Hormones and hair
Ovcharenko Yu.S. Hormones and Hair //Les Nouvelles Esthetiques Ukraine. — 2015. — No.2 (90). — pp. 64-71
Anti-aging medicine is concerned with finding and applying treatment methods aimed at changing, slowing, or weakening the ailments that progress with age. Among the many approaches, specialists pay particular attention to hormone replacement therapy, based on the assumption that the gradual reduction and imbalance of hormones with age is closely linked to the aging process. In both sexes, levels of growth hormone, melatonin, dehydroepiandrosterone (DHEA) and its sulfate form (DHEAS) reach their peak in the third decade of life and then gradually decline. In addition, men experience a steady decline in the production of biologically active free testosterone of roughly 1% per year. A sharp cessation of sex hormone production is not typical for men, unlike women [1].
Target organs, which include the skin and hair, signal these involutional changes. The hair follicle (HF) is a constantly changing organ, capable of regenerating new and different hair under hormonal regulation, ensuring that hair type matches the season, age, or sex. It is therefore not only a major marker of aging, but also a stigma that reflects endocrine and somatic status. Additionally, since hormones were identified as an important factor in the hair growth cycle, new therapeutic possibilities have emerged that make it possible to influence hair growth through the regulation of hormonal effects.
Among the hormones affecting hair condition, the most significant are androgens, estrogens, thyroid and parathyroid hormones, prolactin, corticosteroids, growth hormone, and melatonin [2]. In this publication, we propose to examine these clinically important and sometimes paradoxical interactions in more detail.
Influence of Androgens on Hair Growth
Androgens are the main regulator of human hair growth, with paradoxical differences in follicular response depending on body location: from stimulating beard growth, for example, to stopping hair growth on the scalp, without any effect on the eyelashes. At the same time, the sensitivity of the HF to androgens varies across different growth zones on the head: it is elevated in the crown and vertex area, leading to slow progression of miniaturization; in the occipital area, the HF is insensitive to androgen action. Transplanted follicles retain this diversity of responses, and this fact underlies corrective cosmetic surgeries for androgenetic alopecia (AGA) [3]. One of the first signs of puberty is the gradual replacement of the finest vellus hair with larger pigmented intermediate hair on the pubis and later in the armpits, eventually producing larger, darker terminal hair. These changes occur in parallel with the pubertal rise in plasma androgens, which occurs earlier in girls than in boys. The same transformations occur in many other areas of the body in young men, leading to beard growth, pubic hair, the appearance of chest hair, and an increase in hair on the limbs — features by which an adult man is easily distinguished. Beard growth increases sharply during puberty and continues to intensify until approximately age 35–40, while terminal hairs on the chest or in the ear canals may only appear several years after puberty. However, androgens have no obvious effect on many follicles that produce terminal hair in childhood, such as the eyelashes, or on many scalp follicles. Paradoxically, in genetically predisposed individuals, androgens promote the gradual transformation of large terminal scalp follicles into vellus follicles, causing AGA. Beyond the role of androgens, the precise mechanisms of such responses within the hair follicle are not fully understood, although it is clear that these responses are individual and depend on the follicle's location on the body [4].
Steroid hormones regulate cell growth, differentiation, and metabolism. Adrenal gland dysfunction can lead either to increased glucocorticoid activity, or to insufficient activity, excessive androgen activity, or insufficient androgen activity.
Increased androgen activity manifests as early puberty in children and virilization in women, while in men it proceeds asymptomatically. Androgen excess can result from a variety of conditions of both the adrenal glands and the ovaries. These include congenital adrenal hyperplasia (adrenogenital syndromes), adrenal tumors, Cushing's syndrome, polycystic ovary syndrome and ovarian tumors, as well as other neoplasms unrelated to the adrenal glands and ovaries. Dermatological signs of virilization include, among others, hirsutism and AGA. Rapid onset of virilization signs, DHEAS levels exceeding 600 ng/L, and free testosterone levels exceeding 200 ng/L suggest the presence of an androgen-secreting tumor. Adrenogenital syndromes result from genetically determined disorders of cortisol synthesis. Increased ACTH production, which provokes excessive adrenal stimulation, combined with a block in the cortisol production pathway, leads to accumulation of adrenal androgens, causing virilization in women. Partial 21-hydroxylase deficiency may present as hirsutism, even in elderly women. Hypercortisolism, or Cushing's syndrome, represents the signs of excessive cortisol secretion by the adrenal glands from any cause. This condition is most often iatrogenic, resulting from glucocorticosteroid (GCS) intake, however similar signs are present in patients with endogenous hypercortisolism, due to adrenocorticotropic hormone (ACTH) production by the pituitary gland (Cushing's disease), adrenal tumors, or ectopic ACTH production. Hypertension and weight gain are early manifestations of the disease; among the typical skin symptoms observed are fat redistribution, truncal obesity, a "moon" face and thin limbs, skin atrophy with easy bruising, pigmented facial hypertrichosis, general increase in lanugo hair, and alopecia. These phenomena may initially be dismissed as secondary to normal skin aging.
Insufficient androgen activity can lead to decreased libido, loss of muscle tone, dry skin, and reduced vitality. The development of androgen deficiency after puberty is characterized by slow-growing pubic hair, since the maintenance of already-formed pubic hair depends less on androgens than its initial production.
Addison's disease is chronic adrenal cortex insufficiency. The most striking dermatological sign is increased skin pigmentation; hair may also darken [1].
Menopause and Hair Condition
During menopause, the ovaries stop producing the hormones responsible for reproduction and that can affect sexual behavior. A decline in circulating estrogen levels affects the entire chain of a woman's reproductive function — from the brain to the skin. The typical age of menopause onset falls between 45 and 55 years. Postmenopausal women face dermatological problems such as atrophy, dryness, itching, loss of skin elasticity and flexibility, increased skin vulnerability, dry hair, and alopecia [5]. It is currently believed that these phenomena are caused by low estrogen levels.
Clinical evidence of estrogen's influence on hair growth has been obtained by observing the effects of pregnancy, hormonal medications affecting estrogen metabolism, and menopause on hair condition. During the second half of pregnancy, the proportion of anagen hairs increases from 85 to 95% [6], while the proportion of hairs with larger shaft diameter is also higher than in women of the same age who are not pregnant. After childbirth, a rapid transition of follicles from a prolonged anagen phase to the catagen phase, and then telogen, occurs, followed by increased hair loss noticeable after 1–4 months (postpartum effluvium). Increased hair loss observed in many women between 2 weeks and 3–4 months after discontinuing oral contraceptives resembles the hair loss typically observed after childbirth. Contraceptive pills or hormone replacement therapy with progestins that have androgenic activity (norethisterone, levonorgestrel, tibolone) more often cause generalized hair loss in genetically predisposed women. It has been suggested that in genetically predisposed individuals, the estrogen-to-androgen ratio may act as a triggering factor for hair loss in women [7]. This is consistent with hair loss provoked in predisposed women by aromatase inhibitor treatment for breast cancer [8]. Finally, postmenopausal women show an increased tendency toward male-pattern hair loss [9].
Estrogens undoubtedly perform an important function in many areas of human skin, including the epidermis, dermis, vasculature, hair follicle, as well as the sebaceous and sweat glands, playing a significant role in skin aging, pigmentation, hair growth, and sebum production [10]. In addition to altering gene transcription via estrogen-responsive elements, 17-beta-estradiol (E2) also alters androgen metabolism in the pilosebaceous complex, which itself demonstrates notable aromatase activity — the key enzyme in converting androgens to E2. Thus, the hair follicle is simultaneously both a target for estrogens and their source. It has been established that estrogens influence hair follicle growth and cycling by binding to locally expressed high-affinity estrogen receptors (ER). The discovery of a second intracellular estrogen receptor (ERbeta), which performs cellular functions distinct from the classical estrogen receptor (ERalpha), as well as the identification of membrane estrogen receptors in the hair follicle, are areas requiring further research to understand the mechanism of estrogen's action on hair growth [11].
Influence of Thyrotropic Hormones
Thyroid hormones influence the growth and differentiation of many tissues and the body's overall energy expenditure, as well as the turnover of many substrates, vitamins, and other hormones. Thyroid activity affects oxygen consumption, protein synthesis, and mitosis, and therefore has significant importance for hair formation and growth. Expression of the thyroid hormone beta-1 receptor has been demonstrated in the human hair follicle. Triiodothyronine has been shown to significantly increase human hair survival in vitro [12]. The influence of thyroid hormone activity on hair is most apparent in cases of deficiency or excess. Schell et al. [13], using flow cytometry to analyze DNA for the first time, demonstrated the influence of thyroid hormones on the in vivo cell cycle dynamics of human scalp hair bulbs. Clinically, the effects of thyroid disease on hair are nonspecific; however, the associated symptoms and signs of thyroid hormone deficiency or excess can provide important data for identifying thyroid disease.
Hypothyroidism results from thyroid hormone deficiency. It most often occurs due to chronic autoimmune thyroiditis (Hashimoto's disease) or iatrogenic thyroid ablation (treatment with sodium iodide-131 or surgical thyroidectomy). Hypothyroidism is observed in women approximately ten times more often than in men, and is particularly common between the ages of 40 and 60. Patients have dry, rough skin; in severe cases, the condition may resemble ichthyosis. Facial skin appears puffy, with increased wrinkling, and the face may have an "empty," expressionless appearance. Hair becomes dull, coarse, and brittle; diffuse alopecia with thinning of the lateral eyebrow area may be observed. Hair growth rate slows, and the proportion of telogen hairs increases. Alopecia is characterized by a gradual onset. In genetically predisposed individuals, prolonged hypothyroidism may be accompanied by AGA. The presumed mechanism is an increase in free androgens in plasma [1].
Hyperthyroidism is caused by an excess of circulating thyroid hormones. The most common cause of hyperthyroidism today is Graves' disease, with an estimated prevalence in the population of patients aged 60 and older of 5.9%. This is an autoimmune disease that affects women far more often than men. The most common symptoms of hyperthyroidism are systemic rather than cutaneous and are due to the hypermetabolic state known as thyrotoxicosis. Nevertheless, diffuse hair loss is observed in 20–40% of cases, and axillary hair loss in 60% [14]. The severity of hair loss does not correlate with the severity of thyrotoxicosis. The hair itself is thin, soft, straight, and reportedly does not hold a permanent wave. It should also be kept in mind that hair loss can be caused by medications used to treat thyroid conditions, or drugs that interfere with thyroid metabolism: carbimazole, thiamazole, methylthiouracil, propylthiouracil, iodine, levothyroxine, lithium, and amiodarone [2].
Hypoparathyroidism is most often observed in the geriatric population following inadvertent removal of the parathyroid glands during thyroid surgery, or radical neck dissection for oncological disease. Patients experience episodes of hypocalcemia with tetany. Hair thinning or complete hair loss may be observed. Horizontal grooves (Beau's lines) often form on the nails, appearing at the nail base approximately three weeks after a tetanic episode. Tooth enamel damage may be mistakenly interpreted as poor oral hygiene, especially in elderly patients [1].
Prolactin and Hair Loss
Prolactin is a lactotropic hormone from the anterior pituitary gland that stimulates mammary gland growth, leads to lactation, and triggers the instinct to care for offspring (including in males). Prolactin secretion follows a circadian rhythm via mediator substances in the hypothalamus — prolactin-releasing hormone (PRH+), prolactin-release-inhibiting hormone (PRIH−), and dopamine (−). Clinically, hyperprolactinemia manifests as the galactorrhea-amenorrhea symptom complex with hair loss, galactorrhea (in 30–60% of cases), menstrual cycle abnormalities, secondary amenorrhea, seborrhea, acne, and hirsutism. The interactions between prolactin and hair growth are complex; prolactin affects the hair follicle not only directly, but also indirectly, through increased adrenal cortex para-androgen levels. Consequently, hyperprolactinemia can be a cause not only of diffuse telogen hair loss, but also of AGA and hirsutism [15]. Schmidt's work indicates a possible influence of prolactin on AGA in women [16].
Significance of Growth Hormone
Growth hormone, or somatotropin, is also important for hair, as is evident from clinical observation of conditions with elevated or reduced levels of this hormone. If the growth factor receptor has been altered by mutations, cells respond more weakly to somatotropin. This condition is called somatotropin resistance, or Laron syndrome. In addition to proportional dwarfism, which manifests in childhood, this syndrome is characterized by hypotrichosis, premature alopecia, and hair shaft abnormalities [17]. In this case, the action of GH is manifested indirectly: it binds to the growth hormone receptor, which is a transcription factor and increases the expression of insulin-like growth factor 1 (IGF-1). IGF-1 is a growth factor structurally similar to insulin, and as a growth factor it influences cell growth and differentiation. IGF-1 also plays a certain role in the development of hair follicles and hair growth. Itami and Inui found that IGF-1 is produced in the dermal papillae of hair follicles. Since the presence of IGF-1 receptor mRNA in keratinocytes has been demonstrated, it is suggested that IGF-1 from dermal papilla fibroblasts is able to induce hair growth by stimulating the proliferation of hair follicle keratinocytes [12]. Conversely, hypertrichosis develops in acromegaly [2].
Melatonin in Hair Life
Originally discovered as a neurohormone produced and released by the pineal gland during daily rhythms [18], melatonin regulates various physiological processes: seasonal biorhythms and daily sleep-wake cycles, and influences the aging process [19]. Nevertheless, the most notable feature of melatonin is its protective and anti-apoptotic action, which can ensure the functional integrity of non-tumor cells thanks to its strong antioxidant properties and ability to actively scavenge free radicals [20, 21]. These described potent antioxidant properties of melatonin (N-acetyl-5-methoxytryptamine) allow it to be considered as a possible option for counteracting oxidative stress associated with generalized hair loss, as well as AGA, and as a preventive measure against graying [22]. According to the latest data, numerous peripheral organs are not only targets of melatonin's biological activity, but also sites of extrapineal melatonin synthesis, regulation, and metabolism. Human skin has been shown to possess a melatoninergic enzyme system that fully expresses the specific enzymes needed for melatonin biosynthesis. In addition, keratinocytes, melanocytes, and fibroblasts have functional melatonin receptors involved in phenotypic effects such as cell proliferation and differentiation. An active melatoninergic antioxidant system has been identified in the skin, protecting against damage caused by ultraviolet (UV) exposure. Like the skin, human follicles synthesize melatonin and express its receptors, and an influence on the hair growth cycle is also observed [23].
Hormonal Treatment to Combat Signs of Aging
The results of the menopause and hormone replacement therapy study conducted by the Women's Health Initiative [24] have led many women to develop a negative attitude toward systemic estrogen replacement therapy. In a study of topical estrogen supplements with E2 or its stereoisomer 17-alpha-estradiol (alfatradiol), only a modest therapeutic effect was recorded [25].
In using anti-aging hormonal preparations containing recombinant human GH, Edmund Chein of the Palm Springs Life Extension Institute reported improvements in hair thickness and structure in 38% of patients, as well as isolated cases of hair darkening and improved growth [26].
In individuals with androgenetic alopecia, hormonal therapy with androgens, androgen precursors (DHEA), or progestins with androgenic action (norethisterone, levonorgestrel, tibolone) may provoke hair loss.
Blocking androgen receptor activation with anti-androgens is theoretically useful, but impractical in reality, since anti-androgens block all actions of androgens, leading to unacceptable side effects on the expression of male characteristics in men and possible feminization of a male fetus in a pregnant woman. Nevertheless, cyproterone acetate — an anti-androgen with progestogenic action, indicated for hirsutism and acne [27] — is also used for AGA in women, usually in combination with estrogen as an oral contraceptive for premenopausal women. This treatment method stabilizes progression of the condition. Spironolactone, an aldosterone antagonist with moderate anti-androgenic action, is often used in the US [28].
The most successful modern therapeutic agent for treating AGA in men is oral finasteride — a type II 5α-reductase inhibitor that blocks the conversion of testosterone to 5α-dihydrotestosterone [29]. Finasteride, developed for treating benign prostatic hyperplasia, slows the progression of pattern hair loss; it is also useful for elderly men. It is unknown whether the inhibitor acts centrally or within the follicles, since plasma 5α-dihydrotestosterone levels are reduced [30]. Unfortunately, finasteride is not effective in postmenopausal women [31], and its use by premenopausal women is limited, similar to anti-androgens. Recently, a short-term trial of dutasteride, a dual type I and II 5α-reductase inhibitor, demonstrated a similar and possibly superior effect [32]. Melatonin, the principal secretory product of the pineal gland, is known to modulate hair growth and pigmentation, presumably acting as a key neuroendocrine regulator that links the coat phenotype and its function to photoperiod-dependent environmental changes and reproductive status. It has recently been demonstrated that significant melatonin synthesis occurs in human anagen scalp hair follicles (outside the pineal gland), where melatonin, through deactivation of apoptosis, may functionally participate in regulating the growth cycle. To study the effect of topical melatonin application on hair growth and loss in 40 healthy women complaining of hair loss, a double-blind, randomized, placebo-controlled study was conducted. A 0.1% melatonin solution or a placebo solution was applied to the scalp once daily for six months, and trichograms were performed. This pilot study was the first to demonstrate the effect of topical melatonin on hair growth in humans in vivo. The mechanism of action presumably involves activation of the anagen phase. Since melatonin has additional properties as a free radical scavenger and DNA repair activator, the anagen hair bulb, characterized by high metabolic and proliferative activity, may use in loco melatonin synthesis as its own cytoprotective strategy [20, 21, 23].
References
1. Ralph M. Trüeb. Desmond J. Tobin (Eds.) // Aging Hair — Springer, 2010. — 270 p.
2. Trüeb R. M. Hormone und Haarwachstum // Hautarzt. — 2010. — 61: 487–95.
3. Zlotogorski A., Shapiro D. [et al.]. Trichology / Ed. by A. Litus. Transl. from English by Yu. Ovcharenko. — Kyiv: Rud, 2013. — 160 p., ill.
4. Hamilton J. B. Age, sex and genetic factors in the regulation of hair growth in man: a comparison of Caucasian and Japanese populations. In: Montagna W, Ellis RA (eds) // The biology of hair growth. Academic Press, New York. — 1958. P. 399–433.
5. Phillips T. J., Demarcay Z., Sahu M. Hormonal effects on skin aging // Clin Geriatr Med. — 2001. — 17: 661–672.
6. Lynfield Y. L. Effect of pregnancy on the human hair cycle // J Invest Dermatol. — 1960. — 35: 323–327.
7. Riedel-Baima B., Riedel A. Female pattern hair loss may be triggered by low oestrogen to androgen ratio // Endocr. Regul. — 2008. — 42 (1): 13–16.
8. Carlini P., Di Cosimo S., Ferretti G., Papaldo P., Fabi A., Ruggeri E. M., Milella M., Cognetti F. Alopecia in a premenopausal breast cancer woman treated with letrozole and triptorelin // Ann Oncol. — 2003. — 14 (11): 1689–1690.
9. Venning V. A., Dawber R. P. Patterned androgenetic alopecia in women // J Am Acad Dermatol. — 1988. — 18: 1073–1077.
10. Thornton M. J. The biological actions of estrogens on skin // Exp Dermatol. — 2002. — 11 (6): 487–502.
11. Ohnemus U., Uenalan M., Conrad F., Handjiski B., Mecklenburg L., Nakamura M., Inzunza J., Gustafsson J. A., Paus R. Hair cycle control by estrogens: catagen induction via estrogen receptor (ER)-alpha is checked by ER beta signaling // Endocrinology. — 2005. — 146 (3): 1214–1225.
12. Billoni N., Buan B., Gautier B., Gaillard O., Mahé Y. F., Bernard B. A. Thyroid hormone receptor beta1 is expressed in the human hair follicle // Br J Dermatol. — 2000. — 142 (4): 645–652.
13. Schell H., Kiesewetter F., Seidel C., von Hintzenstern J. Cell cycle kinetics of human anagen scalp hair bulbs in thyroid disorders determined by DNA flow cytometry // Dermatologica. — 1991. — 182 (1): 23–26.
14. Williams R. H. Thyroid and adrenal interrelations with special reference to hypotrichosis axillaries in thyrotoxicosis // J Clin Endocrinol. — 1947. — 7: 52–57.
15. Orfanos C. E., Hertel H. Haarwachstumsstörungen bei Hyperprolaktinämie // Z Hautkr. — 1988. 63: 23–26.
16. Schmidt J. B. Hormonal basis of male and female androgenic alopecia: clinical relevance // Skin Pharmacol. — 1994. — 7: 61–66.
17. Lurie R., Ben-Amitai D., Laron Z. Laron syndrome (primary growth hormone insensitivity): a unique model to explore the effect of insulin-like growth factor 1 deficiency on human hair // Dermatology. — 2004. — 208: 314–318.
18. Lerner A. B., Case J. D., Takahashi Y. Isolation of melatonin, a pineal factor that lightens melanocytes // J Am Chem Soc. — 1958. — 80: 2587.
19. Karasek M., Reiter R. J. Melatonin and aging // Neuroendocrinol Lett. — 2002; 23 Suppl. 1: 14–6.
20. Reiter R. J., Tan D. X., Poeggeler B., Menendez-Pelaez A., Chen L. D., Saarela S. Melatonin as a free radical scavenger: implications for aging and age-related diseases // Ann N Y Acad Sci. — 1994. — 719: 1–12.
21. Slominski A., Fischer T. W., Zmijewski M. A., Wortsman J., Semak I., Zbytek B., et al. On the role of melatonin in skin physiology and pathology // Endocrine. — 2005. — 27: 137–48.
22. Tan D. X., Chen L. D., Poeggeler B., Manchester L. C., Reiter R. J. Melatonin: A potent, endogenous hydroxyl radical scavenger // Endocr J. — 1993. — 1: 57–60.
23. Fischer T. W., Trüeb R. M., Hänggi G., Innocenti M., Elsner P. Topical Melatonin for Treatment of Androgenetic Alopecia // Int J Trichol. — 2012. — 4: 236–45.
24. Rossouw J. E., Anderson G. L., Prentice R. L., et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial // JAMA. — 2002. — 288 (3): 321–333.
25. Blume-Peytavi U., Kunte C., Krisp A., Garcia Bartels N., Ellwanger U., Hoffmann R. Comparison of the efficacy and safety of topical minoxidil and topical alfatradiol in the treatment of androgenetic alopecia in women // J Dtsch Dermatol Ges. — 2007. — 5 (5): 391–395.
26. Chein E. Age reversal, from hormones to telomeres // WorldLink Medical Publishing. — 1998.
27. Fruzetti F. Treatment of hirsutism: antiandrogen and 5a-reductase inhibitor therapy. In: Azziz R, Nestler JE, Dewailly D (eds). Androgen excess disorders in women // Lippincott-Raven, Philadelphia. — 1997. — P. 787–797.
28. Hoffmann R., Happle R. Current understanding of androgenetic alopecia. Part II: clinical aspects and treatment // Eur J Dermatol. — 2000. — 10: 410–417.
29. Shapiro J., Kaufman K. D. Use of finasteride in the treatment of men with androgenetic alopecia (male pattern hair loss) // J Invest Derm Symp Proc. — 2003. — 8: 20–23.
30. Kaufman K. D., Olsen E. A., Whiting D., et al. Finasteride in the treatment of men with androgenetic alopecia // J Am Acad Dermatol. — 1998. — 39: 578–589.
31. Price V. H., Roberts J. L., Hordinsky M., Olsen E. A., Savin R., Bergfeld W., Fiedler V., Lucky A., Whiting D. A., Pappas F., Culbertson J., Kotey P., Meehan A., Waldstreicher J. Lack of efficacy of finasteride in postmenopausal women with androgenetic alopecia // J Am Acad Dermatol. — 2000. — 43: 768–776.
32. Olsen E. A., Hordinsky M., Whiting D., Stough D., Hobbs S., Ellis M. L., Wilson T., Rittmaster R. S., Dutasteride Alopecia Research Team. The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride // J Am Acad Dermatol. — 2006. — 55: 1014–1023.