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The Holy Grail of Acne?

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#21 SweetJade1980

SweetJade1980

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Posted 30 January 2005 - 10:44 PM

QUOTE(bryan @ Jan 30 2005, 09:04 PM)
Because I _am_ kind of a stickler for details, I can't let this go by without comment:  as I indicated in that previous post above, dutasteride in the standard approved dose of 0.5 mg/day does in fact inhibit the type II enzyme to the tune of 98%-99%, but it inhibits the type I enzyme by only a little over half (dut is considerably more potent against type II than type I, and the type I enzyme is produced in the cell more rapidly than type II).  If anyone's interested in seeing the justification for those statements, the relevant data was published in a recent study which exhaustively examined the pharmacological properties of dutasteride.  I even scanned several of the graphs from that study and posted them...I'll post the links here, if anyone's interested in seeing them.

Acne is thought to be caused by Type I 5 AR enzymes, but as Bryan pointed out a Type I Inhibitor didn't stop oil production.

Well, here's a very CRUCIAL correction:  the study didn't measure sebum production at all!  All it did was measure the final effect on acne, and acne wasn't affected one way or the other!  I expect that in the near future, they WILL measure sebum production with 5a-reductase inhibition, because they were clearly surprised at the results, just like the rest of us.  I'm sure they want to get to the bottom of just exactly what IS the role of DHT in acne!

Avodart doesn't stop acne either. In fact it gave some males that never had acne acne, but did clear some others. There's a member of this board, Evigrex that took Avodart or Finasteride (Type II 5AR inhibitor) and it caused him to breakout and he had been clear previously due to accutane (correct me if I'm wrong). Futhermore someone on absolute acne boards was taking Finasteride for hair loss, but had to stop as it increased his testosterone (as expected since it's not converting into DHT or estrogen) and gave him acne that he's never had before.

I guess it's not all THAT surprising that finasteride could worsen acne a little in some people, because finasteride is just a specific type 2 inhibitor, whereas the 5a-reductase inside sebaceous glands appears to be exclusively type 1.  Therefore, I suppose you could argue that the small increase in testosterone that you get from using finasteride (~10% or so) could conceivably function as additional substrate for the type 1 enzyme in sebocytes that obviously isn't inhibited by the finasteride.  However, the failure of MK386 (or dutasteride?) to favorably affect acne is still quite puzzling, and there's no obvious explanation...

Anyway, below is the abstract being referred to, Bryan can you give us the full text?

I have a paper-copy of the study right here, but I don't have it in electronic form, unfortunately.  But if there's enough general interest in it, I can certainly scan it and post it on my Web site, which I've done with a number of other studies.  This one is only about three pages long.

Bryan

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I created my post before you had already responded about Avodart (but you beat me to it), yet I knew you would further correct me. Thank you ;-) Anyway, I would love to see your website, whats the address?

#22 SweetJade1980

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Posted 30 January 2005 - 11:23 PM

QUOTE(blackbirdbeatle @ Jan 29 2005, 07:12 PM)
Jade: Nice tree falling in the woods question of acne. Yes, I think we would have acne if we didn't have inflamation, they just wouldn't be red and raised. That is if you still think blocked pores by sebum and skin cells and bacteria thriving in it is acne. If we did get to the point where we didn't get inflammation from acne, I would be worried what other injuries we would have ignored from the lack of the body's natural defences.

I'm acne free but I don't understand why I grew out of it. Here's my thinking. You will always produce oil, and now that I've grown out of it, I still do. I also will still have the infalmmation response and the bacteria there to thrive if I ever get a spot again. This leads me to guess it's the keratinization that all of a sudden went right. But how? How can all of a sudden my cells become too sticky and plug the pores when I had acne, yet now, with nothing really changed, all of a sudden they dissolve in the sebum and are released on the surface of my skin like they are supposed to? How did they all of a sudden normalize? I know things like glycolic and such actually help to normalize it but that is with continued use and I'm at a complete loss as to why my body decided now that things would work right.

Any ideas?(I know that azelic acid, pine bark extract and sulphur all normalize this, along with retaniods in case anyone wants to use it).

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You know, I honestly don't know your acne history (& your parents acne history). I know you believe in certain natural treatments and practice eating certain types of healthy foods, but after that I'm at a loss. So, perhaps it might help if you share how long you had acne and when it disappeared? Did you ever take accutane? Of course during this time period were you always as physically active as you are now?

So if I was to assume your acne went away as a result of puberty ceasing (early 20s?) then it went away because your temporary hormonal imbalance no longer existed. However if you want a further breakdown, from what I've read androgens are responsible for sebum secretion. However you can be the oiliest person and not have acne and have very dry skin and have acne, so it must be something beyond just the sebum. My thoughts are thought it may be the contents of the sebum (inflammatory products, proteins, hormones, bacteria, etc) that may contribute to further progression into the development of acne.

Before I forget, yup, it appears that you agree with myself and someone else in that without the inflammation you would still have acne, only it would just be clogged pore acne as there probably wouldn't be any edema from lack of an immune response. Clogged pore acne wouldn't be much acne, no cystic acne, but still skin quality probably wouldn't be so great. Yet this is where AHAs come to play, right? However you are correct in wondering about the hyperkeritinization as this is so far thought to be the reason for the clogged pores. Yes, once again, androgens are responsible for the initiation of a rather complex chain of events culminating in acne, one of which is hyperkeritinization.

Bear with me here, as this is rather new area for me and I must research further on it, but what I know is that IGF-1 is responsible for sebeceous gland growth and sebum secretion as well as skin cell proliferation. However Peroxisome Proliferator-Activating Receptors (PPARs) are also upregulated during this process. There are 3 or 4 types: PPAR-alpha, PPAR-beta/delta, & PPAR-gamma. In this thread here http://www.acne.org/...pic=39194&st=20 I posted more indepth info on these, but what is of particular intesterest is that PPAR-alphas & PPAR-gammas seem to suppress sebum production (they also form complexes with the retinoid x receptor), where as PPAR-beta increases sebum production. Furthermore, PPAR-beta is responsible for keritnocyte proliferation and happens to produce far more sebum than DHT alone!

I remember a few years ago when I first found these boards, and came across a thread discussing the wonders of Vitamin D. So I ran to my endocrinologist and told him about Vitamin D helping to clear acne and he said what type of Vitamin D? Vitamin D3? Well, at the time I was clueless, but I just bumped into an article http://www.ingentaco...000004/art00017 and it mentions the use of Vitamin D3 in reducing kertinocyte hyperproliferation.... to bad I don't know that then. Sorry just a side thought for ya ;-)

So anyway, I suppose that with too much of the "wrong" sebum in conjunction with keritinocyte hyperproliferation, this would result in hyperkeritinization (?). If that's the case, then yup this is another reason retinoids are so beloved. Yet there seems to be other things that can also reduce keritinocyte proliferation and well...I'll have to investigate another day cuz I am just too sleepy, but I shall leave you with these:

QUOTE
The pathogenesis of acne vulgaris is multifactorial. Four key factors are responsible for the development of an acne lesion: follicular epidermal hyperproliferation and hyperkeratinization, excess sebum, Propionibacterium acnes, and inflammation.

Follicular epidermal hyperproliferation and hyperkeratinization appears to be one of the primary events in the development of an acne lesion. The follicular epidermis is hyperproliferative; abnormal production of keratins 6 and 16 could play a role. Increasing levels of the adrenally derived androgen dehydroepiandrosterone sulfate (DHEAS) are correlated with the development of the microcomedo, the primary acne lesion; therefore, these levels may trigger follicular epidermal hyperproliferation. This hyperproliferation may also be stimulated by an alteration in sebum and lipid levels in acne lesions. For example, linoleic acid levels are decreased in acne lesions, and the levels normalize after successful treatment with isotretinoin. Other factors that may lead to follicular hyperproliferation include the presence and the action of proinflammatory interleukin 1a (IL-1a) and other cytokines.

Excess sebum is also a key factor in the development of acne vulgaris. The amount of sebum produced and the degree and the severity of the acne are strongly correlated. Sebum excretion is under hormonal control. Androgens stimulate sebocyte differentiation and sebum production, whereas estrogens have an inhibitory effect. Sebocytes have nuclear androgen receptors. They also have 5 alpha reductase enzymes that convert testosterone to the more potent dihydrotestosterone. The androgen hormones bind their nuclear receptors and stimulate terminal sebocyte differentiation and the production of sebum. Most men and women with acne have normal circulating levels of androgen hormones. An end-organ hyperresponsiveness to androgens has been hypothesized.

P acnes is a microaerophilic organism present in many acne lesions. Although, it has not been shown to be present in the earliest lesions of acne, the microcomedo, its presence in later lesions is almost certain. P acnes stimulates inflammation by producing proinflammatory mediators that diffuse through the follicle wall. Recent studies have shown that P acnes binds to the toll-like receptor on monocytes and neutrophils. Binding of the toll-like receptor then leads to the production of multiple proinflammatory cytokines, including interleukin 12 (IL-12), interleukin 8 (IL-8), and tumor necrosis factor (TNF). Hypersensitivity to P acnes may also explain why some individuals develop inflammatory acne vulgaris.

Inflammation may be a primary phenomenon or a secondary phenomenon. Most of the evidence to date suggests a secondary inflammatory response to P acnes as mentioned above. However, IL-1a expression has been identified in the microcomedone, and it may play a role in the development of acne.

http://www.emedicine...DERM/topic2.htm



QUOTE
Clin Dermatol. 2004 Sep-Oct;22(5):360-6. Related Articles, Links 

 
Acne and sebaceous gland function.

Zouboulis CC.

Department of Dermatology, Charite University Medicine Berlin, Campus Benjamin Franklin, Fabeckstrasse 60-62, 14195 Berlin, Germany. christos.zouboulis@charite.de

The embryologic development of the human sebaceous gland is closely related to the differentiation of the hair follicle and the epidermis. The number of sebaceous glands remains approximately the same throughout life, whereas their size tends to increase with age. The development and function of the sebaceous gland in the fetal and neonatal periods appear to be regulated by maternal androgens and by endogenous steroid synthesis, as well as by other morphogens. The most apparent function of the glands is to excrete sebum. A strong increase in sebum excretion occurs a few hours after birth; this peaks during the first week and slowly subsides thereafter. A new rise takes place at about age 9 years with adrenarche and continues up to age 17 years, when the adult level is reached. The sebaceous gland is an important formation site of active androgens. Androgens are well known for their effects on sebum excretion, whereas terminal sebocyte differentiation is assisted by peroxisome proliferator-activated receptor ligands. Estrogens, glucocorticoids, and prolactin also influence sebaceous gland function. In addition, stress-sensing cutaneous signals lead to the production and release of corticotrophin-releasing hormone from dermal nerves and sebocytes with subsequent dose-dependent regulation of sebaceous nonpolar lipids. Among other lipid fractions, sebaceous glands have been shown to synthesize considerable amounts of free fatty acids without exogenous influence. Sebaceous lipids are responsible for the three-dimensional skin surface lipid organization. Contributing to the integrity of the skin barrier. They also exhibit strong innate antimicrobial activity, transport antioxidants to the skin surface, and express proinflammatory and anti-inflammatory properties. Acne in childhood has been suggested to be strongly associated with the development of severe acne during adolescence. Increased sebum excretion is a major factor in the pathophysiology of acne vulgaris. Other sebaceous gland functions are also associated with the development of acne, including sebaceous proinflammatory lipids; different cytokines produced locally; periglandular peptides and neuropeptides, such as corticotrophin-releasing hormone, which is produced by sebocytes; and substance P, which is expressed in the nerve endings at the vicinity of healthy-looking glands of acne patients. Current data indicate that acne vulgaris may be a primary inflammatory disease. Future drugs developed to treat acne not only should reduce sebum production and Propionibacterium acnes populations, but also should be targeted to reduce proinflammatory lipids in sebum, down-regulate proinflammatory signals in the pilosebaceous unit, and inhibit leukotriene B(4)-induced accumulation of inflammatory cells. They should also influence peroxisome proliferator-activated receptor regulation. Isotretinoin is still the most active available drug for the treatment of severe acne.

http://www.ncbi.nlm....t_uids=15556719

(FYI: all of these factors, and then some, are affected by our diet)


Nighty night