Medical hypothesis: Androgenetic Alopecia indicative of potential cancer

[bornthisway]

Androgenic alopecia may have evolved to protect men from prostate cancer by increasing skin exposure to ultraviolet radiation.

Peter Kabai

Department of Ecology, Faculty of Veterinary Science, AOTK, SZIE, Szent István University, P.O. Box 2, H-1400 Budapest, Hungary

Received 27 July 2007;

Summary:

Androgenic alopecia affects populations adapted to colder climate, and individuals at an age and hormonal status susceptible to prostate cancer. Male pattern baldness enhances absorption of UV radiation on the top of the head, an area directly exposed to sunlight during everyday activities. Ultraviolet radiation is reported to reduce the risk of advanced prostate cancer. Here I propose that progression of androgenic alopecia rather than being a risk factor is a finely tuned mechanism evolved to protect against prostate cancer.

Introduction:

Ethologists perceive androgenic alopecia (Androgenetic Alopecia) as a social signal evolved to indicate senescence [1], whereas in the medical literature it is discussed as an abnormal benign condition with no physiological effect [2].

Social signal theory has been supported by image manipulation experiments, where pictures of bald men are perceived older than the same faces with full hair [3]. The exact nature of the information conveyed, however, has been debated. Some believe that baldness is a signal of social competence and aggressive dominance [4], others suggest it indicates maturity and a non-threatening form of dominance [1].

In any case, young women perceive bald men sexually less attractive and less active [1]. As Androgenetic Alopecia affects about 30% of Caucasian males at the age of 30 years [5], signalling senescence at the age of the highest reproductive potential might be premature and therefore costly for many men. Even though the social signal theory has not been incorporated into mainstream medical science, the notion that Androgenetic Alopecia is not simply a disordered condition but has specific functions deserves attention, considering the genetically pre-programmed nature of the process.

Hair follicles react to androgens in a site-specific manner. In man, with genetic predisposition to Androgenetic Alopecia, terminal hairs in the temporal and frontal regions and later over the vertex of the scalp are miniaturized into vellus hairs, whereas follicles at other areas are not affected under the influence of androgens. Such differential reaction to the same hormone is pre-programmed in the individual follicles: follicles transplanted from non-balding areas to the bald vertex develop into full hair. Although the mechanism of differential reaction of hair follicles to androgens is not fully understood [6], it is very likely that Type 2 5a reductase (5aR-2) converting testosterone to more potent dihydrotestosterone in the follicles is involved. Besides hair follicles, 5aR-2 is expressed in the prostate, testes, seminal vesicles, and the liver. Inherited deficiency in 5aR-2 activity prevents Androgenetic Alopecia and results in small prostate. Finasteride, a 5aR-2 inhibitor has been useful in the treatment of Androgenetic Alopecia as well as prostatic hypertrophy [7]. As changes in the level of 5aR-2 activity affect Androgenetic Alopecia and prostatic hyperplasia in a similar manner, Androgenetic Alopecia as a risk factor for prostate cancer has been a target of epidemiological studies. Although findings have been inconsistent, one of the largest study including 1446 prostate adenocarcinoma cases and 1390 controls depicted an association between vertex baldness and prostate cancer [8].

Another line of epidemiological studies suggest reduced risk of prostate cancer associated with sun exposure, outdoor activity, highly active vitamin D receptor variants [9], high level of vitamin D [10], childhood sunburn, regular foreign holidays, sunbathing score, high exposure to UVR [11] or living at lower latitude [12], results all pointing at the protective role of sun exposure.

The hypothesis:

Male pattern baldness exposes a relatively large skin area to sunlight during everyday activity performed in a vertical position. I propose that Androgenetic Alopecia evolved to elevate UV absorbance and thus to provide some protection against prostate cancer. Moreover, the shared androgen pathways leading to Androgenetic Alopecia and prostate cancer indicate a finely tuned mechanism of inducing baldness in men susceptible for prostate cancer at an age preceding the predicted onset of the disease. According to this interpretation if baldness is a social signal, then it has gained this function secondarily.

This hypothesis comprises two testable relations. Whether Androgenetic Alopecia was positively selected for in populations susceptible for prostate cancer can be directly tested when genetic background of Androgenetic Alopecia as well as of predisposition to prostate cancer are known. Indirect evidence of shared genetic control might be revealed by possible genetic correlations between Androgenetic Alopecia, sun exposure and prostate cancer in family history studies. The possible protective role of Androgenetic Alopecia against prostate cancer can be easily resolved. Epidemiological studies on risk factors for prostate cancer should involve questions on Androgenetic Alopecia status as well as on the level, and surface area exposed to sunlight.

Consequences of the hypothesis:

This hypothesis might be relevant for the design of epidemiological studies as well as for the treatment of Androgenetic Alopecia and prostate cancer. Epidemiological studies on the link between Androgenetic Alopecia and prostate cancer can be confounded by the varying level of sun exposure of bald men with high or low outdoor activity, wearing or not wearing a sun protective hat, and living at lower or higher altitudes. Similarly, sun exposure measured as difference in pigmentation between areas protected or not protected from the sun without considering the surface area exposed may weaken the power of testing the cancer-protective role of UV radiation. Controlling for both Androgenetic Alopecia and sun exposure in both lines of studies might reveal stronger associations between sun exposure and lower risk of non-skin cancers.

Benign prostatic hyperplasia has been treated with finasteride, a potent 5aR-2 inhibitor [7]. As such treatment also halts or reverses Androgenetic Alopecia, treated men with prostatic hyperplasia might receive less UV radiation during everyday activities than without finasteride treatment. Careful studies are needed so that advice on compensating for reduced sunlit areas could be given to patients. As association between low level of sun exposure with various forms of non-skin cancers, coronal heart disease, and hypertension has been suggested [13,14], links between predisposition to baldness and such conditions would be worthy to seek.

Acknowledgement:

I am grateful to T.O’Keeffe for his valuable comments.

References:

[1] Muscarella F, Cunningham MR. The evolutionary signifi-
cance and social perception of male pattern baldness and
facial hair. Ethol Sociobiol 1996;17:99–117.

[2] Sinclair RD. Male androgenetic alopecia. JMGH 2004;1(4):
319–27.

[3] Henns R. Social perceptions of male pattern baldness. A
review. Dermatol Psychosom 2001;2:63–71.

[4] Keating CF, Mazur A, Segall MH. A cross-cultural exploration
of physiognomic traits of dominance and happiness. Ethol
Sociobiol 1981;2:41–8.

[5] Hamilton JB. Patterned loss of hair in man: types and
incidence. Ann NY Acad Sci 1951;53:708–28.

[6] Trüeb RM. Molecular mechanisms of androgenetic alopecia.
Exp Gerontol 2002;37:981–90.

[7] D’Amico AV, Roehrborn CG. Effect of 1 mg/day finasteride
on concentrations of serum prostate-specific antigen in
men with androgenic alopecia: a randomised controlled
trial. Lancet Oncol 2007;8:21–5.

[8] Giles GG, Severi G, Sinclair R, English DR, McCredie MRE,
Johnson W, et al. Androgenetic alopecia and prostate
cancer: findings from an australian case-control study.
CEPB 2002;11:549–53.

[9] John EM, Schwartz GG, Koo J, Van Den Berg D, Ingles SA.
Sun exposure, vitamin D receptor gene polymorphisms, and
risk of advanced prostate cancer.
Cancer Res 2005;65:5470–9.

[10] Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS,
Stampfer MJ, et al. Prospective study of predictors of
vitamin D status and cancer incidence and mortality in
men. J Natl Cancer Inst 2006;98:451–9.

[11] Luscombe CJ, Fryer AA, French ME, Liu S, Saxby MF, Jones
PW, et al. Exposure to ultraviolet radiation: association
with susceptibility and age at presentation with prostate
cancer. Lancet 2001;358(9282):641–2.

[12] Hanchette CL, Schwartz GG. Geographic patterns of pros-
tate cancer mortality: evidence for a protective effect of
ultraviolet radiation. Cancer 1992;70:2861–9.

[13] Schwartz GG, Skinner HG. Vitamin D status and cancer: new
insights. Curr Opin Clin Nutr Metab Care 2007;10:6–11.

[14] Grimes DS. Are statins analogues of vitamin D? Lancet
2006;368(9529):83–6.

 

[bornthisway]

Androgenic Alopecia and Stress-Induced Premature Senescence by Cumulative Ultraviolet Light Exposure

Department of Dermatopathology, University Medical Center Sart Tilman, Liège, Belgium;
R & D L'Oréal Laboratories
Exog Dermatol 2002;1:203-206 (DOI: 10.1159/000066146)

Ultraviolet light radiations (UVR) may be responsible for hair cycle synchronization and telogen effluvium in the animal and humans. The effect if any of cumulative UVR on chronic hair shedding and androgenic alopecia (Androgenetic Alopecia) is largely unknown. Objective: To compare the severity of Androgenetic Alopecia with the extent of solar elastosis. Method: The present study combining immunohistochemistry and computerized image analysis was undertaken in 140 men with Androgenetic Alopecia and 50 non-alopecic men. Solar elastosis was identified using the antibody to lysozyme, and collagen was revealed by Sirius red staining. The number and diameter of hair shafts were also assessed. Results: The scalp dermis was significantly thicker in Androgenetic Alopecia than in unaffected subjects. The difference was mainly due to a severer elastosis in baldness. The earliest signs of solar elastosis preceded hair thinning. When elastosis was thicker than 0.2 mm, a negative exponential correlation was found between hair diameter and severity of solar elastosis. Conclusion: Chronic UVR exposure of the scalp may affect the hair cycle and be one of the exogenous factors influencing negatively the progression of Androgenetic Alopecia. The induction of stress-induced premature senescence by reactive oxygen species and micro-inflammation might be operative at the level of the follicular stem cells.

 

[bornthisway]

Is androgenetic alopecia a photoaggravated dermatosis?

Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland. ramitru@derm.unizh.ch

Progressive thinning of the scalp hair in androgenetic alopecia (Androgenetic Alopecia) results in a gradual decline in natural protection of the scalp from ultraviolet radiation (UVR). A number of pathologic conditions of the scalp are evidently related to UVR, particularly photosensitive diseases and disorders of the chronically photodamaged bald scalp. The most important chronic effects of UVR are photocarcinogenesis and solar elastosis. Besides these, erosive pustular dermatosis and 'red scalp' are distinct disorders peculiar to the balding scalp. While the consequences of sustained UVR on the unprotected scalp are well appreciated, the effects of UVR on hair loss have widely been ignored. However, clinical observations and theoretical considerations suggest that UVR may have negative effects: acute telogen effluvium from UVR has been described, and the production of porphyrins by Propionibacterium sp. in the pilosebaceous duct, with photoactivation of porphyrins leading to oxidative tissue injury, has been implicated in follicular microinflammation. Alternatively, keratinocytes themselves may respond to physicochemical stress from UVR, besides irritants and pollutants, by producing radical oxygen species and nitric oxide and by releasing proinflammatory cytokines, eventually leading to injury of the putative site of follicular stem cells in the superficial portion of the hair follicle. Since all of these processes involved in hair loss share the common feature that they are induced or exacerbated by exposure to sunlight, it is proposed that Androgenetic Alopecia is a photoaggravated dermatosis that requires photoprotection. Copyright 2003 S. Karger AG, Basel

PMID: 14657623 [PubMed - indexed for MEDLINE]

 

[michael barry]

The thing is......................that we keep running into hair transplants as a "killer" of these ideas. Hair transplants survive in frontal scalp for decades as ones that were done in the seventies are still going strong. Problematic.



On the cancer angle.................as Ive had time to think about it...............lots of Indians and Pakis go bald. Lots of east Africans go bald as well as many primate species (stumptailed macaques, chimps, orangutans, bonoboos). We evolved in a time when most men didn't live until 45 or so.................before baldness became common. Maybe it just is a screw up involving the androgen receptor gene with no evolutionary purpose except (maybe) to show "maturity" and perhaps some intelligence (mice that have hyperplasia of sebaceous glands and thinner coats also do well in mazes, leading some researchers to postulate a link between intelligence in these mice and a preponderance of higher intellect vs. control-----come to think of it there sure are a hell of alot of bald scientists).

I keep thinking the decoding of the human genome is going to lay all the genes out on the table and we will find things that counteract them...............bummer

 

[bornthisway]

Prostate cancer risk and exposure to ultraviolet radiation: further support for the protective effect of sunlight.

Department of Urology, North Staffordshire Hospital, Staffordshire, Stoke-on-Trent, UK.

Recent studies have suggested that exposure to ultraviolet (UV) radiation may be protective to some internal cancers including that in the prostate. We describe a confirmatory study in 212 prostatic adenocarcinoma and 135 benign prostatic hypertrophy patients designed to determine whether previous findings showing a protective effect for UV exposure could be reproduced. We used a validated questionnaire to obtain data on aspects of lifetime exposure to UV. The data confirmed that higher levels of cumulative exposure, adult sunbathing, childhood sunburning and regular holidays in hot climates were each independently and significantly associated with a reduced risk of this cancer.

PMID: 12668278 [PubMed - indexed for MEDLINE]

 

[bornthisway]

The thing is......................that we keep running into hair transplants as a "killer" of these ideas. Hair transplants survive in frontal scalp for decades as ones that were done in the seventies are still going strong. Problematic.



On the cancer angle.................as Ive had time to think about it...............lots of Indians and Pakis go bald. Lots of east Africans go bald as well as many primate species (stumptailed macaques, chimps, orangutans, bonoboos). We evolved in a time when most men didn't live until 45 or so.................before baldness became common. Maybe it just is a screw up involving the androgen receptor gene with no evolutionary purpose except (maybe) to show "maturity" and perhaps some intelligence (mice that have hyperplasia of sebaceous glands and thinner coats also do well in mazes, leading some researchers to postulate a link between intelligence in these mice and a preponderance of higher intellect vs. control-----come to think of it there sure are a hell of alot of bald scientists).

I keep thinking the decoding of the human genome is going to lay all the genes out on the table and we will find things that counteract them...............bummer

Regarding transplanted hair, from the hypothesis:
"Such differential reaction to the same hormone is pre-programmed in the individual follicles: follicles transplanted from non-balding areas to the bald vertex develop into full hair."

Regardless of whether UV helps delay cancer or not in Androgenetic Alopecia predisposed individuals is speculative for now... but UV exposure is beneficial against prostate cancer and hair loss is either induced or exacerbated by exposure to sunlight in predisposed individuals (microinflammation, premature hair follicle senesence via ROS, consequently injuring follicular stem cells).

 

[jambri]

So here's a totally non-scientific puzzle to think about which fits in to this hypothesis nicely (has been mentioned here before):

Name a bald or balding professional golfer under 70.

 

[bornthisway]

Inhibitory autocrine factors produced by the mesenchyme-derived hair follicle dermal papilla may be a key to male pattern baldness.

BACKGROUND: Androgenetic alopecia, or male pattern baldness, is a common, progressive disorder where large, terminal scalp hairs are gradually replaced by smaller hairs in precise patterns until only tiny vellus hairs remain. This balding can cause a marked reduction in the quality of life. Although these changes are driven by androgens, most molecular mechanisms are unknown, limiting available treatments. The mesenchyme-derived dermal papilla at the base of the mainly epithelial hair follicle controls the type of hair produced and is probably the site through which androgens act on follicle cells by altering the regulatory paracrine factors produced by dermal papilla cells. During changes in hair size the relationship between the hair and dermal papilla size remains constant, with alterations in both dermal papilla volume and cell number. This suggests that alterations within the dermal papilla itself play a key role in altering hair size in response to androgens. Cultured dermal papilla cells offer a useful model system to investigate this as they promote new hair growth in vivo, retain characteristics in vitro which reflect their parent follicle's response to androgens in vivo and secrete mitogenic factors for dermal papilla cells and keratinocytes. OBJECTIVES: To investigate whether cultured dermal papilla cells from balding follicles secrete altered amounts/types of mitogenic factors for dermal papilla cells than those from larger, normal follicles. We also aimed to determine whether rodent cells would recognize mitogenic signals from human cells in vitro and whether factors produced by balding dermal papilla cells could alter the start of a new mouse hair cycle in vivo. METHODS: Dermal papilla cells were cultured from normal, balding and almost clinically normal areas of balding scalps and their ability to produce mitogenic factors compared using both human and rat whisker dermal papilla cells as in vitro targets and mouse hair growth in vivo. RESULTS: Normal scalp cells produced soluble factors which stimulated the growth of both human scalp and rat whisker dermal papilla cells in vitro, demonstrating dose-responsive mitogenic capability across species. Although balding cells stimulated some growth, this was much reduced and they also secreted inhibitory factor(s). Balding cell media also delayed new hair growth when injected into mice. CONCLUSIONS: Human balding dermal papilla cells secrete inhibitory factors which affect the growth of both human and rodent dermal papilla cells and factors which delay the onset of anagen in mice in vivo. These inhibitory factor(s) probably cause the formation of smaller dermal papillae and smaller hairs in male pattern baldness. Identification of such factor(s) could lead to novel therapeutic approaches.

 

[bornthisway]

Cutaneous immunopathology of androgenetic alopecia
JW Young, ET Conte, ML Leavitt, MA Nafz, and AL Schroeter

Male pattern baldness is assumed to result from a combination of normal serum concentrations of androgen and an appropriate genetic background. To study whether inflammation contributes to the development of androgenetic alopecia, direct immunofluorescence and dermatopathologic studies were performed on biopsy specimens from bald scalp of patients, with specimens from uninvolved scalp of these patients or from scalp of volunteers who were not bald serving as controls. Granular deposits of Immunoglobulin M or C3 (or both) were found at the basement membrane in 25 (96%) of 26 study patients and 1 (12%) of 8 control subjects. Granular C3 was also deposited on eccrine myoepithelial cells in 8 (31%) of 26 study patients, but no control subjects. Porphyrins were found in the pilosebaceous canal in 15 (58%) of 26 study subjects and in 1 (12%) of 8 control subjects. These results support an inflammatory pathogenesis of androgenetic alopecia. Propionibacterium acnes is known to produce porphyrins. Ultraviolet radiation may excite microbiologic porphyrins that could activate C3 and, subsequently, the complement cascade producing inflammatory mediators.

 

[bornthisway]

This is a reply to Barry saying Indians bald too and have more sun exposure..:

I think the prostate cancer and Androgenetic Alopecia (vertex balding) link needs to be furthur researched as relations have been drawn. There's too much inconclusive data on hair loss as a whole (and there are far too many factors) .. also we really don't understand the majority of why in the process. Regardless, UV plays a part in the progression of Androgenetic Alopecia and inflammation (as do many other factors), etc... whether it evolved to protect against prostate cancer is still rather speculative.

Melanin acts as a natural sunscreen absorbing UV and regulating how much is absorbed in the skin, the majority of Indians have quite dark skin so there is less UV absorption (~5% absorption versus 20-30% in white skin -- hence the higher prevalence of Androgenetic Alopecia in caucasians if we're going to address that specific theory). [Skin pigmentation evolved to adapt to environmental factors such as the increased sunlight exposure.]

Regarding Indians getting Androgenetic Alopecia later is due to time relative stimulus factors, less UV absorption and genetic predisposition to prostate cancer and Androgenetic Alopecia... Androgenetic Alopecia doesn't necessarily occur at the same time in all individuals and it's based on individual mechanisms that trigger it (follicles are preprogrammed and react upon given stimulus) which also triggers the hair follicle to secrete inhibitory factors to lessen growth and the onset of Androgenetic Alopecia. Prostate cancer prevalence is highest in blacks who also are less likely to bald than caucasians. There is a definite genetic difference between the races for Androgenetic Alopecia and prostate cancer.. the linking I made is still somewhat broad and may not be as applicable to other races.

However, I'm not as concerned about the evolutionary theory as I am of learning about less addressed processes which worsen male pattern baldness which it did touch on such as UV and resulting microinflammation (porphyrins), ROS, etc.

Regarding Indians getting Androgenetic Alopecia later is due to time relative stimulus factors, less UV absorption and genetic predisposition to prostate cancer and Androgenetic Alopecia... Androgenetic Alopecia doesn't necessarily occur at the same time in all individuals and it's based on individual mechanisms that trigger it (follicles are preprogrammed and react upon given stimulus) which also triggers the hair follicle to secrete inhibitory factors to lessen growth and the onset of Androgenetic Alopecia. Prostate cancer prevalence is highest in blacks who also are less likely to bald than caucasians. There is a definite genetic difference between the races for Androgenetic Alopecia and prostate cancer.. the linking I made is still somewhat broad and may not be as applicable to other races.

However, I'm not as concerned about the evolutionary theory as I am of learning about less addressed processes which worsen male pattern baldness which it did touch on such as UV and resulting microinflammation (porphyrins), ROS, etc.

 

[michael barry]

Of the Indians Ive had to deal with.......................if anything I'd say they seem to bald earlier than whites and more often. Maybe its just the ones Ive dealt with over the years but it seems its unusual to meet them past 30 who aren't losing their hair. Ive seen a couple of NW7 Indians who were in their mid-20's. Hair just flys out.


People "think" that rarely do people in other parts of the world bald................but its not really the case. I'll never forget watching a documenturary on various parts of Africa and noting alot of baldness in some of the East African tribes. If you have watched alot of the television coverage on the situation in Iraq, you'll note some very full heads of hair..................and some extremely bald men there. The only group that doesn't seem to bald very much at all are various Central and South American tribes, in which it seems very rare.



I dont think baldness "evolved"..................Apes have baldness. Stumptailed Macaques have baldness more than we do, chimps oft go bald, Oranguatans very often bald, bonoboos (our closest genetic match) very very often go bald. Why?
They live out in the sun, they eat a very healthy diet (no McDonalds out there in the jungle). If given finasteride, they dont go bald, and will grow back more hair than we do. They dont have inflammation and there is no immunological component to their balding. Hideo Uno, legendary baldness researcher, noted this. We wouldn't be the only species that developed a baldness in members with androgen abnormalities........................lions sometimes have this, and the legendary lions with no manes that killed all those railroad worker had high androgens or so its been asserted.

You are looking for a reason for baldness to have "evolved", but there are other conditions like psoriasis that have an autoimmune component that have no evolutionary reason to have evovled whatsoever, but they are pretty common---but we have better means of dealing with it. Acne doesn't really serve an evolutionary purpose either (unless it keeps people from breeding until they are older because it makes them unnatractive to each other during adolescence.).


Green eyes or freckles or cleft chins or the abiltity to roll up your tounge or finger digit ratios (associated with high prenatal androgens) that have the ring finger be longer than the index finger (like mine) dont have any evolutionary advantage..............but they exist. Baldness can very much be like this.......................we know that a mutation on the androgen receptor gene is carried by 98.6% of baldning men vs 76% of controls.................so that is one thing we have found.

 

[bornthisway]

I'm not necessarily looking for a reason for baldness to have evolved as much as interest in the negative effects of UV on Androgenetic Alopecia. Though, all areas of Androgenetic Alopecia need more research, especially links to prostate cancer. I thought you implied Indians bald 'later' but I must have misread something. The incidence of prostate cancer is about 10 times more in America than it is in India. I couldn't find statistics on Androgenetic Alopecia, but haven't really had the time to look. If Indians indeed bald earlier due to increased sun exposure and if we're to believe the statistic then there was an overall lower prevalence in prostate cancer. More interestingly, why do balding dermal papilla cells secrete inhibitory growth factors of their own accord even when injected into mice?

 

[michael barry]

More interestingly, why do balding dermal papilla cells secrete inhibitory growth factors of their own accord even when injected into mice?

First, I want you to look at this video, http://www2.oprah.com/tows/pastshows/20 ... 0916.jhtml
Those are transgendered TWINS. They have the exact same DNA. One is balding and the other has slight thinning over her sister. I say "her" , because she still doesn't have male genitalia even though she looks like a man. Note the grey facial hair (beard) and aged skin. There are pictures you can pull up and see her face up close.............and how much more aged it is. The other balding twin woman (yup, she is still a woman) speaks for itself. Right beside her sister, with all her hair.
What this tells me is that although we were always told that some "change" happens in hair at puberty and its forevermore destined to be what it is...............that clearly cant be true. If a woman has baldness genes, and you give her testosterone cream for about a year...........she will start going male pattern bald just like her brothers or dad.
I have seen other pictures of former women who take testosterone who go male pattern bald very quickly. Here is another woman "before" testosterone, http://worldofwonder.net/ring/BuckBefore.jpg . Now look at her "after", http://images.google.com/imgres?imgurl= ... n%26sa%3DN

I seen a study, but dont have the link handy of women who take testosterone and used to have a webpage of them (a support group) of female-to-male transexuals. Alot of them were going male pattern bald, and the moderator of the discussion went entirely NW6 bald. "She", who really was a "he" by that time, talked about taking finasteride and using minoxidil, but the minoxidil wasn't all that effective and the finas just killed "his" sex drive. Alot of the pictures showed balding women, who looked alot like men, but even the ones who werent balding in may cases had greying hair and always masculine, ageing faces as compared with their befores. Beards, body hair..........all of that.

Regarding the inhibitory growth factors secreted by the dp cells, believe me, I have wondered about that a great deal. We know, via harold, that balding hairs lose CD200 molecules around them that seem to tell the immune system "not" to attack, making one real clear difference between balding and non-balding hairs....................it seems (to me anyway) that after hairs get "enough" androgen, they simply turn their response to androgen from good to bad and the papilla starts releasing the wrong things to the rest of the follicle. Like I said...........if we could apply topical DHT to Brad Pitt, giving him about three times the amount he would normally have, or if we could somehow stimulate his hairs androgen receptors to be three times as active, I'd bet he'd start losing his hair in about a year and a half to two years. Thats just my opinion. Its hard for me to believe that human beings evolved to have "two different" kinds of head hair, and experiments prove me to be right because as Ive posted, when "donor" area hair is given enough testosterone (not even DHT!) in experiments, it starts to react negatively to it.


There are a few other female-to-male women's pics Ive found online. One a "pornstar" that is very yucky of a bald woman who still has female genitalia and a hairy body and very thick beard whose name escapes me and there were some video footage of a woman on Maury Povitch's talk show that looked like any other balding middle aged man. Just add testosterone.

 

[Armando Jose]

More interestingly, why do balding dermal papilla cells secrete inhibitory growth factors of their own accord even when injected into mice?

First, I want you to look at this video, http://www2.oprah.com/tows/pastshows/20 ... 0916.jhtml
Those are transgendered TWINS. They have the exact same DNA. One is balding and the other has slight thinning over her sister. I say "her" , because she still doesn't have male genitalia even though she looks like a man. Note the grey facial hair (beard) and aged skin. There are pictures you can pull up and see her face up close.............and how much more aged it is. The other balding twin woman (yup, she is still a woman) speaks for itself. Right beside her sister, with all her hair.
What this tells me is that although we were always told that some "change" happens in hair at puberty and its forevermore destined to be what it is...............that clearly cant be true. If a woman has baldness genes, and you give her testosterone cream for about a year...........she will start going male pattern bald just like her brothers or dad.

Hi Michael;

Thank you for the video link, where clearly we see to "Juanita" with a curly hair in the adolescence, and after she/he straightened his hair
http://www2.oprah.com/tows/slide/200509 ... _107.jhtml
and probably after then, he/she cut severily his/her hair.

Other thing is the first case, where he conserved his/her hair probably, and according to my theory, due at his hair have a sufficient lenght to avoid problems with sebu flow.

OTOH, I am with you that androgens give us a gender difference in skin, but this is not the case with hair.

Have a nice day

Armando

 

[bornthisway]

Do we know which growth inhibitory factors are secreted by balding dermal papilla, bmp signal inhibition?

BMP signaling in dermal papilla cells is required for their hair follicle-inductive properties

Hair follicle (HF) formation is initiated when epithelial stem cells receive cues from specialized mesenchymal dermal papilla (DP) cells. In culture, DP cells lose their HF-inducing properties, but during hair growth in vivo, they reside within the HF bulb and instruct surrounding epithelial progenitors to orchestrate the complex hair differentiation program. To gain insights into the molecular program that maintains DP cell fate, we previously purified DP cells and four neighboring populations and defined their cell-type-specific molecular signatures. Here, we exploit this information to show that the bulb microenvironment is rich in bone morphogenetic proteins (BMPs) that act on DP cells to maintain key signature features in vitro and hair-inducing activity in vivo. By employing a novel in vitro/in vivo hybrid knockout assay, we ablate BMP receptor 1a in purified DP cells. When DPs cannot receive BMP signals, they lose signature characteristics in vitro and fail to generate HFs when engrafted with epithelial stem cells in vivo. These results reveal that BMP signaling, in addition to its key role in epithelial stem cell maintenance and progenitor cell differentiation, is essential for DP cell function, and suggest that it is a critical feature of the complex epithelial-mesenchymal cross-talk necessary to make hair.

 

[michael barry]

Bornthisway.........

I used to know the positive and negative growth factors secreted by the papilla. Right off the top of my head some of the negative growth factors were FGF-7, TGF-beta, TNF-alpha (I think, cant remember), Protien Kinease C seems to have been one, and Thrombospondin for sure, and they were looking for a couple of more.

I used to know the positive ones............It seels like a couple of Interluekins were "positive" growth factors. If you look into my posts from 2-3 years ago you might find them, but it would be much easier to do a pubmed or google search for "dermal papilla growth factors" and get various results.



[b]Did you look at the photographs? That is what I wanted you to see. The women had fine hair.................until they too testosterone and then they went bald. Ive seen more, hell several more. Thats why I kinda think different than what I used to about "finding" what negative growth factor in the papilla is "causing" it. [/b]

If you think about it, Harold pointing out that CD200 is lost to the hair follicle, hence giving the immune system the green light to attack the follicle, finding out what is exactly upstream of it might be mitochonidrial dna respoding to instructions pre-programmed before birth telling it "when you recieve x-amount of androgen, you will then react badly to it at that point"----kinda like when a buzz becomes "drunk" when you are drinking alcohol. The only way to get more sober at that point is to stop drinking more. We keep looking for something that goes wrong, but my point is that NOTHING may be going wrong, we might just be hardwired to bald. Plenty of primates are. In fact most all macaques and oranguatans and bonoboos do indeed bald. Even the macaque females bald. It might not have anything to do with selection, it might just be God kicking us in the balls.


Its been pointed out on the board in the past that mice who test better in mazes (and thus are smarter) also have sebaceous gland hyperplasia and much thinner coats as they age as a result of an overexpression of the SMAD-7 protien. Ever notice how many really smart scientists go bald? Maybe its natural selections way of penalizing men who are so much smarter than other men or something.

Then again, maybe its just hyperkeratinization like Doctor thinks it is and your hair is growing too fast at the kertainocyte cell "factory" and to ward off cancer, the body starts reacting negatively too it to save you from a cancer of the scalp by overexpressing TGF beta, which then induces and immuno response, which then gets excessive collagen secreted around the dermal papilla------all the fault of an overactive androgen receptor.......His "theory" is the best "somethings merely going wrong" theory Ive ever seen. He doenst seem to post anymore though, Ive not seen him in a while. You can look back at his old post.

Ive also seen it reasoned that we have hair cycles to protect us from positive growth factors going on "too long" and inducing cancer up there----perhaps thats a possibility.



Thats about all I can really speculate on for my own part. You have probably noticed that I focus on things that "make" new hair follicles like Hair Multiplication (ICX, Adearns, Phoenixbio) and Follica's research (wounding and de noveau hair growth) more than finding out what is going on in baldness. I just think that the best we can do at this point is to find a good anti-androgen that works for us.

Finasteride+Fluridil might be a good way for you to keep what you have in other words.......while waiting for "them" to come up with "new" hair in the future. Ive long ago decided I wasn't smart enough to figure out baldness and left it to the brainiac scientists like Peter Procotor who study that stuff.

 

[bornthisway]

I agree, I was curious which factors that particular study was referring to since I don't believe I've found the full text. Though, finding an agent to better suppress inflammation or that is also anti-androgenic is sort of the purpose of my attempts at probing and understanding (or an agent that safely promotes a positive growth factor).. there are actually a lot of compounds out there that may prove useful. I think magnolia obovata seems interesting, at least its constituents such as magnolol, honokiol, obovatol topically. Another route would be internally, as it is effective against prostate cancer.

Some interesting studies below.. the first two imply it would prevent skin photoaging, the others talk about anti-bacterial and anti-inflammatory aspects. Then a few studies regarding cancer/prostate cancer.

Increase of collagen synthesis by obovatol through stimulation of the TGF-beta signaling and inhibition of matrix metalloproteinase in UVB-irradiated human fibroblast.

Dermatol Sci. 2007 May;46(2):127-37. Epub 2007 Mar 7

College of Pharmacy, Chungbuk National University, 48, Gaesin-dong, Heungduk-gu, Cheungju, Chungbuk 361-763, South Korea.

BACKGROUND: Alterations of the extracellular matrix (ECM) is critical in the photo and age-damaged skin. Thus any compounds keep ECM can protected from photo and aged-damaged skin. ECM is predominantly composed of type I and type III collagens in the dermis. Transforming growth factor (TGF-beta)s play important roles in cellular biosynthesis of extracellular matrix. Activator protein 1 (AP-1) and Smad are significant factors that mediate TGF-beta. OBJECTIVE: We have investigated increasing effects of obovatol, a biphenolic compound isolated from leaves of Magnolia obovata on the collagen synthesis through stimulation of the TGF-beta signaling and inhibition of matrix metalloproteinase, thereby protect against from UV damages via maintain of collagen in the UVB irradiated human fibroblast cells. METHODS: The fibroblasts were pretreated with obovatol for 24h and then the cells were irradiated with UVB. UVB-exposed cells were further cultured for 24h. Type I procollagen, MMP-3, TGF-beta and Smad as well as phosphorylation of MAPK family expression were determined by Western blot. The activation of AP-1 was investigated using EMSA. The released type I procollagen and TGF-beta into cell culture medium were determined by Western blot after concentration of these proteins. RESULTS: The results showed that obovatol stimulated type I procollagen, TGF-beta, and Smad expression and inhibited matrix metalloproteinase-3 (MMP-3) in dose-dependent manner (1-5muM) in UVB-irradiated human fibroblast cells. Obovatol also inhibited UVB-induced activation of AP-1 and MAP kinases. CONCLUSION: These results suggest that obovatol increases collagen synthesis through stimulation of the TGF-beta signaling and inhibition of matrix metalloproteinase in UVB-irradiated human fibroblast, thus obovatol could be effective against photo-damaged skin.

PMID: 17346934

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Magnolia ovovata extract and its active component magnolol prevent skin photoaging via inhibition of nuclear factor ?B

Eur J Pharmacol. 2007 Jun 22;565(1-3):212-9. Epub 2007 Feb 17.
PMID: 17346696

Abstract

Transcriptional activity of nuclear factor ?B (NF-?B) is induced by environmental signals including inflammation, UV irradiation and oxidative stress. It was shown that the NF-?B activity greatly contributes to the skin photoaging process. Thus, it is plausible that NF-?B inhibitors could directly prevent skin photoaging. In this study, we found that Magnolia ovovata extract inhibited NF-?B-mediated gene expression and demonstrated that external swabbing with Magnolia extract preventing skin photoaging processes through keratinocyte hyperproliferation and degradation of collagen fibers in mice skin. We have identified magnolol as the solely responsible active compound in Magnolia extract. Magnolol effectively inhibited the NF-?B-dependent transcription, but no effect was observed with other inducible transcription factors such as activator protein-1 (AP-1) and cyclic-AMP responsive element-binding protein (CREB). In addition, magnolol was effective in inhibiting the production of basic fibroblast growth factor (bFGF) and matrix metalloprotease-1 (MMP-1) from the cells overexpressing p65, a major subunit of NF-?B. Although magnolol did not affect the phosphorylation and degradation of I?B?, it inhibited the nuclear translocation of the activated NF-?B. These findings suggest that Magnolia extract and its active component magnolol can be used to prevent the skin photoaging via inhibiting NF-?B by external topical application.

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In vitro antibacterial and anti-inflammatory effects of honokiol and magnolol against Propionibacterium sp.

Biol Pharm Bull. 2007 Nov;30(11):2201-3.
PMID: 17978501

Abstract:

Honokiol and magnolol, two major phenolic constituents of Magnolia sp., have been known to exhibit antibacterial activities. However, until now, their antibacterial activity against Propionibacterium sp. has not been reported. To this end, the antibacterial activities of honokiol and magnolol were detected using the disk diffusion method and a two-fold serial dilution assay. Honokiol and magnolol showed strong antibacterial activities against both Propionibacterium acnes and Propionibacterium granulosum, which are acne-causing bacteria. The minimum inhibitory concentrations (MIC) of honokiol and magnolol was 3-4 µg/ml (11.3-15 µM) and 9 µg/ml (33.8 µM), respectively. In addition, the killing curve analysis showed that magnolol and honokiol killed P. acnes rapidly, with 105 organisms/ml eliminated within 10 min of treatment with either 45 µg (169.2 µM) of magnolol or 20 µg (75.2 µM) of honokiol per ml. The cytotoxic effect of honokiol and magnolol was determined by a colorimetric (3-(4,5-dimetyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) (MTT) assay using two animal cell lines, human normal fibroblasts and HaCaT. In this experiment, magnolol exhibited lower cytotoxic effects than honokiol at the same concentration, but they showed similar cytotoxicity when triclosan was employed as an acne-mitigating agent. In addition, they reduced secretion of interleukin-8 and tumour necrosis factor ? (TNF-?) induced by P. acnes in THP-1 cells indicating the anti-inflammatory effects of them. When applied topically, neither phenolic compound induced any adverse reactions in a human skin primary irritation test. Therefore, based on these results, we suggest the possibility that magnolol and honokiol may be considered as attractive acne-mitigating candidates for topical application.

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Magnolol Inhibits iNOS, p38 Kinase, and NF-?B/Rel in Murine Macrophages

Mei Hong Li · In Youp Chang · Ho Jin You · Dae Sik Jang · Jin Sook Kim · Young Jin Jeon ? pp. 293~299(7 pages)

We demonstrate that magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, inhibits LPS-induced expression of iNOS gene in RAW 264.7 cells (murine macrophage cell line).

Treatment of RAW 264.7 cells with magnolol inhibited LPS-stimulated nitric oxide production in a dose-related manner. RT-PCR analysis showed that the decrease of NO was due to the inhibition of iNOS gene expression.

Western immunoblot analysis of phosphorylate p38 kinase showed magnolol significantly inhibited the phosphorylation of p38 kinase which is important in the regulation of iNOS gene expression.
The specific p38 inhibitor SB203580 abrogated the LPSinduced NO generation and iNOS expression, whereas the selective MEK-1 inhibitor PD98059 did not affect the NO induction.

Immunostaining of p65 and reporter gene assay showed that magnolol inhibited NF-?/Rel nuclear translocation and transcriptional activation, respectively. Collectively, this series of experiments indicates that magnolol inhibits iNOS gene expression by blocking NF-?/Rel and p38 kinase signaling.

Due to the critical role that NO release plays in mediating inflammatory responses, the inhibitory effects of magnolol on iNOS suggest that magnolol may represent a useful anti-inflammatory agent.

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Here are some studies regarding prostate cancer.

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Honokiol, a Constituent of Oriental Medicinal Herb Magnolia officinalis, Inhibits Growth of PC-3 Xenografts In vivo in Association with Apoptosis Induction.

Clin Cancer Res. 2008 Feb 15;14(4):1248-57.
PMID: 18281560

Authors' Affiliations: Department of Pharmacology, University of Pittsburgh Cancer Institute, and Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

PURPOSE: This study was undertaken to determine the efficacy of honokiol, a constituent of oriental medicinal herb Magnolia officinalis, against human prostate cancer cells in culture and in vivo.

EXPERIMENTAL DESIGN: Honokiol-mediated apoptosis was assessed by analysis of cytoplasmic histone-associated DNA fragmentation. Knockdown of Bax and Bak proteins was achieved by transient transfection using siRNA. Honokiol was administered by oral gavage to male nude mice s.c. implanted with PC-3 cells. Tumor sections from control and honokiol-treated mice were examined for apoptotic bodies (terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay), proliferation index (proliferating cell nuclear antigen staining), and neovascularization (CD31 staining). Levels of Bcl-2 family proteins in cell lysates and tumor supernatants were determined by immunoblotting.

RESULTS: Exposure of human prostate cancer cells (PC-3, LNCaP, and C4-2) to honokiol resulted in apoptotic DNA fragmentation in a concentration- and time-dependent manner irrespective of their androgen responsiveness or p53 status. Honokiol-induced apoptosis correlated with induction of Bax, Bak, and Bad and a decrease in Bcl-xL and Mcl-1 protein levels. Transient transfection of PC-3 cells with Bak- and Bax-targeted siRNAs and Bcl-xL plasmid conferred partial yet significant protection against honokiol-induced apoptosis. Oral gavage of 2 mg honokiol/mouse (thrice a week) significantly retarded growth of PC-3 xenografts without causing weight loss. Tumors from honokiol-treated mice exhibited markedly higher count of apoptotic bodies and reduced proliferation index and neovascularization compared with control tumors.

CONCLUSION: Our data suggest that honokiol, which is used in traditional oriental medicine for the treatment of various ailments, may be an attractive agent for treatment and/or prevention of human prostate cancers.

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Growth inhibitory effects of obovatol through induction of apoptotic cell death in prostate and colon cancer by blocking of NF-kappaB.

Eur J Pharmacol. 2008 Mar 17;582(1-3):17-25. Epub 2008 Jan 5.
PMID: 18241858 [PubMed - in process]

College of Pharmacy, Chungbuk National University, 48, Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763, South Korea.

Biphenolic components in Magnolia obovata including magnolol and honokiol have shown several pharmacological activities such as anti-tumor, anti-oxidant and anti-inflammatory effects. Previously in cultured macrophage Raw264.7 cells and fibroblast, we found that obovatol, an active compound isolated from M. obovata inhibited NF-kappaB activity which has been known to be a significant transcriptional factor to control of cancer cell growth. We investigated here whether obovatol could inhibit NF-kappaB activity, and thereby inhibit cancer cell growth in prostate (LNCaP and PC-3) and colon cancer (SW620 and HCT116) cells. Treatment of obovatol (10, 15, 20, 25 muM) inhibits cancer cell growth in the absence or the presence of tumor necrosis factor-alpha (TNF-alpha , 10 ng/ml) and tetradecanoyl phorbol acetate (TPA 10 or 50 nM) in a concentration-dependent manner through induction of apoptotic cell death. Cytotoxic activity was not observed in normal cells with up to 50 muM obovatol. It was also found that obovatol inhibited TNF-alpha and TPA-induced transcriptional and DNA binding activities of NF-kappaB. In further study, obovatol decreased translocation p65 and p50 into nucleus via decrease of phosphorylation of IkappaB. Correlated well with the induction of apoptosis, obovatol increased the expression of the apoptotic genes; Bax, caspase-3, caspase-9, whereas inhibited expression of anti-apoptotic genes; Bcl-2, inhibitor of apoptosis protein (IAP-1) and X chromosome IAP (XIAP) as well as the cell proliferation marker genes; Cox-2, c-Fos, c-Jun and cyclin D1. These results suggest that obovatol inhibits prostate and colon cancer cell growth via induction of apoptotic cell death, and that inhibition of NF-kappaB may be a significant as its action mechanism.

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Honokiol causes G0-G1 phase cell cycle arrest in human prostate cancer cells in association with suppression of retinoblastoma protein level/phosphorylation and inhibition of E2F1 transcriptional activity

Mol Cancer Ther. 2007 Oct;6(10):2686-95
Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

The present study was undertaken to gain insights into the mechanism of cell cycle arrest caused by honokiol, a constituent of oriental herb Magnolia officinalis. The honokiol treatment decreased the viability of PC-3 and LNCaP human prostate cancer cells in a concentration- and time-dependent manner, which correlated with G0-G1 phase cell cycle arrest. The honokiol-mediated cell cycle arrest was associated with a decrease in protein levels of cyclin D1, cyclin-dependent kinase 4 (Cdk4), Cdk6, and/or cyclin E and suppression of complex formation between cyclin D1 and Cdk4 as revealed by immunoprecipitation using anti-cyclin D1 antibody followed by immunoblotting for Cdk4 protein. The honokiol-treated PC-3 and LNCaP cells exhibited a marked decrease in the levels of total and phosphorylated retinoblastoma protein (Rb), which correlated with the suppression of transcriptional activity of E2F1. Exposure of PC-3 and LNCaP cells to honokiol resulted in the induction of p21 (PC-3 and LNCaP) and p53 protein expression (LNCaP). However, small interfering RNA (siRNA)-mediated knockdown of either p21 (PC-3 and LNCaP) or p53 (LNCaP) protein failed to confer any protection against honokiol-induced cell cycle arrest. The honokiol treatment caused the generation of reactive oxygen species (ROS), and the cell cycle arrest caused by honokiol was partially but significantly attenuated in the presence of antioxidant N-acetylcysteine. In conclusion, the present study reveals that the honokiol-mediated G0-G1 phase cell cycle arrest in human prostate cancer cells is associated with the suppression of protein level/phosphorylation of Rb leading to inhibition of transcriptional activity of E2F1.

PMID: 17938262

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About the components...

Pharmacology of obovatol

The biphenyl ether lignan obovatol from M. obovata (Ito et al. 1982) is slightly different from magnolol and honokiol not only chemically but also pharmacologically. Obovatol inhibited the chitin synthase 2 activity of Saccharomyces cerevisiae with an IC50 of 38 µM. Its derivative, tetrahydroobovatol, inhibited chitin synthase 2 activities under the same conditions with an IC50 of 59 µM. These compounds exhibited no inhibitory activity for chitin synthase 3, and showed less inhibitory activity for chitin synthase 1 than for chitin synthase 2 (IC50 > 1 mM). These results indicated that obovatol and tetrahydroobovatol are specific inhibitors of chitin synthase 2. Furthermore, obovatol and tetrahydroobovatol showed antifungal activities against various pathogenic fungi, with a particularly strong inhibitory activity against Cryptococcus neoformans (MIC 7.8 mg/L). The results indicate that obovatol and tetrahydroobovatol can potentially serve as antifungal agents (Hwang et al. 2002).


Pharmacology of magnolol and honokiol
Magnolol and honokiol, two major phenolic constituents of Magnolia species which are abundantly found in the medicinal plants M. officinalis and M. obovata, show multiple pharmacological effects (Chen et al. 2006). Research has elucidated the underlying mechanism of some of their anti-inflammatory and anti-oxidative effects. It has been found, for example, that magnolol is 1000-fold more potent than ?-tocopherol in inhibiting lipid peroxidation in rat mitochondria (Chang et al. 2003). All active Magnolia constituents (magnolol, honokiol, obovatol) showed weak inhibition for inducible NO synthase (iNOS) activity, but potent inhibition of iNOS induction and activation of nuclear factor-kappa B (Matsuda et al. 2001). They also inhibit rat liver acyl-CoA: cholesterol acyltransferase (ACAT) with IC50 values of 42, 71, and 86 µM, respectively (Kwon et al. 1997). Honokiol may protect the myocardium against ischemic injury and suppress ventricular arrhythmia during ischemia (Tsai et al. 1999). The mechanism of anxiolytic activity of various Magnolia extracts has been studied. The observed antimicrobial activity demonstrates the potential of Magnolias to be an adjunct in the treatment of periodontitis (Ho et al. 2001).

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CHEMISTRY OF MAGNOLIA GENUS

The principal substantial compounds present in plants of the Magnoliaceae family are different phenolic compounds and terpenoids. Many phenolic compounds have been found in the leaves and bark; for example gallic acid, sennosides A and B, hesperidin, naringin, syringin, and especially two neolignan compounds, magnolol (I) and honokiol (II) (Fig.1). The magnolol content of magnolia bark is generally in the range of 2-10 %, while honokiol tends to occur naturally at 1-5 percent in the dried bark. Magnolol and honokiol are without question pharmacologically the most meaningful constituents of magnolia bark (Watanabe et al. 1983, Liu et al. 2006). From the leaves and bark of M. obovata, the novel biphenyl ether lignans, obovatol (III) (Fig. 1) and obovatal were isolated (Ito et al. 1982), together with some sesquiterpene-neolignans, eudesobovatols A and B, eudesmagnolol, eudeshonokiols A and B, clovanemagnolol, and caryolanemagnolol (Fukuyama et al. 1992).

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It would appear magnolia obovata has all 3 components, while officinalis has 2. The studies were plant specific taking magnolol or honokiol from either.

 

[bornthisway]

More on the importance of inflammation in Androgenetic Alopecia (including UV, porphyrins via Propionibacterium sp).. interesting article I read a while ago. Magnolia perhaps will prove useful against Propionibacterium sp and UV as well (aside bacteria/inflammation in general). The statistics for porphyrins in this article were taken from the earlier study I posted.

Presence of porphyrins (produced by Propionibacterium sp.) in the pilosebaceous duct of 58% of Androgenetic Alopecia patients (compared with 12% of control subjects), which are able to induce the production of complement (C5) chemotactic factor, is considered to be a possible cofactor of this initial pro-inflammatory stress.

Androgenetic alopecia and microinflammation

Yann F. Mahé,PhD, Jean-François Michelet,MSc, Nelly Billoni, MSc, Françoise Jarrousse, BTS , Bruno Buan, BTS , Stephane Commo, BTS, Didier Saint-Léger,PhD and Bruno A. Bernard,PhD

International Journal of Dermatology Volume 39 Issue 8 Page 576 - August 2000

Today, androgenetic alopecia (Androgenetic Alopecia) is considered to be an alteration of hair growth and/or a premature aging of the pilosebaceous unit with a multifactorial and even polygenic etiology. 1 The fact that the success rate of treatment with either antihypertensive agents, or modulators of androgen metabolism, barely exceeds 30% means that other pathways may be envisioned. The implication of various activators of inflammation in the etiology of Androgenetic Alopecia has progressively and recently emerged from several independent studies. 2,3,4,5,6,7,8,9,10,11 A fibroplasia of the dermal sheath, which surrounds the hair follicle, is now suspected to be a common terminal process resulting in the miniaturization and involution of the pilosebaceous unit in Androgenetic Alopecia. 2 8 We review here several observations underlining the possible implication of a slow, silent, and painless process in Androgenetic Alopecia. Because we think that it should not be confused with a classical inflammatory process, we have called it microinflammation. An early study referred to an inflammatory infiltrate of mononuclear cells and lymphocytes in about 50% of the scalp samples studied. 2 Another more recent study by Jaworsky et al . 3 confirmed an inflammatory infiltrate of activated T cells and macrophages in the upper third of the hair follicles from transitional regions of alopecia (i.e. which are characterized by actively progressing alopecia). This study also reported the occurrence of a developing fibrosis of the perifollicular sheath, together with the degranulation of follicular adventitial mast cells. The miniaturization of the hair follicles was found to be associated with a deposit of so-called "collagen or connective tissue streamers" beneath the follicle, 2,7 as well as a 2 2.5 times enlargement of the follicular dermal sheath composed of densely packed collagen bundles. 3 This thickening of the dermal sheath in progression zones of Androgenetic Alopecia has also recently been observed in our laboratory using immunohistochemical staining ( Fig. 1 ).

Horizontal section studies of scalp biopsies indicate that the so-called perifollicular fibrosis is generally mild, consisting of loose, concentric layers of fibrotic collagen that must be distinguished from cicatricial alopecia. 4 It is unclear whether or not the fibrosis seen in follicular streamers (stelae or fibrous tracts) is permanent and/or alters the downgrowth of anagen hair follicles. Only 55% of male pattern Androgenetic Alopecia patients with microinflammation had hair regrowth in response to minoxidil treatment, which was less than the 77% of patients with no signs of inflammation, 4 suggesting that, to some extent, perifollicular microinflammation may account for some cases of male pattern Androgenetic Alopecia which do not respond to minoxidil. 4 Another study on 412 patients (193 men and 219 women) confirmed the presence of a significant degree of inflammation and fibrosis in at least 37% of Androgenetic Alopecia cases. 5 The upper location of the infiltrate near the infrainfundibulum 2 7 clearly distinguishes Androgenetic Alopecia from alopecia areata (AA), the latter disease being characterized by infiltrates in the bulb and dermal papilla zone. 12

The aim of this review is to determine the location and chronology of the microinflammation process within the complex pathophysiology of the human pilosebaceous unit in order to improve the possible approaches for the reduction or prevention of the development of Androgenetic Alopecia. Classically, an inflammatory process is ascribed to a central major mediator or pathway. Such a monofactorial vision has been historically well exemplified by the famous interleukin-1 (IL-1) scheme developed by Oppenheim et al . 13 which is still valid even after 13 years. In fact, many inflammatory agents are at the center of a huge array of effects, involving cells, enzymes, adhesion molecules and other biological mechanisms. The identification of the effects of isolated factors is only part of the problem; it may be more important to determine when and where the individual factors are involved in the complex sequence. This pathway has been clearly identified, and several inhibitory anti-inflammatory drugs acting on this aspect of inflammation have been developed and clinically evaluated. 14,15 , 16,17 The cytokine/chemokine side of microinflammation

Why does microinflammation take place in the pilosebaceous unit and for what benefit and purpose? Fig. 2 and Fig. 3 show, in a simplified sequence, that inflammation is a multistep process which may start from a primary event. Let us look at the clues at the "crime scene" of Androgenetic Alopecia: we observe a perifollicular infiltrate in the upper follicle near the infundibulum. 2 7 This suggests that the primary causal event for the triggering of inflammation might occur near the infundibulum. 3,7 Supporting this point of view, improvement of the inflammatory aspect of Androgenetic Alopecia has been reported in a pilot study with an antimicrobial lotion. 7 One could speculate that several inhabitants of the scalp, such as the "triad" ( Propionibacterium sp.; Staphylococcus sp.; Malassezia ovalis ) or other members of the transient flora, could be involved in this complex inflammatory process. 7 The presence of porphyrins (produced by Propionibacterium sp.) in the pilosebaceous duct of 58% of Androgenetic Alopecia patients (compared with 12% of control subjects), which are able to induce the production of complement (C5) chemotactic factor, is considered to be a possible cofactor of this initial pro-inflammatory stress. 6,7 Keratinocytes are also known to respond within minutes to chemical stress, pollutants, UV irradiation or even mechanical stress. 37 Not only are radical oxygen species, 38 NO, 39 PGs, and histamine 40 produced, but also intracellularly stored IL-1 is released 37,41 (see Fig. 2 and step 1 of Fig. 3 ). By itself, this pro-inflammatory cytokine (as well as IL-1 which binds to the same receptor) is able to inhibit the growth of isolated hair follicles in culture in vitro. 9 11 This concentration-dependent inhibition of human hair elongation and survival indicates a high sensitivity to IL-1 of the isolated organ in culture in vitro (IC 50 = 10 pg/mL 11 ). In vivo , transgenic mice which overexpress IL-1 in the basal epidermis and in the outer root sheath of their pelage hair follicles exhibit a spontaneous cutaneous phenotype characterized by a sparseness of hair. 42 As a response to an IL-1 signal, adjacent keratinocytes which express receptors for IL-1 start to engage the transcription of IL-1 responsive genes 41 ( Fig. 3 , step 2). In vitro , following IL-1 stimulation, this transcriptional activation cascade is induced within 6 h in plucked human hair follicles. 11

Alternatively, skin keratinocytes, which may also have antigen presenting capabilities, could theoretically induce T-cell proliferation in response to bacterial antigens. 51 These antigens, once they have been "tagged," are then selectively destroyed by infiltrating macrophages, Langerhans cells, or natural killer cells. 50,52 On many occasions, however, the causal agent persists, resulting in sustained inflammation ( Fig. 3, step 4). This corresponds partly to the situation which has been pictured in the progression zone of roughly one-third of alopecia cases: infiltrating T lymphocytes, together with mastocytes and macrophages, located in the upper perifollicular adventitial dermal sheath perpetuate a local inflammatory stage. 27 This phase of inflammation often results in tissue remodeling, where collagenases, such as matrix metalloproteinase (MMP)-9 (transcriptionally activated by pro-inflammatory cytokines) or MMP-8 (directly produced by infiltrating cells), may play an active role. 5355 Thus, collagenases are suspected to contribute to the tissue changes and the so-called "perifollicular fibrosis" by "preparing" tissue matrix and basal membranes for macrophages and T-cell adhesion. Accordingly, this scenario facilitates the secretion of membrane-anchored cytokines, such as TNF-. 55 Other factors, such as MCP-1, have been directly suspected to contribute to organ fibrosis in an experimental model of renal inflammation. 56 As MCP-1, together with other chemokines, was found to be expressed in human hair follicles in vitro, 11 as well as in the eccrine ducts of sebaceous glands in vivo, 57 it might also be actively involved in the progression of perifollicular fibrosis detected in Androgenetic Alopecia. 26 The development of perifollicular fibrosis might thus appear as the signature of a disequilibrium between pro-and anti-inflammatory pathways.

Relations between inflammation and steroidogenesis: the missing link

There is no question that androgens are major modulators of hair loss. Recently, it was shown that testosterone inhibited the growth of outer root sheath keratinocytes only when they were cocultured with dermal papilla cells derived from the bald scalp of an adult macaque, 58 reinforcing the hypothesis of an androgen influence on hair growth via the dermal papilla. 59 The potent metabolite of testosterone (i.e. 5-dihydrotestosterone, 5-DHT) is considered as a "culprit". 60 5-DHT is generated from testosterone through the activity of 5-reductase (5-R). Two active isoforms of 5-R, which differ both in tissue site distribution as well as in optimal pH for enzymatic activity, have been identified and cloned. 61,62, 63 While the type II isoform is considered to be the major isozyme in genital tissues, 61 the type I isoform is considered to be the major isoform expressed in skin and in the pilosebaceous unit. 64,65 Isoform II, however, has recently been detected in the inner root sheath of the pilosebaceous unit by immunohistochemistry, 66,67 Northern blotting, 67 and the pH dependence of optimal enzymatic activity. 67 Thus, the contribution of both isoforms in the regression of the pilosebaceous unit is still a matter of debate. Recently, a clinical study using finasteride, a strong inhibitor of 5-RII (and weak inhibitor of 5-RI), showed that intervention in androgen metabolism could, to some extent, modulate the progression of Androgenetic Alopecia, when the drug was given by the oral route, 68 but not topically. 69 After oral ingestion, an improvement of hair growth was observed, which was associated with a drastic reduction of serum levels of 5-DHT, corresponding to those observed in castrates. 68 Despite such a reduction of circulating 5-DHT levels, however, a number of individuals (60-70%) still remained unresponsive to this treatment, indicating again that simple dysregulation of 5-DHT synthesis levels or a genetic polymorphism of 5-R genes cannot account for all cases of Androgenetic Alopecia, and a polygenic etiology should be considered. 1

Thus, to date, the only evident link that can be established between androgen metabolism and the complex inflammatory process is sebum production which is controlled by androgens. 70 As sebum harbors a large amount of microorganisms which use lipids as nutrients, 8 it cannot be excluded that, at least for some individuals, androgen metabolism might facilitate the colonization of the sebaceous infundibulum and sebaceous ducts by such microorganisms which may be involved in the first steps of pilosebaceous unit inflammation.

We propose here working hypotheses which do not invalidate the contribution of a hereditary genetic androgen imbalance in Androgenetic Alopecia, 60 but rather attempt to integrate the neglected microinflammatory aspects of alopecia into the complex etiology of Androgenetic Alopecia. On the one hand, excessive local and/or endocrine, genetically exacerbated 5-DHT synthesis results in sebaceous gland enlargement; 2,60 as a consequence, some scalps might offer more comfortable niches to harbor the previously mentioned pro-inflammatory microorganisms. 6,7 On the other hand, androgen imbalance and metabolism may be locally exacerbated by pro-inflammatory cytokines. For example, gingival fibroblasts have been reported to modify their androgen metabolism through the action of several growth factors, such as epidermal growth factor (EGF), transforming growth factor beta (TGF-), and the pro-inflammatory cytokines IL-1 and TNF-. 71 Therefore, one could speculate that, once the inflammatory process has been triggered, the androgenetic mechanism of alopecia could subsequently be locally amplified. This upregulation of androgen metabolism by pro-inflammatory cytokines remains, however, to be established at the pilosebaceous unit level.

Our visit to the "crime scene" of Androgenetic Alopecia yielded many clues ( Fig. 4 ). We know now that, at least in about one-third of cases, the tool which causes the lethal damage is a microinflammatory process. Several factors are present, however, which are suspected to have handled the tool: androgens, microbial flora, endogenous or exogenous stress, genetic imbalance, and possibly others. Although other suspects or tools are likely to be discovered in the future, it cannot be excluded that, for each individual, the causal agent, as well as the sequence of events or combined factors, may be different. The large number of molecules claimed to be active and patented in this field, 89 and their limited efficacy in offering a definite and extensive cure of Androgenetic Alopecia, confirm that the mechanism of Androgenetic Alopecia is highly complex. Accordingly, it appears that, due to the complexity and multiple interactivities and cooperations involved throughout the distinct inflammatory pathways (partly described in Fig. 2 ), an anti-inflammatory strategy should be targeted to the appropriate effector(s) at the right moment. For this purpose, we have developed a simple assay to evaluate individuals with potentially affected hair follicles. 11 We observed that plucked hair specimens of 33% of the 116 volunteers evaluated could be classified as highly inflammatory in terms of spontaneous IL-1 production. 11 Consequently, the identification of the "inflammatory alopecic individuals" may help to adapt the right answer to the right cause. Such a selective approach might be valuable for other parameters, such as an imbalance in 11 HSD activity, 5-DHT synthesis, or microorganism colonization. Encompassing individual diversity is thus a prerequisite for appropriately addressing the biological conditions contributing to Androgenetic Alopecia. Our findings and a review of the literature suggest that inflammation in its diversity is a potentially active player to consider in this approach.

 

[michael barry]

Bornthisway,

Very interesting stuff................you really are "working on this" arent you?



The Bertand paper pointed out:

Thus, to date, the only evident link that can be established between androgen metabolism and the complex inflammatory process is sebum production which is controlled by androgens. 70 As sebum harbors a large amount of microorganisms which use lipids as nutrients, 8 it cannot be excluded that, at least for some individuals, androgen metabolism might facilitate the colonization of the sebaceous infundibulum and sebaceous ducts by such microorganisms which may be involved in the first steps of pilosebaceous unit inflammation

Bornthisway,
can I show you something?......

A. METHODS

1. Determination of Forehead Sebum Production

A 63-year old Asian male volunteer was used to test and analyze sebum production from the forehead region. The forehead was washed thoroughly by soap twice and cleaned by 70% isopropyl alcohol twice. Sebum production was measured 30 to 60 minutes later by a sebum meter (Courage/Khazaka Electronic GmbH, Germany). The sebum meter tape probe (7 mm×8 mm) covered 56 mm 2 area in each measurement. Ten measurements were made within the 4 cm square area (16 cm 2 ) located at the middle of the left or right side forehead between the eyebrow and the hair line.

The sebum meter detected the difference in the transparency of the tape before and after the tape was placed on the forehead for 30 seconds and expressed the difference in an arbitrary number (S-value) between 0 to 300 (or higher). S-values of sebum accumulated on the foreheads of men are usually 200 to 300. Skin surface on hands usually showed a very low number (5 to 20). The S-value for forehead immediately after washing was less than 5. For men, the S-value gradually increased to about 50 within 30 minutes after washing and reached 100 to 200 in 45 minutes to 55 minutes.

To determine the rate of sebum production, the left and the right forehead areas were measured alternatively and each time at the comparable areas on the two sides. Ten measurements on each side (i.e., 20 measurements for two sides) could take about 15-20 minutes and the sebum-values ranged between 30 to 200. The S-values were different considerably at different areas of the forehead and could be influenced by environmental, including weather, diet, and physiological conditions. However, the ratio of the total S-value (the sum of 10 measurements) for the left and the total S-value for the right forehead was constant. For the Asian male tested in this experiment, the L/R ratios measured over a six month's period was within 1.15 to 1.38 if the S-values were determined 30 to 50 minutes after the forehead was washed thoroughly. Therefore, compounds applied to the left forehead that reduced the L/R ratio to lower than 1.1 were considered as topically active agents for suppression of sebum production.

B. RESULTS

1. ?-LA Inhibition of Human Forehead Sebum

In the experiment shown in FIG. 24, 0.2 ml of borage oil (containing 18% of ?LA) in a gel capsule was applied to the left forehead twice daily for 23 days. During this period, L/R ratio reduced from 1.28±0.03 down to 1.05±0.01. After the borage oil treatment was stopped, the L/R ratio returned to 1.20±0.14. The effect of borage oil on the sebum production on the left forehead was relatively small, possibly due to the fact that most ?LA in the borage oil was in the form of triglyceride that did not inhibit 5?-reductase (see Table 2). Free acid released from the glyceride by nonenzymic or enzymic action was probably responsible for the effect.

After the borage oil application was stopped and the L/R ratio recovered to 1.33, 20 mg of pure ?-LA was applied to the left forehead twice each day for 6 days. The L/R ratio decreased to 0.22 during this period. After the ?-LA application was stopped, the L/R ratio recovered slowly to 1.20±0.14 over the period of 16 days. The finding clearly showed that ?-LA was superior than borage oil in quickly suppressing sebum production from forehead of a human male subject.

2. Catechin Inhibition of Human Forehead Sebum Production

Twenty mg of (-)epigallocatechin gallate (EGCG) in 0.2 ml 70% ethanol was applied to the left forehead twice a day for 6 days (FIG. 25). The L/R ratio decrease from 1.20±0.02 to 0.71±0.04 during this period. After the EGCG treatment was stopped, the L/R ratio gradually recovered to 1.19±0.02 within 16 days. Subsequent treatment of the left forehead with 20 mg (-)epicatechin in 0.2 ml 70% ethanol twice a day for 6 days reduced the L/R ratio to 1.02±0.1. After the application was stopped, the L/R ratio gradually increased to the normal value of 1.21±0.01 in 10 days. Clearly EGCG was more effective in reducing the sebum production from forehead than (-)epicatechin.




You will also note that ECGC is ALSO an alpha five reductase type one inhibitor and type 2 inhibitor (at higher levles). 45% of Beyond-a-Century's green tea extract is ECGC. You can make your own topical with it by adding it to purified water and alcohol (as a carrier) at about a 60/40 ratio. I just put the GTE pills in there until the solubility limit is reached. Trust me.......it will dry up your sebum very much. GTE has also been shown to be extremely photoprotective, as well as black tea topically.



I hope this picture sends.............
http://www.applepoly.com/procyanidin-b-2/enlarge_2.htm

That is from apple proanthocyandins. The thing is.....................is that apple b-2 proanthocyanidins actually inhibit PKC and TGF beta 1 and 2. If you look through my old posts (go way back) you can find pictures of mice given apple, barley, grape proanthocyanindin oligomers and mice given minoxidil. The mice given apple b-2 and barley b3 proanthocyanidins had the best growth. Proanthos are very photoprotective also.

 

[bornthisway]

Bornthisway,

Very interesting stuff................you really are "working on this" arent you?



The Bertand paper pointed out:

Thus, to date, the only evident link that can be established between androgen metabolism and the complex inflammatory process is sebum production which is controlled by androgens. 70 As sebum harbors a large amount of microorganisms which use lipids as nutrients, 8 it cannot be excluded that, at least for some individuals, androgen metabolism might facilitate the colonization of the sebaceous infundibulum and sebaceous ducts by such microorganisms which may be involved in the first steps of pilosebaceous unit inflammation

Bornthisway,
can I show you something?......

A. METHODS

1. Determination of Forehead Sebum Production

A 63-year old Asian male volunteer was used to test and analyze sebum production from the forehead region. The forehead was washed thoroughly by soap twice and cleaned by 70% isopropyl alcohol twice. Sebum production was measured 30 to 60 minutes later by a sebum meter (Courage/Khazaka Electronic GmbH, Germany). The sebum meter tape probe (7 mm×8 mm) covered 56 mm 2 area in each measurement. Ten measurements were made within the 4 cm square area (16 cm 2 ) located at the middle of the left or right side forehead between the eyebrow and the hair line.

The sebum meter detected the difference in the transparency of the tape before and after the tape was placed on the forehead for 30 seconds and expressed the difference in an arbitrary number (S-value) between 0 to 300 (or higher). S-values of sebum accumulated on the foreheads of men are usually 200 to 300. Skin surface on hands usually showed a very low number (5 to 20). The S-value for forehead immediately after washing was less than 5. For men, the S-value gradually increased to about 50 within 30 minutes after washing and reached 100 to 200 in 45 minutes to 55 minutes.

To determine the rate of sebum production, the left and the right forehead areas were measured alternatively and each time at the comparable areas on the two sides. Ten measurements on each side (i.e., 20 measurements for two sides) could take about 15-20 minutes and the sebum-values ranged between 30 to 200. The S-values were different considerably at different areas of the forehead and could be influenced by environmental, including weather, diet, and physiological conditions. However, the ratio of the total S-value (the sum of 10 measurements) for the left and the total S-value for the right forehead was constant. For the Asian male tested in this experiment, the L/R ratios measured over a six month's period was within 1.15 to 1.38 if the S-values were determined 30 to 50 minutes after the forehead was washed thoroughly. Therefore, compounds applied to the left forehead that reduced the L/R ratio to lower than 1.1 were considered as topically active agents for suppression of sebum production.

B. RESULTS

1. ?-LA Inhibition of Human Forehead Sebum

In the experiment shown in FIG. 24, 0.2 ml of borage oil (containing 18% of ?LA) in a gel capsule was applied to the left forehead twice daily for 23 days. During this period, L/R ratio reduced from 1.28±0.03 down to 1.05±0.01. After the borage oil treatment was stopped, the L/R ratio returned to 1.20±0.14. The effect of borage oil on the sebum production on the left forehead was relatively small, possibly due to the fact that most ?LA in the borage oil was in the form of triglyceride that did not inhibit 5?-reductase (see Table 2). Free acid released from the glyceride by nonenzymic or enzymic action was probably responsible for the effect.

After the borage oil application was stopped and the L/R ratio recovered to 1.33, 20 mg of pure ?-LA was applied to the left forehead twice each day for 6 days. The L/R ratio decreased to 0.22 during this period. After the ?-LA application was stopped, the L/R ratio recovered slowly to 1.20±0.14 over the period of 16 days. The finding clearly showed that ?-LA was superior than borage oil in quickly suppressing sebum production from forehead of a human male subject.

2. Catechin Inhibition of Human Forehead Sebum Production

Twenty mg of (-)epigallocatechin gallate (EGCG) in 0.2 ml 70% ethanol was applied to the left forehead twice a day for 6 days (FIG. 25). The L/R ratio decrease from 1.20±0.02 to 0.71±0.04 during this period. After the EGCG treatment was stopped, the L/R ratio gradually recovered to 1.19±0.02 within 16 days. Subsequent treatment of the left forehead with 20 mg (-)epicatechin in 0.2 ml 70% ethanol twice a day for 6 days reduced the L/R ratio to 1.02±0.1. After the application was stopped, the L/R ratio gradually increased to the normal value of 1.21±0.01 in 10 days. Clearly EGCG was more effective in reducing the sebum production from forehead than (-)epicatechin.




You will also note that ECGC is ALSO an alpha five reductase type one inhibitor and type 2 inhibitor (at higher levles). 45% of Beyond-a-Century's green tea extract is ECGC. You can make your own topical with it by adding it to purified water and alcohol (as a carrier) at about a 60/40 ratio. I just put the GTE pills in there until the solubility limit is reached. Trust me.......it will dry up your sebum very much. GTE has also been shown to be extremely photoprotective, as well as black tea topically.



I hope this picture sends.............
http://www.applepoly.com/procyanidin-b-2/enlarge_2.htm

That is from apple proanthocyandins. The thing is.....................is that apple b-2 proanthocyanidins actually inhibit PKC and TGF beta 1 and 2. If you look through my old posts (go way back) you can find pictures of mice given apple, barley, grape proanthocyanindin oligomers and mice given minoxidil. The mice given apple b-2 and barley b3 proanthocyanidins had the best growth. Proanthos are very photoprotective also.

I rarely find myself intrigued by many subjects, but since this does directly affect me and others I do think it's interesting to attempt to understand the means of making an environment for growth promotion. I also am not fond of finasteride but realize that it tapered off most likely due to inflammation.. since for many it appears to lose effectiveness after ~2 years, minoxidil similarly loses therapeutic effect. By attempting to target the inflammation, both of these agents would have some desirable effect (as would any other which promotes hair growth, targeting inflammation alone makes the scalp environment better suitable for hair growth). I personally rather topically address the issue rather than internally, or at least take a supplement such as magnolia (often used in weight loss supplements, including the best seller Relora product -A proprietary blend of plant extracts Magnolia officinalis and Phellodendron amurense. Standardized to 1.5% Honokiol and 0.1% Berberine, 300mg-) which has a myriad of benefits as opposed to finasteride. I also read a negative aspect for a proscar study and a comment that further research is needed to determine if this holds true for 1 mg as well. "Of the 4,368 men who received finasteride, 6.4% had diagnosed prostate cancer of higher malignancy by the end of the study. Of the 4,692 men who received placebo, 5.1% had diagnosed prostate cancer of higher malignancy by the end of the study. The reason for this small 1.3% difference is unexplained by the study results, but a number of possible explanations were suggested by the investigators: (1) androgen deprivation therapy (therapy that lowers the level of androgen available to tissues and organs) can cause tissue changes that mimic high-grade malignancy when no malignancy is really present; (2) finasteride 5 mg may induce high-malignancy prostate cancers by its actions within prostate tissue cells; or, (3) finasteride 5 mg selects for high-malignancy cancers by selectively inhibiting low-malignancy cancers."

But I do think that, 2% Nizoral and 1% PTO are two good topical anti-inflammatory shampoos to alternate by (as well as increasing diameter).
Topicals:
GTE (would ECGC concentrations higher than the study [I believe 10%] cause a difference in results? i.e. 45-50%)
RK (0.01%) - seems to have promise, and is very cheap (dissolve in polysorbate 20 or coconut oil).
Vitamin B12 (0.03%) - will aid in growth, mechanisms not fully understood.. also cheap (water & ethanol)
Curcumin topically visually increases hair shaft diameter (at least for me, I believe some others noticed aesthetic improves as well) -- but it can be annoying to use (mostly due to length of time it needs to be in the hair) -- and the effect lasts only for a day requiring reapplication, I think internally curcumin and resveratrol would benefit.. but a more concentrated topical route would be interesting (especially if it degrades follicular androgen receptors).
Cayenne - I know there was a negative aspect in the RK study.. but it also states near the end: "RK, like capsaicin, might promote hair growth by decreasing androgen action through androgen receptor down-regulation on dermal papilla cells." There is also a study of cayenne and minoxidil being more effective, and SD PLISSKEN claiming almost total regrowth from that formulation. I believe IH (a hair veteran elsewhere) also used this topically w/o minoxidil. for a number of years (if it didn't help, I can't imagine using it for a prolonged period of time).
Applepoly - it seems their product is superior to most other formulations, it is also very experience. Unless a similar topical can be produced by a high grade extract, it is not cost effective. Cocoa is also rich in polyphenols and in one study there were 51mg procyanidin per 100mg of cocoa extract. B2 is one of the major procyanidins in cocoa. Compared to 500mg applepoly, the procyanidin content would be at least equal or slightly greater (250mg vs 215mg) but I'm sure there is going to be variation.. and also which powder/extract (perhaps all?) have similar content needs to be determined. It would be many times cheaper.

The following is an email from Applypoly replying to a customer regarding 'competition' (pulled off a forum):
" Here are some mails i recieved from Applepoly:

The total polyphenol content on one capsule (500 mg.) is approximately 420 mg. The procyanidin content is approximately 215 mg. The source crop is commercially grown. In the opinion of the foremost U.S. researcher (Dr. C.Y. Lee, Cornell University), organic apple production (on a commercial scale) is impossible. He's spent 30 years trying, he told me. One of the reasons we use our current raw materials production facility is that they are able to provide assays for pesticide residues. Other manufacturers are unable to give us this assurance. In development of Apple Poly, a great deal of attention was given to this matter. We wanted to make sure we were concentrating only the beneficial natural apple chemicals, and not pesticides, bacteria, mold and heavy metals. All of these are tested before each batch is bottled. About Poly-GRO:

We use denatured alcohol Poly-GRO because it is included in the original laboratory formula. The alcohol content of our product is far less that used in the clinical hair growth studies. Some is necessary for stability and absorption. I have a new formulation in development and may have that for you to test soon. We are trying to achieve stability and penetration with fewer synthetic ingredients. I like to have current clients give their opinions on our new products. Remind me in a month or so and I'll send some for you to try if it's ready. On your second question, it is difficult to compare "apples to apples" between Apple Poly and Applephenon. I met with representatives from Asahi in 2005 and offered our ORAC test results. They took a look, and acknowledged that they had ORAC tests on their product, and would not divulge their results. If their product had tested superior to ours, I think they would have been delighted to tell me. Apple Poly is standardized at 82% polyphenols by UV measurement. The main ingredients are procyanidin oligomers (appx. 50%), cholorogenic and caffeic acids, and catechins. Because ORAC measures the antioxidant speed and power of different substances, we consider it the best measure of potency.

Purple POly: (it's also from ogranic Grapes)

Purple Poly is standardized at 95% polyphenols and 85% polymers. Most grape seed in the US- virtually all of it- is >90% monomers. Monomer extracts are quite cheap and are primarily gallic acid, a weak antioxidant. Gallic acid has benefits, but weak compared to polymeric proanthocyanidins. Again, ORAC specification is a useful measure when comparing grape seed products. Purple Poly exceeds 20,000 ORAC units per gram. I can't find another grape seed extract manufacturer that even lists ORAC ratings. I might add that PurplePoly (they send free 10X500 caps of it with every order, didn't buy it) tested pretty good...or bad, depending how you look at it, compared to Swansons grapseed Leucoselct 200mg extract. I couldn't take two pills of Swanson's 200mg extract (bad on a test), but i could take two (didn't try for more) of PurplePoply's 500mg. (good on a test)

So it's looks like they have some great products (even if way they are presented on their website tends to make you puke) but are really to expensive, esspecialy for us foreigners (unless you're bloody rich of course). If i added how much money i spent on inernational shipping and taxes so far on hair products i'd probably go bald overnight!"

There are other topicals/compounds/formulations, but for the most part few have received much feedback or attention, or there were inherent flaws.. there's lots of gray area but I do feel comfortable with that list. Personally, I could see myself using a GTE and RK topical. Too many agents can be a pain (& costly), and with two of those shampoos, I think that would produce a pretty suitable environment for hair growth (less inflammation, stimulus growth factors). The B12 is also quite cheap, if it complimented another (maybe the GTE), it would be simple to mix the two (it's a .03% concentration, which is very little -- I wonder if there would be a major difference with a 1% concentration as there is with RK -- hopefully not). There were no issues when combining B12 with minoxidil resulting in better growth.