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.

Complementing 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 it 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 deleterious 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.”