Juveline

[bcapop]

Hello,

I have a few questions about Juveline. I don't understand why you keep on inhibiting aromatase since research actually shows that estrogen is good for scalp hair. This is from Bryan @ HLH:

This is the study "Estrogen Reduction by Aromatase Inhibition for Benign Prostatic Hyperplasia: Results of a Double-Blind, Placebo-Controlled, Randomized Clinical Trial Using Two Doses of the Aromatase-Inhibitor Atamestane", Radlmaier et al, The Prostate 29:199-208 (1996).

The use of the aromatase inhibitor atamestane caused a reflexive INCREASE in serum androgens, including DHT! Here are the approximate numbers involved (I'm reading this off a graph they provide): after 48 weeks of therapy, the smaller dose of the drug raised serum DHT by about 23%, and the larger dose raised serum DHT by about 35%.

There was no question at all in my mind that reducing estrogen causes an increase in testosterone, because it's been thoroughly documented that estrogen plays an important role in the regulation of androgen synthesis; the only thing I wasn't completely sure about was whether or not it also raises DHT, although I felt it was highly likely that it would. It was just a little while ago that I remembered that they had probably areducing estrogen with an aromatase inhibitor raises not only testosterone, but also DHT.

Some people on these forums have the rather odd belief that estrogen is involved in hairloss in a negative way; that is, it actually causes or contributes to balding. They seriously entertain the idea of using powerful systemic aromatase inhibitors like Arimidex! Despite the evidence that I've presented in the past that contradicts that notion and shows that estrogen is actually beneficial for hair follicles, those people continue to believe what they WANT to believe, the evidence be damned. Well, I've just recently found still more evidence which supports a beneficial role for estrogen: it's the chapter "Estrogen Treatment of Hair Diseases", written by U. Schumacher-Stock, in the book "Hair Research" (ed.: Orfanos, Montagna, Stuttgen; Springer-Verlag 1981). I don't want to type out the entire chapter, but let me judiciously pick-and-choose a few excerpts, especially the small test they did with topical estrogen for MPB:

[...] "In the light of this favourable effect of estrogen on senile skin, the obvious supposition is that these steroids also have a similarly favourable effect on hair follicles. Estrogens prolong the growth period of hair (Taubert 1976, Winkler 1969) and, in addition, inhibit mitosis (Stuuttgen and Schaefer 1977). Some investigations point, that systemic estrogens increase the proliferation rate, slow down differentiation and, thus, postpone fallout of telogen hairs (Moretti et al. 1977).

"Orentreich (1969) observed a decrease in daily hair fall-out during therapy with systemic doses of estrogen...Lubowe saw good results in androgenetic alopecia by means of the conjugated estrogen Presomen (Lubowe 1972). It can be assumed that the semi-synthetic estrogens, like mestranol and ethinylestradiol, have a stronger effect on hair growth than conjugated estrogens.

"In the treatment of hair diseases, there have been few reports on systemic estrogen. But some authors have been using estrogens for topical treatment of hair diseases for many years (e.g. Funk as long ago as 1951).

"Androgenetic Alopecia, which in many cases causes great suffering, is of particular significance for topical use of estrogens... Topical estrogen treatment can be considered particularly in those cases in which systemic antiandrogen therapy...is not possible.

"According to Zondek, topical use of estrogen solutions is almost as effective as systemic administration of this hormone. Wendker et al. (1976) have demonstrated the good penetration of estradiol solutions right into the cutis. However, no reports of concentration in the subcutis and, thus, at the hair follicle are available.

We carried out investigations into the effect of estradiol benzoate, incorporated in isopropyl alcohol, on androgenetic alopecia... We selected 35...patients with androgenetic alopecia in whom typical androgenetic alopecia was also present on the basis of history and clinical findings. We treated these patients for at least 6 months with the above-mentioned estrogen solution, in some cases for a year, and in some cases for even longer. Every day a few drops of the prescribed solution were applied to the scalp...

"Trichogram investigations according to the standardized method of Meiers (1975) were carried out on the 5th day after the last hair wash and after withdrawal of all topical therapeutic agents; this was done prior to therapy and 6 to 8 months later during therapy. During the treatment, the patients were only allowed to use a mild shampoo to wash their hair.

"The therapeutic results were evaluated on the basis of the trichogram findings, corresponding to the change in the telogen rate (TR). A decrease in the telogen rate of more than 20% was rated as improvement, values of +/-20% as no improvement, and an increase in the telogen rate of more than 20% as deterioration. The results are summarized in the Table 1.

Table 1. A decrease in the telogen rate of more than 10% was seen
in a total of 22 patients = 63%
---------------------------------------------------------------------------
Evaluation ..... Telogen rate (TR) ...... No. of patients (35 = 100%)
----------------------------------------------------------------------------
improvement ..... >20% decrease ......... 18 = 51.5%
no improvement +/-20% ....................... 12 = 34.2%
deterioration ...... >20% increase ........... 5 = 14.3%
----------------------------------------------------------------------------

"Here you can see two particularly good examples of therapeutic success in a woman and a man: a 51-year-old woman patient, telogen rate in the frontal area prior to treatment 42.9%, after treatment 18.0%; a 33-year-old man, telogen rate in the frontal area prior to treament 46.6%, after treatment 20.0%.

"The deterioration of androgenetic alopecia in five patients had to be attributed partly to very irregular use of, and partly to premature withdrawal of, the estrogen tincture. For example, one patient who initially noticed a subjective improvement after 3 months' regular use of the estrogen spirit discontinued treatment on the advise of his general practitioner, who did not consider the therapy meaningful...

"Our results have confirmed the studies by Wustner and Orfanos (1974), who saw an improvement, that is, a decrease of the telogen-rate in 52% of androgenetic alopecia treated with Alpicort-F and Crinohermal-fem. These authors did not find side effects when their preparations were used.

"Our patients too did not report any side effects. [...] Hence, we can say topical use of estrogen is a suitable therapy for androgenetic alopecia. We cannot say whether the hair follicles become accustomed to estrogen application after 10 or more years because the observation period was not longer than 2 years."

It all goes against the idea of inhibiting aromatase. So please explain me why you think that estrogen isn't welcome.

[bcapop]

And another study shows that an anti-estrogen topical doesn't work against hairloss:

Topical fulvestrant solution has no effect on male and postmenopausal female androgenetic alopecia: results from two randomized, proof-of-concept studies.

Gassmueller J, Hoffmann R, Webster A.

Bioskin Institute for Dermatological Research and Development GmbH, Poppenbuetteler Bogen 25, 22399 Hamburg, Germany.

Background Androgenetic alopecia (pattern baldness) affects approximately half of all white-skinned men and women over the age of 40 years. Based on preclinical studies in mice in which topical fulvestrant (ICI182,780, an anti-oestrogen) caused telogen hair follicles to enter anagen, thereby causing hair growth, a topical formulation of fulvestrant was developed for the potential treatment of androgenetic alopecia. Objectives To evaluate the efficacy of fulvestrant solution in stimulating hair growth in men and postmenopausal women with androgenetic alopecia in two randomized, phase II, minoxidil- and/or vehicle-controlled studies. Methods One hundred and two white-skinned men aged 18-50 years with Norwood/Hamilton grades III, IIIv, IV, V or Va androgenetic alopecia received topical fulvestrant 70 mg mL(-1) solution, vehicle or minoxidil 2% solution twice daily for 16 weeks. Seventy postmenopausal women with Ludwig grade 1 or 2 androgenetic alopecia received topical fulvestrant 70 mg mL(-1) solution or vehicle twice daily for 16 weeks. The endpoints in both studies were hair density, cumulative hair thickness and hair growth rate, measured by TrichoScan analysis of digital images. Results There were no statistically significant differences favouring fulvestrant over vehicle at study end (day 113) for any of the efficacy parameters in men or women. Statistically significant differences in favour of minoxidil over fulvestrant were seen from day 57 onwards for hair density, cumulative hair thickness and hair growth rate in men. Conclusions These results indicate a lack of effect of topical fulvestrant in the treatment of subjects with androgenetic alopecia. The reasons for this lack of effect remain unclear.

This one is from Br J Dermatol. 2007 Nov 6.

[DrYechiel]

Hello, bcapop. I’ll respond to the quotes one by one.

As for the first quote,  it does not necessarily prove that reduction in estrogen or increase in testosterone are the source of the problem since there is a third variant: DHT. Testosterone may be actually beneficial. As sporadic research keeps building up, more evidence about positive contributions of testosterone are stated. The bad thing about having aromatase inhibitors alone is that the only remaining avenue for testosterone transformation is DHT. Using anti-reductase will reduce the generation of DHT and you will get an initial up-shot of testosterone which will stabilize in a few days into a high but physiological range. JuveLine includes extracts of  botanicals which contain ingredients which, in medicinal formulation, showed both significant anti-aromatase and anti-reductase.

In the second example, you are referring to estrogen’s ability to maintain hair by reducing mitosis and differentiation. Well, if true, than you may keep some hair longer but those which eventually fall (it is normal for individual hairs to be regularly lost and replaced), are less likely to be replaced because this restricts the ability of stem cells (and other cells) to differentiate and build and renew (or stimulate to action) dormant follicles. Indeed, estrogen is long known for its good effects on skin but so is testosterone. Estrogen also competes with DHT and may indirectly reduce the active DHT fraction in the DHT pool. Also, the author refers to his statement as “supposition” and so, it is a nice theory with, maybe, some merit to it but still, the activity may be partially explained by competition with DHT.

In the third reference, the statement about considering “increase in the telogen rate of more than 20% as deterioration” is questionable because hairloss is more than a long “telogen”. If the follicles can be activated, temporary shedding or slowing in growth are not indicators of hairloss. In addition, it could still be competition of the estrogen with DHT, reducing the active DHT fraction.

Overall, lack of differentiation between testosterone and DHT as to their respective roles in hairloss is a great concern to me. Testosterone (at reasonable levels, not the bizarre extremes sometimes sought by body-builders) is extremely beneficial to men and women, as is estrogen, though estrogen is the leading hormone in women and vice-versa in men. While DHT may be one of the major causes of MPB, diminishing testosterone leves (due to transformation to DHT or to estrogen) and thus, the active fraction of testosterone may be contributing to the inability of follicles to recover and do what they normally do.

In addition, testosterone itself it a major competitor of DHT, and since reductase only reduces but does not completely eliminate DHT, physiologically-higher levels of testosterone may compete very successfully with reduced levels of DHT.

This is part of the philosophy behind JuveLine.

[bcapop]

Thanks.

But how do you explain this study?

Effect of 5alpha-dihydrotestosterone and testosterone on apoptosis in human dermal papilla cells.

Pathogenetic mechanisms in androgenetic alopecia are not yet fully understood; however, it is commonly accepted that androgens like testosterone (T) and 5alpha-dihydrotestosterone (5alpha-DHT) inhibit hair follicle activity with early induction of the catagen. Thus, we investigated the influence of T and 5alpha-DHT on proliferation, cell death and bcl-2/bax expression in cultured dermal papilla cells (DPC) from nonbalding scalp regions of healthy volunteers. T and 5alpha-DHT induced apoptosis in DPC in a dose-dependent and time-related manner; in addition a necrotic effect due to T at 10(-5) M was found. Interestingly, bcl-2 protein expression was decreased in T- and 5alpha-DHT-treated cells, leading to an increase in the bax/bcl-2 ratio. In addition, T and 5alpha-DHT induced proteolytic cleavage of caspase 8 and inhibited proliferation of DPC at 10(-5) M. High concentrations of T and 5alpha-DHT were needed to induce apoptotic effects in DPC. These data suggest that DPC from nonbalding scalp regions do have the capacity to undergo apoptosis, but need a high androgen stimulus. The present study provides an interesting new pathogenetic approach in androgenetic alopecia.

http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16931898&query_hl=6&itool=pubmed_docsum

[DrYechiel]

Hello bcapop,

As I often say: you cannot draw any conclusions from an abstract; read the complete article! Then, think about how vague (headline-like) terms in an abstract gain clearer meanings in light of all the details in the article: Does “dose-dependent” refer to extremely high levels that would harm a person? Does “time-related” require leaving material in place longer than a multicellular organism will sit still for it? Do “decreased” and “increased”  and “induced” and “inhibited” refer to tiny fluctuations that could have occurred by chance, or to statistically-significant patterns of cause and effect? Why are the findings described in weak (“suggest”) and non-specific (“high”) terms, and summarized as merely “interesting”? Writers of scientific articles agonize over the choice of every word and phrase; such articles are not meant to be skimmed like popular magazines, but read with the same excruciating attention to detail with which they were written.

The article is “Effect of 5alpha-dihydrotestosterone and testosterone on apoptosis in human dermal papilla cells” in the August 2006 issue of Skin Pharmacology and Physiology. The journal is available electronically by subscription, and your local public or University library may be a subscriber; ask them for help if necessary.

The “generally accepted” notion that shortening of the anagen-telogen ratio defines hairloss is a naïve oversimplification of a complex biochemical process. If indeed anagen is shorter (and not totally eliminated), then the result may be thinner hair due to a less favorable steady-state for the hair-growing period, but the result will not be total non-hairgrowth in certain regions. What this means in reality is:

• The scalp will grow normal hair at every potential hair-growing point on the scalp. There will be longer periods in which potentially hair-growing loci are bare (as compared to scalps with longer anangens) but this will not coincide with permanent bald paches.
• The normal hair will grow to a limited length only, but it will grow, since the shorter anagen will not accommodate prolonged hair growth over years and years without shedding but will not prevent hairgrowth during the shorter anagen periods.
• It will not correspond to patchy patterns of balding as in MPB.

Of course, when there is a balding problem, short anagen periods don’t help the situation, and contribute to faster loss of hair, for which recovery is not available (due to reasons other than anagen duration). At any rate (read the article!), the author of the article you pointed out accepts the role of DHT (not testosterone) in miniaturization of hair and follicles (which is in itself only an accepted mode, not to be confused with actual proven mechanism of action) and in shortening of the anagen phase, and only in genetically pre-disposed hairs which are also pre-disposed to higher than normal levels of 5-alpha-reductase.

DHT is reported to be 5-10 times more potent than testosterone. Reducing a mere 10 percent of DHT (10% DHT as measured when the entire pool of androgens is regarded as 100%) reduces the overall androgen power by more than half while leaving testosterone concentration more or less the same (somewhat on the higher normal level). Testosterone differs from DHT not only in affinity to receptors but in other ways (much is not yet known in this field) which are critical to developmental and growth cycles. Reduction of testosterone may cause too many problems, including pre-mature aging and increased catabolic-anabolic ratio throughout the bio-sysytem. Testosterone reduction in men can be compared to menopause in women, but in men it happens more gradually.

Some additional comments:

1. Hormonal treatment in tissue culture is very far removed from real tissue in comparison to other tissue culture models because in tissue culture there is no room for cyclical (rythmical) behavior of hormones, which means they are in constant concentration. In real tissue they are often pulsating.

2. Cells were not confluent when treated and that furthur removes them from normal intact skin.

3. Treatments were given with 0.1% DMSO which increases penetration in a significant way which is very different from the ordinary physiological processes. Controls with DMSO also showed much higher than normal cell death rate, even without the hormones.

Statements by the author in the discussion chapter:

1. “Non-physiological concentrations of 5-alpha-DHT or T (10 –5 M ) induced significant apoptosis in occipital-scalp-derived DPC from healthy patients.”
(My comment: 10micromolar concentration of DHT or testosterone is so much higher than normal concentrations that the effects have not much value to our discussion. It is like forcing someone to drink a bathtub full of water in a few minutes, a quantity that would certainly kill him, and then concluding that drinking water is dangerous).

2. “Proliferation of cultured DPC was inhibited by T only at these high, non-physiological concentrations, as well as by 5-alpha-DHT.”
(My comment: He is saying it again).

3. “Androgens are believed to act on growth and signaling mechanisms in the hair follicle via the mesenchyme-derived DPC, by secreting soluble mitogenic factors and/or extracellular matrix components, subsequently influencing DP activity and follicular keratinocytes.”
(My comment: So, you really want them to stay, don’t you?).

Basically, the article actually says that in physiological concentrations neither DHT nor testosterone have a significant effect on the parameters stated in the abstract.

[bcapop]

Thanks for the explanation. I don't have access to the full articles, but I see your point.