- Email: [email protected]
Could tea polyphenols be beneficial for preventing the precocious puberty?
Accepted Manuscript Could tea polyphenols be beneficial for preventing the precocious puberty? Youmei Wu, Jialu Wang, Wei Cai, Xiuhua Shen PII: DOI: Reference:
S0306-9877(16)30368-1 http://dx.doi.org/10.1016/j.mehy.2016.07.017 YMEHY 8348
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
18 July 2016 18 July 2016
Please cite this article as: Y. Wu, J. Wang, W. Cai, X. Shen, Could tea polyphenols be beneficial for preventing the precocious puberty?, Medical Hypotheses (2016), doi: http://dx.doi.org/10.1016/j.mehy.2016.07.017
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Could tea polyphenols be beneficial for preventing the precocious puberty? Youmei Wua, Jialu Wanga, Wei Caia,b,Ph.D. M.D., Xiuhua Shena,b, Ph.D. M.D. a
Department of Nutrition, School of Public Health, Shanghai Jiao Tong University,
Shanghai200025, China b
Department of Clinical Nutrition, Xin Hua Hospital, School of Medicine, Shanghai
Jiao Tong University, Shanghai200092, China Address for Correspondence: Xiuhua Shen, Department of Clinical Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai200092, China Tel: +86-21-25076419 Fax numbers: +86-21-65011627 E-mail: [email protected]
Introduction Precocious puberty is defined as the precocious onset of pubertal manifestations the advanced occurrence of secondary sexual characteristics, which happen before the 9-year old in boys and 8-year old in girls [1]. There are two types of precocious puberty. Central precocious puberty is due to the early activation of pulsatile gonadotropin-releasing hormone (GnRH) secretion, which is the major type of precocious puberty. Peripheral precocious puberty ,another type of precocious puberty, may result from gonadal tumors[2].The onset of puberty was assumed to be associated with genetic factors, as well as other factors such as nutrition, obesity, psychological factors,immigration and ethnicity[3],but the association is unclear. The incidence of precocious puberty is rising. A report on the New England Journal of Medicine has shown a decrease in the average age of menarche from mid-19th to mid-20th centuries in the USA and in some European countries[4].An epidemiological study, based on national registries in Denmark from 1993 to 2001, estimated that 0.2% of all Danish girls and <0.05% of Danish boys had some form of precocious pubertal development [5].In Spain, an observational study of children diagnosed with central precocious puberty displayed the prevalence of central precocious puberty in girls was 0.037% in 2009. The incidence has increased since 2000[6].In a recent Copenhagen study, compared with the girls studied in 1991-93, those who studied in 2006-08 had substantially earlier breast development[7]. Precocious puberty leads to accelerated growth, accelerated bone maturation and
ultimately reduced stature[1].Also, from both social and psychological perspectives, early maturation may cause excessive stress and be a risk factor for disease. For girls, early timing of the onset of puberty has been associated with psychosomatic symptoms, eating disorders, depression, anxiety and disturbed self-image suicide attempts, substance use and delinquent behavior. Among boys, substance use and delinquency correlate with early maturation as do suicide attempts. Bulimia and depression are associated with early maturation among boys[8].In accordance, early timing of menarche have been associated with long-term health risk of metabolic syndrome, osteoporosis, psychosocial problems and cancer[9]. The hypothalamic-pituitary-gonadal axis controls puberty and reproduction, and is tightly regulated by a complex network of excitatory and inhibitory factors[10].The molecular mechanisms of the onset of puberty are not completely known. A growing amount of evidence from both rodent and human studies suggested that leptin, a circulating hormone product of the ob gene, may be a critical factor for earlier puberty. Leptin-deficient mice and humans failed to enter puberty unless leptin was administered. Rodent studies indicated that low levels of leptin stimulated gonadotropin secretion at the hypothalamic, as well as the pituitary level. It had been proposed as a permissive role in initiating puberty[11]. Also, our previous experiments found that tea polyphenols reduced serum leptin level in diet-induced obese rats. Consistently, previous studies in rodents showed that tea polyphenols can reduce serum leptin levels in vivo[12-14]. For instance, a study of obese male Wistar rats which were given by low energy diets containing Awa(a
traditional tea in Tokushima area) and green tea extracts respectively, or without any tea extracts (control), for 4 weeks showed that compared with control diet, the diets containing Awa and green tea extracts further decreased whole body weight, fat tissue mass and plasma leptin level[15]. Thus, in this article, we explore the possibility for tea polyphenols on preventing precocious puberty and develop a new research direction for future studies.
The hypothesis We hypothesized that green tea, or the tea polyphenol, may prevent precocious by reducing leptin level.
Evaluation of the hypothesis Leptin level may signal the onset of puberty The protein hormone leptin, which is produced and secreted by white adipose tissue, is encoded by the ob gene. It can regulate glucolipid metabolism and inhibit the secretion of insulin [16, 17]. Leptin is recognized as a multi-functional hormone because its receptor was reported to be expressed in many organs, including hypothalamus, pituitary, ovary and uterus[18-20]. In anterior pituitary cells, leptin receptor is expressed in luteinizing hormone (LH), follicle-stimulating hormone (FSH) secreting cells[21]. Therefore, leptin may play an important role in reproductive function. A previous study presented an investigation that leptin had effects on neurons of the hypothalamus and induced gonadotropin-releasing hormone (GnRH)
secretion which induced the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in turn[22]. Although leptin signaling contributes to the regulation of the hypothalamic-pituitary-gonadal axis, leptin receptors are not expressed on GnRH neurons which is essential for normal reproductive function[23]. Therefore, leptin may act to regulate GnRH neuron activity indirectly via its downstream targets, such as NPY, AGRP, POMC, kisspeptin, and nitric oxide synthase (NOS), which all modulate GnRH neuron activity and/orgonadotropin levels[24]. Several decades ago, Frisch and colleagues initiated the theory that attainment of a certain minimum weight or body fat percentage was requisite for pubertal development and menstrual function(the “critical weight hypothesis”)[11]. Nowadays, the theory has been accepted widely. Current evidence indicates that leptin appears to play a permissive role rather than acting as the critical metabolic signal to initiate puberty[11]. Leptin concentration is directly correlated with fat mass, and leptin serves as a signal to the hypothalamus regarding energy stores in the adipose tissue compartment. Leptin plays a role in energy regulation via hypothalamic receptors to inhibit feeding and increase thermogenesis in rodents. Serum leptin concentration is related to the size of adipose tissue mass. Then, effector systems control the energy intake and energy expenditure after hypothalamic centers receive and integrate the intensity of the leptin signal through leptin receptors[25]. It is assumed that an adequate concentration of leptin convey a signal that energy stores are adequate for the pubertal development to the central nervous system, which allows central activation of GnRH and gonadotropin secretion[26]. Female rodents and humans with
deficient leptin have atrophic uterine and ovarian size, abnormal estrous cycle, and impaired mammary gland morphology and function. Male mice with deficient leptin signaling have atrophic testicles, impaired spermatogenesis and behavioral responses to normal receptive females[16, 27].Mice lacking leptin or the leptin receptor (LepR) are infertile or fail to initiate puberty. Nevertheless, leptin administration to leptin-deficient mice induces pubertal development and maturation of reproductive organs, increases LH secretion, and restores fertility[28]. A study of 343 healthy, white girls from central Ohio who were recruited at Tanner stage 2 of puberty between the ages of 8.3 and13.1 showed that an increase of 1 ng/mL in serum leptin lowered the age at menarche by 1 month[29]. Based on the above evidence, we speculate that the development of puberty may require a threshold level of serum leptin to start.
Tea polyphenols reduce the serum leptin level The anti-obesity effect of tea polyphenols is widely reported. Green tea has benefits on losing weight, lowering serum total cholesterol and triglyceride [30, 31]. Our laboratory research group studied the anti-obesity effect of tea polyphenols. During this period, we found that tea polyphenols reduced serum leptin level in diet-induced obese rats. Consistently, four studies in model of diet-induced obesity, which were in rats and mice, showed that supplementation of tea polyphenols in drinking water or diets would increase the percentage of fat-free mass and decrease adipose tissue weight and serum leptin level. Moreover, leptin mRNA expression in
epididymal adipose tissue was also reduced in EGCG-supplemented mice [13-15, 32]. Furthermore, a study of hyperlipidemia and hyperleptinemiarats induced by high-fructose diet suggested that supplementation of green, black, and pu-erh tea leaves significantly decreased serum leptin level, and hepatic fatty acid synthase mRNA, compared with those of rats fed with fructose only[33]. Population-based epidemiologic studies and animal experiments have revealed the close relationships between leptin and the onset of puberty. The leptin level is possibly permissive for initiating puberty. For those adolescents, especially obese children, who are at high risk of precocious puberty, they have elevated leptin level. Then elevated leptin level may activate the hypothalamus-pituitary-gonadal axis, and triggers the onset of puberty, and lead to precocious puberty eventually. Having shown that supplementation with tea polyphenols may reduce leptin level, we thus hypothesize that tea polyphenols administration may postpone initiating puberty.
Empirical data/supportive results To test the hypothesis, we conducted a pilot experiment to investigate the effect of tea polyphenols on female Sprague Dawley(SD) rat’s sexual development. We designed the animal experiment by dividing female SD rats into 3 groups randomly: control group was fed with normal diet and drinking water; estrogen group was fed with diet containing 5.6mg/kg 17 β-Estradiol and normal drinking water; tea polyphenols group was fed with diet combining 5.6mg/kg 17 β-Estradiol and water with tea polyphenols.Table1 illustrates female SD rats in estrogen group significantly
advanced the day of vaginal opening(control group: 34.50±0.850, n=10;estrogen group: 26.50±0.707,n=10; P<0.05). And the day of vaginal opening of tea polyphenols group was later than the estrogen group(estrogen group:26.50±0.707, n=10; tea polyphenols group: 28.30±1.567, n=10;P<0.05). The result suggested that tea polyphenols may delay the date of vaginal opening of precocious puberty rats.
Implications The possibility of tea polyphenols administration on preventing precocious puberty may provide a potential way for the treatment and prevention for precocious puberty. Drinking tea is convenient to control weight and is healthier than consuming sugared beverages.
Consequences of the hypothesis Evidences mentioned above supported that the tea polyphenols can reduce leptin level, and the leptin level is possibly permissive for initiating puberty. We hypothesized that tea polyphenols may prevent precocious puberty. It provides a potential way to prevent precocious puberty. In addition, further studies in animals and humans are still needed to confirm whether tea polyphenols can postpone initiating puberty. The mechanism of tea polyphenols preventing precocious puberty is worthy of being explored.
Acknowledgement
We thank Dr.Bill Shang and Ms.Nan Dou for the English editing. References [1]
Carel JC LN, Roger M, Chaussain JL. Precocious puberty and statural growth. Hum Reprod Update 2004; 10(2):135-147.
[2]
Carel JC LJ. Clinical practice. Precocious puberty. N Engl J Med 2008; 358(22):2366-2377.
[3]
Tinggaard J MM, Sørensen K, Mouritsen A, Hagen CP, Aksglaede L, Wohlfahrt-Veje C, Juul A. The physiology and timing of male puberty. Current opinion in endocrinology, diabetes, and obesity 2012; 19(3):197-203.
[4]
Wyshak G, Frisch
RE. Evidence for a Secular Trend in Age of Menarche.
New England Journal of Medicine 1982; 306(17):1033-1035. [5]
Teilmann G PC, Jensen TK, Skakkebaek NE, Juul A. Prevalence and incidence of precocious pubertal development in Denmark: an epidemiologic study based on national registries. Pediatrics 2005; 116(6):1323-1328.
[6]
Soriano-Guillen L, Corripio R, Labarta JI, Canete R, Castro-Feijoo L, Espino R, Argente J. Central precocious puberty in children living in Spain: incidence, prevalence, and influence of adoption and immigration. J Clin Endocrinol Metab 2010; 95(9):4305-4313.
[7]
Aksglaede L, Sorensen K, Petersen JH, Skakkebaek NE, Juul A. Recent decline in age at breast development: the Copenhagen Puberty Study. Pediatrics 2009; 123(5):e932-939.
[8]
Kaltiala-Heino R, Marttunen M, Rantanen P, Rimpelä M. Early puberty is associated with mental health problems in middle adolescence. Social Science & Medicine 2003; 57(6):1055-1064.
[9]
Golub MS, Collman GW, Foster PM, Kimmel CA, Rajpert-De Meyts E, Reiter EO, Sharpe RM, Skakkebaek NE, Toppari J. Public health implications of altered puberty timing. Pediatrics 2008; 121 Suppl 3:S218-230.
[10]
Abreu AP, Kaiser UB. Pubertal development and regulation. The Lancet Diabetes & Endocrinology 2016; 4(3):254-264.
[11]
Kaplowitz PB. Link between body fat and the timing of puberty. Pediatrics 2008; 121 (Suppl 3):208-217.
[12]
Kao YHH, R.A., Liao S. Modulation of Endocrine Systems and Food Intake by Green Tea Epigallocatechin Gallate. Endocrinology 2000; 141(3):980-987.
[13]
Shen CL, Cao JJ, Dagda RY, Chanjaplammootil S, Lu C, Chyu MC, Gao W, Wang JS, Yeh JK. Green tea polyphenols benefits body composition and improves bone quality in long-term high-fat diet-induced obese rats. Nutrition research 2012; 32(6):448-457.
[14]
Wolfram S, Raederstorff D, Wang Y, Teixeira SR, Elste V, Weber P. TEAVIGO (epigallocatechin gallate) supplementation prevents obesity in rodents by reducing adipose tissue mass. Annals of nutrition & metabolism 2005; 49(1):54-63.
[15]
Sogawa M ST, Kohno S, Hirasaka K, Yamaguchi Y, Takagaki R, Harada A, Okumura Y, Yamamoto S, Kishi K, Nikawa T. Awa (Tokushima)
lactate-fermented tea as well as green tea enhance the effect of diet restriction on obesity in rats. J Med Invest 2009; 56(1-2):42-48. [16]
Israel D, Chua S, Jr. Leptin receptor modulation of adiposity and fertility. Trends in endocrinology and metabolism: TEM 2010; 21(1):10-16.
[17]
Shimizu F MT, Iwasa T, Tanaka N, Minakuchi M, Kuwahara A, Yasui T, Furumoto H, Irahara M. Transition of Leptin Receptor Expression during Pubertal Development in Female Rat Pituitary. Endocr J 2008; 55(1):191-198.
[18]
Zamorano PL, Mahesh VB, De Sevilla LM, Chorich LP, Bhat GK, Brann DW. Expression and localization of the leptin receptor in endocrine and neuroendocrine tissues of the rat. Neuroendocrinology 1997; 65(3):223-228.
[19]
Smith JT WB. Developmental changes in plasma leptin and hypothalamic leptin receptor expression in the rat: peripubertal changes and the emergence of sex differences. J Endocrinol 2003; 176(3):313-319.
[20]
Sone M, Nagata H, Takekoshi S, Osamura RY. Expression and localization of leptin receptor in the normal rat pituitary gland. Cell and tissue research 2001; 305(3):351-356.
[21]
Jin L ZS, Burguera BG, Couce ME, Osamura RY, Kulig E, Lloyd RV. Leptin and leptin receptor expression in rat and mouse pituitary cells. Endocrinology 2000; 141(1):333-339.
[22]
Woller M1 TS, Neff D, Nguema AA, Roo BV, Waechter-Brulla D. Leptin stimulates gonadotropin releasing hormone release from cultured intact
hemihypothalami and enzymatically dispersed neurons. Exp Biol Med (Maywood) 2001; 226(6):591-596. [23]
Quennell JH, Mulligan AC, Tups A, Liu X, Phipps SJ, Kemp CJ, Herbison AE,
Grattan
DR,
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GM.
Leptin
indirectly
regulates
gonadotropin-releasing hormone neuronal function. Endocrinology 2009; 150(6):2805-2812. [24]
Ojeda SR, Lomniczi A, Mastronardi C, Heger S, Roth C, Parent AS, Matagne V, Mungenast AE. Minireview: the neuroendocrine regulation of puberty: is the time ripe for a systems biology approach? Endocrinology 2006; 147(3):1166-1174.
[25]
e., E J. Leptin signaling, adiposity, and energy balanc. Ann N Y Acad Sci 2002; 967:379-388.
[26]
Burt Solorzano CM, McCartney CR. Obesity and the pubertal transition in girls and boys. Reproduction 2010; 140(3):399-410.
[27]
Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, Lank E, Bottomley B, Lopez-Fernandez J, Ferraz-Amaro I et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. The New England journal of medicine 2007; 356(3):237-247.
[28]
Donato J, Jr., Cravo RM, Frazao R, Gautron L, Scott MM, Lachey J, Castro IA, Margatho LO, Lee S, Lee C et al. Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. The Journal of clinical investigation 2011; 121(1):355-368.
[29]
Matkovic V IJ, Skugor M, Badenhop NE, Goel P, Clairmont A, Klisovic D, Nahhas RW, Landoll JD. Leptin is inversely related to age at menarche in human females. J Clin Endocrinol Metab 1997; 82(10):3239-3245.
[30]
Raederstorff DG, Schlachter MF, Elste V, Weber P. Effect of EGCG on lipid absorption and plasma lipid levels in rats. The Journal of Nutritional Biochemistry 2003; 14(6):326-332.
[31]
Richard D, Kefi K, Barbe U, Poli A, Bausero P, Visioli F. Weight and plasma lipid control by decaffeinated green tea. Pharmacological research 2009; 59(5):351-354.
[32]
Murase T, Haramizu S, Shimotoyodome A, Tokimitsu I. Reduction of diet-induced obesity by a combination of tea-catechin intake and regular swimming. International journal of obesity 2006; 30(3):561-568.
[33]
Huang HC, Lin JK. Pu-erh tea, green tea, and black tea suppresses hyperlipidemia, hyperleptinemia and fatty acid synthase through activating AMPK in rats fed a high-fructose diet. Food & function 2012; 3(2):170-177.
Abstract Precocious puberty which impacts children physically and psychologically has become one of the health problem over the world. However, the mechanism and preventive measures of precocious puberty is still not clear. Recent studies suggested that leptin may act as the ‘permissive factor’ to initiate the puberty by regulating gonadotrophin-releasing hormone secretion. Previous evidence from animal and human studies found that tea polyphenols can reduce serum leptin levels in vivo and inhibit the expression of leptin in adipose tissue. This article focus on whether tea polyphenols could delay the onset of puberty by reducing leptin levels. To verify the possibility of tea polyphenols on preventing precocious puberty, animal experiment can be used. Our hypothesis that tea polyphenols could prevent the precocious puberty may provide important potential way for the prevention and control of children precocious puberty. Keywords: tea polyphenols, precocious puberty, leptin
Table TABLE1. Effects of tea polyphenols on the day of vaginal opening(VOD) in female Sprague Dawley rats Group
VOD(d)
Control group
34.50±0.850
Estrogen group
26.50±0.707*
Tea polyphenols group
28.30±1.567*#
Data is expressed as the mean ±SD. * p<0.05, compared with Sprague Dawley rats in control group. # p<0.05, compared with Sprague Dawley rats in estrogen group.
S0306-9877(16)30368-1 http://dx.doi.org/10.1016/j.mehy.2016.07.017 YMEHY 8348
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
18 July 2016 18 July 2016
Please cite this article as: Y. Wu, J. Wang, W. Cai, X. Shen, Could tea polyphenols be beneficial for preventing the precocious puberty?, Medical Hypotheses (2016), doi: http://dx.doi.org/10.1016/j.mehy.2016.07.017
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Could tea polyphenols be beneficial for preventing the precocious puberty? Youmei Wua, Jialu Wanga, Wei Caia,b,Ph.D. M.D., Xiuhua Shena,b, Ph.D. M.D. a
Department of Nutrition, School of Public Health, Shanghai Jiao Tong University,
Shanghai200025, China b
Department of Clinical Nutrition, Xin Hua Hospital, School of Medicine, Shanghai
Jiao Tong University, Shanghai200092, China Address for Correspondence: Xiuhua Shen, Department of Clinical Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai200092, China Tel: +86-21-25076419 Fax numbers: +86-21-65011627 E-mail: [email protected]
Introduction Precocious puberty is defined as the precocious onset of pubertal manifestations the advanced occurrence of secondary sexual characteristics, which happen before the 9-year old in boys and 8-year old in girls [1]. There are two types of precocious puberty. Central precocious puberty is due to the early activation of pulsatile gonadotropin-releasing hormone (GnRH) secretion, which is the major type of precocious puberty. Peripheral precocious puberty ,another type of precocious puberty, may result from gonadal tumors[2].The onset of puberty was assumed to be associated with genetic factors, as well as other factors such as nutrition, obesity, psychological factors,immigration and ethnicity[3],but the association is unclear. The incidence of precocious puberty is rising. A report on the New England Journal of Medicine has shown a decrease in the average age of menarche from mid-19th to mid-20th centuries in the USA and in some European countries[4].An epidemiological study, based on national registries in Denmark from 1993 to 2001, estimated that 0.2% of all Danish girls and <0.05% of Danish boys had some form of precocious pubertal development [5].In Spain, an observational study of children diagnosed with central precocious puberty displayed the prevalence of central precocious puberty in girls was 0.037% in 2009. The incidence has increased since 2000[6].In a recent Copenhagen study, compared with the girls studied in 1991-93, those who studied in 2006-08 had substantially earlier breast development[7]. Precocious puberty leads to accelerated growth, accelerated bone maturation and
ultimately reduced stature[1].Also, from both social and psychological perspectives, early maturation may cause excessive stress and be a risk factor for disease. For girls, early timing of the onset of puberty has been associated with psychosomatic symptoms, eating disorders, depression, anxiety and disturbed self-image suicide attempts, substance use and delinquent behavior. Among boys, substance use and delinquency correlate with early maturation as do suicide attempts. Bulimia and depression are associated with early maturation among boys[8].In accordance, early timing of menarche have been associated with long-term health risk of metabolic syndrome, osteoporosis, psychosocial problems and cancer[9]. The hypothalamic-pituitary-gonadal axis controls puberty and reproduction, and is tightly regulated by a complex network of excitatory and inhibitory factors[10].The molecular mechanisms of the onset of puberty are not completely known. A growing amount of evidence from both rodent and human studies suggested that leptin, a circulating hormone product of the ob gene, may be a critical factor for earlier puberty. Leptin-deficient mice and humans failed to enter puberty unless leptin was administered. Rodent studies indicated that low levels of leptin stimulated gonadotropin secretion at the hypothalamic, as well as the pituitary level. It had been proposed as a permissive role in initiating puberty[11]. Also, our previous experiments found that tea polyphenols reduced serum leptin level in diet-induced obese rats. Consistently, previous studies in rodents showed that tea polyphenols can reduce serum leptin levels in vivo[12-14]. For instance, a study of obese male Wistar rats which were given by low energy diets containing Awa(a
traditional tea in Tokushima area) and green tea extracts respectively, or without any tea extracts (control), for 4 weeks showed that compared with control diet, the diets containing Awa and green tea extracts further decreased whole body weight, fat tissue mass and plasma leptin level[15]. Thus, in this article, we explore the possibility for tea polyphenols on preventing precocious puberty and develop a new research direction for future studies.
The hypothesis We hypothesized that green tea, or the tea polyphenol, may prevent precocious by reducing leptin level.
Evaluation of the hypothesis Leptin level may signal the onset of puberty The protein hormone leptin, which is produced and secreted by white adipose tissue, is encoded by the ob gene. It can regulate glucolipid metabolism and inhibit the secretion of insulin [16, 17]. Leptin is recognized as a multi-functional hormone because its receptor was reported to be expressed in many organs, including hypothalamus, pituitary, ovary and uterus[18-20]. In anterior pituitary cells, leptin receptor is expressed in luteinizing hormone (LH), follicle-stimulating hormone (FSH) secreting cells[21]. Therefore, leptin may play an important role in reproductive function. A previous study presented an investigation that leptin had effects on neurons of the hypothalamus and induced gonadotropin-releasing hormone (GnRH)
secretion which induced the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in turn[22]. Although leptin signaling contributes to the regulation of the hypothalamic-pituitary-gonadal axis, leptin receptors are not expressed on GnRH neurons which is essential for normal reproductive function[23]. Therefore, leptin may act to regulate GnRH neuron activity indirectly via its downstream targets, such as NPY, AGRP, POMC, kisspeptin, and nitric oxide synthase (NOS), which all modulate GnRH neuron activity and/orgonadotropin levels[24]. Several decades ago, Frisch and colleagues initiated the theory that attainment of a certain minimum weight or body fat percentage was requisite for pubertal development and menstrual function(the “critical weight hypothesis”)[11]. Nowadays, the theory has been accepted widely. Current evidence indicates that leptin appears to play a permissive role rather than acting as the critical metabolic signal to initiate puberty[11]. Leptin concentration is directly correlated with fat mass, and leptin serves as a signal to the hypothalamus regarding energy stores in the adipose tissue compartment. Leptin plays a role in energy regulation via hypothalamic receptors to inhibit feeding and increase thermogenesis in rodents. Serum leptin concentration is related to the size of adipose tissue mass. Then, effector systems control the energy intake and energy expenditure after hypothalamic centers receive and integrate the intensity of the leptin signal through leptin receptors[25]. It is assumed that an adequate concentration of leptin convey a signal that energy stores are adequate for the pubertal development to the central nervous system, which allows central activation of GnRH and gonadotropin secretion[26]. Female rodents and humans with
deficient leptin have atrophic uterine and ovarian size, abnormal estrous cycle, and impaired mammary gland morphology and function. Male mice with deficient leptin signaling have atrophic testicles, impaired spermatogenesis and behavioral responses to normal receptive females[16, 27].Mice lacking leptin or the leptin receptor (LepR) are infertile or fail to initiate puberty. Nevertheless, leptin administration to leptin-deficient mice induces pubertal development and maturation of reproductive organs, increases LH secretion, and restores fertility[28]. A study of 343 healthy, white girls from central Ohio who were recruited at Tanner stage 2 of puberty between the ages of 8.3 and13.1 showed that an increase of 1 ng/mL in serum leptin lowered the age at menarche by 1 month[29]. Based on the above evidence, we speculate that the development of puberty may require a threshold level of serum leptin to start.
Tea polyphenols reduce the serum leptin level The anti-obesity effect of tea polyphenols is widely reported. Green tea has benefits on losing weight, lowering serum total cholesterol and triglyceride [30, 31]. Our laboratory research group studied the anti-obesity effect of tea polyphenols. During this period, we found that tea polyphenols reduced serum leptin level in diet-induced obese rats. Consistently, four studies in model of diet-induced obesity, which were in rats and mice, showed that supplementation of tea polyphenols in drinking water or diets would increase the percentage of fat-free mass and decrease adipose tissue weight and serum leptin level. Moreover, leptin mRNA expression in
epididymal adipose tissue was also reduced in EGCG-supplemented mice [13-15, 32]. Furthermore, a study of hyperlipidemia and hyperleptinemiarats induced by high-fructose diet suggested that supplementation of green, black, and pu-erh tea leaves significantly decreased serum leptin level, and hepatic fatty acid synthase mRNA, compared with those of rats fed with fructose only[33]. Population-based epidemiologic studies and animal experiments have revealed the close relationships between leptin and the onset of puberty. The leptin level is possibly permissive for initiating puberty. For those adolescents, especially obese children, who are at high risk of precocious puberty, they have elevated leptin level. Then elevated leptin level may activate the hypothalamus-pituitary-gonadal axis, and triggers the onset of puberty, and lead to precocious puberty eventually. Having shown that supplementation with tea polyphenols may reduce leptin level, we thus hypothesize that tea polyphenols administration may postpone initiating puberty.
Empirical data/supportive results To test the hypothesis, we conducted a pilot experiment to investigate the effect of tea polyphenols on female Sprague Dawley(SD) rat’s sexual development. We designed the animal experiment by dividing female SD rats into 3 groups randomly: control group was fed with normal diet and drinking water; estrogen group was fed with diet containing 5.6mg/kg 17 β-Estradiol and normal drinking water; tea polyphenols group was fed with diet combining 5.6mg/kg 17 β-Estradiol and water with tea polyphenols.Table1 illustrates female SD rats in estrogen group significantly
advanced the day of vaginal opening(control group: 34.50±0.850, n=10;estrogen group: 26.50±0.707,n=10; P<0.05). And the day of vaginal opening of tea polyphenols group was later than the estrogen group(estrogen group:26.50±0.707, n=10; tea polyphenols group: 28.30±1.567, n=10;P<0.05). The result suggested that tea polyphenols may delay the date of vaginal opening of precocious puberty rats.
Implications The possibility of tea polyphenols administration on preventing precocious puberty may provide a potential way for the treatment and prevention for precocious puberty. Drinking tea is convenient to control weight and is healthier than consuming sugared beverages.
Consequences of the hypothesis Evidences mentioned above supported that the tea polyphenols can reduce leptin level, and the leptin level is possibly permissive for initiating puberty. We hypothesized that tea polyphenols may prevent precocious puberty. It provides a potential way to prevent precocious puberty. In addition, further studies in animals and humans are still needed to confirm whether tea polyphenols can postpone initiating puberty. The mechanism of tea polyphenols preventing precocious puberty is worthy of being explored.
Acknowledgement
We thank Dr.Bill Shang and Ms.Nan Dou for the English editing. References [1]
Carel JC LN, Roger M, Chaussain JL. Precocious puberty and statural growth. Hum Reprod Update 2004; 10(2):135-147.
[2]
Carel JC LJ. Clinical practice. Precocious puberty. N Engl J Med 2008; 358(22):2366-2377.
[3]
Tinggaard J MM, Sørensen K, Mouritsen A, Hagen CP, Aksglaede L, Wohlfahrt-Veje C, Juul A. The physiology and timing of male puberty. Current opinion in endocrinology, diabetes, and obesity 2012; 19(3):197-203.
[4]
Wyshak G, Frisch
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Abstract Precocious puberty which impacts children physically and psychologically has become one of the health problem over the world. However, the mechanism and preventive measures of precocious puberty is still not clear. Recent studies suggested that leptin may act as the ‘permissive factor’ to initiate the puberty by regulating gonadotrophin-releasing hormone secretion. Previous evidence from animal and human studies found that tea polyphenols can reduce serum leptin levels in vivo and inhibit the expression of leptin in adipose tissue. This article focus on whether tea polyphenols could delay the onset of puberty by reducing leptin levels. To verify the possibility of tea polyphenols on preventing precocious puberty, animal experiment can be used. Our hypothesis that tea polyphenols could prevent the precocious puberty may provide important potential way for the prevention and control of children precocious puberty. Keywords: tea polyphenols, precocious puberty, leptin
Table TABLE1. Effects of tea polyphenols on the day of vaginal opening(VOD) in female Sprague Dawley rats Group
VOD(d)
Control group
34.50±0.850
Estrogen group
26.50±0.707*
Tea polyphenols group
28.30±1.567*#
Data is expressed as the mean ±SD. * p<0.05, compared with Sprague Dawley rats in control group. # p<0.05, compared with Sprague Dawley rats in estrogen group.