- Email: [email protected]
Applied physiology: the control of puberty
Current Paediatrics (2003) 13, 371--375
c 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0957-5839(03)00060 -5
Applied physiology: the control of puberty Catherine Margaret Hall Consultant Paediatric Endocrinologist, Royal Manchester Children’s Hospital, Hospital Road, Pendlebury, Manchester M27 4HA, UK
KEYWORDS puberty; neuropeptide-Y; GABA; leptin; gene
Summary Puberty results from the re-activation of a quiescent hypothalamo-pituitary-gonadal process and results in the acquisition of secondary sexual characteristics, adult height and fertility. Genetic and environmental factors influence the central nervous systemto trigger the process. Animal data indicate thatthe neuropeptides g-amino butyric acid (GABA) and neuropeptideY (NPY) are important in restraining the pubertalprocess. Animal and human data support a facilitatoryrole for the adipocyte-derived hormone leptin to act as a metabolic gate between nutritional status and the central nervous system to facilitate the onset of puberty. There are exciting new data in rats which suggests thatthe homeodomain gene Oct-2 POUmay play a role intriggering puberty, and the challenge for the future is to identify master gene(s) in humans which control the timing of puberty.
c 2003 Elsevier Ltd. All rights reserved.
INTRODUCTION PRACTICE POINTS *
*
*
*
Puberty follows the re-activation of the hypothalamo-pituitary-gonadal axis, which has remained quiescent after the f|rst 6 months of life There is an association between nutrition and pubertal status: undernutrition delays the adolescent growth spurt, whereas obesity is associated with earlier puberty and menarche In developed countries, there has been a secular trend for puberty to occur earlier, which is thought to be due, in part, to improved nutritional status Leptin is secreted by adipocytes in response to feeding. It acts centrally to suppress appetite, stimulate energy expenditure and modulate the reproductive axis. It appears to play a permissive role in the onset of puberty
RESEARCH DIRECTIONS * * *
The role of NPYand GABA in human puberty The role of leptin in human puberty The identif|cation of genes which regulate human puberty
Correspondence to: CMH.Tel.: +44(0)-161-727-2581; fax: +44(0)-161727-2583.; E-mail: [email protected]
Puberty is the developmental phase characterized by the appearance of secondary sexual characteristics, the adolescent growth spurt and the attainment of fertility. Puberty may be viewed as the culmination of a neuroendocrine gonadal regulatory process which originates in fetal life. The hypothalamo-pituitary-gonadal system is active during fetal life and early infancy, but is quiescent in childhood during the‘juvenile pause’ and is re-activated at the start of puberty although the process is not fully understood.1 In this article, animal and human data which elucidate the neurobiological mechanisms of pubertal restraint and re-activation will be discussed, with particular focus on the role of the adipocyte-derived hormone leptin.
THE HUMANHYPOTHALAMICPITUITARY-GONADAL AXIS The mechanics of the hypothalamo-pituitary-gonadal axis have been reviewed extensively by Grumbach and Styne.1 Within the hypothalamus, the luteinizing-hormone-releasing hormone (LHRH) neurosecretory neurones translate neural signals into periodic oscillatory chemical signals of LHRH (the LHRH pulse generator). LHRH is released episodically into the hypothalamichypophyseal portal circulation and transported to the anterior pituitary gland, where it is essential for the release of follicle-stimulating hormone (FSH) and
372
luteinizing hormone (LH). The amplitude and frequency of the LHRH signal are attenuated by catecholaminergic and serotinergic neurones via their effect on hypothalamic norepinephrine, dopamine and serotonin and by neuropeptideY (NPY), leptin,GABA, opioid peptide, galanin, corticotrophin-releasing hormone and excitatory amino acid neural networks. Hypothalamic LHRH binds pituitary Gs-proteincoupled LH/hCG receptors to stimulate the pulsatile release of LH and FSH from pituitary gonadotropes. The gonads are modulated by the amplitude of the gonadotropin pulse, and secrete gonadal steroids in a pulsatile fashion. Gonadal steroids, inhibin, activin and follistatin exert feedback on the hypothalamic-pituitary unit. Inhibin and follistatin inhibit and activin stimulates FSH biosynthesis and secretion.
HYPOTHESIZED MECHANISMS FOR THE CONTROLOF PUBERTY There appear to be two mechanisms that contribute to the gonadotropin restraint seen in the juvenile pause: the negative feedback (gonadal steroid-dependent) mechanism and the intrinsic central nervous system (CNS) inhibitory mechanism (gonadal steroid-independent).2,3 The negative feedback mechanism is supported by the fact that gonadotropins are present at low concentrations in pre-pubertal children, but are elevated in children with gonadal dysgenesis. Evidence for intrinsic CNS inhibition is provided by observations that in agonadal children, gonadotropins are high in infancy and puberty but suppressed during childhood. Thus, puberty appears to be restrained in the f|rst few years by negative feedback of gonadal steroids, and is restrained centrally in mid childhood by CNS inhibition. Just before puberty, the CNS inhibitory mechanism wanes, especially during sleep, when the LHRH pulse generator is less sensitive to gonadal steroid negative feedback.2 Indirect evidence for a central inhibitory network, which has projections through the posterior hypothalamus, is derived from children with lesions that disrupt this area -- midline abnormalities (septo-optic dysplasia), hypothalamic pilocytic astrocytomas, cranial irradiation or suprasellar lesions -- who develop gonadotropindependent precocious puberty.2
NUTRITION AND PUBERTY In humans, there is an important interaction between nutritional status and puberty.4 Undernutrition delays the adolescent growth spurt and menarche, and increasing food intake leads to weight gain and menstrual function. Chronic undernutrition or rapid weight loss in normal women results in cessation of menstrual cycles,
CURRENT PAEDIATRICS
and amenorrhoea is also a feature of anorexia nervosa. Conversely, moderate obesity (up to 30% above the normal weight for age) is associated with earlier menarche.5 In developed countries, there has been a secular trend for puberty to occur earlier than in previous centuries, which is thought to be attributable to the increasing stability in socio-economic conditions and improved nutritional status.6,7
NEUROTRANSMITTERS AND PUBERTY Studies in primates indicate that g amino-butyric acid (GABA) and neuropeptide-Y (NPY) are important inhibitory neurotransmitters during the juvenile pause. Their roles have been reviewed extensively by Terasawa and Fernandez,8 and are summarized below.
GABA GABA is the main inhibitory neurotransmitter in the hypothalamus. In non-human primates, GABA tonically inhibits the LHRH system pre-pubertally -- hypothalamic GABA levels are higher in pre-pubertal rhesus monkeys than in pubertal monkeys. Infusion of GABAA antagonist stimulates LHRH release in pre-pubertal monkeys, and pulsatile infusion of GABAA antagonist into the third ventricle of pre-pubertal monkeys induces precocious menarche and precocious ovulation.
NeuropeptideY NPYis a potent orexigenic agent that is widely expressed throughout the brain. In male rhesus monkeys, there is evidence that it has a role in the pubertal restraint of the juvenile pause -- NPY messenger RNA decreases at the onset of puberty, concomitant with an increase in LHRH mRNA, whereas infusion of an NPY antagonist into the lateral ventricle stimulates LH release.
LEPTIN AND PUBERTY Leptin, the protein product of the ob gene,9 has been implicated in the control of murine body weight and thermogenesis, and also independently stimulates the reproductive axis. In ob/ob mice, a homozygous deletion in the coding sequence of the ob gene results in failure to produce leptin.The phenotype of ob/ob mice is characterized by hyperphagia, obesity, insulin resistance and infertility. Leptin treatment of ob/ob mice reduced food intake and body weight, increased metabolic rate, body temperature and activity levels,10 --13 and restored fertility.14 Thus, leptin potently suppresses appetite, stimulates energy expenditure and also modulates the reproductive axis.
APPLIED PHYSIOLOGY: THE CONTROL OF PUBERTY
The relationship between body fat and reproductive ability in humans has long been recognized, and the tempo of pubertal maturation is more closely associated with changes in body composition than chronological age. It has been postulated that a critical mass is required before menarche is achieved.4 Serum leptin concentrations are low in trained athletes15 and in amenorrhoeic females with anorexia nervosa.16 The relationship between leptin and the reproductive axis has been examined in normal mice and rats, where reproductive potential is closely linked to nutritional supply. Food restriction would normally prevent vaginal opening in mice, but infusion of leptin into the lateral ventricle of food-restricted mice induced sexual maturation despite a decrease in body weight.17 Furthermore, exogenous leptin brought forward the onset of reproductive function in normal pre-pubertal mice.18 Starvation-induced delay in sexual maturation could be overcome in leptin-treated animals when food was restricted to 80% of normal, but not when it was restricted to 70% of that of ad-libitum-fed controls.19 These data would suggest that leptin is not the primary signal to initiate the onset of puberty in rodents, but acts as a metabolic gate, permitting pubertal maturation in response to suff|cient metabolic resources. Although leptin administration can advance puberty onset in rodents, the fact that circulating leptin concentrations remain unchanged during puberty is not consistent with a leptin surge triggering puberty. However, recent observations in rats demonstrated that hypothalamic leptin receptor Ob-Rb expression increased three-fold from fetal life to post-pubertal life. It is possible that this change in hypothalamic response to leptin could enhance leptin action and trigger puberty without a rise in circulating plasma leptin concentrations.20 Studies in normal children have tended to be crosssectional in design. Many investigators have reported that leptin increased gradually in both sexes over the pre-pubertal years and that, at each age, girls tended to have higher leptin concentrations than boys.21--25 In a cross-sectional study of 290 healthy Manchester schoolchildren (males: 137, females: 153)22 leptin concentrations peaked in Tanner stage (TS) 2--3 in males and then declined to pre-pubertal values. However, in females, leptin concentrations continued to rise through puberty to peak in TS 4 --5 (Fig. 1). Body mass index (BMI) standard deviation score was positively correlated with serum leptin concentrations, and measures of body fatness were the most signif|cant determinants of leptin through childhood. The pre-pubertal rise in leptin concentration was observed to precede those of the gonadotrophins in a cross-sectional study of 789 normal children and adolescents,24 and to precede the surge in testosterone in a longitudinal study of eight pre-pubertal boys.26 A longitu-
373
Figure 1 The error bars representthe mean (71SD) values of Loge leptin in males (dots) and females (diamonds) at Tanner stages1, 2 & 3, and 4 & 5. + In males, leptin concentrations are higher inTS 2 & 3 than TS1 (P = 0.007) and TS 4 & 5 (P = 0.001). ΠIn females, leptin concentrations are higher in TS 2 & 3 than TS1 (P = 0.001) and # higher at TS 4 & 5 than at TS 2 & 3 (P = 0.01). *In TS 4 & 5, leptin concentrations are higher in females than males (Po0.001). From: Hall CM. Leptin and the Insulin-like Growth Factor (IGF) Axis through Childhood and Adolescence. University of Manchester,MD Thesis,1999.
dinal study of 343 Caucasian girls demonstrated an inverse relationship between age of menarche and leptin concentration.27 In addition, serum leptin concentrations were modestly elevated in girls with central precocious puberty.28 These studies suggest that leptin may be linked to both the onset of puberty and the timing of menarche. Evidence that leptin may have a role in regulating the tempo of pubertal development was provided by data from boys with constitutional delay in growth and puberty where serum leptin concentrations were lower than predicted for age and BMI at the onset of puberty.29 The strongest evidence supporting a role for leptin in human puberty is derived from rare familial cases associated with mutations in the leptin gene30 --32 or the leptin receptor gene.33 Affected adults with either condition are hypogonadal, while leptin treatment of a peripubertal child with leptin def|ciency acutely increased nocturnal gonadotropin secretion.34 Leptin exerts its central effects on satiety through several neuroendocrine systems. Some of the neuropeptides involved -- NPY, pro-opiomelanocortin-C (POMC) and cocaine- and amphetamine-related transcript
374
(CART) -- also interact with GnRH neurones. Thus neural mechanisms exist by which leptin might signal peripheral energy stores to the CNS and modulate both appetite and reproduction. In the mouse and human, leptin appears to be necessary for both pubertal development and the maintenance of secondary sexual characteristics. Under normal circumstances, leptin has a permissive role, but in the leptin-def|cient child, as in the ob/ob mouse, exogenous leptin seems able to induce activity within the reproductive axis.
GENES AND PUBERTY It is possible that there is a master gene or a number of genes that regulate the onset of puberty. Homeodomain genes of the POU family are widely expressed in the developing forebrain of mammals35 and Oct-2 POU gene has been identif|ed as a physiological component of the cell cycle regulatory process by which glial cells upregulate LHRH secretion in rats at puberty,36 suggesting that it may play an important role in triggering puberty in mammals. In pedigree analysis of 41 families with constitutional delay in growth and puberty, many families exhibited an autosomal-dominant pattern with varying penetrance, suggesting that there may be single genes with major effects whose penetrance is affected by genetic or environmental factors.37 Candidate genes include genes encoding GnRH or its receptor, or upstream regulators such as leptin or its receptor. The search for master gene(s) that control the timing of puberty is an exciting challenge, as identif|cation of these genes would improve our understanding of the regulation of human puberty and reproductive function.
REFERENCES 1. Grumbach M, Styne D. Puberty: ontogeny, neuroendocrinology, physiology, and disorders. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS (eds). Williams Textbook of Endocrinology. Tenth Edition. Philadelphia: Elsevier Science 2002; 1115--1286. 2. Grumbach M, Kaplan S. The neuroendocrinology of puberty: an ontogenic perspective. In: Grumbach M, Sizonenko P, Aubert ME (eds). Control of the Onset of Puberty. Baltimore: Williams & Wilkins, 1990; 1--68. 3. Conte FA, Grumbach MM, Kaplan SL, Reiter EO. Correlation of luteinizing hormone-releasing factor-induced luteinizing hormone and follicle-stimulating hormone release from infancy to 19 years with the changing pattern of gonadotropin secretion in agonadal patients: relation to the restraint of puberty. J Clin Endocrinol Metab 1980; 50: 163--168. 4. Frisch RE, McArthur JW. Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset. Science 1974; 185: 949--951.
CURRENT PAEDIATRICS
5. Styne D. The physiology of puberty. In: Brook CGD (ed.). Clinical Paediatric Endocrinology. Oxford: Blackwell Science, 1995; 234--252. 6. Tanner JM. Trend towards earlier menarche in London, Oslo, Copenhagen, the Netherlands and Hungary. Nature 1973; 243: 95--96. 7. Herman-Giddens ME, Slora EJ, Wasserman RC et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics 1997; 99: 505--512. 8. Terasawa E, Fernandez DL. Neurobiological mechanisms of the onset of puberty in primates. Endocr Rev 2001; 22: 111--151. 9. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425--432. 10. Halaas JL, Gajiwala KS, Maffei M et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 543--546. 11. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995; 269: 546--549. 12. Pelleymounter MA, Cullen MJ, Baker MB et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995; 269: 540--543. 13. Weigle DS, Bukowski TR, Foster DC et al. Recombinant ob protein reduces feeding and body weight in the ob/ob mouse. J Clin Invest 1995; 96: 2065--2070. 14. Chehab FF, Lim ME, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet 1996; 12: 318--320. 15. Haluzik M, Boudova L, Nedvidkova J et al. Lower serum leptin concentrations in rugby players in comparison with healthy nonsporting subjects -- relationships to anthropometric and biochemical parameters. Eur J Appl Physiol Occup Physiol 1998; 79: 58--61. 16. Grinspoon S, Gulick T, Askari H et al. Serum leptin levels in women with anorexia nervosa. J Clin Endocrinol Metab 1996; 81: 3861--3863. 17. Gruaz NM, Lalaoui M, Pierroz DD et al. Chronic administration of leptin into the lateral ventricle induces sexual maturation in severely food-restricted female rats. J Neuroendocrinol 1998; 10: 627--633. 18. Chehab FF, Mounzih K, Lu R, Lim ME. Early onset of reproductive function in normal female mice treated with leptin. Science 1997; 275: 88--90. 19. Cheung CC, Thornton JE, Kuijper JL, Weigle DS, Clifton DK, Steiner RA. Leptin is a metabolic gate for the onset of puberty in the female rat. Endocrinology 1997; 138: 855--858. 20. Smith JT, Waddell BJ. 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: 313--319. 21. Hassink SG, Sheslow DV, de Lancey E, Opentanova I, Considine RV, Caro JF. Serum leptin in children with obesity: relationship to gender and development. Pediatrics 1996; 98: 201--203. 22. Clayton PE, Gill MS, Hall CM, Tillmann V, Whatmore AJ, Price DA. Serum leptin through childhood and adolescence. Clin Endocrinol (Oxf) 1997; 46: 727--733. 23. Blum WF, Englaro P, Hanitsch S et al. Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone. J Clin Endocrinol Metab 1997; 82: 2904--2910. 24. Garcia-Mayor RV, Andrade MA, Rios M, Lage M, Dieguez C, Casanueva FF. Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary-gonadal hormones, and pubertal stage. J Clin Endocrinol Metab 1997; 82: 2849--2855.
APPLIED PHYSIOLOGY: THE CONTROL OF PUBERTY
375
25. Carlsson B, Ankarberg C, Rosberg S, Norjavaara E, AlbertssonWikland K, Carlsson LM. Serum leptin concentrations in relation to pubertal development. Arch Dis Child 1997; 77: 396--400. 26. Mantzoros CS, Flier JS, Rogol AD. A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty. J Clin Endocrinol Metab 1997; 82: 1066--1070. 27. Matkovic V, Ilich J, Badenhop N et al. Gain in body fat is inversely related to the nocturnal rise in serum leptin in young females. J Clin Endocrinol Metab 1997; 82: 1368--1372. 28. Palmert MR, Radovick S, Boepple PA. Leptin levels in children with central precocious puberty. J Clin Endocrinol Metab 1998; 83: 2260--2265. 29. Gill MS, Hall CM, Tillmann V, Clayton PE. Constitutional delay in growth and puberty (CDGP) is associated with hypoleptinaemia. Clin Endocrinol (Oxf) 1999; 50: 721--726. 30. Montague CT, Farooqi IS, Whitehead JP et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387: 903--908. 31. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998; 18: 213--215.
32. Ozata M, Ozdemir IC, Licinio J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptinmediated defects. J Clin Endocrinol Metab 1999; 84: 3686--3695. 33. Clement K, Vaisse C, Lahlou N et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998; 392: 398--401. 34. Farooqi IS, Jebb SA, Langmack G et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341: 879--884. 35. Treacy MN, Rosenfeld MG. Expression of a family of POU-domain protein regulatory genes during development of the central nervous system. Annu Rev Neurosci 1992; 15: 139--165. 36. Ojeda SR, Hill J, Hill DF et al. The Oct-2 POU domain gene in the neuroendocrine brain: a transcriptional regulator of mammalian puberty. Endocrinology 1999; 140: 3774--3789. 37. Sedlmeyer IL, Hirschhorn JN, Palmert MR. Pedigree analysis of constitutional delay of growth and maturation: determination of familial aggregation and inheritance patterns. J Clin Endocrinol Metab 2002; 87: 5581--5586.
c 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0957-5839(03)00060 -5
Applied physiology: the control of puberty Catherine Margaret Hall Consultant Paediatric Endocrinologist, Royal Manchester Children’s Hospital, Hospital Road, Pendlebury, Manchester M27 4HA, UK
KEYWORDS puberty; neuropeptide-Y; GABA; leptin; gene
Summary Puberty results from the re-activation of a quiescent hypothalamo-pituitary-gonadal process and results in the acquisition of secondary sexual characteristics, adult height and fertility. Genetic and environmental factors influence the central nervous systemto trigger the process. Animal data indicate thatthe neuropeptides g-amino butyric acid (GABA) and neuropeptideY (NPY) are important in restraining the pubertalprocess. Animal and human data support a facilitatoryrole for the adipocyte-derived hormone leptin to act as a metabolic gate between nutritional status and the central nervous system to facilitate the onset of puberty. There are exciting new data in rats which suggests thatthe homeodomain gene Oct-2 POUmay play a role intriggering puberty, and the challenge for the future is to identify master gene(s) in humans which control the timing of puberty.
c 2003 Elsevier Ltd. All rights reserved.
INTRODUCTION PRACTICE POINTS *
*
*
*
Puberty follows the re-activation of the hypothalamo-pituitary-gonadal axis, which has remained quiescent after the f|rst 6 months of life There is an association between nutrition and pubertal status: undernutrition delays the adolescent growth spurt, whereas obesity is associated with earlier puberty and menarche In developed countries, there has been a secular trend for puberty to occur earlier, which is thought to be due, in part, to improved nutritional status Leptin is secreted by adipocytes in response to feeding. It acts centrally to suppress appetite, stimulate energy expenditure and modulate the reproductive axis. It appears to play a permissive role in the onset of puberty
RESEARCH DIRECTIONS * * *
The role of NPYand GABA in human puberty The role of leptin in human puberty The identif|cation of genes which regulate human puberty
Correspondence to: CMH.Tel.: +44(0)-161-727-2581; fax: +44(0)-161727-2583.; E-mail: [email protected]
Puberty is the developmental phase characterized by the appearance of secondary sexual characteristics, the adolescent growth spurt and the attainment of fertility. Puberty may be viewed as the culmination of a neuroendocrine gonadal regulatory process which originates in fetal life. The hypothalamo-pituitary-gonadal system is active during fetal life and early infancy, but is quiescent in childhood during the‘juvenile pause’ and is re-activated at the start of puberty although the process is not fully understood.1 In this article, animal and human data which elucidate the neurobiological mechanisms of pubertal restraint and re-activation will be discussed, with particular focus on the role of the adipocyte-derived hormone leptin.
THE HUMANHYPOTHALAMICPITUITARY-GONADAL AXIS The mechanics of the hypothalamo-pituitary-gonadal axis have been reviewed extensively by Grumbach and Styne.1 Within the hypothalamus, the luteinizing-hormone-releasing hormone (LHRH) neurosecretory neurones translate neural signals into periodic oscillatory chemical signals of LHRH (the LHRH pulse generator). LHRH is released episodically into the hypothalamichypophyseal portal circulation and transported to the anterior pituitary gland, where it is essential for the release of follicle-stimulating hormone (FSH) and
372
luteinizing hormone (LH). The amplitude and frequency of the LHRH signal are attenuated by catecholaminergic and serotinergic neurones via their effect on hypothalamic norepinephrine, dopamine and serotonin and by neuropeptideY (NPY), leptin,GABA, opioid peptide, galanin, corticotrophin-releasing hormone and excitatory amino acid neural networks. Hypothalamic LHRH binds pituitary Gs-proteincoupled LH/hCG receptors to stimulate the pulsatile release of LH and FSH from pituitary gonadotropes. The gonads are modulated by the amplitude of the gonadotropin pulse, and secrete gonadal steroids in a pulsatile fashion. Gonadal steroids, inhibin, activin and follistatin exert feedback on the hypothalamic-pituitary unit. Inhibin and follistatin inhibit and activin stimulates FSH biosynthesis and secretion.
HYPOTHESIZED MECHANISMS FOR THE CONTROLOF PUBERTY There appear to be two mechanisms that contribute to the gonadotropin restraint seen in the juvenile pause: the negative feedback (gonadal steroid-dependent) mechanism and the intrinsic central nervous system (CNS) inhibitory mechanism (gonadal steroid-independent).2,3 The negative feedback mechanism is supported by the fact that gonadotropins are present at low concentrations in pre-pubertal children, but are elevated in children with gonadal dysgenesis. Evidence for intrinsic CNS inhibition is provided by observations that in agonadal children, gonadotropins are high in infancy and puberty but suppressed during childhood. Thus, puberty appears to be restrained in the f|rst few years by negative feedback of gonadal steroids, and is restrained centrally in mid childhood by CNS inhibition. Just before puberty, the CNS inhibitory mechanism wanes, especially during sleep, when the LHRH pulse generator is less sensitive to gonadal steroid negative feedback.2 Indirect evidence for a central inhibitory network, which has projections through the posterior hypothalamus, is derived from children with lesions that disrupt this area -- midline abnormalities (septo-optic dysplasia), hypothalamic pilocytic astrocytomas, cranial irradiation or suprasellar lesions -- who develop gonadotropindependent precocious puberty.2
NUTRITION AND PUBERTY In humans, there is an important interaction between nutritional status and puberty.4 Undernutrition delays the adolescent growth spurt and menarche, and increasing food intake leads to weight gain and menstrual function. Chronic undernutrition or rapid weight loss in normal women results in cessation of menstrual cycles,
CURRENT PAEDIATRICS
and amenorrhoea is also a feature of anorexia nervosa. Conversely, moderate obesity (up to 30% above the normal weight for age) is associated with earlier menarche.5 In developed countries, there has been a secular trend for puberty to occur earlier than in previous centuries, which is thought to be attributable to the increasing stability in socio-economic conditions and improved nutritional status.6,7
NEUROTRANSMITTERS AND PUBERTY Studies in primates indicate that g amino-butyric acid (GABA) and neuropeptide-Y (NPY) are important inhibitory neurotransmitters during the juvenile pause. Their roles have been reviewed extensively by Terasawa and Fernandez,8 and are summarized below.
GABA GABA is the main inhibitory neurotransmitter in the hypothalamus. In non-human primates, GABA tonically inhibits the LHRH system pre-pubertally -- hypothalamic GABA levels are higher in pre-pubertal rhesus monkeys than in pubertal monkeys. Infusion of GABAA antagonist stimulates LHRH release in pre-pubertal monkeys, and pulsatile infusion of GABAA antagonist into the third ventricle of pre-pubertal monkeys induces precocious menarche and precocious ovulation.
NeuropeptideY NPYis a potent orexigenic agent that is widely expressed throughout the brain. In male rhesus monkeys, there is evidence that it has a role in the pubertal restraint of the juvenile pause -- NPY messenger RNA decreases at the onset of puberty, concomitant with an increase in LHRH mRNA, whereas infusion of an NPY antagonist into the lateral ventricle stimulates LH release.
LEPTIN AND PUBERTY Leptin, the protein product of the ob gene,9 has been implicated in the control of murine body weight and thermogenesis, and also independently stimulates the reproductive axis. In ob/ob mice, a homozygous deletion in the coding sequence of the ob gene results in failure to produce leptin.The phenotype of ob/ob mice is characterized by hyperphagia, obesity, insulin resistance and infertility. Leptin treatment of ob/ob mice reduced food intake and body weight, increased metabolic rate, body temperature and activity levels,10 --13 and restored fertility.14 Thus, leptin potently suppresses appetite, stimulates energy expenditure and also modulates the reproductive axis.
APPLIED PHYSIOLOGY: THE CONTROL OF PUBERTY
The relationship between body fat and reproductive ability in humans has long been recognized, and the tempo of pubertal maturation is more closely associated with changes in body composition than chronological age. It has been postulated that a critical mass is required before menarche is achieved.4 Serum leptin concentrations are low in trained athletes15 and in amenorrhoeic females with anorexia nervosa.16 The relationship between leptin and the reproductive axis has been examined in normal mice and rats, where reproductive potential is closely linked to nutritional supply. Food restriction would normally prevent vaginal opening in mice, but infusion of leptin into the lateral ventricle of food-restricted mice induced sexual maturation despite a decrease in body weight.17 Furthermore, exogenous leptin brought forward the onset of reproductive function in normal pre-pubertal mice.18 Starvation-induced delay in sexual maturation could be overcome in leptin-treated animals when food was restricted to 80% of normal, but not when it was restricted to 70% of that of ad-libitum-fed controls.19 These data would suggest that leptin is not the primary signal to initiate the onset of puberty in rodents, but acts as a metabolic gate, permitting pubertal maturation in response to suff|cient metabolic resources. Although leptin administration can advance puberty onset in rodents, the fact that circulating leptin concentrations remain unchanged during puberty is not consistent with a leptin surge triggering puberty. However, recent observations in rats demonstrated that hypothalamic leptin receptor Ob-Rb expression increased three-fold from fetal life to post-pubertal life. It is possible that this change in hypothalamic response to leptin could enhance leptin action and trigger puberty without a rise in circulating plasma leptin concentrations.20 Studies in normal children have tended to be crosssectional in design. Many investigators have reported that leptin increased gradually in both sexes over the pre-pubertal years and that, at each age, girls tended to have higher leptin concentrations than boys.21--25 In a cross-sectional study of 290 healthy Manchester schoolchildren (males: 137, females: 153)22 leptin concentrations peaked in Tanner stage (TS) 2--3 in males and then declined to pre-pubertal values. However, in females, leptin concentrations continued to rise through puberty to peak in TS 4 --5 (Fig. 1). Body mass index (BMI) standard deviation score was positively correlated with serum leptin concentrations, and measures of body fatness were the most signif|cant determinants of leptin through childhood. The pre-pubertal rise in leptin concentration was observed to precede those of the gonadotrophins in a cross-sectional study of 789 normal children and adolescents,24 and to precede the surge in testosterone in a longitudinal study of eight pre-pubertal boys.26 A longitu-
373
Figure 1 The error bars representthe mean (71SD) values of Loge leptin in males (dots) and females (diamonds) at Tanner stages1, 2 & 3, and 4 & 5. + In males, leptin concentrations are higher inTS 2 & 3 than TS1 (P = 0.007) and TS 4 & 5 (P = 0.001). ΠIn females, leptin concentrations are higher in TS 2 & 3 than TS1 (P = 0.001) and # higher at TS 4 & 5 than at TS 2 & 3 (P = 0.01). *In TS 4 & 5, leptin concentrations are higher in females than males (Po0.001). From: Hall CM. Leptin and the Insulin-like Growth Factor (IGF) Axis through Childhood and Adolescence. University of Manchester,MD Thesis,1999.
dinal study of 343 Caucasian girls demonstrated an inverse relationship between age of menarche and leptin concentration.27 In addition, serum leptin concentrations were modestly elevated in girls with central precocious puberty.28 These studies suggest that leptin may be linked to both the onset of puberty and the timing of menarche. Evidence that leptin may have a role in regulating the tempo of pubertal development was provided by data from boys with constitutional delay in growth and puberty where serum leptin concentrations were lower than predicted for age and BMI at the onset of puberty.29 The strongest evidence supporting a role for leptin in human puberty is derived from rare familial cases associated with mutations in the leptin gene30 --32 or the leptin receptor gene.33 Affected adults with either condition are hypogonadal, while leptin treatment of a peripubertal child with leptin def|ciency acutely increased nocturnal gonadotropin secretion.34 Leptin exerts its central effects on satiety through several neuroendocrine systems. Some of the neuropeptides involved -- NPY, pro-opiomelanocortin-C (POMC) and cocaine- and amphetamine-related transcript
374
(CART) -- also interact with GnRH neurones. Thus neural mechanisms exist by which leptin might signal peripheral energy stores to the CNS and modulate both appetite and reproduction. In the mouse and human, leptin appears to be necessary for both pubertal development and the maintenance of secondary sexual characteristics. Under normal circumstances, leptin has a permissive role, but in the leptin-def|cient child, as in the ob/ob mouse, exogenous leptin seems able to induce activity within the reproductive axis.
GENES AND PUBERTY It is possible that there is a master gene or a number of genes that regulate the onset of puberty. Homeodomain genes of the POU family are widely expressed in the developing forebrain of mammals35 and Oct-2 POU gene has been identif|ed as a physiological component of the cell cycle regulatory process by which glial cells upregulate LHRH secretion in rats at puberty,36 suggesting that it may play an important role in triggering puberty in mammals. In pedigree analysis of 41 families with constitutional delay in growth and puberty, many families exhibited an autosomal-dominant pattern with varying penetrance, suggesting that there may be single genes with major effects whose penetrance is affected by genetic or environmental factors.37 Candidate genes include genes encoding GnRH or its receptor, or upstream regulators such as leptin or its receptor. The search for master gene(s) that control the timing of puberty is an exciting challenge, as identif|cation of these genes would improve our understanding of the regulation of human puberty and reproductive function.
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