The Mysterious Conductor of the Hair Cycle Clock

 
 

One of the oldest explanations for baldness in the western world was the "exhaustion of nervous energy," that is, the health and capability of the nervous system. In the 1881 book, American Nervousness, George W. Beard explains that baldness and many other problems increase at the expense of nervous energy due to the stress and strain of modern life:

"The increasing popularity of baldness is one of the minor but most instructive expressions of nerve sensitiveness. Among savages in all parts of the earth baldness is unusual, except in extreme age, and gray hairs come much later than with us. So common is male baldness in our large cities that what was once a deformity and exception is now almost the rule, and an element of beauty. One may be bald without being very nervous; but the general prevalence of baldness comes from the general prevalence of nervousness." —George M. Beard (1881)

George Beard called the exhaustion of nervous energy "neurasthenia" and in many ways, the theory was the intellectual stepchild to Hans Selye's 1936 work on metabolic stress. In Beard's view, the person's unfavorable environment caused pattern baldness.

"Complimenting" Beard's environmental view of hair loss was the observation that baldness was noted less often among those engaged in manual labor and more frequently among scientists, academics, ministers, lawyers, and legislators. To advocates of the time, this suggested that simple livin' was hair protective and that "brainy types" were more likely to go bald.

Many intellectuals are bald, but idiots and morons are seldom so.
— Young et al. (1947)

According to an advocate of the theory, If one wanted to keep their hair they "should avoid all excesses or extraordinary excitement," and "shun mental and bodily overstimulation and endeavor to preserve an equable temperament of mind and body."

The dominant view of the time—that something in the environment caused baldness—shifted after James Hamilton's 1942 pioneering experiments with baldness-immune eunuchs and castrates. Turning the attention to hormones and signaling substances in pattern baldness, Hamilton's work formed the foundation of what we know today as "androgen-genetic alopecia" or "male-pattern baldness."[1] However, seven decades later, the androgen-centric model of baldness has yielded unrewarding results and most importantly has failed to clarify the mysterious "conductor" of the long-studied-but-poorly-understood hair cycle clock.[2,3,4]

I: The Missing Conductor

In 2004, Paus et al. explored the dizzying array of growth promoters and inhibitors guiding the telogen, anagen, and catagen phases of the hair cycle.[5] While hair research has come a long way from Hamilton's experiments with castrates, the group acknowledged the limitations of their research:

"Together with numerous colleagues around the world, we have steadily contributed throughout the past decade to the quest to identify ever more ‘‘instruments’’ in the ‘‘hair cycle orchestra’’. However, weand, as far as one can tell from the published literature, everyone elsehave clearly failed to identify the ‘‘conductor’’. The above admission of failure hurts even more since, not so long ago, we were innocently hopeful to have had it all figured out…"

The paper concluded with a call for creativity and competition urging future researchers to explore theoretical frameworks that help direct hair cycle research off-the-beaten track and away from the mainstream:

"Even though this seems wildly unpopular today, especially with molecular biologists investigating the controls of hair follicle cycling, what we need more than anything else is more creativity and competition in terms of theory-building about the hair cycle clock. Whether you like this or not, our experimental designs, consciously or unknowingly, are guided and misguided, anyway, by preconceived notions. Thus, we might as well spend more time with the design and public debate of comprehensive theoretical frameworks that help to direct our future experimental strategies and that may lead us off-the-beaten-track of mainstream hair cycle research."

Rather than starting with the mind-bogglingly large and ever-growing number of regulatory signals currently implicated in hair cycle control, it might be more productive to inspect the "macro events" occurring in the balding individual in an attempt to avoid seeping into the abyss of overcomplexity.

For instance, this year is was noted that balding males 18-35 years old were found to have increased adrenal production of DHEA, which was "significantly associated with increased clinical severity of male pattern androgenic alopecia.”[6] Moreover, the group had a mean thyroid stimulating hormone (TSH) level of 2.5 μIU/mL suggesting a higher functioning pituitary and enhanced cortisol secretion.[7] Another study performed this year also found increased levels of DHEA in those with premature baldness, in addition to higher levels of prolactin, and a lower sex hormone binding globulin (SHBG), which is a common feature of baldness.[8]

A higher functioning of the adrenal glands and pituitary involve changes in the “stress-response modulators,” the mitochondria.[9] Inhibiting mitochondrial energy production increases the reliance on pituitary and adrenal hormones such as cortisol, prolactin, DHEA, and aldosterone, which are all associated with baldness in both sexes. Moreover, these hormonal changes shift the balance between insulin-like growth factor 1 (IGF-1) and transforming growth factor beta 1 (TGF-b1)—two growth factors that appear to be intimately involved in hair growth as well as provide clues for identifying the missing conductor of the hair cycle clock.

II: IGF-1 and TGF-b1

The energy-hungry mini-organ, the hair follicle, normally engages in “violent” proliferative activity requiring safeguards for protection from free radical damage (oxidative stress).[10] Similar to active thyroid hormone,[11] saturated fats,[12] sugars,[13] and insulin,[14] IGF-1 appears to increase the activity of the rate-limiting glucose-6-phosphate dehydrogenase enzyme (G6PDH) that produces NADPH to protect the hair follicle during its volatile growth phase.[15] Polyunsaturated fats,[16] hypothyroidism,[17] and aldosterone, which is increased in males and females with pattern baldness,[18] and is stimulated by low thyroid function and prolactin,[19,20] inhibit G6PDH and the production NADPH.[21] A deficiency of G6PDH and an excess of aldosterone leads to unmitigated oxidative stress, tissue injury, and an increase in the inflammatory cytokine TGF-b1.[22]

Image: A 78 year old man with common male pattern baldness was dozing in his armchair when he fell head first into a coal fire.

Image: A 78 year old man with common male pattern baldness was dozing in his armchair when he fell head first into a coal fire.

TGF-b1 stimulates the formation of collagen, and overtime this overproduction leads to “perifollicular fibrosis” further reducing the hair follicles’ access to oxygen, sugar, and other nutrients. Levels of TGF-b1 are closely related to the progression of pattern baldness,[23] and alongside hypoxia, the accumulation and activation of mast cells,[24] and an increased concentration of prostaglandins reinforce the view that the defining feature of pattern baldness, a decreased anagen to telogen ratio, is the result of chronic scalp inflammation and an inability to repair.[25] The development of fibrosis in baldness might explain why accidentally setting fire to one's scalp can result in a new head of hair.[26, 27]

TGF-b1 appears to share an inverse relationship with the liver's production of IGF-1,[28,29] and in one experiment supplementary IGF-1 stimulated hair follicle development leading the researchers to say that it might be “a promising drug candidate for baldness therapy.”[30] In the 1990s, Keaely et al. demonstrated that IGF-1 inhibits the catagen and telogen phases of the hair growth cycle favoring anagen.[31, 32] More recently, it was discovered that balding hair follicles secreted “significantly less” IGF-1 and “that the downregulation of IGF-1 may be one of the important mechanisms contributing to male pattern baldness.”[33]

Progesterone is generally supportive of hair growth and has been shown to increases IGF-1[34] and lower aldosterone.[35] The historical treatments for pattern baldness cyproterone acetate and spironolactone are both progesterone-like,[36,37] and spironolactone has been shown to reduce TGF-b1.[38] The harzadous drug, finasteride has been shown to lower TGF-b1,[39] and in a small study, its efficancy was related to the upregulation of IGF-1.[40]

Working in the opposite direction of "the most powerful antifibromatogenic steroid" progesterone,[41] estrogen appears to lower IGF-1 and increases aldosterone and TGF-b1.[42,43,44]

Hair follicles and their surrounding tissue are clearly interdependent companions. Therefore, it does not seem correct to separate the responsibilities of one from those of the other in physiological or pathologic events.
— Montagna, W., et al. Hair Research. 1981.

IGF-1 may have other beneficial effects in baldness including lowering SHBG and prolactin.[45] Various problems associated with baldness including metabolic syndrome,[56] heart disease,[47] premature aging,[48] depression and anxiety[49], also appear to be helped by increasing IGF-1 levels. According to a 2012 paper, "IGF-I treatment has never been related to oncogenesis."[50]

III: Identifying The Conductor

The enormous—often redundant—number of regulatory factors involved in hair cycle control is intimidating, however, IGF-1 and TGF-b1 appear to be near the top of the list. In keeping with a focus on what's occurring in the balding individual, I think mitochondrial respiration guided by active thyroid hormone is a candidate for the missing "conductor" of the hair cycle clock.

First and foremost, active thyroid hormone is required for the health and vitality of the the mitochondria, which limits the activity of the the pituitary and adrenal systems that interfere with the hair growth cycle (e.g., cortisol, aldosterone, prolactin, etc.).[51] Moreover, hair follicles are "direct targets" and "sources" of thyroid hormones, the general function of which appears to be to stimulate hair growth by prolonging the anagen growth phase.[52]

A deficiency of thyroid negatively influences the liver, sometimes leading to the development of non-alcoholic fatty liver disease (NAFLD).[53,54] In liver disease, IGF-1 levels are decreased, and the circulating levels correlate to the extent of liver dysfunction.[55] A supplement of thyroid has been shown to restore levels of IGF-1.[56]

In addition to being the main source of IGF-1,[57] the liver is where the metabolism of inactive thyroid hormone (T4) into active thyroid hormone (T3) primarily occurs.[58] In stress, serum levels of T3 tend to decline, with a majority of T4 being metabolized into the antithyroid substance, reverse T3. While the situation is far from clear, in one experiment it was found that the level of reverse T3 rose in parallel with the TGF-b1 level.[59] In the heart, T3 has been shown to reverse fibrosis.[60]

Hair follicles represent one of the most hormone sensitive tissues in the human body and are "exquisitely thyroid hormone-sensitive."[61] While hair follicles appear to be somewhat resistant to shifts in energy due to their massive glycogen stores, I think a chronic deficiency of thyroid explains the high rate of pattern baldness that both men and women experience during a lifetime.[62] An explanation for the degree of baldness probably depends on an organism's available resources and unique ability to adapt to early life stress. For example, in monkeys, food scarcity leads to a hypersensitivity to both TGF-b1 cortisol.[63]

IV: Do No Harm

Video: Reversing Fibrosis in Male Pattern Baldness

Besides increasing thyroid function and keeping the polyunsaturated fats relatively low, sufficient dietary protein is a large variable in the liver’s production of IGF-1.[64] When compared to other proteins, milk was found to have a proportionately greater influence on IGF-1 levels.[65] Moreover, milk and cheese are among the best sources of the amino acid, taurine, which is protective against the deletious effects of TGF-b1 and fibrosis in the hair follicle.[66] If milk digestion has worsened with age (i.e., diarrhea, gas, etc.), a bacterial overgrowth could be involved and can sometimes be resolved with antibiotics.[67]

Another amino acid, glycine, has many anti-inflammatory and anti-fibrotic properties.[68] Oxtail and lamb shank are natural sources of glycine and widely available. Similarly, aspirin is a safe anti-inflammatory that's been found to reverse fibrosis possibly by interfering with the metabolism of arachidonic acid.[69]

Malnutrition is associated with a reduced IGF-1 level,[70] suggesting the use of nutritious foods like eggs, ruminant liver, and oysters regularly. Fasting, a practice that has radically increased in popularity over the last few years, decreases IGF-1 and can lead to a “hypothyroid-like” condition.[71,72] Diets that mimic fasting such as very low-carbohydrate or ketogenic diets have also been found to reduce IGF-1.[73]

Homemade marmalade, sweet orange juice, and guava are sources of the chemicals apigenin and naringenin, which help reduce TGF-b1, protect against fibrosis, and in the case of apigenin, may promote hair growth.[74-77]

Image: "Compared with a moderate sodium intake, salt loading suppressed aldosterone levels and sodium restriction raised them." (1976)

Image: "Compared with a moderate sodium intake, salt loading suppressed aldosterone levels and sodium restriction raised them." (1976)

Adequate salt in the diet has been shown to restrain the release of the pro-fibrotic hormone, aldosterone.[78] An article in 2005, found that the requirement of salt to retain magnesium and calcium was 230% higher than the recommended dietary allowance (RDA).[79]

In my own research, people with pattern baldness very often have deficiencies of vitamin D.[80] The amount of vitamin D in the blood influences the concentrations of IGF-1 and TGF-b1.[81,82] Besides getting adequate calcium and keeping phosphate relatively low (cronometer.com can be used to estimate the content of phosphate and calcium in the diet), in my limited experience, I've found a supplement of vitamin D to be useful.

In the interest of avoiding excessive complexity and possible intestinal allergens, it might be best to use a vitamin D3 (along with other fat soluble vitamins) in oil applied to the skin rather than orally. According to Raymond Peat, about 1/3 or 1/5 is absorbed topically compared to an oral dose. For myself, I've found that applying the vitamins to a lower leg and wrapping it in a thin loose layer of plastic wrap is a smooth way of avoiding the vitamins rubbing off on my pants. Wearing long socks can be helpful, too.

References

  1. Hamilton, J.B. Male hormone stimulation is prerequisite and an incitant in common baldness. Am J Anat 71:451-480 1942.

  2. Trüeb, R., and Tobin, D. Aging Hair. 2010. “The limited success rate of treatment of androgenetic alopecia with finasteride and minoxidil means that further pathogenic pathways may be taken into account.”

  3. Jain, R., et al. Potential targets in the discovery of new hair growth promoters for androgenic alopecia. July 2014, Vol. 18, No. 7 , Pages 787-806. "Till date, only two FDA-approved synthetic drugs, minoxidil and finasteride, are used to cure AGA with only 35 and 48% success, respectively; therefore, a search for new drug based on the mechanism of androgens action is still needed." "It is unlikely that single targeted agents will be sufficient for treating AGA, and therefore, it would be a challenge to obtain compounds with multiple activities." 

  4. Brajac, I. et al. Human Hair Follicle: An Update on Biology and Perspectives in Hair Growth Disorders Treatment. Hair Ther Transplant 2014. "Regarding perspectives, a studies have focused on various innovative pharmacologic targets, but also on some well known molecules. The role of prolactin receptor antagonists, as well as the regulators of thyroid hormones, deserves to be the subject of further research. Also, the relation between vitamin D levels, vitamin D receptor and hair cycling, specifically anagen initiation, represent an attractive area of research nowdays.” "Recent years have witnessed a considerable progress in the research focused on treatment of hair disorders, but with limited success. Therefore, one of the prime challenges of modern hair research is a more profound understanding of the molecular controls of hair follicle cycling. Common diseases such as alopecia areata, telogen effluvium and AGA, until than will remain the unsolved medical problems.”

  5. Paus, R., and Foitzik, K. In search of the "hair cycle clock": a guided tour. Differentiation. 2004 Dec;72(9-10):489-511.

  6. Devi, N., et al. Androgenetic alopecia- Role of androgen levels. 2016. "This study hence focuses on the age group 18 to 35 years which includes both students and working population. This age group is epidemiologically significant because of various social factors effecting the individual at that point of life including marriage, image building and important career options amongst many others.” "Increased mean levels of DHEA-S is significantly associated with increased clinical severity of male pattern androgenic alopecia.” “Mean TSH: 2.5754; 2.4193"

  7. Walter, K.N., et al. Thyroid Res. Elevated thyroid stimulating hormone is associated with elevated cortisol in healthy young men and women. 2012 Oct 30;5(1):13. "Results suggest a positive relationship between TSH and cortisol in apparently healthy young individuals. In as much as this relationship may herald a pathologic disorder, these preliminary results suggest that TSH levels > 2.0 uIU/L may be abnormal."

  8. Sanke, S., et al. A Comparison of the Hormonal Profile of Early Androgenetic Alopecia in Men With the Phenotypic Equivalent of Polycystic Ovarian Syndrome in Women. JAMA Dermatol. 2016 Jun 15. "Compared with the 32 controls, the 57 participants with AGA showed significantly increased mean (SD) levels of testosterone, DHEAS, and prolactin and decreased mean levels of FSH and SHBG.  The mean FAI and LH/FSH ratio were was also increased in the AGA group. These hormonal parameters resemble the well-known profile of women with PCOS.” "Men with early AGA could be considered as male phenotypic equivalents of women with PCOS. They can be at risk of developing the same complications associated with PCOS, including obesity, metabolic syndrome, IR, cardiovascular diseases, and infertility."

  9. Picard, M., et al. Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress. PNAS November 16, 2015. "Central to stress adaptation is cellular energetics, involving mitochondrial energy production and oxidative stress. We therefore hypothesized that abnormal mitochondrial functions would differentially modulate the organism’s multisystemic response to psychological stress.” "We show that mitochondrial dysfunctions altered the hypothalamic–pituitary–adrenal axis, sympathetic adrenal–medullary activation and catecholamine levels, the inflammatory cytokine IL-6, circulating metabolites, and hippocampal gene expression responses to stress. Each mitochondrial defect generated a distinct whole-body stress-response signature.These results demonstrate the role of mitochondrial energetics and redox balance as modulators of key patho-physiological perturbations previously linked to disease. This work establishes mitochondria as stress-response modulators, with implications for understanding the mechanisms of stress pathophysiology and mitochondrial diseases."

  10. Montagna, W. The Biology of Hair Growth. 1958. “Although the bulb of a hair follicle is an epidermal derivative, its pattern of mitotic activity is strikingly different from that of the surface epidermis. While the rate of cell replacement in the surface epidermis is relatively steady, varying only within narrow hmits according to diurnal and hormonal rhythms, the rate of cell production in the follicle is rhythmic, varying sharply between the violent mitotic activity associated with the formation of a new hair and the total lack of activity once that hair has been formed. There may therefore be physiological differences between the mitotic activity of the surface epidermis and that of the growing follicle.”

  11. Heckmann M1, Zimmer HG. Effects of triiodothyronine in spontaneously hypertensive rats (SHR). Studies on cardiac metabolism, function, and heart weight. Basic Res Cardiol. 1992 Jul-Aug;87(4):333-43. "Another aim of this investigation was to elucidate the effect of T3 on the oxidative pentose phosphate pathway (PPP) in the heart of SHR. This pathway, which is an alternative route to glycolysis, generates reducing equivalents in the form of NADPH which is needed for fatty acid synthesis as well as for the removal of oxygen-free radicals via the glutathione system.” “...it could be anticipated that long-term T3-treatment results in the stimulation of cardiac G-6-PD activity. This hypothesis was now tested in the SHR undergoing T3 treatment.” "The activity of glucose-6-phosphate dehydrogenase (G-6-PD) was elevated by 67 % in the hearts of T3-treated SHR…” "A surprising result of this study was that T3 increased the activity of glucose-6-phosphate dehydrogenase (G-6-PD) in the myocardium of SHR."

  12. Salati, L.M., et al. Dietary regulation of expression of glucose-6-phosphate dehydrogenase. Annu Rev Nutr. 2001;21:121-40. “G6PD activity is enhanced by dietary carbohydrates and is inhibited by dietary polyunsaturated fats.” “Addition to the diet of saturated fatty acids, such as palmitate (16:0) and stearate (18:0), and of monounsaturated fatty acids, such as oleate (18:1), do not inhibit G6PD activity.”

  13. Fukuda, H., et al. Effects of high-fructose diet on lipogenic enzymes and their substrate and effector levels in diabetic rats. J Nutr Sci Vitaminol (Tokyo). 1983 Dec;29(6):691-9. “When rats adapted to a stock diet were fed on various high-carbohydrate diets, the hepatic activities of glucose-6-phosphate dehydrogenase, malic enzyme and acetyl-CoA carboxylase were more greatly increased by fructose than by any other carbohydrate. Even in the diabetic state, the enzyme activities were somewhat increased by fructose feeding.”

  14. Weber G, Convery HJ. Insulin: inducer of glucose 6-phosphate dehydrogenase. Life Sci. 1966 Jun;5(12):1139-46. Liver glucose 6-phosphate dehydrogenase activity decreased in metabolic states of hypoinsulinism (starvation, diabetes). When starved animals were refed (which brings about insulin secretion) the enzyme activity rose to high levels. Injection of insulin concurrently with refeeding brought about more pronounced enzyme increases. Insulin increased enzyme activity in normal animals. In diabetic rats the enzyme activity decreased; and insulin treatment returned enzyme activity to levels markedly higher than normal. When diabetic rats were starved the enzyme activity decreased to low levels. Refeeding returned the activity to the diabetic level only. However, when insulin was injected concurrently with refeeding, the enzyme activity markedly increased. Dose-response curves with insulin injected in diabetic rats showed that the increase in this enzyme activity depends on the insulin dose given.

  15. Farquharson, C., et al. Mitogenic action of insulin-like growth factor-I on human osteosarcoma MG-63 cells and rat osteoblasts maintained in situ: the role of glucose-6-phosphate dehydrogenase. Bone Miner. 1993 Aug;22(2):105-15. "The mechanisms involved in the mitogenic actions of insulin-like growth factor-I (IGF-I) on skeletal cells are at present unclear. We have investigated the role of glucose-6-phosphate dehydrogenase (G6PD) in this mechanism and provide strong evidence that stimulation of G6PD activity is required for the growth promoting activities of IGF-I.The culture of metatarsals of 4-week-old rats with IGF-I (10 ng/ml) also stimulated G6PD activity in osteoblasts lining the metaphyseal trabeculae."

  16. Clarke, S.D., et al. Inhibition of triiodothyronine’s induction of rat liver lipogenic enzymes by dietary fat. J Nutr. 1990 Jun;120(6):625-30. “The objective of these studies was to demonstrate that the reduction in lipogenic enzymes caused by ingestion of dietary polyunsaturated fat can in part be attributed to an inhibition of triiodothyronine’s induction of hepatic lipogenic enzymes.” “Triiodothyronine (T3) administration induced (p less than 0.05) the activity of malic enzyme, fatty acid synthase and glucose-6-phosphate dehydrogenase in a dose-dependent manner.” “Beef tallow and safflower oil supplementation of the high glucose, fat-free diet significantly reduced the T3 induction of all the enzymes. Safflower oil was more effective than tallow as a repressor of T3 action. The effect of dietary fat, particularly safflower oil, was to increase the amount of T3 required to induce the activity of lipogenic enzymes.” “These data support the hypothesis that polyunsaturated fats uniquely suppress the gene expression of lipogenic enzymes by functioning as competitive inhibitors of T3 action, possibly at the nuclear receptor level.”

  17. Yilmaz, S., et al. Oxidative damage and antioxidant enzyme activities in experimental hypothyroidism. Cell Biochem Funct. 2003 Dec;21(4):325-30. “Several studies have demonstrated that thyroid hormones regulate G6PD activity. Lombardi et al. generated experimental hypothyroidism in rats by i.p. injection of PTU and iopanic acid in combination. This type of combined application of drugs for induction of hypothyroidism causes serious hypothyroidism and the three known types of diodinase were also inhibited. Rats with serious hypothyroidism were injected with different doses of T2 and T3 for 2 weeks and effects on their livers were evaluated. G6PD activity levels in the liver of rats with hypothyroidism were determined to be 28% lower than that in the control animals, whereas a reduction in the thymus was not significant. T2 and T3 administration caused an increase in the G6PD activity levels. G6PD activity was reported to be mainly regulated by T2. In rats with thyroidectomy, G6PD activity levels were found to be lower compared to controls, but T3 application reversed the effect of thyroidectomy. G6PD activity levels were reported to be increased in patients with thyrotoxicosis compared to controls. In the present study, we found that in the rats with hypothyroidism, G6PD activity levels were not changed in the thymus but were reduced in liver tissues compared to controls. These findings are in agreement with those of Lombardi et al.”

  18. 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."

  19. Gordon, G. G., and Southren, A. L. Thyroid - hormone effects on steroid - hormone metabolism. Bull N Y Acad Med. 1977 Apr; 53(3): 241–259. "Cortisol. An increase in thyroid function to hyperthyroid levels results in a marked increase in the rate of secretion and catabolism of cortisol.” "The latter is evidenced by the shortened half-life and increased pool "turnover" rate of the steroid hormone.” "The metabolic clearance rate (MCR) of cortisol from plasma, using Peterson's data, can be calculated and is elevated significantly.” "The increased rate of secretion of cortisol is a result of the greatly increased plasma clearance of the hormone (i.e., MCR) rather than the converse. This is a specific effect of the increased thyroid function since in instances where cortisol secretion is increased, such as during "stress," ACTH stimulation, or euthyroidal hypermetabolism, a decrease rather than an increase in clearance rate parameters is noted.” "The converse is seen in hypothyroidism, where the metabolic clearance (calculated) and secretion rate of cortisol decreases and its half-life is prolonged.” "Aldosterone: The effects of thyroid dysfunction on the metabolism of aldosterone mimic those found with cortisol, although they are of lesser magnitude.” "It can be seen in Table II that the half-life of aldosterone is shortened and the pool turnover and the metabolic clearance rate are increased in thyrotoxicosis.” "These data suggest a modest increase in the metabolism of aldosterone in hyperthyroidism. Hypothyroid subjects showed opposite effects.” "When the renin-angiotension-aldosterone system in thyrotoxic men was studied during a low sodium diet (10 mEq. Na/day) the normal increase in aldosterone secretion did not occur despite a markedly increased plasma renin level."

  20. Glasow, A., et al. Functional aspects of the effect of prolactin (PRL) on adrenal steroidogenesis and distribution of the PRL receptor in the human adrenal gland. J Clin Endocrinol Metab. 1996 Aug;81(8):3103-11. "Using immunostaining, we could detect the PRL receptor in all three zones of the adrenal cortex.” “After stimulation with PRL (10(-7) mol/L), we measured increased concentrations of cortisol (155 +/- 9.8%; P < 0.005%), aldosterone (122 +/- 3.7%; P < 0.005), and dehydroepiandrosterone (121 +/- 8.6%; P < 0.05) in the cell supernatant.” "We postulate that PRL has a direct effect on adrenal steroidogenesis, thereby regulating adrenal function, which may be of particular relevance in clinical disorders with hyperprolactinemia."

  21. Gilbert, K.C., and Brown, N.J. Aldosterone and inflammation. Curr Opin Endocrinol Diabetes Obes. 2010 Jun;17(3):199-204. "Systemic administration of aldosterone increases nicotinamide adenine dinucleotide phosphate [NADP(H)] oxidase and oxidative stress in macrophages, the heart, vasculature, and kidney.” "Aldosterone also decreases the expression of glucose-6-phosphate dehydrogenase (G6PDH), which reduces NADP+ to NADPH.” "Conversely, anti-oxidant drugs decrease inflammation and injury in aldosterone-treated rodents."

  22. Matsuki, K., et al. Transforming growth factor beta1 and aldosterone. Curr Opin Nephrol Hypertens. 2015 Mar;24(2):139-44. "In addition, a growing number of convincing evidence indicates that both angiotensin II and aldosterone activate TGFbeta signaling, which mediates many of the complications of RAAS-related hypertension including progressive renal dysfunction and cardiac hypertrophy. As such, development of therapeutic strategies targeting TGFbeta signaling may be a way to effectively treat hypertension, heart failure, and chronic kidney disease in patients who cannot tolerate RAAS modulators.” "Increased renal production of TGFbeta1 is associated with various diseases related to the activation of RAAS such as hypertension and diabetes mellitus. Additionally, urinary TGFbeta1 has been found to be associated with increasing interstitial fibrosis as well as proteinuria and mesangial expansion in patients with certain glomerulonephritides. Urinary TGFbeta1 excretion reflects renal TGFbeta1 production. As such, urinary TGFbeta1 excretion is a useful marker to assess the efficacy of treatment with RAAS inhibitors in clinical settings. For example, losartan, an angiotensin II type 1 receptor blocker, and spironolactone, a mineralocorticoid receptor antagonist, were reported to reduce urinary TGFbeta1 excretion."

  23. Shin, H., et al. Induction of transforming growth factor-beta 1 by androgen is mediated by reactive oxygen species in hair follicle dermal papilla cells. BMB Rep.2013 Sep;46(9):460-4. “Therefore, we suggest that induction of TGF-β1 by androgen is mediated by ROS in hair follicle DPCs.” "The progression of androgenetic alopecia is closely related to androgen-inducible transforming growth factor (TGF)-β1 secretion by hair follicle dermal papilla cells (DPCs) in bald scalp.”

  24. Won, C.H., et al. Dermal fibrosis in male pattern hair loss: a suggestive implication of mast cells. Arch Dermatol Res. 2008 Mar;300(3):147-52. "Mast cells are well known to play a critical role in allergic diseases and to be implicated in inflammatory disorders. In addition, mast cell accumulations are often observed in fibrotic disorders of the skin, e.g., keloid, systemic sclerosis, and during wound healing. The effects of activated mast cells on dermal fibroblast proliferation and collagen and glycosaminoglycans synthesis have been well demonstrated. Moreover, it has also been suggested that mediators and enzymes of mast cells are key initiating agents of perifollicular microinfammation and perifollicular fibrosis. MCs may directly or indirectly synthesize and release several mediators capable of modulating extracellular matrix production and degradation. These mediators include TNF-alpha, transforming growth factor (TGF)-beta, prostaglandin D2 (PGD2), and basic fibroblast growth factor (bFGF). TGF-beta is considered a key element in the fibrotic process."

  25. Orfanos, C., and Happle, R. Hair and Hair Diseases. 1990. "Tissue-bound acid mucopolysaccharides were found to be slightly increased in the balding scalp. […] This increase may be linked to the presence of mast cells, reflecting chronic repair processes.” ”Telogen is best viewed as the pre-regeneration state of the hair follicle, that is, whenever a hair follicle seeks to regenerate itself following severe damage, it enters catagen in order to deconstruct itself and become and telogen follicle again. In fact, rapid catagen introduction is the most effective way to return to the telogen state and to reconstruct a new fiber factory. In addition, the return to telogen by partial organ suicide at the extended period of hair growth may also be associated with the inherent risk of hair shaft production going awry.Thus re-entering the telogen state during cycling may be crucial for the prevention of malignant degeneration. The proposed telogen default sate, therefore, is more than a 'mere' resting state, and is clinically important, since it may be pharmaceutically targeted, for example by hair drugs that prolong anagen for the treatment of alopecia".

  26. Buckland, R. Effect of scalp burns on common male pattern baldness. Br Med J (Clin Res Ed) 1986; 293

  27. Montagna, W., et al. Hair Research. 1981. “Hair follicles and their surrounding tissue are clearly interdependent companions. Therefore, it does not seem correct to separate the responsibilities of one from those of the other in physiological or pathologic events.”

  28. Ochiai, H., et al. Inhibition of insulin-like growth factor-1 (IGF-1) expression by prolonged transforming growth factor-β1 (TGF-β1) administration suppresses osteoblast differentiation. J Biol Chem. 2012 Jun 29;287(27):22654-61. "The mRNA expression and protein level of insulin-like growth factor-1 (IGF-1) were remarkably decreased by repeated TGF-β1 administration in human periodontal ligament cells,human mesenchymal stem cells, and murine preosteoblast MC3T3-E1 cells. Repeated TGF-β1 administration subsequently decreased alkaline phosphatase (ALP) activity…” "Additionally, repeated administration significantly reduced the downstream signaling pathway of IGF-1, such as Akt phosphorylation in these cells. Surprisingly, exogenous and overexpressed IGF-1 recovered ALP activity and mRNA expression of osteoblast differentiation marker genes even with repeated TGF-β1 administration.These facts indicate that the key mechanism of inhibition of osteoblast differentiation induced by repeated TGF-β1 treatment is simply due to the down-regulation of IGF-1 expression.” "This study showed that persistence of TGF-β1 inhibited osteoblast differentiation via suppression of IGF-1 expression and subsequent down-regulation of the PI3K/Akt pathway.We think this fact could open the way to use IGF-1 as a treatment tool for bone regeneration in prolonged inflammatory disease.” “IGF-1 administration may recover the suppression of osteogenesis and promotion of bone resorption due to chronic inflammation by TGF-β1.”

  29. Paus, R., and Foitzik, K. In search of the "hair cycle clock": a guided tour. Differentiation. 2004 Dec;72(9-10):489-511."Rather than the long-suspected differences in androgen metabolism or androgen receptor expression between androgen-dependent versus androgen-sensitive hair follicles, these paradoxical effects reflect very different responses of a given hair follicle population to androgen stimulation (e.g., secretion of hair growth-promoting IGF-1 versus hair growth-inhibitory TGFb1 by DP fibroblasts after exposure to androgens. This suggests that androgens (as well as, likely, estrogens, retinoids (see Fotzik et al., in press), calcitriols and thyroxin) alter hair growth and cycling at least in part by changing the intrafollicular signalling milieu of some of those key regulators listed in Figures 3 and 4."

  30. Li, J., et al. Exogenous IGF-1 promotes hair growth by stimulating cell proliferation and down regulating TGF-β1 in C57BL/6 mice in vivo. Growth Horm IGF Res. 2014 Apr-Jun;24(2-3):89-94. "These observations suggest that IGF-1 is an effective stimulator of hair follicle development in wide-type mice in vivo and may be a promising drug candidate for baldness therapy."

  31. Kealey, T., et al. Effects of insulin and insulin-like growth factors on cultured human hair follicles: IGF-I at physiologic concentrations is an important regulator of hair follicle growth in vitro. J Invest Dermatol. 1994 Jun;102(6):857-61.  "However, in the absence of insulin, both IGF-I (0.01-100 ng/ml) and IGF-II (0.01-100 ng/ml) stimulated hair follicle growth in a dose-dependent manner. IGF-I was more potent than either insulin or IGF-II, stimulating maximum rates of hair follicle growth at 10 ng/ml, whereas IGF-II gave maximum stimulation at 100 ng/ml. The rates of hair follicle growth stimulated by 10 ng/ml IGF-I were identical to those stimulated by 10 micrograms/ml insulin. IGF-II (100 ng/ml), however, was unable to stimulate hair follicle growth to the same extent as insulin.” "These data suggest that in vitro IGF-I may be an important physiologic regulator of hair growth and possibly the hair growth cycle. Moreover, the removal of insulin from tissue culture medium may be a useful method of generating large numbers of catagen hair follicles for further in vitro studies."

  32. Kealey, T., et al. Human hair growth in vitro: a model for the study of hair follicle biology. J Dermatol Sci. 1994 Jul;7 Suppl:S55-72. We identify transforming growth factor-beta (TGF-beta) as a possible negative regulator of hair follicle growth and show that physiological levels of insulin-like growth factor-I (IGF-I) can support the same rates of hair follicle growth as supraphysiological levels of insulin. Furthermore, in the absence of insulin hair follicles show premature entry into a catagen-like state. This is prevented by physiological levels of IGF-I.

  33. Panchaprateep, R., et al. Insulin-like growth factor-1: roles in androgenetic alopecia. Exp Dermatol. 2014 Mar;23(3):216-8."DP cells from balding scalp follicles were found to secrete significantly less IGF-1, IGFBP-2 and IGFBP-4 (P < 0.05) than their non-balding counterparts. Our data confirmed that the downregulation of IGF-1 may be one of the important mechanisms contributing to male pattern baldness."

  34. Barengolts, E.I., et al. Effects of progesterone on serum levels of IGF-1 and on femur IGF-1 mRNA in ovariectomized rats. J Bone Miner Res. 1996 Oct;11(10):1406-12. "Local and systemic insulin-like growth factors (IGFs) may be involved in the regulation of bone formation by sex hormones.” The abundance of IGF-1 mRNA was higher in OVX than in SHAM rats. IGF-1 transcripts 7.5 and 0.8 kb were decreased by 72 and 29%, respectively, in estrogen-treated and increased by 44 and 43%, respectively, in progesterone-treated rats compared with vehicle-treated OVX rats. We conclude that in the short term, estrogen lowers and progesterone raises bone IGF-1 mRNA and these changes are followed by coordinated changes in bone formation rate"

  35. Oelkers, W. Antimineralocorticoid activity of a novel oral contraceptive containing drospirenone, a unique progestogen resembling natural progesterone. Eur J Contracept Reprod Health Care. 2002 Dec;7 Suppl 3:19-26; discussion 42-3. "Sex hormones are known to interfere with the renin-angiotensin-aldosterone system (RAAS) in two ways. First, estrogens strongly stimulate the production of renin substrate (angiotensinogen), leading to increased levels of angiotensin and aldosterone, and sodium retention. Second, progesterone is a potent aldosterone antagonist, which acts on the mineralocorticoid receptor to prevent sodium retention."

  36. Neuman, F., and Graf, K.J. Discovery, development, mode of action and clincal use of cyproterone acetate. 1975. "CA has been useful in treating androgen-dependent tumors and "androgenic" diseases such as idiopathic precocious puberty, hirsutism, and male-pattern baldness in adult females, all signs of virilization in females, hypersexuality in adult males, acne and seborrhea, baldness in adult males, and benign prostatic hypertrophy.” "Because of its strong progesterone potency…” "Gynecomastia sometimes develops temporarily in males treated with CA. Serious side effects of CA treatment have not been observed."

  37. Stripp, B., et al.  Effect of spironolactone on sex hormones in man. J Clin Endocrinol Metab. 1975 Oct;41(4):777-81. "Administration spironolactone at a dosage of 400 mg/day to healthy male volunteers for 5 days resulted in a significant rise in plasma progesterone and 17alpha-hydroxyprogesterone which persisted throughout the study.”

  38. Zhang, L., et al. The aldosterone receptor antagonist spironolactone prevents peritoneal inflammation and fibrosis. Lab Invest. 2014 Aug;94(8):839-50. "Spironolactone decreased peritoneal inflammation and fibrosis, which was associated with reduced secretion from peritoneal macrophages, inactivation of the c-Jun N-terminal kinase (JNK) pathway and subsequent downregulation of the expression of TGF-β1."

  39. Yoo, H.G., et al. Perifollicular fibrosis: pathogenetic role in androgenetic alopecia. Biol Pharm Bull. 2006 Jun;29(6):1246-50. "Pretreatment of finasteride decreased the expression of TGF-beta1 protein induced by an average of T (30.4%). The type I procollagen expression after pretreatment of neutralizing TGF-beta1 antibody (10 microg/ml) was inhibited by an average of 54.3%. Our findings suggest that T-induced TGF-beta1 and type I procollagen expression may contribute to the development of perifollicular fibrosis in the AGA, and the inhibitory effects on T-induced procollagen and TGF-beta1 expression may explain another possible mechanism how finasteride works in AGA."

  40. Tang, L., et al. The expression of insulin-like growth factor 1 in follicular dermal papillae correlates with therapeutic efficacy of finasteride in androgenetic alopecia. "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.” “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."

  41. Alexander Lipschütz and Mario Maas. Progesterone Treatment of Uterine and Other Abdominal Fibroids Induced in the Guinea Pig by Alpha-Estradiol. Published 1 January 1944. "Progesterone has been shown to be the most powerful antifibromatogenic steroid in the guinea pig.” "…the antifibromatogenic action of progesterone and other steroids is concomitant with an antiestrogenic action…" "…The antifibromatogenic hormone acts as an antagonist to the estrogen…”  "Regression, i.e.,the difference in the average fibromatogenic effect between the estradiol group and the groups treated subsequently with progesterone, was statistically as significant as was prevention.” "The therapeutic action of progesterone on existing fibroids elicited by estrogens was revealed to be much more considerable when the frequency of animals with large abdominal fibroids and especially the frequency of large fibroids per animal were compared in the different groups."

  42. Andersson, B., et al. Estrogen replacement therapy decreases hyperandrogenicity and improves glucose homeostasis and plasma lipids in postmenopausal women with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1997 Feb;82(2):638-43. "Blood glucose, glycosylated hemoglobin, c-peptide, total cholesterol, low-density lipoprotein cholesterol, and IGF-I decreased significantly (P < 0.01-P < 0.001), whereas high-density lipoprotein cholesterol rose (P < 0.001)."

  43. Bekker, V.I., and Svechnikova, N.V. [Sex and age differences in the peripheral blood aldosterone levels]. Probl Endokrinol (Mosk). 1981 Sep-Oct;27(5):42-5. "An increase in the blood aldosterone content in menopause appears to be due to the hyperestrogenic phase (the first menopausal phase in women) and estrogen-stimulated aldosterone synthesis. Sexual differences in aldosterone secretion disappear with age. Aldosterone content is significantly lower in males and females, age over 80 years, than that in younger subjects, and sexual differences are absent."

  44. Ashcroft, G.S., et al. Estrogen accelerates cutaneous wound healing associated with an increase in TGF-beta1 levels. Nat Med. 1997 Nov;3(11):1209-15. "The cellular mechanism underlying these changes appears to involve an estrogen-induced increase in latent TGF-beta1 secretion by dermal fibroblasts. These results suggest that both the rate and quality of wound healing depend on reproductive hormone levels."

  45. Zvi Laron and Orly Efros. Laron Syndrome - From Man to Mouse. Date: 26 October 2010. "In response to the i.v. IGF-I bolus, there was a small but measurable decrease (20.55 ± 4.29%) in the PRL concentration (nadir at 2 min 9.7 ± 1.1 ng/mL)…” "Sex hormone binding globulin (SHBG) is a glycoprotein produced by the liver and secreted into the circulation (Rosner 1990). It participates in the regulation of estrogen and testosterone by affecting free hormone availability (Damassa et al. 1991) and uptake by the target organs (Nakhla et al. 1990). IGF-I treatment increased significantly the SHBG both during short-term and longterm IGF-I administration. In the 7-day trial of IGF-I, it was seen that the rise of SHBG was progressive, the greatest change being evident in adult Laron syndrome female patients. Seven days after stopping IGF-I administration, serum SHBG returned to close to the pretreatment levels. During the 5-month IGF-I administration, the raised SHBG levels were maintained at about 150% of the pretreatment level."

  46. Aguirre, G.A., et al. Insulin-like growth factor-1 deficiency and metabolic syndrome. J Transl Med. 2016; 14: 3. "Consistent evidence associates IGF-1 deficiency and metabolic syndrome.” "Based on the available data we propose IGF-1 as a key hormone in the pathophysiology of metabolic syndrome; due to its implications in the metabolism of carbohydrates and lipids. Previous data demonstrates how IGF-1 can be an effective option in the treatment of this worldwide increasing condition.”

  47. Sukhanov, S., et al. IGF-1 reduces inflammatory responses, suppresses oxidative stress, and decreases atherosclerosis progression in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2684-90. "Our data indicate that an increase in circulating IGF-1 reduces vascular inflammatory responses, systemic and vascular oxidant stress and decreases atherosclerotic plaque progression. These findings have major implications for the treatment of atherosclerosis."

  48. Maggio, M., et al. IGF-1, the Cross Road of the Nutritional, Inflammatory and Hormonal Pathways to Frailty. Nutrients. 2013 Oct; 5(10): 4184–4205. “The decline in functional capacity is a heterogeneous phenomenon in the elderly. An accelerated ageing determines a frail status. It results in an increased vulnerability to stressors for decreased physiological reserves. The early identification of a frail status is essential for preventing loss of functional capacity, and its clinical consequences. Frailty and mobility limitation result from an interplay of different pathways including multiple anabolic deficiency, inflammation, oxidative stress, and a poor nutritional status. However, the age-related decline in insulin-like growth factor 1 (IGF-1) bioactivity deserves special attention as it could represent the ideal crossroad of endocrine, inflammatory, and nutritional pathways to frailty. Several minerals, namely magnesium, selenium, and zinc, appear to be important determinants of IGF-1 bioactivity. This review aims to provide an overview of the potential usefulness of nutrients modulating IGF-1 as potential therapeutic targets in the prevention of mobility limitation occurring in frail older subjects.”

  49. Malberg, J.E., et al. Increasing the levels of insulin-like growth factor-I by an IGF binding protein inhibitor produces anxiolytic and antidepressant-like effects. Neuropsychopharmacology. 2007 Nov;32(11):2360-8. 

  50. Puche JE1, Castilla-Cortázar I. Human conditions of insulin-like growth factor-I (IGF-I) deficiency. J Transl Med. 2012 Nov 14;10:224. “Insulin-like growth factor I (IGF-I) is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple tissues for autocrine/paracrine purposes. IGF-I is partly responsible for systemic GH activities although it possesses a wide number of own properties (anabolic, antioxidant, anti-inflammatory and cytoprotective actions). IGF-I is a closely regulated hormone.” “Consequently, its logical therapeutical applications seems to be limited to restore physiological circulating levels in order to recover the clinical consequences of IGF-I deficiency, conditions where, despite continuous discrepancies, IGF-I treatment has never been related to oncogenesis. Currently the best characterized conditions of IGF-I deficiency are Laron Syndrome, in children; liver cirrhosis, in adults; aging including age-related-cardiovascular and neurological diseases; and more recently, intrauterine growth restriction.”

  51. Picard, M., et al. Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress. PNAS November 16, 2015. 
    "Central to stress adaptation is cellular energetics, involving mitochondrial energy production and oxidative stress. We therefore hypothesized that abnormal mitochondrial functions would differentially modulate the organism’s multisystemic response to psychological stress.” "We show that mitochondrial dysfunctions altered the hypothalamic–pituitary–adrenal axis, sympathetic adrenal–medullary activation and catecholamine levels, the inflammatory cytokine IL-6, circulating metabolites, and hippocampal gene expression responses to stress. Each mitochondrial defect generated a distinct whole-body stress-response signature.These results demonstrate the role of mitochondrial energetics and redox balance as modulators of key patho-physiological perturbations previously linked to disease. This work establishes mitochondria as stress-response modulators, with implications for understanding the mechanisms of stress pathophysiology and mitochondrial diseases."

  52. hvan Beek, N., et al. Thyroid hormones directly alter human hair follicle functions: anagen prolongation and stimulation of both hair matrix keratinocyte proliferation and hair pigmentation. J Clin Endocrinol Metab. 2008 Nov;93(11):4381-8. Epub 2008 Aug 26. "Studying microdissected, organ-cultured normal human scalp HFs, we show here that T4 up-regulates the proliferation of hair matrix keratinocytes, whereas their apoptosis is down-regulated by T3 and T4. T4 also prolongs the duration of the hair growth phase (anagen) in vitro, possibly due to the down-regulation of TGF-beta2, the key anagen-inhibitory growth factor. Because we show here that human HFs transcribe deiodinase genes (D2 and D3), they may be capable of converting T4 to T3.""Thus, we present the first evidence that human HFs are direct targets of thyroid hormones and demonstrate that T3 and/or T4 modulate multiple hair biology parameters, ranging from HF cycling to pigmentation.”

  53. Chung, G.E., et al. Non-alcoholic fatty liver disease across the spectrum of hypothyroidism. J Hepatol. 2012 Jul;57(1):150-6. "The prevalence of NAFLD and abnormal liver enzyme levels (ALT>33/25 IU/L) increased steadily with increasing grades of hypothyroidism (for NAFLD, subclinical: 29.9% and overt: 36.3%; for abnormal ALT, 20.1% and 25.9%, p<0.001, respectively).” "Subclinical hypothyroidism, even in the range of upper normal TSH levels, was found to be related to NAFLD in a dose-dependent manner. Hypothyroidism is closely associated with NAFLD independently of known metabolic risk factors, confirming a relevant clinical relationship between these two diseases."

  54. Pagadala, M.R., et al. Prevalence of hypothyroidism in nonalcoholic fatty liver disease. Dig Dis Sci. 2012 Feb;57(2):528-34. "A higher prevalence of hypothyroidism was demonstrated in patients with NAFLD compared to controls. Among subjects with NALFD, female gender, increased BMI and history of abstinence from alcohol were associated with hypothyroidism. Patients with hypothyroidism were also more likely to have NASH.” "Although the precise cause of the increased prevalence of NAFLD and NASH in hypothyroidism patients remain unclear, insulin resistance in hypothyroidism is likely to exacerbate free fatty acid influx and subsequent hepatic steatosis. Furthermore, hypothyroidism has been reported to modulate mitochondrial nitric oxide synthesis and alter mitochondrial inner membrane composition and perme- ability which alters respiratory gene expression and mito- chondrial oxygen uptake. Such abnormalities would result in increased ADP concentration and generation of reactive oxygen species. The clinical importance of these findings is emphasized by the nascent but important data indicating that fatty liver may improve with liver-specific thyromimetics."

  55. Bonefeld, K., and Møller, S. Insulin-like growth factor-I and the liver. Liver Int. 2011 Aug;31(7):911-9. "Insulin-like growth factors (IGFs) play an essential role in growth and development, as well as in the overall cellular regulation and metabolism in the human body. In chronic liver disease, IGF levels are decreased, and the circulating levels correlate to the extent of hepatocellular dysfunction. Patients with cirrhosis are characterised by a variety of metabolic disturbances, including nutritional and metabolic complications such as insulin resistance, malnutrition, osteopenia and hypogonadism, all related to IGF-I deficiency. The complex process of hepatic fibrogenesis and the systemic consequences in cirrhosis are only partly understood. Disruption of the growth hormone (GH)-IGF-I axis seems to be closely associated with the development of liver disease, and treatment with recombinant human IGF (rhIGF)-I has been shown to halt, and even reverse, the fibrotic degeneration. IGF-I in itself has a strong antifibrotic effect that acts directly through the GH/IGF system and indirectly by the regulation of hepatoprotective and profibrogenic factors. It is most likely that IGF-I deficiency contributes to the diverse metabolic complications of cirrhosis. At present, liver transplantation remains the only efficient treatment of cirrhosis, and thus new methods of managing the disease are called for. RhIGF-I supplementation and IGF-I gene therapy may represent future perspectives of treatment."

  56. Bona, G., et al. IGF-1 and IGFBP in congenital and acquired hypothyroidism after long-term replacement treatment. Minerva Endocrinol. 1999 Jun;24(2):51-5. "Our data demonstrate that long term replacement therapy in children with hypothyroidism is associated with a physiological increase in IGF-1 and IGFBP-3.”

  57. Miell, J.P., et al. Effects of hypothyroidism and hyperthyroidism on insulin-like growth factors (IGFs) and growth hormone- and IGF-binding proteins. J Clin Endocrinol Metab. 1993 Apr;76(4):950-5. "IGF-I is synthesized in most tissues, but the liver is the main source of circulating IGF-I.” "We have confirmed that IR IGF-I levels are low in hypothyroidism and have demonstrated a reduction in IGF bioactivity and IGF-II and IGFBP-3 levels, and low GH-binding activity, which may reflect a reduction in the processing of GH receptors."

  58. Kabidi, U.M., et al. Serum T3 and reverse T3 levels in hepatic cirrhosis: relation to hepatocellular damage and normalization on improvement in liver dysfunction. Am J Gastroenterol. 1983 Nov;78(11):750-5. “Liver is one of the major sites of T4 metabolism. Several studies have reported low serum T3 concentrations and elevated reverse T3 (rT3) levels in hepatic cirrhosis. This study examined the influence of degree of the hepatocellular damage and the effect of improvement in clinical state on thyroid hormone concentrations in 44 cirrhotic patients. Low serum T4 and T3 as well as raised rT3 were observed in cirrhotic patients with advanced liver dysfunction alone. T3 resin uptake was increased in some of these patients suggesting decrease in serum thyroid-binding globulin concentration. In patients with histological changes but with normal liver function tests, serum T4, T3, and rT3 were not altered. Serum T3 and rT3 correlated significantly with liver function tests. T4, T3, and rT3 normalized on improvement in clinical status and liver function tests. Lowest levels of T4 and T3 with extremely high rT3 were seen in patients with extremely advanced liver dysfunction. In these patients, the mortality was high. Therefore, in hepatic cirrhosis, 1) T4 metabolism is altered with lowering of T4 and T3 and a rise in rT3. 2) These changes may be dependent on the degree of hepatocellular damage and reverse on improvement in liver function. 3) T4, T3, and rT3 levels are useful prognostic indices.”

  59. Corica, F., et al. Increased transforming growth factor-b1 plasma concentration is associated with high plasma 3,30 ,50 -tri-iodothyronine in elderly patients with nonthyroidal illnesses. Eur J Endocrinol 1998; 138:47e50. "The main findings in our study were the higher TGF-b1 levels in patients with low T3 syndrome and the direct correlation between TGF-b1 and rT3 found in the whole group of NTI patients."

  60. Yao, J. and Eghbali, M. Decreased collagen gene expression and absence of fibrosis in thyroid hormone-induced myocardial hypertrophy. Response of cardiac fibroblasts to thyroid hormone in vitro. Circ Res. 1992 Oct;71(4):831-9."Thyroid hormone may selectively prevent the induction of cardiac fibrosis and play an important role in regression of cardiac fibrosis via endocrine pathways."

  61. Bodó, E., et al. Human female hair follicles are a direct, nonclassical target for thyroid-stimulating hormone. J Invest Dermatol. 2009 May;129(5):1126-39. "Hair follicles (HFs) represent one of the most hormone sensitive tissue interaction systems in the mammalian body and are exquisitely thyroid hormone-sensitive. It has been known for decades that thyroid disorders that lead to elevated or decreased thyroid hormone serum levels are associated with altered human skin and hair structure as well as function. This includes, for example a higher telogen rate altered hair diameter, dry, brittle, coarse hair, reduced hair bulb cell proliferation, in hypothyroidism, as well as increased hair bulb cell proliferation, and hair loss, and hair loss in hyperthyroidism."

  62. Trüeb, R., and Tobin, D. Aging Hair. "Although there are no precise statistics, the incidence in Caucasians is often quoted as approaching 100%"

  63. Smith, E.L., et al. Transforming growth factor-beta 1 and cortisol in differentially reared primates. Brain Behav Immun. 2002 Apr;16(2):140-9. "Exposure of primate infants to adverse rearing conditions during the first half year of life can result in enduring behavioral, neuroendocrine, and immunologic abnormalities.” "The present study explored the relationship between circulating levels of transforming growth factor-beta 1 (TGF-beta 1) and cortisol in macaques reared either normally or under conditions of variable foraging demand (VFD). Under VFD rearing, for a period of 4 months, the infants' mothers intermittently had to expend more time and effort to obtain food than did the mothers of normally reared control subjects. Two years after cessation of the rearing experience, exposure to a moderate stressor (confinement in an unfamiliar room for 90 min) induced elevated levels of serum TGF-beta 1 and plasma cortisol in VFD-reared monkeys compared to normally reared controls."

  64. Bonjour, J.P. Dietary protein: an essential nutrient for bone health. J Am Coll Nutr. 2005 Dec;24(6 Suppl):526S-36S. "Dietary proteins positively influ- ence the production and action of the bone anabolic agent, insulin-like growth factor-1 (IGF-1) in both animal and human studies. The “Dietary protein > IGF-1 > Bone Health” axis plays a key role in the prevention of osteoporosis.”  "Preclinical studies in adult animals have documented that an isocaloric low protein diet reduces IGF-1, induces negative bone balance with both decreased formation and increased resorption, thereby leading to a decline in bone strength. All these negative effects can be reversed by amino acids administered in the same proportion as in casein."

  65. Hoppe, C., et al. High intakes of skimmed milk, but not meat, increase serum IGF-I and IGFBP-3 in eight-year-old boys. Eur J Clin Nutr. 2004 Sep;58(9):1211-6. "High intake of milk and not meat, increased concentrations of s-IGF-I and s-IGF-I/s-IGFBP-3 significantly. Compounds in milk and not a high PI as such seem to stimulate IGF-I. This might explain the positive effect of milk intake on growth seen in some studies."

  66. Collin, C., et al. Protective effects of taurine on human hair follicle grown in vitro. Int J Cosmet Sci. 2006 Aug;28(4):289-98. "Taurine is a naturally occurring beta-amino acid produced by methionine and cysteine metabolism. It is involved in a variety of physiological functions, including immunomodulatory and antifibrotic. Taking advantage of the ability of human hair follicle grown in vitro to recapitulate most of the characteristic features of normal hair follicle in vivo, we studied (i) taurine uptake by isolated human hair follicles; (ii) its effects on hair growth and survival rate; and (iii) its protective potential against transforming growth factor (TGF)-beta1, an inhibitor of in vitro hair growth and a master switch of fibrotic program. We showed that taurine was taken up by the connective tissue sheath, proximal outer root sheath and hair bulb, promoted hair survival in vitro and prevented TGF-beta1-induced deleterious effects on hair follicle."

  67. Lauritano, E.C., et al. Association between hypothyroidism and small intestinal bacterial overgrowth. J Clin Endocrinol Metab. 2007 Nov;92(11):4180-4. "A total of 27 patients with a history of hypothyroidism demonstrated a positive result to the breath test (27 of 50, 54%), compared with two in the control group (two of 40, 5%). The difference was statistically significant (P < 0.001). Abdominal discomfort, flatulence, and bloating were significantly more prevalent in the bacterial overgrowth positive group.” "The history of overt hypothyroidism is associated with bacterial overgrowth development. Excess bacteria could influence clinical gastrointestinal manifestations. Bacterial overgrowth decontamination is associated with improved gastrointestinal symptoms."

  68. Senthilkumar, R., Nalini, N. Glycine prevents hepatic fibrosis by preventing the accumulation of collagen in rats with alcoholic liver injury. Pol J Pharmacol. 2004 Jan-Feb;56(1):121-8. "We studied the effect of administering glycine, a non-essential amino acid, on liver collagen content and its characteristics in experimental hepatotoxic Wistar rats. All the rats were fed standard pellet diet. Hepatotoxicity was induced by orally administering ethanol (7.9 g kg(-1)) for 30 days. Control rats were given isocaloric glucose solution. Glycine was administered subsequently at a dose of 0.6 g kg(-1) po every day, along with alcohol for the next 30 days. Alcohol administration significantly elevated the levels of liver hydroxyproline and total collagen content, cross-linked fluorescence, shrinkage temperature and lipid peroxidation, whereas it significantly decreased the solubility of liver collagen as compared with the control rats. Simultaneous glycine supplementation to alcohol-fed rats significantly reduced the levels of liver hydroxyproline and total collagen content, cross-linked fluorescence, shrinkage temperature and lipid peroxidation and enhanced the solubility of liver collagen as compared with the unsupplemented alcohol-fed rats. In conclusion, administration of glycine had a positive influence both on the quantitative and qualitative properties of hepatic collagen in alcoholic liver injury."

  69. Assy, N., et al. The beneficial effect of aspirin and enoxaparin on fibrosis progression and regenerative activity in a rat model of cirrhosis. Dig Dis Sci. 2007 May;52(5):1187-93. "Recently, it has been shown that thrombosis of medium and large intrahepatic vessels is very common in cirrhosis and an important factor in the progression of fibrosis.” "Few treatments have been proposed to alter the hepatocyte regenerative activity in the cirrhotic liver. To date, none has proven effective.” “ "Hepatic regenerative activity was significantly improved in the aspirin group (57.3% ± 6.8%, versus 34.2% ± 7.2% in untreated cirrhotic controls; P < 0.01) but unchanged in the enoxaparin group.” "We conclude that aspirin and enoxaparin hold promise as a useful therapy for patients with extensive fibrosis.” "The finding that bromophenacylbromide, which, like aspirin, is a specific inhibitor of phospholipase A2, also exerts inhibitory effects on the induction of cirrhosis caused by a choline-deficient L-amino acid-defined diet indicates the possible direct involvement of arachnoid acid metabolism in the causative mechanism of hepatocyte injury"

  70. Ketelslegers, J.M., et al. Nutritional regulation of insulin-like growth factor-I. Metabolism. 1995 Oct;44(10 Suppl 4):50-7. “Several lines of evidence indicate that in the human, insulin-like growth factor-I (IGF-I) is nutritionally regulated. Both energy and protein availability are required for maintenance of IGF-I. Measurements of serum IGF-I constitute a sensitive means for monitoring the response of acutely ill patients to nutritional intervention. Serum IGF-I may also serve as a marker for evaluation of nutritional status.” "Amino acid availability to the hepatocytes is essential for IGF-I gene expression.Protein malnutrition not only decreases IGF-I production rate, but also enhances its serum clearance and degradation.”

  71. Mezey E. Insulin growth factor I and hypogonadism in cirrhosis. Hepatology. 2000 Mar;31(3):783-4. “Decreased serum igf-1 concentrations are well documented in children with kwashiorkor, in malnourished adults, and after long-term fasting in obese male subjects."

  72. van der Wal, A.M., et al. The decrease of liver LDL receptor mRNA during fasting is related to the decrease in serum T3. Int J Biochem Cell Biol. 1998 Feb;30(2):209-15. "Fasting is associated with a reduction in serum T3 and T4 and a rise of plasma LDL cholesterol. We hypothesized that an hypothyroid-like condition induced by fasting is responsible for the rise in LDL cholesterol.” "(1) Fasting induces a hypothyroid-like condition in which inhibition of hepatic conversion of T4 into T3 may be responsible for the decrease of serum T3. (2) Fasting induces an increase of plasma LDL cholesterol, apparently caused by a decrease of hepatic LDL receptor gene expression which is (partly) related to the fall in serum T3."

  73. Bielohuby, M., et al. Lack of dietary carbohydrates induces hepatic growth hormone (GH) resistance in rats. Endocrinology. 2011 May;152(5):1948-60. "In addition, we confirmed that circulating IGF-I is markedly reduced with LC-HFD. In general, protein intake is of critical importance for the regulation of the GH/IGF-axis (19). This observation could be confirmed in our study, because the LC-HFD with the low protein con- tent (LC-HF-2) showed the lowest levels of cir- culating IGF-I. However, the results obtained from our LC-HF-1 diet, which was matched in protein content to the control CH diet, dem- onstrates that already the low carbohydrate content of LC-HFD per se induces hepatic GH insensitivity, leading to lower IGF-I levels.” "Furthermore, also a 9-d dietary intervention study in healthy vol- unteers exposed to a LC diet has shown about 30% decreased IGF-I concentrations…" "The only protein source in the CH diet was sodium-casein; the only carbohydrate source was starch. Fat in the CH diet was composed of beef tallow and soy oil (50% each). In LC-HFD, the only protein source used was sodium-casein, and the only fat source was beef tallow. The LC-HFD contained virtually no carbohydrates, except a very little amount ( 2% of ME), which was technically necessary to deliver minerals and vitamins."

  74. Huh, S., et al. A cell-based system for screening hair growth-promoting agents. Arch Dermatol Res. 2009 Jun;301(5):381-5."Taken together, these findings suggest that apigenin, which is known to have antioxidant, anti-inflammatory, and anti-tumor properties, stimulates hair growth through downregulation of the TGF-beta1 gene. In addition, these results suggest that this assay system could be used to quantitatively measure TGF-beta1 promoter activity in HaCaT, thereby facilitating the screening of agents promoting hair growth."

  75. Liang, Y.C., et al. Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. Carcinogenesis. 1999 Oct;20(10):1945-52. "Prostaglandins biosynthesis and nitric oxide production have been implicated in the process of carcinogenesis and inflammation.” “Apigenin, genistein and kaempferol were markedly active inhibitors of transcriptional activation of COX-2, with IC(50) < 15 microM. In addition, apigenin and kaempferol were also markedly active inhibitors of transcriptional activation of iNOS, with IC(50) < 15 microM. Of those compounds tested, apigenin was the most potent inhibitor of transcriptional activation of both COX-2 and iNOS.” "Transient transfection experiments showed that LPS caused an approximately 4-fold increase in both COX-2 and iNOS promoter activities, these increments were suppressed by apigenin. Moreover, electrophoretic mobility shift assay (EMSA) experiments indicated that apigenin blocked the LPS-induced activation of nuclear factor-kB (NF-kB).” "This study suggests that modulation of COX-2 and iNOS by apigenin and related flavonoids may be important in the prevention of carcinogenesis and inflammation.”

  76. Du, G., et al. Naringenin: a potential immunomodulator for inhibiting lung fibrosis and metastasis. Cancer Res. 2009 Apr 1;69(7):3205-12. "A fibrotic environment in the lung results in increased abundance of transforming growth factor-beta1 and CD4(+)CD25(+)Foxp3(+) regulatory T cells and a decreased proportion of activated effector T cells.” "Naringenin significantly reduces lung metastases in mice with pulmonary fibrosis and increases their survival by improving the immunosuppressive environment through down-regulating transforming growth factor-beta1 and reducing regulatory T cells. Naringenin could be an ideal therapeutic agent in the treatment of both cancer and fibrosis."

  77. Lee, M.H., et al. The flavonoid naringenin inhibits dimethylnitrosamine-induced liver damage in rats. Biol Pharm Bull. 2004 Jan;27(1):72-6. "In conclusion, these results demonstrate that naringenin exhibited in vivo hepatoprotective and anti-fibrogenic effects against DMN-induced liver injury. It suggests that naringenin may be useful in preventing the development of hepatic fibrosis."

  78. Whipp, G.T., et al. Regulation of aldosterone in the guinea-pig--effect of oestrus cycle, pregnancy and sodium status. Aust J Exp Biol Med Sci. 1976 Feb;54(1):71-8. "Compared with a moderate Na intake, salt loading suppressed aldosterone levels and Na restriction raised them."

  79. Nishimuta, M., et al. Positive correlation between dietary intake of sodium and balances of calcium and magnesium in young Japanese adults--low sodium intake is a risk factor for loss of calcium and magnesium. J Nutr Sci Vitaminol (Tokyo). 2005 Aug;51(4):265-70. "The content of calcium (Ca) and magnesium (Mg) in sweat during exercise is considerably higher during a relatively low intake of sodium (Na) of 100mmol/d than with an intake of 170 mmol/d. For this reason and also because Ca and Mg have a negative balance with a Na intake of 100 mmol/d, we analyzed the relationship between Na intake and balances of Ca and Mg in data from 11 balance studies. "These values are considerably higher than Na requirements estimated by inevitable Na loss. Low dietary Na may therefore be a risk factor for maintaining positive balances of Ca and Mg."

  80. Fawzi, M.M., et al. Assessment of vitamin D receptors in alopecia areata and androgenetic alopecia. J Cosmet Dermatol. 2016 May 6. "This study suggests an important role for VDR in the pathogenesis of AA and AGA through documenting lower serum and tissue VDR levels in AA and AGA patients in comparison with controls.” "From the results of the present study, we suggest the performance of further studies on VDR mutations in AA and AGA, and the evaluation of a possible link between vitamin D, VDR, and sex hormones in the pathogenesis of AGA. In addition, the use of topical vitamin D analogs, which upgrade the expression of VDR, in the treatment of AA and AGA and the evaluation of s.VDR, as an indicator of t.VDR, and a marker of rate of response would be an attractive area of research."

  81. Ameri, P., et al. Vitamin D increases circulating IGF1 in adults: potential implication for the treatment of GH deficiency. Eur J Endocrinol. 2013 Oct 21;169(6):767-72. "Vitamin D increases circulating IGF1 in adults. As a result, a better vitamin D status may ease the achievement of normal IGF1 values in GHD."

  82. Irani, M., et al. Vitamin D Supplementation Decreases TGF-β1 Bioavailability in PCOS: A Randomized Placebo-Controlled Trial. J Clin Endocrinol Metab. 2015 Nov;100(11):4307-14. "There is an abnormal increase in TGF-β1 bioavailability in women with polycystic ovary syndrome (PCOS), which might play a role in the pathophysiology of this syndrome. Vitamin D (VD) supplementation improves various clinical manifestations of PCOS and decreases TGF-β1 levels in several diseases including myelofibrosis.” "VD supplementation in VD-deficient women with PCOS significantly decreases the bioavailability of TGF-β1, which correlates with an improvement in some abnormal clinical parameters associated with PCOS. This is a novel mechanism that could explain the beneficial effects of VD supplementation in women with PCOS. These findings may support new treatment modalities for PCOS, such as the development of anti-TGF-β drugs.”

Reversing Fibrosis in Male Pattern Baldness (Apigenin, Naringenin, Aspirin, and Gelatin)

Inflammation is an umbrella concept in pattern baldness that is given little attention in the mainstream. Polyunsaturated fats, mast cell migration and activation, prostaglandins, inflammatory cytokines, and the fibrotic environment these substances promote all appear to be involved in the progression of "the baldness field." Luckily, simple, safe, and available substances such as apigenin, naringenin, aspirin, and gelatin can help guard against the harmful effects of these inflammatory substances and in some cases help restore coherence to fibrotic tissues.

00:57 - Mitochondria, Oxidative Stress, and Fibrosis
03:03 - TGF-b1 and Fibrosis in The Bald Scalp
03:55 - Will a "Single Bullet" Approach Work?
04:49 - Fibrosis, Thyroid Function, Progesterone, and Helpful Foods
05:44 - Apigenin
06:44 - Naringenin
07:43 - Aspirin
08:57 - Gelatin


 

Generative Energy #30: What Keeps a Creative Person Going?

 
 

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01:09 - Danny’s thoughts on a purpose-driven life and meaningful work
02:22 - Should you wait until you’re better before being creative?
02:50 - “I was laying on the ground, maybe just four or five inches away and I was spreading the paint, mixing some different colours in. I was thinking to myself, ‘Man, what am I going to do now? Because this is one of the best, most fun things I’ve ever done.’” Taylor Phinney
04:59 - Creativity and the risk of being misunderstood
06:12 - Reinforcement of learned helplessness
07:12 - Danny’s many failings and mental anguish
08:33 - "People tend to hold overly favorable views of their abilities in many social and intellectual domains. The authors suggest that this overestimation occurs, in part, because people who are unskilled in these domains suffer a dual burden: Not only do these people reach erroneous conclusions and make unfortunate choices, but their incompetence robs them of the metacognitive ability to realize it. Across 4 studies, the authors found that participants scoring in the bottom quartile on tests of humor, grammar, and logic grossly overestimated their test performance and ability. Although their test scores put them in the 12th percentile, they estimated themselves to be in the 62nd. Several analyses linked this miscalibration to deficits in metacognitive skill, or the capacity to distinguish accuracy from error. Paradoxically, improving the skills of participants, and thus increasing their metacognitive competence, helped them recognize the limitations of their abilities." Unskilled and unaware of it: how difficulties in recognizing one's own incompetence lead to inflated self-assessments (1999)
13:58 - “If the path before you is clear, you're probably on someone else's.” Joseph Campbell
15:29 - Creating for yourself rather than others
17:41 - “It is the urge, which is evident in all organic and human life — to expand, extend, become autonomous, develop, mature — the tendency to express and activate all the capacities of the organism, to the extent that such activation enhances the organism or the self. This tendency may become deeply buried under layer after layer of encrusted psychological defenses; it maybe hidden behind elaborate facades which deny its existence; but it is my belief that it exists in every individual, and awaits only the proper conditions to be released and expressed.” Carl Rogers
18:38 - "The serial monogamies you mention are really important expressions of the rigidity that's the essence of the authoritarian culture. Just by putting them together you have illuminated them. In his later years Wilhelm Reich worried about how hard adults were to heal emotionally, but I think Freudianism just distracted him from what he probably knew as a communist, that people won't choose to change as long as there are no viable alternatives. " Ray Peat
20:25 - “You never change things by fighting the existing reality. To change something, build a new model that makes the existing model obsolete.” Buckminster Fuller
23:43 - “To avoid criticism say nothing, do nothing, be nothing.” Aristotle
24:43 - You don’t care what people think? Prove it!
28:13 - The journey of creativity would be cheap without risk
30:36 - "Everyday, I walk myself into a state of well-being and walk away from every illness. I have walked myself into my best thoughts, and I know of no thought so burdensome that one cannot walk away from it. But by sitting still, and the more one sits still, the closer one comes to feeling ill. Thus if one just keeps on walking, everything will be all right.” Kierkegaard
33:07 - "You never know what is enough unless you know what is more than enough." William Blake
33:59 - Danny’s experience with health authorities
34:43 - Celebrating “the expert”
36:36 - Choice and creativity
39:35 - Free speech as a creative act
40:04 - Why did Danny move to Mexico?

The Misunderstood Role of DHT in Male Pattern Baldness

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01:59 - Testosterone, 5-Alpha Reductase, and DHT in Normal Hair Growth
04:20 - The Relationship Between Serum Androgens and Baldness
06:17 - The Relationship Between 5-Alpha Reductase and Androgens in The Balding Scalp
12:53 - Summary

Generative Energy #29: How to Burn Fat on a Keto Diet (And Why You Shouldn’t)

 
 

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03:39 - Kyle Mamounis and Danny Roddy meet at AHS 2011
05:01 - Kyle’s origin story
06:41 - What is Kyle studying?
08:35 - Details on Kyle’s AHS 2016 talk
10:45 - Injecting CO2 and prostaglandins into ketosis
11:56 - Lactic acid in diabetes
13:24 - Glycolysis and mitochondrial respiration
14:30 - Is fat a superior fuel compared to glucose?
17:09 - The low carb fantasy view of metabolic stress
18:53 - Low carb people and “autoimmunity” issues
20:07 - Danny’s thoughts on “adrenal fatigue”
22:11 - What Kyle is researching
24:45 - Where do the genes fit in?
26:48 - The Randle effect as an “on” “off” switch for glucose metabolism
28:00 - Hepatic glycogen and the production of active thyroid hormone
30:20 - Turning down the generation of CO2 with ketosis
35:29 - Omega-3’s and mitochondrial respiration
38:18 - Thoughts on electrons and respiration
40:18 - Kyle’s future plans for AHS
43:08 - The “benefits” of ketosis — decreased endotoxin
47:24 - Products and objective science in nutrition
49:58 - How do you lose fat without entering ketosis?
51:26 - Danny was fatty on zero-carb
55:03 - Is it good to have a slow metabolism?
56:59 - Kyle’s final thoughts
57:45 - Kyle’s blog and where you can find him

Specialized Nutrition for Male Pattern Baldness

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Carbon Dioxide: The "Cure" for Male Pattern Baldness?

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Since producing 'Explaining The "Horseshoe" Shape of Male Pattern Baldness' I've been receiving a lot of questions about scalp massage and microneedling as potential therapies to increase blood flow and the delivery of oxygen and nutrients to balding hair follicles. While I don't think a relaxing massage would hurt, I'm extremely skeptical of microneedling as it seems to fall under the cut, burn, poison model of modern medicine. This video is an attempt at shifting the conversation away from methods that are as old as baldness itself, and towards a bioenergetic view of pattern hair loss with an emphasis on carbon dioxide.

Explaining The "Horseshoe" Shape of Male Pattern Baldness

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“The role of mast cells in male-pattern baldness is unknown, but the large numbers often present is a striking feature.”[1] 

"We postulate that because of the underlying anatomy, there is a relative microvascular insufficiency to regions of the scalp that lose hair in male pattern baldness and that is associated with local tissue hypoxia in those regions. The vascular supply of the scalp is derived from branches of the internal carotid artery and branches of the external carotid artery. The frontal region of the scalp, which loses hair in male pattern baldness, is supplied by the supraorbital and the supratrochlear arteries. These are relatively small branches of the internal carotid artery system. The temporal [sides] and occipital [back of head] regions of the scalp, which do not lose hair in male pattern baldness, are supplied by larger branches of the external carotid artery. Specifically, these are the superficial temporal, posterior auricular, and occipital arteries. Further, the frontal and vertex regions of the scalp overlie the galea aponeurotica, which is relatively avascular. The temporal and occipital regions of the scalp overlie the temporalis and occipitalis muscles, which provide a rich network of musculocutaneous perforator blood vessels. These anatomic differences contribute to the tenuous nature of the dermal blood supply to the frontal and crown regions of the scalp."[2]

"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.” "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.”[3] 

"Mast cells express the high-affinity estrogen receptor and studies have shown that estrogens augment their activities: in the presence of high levels of estrogens, mast cell responses to compound 48/80 are increased, leading to more substantial degranulation and release of histamine and serotonin.” "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 mast cells in response to chemokines and down-regulate surface chemokine receptor expression. In addition, mast cell function can be altered by the presence of high concentrations of progesterone. For example, progesterone inhibits the secretion of histamine from mast cells. Notably, these observations would suggest that mast cells present within the uterus during pregnancy are quiescent and inhibited by high levels of progesterone, and also that recruitment of mast cell progenitors from the circulation may be limited.” "At present the prevalence of allergies, including allergic rhinitis, hayfever, eczema, food allergies and urticaria, is rising." [4]

"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." [5]

1. Male pattern alopecia a histopathologic and histochemical study (1975) 
2. Transcutaneous PO2 of the scalp in male pattern baldness: a new piece to the puzzle (1996)
3. A prostaglandin D-synthase-positive mast cell gradient characterizes scalp patterning (2014) 
4. The role of mast cells and their mediators in reproduction, pregnancy and labour (2010) 
5. Treatment of mast cells with carbon dioxide suppresses degranulation via a novel mechanism involving repression of increased intracellular calcium levels (2011)

Male Pattern Baldness: Hypothyroidism in Disguise?

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Do The "Essential Fatty Acids" Cause Pattern Hair Loss?

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“All members of this group [prostaglandins] are synthesized from ‘polyunsaturated’ fatty acids that must be supplied by the diet. From a quantitative standpoint, arachidonic acid is the major precursor.” “Meats and peanuts contain small amounts [of arachidonic acid], but the liver forms most of it from linoleic acid. Arachidonic acid is the precursor of the prostaglandins with two double bonds, and of the several other biologically potent substances."[1] 

"These results define PGD2 as an inhibitor of hair growth in male-pattern baldness and suggest the PGD2-GPR44 pathway as a potential target for treatment.”[2] 

"EFA deficiency has been shown to exert an anti­inflammatory effect."[3] 

"In summary, the anti-inflammatory effect of EFA deficiency was more marked that that of dietary (n-3) fatty acid supplementation in acute inflammation."[4]

1. Endocrine Physiology by Constance R. Martin (1985)
2. Prostaglandin d2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia (2012)
3. Essential fatty acid deficiency: a new look at an old problem (1986)
4. Manipulation of the acute inflammatory response by dietary polyunsaturated fatty acid modulation (1990)

Higher Prolactin in Pattern Baldness?

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"A conclusion has been made that one of the most important mechanisms of the adaptive effect of prolactin is its ability to suppress thyroid function, thus decreasing the metabolism level, which results in reduction of oxygen consumption…"[1]

"Subsequent actions of prolactin may involve the following: a) an increased intracellular concentration of potassium and a reduced level of sodium, b) an increased level of cGMP and a reduced level of cAMP, c) an enhanced rate of prostaglandin biosynthesis mediated by a stimulation of phospholipase A2 activity, and d) a stimulation of polyamine synthesis."[2]

"...serum prolactin concentrations reflect endogenous serotonin..." "...aromatase activity correlated significantly with prolactin..."[3]
 
"After glucose load the hyperprolactinaemic patients showed a decrease in glucose tolerance and a hyperinsulinaemia." "These findings suggest a diabetogenic effect of prolactin."[4]

"These observations indicate that cutaneous symptoms such as seborrhea, acne, hypertrichosis/hirsutism, alopecia may evidently occur in hyperprolactinemia, representing or mimicking androgen-induced skin symptoms. In such cases, therefore, evaluation of prolactin levels together with androgen blood levels and thyroid gland function tests should be performed to exclude underlying endocrinopathy."[5]

1. Metabolism of thyroid gland cells as affected by prolactin and emotional-physical stress (1991)
2. Mechanism of prolactin action (1980)
3. Effects of aromatase inhibition and androgen activity on serotonin and behavior in male macaques (2013)
4. Prolactin: a diabetogenic hormone (1977)
5. Disorder of hair growth in hyperprolactinemia (1988)

Generative Energy #28: Talking with Ray Peat: The Origins of Authoritarianism

 
 

I’m incredibly excited to share my third interview with Ray about the origins of authoritarianism. The conversation covers a wide range of topics including Ray’s philosophical influences, former CIA director Allen Dulles, Wilhelm Reich, authoritarianism as a sickness, Nicole Foss’s idea of degrowth, and Ray’s thoughts on an “optimal” society. The conversation was originally recorded on June 24th, 2016. Special thanks to Ray for providing me with his time and my Patrons for making this content possible.

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• Song: Astronomyy - Nothin On My Mind

“The Anarchists are right in everything; in the negation of the existing order, and in the assertion that, without authority, there could not be worse violence than that of authority under existing conditions. They are mistaken only in thinking that Anarchy can be instituted by a revolution. "To establish Anarchy." "Anarchy will be instituted." But it will be instituted only by there being more and more people who do not require protection from governmental power, and by there being more and more people who will be ashamed of applying this power.” — Leo Tolstoy (1899)
“‘When ignorance reigns in society and disorder in the minds of men, laws are multiplied, legislation is expected to do everything, and each fresh law being a fresh miscalculation, men are continually led to demand form it what can proceed only from themselves, from their own education and their own morality.’ It is no revolutionist who says this, nor even a reformer. It is the jurist, Dalloy, author of the Collection of French law known as ‘Repertoire de la Legislation.’ And yet, though these lines were written by a man who was himself a maker and admirer of law, they perfectly represent the abnormal condition of our society. 
In existing States a fresh law is looked upon as a remedy for evil. Instead of themselves altering what is bad, people begin by demanding a law to alter it. If the road between two villages is impassable, the peasant says: -‘There should be a law about parish roads.’ If a park-keeper takes advantage of the want of spirit in those who follow him with servile observance and insults one of them, the insulted man says: -- ‘There should be a law to enjoin more politeness upon park-keepers.’ If there is stagnation in agriculture or commerce, the husbandman, cattle-breeder, or corn speculator argues, ‘It is protective legislation that we require.” Down to the old clothesman there is not one who does not demand a law to protect his own little trade. If the employer lowers wages or increases the hours of labour, the politician in embryo exclaims, “We must have a law to put all that to rights,’ instead of telling the workers that there are other, and much more effectual means of settling these things straight; namely, recovering from the employer the wealth of which he has been despoiling the workmen for generations. In short, a law everywhere and for everything! A law about fashions, a law about mad dogs, a law about virtue, a law to put a stop to all the vices and all the evils which result from human indolence and cowardice.” — Peter Kropotkin (1886)
“Probably about 20 to 25 percent of the adult American population is so authoritarian, so scared, so self-righteous, so ill-informed, and so dogmatic that nothing you can say or do will change their minds.” “Dogmatism is by far the best fall-back defense, the most impregnable castle, that ignorance can find. It’s also a dead give-away that the person doesn’t know why he believes what he believes.” — Bob Altemeyer (2006)

01:10 - Chatting about Ray’s 2003 Newsletter
01:59 - Defining authoritarianism and Ray’s experience
09:45 - Where did authoritarianism originate from? (Parmenides, Zeno, Plato, Aristotle, and Heraclitus)
12:41 - “The principle of forgiveness was presented as the appropriate response to a world which is always new. The desire for vengeance comes from a delusive commitment to the world of memory. Virginity is constantly renewed in the world of imaginative life. While Blake said that you can’t forgive someone until they stop hurting you, the desire to be forgiven indicates that there is an opportunity to resolve the problem.” (http://raypeat.com/articles/articles/william-blake.shtml)
16:41 - “In 1933 Reich published The Mass Psychology of Fascism, and the next year Freud expelled him from psychoanalysis; that was the year that Andre Breton excommunicated Dali from surrealism. Both Reich and Dali had important (but dangerous) insights into the effects of the authoritarian culture on consciousness—the destruction of reality by the imposition of an “essentialist” attitude. Dali’s Persistence of Memory, 1931, described the fluidity of reality and consciousness. Later, Dali aligned himself with the fascist side, and his 1954 Decomposition of the Persistence of Memory shows the quantized consciousness. Starting in 1945, the fascist culture blossomed in the US, so people who speak English now have constant contact with the dead essences, and very little incentive to evaluate them. Business/government marketing techniques adjust the meaning-units periodically, so that they are always available to provide the needed frame for the discourse of the moment. A lot of work goes into it.” —Raymond Peat
16:54 - The Dulles brothers (The Devil’s Chessboard by David Talbott)
18:04 - Is authoritarianism a disease?
20:38 - Is the environment bracketing our current progress?
21:08 - Nicole Foss on degrowth (https://www.youtube.com/watch?v=lDr71LHO0Jo)
23:37 - Increasing the people’s knowledge, ability and power
24:31 - Food as way to heighten someone’s awareness
26:19 - The food pyramid as a form of oppression
27:44 - America’s authoritarianism vs. other places
31:29 - “In a speech before the National Alumni Conference at Princeton University on April 10, 1953, newly appointed CIA director Allen Dulles lectured his audience on ‘how sinister the battle for men's minds had become in Soviet hands.’ The human mind, Dulles warned, was a ‘malleable tool,’ and the Red Menace had secretly developed ‘brain perversion techniques.’ Some of these methods were ‘so subtle and so abhorrent to our way of life that we have recoiled from facing up to them.’ Dulles continued, ‘The minds of selected individuals who are subjected to such treatment are deprived of the ability to state their own thoughts. Parrot-like, the individuals so conditioned can merely repeat the thoughts which have been implanted in their minds by suggestion from outside. In effect the brain becomes a phonograph playing a disc put on its spindle by an outside genius over which it has no control.’ Three days after delivering this address Dulles authorized Operation MK-ULTRA, the ClA's major drug and mind control program during the Cold War.” — Acid Dreams (1985)
32:26 - What impact would you like to see your research make on society? Reaching the largest amount of people? or a certain type of person? Or are you completely detached from the outcome? “I’d like to see it lead to the disestablishment of medicine. The same general outcomes Ivan Illich worked for.” —RP (https://raypeatinsight.com/2013/06/06/raypeat-interviews-revisited/)
33:20 - Does Ray think an “optimal” society should include medicine or government?
34:59 - David Alfaro Siqueiros (https://en.wikipedia.org/wiki/David_Alfaro_Siqueiros)

Generative Energy #27: On The Back of a Tiger Interview #2

 
 

“Making an effort to learn how to use techniques of food, hormones, light, activity, etc., is similar to the effort needed to work with a psychologist, and the effort itself is part of the therapy—the particular orientation of the psychotherapist isn’t what’s therapeutic, it’s the ability to participate in meaningful interactions, that is, the ability to provide a situation in which the person can practice being human. When people start thinking about the things in their life that can be changed, they are exercising aspects of their organism that had been atrophied by being in an authoritarian culture. Authoritarians talk about protocols, but the only valid ‘protocol’ would be something like ‘perceive, think, act.’” —Raymond Peat, PhD

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01:17 - Details on the successful Kickstarter
02:04 - A heartened Brad and Jeremy
03:39 - What have you guys been up for the last year?
05:30 - Has the film changed at all?
07:16 - Where are you guys in the filmmaking process?
08:26 - Jeremy and Brad asking big questions
10:25 - Warming up the audience to the cast of Mavericks
11:40 - Uncut audio from the interviews
12:28 - Problems in the establishment
13:31 - Animations and filming experiments
15:16 - Issues in biology and medicine
16:15 - How the script is being written
17:49 - Will consciousness be explored in the film?
18:54 - Will cosmology be explored in the film?
19:07 - How do you empower people without giving recommendations?
20:54 - Will stress and energy be explored in the film?
23:38 - Danny doesn’t understand epigenetics
24:40 - Eugenics is still part of science culture
26:25 - Will politics be explored in the film?
27:48 - Danny thinks the ‘serotonin-makes-you-feel-good’ idea is crumbling
28:34 - Has Brad and Jeremy’s views changed at all since filming the movie?
31:32 - Danny thinks leaving your comfort zone can increase self-awareness
33:01 - ‘Never be in a rush to do anything’
33:25 - Will the film be accessible to lay people?
34:03 - How are Brad and Jeremy stringing the narrative between all the subjects?
34:48 - The passing of Mae-Wan Ho
35:31 - Respecting the life’s work of some of the subjects
35:05 - Keeping up to date with On The Back of a Tiger
40:04 - Next week’s episode with Ray

Generative Energy #26: Talking with Ray Peat: CO2, NAD+/NADH, Antibiotics, Coffee, and More

 
 

“Since the contextuality of communication is always in the foreground when I talk or write, you know that someone is confusing me with an authority when they talk about my ‘protocol’ for something. Context is everything, and it’s individual and empirical.” —Raymond Peat, PhD

“Making an effort to learn how to use techniques of food, hormones, light, activity, etc., is similar to the effort needed to work with a psychologist, and the effort itself is part of the therapy—the particular orientation of the psychotherapist isn’t what’s therapeutic, it’s the ability to participate in meaningful interactions, that is, the ability to provide a situation in which the person can practice being human. When people start thinking about the things in their life that can be changed, they are exercising aspects of their organism that had been atrophied by being in an authoritarian culture. Authoritarians talk about protocols, but the only valid ‘protocol’ would be something like ‘perceive, think, act.’” —Raymond Peat, PhD

01:10 - Show outline
01:40 - The passing of Mae-Wan Ho
03:44 - The organisms as a liquid crystalline
04:55 - Magneto biology
06:59 - Ray’s discovery of Vladimir Vernadsky
09:07 - Background on Ray’s books
10:36 - When Ray became more interested in carbon dioxide
15:10 - Carbon dioxide and evolution
17:11 - Ketosis, Carbon Dioxide, and NAD+/NADH
21:24 - The ketone body ratio and electrode physiology
33:35 - Why wasn’t Albert Szent-Györgyi’s work more accepted?
34:29 - “Old” and “new” hormones and signaling substances
38:53 - The “optimal” metabolic state
40:26 - Ray’s thoughts on antibiotics
43:25 - Ray’s thoughts on thyroid brands
44:52 - Ray’s thoughts on synthetic vs. desiccated
45:07 - How Ray makes his coffee
46:45 - The quality of commercial supplements
48:23 - Ray’s upcoming newsletter

Antihistamines for Pattern Hair Loss?

 
 

Over the years, a few people have been interested in the ability of antihistamine drugs to completely reverse baldness. For instance, in a small group of ten women with so-called androgenic alopecia an antihistamine called cimetidine showed good to excellent regrowth of hair in seven out of the ten women.[1] In addition to hair regrowth, acne, seborrhea, and hirsutism, which were present in three of the patients, showed significant improvement. Most of the women said that their scalps had become less greasy taking the drug similar to Hamilton's famous immune-to-baldness castrates. 

Around the same time, it was recorded that another antihistamine drug, benoxaprofen, was able to spontaneously reverse baldness in two men. The first case was a 75-year-old man with “hereditary male-pattern baldness” since he was 45. After five months of antihistamine treatment, the gentleman noticed new hairs on previously bald areas of his scalp. The other case, a 45-year-old man who had been balding in a pattern fashion since he was 40, experienced an increased growth of hair over the area of scalp previously lacking hair after nine months of taking benoxaprofen.[2] 

Cetirizine is another antihistamine drug that is currently being explored on various hair loss forums as an antiinflammatory.[3] Unfortunately, similar to cimetidine and benoxaprofen, cetirizine has a host of gnarly side effects that exclude it from being useful in the long-term.

A historical treatment for baldness that hints at a more physiological approach to controlling mast cell degranulation and the subsequent release of histamine is cyproterone acetate.[4] Cyproterone acetate has a semi-successful track record for resolving hair loss orally as well as topically in both men and women.[5] While the drug is commonly referred to as an “antiandrogen” it opposes estrogen (“to castration levels”) and exerts a progesterone-like effect.[6] Estrogen has long been known to activate mast cells while progesterone, working in the opposite direction, quiets them.[7]

Although some of the studies attempting to explain the positive effects of antihistamines on hair regrowth have attributed it to their alleged "anti-androgenic" actions, (specious at best in the case of cimetidine)[8], I have a different take.

I: Histamine and Ordinary Hair Growth

The defining feature of pattern hair loss is a higher ratio of telogen (resting) to anagen (growing) hairs. I think this reframes the conversation away from androgens and "the genes" and helps refocus thinking about the complicated growth cycle of the hair follicle and its interaction with the environment. 

In physiological amounts, histamine appears to play an important role in the cyclical growth of hair. For example, in the energetically expensive early anagen growth phase, the skin content of histamine in mast-cell granules is high promoting quick glycolytic growth. However, when hair follicles reach late anagen, a gradual but radical decrease in histamine begins and the mast cell population diminishes by a third leading to a more differentiated state of growth. During the resting telogen phase of hair growth, the mast cells and histamine increase again and continue to rise in the subsequent anagen preparing the hair for the next growth phase.[9] 

Early Anagen: High Histamine Late Anagen: Low Histamine Telogen: High Histamine

Early Anagen: High Histamine Late Anagen: Low Histamine Telogen: High Histamine

If histamine is tightly regulated during stages of early anagen, turned off during the differentiated period of late anagen, and increased once again during the resting telogen phase, we might expect an excess of histamine (and other mast cell products) to retard normal growth. While I’m not aware of any direct research on the histamine levels of people with pattern baldness, some pieces evidence suggest that the stress substances that promote mast cell accumulation, activation, and histamine release become excessive in pattern baldness.

II: When Energy Fails: Estrogen, Prostaglandins, and Histamine

The accumulation of degranulated mast cells was found to define “the baldness field” or typical horseshoe shape of pattern baldness.[10,11] The migration and activation of mast cells in a tissue are influenced by various hormones and signaling substances. For example, during stress, corticotropin-releasing hormone (CRH) is secreted from the hypothalamus and can induce mast cell degranulation in a dose-dependent manner.[12] CRH also activates the pituitary hormones: luteinizing hormone (LH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), which were found to increase the concentration and degranulation of mast cells. The hormone estrogen, which is increased in stress and age in both sexes, was found to be the most potent activator of mast cells tested.[13]

Image: serotonin, histamine, and mast cells in the hair cycle

Image: serotonin, histamine, and mast cells in the hair cycle

Estrogen inhibits mitochondrial respiration[14.15] reducing carbon dioxide production promoting mast cell degranulation,[16,17] and promoting what has been called "the inherent terminal-to-vellus switch" of the hair growth cycle.[18] Activating mitochondrial uncoupling proteins that dissociate ATP production from carbon dioxide production (generating more carbon dioxide and clearing lactic acid) were found to inhibit mast cell activation.[19] Another way of thinking about it is that the biological functions of estrogen and histamine overlap and reducing either one tends to reduce the other.[20] 

A consequence of the hypoglycemia that an excess of estrogen can create[21,22] is an increased concentration of free fatty acids in the blood. While the saturated fats tend to help terminate the stress reaction,[23] the composition of released fat probably leans towards the polyunsaturated fats that the hormone-like prostaglandins are synthesized from.[24] In 2012, Garza et al. found that a type of prostaglandin, prostaglandin D2, was elevated in the scalps of balding men and inhibited hair growth.[25] Prostaglandin D2 also promotes histamine release from mast cells[26] and is involved in the pathology of many allergenic problems. For instance, asthmatics were found to have 12 to 22 times higher levels of prostaglandin D2 and 4 times higher levels of histamine compared to controls.[27]

Estrogen, free fatty acids, prostaglandins, mast cells, and histamine are involved in the development of fibrosis, or the abnormal progression of the normal formation of fibrous material between cells due to inflammation. In 1992, Jaworsky et al. found that a prominent feature of baldness was mast cell degranulation and the activation of fibroblasts resulting in fibrotic thickening of the hair follicle.[28] In another experiment, 412 people with pattern baldness (193 men and 219 women) confirmed the presence of a significant degree of perifollicular fibrosis in at least 37% of cases. Moreover, balding men with higher levels of inflammation and fibrosis led to worse outcomes using the traditional hair loss remedy minoxidil compared to those with lower levels.[29] 

III: Prolactin, Light, and The Seasonal Variation of Hair Growth

“In birds, prolactin seems to be involved in stimulation of the feather papillae to produce a new plumage. It acts synergistically with estrogen to produce brood patches in birds.” Donnel, C. General Endocrinology (1966)

“In birds, prolactin seems to be involved in stimulation of the feather papillae to produce a new plumage. It acts synergistically with estrogen to produce brood patches in birds.” Donnel, C. General Endocrinology (1966)

Estrogen tends to increase the anti-respiratory pituitary hormone prolactin.[30] In mammals, prolactin has been called the “molting hormone” for its well-known ability to shed old feathers, hair, or skin, to make way for a new growth. Like other mammals, humans appear to be subject to seasonal differences in hair growth, with evidence that both the duration of hair growth and daily growth rates are greater in summer than winter.[31] In fact, an old paper from 1947 explained that one constant feature of hair growth in man was that “summer” hair was more long-lived than “winter” hair.[32] More recently, it was proposed that the hair follicle functioned as a “specialized UV receptor” responding to the nuances of seasonal light input.[33] The marked seasonal effect of hair growth is so remarkable that it has been suggested that any new drug or treatment for baldness should be studied for at least a year to separate any effects from normal seasonal variations.[34] 

Prolactin responds readily to cycles of light and darkness,[35,36] temperature, nutrition, stress, and the feeding rhythm. An excess of prolactin is associated with the development of pattern baldness in both sexes.[37,38] One way prolactin exerts a negative effect on hair is by reducing the intracellular level of cyclic amp (cAMP), a “secondary” regulatory substance that is associated with normal cellular differentiation and function in hair growth. Prolactin also activates the phospholipase A2 enzyme that liberates arachidonic acid from cells for prostaglandin production.[39] Moreover, alterations in mood can sometimes be attributed to higher prolactin levels,[40,41] and might be another aspect of the “balding personality” that I have mentioned previously.

Prolactin tends to rise with another adaptive hormone that activates mast cells, parathyroid hormone.[42] Both parathyroid hormone and prolactin decrease the concentration of carbon dioxide,[43,44] which helps stabilize mast cells.[45] Thyroid hormone is the master regulator of carbon dioxide and in sufficient quantities, carbon dioxide inhibits an excess of both prolactin and parathyroid hormone.[46,47] 

IV: Expand, Extend, Develop, Mature

"It is the urge, which is evident in all organic and human life — to expand, extend, become autonomous, develop, mature — the tendency to express and activate all the capacities of the organism, to the extent that such activation enhances the organism or the self. This tendency may become deeply buried under layer after layer of encrusted psychological defenses; it maybe hidden behind elaborate facades which deny its existence; but it is my belief that it exists in every individual, and awaits only the proper conditions to be released and expressed.” —On Becoming a Person by Carl Rogers (1961)

"It is the urge, which is evident in all organic and human life — to expand, extend, become autonomous, develop, mature — the tendency to express and activate all the capacities of the organism, to the extent that such activation enhances the organism or the self. This tendency may become deeply buried under layer after layer of encrusted psychological defenses; it maybe hidden behind elaborate facades which deny its existence; but it is my belief that it exists in every individual, and awaits only the proper conditions to be released and expressed.” —On Becoming a Person by Carl Rogers (1961)

My perennial argument for the last few years has been that pattern hair loss means that something is wrong. A nontechnical way of viewing the problem might be that the balding person is perpetually experiencing the effects of a “winter metabolism,” or: a chronic light deficiency, lower vitamin D level, higher local levels of estrogen, histamine, cortisol, and prolactin, some degree of insulin resistance, hypertension, higher circulating free fatty acids, higher levels of the inflammatory prostaglandins, deranged calcium metabolism, and a reduced resting pulse rate and body temperature.

Another way of looking at those facts is that red light, thyroid, calcium, vitamins D, K2 and A, sugars, salt, aspirin, caffeine, niacinamide, and maybe even a small dose of an antihistamine drug like cyproheptadine would be simple, cheap, and effective therapies for protection against the inflammation, fibrosis, and maladaptive stress reactions associated with pattern baldness. 

The heavy focus on androgen hormones and “the genes” as causes of baldness have led people to believe that pattern hair loss is a compartmentalized problem rooted in vanity that has nothing to do with their metabolism or lifestyle. Confusion about the role of androgens probably relates to testosterone’s conversion into estrogen during metabolic stress and that dihydrotestosterone (DHT), like DHEA, can increase to buffer the effects of metabolic stress, for example, as an anti-estrogen.[48,49]

References

  1. Aram, H. Treatment of female androgenetic alopecia with cimetidine. Int J Dermatol. 1987 Mar;26(2):128-30. "Ten white women with moderate to severe androgenetic alopecia were treated with cimetidine 300 mg by mouth five times a day. Duration of therapy ranged from 1.59 months, with a median of 5 months. Seven patients (70%) showed good to excellent regrowth of hair.” "The mechanism of cimetidine's action in patients with androgenetic alopecia is presumably due to its antiandrogenic activity, although a placebo effect cannot be discounted.” "Management of androgenetic alopecia in men or endocrinologically normal women has been unrewarding, as there are no consistently successful therapeutic agents available. The possibility of cimetidine offering a useful form of therapy for patients with this disorder prompted the undertaking of the present open study.” "The pattern of hair loss was usually diffuse, most marked on the vertex.” "Acne, seborrhea, and hirsutism, which were present in three of the patients, showed significant improvement. Most patients said that the scalp had become less greasy. No correlation was found between the severity of hair loss and the serum levels of testosterone.” "However, application of 0.025% 17-a-estradiol solution resulted in decrease of the rate of hair loss, but regrowth of hair did not occur."
  2. Fenton, D., et al. Reversal of male-pattern baldness, hypertrichosis, and accelerated hair and nail growth in patients receiving benoxaprofen. Br Med J (Clin Res Ed). 1982 Apr 24; 284(6324): 1228–1229. "Benoxaprofen is a non-steroidal anti-inflammatory drug used to relieve symptoms of rheumatoid arthritis and osteoarthrosis. Reported side effects include photosensitivity, onycholysis, urticarial rashes and pruritus, gastrointestinal ulceration and haemorrhage, and the Stevens-Johnson syndrome. We have reported the development of toxic epidermal necrolysis, leucopenia, and thrombocytopenic purpura in a patient after nine days' treatment with benoxaprofen. We report here on five patients who developed hypertrichosis and accelerated hair and nail growth, two of whom showed reversal of male-pattern baldness." 
  3. Charlesworth, E., et al. Effect of cetirizine on mast cell-mediator release and cellular traffic during the cutaneous late-phase reaction. J Allergy Clin Immunol. 1989 May;83(5):905-12. “Histamine release was not altered by cetirizine treatment, but prostaglandin D2 (PGD2) production, which peaked at 3 to 5 hours, was clearly reduced by cetirizine treatment, being lower at all time points during the reaction…” “The inhibition was most marked during the fifth hour of the reaction when there was a 50% suppression of the PGD2 level by cetirizine.”
  4. Mayo, J., et al. Androgen-dependent mast cell degranulation in the Harderian gland of female Syrian hamsters: in vivo and organ culture evidence. Anat Embryol (Berl). 1997 Aug;196(2):133-40. "The antiandrogen cyproterone acetate prevents the degranulation of mast cells induced by testosterone in both in vivo and in vitro."
  5. Neuman, F., and Graf, K.J. Discovery, development, mode of action and clinical use of cyproterone acetate. "CA has been useful in treating androgen-dependent tumors and "androgenic" diseases such as idiopathic precocious puberty, hirsutism, and male-pattern baldness in adult females, all signs of virilization in females, hypersexuality in adult males, acne and seborrhea, baldness in adult males, and benign prostatic hypertrophy.” "Because of its strong progesterone potency…” "Gynecomastia sometimes develops temporarily in males treated with CA. Serious side effects of CA treatment have not been observed."
  6. Geller, J., et al. Effect of cyproterone acetate on clinical, endocrine and pathological features of benign prostatic hypertrophy. Journal of Steroid Biochemistry, 1975. Vol. 6, pp. 837-843. "Clinical effects of CPA in patients with BPH. In five patients treated with CPA, 250 mg daily by mouth for two-to-four months, all improved clinically (Table 2) by both objective (residual urine and ability to void) and subjective criteria. The resected prostate was surprisingly small compared to the expected values estimated prior to drug treatment.” "The decrease in estrogen to the castration levels demonstrated in two patients during CPA therapy may reflect either a decrease in estrogen secondary to a decrease in testosterone which serves as a precursor for the estrogen, or it may reflect the direct inhibition of estrogen synthesis by Leydig cells. Since estrogen may stimulate squamous metaplasia and fibromuscular growth in the middle and lateral lobes of prostate, the usual anatomic sites of BPH, decreased estrogen production rates with CPA may have relevance to the clinical effects of the drug in BPH."
  7. 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 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."
  8. Orfanos, C., and Happle, R. Hair and Hair Diseases. 1990. “Of the three drugs presently available with antiandrogenic potency, Cimetidine (CI) is the drug which is weakest in this respect, and also that which is the least investigated. Its antiandrogenicity was suspected from side effects which occurred in men during CI treatment for peptic ulcer and other indications, namely gynaecomastia, impotence and reduction in sperm count, despite a rise in plasma testosterone. The antiandrogenic property is not intrinsic to histamine H2-receptor blockade since other histamine H2-receptor antagonists such as ranitidine and tiotidine are devoid of this activity. CI, unlike CPA and SL, is obviously devoid of additional endocrine activities. Thus, common endocrine parameters such as plasma testosterone,free testosterone, DHT, oestradiol, progesterone, FSH, LH and prolactin do not change under the influence of CI.”
  9. Morettie, G., et al. The Hair Cycle Re-Evaluated. International Iournal Of Dermatology (1976). "The skin content of histamine and heparin contained in the mast-cell granules is high at this time [ANA 4].” "The rise in heparin in the first week of anagen probably helps to maintain normal blood fluidity in the simultaneously increased perifollicular vessel networks, which are dilated and made more permeable by histamine.” "When follicles have reached ANA 6, however, a gradual but radical decrease in mast cells, histamine and heparin begins. This continues through the rest of ANA 6 and the whole of catagen. The mast cell population diminishes by a third, when it retreats to the lower dermis and hypodermis."During telogen the mast cells, histamine, and probably heparin, increase again and continue rising in the subsequent anagen, as we know from studies on consecutive hair cycles. The final stage of telogen probably prepares the hair for the next growth phase. This stage and anagen, until the point when the follicles are differentiated and emerge, are characterized by an increase in mast cell population and in their secretory activity.” "During telogen, hair survival is dependent on energy (ATP), mainly produced by anaerobic glycolysis,” "Thyroxine shortens the resting phase, whereas estradiol, adrenal hormones and testosterone prolong telogen."
  10. Lattanand, A. and Johnson, W.C. Male pattern alopecia a histopathologic and histochemical study. J Cutan Pathol. 1975;2(2):58-70. “The role of mast cells in male-pattern baldness is unknown, but the large numbers often present is a striking feature.”
  11. 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.”
  12. Theoharides, T., et al. Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects. Endocrinology. 1998 Jan;139(1):403-13. “Mast cells are involved in atopic disorders, often exacerbated by stress, and are located perivascularly close to sympathetic and sensory nerve endings.” “Moreover, acute psychological stress induces CRH-dependent mast cell degranulation.Intradermal administration of rat/human CRH (0.1-10 microM) in the rat induced mast cell degranulation and increased capillary permeability in a dose-dependent fashion.” “To investigate which vasodilatory molecules might be involved in the increase in vascular permeability, the CRH injection site was pretreated with the H1-receptor antagonist diphenhydramine, which largely inhibited the CRH effect, suggesting that histamine was involved in the CRH-induced vasodilation.” “The present results have implications for the pathophysiology and possible therapy of skin disorders, such as atopic dermatitis, eczema, psoriasis, and urticaria, which are exacerbated or precipitated by stress.”
  13. Jaiswal K., and Krishna, A. Effects of hormones on the number, distribution and degranulation of mast cells in the ovarian complex of mice. Acta Physiol Hung 1996;84(2):183-90. “The changes in the number and degranulation pattern of mast cells varied with the types of hormonal treatment and ovarian compartment. Luteinizing hormone (LH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH) and 17-beta estradiol (E2) treatment caused increase (P < 0.05) in the number of mast cells in the hilum as compared with the controls. Increase (P < 0.05) in the number of mast cells in the whole ovarian complex was observed only following FSH and E2 treatment. All the hormones used in the present study increased the percentage degranulation of mast cells in the hilum. However, only LH, FSH and E2 increased the percentage degranulation of mast cells in other compartments of the ovary (medulla, bursa and cortex). TSH and ACTH failed to cause any increase in the percentage degranulation of mast cells in these compartments. The present findings indicate E2 to be the most potent among the hormones tested in causing degranulation of mast cells in all ovarian compartments.” 
  14. 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 percent 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.”
  15. Nagy, P., and Csaba, I.F. [Action of oestrogens on in vitro metabolism of trophoblast from human early pregnancy]. 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.”
  16. Vliagoftis, H., et al. Estradiol augments while tamoxifen inhibits rat mast cell secretion. Int Arch Allergy Immunol. 1992;98(4):398-409. “...17 beta-estradiol augmented secretion of histamine and serotonin, starting at 1 microM and in a dose-dependent manner…” "Tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibited serotonin and histamine release from purified rat peritoneal mast cells triggered by compound 48/80 or substance P. Tamoxifen also inhibited the increase in intracellular free Ca2+ originating from an influx of extracellular Ca2+ in response to compound 48/80.” "Tamoxifen may, therefore, have a beneficial effect in other neuroimmunoendocrine disorders both through estrogen receptor blockade and inhibition of mast cell secretion."
  17. Terral, C., et al. [Influence of estrogens on histamines liberation by whole blood induced by allergens in vitro]. Soc Bioi Fil 1981; 175(2):247-52. “A relapse o f bronchial obstruction during women's menstrual cycle in often observed. Incubating blood and rising rates of estrogens produce an increase of histamine-release induced by allergens."
  18. 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.”
  19. Theoharides, C., et al. Mast cells and inflammation. Biochim Biophys Acta. 2012 Jan; 1822(1): 21–33. "Recent evidence indicates that mitochondria are involved in the regulation of mast cell degranulation. Mitochondrial uncoupling protein 2 (UCP2) inhibits mast cell activation."
  20. Martin, C. Endocrine Physiology. 1985. “Estrogens stimulate the secretion of growth hormone and prolactin. They also exert localized influences. The most prominent of which is rapidly developing retention of water in the uterus. This is attributed to the release of histamine and prostaglandins.” "Estradiol promotes histamine release, and histamine accelerates endometrial estradiol uptake.” "Subthreshold amounts of estrogen and histamine synergize to invoke a response."
  21. Martin, C. Endocrine Physiology. 1985. "Sustained high estrogen concentrations increase both insulin requirements and insulin secretion."
  22. Goodman, M., et al. Short-term effects of oestradiol benzoate in normal, hypophysectomized and alloxan-diabetic male rats. "In normal rats, OEB decreased plasma glucose, increased plasma immunoreactive insulin, growth hormone and corticosteroid levels, increased pancreatic β-cell granulation, and enhanced glucose stimulation of insulin release in vitro.” "These results suggest that OEB affects experimental diabetes by a direct action on the pancreas, promoting insulin formation, and possibly by an indirect action mediated through hypophysial secretions."
  23. Katoh, K., et al. Saturated fatty acids suppress adrenocorticotropic hormone (ACTH) release from rat anterior pituitary cells in vitro. Comp Biochem Physiol A Mol Integr Physiol. 2004 Feb;137(2):357-64. Addition of saturated fatty acids (butyrate, caprylate, laurate, palmitate and stearate) in a medium at 1 mmol/l, despite effects on the basal release, significantly reduced the ACTH release induced by CRH (1 nmol/l) stimulation. Caprylate suppressed ACTH release in a concentration-dependent manner. However, unsaturated C18 and C20 fatty acids (oleate, linolate, linolenate and arachidonate) at 1 mmol/l significantly increased the basal release, but none of them suppressed CRH (1 nmol/l)-induced ACTH release. In the presence of caprylate (1 mmol/l), CRH (1 nmol/l)-stimulated increase in cellular calcium ion concentration was diminished. From these results we conclude that saturated fatty acids have a suppressing effect on CRH-induced ACTH increase in primary cultured rat anterior pituitary cells.
  24. Speake, B., et al. The preferential mobilisation of C20 and C22 polyunsaturated fatty acids from the adipose tissue of the chick embryo: potential implications regarding the provision of essential fatty acids for neural development. Biochim Biophys Acta. 1997 Apr 21;1345(3):317-26. "The composition of the FFA released into the medium under conditions of basal (i.e., unstimulated) lipolysis was markedly different in several respects from that of the TAG from which it originated. The polyunsaturated fatty acids, 20:4n-6, 20:5n-3, 22:5n-3 and 22:6n-3, were consistently found to be preferentially released into the medium, whereas the major fatty acyl constituents of the tissue, 16:0 and 18:1n-9, were selectively retained in the TAG. For example, at day 18 of development, the proportions (% w/w of fatty acids) of 20:5n-3 and 22:6n-3 released into the incubation medium were respectively 6.5 and 7.5 times higher than in the original tissue TAG.” "Although the regulation of fatty acid mobilisation from adipose tissue TAG has been an area of intensive research for 3 decades, relatively few studies have focussed on the composition of the mobilised fatty acids” "Their observations on the differential release of 52 fatty acids into the medium during the in vitro incubation of rat adipocytes were found to be summarised by the general rule that the Relative Mobilisation of a particular fatty acid is directly proportional to its degree of unsaturation and inversely proportional to its chain length. Thus the proportion of highly polyunsaturated fatty acids such as 20:4n-6 and 20:5n-3 was significantly greater in the medium FFA than in the original cellular TAG.” "A mechanistic explanation for selective mobilisation was proposed based on the differential aqueous solubilities of the various fatty acids. It was suggested that TAG species containing the more polar short and unsaturated fatty acids would be preferentially located at the periphery of the cytoplasmic lipid droplet of the adipocyte and would therefore be more accessible to the hormone sensitive lipase…”
  25. 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.”
  26. Peters, S., et al. Effect of prostaglandin D2 in modulating histamine release from human basophils. J Pharmacol Exp Ther. 1984 Feb;228(2):400-6. "Prostaglandin (PG) D2 is the major cyclooxygenase metabolite of arachidonic acid released after immunologic stimulation of mast cells. In this report, we demonstrate that this PG is unlike other PGs previously investigated in that it enhances human basophil histamine release at concentrations of 1 to 100 nM.” "These data suggest that PGD2 may play an important role in allergic and immunologic reactions and suggest a mechanism by which mast cells and basophils can interact during these reactions."
  27. Liu, M., et al. Evidence for elevated levels of histamine, prostaglandin D2, and other bronchoconstricting prostaglandins in the airways of subjects with mild asthma. Am Rev Respir Dis. 1990 Jul;142(1):126-32. "Histamine and certain cyclooxygenase products of arachidonic acid have been implicated as mediators of inflammation and are potent constrictors of human airways.” "Levels of PGD2, 9 alpha,11 beta-PGF2 and PGF2 alpha were 12 to 22 times higher in asthmatic than in normal subjects…” "Levels of PGD2 and 9 alpha,11 beta-PGF2 were increased nearly tenfold in asthmatic subjects compared with those in rhinitic subjects…” "Histamine levels were increased fourfold in asthmatic subjects compared with those in normal subjects (p less than 0.001); however, similar increases were found in rhinitic subjects."
  28. 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 fibroblast 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 cell epithelium. Injury to follicular stem cell epithelium and/or thickening of adventitial sheaths may impair normal pilar cycling and result in hair loss.” "Mast cell degranulation was a prominent feature in sheaths of affected follicles, and was associated with ultrastructural evidence of biosynthetic activation of fibroblasts resulting in sheath widening and fibrosis.”
  29. Mahe, Y.F., et al. Androgenetic alopecia and microinflammation. Int J Dermatol. 2000 Aug;39(8):576-84. "Only 55% of male pattern AGA patients with microinflammation had hair regrowth in response to minoxidil treatment, which was less than the 77% of patients with no signs of inflammation, suggesting that, to some extent, perifollicular microinflammation may account for some cases of male pattern AGA which do not respond to minoxidil. Another study on 412 patients (193 men and 219 women) confirmed the presence of a significant degree of inflammation and fibrosis in at least 37% of AGA cases.""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 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.” 
  30. Martin, C. Endocrine Physiology. 1985. "Plasma PRL concentrations undergo diurnal variations that include sleep-associated elevations. The levels also rise in response to demanding activity and some forms of stress, and sharp peaks have been observed following food ingestion. Estrogens are potent stimulants that affect DA turnover in the brain. In cycling females. plasma PRL reaches its highesl levels during the times of maximal estrogen secretion."
  31. Montagna, W., et al. Hair Research. 1981. 
  32. Pinkus, F. The story of a hair root. J Invest Dermatol. 1947 Aug;9(2):91-3. "In spite of the differences in generation of hair, one feature is constant. ‘Summer’ hair is more long-lived than ‘winter’ hair in man, a fact established by earlier observations.”
  33. Iyenger, B. The hair follicle: a specialised UV receptor in the human skin? Biol Signals Recept. 1998 May-Jun;7(3):188-94. “From the present study, it appears that light is guided to the hair bulb to activate the melanocytes within the hair follicles. Thus the hair follicles function as specialised UV receptors in the skin responding to nuances of seasonal photic inputs in man. This would explain the coat colour changes seen in animals exposed to large variations in the day-night cycle.”
  34. Trüeb, R., and Tobin, D. Aging Hair. 2010.
  35. Kizer, J., et al. The nyctohemeral rhythm of plasma prolactin: effects of ganglionectomy, pinealectomy, constant light, constant darkness or 6-OH-dopamine administration. Endocrinology. 1975 May;96(5):1230-40. "In addition, there is evidence that environmental lighting in the form of altered length of a photo periods has a profound influence upon the endocrine system.” "Plasma prolactin, on the other hand, is decreased in rats exposed to constant light and increased by constant darkness.""In male rats maintained on a 12 h light-dark schedule (6 AM-6 PM), there is a nyctohemeral cycle of plasma prolactin which consists of a nadir at 11:30 AM and an apogee at approximately 11:30 PM.” "…there is a nyctohemeral rhythm of plasma prolactin, which is reversed by constant light…" “ ...a rhythm of plasma prolactin develops in constant light which is the exact opposite of the normal diurnal variation…”
  36. Relkin, R., et al. Effects Of Pinealectomy And Constant Light And Darkness On Prolactin Levels In The Pituitary And Plasma And On Pituitary Ultrastructure Of The Rat. 1972. "Compared with sham-operated diurnally-illuminated controls, constant darkness caused a decrease in pituitary prolactin content and a rise in plasma prolactin levels. Pinealectomy or constant illumination reversed the effect of constant darkness, resulting in an increase in pituitary prolactin content and a fall in plasma prolactin levels when compared with sham-operated diurnally-illuminated controls."
  37. 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 F [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."
  38. 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 hyperprolactinemia is associated with an androgenetic alopecia-type hair loss pattern, along with hirsutism (in females)."
  39. Rillema, J. A. Mechanism of prolactin action. Federation Proceedings [1980, 39(8):2593-2598] "Subsequent actions of prolactin may involve the following: a) an increased intracellular concentration of potassium and a reduced level of sodium, b) an increased level of cGMP and a reduced level of cAMP, c) an enhanced rate of prostaglandin biosynthesis mediated by a stimulation of phospholipase A2 activity, and d) a stimulation of polyamine synthesis."
  40. Kellner, R. et al. Hyperprolactinemia, distress, and hostility. Am J Psychiatry. 1984 Jun;141(6):759-63. “Hyperprolactinemic patients were significantly more hostile, depressed, and anxious and had more feelings of inadequacy than family practice patients and non patient employees. The authors recommend measuring the serum prolactin levels of women with depression, hostility, anxiety, and symptoms or signs suggestive of hyperprolactinemia.”
  41. Hollander, E., et al. Prolactin and sodium lactate-induced panic. Psychiatry Res. 1989 May;28(2):181-91. "Sodium lactate infusions reliably induce panic attacks in panic disorder patients but not in normal controls, but the mechanism underlying this response is unknown. We studied the plasma prolactin response to infusion of 0.5 molar sodium lactate in 38 patients with panic disorder or agoraphobia with panic attacks, and 16 normal controls. As expected, baseline plasma prolactin was significantly higher in female subjects than in male subjects. However, the males who experienced lactate-induced panic had significantly elevated baseline prolactin levels compared to male nonpanickers and controls. Prolactin levels increased in all groups during lactate infusion, which may reflect osmotic effects, but were blunted in the late panickers compared to nonpanickers and controls. The elevated baseline prolactin for male panickers supports a relationship between prolactin and anticipatory anxiety. The blunted prolactin response for late panickers suggests a net diminution, rather than a sensitization, of prolactin response in panic anxiety."
  42. Raymond, J., et al. Comparison between the plasma concentrations of prolactin and parathyroid hormone in normal subjects and in patients with hyperparathyroidism or hyperprolactinemia. J Clin Endocrinol Metab. 1982 Dec;55(6):1222-5. "These results show that an excess of plasma PRL is associated with an excess of plasma PTH and vice versa."
  43. Spätling, L., et al. Influence of prolactin on metabolism and energy production in perfused corpus luteum bearing bovine ovaries. "Under the influence of PRL anaerobic glucose metabolism was stimulated by 40.5% and oxidative phosphorylation was inhibited. Energy production from aerobic glucose metabolism rose by only 0.25%.” "This may indicate that PRL is the "older" hormone in phylogenetic terms."
  44. Martin, C. Endocrine Physiology. 1985. “When moderate dosages of PTH are injected into parathyroidectomized animals, the responses include increased urinary excretion of sodium, phosphate, bicarbonate, and amino acids, along with decreased excretion of calcium and hydrogen."
  45. 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."
  46. Ljunhgall, S., et al. Effects of epinephrine and norepinephrine on serum parathyroid hormone and calcium in normal subjects. Exp Clin Endocrinol. 1984 Dec;84(3):313-8. "During infusion of epinephrine there was a clear rise of the serum parathyroid hormone (PTH) levels already at the lowest concentration. Concomitantly there was a fall in the serum concentrations of calcium. The PTH levels returned to baseline promptly after termination of infusion whereas hypocalcaemia persisted up to 30 minutes, indicating a primary response of PTH to epinephrine.” (Low thyroid people tend to have very high adrenaline.)
  47. Richalet, J.P., et al. Effects of high-altitude hypoxia on the hormonal response to hypothalamic factors. Am J Physiol Regul Integr Comp Physiol. 2010 Dec;299(6):R1685-92. "Thyroid hormones were elevated at altitude (+16 to +21%), while TSH levels were unchanged, and follicle-stimulating hormone and prolactin decreased, while luteinizing hormone was unchanged."
  48. Kunelius, P., et al. The effects of transdermal dihydrotestosterone in the aging male: a prospective, randomized, double blind study. J Clin Endocrinol Metab. 2002 Apr;87(4):1467-72. "The objective of the study was to investigate the effects of dihydrotestosterone (DHT) gel on general well-being, sexual function, and the prostate in aging men. A total of 120 men participated in this randomized, placebo-controlled study (60 DHT and 60 placebo). All subjects had nocturnal penile tumescence once per week or less, andropause symptoms, and a serum T level of 15 nmol/liter or less and/or a serum SHBG level greater than 30 nmol/liter. The mean age was 58 yr (range, 50-70 yr).” "Serum concentrations of LH, FSH, E2, T, and SHBG decreased significantly during DHT treatment. Treatment with DHT did not affect liver function or the lipid profile. Hemoglobin concentrations increased from 146.0 +/- 8.2 to 154.8 +/- 11.4 g/liter, and hematocrit from 43.5 +/- 2.5% to 45.8 +/- 3.4% (P < 0.001). Prostate weight and prostate-specific antigen levels did not change during the treatment. No major adverse events were observed. Transdermal administration of DHT improves sexual function and may be a useful alternative for androgen replacement. As estrogens are thought to play a role in the pathogenesis of prostate hyperplasia, DHT may be beneficial, compared with aromatizing androgens, in the treatment of aging men."
  49. Casey, R., et al. Antiestrogenic action of dihydrotestosterone in mouse breast. Competition with estradiol for binding to the estrogen receptor. J Clin Invest. 1984 Dec;74(6):2272-8. "...Feminization in men occurs when the effective ratio of androgen to estrogen is lowered.” "Administration of estradiol via silastic implants to castrated virgin CBA/J female mice results in a doubling in dry weight and DNA content of the breast. The effect of estradiol can be inhibited by implantation of 17 beta-hydroxy-5 alpha-androstan-3-one (dihydrotestosterone), whereas dihydrotestosterone alone had no effect on breast growth. Estradiol administration also enhances the level of progesterone receptor in mouse breast." "Dihydrotestosterone does not compete for binding to the progesterone receptor, but it does inhibit estrogen-mediated increases of progesterone receptor content of breast tissue cytosol from both control mice and mice with X-linked testicular feminization (tfm)/Y.” "Dihydrotestosterone also promotes the translocation of estrogen receptor from cytoplasm to nucleus; the ratio of cytoplasmic-to-nuclear receptor changes from 3:1 in the castrate to 1:2 in dihydrotestosterone-treated mice. Thus, the antiestrogenic effect of androgen in mouse breast may be the result of effects of dihydrotestosterone on the estrogen receptor. If so, dihydrotestosterone performs one of its major actions independent of the androgen receptor."

Generative Energy #25: A Bioenergetic View of Osteoporosis

 
 

“The true method of knowledge is experiment.” —William Blake

“Experience is, for me, the highest authority. The touchstone of validity is my own experience. No other person’s ideas, and none of my own ideas, are as authoritative as my experience. It is to experience that I must return again and again, to discover a closer approximation to truth as it is in the process of becoming in me. Neither the Bible nor the prophets — neither Freud nor research — neither the revelations of God nor man — can take precedence over my own direct experience. My experience is not authoritative because it is infallible. It is the basis of authority because it can always be checked in new primary ways. In this way its frequent error or fallibility is always open to correction.” —Carl Rogers

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01:18 - Estrogen and bone metabolism
06:12 - Women's Health Initiative
10:30 - Mainstream therapies for osteoporosis
11:45 - Osteopotrosis, carbon dioxide, and lactic acid
15:55 - The hormone-like prostaglandins
18:21 - Thyroid, copper, and cytochrome c oxidase
19:55 - Are there any good iron tests?
26:24 - SSRIs, prolactin, and bone health
31:08 - Is Serotonin and Upper or Downer? (2015)
32:35 - Parathyroid hormone, calcium, and phosphate
36:22 - Clickbait health articles
39:33 - Tetracycline antibiotics for osteoporosis
41:50 - What tests would help with determining bone health?
46:45 - Are lab tests infallible?
49:35 - Georgi, where can we find more of your work this week?

Generative Energy #24: Q&A - Tooth Decay, Supplements vs. Food, Long Walks, and Ray Peat's Work

 
 

“The true method of knowledge is experiment.” —William Blake

“Experience is, for me, the highest authority. The touchstone of validity is my own experience. No other person’s ideas, and none of my own ideas, are as authoritative as my experience. It is to experience that I must return again and again, to discover a closer approximation to truth as it is in the process of becoming in me. Neither the Bible nor the prophets — neither Freud nor research — neither the revelations of God nor man — can take precedence over my own direct experience. My experience is not authoritative because it is infallible. It is the basis of authority because it can always be checked in new primary ways. In this way its frequent error or fallibility is always open to correction.” —Carl Rogers

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01:58 - Thoughts on tooth decay, carbon dioxide, and lactic acid
05:09 - “In the presence of hypothyroidism and magnesium deficiency everything is dangerous, but calcium and sodium are probably among the least dangerous things.” —Raymond Peat, PhD
07:20 - Children with food allergies
11:16 - Is there any reason to treat a child like a small adult?
13:14 - Food or supplements?
20:24 - Can supplements replace liver, oysters, and eggs?
24:35 - Caffeine, aspirin, niacinamide and fatty liver
30:53 - Enriching the environment and day-to-day metabolic enhancing activities
24:16 - Idealabs’ desiccated thyroid product, Tyromax
38:39 - Danny thinks desiccated thyroid should be taken orally
42:55 - Are Danny and Georgi slaves to Ray Peat?
48:24 - What Ray Peat’s work means to Danny
51:36 - Georgi, where can we find more of your work on the Internet this week?
52:30 - Info about next week’s episode

Generative Energy #23: Q&A - Weight Loss, Dating, Red Light, Authorities, Starch Diets

 
 

*I want to clarify at 35:02 that I don’t think that people who disagree with me are authoritarians. Rather, for the second half of the example, I should have emphasized that the people who were intolerant of ideas that collided with their world view were aggressive, inflexible, had an unwarranted level of certitude about what they were saying, and attacked my character when confronted with contrary evidence to their world view. I think those traits are consistent with Bob Altemeyer’s work in the book, The Authoritarians. 

“The true method of knowledge is experiment.” —William Blake

“Experience is, for me, the highest authority. The touchstone of validity is my own experience. No other person’s ideas, and none of my own ideas, are as authoritative as my experience. It is to experience that I must return again and again, to discover a closer approximation to truth as it is in the process of becoming in me. Neither the Bible nor the prophets — neither Freud nor research — neither the revelations of God nor man — can take precedence over my own direct experience. My experience is not authoritative because it is infallible. It is the basis of authority because it can always be checked in new primary ways. In this way its frequent error or fallibility is always open to correction.” —Carl Rogers

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01:18 - Should someone eliminate PUFA as fast as possible?
03:11 - Is the goal to completely inhibit lipolysis?
05:28 - An Overfeeding day when consuming low calories for weight loss?
06:25 - Spread dietary fat intake throughout the day?
07:42 - Georgi’s opinion of commercial shampoos and soaps
11:14 - Taking thyroid but the metabolism is still low
14:17 - Does fructose contribute to “hyperlipidemia”?
18:11 - Thoughts on excess urination—the role of aldosterone
20:13 - Hypothetical scenarios with HF and LF diets
22:28 - Georgi’s thoughts on autism
24:18 - Thoughts on dating from Danny and Georgi
27:59 - Overcoming cold and flu symptoms
30:50 - Thoughts on red light (cytochrome C oxidase)
33:00 - Clarifying our use of the word “authoritarian”—the initiation of force
41:09 - High-starch low-fat diets—how could so many physicians be wrong?
47:39 - Georgi, where can we find more of your work on the internet this week?
48:36 - Details on next week’s episode

Generative Energy #22: A Bioenergetic View of Heart Disease and Stroke

 
 

“The heart’s unique behavior has given cardiologists a particularly mechanical perspective on biology. If a cardiologist and an oncologist have anything to talk about, it’s likely to be about why cancer treatments cause heart failure; a cardiologist and an endocrinologist might share an interest in “cardioprotective estrogen” and “cardiotoxic obesity.” Cell physiology and bioenergetics aren’t likely to be their common interest. Each specialty has its close involvement with the pharmaceutical industry, shaping its thinking. —Heart and hormones by Ray Peat ► http://bit.ly/1p6ZDo8

“Alterations in cardiac energy metabolism can profoundly affect cardiac efficiency. Excessive use of free fatty acids has been shown to be especially important, either by decreasing the efficiency of producing ATP, or by decreasing ATP availability for contractile function.” —Impact of fatty acid oxidation on cardiac efficiency ► http://bit.ly/1p6ZvVC

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01:18 - Rising interest in heart disease and stroke
05:45 - Heart disease begins at a very young age
07:27 - What’s the role of cholesterol in heart disease?
11:13 - The heart and hormones
17:55 - What’s the role of aldosterone “the salt-retaining hormone” in heart disease?
25:38 - Blood volume, sodium, and dietary protein
30:34 - The role of endotoxin in heart disease and stroke
33:09 - Aspirin for heart disease?
38:57 - “Normal” TSH and fatal coronary heart disease
40:20 - Is heart disease a mystery?
42:13 - Where can we find more of your work, Georgi?
42:57 - Do your own research and come to your own conclusions

Generative Energy #21: Are You Listening?

 
 

01:13 - Danny’s teaching experience
03:42 - The folly of solving each other
04:48 - Pain and struggle
06:41 - Struggle leading to creation
07:36 - Carl Rogers’s work
10:35 - ‘Drive in your own lane’
11:29 - ‘Seeking authority to avoid pain’
13:18 - The listening robot
13:58 - Danny’s thinks learning is painful
14:51 - ‘So many people willing to be the final say’
15:33 - Ray’s email responses and learning on your own
18:16 - Karen’s experience with medical professionals
20:25 - What to look for in a listener
22:04 - Acceptance and belonging: ’That’s natural’
23:02 - Danny’s character armor
25:01 - Karen’s experience with rock climbing
26:34 - Therapy led to a higher degree of tolerance for others
29:27 - ‘Your passion as a metaphor for life’
30:57 - A Very Special Genie (http://bit.ly/1ota19m)
32:11 - Anecdote from Danny
36:13 - Percival myth (http://bit.ly/1otazft)