Recharging The Mosaic Cycle: The Role of G6PDH in Baldness

 
 

One of my favorite films of 2014 was The Internet’s Own Boy, a film that chronicled the life and death of boy genius and anti-authoritarian activist, Aaron Swartz. Almost immediately after the film was over (you can watch it here on YouTube), I remember reaching out to my friend Karen to tell her how much I enjoyed the film. Half way into our conversation we both noted that Aaron had a great head of hair, and Karen went on to say that she noticed that Aaron’s hair seemed to dim during the times of the film that the documentary discussed Aaron’s digestive ailment, Crohn’s disease. 

The connection between health and hair growth is not fringe and has been widely discussed over the last few decades. As early as 1993, it was known that baldness was associated with developing heart disease[1,2,3,4]. Later, baldness was found to be related to other problems like metabolic syndrome,[5] high cholesterol,[6] reduced bone mineral density,[7] and cancer.[8] 

The evidence that hair growth and health are interconnected doesn’t appear to have penetrated the mainstream, and instead, you’re likely to be blunted over the head with an endless array of pseudo-intellectual blowhards progressing the idea that baldness is simply the result of bad genes and excess masculinity. Their science comprises of rattling off model after model of ever growing complexity that is divorced from the individual and their environment. This compartmentalized anti-science approach to hair loss is often reflected in the phases of the hair growth cycle or the mosaic cycle.

I: The Mosaic Cycle

Hair follicles go through a cyclical growth phase composed of three phases: anagen, the phase of active growth; catagen, the phase of regression; and telogen, the resting period. The proportion of anagen follicles is highest in childhood and lowest in old age, and there are small, relatively constant variations in different regions of the scalp.

When a hormone or drug is said to increase the anagen growth of hair sometimes the substance is deemed good or useful for hair growth. For example, finasteride can increase the anagen growth of hair follicles, but also may be carcinogenic.[9] Similarly, the hormone-like unsaturated fatty acid breakdown product, prostaglandin E2 (PGE2), is said to promote anagen growth and is also associated with cancer.[10,11] Substances that promote growth like finasteride or PGE2 stimulate mitosis, which might appear to have a “positive” effect on hair growth while having a negative systemic effect on the organism. Thus, I think its important to attempt to understand the overall physiology of the balding person and hair growth rather than identifying substances that simply promote anagen growth

Similar to bone marrow, skin, intestine, and other highly proliferative glucose-dependent tissues, the hair follicle is composed of rapidly dividing cells that convert more than 85% of their glucose to lactic acid via glycolysis (fermentation). When the various glucose pathways are studied in growing and resting follicles, the metabolic activities are found to be much higher during the growing anagen phase. For example, in growing follicles glucose utilization increases 200%, glycolysis 200%, the activity of pentose phosphate cycle 800%, metabolism by other pathways 150%, and ATP production via the respiratory chains 270%.[12] 

In the bulb portion of growing follicles, the activity of glucose-6-phosphate dehydrogenase (G6PDH), a key enzyme and rate-limiting factor in the pentose phosphate cycle, increased 350% over that in resting follicles. Clearly, by activating the pentose phosphate cycle, glucose assimilation in growing hair follicles produces not only sufficient energy for itself but also essential substances like the electron carrier, NADPH.

Two important functions of NADPH is to help produce steroids within the hair follicle and to provide “reducing power” to recycle reduced glutathione (GSSG) back to glutathione (GSH), protecting the hair follicle from oxidative damage

II: Glucose-6-Phosphate Dehydrogenase (G6PDH)

A decrease in anagen to telogen hairs (mainly in the frontal-parietal region) is a major symptom of male-pattern baldness. In 1999, Adachi et al. found that G6PDH activity decreases in direct relationship with the decreasing ratio of anagen hairs. In fact, the researchers suggested that “G6PDH could be a suitable marker for diagnosis of alopecia” and that “energy metabolism may be a new strategy to prevent and cure male-pattern alopecia”.[13] 

A decrease in the activity of G6PDH increases the ratio of NADP/NADPH. As the availability of NADPH declines, GSSG cannot be recycled back into GSH to protect the hair follicle from oxidative stress. In 2015, a group found that balding dermal papilla cells have “significantly higher concentrations of GSSG” compared to occipital dermal papilla cells, and that the balding hair follicles “appear to be less able to handle oxidative stress”. The group concluded the abstract with, “there may be a role for oxidative stress in the pathogenesis of [male-pattern baldness]”.[14]

The energy metabolism done by G6PDH in hair follicles of male-pattern alopecia may be related to the hair growth, and activation of the energy metabolism may be a new strategy to prevent and cure male-pattern alopecia.
— Activity of glucose-6-phosphate 1-dehydrogenase in hair follicles with male-pattern alopecia (1999)

If supporting energy metabolism can be thought of as ‘a strategy for preventing and curing so-called male-pattern baldness,’ as Adachi et al. suggested, I think it’s important to look at factors in the environment that contribute to decreasing the activity of G6PDH and production of NADPH. 

III: G6PDH Regulation

Unsaturated fatty acids have increased 1000 fold from 1909 to 1999,[15] and have a dominant position in the world's food supply. In addition to being the precursor for the prostaglandin Garza et al. discovered accumulated in the scalp's of balding men and inhibited hair growth,[16] they appear to be inhibitors of G6PDH. In one experiment, rats were switched from a non-fat diet to one containing 15% unsaturated fatty acids and there was an 8-fold decrease in the level of G6PDH. When the rats fasted for two days and were fed a high-carbohydrate, non-fat diet, the activity of G6PDH increased to an amount larger than that of the "normal" fed state.[17]

In contrast to the unsaturated fats, adding saturated fats (palmitate or stearate), or a monounsaturated fat (oleate), does not inhibit, or inhibits G6PDH activity to a lesser degree,[18] suggesting that the inhibition of G6PDH is not solely a consequence of reduced carbohydrate intake. In an experiment with rodents, 20% of calories from safflower oil inhibited the activity of G6PDH to a greater degree than 20% of calories from beef tallow.[19] Similar to safflower oil, the so-called "essential fatty acids" were found to inhibit G6PDH activity, too.[20]

In comparison to the inhibitory effect of the unsaturated fats, carbohydrates appear to stimulate G6PDH activity. The greatest change in G6PDH activity is observed when rats are fed diets containing glucose or fructose, compared with starch, and stimulation by fructose is greater than by glucose.[21] In diabetic rats, fructose increased the activity of G6PDH more than glucose, suggesting that it might be the most useful carbohydrate for increasing G6PDH activity.[22]

IV: Recharging The Mosaic Cycle

The microinflammatory process of baldness suggests that the hair follicle is undergoing stress,[23] and the energy requirements for highly proliferative tissues are amplified in stress. For example, in 3-day old wounds, the activities of glycolytic enzymes increase 4 times over normal levels, there's a 5-fold increase in oxygen uptake, and the rate of lactate production is tripled. G6PDH activity triples in psoriasis increases 5-fold in tumors and hyperplasia and 7-fold in the epidermis during wound healing. There is a 50% increase in glucose flow along the pentose phosphate pathway during wound healing.[24] 

Sugars stimulate the hormone insulin, an “inducer“ of G6PDH. In rats, when insulin levels drop, there is a concomitant decrease in G6PDH activity, and when animals are refed, G6PDH activity is restored. Moreover, administration of insulin alone increased G6PDH enzyme in a dose-dependent manner. It was proposed in Montagna's epic, The Biology of Hair Growth that insulin—and not glucose—might be the critical factor in the growth of hair follicles.[25] 

In addition to inducing G6PDH, insulin activates another regulator of G6PDH, thyroid hormone.[26] Thyroid hormone is essential for the initiation as well as the maintenance of hair growth, and the main effect of this hormone is to preserve the anagen state. Low thyroid function is associated with an increase in the percentage of telogen to anagen hairs, as well as higher levels of total cholesterol.[27] In 2010, it was found that men and women with androgenic alopecia had higher levels of cholesterol, and that the anomalous lipid values "...may contribute, alongside other mechanisms, to the development of cardiovascular disease in patient with androgenic alopecia."[28] 

Both thyroid hormones, T2 and T3, increased the activity of G6PDH in hypothyroid rats, and G6PDH activity was elevated in patients with thyrotoxicosis.[29] As I’ve mentioned previously, Vidali, et al. called for a repositioning of thyroid hormone as “mitochondrial hair medicine” in 2013.[30] 

Disturbances of hair cycles involve modification of the relative duration of the phases of the cycle and are most characteristically determined by excess or deficiency of glucocorticosteroids or thyroid hormones. They are usually completely reversible.
— Rook, A. Endocrine Influences on Hair Growth. 1965.

Insulin and thyroid hormone tend to shift the metabolism away from the oxidation of free fatty acids and the production of the adaptive "stress" hormones and toward the constructive use of sugar. A lowered rate of metabolism (or the "stress" metabolism)—and not “bad genes” or an excess of masculinity—I think, is the most coherent explanation for the development of pattern baldness in both men and women. 

References

  1. Lesko, S.M., et al. A case-control study of baldness in relation to myocardial infarction in men. JAMA. 1993 Feb 24;269(8) “The relationship between vertex baldness and myocardial infarction was consistent within strata defined by age and other risk factors for coronary artery disease.””These data support the hypothesis that male pattern baldness involving the vertex scalp is associated with coronary artery disease in men under the age of 55 years.”
  2. Morteza, et al. Prevalence of Dermatologic Features in Patients With Ischemic Heart Disease. Shiraz E-Medical Journal. 2015 January. “Male pattern baldness, hair graying, xanthoma, and earlobe crease are associated with increased risk of ischemic heart disease. These dermatologic signs can be considered as CVD risk factors for screening.”
  3. Lotufo, P.A., et al. Male pattern baldness and coronary heart disease: the Physicians’ Health Study. Arch Intern Med. 2000 Jan 24;160(2):165-71. “Vertex pattern baldness appears to be a marker for increased risk of CHD events, especially among men with hypertension or high cholesterol levels.”
  4. 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.”
  5. Su, L.H., et al. Association of Androgenetic Alopecia with Metabolic Syndrome in Men: A Community-based Survey. Br J Dermatol. 2010 Aug;163(2):371-7. “Conclusions: Our population-based study found a significant association between AGA and MetS; among MetS components, HDL was found to be of particular importance. This finding may have significant implications for the identification of MetS in moderate or severe AGA patients. Early intervention for MetS is critical to reduce the risk and complications of cardiovascular disease and type 2 diabetes mellitus later in life.”
  6. Arias-Santiago, S., et al. A comparative study of dyslipidaemia in men and woman with androgenic alopecia. Acta Derm Venereol. 2010 Sep;90(5):485-7. doi: 10.2340/00015555-0926. “A higher prevalence of dyslipidemia in women and men with androgenic alopecia has been found. The elevated lipid values in these patients may contribute, alongside other mechanisms, to the development of cardiovascular disease in patient with androgenic alopecia.”
  7. Morton, D.J., et al. Premature graying, balding, and low bone mineral density in older women and men: the Rancho Bernardo study. J Aging Health. 2007 Apr;19(2):275-85. “Balding men averaged 5% lower total body BMD (p </= 0.05), and balding women had ~24% higher mean hip BMD (p </= 0.05). Graying and balding women reported a higher proportion of current estrogen use; balding women reported more use of glucocorticosteroids. Balding women using estrogen may explain the higher BMD.”
  8. 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.”
  9. Kleenmann, D., et al. [The effect of hormonal agents on the development of chronic laryngitis and tumor disease. Report of two cases]. HNO. 2010 Mar;58(3):305-12. “In the first case of a patient suffering from chronic hyperplastic laryngitis for 17 years, a close correlation was found between the treatment with the 5alpha-reductase inhibitor Finasteride, the drop in serum levels of dihydrotestosterone (DHT), and the appearance of an invasive squamous cell carcinoma of the vocal cord. During the postoperative 7-year follow-up without recurrence the androgen serum levels were within normal range.” “ In the second patient, who had undergone previous surgery for mesopharyngeal cancer at another site before the present tumor operation, rapid recurrence was seen within 2 years. Despite radical revision surgery and subsequent irradiation the patient insisted on carrying on with his work. He complained about a general lack of stamina and libido. His androgen serum levels were at the low-end of the normal range and even below that. The daily administration of 25 mg dehydroepiandrosterone (DHEA) resulted in normal androgen serum levels and improved his wellbeing. He has been free of recurrence for 10 years.” “”…cofactor in the genesis and development of malignant tumors of the upper aerodigestive tract.”
  10. Badawi, A.F. The role of prostaglandin synthesis in prostate cancer. BJU Int. 2000 Mar;85(4):451-62. “It was suggested recently that PGE2 plays a major role in the growth of prostate cancer cells through the activation of COX-2 expression. Increased levels of PGs have been widely reported in malignant human prostate tumours and in carcinogen-induced rat and mouse prostate cancers. In vitro studies with tissue explants or primary cultures of prostate tumour cells have also shown higher PG production in malignant tissue than in benign or normal tissue. Increased synthesis of PGs was associated with advancing prostate cancer and the concentrations increased as the degree of tumour differentiation progressed, i.e. a worse prognosis.”
  11. Greenhough, A., et al. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis. 2009 Mar;30(3):377-86. “It is widely accepted that alterations to cyclooxygenase-2 (COX-2) expression and the abundance of its enzymatic product prostaglandin E(2) (PGE(2)) have key roles in influencing the development of colorectal cancer.” “Future studies into the emerging players within the COX-2/PGE2 pathway may reveal novel approaches for more safely targeting this pathway for both cancer chemoprevention and therapy.”
  12. Motagna, W. The Structure and Function of Skin. 1974. The general metabolic pattern is extremely “glycolytic,” i.e., more than 85% of the glucose consumed is reduced to lactate. When the various glucose pathways are studied in growing and resting follicles, the metabolic activities are found to be much higher during the growing phase. For example, in growing follicles glucose utilization increases 200%, glycolysis 200%, the activity of pentose cycle 800%, metabolism by other pathways 150%, and ATP production via the respiratory chains 270%.” “Clearly, by activating the pentose cycle, glucose assimilation in growing hair follicles produces not only sufficient energy for itself but also essential substances (TPNH, ribose, etc.) for the follicle to metabolize fatty acid, nucleic acids, and steroid hormones. When the enzymes of carbohydrate metabolism were assayed with the microtechnique of Lowry (1953), the results agreed with those obtained above. For example, in the bulb portion of growing follicles, the activity of glucose-6-phosphate dehydrogenase, a key enzyme of the pentose cycle, increased 350% over that in resting follicles.”
  13. Rushton, H., et al. The unit area trichogram in the assessment of androgen-dependent alopecia. Br J Dermatol. 1983 Oct;109(4):429-37.
  14. Upton, J.H., et al. Oxidative stress-associated senescence in dermal papilla cells of men with androgenetic alopecia. J Invest Dermatol. 2015 May;135(5):1244-52. “Balding DPCs had higher levels of catalase and total glutathione but appear to be less able to handle oxidative stress compared with occipital DPCs. These in vitro findings suggest that there may be a role for oxidative stress in the pathogenesis of AGA both in relation to cell senescence and migration but also secretion of known hair follicle inhibitory factors.”
  15. Blasbalg, T.L., et al. Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. Am J Clin Nutr. 2011 May;93(5):950-62. “The estimated per capita consumption of soybean oil increased >1000-fold from 1909 to 1999.”
  16. Garza, L.A., et al. Prostaglandin d2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia. Sci Transl Med. 2012 Mar 21;4(126):126ra34. “Given the androgens are aromatized into estrogens, these results may be relevant to hair growth and alopecia in both men and women. Thus, these or similar pathways might be conserved in the skin and suggest that sex hormone regulation of Ptgds may contribute to the pathogenesis of AGA.” “…demonstrates elevated levels of PGD2 in the skin and develops alopecia, follicular miniaturization, and sebaceous gland hyperplasia, which are all hallmarks of human AGA. These results define PGD2 as an inhibitor of hair growth in AGA and suggest the PGD2-GPR44 pathway as a potential target for treatment.”
  17. Gozukara, E.M., et al. The effect of unsaturated fatty acids on the rate of synthesis of rat liver glucose-6-phosphate dehydrogenase. Biochim Biophys Acta. 1972 Nov 24;286(1):155-63.
  18. 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.”
  19. 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.”
  20. Clarke, S.D., et al. Specific inhibition of hepatic fatty acid synthesis exerted by dietary linoleate and linolenate in essential fatty acid adequate rats. Lipids. 1976 Jun;11(6):485-90. “However, 18:2 addition to the basal diet did result in a significant (P less than 0.05) decline of liver fatty acid synthetase (FAS) and glucose-6-phosphate dehydrogenase (G6PD) activities. When the safflower oil content of the basal diet was reduced to 1%, the addition of 3% 18:2 or linolenate 18:3 significantly (P less than 0.05) depressed hepatic FAS, G6PD, and in vivo fatty acid synthesis by 50%.”
  21. Kastrouni, E., et al. Activity changes of glucose-6-phosphate dehydrogenase in response to diet and insulin. Int J Biochem. 1984;16(12):1353-8.
  22. 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.”
  23. Mahe, Y.F., et al. Androgenetic alopecia and microinflammation. Int J Dermatol. 2000 Aug;39(8):576-84. "Despite such a reduction of circulating 5-DHT levels, however, a number of individuals (60–70%) still remained unresponsive to this treatment, indicating again that simple dysregulation of 5-DHT synthesis levels or a genetic polymorphism of 5α-R genes cannot account for all cases of AGA, and a polygenic etiology should be considered.” "The fact that the success rate of treatment with either antihypertensive agents, or modulators of androgen metabolism, barely exceeds 30% means that other pathways may be envisioned.” "Once aa is released from the cell membrane phospholipids by phospholipase A2,18,19 it is metabolized through a complex equilibrium between two families of enzymes, generating either prostaglandins (PGs) (through the activity of PGH synthases, PGHSs) or leukotrienes…” "This upregulation of androgen metabolism by proinflammatory cytokines remains, however, to be established at the pilosebaceous unit level.” "We know now that, at least in about one-third of cases, the tool which causes the lethal damage is a microinflammatory process."
  24. Motagna, W. The Structure and Function of Skin. 1974. “A specific feature of the epidermis—intense glycolytic activity in the presence of oxygen—is amplified by trauma. For example, during wound healing, glycolytic activity increases in the regenerating epidermis and a minor alteration in glucose catabolism occurs through the tricarboxylic acid cycle. Wounded skin also exhibits increased glucose utilization and lactate production. The activities of glycolytic enzymes increase 4 times over normal levels, and the rate of lactate production from uniformly labeled glucose-14C is tripled in 3-day-old wounds. The activities of key glycolytic enzymes increase in some skin disorders and in experimental lesions.” “Healing wounds show a fivefold increase in oxygen uptake.” “However, a small part of glucose metabolism through the tricarboxylic acid cycle decreases to half that of normal skin. Presumably, then, the fuel for increased respiratory oxidation in healing skin comes from other sources of nutrient. Glucose metabolism through the pentose phosphate shunt supplies the pentose needed for nucleic acid formation and for reduced nicotinamide denucleotide phosphate (NADPH), a reducing equivalent needed for lipogenesis and indirectly for keratinization. Increased activity in this shunt in psoriasis, hyperplasia, tumors, and wound healing reflects the increased demands of the epidermis for synthetic activities. Glucose-6-phosphate dehydrogenase activity of the pentose phosphate shunt triples in psoriasis, increases 5-fold in tumors and hyperplasia, and 7-fold in the migrating epidermis during wound healing. There is a 50% increase in glucose flow along the pentose phosphate shunt during wound healing.” 
  25. Montagna, W. The Biology of Hair Growth. 1958. “Insulin and not glucose seems to be the critical factor in the growth of hair follicles. Unlike the epidermis, hair follicles are able to grow normally despite changes in the concentration of blood glucose. Although both oxygen and a carbohydrate source are essential for maintaining the mitotic activity of a hair follicle in vitro, drastic conditions such as starvation or shock are required to influence such activity in vivo. The abundant supply of glycogen in growing hair follicles may partially account for the relative independence of the hair follicle from the level of circulating glucose.”
  26. Jennings, A.S., et al. Regulation of hepatic triiodothyronine production in the streptozotocin-induced diabetic rat. Am J Physiol. 1984 Oct;247(4 Pt 1):E526-33. “Induction of diabetes with streptozotocin resulted in decreased serum thyroxine (T4) and T3 levels and a progressive decline in hepatic T3 production over 5 days. The decline in T3 production resulted from decreased conversion of T4 to T3, whereas T4 uptake was unchanged. Insulin administration restored serum T4 and T3, hepatic conversion of T4 to T3, and T3 production to normal levels. When serum T4 levels in diabetic rats were maintained by T4 administration, the conversion of T4 to T3 and T3 production returned to control levels. However, restoration of serum T4 levels in fasted rats failed to correct the decrease in hepatic T4 uptake or T3 production.” “These data suggest that the fall in serum T4 levels observed in diabetic rats is important in mediating the decreased hepatic conversion of T4 to T3 and T3 production.”
  27. Saito, R. and Nishiyama, S. Alopecia in Hypothyroidism. Hair Research 355-357 (1981). "Freinkel and Freinkel studied the relative proportions of telogen to anagen hairs in the scalps of hypothyroid subjects with hair loss and found that deficiency of thyroid hormone was associated with an increase in the percentage of telogen hairs in all instances.” "Not only the duration and grade of hypothyroidal condition, but also anemia, hypercholesteremia, disturbances of Vitamin A metabolism, and local deposition of mucin induced by hypothyroidism must be considered as factors inducing hair loss in hypothyroidism.” "Vitamin A is essential for preserving the function of the epidermis, and deficiency of Vitamin A may induce dyskeratosis of follicular openings and hair loss. Inasmuch as deposition of mucin in whole tissues (including perifollicular tissue) is observed, mucin may have some effect of keratin synthesis."
  28. Arias-Santiago, S., et al. A comparative study of dyslipidaemia in men and woman with androgenic alopecia. Acta Derm Venereol. 2010 Sep;90(5):485-7. doi: 10.2340/00015555-0926. "A higher prevalence of dyslipidemia in women and men with androgenic alopecia has been found. The elevated lipid values in these patients may contribute, alongside other mechanisms, to the development of cardiovascular disease in patient with androgenic alopecia."
  29. 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.”
  30. Vidali, S., et al. Hypothalamic-Pituitary-Thyroid Axis Hormones Stimulate Mitochondrial Function and Biogenesis in Human Hair Follicles. J Invest Dermatol. 2013 Jun 27. “HPT-axis hormones did not increase reactive oxygen species (ROS) production. Rather, T3 and T4 reduced ROS formation, and all tested HPT-axis hormones increased the transcription of ROS scavengers (catalase, superoxide dismutase 2) in HF keratinocytes. Thus, mitochondrial biology, energy metabolism, and redox state of human HFs are subject to profound (neuro-)endocrine regulation by HPT-axis hormones. The neuroendocrine control of mitochondrial biology in a complex human mini-organ revealed here may be therapeutically exploitable.“ “The current data also provide clinically relevant pointers to how HF aging and disease correlated with declining mitochondrial function might be effectively counteracted in the future by endogenous neurohormones produced in the human epithelium, e.g., TRH and TSH. This also applies to THs [thyroid hormones], which have long been known to modulate hair shaft quality and/or pigmentation. Both TRH and T4 are administered routinely in thyroid medicine and are FDA-approved agents with a well-known toxicity profile. Therefore, regulatory hurdles to reposition these hormones for novel ‘mitochondrial hair medicine’ approaches are relatively low.”