Antihistamines for Pattern Hair Loss?

 
 

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

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

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

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

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

I: Histamine and Ordinary Hair Growth

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

IV: Expand, Extend, Develop, Mature

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

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

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

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

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

References

  1. Aram, H. Treatment of female androgenetic alopecia with cimetidine. Int J Dermatol. 1987 Mar;26(2):128-30. "Ten white women with moderate to severe androgenetic alopecia were treated with cimetidine 300 mg by mouth five times a day. Duration of therapy ranged from 1.59 months, with a median of 5 months. Seven patients (70%) showed good to excellent regrowth of hair.” "The mechanism of cimetidine's action in patients with androgenetic alopecia is presumably due to its antiandrogenic activity, although a placebo effect cannot be discounted.” "Management of androgenetic alopecia in men or endocrinologically normal women has been unrewarding, as there are no consistently successful therapeutic agents available. The possibility of cimetidine offering a useful form of therapy for patients with this disorder prompted the undertaking of the present open study.” "The pattern of hair loss was usually diffuse, most marked on the vertex.” "Acne, seborrhea, and hirsutism, which were present in three of the patients, showed significant improvement. Most patients said that the scalp had become less greasy. No correlation was found between the severity of hair loss and the serum levels of testosterone.” "However, application of 0.025% 17-a-estradiol solution resulted in decrease of the rate of hair loss, but regrowth of hair did not occur."
  2. Fenton, D., et al. Reversal of male-pattern baldness, hypertrichosis, and accelerated hair and nail growth in patients receiving benoxaprofen. Br Med J (Clin Res Ed). 1982 Apr 24; 284(6324): 1228–1229. "Benoxaprofen is a non-steroidal anti-inflammatory drug used to relieve symptoms of rheumatoid arthritis and osteoarthrosis. Reported side effects include photosensitivity, onycholysis, urticarial rashes and pruritus, gastrointestinal ulceration and haemorrhage, and the Stevens-Johnson syndrome. We have reported the development of toxic epidermal necrolysis, leucopenia, and thrombocytopenic purpura in a patient after nine days' treatment with benoxaprofen. We report here on five patients who developed hypertrichosis and accelerated hair and nail growth, two of whom showed reversal of male-pattern baldness." 
  3. Charlesworth, E., et al. Effect of cetirizine on mast cell-mediator release and cellular traffic during the cutaneous late-phase reaction. J Allergy Clin Immunol. 1989 May;83(5):905-12. “Histamine release was not altered by cetirizine treatment, but prostaglandin D2 (PGD2) production, which peaked at 3 to 5 hours, was clearly reduced by cetirizine treatment, being lower at all time points during the reaction…” “The inhibition was most marked during the fifth hour of the reaction when there was a 50% suppression of the PGD2 level by cetirizine.”
  4. Mayo, J., et al. Androgen-dependent mast cell degranulation in the Harderian gland of female Syrian hamsters: in vivo and organ culture evidence. Anat Embryol (Berl). 1997 Aug;196(2):133-40. "The antiandrogen cyproterone acetate prevents the degranulation of mast cells induced by testosterone in both in vivo and in vitro."
  5. Neuman, F., and Graf, K.J. Discovery, development, mode of action and clinical use of cyproterone acetate. "CA has been useful in treating androgen-dependent tumors and "androgenic" diseases such as idiopathic precocious puberty, hirsutism, and male-pattern baldness in adult females, all signs of virilization in females, hypersexuality in adult males, acne and seborrhea, baldness in adult males, and benign prostatic hypertrophy.” "Because of its strong progesterone potency…” "Gynecomastia sometimes develops temporarily in males treated with CA. Serious side effects of CA treatment have not been observed."
  6. Geller, J., et al. Effect of cyproterone acetate on clinical, endocrine and pathological features of benign prostatic hypertrophy. Journal of Steroid Biochemistry, 1975. Vol. 6, pp. 837-843. "Clinical effects of CPA in patients with BPH. In five patients treated with CPA, 250 mg daily by mouth for two-to-four months, all improved clinically (Table 2) by both objective (residual urine and ability to void) and subjective criteria. The resected prostate was surprisingly small compared to the expected values estimated prior to drug treatment.” "The decrease in estrogen to the castration levels demonstrated in two patients during CPA therapy may reflect either a decrease in estrogen secondary to a decrease in testosterone which serves as a precursor for the estrogen, or it may reflect the direct inhibition of estrogen synthesis by Leydig cells. Since estrogen may stimulate squamous metaplasia and fibromuscular growth in the middle and lateral lobes of prostate, the usual anatomic sites of BPH, decreased estrogen production rates with CPA may have relevance to the clinical effects of the drug in BPH."
  7. Menzies, F.M., et al. The role of mast cells and their mediators in reproduction, pregnancy and labour. Human Reproduction Update, 2010, Volume 17, Issue 3, Page 383–396. "MCs express the high-affinity estrogen receptor and studies have shown that estrogens augment their activities: in the presence of high levels of estrogens, MC responses to compound 48/80 are increased, leading to more substantial degranulation and release of histamine and serotonin.” "MCs are found in a diverse range of tissues and have the ability to adapt their function to the microenvironment.” "Interestingly, however, there is an increase in testicular MCs in infertile men through MC activation of fibroblasts and promotion of collagen synthesis, could contribute to testicular fibrosis.” "Progesterone is necessary for the maintenance of pregnancy and plays a key role in maintaining cervical integrity prior to labour induction. Progesterone can prevent the migration of MCs in response to chemokines and down-regulate surface chemokine receptor expression. In addition, MC function can be altered by the presence of high concentrations of progesterone. For example, progesterone inhibits the secretion of histamine from MCs (Vasiadi et al., 2006). Notably, these observations would suggest that MCs present within the uterus during pregnancy are quiescent and inhibited by high levels of progesterone, and also that recruitment of MC progenitors from the circulation may be limited.” "At present the prevalence of allergies, including allergic rhinitis, hayfever, eczema, food allergies and urticaria, is rising."
  8. Orfanos, C., and Happle, R. Hair and Hair Diseases. 1990. “Of the three drugs presently available with antiandrogenic potency, Cimetidine (CI) is the drug which is weakest in this respect, and also that which is the least investigated. Its antiandrogenicity was suspected from side effects which occurred in men during CI treatment for peptic ulcer and other indications, namely gynaecomastia, impotence and reduction in sperm count, despite a rise in plasma testosterone. The antiandrogenic property is not intrinsic to histamine H2-receptor blockade since other histamine H2-receptor antagonists such as ranitidine and tiotidine are devoid of this activity. CI, unlike CPA and SL, is obviously devoid of additional endocrine activities. Thus, common endocrine parameters such as plasma testosterone,free testosterone, DHT, oestradiol, progesterone, FSH, LH and prolactin do not change under the influence of CI.”
  9. Morettie, G., et al. The Hair Cycle Re-Evaluated. International Iournal Of Dermatology (1976). "The skin content of histamine and heparin contained in the mast-cell granules is high at this time [ANA 4].” "The rise in heparin in the first week of anagen probably helps to maintain normal blood fluidity in the simultaneously increased perifollicular vessel networks, which are dilated and made more permeable by histamine.” "When follicles have reached ANA 6, however, a gradual but radical decrease in mast cells, histamine and heparin begins. This continues through the rest of ANA 6 and the whole of catagen. The mast cell population diminishes by a third, when it retreats to the lower dermis and hypodermis."During telogen the mast cells, histamine, and probably heparin, increase again and continue rising in the subsequent anagen, as we know from studies on consecutive hair cycles. The final stage of telogen probably prepares the hair for the next growth phase. This stage and anagen, until the point when the follicles are differentiated and emerge, are characterized by an increase in mast cell population and in their secretory activity.” "During telogen, hair survival is dependent on energy (ATP), mainly produced by anaerobic glycolysis,” "Thyroxine shortens the resting phase, whereas estradiol, adrenal hormones and testosterone prolong telogen."
  10. Lattanand, A. and Johnson, W.C. Male pattern alopecia a histopathologic and histochemical study. J Cutan Pathol. 1975;2(2):58-70. “The role of mast cells in male-pattern baldness is unknown, but the large numbers often present is a striking feature.”
  11. Larson, A.R., et al. A prostaglandin D-synthase-positive mast cell gradient characterizes scalp patterning. J Cutan Pathol. 2014 Apr;41(4):364-9. "We hypothesized that this difference in pattern of prostaglandin D-synthase expression may constitute a developmental pattern inherent to normal as well as alopecic scalp skin, thus defining a ‘field’ vulnerable to acquired hair loss." “These data indicate that scalp is spatially programmed via mast cell prostaglandin D-synthase distribution in a manner reminiscent of the pattern seen in androgenetic alopecia.” "Currently the main successful treatment options for androgenetic alopecia are finasteride, an androgen-based systemic therapy with numerous side effects…” "In a prior study of male pattern alopecia, increased numbers of mast cells have been seen in balding vertices compared to non-balding occipital scalp and, in fact, this pattern was also observed in five control subjects studied, though there were greater numbers of mast cells in the patients with alopecia.” "In the 1990’s mast cells were found to be actively degranulating in the inflammatory infiltrates of scalp with male pattern alopecia and this was proposed to contribute to perifollicular fibrosis.”
  12. Theoharides, T., et al. Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects. Endocrinology. 1998 Jan;139(1):403-13. “Mast cells are involved in atopic disorders, often exacerbated by stress, and are located perivascularly close to sympathetic and sensory nerve endings.” “Moreover, acute psychological stress induces CRH-dependent mast cell degranulation.Intradermal administration of rat/human CRH (0.1-10 microM) in the rat induced mast cell degranulation and increased capillary permeability in a dose-dependent fashion.” “To investigate which vasodilatory molecules might be involved in the increase in vascular permeability, the CRH injection site was pretreated with the H1-receptor antagonist diphenhydramine, which largely inhibited the CRH effect, suggesting that histamine was involved in the CRH-induced vasodilation.” “The present results have implications for the pathophysiology and possible therapy of skin disorders, such as atopic dermatitis, eczema, psoriasis, and urticaria, which are exacerbated or precipitated by stress.”
  13. Jaiswal K., and Krishna, A. Effects of hormones on the number, distribution and degranulation of mast cells in the ovarian complex of mice. Acta Physiol Hung 1996;84(2):183-90. “The changes in the number and degranulation pattern of mast cells varied with the types of hormonal treatment and ovarian compartment. Luteinizing hormone (LH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH) and 17-beta estradiol (E2) treatment caused increase (P < 0.05) in the number of mast cells in the hilum as compared with the controls. Increase (P < 0.05) in the number of mast cells in the whole ovarian complex was observed only following FSH and E2 treatment. All the hormones used in the present study increased the percentage degranulation of mast cells in the hilum. However, only LH, FSH and E2 increased the percentage degranulation of mast cells in other compartments of the ovary (medulla, bursa and cortex). TSH and ACTH failed to cause any increase in the percentage degranulation of mast cells in these compartments. The present findings indicate E2 to be the most potent among the hormones tested in causing degranulation of mast cells in all ovarian compartments.” 
  14. Gross. Reproductive cycle biochemistry. Fertility & Sterility 12(3), 245-260, 1961. “The maintenance of an environment conducive to anaerobic metabolism—which may involve the maintenance of an adequate supply of the substances that permit anaerobiosis…seems to depend primarily upon the action of estrogen.” “Glycolytic metabolism gradually increases throughout the proliferative phases of the cycle, reaching a maximum coincident with the ovulation phase, when estrogen is at a peak. Following this, glycolysis decreases, the respiratory mechanisms being more active during the secretory phase. Eschbach and Negelein showed the metabolism of the infantile mouse uterus to be less anaerobic than that of the adult. If estrogen is administered, however, there is a 98 percent increase in glycolytic mechanisms.” “The effect of the progestational steroids may be such as to interfere with the biochemical pattern required for support of this anaerobic environment.”
  15. Nagy, P., and Csaba, I.F. [Action of oestrogens on in vitro metabolism of trophoblast from human early pregnancy]. Zentralbl Gynakol. 1982;104(2):111-6. “Warburg’s manometric method was used to check the action of oestrone, oestradiol, and oestriol on aerobic and anaerobic glycolysis of placental respiration. Oestrogen concentrations of 10(-4) M were found to reduce oxygen consumption and to increase aerobic glycolysis. Such reduction of oxygen consumption was most strongly pronounced in connection with oestradiol, while the strongest rise in aerobic glycolysis took place in the wake of oestradiol and oestrone. Oestrogen action upon anaerobic glycolysis was variable, with the latter remaining unchanged by oestradiol, reduced in response to oestriol, and slightly increased by oestrone.”
  16. Vliagoftis, H., et al. Estradiol augments while tamoxifen inhibits rat mast cell secretion. Int Arch Allergy Immunol. 1992;98(4):398-409. “...17 beta-estradiol augmented secretion of histamine and serotonin, starting at 1 microM and in a dose-dependent manner…” "Tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibited serotonin and histamine release from purified rat peritoneal mast cells triggered by compound 48/80 or substance P. Tamoxifen also inhibited the increase in intracellular free Ca2+ originating from an influx of extracellular Ca2+ in response to compound 48/80.” "Tamoxifen may, therefore, have a beneficial effect in other neuroimmunoendocrine disorders both through estrogen receptor blockade and inhibition of mast cell secretion."
  17. Terral, C., et al. [Influence of estrogens on histamines liberation by whole blood induced by allergens in vitro]. Soc Bioi Fil 1981; 175(2):247-52. “A relapse o f bronchial obstruction during women's menstrual cycle in often observed. Incubating blood and rising rates of estrogens produce an increase of histamine-release induced by allergens."
  18. Ohnemus, U., et al. The hair follicle as an estrogen target and source. Endocr Rev. 2006 Oct;27(6):677-706. Epub 2006 Jul 28. “The transformation of terminal to vellus hair follicles in androgenetic alopecia is also associated with a discrete infiltration of perifollicular macrophages and with mast cell activation, which has been proposed to be inherent to the terminal-to-vellus switch itself.”
  19. Theoharides, C., et al. Mast cells and inflammation. Biochim Biophys Acta. 2012 Jan; 1822(1): 21–33. "Recent evidence indicates that mitochondria are involved in the regulation of mast cell degranulation. Mitochondrial uncoupling protein 2 (UCP2) inhibits mast cell activation."
  20. Martin, C. Endocrine Physiology. 1985. “Estrogens stimulate the secretion of growth hormone and prolactin. They also exert localized influences. The most prominent of which is rapidly developing retention of water in the uterus. This is attributed to the release of histamine and prostaglandins.” "Estradiol promotes histamine release, and histamine accelerates endometrial estradiol uptake.” "Subthreshold amounts of estrogen and histamine synergize to invoke a response."
  21. Martin, C. Endocrine Physiology. 1985. "Sustained high estrogen concentrations increase both insulin requirements and insulin secretion."
  22. Goodman, M., et al. Short-term effects of oestradiol benzoate in normal, hypophysectomized and alloxan-diabetic male rats. "In normal rats, OEB decreased plasma glucose, increased plasma immunoreactive insulin, growth hormone and corticosteroid levels, increased pancreatic β-cell granulation, and enhanced glucose stimulation of insulin release in vitro.” "These results suggest that OEB affects experimental diabetes by a direct action on the pancreas, promoting insulin formation, and possibly by an indirect action mediated through hypophysial secretions."
  23. Katoh, K., et al. Saturated fatty acids suppress adrenocorticotropic hormone (ACTH) release from rat anterior pituitary cells in vitro. Comp Biochem Physiol A Mol Integr Physiol. 2004 Feb;137(2):357-64. Addition of saturated fatty acids (butyrate, caprylate, laurate, palmitate and stearate) in a medium at 1 mmol/l, despite effects on the basal release, significantly reduced the ACTH release induced by CRH (1 nmol/l) stimulation. Caprylate suppressed ACTH release in a concentration-dependent manner. However, unsaturated C18 and C20 fatty acids (oleate, linolate, linolenate and arachidonate) at 1 mmol/l significantly increased the basal release, but none of them suppressed CRH (1 nmol/l)-induced ACTH release. In the presence of caprylate (1 mmol/l), CRH (1 nmol/l)-stimulated increase in cellular calcium ion concentration was diminished. From these results we conclude that saturated fatty acids have a suppressing effect on CRH-induced ACTH increase in primary cultured rat anterior pituitary cells.
  24. Speake, B., et al. The preferential mobilisation of C20 and C22 polyunsaturated fatty acids from the adipose tissue of the chick embryo: potential implications regarding the provision of essential fatty acids for neural development. Biochim Biophys Acta. 1997 Apr 21;1345(3):317-26. "The composition of the FFA released into the medium under conditions of basal (i.e., unstimulated) lipolysis was markedly different in several respects from that of the TAG from which it originated. The polyunsaturated fatty acids, 20:4n-6, 20:5n-3, 22:5n-3 and 22:6n-3, were consistently found to be preferentially released into the medium, whereas the major fatty acyl constituents of the tissue, 16:0 and 18:1n-9, were selectively retained in the TAG. For example, at day 18 of development, the proportions (% w/w of fatty acids) of 20:5n-3 and 22:6n-3 released into the incubation medium were respectively 6.5 and 7.5 times higher than in the original tissue TAG.” "Although the regulation of fatty acid mobilisation from adipose tissue TAG has been an area of intensive research for 3 decades, relatively few studies have focussed on the composition of the mobilised fatty acids” "Their observations on the differential release of 52 fatty acids into the medium during the in vitro incubation of rat adipocytes were found to be summarised by the general rule that the Relative Mobilisation of a particular fatty acid is directly proportional to its degree of unsaturation and inversely proportional to its chain length. Thus the proportion of highly polyunsaturated fatty acids such as 20:4n-6 and 20:5n-3 was significantly greater in the medium FFA than in the original cellular TAG.” "A mechanistic explanation for selective mobilisation was proposed based on the differential aqueous solubilities of the various fatty acids. It was suggested that TAG species containing the more polar short and unsaturated fatty acids would be preferentially located at the periphery of the cytoplasmic lipid droplet of the adipocyte and would therefore be more accessible to the hormone sensitive lipase…”
  25. Garza, L.A., et al. Prostaglandin d2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia. Sci Transl Med. 2012 Mar 21;4(126):126ra34. “Given the androgens are aromatized into estrogens, these results may be relevant to hair growth and alopecia in both men and women. Thus, these or similar pathways might be conserved in the skin and suggest that sex hormone regulation of Ptgds may contribute to the pathogenesis of AGA.” “…demonstrates elevated levels of PGD2 in the skin and develops alopecia, follicular miniaturization, and sebaceous gland hyperplasia, which are all hallmarks of human AGA. These results define PGD2 as an inhibitor of hair growth in AGA and suggest the PGD2-GPR44 pathway as a potential target for treatment.”
  26. Peters, S., et al. Effect of prostaglandin D2 in modulating histamine release from human basophils. J Pharmacol Exp Ther. 1984 Feb;228(2):400-6. "Prostaglandin (PG) D2 is the major cyclooxygenase metabolite of arachidonic acid released after immunologic stimulation of mast cells. In this report, we demonstrate that this PG is unlike other PGs previously investigated in that it enhances human basophil histamine release at concentrations of 1 to 100 nM.” "These data suggest that PGD2 may play an important role in allergic and immunologic reactions and suggest a mechanism by which mast cells and basophils can interact during these reactions."
  27. Liu, M., et al. Evidence for elevated levels of histamine, prostaglandin D2, and other bronchoconstricting prostaglandins in the airways of subjects with mild asthma. Am Rev Respir Dis. 1990 Jul;142(1):126-32. "Histamine and certain cyclooxygenase products of arachidonic acid have been implicated as mediators of inflammation and are potent constrictors of human airways.” "Levels of PGD2, 9 alpha,11 beta-PGF2 and PGF2 alpha were 12 to 22 times higher in asthmatic than in normal subjects…” "Levels of PGD2 and 9 alpha,11 beta-PGF2 were increased nearly tenfold in asthmatic subjects compared with those in rhinitic subjects…” "Histamine levels were increased fourfold in asthmatic subjects compared with those in normal subjects (p less than 0.001); however, similar increases were found in rhinitic subjects."
  28. Jaworsky, C., et al. Characterization of inflammatory infiltrates in male pattern alopecia: implications for pathogenesis. Br J Dermatol. 1992 Sep;127(3):239-46. "Ultrastructural studies disclosed measurable thickening of the follicular adventitial sheaths of transitional and alopecic zones compared with those in the non-alopecic zones. This finding was associated with mast cell degranulation and fibroblast activation within the fibrous sheaths.” "The data suggest that progressive fibrosis of the perifollicular sheath occurs in lesions of pattern alopecia, and may begin with T-cell infiltration of follicular stem cell epithelium. Injury to follicular stem cell epithelium and/or thickening of adventitial sheaths may impair normal pilar cycling and result in hair loss.” "Mast cell degranulation was a prominent feature in sheaths of affected follicles, and was associated with ultrastructural evidence of biosynthetic activation of fibroblasts resulting in sheath widening and fibrosis.”
  29. Mahe, Y.F., et al. Androgenetic alopecia and microinflammation. Int J Dermatol. 2000 Aug;39(8):576-84. "Only 55% of male pattern AGA patients with microinflammation had hair regrowth in response to minoxidil treatment, which was less than the 77% of patients with no signs of inflammation, suggesting that, to some extent, perifollicular microinflammation may account for some cases of male pattern AGA which do not respond to minoxidil. Another study on 412 patients (193 men and 219 women) confirmed the presence of a significant degree of inflammation and fibrosis in at least 37% of AGA cases.""Despite such a reduction of circulating 5-DHT levels, however, a number of individuals (60–70%) still remained unresponsive to this treatment, indicating again that simple dysregulation of 5-DHT synthesis levels or a genetic polymorphism of 5α-R genes cannot account for all cases of AGA, and a polygenic etiology should be considered.” "The fact that the success rate of treatment with either antihypertensive agents, or modulators of androgen metabolism, barely exceeds 30% means that other pathways may be envisioned.” "Once aa is released from the cell membrane phospholipids by phospholipase A2 it is metabolized through a complex equilibrium between two families of enzymes, generating either prostaglandins (PGs) (through the activity of PGH synthases, PGHSs) or leukotrienes…” "This upregulation of androgen metabolism by proinflammatory cytokines remains, however, to be established at the pilosebaceous unit level.” "We know now that, at least in about one-third of cases, the tool which causes the lethal damage is a microinflammatory process.” 
  30. Martin, C. Endocrine Physiology. 1985. "Plasma PRL concentrations undergo diurnal variations that include sleep-associated elevations. The levels also rise in response to demanding activity and some forms of stress, and sharp peaks have been observed following food ingestion. Estrogens are potent stimulants that affect DA turnover in the brain. In cycling females. plasma PRL reaches its highesl levels during the times of maximal estrogen secretion."
  31. Montagna, W., et al. Hair Research. 1981. 
  32. Pinkus, F. The story of a hair root. J Invest Dermatol. 1947 Aug;9(2):91-3. "In spite of the differences in generation of hair, one feature is constant. ‘Summer’ hair is more long-lived than ‘winter’ hair in man, a fact established by earlier observations.”
  33. Iyenger, B. The hair follicle: a specialised UV receptor in the human skin? Biol Signals Recept. 1998 May-Jun;7(3):188-94. “From the present study, it appears that light is guided to the hair bulb to activate the melanocytes within the hair follicles. Thus the hair follicles function as specialised UV receptors in the skin responding to nuances of seasonal photic inputs in man. This would explain the coat colour changes seen in animals exposed to large variations in the day-night cycle.”
  34. Trüeb, R., and Tobin, D. Aging Hair. 2010.
  35. Kizer, J., et al. The nyctohemeral rhythm of plasma prolactin: effects of ganglionectomy, pinealectomy, constant light, constant darkness or 6-OH-dopamine administration. Endocrinology. 1975 May;96(5):1230-40. "In addition, there is evidence that environmental lighting in the form of altered length of a photo periods has a profound influence upon the endocrine system.” "Plasma prolactin, on the other hand, is decreased in rats exposed to constant light and increased by constant darkness.""In male rats maintained on a 12 h light-dark schedule (6 AM-6 PM), there is a nyctohemeral cycle of plasma prolactin which consists of a nadir at 11:30 AM and an apogee at approximately 11:30 PM.” "…there is a nyctohemeral rhythm of plasma prolactin, which is reversed by constant light…" “ ...a rhythm of plasma prolactin develops in constant light which is the exact opposite of the normal diurnal variation…”
  36. Relkin, R., et al. Effects Of Pinealectomy And Constant Light And Darkness On Prolactin Levels In The Pituitary And Plasma And On Pituitary Ultrastructure Of The Rat. 1972. "Compared with sham-operated diurnally-illuminated controls, constant darkness caused a decrease in pituitary prolactin content and a rise in plasma prolactin levels. Pinealectomy or constant illumination reversed the effect of constant darkness, resulting in an increase in pituitary prolactin content and a fall in plasma prolactin levels when compared with sham-operated diurnally-illuminated controls."
  37. Schmidt JB. Hormonal basis of male and female androgenic alopecia: clinical relevance. Skin Pharmacol. 1994;7(1-2):61-6. "Our findings showed a significant elevation of F [cortisol] in both male and female AH patients compared to controls, pointing to the suprarenes as a contributing factor in AH. This is confirmed by the observation of exacerbated AH in periods of increased stress.” "The mainly peripheral activity of this hormone and elevated E2 levels in males stress the importance of androgen metabolism especially at the peripheral level.” "Another significant finding was elevated PRL after TRH stimulation. Thus, the androgen-stimulating effect of PRL may also play a role in female AH. Our findings show multilayered hormonal influences in AH."
  38. Foitzik, K., et al. Human scalp hair follicles are both a target and a source of prolactin, which serves as an autocrine and/or paracrine promoter of apoptosis-driven hair follicle regression. Am J Pathol. 2006 Mar;168(3):748-56. "PRL has also been implicated in the pathogenesis of androgenetic alopecia by modulation of androgens, and hyperprolactinemia is associated with an androgenetic alopecia-type hair loss pattern, along with hirsutism (in females)."
  39. Rillema, J. A. Mechanism of prolactin action. Federation Proceedings [1980, 39(8):2593-2598] "Subsequent actions of prolactin may involve the following: a) an increased intracellular concentration of potassium and a reduced level of sodium, b) an increased level of cGMP and a reduced level of cAMP, c) an enhanced rate of prostaglandin biosynthesis mediated by a stimulation of phospholipase A2 activity, and d) a stimulation of polyamine synthesis."
  40. Kellner, R. et al. Hyperprolactinemia, distress, and hostility. Am J Psychiatry. 1984 Jun;141(6):759-63. “Hyperprolactinemic patients were significantly more hostile, depressed, and anxious and had more feelings of inadequacy than family practice patients and non patient employees. The authors recommend measuring the serum prolactin levels of women with depression, hostility, anxiety, and symptoms or signs suggestive of hyperprolactinemia.”
  41. Hollander, E., et al. Prolactin and sodium lactate-induced panic. Psychiatry Res. 1989 May;28(2):181-91. "Sodium lactate infusions reliably induce panic attacks in panic disorder patients but not in normal controls, but the mechanism underlying this response is unknown. We studied the plasma prolactin response to infusion of 0.5 molar sodium lactate in 38 patients with panic disorder or agoraphobia with panic attacks, and 16 normal controls. As expected, baseline plasma prolactin was significantly higher in female subjects than in male subjects. However, the males who experienced lactate-induced panic had significantly elevated baseline prolactin levels compared to male nonpanickers and controls. Prolactin levels increased in all groups during lactate infusion, which may reflect osmotic effects, but were blunted in the late panickers compared to nonpanickers and controls. The elevated baseline prolactin for male panickers supports a relationship between prolactin and anticipatory anxiety. The blunted prolactin response for late panickers suggests a net diminution, rather than a sensitization, of prolactin response in panic anxiety."
  42. Raymond, J., et al. Comparison between the plasma concentrations of prolactin and parathyroid hormone in normal subjects and in patients with hyperparathyroidism or hyperprolactinemia. J Clin Endocrinol Metab. 1982 Dec;55(6):1222-5. "These results show that an excess of plasma PRL is associated with an excess of plasma PTH and vice versa."
  43. Spätling, L., et al. Influence of prolactin on metabolism and energy production in perfused corpus luteum bearing bovine ovaries. "Under the influence of PRL anaerobic glucose metabolism was stimulated by 40.5% and oxidative phosphorylation was inhibited. Energy production from aerobic glucose metabolism rose by only 0.25%.” "This may indicate that PRL is the "older" hormone in phylogenetic terms."
  44. Martin, C. Endocrine Physiology. 1985. “When moderate dosages of PTH are injected into parathyroidectomized animals, the responses include increased urinary excretion of sodium, phosphate, bicarbonate, and amino acids, along with decreased excretion of calcium and hydrogen."
  45. Strider, J.W., et al. Treatment of mast cells with carbon dioxide suppresses degranulation via a novel mechanism involving repression of increased intracellular calcium levels. Allergy. 2011 Mar;66(3):341-50. "Results from this study provide the first evidence of a unique regulatory mechanism by which CO₂ inhibits mast cell degranulation and histamine release by repressing stimulated increases in intracellular calcium. Thus, our data provide a plausible explanation for the reported therapeutic benefit of noninhaled intranasal delivery of 100% CO₂ to treat allergic rhinitis."
  46. Ljunhgall, S., et al. Effects of epinephrine and norepinephrine on serum parathyroid hormone and calcium in normal subjects. Exp Clin Endocrinol. 1984 Dec;84(3):313-8. "During infusion of epinephrine there was a clear rise of the serum parathyroid hormone (PTH) levels already at the lowest concentration. Concomitantly there was a fall in the serum concentrations of calcium. The PTH levels returned to baseline promptly after termination of infusion whereas hypocalcaemia persisted up to 30 minutes, indicating a primary response of PTH to epinephrine.” (Low thyroid people tend to have very high adrenaline.)
  47. Richalet, J.P., et al. Effects of high-altitude hypoxia on the hormonal response to hypothalamic factors. Am J Physiol Regul Integr Comp Physiol. 2010 Dec;299(6):R1685-92. "Thyroid hormones were elevated at altitude (+16 to +21%), while TSH levels were unchanged, and follicle-stimulating hormone and prolactin decreased, while luteinizing hormone was unchanged."
  48. Kunelius, P., et al. The effects of transdermal dihydrotestosterone in the aging male: a prospective, randomized, double blind study. J Clin Endocrinol Metab. 2002 Apr;87(4):1467-72. "The objective of the study was to investigate the effects of dihydrotestosterone (DHT) gel on general well-being, sexual function, and the prostate in aging men. A total of 120 men participated in this randomized, placebo-controlled study (60 DHT and 60 placebo). All subjects had nocturnal penile tumescence once per week or less, andropause symptoms, and a serum T level of 15 nmol/liter or less and/or a serum SHBG level greater than 30 nmol/liter. The mean age was 58 yr (range, 50-70 yr).” "Serum concentrations of LH, FSH, E2, T, and SHBG decreased significantly during DHT treatment. Treatment with DHT did not affect liver function or the lipid profile. Hemoglobin concentrations increased from 146.0 +/- 8.2 to 154.8 +/- 11.4 g/liter, and hematocrit from 43.5 +/- 2.5% to 45.8 +/- 3.4% (P < 0.001). Prostate weight and prostate-specific antigen levels did not change during the treatment. No major adverse events were observed. Transdermal administration of DHT improves sexual function and may be a useful alternative for androgen replacement. As estrogens are thought to play a role in the pathogenesis of prostate hyperplasia, DHT may be beneficial, compared with aromatizing androgens, in the treatment of aging men."
  49. Casey, R., et al. Antiestrogenic action of dihydrotestosterone in mouse breast. Competition with estradiol for binding to the estrogen receptor. J Clin Invest. 1984 Dec;74(6):2272-8. "...Feminization in men occurs when the effective ratio of androgen to estrogen is lowered.” "Administration of estradiol via silastic implants to castrated virgin CBA/J female mice results in a doubling in dry weight and DNA content of the breast. The effect of estradiol can be inhibited by implantation of 17 beta-hydroxy-5 alpha-androstan-3-one (dihydrotestosterone), whereas dihydrotestosterone alone had no effect on breast growth. Estradiol administration also enhances the level of progesterone receptor in mouse breast." "Dihydrotestosterone does not compete for binding to the progesterone receptor, but it does inhibit estrogen-mediated increases of progesterone receptor content of breast tissue cytosol from both control mice and mice with X-linked testicular feminization (tfm)/Y.” "Dihydrotestosterone also promotes the translocation of estrogen receptor from cytoplasm to nucleus; the ratio of cytoplasmic-to-nuclear receptor changes from 3:1 in the castrate to 1:2 in dihydrotestosterone-treated mice. Thus, the antiestrogenic effect of androgen in mouse breast may be the result of effects of dihydrotestosterone on the estrogen receptor. If so, dihydrotestosterone performs one of its major actions independent of the androgen receptor."