- Why are the genetics of MPB so unusual/non-Mendelian? There are too many males with MPB in the same family. This points to some hereditary predisposition, but with a major environmental component, e.g. “inherited gut flora.”
- Why are only a few of the people treated with 5-alpha reductase inhibitors rendered permanently impotent?
- There is anecdotal evidence that dexamethasone (or prostate message and antibiotics) can reverse some impotence. Does this indicate that inflammation is involved in hair loss and/or impotence? Where do the antibiotics act and is their action to kill bacteria?
Tuesday, July 19, 2011
Male pattern baldness appears to result from the interaction between enzyme-modified male sex hormones (DHT) and receptors in some hair follicles of the scalp. Inhibition of the enzyme by topical (Rogaine) or oral administration (Propecia) of an inhibitor, e.g Finasteride, can stop hair loss. One of the significant side effects of oral use of Finasteride is loss of all sexual functions, which can be temporary and reversible after the drug is stopped, or permanent. I think that inflammation may play a critical role in both hair loss (and prostatitis) and loss of sexual functions in response to Finasteride and an anti-inflammatory approach my be helpful.
Testosterone is Converted to Dihydrotestosterone (DHT) by 5-Alpha Reductase
The male hormone, testosterone, is produced in the testes and travels to hair follicle or to other parts of the body via the blood in either a free state, or bound to a carrier protein. Only the free form interacts with the 5-alpha reductase enzyme in the scalp to produce the DHT that diminishes hair follicles. Application of the Reductase inhibitor, Finasteride, directly to the scalp stops the production of DHT in the scalp. Taking oral Finasteride blocks DHT production throughout the body, and unlike topical application, can also result in apparent changes in the brain, which can explain loss of sexual behavior.
DHT Role in Hair Loss and Brain-Based Sexual Behavior is Poorly Understood
Surprisingly, the molecular biology of male pattern baldness (MPB) is not known, even though this is one of the classic examples of a dominant, sex-associated phenotype, i.e. a single copy of the baldness allele in males produces baldness. Of course, this is not a sex linked gene, since baldness is not inherited from mothers with their X chromosome, and in some cases as many as 80% of the males in a single family exhibit male pattern baldness. It appears to me that baldness is also likely to have an environmental, e.g. gut flora, heritability similar to obesity. In fact, metabolic syndrome and type 2 diabetes are substantial risk factors for male pattern baldness.
There is also an association between MPB and polycystic ovary syndrome (PCOS) in females of the same family. I would also expect that MPB is related to prostatitis, since the prostate is a major processor of testosterone to DHT via 5-alpha reductase and prostatitis can be treated with Finasteride. PCOS is also treated with Finasteride. PCOS is also associated with obesity and metabolic syndrome. Prostatitis, PCOS, obesity and metabolic syndrome can all be treated as inflammatory diseases with significant contribution of dysfunction of gut flora.
PMB, Testosterone, 5-Alpha Reductase and Aromatase
In PMB, testosterone levels are lower and 5-alpha reductase is higher. This suggests that testosterone has been converted into DHT in scalp hair follicles. In order for DHT levels to make a difference, the hair follicles have to have specific receptors for DHT. Testosterone/DHT receptors, like all steroid hormone receptors, are proteins in the cytoplasm of cells, which bind the hormone and become activated as transcription factors that migrate to the nucleus and control the expression of particular genes.
Testosterone can also be converted by another enzyme, aromatase, into estrogen. DHT cannot be converted enzymatically into estrogen. Estrogen has a separate receptor and controls a different set of genes. Thus, enhanced conversion of testosterone into DHT in MPB follicles, may shift the balance away from estrogenic in favor of androgenic effects. Women exposed to aromatase inhibitors, stop converting their limited testosterone into estrogen and more is converted into DHT, resulting in rapid signs of baldness. All brain estrogen is produced from testosterone via aromatase in the brain and aromatase inhibitors can reduce libido in women.
DHT Activates Inflammatory NFkB (and Block Nerve Apoptosis?)
Prolonged exposure of cerebral blood vessels to DHT has been shown to activate the inflammatory transcription factor NFkB. Conversion of testosterone to DHT by 5-alpha reductase may amplify the inflammatory impact of testosterone by virtue of the stronger activation of the androgen receptor by DHT. Activation of NFkB also suppresses apoptosis and may be necessary to maintain some neural cells. Reducing DHT production by 5-alpha reductase inhibitors, may reduce NFkB activation in the brain and expose androgen-sensitive parts of the brain to apoptosis. This loss of brain cells may result in loss of sexual behavior.
Vitamin D is also Steroid Hormone/Co-Transcription Factor
It should be remembered that vitamin D also has a cytoplasmic receptor that acts as a transcription factor and that vitamin D deficiency can result in hair loss. If fact, vitamin D is required for the normal hair growth cycle, as well as intestinal villi development (defensin production). The vitamin D receptor can also inhibit the inflammatory transcription factor NFkB.
Thus, multiple steroid hormone receptors are involved in hair development, prostate function and brain sexual behavior. Modification of the conversion of testosterone into DHT or estrogen can have diverse consequences directly or indirectly by modification of inflammation/development signaling. This is also true of fertility/menstrual cycles, mammary tissue and perhaps intestinal epithelial villi or skin/follicle development in the case of rosacea. All of these processes are affected by enzymatic interconversion of steroid hormones and interaction of hormone/receptor and NFkB transcription factors.
The questions that I have about hair loss (or prostatitis), treatment with 5-alpha reductase inhibitors, and subsequent loss of sexual function are:
Treatment for Finasteride-Induced Impotence
Impotence is a severe side effect of a few men using Finasteride to treat baldness or prostatitis. I doubt that those with induced impotence are genetically predisposed, but rather these individuals probably had an altered immune system. I suspect two types of alterations: a compromised blood/brain barrier and a compromised suppressive immune system. Diet-based chronic inflammation is a typical path to a leaky blood/brain barrier that facilitates the penetration of Finasteride into the brain to alter 5-alpha reductase in the DHT-responsive regions responsible for sexual function. I presume that the subsequent reduction of DHT also results in inflammation that contributes to loss of function. Dexamethasone and some antibiotics could attenuate the inflammation and return normal function.
Suppression of attack of normal tissues by the immune system is mediated by development of the suppressive immune system in the gut in response to specific bacteria of the gut flora. A history of antibiotic treatment can yield a dysfunctional gut flora and a compromised immune system that results in allergies and autoimmunity. Prostatitis may have an autoimmune component and may result from compromised gut flora.
All of the symptoms discussed from hair loss to prostatitis to impotence should be improved by normal function of the gut and immune system by my anti-inflammatory diet and normal gut flora. Use of antibiotics will always lead to further side effects by perturbing and limiting the function of gut flora and the immune system that is dependent on the gut flora.
I particularly suspect that vitamin D deficiency is a significant contributor. Most “anti-inflammatory diets” will lead to chronic inflammation, because they are just high carb diets with a few vegetables. All of the complex phytochemicals produced by plants will be “antioxidants”. Adding these antioxidants to an inflammatory diet has no impact. Look at my anti-inflammatory diet and note that it requires attention to serum vitamin D levels, gets most calories from saturated fat and not carbs (low carb/high saturated fat), no vegetable oils and high omega-3 (EPA, DHA) to 6 ratio. That means meat/fish/eggs/dairy and lots of fresh vegetables for new gut bacteria.