Zhng Mioling（張妙良）, Yng Bilin（楊碧蓮), Wu Di（吳迪）, Zhng Liyun（張歷元）, Chen Xueyn(陳雪燕), Wng Yu'nong(王羽儂), Wu Meicho(吳美超), Ji Yunning(賈苑凝), nd Ci Lingling(蔡玲玲)＊

Mechanism of sex hormone level in biological clock disorder induced acne and analysis of TCM Pathogenesis

Zhang Miaoliang（張妙良）a, Yang Bilian（楊碧蓮)b, Wu Di（吳迪）a, Zhang Liyuan（張歷元）a, Chen Xueyan(陳雪燕)a, Wang Yu'nong(王羽儂)a, Wu Meichao(吳美超)a, Jia Yuanning(賈苑凝)a, and Cai Lingling(蔡玲玲)b＊

Acne vulgaris is a common chronic inflammatory disease of pilosebaceous units. And sex hormone level disorder has became a hot research topic in the pathogenesis of acne. Studies show that the biological clock disorder can result in the disorder of sex hormone levels which causes or aggravates acne. Biological clock disorder coincides naturally with “sleep rhythm disorder”in Traditional Chinese Medicine(TCM). In this paper, we will discuss the modern medical mechanism of the biological clock disorder resulting in acne from the angle of sex hormones, and analyze the TCM pathogenesis of the disease caused by the disorder of the biological clock.

Acne; Biological clock disorder; Sex hormone level; Etiology and pathogenesis of TCM

Ance Vulgaris is a common chronic and inflammatory disease of folliculosebaceous. The exact mechanism is still unclear. It is currently believed that occurrence of Ance Vulgaris is correlated with the immune response, genetic and psychological factors caused by endocrine factor and the excessive proliferation of propionibacterium acnes. Among these factors, the relationship between acne and sex hormone levels in the endocrine factors has become a hot research topic in recent years. Research shows that certain risk factors can induce the increase or comparative increase of serum androgen levels due to the decline of estrogen, or increase the sensitivity of the target organ to androgen, which can cause the ance, last and aggravate by increaseing the secretion of sebaceous glands1. Clinical observation also found that with the change of modern life rhythm, chronobiology disorders, caused by reduced sleep time, poor sleep quality, irregular work and rest and so on, lead to the increaseing in incidence and the decline in cure rate of ance. This view happens to coincide with“irregular life leads to disease”, which is proposed in “Huangdi’s Internal Classics, Plain Questions”.This article intends to explore the modern pathogenesis and analyze the tcm pathogenesisan of ance caused by chronobiology disorders.

INFLUENTIAL MECHANISM OF CHRONOBIOLOGY DISORDERS ON SEX HORMONES LEVELS

Biological clock, also known as biological rhythms, is cyclical behavioral and physiological phenomena in organism2. With the accelerating pace of life, lack of sleep, sleep disorder, sleep deprivation and irregular sleep, staying up late and other factors can cause biological rhythm disorders. Chronobiology disorders can affect the body’s hormone levels and thus lead to the occurrence and aggravation of acne.

Growth hormone

Growth hormone（GH） belongs to sleep dependent hormones. Studies have shown that both the short-term sleep deprivation and long-term sleep loss can reduce the secretion of GH3. By directly binding to receptors on the ovary or through the function of insulin like growth factor (IGF), namely, growth hormone/insulinlike growth factor-1 axis, GH acts on the ovary to increase the secretion of estradiol (E2)4. GH secretion decreased, resulting in reduced secretion of estrogen and relative increased secretion of androgen, which induced or aggravated ance.

Thyroid stimulating hormone

Thyroid stimulating hormone (TSH) is a hormone secreted by adenohypophysis to promote the growth and function of the thyroid gland and the secretion of thyroid hormone. Study found that long-term partial sleep deprivation in patients resulted in a significant decrease in TSH concentration5However, short-term total sleep deprivation increased the secretion of TSH6. On the second day after short-term total sleep deprivation, increased secretion of TSH would promote the secretion of thyroid hormone at high levels. But thyroid hormone’s half-life is longer, which would be negative feedback inhibition of the subsequentsecretion of TSH6, and eventually leads to the decrease of thyroid hormone level. The function change of hypothalamus-pituitarythyroid axis may affect the function of hypothalamus-pituitarygonadal axis7. Thyroid hormone can promote the secretion of luteinizing hormone (LH), increase the synthesis of sex hormone binding globulin (SHBG), and further multiply the conversion of androgen to estrogen7. Lack of sleep reduces the secretion of TSH, secondarily decreases the level of thyroid hormone, results in the decrease of estrogen.

Cortisol

Studies found that8,9, as a kind of endogenous stress, long-term or short-term sleep deprivation could activate hypothalamuspituitary-adrenal axis (HPA axis), and elevate the cortisol concentration in serum significantly. And the increased secretion of cortisol may also induce or aggravate acne10.

Insulin

It has been confirmed that insulin can effect on ovaries and play a similar role of gonadotropin1, here are some possible pathways: Increaseing the sensitivity of the ovaries to gonadotropin and stimulating the ovary secretesteroid hormones，together with the FSH and LH2; Inhibiting liver synthesis sex hormone binding globulin (SHBG); Increasing the level of serum free gonadal hormones, including testosterone (T)3; Increasing the pituitary’s sensitivity of gonadotropin-releasing hormone (GnRH). So patients with insulin resistance and compensatory hyperinsulinemia (have higher level of serum insulin) may have a higher level of gonadotropin, and their ovaries would be overstimulated, resulting in an increased androgen secretion4. A study found that sleep-deprivation can lead to abnormal glucose tolerance and increase the risk of insulin resistance5,6. In short, lack of sleep can induce increased male hormone level and consequently cause or aggravate acne.

Leptin

Leptin is a kind of hormone released by adipose tissue which can adjust the serum sex hormone level. It is known that leptin inhibiting testosterone release7, inhibiting insulin’s synthesis and secretion，and the power is proportional to the concentration8; directly inhibiting adrenal cortex to secrete glucocorticoids9. Chronic sleep deprivation can reduce leptin secretion[vii]. Low level lepti can not only lead to elevated testosterone level, but also cause subsequent increasing in the number of synthesis and secretion of insulin, both eventually lead to of which increased androgen secretion.Besides, a lower leptin level leads to a higher level of glucocorticoid, secretion of TRH and E2 would be inhibited, which would cause acne or make it worse.

Sex hormones

Testosterone (T) can promote skin cutin formation, make sebaceous glands active, cause the sebaceous glands catheter hyperkeratosis. It is found that sleeping late（over 23:00）can low down the E2 level in blood, and cause a relatively high T level, make acne even worse. Under the effect of 5 - alpha reductase, excessive T turns to dihydrotestosterone (DHT), which is more efficient. DHT combines with sebaceous glands cell receptors, stimulates the sebaceous glands cell hyperplasia, synthesizes and secretes sebum. As the results, hair follicle and sebaceous glandducts hyperkeratosis, sebum over accumulate in local sebaceous gland，from tiny Comedo——foundation of acne vulgaris10.

TCM PATHOGENESIS OF INNER CLOCk DISORDER

In traditional Chinese medicine，Acne is called “粉刺” “暗瘡”. TCM believes that dynamic balance of yin and yang depends on the regular cycle of sleeping and awaking, normal circulation of qi and xue relies on it too. Disorder of sleeping and awaking caused by any reason can broke the rhythm of yin and yang, hinder the circulation of qi and xue, and finally leads to illness. Modern medicine names the innate mechanism that controls periodicity of many physiological functions in living organisms as “inner clock”or “circadian rhythm”, and supports that circadian rhythm disorder takes an important part in the development of acne.

Inner clock disorder and liver-kidney Yin deficiency

In human’s body, Yin and Yang ebb and flow regularly. In ancient China, one day can be divided into 12 “ShiChen” (one of the 12 two-hour periods into which the day was traditionally divided, each being given the name of one of the 12 Earthly Branches), each is about two hours long and has being given the name of one of the 12 Earthly Branches. ZiShi, the period of the day from 11 pm to 1 am, is time for rendezvous of human body’s Yin and Yang. Falling asleep during this time can help heart and kidney harmonize with each other. Besides, Yin of the world is at its maximium at this time, falling asleep during ZiShi is helpful to enrich body’s Yin.That’s why TCM believe sleep before midnight is essential. According to the law of “Zi-Wu ebb flow”, Qi and blood disembogue into gallbladder channel at ZiShi, next, into liver channel. Liver takes the charges of storing blood，“The blood flows back to liver while one goes to bed”，people who has inner clock disorder can’t fell asleep during ZiShi and it is harmful to liver-Yin. Actually,“the liver and the kidney are the same source”，chronic inner clock disorder usually leads to asthenia of kidney-Yin. Liver-kidney yin deficiency is reallycommon among female adults acne patients and is one of the most important pathogenesis of acne: fire becomes excess from Yin deficiency，then deficient fire flares up and is obstructed at skin，which causes acne lesions.

Chronobiology Disorders causing Liver

Dysfunction

The most active period of the gallbladder meridian and liver meridian was from 11 p.m. to 1 a.m. and from 1 a.m. to 3 a.m. respectively, which was the important period of human metabolism. The liver possessed physiological characteristics of governing free flow of Qi, preference to dispersing and aversion to accumulating. If someone kept staying up during the period from 11 p.m. to 1 a.m. that would cause disorder of the liver-yin and kidney-yin, or liver dysfunction and emotional disturbance leading to pathogenic fire derived from stagnation of liver and further damaging the kidney-yin, what’s worse, pathogenic fire-heat ascending to the face would cause adult women acne due to liver depression and kidney deficiency. Many modern epidemiologic studies showed that biological rhythmic disorders caused by staying up late and night shifts can aggravate patient’s anxiety, depression and irritability and other negative emotions11, which induced or exacerbated acne.

Chronobiology disorders lead to damp-heat in the stomach and intestine

“Getting up at sunrise”, Mao Period of the day from 5 a.m to 7 a.m is the start of daylight and the best time to wake up, which is the most exuberant time of large intestine channel. Right now, the clear is up-bearing and the turbid is down-bearing. While due to the large intestine governing transmission and translation of the waste of food stuff, a host of healthy people defecate upon getting up, for a regular time of defecation. Now because more and more people form the habit of sleeping late, making the time of defecation delayed and irregular, which leads astriction. The lung and the large intestine are interior and exterior. Retained excrement stasises in large intestine, which produces damp-heat, that fumes on the face which cause acen. Modern research also shows that the abnormal sleeping function leads to the abnormal gastrointestinal function, effecting astriction. And astriction also has a close relationship with acen’s generating and aggravating.

DISCUSSION

In conclusion, according to analysis from the perspective of the modern medicine, Chronobiology disorders leads to anomaly of body’s endohormone standard, finally results in acen’s generating, whose primary cause is the imbalance of the sex hormone levels. According to analysis from the perspective of the traditional Chinese medicine’s pathogeny, Chronobiology disorders can lead to the function of internal organs disorder, especially liver and kidney, causing deficiency of liver-yin and kidney-yin, liver depression and kidney deficiency and so on. It provides direction for clinical treatment of TCM. On the one hand we should attach importance to the treatment from the standpoint of liver and kidney, meanwhile, the treatment should be combined with modern pharmacology result.We can use drugs with hormone effects to regular the bady’s sex hormone levels. On the other hand, it emphasizes the importance of the Chronobiology disorders in prevention and treatment of acne.We also need to educate patients in the clinical treatment that they could prevent diseases or accelerate healing by adjusting the schedule.

REFERENCES

1 W Robert, VK Somers. Sleep and the metabolic syndrome. Exp Physiol, 2007, 92(1):67-78.

2 Li Xiaoyong, Zhang Shihong. Polycystic ovary syndrome and regulating system of ovarian function. Guowai Yixue, 2003,30 (05):277-281.

3 Zhao Yingwei, Yuan Chongsheng, Sun Meng, et al. Relationship between obesity, cortisol, estrogen, other factors and type 2 diabetes. SUZHOU UNIVERSITY JOURNAL OF MEDICAL SCIENCE, 2007, 27(05):787-789.

4 Greisen S, Ledet T, Meller N, etc.Effects of leptin on basal and FSH stimulated steroidogenesis in human granulosa luteal cells.Acta Obstet Gynecol Scand, 2000,79(11):931-935.

5 W Robert, VK Somers. Sleep and the metabolic syndrome. Exp Physiol, 2007, 92(1):67-78.

6 Trenell MI. Marshall NS, Rogers NL. Sleep and metabolic control: waking to a problem? Clin Exp Pharmacol Physiol, 2007, 34(1-2):1-9.

7 Taheri S, Lin L, Austin D, etc. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med, 2004, 1(3):e62.

8 Tena-sempere M, Pinilla L, Gonzalez LC, etc. Leptin inhibits testosterone secretion from adult rat test is in vitro. J Endocrinol, 1999, 161(2):211-218.

9 Wang Lihong, Chen Jinfeng, Ma Hongying, et al. The inhibitory effect of leptin on islet β-cell insulin synthesis and secretion in rats.ACTA ACADEMIAE MEDICINAE MILITARIS TERTIAE, 2010, 32(08):850-851.

10 Brown SA, Kunz D, Dumas A, etc. Molecular insights into human daily behaviors. Proc Natl Acad Sci USA, 2008,105(5):1602-1607.

(Accepted: March 15, 2016)

a: Beijing University of Chinese Medicine, Beijing 100029, China

b: Dermatology Department, DongFang Hospital of Beijing University of Chinese Medicine, Beijing 100078, China

＊ E-mail: lingling89159166@126.com