Recently, I've been writing about a possible explanation for the "horseshoe" shape of pattern baldness, as well as a more specific pathology for the loss hair. I tackled these subjects a little bit in The Baldness Field but ironically didn’t go over them at all in the book, Hair Like a Fox. I think this was because, 1) I didn’t know and, 2) I didn’t have the same access to research that I do now. Access to research is actually one of the biggest steps forward I’ve ever encountered, and being able to peruse the history of baldness—while others cannot—is a certifiable tragedy.
Here’s a summary of The Baldness Field:
- Hair follicles have high energy demands requiring both glucose and oxygen to grow. However, hair follicles engage in aerobic glycolysis (the "Warburg effect")—a very "inefficient" way of producing energy.
- Metabolic stress limits the availability of oxygen and glucose to peripheral tissues (e.g., scalp, hands, feet), and shifts the fuel source away from glucose to fatty acids. Compared to glucose, fatty acids are "poor energetic substitutes" for hair follicles.
- A deficiency of oxygen (hypoxia) increases the concentration of mast cells within a tissue.
- The classical horseshoe shape or baldness field is characterized by an increased concentration of mast cells.
I wanted to expand on the above to include how the presence of polyunsaturated fats changes the role of mast cells from physiological to pathological, and more importantly, how a model of metabolic stress-induced pattern baldness ties together some anomalous information in androgenic-centric pattern hair loss research. I’ll close the article with some strategies to restore energy metabolism within the hair follicle.
I: What Are Mast Cells?
Mast cells are noncirculating cells in connective tissue, skin, nervous tissue, the linings of the stomach and intestine, and other tissues in contact with the outside world. They differ from other types of cells by containing large granules in their cytoplasm. Mast cells are known to degranulate under both physical (cold, heat, and ultraviolet and x-ray radiation) and chemical (various bacterial or animal toxins) conditions. When degranulation occurs, histamine, serotonin, prostaglandin D2, and other substances contained in the granules are released. After degranulation, the granules are regenerated.
As for their physiological function, they've been referred to as “switchboards” of inflammation during the stress responses. They're activated by various stress substances, including estrogen, and in a vicious cycle, mast cells can also generate stress substances themselves.[2,3] In an email correspondence, Raymond Peat referred to them as "potential agents of tissue renewal or regeneration":
"Following from my understanding of the implantation process of an embryo in the uterus, and the function of mast cells there, leading to formation of the placenta, I’m inclined to think of them as potential agents of tissue renewal or regeneration. I think their activation by estrogen, and quieting by progesterone, suggests that they are probably activators and guides for stem cell formation and differentiation, depending on the availability of support. Their presence in cancers has always seemed to me to indicate that both allergies and cancer are mainly systemic energy problems." — Raymond Peat (2015)
I think Ray's thoughts on mast cells as "potential agents of renewal" and their activation by estrogen reflects his extensive work on estrogen's involvement in tissue repair and reproduction. Constance R. Martin noted that "...estrogens are among the best known of the growth stimulants," and estrogen achieves a proliferative growth state by inhibiting oxidative metabolism preparing cells to take up water, divide, and grow.[4,5] Similarly, we know that hair growth is an energy intensive proliferative process, with hair follicles converting proportionately more glucose to lactic acid than carbon dioxide. Mast cells have been proposed as regulators hair growth and their accumulation and activation is in flux during the hair growth cycle. However, as the organism ages and interacts with its environment, accumulating various stressors, this well controlled regulatory process of mast cell activation and growth might spiral out of control.
II: Metabolic Stress & Mast Cells
In 1992, young men with pattern baldness were found to experience "adrenal hyperactivity" leading researchers to propose that metabolic stress initiated pattern baldness. Metabolic stress substances such as cortisol, prolactin,[9,10] and aldosterone have long been associated with pattern baldness, however, their involvement and meaning in the loss of scalp hair remains relatively unexplored.
A feature of metabolic stress is exchanging glucose for fatty acids as a main source of fuel. Oxidizing fatty acids, rather than glucose, produces less carbon dioxide and restrains the availability of oxygen to tissues. An increase in free fatty acids and a decrease in the generation of carbon dioxide might help explain why balding areas of the scalp were found to be less well oxygenated when compared to controls.
Another feature of metabolic stress and carbon dioxide deficiency (or hypocapnia) is the accumulation of mast cells. An accumulation of mast cells reminiscent of the classical horseshoe shape of pattern baldness was discovered in the scalps of balding men in 2012. While researchers didn't hypothesize what the finding might mean, I think, the accumulation of mast cells in the scalp and their chronic activation is analogous to a large injury. For example, simply plucking a hair causes surrounding mast cells to degranulate, temporarily suppressing energy metabolism, inciting mast cell degranulation, and stimulating cell division; an example of how injury can lead to renewal.
However, In the balding scalp, something is different—instead of injury and mast cell activation leading to renewal of the hair follicles, it leads to inflammation, edema, fibrosis, and eventually the complete loss of function. The activation of mast cells as physiological agents of renewal or pathological horseman of the hairpocalypse appears to be influenced and defined by the individual possessing mast cells and the environment that the individual lives in.
III: From Physiological To Pathological
In 1992, Jaworsky et al. found that mast cell degranulation was a normal event in the anagen growth cycle, however, the process was exaggerated in baldness, involving chronic activation of T-cells, the overproduction of collagen by fibroblasts, and eventually fibrosis in the hair follicle.
In 2000, the role of "microinflammation" was confirmed in a significant degree of those with pattern hair loss. The authors felt that the "crime scene" of pattern hair loss led back to the metabolism of the so-called essential fat, arachidonic acid into hormone-like messengers called prostaglandins. In 2012, it was discovered that a specific prostaglandin, prostaglandin D2, which is produce mainly by mast cells, accumulates in the scalp's of balding men and inhibits hair growth.
Phospholipase A2 > Arachidonic Acid > Cyclooxygenase-2 > Prostaglandin D2 synthase > Prostaglandin D2
The accumulation of prostaglandin D2 in the scalp's of balding men was proposed as a hormonally regulated process, and the authors noted estrogen's ability to activate prostaglandin D2 synthase. Estrogen also activates phospholipase A2 and cyclooxygenase-2, appearing to contribute to the production of prostaglandins on many levels.[19,20] Moreover, estrogen activates mast cells causing them to degranulate releasing their inflammatory mediators into the surrounding tissue.
Like the classical metabolic stress hormones, estrogen is increased during stressful situations, for instance, just immobilizing an animal increases its production of estrogen. However, animals made "essential fatty acid deficient" produce less estrogen, prostaglandins, and are incredibly resistant to stress. Increased stress resistance attributed to "essential fatty acid deficiency" might be due the animal's enhanced respiratory intensity,[26,27] and the production of mead acid, which was found to "exert an antiinflammatory effect."
Considering the rate-limiting precursor for prostaglandin D2 is arachidonic acid, and that arachidonic acid is mainly produced from another so-called essential fatty acid, linoleic acid in the liver, and that essential fatty acids are estrogenic, promoting mast cell activation, and at the same time can inhibit the production of progesterone, which quiets mast cells, it appears that the accumulation of the essential fatty acids in the tissues over time play an essential role in the genesis of pattern baldness.
Many changes occur in the organism during aging: the accumulation of the "essential" polyunsaturated fats in the tissues, the replacement of copper for iron in the mitochondria, the increased absorption of bacterial endotoxin, various nutrient deficiencies, and an enhanced reliance on free fatty acids as fuel instead of glucose. Together, these things tend to shift steroid synthesis away from the antiestrogenic protective "youth-associated" substances, progesterone, pregnenolone, and DHEA, towards the stress substances, estrogen, cortisol, prolactin, growth hormone, parathyroid hormone, and aldosterone. In the case of pattern baldness, this shift probably leads to the accumulation of mast cells in the scalp, their chronic activation, and an increased exposure to the inflammatory mast cell end products (i.e., prostaglandin D2, etc.) explaining many of the features that are usually blamed on androgens in pattern baldness (e.g., oxidative stress, inflammation, edema, and fibrosis).
While many people believe their hair loss (or health problems) began "a few years ago," they probably began early in development. This is why I think it's important not only to engage in self-metrics such as monitoring the resting pulse and temperature to assess the rate of metabolism, but if possible, investing in some basic labs such as thyroid stimulating hormone, prolactin, total cholesterol, carbon dioxide, serum calcium, serum phosphate, vitamin D, and parathyroid hormone to get a better picture of the metabolic situation.
In addition to a satisfying easy-to-digest diet low in the "essential fats" that helps maintain a higher pulse rate and temperature, thyroid (to increase carbon dioxide and quiet mast cells), vitamin A (to increase the synthesis of the "youth-associated" substances and decrease estrogen), pregnenolone (to lower cortisol), progesterone (to lower estrogen in women), aspirin with vitamin K (to lower the prostaglandins), vitamin D (to lower parathyroid hormone, which activates mast cells), and a daily carrot (or activated charcoal, or an antiserotonin drug) to decrease intestinal inflammation and lower bacterial endotoxin, seem like reasonable therapies to investigate.
- Montagna, W., et al. Hair Research. 1981
- Arck, P.C., et al. Neuroimmunology of stress: skin takes center stage. J Invest Dermatol. 2006 Aug;126(8):1697-704. “Thus, skin mast cells not only are highly sensitive to modulation of their activities by classical stress hormones but also generate key stress hormones (at least CRH) themselves.” “Skin mast cells and their functional role as ‘switchboards’ of neurogenic inflammation during stress responses.”
- Arck, P.C., et al. Indications for a ‘brain-hair follicle axis (BHA)’: inhibition of keratinocyte proliferation and up-regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P. FASEB J. 2001 Nov;15(13):2536-8. Epub 2001 Sep 17. “These stress-induced immune changes could be mimicked by injection of the neuropeptide substance P in nonstressed mice and were abrogated by a selective substance P receptor antagonist in stressed mice. We conclude that stress can indeed inhibit hair growth in vivo, probably via a substance P-dependent activation of macrophages and/or mast cells in the context of a brain-hair follicle axis.” “…[CRH], substance P [SP], ACTH, β-endorphin, prolactin, progesterone, and catecholamines) mediates and modulates systemic stress responses.7-10 A growing body of evidence now supports that these factors can indeed alter hair growth, certainly in mice2, 3, 11-13 and probably also in humans.”
- Gross. Reproductive cycle biochemistry. Fertility & Sterility 12(3), 245-260, 1961. “The maintenance of an environment conducive to anaerobic metabolism—which may involve the maintenance of an adequate supply of the substances that permit anaerobiosis…seems to depend primarily upon the action of estrogen.” “Glycolytic metabolism gradually increases throughout the proliferative phases of the cycle, reaching a maximum coincident with the ovulation phase, when estrogen is at a peak. Following this, glycolysis decreases, the respiratory mechanisms being more active during the secretory phase. Eschbach and Negelein showed the metabolism of the infantile mouse uterus to be less anaerobic than that of the adult. If estrogen is administered, however, there is a 98 per cent increase in glycolytic mechanisms.” “The effect of the progestational steroids may be such as to interfere with the biochemical pattern required for support of this anaerobic environment.”
- Nagy, P., and Csaba, I.F. [Action of oestrogens on in vitro metabolism of trophoblast from human early pregnancy (author’s transl)]. Zentralbl Gynakol. 1982;104(2):111-6. “Warburg’s manometric method was used to check the action of oestrone, oestradiol, and oestriol on aerobic and anaerobic glycolysis of placental respiration. Oestrogen concentrations of 10(-4) M were found to reduce oxygen consumption and to increase aerobic glycolysis. Such reduction of oxygen consumption was most strongly pronounced in connection with oestradiol, while the strongest rise in aerobic glycolysis took place in the wake of oestradiol and oestrone. Oestrogen action upon anaerobic glycolysis was variable, with the latter remaining unchanged by oestradiol, reduced in response to oestriol, and slightly increased by oestrone.”
- Ohnemus, U., et al. The hair follicle as an estrogen target and source. Endocr Rev. 2006 Oct;27(6):677-706. Epub 2006 Jul 28. “The transformation of terminal to vellus hair follicles in androgenetic alopecia is also associated with a discrete infiltration of perifollicular macrophages and with mast cell activation, which has been proposed to be inherent to the terminal-to-vellus switch itself.”
- Pitts, R. L. Serum elevation of dehydroepiandrosterone sulfate associated with male pattern baldness in young men. J Am Acad Dermatol. 1987 Mar;16(3 Pt 1):571-3. “Eighteen men aged 18 to 32 with rapidly progressive male pattern baldness had serum dehydroepiandrosterone sulfate and testosterone measured. Dehydroepiandrosterone sulfate levels were elevated in all patients, ranging from 340 to 730 micrograms/dl. The patients were otherwise healthy and serum testosterone levels were within normal limits. A control group of men of similar age without hair loss had lower dehydroepiandrosterone sulfate levels ranging from 124 to 300 micrograms/dl (p less than 0.005). The biochemistry of androgens, particularly dehydroepiandrosterone sulfate, suggests that adrenal hyperactivity may initiate alopecia in young men who are genetically susceptible.
- Schmidt JB. Hormonal basis of male and female androgenic alopecia: clinical relevance. Skin Pharmacol. 1994;7(1-2):61-6. “Our findings showed a significant elevation of cortisol in both male and female AH patients compared to controls, pointing to the suprarenes as a contributing factor in AH. This is confirmed by the observation of exacerbated AH in periods of increased stress.” “The mainly peripheral activity of this hormone and elevated E2 levels in males stress the importance of androgen metabolism especially at the peripheral level.” “Another significant finding was elevated PRL after TRH stimulation. Thus, the androgen-stimulating effect of PRL may also play a role in female AH. Our findings show multilayered hormonal influences in AH.”
- Foitzik, K., et al. Prolactin and its receptor are expressed in murine hair follicle epithelium, show hair cycle-dependent expression, and induce catagen. Am J Pathol. 2003 May;162(5):1611-21. “In addition we show that PRL exerts functional effects on anagen hair follicles in murine skin organ culture by down-regulation of proliferation in follicular keratinocytes.””The regressing (catagen) follicle showed a strong expression of PRL in the proximal ORS.” “Addition of PRL (400 ng/ml) to anagen hair follicles in murine skin organ culture for 72 hours induced premature catagen development in vitro along with a decline in the number of proliferating hair bulb keratinocytes. These data support the intriguing concept that PRL is generated locally in the hair follicle epithelium and acts directly in an autocrine or paracrine manner to modulate the hair cycle.”
- Foitzik, K., et al. Human scalp hair follicles are both a target and a source of prolactin, which serves as an autocrine and/or paracrine promoter of apoptosis-driven hair follicle regression. Am J Pathol. 2006 Mar;168(3):748-56. “PRL has also been implicated in the pathogenesis of androgenetic alopecia by modulation of androgens, and hyperprolactemia is associated with an androgenetic alopecia-type hair loss pattern, along with hirsutism (in females).”
- Arias-Santiago, S., et al. Br J Dermatol. 2009 Nov;161(5):1196-8. Elevated aldosterone levels in patients with androgenetic alopecia. “Patients with AGA showed significantly higher systolic blood pressure values (136.23 vs. 124.10 mmHg, P = 0.01) and aldosterone levels (197.35 vs. 133.71 pg mL(-1), P = 0.007) vs. controls.” “The elevated aldosterone values in these patients may contribute, together with other mechanisms, to the development of AGA and may also explain the higher prevalence of hypertension. Blood pressure screening of patients with AGA will permit earlier diagnosis of an unknown hypertension and initiation of appropriate treatment.”
- Goldman, B.E., et al. Transcutaneous PO2 of the scalp in male pattern baldness: a new piece to the puzzle. Plast Reconstr Surg. 1996 May;97(6):1109-16; discussion 1117. “Transcutaneous PO2 also was significantly lower in the frontal scalp of male pattern baldness subjects (32.2 +/- 2.0 mmHg) than in either frontal or temporal scalp of controls (53.9 +/- 3.5 mmHg and 61.4 +/- 2.7 mmHg, respectively). There is a relative microvascular insufficiency to regions of the scalp that lose hair in male pattern baldness. We have identified a previously unreported tissue hypoxia in bald scalp compared with hair-bearing scalp.”
- Jin, Y., et al. Mast cells are early responders after hypoxia-ischemia in immature rat brain. Stroke. 2009 Sep;40(9):3107-12. “MCs are early responders to HI in neonatal brain. MC stabilization provides lasting protection and suggests a new target for therapeutic interventions.”
- Larson, A.R., et al. A prostaglandin D-synthase-positive mast cell gradient characterizes scalp patterning. J Cutan Pathol. 2014 Apr;41(4):364-9. “We hypothesized that this difference in pattern of prostaglandin D-synthase expression may constitute a developmental pattern inherent to normal as well as alopecic scalp skin, thus defining a ‘field’ vulnerable to acquired hair loss.”“These data indicate that scalp is spatially programmed via mast cell prostaglandin D-synthase distribution in a manner reminiscent of the pattern seen in androgenetic alopecia.” “Currently the main successful treatment options for androgenetic alopecia are finasteride, an androgen-based systemic therapy with numerous side effects…” “In a prior study of male pattern alopecia, increased numbers of mast cells have been seen in balding vertices compared to non-balding occipital scalp and, in fact, this pattern was also observed in five control subjects studied, though there were greater numbers of mast cells in the patients with alopecia.” “In the 1990’s mast cells were found to be actively degranulating in the inflammatory infiltrates of scalp with male pattern alopecia and this was proposed to contribute to perifollicular fibrosis.”
- Maurer, M., et al. What is the physiological function of mast cells? Exp Dermatol. 2003 Dec;12(6):886-910. “Under physiological conditions, skin mast cells preferentially localize around nerves, blood vessels and hair follicles. A given mast cell function plays a physiological role in some situations, but the same function may play a pathological role in other situations. In a sense, the mast cell might be compared with an excellent actor: the actor may beautifully play the role of either a good or evil character. Taken together, the specific physiological or pathological roles of mast cells appear to be influenced and defined by the individual possessing mast cells and the environment that the individual lives in.” “Some doubt as to the normality of these observations lurk, however, in the back of my mind, as in the model employed, anagen is induced by plucking of hair and thus by mechanical trauma with an associated massive mast-cell degranulation. Possibly, tissue traumatization and associated mast-cell-dependent processes in the context of wound healing may therefore be operative in the model employed.”
- Jaworsky, C., et al. Characterization of inflammatory infiltrates in male pattern alopecia: implications for pathogenesis. Br J Dermatol. 1992 Sep;127(3):239-46. “Ultrastructural studies disclosed measurable thickening of the follicular adventitial sheaths of transitional and alopecic zones compared with those in the non- alopecic zones. This finding was associated with mast cell degranulation and fihroblast activation within the fibrous sheaths.” “The data suggest that progressive fibrosis of the perifollicular sheath occurs in lesions of pattern alopecia, and may begin with T-cell infiltration of follicular stem cefi epithelium. Injury to follicular stem cefi epithelium and/or thickening of adventitial sheaths may impair normal pilar cycling and result in hair loss.
- Mahe, Y.F., et al. Androgenetic alopecia and microinflammation. Int J Dermatol. 2000 Aug;39(8):576-84. “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 5α-R genes cannot account for all cases of AGA, and a polygenic etiology should be considered.” “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.” “Once aa is released from the cell membrane phospholipids by phospholipase A2,18,19 it is metabolized through a complex equilibrium between two families of enzymes, generating either prostaglandins (PGs) (through the activity of PGH synthases, PGHSs) or leukotrienes…” “This upregulation of androgen metabolism by proinflammatory cytokines remains, however, to be established at the pilosebaceous unit level.” “We know now that, at least in about one-third of cases, the tool which causes the lethal damage is a microinflammatory process.”
- Garza, L.A., et al. Prostaglandin d2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia. Sci Transl Med. 2012 Mar 21;4(126):126ra34. “Given the androgens are aromatized into estrogens, these results may be relevant to hair growth and alopecia in both men and women. Thus, these or similar pathways might be conserved in the skin and suggest that sex hormone regulation of Ptgds may contribute to the pathogenesis of AGA.” “…demonstrates elevated levels of PGD2 in the skin and develops alopecia, follicular miniaturization, and sebaceous gland hyperplasia, which are all hallmarks of human AGA. These results define PGD2 as an inhibitor of hair growth in AGA and suggest the PGD2-GPR44 pathway as a potential target for treatment.”
- Thomas, W., et al. Estrogen induces phospholipase A2 activation through ERK1/2 to mobilize intracellular calcium in MCF-7 cells. Steroids. 2006 Mar;71(3):256-65. Epub 2005 Dec 22. “The principal secreted estrogen, 17beta-estradiol rapidly activates signaling cascades that regulate important physiological processes including ion transport across membranes, cytosolic pH and cell proliferation. “ “Here, we demonstrate that a physiological concentration of 17beta-estradiol caused a rapid, synchronous and transient increase in intracellular calcium concentration in a confluent monolayer of MCF-7 cells 2-3 min after treatment. “ “Here we show, for the first time, that PLA(2) and the eicosanoid biosynthetic pathway are involved in the 17beta-estradiol induced rapid calcium responses of breast cancer cells.”
- Luo, C., et al. Constant expression of cyclooxygenase-2 gene in prostate and the lower urinary tract of estrogen-treated male rats. Z Naturforsch C. 2001 May-Jun;56(5-6):455-63.
- Zierau, O., et al. Role of female sex hormones, estradiol and progesterone, in mast cell behavior. Front Immunol. 2012 Jun 19;3:169. “Postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma.” Alongside the authors have also shown that E2 rapidly stimulated MC degranulation which could be blocked by tamoxifen, a tissue specific ER antagonist, clearly indicating that stradiol-induced MC degranulation throughout one of its receptors. In addition to female sex hormone receptor expression, MCs have been also shown to express androgen receptor. However, testosterone treatment had no effect on MC degranulation.
- Shors, T.J., et al. Acute stress persistently enhances estrogen levels in the female rat. Stress. 1999 Dec;3(2):163-71. “These results indicate that exposure to a relatively acute stressful event immediately and persistently enhances serum estradiol and are discussed in the context of reports that exposure to the same stressors immediately and persistently impairs associative learning in the female rat.“
- Obinata, K., et al. The effect of essential fatty acid deficiency on hepatic bile salt sulphotransferase in rats. J Steroid Biochem Mol Biol. 1992 Jul;42(6):625-7. “The decrease in hepatic BSS activity in female rats caused by EFA deficiency may be mediated via a decreased estrogenic action on the liver.”
- Ball, H.A., et al. Essential fatty acid-deficient rats are resistant to oleic acid-induced pulmonary injury. Journal of Applied Physiology August 1989 vol. 67 no. 2 811-816. “Because leukotrienes and prostaglandins are inflammatory mediators derived from arachidonic acid, their potential role in oleic acid-induced lung injury was evaluated in control and in essential fatty acid-deficient (EFAD) rats depleted of arachidonic acid substrate.” “In EFAD rats, oleic acid failed to significantly increase the lung permeability index at 5 and 50 min. In contrast to control rats, oleic acid failed to cause hypoxemia in the EFAD rats.” “Treatment with intraperitoneal ethyl arachidonate (400 mg over 2 wk) reversed the resistance of EFAD rats such that the pulmonary edema (P less than 0.05) was evident after oleic acid. This latter group also manifested a significant (P less than 0.05) rise in the bronchoalveolar lavage levels of iLTB4 and i6-keto-PGF1 alpha. These results suggest that arachidonic acid metabolites contribute to oleic acid-induced pulmonary permeability.”
- Cook, J.A., et al. Essential fatty acid deficient rats: a new model for evaluating arachidonate metabolism in shock. Adv Shock Res. 1981;6:93-105. “Essential fatty acid deficient (EFAD) rats are significantly more resistant to the lethal effects of S. enteritidis endotoxin (20 mg/kg, IV) than normal control rats. Compared to endotoxin-treated normal rats, EFAD rats also manifested less severe alterations of hepatic and lysosomal integrity and became less hypoglycemic. Administration of the ethyl ester of the essential fatty acid, arachidonic acid (100 mp, IP) two days prior to challenge with S. enteritidis endotoxin (20 mg/kg) in EFAD rats restored their sensitivity to endotoxin, as denoted by a 100% mortality compared to a 24% mortality (P less than 0.01) in EFAD rats.” “ These observations suggest a deleterious role for arachidonic acid and its conversion to TxA2 in the pathogenesis of endotoxic shock.”
- Piquet, M.A., et al. Polyunsaturated fatty acid deficiency reverses effects of alcohol on mitochondrial energy metabolism. J Hepatol. 2004 Nov;41(5):721-9. “Mitochondria from ethanol fed rats showed a dramatic decrease in oxygen consumption rates and in cytochrome oxidase activity. PUFA deficiency showed an opposite picture…” “PUFA deficiency reverses alcohol-related mitochondrial dysfunction via an increase in phospholipid arachidonic over linoleic ratio, which raises cytochrome oxidase activity. Such deficiency may be an adaptive mechanism.”
- Kunkel, H., Williams, J. The effects of fat deficiency upon enzyme activity in the rat. J Biol Chem. 1951 Apr;189(2):755-61. “A fat deficiency in the rat causes a marked increase in liver cytochrome oxidase activity… “ “Supplementation with 100 mg. of methyl linoleate per rat per day reduced the cytochrome oxidase to the level of that produced by a 5 percent corn oil diet.”
- Lefkowith, J.B., et al. Essential fatty acid deficiency: a new look at an old problem. Prostaglandins Leukot Med. 1986 Aug;23(23):1237. “EFA deficiency has been shown to exert an antiinflammatory effect.”
- Martin, C. Endocrine Physiology. 1985. “All members of this group are synthesized from ‘polyunsaturated’ fatty acids that must be supplied by the diet. From a quantitative standpoint, arachidonic acid is the major presurosor.” “Meats and peanuts contain small amounts [of arachidonic acid], but the liver forms most of it from linoleic acid. Arachidonic acid is the presurosor of the prostaglandins with two double bonds, and of the several other biologically potent substances.”
- Klimek, J. The influence of NADPH-dependent lipid peroxidation on the progesterone biosynthesis in human placental mitochondria. J Steroid Biochem Mol Biol. 1992 Aug;42(7):729-36. “In an in vitro system consisting of human term placental mitochondria and an NADPH-generating system plus Fe2+, significant lipid peroxidation was observed along with a concomitant inhibition of progesterone biosynthesis. This inhibition could be markedly blocked by Mn2+, superoxide dismutase and dimethylfuran, inhibitors of NADPH-dependent lipid peroxidation. In addition, it has been found that malondialdehyde formation is accompanied by a corresponding decrease in placental mitochondrial cytochrome P-450 content. Inhibitors of lipid peroxidation also prevent the loss of cytochrome P-450, further demonstrating a direct relationship between NADPH-dependent lipid peroxidation and degradation of cytochrome P-450 in cell-free systems. These measurements provide the first evidence that the inhibition of progesterone biosynthesis by a NADPH-dependent lipid peroxidation in placental mitochondria is a consequence of cytochrome P-450 degradation due to lipid peroxidation.”
- Menzies, F.M., et al. The role of mast cells and their mediators in reproduction, pregnancy and labour. Human Reproduction Update, 2010, Volume 17, Issue 3, Page 383–396. “MCs express the high-affinity estrogen receptor (Pang et al., 1995) and studies have shown that estrogens augment their activities: in the presence of high levels of estrogens, MC responses to compound 48/80 are increased, leading to more substantial degranulation and release of histamine and serotonin.” “MCs are found in a diverse range of tissues and have the ability to adapt their function to the microenvironment.” “Interestingly, however, there is an increase in testicular MCs in infertile men through MC activation of fibroblasts and promotion of collagen synthesis, could contribute to testicular fibrosis.” “Progesterone is necessary for the maintenance of pregnancy and plays a key role in maintaining cervical integrity prior to labour induction. Progesterone can prevent the migration of MCs in response to chemokines and down-regulate surface chemokine receptor expression. In addition, MC function can be altered by the presence of high concentrations of progesterone. For example, progesterone inhibits the secretion of histamine from MCs (Vasiadi et al., 2006). Notably, these observations would suggest that MCs present within the uterus during pregnancy are quiescent and inhibited by high levels of progesterone, and also that recruitment of MC progenitors from the circulation may be limited.” “At present the prevalence of allergies, including allergic rhinitis, hayfever, eczema, food allergies and urticaria, is rising.”
- Strider, J.W., et al. Treatment of mast cells with carbon dioxide suppresses degranulation via a novel mechanism involving repression of increased intracellular calcium levels. Allergy. 2011 Mar;66(3):341-50. "Results from this study provide the first evidence of a unique regulatory mechanism by which CO₂ inhibits mast cell degranulation and histamine release by repressing stimulated increases in intracellular calcium. Thus, our data provide a plausible explanation for the reported therapeutic benefit of noninhaled intranasal delivery of 100% CO₂ to treat allergic rhinitis."
- Tsakolos, N.D., et al. Induction of mast cell secretion by parathormone. Biochem Pharmacol. 1983 Jan 15;32(2):355-60. "Release of serotonin and histamine was demonstrated with 25 units/ml PTH or higher.” "These results demonstrate that elevated levels of PTH can induce mast cell secretion in vitro and in vivo and suggest a possible role for mast cells in the pathophysiology of non-allergic disease states."