michael barry
Senior Member
- Reaction score
- 14
Wook attempted to post a link to this from another place, which we aren't allowed to do anymore. The info about globulin and albium binding your free testosterone is very relevant. Take a look:
I want to take a comprehensive look at what our problem is here.
1. ( The Basics )
Testosterone is a steroidal hormone derived from cholesterol. Its production begins in the brain when the hypothalamus detects a deficiency of testosterone in the blood and sends a messenger hormone called gonadotrophin-releasing hormone (GnRH) to the pituitary gland. This prompts the pituitary to secrete luteinizing hormone (LH), which in turn prompts the Leydig cells in the testes to produce testosterone. About 60 percent of the circulating
testosterone is carried in blood plasma bound to a plasma protein called sex hormone binding globulin. Thirty-eight percent is bound to albumin, while only two percent of the circulating testosterone is free. "Free" refers to unbound testosterone, which is able to
enter cells and exert its metabolic effects. The conversion of testosterone to the more active dihydrotestosterone(DHT) in certain target cells depends upon the presence of the enzyme 5-a-reductase. The primary catabolic product of androgen metabolism in either
growing or resting hair follicles is androstenedione. The conversion of testosterone to androstenedione via 17-l-hydroxysteroid dehydrogenase is tenfold the rate of the 5-a-reductase system that yields DHT.
( What Does DHT Do? )
DHT combines with a cytosol receptor to form a complex that enters the nucleus and joins with chromatin to initiate protein synthesis. DHT also inhibits energy production by keeping phosphodiesterase relatively inactive and by suppressing various protein (enzyme)
synthetases.
( How Does DHT Do It? )
The effects of DHT on scalp-hair is mediated through changes in intracellular concentrations of cyclic AMP (cAMP). The "second messenger" rule of cAMP states that the first messenger (a hormone, DHT) is carried to the plasma membrane of its target tissue where adenyl cyclase recognizes only the specific first messenger. Simultaneously, a catalytic subunit of adenyl cyclase produces a second messanger, a molecule, (cyclic adenosine monophosphate) which
initiates a specific physiologic function.
( Physiologic Changes In The Follicle )
The rate at which cells divide is controlled by a complex balance between two compounds: cyclic adenosine monophosphate (AMP), and cyclic guanidine monophosphate (GMP). Higher than normal levels of GMP cause cells to divide too fast. Higher levels of AMP reduce the rate of cell replication. The key to normal replication must be the balance between the two. The diverse biologic effects of cAMP are mediated through activation of a family of protein kinases, which consist of a regulatory (R) and a catalytic (C) subunit; and when bound, these kinases are not active. Cyclic AMP binds to the R subunit, (a binding protein) for cAMP and subsequently releases the C subunit to form an active enzyme. Therefore, the more cAMP available in the androgen-sensitive hair follicles, the stronger the activation of the protein kinase. An increase in cAMP concentrations in hair follicles would produce diverse effects on various enzymes and reaction pathways. Inhibition of glycolysis - by the action
of the active C subunit on the enzyme phosphofructokinase – decreases the energy available for the cell to maintain its metabolic functions. The same active subunit effectively slows
posttranslational protein synthesis and interferes with cell cycles at the C1 and S phases. These combined effects of high cAMP concentrations result in premature completion of the anagen stage; and this, in turn, yields follicles that are thinner and shorter than those of normal terminal hair. Apparently, the differences in sensitivities for androgens of various types of hair follicles reside in the cAMP protein-kinase system.
2. ( Minoxidil )
Minoxidil works in the follicles that contain Phenol-sulfating phenol sulfotransferase 1, which metabolizes minoxidil to minoxidil sulfate. Minoxidil Suflate stimulates the production of vascular endothelial growth factor, a possible promoter of hair growth. The
mechanism of production of vascular endothelial growth factor remains unclear, however, we do know that adenosine serves as a mediator of vascular endothelial growth factor production. Dermal papilla cells have both adenosine receptors and sulfonylurea receptors, the latter of which is a well-known target receptor for adenosine-triphosphate-sensitive potassium channel openers. So, the effect of minoxidil sulfate is mediated by adenosine, which triggers intracellular signal transduction via both adenosine A1 and A2 receptors, and the expression of sulfonylurea receptor 2B in dermal papilla cells might play a role in the production of adenosine.
( male pattern baldness Out-Thinks Minoxidil )
We all notice that male pattern baldness 'figures out' Minoxidil after a while and starts to counteract its positive effects. One reason for this could be that a chemical reaction is produced to block the conversion of Minoxidil to Minoxidil Sulfate. This reason has been noticed in many studies that showed minoxidil ineffective in follicles that did not have Phenol-Sulfating phenol sulfotransferase 1. If true, that would explain why minoxidil only grows hair on certain places of the scalp and not others. Minoxidil also increases NO, and male pattern baldness matches the increase with Superoxide. The reaction produces Peroxynitrite which puts stress on the mitochondria (minoxidil speeds this up creating a "resistance" of sorts and the detrimental reaction between NO & SO occurs at a rate 6 times greater than that which current treatments containing Cu/Zn are able to inhibit it(i.e. copper & zinc... foliigen/tricomin/zix). In other words by a paradoxical twist of biological and chemical
fate, the more you supplement NO (i.e. through minoxidil) the more there is to react in a detrimental fashion with the Superoxide to form Peroxynitrite which then actually further inhibits your attempts to achieve beneficial vasodilation amongst other things, which you want from minoxidil.) Peroxynitrite, which itself seems to be responsible for depleting NO bioavailability, and subsequently hindering vasodilation, and causing ultimate endothelial dysfunction. The toxicity of Peroxynitrite is mediated through mitochondrial dysfunction which leads to the mitochondria releasing cytochrome C.
3. ( PROGRAMMED CELL DEATH )
Whether a person uses Minoxidil or not, the activation of the chemical processes ( such as cytochrome C ) caused by DHT starts the caspase 9 cascade. The Caspase 9 cascade is activated as TGF-B and A increase around our follicles, TGF-beta1 activates interleukin
(IL)-6 via multiple signaling pathways including Smad2, nuclear factor-kappaB (nuclear factor (NF)-kappa B, which activates genes encoding inflammatory cytokines ), JNK, and Ras. Following different stimuli, such as cytokines or DNA-damaging agents, Ik-B is
phosphorylated by the IKK kinase complex, polyubiquitinated and degraded. Then, the NF-B nuclear localization signal (NLS) is freed allowing the nuclear translocation of the transcription factor and the induction of its target genes. These target genes code for
proinflammatory molecules as well as pro or antiapoptotic proteins. cells that are attacked by TGF-B cause apoptosis induction by macrophages,TGF-A efficiently eliminates cells during intercellular induction of apoptosis, both factors act synergistically during apoptosis.
4. ( Caspase 3 )
This propogates into caspase 3 which tells the hair follicle to "sleep" through TNF-A, and B. TNF-A activates a sphingomyelinase that induces apoptosis through the generation of ceramides from sphingomyelin. TNF-A, ionizing radiations and chemotherapeutic drugs have been shown to induce (NF)kappa-B. The expression of an unresponsive mutated Ik-B inhibitor sequestered (NF)kappa-B in the cytoplasm and increased apoptosis following treatment by cytotoxic agents. TNF-b causes an inhibition of lipoprotein lipase present on the surface of vascular endothelial cells. The predominant site of TNF-b synthesis is T-lymphocytes, in particular the special class of T-cells called cytotoxic T-lymphocytes (CTL cells). The induction of TNF-b expression results from elevations in IL-2 as well as the interaction of antigen with T-cell receptors.
*(The expression of both IL-2 and the IL-2 receptor by T-cells is induced by IL-1. The predominant function of IL-1 is to enhance the activation of T-cells in response to antigen. IL-2 is the major interleukin responsible for clonal T-cell proliferation. IL-2 also exerts effects on B-cells, macrophages, and natural killer (NK) cells. The production of IL-2 occurs primarily by CD4+ T-helper cells)
5. ( A chlorine bath for our follicles )
The immune system see's these signals as a foreign antigen and goes to the source to uleash armageddon on our follicles by spraying them with cholorine bleach, not to mention that the cell death occurs due to the properties of all the other chemicals involved.
6. ( Physical Result on the Follicle )
Normally, cells multiply in the lower dermal sheath and then migrate into the dermal papilla at the start of a new hair growth cycle. At the end of the hair growth cycle the cells migrate out again either back into the dermal sheath or out into the dermis. In Androgenic
Alopecia the difference comes at the end of each growth cycle, when the dermal papilla cells migrate away from the follicle and do not return, which makes the dermal papilla structure become progressively smaller with each growth cycle.
I want to take a comprehensive look at what our problem is here.
1. ( The Basics )
Testosterone is a steroidal hormone derived from cholesterol. Its production begins in the brain when the hypothalamus detects a deficiency of testosterone in the blood and sends a messenger hormone called gonadotrophin-releasing hormone (GnRH) to the pituitary gland. This prompts the pituitary to secrete luteinizing hormone (LH), which in turn prompts the Leydig cells in the testes to produce testosterone. About 60 percent of the circulating
testosterone is carried in blood plasma bound to a plasma protein called sex hormone binding globulin. Thirty-eight percent is bound to albumin, while only two percent of the circulating testosterone is free. "Free" refers to unbound testosterone, which is able to
enter cells and exert its metabolic effects. The conversion of testosterone to the more active dihydrotestosterone(DHT) in certain target cells depends upon the presence of the enzyme 5-a-reductase. The primary catabolic product of androgen metabolism in either
growing or resting hair follicles is androstenedione. The conversion of testosterone to androstenedione via 17-l-hydroxysteroid dehydrogenase is tenfold the rate of the 5-a-reductase system that yields DHT.
( What Does DHT Do? )
DHT combines with a cytosol receptor to form a complex that enters the nucleus and joins with chromatin to initiate protein synthesis. DHT also inhibits energy production by keeping phosphodiesterase relatively inactive and by suppressing various protein (enzyme)
synthetases.
( How Does DHT Do It? )
The effects of DHT on scalp-hair is mediated through changes in intracellular concentrations of cyclic AMP (cAMP). The "second messenger" rule of cAMP states that the first messenger (a hormone, DHT) is carried to the plasma membrane of its target tissue where adenyl cyclase recognizes only the specific first messenger. Simultaneously, a catalytic subunit of adenyl cyclase produces a second messanger, a molecule, (cyclic adenosine monophosphate) which
initiates a specific physiologic function.
( Physiologic Changes In The Follicle )
The rate at which cells divide is controlled by a complex balance between two compounds: cyclic adenosine monophosphate (AMP), and cyclic guanidine monophosphate (GMP). Higher than normal levels of GMP cause cells to divide too fast. Higher levels of AMP reduce the rate of cell replication. The key to normal replication must be the balance between the two. The diverse biologic effects of cAMP are mediated through activation of a family of protein kinases, which consist of a regulatory (R) and a catalytic (C) subunit; and when bound, these kinases are not active. Cyclic AMP binds to the R subunit, (a binding protein) for cAMP and subsequently releases the C subunit to form an active enzyme. Therefore, the more cAMP available in the androgen-sensitive hair follicles, the stronger the activation of the protein kinase. An increase in cAMP concentrations in hair follicles would produce diverse effects on various enzymes and reaction pathways. Inhibition of glycolysis - by the action
of the active C subunit on the enzyme phosphofructokinase – decreases the energy available for the cell to maintain its metabolic functions. The same active subunit effectively slows
posttranslational protein synthesis and interferes with cell cycles at the C1 and S phases. These combined effects of high cAMP concentrations result in premature completion of the anagen stage; and this, in turn, yields follicles that are thinner and shorter than those of normal terminal hair. Apparently, the differences in sensitivities for androgens of various types of hair follicles reside in the cAMP protein-kinase system.
2. ( Minoxidil )
Minoxidil works in the follicles that contain Phenol-sulfating phenol sulfotransferase 1, which metabolizes minoxidil to minoxidil sulfate. Minoxidil Suflate stimulates the production of vascular endothelial growth factor, a possible promoter of hair growth. The
mechanism of production of vascular endothelial growth factor remains unclear, however, we do know that adenosine serves as a mediator of vascular endothelial growth factor production. Dermal papilla cells have both adenosine receptors and sulfonylurea receptors, the latter of which is a well-known target receptor for adenosine-triphosphate-sensitive potassium channel openers. So, the effect of minoxidil sulfate is mediated by adenosine, which triggers intracellular signal transduction via both adenosine A1 and A2 receptors, and the expression of sulfonylurea receptor 2B in dermal papilla cells might play a role in the production of adenosine.
( male pattern baldness Out-Thinks Minoxidil )
We all notice that male pattern baldness 'figures out' Minoxidil after a while and starts to counteract its positive effects. One reason for this could be that a chemical reaction is produced to block the conversion of Minoxidil to Minoxidil Sulfate. This reason has been noticed in many studies that showed minoxidil ineffective in follicles that did not have Phenol-Sulfating phenol sulfotransferase 1. If true, that would explain why minoxidil only grows hair on certain places of the scalp and not others. Minoxidil also increases NO, and male pattern baldness matches the increase with Superoxide. The reaction produces Peroxynitrite which puts stress on the mitochondria (minoxidil speeds this up creating a "resistance" of sorts and the detrimental reaction between NO & SO occurs at a rate 6 times greater than that which current treatments containing Cu/Zn are able to inhibit it(i.e. copper & zinc... foliigen/tricomin/zix). In other words by a paradoxical twist of biological and chemical
fate, the more you supplement NO (i.e. through minoxidil) the more there is to react in a detrimental fashion with the Superoxide to form Peroxynitrite which then actually further inhibits your attempts to achieve beneficial vasodilation amongst other things, which you want from minoxidil.) Peroxynitrite, which itself seems to be responsible for depleting NO bioavailability, and subsequently hindering vasodilation, and causing ultimate endothelial dysfunction. The toxicity of Peroxynitrite is mediated through mitochondrial dysfunction which leads to the mitochondria releasing cytochrome C.
3. ( PROGRAMMED CELL DEATH )
Whether a person uses Minoxidil or not, the activation of the chemical processes ( such as cytochrome C ) caused by DHT starts the caspase 9 cascade. The Caspase 9 cascade is activated as TGF-B and A increase around our follicles, TGF-beta1 activates interleukin
(IL)-6 via multiple signaling pathways including Smad2, nuclear factor-kappaB (nuclear factor (NF)-kappa B, which activates genes encoding inflammatory cytokines ), JNK, and Ras. Following different stimuli, such as cytokines or DNA-damaging agents, Ik-B is
phosphorylated by the IKK kinase complex, polyubiquitinated and degraded. Then, the NF-B nuclear localization signal (NLS) is freed allowing the nuclear translocation of the transcription factor and the induction of its target genes. These target genes code for
proinflammatory molecules as well as pro or antiapoptotic proteins. cells that are attacked by TGF-B cause apoptosis induction by macrophages,TGF-A efficiently eliminates cells during intercellular induction of apoptosis, both factors act synergistically during apoptosis.
4. ( Caspase 3 )
This propogates into caspase 3 which tells the hair follicle to "sleep" through TNF-A, and B. TNF-A activates a sphingomyelinase that induces apoptosis through the generation of ceramides from sphingomyelin. TNF-A, ionizing radiations and chemotherapeutic drugs have been shown to induce (NF)kappa-B. The expression of an unresponsive mutated Ik-B inhibitor sequestered (NF)kappa-B in the cytoplasm and increased apoptosis following treatment by cytotoxic agents. TNF-b causes an inhibition of lipoprotein lipase present on the surface of vascular endothelial cells. The predominant site of TNF-b synthesis is T-lymphocytes, in particular the special class of T-cells called cytotoxic T-lymphocytes (CTL cells). The induction of TNF-b expression results from elevations in IL-2 as well as the interaction of antigen with T-cell receptors.
*(The expression of both IL-2 and the IL-2 receptor by T-cells is induced by IL-1. The predominant function of IL-1 is to enhance the activation of T-cells in response to antigen. IL-2 is the major interleukin responsible for clonal T-cell proliferation. IL-2 also exerts effects on B-cells, macrophages, and natural killer (NK) cells. The production of IL-2 occurs primarily by CD4+ T-helper cells)
5. ( A chlorine bath for our follicles )
The immune system see's these signals as a foreign antigen and goes to the source to uleash armageddon on our follicles by spraying them with cholorine bleach, not to mention that the cell death occurs due to the properties of all the other chemicals involved.
6. ( Physical Result on the Follicle )
Normally, cells multiply in the lower dermal sheath and then migrate into the dermal papilla at the start of a new hair growth cycle. At the end of the hair growth cycle the cells migrate out again either back into the dermal sheath or out into the dermis. In Androgenic
Alopecia the difference comes at the end of each growth cycle, when the dermal papilla cells migrate away from the follicle and do not return, which makes the dermal papilla structure become progressively smaller with each growth cycle.
