Aristotle's Radiator, or: Hair Growth in Context (Carbon Dioxide, Serotonin, and The Global Cooling of Aging)

 
There is no real difference between structure and function; they are the two sides of the same coin. If structure does not tell us anything about function, it means that we have not looked at it correctly.
— Albert Szent-Györgyi
 

Key Points:

  • Our evolutionarily advanced hot brains may induce hair growth.
  • Melanin, the protein responsible for hair pigment, traps heat, serves a vital function as a chain breaking "antioxidant," is sensitive to light and temperature, and helps regulate the differentiation and metabolism of keratinocytes.
  • Produced under the direction of sufficient thyroid function, carbon dioxide serves as a potent vasodilator promoting the flow of blood to tissues. Additionally, by enhancing the use of glucose and oxygen, carbon dioxide supports the production of energy and heat through the mitochondria in a reciprocal process.
  • Insufficient carbon dioxide production increases serotonin, which decreases mitochondrial energy metabolism, constricts the flow of blood, and reduces the temperature.
  • Serotonin increases aldosterone, prolactin, and parathyroid hormone. Aldosterone and prolactin are associated with pattern baldness. Parathyroid hormone can overload cells with calcium. An excess of intracellular calcium turns on nitric oxide. 
  • Nitric oxide may interfere with the high energy supply of stem cells needed to regenerate hair follicles. Differences in the production of nitric oxide, which is influenced by the concentration of polyunsaturated fatty acids in the tissues, may account for differences in baldness between people.
  • If a man or woman lives long enough, they will experience some degree of pattern hair loss. Early pattern baldness in males has been called a phenomenon of "premature aging." The inflammatory-stress processes of aging are stimulated by serotonin, nitric oxide, and related hormones.
  • I think thyroid, vitamin D, vitamin K2, Parmigiano-Reggiano, milk, sweet orange juice (not sour or tart), red light, DHEA, saturated fats, well-cooked white button mushrooms, dark roast coffee, salt, gelatin, anti-inflammatory antibiotics (penicillin VK, macrolides, tetracyclines), and aspirin are some easily accessible and safe interventions to increase carbon dioxide, and lower serotonin, parathyroid hormone, nitric oxide and related hormones for treating so-called "androgenic alopecia" (androgenic alopecia is not caused by androgens or genetics). Topical carbonic anhydrase inhibitors may be useful if a person has exhausted the basic therapies, with the understanding that some of them can be used in generous amounts.

Part I: Aristotle's Radiator

Something that's lost within the complex realm of discussing pattern baldness is the actual function of hair. While I plan to cover the topic in my upcoming free book, The Baldness Field, it might be nice to compile some of my thoughts here as I'm not sure when the book will be completed.

  Image : Brain weight as a function of the degree of encephalization multiplied by the basal metabolic rate. Hofman (1983)

Image: Brain weight as a function of the degree of encephalization multiplied by the basal metabolic rate. Hofman (1983)

As for the function of hair, a good place to start might be connecting the dots between the metabolic rate and the evolutionary tendency to proportionately increase the brain size in relation to body size (cephalization). For instance, M.A. Hofman found that brain weight was "a linear function of the product of cephalization and basal metabolic rate."1 (Interestingly, elephants, who have a larger degree of cephalization than humans, are extremely intelligent and can grow head hair.)

The highly evolved human brain is a locus of intense heat production and accounts for 20% of oxygen consumption in adults and 50% of oxygen consumption in children under four years of age.2 Famously, Aristotle believed that because heat rises and the scalp was blanketed with a rich vascular network, the brain was well suited to act as a radiator.3 (To Aristotle, it was clear that intelligence and sensations stemmed from the heart.)4

...The primary event required for life, even before acquiring food and water, was generating a hot brain.
— Carl V. Gisolfi and Francisco Mora. The Hot Brain: Survival: Temperature, and the Human Body. 2003

All cerebral processes are sensitive to temperature fluctuations with even a mild decrease in temperature causing inflammation.5 It appears that to protect our evolutionarily advanced hot brain, nature developed thousands of streaming mini-organs to blanket the scalp. While hair follicles have a multitude of functions ranging from sensory antennae to camouflage, the most relevant function related to the genesis of pattern baldness might be their function as dynamic insulators for the brain.

Part II: Pigment, Light, and Thermoregulation

Hair follicles are conditioned by a few different types of cells including mast cells, keratin-producing keratinocytes, collagen-producing fibroblasts, and melanin-producing melanocytes. In addition to being responsible for the color of eyes, skin, and hair, the pigment, melanin, makes a significant contribution to the hair follicle's thermal insulation by absorbing sunlight and trapping radiant heat.6,7

In aging, melanin tends to be lost from hair,8 and in 2001 Paus and Tobin found that gray and white hair follicles went through morphological changes to compensate for the reduced thermal insulatory properties of melanin.9

In an attempt to explain the loss of melanin with aging, the "free radical theory of graying" was introduce by Arck et al. in 2006.10 In their article, the group detailed that melanocytes were particularly sensitive to reductive stress — or a reduction-oxidation balance that favored the reduced, electron-carrying form of nicotinamide adenine dinucleotide, NADH, over the oxidized (electron-free) form, NAD+ that is mainly produced in the mitochondria. It appears that when the redox balance shifts towards reduction, electrons are excessively donated to melanin, which has an "antioxidant" function, causing the gradual loss of pigment over time.

  Image : Lennart Nilsson's A Child is Born

Image: Lennart Nilsson's A Child is Born

Besides thyroid hormone that regulates a cell's defenses against free radical damage helping to maintain the oxidized NAD+/NADH ratio,11 light and temperature appear to be central to melanocyte health. For example, in 1998, Iyenger et al. found that light activated melanocytes, causing the group to call hair follicles "photosensitive UV receptors." Even though the melanocytes within the hair follicle are not directly exposed to UV light in the basal layer of the hair follicle, the communication system between keratinocytes and melanocytes orients itself towards the UV exposure acting as an "efficient fiber-optic system" that transmutes light.12

Similar to light, the melanocyte's synthesis of melanin appears to be temperature-dependent as Kim et al. discovered in 2003. While subjecting melanocytes to hotter temperatures increased melanin synthesis, the group found that lower temperatures induced hypopigmentation and the steady drop off of melanin production.13 In addition to the exogenous heat from the environment, the hair follicle's mitochondrial metabolism strongly contributes to overall heat production:

"In contrast to glycolysis and glutaminolysis, intramitochondrial redox processes strongly contribute to the overall heat production. Therefore, changes in the measured heat rate indicate an increase/decrease of the electron transfer rate in the mitochondrial chain [of hair follicles]." Vidali, et al. (2013)

Taken together, it appears that a warm sunny climate along with our hot brains induces the production of melanin. In return, melanin traps exogenous radiant heat helping to insulate the head. Moreover, melanin serves an important role in regulating hair follicle growth by buffering reductive stress,14 suggesting that excessive free radical damage, a lack of light, or a reduced body temperature might not only be involved in the development of white and gray hair but also ordinary baldness.

Part III: Carbon Dioxide, Serotonin, and The Global Cooling of Aging

The temperature of any organ is dependent on the blood it's receiving, which delivers sugar, oxygen, and other nutrients to cells to make energy and carbon dioxide through the mitochondria. In return, carbon dioxide functions as a potent vasodilator, widening the blood vessels and increasing the delivery of nutrients to tissues in a reciprocal process.15,16,17 Additionally, similar to melanin, carbon dioxide is also an antioxidant or an electron withdrawing agent — favoring the oxidized NAD+/NADH redox balance.18,19,20

Carbon dioxide (CO2) is generated mainly through the Krebs cycle as a result of glucose oxidation and serves as a potent vasodilator...
— Kashiba M., et al. From O2 to H2S: a landscape view of gas biology (2002)

In stress and aging, there is a tendency to produce proportionately more lactic acid from glucose that carbon dioxide, affecting the extra- and intracellular pH of cells. As lactic acid displaces carbon dioxide in the cell, the intracellular pH, which is low under the influence of carbon dioxide keeping cells slightly acidic, is increased.21-26

  Image : Cerebral hypoperfusion in a mouse.

Image: Cerebral hypoperfusion in a mouse.

In response to the increased pH, serotonin, which is produced primarily in the intestine27 in proportion to the amount of irritation28 and bacteria,29 is liberated from blood platelets and other cells (where it's inactive) into the blood.30-33

Consistent with its essential role in mammalian hibernation, serotonin sends an organism into a state of torpor by suppressing mitochondrial energy metabolism,34 constricting the flow of blood,35 and reducing the temperature.36

For example, upon injecting serotonin into rats, Aleksandrin et al. found that "serotonin rapidly decreased local cerebral blood flow (by almost 30%)..."37 In another experiment, a serotonin injection "induced a dramatic fall in [the] brain ATP level" followed by a "marked increase in [brain] lactate content."38

Two other hormones involved in pattern baldness, aldosterone, which is released from the adrenal glands, and the pituitary hormone, prolactin, are increased by serotonin.39-42 Additionally, serotonin increases the parathyroid gland's release of parathyroid hormone ( PTH ) — that in excess, can overload cells with calcium.43 For instance, under the influence of PTH, soft tissues such as the arteries tend to accumulate calcium leading to arterial stiffness.44 In 2014, Agac et al. noted that pattern baldness "might be an indicator of arterial stiffness in asymptomatic young adults."45 Moreover, arterial stiffness may precede and predict the future development of hypertension,46 which is "strongly associated" with developing pattern baldness.47

In Fujita's 1991 paper, Calcium, parathyroids, and aging, he says "all cell death is characterized by an increase of intracellular calcium..." To Fujita, aging is in the background of diseases such as hypertension, arteriosclerosis, diabetes, and dementia, which all involve inappropriate calcium accumulation.48

screenshot.png

A few years later, McCann published his paper, The nitric oxide hypothesis of aging, which compliments Fujita's thoughts, as intracellular calcium turns on nitric oxide, suppressing energy metabolism, and accelerating the age of any tissue.49

While there isn't much research on the role of nitric oxide specifically in pattern baldness, Trüeb noted that stressed hair follicles produce nitric oxide,50 which can damage the stem cells necessary for hair follicle regeneration:

"...Keratinocytes themselves may respond to physicochemical stress from UVR, besides irritants and pollutants, by producing radical oxygen species and nitric oxide and by releasing proinflammatory cytokines, eventually leading to injury of the putative site of follicular stem cells in the superficial portion of the hair follicle." Trüeb (2003)

More specifically, nitric oxide blocks mitochondrial energy metabolism, which Tang et al.51 found to be essential for "the high energy supply" needed for the differentiation of stem cells into hair follicles:

"Upon hair follicle stem cells differentiation, mitochondria are elongated with more abundant cristae and show higher activity , accompanying with activated aerobic respiration in differentiated cells for higher energy supply. Also, dysfunction of mitochondrial respiration delays hair regeneration upon injury." Tang, et al. (2016)

In addition to blocking the mitochondrial energy metabolism, nitric oxide activates the enzyme that produces prostaglandins from the polyunsaturated fat, arachidonic acid.52,53 A type of prostaglandin, prostaglandin D2, was found to be elevated in the balding portion of men's scalps in 2012.54

I think the polyunsaturated fats and the intensity of the nitric oxide production to some degree explain the disparity of baldness between individuals. For example, a person's fat tissue reflects the type of dietary fat they've been consuming over a lifetime,55 and the presence of the polyunsaturated fats was found to be a "critical signal switching the regulation of the 'nitric oxide tone' from physiological to pathological."56

  Image : Lennart Nilsson's A Child is Born

Image: Lennart Nilsson's A Child is Born

As for measuring the amount of nitric oxide in the system, the body temperature might be a good estimate. For example, in 2014 Pereira, et al. found that "the lower the body temperature, the higher the concentrations of nitric oxide."57 Nitric oxide rises when the thyroid function is suppressed,58,59 and the outstanding feature of low thyroid function is a reduced body temperature and a slow heart rate.60,61,62

The brain temperature correlates well with the body temperature, although it is often slightly higher.63 While there have been a few investigations into the specific temperature of the balding scalp, I haven't seen any experiments that measured the scalp temperature over the course of a day, which would be needed to represent the natural circadian rhythm of the body temperature.

Part IV: It's Hard to Stay Oxidized in a Reducing World

  Image : Lennart Nilsson's A Child is Born

Image: Lennart Nilsson's A Child is Born

I think the realization that hair is part of an integrated system responding to the environment could potentially shift the conversation away from the tendency to categorize pattern baldness as something people have or don't have. Another way of looking at might be that everyone is balding at different rates as a consequence of aging and the accumulation of stressors over a lifetime. For example, in 1996 Guarrera et al.64 said:

"As androgenic alopecia is a very common condition and displays a large variety in the rate of progression, apparently normal people may be in fact in the early stages of baldness." Guarrera, et al. (1996)

Similarly, in Trueb's 2001 write-up he said:

"...Aging did not appear to follow a perfectly regular course over time. Periods of stability, or even partial remission, alternated with periods of more marked evolution, perhaps reflected the influence of individual factors such as the subjects general health, life-style, and risk factors for accelerated aging." Trueb et al. (2001)

If a person lives long enough, they will most likely experience some degree of so-called male-pattern baldness, and if pattern baldness is experienced in early age, it is a phenomenon of "accelerated" or "premature aging." I think this idea is crystalized by the phenomenon of neonatal pattern baldness,65 which was mentioned by James B. Hamilton in his original 1951 paper on pattern baldness:

"Soon after birth, a marked alopecia develops in many babies in the same areas that become bald in adult men, that is, in the frontoparietal and frontal areas, and even over the tonsure. This process continues for weeks or months and occurs in both sexes. While hairs are still being lost, new hairs appear on the surface of the scalp and, by the end of the first or second year, most children have a completely hairy scalp...” J.B. Hamilton (1951)

Previously, I've speculated that neonatal pattern hair loss was related to increases in prolactin upon exposure to the oxygen-rich environment upon delivery. Something I overlooked was that newborns can experience hypothermia upon delivery,66 which adds to the cumulative stress of being born. The fact that newborns regenerate their head hair, I think, represents their robust metabolism slightly before the onslaught of environmental factors that lead to the life-long decline of the rate of metabolism.

Often, people ask me if their pattern baldness can be reversed. I think the infant overcoming pattern baldness is evidence that it always can be. Although, the intervention has to be proportionally greater than the degeneration that has already taken place. For example, a young person who is losing hair might be able to remedy it by eating more calcium and supplementing vitamins D and K2. An older person might have to quit their job, get a divorce, change their nutrition, take thyroid, get their vitamin D level up, and move to Hawaii.

  Image : Lennart Nilsson's A Child is Born

Image: Lennart Nilsson's A Child is Born

Part of the problem with discussing the complex biochemical web of pattern baldness and the many problems associated with it is the lingering mind virus of finasteride. The 1997 release of finasteride has convinced so many people that not only are bad genes and "male" hormones responsible for pattern baldness but that the problem can be solved with a single substance. Massively contributing to this mind virus is the confabulatory way people talk about pattern baldness on the Internet, i.e., "I saw a homeless person yesterday with hair, and he obviously doesn't subscribe to your dietary recommendations, therefore you're an idiot!" Just to clarify, I think it's the physiology of the person regulating the hair growth, and an empirical approach would be to measure the blood of said homeless man with great head hair. A hypothetical finding might be that a wealthy-balding-business man was objectively more stressed than a homeless man with hair.

I mentioned that the flow of blood to the scalp is impaired in this article, and over the last few years, there's been a resurgence in the idea that massage is a valid and effective therapy for alleviating pattern baldness. While it is a bit difficult to quantify as I imagine everyone's massage technique is different — and I would think that just becoming proactive in some way can help break a person out of the vicious cycle of stress and inflammation — I think when massaging helps it might be from reducing the concentration of prostaglandins,67-68 or inducing an injury, which can sometimes lead to regeneration.69

Just to be completely clear, I've received many, many emails from people who have said that vigorously massaging their scalps made their hair loss worse, and for what it's worth, I'm not sure how safe kneading inflamed scalp tissue is. My biggest concern with a 'massage-centric approach' is that it doesn't address the systemic nature of pattern baldness and the potential serious health problems down the road (e.g., heart disease, prostate cancer).70,71 Lastly, some of the rational used to justify the need for mechanical intervention can be accomplished by increasing the thyroid function and carbon dioxide (i.e., reducing fibrosis).72,73

  Image : "Scalp of 78-year-old white man bald for 30 years. Top, Clinically scalp appears completely bald, except at sides, but close inspection shows barely perceptible fuzz of tiny, downy hairs. Bottom, Same scalp after nine months of topical testosterone. Fine lanugo-type hairs have become coarser and longer. Only follicles which had not completely involuted responded to testosterone, probably no more than 10% of follicles." Papa, C.M. and Kligman, A.M.  Stimulation of Hair Growth by Topical Application of Androgens . JAMA. 1965;191(7):521-525.

Image: "Scalp of 78-year-old white man bald for 30 years. Top, Clinically scalp appears completely bald, except at sides, but close inspection shows barely perceptible fuzz of tiny, downy hairs. Bottom, Same scalp after nine months of topical testosterone. Fine lanugo-type hairs have become coarser and longer. Only follicles which had not completely involuted responded to testosterone, probably no more than 10% of follicles." Papa, C.M. and Kligman, A.M. Stimulation of Hair Growth by Topical Application of Androgens. JAMA. 1965;191(7):521-525.

Painting a more holistic picture of pattern baldness that includes the function of hair as insulation for a hot brain in relation to the intensity of the systemic energy production hopefully allows for a better understanding of how pattern baldness develops along with a greater level of confidence for experimentation. Unfortunately, there are many things in the environment working against the balding individual including the massive subculture that has an ideological commitment to enforcing the genetic-androgen hypothesis.

This life is an ultimately losing attempt to remain oxidized in a reducing world. However, I think the basic therapies: thyroid, aspirin, vitamin D, vitamin K2, DHEA, sugars, gelatin, well-cooked white button mushrooms, sweet orange juice (not tart or sour), coffee with meals, salt, antibiotics (penicillin VK, erythromycin, minocycline), saturated fats, and red light — by helping to increase carbon dioxide, and lower serotonin, parathyroid hromone, nitric oxide, and related hormones — can greatly increase the quality of life, restore hair growth, and be protective against the long list of ailments associated with pattern baldness. If those interventions were not enough, keeping in mind that some of the therapies have extensive ceilings (e.g., grains of thyroid, grams of aspirin, milligrams of vitamin K2, etc.), experimenting with topical carbonic anhydrase inhibitors (e.g., T3, testosterone, progesterone + DHEA, etc.) might be worthwhile.

References

  1. Hofman, M.A. Energy metabolism, brain size and longevity in mammals. Q Rev Biol. 1983 Dec;58(4):495-512. "Brain weight was found to be a linear function of the product of encephalization and basal metabolic rate. The oxygen consumption of the brain is proportional to both encephalization and body weight according to. The ratio of metabolic rate in the cerebral cortex to that in the brain as a whole depends solely upon the degree of encephalization and is independent of the size of the animal. The maximum potential lifespan of a mammal was found to be proportional to the product of its degree of encephalization and the reciprocal of its metabolic rate per unit weight."
  2. Wang, H., et al. Brain temperature and its fundamental properties: a review for clinical neuroscientists. Front Neurosci. 2014 Oct 8;8:307. "The brain comprises only 2% of human body mass, yet accounts for 25% of the body’s total glucose utilization and 20% of oxygen consumption (Squire, 2012). It is a metabolically “demanding” organ with intense heat production. Almost all cerebral processes are sensitive to temperature fluctuations. With its energy expenditure efficiency being highly temperature-dependent, the brain’s thermal regulatory capacity may define its anatomical and physiological architecture and constrain its processing capacity. In this paper, we review the state of our present knowledge concerning brain temperature. Typically, global brain temperature readings assessed in resting clinical patients are congruent with patient body temperature (brain 36.9 ± 0.4◦C, rectal 36.9 ±0.6◦C); differences are noted when brain regions are assessed individually."
  3. Charles G. Gross. Aristotle on the Brain. First Published July 1, 1995. Aristotle argued that the heart was the center of sensation and movement. By contrast, his predecessors, such as Alcmaeon, and his contemporaries, such as the Hippocratic doctors, attributed these functions to the brain.
  4. Pearsall, P., et al. Changes in heart transplant recipients that parallel the personalities of their donors. Integr Med. 2000 Mar 21;2(2):65-72. "Two to 5 parallels per case were observed between changes following surgery and the histories of the donors. Parallels included changes in food, music, art, sexual, recreational, and career preferences, as well as specific instances of perceptions of names and sensory experiences related to the donors (e.g., one donor was killed by a gunshot to the face; the recipient had dreams of seeing hot flashes of light in his face). The incidence of recipient awareness of personal changes in cardiac transplant patients is unknown. The effects of the immunosuppressant drugs, stress of the surgery, and statistical coincidence are likely insufficient to explain the findings. The plausibility of cellular memory, possibly systemic memory, is suggested.doctors, attributed these functions to the brain."
  5. Matsui, T, et al. Mild hypothermia promotes pro-inflammatory cytokine production in monocytes. J Neurosurg Anesthesiol. 2006 Jul;18(3):189-93. "This study demonstrates that mild hypothermia affects the balance of cytokines produced by monocytes, leading to a pro-inflammatory state." — Swinyard, E.A., and Toman, J.E. Effects of alterations in body temperature on properties of convulsive seizures in rats. Am J Physiol. 1948 Aug;154(2):207-10.
  6. Kowichi Jimbow. Formation, Chemical Composition and Function of Melanin Pigments. Biology of the Integument pp 278-292 (1984) "Melanin pigmentation ofthe skin and hair may be associated with... thermoregulation by enhancement of absorption of solar radiation..."
  7. Tobin, D.J., and Paus, R. Graying: gerontobiology of the hair follicle pigmentary unit. Exp Gerontol. 2001 Jan;36(1):29-54. "Another conundrum is the fact that black scalp hair predominates in primates and humans living in tropical climes despite that fact that melanin in skin and hair acts as a thermal insulator by trapping radiant heat."
  8. Ortonne, J.P. Pigmentary changes of the ageing skin. Br J Dermatol. 1990 Apr;122 Suppl 35:21-8. "In subjects older than 25-30 years the number of enzymatically active melanocytes detectable by the dopa reaction decreases by about 10-20% per decade, with exposed skin having approximately twice as many pigment cells as unexposed skin. Chronic exposure to sunlight may stimulate the epidermal melanocyte system rather than accelerating chronological ageing." "Greying of the hair is due to progressive loss of melanocytes from the hair follicles."
  9. Tobin, D.J., and Paus, R. Graying: gerontobiology of the hair follicle pigmentary unit. Exp Gerontol. 2001 Jan;36(1):29-54. "An evolutionary basis for the increased medulla formation (and particularly its subsequent collapse) in senile white hair may reflect the enhanced insulation provided by these hairs which would confer an important benefit for temperature regulation in many animals. In this way, it may compensate for the loss the sunlight-absorbing (and thus heat-trapping) properties of melanized dark hair as gray and white reflects much of the incident radiation." "Another conundrum is the fact that black scalp hair predominates in primates and humans living in tropical climes despite that fact that melanin in skin and hair acts as a thermal insulator by trapping radiant heat." "A recent study reported that individuals with premature canities (with no other identifiable risk factors) were 4 times more likely to develop osteopenia than individuals without canities. A subsequent study found that people who grayed before their 20shas lower bone mineral density compared to those who grayed later. There was also a significant correlation with familial osteoporosis. It may be concluded that premature graying could account for a small fraction of the variance in bone mineral density within the population."
  10. Arck, P.C., et al. Towards a "free radical theory of graying": melanocyte apoptosis in the aging human hair follicle is an indicator of oxidative stress induced tissue damage. FASEB J. 2006 Jul;20(9):1567-9. Oxidative stress is generated by a multitude of environmental and endogenous challenges such as radiation, inflammation, or psychoemotional stress. It also speeds the aging process. Graying is a prominent but little understood feature of aging. Intriguingly, the continuous melanin synthesis in the growing (anagen) hair follicle generates high oxidative stress. We therefore hypothesize that hair bulb melanocytes are especially susceptible to free radical-induced aging." "We conclude that oxidative stress is high in hair follicle melanocytes and leads to their selective premature aging and apoptosis. The graying hair follicle, therefore, offers a unique model system to study oxidative stress and aging and to test antiaging therapeutics in their ability to slow down or even stop this process."
  11. Antipenko, A.Ye., and Antipenko, Y.N. Thyroid hormones and regulation of cell reliability systems. Adv Enzyme Regul. 1994;34:173-98.
  12. 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.”
  13. Kim, D.S., et al. Temperature regulates melanin synthesis in melanocytes. Arch Pharm Res. 2003 Oct;26(10):840-5. "Our results show that melanin synthesis is reduced in a temperature-dependent manner, and that tyrosinase activity correlates with melanin content at each temperature." "...low temperature induced hypopigmentation."
  14. Wood, J.M., Jimbow, K., Boissy, R.E., Slominski, A., Plonka, P.M., Slawinski, J., Wortsman, J., Tosk, J. What's the use of generating melanin? Exp Dermatol. 1999 Apr;8(2):153-64. "In addition, melanin putatively protects the recipient keratinocyte from the potential ROS generated in this very metabolically active cell." "We have proposed that melanized or melanizing melanosomes can act as ‘'regulatory packages’' that are sent to keratinocytes in order to regulate their differentiation level and metabolic status"
  15. Brzecka, A. Role of hypercapnia in brain oxygenation in sleep-disordered breathing. Acta Neurobiol Exp (Wars). 2007;67(2):197-206. "CO2 increases oxygen uptake by its influence on the regulation of alveolar ventilation and ventilation-perfusion matching, facilitates oxygen delivery to the tissues by changing the affinity of oxygen to hemoglobin, and increases cerebral blood flow by effects on arterial blood pressure and on cerebral vessels. Recent clinical studies show improved brain oxygenation when hypoxia is combined with hypercapnia. Anti-inflammatory and protective against organ injury properties of CO2 may also have therapeutic importance. These biological effects of hypercapnia may improve brain oxygenation under hypoxic conditions. This may be especially important in patients with severe OSA syndrome."
  16. Djurberg, H.G., et al. Enhanced catheter propagation with hypercapnia during superselective cerebral catherisation. Neuroradiology [01 Jul 1998, 40(7):466-468] "Carbon dioxide, a most potent cerebral vasodilator..."
  17. Kashiba, M., et al. From O2 to H2S: a landscape view of gas biology. The Keio Journal of Medicine [01 Mar 2002, 51(1):1-10] "Carbon dioxide (CO2) is generated mainly through the Krebs cycle as a result of glucose oxidation and serves as a potent vasodilator..."
  18. Skoumalová, A., et al. Hypercapnia protects erythrocytes against free radical damage induced by hypoxia in exposed rats. Cell Biochem Funct. 2008 Oct;26(7):801-7. "These experiments suggest that the protective effect of hypercapnia might consist in direct interaction of CO(2) with free radical processes."
  19. Baev, V.I., et al. [The unknown physiological role of carbon dioxide]. Fiziol Zh Im I M Sechenova. 1995 Feb;81(2):47-52. "In rats adapted to hypoxia, in gradual increase of CO and decrease in monosialogangliosides, were shown as well as insufficient accumulation of the lipid peroxidation products. The data suggests that carbon dioxide is a natural element of the organism antioxidant defence system.
  20. Boljevic, S., et al. [Carbon dioxide inhibits the generation of active forms of oxygen in human and animal cells and the significance of the phenomenon in biology and medicine]. Vojnosanit Pregl. 1996 Jul-Aug;53(4):261-74. “...It was established that CO2 led to the better coordination of oxidation and phosphorylation and increased the phosphorylation velocity in liver mitochondria."
  21. Barrie Phypers and JM Tom Pierce. Lactate physiology in health and disease. 2006. "Lactate concentrations directly reflect cellular hypoxia." "Endogenous catecholamine release attempts to support the circulation but will also increase glycolysis and lactate formation." "Failure of oxidative mechanisms can affect both production and clearance of lactate." "Glycolysis, gluconeogenesis and pyruvate conversion to and from lactate are linked with NAD+ and NADH." "Lactate concentrations >5 mmol litre−1 with severe metabolic acidosis predicts high mortality." "The normal plasma lactate concentration is 0.3–1.3 mmol litre−1."
  22. Schwartz, L., et al. The Warburg Effect and the Hallmarks of Cancer. Anticancer Agents Med Chem. 2017;17(2):164-170. "The decreased oxidative phosphorylation leads to impairment in CO2 levels inside and outside the cell, with increased intracellular alkalosis and contribution of carbonic acid to extracellular acidosis-mediated by at least two cancer-associated carbonic anhydrase isoforms. The increased intracellular alkalosis is a strong mitogenic signal, which bypasses most inhibitory signals. Mitochondrial disappearance (such as seen in very aggressive tumors) is a consequence of mitochondrial swelling, itself a result of decreased ATP concentration. The transmembrane pumps, which extrude, from the mitochondria, ions, and water, are ATP-dependant. Therapy aiming at increasing both the number and the efficacy of mitochondria could be very useful."
  23. Folgering, H. The pathophysiology of hyperventilation syndrome. Monaldi Arch Chest Dis. 1999 Aug;54(4):365-72."Hyperventilation is defined as breathing in excess of the metabolic needs of the body, eliminating more carbon dioxide than is produced, and, consequently, resulting in respiratory alkalosis and an elevated blood pH." "The spectrum of symptoms ascribed to hyperventilation syndrome is extremely broad, aspecific and varying. They stem from virtually every tract, and can be caused by physiological mechanisms such as low Pa, CO2, or the increased sympathetic adrenergic tone…"
  24. Dager, S.R., et al. Proton magnetic resonance spectroscopy investigation of hyperventilation in subjects with panic disorder and comparison subjects. Am J Psychiatry. 1995 May;152(5):666-72. "Panic disorder subjects exhibited significantly greater rises in brain lactate than comparison subjects in response to the same level of hyperventilation." "This increase in brain lactate may result from decreased cerebral blood flow due to hypocapnia..."
  25. Curely, G., et al. Bench-to-bedside review: carbon dioxide. Crit Care. 2010;14(2):220. "Hypocapnia [low carbon dioxide] remains a common - and generally underappreciated - component of many disease states, including early asthma, high-altitude pulmonary edema, and acute lung injury.” "Hypercapnia may play a beneficial role in the pathogenesis of inflammation and tissue injury…” "In contrast, hypocapnia may be a pathogenic entity in the setting of critical illness."
  26. Stacpoole, P.W., et al. Lactic acidosis and other mitochondrial disorders. Metabolism. 1997 Mar;46(3):306-21. "Lactic acidosis is a common and readily apparent biochemical marker for mitochondrial dysfunction greatly compromise aerobic cellular metabolism and energetics." "Overlooked, however, is that lactic acidosis is frequently linked to a fundamental disturbance of mitochondrial function, for which hyperlactatemia is a marker." "Moreover, similar or identical mitochondrial pathology contributes both to the physiology of aging and to several diseases of metabolic integration in which the efficient conversion of substrate fuel into energy is skewed, in part, by acquired or hereditary abnormalities of mitochondrial oxidative metabolism." "Such a concept is predicated on the hypothesis that defective mitochondrial energy metabolism cuts across disease strata to provide a common pathogenetic denominator, albeit variably expressed as diverse clinical syndromes." "In addition, the usual mendelian genetic paradigm, in which the presence of a single gene defect yields a precisely predictable inheritance pattern, is inconsistent with the pathology of aging and many degenerative diseases of mid- to late-life.”
  27. Constance R. Martin. Endocrine Physiology. 1985. "Approximately 98% of total 5-HT is found outside the central nervous system. The blood platelets and gastrointestinal tract account for 95%, and serotonin is a component of both central and peripheral mast cells."
  28. Spiller, R. Serotonin, inflammation, and IBS: fitting the jigsaw together? J Pediatr Gastroenterol Nutr. 2007 Dec;45 Suppl 2:S115-9. "Clinical conditions with an inflammatory basis, such as coeliac and Crohn disease, also are characterised by excess postprandial serotonin release. Several studies report evidence of low-grade inflammation in IBS with diarrhoea. However, reliable markers of low-grade inflammation that may predict response to serotonin antagonists or other anti-inflammatory agents remain a goal for future research."
  29. Yano, J.M. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis Cell. 2015 Apr 9;161(2):264-76. "The gastrointestinal (GI) tract contains much of the body's serotonin (5-hydroxytryptamine, 5-HT), but mechanisms controlling the metabolism of gut-derived 5-HT remain unclear. Here, we demonstrate that the microbiota plays a critical role in regulating host 5-HT. Indigenous spore-forming bacteria (Sp) from the mouse and human microbiota promote 5-HT biosynthesis from colonic enterochromaffin cells (ECs), which supply 5-HT to the mucosa, lumen, and circulating platelets. Importantly, microbiota-dependent effects on gut 5-HT significantly impact host physiology, modulating GI motility and platelet function. We identify select fecal metabolites that are increased by Sp and that elevate 5-HT in chromaffin cell cultures, suggesting direct metabolic signaling of gut microbes to ECs. Furthermore, elevating luminal concentrations of particular microbial metabolites increases colonic and blood 5-HT in germ-free mice. Altogether, these findings demonstrate that Sp are important modulators of host 5-HT and further highlight a key role for host-microbiota interactions in regulating fundamental 5-HT-related biological processes."
  30. Shen., et al. Aspirin attenuates pulmonary arterial hypertension in rats by reducing plasma 5-hydroxytryptamine levels. Cell Biochem Biophys. 2011 Sep;61(1):23-31. "Because 99% of whole-blood 5-HT is contained in platelets, the plasma 5-HT level is dependent upon 5-HT released from platelets."
  31. Constance R. Martin. Endocrine Physiology. 1985. "Blood platelets do not synthesize serotonin, but they take it up from the cells of the gut and they store it. They release it when small breaks appear in the blood vessels, and the consequent stimulation of smooth muscle of the vascular system contributes to the hemostasis."
  32. Mahler, D.J., and Humoller, F.L. The influence of serotonin on oxidative metabolism of brain mitochondria. Proc Soc Exp Biol Med. 1968 Apr;127(4):1074-9. "It was found that both phosphorus and oxygen uptake were inhibited by the addition of serotonin." "These findings support the hypothesis that serotonin could impede brain function by inhibition of energy producing reactions."
  33. Inoue, Y., and Kaneko, T. [Effects of pH on the endocrine system and metabolism]. Nihon Rinsho. 1992 Sep;50(9):2124-8. "Changes in extra- and intracellular pH affect metabolic states and hormone responses. In general, alkalosis stimulates and acidosis inhibits glycolysis although the relationship is not a simple one. 6-phosphofructo-1-kinase, a rate limiting enzyme in glycolysis, seems to be activated directly by a rise in pH. Alkalosis stimulates the production of pyruvic acid and lactic acid. Citric acid cycle is stimulated in alkalosis and hexose monophosphate shunt pathway is facilitated in acidosis. Acid-base disorders affect the insulin secretion and insulin action. In acidosis, insulin action in the target tissues is reduced. Other hormones, including parathormone, renin-angiotensin-aldosterone system, and adrenocorticotropine, respond to the changes in pH."
  34. Mahler, D.J., and Humoller, F.L. The influence of serotonin on oxidative metabolism of brain mitochondria. Proc Soc Exp Biol Med. 1968 Apr;127(4):1074-9. "It was found that both phosphorus and oxygen uptake were inhibited by the addition of serotonin." "These findings support the hypothesis that serotonin could impede brain function by inhibition of energy producing reactions."
  35. Cohen, Z., et al. Serotonin in the regulation of brain microcirculation. Prog Neurobiol. 1996 Nov;50(4):335-62. "Manipulation of brainstem serotonin (5-HT) raphe neurons induces significant alterations in local cerebral metabolism and perfusion. The vascular consequences of intracerebrally released 5-HT point to a major vasoconstrictor role, resulting in cerebral blood flow (CBF) decreases in several brain regions such as the neocortex."
  36. Popova, N.K., and Voitenko, N.N. Brain serotonin metabolism in hibernation. Pharmacol Biochem Behav. 1981 Jun;14(6):773-7. "It has been shown that notwithstanding 2-fold decreased monoamine oxidase (MAO) activity in brain of hibernating ground squirrels (Citellus erythrogenys major, Brandt), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels in most of the brain areas studied were not significantly different from the ones in active ground squirrels. However, marked changes were revealed in 5-HT and 5-HIAA brain level in entering hibernation (body temperature 11-9 degrees C) and arousing (body temperature 22 degrees C) animals. In entry into hibernation an increase in brain 5-HT, decrease in 5-HIAA level and lowered MAO activity was found. In arousal from hibernation 5-HT was decreased, 5-HIAA was increased and MAO activity was found to be increased to the level of the active ground squirrels."
  37. Aleksandrin, V.V., et al. Effect of serotonin on respiration, cerebral circulation, and blood pressure in rats. Bull Exp Biol Med. 2005 Jan;139(1):64-7. "Serotonin rapidly decreased local cerebral blood flow (by almost 30%) and blood pressure."
  38. Koren-Schwartzer, N., et al. Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of plasma hemoglobin; the protective action of calmodulin antagonists. Gen Pharmacol. 1994 Oct;25(6):1257-62. "1. Injection of serotonin (5-hydroxytryptamine) to rats, induced a dramatic fall in brain ATP level, accompanied by an increase in P(i). Concomitant to these changes, the activity of cytosolic phosphofructokinase, the rate-limiting enzyme of glycolysis, was significantly enhanced. Stimulation of anaerobic glycolysis was also reflected by a marked increase in lactate content in brain. 2. Brain glucose 1,6-bisphosphate level was decreased, whereas fructose 2,6-bisphosphate was unaffected by serotonin. 3. All these serotonin-induced changes in brain, which are characteristic for cerebral ischemia, were prevented by treatment with the calmodulin (CaM) antagonists, trifluoperazine or thioridazine. 4. Injection of serotonin also induced a marked elevation of plasma hemoglobin, reflecting lysed erythrocytes, which was also prevented by treatment with the CaM antagonists. 5. The present results suggest that CaM antagonists may be effective drugs in treatment of many pathological conditions and diseases in which plasma serotonin levels are known to increase.
  39. 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."Aldosterone antagonists may exert a dual beneficial effect in hypertensive patients with AGA by controlling BP and preventing progression of the alopecia, especially if taken in the early stages. Spironolactone, which exerts antiandrogenic action, is administered for the treatment of AGA and may be useful for reducing blood aldosterone concentrations, but its chronic use can produce adverse effects in men, including gynaecomastia or impotence. Hence, there is a need for new selective antagonists of aldosterone receptors to treat AGA in hypertensive patients without causing antiandrogenic side- effects."
  40. 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, LH, 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.”
  41. Shenker, Y., et al. Central serotonergic stimulation of aldosterone secretion. J Clin Invest. 1985 Oct;76(4):1485-90. "We conclude that central serotonergic pathways are involved in the stimulation of aldosterone induced by administration of 5HTP. This mechanism may be an important etiologic factor in the hypersecretion of aldosterone that occurs in patients with idiopathic aldosteronism."
  42. Friesen, H., and Hwang P. Human prolactin. Annu Rev Med. 1973;24:251-70. "A second regulatory system for controlling prolactin secretion has been proposed because infusions of L-tryptophan but not other amino acids caused a marked increase in prolactin secretion without increasing TSH levels. Prior treatment with methysergide maleate blocked these effects of L-tryptophan sug­gesting that they depend upon conversion of tryptophan to serotonin."
  43. Zimmerman, D., et al. Serotonin stimulates adenosine 3',5'-monophosphate accumulation in parathyroid adenoma. J Clin Endocrinol Metab. 1980 Dec;51(6):1274-8. "The present observations demonstrate that parathyroid adenoma tissue has a high content of serotonin, and serotonin stimulates cAMP accumulation in this tissue. Since cAMP acts as a mediator of parathyroid hormone (PTH) release, our results suggest that serotonin could be one of the factors regulating PTH secretion and/or contributing to PTH hypersecretion in various forms of primary hyperparathyroidism."
  44. Rubin, M.R., et al. Arterial stiffness in mild primary hyperparathyroidism. J Clin Endocrinol Metab. 2005 Jun;90(6):3326-30. "The diagnosis of primary hyperparathyroidism was therefore an independent predictor of increased AIx, an early measure of arterial stiffness, and the increase was associated with evidence of more active parathyroid disease."
  45. Agac, M.T., et al. Androgenetic alopecia is associated with increased arterial stiffness in asymptomatic young adults. J Eur Acad Dermatol Venereol. 2014 Mar 14. "We concluded that, AGA might be an indicator of arterial stiffness in asymptomatic young adults." "As a second matter, IR or metabolic syndrome may explain the link between arterial stiffness and AGA. Finally, the association between arterial stiffness and AGA could be established through hypertension. It is well-known that, arterial stiffness may precede and predict future development of hypertension."
  46. Dernellis, J., and Panaretou, M. Aortic stiffness is an independent predictor of progression to hypertension in nonhypertensive subjects. Hypertension. 2005 Mar;45(3):426-31.
  47. Ahouansou, S., et al. Association of androgenetic alopecia and hypertension. Eur J Dermatol. 2007 May-Jun;17(3):220-2.  "Two hundred and fifty Caucasian men aged 35-65 years were consecutively recruited by 5 general practitioners (50 per practitioner)." "Hypertension was strongly associated to androgenetic alopecia (p < 0.001)." "Other variables (diabetes mellitus, hyperlipidemia, smoking, treatment) were not associated with androgenetic alopecia. We were limited by a relatively small study sample but in this study androgenetic alopecia was strongly associated with hypertension. Association of androgenetic alopecia and hyperaldosteronism warrants additional studies. The use of specific mineralocorticoid receptor antagonists could be of interest in the treatment of androgenetic alopecia."
  48. Fujita, T. Calcium, parathyroids and aging. Contrib Nephrol. 1991;90:206-11. "Calcium is unique in its distribution in living organisms with an extremely high hard and soft tissue and extra-intracellular concentration gradient. Calcium deficiency through stimulating parathyroid hormone secretion tends to blunt such a difference by paradoxically increasing the calcium concentration in the soft tissue and intracellular compartment. Since aging is associated with the progressive aggravation of calcium deficiency, such blunting also progresses with aging. The dysfunction, damage and death of cells occurring in all diseases is always associated with a blunting of the extra- and intracellular calcium components. Calcium supplement especially with highly biologically available active absorbable calcium, was associated with the suppression of parathyroid hormone secretion and the normalization of a such blunting of intercompartmental distribution of calcium examples in hypertension and diabetes mellitus with evident improvement of clinical manifestations and laboratory tests.” "All cell death is characterized by an increase of intracellular calcium..." "Increase of cytoplasmic free calcium may therefore be called 'the final common path' of cell disease and cell death. Aging as a background of diseases is also characterized by an increase of intracellular calcium. Diseases typically associated with aging include hypertension, arteriosclerosis, diabetes mellitus and dementia."
  49. McCann, S.M., et al. The nitric oxide hypothesis of aging. Exp Gerontol. 1998 Nov-Dec;33(7-8):813-26. "Nitric oxide (NO), generated by endothelial (e) NO synthase (NOS) and neuronal (n) NOS, plays a ubiquitous role in the body in controlling the function of almost every, if not every, organ system.” "...Excessive production of the free radical, nitric oxide (NO), in the central nervous system (CNS) and its related glands, such as the pineal and anterior pituitary, may be the most important factor in aging of these structures.” "They will also probably be of therapeutic value in rheumatoid arthritis and cardiomyopathy, both thought to be autoimmune diseases caused largely by excess NO.” "...NO blocks cellular enzymes required in metabolism…” "Aspirin blocks cyclooxygenase I, thereby reducing production and toxicity of prostanoids produced by NO, accounting for its protective effect in CHD.” "It appears that in addition to the antibacterial action of these drugs, tetracyclines inhibit the expression of NOS, leading to reduction in the toxic consequences of production of NO."
  50. Trüeb, R.M. Is androgenetic alopecia a photoaggravated dermatosis? Dermatology. 2003;207(4):343-8. "Alternatively, keratinocytes themselves may respond to physicochemical stress from UVR, besides irritants and pollutants, by producing radical oxygen species and nitric oxide and by releasing proinflammatory cytokines, eventually leading to injury of the putative site of follicular stem cells in the superficial portion of the hair follicle."
  51. Tang, Y., et al. Mitochondrial aerobic respiration is activated during hair follicle stem cell differentiation, and its dysfunction retards hair regeneration. PeerJ. 2016 May 3;4:e1821.
  52. 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. “…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.”
  53. Beynen, A.C., et al. A mathematical relationship between the fatty acid composition of the diet and that of the adipose tissue in man. Am J Clin Nutr. 1980 Jan;33(1):81-5. "Based on literature data, the hypothesis is advanced that in human subjects a direct mathematical relationship exists between the average fatty acid composition of the habitual diet and that of the lipid stores of subcutaneous adipose tissue. Since the half-life of adipose tissue fatty acids in man is in the order of 600 days, the fatty acid pattern of depot fat provides a qualitative measure of the fat intake over a period of 2 to 3 years. It is concluded that in long-term experimental and epidemiological nutritional surveys the adipose tissue fatty acid pattern of the subjects is a useful index of the average composition of their habitual dietary fat."
  54. Arias, P., et al. Crosstalk between nitric oxide synthases and cyclooxygenase 2 in the adrenal cortex of rats under lipopolysaccharide treatment. "In conclusion, our results show a significant crosstalk between COX-2 and NOS in the adrenal cortex upon LPS stimulation, in which each activity has a positive impact on the other."
  55. Gross, R.W., et al. Nitric oxide activates the glucose-dependent mobilization of arachidonic acid in a macrophage-like cell line (RAW 264.7) that is largely mediated by calcium-independent phospholipase A2. J Biol Chem 1995 Jun 23;270(25):14855-8. "Since nitric oxide is a potent stimulator of glycolysis (and therefore glycolytically derived ATP)..." "Nitric oxide-induced release of [3H]arachidonic acid..." "Collectively, these results identify a unifying metabolic paradigm in which the generation of lipid second messengers is coordinately linked to the signal stimulated acceleration of glycolytic flux, thereby facilitating integrated metabolic responses to cellular stimuli."
  56. Mariotto, S., et al. Cross-talk between NO and arachidonic acid in inflammation. Curr Med Chem. 2007;14(18):1940-4. "Thus, AA produced at the very early stages of the inflammatory response is a likely critical signal switching the regulation of the "NO tone" from physiological (i.e. mediated by constitutive NOS) to pathological (i.e. mediated by iNOS)."
  57. Pereira, et al. Correlation between body temperature, blood pressure and plasmatic nitric oxide in septic patients. Rev Lat Am Enfermagem. 2014 Jan-Feb; 22(1): 123–128. “The main conclusion of this study is that body temperature is inversely correlated with concentrations of nitric oxide in patients with septic shock. That is, the lower the body temperature, the higher the concentrations of nitric oxide.”
  58. Baskol, G., et al. Oxidative stress and enzymatic antioxidant status in patients with hypothyroidism before and after treatment. Exp Clin Endocrinol Diabetes. 2007 Sep;115(8):522-6. "In conclusion, increased ROS levels in hypothyroidism may result in a pro-oxidation environment…" "NO level was higher in pretreatment hypothyroidism when compared to controls." "In conclusion, increased ROS levels in hypothyroidism may result in a pro-oxidation environment..."
  59. Haluzík, M., et al. The changes of the thyroid function and serum testosterone levels after long-term L-NAME treatment in male rats. J Endocrinol Invest. 1998 Apr;21(4):234-8. "The nitric oxide thus seems to be an important modulator of thyroid and testicular function."
  60. The Merck Manual. 1947. “Hypothyroidism: A disease in middle life, 6 times more common in women than in men, especially liable to occur with menstrual disturbances. Diagnoses: Gradual onset of apathy, gain in weight, and development of nonpitting edema, especially of hands, feet and face (“full moon-like” face and coarse feat*ures). Skin dry and scaly (scales best seen in stockings. Hair becomes brittle and thin, nails rough, striated and break easily. There are lassitude, fatiguability, drowsiness, imperfect cerebration, even psychosis; poor appetite and constipation; pulse slow, blood pressure low, temperature subnormal; menstruation irregular; may cease or become excessive. Anemia in majority of cases.” "Exercise should be very constricted until improvement is well advanced."
  61. Broda Barnes. Hypothyroidism: The Unsuspected Illness. 1976 "The basal temperature can serve as an excellent guide not only to the need for thyroid therapy but also to achieving the proper thyroid dosage. The normal range of basal temperature is between 97.8 and 98.2 degrees Fahrenheit. When symptoms of thyroid deficiency are present, the basal temperature may be one, two, or even three degrees below normal. With thyroid therapy, the temperature will start to rise." "The proper dosage for any individual is the minimum needed to relieve symptoms. Most commonly, in adults, this is two grains; three grains sometimes are needed. rarely four grains may be required. The basal temperature may still be a little low. but one is treating symptoms, not temperature per se." "Thyroid therapy does not produce overnight change. No change may be noted for about a month." "Usually, at some point between one month and two months after the beginning of therapy, some of the symptoms begin to subside and the individual begins to feel better. At that point, an evaluation is in order to determine whether the starting dosage is sufficient for continued use or if an increase in dosage is advisable."
  62. Polikar, R., et al. The thyroid and the heart. Circulation. 1993 May;87(5):1435-41. "Moreover, there is increasing evidence that thyroid hormones have direct chronotropic effect on the heart that are independent of the sympathetic nervous system."
  63. Wang, H., et al. Brain temperature and its fundamental properties: a review for clinical neuroscientists. Front Neurosci. 2014 Oct 8;8:307. "Typically, global brain temperature readings assessed in resting clinical patients are congruent with patient body temperature (brain 36.9 ± 0.4◦C, rectal 36.9 ±0.6◦C); differences are noted when brain regions are assessed individually."
  64. Guarrera, M., and Rebora, A. Anagen hairs may fail to replace telogen hairs in early androgenic female alopecia. Dermatology. 1996;192(1):28-31. "As androgenic alopecia is a very common condition and displays a large variety in the rate of progression, apparently normal people may be in fact in the early stages of baldness."
  65. Hamilton, J.B. Patterned loss of hair in man; types and incidence. Ann N Y Acad Sci. 1951 Mar;53(3):708-28. "The Scalp in the First Two Years of Postnatal Life: Soon after birth, a marked alopecia develops in many babies in the same areas that become bald in adult men, that is, in the frontoparietal and frontal areas, and even over the tonsure. This process continues for weeks or months and occurs in both sexes. While hairs are still being lost, new hairs appear on the surface of the scalp and, by the end of the first or second year, most children have a completely hairy scalp of Type I or IA.”
  66. Laptook, A.R., and Watkinson, M. Temperature management in the delivery room. Semin Fetal Neonatal Med. 2008 Dec;13(6):383-91. "After being in a relatively stable thermoneutral uterus for the whole of pregnancy, the newborn baby enters a cooling environment and might suffer significant heat loss and hypothermia in the first minutes of life.
  67. Verhoeven, E.W. Biopsychosocial mechanisms of chronic itch in patients with skin diseases: a review. Acta Derm Venereol. 2008;88(3):211-8 "For example, it has been shown that repeated scratching decreases prostaglandin D2 (PGD2) levels - an itch inhibitor - in the skin, resulting in an increased desire to scratch and inducing the itch-scratch cycle."
  68. Sugimoto, M., et al. Putative mechanism of the itch-scratch circle: repeated scratching decreases the cutaneous level of prostaglandin D2, a mediator that inhibits itching. Prostaglandins Leukot Essent Fatty Acids. 2007 Feb;76(2):93-101. "Mechanical scratching induced a temporary increase of the skin PGs levels (PGE2, PGD2, 6-ketoPGF1alpha, PGF2alpha). The skin PGD2 level and the ability of PGD2 production decreased at 48 h after repeated scratch, compared to that of normal skin, not so after single scratch. Immunohistochemical analysis and Western blotting revealed a decrease in the levels of cyclooxygenase-1 (COX-1) and hematopoietic PGD synthase in mechanically scratched skin. The reduced ability of the skin for PGD2 production following mechanical scratching could be caused by this decrease in the expression levels of COX-1 and PGD2 synthase. “
  69. Mayumi Ito and George Cotsarelis. Is the Hair Follicle Necessary for Normal Wound Healing? J Invest Dermatol. 2008 May; 128(5): 1059–1061. "The hair follicle contributes cells to the interfollicular epidermis after wounding, but the functional role of these cells has not been resolved. To address this question, Langton et al. (this issue, 2008) take advantage of the Edaradd mutant mouse, which lacks hair follicles on its tail. They discover an initial sluggish response of the hairless tail epidermis to wounding that is rapidly compensated for by recruitment of epidermal cells from outside the normally responsive area. This suggests that the hair follicle is important but not necessary for normal wound healing."
  70. Matilainen, V.A., et al. Early onset of androgenetic alopecia associated with early severe coronary heart disease: a population-based, case-control study. J Cardiovasc Risk. 2001 Jun;8(3):147-51. "Our results support the hypothesis that the early onset of AGA is a risk factor for an early onset of severe coronary heart disease."
  71. Zhou, C., et al. Relationship Between Male Pattern Baldness and the Risk of Aggressive Prostate Cancer: An Analysis of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. 2014. "Our analysis indicates that frontal plus moderate vertex baldness at age 45 years is associated with an increased risk of aggressive prostate cancer and supports the possibility of common pathophysiologic mechanisms."
  72. Yao, J. and Eghbali, M. Decreased collagen gene expression and absence of fibrosis in thyroid hormone-induced myocardial hypertrophy. "Thyroid hormone may selectively prevent the induction of cardiac fibrosis and play an important role in regression of cardiac fibrosis via endocrine pathways."
  73. Ryu, J., et al. Chronic hypercapnia alters lung matrix composition in mouse pups. J Appl Physiol (1985). 2010 Jul;109(1):203-10. "Molecular analysis revealed that several matrix proteins in the lung were downregulated in mouse pups exposed to hypercapnia. Interstitial collagen type I alpha1, type III alpha1, elastin and fibronectin protein, and mRNA levels were less than half of controls while collagen IV alpha 5 was unaffected. This decrease in interstitial collagen could thus account for the thinning of the interstitial matrix and the altered lung biomechanics. Matrix metalloproteinase (MMP)-8, a collagenase that has specificity for collagen types I and III, increased in hypercapnic mouse pups, suggesting increased collagen degradation. Moreover, tissue inhibitor of MMP (TIMP)-1, a potent inhibitor of MMP-8, was significantly decreased.”