The expression of insulin-like growth factor 1 in follicular dermal papillae correlates with therapeutic efficacy of finasteride in androgenetic alopecia

Background: It is generally believed that dihydrotestosterone is one of the pivotal mediators of hair loss in androgenetic alopecia (AGA). Finasteride, which blocks the conversion of testosterone to dihydrotestosterone, has now become an integral part of the current treatment approaches for male AGA. Several lines of evidence support the notion that dermal papilla (DP) cells represent the androgen target within the hair follicle. The specific molecular regulators modulated by androgens within hair follicles in the balding scalp are unknown.

Objective: The purpose of this study was to identify and quantify changes in expression of specific molecular hair growth regulators in DP of men with AGA treated with finasteride and correlate these findings to clinical efficacy.

Methods: Biopsy specimens were collected from 9 male patients from both the balding area and nonbalding occipital area before and after 4 months of finasteride therapy. DP were microdissected and total RNA was extracted from an equal number of DP from each biopsy specimen. The expression of various cytokines, including insulin-like growth factor (IGF)-1, was determined by reverse transcription polymerase chain reaction. The signals were detected by autoradiography. All 9 patients were given finasteride for 1 year and evaluated for efficacy at month 12. Efficacy was graded on a 7-point scale on the basis of comparison with initial baseline photography.

Results: IGF-1 was up-regulated by finasteride treatment in 4 of 9 patients. Among the patients with increased IGF-1 expression, 3 of them showed moderate clinical improvement after 12 months of treatment and another patient remained unchanged. In contrast, 3 patients with decreased IGF-1 expression in the balding scalp showed clinical worsening after 12 months. The other 2 patients without noticeable change in IGF-1 expression showed either slight improvement or no change in their hair condition.

Conclusion: In a small uncontrolled study of 9 patients with AGA, an increased expression of IGF-1 messenger RNA levels in the DP was associated with patient response to finasteride.

http://www.sciencedirect.com/science/article/pii/S0190962203007771

The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of tyrosine kinase receptors.[1] Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis, a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer.[2][3] Biochemically, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms.[4] Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor.[4]

http://en.wikipedia.org/wiki/Insulin_receptor

Maybe finasteride really works for people because it is actually improving insulin sensitivity.. ? And maybe my body is wrecked from it because it completely screwed up my insulin sensitivity.. ?

In testosterone-administrated group, there was a significant increase in the serum insulin levels (P<0.01), whereas testosterone deficiency due to castration significantly reduced serum levels of this hormone in castrated group (P<0.05). Also in finasteride administrated group, serum insulin levels were increased significantly (P<0.05) (Fig. 1D).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600969/

Very good stuff, Sanderson.

AS54 wrote:Very good stuff, Sanderson.

Yes man.. I have some very good stuff I am going to be talking about in regard to this stuff & hairloss very soon. :DI think I found the holy grail diet.

5α-Reductase (5αR) inhibitors decrease prostatic dihydrotestosterone in benign prostatic hyperplasia (BPH) treatment; finasteride inhibits 5αR type 2, while dutasteride inhibits 5αR1 and 2. 5αRs, especially 5αR1, are also expressed in metabolic tissues regulating actions of androgens and other substrates, including glucocorticoids.

Hypothesis: 5αR1 inhibition with dutasteride induces metabolic dyshomeostasis.

Study: With ethical approval, in a double-blind RCT, we studied metabolism in 47 men (20–85 years) before and after 3 months of either dutasteride (0.5 mg daily; n= 17; D), finasteride (5 mg daily; n= 16; F) or control (tamsulosin; 0.4 mg daily; n= 14). The primary outcome was insulin sensitivity, measured during a two-step (10; 40 mU/m2 per min) hyperinsulinaemic euglycaemic clamp, with d2-glucose and d5-glycerol tracers. Data are mean (95% CI; P value) difference in change from baseline, compared by one-way ANOVA with LSD post-hoc tests where appropriate.

Results: D, but not F, impaired insulin sensitivity. During high-dose insulin, the M value (mean steady state glucose infusion rate) decreased with D vs both control and F, by 10.1 mg/kg fat-free mass/min (−16.3; −3.9; P=0.002); signifying impaired skeletal muscle insulin sensitivity. Glucose and glycerol rates of appearance during low-dose insulin were unchanged. Tracer infusion alone induced hyperinsulinaemia only with D by 11 pmol/l (3; 20; P=0.009). D increased HOMA-IR and fasting C-peptide by 15% (3; 27; P=0.015), and 114.5 pmol/l (31.5; 197.6; P=0.007) respectively. Fasting glucose, cholesterol, body mass index, waist:hip ratio and blood pressure were unaltered. Body fat (bioimpedance) increased 2.6% (0.9; 4.2; P=0.003) with D. Post-treatment visceral and subcutaneous adipose volumes (magnetic resonance imaging; L4/5), and hepatic fat (1H spectroscopy), were unchanged. Serum adiponectin, resistin, IL8, and MCP1 were unchanged, however leptin increased 44% (16; 73; P=0.03) with D. In all indices F was not different to control.

Conclusion: 5αR inhibition with dutasteride, but not finasteride, impairs peripheral (principally muscle) insulin sensitivity, and increases body fat and leptin. 5αR1 inhibition is potentially detrimental to metabolic health; this may have important implications for BPH treatment.

http://www.endocrine-abstracts.org/ea/0031/ea0031oc1.5.htm

thoughts: I seem to be experience what D is causing here, even though study says F does not cause it. most people with post fin issues are skinny and possibly more insulin resistant at a baseline when they started treatment, hence the early hair loss. and diabetes runs extremely high in my family. i'm pretty sure I just figured out post fin issues. my prayers have been answered. and I have a diet to fix it. and the bonus is the diet is also making my itch go away as well.. WITH CARBS. big post coming soon.

‘Obesity Paradox’: Why Being Thin with Diabetes Is a Dangerous Combo

Read more: Why Being Thin with Diabetes Is a Dangerous Combo: The Obesity Paradox | TIME.com http://healthland.time.com/2012/08/08/obesity-paradox-why-being-thin-with-diabetes-is-a-dangerous-combo/#ixzz2t2MNWCBG

So, what sets the disease apart in normal weight people? More studies are needed to figure that out, but the authors have a few guesses. Genetic predisposition to improper insulin production may be part of the problem, says Carnethon. “We need to explore the genetic variations related to insulin secretion,” says Carnethon. “It’s possible that genetic factors could be promoting insulin resistance, and influencing something else related to mortality. We really don’t know.”

It’s also possible that body fat may still play a role. The studies measured the participants’ body mass index (BMI), a ratio of their height and weight, but it wasn’t able to take into account their body fat composition, or how much of their overall body weight was made up of fat versus muscle. Many seemingly thin people carry more fat than muscle, making them trim on the outside, but fat on the inside. Even with a healthy BMI, for example, such people may harbor a lot of visceral fat, deep in their abdomen, a type of fat that is particularly dangerous to health, since it secretes hormones and substances that can hamper insulin’s ability to break down sugar. Because many of the thin diabetes patients included in the new study were elderly, they likely had less muscle mass and more fat.

http://healthland.time.com/2012/08/08/obesity-paradox-why-being-thin-with-diabetes-is-a-dangerous-combo/

Chromium serum level in testosterone and finasteride-administrated groups was decreased significantly (P<0.01 and P<0.05, respectively), but in castrated group, it did not show any significant differences (Fig. 1C).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600969/

Chromium should also be mentioned when considering insulin resistance because it is often deficient in insulin resistant individuals. A great book about chromium that I read a couple months back and would definately recommend is Lifting Depression: The Chromium Connection by Dr. Malcolm McLeod. McLeod is a psychiatrist who in the book, outlines his discovery of chromium's role in depression. He talks about how insulin resistance plays a large role in depression and that some researchers are describing depression as diabetes of the brain. His book has been out for a while and is available on amazon used. He also has a website http://www.chromiumconnection.com/index.asp if anyone is interested. One side note: Dr. McLeod began to use chromium in his professional practice after a patient of his reported feeling better using it. From there he searched through tons of research that had already been done and even did some of his own personal research on it. I wanted to mention this because it is inspiring to note that one patient mentioning a supplement to his doctor sparked research and a book that has been read by and had helped many, many of people. If only more psychiatrists/doctors this open minded...

https://immortalhair.forumotion.com/t2570-can-you-cure-insulin-resistance

sanderson - Good post!

This is what makes Brewer's yeast so special. I should mention something important (in case it wasn't mentioned in the book). GTF (Glucose Tolerance Factor) chromium is the stuff to use. It's far more effective than other types of chromium. Or one can obtain it naturally with Brewer's yeast (either way).

CausticSymmetry wrote:sanderson - Good post!

This is what makes Brewer's yeast so special. I should mention something important (in case it wasn't mentioned in the book). GTF (Glucose Tolerance Factor) chromium is the stuff to use. It's far more effective than other types of chromium. Or one can obtain it naturally with Brewer's yeast (either way).

I'm on it. Will pick it up tonight. I started using R-lipoic acid and l-carnitine as well with my meals and i'm noticing a huge difference. That along with a new diet based on low insulin levels, along with your suggestion for immune boost 77 at night is really doing good things. I think my yeast infection had a lot to do with this insulin being all over the place.. and this really explains my extreme brain fog and low energy levels because shocking.. it only happens after i eat carbs!

I'll let ya know how I do.

CS, ok to take l carnitine every meal like lipoic acid, or just limit to 1x/day?

sanderson wrote:CS, ok to take l carnitine every meal like lipoic acid, or just limit to 1x/day?

Yes (absolutely)

Interestingly, if you look at some of the more commonly cited studies on androgens & insulin, most show that DHT treatment increases insulin sensitivity. But the studies Sanderson found seem to show the opposite. Lowering 5-ar, and presumably DHT, increased insulin sensitivity. I was actually at a lecture the other day on nutrition and the professor claimed that the common consensus that estrogen promotes central fat and androgens stimulate fat-burning is wrong. He claimed (without providing evidence unfortunately) that DHT actually promotes central fat through insulin resistance.

At the time it made sense to me because the profile of the balding guy (not all) tends to often fit a certain picture for me. Think agent Schrader from Breaking Bad.

The thinner the person (think ectomorph), the more inflammation there is.

Interesting point, CS.

Now here is what I'm wondering. Is there something inherently protective about fat itself?

Or as a response to the inflammation present, the body becomes resistant to insulin to lower cellular metabolism and reduce further inflammation. This insulin resistance promotes the fat accumulation.

It seems like this tendency for fat accumulation might be because the body is trying to protect itself by reducing sensitivity to insulin. Because I can't see anything about a fat store that would be protective against inflammation in and of itself, it just seems to be a side-effect of the underlying situation. In fact the fat itself can be a source of inflammation, which might feedback on the whole process, which is why obesity is such a difficult issue to tackle.

On some level it seems like the hormones responsible for energy balance just aren't sending their signals, maybe because of the HFCS in the diet. But the lowered metabolic rate isn't causing people to eat less, so they continue to throw in food energy, meanwhile they are becoming undernourished as they feed this cycle. The pre-programmed ability of the body to lower insulin sensitivity in periods of inflammation has probably been historically beneficial, but the tradeoff of increased body fat is overtaking the benefit when abdominal obesity gets to the point we see today (with the high food availability and freak carbs).

There is researching pointing out this phenomenon.

A skinny person often has a load of visceral fat in and around their organs. This generates a lot of inflammation.

A layer of subcutaneous fat protects an obese person from some of this inflammation.

http://advances.nutrition.org/content/2/4/304.full

Fascinating, CS. Thanks sir.

CausticSymmetry wrote:http://advances.nutrition.org/content/2/4/304.full

this is absolutely what has happened with combined with finasteride. i'm totally lacking body fat and have that very skinny frame and I do think I most likely have this as well. I can't workout because I had a back situation and carbs completely make me space the fuck out. this is very complicated for me to figure out a proper diet. i'm hoping I can use exercise and low carb and lipoic acid and have it correct itself over time, but i'm worried it may not work unless I am able to lift weights again.. which could be a very long time. yoga everyday in the mean time.

Anthony, do you have the study about DHT you were referring to earlier? about the insulin and how my study changed the viewpoint? I think actually the DHT inhibition from finasteride increased testosterone which then made people more insulin sensitive, I don't think it was a direct correlation between actually the DHT going down and insulin sensitivity. and I think some people are more prone to the negative effects, like me being the usual profile of a PFS person.. skinny, young, balding early.. (I took it at 19)

Hey Sanderson,

That could very well be. I had just mentioned that a professor was discussing that DHT tends to promote abdominal, visceral fat. That doesn't necessarily mean subcutaneous. So I was interested in whether or not DHT did independently effect insulin levels.

There wasn't a particular study. If anything, almost every study I've found on the subject showed insulin sensitivity increasing with DHT treatment. But I think there could be other variables at play that might allow things to play out differently when we're dealing with endogenous levels of DHT and SHBG.

I think it would be better to focus on 5-AR and not DHT, because there's a difference between serum and salivary levels.

DHT treatment is generally anti-inflammatory. So rather, focusing on the elevation of 5-AR will create less confusing results.

CausticSymmetry wrote:I think it would be better to focus on 5-AR and not DHT, because there's a difference between serum and salivary levels.

DHT treatment is generally anti-inflammatory. So rather, focusing on the elevation of 5-AR will create less confusing results.

How do we go about doing that?

Growdamnit wrote:

CausticSymmetry wrote:I think it would be better to focus on 5-AR and not DHT, because there's a difference between serum and salivary levels.

DHT treatment is generally anti-inflammatory. So rather, focusing on the elevation of 5-AR will create less confusing results.

How do we go about doing that?

For example, research exists showing that elevated levels of 5-AR can be stimulated by things/conditions that cause higher levels of prolactin and/or thyroid abnormalities. However stress or conditions that create restraint or anxiety also elevate this enzyme.

Worrying about DHT is a waste of time. It really comes down to where/how/why is the inflammation occurring, that leads of elevated 5-AR.

FEBS J. 2013 Jan;280(1):93-101. doi: 10.1111/febs.12052. Epub 2012 Nov 22.
Expression of steroid 5α-reductase isozymes in prostate of adult rats after environmental stress.
Sánchez P, Torres JM, Castro B, Olmo A, del Moral RG, Ortega E.

The elevated incidence of prostate cancer and benign prostatic hypertrophy is a cause of increasing public health concern in the Western world. The normal and pathological growth of the prostate are both dependent on stimulation by dihydrotestosterone, which is synthesized from circulating testosterone by two 5α-reductase (5α-R) isozymes, 5α-reductase type 1 (5α-R1) and 5α-reductase type 2 (5α-R2). Both isozymes have been implicated in prostate disease. We used quantitative RT-PCR and immunohistochemistry, respectively, to quantify mRNA and protein levels of 5α-R isozymes in the ventral prostate of adult rats under environmental stress conditions analogous to those found in some common workplace situations, i.e. artificial light, excessive heat, and the sensation of immobility in a small space. Transcription and expression levels of both 5α-R isozymes were significantly higher in environmentally stressed rats than in unstressed rats. Increased 5α-R isozyme levels may play a role in the development or maintenance of prostate disease. Further research is warranted to explore these effects of environmental stress on human health and their implications for environmental and occupational health policies.

CausticSymmetry wrote:The thinner the person (think ectomorph), the more inflammation there is.

This is me! I find it really hard gaining weight but in saying that my entire family is skinny.

Does a skinny and tall person (ektomorph) fall into a particular category in terms of potential problems in regards to MPB?

What are we dealing with here CS?

I am a skinny and lanky bastard too... Is there any testing we can do to evaluate our skinny-diabetic/inflammation risk?

The PCOS method of a women can often be compared to MPB in man. Here's something on it:

http://www.ptantropologiczne.pl/en/ckfinder/userfiles/images/AR/vol76_2/AR_76-2_183-198.pdf

Check out the Table 1. Clinical, hormonal and biochemical data of studied women (number of patients, mean ± SD)

Free androgen index is high, low levels of SHBG, lower HDL, higher LDL, higher triglycerides, elevation of
Glucose, Insulin, HOMA-IR.

As in other discussions in the past (check carbohydrate sensitivity), insure minerals, especially GTC chromium, iodine, selenium, magnesium, sulfur, silicon.

So, CS, how often can we have grains? I think that is what I have been doing wrong.

CS, a female recently emailed me to ask some advice on hair loss, as she has PCOS. I found it particularly interesting to find a significant link between PCOS and high grain consumption, and this female, in question, told me that the mass bulk of her diet is, and always has been, grains. She further told me that whenever she eats hot spicy foods she feels an intense agonizing burn in her stomach, so I thought that this may signify some gut lining issues, perhaps a leaky gut or ulcer.

I'm not an expert on leaky guts or PCOS by any means, but I started thinking about the ovaries and how close they are to the small intestine, and I wondered if toxins from a leaky gut could be having a direct inflammatory effect upon the ovaries and causing hormonal disturbances?

Any thoughts on this?