα action in murine hair biology. (An additional list on reported expression of estrogen signaling components is provided in Table 2⇑).

C. Estrogen target genes in the pilosebaceous unit
The classical mechanism of estrogen action involves binding to its receptors in the nucleus, after which the receptors dimerize and bind to specific response elements known as EREs located in the promoters of target genes. However, ERs can also regulate gene expression without directly binding to DNA. This occurs through protein-protein interactions with other DNA-binding transcription factors in the nucleus (261). About one third of the genes in humans that are regulated by ERs do not contain ERE-like sequences (262). Candidates of estrogen target genes with relevance to pilosebaceous biology that are activated without ERE promoter include IGF-I, collagenase, EGF, EGFR, and cyclin D1 (261, 263). Instead, progesterone receptor, prolactin, and lactoferrin are examples of relevant target genes in the pilosebaceous unit with consensus EREs (263, 264, 265).

Zouboulis et al. (266) showed that, in sebocytes, the expression of peroxisome proliferator-activated receptor (PPAR) γ, postulated to be required for androgen-induced lipogenesis, was down-regulated by the phytoestrogen genistein, whereas E2 enhanced the metabolism of prostaglandin D2 to Δ12-prostaglandin J2, a natural PPARγ ligand. Additionally, the same group found that E2 increases IGF-I synthesis and down-regulates IGF-I receptor expres​sion(266).

Recently, we have employed cDNA microarray to screen for genes in organ-cultured human scalp hair follicles that respond to E2 stimulation with transcriptional changes, using a skin focus chip and comparing the E2 response of male and female human frontotemporal scalp hair follicles. Of 1300 genes screened, more than 60 E2-responsive genes were detected. Several genes were modulated equidirectionally in both sexes (e.g., down-regulation of osteopontin and hevin = highly expressed endothelial venule protein; up-regulation of cytokeratin type II and bone morphogenetic protein 7). Intriguingly, however, several genes showed distinct regulatory responses in male and female hair follicles: e.g., down-regulation of filaggrin and FGF receptor 2 in males; up-regulation of nuclear receptor subfamily 4, group A, member 1 in females; whereas cysteine-rich 61, fos-like antigen 2, and collagen IV A6 were up-regulated in males, yet down-regulated in females (10). This reveals that terminal human scalp hair follicles from one defined region show strikingly different, sex-dependent biological responses to stimulation with the same ER ligand, strongly advocating gender-tailored management of female vs. male pattern balding (androgenetic alopecia) (10).

CS,

So basically the response to estrogen is different in both sexes, and the same ER ligand can have two different effects depending on whether is ERa or ERb. It also appeared that ERb in the keratinocytes surrounding the papilla is very important for promoting hair growth. It also looked like vertex papilla cells showed less expression of ER of both types.

So are you pointing to the fact that trying to inhibit aromatase is a bad idea for people with hair loss? Because here's my dilemma.

Without actually knowing what my E levels are, awaiting blood test results, I display all of the symptoms of a high E to T ratio: central fat distribution sparing the limbs, pseudo-gyno, lowered libido, however, I am able to put on muscle very easily and have a very strong build. So I'm just confused about what to do, because on one hand I want to handle this E situation (which could also be a prolactin or cortisol problem in retrospect) but it seems that E is so important for hair growth. If this is the case and my E is high, why would I be losing hair so quickly, is it an issue with ER distribution?

anthonyspencer54 - Would focus on optimizing thyroid health and normalizing cortisol. Beyond that, eliminating some culprits such as endocrine disruptors will keep Thyroid and Testosterone levels optimal. So in other words, no need to focus too strongly on inhibiting aromatase.

Endocrine disruptors are frequently found in many types of cream or sun tan lotion applied on the skin.

Thanks CS. I'm awaiting the blood test results. But this test only tested TSH, which I know from other posts I've seen from you is pretty much a joke. I'm hoping the doc will work with me and give me a more comprehensive thyroid test. I should be looking at t4, t3, reverse t3 and parathyroid right?